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Complimentary Contributor CopyComplimentary Contributor Copy BOTANICAL RESEARCH AND PRACTICES MEDICINAL PLANTS ANTIOXIDANT PROPERTIES, TRADITIONAL USES AND CONSERVATION STRATEGIES No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Complimentary Contributor Copy BOTANICAL RESEARCH AND PRACTICES Additional books in this series can be found on Nova’s website under the Series tab. Additional e-books in this series can be found on Nova’s website under the e-book tab. Complimentary Contributor Copy BOTANICAL RESEARCH AND PRACTICES MEDICINAL PLANTS ANTIOXIDANT PROPERTIES, TRADITIONAL USES AND CONSERVATION STRATEGIES DAVID ALEXANDRE MICAEL PEREIRA, PH.D. EDITOR New York Complimentary Contributor Copy from the readers’ use of. but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. tape. The Publisher shall not be liable for any special. Library of Congress Cataloging-in-Publication Data Medicinal plants : antioxidant properties. or reliance upon. stored in a retrieval system or transmitted in any form or by any means: electronic. traditional uses and conservation strategies / editor: David Alexandre Micael Pereira. in whole or in part. this material. I. QK99. If legal or any other expert assistance is required. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Medicinal plants--Utilization. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. Independent verification should be sought for any data. ISBN:  (eBook) 1. Inc. or exemplary damages resulting. For permission to use material from this book please contact us: Telephone 631-231-7269.6'34--dc23 2013035640 Published by Nova Science Publishers. All rights reserved. the services of a competent person should be sought. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. mechanical photocopying. Pereira. products.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book.Copyright © 2014 by Nova Science Publishers. no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods. † New York Complimentary Contributor Copy . advice or recommendations contained in this book. David Alexandre Micael. electrostatic. Fax 631-231-8175 Web Site: http://www. instructions. ideas or otherwise contained in this publication. Antioxidants. cm. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. No part of this book may be reproduced. Includes index. magnetic. Additional color graphics may be available in the e-book version of this book. Inc. p.A1M428 2013 581.novapublishers. consequential. recording or otherwise without the written permission of the Publisher. 2. In addition. S. Vítor Spínola and Paula C. Ulises Osuna-Martínez. Bernardino Huerta-Gertrudis. Shilpa 117 Chapter 5 Use of Antioxidants to Control Obesity and Promote Weight Loss Vandana Gulati. José Luis Rodríguez-Chávez and Elvia Coballase-Urrutia Complimentary Contributor Copy 91 183 227 . Abdullah Dalar and Konrad A.Contents Preface Chapter 1 Chapter 2 vii Phenolic Compounds and Antioxidant Capacity of Medicinal Plants: A Review Sandra C. Castilho Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables around the World Lourdes Rodríguez-Fragoso. Antioxidant Properties and Phytochemical Composition of Traditional Medicinal Plants from Eastern Anatolia Izabela Konczak. Lakshmi. Noemí Cárdenas-Rodríguez. Fernandes and David M. Sangeetha and K. Konczak-Islam Chapter 8 Hetherotheca inuloides (Mexican Arnica) a Potent Antioxidant Effect as Neuro and Hepato-Protective Liliana Carmona-Aparicio. Gouveia. Palombo 143 Chapter 6 Application of Antioxidant Plants as Anti-Hemolytic Agents João C. Pereira 165 Chapter 7 Health Attributes. Claudia Kiferle and Alberto Pardossi Chapter 4 Flavonoids as Antioxidant Therapy for Metabolic Disorders B. K. N. Pankaj Gulati and Enzo A. Ana Isabel Gonzaga-Morales and Jorge Reyes-Esparza 1 41 Chapter 3 Hydroponic Production of Medicinal Plants Rita Maggini. Chemistry and Pharmacology Haifeng Wu. Yan Zhou. Xiaopo Zhang. Yao Li. Traditional Uses and Conservation Strategies Henry Lowe and Joseph Bryant Index 243 259 267 Complimentary Contributor Copy . Jingyi Zhang.vi Contents Chapter 9 Meconopsis: Traditional Uses. Lisheng Ding. Junshan Yang and Xudong Xu Chapter 10 A Case Study of Indigenous Medicinal Plants: Antioxidant Properties. Xiaofeng Zhang. biological properties. there are increasing evidences that modest long-term intakes of some specific classes of these compounds can favorable reduce and/or prevent the incidence of cancers and many chronic diseases such as cardiovascular disease. Oxidative stress and human health. Primary metabolites are compounds that possess fundamental roles in plant development steps such as phytosterols. Indian and Mediterranean. This effect is increased when there are not enough antioxidants to quench these harmful radicals.Plants have been used for medicinal purposes since the origin of human civilization and their uses were described by the great civilizations of the ancient Chinese. Secondary plant metabolites are structurally diverse and many are distributed among a limited number of plant species. neurodegenerative disease. acyl lipids. natural products and in particular medicinal plants. Chapter 1 . into four groups: phenolic compounds. namely in the pathogenesis of various diseases and disorders are related in different ways. Across the world. Herbal medicinal products are defined as any medicinal product. amino acids and organic acids. Complimentary Contributor Copy . they continue to be the source of new medicines either by providing lead molecules or as natural herbal products (teas. Nowadays. play an important role in human health and therapeutics. type II diabetes and hypertension. Plant secondary metabolites can be grouped. poultices. tinctures. inducing cell damage.Preface Nowadays. conservation and traditional use of medicinal plants used around the world. as well as the ageing process. the human body will produce more harmful species. Moreover. or one or more such herbal substances in combination with one or more such herbal preparations. as well as their traditional uses and conservation strategies. based on their biosynthetic formation. the authors address the antioxidant properties of several medicinal plants. powders. without a doubt. alkaloids and sulphur-containing compounds. In this book. such as reactive oxygen species (ROS) than enzymatic antioxidants and nonenzymatic antioxidants. infusions as well as other formulations). several different cultures employ medicinal plants for the treatment of a wide range of pathological conditions. a wonderful opportunity to have a closer insight into the chemistry. Compounds produced by plants are divided in two groups: primary and secondary metabolites. nucleotides. This is. Under stress. Some of these compounds were found to have a key role in the protection of plants in several ways. Phenolic compounds are of great interest mainly due to their bioactive functions involved in human health-related issues. exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations. terpenoids. However. which respectively decompose hydroperoxides. climatic and seasonal variations.Reactive oxygen species (ROS) play a crucial role in human health.viii David Alexandre Micael Pereira During a large period. such as response to growth factor stimulation and control of inflammatory responses. growth. including ascorbic acid. Polyphenols can induce antioxidant enzymes such as glutathione peroxidase. The present chapter is limited to commonly consumed fruits and vegetables with significant nutritional and antioxidant beneficial effects in folk medicine. also inhibiting the expression of enzymes such as xanthine oxidase. Many in vitro and animal studies have shown that a large range of dietary antioxidants. cytoskeletal regulation. In this paper. proliferation. inflammation disorders. geographical regions of growth. mango. their use is now restricted since they are associated with high levels of cytotoxicity and carcinogenic effects. grapefruit. carrot. papaya. pepper. and contraction. broccoli. Dietary polyphenols have received a lot of attention from nutritionists. They participate in the regulation of many cellular processes. grape. Therefore. cranberry. avocado. The antioxidant properties of medicinal plants depend on the plant. detection and quantification of phenolic compounds and antioxidant capacity assays are revised and examples of important medicinal plants are presented. Here. However. food scientists and consumers due to the role they play in human health. and a wide range of phytochemicals such as polyphenols. Methods for extraction. An antioxidant can be defined as a compound that inhibits or significantly delays the oxidation of substrates even if the compound is present in lower concentration than the oxidized substrate. its variety. hydrogen peroxide and superoxide anions. environmental conditions. catalase and superoxide dismutase. Complimentary Contributor Copy . Chapter 2 . ROS are involved in many vital physiological processes. tomato. there is a major need to find natural compounds with antioxidant properties and low toxicity associated. migration. regulated levels. The present chapter evidences the authors’ knowledge of the therapeutic properties of the antioxidant qualities of some fruits and vegetables is limited and seeks to provide an overall clear view of the antioxidant role of common fruits and vegetables. tocopherols. the authors discuss the phytochemistry and antioxidant pharmacological properties of the following plant species: apple. taken as extracts or as food components. orange. It is common knowledge that plant-derived foods contain hundreds of active antioxidant compounds. and many other factors such as post-harvest treatment and processing. Medicinal plants are traditionally used in folk medicine as natural healing remedies with therapeutic effects such as the prevention of cardiovascular diseases. along with their health and diseasereduction benefits. spinach. including differentiation. cauliflower. butylated hydroxytoluene (BHT). growing practices. or reducing the risk of cancer. berries. degree of ripeness. have beneficial effects because they modulate oxidative stress and protect against oxidative damage and its complications. pomegranate. propyl gallate (Pg) and tert-butyl hydroquinone (TBHQ) were used as additives in foods and beverages. the authors present an overview on phenolic compounds and their relation with antioxidant capacity of medicinal plants. They have a role in various signaling cascades. tangerine. artificial antioxidants such as butylated hydroxyanisole (BHA). and watercress. carotenoids. ROS also play an important role in a wide range of pathologies and many implicated diseases that are leading causes of death. apoptosis. cactus. At low. Phenolic compounds and aromatic amines are free-radical scavengers and also present reducing properties. Enhanced production of reactive oxygen species (ROS) and perturbed antioxidant defenses determine the chemical changes in virtually all cellular components resulting in their damage. it also underlines the lack of information concerning the specific growing needs of the individual medicinal species. the interest by pharmaceutical companies towards the production of bioactive compounds from medicinal plants has considerably increased. Greenhouse hydroponics can contribute to overcome the drawbacks of conventional field cultivation. On the other hand. and medicinal plants are increasingly cultivated on a commercial scale. The present chapter points out the opportunities offered by the hydroponic growing of medicinal plants for the agro-industrial production of bioactive compounds. which are products of plant secondary metabolism with proven beneficial effects on human health. This chapter presents some fundamental issues concerning the hydroponic production of raw plant material for the extraction of bioactive compounds. Literature data are reported on recent research concerning the hydroponic growing of medicinal plants. during the metabolism of excessive glucose and free fatty acids. ROS is generated through several mechanisms including oxidative phosphorylation. the traditional harvesting from the wild has become inadequate to sustain the market demand. basil is presented as a case study for the application of the hydroponic technique to the production of plant material for the extraction of rosmarinic acid. On the other hand. compounds that can manage these conditions Complimentary Contributor Copy . The application of a stress condition through a proper manipulation of the nutrient solution can stimulate secondary metabolism and promote the synthesis and accumulation of bioactive substances in plant tissues. glucose auto-oxidation. activation of protein kinase C (PKC).Medicinal plants are specifically used for their contents of bioactive compounds. usually phytochemicals and micronutrients called as quenchers act either directly by free radical scavenging mechanisms or indirectly by enhancing the antioxidant status (enzymatic and non-enzymatic). they generally exhibit antioxidant properties and often act as defense molecules that are synthesized by plants in response to stress conditions. As a consequence. the market requirement for standardized plant material cannot be fully satisfied by field crops. Finally. especially in developed countries.Preface ix Chapter 3 . in consideration of the consumers’ sensibility towards naturally sourced remedies. Antioxidants.Metabolic disorders. suitable growing protocols are still required. advanced glycation end product (AGE) formation. due to a disproportionate release of free radicals. have been strongly associated with oxidative stress. These substances are known to play a key role in the mechanisms of plant adaptation to the environment. Chapter 4 . In the last decades. They also act as secondary messengers in the regulation of several intracellular signaling pathways. as it ensures a fast plant growth and allows both to control the growing environment and to change the composition of the nutrient solution that is fed to the plants. both under optimal conditions or under stress conditions to stimulate the production of secondary metabolites. nitric oxide synthase (NOS) and aldose reductase pathway among others. which are highly susceptible to year-to-year variability. a bioactive secondary metabolite of well-known antioxidant activity. including diabetes and obesity. Despite the fact that at present a lot of molecules of pharmaceutical interest can be obtained from hydroponically-grown medicinal plants. As diabetes and obesity conditions initiate generation of free radicals. The most promising strategy to mitigate the effect of ROS induced oxidative damage is through the use of antioxidant molecules. The use of medicinal plants represents the oldest and most common form of medication. anthocyanins. have been in some cases further analyzed for a hypothetical anti-hemolytic potential. rutin. anti-diabetic. In 2008.8 million people die each year as a result of being overweight or obese. isoflavones and chalcones. antithrombotic. Therefore. diabetes and heart diseases. The associated risks with obesity are cancer. procyanidin. The therapeutic effect of phytochemicals found in natural products to combat oxidative stress is gaining significance as they are recognized to be safe with a wide range of biological and pharmacological activities. Flavonoids. thus. modulating the genes associated with metabolism and stress defense. According to the World Health Organization. This review will focus on recent examples of antioxidant nutrients. Among the hundreds of studies published in the last two decades on medicinal plants research. Dietary components from plants such as polyphenols (flavonoids). can be helpful in preventing the deleterious effects caused by reactive oxygen species. including oxidation of cell membranes and proteins in conjunction with disturbances of cellular redox homeostasis. it is known that increased production of reactive oxygen species (ROS) is associated with cellular damage. Obesity has become one of the most important avoidable risk factors for morbidity and mortality. Although oxidative stress is not the primary etiology of diseases such as hemolytic anemias. antioxidants are capable of reversing these pathways and. therapeutic intervention with the ability to reduce oxidative stress can impede or delay the onset of the metabolic disorder.4 billion adults were overweight and more than half a billion were obese. pycnogenol. terpenes and tannins are ubiquitous in nature and can effectively scavenge reactive oxygen and nitrogen species. Thus. Obesity is the leading cause of death which can be prevented by diet and lifestyle modifications. Antioxidants are widely present in the plant kingdom and are known to prevent various disorders. At least 2. anti-inflammatory and anti-HIV activities. a ratio of height to weight) greater than 30 whereas a healthy BMI should be 18. thus increasing myocardial oxygen consumption. In this perspective. the quest for new antioxidant drugs has a been pivotal. in fact. However. especially flavones. and tea catechins. Although the exact link between obesity and its associated risks is not clear. inositol and various herbs are effective in reducing obesity and promoting weight loss.9. genistein. more than 1. flavanols (catechins). their potential antioxidant properties and the mechanism through which they exert their pharmacological effects in diabetes and obesity. obesity is defined as abnormal or excessive fat accumulation that may impair health. traditional medicines and foods that have been validated by scientific evaluation for controlling obesity or promoting weight loss. Chapter 5 . Complimentary Contributor Copy . agents possessing dual effect such as antidiabetic/anti-obesity and antioxidant activity are greatly in demand. flavonols. antioxidants do not reduce obesity per se. are considered effective antioxidants associated with other pharmacological properties such as anti-cancer. carnitine.The prevalence of overweight and obese individuals is increasing at an alarming rate across the globe. as well as their bioactive components. esculetin. This chapter discusses the sources of flavonoids. choline. cancer and hypertension.x David Alexandre Micael Pereira serve to be effective against these diseases and their complications. Obesity also increases the mechanical and metabolic loads on the myocardium. EGCG. Free radicals are known to be involved in a number of human pathologies including atherosclerosis. CoQ10. Studies have shown that obesity promotes increased plasma lipid peroxidation. Some of those plants with antioxidant activity. Many studies have indicated that phenolic compounds such as o-coumaric acid. Chapter 6 . anti-mutagenic.5 to 24. flavanones. it is believed to aggravate them. A person is considered obese if they possess a body mass index (BMI. which are all alleviated by antioxidant compounds. The mountainous and strongly fragmentized area is a home to over 11. antimicrobial. decoction. the green coffee beans decoction (Coffee arabica).As the second-largest genus in the family Papaveraceae. of these 51 possessing anti-oxidant properties. it has attracted considerable interest because of the involvement of oxidative stress in various diseases affecting systemic and central levels. diabetes. herbal tea) and externally (e. The chemical constituents have been examined and the isolation of alkaloids. Chapter 10 . Chapter 9 . the Eupatorium odoratum (jack in the bush) and Momordica charantia (cerasee) are among the common plants used on the island to promote oxidative relief. Meconopsis comprises about 57 species among which 32 species are distributed in Qinghai-Tibet Plateau. Endemic plants are utilized daily in preparation of main meals. The extensive daily use of local plants for foods and medicine in Eastern Anatolia continues today and traditionally used plants outnumber the conventional sources of plant-based foods. Complimentary Contributor Copy . poultice. The phytochemical and pharmacological studies on medicinal plants of Meconopsis genus have been reviewed in this chapter. The Petiveria alliacea (guinea hen weed).Preface xi Therefore. phytochemical compositions and antioxidant capacities.Anatolia . may prevent or at least slow down free radical reactions that are responsible for provoking damage to essential red blood cell molecules. infusion. as well as the mechanism of action is given.g. Herbal medicine has been the source for many pharmaceutical and nutraceutical products based on well-researched and developed ethno-medicinal practices worldwide. Hibiscus sabdariffa (Jamaican sorrel). is at the forefront of the world richest sources of plant species. it is used in various presentations (tablets. hypertension among others. This chapter presents the most frequently used traditional plants from the Eastern Anatolia and describes their uses. flavonoids and essential oils has been reported. 1788 plants have been identified to contain two or more bioactive compounds. The plants of Meconopsis have been prescribed as popular Tibetan medicine for the treatment of tuberculosis and hepatitis. ointment) to cure a number of ailments. Chapter 8 . It provides an alternative method for the management of various diseases.g. They are used internally (e. Pharmacological activities include hepatoprotection and analgesic effects. the focus of this chapter is to describe the evidence that demonstrates the ability of Mexican arnica to be used as a potent antioxidant. In this Chapter. such as cancer. in experimental models affecting these organs. the use of natural antioxidants. Many of the world’s contemporary staple foods originated here.000 plant species. beverages. As an antioxidant. analgesic. either as additives or as pharmaceutical supplements.Jamaica’s flora has a rich source of medicinal plants. Chapter 7 .the westernmost protrusion of Asia. ointments) for therapeutic purposes due to its anti-inflammatory. the authors review the current knowledge regarding the use of medicinal plants as anti-hemolytic agents. In particular. and how it can help protect the liver and brain.Hetherotheca inuloides (Mexican arnica) is a plant used in traditional medicine in different parts of the world. of which 30% are endemic. in salads and as herbal teas. and antioxidant effects. Their applications in ethnopharmacology in light of scientifically proven physiological activities are discussed. with over 2900 species of identified flowering plants. Anti-oxidant activity is often times found in those plants that are edible and as such is able to alleviate oxidative stress when eaten. Particular emphasis in the compounds responsible for this activity. Due to their usefulness as medicinal plants tissue culture has been used as a part of the conservation strategies that have been employed in preserving and maintaining the island’s flora. including decoctions. macerations. Complimentary Contributor Copy . infusions.xii David Alexandre Micael Pereira These plants are often administered in many different ways. tinctures or by cooking. tinctures. alkaloids and sulphur-containing compounds. Inc. Gouveia. nucleotides. amino acids and organic acids. exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations. neurodegenerative disease. Primary metabolites are compounds that possess fundamental roles in plant development steps such as phytosterols. Moreover. as well as the ageing process. acyl lipids. Departamento de Química. Plant secondary metabolites can be grouped. Vítor Spínola and Paula C. Phenolic compounds are of great interest mainly due to their bioactive functions involved in human health-related issues. Chapter 1 Phenolic Compounds and Antioxidant Capacity of Medicinal Plants: A Review Sandra C. there are increasing evidences that modest long-term intakes of some specific classes of these compounds can favorable reduce and/or prevent the incidence of cancers and many chronic diseases such as cardiovascular disease. type II diabetes and hypertension. into four groups: phenolic compounds. they continue to be the source of new medicines either by providing lead molecules or as natural herbal products (teas. Indian and Mediterranean. Campus Universitário da Penteada. Complimentary Contributor Copy . Castilho Centro de Química da Madeira. infusions as well as other formulations). Herbal medicinal products are defined as any medicinal product. Secondary plant metabolites are structurally diverse and many are distributed among a limited number of plant species. or one or more such herbal substances in combination with one or more such herbal preparations. Portugal Abstract Plants have been used for medicinal purposes since the origin of human civilization and their uses were described by the great civilizations of the ancient Chinese. powders. Compounds produced by plants are divided in two groups: primary and secondary metabolites. Universidade da Madeira. Funchal. poultices. Some of these compounds were found to have a key role in the protection of plants in several ways. Nowadays. terpenoids.In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers. based on their biosynthetic formation. 8 billion (Phillipson. Complimentary Contributor Copy . detection and quantification of phenolic compounds and antioxidant capacity assays are revised and examples of important medicinal plants are presented. (cf.who. The public access to these herbal medicinal products (HMP) led to the need of up-to-date monographs and to the use of standardized materials to prevent adverse effects including drug interactions in patients taking other over-the-counter or prescription medicines. Germany is the country with the highest share of the herbal medicines market and it was reported that the sales of herbal medicinal products (HMPs) in 1997 were US$ 1. 2006). However. such as reactive oxygen species (ROS) than enzymatic antioxidants and non-enzymatic antioxidants. artificial antioxidants such as butylated hydroxyanisole (BHA). Keywords: Phenolic compounds. Gouveia. powders. In Europe. Therefore. 2007). as well as other formulations (Balunas and Kinghorn. Herbal medicine revenue in Brazil was US$ 160 million in 2007. Castilho Oxidative stress and human health. During a large period. 2005). Medicinal plants Introduction 1. sales of products totaled US$ 14 billion in 2005. butylated hydroxytoluene (BHT).int/ mediacentre/factsheets/fs134/en/. and are highly lucrative in the international marketplace. Traditional medicine Fact sheet N°134 December 2008. The consumption of herbal products in the more affluent countries has increased in the past decades. tinctures. we present an overview on phenolic compounds and their relation with antioxidant capacity of medicinal plants. 2001). In China. Medicinal plants can be used in the form of crude drugs such as teas. propyl gallate (Pg) and tert-butyl hydroquinone (TBHQ) were used as additives in foods and beverages. there is a major need to find natural compounds with antioxidant properties and low toxicity associated. the human body will produce more harmful species. inducing cell damage. Methods for extraction. Herbal treatments are still the most popular form of traditional medicine. accessed on 21st March 2011). poultices and infusions. namely in the pathogenesis of various diseases and disorders are related in different ways. Annual revenues in Western Europe reached US$ 5 billion in 2003-2004. Vítor Spínola and Paula C.2 Sandra C. This effect is increased when there are not enough antioxidants to quench these harmful radicals. Phenolic compounds and aromatic amines are free-radical scavengers and also present reducing properties. Medicinal Plants The use of plants in medicine is reported since the origin of human civilizations (Phillipson. An antioxidant can be defined as a compound that inhibits or significantly delays the oxidation of substrates even if the compound is present in lower concentration than the oxidized substrate. Antioxidant. Under stress. in: http://www. The United States of America (USA) and Europe (EU) have been doing a great effort to regulate and license the commercialization of medicinal herbs to those patients who request to be treated with these products (Gurib-Fakim. In this paper. their use is now restricted since they are associated with high levels of cytotoxicity and carcinogenic effects. and the knowledge of new biological active compounds is still a challenge since only a small percentage of plants over the world have been fully studied in a scientific manner. against a placebo).Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 3 At the international level. In many developed countries. In the EU. synergy determination and validation of mode of action of active substances. In the USA. Pharmacognosy has provided information on pure natural compounds and foods with health benefits (Phillipson. 2006). In summary. 2001). improve or treat physical and mental illnesses. among others. Herbal medicinal products are defined as any medicinal product. Wherever we are. formed in 1989) has as its main goal to advance the scientific status of phytomedicine and to assist with the harmonization of their regulatory status at the European level. the WHO has developed a strategy to review traditional medicines which includes a program to develop monographs for herbal ingredients. biotransformations. the traditional medicine must be supported by the isolation. following a public consultation. trends to the rational use of medicinal plants dominate the measures being implemented by health and food authorities. Standardization permits comparison of the clinical effectiveness. diagnose. pharmacological effects and side effects of a series of products (for example. standardization only applies to extracts. 2007) and seeks the search for new drugs from natural sources combining different fields such as phytochemistry. organic and analytical chemistry. phytotherapy or acupuncture) (Phillipson. the FDA Scientific Committee published a guidance document for the safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements. ESCOP produces state-of-theart reviews of the therapeutic use of herbal medicinal products based on leading expertise across Europe. 80% of the population depend on traditional medicine for primary health care. In the field of phyto-medicines. the EFSA Scientific Cooperation (ESCO) Working Group was created to advice on the adequacy of the proposed approach for the safety assessment of botanicals preparations. skills and practices based on the theories. the European Scientific Cooperative on Phytotherapy (ESCOP.g. 2006). Standardization is a system that guarantees a minimum level of active components in the extract and is becoming increasingly important as a means of ensuring a consistent supply of high-quality phyto-pharmaceutical products. in some Asian and African countries. the Food and Drug Administration (FDA) has responsibility for both food and drug products (Gurib-Fakim. In EU. exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations. biosynthesis. beliefs and experiences indigenous to different cultures that are used to maintain health. or one or more such herbal substances in combination with one or more such herbal preparations. traditional medicine is the combination of knowledge. microbial chemistry. In June 2008. as well as to prevent. At its essence. above). Standards for active ingredients to be used in medicinal products may be found in monographs and/or pharmacopeas (GuribFakim. characterization. It can be defined as the establishment of reproducible pharmaceutical quality by comparing a product with established standard compounds and by defining minimum amounts of one or several compounds. Standardized products provide more security and increase the level of trust people have in herbal drugs. 70% to 80% of the population has used some form of alternative or complementary medicine (e. Complimentary Contributor Copy . According to a WHO Fact Sheet published in 2008 (cf. based on their biosynthetic formation. Gouveia. Plant secondary metabolites can be grouped. Phenolic Compounds Phenolic compounds are a class of low and medium molecular weight secondary metabolites biosynthesized both during normal plant development and in response to stress conditions. hydroxybenzoic and hydroxycinnamic acids). They can also be classified into different groups as a function of their number of phenol rings. as well as the ageing process (Katalinic et al.1. act as deterrents against herbivores and/or provide protection against harmful sun radiation. Secondary plant metabolites are structurally diverse and numerous but are distributed among a very limited number of plant species. Depending on the position of the linkage of the aromatic ring to the benzopyran (chroman) moiety. 2009). lignans and proanthocyanidins.1. Castilho 2. 2010). Modest long-term intakes of some specific classes of these compounds can favorable reduce and/or prevent the incidence of cancers and many chronic diseases such as cardiovascular disease.1. as well as in the structural elements that bind these rings to one another. type II diabetes and hypertension. they can assist reproduction by attracting pollinators. Some of these compounds were found to have a key role in the protection of plants in several ways (Crozier et al. stilbenes. Some also have a role in human wellbeing. alkaloids and sulphur-containing compounds. lignins. Distinctions are thus made between flavonoids. nucleotides. due to their bioactive functions involved in human health-related issues. sugars. wounding and UV radiation (Naczk and Shahidi. isoflavonoids (3-benzopyrans) 2. The chemical structure of phenolic compounds is characterized by the presence of at least one aromatic ring with one or more hydroxyl group attached. Phytochemicals in Plants Compounds produced by plants are divided in two groups: primary and secondary metabolites. Vítor Spínola and Paula C.g. Phenolic compounds are the most investigated. such as infection.. although in some cases they can be found in high concentrations. phenylbenzopyran functionality.4 Sandra C. terpenoids. acyl lipids. Primary metabolites are compounds that have fundamental roles in plant development steps (photosynthesis. Phytosterols. 2. respiration and growth). 2006). 2. this group of natural products may be divided into three classes (Figure 1): the flavonoids (2-phenylbenzopyrans) 1. Flavonoids The term “flavonoid” is generally used to describe an extensive collection of natural products that include a C6-C3-C6 carbon framework or. There are more than 5000 phenolic compounds described (Pyrzynska and Biesaga.. phenolic acids (e. 2006). into four groups: phenolic compounds. They are classified based on the number and arrangement of the carbon atoms of the basic structure (Table 1) and can be found in the free form or conjugated to sugar and organic acids residues. and the Complimentary Contributor Copy . In the lifecycle of the plant. They represent an expression of the individuality of species. more specifically. amino acids and organic acids are examples of primary metabolites. neurodegenerative disease. methylation and/or glycosylation. These groups usually share a common chalcone precursor and therefore are biogenetically and structurally related (Marais et al. 2006) Number of carbons Skeleton Classification Example 7 C6-C1 Phenolic acids Gallic acid 8 C6-C2 Acetophenones Gallacetophenone 8 C6-C2 Phenylacetic acid p-Hydroxyphenyl-acetic acid 9 C6-C3 Hydroxycinnamic acids p-Coumaric acid 9 C6-C3 Coumarins Esculetin 10 C6-C4 Naphthoquinones Juglone 13 C6-C1-C6 Xanthones Mangiferin 14 C6-C2-C6 Stilbenes Resveratol 15 C6-C3-C6 Flavonoids Naringenin Basic structure The basic flavonoid skeleton is planar and may occur in several modified forms corresponding to additional hydroxylation. methylenedioxyl or isoprenyl groups attach to the flavonoid structure and its glycosides. however. Classification of phenolic compounds. prenyl. Complimentary Contributor Copy .Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 5 neoflavonoids (4-benzopyrans) 3. It is also possible to have aromatic and aliphatic acids. methyl groups and isopentyl units turn flavonoids lipophilic. Adapted from (Crozier et al. 2006). The water solubility of flavonoids increases with the presence of glycoside and hydroxyl groups.. Table 1. sulfate.. 2004). Flavonols are the most abundant flavonoids and more than 450 flavonol aglycones are known. flavanones and anthocyanidins are the most abundant and dihydroflavonols. kaempferol and isorhamentin are the most common flavonol-type flavonoids found in fruits and vegetables (Prasain et al. Isoflavones Isoflavones possess the B-ring linked at the C-3 rather than the C-2 position (as in flavones) (Figure 2).. these types of flavonoids only appear in a few families of plants. 2004). chalcones. C. they are consequently classified as phytoestrogens. Apigenin and luteolin are the major flavones found in the human diet. Flavones Flavones are structurally similar to flavonols with a double bond between C-2 and C-3 but they lack hydroxylation at position 3. however. Figure 1. As such. 2004).and C-alkylation.and 7-positions of the A-ring although substitutions at the 5. including the ability to bind to estrogens receptors. 2006). 2010). 4’. The most common conjugated flavones are 7-O-glycosides and the Cglycosylation occurs mainly at C-8 and C-6 positions (Figure 2) (Cuyckens and Claeys... Flavonols Flavonols are characterized by an unsaturated 3-C chain with a double bond between C-2 and C-3 and by the presence of a hydroxyl group in position 3 (Figure 2).4-diols. leafy vegetables and herbs (Zhang et al. isoflavones. However. Types of flavonoids (Marais et al. Vítor Spínola and Paula C. These compounds also present a variety of substitutions like hydroxylation. O. Complimentary Contributor Copy . 7. dihydrochalcones and aurones are much less present in the common components of the human diet (Cuyckens and Claeys. flavan-3-ols. 2004). A. methylation. Castilho The basics structures of the main classes of flavonoids are presented in Figure 2: Flavones. This confers pseudo hormonal properties to these compounds. Gouveia. B. They have structural similarities to estrogens but they are not steroids and normally have hydroxyl groups in C-7 and C-4’ positions in a configuration analogous to that of the hydroxyls in the estradiol molecule (Manach et al. and glycosylation (Manach et al. flavonols. flavan-3.. 2004).6 Sandra C. in grains. O-glycosylation occurs with sugar groups linked preferentially to the 7-position of A-ring. Conjugation commonly occurs at the 3.. the number of flavonol conjugates is much higher due to the great number of glycosides moieties combinations. coumarins. Quercetin. 3’ and 5’ positions of the carbon ring have also been reported. 2007). such as soybeans and their processed products (Naczk and Shahidi. A large number of flavanones have the C-ring attached to the B-ring at C-2 Complimentary Contributor Copy . D. malonyl and hexoside forms.. These three aglycones can also occur in their acetyl. Basic structures of the main classes of flavonoid. Regarding the type of substitution on carbons C-5 and C-6. Figure 2.and C-glycosylation positions are indicated with an arrow (Cuyckens and Claeys. three main isoflavones aglycones are known: daidzein. 2004). Common O. genistein and glycitein (Luthria et al. Flavanones This type of flavonoid is characterized by the absence of a double bond between the C-2 and C-3 carbons of the B-ring. 2006).Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 7 Isoflavones are widely distributed in the plant kingdom but are found at high levels only in plants of the Leguminosae family. which gives an asymmetric carbon (C-2) as a chiral center (Figure 2). Flavan-3-ols. R1 and R2 are H. like hesperitin-7-O-rutinoside (hesperidin) and naringenin-7-O-rutinoside in oranges. proanthocyanidins and flavanones are molecules of low polarity due to the saturated bond between the C-2 and C-3 carbons in the C-ring. 2009). F. chemical and enzymatic Complimentary Contributor Copy .. These compounds are present in edible species and are found in tomatoes and certain aromatic plants such as mint. to the oligomeric and polymeric proanthocyanidins (condensed tannins). Castilho position with an α-configuration (Crozier et al. 2004). They are glycosides of polyhydroxy and polymethoxy derivatives of 2phenylbenzopyrylium or flavylium salts (Figure 3) (Kong et al. Rutinose conjugated flavanones are tasteless. E. R3 is a glycosyl or H. peonidin and malvidin which are found as their glycosides in plants (Guzmán et al. Anthocyanidins always present a sugar moiety at the C-3 position and frequently on C-7. The flavylium cation.. Hydroxylation. vegetables. or OCH3. The typical bitter taste of grapefruit is related to the glycosylation with neohesperidose of the flavanone aglycones. Figure 3. pelargonidin. Catechins are found largely in green tea but also in fruits. Anthocyanidins Anthocyanidins. and eriodictyol in lemons. OH.. 2006). Gouveia. Conjugation with hydroxycinnamates and organic acids is also common. The most important anthocyanidins are cyanidin.. 2003). but are very rare in fruits with exception of the Citrus genus. hesperetin in oranges. varying from the simple monomers (+)catechin and its isomer (-)-epicatechin. such as matured red wines and ports. and R4 is OH or a glycosyl. delphinidin. Anthocyanidins are more unstable than anthocyanins. The main aglycones of flavanones are naringenin in grapefruit. These compounds do not present glycosylated forms in foods but can be hydroxylated to form the gallocatechins and can be esterified with gallic acid.. are the most important pigments in plants and fruits (red. glycosylation and methylation are normal types of substitution for flavanones aglycones on the 7-position. In certain products. The two asymmetrical carbons C-2 and C-3 produce four isomers for each level of B-ring hydroxylation. at the C-7 position: naringenin-7-O-neohesperidose. where they can be found in high concentrations (Peterson et al. blue and purple colors). Flavan-3-ols This is the most complex type of flavonoids. mainly their glycosides and acylglycosides derivatives denominated anthocyanins. 2006). red wine and chocolate (Manach et al. C-3’ and C-5’.8 Sandra C. Vítor Spínola and Paula C. Cinnamic acid is a C6–C3 phenolic acid that is converted to a wide range of hydroxycinnamates. This contributes to the increase of the total intake of dietary phenols (Crozier et al. forming hydrolysable tannins (polymers of gallic and ellagic acids). 2006). black radish and onions. A.Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 9 transformations occur and increase the number of ‘anthocyanin-derived polyphenols’. The content of these compounds in edible plants is generally very low. in some cases. 2011). and the polyphenolic C6– C2–C6 stilbenes.. Complimentary Contributor Copy . the hydroxybenzoic and hydroxycinnamic acids and exist primarily as conjugates and are rarely found in their acidic forms. 2004). Gallic acid can be converted to ellagic acid. Chemical structures of the most common hydroxybenzoates R1 R2 Compound H H p-Hydroxybenzoic acid OH OH Gallic acid H OH Protocatechuic acid H OCH3 Vanillic acid OCH3 OCH3 Syringic acid B.. which is the base unit for a wide range of gallotannins. Non-Flavonoids The main non-flavonoid phenolic compounds found in nature are the C6–C1 hydroxybenzoates. which is the precursor of hydrolysable tannins. These compounds may be found in plants in their soluble form conjugated with sugar groups or organic acids and.2. bound to cell wall fractions (lignin).. Table 2. 2. Phenolic acids consist of two subgroups. Hydroxycinnamates This class of compounds presents a much higher quantity and diversity rather than hydroxybenzoates. sugars.. vanillic. tea is an important source of gallic acid (4. Hydroxybenzoates Hydroxybenzoate compounds include p-hydroxybenzoic. or organic acids through ester bonds (Ignat et al. often found bound to alcohols. 2008). protocatechuic.1. These are products of the phenylpropanoid pathway and are generally designated as phenylpropanoids (Crozier et al. biosynthesized from phenylalanine via 3dehydroshikimic acid. most notably gallic acid. gentisic and syringic acids (Table 2) (Parveen et al. polysaccharides. 2006).. For example. The principal hydroxybenzoate is gallic acid. with exception of certain red fruits. the C6–C3 hydroxycinammates and their conjugated derivatives.5 g/Kg fresh wt) (Manach et al. gallic. Hydroxycinnamates usually occur in several conjugated forms such as esters of hydroxyacids like quinic. bacterial and viral pathogens attacks). Castilho The most important hydroxycinnamates are caffeic. cranberries. ferulic acids and their derivatives (Table 3). 5-O-Caffeoylquinic acid structure. hops. The number of caffeoyl moieties. as well as their sugar derivatives. Stilbenes This group of phenolic compounds has a C6-C2-C6 structure and is known to act as phytoalexins. 2006). Complimentary Contributor Copy . They occur in diversified sources like grapes.5-1 g/day (Clifford. blueberries. their location and relative isomer abundance is often characteristic of a species. 2000). peanuts. strawberries. Figure 4. 2007). Resveratrol (3. shikimic and tartaric acid. Gouveia. Table 3. it is present primarily as trans-resveratrol3-O-glucoside (piceid). peanuts and their products are considered the most important dietary sources of resveratrol. C. Trans-resveratrol and its hexoside are also present in high amounts in Polygonum cuspidatum (Japanese knotweed) (Crozier et al. red currants and some other botanical sources (Lee and Rennaker.. In plants tissues.4-trihydroxy-stilbene) is the most common stilbene and occurs as both cis and trans isomers (Figure 5). Coffee is a major dietary source of chlorogenic acids with intakes estimated at 0. Grapes. Chlorogenic acid. antibiotic compounds produced as part of a plant's defense system against disease (fungal. The true chlorogenic acid is 5-Ocaffeoylquinic acid (Figure 4). p-coumaric. Chemical structure of three common hydroxycinnamates R1 Compound OH Caffeic acid H p-Coumaric acid OCH3 Ferulic acid Caffeic acid occurs mainly as esters of quinic acid and the whole group of related isomers is generally denominated as “chlorogenic acids”. Vítor Spínola and Paula C.5.10 Sandra C. 3. p-coumaric acid and p-coumaroyl-CoA. and presumably related caffeoylquinic acids. ferulic. The biosynthesis of phenolic compounds.. This type of compounds is also associated to the plant morphology (color and mechanical support in the case of lignin). namely flavonoids. Initially. 2012. Functions and Biosynthesis of Phenolic Compounds Phenolic compounds play different roles in plant physiology. herbivores and UV radiation of the sun (flavonoids). (2006) gallic acid appears to be formed primarily via the shikimic acid pathway from 3-dehydroshikimic acid (Figure 6) although there are alternative routes from hydroxybenzoic acids. phenylpropanoid and flavonoid pathways. recent molecular biology studies (Hoffmann et al. the hydrolysable tannins (Crozier et al.. produced in plants via the shikimate pathway. However. Another possibility is that 3-dehydroshikimic acid to be directed to L-phenylalanine and start the phenylpropanoid pathway (Salminen and Karonen. against attacks by pathogens. 2006). 2007). Lallemand et al. is from p-coumaroyl-CoA via 5-O-p-coumaroylquinic acid (Figure 6). Phenolics and Hydroxycinnamates According to Crozier et al. caffeic acid was considered as the immediate precursor of 5-O-caffeoylquinic acid. Enzyme studies with extracts from oak leaves have shown that gallic acid is converted to β-glucogallin which. Complimentary Contributor Copy . 2011). 2007). protein synthesis and enzyme activity) and reproduction (flavones. 2004) indicate that the main route to 5-O-caffeoylquinic acid.1. Structures of trans and cis-Resveratrol. Penta-O-galloyl-glucose is a pivotal intermediate that is further galloylated resulting in the synthesis of gallotannins and ellagitannins.. p-Coumaroyl-CoA is also a vital intermediate leading to the synthesis of flavonoids and stilbenes. 2011. Cinnamic acid can also be metabolized to benzoic acid and salicylic acid. Phenylalanine. is converted via a series of position-specific galloylation steps to penta-O-galloyl-glucose.. 3. flavonols and anthocyanidins colors may attract pollinators) (Stalikas. 2006). hydroxycinnamates and phenolic acids involves a complex network of routes based principally on the shikimate. growth (nutrient uptake. in turn. 5-hydroxyferulic and sinapic acids (Gallego-Giraldo et al. p-Coumaric acid is also metabolized via a series of hydroxylation and methylation reactions forming caffeic. Consecutive enzyme reactions give cinnamic acid. Shadle et al. is a common precursor for most phenolic compounds in higher plants (Crozier et al..Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 11 Figure 5.. ACoAC. Gouveia. BA2H. The bridge and the B-ring represent a phenylpropanoid unit synthesized from pcoumaroyl-CoA. The six carbons of ring-A originate from the condensation of three acetate units via the malonic acid pathway) (Crozier et al. Figure 6. C4H. GT. flavanones. flavonols.. 4CL.2006. coumarate CoA ligase. benzoic acid 2-hydroxylase. hydroxycinnamates and 5-O-Caffeoylquinic acid. The stereospecific conversion of naringenin-chalcone to naringenin by chalcone isomerase (CHI) is the central point of the flavonoid biosynthetic pathway. acetylCoA carboxylase. COMT-1. Enzyme abbreviations: PAL.. phenylalanine ammonia-lyase. Adapted from Crozier et al.. salicylic acid. Castilho 3. F5H. ferulate 5-hydroxylase.1. Vítor Spínola and Paula C.1. galloyltransferase.12 Sandra C. Schematic of the main pathways and key enzymes involved in the biosynthesis of hydrolysable tannins. flavones. caffeic/5-hydroxyferulic acid O-methyltransferase. flavan-3-ols and anthocyanins (Figure 8) (Crozier et al. 2006). Complimentary Contributor Copy . Flavonoids The C6–C3–C6 flavonoid structure is the product of two separate biosynthesis pathways (Figure 7). Isoflavones are produced in a slightly modified pathway through isoliquiritigenin. The conjugation of these two parts in a reaction catalysed by chalcone synthase (CHS) results in naringenin-chalcone. cinnamate 4hydroxylase. which lacks a 2’-hydroxyl group. From this point several side branches are formed resulting in the production of different classes of flavonoids such as isoflavones. 2006). ANR. ANS. Enzyme abbreviations: SS. FNS. flavonol 3’-hydroxylase. terminal unit (Adapted from Crozier et al.. F3H. DFR. Complimentary Contributor Copy 13 . FLS. stilbene synthase. anthocyanidin 4-reductase. 2006). extension units.Phenolic Compounds and Antioxidant Capacity of Medicinal Plants Figure 7. flavonol synthase. CHR. Biosynthetic origin of the flavonoid skeleton. leucocyanidin deoxygenase. chacone isomerase. IFS. LDOX. TU. flavanone 3hydroxylase. Schematic of the main pathways and enzymes involved in the biosynthesis of stilbenes and flavonoids. isoflavone synthase. EU. flavones synthase. F3’H. dihydroflavonol 4-reductase. chalcone reductase. chalcone synthase. F3H Figure 8. anthocyanidin reductase. CHI. CHS. LAR. leucocyanidin 4-reductase. C. 2010). However. inflammatory. flavones and isoflavones (Tringali. the key factor is their chemical structures and the different mechanisms of actions that they can undergo. in particular the diet.) allows humans to consume them on a daily basis. the incidence of chronic and degenerative diseases (such as cardiovascular disease. The resulting aglycones can be absorbed. 2009). reduce fevers and inflammation. Even if negative effects have not been comprehensively reported. to ease aches and pains. such as anti-inflammatory. Phenolic Compounds and Health Benefits Since ancient cultures.. The bioavailability of phenolic compounds in foods (fruits. 2000). One of the most important biological properties of phenolic compounds is the antioxidant activity against reactive species involved in ageing and in chronic. 2009. form complexes with polysaccharides. some phenolic compounds can be harmful when consumed in large doses. The effects of phenolic compounds on human health have been well established in the last decades. the willow bark was used in the centuries B. affect lipid metabolism and interfere with the bioavailability of metal ions. type II diabetes and some types of cancer) can be significantly reduced by changing lifestyle. 2011. Flavonoid glycosides are poorly absorbed until they have undergone hydrolysis by bacterial enzymes in the intestine. spices. 2007). 2007. flavanones. Vermerris and Nicholson.. Among these flavonoids there are chalcones.14 Sandra C. recent studies suggest that a fair degree of absorption of flavonol glycosides can also occur in the small intestine (Stalikas. 2006). phenolic compounds have been used in different medicinal applications. Important biological and pharmacological properties. In all the health benefits described and associated to phenolic compounds. Nowadays. several recent studies have proven that interactions between various phytochemicals with different modes of action can increase efficacy and minimize toxicity (Mertens-Talcott et al.. However. coffees. teas. 2011. In the past decades. For example. certain flavonoids have been shown to interact in the cancer development stages of initiation and promotion/progression. 2006). Stalikas. Castilho 4. The estimated range of consumption is 25 mg to 1 g a day. Soto et al. 2003). Accumulated evidence on the absorption and bioavailability of phenolic compounds and flavonoids in humans reveals that most of these compounds are modified during absorption and the metabolites that reach the cells and tissues are chemically and/or functionally distinct from the dietary sources (Fraga. 2007. flavonols. 2007). the substance responsible for these properties is a phenolic compound – salicin (isolated by Henri Leroux in 1829) (Mahdi. etc. Gouveia. The mode of action of phenolic compounds was initially thought to be due to direct scavenging of free radicals (reactive oxygen species) (Fraga... depending on diet (Stalikas. The reported negative properties attributed to phenolic compounds are the capacity to precipitate proteins. vegetables. Vermerris and Nicholson. Complimentary Contributor Copy . 2007). Vítor Spínola and Paula C. autoimmune. antimutagenic and anticarcinogenic activities have been associated to phenolic compounds (Fang et al. coronary and degenerative diseases (Soto et al. grains. In particular. 2007). Stalikas. several studies were performed in order to correlate the consumption of high levels of dietary phenolic compounds and flavonoids (mainly in fruits and vegetables) to the reduction of degenerative diseases (Fang et al. The extraction method must be selected according to the plant material and type of compounds to be studied. often with different proportions of water (Ignat et al. using aqueous methanol or acetonitrile. Extraction and Recovery of Phenolic Compounds Analysis of phenolic compounds present in crude plant extracts is based in a three steps procedure. The main disadvantages are long extraction times that can range from 12 hours to 24 hours and possible deterioration of thermolabile compounds (Li et al. close to the critical point. is frequently performed by liquid–liquid extraction (Ignat et al. microwave-assisted (MAE). the analysis of the extract and characterization of the compounds (Vichapong et al. ultrasound. Several recent reviews have compared and discussed the various techniques for extraction and analysis of plant phenolics (Khoddami et al. Santana et al. SFE is based on the fact that.. Also. the interaction between phenolic compounds with other plant compounds may lead to the formation of insoluble complexes difficult to extract.. propanol. lipids.. 2006). wide-range of applicability and its easy operation (Stalikas.. Recovery of phenolic compounds from agriculture activities and beverages industries. avoiding chemical modification and/or destruction of the compounds. which improves solvent access to interior components resulting in a higher efficiency (Schantz. the solvent changes its properties rapidly with only slight variations of pressure. 2010) as well as solid adsorption (Vichapong et al. supercritical fluid (SFE). ethyl acetate. dimethylformamide and their combinations. such as olive mill waste waters. Soxhlet extraction.. 2005). Solid-liquid and liquid-liquid extractions are the most used methods to recover phenolic compounds from plants. second.. The extracts obtained by SFE technique are free from compounds degradated due to high temperatures and oxygen exposure. 2010).. 2013.. such as the shake-flask technique. 2007). citrus transformation and wine making. The extracts are also free from chlorophylls and other non-polar compounds insoluble in supercritical fluids (Ignat et al. extraction of compounds. They are widely used due to their efficiency. acetone.Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 15 5. methanol. Naczk and Shahidi. Soxhlet. finally. 2009). The solubility of the compounds plays a very important role since it is dependent on their chemical frame which may vary from simple to highly polymerized structures. 2011.. The main aim is to achieve complete extraction. clean-up of the extracts to eliminate interferences and/or concentrate phenolic compounds and. 2011). For all these reasons. pressurized liquid (PLE) and solid-phase extraction (SPE) matrix solid phase disruption (MSPD) (Capriotti et al. 2011). Solid-liquid extraction is mainly used to recover food components such as sucrose. 2006). There are other techniques beside solvent extraction. Ultrasound method relies on the particles being broken apart mechanically. is frequently used to isolate flavonoids from crude extracts. proteins and also phenolic compounds (Ignat et al.. First. it has been difficult to establish a universal method for phenolic compounds extraction. The most common solvents for phenolic compounds extraction are ethanol. The most common used critical fluid is supercritical carbon dioxide Complimentary Contributor Copy . 2010). 2011). There was a notable increase in the development of the methodologies of separation in the last decades. continuous rotation and vortexing (Stalikas.. Often organic modifiers (like methanol) must be added to CO2 to recover polar phenolic compounds in particular flavonoids (Stalikas. methods of sample extraction. This type of extraction was presented for the isolation of catechin and epicatechin from tea leaves and grape seeds (Stalikas. This is very convenient for the purposes of automation. 2007). The MAE method uses microwave energy to heat the sample–solvent mixtures in sealed or open vessels. and other normally used in industrial processes are being replaced by supercritical fluids due to regulatory and environmental pressures on hydrocarbon and ozone-depleting emissions (Ignat et al. disposable cartridges. the solid or semisolid sample is placed in a closed cell. The higher efficiency of this method is related to the fact that it uses organic solvent at high temperature and pressure to extract analytes. Utilizing low cost. reduction of processing time. dichloromethane. chloroform. Gouveia. although the use of solvent mixtures with and without dipole moments opens up a variety of potential solvent mixtures (Schantz.. Thin-layer chromatography (TLC) and open column chromatography (CC) are still used as separation tools for many phenolic compounds (anthocyanins. 2006). low toxicity. due to its benign effect on the environment. 6. 2007). shorter extraction time. flavonols. The extraction solvents used for MAE must absorb microwaves. Conventional solvents are used in this technique and they are added to the cell at the start of the heating cycle.16 Sandra C. Separation and Detection of Phenolic Compounds Due to the multiple possibilities of isomer formation. thin-layer and packed open columns chromatographic methods have been used for the separation and purification of complex matrixes such as plant extracts. condensed Complimentary Contributor Copy . Conventional Chromatography Paper. 2006). namely in chromatographic techniques. In PLE. Besides the extraction techniques presented above mechanical processes are occasionally applied to enhance molecular interaction: mechanical stirring. Castilho (SC–CO2). SPE is one of the most effective and versatile.1. 2010). the exact identification of phenolic compounds present in crude plant extracts requires separation and isolation. 2011). 2007). The extraction is performed in an inert atmosphere and protected from light. pre-packed. sample components of interest are separated from other species by applying the extract to an appropriate chosen solid sorbent and selectively eluting the desired components. Solvents such as n-hexane. lower solvent consumption and on-line coupling of the extraction and separation techniques (Vichapong et al. non-flammability and compatibility with processed foodstuffs. 6. One drawback of PLE is that wet samples require a drying step prior to analysis when using a non-polar extraction solvent (Schantz. Vítor Spínola and Paula C. it is very difficult to analyze flavonoid glycosides even after derivatization. HPTLC is also appropriate for the preliminary screening of plant crude extracts before HPLC analysis (Marston. in most cases. 6. However. Even so. polyamide. combined with different mixtures of solvents. such as lower costs. and specific chemical modification on the same plate (Ignat et al. Prior to chromatography separation.Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 17 tannins and phenolic acids) (Naczk and Shahidi. Generally. Capillary Electrophoresis Capillary electrophoresis (CE) separation is based on the different electrophoretic mobilities in solution of charged species in an electric field in small-diameter capillaries Complimentary Contributor Copy . 2004). The application of electron impact ionization (EI) with a selected ion monitoring (SIM) method generates a simplified ion chromatogram of the ions of interest (Prasain et al. with columns that can withstand temperatures up to 400 ºC (dos Santos Pereira et al. Usually. silica-diatomaceous earth.. diatomaceous earth. allow for separation of different types of phenolic compounds (Tsao and Deng. these compounds are hydrolyzed and converted into their derivatives. 2011). silica..2. short analysis time. cellulose. is a powerful tool in separation and analysis but the lack of volatility of the majority of phenolic compounds makes this technique labor intensive since. 2007). There are a large variety of stationary phases such as alumina. the possibility of multiple detection. phenolics are usually transformed into more volatile derivatives by methylation. In conventional GC. The implementation of a modern standardized methodology led to an increasing acceptance and recognition of high-performance thin-layer chromatography (HPTLC) as a competitive analytical method. cyano. either gravimetrically or aided by the application of low pressure inert gas (flash column) (Cseke. 2004). conversion into trimethylsilyl (TMS) derivatives.. 2007). 2004). densitometry was successfully used in several studies. 6. inexpensive and relatively fast. HPTLC has many advantages. or derivatization with N-(tert-butyldimethylsily)-N-methyltrifluoroacetamide. the use of GC-MS as a routine technique for screening samples for target analytes or unknown phenolic compounds is not the most suited due to the limitations mentioned above. Glycoside hesperidin has been analyzed by high-temperature-high-resolution (HT-HR) GC-MS. A simple way to visualize certain phenolic compounds is by UV light (350–365 nm or 250–260 nm).3. 2006) since they have the advantage of being simple. 2006 ). Gas Chromatography Gas chromatography (GC) coupled with mass spectrometry (MS). quantification is not the main goal of TLC studies. derivatization is necessary. injected into a non-polar column (Stalikas. CC is most often employed for the preparative scale separation of components from a crude plant extract. since some phenolic compounds fluoresce under this type of radiation. diol and amino silica stationary phases which. .. 6. universal detection and selectivity with the capability of providing structural information. CE has been coupled to a large diversity of MS systems (Nevado et al... Castilho (Prasain et al. In the HSCCC the stationary phase is immobilized by a centrifugal force and pressure. MEKC has been extensively applied to separate phenolic acids and flavonoids (Česla et al. which form a charged complex with the cis-diol moiety of the sugar ring (Prasain et al.. 2005b. There are two different modes in CE separations based on the used buffers: capillary zone electrophoresis (CZE) and micellar electrokinetic chromatography (MEKC). Risso et al. 2006. complex formation with tetraborate molecules may influence negatively the separation. Vítor Spínola and Paula C. The low flow rates of CE (< 1µL/min) are also an advantage when using CE coupled with MS instruments.. MEKC uses surfactants. In this technique one should distinguish between neutral and charged analytes. High-Speed Counter Current Chromatography (HSCCC) In counter-current chromatography (CCC) there is no solid column packing material involved. whereas all neutral species migrate at the same speed. Electrospray ionization (ESI) has been reported as the ionization interface with the highest efficiency to use coupled with CE. 2007). For the separation of phenolic compounds. 2004). 2006). Neutral compounds are separated based on hydrophobicity. The force provides vigorous mixing between the two immiscible liquid phases. but electrochemical. β-glycosides of flavonoids can be separated by CE using a borate buffer. 2011). 2007. The role of the phases can be switched during a run. so alkaline buffers are used to ensure that the phenolic moiety is charged for electrophoretic separation. Tsao and Deng. ESI allows the detection of multiple chargeable species of high molecular mass and permits that CE eluted matrix can be introduced into the mass spectrometer through an ESI interface without splitting (Nevado et al. Gouveia. Stalikas.18 Sandra C. CZE is the simplest mode of CE and has been applied to separate phenolic compounds. 2004). Huang et al.. Charged species are separated from each other in the capillary. Most of the flavonoids are weak acids. The phase density difference and the centrifugal field are the only parameters involved in the equilibrium between the two liquid phases. fluorescence and MS detectors are also used (de Rijke et al. like sodium dodecyl sulfate (SDS) which form highly organized spherical micelles at levels above their critical micellar concentrations in the buffer.. The centrifugal field allows for the use of a liquid stationary phase in an open tube. For charged analytes the separation by MEKC is based on both the degree of ionization and the hydrophobicity (de Rijke et al. 2004). Complimentary Contributor Copy . Detection is usually performed by UV. 2007).. It is an all-liquid separation technique which relies on the partition of a sample between two immiscible solvents and separation is dependent on the partition coefficient (k) (Marston. 2010). 2010. 2010). which affects the analyte partitioning between the aqueous (moving with the electro-osmotic flow) and the micellar phases (charged and migrating with a different velocity). 2004).4. and retention of a very large fraction of the stationary phase (Tsao and Deng. consisting in the dual-mode of this technique (Ignat et al. Mass spectrometry (MS) revealed to be an excellent detector due to its high sensitivity.. Band I with a maximum in the 300-550 nm range. possibly acidified (Tsao and Deng. f) it reflects the real distribution profile of the extract. Hydroxybenzoates have maximum absorption bands between 200 and 290 nm with exception of gentisic acid. For each specific group of phenolic compounds. show absorption bands in the range 270 to 360 nm due to additional conjugation (Stalikas. 2004). arises from the B-ring. 2007). The identification of the compounds is achieved by combining the retention time and various detectors such as ultraviolet/visible (UV-Vis). High-Performance Liquid Chromatography High performance liquid chromatography (HPLC) has been described as the most useful tool for the qualitative and quantitative separation of phenolic compounds (Vichapong et al. 2000). Tsao and Deng. 6. 2006). mass spectrometry (MS). 2007. ideally in a sequential manner..Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 19 The main advantages are related to the absence of a solid stationary phase: a) no irreversible adsorption. Reverse-phase C18 columns are extensively used with a binary solvent system containing acidified water (acetic. electrochemical colorimetric array detection and nuclear magnetic resonance (NMR) (Vermerris and Nicholson. Flavonoids have two characteristic UV absorptions bands. which has an absorbance that extends to 355 nm. or to lower wavelengths (hypsochromic shifts) due to O-glycosilation (Määttä et al. and g) low-cost (once the initial investment in an instrument has been made. diode-array (DAD). Ignat et al. The application of HSCCC technique has been used recently for the separation of phenolic compounds. 2004). d) low risk of sample decomposition. (2011) recently published a review on this subject with several references to the use of HSCCC in the separation of phenolic compounds from plant extracts. 2010). e) low solvent consumption. formic or phosphoric acid) and a less polar organic solvent as acetonitrile or methanol. Kalili and Villiers (2011) published recently a review of the recent developments in separation of phenolic compounds by HPLC. fluorescence. Changing the pH and/or ionic strength of the solution will allow all compounds of interest to elute. Detectors Ultraviolet Detection Phenolic compounds have absorptions bands in the UV or UV/Vis region due to their conjugated double bonds and at least one aromatic ring present in their structures. no expensive columns and absorbents are required and only common solvents are consumed) (Marston.5. b) total recovery of injected sample. and band II with a maximum between 240-285 nm. there are specific wavelengths of maximum absorption: hydroxybenzoic acids. 2003). Simultaneous separation of mixtures of phenolic compounds is commonly detected at 280 nm for identification and quantification purposes. c) tailing minimized. The hydroxycinnamates. Complimentary Contributor Copy . from the A-ring (Merken and Beecher.. These absorption maxima can experience shifts to higher wavelengths (bathochromic shift) due to conjugation to sugar esters. Vítor Spínola and Paula C. the use of mass spectrometry has increased as it became an essential analytical technique. 2007). 1996).. 2007). derivatization must be employed. and anthocyanins at 520 nm (Rice-Evans et al. Castilho flavan-3-ols and proanthocyanidins are collected at 280 nm. flavones at 340 nm. Wittemer and Veit.20 Sandra C. 2004). electrospray ionization (ESI). 2003) and plant extracts. The ionization sources reported in the analysis of phenolic compounds are diverse: fast atom bombardment (FAB). Classes of flavonoids that show native fluorescence include the isoflavones. The development of multi-electrode array detection allowed the detection of phenolic compounds separated with a gradient elution in a wide range of samples such as wine (Mahler et al. 2007). and second that they are separated as a function of their m/z values. flavonoids with an OH group in the C3-position. Amperometric and conventional coulometric electrochemical detection are generally not compatible with the gradient elution mode (Stalikas. catechins and methoxylated flavones (de Rijke et al. matrix-assisted laser desorption ionization (MALDI) and thermospray analysis (TSP). Mass Spectrometry Detection UV-Vis data are a very important analytical tool but they are not enough for the complete identification of the composition of a complex mixture. biological matrices (Bugianesi et al. Electrochemical Detection Electrochemical detection is based on the capability of compounds to be oxidized or reduced at low-voltage potentials. that compounds under analysis have been charged (often by deprotonation or protonation) and transferred into the gas phase. This requires. atmospheric pressure ionization (API) including atmospheric pressure chemical ionization (APCI) and atmospheric pressure photo-ionization (APPI). 1988). Mass spectrometry detectors coupled online to HPLC (HPLCMS) dominate the literature related to the analysis of phenolic compounds in natural products (Stalikas... Fluorescence Detection The use of fluorescence detection in phenolic compounds is used only occasionally. 2007). flavonols at 360 nm. Gouveia. These two steps are achieved by the mass spectrometer source and analyzer. because the number of natural occurring phenolic compounds capable of fluorescence is limited. In the last two decades. respectively. hydroxycinnamic acids at 320 nm. first.. quercetin and kaempferol can form complexes with metal cations exhibiting intense fluorescence (Stalikas. Complimentary Contributor Copy . There are two main types of ionization: the ion-spray techniques and the ion-desorption techniques (Tsao and Deng. Using fluorescence detection combined with UV detection allows distinguishing between fluorescent and non-fluorescent co-eluting compounds. For example. but the establishment of the correct excitation and emission wavelength is crucial for a good detection (Stalikas. Mass spectrometers use the difference in mass-to-charge ratio (m/z) of ionized molecules to differentiate them. To extend the use of this type of detection to a larger number of compounds. 2000. 2006). An electric field is generated at the tip of a sprayer by applying a high voltage. ion-trap (IT). In the infusion mode. FAB and MALDI can operate in both positive (PI) and negative ionization mode (NI) (Tsao and Deng. 2008). The main advantage of IT is the possibility to perform MSn experiments to obtain structural information. the ions are formed at atmospheric pressure. 2004). due to the reduced number of ions in the spectral range of < 300 amu originating from the matrix and spraying solvent (Prasain et al. APCI. Further information on the molecular structures of unknowns can be obtained by tandem mass spectrometry (MS/MS or MSn) experiments. which is largely applied to phenolic compounds. among other factors. Ions of one polarity are preferentially drawn into the drops by the electric field as they are separated from the bulk liquid. In the APCI technique. the sample is introduced into a continuous liquid stream via an injection valve. One advantage of ESI source is a better S/N. A sample solution flows through a heated tube where it is volatilized and sprayed into a corona discharge with the aid of nitrogen nebulization. 7. MSn Identification and Structural Characterization of Phenolic Compounds The complete and unequivocal identification of each phenolic compound found in a plant extract can only be performed using NMR spectroscopy isolated and/or combined with other Complimentary Contributor Copy . TOF gives access to a theoretically unlimited mass range and is thus well suited for analysis of high molecular weight polymers.Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 21 In the ESI technique. Quadrupole analyzer is one of the most used in mass spectrometers since it is easy to handle. This technique is typically performed either in the infusion mode or in combination with HPLC or capillary electrophoresis. FT-ICR provides the highest mass resolution and most accurate mass determination.. making it theoretically possible to assign molecular formula unambiguously for smaller molecules. Ions are produced in the discharge and extracted into the mass spectrometer. with a close proximity of a counter electrode. with a small size and relatively low cost.. magnetic sector. This consists in isolating specific ions for fragmentation in a first stage of mass analysis and then inducing their dissociation by collision with inert gas molecules (argon or helium) to analyze the fragments thereby yielded in the second stage of mass analysis (Fulcrand et al. 2007). 2004). There are different types of analyzers used in mass spectrometry and those reported for the study of phenolic compounds are: quadrupole (Q). ESI. and Fourier-transform ion cyclotron resonance (FT-ICR) that differ. and also provides high resolution with accurate mass determination as low as 10 ppm (Xing et al. 2010). time-offlight (TOF).. by the available mass range and resolution. highly charged droplets are formed and ions are ejected by an ion evaporation process. The electrospray stability has been improved and contamination of the source minimized by switching from the off axis sprayer geometry to an orthogonal sampling position (Nevado et al.. 2004). Complimentary Contributor Copy . the negative-ion mode is more sensitive and the fragmentation behavior is different. the use of HPLC coupled to mass spectrometry. flavonoid O-glycosides undergo collision-induced cleavage of the O-glycosidic bonds producing the free deprotonated aglycone. . giving additional and complementary information.22 Sandra C. For conjugated aglycones.. Figure 9. 2004). mostly ESI-MS has been widely used for structural identification of phenolic compounds present in several natural samples (Ablajan et al. de Rijke et al. (2004). FAB was also used for identification of phenolic compounds after HPLC separation (Edenharder et al. Ion nomenclature used for flavonoid glycosides (illustrated on apigenin 7-O-rutinoside). Fabre et al. (1997) proposed a nomenclature for the main fragment ions obtained (Figure 9) (Cuyckens and Claeys. the ions are denotade A and B . 2004.. 2006. Gouveia. respectively. 2007). Flavonoids Cuyckens and Claeys (2004) found that in the structure analysis of flavonoids by HPLC/ESI-MS/UV-DAD. then the positive mode. Castilho analytical techniques..1. Vítor Spínola and Paula C. When positive mode is used. either as free aglycones and/or O-glycosilated aglycones. 7. A review on the application of MS techniques for the determination of flavonoids in biological samples was reported by Praisan et al. 2001. There are recent studies using HPLC for separation of components from crude extracts and the eluent is split between MS and NMR (March and Brodbelt. . Adaptaded from(Cuyckens and Claeys. Cuyckens and Claeys. A large number of phenolic compounds have been studied directly or extracted from plants and characterized by 13C and 1H-NMR experiments. 2001. Nevertheless. . for simultaneous HPLC-MS and HPLC-NMR analysis. Sano et al. This fact comes from the existence for a wide range number of phenolic compounds with positional isomers or chiral carbons. Y is used to refer to the aglycone fragment .. the A and B labels correspond to ions containing intact A.. Ye et al. In the negative mode for free aglycones. in which i and j indicate the C-ring bonds that have been broken.. In order to help the analysis of mass fragmentation of flavonoid compounds. respectively. [M–H–glycoside]-. 1999). 2008). Ma et al. Depending on the structure.and B-rings. 2003. 2006). B fragment ions. 2004). 2004) represented in Figure 9. the cleavage of two -bonds and the formation of two π-bonds take place. In some cases.4’-dihydroxyflavonol (quercetin and fisetin) give characteristic 1.C-glycosides can be distinguished based on their MSn fragmentation pattern. . The RDA C-ring cleavage of the 1.. B fragment ions appears as the main fragments in the negative ion mode.and C-rings. Compounds presenting methoxyl groups have a typical loss of 15 Da resulting in a [M − H − CH ]. 1995. resulting in an [M-Bring-H]. radical ion (Cuyckens and Claeys. a direct cleavage of the bond between the B. the relative sugar fragments are labeled B1 and B0. Flavonols with two or more hydroxyl groups in the B-ring display . with fragments that contain the aglycone part being denominated Y1 (loss of one sugar unit) and Y0 (loss of two sugar units). The number of hydroxyl groups in the B-ring is clearly observed in the fragmentation pattern. CO (28 Da). A and . de Rijke et al. with the glycosidic bond linking the glycose part to the aglycone being numbered 0 (de Rijke et al.fragment ion. CO2 (44 Da) and C2H2O (42 Da).. resulting in structurally informative A . rhamnose. 2003). and which contain the aglycone. for example. A ions have also been detected from the fragmentation of two isoflavones (formononetin and biochanin A) (Aramendia et al. loss of small groups. are commonly detected in negative and positive ion mode. Fragment ions from glyconjugate flavonoids are labelled based on the nomenclature introduced by Domon and Costello (Cuyckens and Claeys. 2001). cyclohexene will fragment into butadiene and ethylene (de Rijke et al. Y represents the diglycoside unit. The MSn analysis and main fragment ions of several flavonoid aglycones in the negative mode were reported by Fabre et al. O-glycosides. this type of cleavage is not observed for other flavonols (Fabre et al. RDA reactions occur in six-membered cyclic structures containing a double bond and involve the relocation of three pairs of electrons in the cyclic ring. such as H2O (18 Da). A and . where j is the number of the interglycosidic bonds broken. that require cleavage of two C-C bond of the C-ring.. X . Glucose is the most commonly found sugar moiety followed by galactose. These ions are obtained by specific retro Diels-Alder (RDA) reactions and give information on the number and type of substituent in the A. 3’.3 bonds giving .and B-rings (Cuyckens and Claeys. In addition to RDA reaction fragment ions.. 2006). 2004).. C-glycosides and O.2 C-ring cleavage with . Flavonoids are found in nature often conjugated with sugar units. . rather than the . counting from the aglycone. These fragments are helpful in the identification of those specific functional groups. A and . A ions as more abundant. and B ions. B ion is the major peak and it is characteristic for isoflavones (daidzein and genistein) (de Rijke et al. The . B . As a result. can be observed (Cuyckens and Claeys. (2001).Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 23 The most useful fragmentations for the identification of flavonoid aglycones are those . Ions formed due to the cleavage of the sugar ring. 2006). as it is also true for the positive mode. 2004). are designated . xylose and arabinose. B fragments are reported at low intensity for some members of the main types of flavonoids. the superscripts k and l indicate the interglycosidic bonds. Complimentary Contributor Copy .. 2004). Y (Hvattum and Ekeberg. 2004). Vítor Spínola and Paula C. Castilho Flavonoid O-glycosides can suffer both a collision-induced homolytic and heterolytic cleavage of the O-glycosidic bond producing deprotonated radical aglycone [Y − H].24 Sandra C. Flavonoid C-glycosides have the sugar moiety linked directly to the flavonoid aglycone via an acid-resistant C-C bond. Loss of water observed for 6-C-glycosyl flavonoids involving the hydroxyl group at the 2’’position of the sugar residue and the hydroxyl group at the 5-or 7-position of the aglycone (Cuyckens and Claeys. Figure 11. The nature and position of the glycoside group on the flavonol structure plays an important role on the formation of radical aglycone ions. Characteristic product ions formed by cross-ring cleavages in a pentose and hexose residue (Cuyckens and Claeys. B products . whereas A fragments are more abundant for 4’O-glycosides (Cuyckens and Claeys. Hvattum and Ekeberg (2003) verified that the product ion spectrum of kaempferol-7-O-neohesperidoside showed only a minor radical aglycone product ion. are more easily formed for 7-O-glycosides. 2003). The major fragment ions observed are related to the cross-ring cleavages of the sugar residue (Figure 10) and the loss of water molecules (Figure 11) (Cuyckens and Claeys. Tandem MSn analysis in combination with CID allows for the characterization of this type of compounds both in negative and positive ion modes. 2005). Complimentary Contributor Copy . Figure 10. There are minor differences between positional isomers: . Gouveia. and deprotonated aglycone ion. The homolytic to heterolytic cleavage ratio increases with the increasing number of OH groups in the B-ring. 2004). as opposed to kaempferol-3-O-rutinoside. The radical aglycone ions are very common for deprotonated flavonol 3-O-glycosides. [M-H]-) or positive (protonation. in positive and negative ion modes. 7. sugar residues of different mass can be located. Complimentary Contributor Copy . These acyl groups can be observed in mass spectrometry experiments. but they appear to be mainly linked at the 6-position of a hexose moiety which is confirmed when a .and 8-C-glycosyl flavonoids. there are other plants rich in CQA and substitution at position C-1 has been reported in some Asteraceae. the main goal is to differentiate 6-C. This class of compounds is found in high levels in coffee. galloyl..Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 25 The known C-glycosilation positions are the C-6 and/or C-8 of the flavonoid nucleus. The application of tandem MSn fragmentation of the different isomers makes it possible to discriminate each one. For dicaffeoylquinic acids. 2005). malonyl.2. Very few flavonoid glycosides are commercially available as standards. and it is more pronounced for 6-Cthan 8-C-glycosyl compounds. 2005). [M+H]+) ion mode. where esterification occurs at positions 3. The discrimination between the 1-CQA and 5-CQA is easy to establish on HPLC using a reverse phase column since 5-CQA is more hydrophobic and therefore elutes later (Clifford et al. 2003. such as arnica and artichoke (Clifford et al. several flavonoids have been described containing an acyl group linked to the sugar part. ferulic and tartaric) and (-)-quinic acid. 2004). coumaroyl. only few commercial standards are available. therefore accurate identification of individual compounds in complex samples is quite difficult. depending on which position of quinic acid it is connected. since the C6-sugar residue shows more extensive fragmentation than the C8-sugar residue. feruloyl and sinapoyl (Cuyckens and Claeys. benzoyl. X fragment is present in the spectrum. This key was also used for the identification of a large number of hydroxycinnamate esters of quinic. Non –flavonoids Ionization of hydroxybenzoic and hydroxycinnamic acids can be performed either in the negative (deprotonation. in the following order: 1~5 > 3 > 4. di and tri-isomers). In di-C-glycosides. The most common acyl groups naturally occurring in flavonoids are acetyl. Usually. The exact linkage position of acyl groups to sugar units is difficult to define through ESI/MSn data. The loss of a water molecule is observed. the caffeoyl group is more or less easily removed. 2005). 2005) studied exhaustively these compounds by HPLC-ESI/MSn and presented a hierarchical key for the identification of caffeoylquinic acid (mono. As mentioned before.. tartaric and shikimic acid in several species of Asteraceae (Clifford et al.. coumaric. so their quantitative analysis is seldom performed. Despite that this class of compounds is widely distributed in nature. Thus. [M-H-CO2]-. In addition to glycosilation. Clifford and co-workers (Clifford. plant extracts are subject to hydrolysis of those glycosides and the released aglycones are identified and quantified. chlorogenic acids (CQA) are a family of esters formed between some trans-cinnamic acids (caffeic. In addition to coffee. 4 and 5 of the quinic acid structure. Tandem mass spectrometry in the negative-ion mode of deprotonated phenolic acids produce a common loss of 44 Da by elimination of a carboxyl group from the deprotonated molecular ions. based on typical neutral losses. coumaroylquinic acids and feruloylquinic acids. and repair and de novo antioxidants and they have their established roles in the defense network in vivo (Niki. In addition. The scavenging antioxidants remove active species quickly before they attack biologically essential molecules. the adaptation mechanism functions as the fourth defense line. namely in the pathogenesis of various diseases and disorders has become a serious issue and as such has attracted much attention in the scientific community. 2008). 2010). Complimentary Contributor Copy . their use is now restricted since they are associated with high levels of cytotoxicity and carcinogenic effects. Antioxidant Capacity The relation between oxidative stress and human health. glutathione. Therefore. For example. Under stress. carotenoids. human diet should be enriched with antioxidant compounds that can be of either artificial or natural origin. glutathione peroxidase (GPx). remove waste by-products and reconstitute the lost function. in which appropriate antioxidants are generated at the right time and transferred to the right position in the right concentration (Niki.. 2010). scavenging antioxidants. Foodstuffs themselves are prone to oxidation. The first line of defense is performed by the preventing antioxidants by suppressing the formation of reactive oxygen and nitrogen species (ROS/RNS).26 Sandra C. Thus. α-tocopherol (vitamin E). This type of mechanism is the second line of defense in vivo. This effect is increased when there are not enough antioxidants to quench these harmful radicals.1. The third line of defense is composed by various enzymes which repair damage. Antioxidant Capacity and Phenolic Compounds 8. than enzymatic antioxidants (superoxide dismutase (SOD). inducing cell damage (Krishnaiah et al. the human body will produce more harmful species. The antioxidants can be divided into preventing antioxidants. artificial antioxidants such as butylated hydroxyanisole (BHA). propyl gallate (Pg) and tert-butyl hydroquinone (TBHQ) were used as additives in foods and beverages. Vítor Spínola and Paula C. hydroxyl radicals and hydrogen peroxide). butylated hydroxytoluene (BHT). and catalase) and non-enzymatic antioxidants (ascorbic acid (vitamin C). 2010). relative retention times and UV irradiation response. such as reactive oxygen species (ROS) (superoxide anion radicals. During a large period. 8. ion or a stable radical) that inhibits or significantly delays the oxidation of substrates even if the compound is present in lower concentration than the oxidized substrate (Matkowski. and flavonoids). Castilho These authors found cis and trans hydroxycinnamate moieties in CQAs and were able to distinguish them based on their fragmentation patterns. An antioxidant can be defined as a compound (molecule. Phenolic compounds and aromatic amines are free-radical scavengers. Gouveia. carotenoids scavenge singlet oxygen either physically or chemically. However. there is a major need to find natural compounds with antioxidant properties and low toxicity associated. It can refer to the capacity of a compound to scavenge free radicals or the capacity of a compound to resist to oxidation (Niki. based in competitive and non-competitive mechanisms followed by Complimentary Contributor Copy . 2010). Still. that is. The several types of antioxidant compounds are usually defined by their structure and mechanism of action and can be grouped in different ways according to the different authors.Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 27 8. food and biological samples. 2010). The RSC of a compound is determined by several factors: 1) the chemical reactivity toward free radicals and stoichiometric number. (A) Competitive scheme (B) Non-Competitive scheme Figure 12. and metabolism (Niki. 3) interaction with other antioxidants. The term “antioxidant capacity” presents different meanings depending on the type of experiment and operator. Methods to Determine Antioxidant Capacity In Vitro Many in vitro models have been applied for the evaluation of the antioxidant capacity of pure compounds and complex mixtures such as plants. 5) absorption. distribution. 2) rate of antioxidant-derived radical. the comparison and correlation of the results obtained from these distinct methods has to be formed carefully due to the different operating conditions and mechanisms of reaction.1. Representation of competitive (A) and non-competitive (B) approaches for in vitro determination of antioxidant capacity. retention. 8. The most common and widely used methods to establish the antioxidant activity are colorimetric ones. The impact of these two mechanisms is dependent on the environment. Factors That Determine Radical Scavenging Capacity (RSC) The radical scavenging capacity reactions are determined by the redox property and/or ionization potential of the antioxidant. rate of radical scavenging and number of radical molecules scavenged.2.1. 4) concentration and mobility at the environment. the antioxidant capacities assays can be divided into two groups: hydrogen atom transfer (HAT) and single electron transfer (ET). The probe is an oxidant that abstracts an electron from the antioxidant. 2007): ROO. radical can be summarized by the reaction (Apak et al. The ET mechanism of antioxidant action is based on the reactions: (Apak et al. → ROOH + A.) formed from the reaction of antioxidant phenol with peroxyl radical is stabilized by resonance. In close observation of the chemical reactions involved in the antioxidant process.) is subsequently oxidized to the corresponding Complimentary Contributor Copy . + AH/ArOH .. In the non-competitive methods. 2005a). Gouveia. oxidant and the probe. This type of assay involves two components in the initial reaction mixture: the antioxidant sample and the reactive species. ET−based assays measure the reducing capacity of an antioxidant. the antioxidant sample competes for those reactive species (radicals or non-radicals) (Magalhães et al. Effective phenolic antioxidants need to react faster than biomolecules with free radicals to protect the latter from oxidation. Vítor Spínola and Paula C. /ArO. HAT-based assays determine the capability of an antioxidant to scavenge free radicals by hydrogen transfers.. /ArOH . 2007) ROO. the antioxidants react with reactive species without the presence of any other competing target molecule. AH . the target species is a compound with high probability to be attacked in vivo by reactive species. + H O . The majority of HAT assays are kinetics based and involve a competitive reaction in which antioxidant and probe compete for peroxyl radicals thermally generated through the decomposition of azo compounds. R2N2 → 2 R . The HAT mechanisms of antioxidant action in which the hydrogen atom (H) of a phenol (Ar-OH) is transferred to an ROO.28 Sandra C. ↔ ROOH + H O where the reactions are relatively slower than those of HAT– based assays. + AH/ArOH . an oxidizable molecular probe and an antioxidant. The aryloxy radical (ArO. As such. In the competitive assays... + O2 → ROO. HAT-assays are composed of a synthetic free radical generator. respectively. and are solvent and pH dependent. Castilho UV/Visible spectrophotometry (Figure 12). In the reaction mixture there are antioxidants. 2008). /AROH . + AH . /ArO. The AH and ArOH species are the protected biomolecules and antioxidants. → ROO . + H O ROO. + H O ↔ A. where the aryloxy radical (ArO. causing the color changes of the probe (Huang et al. + N2 R. The degree of color change (either an increase or decrease of absorbance at a given wavelength) is correlated to the concentration of antioxidants in the sample. which can lead to false low antioxidant capacity of samples (Huang et al. 8. which is responsible for its characteristic purple color. this calculation is dependent on the specific conditions used in the assay. (a) DPPH radical structure and (b) structure of the reduced radical.2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging assay was first described by Blois in 1958 and has been modified according to specific experimental conditions (Krishnaiah et al. mainly the DPPH initial concentration. However. the DPPH radical Figure 13 (a) is reduced to the corresponding pale yellow hydrazine Figure 13 (b) (Magalhães et al. The reaction is usually performed in an organic solvent (methanol or ethanol) and the decrease of the absorbance at 515 nm is registered until a steady state is reached. 2004). 2010). the easier will be the oxidation from ArOH to Ar=O due to reduced redox potential. Complimentary Contributor Copy .Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 29 quinone (Ar=O).. Therefore. 2005a). The following are examples of the most frequently in vitro systems for the evaluation of antioxidant capacity.. the construction of a calibration curve of a strong standard antioxidant compound like Trolox or ascorbic acid allows for the interpolation of the values of absorbance variation and the results are expressed as equivalent concentration (Magalhães et al. When mixed with an antioxidant/reducing sample. The DPPH assay presents some disadvantages such as the fact that the radical is more suitable for small scavenging molecules and big antioxidant molecules have a slow or inexistent activity towards DPPH. The more stabilized the aryloxy radical is. DPPH (Figure 13) is one of a few commercially and stable free radicals..2. The reaction mechanism was first assumed as being a HAT process but it is now known that the electron transfer (ET) reaction occurs faster than the hydrogen atom abstraction which is a very slow mechanism in strong hydrogen-bond accepting solvents (Foti et al.. DPPH Method The 2. It has a UV-Vis absorption maximum at 515 nm.1.. 2008). The reaction of DPPH with some compounds such as eugenol was found to be reversible. The results are generally expressed as the efficient concentration (EC50) which corresponds to the amount of antioxidant necessary to decrease in 50% the initial DPPH radical concentration. 2008). Deep violet color Yellow-white color Figure 13. It is preferable to perform the detection at a wavelength of 734 nm.6. since the interference from other absorbing components and to sample turbidity will be reduced (Arnao. An important difference between ABTS and DPPH assay it that the ABTS radical cation can be solubilized in both aqueous and organic media. 1996).30 Sandra C. Vítor Spínola and Paula C. 2012). it is necessary to generate the radical cation chromophore 2. 2003). which allows measuring the contribution of hydrophilic and lipophilic compounds from samples (Arnao. 8.tripyridyl-s-triazine complex [Fe(III)-(TPTZ)2]3+ to the blue ferrous complex [Fe(II)-(TPTZ)2]2+ in acidic medium (Figure 15). 645. In this method.2. 8. Reaction times in the range 1 to 30 minute have been reported.2.. the decrease in absorbance is measured until a steady state is achieved. Trolox is the most common positive control used and the sample’s antioxidant capacity is expressed in terms of Trolox-equivalent.3. 2000). Ferric Reducing Antioxidant Power (FRAP) The FRAP assay measures the reducing power of a sample and it was first introduced by Benzie and Strain (Tsao et al. Figure 14.. Complimentary Contributor Copy . Gouveia. Reaction of the generation of ABTS radical cation. ABTS Method or Trolox Equivalent Antioxidant Capacity Method The ABTS method was first describe by Rice-Evans and modified by Miller in 1994 (Rice-Evans et al.2’-azinobis(3-ethylbenzothiazoline-6-sulphonate) (ABTS•+) which has a blue/green colour and absorption maxima at wavelengths of 414. In the same way of the DPPH decolorization assay. 2008)..2.4. A sample with reducing power will reduce the yellow ferric 2. Castilho The absorbance variation can also be affected by compounds such as carotenoids that absorb at the working wavelength and also by the turbidity of the sample. The reaction is followed by an increase of absorbance at 593 nm and the variation in absorbance is related to a Fe(II) standard solution.. 2000). 734 and 815 nm (Magalhães et al. A widely form used to produce the ABTS radical cation is via the chemical reaction of ABTS and potassium persulfate (Figure 14) which is stable for 2 days (Pinchuk et al. 8. The ORAC values are expressed in reference to a calibration curve generally using Trolox as the positive control. yielding better reproducibility and higher sample throughput (Tsao et al. 2008. 2003). the decay of fluorescence is reduced.4. photobleaching after exposure to excitation light. This method has also been modified for the 96-well microplate reader. the ORAC assay has been modified in order to measure lipophilic and hydrophilic compounds. Oxygen Radical Absorbance Capacity (ORAC) Assay The oxygen radical absorbance capacity (ORAC) is one of the most used methods to measure the ROO˙ scavenging capacity. The low pH value used may induce protein precipitation when this method is applied to milk or plasma samples. 2010). The use of fluorescein has overcome these limitations and the products generated from the reaction of fluorescein with peroxyl radicals have been characterized and are consistent with a HAT reaction mechanism (Tsao et al. interaction with polyphenols by nonspecific protein binding and loss of fluorescence even without added radical generator (Magalhães et al. The reaction is followed for large periods normally higher than 30 minutes. 2008) but for polyphenols the reaction occurs more slowly (> 30 minutes) until a plateau is usually observed. compounds with antioxidant properties that act as hydrogen transfers (such as thiols) will not react in FRAP assay.Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 31 The reaction time is typically 4 minutes (Magalhães et al. 2002). The quantification of the antioxidant capacity is measured by the area-under-the-curve (AUC) technique with and without the antioxidant sample. Moreover. The best conditions were found to be a solution of 50% acetone: 50% water containing 7 % of randomly methylated βcyclodextrin as a water solubility enhancer (Huang et al. When a sample with chain-breaking compounds is present in the reaction medium.2.. Structures of the two triazine complexs. Figure 15.... 2008). Since there is a large number of lipophilic antioxidants. The use of phycoerythrin presents some disadvantages like large lot-to-lot variability. A drawback of this method is that any compound with a redox potential lower than that of the redox pair Fe(III)/Fe(II) can theoretically reduce Fe(III) to Fe(II) inducing a false FRAP value (Magalhães et al. The intensity of fluorescence loss of a probe such as beta-phycoerythrin or fluorescein is measured over time under reproducible and constant flux of peroxyl radicals (Magalhães et al. Niki. 2003)... 2008). Complimentary Contributor Copy .. gallic acid is used as reference compound and results are expressed as gallic acid equivalents. The target is the human plasma.. producing a peroxyl radical flow at a constant temperature-dependent rate. (Huang et al. Fe(II). a high correlation between the results obtained by this method and those obtained by other ET-based assays (FRAP.765 nm (Magalhães et al. This method is non-specific to phenolic compounds because other non-phenolic compounds with reducing properties (ascorbic acid. sodium molybdate. This issue can be eliminated by the use of R-phycoerythrin as the fluorescent target/probe which leads to the reaction being fluorimetric monitored. β-Carotene-Linoleic Acid Bleaching Assay The evaluation of the antioxidant activity by the β-Carotene assay is based on the fact that the free radical linoleic acid attacks the highly unsaturated β-Carotene.6.. 2008).. and the presence of compounds with antioxidant properties delay the β-Carotene oxidation by neutralizing the free radicals in the medium (Gursoy et al. since it may not be stable over the necessary period. DPPH. 2005a) Normally. 2005a).2. The measurement of the time period in which oxygen uptake was inhibited by plasma is an indirect way to evaluate the antioxidant capacity. phosphoric acid and water. forming blue complexes that can be detected at 750 . and Momo (2004) proposed a method to assess the total phenolic content in tea using a polyphenol oxidase as being more specific than the Folin-Ciocalteu method.5. Folin-Ciocalteu Method This method is widely used to measure the total phenolic content in different samples. 2008). 8. The exact chemical nature of this solution is not known. The Folin-Ciocalteu reagent is a mixture of sodium tungstate. etc. Fabris.2. 8. since it is simple and reproducible in most of the cases. Vítor Spínola and Paula C.32 Sandra C.. the original FC method has become a routine assay in studying antioxidants. aromatic amines.) can also react (Magalhães et al. 2009). Complimentary Contributor Copy .. Total Radical-Trapping (TRAP) Assay The total radical-trapping antioxidant parameter assay was first described by Wayner in 1985 for the evaluation of the antioxidant capacity of human plasma (Magalhães et al. Cu(I). concentrated hydrochloric acid. 2008).) have been reported and consists on the main advantage of the Folin-Ciocalteu method. but it is believed to contain phosphomolybdic/phosphotungstic acid complexes (Huang et al. One of the main disadvantages of this method comes from the use of an oxygen electrode as detector.2. 2008). The chemistry of this assay is based on the transfer of electrons in alkaline medium from phenolic compounds and other reducing species to molybdenum. This method is based on the thermally decomposition of an azo-compound. to which lithium sulfate is added to give the intense yellow color.. Gouveia.. while the oxygen consumed in the oxidation of plasma material is the probe molecule to follow the action of antioxidants (Magalhães et al. However. ABTS. Nevertheless. sulfur dioxide. etc. Stevanato.7. Castilho 8. 9. 2003). immune regulation. Zhu et al. antioxidative effects. Stagos et al. and subsequent neuronal cell survival. Kim (2010) reviewed the naturally-occurring neuroprotective phenolics and their underlying mechanisms of neuroprotective actions. They found that HCA were also able to strongly protect lysozyme from gamma rays irradiation and to protect proteins against oxidation by scavenging oxidizing species and repairing the damaged protein. 2009) review covers the most recent literature to summarize structural categories and molecular anticancer mechanisms of phenolic compounds from medicinal herbs and dietary plants. such as antioxidant. The inhibition power is normally expressed as percentage of inhibition (Siddhuraju and Becker. Feng et al. anti-inflammation. Medicinal Plants with High Antioxidant Capacity and Phenolic Compounds The literature on medicinal plants phenolics and their bioactivity is huge. catechin. proliferation or differentiation. inhibiting DNA binding and cell adhesion. Since epigenetic marks (epimutations) are reversible in contrast to genetic defects. There are several comprehensive reviews focused on the antioxidant properties of different medicinal plant and the mechanisms of action of the various types of phenolic compounds. stimulation of macrophage phagocytic activity and induction of gene expression and production of macrophage-related cytokines. especially reduction of oxidative stresses. The role of antioxidant versus pro-oxidant effects of green tea polyphenols in cancer prevention is discussed by endless researchers and a large number of reviews is available. (2010) demonstrated that hydroxycinnamic acids have a significant activity in the prevention and treatment of lung cancer through antiproliferation. regulation of tumor cell division cycle. Huang and co-workers’ (Huang et al. They conclude that various bioactivities of phenolic compounds. promotion of apoptosis. Vanden Berghe (2012) discusses the possible epigenetic contributions of dietary polyphenols in cancer chemoprevention. or anti-mutagenic and antiinflammatory effects are responsible for their chemopreventive properties and also contribute to their inducing apoptosis by arresting cell cycle. (2006) showed that hydroxycinnamic acid derivatives (HCA) were able to inhibit the cross-linking of protein induced by riboflavin mediated photo-oxidation. The neuroprotective activities of diverse polyphenol groups are potentially due to their capacity to modulate several cellular responses. (2012) review the chemopreventive properties plant polyphenols against HCC and discuss the molecular mechanisms accounting for this activity. They also emphasize that more information about the health benefits and the possible risks of dietary supplement or herbal medicines is needed to ensure their efficacy and safety. resveratrol. regulating carcinogen metabolism and ontogenesis expression.. migration. genistein. chemopreventive nutritional polyphenols (soy. curcumin) are currently evaluated for their ability to reverse adverse epigenetic marks in cancer (stem) cells to attenuate tumorigenesis-progression. anticarcinogenic. and blocking signaling pathways. antimutagenic effects. Complimentary Contributor Copy .Phenolic Compounds and Antioxidant Capacity of Medicinal Plants 33 Readings are taken at a wavelength of 490 nm immediately after the beginning of reaction and at 15 minutes time intervals for 200-300 minutes. prevent metastasis or sensitize for drug sensitivity. . Ferro-Luzzi. since polyphenols are known for their ability to prevent oxidative decay and provide a defense against the oxidative stress of free radicals for the plant itself.. Kinghorn.-Y.-M. The standardization of these methods is highly desirable in order to make comparison of data an easier task for the scientific community and to the final consumer. K. D. F. Structural characterization of flavonol 3. J. Demirata. (2007).. Azzini.. Bektaşoğlu. 352-360. A. 327-333. Aramendia.7-di-O-glycosides and determination of the glycosylation position by using negative ion electrospray ionization tandem mass spectrometry. M.. 41. Balunas... 12. Vítor Spínola and Paula C. Chromatogr. 2012b). X... J. Drug discovery from medicinal plants. Lafont. K.. separation and identification of these compounds from natural sources. However. 707. References Ablajan. Shi. 2012a... 2010. J. M.. S. R. (1995).. 2012. A. Bugianesi. Özyürek. 2011.. A. 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Double roles of hydroxycinnamic acid derivatives in protection against lysozyme oxidation. migration. and a wide range of phytochemicals such as polyphenols. Cualiacán. Ana Isabel Gonzaga-Morales1 and Jorge Reyes-Esparza1 1 Universidad Autónoma del Estado de Morelos. food scientists and consumers due to the role they play in human health. Many in vitro and animal studies have shown that a large range of dietary antioxidants. It is common knowledge that plant-derived foods contain hundreds of active antioxidant compounds. also inhibiting the expression of enzymes such as xanthine oxidase. Facultad de Ciencias Químico Biológicas.mx. Polyphenols can induce antioxidant enzymes such as glutathione peroxidase. catalase and superoxide dismutase. However. They participate in the regulation of many cellular processes. regulated levels. Dietary polyphenols have received a lot of attention from nutritionists. growth. México Abstract Reactive oxygen species (ROS) play a crucial role in human health. and contraction. apoptosis. which respectively decompose hydroperoxides. Facultad de Farmacia. taken as extracts or as food components. Medicinal plants are traditionally used in folk medicine as natural healing  Corresponding author: mrodriguezf@uaem. tocopherols. proliferation. Complimentary Contributor Copy . carotenoids. Inc.In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers. such as response to growth factor stimulation and control of inflammatory responses. including differentiation. cytoskeletal regulation. México 2 Universidad Autónoma de Sinaloa. including ascorbic acid. Chapter 2 Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables around the World Lourdes Rodríguez-Fragoso1. hydrogen peroxide and superoxide anions. ROS also play an important role in a wide range of pathologies and many implicated diseases that are leading causes of death. At low. Cuernavaca. have beneficial effects because they modulate oxidative stress and protect against oxidative damage and its complications. Ulises Osuna-Martínez2. ROS are involved in many vital physiological processes. They have a role in various signaling cascades. have unpaired valence electrons or unstable bonds. people are advised to increase their intake of fresh fruit and vegetables based on the presumed benefits of the antioxidant content of plant substances. and watercress. tomato. and watercress. The present chapter evidences our knowledge of the therapeutic properties of the antioxidant qualities of some fruits and vegetables is limited and seeks to provide an overall clear view of the antioxidant role of common fruits and vegetables. we have discovered that reactive oxygen species (ROS) exert a multiplicity of biological effects across a wide spectrum that ranges from physiological regulatory functions to damaging alterations involved in the pathogenesis of an increasing number of diseases. these are the most frequently sought fruits and vegetables by people with health problems. cactus. Epidemiologic evidence suggests that regular consumption of fruits and vegetables may reduce the risk of some diseases. pomegranate. including superoxide anions and hydrogen peroxide. ROS react readily with proteins. climatic and seasonal variations. tomato. carrot. berries. pepper. environmental conditions. cauliflower. orange. tangerine. pomegranate. orange. pepper. Although there have been numerous studies on ROS scavenging involving fresh food products. broccoli. grape. Clinical pharmacologic interest in the efficacy and safety of the phytochemicals present in fruits and vegetables has grown during recent years due to the realization that many people selfmedicate using these agents. At high concentrations. 2007). few studies have focused on whether or not compounds in the diet can modulate ROS levels. avocado. Based on our experience. geographical regions of growth. Introduction Over the past decades. cauliflower. Here. papaya. its variety. Here we review some of the antioxidant properties of the most widely used varieties to give medical practitioners an overview of the possible pharmacological and physiological effects of the common fruits and vegetables used by their patients. tocopherols. including ascorbic acid. carotenoids. berries cranberry. tangerine. mango. It is now clear that organisms have also developed methods for utilizing ROS in critical physiological processes (D’Autreaux and Toledano. The present chapter is limited to species such as apple. lipids. avocado. carbohydrates. Rodríguez-Fragoso. It is common knowledge that plant-derived foods contain hundreds of active antioxidant compounds. spinach. All ROS types. inflammation disorders. grape. and a wide range of phytochemicals such as polyphenols. growing practices. broccoli.42 L. and many other factors such as post-harvest treatment and processing. we discuss the phytochemistry and antioxidant pharmacological properties of the following plant species: apple. grapefruit. grapefruit. in other cases. When ROS were initially established as a biomedical concept it was thought they had exclusively toxic effects and were associated with pathologies. cranberry. degree of ripeness. including cancer. or reducing the risk of cancer. mango. The antioxidant properties of medicinal plants depend on the plant. Ana Isabel Gonzaga-Morales et al. Many have no consistently used. The present chapter is limited to commonly consumed fruits and vegetables with significant nutritional and antioxidant beneficial effects in folk medicine. Ul. the English name may Complimentary Contributor Copy . cactus. along with their health and disease-reduction benefits. popular name in English. papaya. spinach. Osuna-Martínez. and nucleic acids. Nowadays. often inducing irreversible functional alterations or even complete destruction. carrot. remedies with therapeutic effects such as the prevention of cardiovascular diseases. Oxygen is the terminal electron acceptor during energy production. The arsenal of cellular defenses to control the magnitude of ROS generation is extensive and includes enzymatic (superoxide anion dismutases. 2004). or studies that systematically explore their benefits. The second-messenger properties of ROS are believed to activate signaling pathways by activating tyrosine kinases. 2003). thus handling different pools of superoxide anion generated extra. pulse duration.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 43 refer to two or more botanically distinct species. thioredoxins. and E. However. Presently. NADPH oxidases. Reactive Oxygen Species: Source and Defense ROS are oxygen-containing molecules that are highly reactive in redox reactions. 2001). sulfiredoxins) and nonenzymatic antioxidants (vitamins A. catalases. living organisms have not only adapted to an unfriendly coexistence with these potentially toxic species. SOD is localized in the cytosol (Cu/Zn SOD) or in the mitochondria. glutathione peroxidase (GPx). 2007). This dual function of ROS as signaling molecules or toxins could result from differences in concentration. myeloperoxidase.. In addition. or ion channels. and peroxiredoxins control the fate of hydrogen peroxide produced from superoxide anion. and nitric oxide synthase (Bartosz. is found in the cytosol Complimentary Contributor Copy . which. Considering the reactivity and site localization where free radicals and ROS are generated within cells. ROS are primarily produced intracellularly by two metabolic sources: the mitochondrial electrontransport chain. Most eukaryotic organisms require oxygen to survive. but have also developed mechanisms that use them advantageously (Bakkenist and Kastan. extracellular SOD (ecSOD) is predominantly found in the extracellular matrix and is known to regulate endothelial cells by preventing nitric oxide (NO) from reacting with superoxide anion. GPx. Furthermore. It is not possible at this point to list all the fruits and vegetables commonly used by healthy and non-healthy people. a more reactive form of oxygen. urate. enzymatic antioxidant defenses are compartmentalized to neutralize these species more efficiently (Droge. ROS were traditionally thought of as toxic by-products of living in an aerobic environment because they are known to damage cellular macromolecules. Like ecSOD. especially in regards to their antioxidant properties. MAP kinases. there are only a few studies that combine a phytochemical and detailed analysis of the antioxidant properties of given fruits and vegetables (Heinrich. catalase. the superoxide dismutases (SOD) catalyze the dismutation of superoxide anion into hydrogen peroxide. For instance. Despite the constant generation of free radicals and oxidant species.or intramitochondrially. C. ROS levels are also dependent on oxygen concentrations. GPx-1. GPx has also been found in plasma. 2009). including proliferation (Sauer et al. 2002). peroxiredoxins. tyrosine phosphatases. It accepts an additional electron to create superoxide. interactions between specific receptor-ligands are also known to generate ROS. bilirrubin). glutaredoxins. a selenoprotein. in recent years. The coordinated action of antioxidant enzymes ensures efficient ROS removal. several studies have shown that ROS can function as signaling molecules that regulate numerous cellular processes. glutathione (GSH). in turn. which could subsequently. and subcellular localization (Menon and Goswami. the cytochrome P450 system. For example. lead to cell death. Superoxide can be converted to hydrogen peroxide (H2O2) spontaneously. and oxygen-metabolizing enzymatic reactions such as xanthine oxidases. is converted into water and oxygen by GSH peroxidases and catalase. Glutathione GPx reduces lipid hydroperoxides to alcohols and reduces hydrogen peroxide to water. 2011). 2011).. 2011). modulating the aging process (Salminen and Kaarniranta.. having a role in neuronal apoptosis during brain development. Three superoxide dismutases differing in their subcellular location catalyze the reaction of superoxide into oxygen and hydrogen peroxide.44 L.. some of which collaborate with enzymatic partners such as GSH. In addition to these efficient ROS scavenging enzymatic systems. It is synthesized in the cytosol of all cells from its constituents (amino acids. The nuclear transcription factor Nrf2 is the master regulator of the gene expression of antioxidant enzymes. uric acid. the term “redox regulation” seems to better describe the redox status and its consequences. mounting an effective immune response (Tschopp. In addition. This critical antioxidant is a tripeptide (L-g-glutamyl-L-cysteinylglycine) that owes its antioxidant function to the sulfhydryl group of cysteine. These biomolecules include tocopherol (vitamin E). acting as possible signaling molecules in regulating skeletal muscle glucose uptake (Sandstrom et al. GSH synthetase is responsible for synthesis of the major cellular antioxidant glutathione and therefore also plays an important role in ROS detoxification. There is evidence of the roles played by ROS in several physiological processes. cysteine. and polyphenols (Hybertson et al. muscular exercise renders us more resistant to oxidative damage. enable the reduction of oxidized proteins by cysteine thiol-disulfide exchange. such as maintaining vascular diameter and normal vascular cell function. 2008). Complimentary Contributor Copy .. Rodríguez-Fragoso. GSH is a versatile antioxidant because of its function as a cofactor for GPx and glutathione reductase (GSR) in the so-called GSH redox cycle. thereby affecting signal transduction. and regulating gene stability and transcription by affecting chromatin stability (Rajendran et al. 2012). The natural defense against ROS consists of antioxidant enzymes and antioxidant scavengers. Ul. and mitochondria of all cell types. 2011). In addition to its redox-modulating effects. glutamate. Both ROS and the protective antioxidant systems have to work in coordination to reach a state of redox homeostasis. which also consist of several isoforms differing in subcellular localization. as well as in cognitive function (Massaad and Klann. Thioredoxins. where it plays a critical role in the detoxification of hydrogen peroxide produced from superoxide anion. whereas distinct peroxiredoxins can be located in the cytosol (Prx) or mitochondria (Prx-III). ascorbic acid (vitamin C). Ana Isabel Gonzaga-Morales et al. Most of these molecules are present in fruits and vegetables in our diet and play an important role in maintaining health because they act as free radical scavengers and antioxidants. there are also critical nonenzymatic antioxidants. carotenoids. there is increasing evidence of their use in regulating and maintaining normal processes in living organisms (Assim et al. Osuna-Martínez. Peroxiredoxins control cytokineinduced peroxide levels. glycine) and is then compartmentalized in various suborganelles. participating with the tumor-relevant transcription factor and hypoxia-inducible factor (HIF) in sensing oxygen availability and initiating responses appropriate for cell survival.. acting as a necessary cofactor for thyroperoxidase. Antioxidant scavengers are predominantly of dietary origin. the enzyme participating in a final step of thyroid hormone production (Erdamar et al. 2012). Impact of ROS in Health and Disease Although ROS have been classically known for their damaging effects. 2006). Therefore. and oxidative phosphorylation (Robertson. proteins. 2006). which illustrates yet more complicated and interesting roles for ROS (Sorse and Krause. 2012). are thought to involve oxidative stress. ageassociated hearing loss is thought to be a ROS-mediated disease (Bánfi et al. Cancers. Diabetic retinopathy. primarily through the expression of NOX enzymes in microglia cells.. ROS and oxidant generation can disturb the functions of these vital cellular constituents. including glyceraldehydes autoxidation. hypertrophy. 2004). protein kinase C activation. angiogenesis. chemotactic molecules. and metastasis. glycation.. On the other hand. 2009). 2012). As a consequence. as shown in cell-free or in in vitro cell systems. NOX4 mediates differentiation. NADPH oxidase (NOX) 1 is required for migration.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 45 Cumulative evidence found over the years clearly supports the idea that ROS and oxidants are important factors in many different pathological processes (Brieger et al. 2001). In most cases. resulting in cell dysfunction or death.. more specifically. and adipokines. high ROS concentrations contribute to diseases due to neurotoxicity (Sorce and Krause. 2009). augment the chronic inflammatory state and result in the excessive production of ROS. it was also demonstrated that ROS induce the assembly and Complimentary Contributor Copy . cardiovascular diseases (CVD). many age-associated diseases of the eye. 2009). and NOX1 and 2 are implicated in hypertension (Streeter et al. Excess glucose increases oxidative stress through several biochemical mechanisms. Thus. has been the focus of intensive research that demonstrates oxidative stress plays a vital role in its pathogenesis (Zhang et al. Alzheimer´s disease. but also via dysregulation. and proliferation. While low ROS concentrations are required for brain function. including depression and autism.. ROS have been implicated in several psychiatric diseases. where tissue-infiltrating monocytes/macrophages increase in number and in activity. In vascular smooth muscle cells from large arteries. The foundation for this pathophysiological role derives from the reactivity of these species to different cellular components such as lipids or DNA and.. causing systemic oxidative stress (Chen and Tinnett. cytokines. Similarly. Obesity is also associated with a state of chronic inflammation in the adipose tissues as well as in other organs. It is increasingly acknowledged that diabetic complications are also strongly linked to a state of oxidative stress. 2004). the simultaneous loss of a tumor suppressor and generation of ROS leads to a major alteration of the post-translational processing of the HIF-1α (Sarsour et al. the hexosamine pathway. ROS are also involved in a large number of CVD and the causal mechanisms are complex. ROS also have an important pathological role in the pathogenesis of some neurodegenerative disorders: Parkinson’s disease. ROS contribute to a wide range of pathologies and many of the implicated diseases are leading causes of death.” in which excess extracellular glucose and fatty acids (FAs) exert various damaging effects. Several active mediators. and amyotrophic lateral sclerosis (Terashvili et al. we could say that the prevalent metabolic state is the one described by the term “glucolipotoxicity. and neurological diseases all show robust evidence for ROS involvement. ROS have a role in neurological disease progression. 2008). Regarding the function of ROS in metabolic disease and chronic inflammation. ROS may not only contribute to cancer development through oncogenic mutations.. such as cataract and retinal degeneration. The most thoroughly studied example is schizophrenia. a major worldwide cause of blindness among adults. 2011). because of the presence of cysteine residues. Recently. as in renal cell carcinoma (Perera and Bardeesy. Elevated levels of the HIF-1α contribute to tumor growth. methyl glyoxal and sorbitol production. fiber.. cellular organelle functions. the results of recently conducted research on molecular. Taken together. Ana Isabel Gonzaga-Morales et al. subcellular organelles and cellular mechanisms involved in mediating ROS action offer promising avenues and propose novel. Ul. Figure 1. potentially therapeutic agents for ROS-linked diseases. Osuna-Martínez. There is no doubt that redox regulators. and surrounding environments are all tied together in intricate networks affecting the whole body. since they have low energy density and are sources of micronutrients. related active mediators. Food as a Natural Source of Antioxidants Fruits and vegetables are known to be important components in a healthy diet. and even lifespan. and other components with functional properties known as phytochemicals (Figure 1 and 2). 2011). metabolism. Phytochemicals polyphenols present in fruit and vegetables. Rodríguez-Fragoso.46 L. Complimentary Contributor Copy . activation of inflammasomes and inhibit mitochondrial autophagy. state of health and disease. both processes are related to aging and age-related diseases (Zhou et al. Clinical studies using antioxidant food supplements have been largely disappointing. there is an apparent contradiction: on the one hand there is ample evidence of the role played by ROS in various diseases and antioxidant-rich food is generally associated with good health.. vitamin C) may also have pro-oxidant activity under certain circumstances. 2011). including those with antioxidant activity (multivitamins. However. Reportedly. Antioxidant food supplements (e. typically upon interaction with ROS. and E. In fact. They are incapable of preventing oxidation of molecules that have a very high affinity for ROS. Others phytochemicals non-polyphenols present in fruit and vegetables. certainly through mechanisms unrelated to oxidative stress.g. peroxidase and mimetics. where vitamin and mineral supplements were assessed for their relationship to total mortality in more than 30. An example of this was the Iowa Women’s Health Study. This is obviously not a problem with antioxidants of dietary origin (1 glass of red wine provides more than 1000 different compounds with antioxidant capacity).000 elderly women. but antioxidant supplements do not prevent disease and are even associated with a poor health outcome. Vitamins A. and bioflavoids. this is a limiting factor for single molecule supplements. The only supplements found to decrease mortality risk were calcium and vitamin D. β-carotene. vitamin B6). antioxidants scavenge ROS after their production. C. Antioxidants preferentially localize to subcellular compartments based on solubility. Antioxidants are most effective in Complimentary Contributor Copy . Thus.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 47 Figure 2. coenzyme Q10. Several antioxidant supplementation strategies have been tested in humans based on the assumption that they will increase degradation of ROS and thereby reduce ROS-associated diseases. On the other hand. the long-term health consequences of many supplements are dubious. which has an extremely rapid rate of reaction with superoxide. Notable treatments have included SOD and mimetics. The use of food supplements. was associated with increased risk of total mortality (Mursu et al.. the tissue concentrations that can be achieved with antioxidants might be far below the levels required to counteract a ROS-generating system. such as nitric oxide. caffeic acid. and other natural antioxidants (including vitamins A. Cho et al. combating low levels of ROS generation. and anthocyanins (Yoon et al. phenolic acids. The World Health Organization’s (WHO) study group on diet. whether in crude or processed state (De Smet. Ana Isabel Gonzaga-Morales et al. nutrition and prevention of communicable diseases have recommend daily consumption of at least 400 g (14 oz) of fruits and vegetables (WHO. epicatechin. sugar or salt. polyphenols.. 2005). (Kammerer et al. 2010). roots or leaves)... calcium. procyanidins. myricetin. phenolic acids.48 L. flavonoids and anthocyanins (Vislocky and Fernandez. It has also been proposed that the additive and synergistic effects of phytochemicals in fruits and vegetables are responsible for their antioxidants activities. flowers. The regular consumption of foods that are naturally high in antioxidants (fruits. whole grains. Ul. phloridzin. coumaric acid. Osuna-Martínez. vegetables. parts of the plant (e. C. and whole grains) is associated with substantial health benefits. flavonoids. lutein. procyanidin. and hypertension. 2003) (See Table 1 and 2). diabetes. catechin. E and folic acid. and procyanidins.g. 2003. Fruits and their most common phytochemicals Fruit Apple Malus domestica Commonly used parts Fruit pulp and peel Cranberry Vaccinium macrocarpon Fruits Berries Rubus coreanus Rubus idaeus Rubus fruticosus Rubus leucodermis Grapes Vitis vinifera Fruits Fruits and seeds Bioactive compounds Flavonoids. and selenium (Tian et al. but have a limited capacity to reduce high levels (Stanner et al.. phenolics. and E) that have been associated with protection from and/or treatment of chronic diseases such as heart disease. Rodríguez-Fragoso. 2005). 2009) Phenolics compounds. organic acids. It is generally accepted that the beneficial effects of medicinal plants can be obtained from active constituents present in the whole plant. as well as other medical conditions. anthocyanins. carotenoids (Bunea. fruits. gallotannin. and chlorogenic acid (Golding et al. 2002). catechins. ß-carotene. carotenoids. Table 1. The US Department of Agriculture’s Food Guide Pyramid recommends that adults consume 5 to 9 servings of fruits and vegetables a day. phloretin glycosides. fruits. Increased fruit and vegetable consumption can also help displace food that is high in saturated fats. C. triterpenoids. tannins. terpenoids. chlorogenic acid. or plant materials or combinations thereof. Complimentary Contributor Copy .. nonnutritive substances in plants that possess health-protective effects. resveratrol. 2001). Flavonols. Consuming a diet rich in such plant foods will provide a wealth of phytochemicals. ellagitannin. Phenolics compounds: phenolic acids Flavonoids: anthocyanidins and proanthocyanidins. 2012). cancer. 2004). 2004). Aglycones. 2003). Vitamins A. and that the benefits of plant-based diets are in part attributable to the complex mixture of phytochemicals present in whole foods (Liu. Low fruit and vegetable intake is among the top 10 risk factors contributing to mortality. pigments. Nuts. The concept of several active principle ingredients acting in a synergistic manner in natural remedies may be somewhat unusual to pharmaceutical scientists who are more accustomed to monotherapy using specific therapeutic agents. quercetin and kaempferol (Singh et al. and vegetables contain an abundance of phenolic compounds. gallic acid.. betacyanins and flavonoids (Stintzing and Carle. 2005). tannins. γ -carotene. 2011). aromadendrin. polyphenols. 2001). peel and seeds Orange Citrus sinensis Fruit pulp. 1999). anthocyanidins (Surles et al. α. Materska and Perucka. polymethoxylated flavones (tangeretin. flavonoids (Mahmood et al. flavonoids and furanocoumarins (Hanley and others. sinapic. Flavonoid glycosides. carpasemine). phenolic compounds. sinestein and nobiletin) (Gattuso et al. Ellagitannins. p-coumaric acid.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … Grapefruit Citrus paradisi Mango Mangifera indica Fruit pulp and peel Fruit pulp. terpenoid) glycosides. Proteolytic enzymes (papain.and β-carotene. flavonoids (hesperidin and naringenin). β-carotene (Holden et al. quercetin. 2005). isorhamnetin. phytoene. alkaloids (carpain. Glucosinolates (thioglycosides). quercetin. triterpenes. 1999) Isothiocyanates. anthocyanins (Mahmood et al. phenols. 1999). flavonoids (rutin. β-cryptoxanthin esters (Breithaupt and Bramedi. phytofluene. isorhamnetin. carotenoids. ellagic acid.. carotenoids and capsaicinoids (dihydrocapsaicin and capsaicin) (Watanabe and others. 2005). b-cryptoxanthin. polyphenols and kaempferol (Rao and Agarwal. vitamins C. and ascorbic acid (Kim et al. Complimentary Contributor Copy . derivatives of pyrone. Tannins. carotenoids (lycopene. 2001).. dihydroquercetin. Vegetables and their most common phytochemicals Vegetable Avocado Persea americana Commonly used parts Seeds and peel Broccoli Brassica oleracea Flowers and stem Cauliflower Brassica oleracea Cactus Opuntia ficusindica Flowers and stem Carrot Daucus carota Root Pepper Capsicum annuum Fruit Spinach Spinacia oleracea Leaves Tomate Lycopersicum esculentum Watercress Nasturtium officinale Fruit Fruit and cladodes Leaves 49 Bioactive compounds Vitamin E. flavonoids (quercetin and hydroxycinnamic acids) (Gill et al. quercetin. Aliphatics glucosinolate and glucoraphanin (Cartea et al. and protocatechuic acid). B1. vitamin E. Carotenoids. 2005).. 2007). 2005). kaempferol.. and querceti) and coumarin (Deuester. caffeic acid. Phenolic compounds (Gallic acid. taxifolin. neurosporene. mucilage. ascorbic acid. ascorbic acid. vitamin C. terpenoids. 2007).. B2 and B3. 2006). A. quercetin. carotenoids. panaxynol. vitexin. Pectin. flavonoids.. vitamin E and vitamin C (Ajila et al. phytofluene. Vitamin C. catechin. ferulic. S-methyl cysteine sulfoxide. and caffeic acid). 2011). Vitamin C.. and isothiocyanate sulforaphane (Rodríguez-Hernández et al. hymopapain). phytoene. 2005). myrecetin. and b-carotene) (Ajlia et al. carotenoids (Benavente-García and Castillo 2008) and nthocyanins (Tarozzi et al. anthocyanins. 2012). 2011). ferulic acid. coenzyme Q10. sulfurous compounds (benzyl isothiocyanate). diosmin. Table 2. 2010). 2010). betalains. Vitamins C. caffeic and p-coumaric acids) (Velasco et al. 2004). 2007). Flavonoids (kaempferol. flavonoids (quercetin and glycosylated xanthones such as mangiferin) (Berardini and others.. lycopene. β-carotene. aliphatic acetogenins. monounsaturated fatty acids and sterols (alkanols. 2010). chlorogenic. peel Papaya Carica papaya Fruit pulp. vitamins C and E. and phenolics (p-coumaric.. and E. glucuronides and acylated di-and triglycosides of methylated and methylene dioxide derivatives of 6-oxygenated flavonols (Bergquist et al. Carotenoids. and lipoic acid (Viuda-Martos et al. 2001. lutein and glucosinolates (Getahun and Chung. leaves and seeds Pomegranate Punica granatum Fruits Tangerine Citrus tangerina Citrus reticulata Citrus deliciosa Fruit pulp and peel Vitamin C. p-coumaric acid. lutein and zeaxanthin. Antioxidative properties in vitro (Aviram et al. Protection cells against the oxidative damage caused by free radicals (Hanley et al. Augmented intracellular GSH and catalase levels in SH-SY5Y neuronal cells treated with H2O2 insults and improvement the oxidant inhibitory effect of H2O2 on the assayed antioxidant enzymes (SOD. Osuna-Martínez. Yan et al. Prevent lipid oxidation. Mehdipour et al. 2006). 2008). 2009) Prevention of radical scavenging and inhibition of lipid peroxidation. 2011). 2009). it is sensible to encourage an assorted diet. 2006. (Kim et al. in vivo (Ajila et al. Reduction oxidative damage and effectively reduction the presence of tert-butylhydroperoxide induced ROS in vitro (Schaefer et al. 2010.... 2006). 2006) Improvement in antioxidant status. Ul. The exact amounts of fruits and vegetables needed each day to minimize disease risk are not known and will require a great deal of additional research. Pardo-Andreu et al. Table 3. Antioxidant and radical-scavenging properties (Guimarães et al. 2008. 2010). data on the antioxidant benefits of fruits and vegetables suggest that it is not premature to advise increased intake of a variety of colorful fruits and Complimentary Contributor Copy . Antioxidant activity in humans (Zhang K et al.. Favorable effects on antioxidant enzymes in liver including SOD. Protection against H2O2-induced oxidative DNA damage in rat pheochromocytoma tumor cells (Aruoma et al.and MMP-2-mediated pathways for antiulcer action . Reduction lipid peroxidation and to scavenge free radicals (Dherani et al. Experimental and clinical evidences of antioxidant effects of fruits Fruit Apple Cranberry Berries Grapes Grapefruit Mango Orange Papaya Pomegranate Tangerine Evidences. Clearly. no single antioxidant can replace the natural combination of the thousands of phytochemicals that exist in whole foods. Inhibition the oxidative hemolysis of erythrocytes induced by H2O2 (Alija and Prasada. 2009). CAT and GPX) (Guizani et al.. 2004). 2006b). by the decline on GSH and GSSG levels without change of the GSH/ GSSG ratio. Ana Isabel Gonzaga-Morales et al. Reduction of reactive oxygen species (ROS) generation in vitro results (Milenkovic et al.. Decrease of protein and DNA damage. 2012). Zikri et al. protection from oxidation in a dose-dependent manner in atherosclerosis in humans (Steinberg. in vivo (Arscott et al. 2013). SOD and GST) in vivo (Faria et al. 2007). Reduction LDL oxidation and macrophage oxidative status in clinical trials (Aviram et al. Given the history of the diverse intake of plant foods by mankind. Regulation the expression of proinflammatory molecules in the ROS.. 2011). reduction of oxidative stress and improve glutathione/ oxidized glutathione in humans (Kar et al. Antioxidant activity. Radical scavengers and chelating agents help to reduce physiological reactive oxygen species (Apostolou et al. Suppression ROS generation in vitro (Seeram. 2010.. Reduction oxidized molecules of phosphatidylcholine liposome in an autooxidation process (Wolfe and Liu. Antioxidant activity (Puttongsiri and Haruenkit. Milbury et al. 2011).. Free radical scavenging property in vitro. Reduction oxidative damage in women with metabolic syndrome (Basu et al.. Protection against oxidative damage in cells by ROS in vitro.50 L. protecting low-density lipoprotein (LDL) against oxidation in vitro systems.. Antioxidant activity in vitro (Eberhardt et al. 2008).. Bischoff. Antioxidant activity (Seeram et al. 2008). and by the decrease in antioxidant endogenous enzymes (GPx. 2010). CAT. inhibit the production of reactive oxygen species (ROS).. Protection membranes of living organism against the oxidative damage (Wojnicz et al. 2007.. 2004. and reducing oxidative stress in PC12 cells induced by addition of Fe2+ and t-butyl hydroperoxide (Dai et al. 2002.. preventing spleen cells from DNA damage induced by hydrogen peroxide (H2O2). 2009). Reduction oxidative stress.. 2008). 2008).. 2006). However. Antioxidant activity in vitro. 2011)... Rodríguez-Fragoso. 2008). 2000). 2007). GSHPx in vivo (Décordé et al. Reduction oxidative DNA damage and prevent meal-induced oxidative and inflammatory stress in circulating blood mononuclear cells.. Duthie et al.. vegetables... 2006). procyanidins. 2011). Delays the pro-oxidative effects of proteins. Decreases lipid peroxidation in humans (Potter et al. gallic acid. Antioxidant activity and inhibition of HMG-CoA reductase activity in vitro (Park et al. Reduction oxidative DNA damage. cyanidin-3-galactoside... 2005). 1998. and GST enzymes in vivo (Evan. Free radical scavenging activity in vitro (Kim et al. 2010). Protection erythrocytes against lipid oxidation induced in vitro by organic hydroperoxide (Butera et al. 2000). The antioxidant and antiproliferative activities of unpeeled apples were greater than those of peeled apples (Eberhardt et al. 1998). and whole grain products (See Table 3 and 4). Table 4. 2004). Induction of SOD in vivo (Schirrmacher et al.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 51 vegetables. 2008). Scavenging activities against oxygen radicals in cell-free systems (Lim et al. 2012). 2011) Antioxidant activity in vivo (Pahua-Ramos et al. 2012).. epicatechin. such as phenolics. The flesh contains catechins. Complimentary Contributor Copy . 2010). Experimental and clinical evidences of antioxidant effects of vegetables Vegetable Avocado Broccoli Cauliflower Cactus Carrot Pepper Spinach Tomato Evidences. Fruits and Vegetables: Examples with Clinical Relevance Apple (Malus domestica) Apple is one of those fruits that can play a role in decreasing the risk of chronic diseases due to its fiber content and chemical components such as flavonoids. Mahadeva et al. The concentration of phytochemicals in the apple peel varies greatly from that in the apple flesh. It is also known that the concentration of total phenolic compounds is much greater in the peel than in the flesh (Escarpa and González. 2009).. Antioxidants and free-radical scavenging in vitro (Aritomi et al. Induction the expression of antioxidant enzymes such as glutathione reductase (GSSG-red) and NAD(P)H:quinine reductase (NQO1) in vivo (Guerrero-Beltrán et al. coumaric acid. DNA and lipids (Feugang et al.. 2011). Antioxidant activity in humans (Collera-Zuñiga et al. The safety of consuming concentrated extracts of fruits and vegetables that contain very high levels of phytochemicals is unknown and unwarranted at this time.. CAT. Vitamin C was responsible for less than 0. catechin. Some of the best-studied antioxidant compounds in apples include quercetin-3-galactoside. chlorogenic acid. procyanidin.. GPx. quercetin-3-glucoside. were the main contributors. Free radical-scavenging property... 2012). However. Antioxidant activity (Herr and Buchler. increases levels of plasma antioxidants. polyphenols and carotenoids (Hyson. indicating that other elements.. the protective benefit of a phytochemical-rich diet is best obtained from frequent consumption of fruits. increases activities of SOD. It has been previously shown that peeled and unpeeled apples had high antioxidant activity and inhibited the growth of human cancer cells in vitro... Free radical scavenger and potent inhibitor of lipid peroxidation in vivo (Periago et al. 2002). Antioxidant activity in vitro (Shebaby et al. and phloridzin (Guyot et al. 1997).. quercetin-3-rhamnoside. 2007). 2003). and reduction inflammation (Hu et al.. 1986). 2003).4% of the antioxidant activity. Antioxidant and decreases lipid peroxidation in vivo (Visioli et al. including rutin. improved potential (Hyson. Osuna-Martínez. and general markers of oxidation (hepatic TBARS) were significantly reduced (Décordé et al. There was no effect on endogenous DNA strand breaks and Fpg-sensitive sites in peripheral blood lymphocytes. It has been found on in vitro studies that intervention with either organic or conventionally grown apples (1 kg) did not affect antioxidant capacity on low-density lipoprotein (LDL) lag time tests in peripheral blood human lymphocytes. 1999). As for the properties of individual compounds known to be present in apples. Complimentary Contributor Copy . Ana Isabel Gonzaga-Morales et al. caffeic acid. 2001). crushed and extracted juice from cider and table apples harvested in Germany to prepare several polyphenolic mixtures. Schaefer et al. GSHPx. but apples strongly decreased oxidative DNA damage recognized by Endo III and increased the capacity to protect DNA against damage induced by iron chloride. 2007). It was found that apple consumption increased antioxidant enzymes.. and early aortic lesions. Hamsters were provided with apples to an approximate human intake of 600 g/d (~2. in some cases. the effective range was comparable to quantities of phytochemicals found in apple juice (Schaefer et al. Both products reduced the percentage of aortic surface area covered by foam cells (aortic fatty streak lesion area) by 48% in the apple group and 60% in the apple juice group compared to controls. Rodríguez-Fragoso. in erythrocytes and overall antioxidant potential in plasma. apple extracts. chlorogenic acid.. Interestingly.. 2006b).. Of the catechins.5 large apples) or 500 mL of juice/d. Pre. including SOD and GPx. and chlorogenic acid. Although there were observed differences in effectiveness and specificity between each extract preparation. 2006a). oxidative markers. Favorable effects on antioxidant enzymes in liver including SOD. 2011). it has been found that prolonged exposure to apple products resulted in even greater antioxidant capacity for some compounds.. suggesting that metabolic products formed over a period of time may have differing antioxidant capacities from those of the parent phytochemicals and. 8 female. only (+)-catechin and (-)-epicatechin are present in appreciable amounts.and post study values were compared to assess antioxidant activity in the participants’ erythrocytes and plasma. including inhibition of copper induced LDL oxidation (Pearson et al.. indicating that both organically and conventionally grown apples have antigenotoxic potential (Briviba et al. 7 male) who ate fresh apples at a daily dose of 2 g/kg for 1 month. phloretin glycosides. such as quercetin glycosides. Another study in hamsters evaluated the effects of adding daily apples and apple juice (pressed from fresh apples) to an atherogenic diet on lipids. A study conducted in Turkey included 15 elderly participants (mean age 72 yrs. individual phytochemicals. 2008). They found that all extracts significantly reduced oxidative damage and effectively reduced the presence of tert-Butyl hydroperoxide induced ROS. Ul. The most effective compounds on all antioxidative parameters included quercetin and phloretin (Schaefer et al. A number of in vitro studies have demonstrated that apples. and apple polyphenols possess high antioxidant capacity in vitro.52 L. phloridzin. with some reconstituted mixtures being more successful than the original in terms of antioxidant capacity and reducing DNA damage.. with epicatechin being approximately twice as concentrated as catechin in the peels (Golding et al. 2007). among others. and caffeic acid were all effective. The upregulation of these enzymes suggests that regular apple consumption might promote a favorable milieu to reduce oxidation (Avci et al. the peel possesses all of these compounds and has additional flavonoids not found in the flesh. this effect was more strongly associated with an increase in the ascorbate level and not with the polyphenols present in blackberry fruits.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 53 There are inconsistencies in the correlation between in vitro outcomes and in vivo antioxidant activity mediated by apple. Basu et al. and cancer (Brownmiller et al. E and folic acid... the antioxidant capacity in the urine was associated with anthocyanins and urate levels. organic acids. and they have been reported as responsible for the high antioxidant capacity of these fruits (Beekwilder et al. C.). which could indicate the in vivo antioxidant potential. The consumption of blackberry juices led to an increase in plasma and urine antioxidant capacities. 2005).). However. suggesting that oxidative stress levels were relatively low in those subjects. types of ROS. tannins. calcium. triterpenoids. 2010).. 2009. cardiovascular and neurodegenerative diseases. They have been shown to have a positive impact on several chronic conditions. quercetin. RCM) has been used as a traditional remedy for several diseases (But et al. and selenium (Tian et al. Berries also contain vitamins A. ellagitannin. Cho et al. 2003. Blackberry juices in two different preparations. flavonoids.. ellagic acid. These results suggest that the endogenous antioxidant defense system and antioxidant intake from the diet could adequately prevent oxidative stress in healthy subjects. Berries (Rubus coreanus. and raspberries (Rubus idaeus L. including obesity. but extra antioxidants do not reduce oxidative stress. Korean raspberry (Rubus coreanus Miquel. This variability might be partially attributed to the many types of apples and apple components studied. cyanidins. gallic acid... Rubus leucodermis) Berries biological properties have been largely attributed to high levels of various phenolic compounds.. 2005). An increase in plasma catalase activity (CAT) concurrent with plasma anthocyanin levels was therefore observed (Hassimoto et al. Several studies have shown that a RCM extract has higher electron donation ability and prevents LDL oxidation in in vitro studies. phenolic acids.g.. Rubus fruticosus.. and anthocyanins (Yoon et al. gallotannin. concentration. In plasma. with water and defatted milk.. kaempferol and salicylic acid). strawberry supplementation significantly reduced oxidative damage and lowered total cholesterol and LDL-cholesterol levels in women with metabolic syndrome or hyperlipidemia (Basu et al. 2008). Sanguiin H-6 and lambertianin C are considered the two major ETs of strawberries (Fragaria x ananassa Duch. Rubus idaeus. catechins. Scientists have studied the active components in raspberry and found it contains various antioxidants such as polyphenols. In contrast. 1997).) fruits are anthocyanins and ellagitannins (ETs). pelargonidins. blackberries (Rubus fruticosus). as well as the interactive synergies among their natural phytochemical components (e. were administered to subjects in order to evaluate the possible effects of food matrix on plasma antioxidant capacity and enzymatic and non-enzymatic antioxidants. Previous studies have shown that weeks of Korean raspberry supplementation did not reduce lipid peroxidation in healthy males who did not smoke or drink alcohol. anthocyanidins. 2006). Complimentary Contributor Copy . 2005). in addition to varied reaction conditions including pH. The major phenolic compounds present in blackberry (Rubus fruticosus L. and other study conditions. Benzoic.. anthocyanins can regulate the expression of proinflammatory molecules in the ROS. Ul. 2004). suggesting they could be metabolites from other phenolics from cranberries (Zhang and Zuo. Also. the health benefits of which have been extensively studied (Singh et al. All of these data provide sufficient evidence of the antioxidant properties of berries. 2009). ferulic and sinapic acids were found in human plasma from 45 up to 270 min after consumption. 2010). 2011). resulting in reduced tumor development. These phenolics vary according to the degree of unsaturation.. several free phenolic acids have been found in human plasma following CJ consumption. Previous data have shown that anthocyanins from R. 2001) at portions of 44 and 56% respectively.. 2004). Raspberry constituents also have antioxidant and anti-inflammatory properties and inhibit cancer cell growth (Seeram et al. 2007). this may be due to preferential uptake and retention of its component anthocyanidins. Ana Isabel Gonzaga-Morales et al. 2001). Phenolic acids are also identified in plasma but are not present in significant quantities in CJ. As far as cranberry antioxidants are concerned. When one thinks of cranberries. which may influence their biological activity. On the other hand. inflammation and angiogenesis while stimulating apoptosis and differentiation of premalignant cells and tissues. Polyphenol antioxidants have previously been found in human plasma after drinking cranberry juice (CJ) and reached a maximum of 10 µM. 2001). coreanus cause the reversal of naproxen-induced gastric epithelial cell damage through the prevention of radical scavenging and inhibition of lipid peroxidation. quercetin and kaempferol. 2009).. 2010) and patients with metabolic syndrome.. the color red comes to mind: this is due to the presence of anthocyanidins. Osuna-Martínez. and polymerization. The results of these and other studies lead us to believe that the high antioxidant activity of cranberry. On the other hand. in studies using a rat model of nitrosamineinduced esophageal squamous cell carcinoma. Genes associated with these cellular functions were also protectively modulated by black raspberry diets (Stoner et al... including simple phenolic acids.. which may also be responsible for the greater inhibitory effects of freeze-dried whole berries on tumor cells in vivo (Zikri et al. cranberry ranks highly among the fruits for both its antioxidant qualities and quantity (Vinson et al. they mostly come under the form of phenolic acids and flavonoids (Chen et al.and MMP-2-mediated pathways for antiulcer action (Kim et al. flavonoids that include anthocyanidins and proanthocyanidins. based on total dry weight of non-nutrient antioxidants.54 L. and flavonols (Rossi et al. Rodríguez-Fragoso. Cranberry contains a great amount of phenolics. The presence of phenolic antioxidants in human plasma has been found in bioavailability studies in healthy volunteers (Zhang K et al. and its extracts plays Complimentary Contributor Copy . anthocyanins have an antiulcer effect due to their regulation of matrix metalloproteinase-2 (MMP-2) activity. Due to its high content of flavonoids and phenolic acids. Black raspberries have a selective effect on the growth and apoptosis of highly tumorigenic rat esophageal epithelial cells in vitro.. in patients with coronary artery disease (Milbury et al. Only a small percentage of the total flavonol content in cranberry or cranberry juice exists as aglycones such as free myricetin. Furthermore. oxidation of the three-carbon segment. black raspberries induced a reduction of proliferation. Cranberry (Vaccinium macrocarpon) American cranberry is a fruit used as a prophylactic agent against urinary tract infections. Extensive research both on identification of the phytochemical in cranberries and their bioactivity indicates. β-carotene. Complimentary Contributor Copy . For instance.. while procyanidins concentrate in the seeds (Kammerer et al. and neurotoxicity. Most grape phenolic antioxidants are distributed in grape skins or seeds. dyslipidemia. cancer. and other structural features. and reducing oxidative stress in PC12 cells induced by addition of Fe2+ and t-butyl hydroperoxide (Apostolou et al. procyanidin oligomers and their gallates. Duthie et al. resveratrols. enzymes. oxygen-centered radical-generating 2. 2006).. free carboxylic groups. lutein. reducing the oxidized molecules of the phosphatidylcholine liposome in an autooxidation process (Wolfe and Liu. 1989). and atherosclerotic markers in healthy volunteers (Ruel et al. organic acids. which typically include anthocyanins. which might be beneficial in the case of chronic diseases. 2012). 2009). flavonoids and anthocyanins (Vislocky and Fernandez. This second effect is directly related to atherosclerosis (Steinberg. mineral salts. resveratrol. it is also used in the manufacturing of various industrial products (Yadav et al. 2002. Grapes contain a wide range of chemical substances such as sugars. among other things. and also phytochemicals responsible for the sensory characteristics of wines and their health-related properties. 2008) as well as in patients with type 2 Diabetes Mellitus (Lee et al. antochyanins and catechins are concentrated in the skin. postprandial glycemic response. keto groups.2’-azobis(2-methylpropionamidine) dihydrochloride (AAPH). LDL and very-low-density lipoprotein can be protected from oxidation in a dose-dependent manner. It has been shown that when CJ is spiked on human plasma. Duthie et al. 2012). 2006). 2008). or peroxynitrite generating 3-morpholinosydnonimine in vitro systems. It is very likely that the components of cranberry extract undergo oxidation. with or without placebo control and ranging from 2 to 16 weeks have reported cranberries improve oxidative stress.. In contrast to these significant findings. 2004).. Phytochemicals in grapes are mostly phenolic compounds. A major group is that of phenolic antioxidants. preventing spleen cells from DNA damage induced by hydrogen peroxide (H2O2). Grapes (Vitis vinifera) The grape is considered a source of unique and potentially useful natural medicinal products.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 55 a substantial role in cardiovascular disease protection. Intervention trials.. The antioxidant activities of the individual phenolic compounds may depend on structural factors such as the number of phenolic hydroxyl or methoxyl groups.. The antioxidant activities of grape phenolics have been demonstrated in various model systems including protecting LDL against oxidation brought about by Cu2+. 2007). 2010). for example (Yan et al. phenolic acids. resveratrol.. that anthocyanins and flavonoids are strong antioxidants with the potency to protect the membranes of living organisms against oxidative damage (Wojnicz et al. did a 2-week study of healthy female volunteers and reported no substantial changes in blood. catechins. flavone hydroxyl. cellular antioxidant status or surrogate biomarkers of CVD and cancer risks following cranberry juice versus placebo intervention (Duthie et al. The beneficial effects of grape and relevant grape-derived food products are believed to be related to a variety of bioactive components such as epicatechin gallate. Cranberry compounds can cause an improvement in antioxidant status. and procyanidins (Bunea. 2013). vitamins. A number of studies have shown that. particularly a reduction in the risk of CVD. including lymphoid and myeloid cancer cells as well as skin.. 2001). 2009). In the past years. 2012). 2011). since it aids tissue elasticity.. The anticancer effects of grape antioxidants have been demonstrated in in vitro and in vivo models. certain types of cancers. Some studies showed that dietary intake of grape antioxidants helps prevent lipid oxidation and inhibit the production of ROS. prostate.. type-2 diabetes. reducing platelet aggregation and preventing heart attacks. which is known for its various medicinal properties in the treatment of human diseases (Yadav et al. reduces swelling and edema.. and other chronic complications (Mellen et al. It has been observed that grape antioxidants could act as free radical scavengers and chelating agents. Another biologically active and well-characterized constituent of the grape is resveratrol. Grape antioxidants have been shown to induce cell cycle arrest and apoptosis in cancer cells as well as prevent carcinogenesis and cancer progression in rodent models (Aggarwal et al. In addition. and hepatic tumorigenesis. pancreas. Grapes also decreased the levels of lipid peroxidation in the liver and concomitantly increased the levels of hepatic enzymatic and nonenzymatic antioxidants (Pari and Suresh. 2009). pancreatic. Resveratrol has also been shown to possess in vitro cytotoxic effects against a wide variety of human tumor cells. It may be used to treat obesity. small intestinal. wine. Feringa et al. 2010. Another study also demonstrated that grape seed extract supplementation (2× 300 mg/day) improved plasma antioxidant capacity (Vinson et al. and improves peripheral circulation (Agostini et al. For instance. 2006). and grape juice with a wide variety of health-promoting effects. Ul. studies have also shown that the red wine prepared from grapes ameliorates oxidative stress in the liver of alcohol-fed rats. in order to reduce the presence of ROS. One research group demonstrated that grape extracts exhibited strong antioxidant activity and prevented ROS-induced DNA damage (Apostolou et al. dietary supplementation of grape seed extract (600 mg/day) for 4 weeks in high-cholesterol human subjects produced a reduction of oxidative stress and improved GSH/oxidized glutathione (GSSG) and total antioxidant status in a double-blinded randomized crossover human trial (Kar et al. colonic. it can prevent hypertension and aid in the normalization of injuries caused by poor circulation due to obesity and diabetes. and prostate tumors. Osuna-Martínez.56 L. cervix. plant polyphenols exhibit stronger antioxidant activity compared to their individual one (Dai et al. restores collagen. Rodríguez-Fragoso. 2012).. Additionally. colon. as well as esophageal.. and helps prevent fatty liver and hepatic fibrosis (Assuncáo et al... when combined with each other or with other antioxidants. 2013). resveratrol prevented or delayed the development of skin. In animal studies. 2009). 2008).. liver and thyroid carcinoma (Morré and Morré. Complimentary Contributor Copy . Many studies have demonstrated that the phenolic compounds present in grapes could reduce the incidence of serious chronic problems such as atherosclerosis and CVD due to their antioxidant abilities (Zhu et al. Ana Isabel Gonzaga-Morales et al.. the source behind the beneficial effects of red wines on cancer prevention and against coronary heart disease. 2008). ovary. grape oil helps dissolve thrombi in arteries. breast. 2004). a growing body of epidemiological studies and randomized controlled human trials have associated the consumption of grapes.. stomach. gastric. mammary. and stretch marks. cellulite. The skin of grapes has a significant amount of resveratrol. carotenoids and reducing sugars. 2005). and ascorbic acid (Kim et al. The improvement in the bone quality of grapefruit-fed rats observed in this study could have been partially attributed to slowed-down bone resorption. including natural antioxidants such as phenolic acids and flavonoids (Manthey and Grohmann. lower oxidative stress. flavonoids. including flavonoids and furanocoumarins (Hanley et al. 2001). hyperlipidemia.. Peel polar fractions revealed the highest contents in phenolics.11’. including ascorbic acid. and it has been found that these phytochemical compounds contribute to disease-risk reduction (Shah et al. the maintenance of plasma antioxidant capacity and decreased urinary magnesium excretion. Previous studies of mango fruit have shown that it contains various classes of polyphenols. and polyphenols.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 57 Grapefruit (Citrus paradise) Citrus fruits have many healthy properties. Grapefruit juice is rich in a number of phytochemicals. The peel of grapefruit has five isolated compounds: friedelin. Overall it was found that the peels of fruits are major sources of different antioxidants and these by-products of the juice extraction industry could be used as natural antioxidants. Mangifera pajang) Mango is one of most widely consumed tropical fruits. increased bone mineral deposition.14’-tetramethy)-pentadec-2’. limonin and cordialin B (Meera and Kalidhar. ascorbic acid. 2004). It has been reported that heat treatment may liberate some low molecular weight phenolic compounds and hence increase the antioxidant capacity of citrus peel (Seok-Moon. most of them due to their high content of nutrients such as vitamin C. 2008). including quercetin and glycosylated xanthones such as mangiferin (Berardini et al. Many people suffer from chronic metabolic diseases (including hypertension. 2007). Preliminary phytochemical screening revealed the presence of flavonoids. Consumption of grapefruit and grapefruit juice may result in cardiometabolic benefits... These phytochemicals have antioxidant capacities and may protect cells against the oxidative damage caused by free radicals. since trials have shown it can increase serum HDL-cholesterol concentrations (Silver et al. 2011). Many authors have reported antioxidant and radical-scavenging properties of essential oils and in some cases.. increased calcium absorption. 2010). a direct food-related application as well. which certainly contribute to the highest antioxidant potential found in these fractions (Guimarães et al. carotenoids.. it is rich in nutritive and nonnutritive compounds. and may even reduce bone fracture risk (Deyhim et al.. β-sitosterol. carotenoids. Medical data suggest grapefruit juice reduces atherosclerotic plaque formation and inhibits breast cancer cell proliferation and mammary cell tumorigenesis (Kiani and Imam. It has been demonstrated Complimentary Contributor Copy .. 2006). 2011). 2011). 2010). carotenoids.. Mango (Mangifera indica. 7(3’. It has also been shown that grapefruit juice positively affects bone quality and normalizes osteoclasts and decreased bone loss (Deyhim et al. and phenolic compounds. and CVD) and they receive calcium channel antagonist therapy and 3hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors.7’. Citrus peel is the main waste fraction of citrus fruits and has been widely studied because of its numerous biologically active compounds.10’-trienyloxycoumarin.6’. terpenoids. Removing free radicals by eating foods rich in antioxidants will potentially improve antioxidant status. 2008). antitumor. and potentiates chemotherapeutic agent-mediated cell death. including tumor nuclear factor alpha (TNF-α). It has been found that the peel is a major source of different antioxidants and this by-product of the juice extraction Complimentary Contributor Copy . Ana Isabel Gonzaga-Morales et al. suppresses NF-κB activation induced by inflammatory agents.. it contains a host of flavonoids. 2008). anti-atherosclerotic. peels. All these data suggest a potential role in combination cancer therapy (Knodler et al.. Studies on the bioactive compounds and antioxidant activity of citrus have mainly focused on the fruits (peel. Osuna-Martínez. 2006). and anti-tumor promotion activity. 2008). potassium. The peel is a good source of phytochemicals such as polyphenols. Ul. antihypertensive. as well as prevention of age-associated oxidative stress (Pardo-Andreu et al. It has been reported that polyphenol content of mango peel is higher than that of pulp and that peel extract from M.. p-coumaric acid. 2010). It has been reported that mango contains compounds that have antioxidant activity. and seed kernels a very healthy habit (Selles et al. Its role in the prevention of several diseases has already been reported (Benavente-García and Castillo. and antiinflammatory properties (Bischoff. Peels and seeds are the major by-products generated during the processing of mango. the phytochemicals present in mango peel may exhibit protection against oxidative damage in cells by ROS. vitamin E and vitamin C (Ajila et al. 2011). The major phenolic compounds were gallic acid. The significant cytotoxic activities of stem bark mango extract have been tested against the MCF 7. and protocatechuic acid. 2007) and exhibits good antioxidant properties. Phenolics have a potent antioxidant activity and are believed to have health-promoting properties that make the consumption of fruits and derived processed products from fruit pulp. 2010).. growth-arresting activity. All these phenolic compounds were shown to exhibit antioxidant properties (Abdulrahman et al. in addition to providing an ample supply of vitamin C. that quercetin possess antioxidant. Due to their antioxidant properties. as well as against the SW-620 colon cancer cell line and the 786-0 renal cancer cell line (Shah et al. 2008). It has been previously reported that mango peel extract isolated from two varieties of mangoes at two different stages of maturity could inhibit the oxidative hemolysis of erythrocytes induced by H2O2 under experimental conditions (Ajila and Prasada. report potent in vitro and in vivo antioxidant and anti-inflammatory activity. ascorbic acid and carotenoids that can potentially protect health. 2008). 2002). Mangiferin also mediates the down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). MDA-MB-435 and MDA-N breast cancer cell lines. Whether these anticancer properties are maintained after digestion. amounting to 35-60% of the total fruit weight. Previous studies of aqueous stem bark extract from a selected species of mango that was used in pharmaceutical formulations and as a food supplement in Cuba under the brand name of Vimang. increases intracellular GSH levels.. 2001).. Orange (Citrus sinensis) Citrus is one of the world’s most popular fruit crops. 2008). although anticancer activity has been related to antioxidant activity in many studies (Percival et al. ellagic acid. folic acid. absorption. and pectin.. carotenoids. mangiferin. Rodríguez-Fragoso.58 L. and metabolism is unknown. pajang fruits is a rich source of polyphenols (Ajila and Prasada.. pulp and juice) and polar fractions (Gorinstein et al. 2006). organic acids and oils (Mahmood et al. anthocyanins.. It was recently found that seven days consumption of red orange juice ameliorated endothelial function and reduced inflammation in non-diabetic subjects with increased cardiovascular risk (Buscemi et al. and are considered a preventive treatment against atherosclerosis and coronary heart diseases. phenolics. Oroval (Citrus clementina Hort. 2011). flavanones. 2010). flavonoids. which are two flavonoids that suppress ROS generation in vitro (Seeram. At maturity stage... 2005). Papaya epicarp extracts were effective in promoting wound-healing processes and cellular skin Complimentary Contributor Copy . 2008). total acidity. 2010a). 2012). anthocyanins and ascorbic acid).. Other clinical studies in healthy subjects have shown that orange juice consumption reduced oxidative DNA damage and may prevent meal-induced oxidative and inflammatory stress in circulating blood mononuclear cells. It has been found that organic red oranges have a higher phytochemical content (i. and β-carotene) and vitamin C.. A comprehensive study conducted on 21 Mauritian Citrus species demonstrated. total antioxidant activity and bioactivity than integrated red oranges (Tarozzi et al. leaves and seeds are known to contain proteolytic enzymes (papain. an effect at least partially attributed to the presence of hesperidin and naringenin. caffeic acid. carpasemine). Extracts from different papaya tissues have been shown to be bioactive.. and phenolic acids. Papaya was reported to have in vitro free radical scavenging properties and effectively improve antioxidant defense while significantly decreasing the risk of age-related macular degeneration in human clinical trials (Arscott et al. Carica papaya L. that polyphenolic-rich extracts exhibited important antioxidant propensities in various test systems (Ramful et al. total soluble solids. carotenoids (mostly lycopene. alkaloids (carpain.) and Moro orange [Citrus sinensis (L. with established correlations. with a novel antioxidative role at the adipose tissue level and beneficial effects of antioxidant citrus extracts in a model of obesity-linked metabolic disorder (Ramful et al. Papaya (Carica papaya) Papaya fruit and seeds are widely used in medicine to prevent lipid peroxidation because of their high antioxidant contents. The reduction of ROS generation and NF-κB binding following orange juice intake might be due to its flavonoid content. triterpenes.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 59 industry could be used as a natural antioxidant.e. pcoumaric acid. flavanones. 2006).. 2010b). ex Tan. Recent results clearly show that Mauritian Citrus fruit extracts represent an important source of antioxidants. as suggested by in vitro results (Milenkovic et al. Such high level of antioxidant substances makes this new fruit important for its nutritional benefits (Rapisarda et al.. Papaya fruit skin contains different bioactive compounds. such as ferulic acid. hymopapain).) Osbeck] were analyzed during fruit maturation to determine juice yield.. and potentially beneficial components such as vitamin C. sulfurous compounds (benzyl isothiocyanate). β-cryptoxanthin. and hydroxycinnamic acids in Omo-31 was found to be notably higher than in its parents. Fruit juice of a new pigmented citrus hybrid named Omo-31 and those of its parents clementine cv. Orange juice antagonizes oxidative and inflammatory stress. which can collectively protect human cells from oxidative stress. 2003). the amount of anthocyanins. It was also reported to protect against H2O2-induced oxidative DNA damage in rat pheochromocytoma tumor cells (Aruoma et al.. adriamycin. The antioxidant activity is related to the diverse phenolic compounds present in the pomegranate. Studies about the toxicological and antioxidant potential of dried C. granatum play an important role in the prevention of free radical-related disease. 2011). 1998). It has been suggested that free radical scavenging and antioxidant activities of extracts from various parts of P. Fermented papaya preparation is a natural health food that has been commercially sold in Japan for 2 years.. including the punicalagin isomer. lung. antiangiogenesis. This fermented papaya preparation has been shown to increase SOD activity in the cortex and hippocampus in iron-induced epileptic foci of rats. Rodríguez-Fragoso. ellagic acid. Pomegranate preparations contain very high levels of antioxidants compared to those of any other fruit or vegetable. colorectal. 2006)... they even give the fruit or juice its color (Viuda-Martos et al. coenzyme Q10. and anthocyanin content. 2007). and IGF-BP3 (Amin et al.. especially in the Middle East. Sp-1.. and anthocyanins (de Nigris et al. Synergistic interaction with genistein. Anthocyanins are the most important group present in the arils or juice.60 L. including aging. head. pancreas. 2010). Another compound found in papaya is licopene. Osuna-Martínez. Different targets include cyclin D1. tannins. neck and skin cancer. breast. including vitamin C. and cisplatin was also observed. 2009). Tzulker et al. This has been linked to antioxidant. with anthocyanin playing a minor role (Tzulker et al. Bcl-2. BAD. 2007). papaya juice in vitro and in vivo indicated its safety and antioxidative stress potential. Leaf extracts have shown free radical scavenging activity and antioxidant effects in vitro (Al-Muammar and Khan. suggested punicalagin is one of the major phytochemicals that contribute to the total antioxidant capacity of pomegranate juice. apoptosis). NF-κB. 2010).. these remarkable effects were attributed to its photochemical and antioxidant activities (Ajlia et al. It is made by yeast fermentation of Carica papaya Linn. CAT and GPx) (Guizani et al. Complimentary Contributor Copy . The juice is known to be a rich source of antioxidants given its polyphenol. wounds and ulcers (Harmam. MMP-9. which was found to be comparable to the standard antioxidant compound alpha-tocopherol (Mehdipour et al. and lipoic acid. 2001). Ul. liver. 2002). These results suggest that the preparation has antioxidant actions and may serve as prophylactic food against age related and neurological diseases associated with free radicals (Imao et al. antiinflammatory. AKT.. antiproliferative (growth inhibition. vitamin E. Pomegranate (Punica granatum) Pomegranate is commonly eaten around the world and has been used in folk medicine across many cultures.. Papaya epicarp extract can significantly ameliorate the oxidant inhibitory effect of H2O2 on the assayed antioxidant enzymes (SOD. and immunomodulation in prostate. for a wide variety of therapeutic purposes (Shabtay et al. 2008). Ana Isabel Gonzaga-Morales et al. 2012). Bcl-xL. including the amount of flavonoids and polyphenols.. It was recently found that papaya epicarp extracts augmented intracellular GSH and catalase levels in SH-SY5Y neuronal cells treated with H2O2 insults. development. These compounds are known for their free radicalscavenging properties and inhibit lipid oxidation in vitro (Noda et al. gastric.. cell cycle arrest. analyzed the action mechanism of pomegranate fruit parts (i. and flower) in vivo and in vitro. and a decrease in antioxidant endogenous enzymes like GPx. In preclinical animal studies. CAT. 2012). Citrus tangerine) Tangerines. lutein and zeaxanthin. and zeaxanthin (Holden et al. the peel. 2006). also reported that the consumption of pomegranate juice by diabetic patients led to a decrease in oxidative stress in the patients’ serum and the macrophage uptake of oxidized LDL (Rosenblat et al. In a limited study of hypertensive patients. macrophage oxidative status.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 61 These antioxidants have been shown to protect against cholesterol oxidation and have anti-aging effects (de Nigris et al. 2001). and green tea (Rosenblat et al. Ellagitanins. contain high amounts of β-cryptoxanthin esters (Breithaupt and Bramedi. and also scavenged the free radicals in brain tissue when they were coadministered with AlCl3 (Abdel. SOD and glutathione Stranferase (GST) (Faria et al. the decline of GSH and GSSG levels without change of the GSH/GSSG ratio. Aviram et al. All extracts were shown to possess antioxidative properties in vitro and pomegranate flower extract consumption resulted in lower serum lipids and glucose levels by 18% to 25% (Aviram et al. including anti-inflammatory.. seeds. arils. 2001). colon.. consumption of pomegranate juice for two weeks reduced systolic blood pressure by inhibiting the serum angiotensin-converting enzyme (Aviram and Dornfeld.. On the other hand. The high antioxidant activities of the phytochemicals found in the pomegranate have led to the development of dietary supplements that contain biologically active polyphenols and ellagitannins. and foam cell formation (Aviram et al. vitamins C.. B1. Citrus reticulate. the smallest species in the economically important family of citrus fruits. Recent research has shown that pomegranate extracts selectively inhibit the growth of breast. lutein. prostate. 2006). Like Complimentary Contributor Copy . skin. 2001).e.. tangerines are a source for β-carotene. red wine. magnesium. Additionally.. and on cholesterol biosynthesis in a J774. 2007).A1 macrophage-like cell line has also been studied. 2009)... on cellular oxidation stress. Tangerine (Citrus deliciosa. 1999). This was supported by the decrease of protein and DNA damage. Preliminary laboratory research and clinical trials showed that the juice of the pomegranate may be effective in reducing heart disease risk factors such as LDL oxidation. hepatoprotective and antigenotoxic ones (Lin et al. oral consumption of pomegranate extract inhibited growth of lung. Cells treated with pomegranate juice (polyphenol 75 mmol/L) showed a 40% decrease in the degradation of oxidized LDL.. The effect of pomegranate juice on cholesterol accumulation in macrophages. namely punicalagin. An initial phase II clinical trial of pomegranate juice in patients with prostate cancer reported significant prolongation of prostate specific antigen doubling time (Mustafa et al.. a decrease of 50% in the rate of macrophage cholesterol synthesis and a decrease of oxidative stress (Fuhrman et al. colon and lung cancer cells in culture. 2005). 2006). Rosenblat et al.. The use of pomegranate juice for 4 weeks in animals with hepatic oxidative stress showed a state of reduced oxidative stress. also have remarkable pharmacological activities. and prostate tumors.. 2008). They also contain some potassium. The overall antioxidant activity of pomegranate juice has been previously reported to exceed that of other red-purple fruits.. B2 and B3. 2004). The flavonoids of pomegranate peel methanolic extract have also been shown to reduce lipid peroxyde and nitric oxide levels. Sainampueng grown in northern Thailand is an excellent source of the polymethoxylated flavones tangeretin. Rodríguez-Fragoso. phenolic acids and antioxidant activity in juice extracted from coated Kiew Wan tangerine during storage at 4. such as tangeretin and nobiletin. β-carotene and β-cryptoxanthin have pro-vitamin A activity as well as biological actions such as the ability to reduce lipid peroxidation and scavenge free radicals that may be important in maintaining health and preventing serious diseases such as cancer.. nerol. nobiletin. 2010). and cataracts (Dherani et al. and β-cryptoxanthin might prove effective in reducing hypercholesterolemia. but only small amounts of polymethoxylated flavones compared to the juice. Storage of coated tangerine at 4. 2008).. Osuna-Martínez. 2010). 2007). neryl acetate. citronellal. and vitamin A deficiency. Consumption of hand-pressed tangerine juice with high concentrations of tangeritin and nobiletin as well as a high content of flavanone glycosides. These compound classes may be divided Complimentary Contributor Copy . Ul. It has been found that hand-pressed tangerine juice of C. Avocado (Persea americana) Avocado is a good source of bioactive compounds. 12 and 20 °C have been observed. 2004). all citrus oils. These peeled fruits had higher quantities of the flavanone glycosides narirutin. geranyl acetate. The ascorbic acid content decreased during the storage period. ascorbic acid. Coating fruits. pulmonary disorders.. Coating and storage temperature may lead to other chemical changes in fruits. along with alpha-pinene. myrcene. hesperidin. The results of that study indicated that changes in the levels of ascorbic acid. thymol. vitamin C and hydroxycinnamicacids in blood oranges increased during storage at low temperatures (Rapisarda et al. the level of each one increased during the early stage of storage and declined slightly at the end. irrespective of temperature. and sinensetin. such as total polyphenol. Changes in ascorbic acid. it was reported that bioactive compounds. Polymethoxylated flavones.62 L. tangerine oil has limonene as its major constituent. including vitamin E. Previous studies on hamsters fed supplements with mixtures of 1% polymethoxylated flavonoids that contained tangeretin and nobiletin showed lower plasma concentrations of both triglycerides and cholesterol and reduced hepatic triglycerides (Kurowska and Manthey. carotenoids and soluble phenolics (Deuester. p-coumaric. Diosmin is one of the main components of citrus fruits. total polyphenol. As for the phenolic acids found (caffeic. An analysis of carotenoids and antioxidants in juice samples confirmed β-cryptoxanthin as the predominant carotenoid in these tangerines and revealed significantly higher levels of R-tocopherol in organic tangerine juice than that produced using conventional agrochemical-based and agrochemical safe grown fruits (Stuetz et al. exist exclusively in the citrus genus and are especially common in the peels of tangerine (Gattuso et al. 12 and 20°C did not affect the antioxidant components (Puttongsiri and Haruenkit. reticulata Blanco cv. gamma-terpinene. 2006). antioxidants. total polyphenol. to extend shelf life and improve glossiness has long been common method. including citrics. and didymin.. phenolic acids and antioxidant activity in coated tangerines were affected by storage period. Tangerines are sources of important nutrients for human health and the antioxidant activity in tangerine is associated with more than a single compound. regardless of temperatures. Ana Isabel Gonzaga-Morales et al. 2001). linalool. sinapic and ferulic acid). geraniol. 2008). Phenolic acids also contributed to antioxidant activity in coated tangerines. incidence of atherosclerosis and cardiovascular disease. and carvone (Lyle. . The reason for these phenomena may be linked to the fact that the ascorbic acid and total phenolic contents. and quercetin are widespread in nature and may act as powerful antioxidants in avocado (Terpinc et al. Avocado seeds reduced total cholesterol and LDL-cholesterol levels.. Therefore. In addition. Growing data on the health benefits of avocadoes have led to increased consumption and further research (Whiley and Schaffer. americana fruit extract may contribute to the free radical-scavenging property of the extract (Mahadeva et al. 2007).. Complimentary Contributor Copy . CAT. 2011). or to a favorable effect on regenerated β-cells. The anti-hyperglycaemic effect of avocado fruits may be due to their stimulatory effect on remnant β-cells. Recent studies indicate that phytochemicals extracted with 50% methanol from avocado fruits aid the proliferation of human lymphocyte cells and decrease chromosomal aberrations induced by cyclophosphamide (Paul et al. Ascorbic acid and GSH are the two major low molecular weight antioxidants that prevent oxidative damage in fruit.. Avocado has traditionally been used due to its hypotensive. 2010). Rutin.. 1998).. This may be attributed to the free radical scavenging and anti-hyperglycaemic activities of P.. All of these data seem to indicate that the beneficial effects of P. 2012).Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 63 into alkanols (also sometimes termed “aliphatic acetogenins”).. 2012). 2002). allowing them to secrete more insulin. along with antioxidant activity. and immune-enhancing effect (Adeyemi et al. It has been shown that oral treatment with avocado extract significantly decreased blood glucose levels and increased the insulin level in STZ-induced diabetic rats. Mahadeva et al. Americana fruit extract (Evan.. and coumarin (Corral-Aguayo et al. The mechanisms regulating the pool sizes of the two components are not yet fully understood. 2011). 1998. Avocado seeds contain elevated levels of phenolic compounds and exhibit antioxidant properties. Furthermore. The phytochemicals present in P. anti-inflammatory. the seeds and peels of avocado also contribute 57% and 38% of the antioxidant capacities of the entire fruit. Oral treatment with P. the antioxidant activity of phenolic compounds and dietary fiber in avocado seeds may be responsible for their hypocholesterolemic activity in a hyperlipidemic model of mice (Papua-Ramos et al. 2011). 23% in peel. preventing the formation of glycosylated haemoglobin. A similar trend was observed in ascorbic acid changes (Kevers et al. americana are due to its antioxidants properties. various furan ring-containing derivatives. americana fruit extract in STZ-induced diabetic rats resulted in increased activities of SOD. Phytochemicals extracted from avocado can selectively induce several biological functions (Plaza et al.. and GST enzymes. GPx. avocado juice made from ripe fruit is very popular due to its numerous health benefits (Mahadeva et al. as well as the prediction of the atherogenic index. Several beneficial medicinal properties of compounds present in the avocado seed and peel have been reported and are related to elevated levels of phenolic compounds (64% in seed. Enzymatic antioxidants are also involved in the detoxification of free radicals and peroxides formed during the course of oxidative stress. and reducing liver peroxides (Mahadeva et al. may be associated with the high levels of ascorbic acid in the fruit (Noctor and Foyer. respectively (Wang et al. are influenced by the harvest date of the avocado fruits during storage... catechin. 2012).. terpenoid glycosides. However. flavonoids. and 13% in pulp). 2002). 2008). It has been shown that the GSH content increased in early harvested fruits and decreased in late harvested ones during storage. but high levels of GSH. 2009). 2011). seeds contain the strongest antioxidant properties and highest phenol and procyanidin content compared to the pulp and edible portions (Wang et al. 2011). may have protective effects against various types of cancers (Juge et al. Initial clinical trials in women have shown that indole-3carbinol may prove a promising agent against cervical and breast cancers. and vitamin C. glycosylated flavonoids.. as well as in cultured human cancer cells. 2011). Both of them exhibit protective activities against different types of cancer (Velasco et al. the United States and Europe suggest that the consumption of vegetables from the Brassicaceae family. Indole-3-carbinol is the main hydrolysis product of the glucosinolate glucobrassicin and can provide significant protection against cancer in animal models with a variety of chemical carcinogens. Osuna-Martínez. Isothiocyanates and indoleglucosinolate metabolites (in particular indol-3-carbinol) are the two major groups of autolytic breakdown products of glucosinolates. suggesting that the flavonoid-glycoside molecules were linked to hydroxycinnamic acid derivatives. Italica) has a high content of bioactive compounds.. thus pointing to the fundamental role of isothiocynates. broccoli and cauliflower. Ul. Upon cellular disruption. Their overall protective effects have been generally attributed to different biological activities.. and these may be further substituted with hydroxycinnamic residues (Vallejo et al. 2012). Rodríguez-Fragoso. caffeic and pcoumaric acids were the most abundant (Velasco et al. 2009).64 L. glucosinolates are hydrolysed to various bioactive breakdown products by the endogenous enzyme myrosinase MYR).. Brassicaceae are also able to attenuate oxidative stress. rather than glucosinolates. They are abundant in Brassica vegetables and believed to be the bioactive compounds responsible for many of the biological effects attributed to these greens. 2004). containing up to five sugar residues. Broccoli and cauliflower (Brassica oleracea) These leafy vegetables are unique among the common cruciferous vegetables that contain high levels of the aliphatics glucosinolate and glucoraphanin (Carteaet al. Broccoli (Brassica oleracea var. It also has anthocyanins from among the colored flavonoids. ferulic. Ana Isabel Gonzaga-Morales et al.3'diindolylmethane. Also. Several epidemiological studies in Asia. which are multifunctional food components given their antioxidant activity (Moreno et al. There is a wide variety of glucosinolates.. Complimentary Contributor Copy . in up-regulating these xenobiotics metabolizing enzymes (Paolini and Nestle. containing a β-D-glucopyranosyl moiety and a variable side-chain derived from methionine. such as antioxidant properties. 2007). apoptosis and cell cycle controlling activities (Herr and Buchler.. Flavonoids in Brassica foods are complex. It has been shown that Brassicacea extract enhanced GST and UDP-glucuronosyltransferase activities only after the breakdown of the glucosinolates by the intestinal or exogenous MYR. Glucosinolates are a class of organic compounds that contain sulfur and nitrogen and are derived from glucose and an amino acid. influencing the redox status of the cell by affecting GSH levels and inducing expression of antioxidant enzymes such as GSR and NAD(P)H:quininereductase (NQO1) in rat liver. kidney. Acylated flavonoids were detected in the extract and their UV spectra.. and cardiovascular tissues (Guerrero-Beltrán et al. e.. including glucosinolates. 2011). an indole derivative produced in the stomach after the consumption of broccoli and other cruciferous vegetables.g. 2010). tryptophan or phenylalanine. 2010). 3. characterized by a high maximum absorption of 330 nm and a little maximum between 255 and 268 nm. has been shown to exert anticancer effects in both in vivo and in vitro models (Choi et al. 2003).. but all share a β-thioglucoside N-hydroxysulfate common structure. in which sinapic. among them the modulation of phase-I (inhibition) and phase-II (induction) via xenobiotics metabolizing enzymes. enzyme modulation. 2010). 2006).. ficus-indica is widely distributed in Mexico and in all the American hemispheres. These compounds. A number of studies have Complimentary Contributor Copy . O. 1997). ficus-indica (nopal) has been employed since pre-Columbian times as an important dietary and economic element (Betancourt-Domínguez et al. a recent study (Zourgui et al. and the antioxidant status of hypercholesterolemic men (Kim et al. The fruit and cladode of Opuntia ficus yield high values of important nutrients such as minerals. it is utilized to treat several disorders. betacyanins.. and a flavonoid fraction that consists mainly of rutin and isorhamnetin derivatives (Alimi et al.. food handling. Kale juice supplementation (150 mL/day for 12 weeks) resulted in substantial improvements in serum lipid profiles. which could lower the levels of antioxidant nutrients and increase oxidative stress (Kim et al.. 2012). This depletion may be primarily due to the highly oxidant effect of tobacco smoke. Kim et al. the O. in addition. the ratio of HDL. vitexin. 1997). In Sicilian folk medicine it is used for treating gastric ulcers (Galati et al. especially with respect to HDL and LDL-cholesterol levels. whereas levels and GSH-Px activities responded more to kale juice supplementation in non-smokers. the cited study demonstrated that kale juice supplementation favorably influences serum lipid profiles and antioxidant systems. The presence of total phenolic compounds (free and conjugated) with concentrations of 80-90 mg/100 g dried weight include aromadendrin. 2001). The hypocholesterolemic effect of kale extract on cholesterol metabolism through HMGCoA inhibition and bile acid synthesis has been studied in vitro systems (Park et al. 2012).Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 65 Cauliflower has glucosinolates (thioglucosides) and S-methyl cysteine sulfoxide. a potent estrogenic metabolite.. and derivatives like myricitin. On the other hand. which are derived in plant tissue by amino acid biosynthesis. many phenol compounds.. betalains.to LDL-cholesterol. and inhibition of HMG-CoA reductase activity (Park et al. However... quercetin. taxifolin or dihydroquercetin.. The percentage of isothiocyanate sulforaphane present in these vegetables may vary depending on conditions of hydrolysis. 2005).. 2008). Biological activities of kale extract have been demonstrated in in vitro systems. such as increased levels of Se and the activity of GPx. orientin and some derivatives of pyrone (Stintzing and Carle. compared changes in serum variables and net differences with respect to smoking status to evaluate if there was a difference in response to kale juice supplementation. However. as well as in Africa and the Mediterranean basin (Acevedo et al. In Mexico. kaempferol. and preparation procedures (Rodríguez-Hernández et al. O. 1985). which imply the improvement of the serum antioxidant defense system (Kim et al.. ascorbic acid. isorhamnetin. 2008). 2008) showed the potential antigenotoxic activities of cactus cladodes against a single dose of mycotoxinzearalenone. inhibitory effect of abnormal cell growth. Cactus (Opuntia ficus-indica) Cactus O. ficus-indica fruit juice contains a rich variety of natural antioxidants. 2008). These data have made cactus pear fruits and cladodes perfect candidates for cytoprotective research. ficus-indica prickly pads are an important source of nutritional elements like pectin. show quite different toxicological effects and appear to possess anticarcinogenic properties. Kale juice supplementation has led to changes in serum antioxidant biokarmers. serum Se responded more among smokers. mucilage and minerals. they include antioxidant activity. vitamins and other antioxidants. luteolin and kaempferol. It has been observed that O.2 mg/100 g fresh fruit) at the same level of Sicilian cultivars of O. anticancer. 2002). 2005). analgesic. with quercetin followed by isorhamnetin. but other compounds.. which could modulate the intrinsic imbalance between oxidant species and the antioxidant defense system. probably via its antioxidant effects and by reducing lipid peroxidation (Oh et al. Scavenging activity was restored in a dose dependent manner to near normal level in ethanolfed rats given prickly pear juice. are able to delay the pro-oxidative effects on proteins. it has been demonstrated that red-skinned cactus pear fruits contain taurine (7. DNA and lipids through the generation of stable radicals (Feugang et al. either directly or indirectly. A previous study showed that O. 2011). ficus-indica glycoprotein did not have any cytotoxic effect and instead protected liver cells due to its scavenging activity against G/GO-induced radical production (Oh and Lim. Ascorbic acid is an important antioxidant and its content in cactus pear fruits is considerably higher than average ascorbic acid contents among some common fruits such as plums (7 mg/100 g fresh fruit). flavonoids and phenolic acids actually detected in fruits and vegetables of different varieties of cactus (Shin et al. carotenoids. such as vitamin C and betalains. Anti-atherogenic effects have also been reported. since flavonoids.. Complimentary Contributor Copy . These compounds are more efficient antioxidants than vitamins. revealed a positive correlation between a diet rich in plant-based foods and reduced risk of diseases associated with oxidative stress such as cancer and cardiovascular and neurodegenerative diseases. All the Opuntia species tested had significant amounts of flavonoids.. ficus-indica fruit extract reportedly protected erythrocytes against lipid oxidation induced in vitro by organic hydroperoxide (Butera et al. hypoglycemic. 2006). 2008). On the other hand. Osuna-Martínez. These results show that O. The pre and post-administration of cactus cladode extract with aflatoxin B significantly reduced this oxidative effect. hypolipidemic and hypocholesterolemic properties (Guevara-Arauza. 2009). 2005). Rodríguez-Fragoso.. Zou et al.. reduced GSH. O. nectarines (10 mg/100 g fresh fruit) or peaches (9 mg/100 g fresh fruit) (Fernández-López et al. anti-inflammatory. which dropped to control level (Brahmi et al. anticancer and hepatoprotective activities (Kuti. including antiulcerogenic. ficus-indica glycoprotein decreased NO amounts in hyperlipidemic mice. antiulcerogenic. 2004. antioxidant. 2005). 2006).66 L. The normalization of scavenging activity by prickly pear juice supplement could be due to the natural antioxidants.. 2012). ficus-indica glycoprotein had scavenging activities against oxygen radicals in cell-free systems.. could synergistically counteract many degenerative processes by means of their antioxidant activity (Galati et al. The administration of O. ficus-indica but at a lower concentration than that reported for American and African cultivars (Tesoriere et al. 2006).. and phenolic compounds in general. 2006). as well as cytoprotective and anti-apoptotic acitivities in oxygen radical-induced NIH/3T3 cells (Lim et al. O. Hepatoprotection may be related to the flavonoid fraction of the juice. vitamin E. The oxidative damage caused by aflatoxin is considered the main mechanism leading to subsequent hepatoxicity. These fruits have shown several effects. The protective effects of cactus cladode extract to prevent and protect against oxidative damage is certainly associated to the presence of several antioxidants such as ascorbic acid.. and restoration of GSH levels was also observed (Alimi et al.. Ana Isabel Gonzaga-Morales et al. ficus-indica glycoprotein exerts antioxidant and cytoprotective effects in vitro. Ul. ficus-indica phenolic compounds have antioxidant.7–11. 2010).. it may also protect the cardiovascular system by increasing total antioxidant status and decreasing lipid peroxidation independent of any of the cardiovascular risk markers (Potter et al. Carrot juice significantly increased total plasma antioxidant capacity and decreased plasma malondialdehyde production. The enhancement of liver antioxidant capacity observed in gerbils consuming biofortified carrots was likely due to the combined bioactivities of multiple compounds rather than the Complimentary Contributor Copy . carota oil extract could be partly explained by the presence of several sesquiterpenes and phenylpropanoids.. carotenoids. A study on the dichloromethanemethanol extracts of the flower of wild carrot from Turkey revealed significant antioxidant properties and activities against several human cancer cell lines (Shebaby et al.. and phenolics such as p-coumaric. 2004)... and caffeic acid.. 2004). -carotene. followed by purple-orange carrots. including reduced oxidative DNA damage. Oral intake of carrot juice also displays other beneficial physiological effects. have been amply studied (Surleset al.. phenols and polyphenols. or might be attributed to major/minor unknown compounds acting in synergy. 2012).. such as α-carotene. The intake of biofortified carrot enhanced liver antioxidant capacity and vitamin A status in Mongolian gerbils. are also antioxidants capable of reducing the risk of chronic diseases like cardiovascular ailments and cancer (Mech-Nowak et al. The chemical composition of the D. Carotenoids do not contribute to total antioxidant capacity. and reduced inflammation (Hu et al. 2012). 2009). The carotenoids present in D.Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 67 Carrot (Daucus carota) Carrots are widely consumed as food. The biofortification of carrots has resulted in increased concentrations of bioactive compounds. sesquiterpenes. vitamins C and E. which include flavonoids (Maxia et al. monoterpenes. 2011). Their active components. A possible explanation for the lack of effect on antioxidant status and LDL oxidation was that 2 weeks of intervention with blanched carrots might not be enough to enhance antioxidative status and protect LDL against oxidation. 2009). The decreased lipid peroxidation evident from drinking carrot juice is associated with increased antioxidant status independent of inflammatory markers. chlorogenic. namely carotenoids and polyphenols. but correlate with the antioxidant capacity of hydrophobic extracts. suggesting that the bioactive compounds in colored carrots. Liver antioxidant capacities in gerbils fed white carrots and supplemented with oil or vitamin A were lower. which was higher in gerbils fed colored carrots than in those fed white carrots and supplemented with vitamin A (Mills et al. which include fibers. 2008). 2011). increased levels of plasma antioxidants. carota oil extracted from different parts of the plant consists mainly of phenylpropanoids. The anticancer activity of D. Anthocyanidins are the main antioxidants in purple-yellow and purple-orange carrots. chlorogenic acid is a major antioxidant in all carrots. Purple-yellow carrots have the highest antioxidant capacity. or increased cholesterol and triglyceride concentrations. the other carrots do not significantly differ (Potter et al. hormones. may have enhanced liver antioxidant capacity either by acting directly as an antioxidant or indirectly by sparing -tocopherol. It was observed that the plasma antioxidant capacity of volunteers measured after 2 weeks of intervention with carrots had no effect on their antioxidant status despite an increase in plasma carotenoid concentration (Stracke et al. lycopene and anthocyanins... carota L. 5 mg/g extract in fresh and fried peppers. it has therefore been associated with potent antimutagenic and anticarcinogenic activities (Materska and Perucka.5 and 24. inhibits α-glucosidase at 43% at 200 μM (Tadera et al. It is also used to treat scarlet fever. annuum var. A comparative study. Previous studies have shown that fresh C. This fraction showed phytol. annuum var.7 mg/g extract respectively. which possess a variety of biological properties and give it its spicy flavor. cerasiferum. Tundis et al. but frying drastically reduces the phytochemical content. While both fresh and dried peppers exhibit a comparable phenol content of 127. 2005). 2013). externally. or phenolic acids. Administration of this flavone for 10 consecutive days in alloxan-treated diabetic animals increased levels of serum insulin while hardly inhibiting the Complimentary Contributor Copy . methyl andethyl esters. anthocyanins. made by the same author showed that the best hypoglycaemic activity was exerted by C. Two major capsaicinoids. individual activities of carotenoids. Peppers (Capsicum annuum) Red pepper is used as a spice for enhancing the palatability of food and as a counterirritant in stomach medicines in many countries (Watanabe et al. However. 2011).8 μg/ml and 356. illustrating the synergistic benefits associated with the intake of whole foods. especially of phenols. acuminatum small also had the highest concentrations of luteolin and kaempferol.. as a rubefacient. a drastic reduction was observed after the frying process with a value of 15mg/g extract. Senise cultivar. dyspepsia.5 and 116. yellow fever. and these can affect attributes like texture. with an IC value of 256. Rodríguez-Fragoso. piles and snakebite (Ishtiaq et al. Osuna-Martínez. color. annuum var.2-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid solution radicals (Loizzo et al..2-azino-bis(3ethylbenzothiazoline-6-sulphonic acid solution radicals in a concentration dependent-manner. putrid sore throat.6 μg/g dw). Capsicum annuum var.0 μg/g dw). where the estimated total phenol content was 224. The pungent principle of red pepper comes from a group of compounds called capsaicinoids. flavor and nutritional value. annuum var. Roggiano and Senise cultivar were capable of scavenging both 2. as major constituents (Tundis et al. acuminatum small has the highest observed quercetin content (56. This value is 10 times higher than C. apigenin. cerasiferum (5.8 μg/ml against α-amylase and α-glucosidase. hoarseness. β-sitosterol. It is well known that vegetables undergo physical. The results clearly evidenced the drying process allows for the retention of those phytochemicals able to exert their bioactivity. 2006). A similar decrease was observed with C.. Ana Isabel Gonzaga-Morales et al. in the lipophilic fraction.68 L. annuum var. 2007). and consequently reduces both antioxidant activity and inhibition of carbohydrate-hydrolyzing enzymes.. respectively. 2013). Ul. C. campesterol and certain FAs.. the drying and frying process drastically reduced the ability of samples to scavenge the 2. The best free radical scavenging activity was exerted by Capsicum annuum var.2-diphenyl-1-picrylhydrazyl and 2. vitamin E. In traditional medicine. dihydrocapsaicin and capsaicin are responsible for up to 90% of the total pungency of pepper fruits. respectively (Loizzo et al. observed that the C. 2001).0 μg/ml). chemical and nutritional changes during hot-air drying. acuminatum (IC50 of 153. structural. annuum is used as a stimulant and. Capsaicin (8-methyl-Nvanillyl-6-nonenamide) is a principal component of Capsicum fruits and is known to have antioxidant properties. It has been shown that the most abundant flavonoid identified in both pepper cultivars.. . exert antioxidative and anti-tumor activities (Kim and Hwang. and capsaicinoids. a number of authors have identified capsanthin as the main carotenoid in several varieties of red peppers (Collera-Zuñiga et al. 2005). 2010).. It is a dietary powerhouse. 2008). 2012). It is a rich source of chemoprotective substances such as folic acid. Red hot peppers (C.. probably because of their higher total phenol content and Fe chelating ability (Oboh. zeaxanthine. Paprika leaves also display potent biological actions such as free radical scavenging. 2010). improvement of HDL-cholesterol. β-carotene and chlorophylls. It was also found that pepper leaves not only possess antioxidant activity but also antiproliferative activity against HCT116 human colorectal carcinoma and MKN 45 gastric adenocarcinoma cell (Jeon et al.. even though paprika leaves possesses phytochemicals such as lutein. et al. 2004.. These data provide basic evidence of peppers’ beneficial antioxidant properties. lutein. carotenoids. especially lutein and γ-tocopherol (Kim et al. red paprika showed the strongest antioxidant activity. All varieties of red hot dried peppers. which are unique to red paprika. The antioxidant activity of paprika leaves appeared to be considerable when compared with β-carotene.. reported that.. Aizawa and Inakuma 2009). Kim et al. is an annual plant (occasionally biennial). full of vitamins and minerals (Nayak et al. These studies show that the carotenoids in red paprika play a key role in these beneficial effects. annuum Tepin and Capsicum chinese Habanero) prevent Fe2+induced lipid peroxidation. 2011). Regarding C. Carotenoids have been found to play an important role in preventing oxidative damage. Spinach (Spinacia oleracea) Spinacia oleracea L. which might be due to the combined activities of several phytochemicals. showed that arbol and chipotle varieties presented the highest values of antioxidant activities. and the occurrence of at least 10 flavonoid glycosides has Complimentary Contributor Copy . Capsaicin could also prevent the oxidation of oleic acid at cooking temperatures. which may contribute to the maintenance of the genetic material. which is caused by free radicals in age related diseases such as cancer. Hervert-Hernández et al. followed by morita and guajillo (Hervert-Hernández et al. var. 2007). special. capsanthin and capsorubin in particular. Freshly cut spinach leaves contain approximately 1g of total flavonoids per kilogram. 2010). and other phenolic compounds. Several studies of red paprika have offered biological evidence of antitumor-promoting activity. it has been proved that colored peppers (C... 2011). flavonoids. annuum L. In addition to the carotenoid composition of red dried hot peppers. 2008).Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 69 glycation of plasma proteins (Liu et al. both extractable polyphenols and hydrolyzable polyphenol extracts. and antimicrobial and tyrosinase inhibitory activities in various solvent fractions (Kim et al. annuum) exhibit radical-scavenging activity (Chuah. native to central and southwest. et al. and hepatic gene regulation (Maokaa et al. as well as the formation of lipid hydroperoxides from the autoxidation of linoleic acid. Additionally. 2009). γ-tocopherol. showed a high antioxidant capacity per g of dry matter. An important antioxidant.. The antioxidant activity of pepper fruits may be mainly attributed to ascorbic acid.. and ageing itself (Tundis et al. reduction or prevention of chronic diseases such as cardiovascular disease. 2007). it is usually consumed after boiling the fresh or frozen leaves (Schirrmacher et al. 70 L. Rodríguez-Fragoso, Ul. Osuna-Martínez, Ana Isabel Gonzaga-Morales et al. been reported. These are glucuronides and acylated di- and triglycosides of methylated and methylene dioxide derivatives of 6-oxygenated flavonols (Bergquist et al., 2005). Extensive conjugation across the flavonoid structure and numerous hydroxyl groups enhance their antioxidative properties, allowing them to act as reducing agents, hydrogen- or electron-donating agents, or singlet oxygen scavengers (Aritomi et al., 1986). The antioxidant capacity of spinach flavonoids has been determined by the free-radical scavenging assay using DPPH (2,2-diphenyl-1-picrylhydrazyl) radical and was compared with that of Trolox, a synthetic analogue of vitamin E. The most active products were those derived from patuletin with a 3′,4′-dihydroxyl group. The incorporation of a feruloyl residue increased the freeradical scavenging activity. Boiling fresh-cut spinach leaves extracted approximately 50% of the total flavonoids and 60% of the vitamin C; a decrease in the total antioxidant activity was observed during storage of leaves (Gil et al., 1999). A pronounced antioxidant effect has been observed immediately after spinach consumption and this can be taken as an indication that this effect is at least partly attributable to direct scavenging effects and not to indirect mechanisms such as induction of antioxidant enzymes, which are seen only after extended time periods (Moser et al., 2011). The observed antioxidant effects of spinach intake are partly supported by the research of Schirrmacher et al., who found a slight induction of SOD and a modest reduction in the malondialdehyde levels in human plasma after a 10-day consumption trial (Schirrmacher et al., 2010). Preadministration of glycolipid extracts from spinach (20 mg/kg body weight) prevented villous atrophy, misaligned crypts, and increased inflammatory cytokines in rat jejunum treated with 5-FU (300 mg/kg body weight). Mono-galactosyl-diacylglycerol and digalactosyldiacylglycerol are primary components of the extracts, and have anti-oxidative and antiinflammatory effects. In Caco-2 cells, monogalactosyl-diacylglycerol and diglactosyldiacylglycerol inhibited the production of ROS induced by phorbol ester (Shiota et al., 2010). The effect of spinach product consumption on antioxidant activity in human blood has been tested in healthy volunteers. The spinach groups received 20 g/day/subject of whole-leaf minced, liquid, or liquefied spinach for 3 weeks and were compared with a control group that received a basic diet. The consumption of spinach resulted in greater erythrocytic GSR activity and lower erythrocytic catalase and serum α-tocopherol responses (Castenmiller et al., 1999). The beneficial effect conferred by the natural antioxidants present in spinach may be mediated through its antioxidative and/or anti-inflammatory properties. Tomato (Lycopersicum esculentum) Tomatoes (Lycopersicon esculentum) and tomato-based products are a source of phytochemicals such as carotenoids (e.g., phytofluene, phytoene, neurosporene, γ-carotene, and ζ-carotene, flavonols (e.g., quercetin and kaempferol), phytosterols, and phenylpropanoids (Tan et al., 2010). Tomatoes and tomato sauces and puree are said to help reduce urinary tract disease symptoms and may have anticancer properties (Polívkováet al., 2010). Tomato consumption might be beneficial for reducing cardiovascular risks associated with type 2 Diabetes (Shidfar et al., 2011). Tomato plants produce two tomato monoterpene synthases, LeMTS1, and LeMTS2 (Van Schie et al., 2007). Tomato consumption has been Complimentary Contributor Copy Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 71 associated with decreased risk of breast cancer (Zhang et al., 2009), head and neck cancers (Freedman et al., 2008), and might also offer strong protection against neurodegenerative diseases (Rao and Balachandran, 2002). It has been shown that the regular intake of tomato products for 3 weeks decreases lipid peroxidation markers associated with cardiovascular disease (Visioli et al., 2003). It has been reported that daily intake of a tomato drink (LycoMato), formulated with a lycopene, phytoene, phytofluene, and R-tocopherol oleoresin increases plasma and lymphocyte carotenoid concentrations while augmenting cellular antioxidant protection (Porrini et al., 2005). Tomato ripening involves the breakdown of chlorophylls and build-up of carotenoids, accompanied by a continuous increase in lycopene, the carotenoid responsible for the red color of ripe tomatoes. The ascorbic acid content was significantly higher in Ronaldo tomatoes than in Siena and Copo. The values ranged from 5.05 to 8.21 mg/100 g for green samples, from 5.99 to 8.26 mg/100 g for pink tomatoes, and from 7.91 to 15.41 mg/100 g for red tomatoes, thus displaying a significant increase during ripening (Shi and Maguer, 2000). Antioxidant activity was higher in red tomatoes of the Siena and Copo cultivars than in the Ronaldo variety, which may be due to the differences in the antioxidant compound content and their synergistic effect in measured antioxidant activity. The ferric reducing ability of both tomato extracts and hydrophilic tomato extracts increased significantly from green to red tomatoes in all three cultivars, since ripe tomatoes had higher antioxidant-compound content than unripe tomatoes (Periago et al., 2009). Red tomatoes exhibit a better antioxidant composition based on their higher lycopene, total phenolic, flavonoid and ascorbic acid contents. As a result of this antioxidant content, they display greater ferric reducing capacity but have reduced lipid oxidation inhibition activity. The antioxidant activity of tomatoes is most probably due to hydrophilic antioxidants, especially total phenols and flavonoids. Lycopene is a highly unsaturated hydrocarbon containing 11conjugated and 2 unconjugated double bonds. A sapolyene, it undergoes cis-transisomerization induced by light, thermal energy and chemical reactions. In human plasma, lycopene is present as an isomeric mixture, with 50% as cis isomers. Although comparative bioavailability values for lycopene from 67 different tomato products are unknown, lycopene from processed tomato products appears to be more bioavailable than that from raw tomatoes (Rao and Agarwal, 1999). Processed tomato products such as juice, ketchup, paste, sauce and soup are all good dietary sources of lycopene. Several studies have indicated that lycopene is an effective antioxidant and free radical scavenger (Mourvaki et al., 2005), and is also a potent inhibitor of lipid peroxidation and low-density lipoprotein oxidation in vivo (Periago et al., 2009). Lycopene is the most important carotenoid present in tomatoes and tomato products, and their dietary intake of the latter has been linked to a decreased risk of chronic illnesses such as cancer and cardiovascular disease (Riccioniet al., 2008; Waliszewski and Blasco, 2010). The protective effects of resveratrol against cardiovascular disease are due to its effects on the platelet aggregation inhibition activity and its strong antioxidant potential (Olas and Wachowics, 2005). Concentrations of total resveratrol in tomato skin ranged from 18.4 ng/g in the MicroTom variety, 2 orders of magnitude below those determined in the skin of seedless red grapes (2.78 mg/g), suggesting that this tomato variety is unlikely to contribute adequate amounts of resveratrol in a normal diet to produce the health benefits associated with this phytonutrient (Ragab et al., 2006). Complimentary Contributor Copy 72 L. Rodríguez-Fragoso, Ul. Osuna-Martínez, Ana Isabel Gonzaga-Morales et al. A number of studies have shown that flavonoids and hydroxycinnamic acids are the major phenolics in tomatoes (Fleuriet et al., 1985). Among the many tomato components (e.g., vitamin C and polyphenols) credited with healthful properties, carotenoids and lycopene, in particular, are being actively researched. Watercress (Nasturtium officinale) The leaves of watercress (Nasturtium officinale) are also widely used as a home remedy (Launert, 1981). Watercress contains one of the highest concentrations of glucosinolates per gram weight of any vegetable as well as containing high concentrations of carotenoids such as lutein, and β-carotene, along with other important bioactive phytochemicals (Getahun and Chung 1999). These phytochemicals have also been associated with various anticarcinogenic properties, including antioxidant activities. Members of the Cruciferae family have also been shown to contain high amounts of phenolic compounds (Gill et al., 2007). Watercress supplementation was associated with reductions in basal DNA damage, in basal plus oxidative purine DNA damage, and in basal DNA damage in response to ex vivo hydrogen peroxide challenge. The mechanisms of antigenotoxic effects due to watercress supplementation are unknown, although this may be related to antioxidant status and changes in GST activity (Torbergsen and Collins, 2000). A diet high in watercress is associated in a number of epidemiological studies with a reduced cancer risk in a number of sites, including colon, lung, lymphatic system and possibly prostate, (Higdon et al., 2007; London et al., 2009). Beneficial changes after watercress intervention were associated with an increase in plasma lutein and β-carotene (100% and 33%, respectively). These results support the theory that consumption of watercress can be linked to a reduced risk of cancer via decreased damage to DNA and possible modulation of antioxidant status by increasing those phytochemicals (Gill et al., 2007). Phenethylisothiocyanate has been reported to have several anti-carcinogenic effects, including the inhibition of phase I enzymes and/or the activation of phase II enzymes (Canistro et al., 2004). It has been observed that, in the rat liver and colon, phenethylisothiocyanate (PEITC) leads to an induction of the total GST activity, such as the induction of the quinine reductase by 7-methylsulfinylheptyl-isothiocyanates and 8methylsulfinyloctyl-isothiocyanates (Rose et al., 2000). In vitro studies showed that watercress extract increased SOD2 activity while PEITC had no impact. This may be due to the potential influence of further bioactive watercress constituents such as quercetin glycosides or hydroxycinnamic acids (Buettner et al., 2006). Another study demonstrated that an extract from watercress modulated gene expression in human peripheral blood cells in vitro and that this was also reflected in a modulation of enzyme activity in vivo, particularly in individuals with the GSTM1*0 genotype (Hofmann et al., 2009). The level of ROS produced by polymorphonuclear leucocytes also increases, accompanied by a decrease in the activity of many tissue antioxidant enzymes. It has been observed that watercress reduces oxidative stress and enhances antioxidant capacity in hypercholesterolaemic rats. Watercress extract prevented the high-fat diet-induced elevation of malondialdehyde (MDA), significantly reduced MDA content in liver homogenates, and Complimentary Contributor Copy Potential Antioxidant Benefits of Commonly Used Fruits and Vegetables … 73 increased GSH level in liver. This suggests that watercress extract can either increase the biosynthesis of GSH or reduce the extent of oxidative stress leading to less GSH degradation; it may, in fact, have both of these effects (Yazdanparast et al., 2008). Conclusion Exploring the healing powers of plants is an ancient phenomenon. Hippocrates (460-377 B.C), the father of medicine, said, “Let thy food be thy medicine and thy medicine be thy food.” Such an idea reflected the importance of dietary supplements for their therapeutic and preventive bioactive components, elevated margin of safety, and desired range of efficacy. Although traditional healers have long used plants to prevent or cure various conditions, nowadays there is an increased interest in the health benefits of foods and researchers have begun to look beyond the basic nutritional benefits of foodstuffs into disease prevention and health enhancing ingredients. This chapter brings together evidence of the beneficial influence of fruits, vegetables or their components (phytochemicals) given their potential antioxidant properties (Figure 3). Interestingly, most of the fruits and vegetables here examined contain a very similar phytochemical mix. Figure 3. Potential antioxidant properties of phytochemicals present in fruit and vegetable. Complimentary Contributor Copy 74 L. Rodríguez-Fragoso, Ul. Osuna-Martínez, Ana Isabel Gonzaga-Morales et al. Currently, most of the fruits and vegetables produced worldwide are still consumed fresh. A very small quantity (1.5%) goes into the manufacturing of pickled products, fruit and vegetable drinks, purées, jellies, candy, juices, jam, and dried fruits. The demand for fruit and vegetable beverages has increased in many countries over the last few years. This may be attributed to changes in dietary habits, taste preferences, and the lifestyle of present-day consumers. It is well known that fruit and vegetable beverages have higher nutritional, medicinal, and calorific values compared to synthetic beverages. Moreover, owing to high acidity, astringency, bitterness, and such other factors in some of these foodstuffs, the preparation of processed products becomes limited despite having high nutritional value. Epidemiological studies suggest that vegetarianism is associated with reduced risks of cancer, cardiovascular and neurodegenerative disorders. This is consistent with the fact that the incidence of these disorders is lower among some populations where fruits and vegetables are the main elements in the human diet. Since diseases like cancer are multifactorial phenomena in which many normal cellular pathways become aberrant, it is highly unlikely that one agent could prove effective against such disorders. This chapter presented evidence of the potential antioxidant properties of fruits and vegetables and their role in regulating and maintaining normal processes in living organisms. The presence of multiple phytochemicals in these foodstuffs suggests that the combined bioactivities of multiple compounds result in the synergistic benefits associated with the intake of whole foods. There is no doubt regarding the protective benefits of phytochemical-rich foodstuffs, but these effects are most successfully obtained from frequent consumption of unprocessed natural fruits and vegetables. The concept of food as medicine needs to be propagated to ensure healthy feeding habits. However, more studies are required to acquire a better understanding of the mechanisms behind the potential health benefits of dietary phytochemicals. References Abdel Moneim, A.E. (2012). 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The application of a stress condition through a proper manipulation of the nutrient solution can stimulate secondary metabolism and promote the synthesis and accumulation of bioactive substances in plant tissues.In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers.maggini@unipi. which are products of plant secondary metabolism with proven beneficial effects on human health. University of Pisa. These substances are known to play a key role in the mechanisms of plant adaptation to the environment. basil is presented as a case study for the application of the hydroponic technique to the production of plant material for the * rita. the traditional harvesting from the wild has become inadequate to sustain the market demand. the interest by pharmaceutical companies towards the production of bioactive compounds from medicinal plants has considerably increased. As a consequence. in consideration of the consumers’ sensibility towards naturally sourced remedies. and medicinal plants are increasingly cultivated on a commercial scale. the market requirement for standardized plant material cannot be fully satisfied by field crops. as it ensures a fast plant growth and allows both to control the growing environment and to change the composition of the nutrient solution that is fed to the plants. Literature data are reported on recent research concerning the hydroponic growing of medicinal plants. Greenhouse hydroponics can contribute to overcome the drawbacks of conventional field cultivation. Complimentary Contributor Copy . Chapter 3 Hydroponic Production of Medicinal Plants Rita Maggini*. In the last decades. Pisa. both under optimal conditions or under stress conditions to stimulate the production of secondary metabolites. Italy Abstract Medicinal plants are specifically used for their contents of bioactive compounds. This chapter presents some fundamental issues concerning the hydroponic production of raw plant material for the extraction of bioactive compounds. Food and Environment. they generally exhibit antioxidant properties and often act as defense molecules that are synthesized by plants in response to stress conditions. Inc. especially in developed countries. On the other hand. Finally. which are highly susceptible to year-to-year variability. . As secondary metabolites. because of their key role in plant survival.92 Rita Maggini. or to react against an abiotic stress (for example. Because they are anchored to the soil.. 2008. Wang et al. Oxidative imbalances in plants activate several protective mechanisms to eliminate or reduce ROS (Domìnguez-Valdivia et al. secondary metabolites (such as some substances belonging to the class of naphto. Anyway. a major function of secondary metabolites is defense. superoxide radical (O2•-) or hydrogen peroxide (H2O2) (e. these compounds are not directly involved in the fundamental functions that determine plant growth and development. the colours of anthocyanins may attract pronube insects or birds). against herbivores or pathogens).g. it also underlines the lack of information concerning the specific growing needs of the individual medicinal species. 1983). plant growth may be reduced.. 2007. Despite the fact that at present a lot of molecules of pharmaceutical interest can be obtained from hydroponically-grown medicinal plants. These molecules are synthesized by plants either in response to a biotic stress (for example.. 2011)..or benzoquinones) can be involved in allelopatic interactions. 2001. Alternatively. to inhibit germination or development of competing plants. Thus.. such as photosynthesis. It is well known that stress conditions in plants also cause an increase in the production of reactive oxygen species (ROS). Ercal et al. a bioactive secondary metabolite of well-known antioxidant activity. Mehrizi et al. Ksouri et al. suitable growing protocols are still required. catalase (CAT) and Complimentary Contributor Copy . respiration or tissue formation. and play a central role in the mechanisms of plant adaptation to both abiotic and biotic stresses. The present chapter points out the opportunities offered by the hydroponic growing of medicinal plants for the agro-industrial production of bioactive compounds. 2012). they have developed effective biochemical pathways for the synthesis of organic molecules that can counteract the effects of a stress condition. Rather. and this in turn may result in a new pattern of resource partitioning. According to the carbon/nitrogen (C/N) balance hypothesis (Bryant et al. they are involved in the interactions between the plant and the environment where it lives. On the other hand. Introduction Secondary Metabolism and Antioxidants Medicinal plants are specifically used for their contents of bioactive compounds.. stress conditions which limit growth more than photosynthesis cause excessive carbohydrates production. such as hydroxyl radical (HO•). Secondary metabolites accomplish a lot of different functions in plants. The molecules that constitute active principles for the human organism are produced in plants by the secondary metabolism. providing additional carbon skeletons for the synthesis of secondary metabolites. Under stress conditions. UV radiation or toxic substances). These molecules can have an attractive role towards insects or animals for plant reproduction through pollination or seed dispersion (for example. such as the enhancement of the activity of antioxidant enzymes like ascorbate peroxidase (APX). Claudia Kiferle and Alberto Pardossi extraction of rosmarinic acid. which are compounds of proven beneficial effects on human health. plants cannot escape the harmful action of a stress agent. 2006). Antioxidant compounds are involved in the mechanisms of plant tolerance to stress conditions (Iriti and Faoro. are one of the most numerous group of plant secondary metabolites. and can act as antiinflammatory.) copper (Cu) nutrition resulted effective in counteracting salt-induced oxidative damage (Mehrizi et al.. Plant defence metabolites arise from the main secondary metabolic routes. That is why antioxidants generally act as defense molecules. anthocyanins. as Cu reduced lipid peroxidation and membrane permeability. whereas it increased total phenol content of salt-stressed plants.. which are widely distributed throughout the plant kingdom. which are synthesized through the phenylpropanoid metabolic pathway and play a key role in the scavenging of ROS. adverse temperature. phenolic compounds. antibacterial. antimicotic...) could significantly contribute to tolerance towards boron (B) toxicity (Landi et al. osmotic imbalance or mineral disorders). neurodegenerative. The occurrence of an environmental conditions that impairs the plant's aerobic or photosynthetic metabolism (such as high light intensity. Cells under oxidative stress display various dysfunctions due to lesions caused by ROS to lipids. phenolic compounds have a large number of therapeutic applications. with more than 8000 structures currently known (Soobrattee et al. 2000). For example. Houghon (2001) estimated that about 40% of the pharmaceutical products used in western countries were initially discovered from natural sources. 2011. 2010). antiviral.: Foyer and Shigeoka. Excess aluminum (Al) stress increased the concentration of flavonoids in Al-tolerant populations of Cunila galioides Benth. causes inevitably enhanced generation of ROS (Ksouri et al. 2005). higher levels of phenolics have been reported in salt tolerant plant species compared to non-tolerant ones (Gill and Tuteja. diabetes. the radical intermediate of this redox reaction is capable to stabilize the unpaired electron by delocalization. 2005. Hinneburg et al. For instance. 2010). tannins. such as the prevention and treatment of cardiovascular. drought. The medicinal actions of phenolics are mostly ascribed to their antioxidant capacity. secondary metabolites often have pharmacological properties. 2012). Rates (2001) reported that about 25% of the drugs Complimentary Contributor Copy . 2011). Landi et al. anticancer. When the production of ROS prevails over the antioxidant power of cells. Plants with high levels of antioxidants have been reported to have a great resistance to this oxidative damage (e. and the production of antioxidant compounds (Gill and Tuteja. 2005. In addition to the usually strong antioxidant activity. The free radical scavenging and antioxidant activities of phenolic compounds depend on the number and the position of the hydroxyl groups that are linked to the aromatic ring (Soobrattee et al. In particular. Among defence molecules. the molecules with hydroxyl groups in the ortho or para positions of a benzene ring are easily oxidized to the corresponding quinonic forms. it was suggested that the relevant anthocyanins level in the leaves of a red cultivar (Red Rubin) of basil (Ocimum basilicum L. and that 25% of these sources were represented by higher plants.g. Furthermore. 2006). the phenylpropanoid. 2013)... 2007).. In rosemary (Rosmarinus officinalis L. proteins and DNA. 2009). immunomodulating molecules. Hinneburg et al.Hydroponic Production of Medicinal Plants 93 superoxide dismutase (SOD). 2009). which are abundantly contained in plant tissues (Grace and Logan. chelation of redox active metal ions. 2012). caffeic acid derivatives and lignin. a naturally occurring medicinal and aromatic plant native of south Brazil (Mossi et al.. the isoprenoid and the alkaloid pathways (Iriti and Faoro. These include flavonoids. it results in oxidative stress. modulation of gene expression and interaction with the cell signalling pathways (Soobrattee et al. cancer and inflammatory diseases. development and production of active principles from medicinal plants. although the traditional collection from the wild is still a low-cost practice in many developing countries (Prasad et al. and has been the cause of a strong public healthcare concern and a regulatory demand for high quality. Prasad et al. 2012). Moreover. 2005). wild collection has become a danger for ecosystems and for the conservation of plant species. 2006b. which is also the result of the Complimentary Contributor Copy .).. uniformity and safety of medicinal plant products (Stewart and Lovett-Doust. 2003. 2011. Regulatory legislation has been introduced in recent years in North America and in the European Union to discipline the safety and quality specifications of herbal preparations (Zheng et al. 2001). Claudia Kiferle and Alberto Pardossi prescribed worldwide came from plants. researchers and consumers. Furthermore. Despite the recent interest towards medicinal plants. cosmetic and pharmaceutical products... approximately two thirds are obtained from wild collection (Canter et al. Medicinal plants are traditionally collected from the wild. 2001). the plant material collected at the spontaneous state is often of poor quality or even poisonous (Atanassova et al. in particular in developed countries. to ensure the maintenance of germplasm.. 121 such active compounds being in current use. 2012). This has increased the interest by pharmaceutical companies towards the identification.. This represents a serious problem for medical doctors.g. Special attention is required for species at risk of extinction. The sensibility of the consumers towards naturally sourced products is particularly strong when dealing with natural remedies. 2012). although they remain minor crops. As a consequence of these safety and environmental issues. 2011). Market Requirements and Field Cultivation Because of the presence of bioactive molecules... 2012).. 2009). In the last decades the consumption of natural remedies has undergone a substantial increase. 2005).94 Rita Maggini. 2004). The use of herbal medicines has increased in recent years due to their usually low prices.. maximum allowed concentrations of heavy metals) have been enacted and put into effect in many countries (Rahimi et al. and also to the common misconception that herbs are safe and without side effects. Quality and safety standards (e. several important drugs cannot yet be synthesized economically and are still obtained from plants (Rates. currently medicinal plants are also cultivated on a commercial scale. with the increasing popularity and rapid growth of the global market for herbal medicine. Crosby and Cracker (2007) reported about the development of tissue culture techniques for the moringa genus.. It has been reported that environmental destruction due to the harvesting of a wild licorice (Glycyrrhiza glabra Linn. more than 10% of the 252 drugs considered as essential by the World Health Organization are exclusively of plant origin and a significant number of synthetic drugs are obtained from natural precursors (Rates. Atanassova et al. Plant-derived substances are present on the market mainly to satisfy the consumers’ preference towards natural products. Moreover. Although what is sensed as natural is also sensed as safe. Arcostaphylos uva-ursa (bearberry) and Piper methysticum (kava) are two other widely used herbal medicines threatened by wild harvesting (Canter et al.. a lot of plants are regarded as primary sources of important natural substances for food. Vlietinck et al. is becoming a serious problem (Sato et al. Among the 50 thousand medicinal species in use. In addition. being of natural origin (Rahimi et al. 2003). 2000). while Vlietinck et al. For instance. but also on the agronomic techniques (Letchamo et al. (2009) pointed out the necessity of controlled cultivation to ensure the production of herbal substances of high quality. This is due mainly to genetic and geographic factors.. Recently Prasad et al. but also as constant as possible. Echinacea spp. The optimization of the cultural techniques. Complimentary Contributor Copy . the presence and concentration of the bioactive substances which have to be extracted may be not sufficient. which could interfere with post harvest handling and processing and could have a detrimental effect on the quality of the final product. within the frame of either traditional or organic cultivation. and often are responsible of discrepancies between the actual concentration of active principles in medicinal preparations and the concentrations indicated on the label.. Medicinal plants cultivation is mainly controlled by pharmaceutical companies. Some medicinal plants are reported to be difficult to grow in open field (e. 2002). In particular. depending not only on the selection of the plant species and variety.Hydroponic Production of Medicinal Plants 95 consumers' acceptance of new food and health products (Ehret et al. chemical or physical contamination of plant tissues. the main purpose of pharmaceutical industry is to purchase the required amount of raw material for the production of pharmaceutical preparations in a planned and regular way. Nevertheless. 1998) and generally the agronomic techniques are not yet optimized (Briskin. All these factors affect both the biomass production and the synthesis of secondary metabolites. which is principally directed to the herbal market. Li. On the other hand.. which in contrast undergo a marked year-to-year variability. In contrast with the need for high quality standards. that is the biomass production and the concentration of bioactive compounds in the tissues should be not only as high as possible. the first step is quality assessment of the starting material. a lot of cultivation areas are arranged in developing countries. (2007) reported that the components of Hypericum perforatum are often found to vary by a factor of two compared to the concentrations reported on labels for the prepared drug. Anyway. 2002). usually far from the production units. the knowledge about the needs of a lot of medicinal species is still scarce. As a consequence. the quality of the raw material that arrives at the extraction laboratories is often poor. and the whole production process is subjected to a strict quality control. Brechner et al. and generally consists of an intensive cropping system for the production of high quantities of biomass at low cost. Unfortunately. to keep costs at a low level. This has encouraged the organic cultivation of medicinal plants.. The bioactive substances to be used for the commercial preparations are concentrated from the raw plant material by means of industrial extraction processes.. 2005). generally these requirements cannot be fulfilled by field crops. Therefore. soil particles.. but also to the variations in environmental conditions that were experienced by the plants during growth and development (Brechner et al. should be a critical step to improve the quality of the raw material. 2007).g. despite the market trend and the growing interest towards the cultivation of medicinal plants. The plants at harvest could be spoiled by foreign material such as weeds. Another problem connected to field cultivation is the incidence of biological. in Europe only 10% of commercially used medicinal species are cultivated (Canter et al. Similar claims have been reported for Echinacea preparations (Mølgaard et al. soil pollutants and pathogens. During the last years the market of organically-certified natural remedies has also increased in developed countries (Craker. (2012) reported about the need for sustainable and viable production methods. 2007). the market requires standardized plant material both in quantitative and in qualitative terms. 2011). the management of important growing parameters such as climatic conditions or mineral nutrition represents the main tool for the regulation of secondary metabolism. Hydroponics is a growing system. The variability of the content of bioactive compounds is one of the major limitations in using plants as sources of these molecules for the pharmaceutical industry. In a similar way. which strongly contribute to the variability of field crops. In vitro culture allows to regulate plant biosynthetic pathways in a Complimentary Contributor Copy . 2006).g.. Pardossi et al. 2007. because the plants are cultivated in pure nutrient solution (water culture) or in artificial growing media (substrate culture) that replace the common agricultural soil (Pardossi et al. a considerable increase in total biomass production can be obtained if appropriate scheduling of planting and multiple harvesting scheme are adopted. For instance. 2000).g. Greenhouse Hydroponics In consideration of the market requirements for a standardized product with a high content of bioactive principles.96 Rita Maggini. Kiferle et al. A further major advantage of hydroponics is the possibility to deliberately expose the plants to stress factors that are known to elicit an increase in the concentrations of secondary metabolites (Brechner et al. On the other hand. open-field culture does not allow a strict control of the growing conditions and of the secondary metabolism. may represent a valid alternative to conventional agriculture for the production of plant metabolites (e. the plant material is easy to be processed and extracted (e. With hydroponics. which generally differ for the methods employed for the delivery of the nutrient solution to the culture. conventional cultivation cannot remove the effects of the fluctuations in the environmental conditions. Rahimi et al. the management of irrigation and fertilization associated to the effective control and optimization of the climatic conditions enables the standardization of the production process and enhances plant growth and development.. as it offers several advantages over conventional field cultivation. the quantity and quality of the production are highly predictable because do not depend on geographic area or pedoclimatic conditions. both a shorter growing cycle and a higher yield can be obtained in comparison with conventional cultivation. the plants can be grown on a year-round basis. Claudia Kiferle and Alberto Pardossi However..: Mulabagal and Tsay. Hydroponics may fulfill both legal and industrial requirements for medicinal plants. In particular. Therefore. 2004. This system includes several techniques. Therefore. the development of alternative systems for the production of medicinal plants could be an effective tool to overcome the drawbacks linked to field cultivation.. Therefore. 2006.. Hydroponics is also referred to as 'soilless culture'. in vitro culture systems such as tissue or cell culture. The limitation of the growing cycle offers the additional opportunity to set up more consecutive cultures within one year. 2012). the use of water and fertilizers is more efficient with hydroponics. plant contamination is absent or minimal. Raviv and Lieth. where the nutrient elements that are normally found in the soil are dissolved in proper amounts in the irrigation water that is supplied to the plants. several efforts are directed to the setup of suitable growing conditions for the stimulation of the plant secondary metabolism. a proper change of the composition of the nutrient solution could stimulate the secondary metabolism and favour the accumulation of bioactive compounds in the tissues (Briskin. 2007). With this technique. Anyway. for example by partial mechanization of some cultural steps or by means of bioreactors (Ahloowalia and Savangikar. in vitro culture is a complex technology that requires skilled operators and expensive structures (Ahloowalia and Prakash. At present. consistency. In addition.. careful market research and consultation with buyers are essential issues for the production of specialty crops such as medicinal plants in greenhouses (Ehret et al. methyl jasmonate. 2009). Considerable effort has been devoted to the increase of the production efficiency and to the reduction of investment and running costs of in vitro systems. the floating raft system represents a low-cost technology that is suitable for growing leafy vegetables under greenhouse conditions.. which accumulates in the bark of the yew tree. Several strategies can be applied in artificial cultivation systems to stimulate the production of active substances. 2005).. (2003) indicated the floating system as the easiest and least expensive way to produce leafy vegetables when soil cultivation is no longer feasible. an effective cell culture of Taxus was developed for taxol production (Zhong. 2008. the evaluation of the economic profitability of greenhouse hydroponics for the production of niche crops such as medicinal plants should take into account challenges as well as opportunities. Taxus spp. in vitro production of phytochemicals on a commercial scale is still limited only to very few high-value plant secondary metabolites (Weathers et al. Nair et al. Along with production factors (such as disease and pest control. 2002). bioactivity.. is aerated to avoid root zone hypoxia. 2005). Anyway.Hydroponic Production of Medicinal Plants 97 strictly controlled and aseptic environment. the market could undergo either a rapid growth or a rapid decrease. 2013). 2002).. 2009). Wickremesinhe e Arteca (1994) reported about the growing of Taxus x media and Taxus cuspidata for the production of taxol. One example is taxol. Among the different hydroponic systems.. which float on a layer of stagnant nutrient solution. Complimentary Contributor Copy . 2002). and biomass production on a commercial scale. For instance. Nevertheless. where the plants are grown on polystyrene trays. Hayden (2006) reported about the opportunities provided by soilless culture for the production of medicinal crops in controlled environments for improving quality. although bioactive compounds from several species have been obtained by means of tissue culture (Matkowsky. purity. Successful cultivation of medicinal plants on a commercial scale implies to overcome the difficulty of predicting which extracts will remain on the market (Canter et al. and is regularly checked for pH and electrical conductivity to prevent nutrient imbalance. The floating system is a simple technique. the plants are grown with their bare roots dipping directly into the nutrient solution.. Miceli et al. were also the subject of early studies on the hydroponic growing of medicinal plants. Levin and Tanny.g. 2002. 2002). an important anticancer drug produced by Taxus spp. production costs and yield) and the need for local infrastructure (such as warehousing and processing facilities). 2010). In particular. Due to the slow growth of yew trees and to the low bark concentration of taxol. quality. Karuppusamy. 2002. this technique does not ensure such a high level of biomass production per unit area as hydroponics. salicylic acid and yeast extract) is known to enhance the accumulation of bioactive compounds in tissue cultures (Zhao et al. Greenhouse hydroponics involves lower running costs compared to those of in vitro cultivation (Montero et al. This is about 30 cm deep to allow root growth and development. this technique could represent a cost-effective system to produce plant material for the extraction of pharmaceutical molecules. the use of elicitors (e. In the floating raft system. therefore. in 2002 it was estimated that in vitro production of any compound with a market price lower than US$ 1000 per kilogram was not economically sustainable (Rao and Ravishankar. such as the greenhouse or growth chamber. In general. Moreover. Dorais et al. 2006. Hydroponic Growing of Medicinal Plants At present. 2006.98 Rita Maggini. only 430 papers report about the hydroponic culture of medicinal plants. (2012) reported that the hydroponic systems can be an effective platform for the production of clean and good quality Centella asiatica herb for the pharmaceutical companies. Brechner et al. 2005..: Dorais et al. 2001. thus resulting in a high biomass production. about 185. and obtained the highest fresh biomass production using the floating raft system... 2010). high density.. the absence of a growing medium is a particularly favourable condition for the harvesting of the root system. and water status. accessed 13th June 2013). fresh-cut (that is minimally processed) leafy vegetables (Pardossi et al.. the root tissues obtained from the floating system are not spoiled by substrate particles and can be easily removed from the nutrient solution without damage or loss of material. Dall'Acqua et al. The same technique was successfully applied also to the cultivation of Camptotheca acuminata. Léonhart et al.g. because the nutrient elements are readily available at the root zone and can be easily taken up by the plants.url. It was also observed that greenhouse hydroponics could help to overcome germination and establishment problems which may arise with the soil cultivation of medicinal species that are difficult to grow in open field (e. hydroponics ensures a high biomass production. Since the year 2000. Because the plants are grown in pure nutrient solution without the aid of a growing medium. 2010). Complimentary Contributor Copy .g. Rodríguez-Hidalgo et al. 2005).com/home. Letchamo et al. Stewart and Lovett-Doust (2003) pointed out that greenhouse hydroponic cultivation under controlled environmental conditions in Calendula officinalis could ensure pesticide-free conditions.g. 2001. Claudia Kiferle and Alberto Pardossi For its simplicity and low investment and running costs. For example. For example. www. Recently. Hyden. Prasad et al. 2002. which is used for the production of the anticancer molecule camptothecine (Li and Liu. with water culture) compared to that of soil-grown crops (e. (2007) reported that hydroponics could be used for the production of both valerian (Valeriana officinalis var common) and lemon verbena (Lipia citriodora var. a lot of studies have been undertaken relating to the hydroponic growing of medicinal plants.. Therefore. can remove wide variations of common variables such as temperature. Crosby and Cracker. 2002). Tabatabaie et al. insect and disease pressures. 2012). The viability and the advantages of this growing system for the production of secondary metabolites from medicinal plants have been demonstrated for a lot of species (e. lacking environmental contaminants.: Canter et al.000 have been published concerning hydroponics (source: Scopus. higher production of plant material can be obtained with hydroponics (particularly. the plant density is generally much higher than in the soil.. Verbena) under glasshouse. 2007. the floating system offers additional specific advantages over field cultivation. (2007) emphasized that growing Hypericum perforatum in controlled environments. this technique has found practical application in commercial production.000 works have been published concerning medicinal species and about 8. and is typically employed for short cycle. Azarmi et al.. These authors employed different types of soilless culture for both species. Along with the aboveground parts.scopus. resulting in superior product quality and consistency. 1999). 2002). (2012) indicated the floating system as an efficient method to produce large biomass of Aloysia citriodora L with high content of volatile oil. and lemon catmint (Nepeta cataria L. which is traditionally cultivated two to four years in open field. the production yield in Echinacea purpurea was found to increase 2. in all the species under examination the rate of biomass accumulation was faster in the aboveground parts than in the roots. With the exception of Taraxacum officinale.) presented higher contents of alkaloid. Among secondary metabolites.. Moreover. Similarly. hyperforin and pseudohypericin in the flower tissues of hydroponically-grown Hypericum perforatum was similar or higher than those previously reported for field-grown plants (Murch et al. For some officinal plants such as Pelargonium roseum. 2005). Complimentary Contributor Copy . All these studies evidenced that hydroponics could really offer the opportunity to shorten the growing cycle used in conventional field cultivation and increase at the same time the biomass production. plant growth is also much faster in hydroponic culture than in open field. The content of hypericin. tannins and essential oil than those cultivated in the soil. For example. Tadevosyan et al. Cymbopogon citratus.. var.3 times compared to the average soil cultivation in North America (Letchamo et al. (2002) reported that Tanacetum parthenium. Vetiveria zizanioides e Nepeta transcaucasica. in Echinacea angustifolia the root yield harvested in nearly eight months from two consecutive hydroponic cultures was comparable with the yield reported in the literature for field cultivations lasting two years or more (Maggini et al. Stellaria media. In addition to essential oils. Léonhart et al. Together with a higher biomass yield. Humulus plants grown in hydroponics contained higher concentrations of alkaloids.. Dorais et al.Hydroponic Production of Medicinal Plants 99 Generally. It was found that. This result was in agreement with those of a previous study carried out with 31 species belonging to the Asteraceae family and grown hydroponically (Almeida-Cortez et al. under outside hydroponic conditions. Taraxacum officinale and Calendula officinalis were all well adapted to greenhouse hydroponic growing conditions and provided abundant yield and high produce quality in a short time period. Taraxacum officinale and Valeriana officinalis were much higher in the floating system compared to those of field-grown plants. Among them. Inula helenium. Recently. 1999). Ocimum gratissimum. Artemisia vulgaris showed the fastest growth rate. Artemisia vulgaris exhibited the fastest growth rate (0. (2001) evaluated the growth of several medicinal plants in a floating raft system and found that. tannins and vitamin C compared to field cultivated plants (Manukyan. Azarmi et al. essential oils have been often found in higher amounts in plants grown hydroponically compared to those grown in open field.226 g g-1 day-1). Celandine poppy (Chelidonium majus L. For example. Moreover. after 50-120 days. Achillea millefolium. (2005) reported about the hydroponic cultivation of Humulus (a species used in Armenian traditional medicine) as an efficient and prospective technique in the Ararat Valley conditions. 2012). both the root and the shoot dry weight of Achillea millefolium. provided high biomass yields in hydroponics in a much shorter time period (a few months only). hydroponically produced essential oil of Pelargonium roseum had a higher geraniol content and was therefore of better quality (Mairapetyan. tannins and vitamin C. the hydroponic system provided 5-6 times more essential oil than traditional cultivation. 2002). Artemisia vulgaris. citriodora) contained remarkably higher concentrations of essential oil. Echinacea spp. other classes of secondary metabolites have been found at higher concentrations in hydroponically-grown than in soil-grown medicinal plants.. a higher concentration of secondary metabolites has also been obtained with hydroponics for a lot of medicinal species. 2010. In soilless culture. Some authors reported that treating hydroponically-grown plants with growth regulators (Wikremesinhe and Arteca. Kiferle et al. Hou et al. 2011) resulted in larger production of secondary metabolites. 2007.. 2007)... all these studies indicated that. assumes that the C/N ratio within the plant regulates the concentration of C-based secondary metabolites. Briskin.. In Camptotheca acuminata.. 2006b. N is usually supplied as nitrate (NO3-. feeding licorice (Glycyrrhiza glabra Linn. At the same time. For example. 2012. 2008. Plant mineral nutrition may affect both plant growth and secondary metabolism (Briskin. 2006). thus reducing the production of biomass.) plants with dilute nutrient solution (approximately equivalent to a quarter unit of Hoagland solution) provided the highest glycyrrhizin content in root tissues and the highest plant growth (Sato et al. 2007). Some authors (e.g.. 2001. 2000.. 2006a).. 2004). Nitrogen (N) is the most important nutrient for plants. Maia et al. 2006b. 2008. as it limits primary metabolism. decreasing N concentration in the hydroponic nutrient solution increased the content of the secondary metabolite camptothecine (Li and Liu.. Anyhow. which are a major group of C-based antioxidant molecules. (1983).. 2012) than in field-grown crops (Berti et al. 1996) or bio-stimulants (Parađiković et al. such as temperature (McChesney. N deficiency may have an opposite effect on secondary metabolism. As a consequence. Claudia Kiferle and Alberto Pardossi In contrast with these results.. Zheng et al. 2010).. play a central role in plants’ adaptation to N starvation. some studies on the production of secondary metabolites in Echinacea angustifolia reported much lower root concentrations of caffeic acid derivatives (especially of the marker compound echinacoside) in hydroponically-grown plants (Zheng et al. lowering the concentration of N in the nutrient solution resulted in an increase of the content of bioactive secondary metabolites. Pardossi et al. 2010) proposed to lower the NO3concentration in the nutrient solution to reduce the environmental impact of soilless culture Complimentary Contributor Copy . 2005). N deficiency enhances the formation of reactive oxygen species (Kováčik et al. 2002).. whereas field-grown Echinacea plants are commonly harvested after a few years (ontogenetic effect). results in over-production of carbohydrates. Manipulation of Growing Conditions Several studies have shown that in greenhouse hydroponic culture the accumulation of secondary metabolites of pharmaceutical interest can be stimulated by modifying the composition of the nutrient solution (e. A limitation of N supply which restricts growth more than photosynthesis. However. 2000. Zheng et al.. based on the knowledge of their specific growing needs.. Massa et al. Montanari et al. Munoz et al. phenolic compounds. 1999) or light conditions (Giorgi et al.100 Rita Maggini. The C/N balance hypothesis proposed by Bryant et al..g. Sabra et al. N starvation is a primary cause for growth reduction.. For these reasons. 2013) or the climate inside the greenhouse. In chamomile (Matricaria chamomilla) an increase in the production of phenolics was observed in N-deficient plants (Kováčik et al. In several medicinal plants. Maggini et al. These compounds are in part allocated to C-based secondary metabolites. This was probably the consequence of plant harvesting after only a few months of hydroponic cultivation. other species still require further work for the development of profitable growing protocols. although a lot of medicinal species are easily adapted to greenhouse hydroponic conditions and have been successfully cultivated by this growing system. Hydroponic Production of Medicinal Plants 101 associated with NO3- leaching. Decreasing the concentration of NO3- in the nutrient solution also reduces the accumulation of NO3- in leafy vegetables (Santamaria et al., 1998), which is potentially toxic to human health. Like N, phosphorus (P) is an essential nutrient for plants. Stewart and Lovett-Doust (2003) reported that Calendula officinalis showed promise as a medicinal greenhouse crop that requires low P levels for optimal production of inflorescence, which is the target tissue containing bioactive compounds. Moreover, due to the xerophytic characteristics of this species, the best results in terms of flower-head tissues production were obtained when relatively low ratios of P relative to N and potassium (K) were associated to intermittent watering regime. The authors suggested that discontinuous water and nutrient supply in hydroponic culture may be widely applicable to medicinal plants, since a lot of species share Calendula’s xerophytic characteristics. Nutrient solutions differing in concentrations and ratios of N, P, and K were reported to influence also the synthesis of various pharmaceutical compounds such as alkaloids, essential oils, tannins, and vitamin C in Chelidonium majus L. and Nepeta cataria L. (Manukyan, 2005). Sodium (Na+) and chloride (Cl-) are the most common non-nutrient ions dissolved in irrigation water. The induction of a salt stress by addition of sodium chloride (NaCl) to the nutrient solution determines a rise in the electrical conductivity and results in osmotic stress, as well as ion (Na+ or Cl-) cytotoxicity (Saleh and Maftoon, 2008; Silva et al., 2008; Munns and Tester, 2008; Dashti et al., 2010), and oxidative damage to macromolecules and cell structure (Neto et al., 2006; Eraslan et al., 2007). Depending on the species, salt stress may have different effects on the production of plant secondary metabolites. For example, salinity was reported to decrease the production of essential oils in Matricaria chamomilla (Razmjoo et al., 2008) and Melissa officinalis (Ozturk et al., 2004), and to have no significant effect on the content of echinacoside per plant in Echinacea angustifolia (Maggini et al., 2013). Mehrizi et al. (2012) observed that salinity induced oxidative stress in hydroponically-grown rosemary, resulting in lipid peroxidation and increase in cell membrane permeability to toxic ions, which in turn reduced plant growth. As a response to oxidative damage, the total phenolic content in medicinal plants was often reported to be influenced by salinity (Mehziri et al 2012¸ Navarro et al., 2006; Ksouri et al., 2007). A strong correlation between salt tolerance and antioxidant capacity was found in several plant species (Gill and Tuteja, 2010). In particular, higher levels of phenolics were reported in salt tolerant species compared to non tolerant ones. Together with NO3-, ammonium (NH4+) is a main source of N and is readily absorbed by plants. However, likewise excess Na+ or Cl-, excess NH4+ may have a toxic effect on plants, although the biochemical mechanisms of NH4+ toxicity remain to be further elucidated (Britto and Kronzucker, 2002). The concentrations at which the toxic effects are observed depend on plant species. Several studies have been conducted on the effect of NH4+ on the growth of some crop species (e.g.: Britto and Kronzucker, 2002; Savvas et al., 2006; Cárdenas-Navarro et al., 2006; Cao et al., 2011). One of the main effects of NH4+ toxicity is a lower root/shoot ratio (Kiferle et al., 2013), although the opposite was observed in some species (Britto and Kronzucker, 2002). On the other hand, the presence of NH4+ along with NO3- could have also favorable implications, as NH4+ may reduce NO3- absorption. In addition, in hydroponics NH4+ may help in managing the pH of the nutrient solution, as it controls the alkaline drift in pH determined by NO3- assimilation (Savvas, 2001). The pH of the nutrient solution is known to Complimentary Contributor Copy 102 Rita Maggini, Claudia Kiferle and Alberto Pardossi affect plant growth and metabolism, as reported for the hydroponic culture of Artemisia afra Jacq. (Koehorst et al. 2010). At the same time, NH4+ absorption may alter intracellular pH gradients, which affect a lot of metabolic pathways (Dixon and Paiva, 1995). Little information has been reported concerning the response of plant secondary metabolism to N form. Anyway, the use of nutrient solutions supplemented with both NH4+ and NO3- at different ratios was reported to affect the production of bioactive compounds in medicinal species grown in hydroponics. It was observed that the supply of 50% total N as NH4+ enhanced the accumulation of the alkaloids catharanthine and vinblastine in Catharanthus roseus (Guo et al., 2012). In contrast, the supply of a mixture of NH4+ and NO3- in Echinacea angustifolia decreased the concentration of some caffeic acid derivatives (Montanari et al., 2008). At the same time, a decrease was also observed in the activity of phenylalanine ammonia lyase, a key enzyme of the phenylpropanoid pathway involved in the biosynthesis of these secondary metabolites (Montanari et al., 2008). In sweet basil irrigated with a nutrient solution containing 10.0 mM NH4+, the total content of essential oil was markedly reduced as compared to the plants fed exclusively with NO3- (Adler et al., 1989). A scarce oxygen (O2) level in the root zone (hypoxia) is a further cause of metabolism imbalance. Although the effect of hypoxia on the secondary metabolism of medicinal plants has been scarcely investigated, in floating system this condition may occur in the stagnant nutrient solution, especially in warm season, as high temperatures may reduce O2 solubility while increasing root respiration (Gorbe and Calatayud, 2010). An adequate O2 level is necessary to ensure root functionality, whereas O2 deficiency reduces the uptake of both water and nutrients such as NO3- (Horchani et al., 2010; Ferrante et al., 2003). Moreover, O2 deficit enhances the formation of reactive oxygen species (Colmer and Voesenek, 2009). Anyway, a large part of the literature on the effects of hypoxia concerns plant growth with little attention paid to secondary metabolism. Growth reduction is considered one of the first adaptive plant responses to hypoxia, as this allows to conserve energy, inhibiting a wide range of ATP-consuming processes to decrease O2 demand (Geigenberger, 2003). The detrimental effect of low O2 in the root zone of plants grown in hydroponics was observed in several crop species (e.g.: Ferrante et al., 2003; Shi et al., 2007). Plant sensitivity to hypoxia conditions depends on plant species and may vary even among different cultivars of the same species. In some cultivars of Medicago sativa the growth of both roots and shoots was limited by waterlogging, while in other cultivars only root growth was severely restricted, whereas shoot biomass was unaffected (Smethurst and Shabala, 2003). Under root zone hypoxia conditions, a differential response between the root system and the aerial organs may be associated to ethylene entrapment in submerged plant tissues, as a consequence of the much lower gas diffusion rate in water than in air (Visser and Vosenek, 2004). Ethylene plays a key role in the mechanisms of plant adaptation to hypoxia, for instance by regulating the formation of adventitious roots and aerenchyma (Licausi, 2011). On the other hand, this hormone is known to inhibit root growth, even at low concentration (Abeles et al., 1992). In addition to a change in the composition of the nutrient solution, a proper modification of the growing conditions could also result effective in stimulating the secondary metabolism. For example, it was found that: low temperatures increased the accumulation of morphine in Papaver somniferum (McChesney, 1999); water stress increased the concentration of flavonolignans in primary blooms of Silybum marianum (L.) Gaertn. (Belitz and Sams,2007); low irradiance favored the accumulation of glycyrrhizic acid and liquiritin in the roots of Complimentary Contributor Copy Hydroponic Production of Medicinal Plants 103 Glycyrrhiza uralensis Fisch. (Hou et al., 2010). Several experiments demonstrated that supplemental lighting on medicinal plants grown hydroponically under greenhouse accumulated more bioactive molecules compared to field-grown crops (Pedneault et al., 2002; Brechner et al., 2007). In contrast, an opposite effect of supplemental lighting was reported on other medicinal species. For example, the concentration of phenolic compounds from Tarassacum officinale was 6.2 times higher in field-grown plants compared to those cultivated in hydroponic culture. In Inula helenium, sesquiterpene lactones were more concentrated in field-grown root compared to hydroponically-grown root and parthenolide was more concentrated in field-grown flowers and leaves than in the same organs of hydroponically-grown plants (Pedneault et al., 2002). A Case Study: Basil Basil (Ocimum basilicum L.) is one of the most important species belonging to the genus Ocimum, in the Lamiaceae family. The genus Ocimum encompasses a huge number of medicinal species and varieties, characterized by a large variability in morphology and habitats, flavours, scents, and uses (Putievsky and Galambosi, 1999). A lot of them are mainly cultivated to be used for culinary preparations. This species includes a large number of varieties and cultivars with distinct morphological traits and chemotypes (Simon et al., 1999), which range from typical green-leaf varieties (Genovese, Lettuce leaf, Gigante) to purple-colored genotypes (Dark Opal, Red Rubin) or lemon-flavoured cultivars (Citriodorum). Basil is cultivated worldwide, and is also grown hydroponically (Miceli et al., 2003). Whereas some varieties are used as ornamental plants, basil is mainly used for food preparations (Makri and Kintzios, 2007). The fresh green leaves of some cultivars (sweet basil; for example Genovese) are commonly used for the preparation of the well-known Italian ‘pesto’ sauce, now largely diffused all over the world (Miele et al., 2001). Basil is also an important source of essential oils and of rosmarinic acid (Kiferle et al., 2011). The essential oils are extensively used in food and pharmaceutical industry, perfumery, cosmetics and herbal medicine (Makri and Kintzios, 2007; Hussain et al., 2008). The composition and concentration of the essential oils is largely variable in dependence of cultivars and growing conditions. However, linalool, chavicol and methyl-chavicol, eugenol and methyl-eugenol, estragole, methyl-cinnamate, have all been reported as the dominant volatile constituents (Lee et al., 2005; Makri and Kintzios, 2007; Klimánková et al., 2008). The relative content of each constituent can often enable to differentiate among distinct cultivars (Klimánková et al., 2008). Rosmarinic acid is one of the most abundant antioxidant phenolic compounds accumulated by basil (Jayasinghe et al., 2003; Li et al., 2007; Makri and Kintzios, 2007; Juliani et al., 2008; Lee and Scagel 2009). Rosmarinic acid is widely distributed in the plant kingdom, but represents a characteristic secondary metabolite of several medicinal plants (e.g. Salvia officinalis, Mentha x piperita, Thymus vulgaris, Melissa officinalis) in the Boraginaceae and Lamiaceae families (Petersen and Simmonds, 2003; Petersen et al., 2009). As a caffeic acid derivative, rosmarinic acid belongs to the class of phenylpropanoids (Kurkin, 2013). The molecule is formally obtained by esterification of the carboxylic group of Complimentary Contributor Copy 104 Rita Maggini, Claudia Kiferle and Alberto Pardossi caffeic acid with the alpha hydroxyl group of 3,4-dihydroxyphenyllactic acid. The pure compound was isolated for the first time in Rosmarinus officinalis by Scarpati and Oriente (1958), while the complete biosynthetic pathway from the precursors tyrosine and phenylalanine was fully elucidated 45 years later by Petersen and Simmonds (2003). Rosmarinic acid is a strong free radical scavenging agent. The antioxidant properties of this secondary metabolite are due to the presence of two couples of hydroxyl groups, each couple being located in the ortho positions of a benzene ring. A large number of additional biological activities have been described for rosmarinic acid: adstringent, anti-inflammatory, anti-mutagen, anti-bacterial and anti-viral properties have been attributed to this compound (Petersen and Simmonds, 2003; Juliani et al., 2008). Likewise the vast majority of plant secondary metabolites, rosmarinic acid accumulation for a given genotype is strongly affected by many factors, including growing and environmental conditions, phenological stage, plant organ (Del Baño et al., 2003; Juliani et al., 2008; Shiga et al., 2009). Experiments at the University of Pisa This section reports a synthesis of the main results obtained in a series of experiments carried out at the University of Pisa (Italy) with the green-leaf basil cultivar Genovese grown in floating system (Kiferle et al., 2011, 2012, 2013). These experiments were aimed at studying the applicability of greenhouse hydroponics to the agro-industrial production of rosmarinic acid (hereafter indicated as RA). When grown hydroponically, basil plants showed a fast growth and leaf concentration of RA ranged from 4 to 29 mg/g DW (Kiferle et al., 2011). Roots also contained significant concentrations of RA. Although the shoot accounted for more than 90% total dry mass, in principle the whole plant could be processed for RA extraction, as the floating system facilitates also the harvesting of clean root tissues (Kiferle et al., 2011). All the determinations were conducted on non-dehydrated fresh or frozen (-80°C) samples, as desiccation at 70°C was found to reduce the content of RA in basil tissues up to 40% (Kiferle et al., 2011). Leaf RA concentrations reported in the literature for sweet basil varied from less than 0.1 mg/g DW (Sgherri et al., 2010) to nearly 100 mg/g DW (Javanmardi et al., 2002). This wide range is probably the consequence of differences in plant genotype and growing conditions, or in the method used for the determination of rosmarinic acid. In some experiments attempts were made to increase the production of RA in sweet basil while maintaining the same biomass production. In particular, the plants were exposed to a moderate NaCl salinity stress, to a moderate hypoxia condition or to a change in N nutrition. In order to study the effect of salinity, a control treatment and two different saline treatments were compared. In the latter treatments, proper amounts of NaCl were added to the control nutrient solution (Kiferle et al., 2012). Although the response to saline stress may change in different cultivars (Attia et al., 2011; Omer et al., 2008), the cultivar Genovese resulted moderately tolerant to a NaCl-induced salinity stress (Kiferle et al., 2012). In agreement with these results, other authors found that NaCl concentrations up to 50 mM did not affect the growth of sweet basil grown in water culture (Attia et al., 2009; Tarchoune et al., 2009, 2010). In contrast, Bernstein et al. (2010) reported that NaCl salinity reduced Complimentary Contributor Copy Hydroponic Production of Medicinal Plants 105 significantly root and shoot growth in hydroponically-grown sweet basil, especially at concentrations higher than 50 mM. The content of RA in leaf tissues resulted unaffected by NaCl salinity (Kiferle et al., 2012). This result was in disagreement with those observed under slightly different growing conditions by other authors (Tarchoune et al., 2009), which found that 50 mM NaCl markedly reduced the leaf concentration of RA (as well as those of caffeic and vanillic acids) in basil cultivar Genovese. In contrast, the root content of RA was found to increase significantly in both saline treatments (Kiferle et al., 2012). In another experiment, hypoxia conditions were easily induced in the culture by simply disconnecting the aeration of the nutrient solution. The cultivar Genovese appeared moderately tolerant to a moderate hypoxia stress. Hypoxia did not affect significantly shoot growth, while a marked reduction was observed in root dry weight (Kiferle et al., 2012). This result was in agreement with those of other studies (Drew, 1983; Incrocci et al., 2000; Shi et al., 2007). The root tissues were affected by hypoxia also for the accumulation of RA, whereas the leaf content of this metabolite was not modified by the oxygen level in the nutrient solution (Kiferle et al., 2012). In contrast to these findings, some authors observed an increase in the level of phenolic compounds in plants grown under root hypoxia, for instance in both shoots and roots of Hypericum brasiliense (Nacif de Abreu and Mazzafera, 2005) and in the stems of Eucalyptus marginata (Burgess et al., 1999). In the latter work, the increase in the concentration of phenolic compounds was also linked to the increased activity of some enzymes involved in their biosynthesis, such as phenylalanine ammonia lyase, 4-coumarate coenzyme A ligase and cinnamyl alcohol dehydrogenase. Two distinct types of experiments were carried out concerning the influence of N nutrition. In the first one, N was entirely supplied as NO3-, at the concentrations of 10, 5 or 0.5 mM (Kiferle et al., 2013). The former concentration is the standard level of NO3- that is considered as optimal, and similar concentrations are generally employed in hydroponic cultivation (Pardossi et al., 2006; Sonneveld and Voogt, 2009). In the second experiment, the total N content was kept constant at the optimal concentration value, and the NO3-/NH4+ ratio was modified (Kiferle et al., 2013). Overall, the growth parameters were higher at the optimal concentration of 10 mM, except the root dry matter, which increased at the lowest NO3- concentration. This was an expected result, as it is known that N deficiency inhibits shoot growth while stimulating root growth (Clarkson, 1985), because this adaptive mechanism enhances the plant’s ability to absorb nutritive ions from the growing medium. In a similar way, several growth parameters indicated that the supply of NH4+, alone or in mixture with NO3-, had a marked detrimental effect on plant growth (Kiferle et al., 2013). In contrast with these findings, in pot-grown sweet basil the biomass production resulted unaffected by the use of salt fertilizers containing NO3- or NH4+ (Tesi, 1995; Adler et al., 1989). The decrease in NO3- concentration increased the content of RA in the tissues (Kiferle et al., 2013). In agreement with this outcome, an increase in leaf RA content of sweet basil grown under limited N availability was reported by Nguyen and Niemeyer (2008). The concentration of RA was affected also by the N form. In leaf tissues, the presence of NH4+ ion had the undesired effect of decreasing the level of rosmarinic acid, even in the presence of NO3- (Kiferle et al., 2013). The following table (Table 1) summarizes the main effects that were determined in the leaf tissues of sweet basil cultivar Genovese by a change in the composition of the nutrient solution (Kiferle et al., 2012, 2013). Complimentary Contributor Copy e. DW: dry weight. The concentration of RA could be further increased by a proper change in the composition of the nutrient solution. cultivar Genovese.. 2006. Claudia Kiferle and Alberto Pardossi Table 1.supplied to the plants. as a consequence.with nutrient solution discharge is limited. the typical concentration of hydroponic nutrient solutions. Effect of modifications of the nutrient solution on biomass production and leaf content of rosmarinic acid in sweet basil (Ocimum basilicum L. The symbols + and ¯ indicate higher or lower values than those obtained under standard growing conditions while the letters ‘ns’ indicate no significant change. salinity or hypoxia did not have a significant effect either on the leaf biomass production or on the content of RA. A further outcome of the experiments described in this section was that different basil genotypes accumulated different amounts of RA (Kiferle et al. Kiferle et al. as less N fertilisers are applied and the leaching of NO3.concentration in the culture solution results in lower environmental impact. See text for details Dry biomass (g/plant) Rosmarinic acid (mg /g DW) a b Salinitya (NaCl addition) ns ns Low N levelb (N as NO3-) ns + NH4+ additionb (constant total N) _ _ Hypoxiaa ns ns Kiferle et al. Overall. The best results were provided by a decrease in the level of NO3..concentration of 5 mM. When plants were grown with a NO3. The above reported results also have some important operative and environmental implications. 2013. the reduction of NO3. 2011) and that.level compared to the typical concentration of hydroponic nutrient solutions (10 mM or higher). 2012. Thus. specifically by a decrease in the NO3. On the other hand. Sonneveld and Voogt. compared to the standard concentrations generally used in hydroponic culture (Pardossi et al. Furthermore. which remained unchanged in leaf tissues. All these findings suggested the potential of greenhouse hydroponic culture of sweet basil for the agro-industrial production of RA. cultivar selection is recommended for production improvement. Conclusion Greenhouse hydroponic technology is currently applied to the commercial-scale production of fresh or minimally-processed herbs (including basil) for the vegetables market. a clearly detrimental effect was observed for both growth and RA production in the presence of NH4+. Complimentary Contributor Copy . This well-known and commonly employed technology could be easily applied also to the production of biomass for the extraction of bioactive molecules. moderately saline) irrigation water can be used in water culture of sweet basil and that the aeration of nutrient solution is not a crucial factor for optimal plant growth and RA production of this species. as they suggest that poor quality (i.106 Rita Maggini... the use of this ion in the nutrient solution should be avoided for hydroponic cultivation of sweet basil.). leaf and total RA content was significantly greater than at 10 mM. 2009). as a large amount of biomass with a high concentration of this antioxidant compound could be produced in a few weeks. Horticultural Science. PW. Prakash. J. 2011. References Abeles. While this is an evident advantage for biomass production. and suggest that specific cultural protocols should be developed for each species individually. as dried tissues are easier to handle and process. 24. 2013). may also result economically profitable. which contained much more RA than oven dried tissues (Kiferle et al. Nitrogen form alters sweet basil growth and essential oil content and composition. In order to evaluate the profitability of this scheme. FB. With greenhouse hydroponics. The literature data evidence that there is still a lack of information on the suitable growing practices for medicinal plants production in hydroponics. which is clean and easy to be harvested and processed. A low-cost greenhouse hydroponic system such as the floating raft system. the cultural cycle can be sensibly shortened. Ethylene in plant biology. Morgan. The greenhouse hydroponic growing of this species may be considered as a model system for the production of plant material for the extraction of bioactive compounds. as we found in Echinacea angustifolia (Maggini et al. a special production scheme is required for the processing of fresh material. the determinations were conducted on fresh or frozen (80°C) samples.Hydroponic Production of Medicinal Plants 107 The production efficiency of this growing system could be further improved by accurate variety selection. Saltveit. USA: Academic Press. CA. In: Low cost options for tissue culture technology in developing countries. In addition. Medicinal plant material generally undergoes desiccation. Jr. In our experiments on basil. which resembles the one for the industrial production of fresh-cut vegetables. a short-term storage should be planned before extraction and suitable cold rooms should be available. short cycle leafy vegetables. Ahloowalia. N concentration) may increase the production of the metabolite(s) of interest. which has found actual commercial application for the production of high density. 1989.. On the other hand.. BS. In particular. 2011). as the content of bioactive compounds in medicinal plants is strongly dependent on the genotype. proper manipulation of the characteristics of the nutrient solution (e. 2012. In contrast. especially if the species to be grown are selected both for their economic value and bio-active properties. the greenhouses for the cultivation of medicinal plants should be located close to the processing units. it may be a limiting factor for the synthesis and accumulation of sufficient amounts of bioactive substances in the tissues. the overall costs to obtain secondary metabolites from fresh or dry plant material should be compared. we found that the floating raft system provided a suitable growing method for the agro-industrial production of RA from basil (Kiferle et al. 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India Abstract Metabolic disorders. ROS is generated through several mechanisms including oxidative phosphorylation. agents possessing dual effect such as anti-diabetic/anti-obesity and antioxidant activity are greatly in demand. Complimentary Contributor Copy . usually phytochemicals and micronutrients called as quenchers act either directly by free radical scavenging mechanisms or indirectly by enhancing the antioxidant status (enzymatic and non-enzymatic). due to a disproportionate release of free radicals. Chennai. activation of protein kinase C (PKC). thus. nitric oxide synthase (NOS) and aldose reductase pathway among others. India Department of Biochemistry. This chapter discusses the sources of flavonoids. including diabetes and obesity. during the metabolism of excessive glucose and free fatty acids. K. N. compounds that can manage these conditions serve to be effective against these diseases and their complications. therapeutic intervention with the ability to reduce oxidative stress can impede or delay the onset of the metabolic disorder. S. Anna University. advanced glycation end product (AGE) formation. Inc. The therapeutic effect of phytochemicals found in natural products to combat oxidative stress is gaining significance as they are recognized to be safe with a wide range of biological and pharmacological activities. Lakshmi1. Shilpa1 1 2 Centre for Biotechnology. Chennai. The most promising strategy to mitigate the effect of ROS induced oxidative damage is through the use of antioxidant molecules. Enhanced production of reactive oxygen species (ROS) and perturbed antioxidant defenses determine the chemical changes in virtually all cellular components resulting in their damage. As diabetes and obesity conditions initiate generation of free radicals. their potential antioxidant properties and the mechanism through which they exert their pharmacological effects in diabetes and obesity. modulating the genes associated with metabolism and stress defense. glucose auto-oxidation. have been strongly associated with oxidative stress. Sangeetha2 and K. Thus. They also act as secondary messengers in the regulation of several intracellular signaling pathways. terpenes and tannins are ubiquitous in nature and can effectively scavenge reactive oxygen and nitrogen species. Antioxidants. Chapter 4 Flavonoids as Antioxidant Therapy for Metabolic Disorders B. University of Madras. Dietary components from plants such as polyphenols (flavonoids).In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers. 2003]. traditional medicine systems have used plants for the treatment of various diseases and disorders. proteins by structural changes causing loss of activity and damage deoxyribonucleic acid (DNA) by DNA strand breaks leading to cell mutation. aging. codeine and morphine from opium poppy. It has also been observed that 67% of drugs used for the treatment of human cancers and 70% anti-bacterial. 2003]. proteins and nucleic acids. N. Free Radicals and Oxidative Stress In recent years. Isolation of bioactive compounds from various medicinal plants began as early as the 19th century in the ancient Chinese. ROS and RNS are produced as a result of cellular redox processes and have special affinity for lipids. there has been an increasing awareness among people towards understanding the role of free radicals on human health. Any imbalance between the pro-oxidant system and the antioxidant defenses lead to a stressful environment defined as “oxidative stress”. Free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) are known as pro-oxidants. Free radicals at lower concentrations are essential for several physiological functions of cell including gene expression. quinine from Cinchona bark. Natural products and their derivatives or their derived pharmacophore contribute to more than 50% of all the medicines used in the world. free radicals can damage cell membranes and lipoproteins by lipid peroxidation. Cells in our body use oxygen to generate energy and the process results in the production of free radicals by the mitochondria. vinblastine and vincristine from Catharanthus roseus and reserpine from Rauwolfia sp. autoimmune disorders. antiparasitic. cardiovascular and neurodegenerative diseases [Maritim et al. Despite considerable progress in the field of drug discovery. Complimentary Contributor Copy . arthritis. digoxin from Digitalis leaves. and anti-viral are naturally derived / inspired drugs [Gurib-Fakim. Lakshmi. Sangeetha and K. anti-fungal. K.. there is an increase in the progression of these diseases globally. S. the body has certain antioxidant enzymes as special defense mechanisms which can be divided into two categories: enzymatic mechanisms and nonenzymatic mechanisms for neutralizing the effects of these pro-oxidants (Figure 1a). cellular growth. which ultimately ends up in oxidative cell damage with prolonged stress (Figure 1b) [Maritim et al. Indian and North African civilizations. with metabolic disorders being the prime targets. Free radicals such as superoxide anion (•O2-). prominent among them being atropine and hyoscine from Solanaceae sp.. hydroxyl radical (•OH) and nitric oxide (NO•) are produced as by-products of several reactions occurring using oxygen and these free radicals are highly reactive. due to their associated long term complications.118 B. However. Several bioactive molecules have been identified from plants in the past century. Years of research work has led to the discovery of several bioactive principles for the treatment of diseases. diabetes. 2006]. defense against infection and as stimulating agents in biochemical processes. Oxidative stress plays a major role in the development of chronic and degenerative diseases such as cancer. However at higher concentrations. Shilpa Introduction Since ancient civilizations.. 2012]. Plants as an Alternate Therapy In many parts of the world. These synthetic therapies have limited efficacy. there is a need to look for new drugs to modify the course of complications associated with metabolic disorders. It has also been observed that certain cases of metabolic disorders respond well to natural remedies in comparison to conventional drugs. Till date. thus desperately demanding for alternative approaches. secondary metabolites have applications in food and cosmetic industry as additives. Natural products with their structural and chemical diversity. 1994]. At present. the therapy for metabolic disorders relies mainly on approaches using synthetic agents. Although. development of modern medicine has resulted in the advent of modern pharmacotherapeutics. are ideal for screening and identification of bioactive molecules for drug discovery process [Tiwari and Rao. biochemical specificity and molecular characteristics. Pro-oxidant and antioxidant status during a) physiological and b) oxidative stress condition. due to the preservative effects exhibited by the antioxidant and antimicrobial constituents [Škrovánková et al. medicinal plants form the backbone of traditional medicine.Flavonoids as Antioxidant Therapy for Metabolic Disorders 119 Figure 1. limited tolerability and significant mechanism-based side effects. tropical rain forests remain a vast reservoir and continue to provide bioactive compounds used for the development of new drugs. Hence. At present. Additionally.. 2002]. about 50 drugs have been discovered from tropical plants and the possibility of finding more bioactive compounds Complimentary Contributor Copy . there is an urgent need to meet the demands of the disease with a multi-modal therapeutic approach that includes multi-targeted action with lesser side effects. and are the source for several secondary metabolites exhibiting bioactivity for the treatment of various diseases and metabolic disorders [Farnsworth. coumarins.120 B. catchins. odor and oxidative stability. primarily those of developing countries. These medicinal plants are a reservoir of secondary metabolites. The most common natural antioxidants are polyphenols that include flavonoids (flavanols. since there exists a better understanding of human physiology. 2005]. the bioactivities exhibited by plants in the treatment of various diseases and disorders can be understood better. rely on plant based medicines for the treatment of various diseases and disorders. basil. 2001 and Gurib-Fakim. cumin. K. Sangeetha and K. diabetes. cinnamic acid derivatives. mints. tocopherols and poly functional organic acids. color. 2012]. quenchers of singlet oxygen formation. isoflavones. and. astringency. According to WHO survey. They offer protection against development of cancers. lignans and lignins exhibit various biological effects including antioxidant activity [Packer et al. rosemary. fennel and caraway among others [Škrovánková et al. 2006]. 80% of world population. thyme. coumarins. cardiovascular diseases. with the most important remedies being passed on verbally from one generation to another. flavanones). phenylalanine or a close precursor shikimic acid [Ilja and Peter. which act either individually. phenols form the largest group. osteoporosis and neurodegenerative diseases. The main classes Complimentary Contributor Copy . Lakshmi. The commonly used plants exhibiting antioxidant activity include neem. S. 2005].. Polyphenols may be classified into different groups based on the number of phenol rings they contain and the structural elements that bind these rings to one another. Plants as Antioxidants Nearly all plants possess compounds that exhibit antioxidant activity as a defense mechanism.. N. flavor. Shilpa are enormous as only about 1% of tropical species have been explored for their bioactive potential. stroke. diabetes mellitus and cancer. polyphenols contribute to the bitterness. flavones. free radical scavengers. Herbal remedies in traditional cultures have been developed through trial and error methods over several centuries. marjoram. These plant antioxidants play a vital role in human health care by serving as reducing agents. complexes of pro-oxidant metals. Presently. Plant phenolic compounds are formed from the common intermediate. stilbenes. In food. The secondary metabolites such as flavonoids. 1999. turmeric. tannins. Yu-Ling et al 2012] and are involved in the elimination of free radicals that are responsible for various chronic and degenerative diseases. additively or in synergy with several different plants in exhibiting their biological effects [Cragg and Newmann. Polyphenols Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet (UV) radiation or aggression by pathogens. sage. oregano. including inflammation. balm. ranging from simple structures with one aromatic ring to complex polymers such as tannins and lignins [Phillipson. Among the various secondary metabolites produced by plants in response to stress. ginger. The aromatic cycles of flavonoids undergo modifications like hydroxylations. Increasing evidence of different physiological functions exhibited by flavonoids in Complimentary Contributor Copy . nutrient deprivation. 2012]. metal toxicity.. Flavonoids are involved in an array of processes. vegetables.. coffee. parsley. 1995 and Hernández et al. The genes that govern the biosynthesis of antioxidant flavonoids are present in liverworts and mosses and are mostly up-regulated as a consequence of severe stress [Agatia et al. drought. lemon. This chapter will discuss about flavonoids and their role against metabolic diseases like diabetes and obesity. their consumption by humans have been known to improve health by preventing degenerative diseases associated with oxidative stress.. More than 4000 structurally distinctive flavonoids have been identified from plants [Brahmachari. However. roots. such as ascorbate (vitamin C) and α-tocopherol (vitamin E) based on in vitro antioxidant assays because of their strong capacity to donate electrons or hydrogen atoms [Herna´ndez et al. red wine and beer containing large amounts of flavonoids and herbal remedies containing flavonoids being used around the world. Winkel-Shirley 2002. pollination and seed development [Williams and Grayer. glycosylations. broccoli or fruit juices (cranberry and orange) provide relatively low levels of flavonoid [Beecher.. and purple pigments in various plant tissues including fruits. 2004. fruits (apples. various investigations have been carried out to characterize the effect of plant derived secondary metabolites on free radicals scavenging. Plants have been found to produce flavonoids in response to various biotic and abiotic stresses. such as wounding. soyabeans. infection and are also observed to act as a deterrent for herbivores [Winkel-Shirley. Flavonoids act as copigment. Besides their role in protecting plants. which account for the diversity of flavonoid class [Pourcel et al. ginkgo. Flavonoids Flavonoids are plant secondary metabolites that are best known for imparting characteristic red. grains. flavones.. stems. all flavonoids share a basic skeleton structure consisting of C6-C3-C6 with two aromatic C6 rings and a heterocyclic rings containing one oxygen atom. Cadenas 1995. 1986]. 2012]. Flavonoids are available in the form of flavonols. contributing to the colour in plants and help in the pollination by attracting animals by their colours and also in the protection of plants from stress. 1976] with beverages like tea.. dark chocolate and red wine. 1997 and Pourcel et al. 2011] and many of them are been known to perform better than many well-known antioxidants. The molecular structures of flavonoids determine their capacity to act as antioxidants.. formed by addition of malonyl CoA to the phenylpropanoid molecule coumaroyl CoA [Saxena et al. red wine. blue. grape fruit. neem. 2003]. blueberries). such as damage caused by UV [Gurib-Fakim. flavonones in major dietary sources such as tea. 2007]. cherry. Winkel-Shirley. orange. apple. flavonoids. flowers. Van Breusegem and Dat 2006. tomato. onion. 2009]. 2007].. stilbenes and lignans. including plant–pathogen interactions. 2012]. bark. Moderate to high amounts of flavonoids are present in tea. Flavonoids are polyphenolic compounds. 2006 and Cody et al. acylations or prenylations. In recent years. as flavonoids are known to act as scavengers of free radicals such as ROS [Rice-Evans et al. 2009].Flavonoids as Antioxidant Therapy for Metabolic Disorders 121 include phenolic acids. 2001]. methylations. isoflavones. thyme and other legumes [Saxena et al. 2001. whereas. Dixon and Paiva. Human consumption of plant derived flavonoids is approximately 1 g per day [Kuhnau. S. Shilpa response to stress and understanding how plants control the types and amounts of flavonoids that are produced in response.. 1999]. Sangeetha and K. Figure 2.. where cinnamic acid derivative (phenylpropane) acts as a starting compound in polyketide synthesis. flavanols. they appear to occur as aglycones. glycosides and methylated derivatives. following basic substitutions such as hydroxylations and reductions. consisting of two aromatic rings linked through three carbons [Gurib-Fakim.. Flavonoids having small molecular weight are responsible for the tartness and bitterness of many fruits. General structure of a flavonoid. Flavonoids have a common structure of diphenyl propanes ([A] C6 . 2001]. continues to be a high priority for research [Winkel-Shirley. as well as the variation in the number and substitution pattern of the hydroxyl groups and the extent of glycosylation of the heterocyclic rings [Amić et al. flavonones. aid in the process of isolation of these bioactive flavonoids. Lakshmi. In response to this discovery. results in the formation of different classes of flavonoids [Di Carlo et al. Cinnamic acid. The various classes of flavonoids are divided based on the connection of the B ring to the C ring.[B] C3 . in response to diverse environmental cues still remains elusive [Chalker-Scott. N. Investigation of the molecular basis of flavonoid function in reducing stress.122 B. synthesized from shikimic acid. 2006] (Figure 2). but later was identified to be a flavonoid (rutin).. K. whereas larger molecular weight flavonoids especially tannins are responsible for their astringency [Di Carlo et al. Research in the field of flavonoids had increased since the discovery of a new compound isolated from oranges which was believed to be a member of a new class of vitamins (designated as vitamin P).. Biosynthesis of Flavonoids Flavonoids are biosynthesized via a combination of the shikimic acid and acylpolymalonate pathways. 1999]. 2001]. 1999].[C] C6). as well as in defining the mechanisms that control the amounts and varieties of flavonoids produced in plants. along with its contribution in the regulation of biochemical mechanisms and control of the types and amounts of flavonoids synthesized under different conditions. Attempts to understand the role of flavonoids in stress protection. the level of oxidation of the C ring from the basic benzo-γ-pyrone structure. 2002]. and anthocyanidins [Narayana et al. 2003]. flavonols. The flavonoids include flavones. intensive research was undertaken to isolate the individual flavonoids and probe their mechanism of action [Nijveldt et al. Complimentary Contributor Copy . Flavones are characterized by a planar structure because of a double bond in the central aromatic ring such as apigenin. Flavonols are the most ancient and widespread flavonoids and exhibit a wide range of potent physiological activity and are even synthesized in mosses and ferns [Winkel-Shirley. 2001]. proanthocyanidines are examples of flavanol dimers. which include quercetin. luteolin.. 2001].. 2002]. daidezin and biochanin A [Grotewold. whereas isoflavonoids are the class where benzenoid substitution occurs at third position [Narayana et al. broccoli. mostly found in citrus fruits. Flavanols differ from flavonones with hydroxyl group in the third position and a C2-C3 double bond [Narayana et al. 2007]. Isoflavonoids Flavonoids have a second position of the benzenoid substitution. Flavonols and flavones are the most widely distributed flavonoids. quercetin is the most frequently occurring compound in foods like onions. apples. Complimentary Contributor Copy . 2001].. Examples of flavanols include narigin. kaempferol. The second group is the flavanones. The first group. The main dietary sources of flavonols and flavones include tea and onions [Grotewold. and berries.Flavonoids as Antioxidant Therapy for Metabolic Disorders 123 Subclasses of Flavonoids The subclasses of flavonoids and their sources are discussed in detail (Table 1). 1999]. 2001] such as genistein. [Di Carlo et al. Aglycone Aglycone is a flavonoid consisting of a benzene ring (A) condensed with a six membered ring (C). epicatechin and gallocatechin [Nijveldt et al. 2007]. myricetin. Flavanols and Flavonones Flavanols and flavonones are the class of flavonoids in which the six-membered ring is a dihydro derivative. for example naringenin and hesperidin [Grotewold. 2002]. chrysin and apigenin [Winkel-Shirley. which in the 2-position carries a phenyl ring (B) as a substituent. [Nijveldt et al. 2007].. kaempferol and myricetin [Grotewold 2007]. Among the flavonols.. Flavones and Flavonols The flavonoid’s six-membered ring substituted with α-pyrone is classified as flavones and flavonols. flavanols are termed pycnogenols because they tend to form dimers by condensation of two identical compound. .B. tomato etc Citrus foods Green leafy spices likeparsley Teas. 2003) Flavonoid Flavonols Flavonones Flavones Flavanols Flavan-3-o1s Isoflavones Anthocyanins Examples Kaempferol Morin Rutin Myricetin Quercetin Quercetrin Myricitrin Spirenoside Galangin Robinin Kaempferide Fisetin Hesperitin Naringin Naringenin Eriodictyol Hesperidin Pinocembrin Likvirtin Rpoifolin Apigenin Tangeretin Flavone Baicalein Luteolin Chrysin Techtochrysin Diosmetin Diosmin Silibinin Silymarin Taxifolin Pinobanksin Catechin Genistein Daidzin Cyanidin Delphinidin Malvidin Pelargonidin Peonidin Petunidin Rich food sources Nearly ubiquitous in foods such as tea. Sangeetha and K. grape. grapes Soybeans. 2001. purple and blue Berries Complimentary Contributor Copy . N. Nijveldt et al. 2001 and Beecher. olive. Lakshmi. onion. Shilpa 124 Table 1. K. red grapes and red wines Tea. soy foods and legumes Red. S. Natural sources of Flavonoids (Modified From Narayana et al. cranberry.. . Vacuolar Flavonoids Anthocyanins and proanthocyanins have been found to accumulate in vacuoles. 1999]. grapes. They are the class of compounds responsible for the red-blue pigments in plants... contributing to pigmentation and photoprotection. wine. 1951]. 2006. 1999]. Efficient mechanisms have been recently identified for the transport of flavonoids from the endoplasmic reticulum (ER)/ the site of their biosynthesis. Anthocyanins have been found to occur as anthocyanins (glycosides) and anthocyanidins (aglycones). The mechanism underlying flavonoidmediated ROS reduction in plants is still unclear [Agatia et al. Di Carlo et al. Flavonoids in Chloroplast Chloroplasts are considered a major source of intracellular hydrogen peroxide (H2O2) in photosynthetic plant tissues [Mehler. 2003]. 2009].. 2012]. It is noted that vacuolar flavonoids can Complimentary Contributor Copy . acting by scavenging singlet oxygen and stabilizing the outer membrane [Zaprometov and Nikolaeva. Minor Flavonoids Dihydroflavones and dihydrochalcones have been considered as minor flavonoids because of their limited natural distribution [Di Carlo et al. and tea and their examples include cyanidin and pelargonidin [Nijveldt et al. The solubility of each flavonoid ranges from moderately hydrophobic (luteolin and epigallocatechin) to strongly hydrophilic (flavonol glycosides and anthocyanins) [Herna´ndez et al. suggesting that glycosylated flavonoids play a role in the antioxidant machinery. These flavonoids are located within or in the proximity of centres of ROS generation in severely stressed plants. both have been found to be water-soluble [Gurib-Fakim. Location of Flavonoids in Plants Stress-responsive dihydroxy B-ring-substituted flavonoids have great potential to inhibit the generation of ROS. Anthocyanins are found mainly in fruits with red or blue color such as strawberries and other berries. 2001].Flavonoids as Antioxidant Therapy for Metabolic Disorders 125 Anthocyanin Anthocyanins are closely related to flavonoids with an open C-ring. Membrane Flavonoids A number of flavonoids with high in vitro antioxidant activity have been found to be hydrophobic since their biological function is associated with membranes. to different cellular compartments.. Flavonoids present in cuticles and epicuticular waxes serve as an antioxidant barrier against oxidizing pollutants. such as ozone (O3) and sulphur dioxide (SO2) [Toma´s-Barbera´n et al.. 2002]. instead.. Sangeetha and K. anti-diarrhoeal. however no experimental evidence is yet available. Alcerito et al. however.. Diabetes and Oxidative Stress Glucose homeostasis represents the balance between intake (glucose absorption from the gut). no direct antioxidative action of nuclear flavonoids has been reported. N. They contain dihydroxy B-ring substituted flavonoids. anti-hepatotoxic. anti-HIV. Polster et al.. Flavonoids have also been found to inhibit the activity of several enzymes such as aldose. analgesic.. 2005. 2012]. Perturbation in glucose homeostasis leads to a chronic Complimentary Contributor Copy . Extracellular Flavonoids Extracellular flavonoids indirectly protect cellular components from photooxidation by acting as UV-light screen [Jordan.. Lakshmi. anti-spasmodic . anti-viral and anti-microbial [Gurib-Fakim. immunostimulant. Nuclear Flavonoids Flavonoids such as flavonols.. 2006]. which inhibit ROS-generation by making complexes with Iron (Fe) and Copper (Cu) ions [Agatia et al. thereby creating contact with cytosolic oxidizing agents [Gould et al. tissue glucose uptake and hepatic glucose production. anti-fungal. 2006].. tissue utilization (glycolysis. 1999]. anti-osteoporotic. flavan-3-ols and chalcones have been detected in plant nuclei and nucleus of mesophyll cells. Glucose homeostasis is maintained by the highly coordinated interaction of three physiologic processes: insulin secretion. vasodilator. they indirectly protect DNA by screening UV radiation and chelating transition metals. 1999].. Biological Activities of Flavonoids Flavonoids exhibit positive impact on human health by modulating many enzyme activities affecting several cellular systems [Di Carlo et al. tricarboxylic acid cycle activity. S. 1988. It has been suggested that nuclear flavonoids protect DNA from oxidative damage caused due to ROS. pentose phosphate pathway activity. consequently preventing the Fenton reaction [Melidou et al. Shilpa 126 only exhibit their antioxidant potential by disruption of the physical barrier created by tonoplast.B. 1996]. K. Flavonoids have been evidenced for a wide range of biological activities in humans. anti-tumour. anti-lipolytic. anti-ulcerogenic. suggesting that these compounds exhibit numerous pharmacological activities such as anti-inflammatory. antioxidant. 2002].reductase and xanthine-oxidase [Di Carlo et al. glycogen synthesis) and endogenous production of glucose (glycogenolysis and gluconeogenesis) [Shinji et al. 2009]. both vascular (cardiovascular complications. Diabetes . Under hyperglycemic Complimentary Contributor Copy . neuropathy. diabetes develops into numerous other metabolic aberrations. enzymatic and mitochondrial pathways (Figure 3). Non-enzymatic Non-enzymatic sources of oxidative stress originate from the oxidative biochemistry of glucose. The main reason attributed for this effect is that chronic supra-physiological glucose concentration generates free radicals. thus creating an oxidative stress which negatively affects a large number of organs and tissues [King and Loeken.Flavonoids as Antioxidant Therapy for Metabolic Disorders 127 increase in blood glucose concentration.. 2010]. nephropathy. 2006]. Hyperglycemia-induced oxidative stress. In addition. Over a period of time. they bind to various receptors for AGEs (RAGE). retinopathy and embryopathy) or a-vascular (cataract and glaucoma). resulting in the heterogeneous metabolic disorder defined as diabetes. resulting in diabetic complications. 2004]. involving both sugars and lipids would be the relevant source of oxidative stress in diabetes [Ferdinando et al. It has also been proposed that carbonyl stress. Figure 3. 2012]. glucose reacts with proteins in a non-enzymatic manner leading to the development of Amadori products.Induced Oxidative Stress There are multiple sources of oxidative stress in diabetes including non-enzymatic. rather than oxidative stress.. Glucose can undergo autoxidation and generate •OH radicals [Al-Rawi. thereby generating ROS [Alison Goldin et al. followed by formation of AGEs with generation of ROS at multiple steps during the process. Once AGEs are formed. All isoforms of NOS require five cofactors/prosthetic groups such as flavin adenine dinucleotide (FAD). hypertension. The enzyme is derived from xanthine dehydrogenase. Shilpa 128 condition. through four complexes in the inner mitochondrial membrane. heme. renal and neural diseases [Singh et al. Lakshmi. Superoxides can activate several other damaging pathways in diabetes including accelerated formation of AGEs. Complimentary Contributor Copy .B. hyperglycemic condition activates production of ROS thereby stimulating the stress related signaling mechanisms such as NFκB. tetrahydrobiopterin (BH4) and Ca2+-calmodulin. Mitochondrial respiratory chain is another source of non-enzymatic generation of reactive species. 2002]. In the absence of its substrate L-arginine or its cofactors. Excessive levels of glucose leads to an overdrive of the electron transport chain in the mitochondria resulting in overproduction of superoxide anions.and macro vascular complications. and activates Nox [Amiri et al.instead of •NO which is referred to as the uncoupled state of NOS [Jeanette et al. nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase and nuclear factor κB (NF-κB)-mediated cytokine production.. flavin mononucleotide (FMN).generation at the level of Complex II in the respiratory chain. p38-mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription. During the oxidative phosphorylation process.production by the electron reduction of oxygen using electron donors like NAD(P)H or NADH. NAD(P)H oxidase. electrons are transferred from electron carriers nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2). producing superoxide in both the reactions.janus kinase (STAT-JAK) which reduces the expression of antioxidant enzymes by glycation of these proteins [Taniyama and Griendling. there is an enhanced metabolism of glucose through the polyol (sorbitol) pathway. (2000) have demonstrated that generation of excess pyruvate via accelerated glycolysis under hyperglycemic conditions floods the mitochondria and causes •O2.. xanthine oxidase and polyol pathway. S. 2004]..precedes the activation of four major pathways involved in the development of diabetic complications.is the crucial initiator that turns oxidative stress into diabetes by stimulating more ROS and RNS production via downstream activation of PKC. thereby creating oxidative stress.. 2009]. hexosamine pathway and PKC. 2003]. Increased generation of ROS and especially •O2. Enzymatic Sources Enzymatic sources of ROS in diabetes includes nitric oxide synthase (NOS). NOS may produce •O2. and over expression of xanthine oxidase results in increased oxidative stress [Berry and Hare. Xanthine oxidase catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid. 2004]. generating adenosine triphosphate (ATP) in the process [Green et al. to oxygen. Enhanced generation of ROS due to increased expression of Nox has been implicated in diabetes and its associated complications like atherosclerosis. N. Nevertheless. K. which also results in enhanced production of •O2-. polyol pathway. There is plausible evidence that PKC is stimulated in diabetes via multiple mechanisms such as polyol pathway and angiotensin II (Ang II). It has been postulated that mitochondrial •O2. 2005]. all of which have been proven to be involved in micro. NAD(P)H oxidase (Nox). Sangeetha and K. Nishikawa et al. is a membrane associated enzyme that consists of five subunits and is a major source of •O2. . intracellular glucose level rises and glucose is converted to sorbitol by stimulation of enzyme aldose reductase and coenzyme NAD(P)H. 2002 and Keaney et al... 2007]. inadequate antioxidant defenses. The generated ROS controls body weight by exerting different effects on hypothalamic neurons that control satiety and hunger behaviour [Esposito et al.. AGE and deficiency of glutathione (GSH) [Ferdinando et al. 2011. 2013].. 2006]. called the adipokines or adipocytokines (plasminogen activator inhibitor-1 (PAI-1). These adipokines secreted by the adipose tissues induce production of ROS.. upto 30% of glucose can be diverted to polyol pathway... increased tissue lipid levels. 2003]. tumor necrosis factor-alpha (TNF-α). and also potently activates stresssensitive signaling pathways including p38-MAPK and c-jun N-terminal kinase (JNK) which have been proposed to play important role diabetic complications [Newsholme et al. leptin. adipocyte differentiation and size of mature adipocytes [Sonoli et al. tissue dysfunction [Steppan and Lazar. glyceraldehyde autooxidation. Disproportionate diversion of glucose to this pathway leads to production of sorbitol. 2007]. inducing oxidative stress through multiple biochemical mechanisms such as superoxide generation from Nox. However. Barth et al. enzymatic sources within the endothelium. Complimentary Contributor Copy . Other factors that contribute to oxidative stress in obesity are abnormal post-prandial ROS generation [Chrysohoou et al. oxidative stress can be a consequence and also a trigger of obesity by increasing the pre-adipocyte proliferation. resistin. Hence. 2007]. It is a state of chronic oxidative stress that arises due to clustering sources of abnormalities like hyperglycemia. 2011]. Intracellular accumulation of sorbitol is harmful as it causes cell damage. This chronic oxidative stress may be the mechanism underlying the development of co-morbidities in obesity. Obesity and Oxidative Stress Obesity is a chronic disease of multifactorial origin and can be defined as an increase in the accumulation of body fat. paracrine and autocrine action.. Adipocyte secretory proteins: Adipose tissue is a triglyceride (TG) storage tissue as well as a source for substances with endocrine. ROS.Flavonoids as Antioxidant Therapy for Metabolic Disorders 129 Polyol pathway is involved in the conversion of glucose to sorbitol. and chronic inflammation [Vincent and Taylor. leading to oxidative stress [Fernández et al.. 2004]. adipose tissue is considered as an independent factor for the generation of systemic oxidative stress. 2007]. oxidative phosphorylation. Depending upon the severity of hyperglycemia. 2006]. During hyperglycemia. and adiponectin). High fat diet: Chronic hyper-nutrition such as high fat high carbohydrate (HFHC) meals.. chronic inflammation [Patel et al. High fat diet and adipoctyte secretory proteins play a major role in obesity induced oxidative stress. high dietary saturated fatty acids (SFA) and trans-fatty acids leads to the accumulation of fat in the adipose tissue. Adipokines play a role in the homeostasis of various physiological processes. 2010 and Kluth et al. and low antioxidant defenses [Block et al. hyperleptinemia. hyperleptinemia [Hartwich et al. polyol and hexosamine pathways [Isabella et al.. 2010].. increased rates of free radical formation. PKC activation. 2011]. mitochondrial dysfunction along with ER stress characterized by impaired protein folding. Figure 4. Obesity induced oxidative stress. leading to ATP accumulation in mitochondria. Lakshmi. N. During ER stress.Induced Oxidative Stress There are several mechanisms by which obesity induces oxidative stress through ROS generation (Figure 4). promoting electron leakage and free radical release. due to excessive fat accumulation resulting in lipotoxicity. Shilpa Mechanisms of Obesity . Sangeetha and K. protein folding and degradation of aberrantly packaged Complimentary Contributor Copy . K. S. lipid droplet creation and hepatic cholesterol accumulation. Fat cell accumulation: During the state of obesity. Free radical release triggers oxidative stress leading to mitochondrial DNA damage. The mitochondrial adenosine diphosphate (ADP) drop. reduces the speed of oxidative phosphorylation and mitochondrial uncoupling.130 B. adipocytes are unable to function as an energy storage organ. mis-folded proteins activate the unfolded protein response (UPR) that is responsible for ER biogenesis. Intracellular triglycerides inhibit the adenosine nucleotide translocator (ANT). Complimentary Contributor Copy . Protein oxidation: Advanced oxidation protein products (AOPP) are recognized as markers of oxidative damage to proteins during oxidative stress. which are not recognized by the LDL receptor. tissue dietary antioxidants. AOPP are formed during the whole life in small quantities and increase with age. isoprostanes and conjugated dienes. 4-hydroxynonenal. over-consumption of oxygen by the fat cells generates free radicals in the mitochondrial respiratory chain that is found coupled with oxidative phosphorylation in mitochondria [Isabella et al. particularly NO. Similarly. ROS can stimulate oxidation of low-density lipoprotein (LDL) and oxidized LDL. Lipid peroxidation is associated with several indices of adiposity and a low systemic antioxidant defense (antioxidant enzymes. Hyperleptinemia: Mitochondrial and peroxisomal oxidation of fatty acids also induces ROS generation. 2013]. Lipid peroxidation: Lipid peroxidation during obesity is another major cause of oxidative stress. i. are significantly diminished. 2007]. and also bind to the same receptor.Flavonoids as Antioxidant Therapy for Metabolic Disorders 131 proteins. high ROS production and decrease in antioxidant capacity leads to various abnormalities. 2007]. similar to those of AGEs. 2010]. Significant elevation of 8-hydroxydeoxyguanosine. Oxidative stress is the main element in this modification and the most significant is the myeloperoxidase/ H2O2/ halide system. among which endothelial dysfunction is characterized by a reduction in the bioavailability of vasodilators. Hyperleptinemia occurs during obesity and induces oxidative stress. fibrinogen and lipoproteins. GSH) [Isabella et al. Lipid peroxidation leads to an elevation in the formation of end products such as malondialdehyde.e. Leptin is a hormone produced by adipose tissue.. The generated free radicals create a stressful environment and readily react with lipids in the cell membrane forming lipid peroxide that causes oxidative degradation of lipids. hydroperoxides. Hyperleptinemia stimulates proliferation and activation of monocytes/macrophages alongwith production of interleukin 6 (IL-6) and TNF-α [Hartwich et al. an AOPP occurs during obesity induced oxidative stress [Piwowar. If UPR is prolonged. 2013].... AOPP have their own particular biological proprieties. catalase (CAT). Finally. the activity of antioxidant enzymes such as superoxide dismutase (SOD). Similarly. Antioxidant enzyme depletion: Upon increase of adipose tissue. 2007]. can be taken up by scavenger receptors in macrophages leading to foam cell formation and atherosclerotic plaques [Dorien et al.. Fatty acid accumulation during obesity leads to an excessive generation of free radicals. Physiologically. and glutathione peroxidase (GPx). the persistent oxidative protein folding machinery causes ROS production with subsequent systemic release of free fatty acids and inflammatory mediators. RAGE. They are derived from oxidation-modified albumin. mainly by increasing mitochondrial and peroxisomal fatty acid oxidation. and an increase in endothelium-derived contractile factors causing atherosclerotic disease [Amirkhizi et al. which regulates appetite and exerts protective effects against lipotoxicity in non-adipose tissues. Copper exerts its activity with cytosolic SOD and Zn exhibits its activity through alcohol dehydrogenase. alkaline phosphatase and carbonic anhydrase. The third line of antioxidant enzymes includes lipases. N. GRx and some trace elements like Se. albumin and vitamin C.132 B. vitamin E. Sangeetha and K. The antioxidants may be exogenous or endogenous in nature. Copper (Cu). Zn and Mn. are the nutrient antioxidants belonging to exogenous antioxidants. GSH.. Flavonoids are phenolic compounds from plants that inhibits lipid peroxidation and lipoxygenases. Vitamin C directly interacts with superoxides and hydroxyl radicals. CAT. Selenium and vitamin E efficiently scavenge the peroxides from cytosol and cell membrane. proteases. L-arginine. bilirubin among others maintain the antioxidant equilibrium by primarily acting as cofactors for the antioxidant enzymes. Vitamin E scavenges peroxyl radicals. They are a complex group of enzymes that repair the damaged DNA. flavonoids. 2006]. CAT. carotenoids and trace elements like Selenium (Se). carotenoids. GSH is a good scavenger of superoxides. Metabolic antioxidants like lipoic acid. proteins. thus converting them into stable molecules like water and molecular oxygen [Gupta and Sharma. hydroxyl radicals and lipid peroxides. β-carotene is an excellent scavenger of singlet oxygen. uric acid. glutathione reductase (GRx). Second line of defense includes glutathione. bilirubin. which prevent the transformation of ROS. 2006]. thereby inhibiting free radical stimulation. transferases. Flavonoids have been reported to exert anti- Complimentary Contributor Copy . vitamin C. They also play vital role in stopping the chain propagation of peroxyl lipid radicals. First line of defense antioxidants includes SOD. oxidized lipids and peroxides. Their potential role in the treatment of diabetes has become the focus of investigation in recent times due to their remarkable health benefits. SOD acts by quenching superoxides and catalase functions by catalysing the conversion of H2O2 to water and molecular oxygen. Antioxidants can be classified into first line of defense. Another major source of antioxidants. uric acid. GPx. K. the intermediates in lipid peroxidation and is responsible for protecting polyunsaturated fatty acids (PUFA) and low density lipoprotein (LDL) against lipid peroxidation. GPx. Zinc (Zn). Shilpa Antioxidants Antioxidants are substances that interact with and stabilize free radicals thus protecting the cells from damage. Lakshmi. DNA repair enzymes. S. The endogenous antioxidants can be classified as enzymatic and non-enzymatic. Antioxidant Flavonoids with Anti-diabetic Activities Bio-flavonoids are well-known for their multi-directional biological activities. Vitamin C and E helps to minimize the consequences of lipid peroxidation by binding transition metal ions like Cu and Fe. The non-enzymatic antioxidants can be divided into metabolic antioxidants and nutrient antioxidants. and comprising of compounds that can be taken as supplements through foods such as vitamin E. methionine sulphoxide reductases (MSRA) among others. second line of defense and third line of defense antioxidants [Gupta and Sharma. Manganese (Mn) which play a crucial role by preventing lipid peroxidation damage [Ashok et al. 2012]. Enzymatic antioxidants include SOD. Cu. Brahmachari and Gorai. probably by influencing the pleiotropic mechanisms to attenuate the diabetic complications. 2002].dimethylchromano) flavone and flavanone (2S)-4′-O-methyl-6.7-O-(α)-dirhamnopyranoside (kaempferitrin) [De Sousa et al. 2010]..7(3′′. silymarin. quercetin showed promising antidiabetic activity in streptozotocin (STZ)-diabetic rats when treated individually or when complexed with vanadium [Vessal et al. Flavonoid drug candidates have also been found to stimulate glucose uptake in peripheral tissues and regulate the activity of the rate-limiting enzymes involved in carbohydrate metabolism pathway [Matsui et al..induced diabetic rats.. Velussi et al. Shin et al..α -L-rhamnopyranosyl). prunin (naringenin 7-O. 2006. C-glucosidic flavone derivative named as isoaffineyin (5. Brahmachari..4.. 2009 and Qi et al. 2003]. Similarly. 2000]. Flavones such as 4'. 2001] and flavonoid glycosides from Phyllanthus fracternus [Hukeri and Kalyani.5′-pentahydroxyflavone-6-C-glucoside) from Manikara indica [Haraguichi et al. 2002]. 2003].Flavonoids as Antioxidant Therapy for Metabolic Disorders 133 diabetic effects through their capacity to avoid glucose absorption or to improve glucose tolerance [Jung et al. isoquercetrin and rutin showed significant anti-hyperglycemic effects on diabetic rats [Choi et al. a neoflavonoid from the bark of Hintonia latiflora has been reported to exhibit promising anti-diabetic efficacy in menopausal diabetic women [Korec et al. Similarly. 2004] and its structurally similar derivative Kaempferol. Excessive conversion of glucose to sorbitol leads to several diabetic complications andinhibition of this enzyme aids in the protection of micro complications associated with diabetes.methyl-8prenylnaringenin were found to possess promising anti-hyperglycemic activity by decreasing glucose level of STZ. 1988] exhibit potent hypoglycemic activity in diabetic and alloxanised rats respectively. [1′′(R)-5. 2006.. flavonol glycoside. Anti-hyperglycemic Effect in Diabetic Rats It has been demonstrated that various flavonoids including chrysin and its derivatives. Apigenin-6-C-β-L-fucopyranoside and apigenin6-C-(2′′-O.. Hnatyszyn et al. 2006]. Several flavonoids known for their antioxidant potential have been found to be effective in the inhibition of aldose reductase. Aldose Reductase Inhibitory Activity Aldose reductase is an enzyme that catalyzes NAD(P)H-dependent conversion of glucose to sorbitol in polyol pathway of glucose metabolism. Brahmachari.... 1997. 1991.5-dihyroxy-6. a glycosylated flavonoid along with its Vanadium complex (kaempferol-3-neohesperidoside-VO(IV) complex) exhibits significant hypoglycemic effect in normal and alloxan-induced diabetic rats [Cazarolli et al. 2011].4-dihdroxyphenyl)2H-benzo-1.3-neohesperidoside. quercetin 3-O-α-Larabinopyranosyl-β-D-glucopyranoside along with the known flavonoid glycosides such as Complimentary Contributor Copy . Myrciacitrins isolated from Myrcia multiflora [Matsuda et al.1′′-trihydroxy-6.β -D-glucoside). Kaempferol-3. 2006 and Shukla et al. isoorientin isolated from Cecropia obtusifolia [Andrade-Cetto and Wiedenfeld. Coutareagenin (5-hydroxy-7-methoxy-4-(3..pyran-2-one).7dimethoxyflavone-3-O-β-D-xylopyranoside (xylopyranoside)..β -L-fucopyranoside were observed to stimulate glucoseinduced insulin secretion in hyperglycemic rats [Brahmachari. 2006a and 2006b..3′′. 2004].4′.3′. 1999. It has also been demonstrated that flavonoids can act as insulin secretagogues or insulin mimetics.7. (2002) demonstrated that the flavone constituents. Similarly.4′. Lakshmi. 1971. it has been reported that prenylated flavonols isolated from the roots of Dorstenia psilurus were found to exhibit glycosidase enzyme inhibitory activity against α-glucosidase.glycogen synthase kinase 3 (GSK 3) pathway and mitogen-activated protein kinase/extracellular signal regulated kinases (MEK) .β -L-fucopyranoside stimulated glycogen synthesis in rat soleus muscle through insulin signal transduction..6. Insulin Signaling Genistein derivatives significantly stimulated the uptake of glucose through adenosine monophosphate-activated kinase (AMPK). feruloylglucosides such as 6-hydroxyapigenin-7-O-(6-Oferuloyl)-β-D-glucopyranoside. Glycosidase Enzyme Inhibitory Activity The membrane-bound intestinal α-glucosidases hydrolyze oligosaccharides.β -D-glucopyranoside and the flavonoid glycosides... glucose transporter protein 4 (GLUT4) and glucose transporter protein 1 (GLUT1) pathway and also exhibited inhibition of protein tyrosine phosphatase 1B (PTP1B) in L6 myotubes. Shilpa 134 kaempferol 3-O-β-D-glucopyranoside exerted promising inhibition of porcine lens aldose reductase activity [Kim et al. MAPK. thereby exhibiting promising anti-diabetic activity [Lee et al.. 2004].7trihydroxyflavone (baicalein) from Scutellaria baicalensis showed rat intestinal α-glucosidase inhibitory activity [Brahmachari. Hydroxy flavonoids such as 6hydroxyapigenin (scutellarein). 1980. Complimentary Contributor Copy . Certain flavonoids and its derivatives have been reported to exhibit α-glucosidase inhibitory activity.6-hydroxyluteolin-7-O-(6-O-feruloyl)-β-D-glucopyranoside isolated from Origanum majorana and flavonoid 6-hydroxyluteolin and 5. p70s6k. 3′. and α-mannosidase [Kawabata et al. guaijaverin and desmanthin-1 exhibited potential aldose reductase inhibitory activity. Harborne and Williams. 1990.. as a therapeutic measure for diabetes. 1967 and Nishioka et al.6-hydroxyluteolin-7-O. Miyaichi et al. Matsuda et al. Ulubelen et al.B.7-trihydroxyflavone. 1998]. 2003. and reduces phosphoenolpyruvate carboxykinase gene expression through PI3K [Brahmachari. Ravn et al. 3′. luteolin. Ranganathan et al. engeletin.. 2009]. and PI3K activity.protein phosphatase-1 (PP-1) pathway. Sangeetha and K. N.. α-glucosidase inhibitors are in demand to reduce the impact of carbohydrates on blood sugar. luteolin 7-O. 2011].. Likewise. trisaccharides and disaccharides to glucose and other monosaccharides in the small intestine. 1980. 2007 and Lee et al. astilbin (dihydroflavonol glycosides). 1989.. Flavonoid apigenin-6-C. 6-hydroxyapigenin-7-O-β-D-glucopyranoside. isorhamnetin 3-O-β-D-glucoside also possesses significant inhibitory activity against rat lens aldose reductase (RLAR) in vitro [Wirasathien et al. 2011]. Hence. K. Epigallocatechin 3-gallate enhances tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1). Kaempferol-3neohesperidoside stimulated glycogen synthesis in rat soleus muscle through phosphatidylinositol-3-kinase (PI3K) . β-glucosidase. quercitrin. S. Harborne.β -D-glucopyranoside.. 2009].4′dihydroxyflavone. . other flavonoids that inhibit LDL oxidation are morin. Likewise.. 2006].2'-azobis-2-methyl-propanimidamide. Flavonoids have been found to be very effective in inhibiting the formation of advanced glycation products by acting as glycation inhibitors. lipid peroxides and oxysterols. fisetin. The flavonol catechin prevented plasma lipid peroxidation and also inhibited LDL oxidation induced by copper ions [Aviram and Fuhrman. the primary event in the inhibition of NAD(P)H oxidase induced Complimentary Contributor Copy .. 1998]. Glycation is the first step in the evolution of the sugar molecules through a complex series of very slow reactions in the body including Amadori reactions. inhibited the formation of aldehydes.. It also inhibited the consumption of β-carotene and lycopene in the presence of LDL oxidation but could not protect vitamin E from oxidation. Flavonol. and also been implicated in many age-related chronic diseases.Flavonoids as Antioxidant Therapy for Metabolic Disorders 135 Glycation Inhibitors Glycation is the process of covalent bonding of a protein or lipid molecule with a sugar molecule without the controlling action of an enzyme.B. quercetin. few more AGE inhibitors such as the dihydroflavonol glycosides [Wirasathien et al. 2006 and Yoo et al. resulting in reduced cell mediated oxidation by LDL [Rice-Evans and Packer. rutin. p-coumaric acid and isoflavan glabridin. and Maillard reactions which lead to the formation of AGEs. chelation of transition metal ions and protection of cells against oxidative damage by inhibiting xanthine oxidase. α-tocopherol and carotenoids from oxidation. 2008]. thereby impairing the functioning of biomolecules. Also. Flavonoids are suitable for protecting cell membrane from free radical induced oxidative damage. luteolin also inhibited copper induced LDL oxidation more effectively than kaempferol by chelating copper ions.3-dioxygenated flavanone (erigeroflavanone) isolated from Pueraria lobata and Erigeron annuus have also been reported [Kim et al. NAD(P)H oxidase or lipoxygenase. Schiff base reactions. ferulic. Flavonoids such as astragalin. Lipid Peroxidation Inhibitors Flavonoids serve as potent inhibitors of lipid peroxidation process by scavenging free radicals. isoflavone C-glucosides and the 2. 2009]. 3-O. Some AGEs are non-reactive whereas others are more reactive than the sugars they are derived from. gossypetin and hydroxy cinnamic acid derived phenolic acids like caffeic. quercetin. 4-O-methyl glabridin and two chalcones isoprenyl chalcone and isolipuritegenin. 2007] and two flavan-3-ol derivatives from Actinidia arguta showed inhibitory efficacy against AGEs [Jang et al. Luteolin 6-C-(6′′O-trans-caffeoylglucoside) from Phyllostachys nigra [Jung et al.dihydrochloride (AAPH) and copper induced LDL oxidation. Antioxidants isolated from licorice include isoflavans glabridin. 2007].. hispaglabridin A. It inhibited PKC required for p47 phosphorylation. 2004]. Licochalcone B and D from Glycyrrhiza inflata inhibited superoxide production in xanthine/xanthine oxidase system. by releasing highly oxidizing products such as H2O2. Glabridin inhibits 2. as they were both lipophilic and hydrophilic.. protecting LDL associated antioxidants. It also inhibited mitochondrial lipid peroxidation by Fe (III) ADP/NADH and protected red blood cells against oxidative haemolysis.β -D-glucopyranoside (isoquercetin) from the leaves of Eucommia ulmoides were found to be acting as glycation inhibitors [Kim et al. regeneration of vitamin E from oxidized α-tocopherol. however. Shilpa macrophage mediated oxidation of LDL. Flavonoids. influence many biological functions. There are no reports of any enzymes capable of splitting the bond present or secreted into the gut. activators of insulin signaling and inhibition of intestinal α -glucosidase enzyme. Since. Conclusion Metabolic disorders are an epidemic condition progressing rapidly in developing countries thus attracting concern. whereas procyanido lignanes are readily absorbed in mice. aldose reductase activity. are poorly metabolized by the intestinal microflora. epigallocatechin and gallic acid show an inhibition of LDL oxidation [Rice-Evans and Packer.The microorganisms in the colon hydrolyze glucuronides and sulphates. Flavonoids.136 B. The main factor associated with metabolic disorders such as diabetes or obesity is the oxidative stress involving surplus release of free radicals combined with a disturbed antioxidant status. Pharmacokinetics of Flavonoids Limited data is available on the amount of flavonoids absorbed by human. S. making them beneficial in a variety of human disorders [Di Carlo et al. Flavonoids which are metabolized by intestinal bacteria are converted to hormone-like compounds. Quercetin is not absorbed in human and rutin is poorly absorbed. Overall. flavonoids are metabolized primarily in liver [Hackett. therapeutic strategies aimed to counter them should be multifunctional. the metabolic disorders are either a consequence or an initiator of oxidative stress. As these bioflavonoids are multifunctional (antioxidant and anti-diabetic/antiobesity) and represent an unparalleled source of molecular diversity. Sangeetha and K. which then most probably enable absorption of the liberated aglycones. possessing both antioxidant and anti-diabetic/ anti-obesity activities. Among the several phytoactive constituents. studies conducted on animal models have shown that flavonoids bound to p-glycosides are non-absorbable. nevertheless intestinal wall and kidney are considered as the secondary sites of metabolism. whereas only aglycones. the pharmacokinetics depends on the origin of flavonoids. lipid peroxidation and glycation. therapeutic approaches using natural sources mainly from plants have increased. epigallocatechin. It has been observed that flavonoids in citrus fruits. epicatechin gallate. 1999]. Other flavonoids like epicatechin. After absorption.. bioactive principle based treatment approaches have gained greater significance because of their remarkable beneficial effects especially in their multifunctional activities. polyphenols are the front runners of antioxidant activity. 1986]. In recent times. Lakshmi. are naturally occurring phenolic compounds with a broad range of biological activities such as anti-hyperglycemic. their therapeutic role as drug candidates for the treatment of metabolic disorders could be defined in relation to the drug discovery process. It has been observed that only in the colon. Hence. K. without a sugar molecule can pass through the gut wall. 2006]. hydrolysis of l3-glycosidic bonds occurs by micro-organisms which degrade dietary flavonoids. N. once absorbed. Complimentary Contributor Copy . 1605-1616. AC. Block. 1998. antioxidants and saliva: A Review. Polyphenolic flavonoids inhibit macrophage-mediated oxidation of LDL and attenuate atherogenesis. N. 274– 285. 145-149. M. Brahmachari. 2006a. 3248S–3254S. Barth. 133.. Wang.. Caan. M. Blatt. J. Morrow. Siassi. Joshua. 2006b. 2004. S.. Trivandrum: Research Signpost. M. F. S. Rauh. 63-66. 10. ISBN10: 1842654500. Horbach. Negri. 196. G. G. Al-Rawi N H. Bešlo. CE. D. D. 2001. JL. Ed. 61. J. B. Diabetes. D. 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Obesity has become one of the most important avoidable risk factors for morbidity and mortality. antioxidants are capable of reversing these pathways and. Studies have shown that obesity promotes increased plasma lipid peroxidation. especially flavones. a ratio of height to weight) greater than 30 whereas a healthy BMI should be 18. anti-diabetic.edu. Therefore. anthocyanins. However. Inc. diabetes and heart diseases. * Corresponding author: vgulati@swin. more than 1. obesity is defined as abnormal or excessive fat accumulation that may impair health. At least 2. Hawthorn. Chapter 5 Use of Antioxidants to Control Obesity and Promote Weight Loss Vandana Gulati*.8 million people die each year as a result of being overweight or obese. Flavonoids. including oxidation of cell membranes and proteins in conjunction with disturbances of cellular redox homeostasis. Obesity is the leading cause of death which can be prevented by diet and lifestyle modifications. flavonols. Australia Abstract The prevalence of overweight and obese individuals is increasing at an alarming rate across the globe. flavanols (catechins). Antioxidants are widely present in the plant kingdom and are known to prevent various disorders.In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers. The associated risks with obesity are cancer. Victoria. are considered effective antioxidants associated with other pharmacological properties such as anti-cancer. can be helpful in preventing the deleterious effects caused by reactive oxygen species.5 to 24. Palombo Environment and Biotechnology Centre. In 2008. it is known that increased production of reactive oxygen species (ROS) is associated with cellular damage. Although the exact link between obesity and its associated risks is not clear.4 billion adults were overweight and more than half a billion were obese. Obesity also increases the mechanical and metabolic loads on the myocardium.au. isoflavones and chalcones.9. According to the World Health Organization. thus increasing myocardial oxygen consumption. in fact. Free radicals are known to be involved in a number of human pathologies including atherosclerosis. rutin. the lack of long-term studies and reports of some undesirable effects. which means to be ‘stout. lifestyle changes affecting dietary habits and physical activity are essential to promote weight loss (Moro et al. EGCG. pycnogenol. 2000). headache. This review will focus on recent examples of antioxidant nutrients. and impaired glucose intake in muscle and fat related to obesity. and adequate quantities of fibers. esculetin. Many studies have indicated that phenolic compounds such as o-coumaric acid. Obesity was once considered a problem of high-income nations. an inactive lifestyle and high caloric intake lead to obesity. CoQ10. genistein. Several reports indicate that low-carbohydrate diets are effective in producing rapid weight loss and beneficial metabolic changes. dietary factors having potential antioxidant effect would offer an effective and beneficial strategy to reduce oxidative stress and its related complications (Gaillet et al. lowglycemic index carbohydrates (40%). Keywords: Medicinal plants. overweightness and obesity are the fifth leading risk for death. 2012). anti-inflammatory and anti-HIV activities. Globally. traditional medicines and foods that have been validated by scientific evaluation for controlling obesity or promoting weight loss. Pankaj Gulati and Enzo A. The excess energy is stored in adipose tissues. antioxidant. isoflavones. increases healthcare-associated costs and increases the risk of death due to several associated disorders. environmental and social factors. It has also been reported that obesity is a strong independent predictor of systemic oxidative stress which may be the source of several metabolic dysfunctions such as inflammation. Genetic predisposition. procyanidin. carnitine. hypertension. and tea catechins. more than 40 million children under the age of five were overweight. A strong link has been found between increased oxidative stress in accumulated fat and the pathogenic mechanism of obesity and obesity-associated metabolic disorder. at least 2. make it difficult to recommend these diets as a healthy option for weight loss (Strychar 2006). anti-obesity and polyphenols Introduction The word ‘obese’ originates from the Latin word obesus. but it is now on the rise in low. especially. high monounsaturated and omega-3 fatty acids. Body mass index (BMI) is a simple index of weight-for-height that is commonly used to classify overweightness and obesity in adults. constipation and. calcium Complimentary Contributor Copy . Palombo anti-thrombotic. difficulties in maintaining weight loss after the diet. The balance between energy intake and expenditure is influenced by a complex interplay of genetic. Progression to obesity may develop to a stage where some signals trigger cellular and biochemical events that lead to insulin resistance and metabolic syndrome (Achike et al.and middle-income countries. Therefore. According to World Health Organisation data. Therefore. However. such as increased levels of ketone bodies. More than 30 million overweight children are living in developing countries and 10 million in developed countries (WHO 2013). 2011). A review of the scientific evidence stated that an ideal diet may be the one containing moderate protein content (30%). inositol and various herbs are effective in reducing obesity and promoting weight loss. Excess body fat reduces the quality of life.8 million adults die each year as a result of being overweight or obese.’ Obesity develops when energy intake exceeds expenditure. In 2011. choline. high losses of body water. fat or plump.144 Vandana Gulati. Adipocyte life-cycle: Mesenchymal stem cells are the precursors of several different types of cells. and they can mobilize and oxidize lipid when energy output exceeds input. they begin to change shape and undergo cell division known as clonal expansion. 2008). esculetin. Mature adipocytes can continue storing lipid when energy intake exceeds output. modified from Rayalam et al (Rayalam et al. weight maintenance and treatment of metabolic syndrome (Abete et al. Rayalam et al.Use of Antioxidants to Control Obesity and Promote Weight Loss 145 and antioxidant minerals. gallic acid. It is characterized at the cellular level by an increase in the number and size of adipocytes differentiated from preadipocytes in adipose tissue (Hsu et al. Complimentary Contributor Copy . followed by initiation of the genetic program that allows them to synthesize and store triglycerides. Adipocytes are the primary site of energy storage and these accumulate triacylglycerol that results from an energy imbalance (Figure 1). It has been reported that adipocyte dysfunction plays an important role in the development of obesity which occurs when adipocytes accumulate a large amount of fat and become enlarged. genistein. osteoblasts and preadipocytes. Since adherence to healthy dietary patterns can be difficult. Once preadipocytes are triggered to mature. Figure 1. quercetin and naringenin suppress the adipocyte differentiation process and induce apoptosis in 3T3-L1 adipocytes through activation of AMP-activated protein kinase (Figure 2) (Lin et al. Mature adipocytes can also undergo apoptotic cell death under certain conditions. 2010). meal replacement and dietary supplements should be considered as effective strategies for weight loss. including myoblasts. chondroblasts. 2005. Many studies have shown that polyphenolic antioxidants such as EGCG. 2008). 2008). resveratrol and quercetin inhibit preadipocyte proliferation and EGCG. such as vitamins C and E. inclusion of antioxidants and diets rich in fibre would be effective. Adipose tissue has the capacity to directly trigger endothelial dysfunction by secreting a variety of molecules. flavonoids. modified from Rayalam et al (Rayalam et al. a diet high in marine omega-3 fatty acids reduced adipocyte hypertrophy (de Ferranti et al. such as pro-inflammatory cytokines and leptin. 2004). They also trigger lipolysis and induce apoptosis in mature adipocytes. Randomized trials have shown that specific dietary factors impact numerous established and novel cardiovascular and obesity-related risk factors. and polyphenols. which may produce beneficial actions. 2008). in rodent models of obesity. carotenoids. Also. Pankaj Gulati and Enzo A. Fruits are often considered as healthy foods because they contain a variety of compounds with antioxidant capacity. which will further decrease the risk of coronary heart disease. it can be effective for both prevention and reversal of adiposity and its associated health consequences. induce preadipocyte apoptosis and stimulate lipolysis in mature adipocytes. and it can inhibit lipid accumulation in maturing preadipocytes. which can mediate the release of C-reactive protein (CRP) from the liver and also impair endothelial function (Brook et al. Effect of selected natural compounds on the different stages of the adipocyte life-cycle: Genistein. 2008).146 Vandana Gulati. EGCG induces apoptosis in both preadipocytes and mature adipocytes. quercetin and c-lipoic acid suppress lipid accumulation in maturing preadipocytes. If reduction in caloric intake is properly maintained. Palombo Figure 2. Quercetin also has multiple effects: it can inhibit preadipocyte proliferation. Antioxidant enriched diets could be applied in nutritional therapy of obesity by increasing the health benefits related to weight loss and protection against a free radical attack. The ability of two hypo-caloric diets with different fruit contents Complimentary Contributor Copy . Ajoene + CLA are especially potent in inducing apoptosis in mature adipocytes. Diets focused on particular macronutrient intakes such as very low fat diet. some of these dietary factors may be involved in reversing adipocyte changes. fat mass. Over 250 genetic markers have been described in association with obesity-related variables in humans (e. BMI. Instead. The hypothalamus may influence caloric balance due to actions on feeding through effects on the neuroendocrine system involved with appetite and behavior. insulin and sex steroids. cortisol. Endocrine and Metabolic Factors: Both endocrine and metabolic factors contribute to obesity. Studies have also reported that obese patients are sleepier during the day and more likely to experience disturbed sleep at night compared with normal weight controls. Psychological Factors: A few causative personality characteristics are related to obesity and research evidence strongly suggests that obesity is not a unitary syndrome. Circadian Rhythm: A number of studies have provided support for a link between the altered sleep/wake patterns associated with 24-hour lifestyle and obesity. 2011). The increase in obesity can usually be related to the type of food consumed. many obese patients decrease their amount of physical activity. waist-to-hip ratio. resting metabolic rate.. Factors Affecting Obesity Genetic and Environmental Factors: 40% to 80% of the variance of BMI can be attributed to genetic factors. 2011). energy expenditure after overeating. The energy expended on walking at 3 miles per hour is only 15. it appears to be the end result of a complex interaction within and between both physical and psychological factors (George et al.7 kcal/min) and. through effects on energy expenditure and hormone secretion through effects on secretion of growth hormone. Numerous environmental influences also promote adipocyte proliferation and differentiation. during pregnancy or during depressive episodes and are unable to re-establish their former eating habits.Use of Antioxidants to Control Obesity and Promote Weight Loss 147 to improve antioxidant biomarkers related to lipid peroxidation in fifteen obese women was estimated and a significant decrease in Low-density lipoprotein (LDL) cholesterol levels in obese women was observed who followed the high fruit diet (Crujeiras et al. and percent fat mass) (George et al. thyroid-related hormones.5 kJ/min (3. lipoprotein lipase activity and basal rates of lipolysis. Food intake: Some people tend to eat more during periods of heavy exercise. On the other hand. skin-fold thickness. increasing exercise plays only a small part in losing weight (George et al. Thus. therefore. such as increased intake of sugar and fat (George et al. 2011). Obese patients tend to expend more energy during physical activity as they have a larger mass to move. decreased leptin/insulin activity in the central nervous system (CNS) may promote obesity through increased caloric balance and weight gain (Bays 2004). Energy expenditure and thermogenesis: Basal metabolic rate (BMR) in obese subjects is higher than in lean subjects. It is estimated that heredity accounts for factors relevant to energy balance such as body fat distribution. Complimentary Contributor Copy . which is not surprising since obesity is associated with an increase in lean body mass. 2007).g. 2011). These studies suggest that the circadian clock within the adipocyte may also be a potential regulator of triglyceride metabolism and that impairment of this molecular mechanism may contribute towards adiposity (Bray et al. Various disease states in humans result from alterations in circadian patterns of metabolism. 2006). 148 Vandana Gulati, Pankaj Gulati and Enzo A. Palombo Control of Appetite: Appetite is the desire to eat and this usually initiates food intake. Following a meal, cholecystokinin (CCK), bombesin, glucagons-like peptide 1 (GLP1), enterostatin and somatostatin are released from the small intestine and glucagons and insulin from the pancreas. All of these hormones have been implicated in the control of satiety and, therefore, are considered as the most promising antiobesity targets (Bays 2004). The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. Various anti-obesity drugs were launched into the market but withdrawn due to unacceptable side effects (Table 1). A recent review by Rodgers concluded that “the history of anti-obesity drug development is far from glorious, with transient magic bullets and only a handful of agents currently licensed for clinical use” (Rodgers et al. 2010). Table 1. Currently available anti-obesity drugs* Drug name Mechanism of Action Side effects Dextroamphetamine Appetite suppressant Tachycardia and hypertension Sibutramine Noradrenaline and 5-HT uptake inhibitor Increase in blood pressure and heart rate Structure NH2 N Cl Orlistat Lipase inhibitor O Fecal urgency, oily stools, abdominal pain, flatus H3C O (H2C)10 CH3 O H3C H H H O H CH3 NH O H * Reference: Bays (2004). The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions and are influenced by social and psychological factors which limit the effectiveness of pharmacological interventions. The drugs which target metabolic tissue pathways, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none of them has yet reached clinical Complimentary Contributor Copy Use of Antioxidants to Control Obesity and Promote Weight Loss 149 development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide Y Y (PY Y) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities (Rodgers et al. 2012). The pharmacological management of obesity is at an exciting crossroads. For agents that meet preliminary requirements for selectivity of action and potential safety profile, extensive real-world testing is required by regulators for efficacy in terms of weight loss as well as long-term benefits for prevention and treatment. Successful discovery and development of potent and safe drugs for the prevention and treatment of obesity will probably require polytherapeutic strategies (Halford et al. 2010). Current treatments for obesity have not been successful in maintaining long-term weight loss, demonstrating the urgent need for new insight into mechanisms that may lead to obesity and altered metabolism. Therefore, more emphasis should be given on nutrients and botanicals showing antioxidant effects and they may provide a safe and more effective remedy for obesity. Nutritional Therapies in Weight Management Selenium (Se): Selenium is a cofactor for glutathione peroxidase which is required for the reduction of peroxides thus helps in reducing oxidative stress (Lubos et al. 2011). A randomized trial was conducted with 37 morbidly obese women. The participants consumed one Brazil nut, which is a good source of selenium (providing approximately 290 mg of Se a day), for 8 weeks. Blood tests showed that consumption of one Brazil nut daily effectively increased Se status and resulted in increased glutathione peroxidase activity in obese women (Cominetti et al. 2011). Calcium (Ca): Dietary Ca appears to play a pivotal role in the regulation of energy metabolism and obesity risk. Zemel and co-workers observed that patients in the highest quartile of adiposity were negatively associated with Ca and dairy product intake (Zemel 2004). A more recent nutritional intervention trial also demonstrated that higher low-fat dairy intake among overweight type-2 diabetic patients on isocaloric-restricted regimens enhanced the weight-loss process. The proposed mechanisms are primarily mediated by circulating calcitriol. The increased calcitriol produced in response to low-Ca diets stimulates adipocyte Ca influx and consequently, promotes adiposity, while higher Ca diets inhibit lipogenesis, stimulate lipolysis, lipid oxidation and thermogenesis and inhibit diet-induced obesity in mice. Moreover, a published meta-analysis concluded that dietary Ca has the potential to increase fecal fat excretion, which could be relevant for preventing weight (re)gain. However, some investigators did not find dietary Ca enrichment to have beneficial effects during a weight-loss process. Thus, the effect of Ca on weight loss continues to be unclear, indicating that more long-term studies are required (Abete et al. 2010). Another study also investigated the effect of Ca and vitamin D supplemented orange juice on weight loss and reduction of visceral adipose tissue in overweight and obese adults. Two parallel, double-blind, placebo-controlled trials were conducted with either regular or reduced-energy (lite) orange juice for 16-weeks with 171 participants. The treatment groups Complimentary Contributor Copy 150 Vandana Gulati, Pankaj Gulati and Enzo A. Palombo consumed three 240-mL glasses of Orange juice (regular or lite) fortified with 350 mg Ca and 100 IU vitamin D per serving, and the control groups consumed either unfortified regular or lite orange juice. Computed tomography scans of visceral adipose tissue and subcutaneous adipose tissue were performed. The results suggested that, in overweight and obese adults, a moderate reduction in energy intake and supplementation of Ca and vitamin D in juice beverages led to a beneficial reduction in intra-abdominal fat (Rosenblum et al. 2012). Magnesium (Mg): Mg is a cofactor for more than 300 enzymes involved in bioenergetics, protein phosphorylation, glutathione production and synthesis of cyclic adenosine monophosphate (cAMP). It also affects the structure and function of nucleic acids, cell membranes and ion channels. The Mg content of food is greatly reduced by processing. Strong epidemiologic and mechanistic data support a role for Mg deficiency in the genesis of insulin resistance and metabolic syndrome. Deficiency of this mineral contributes to the development of the metabolic syndrome such as obesity, diabetes, diabetic vascular complications, dyslipidemia, hypertension and insulin resistance. The mechanism of this effect in obese humans is multifactorial and involves reduced tyrosine kinase activity at the insulin receptor, modulation of intracellular Ca activity and increased circulating tumour necrosis factor (TNF)-α levels (Cave et al. 2008). Zinc (Zn): Zn is a potent antioxidant and has an important role in immune defence functions. The expression of multiple zinc transporter proteins in adipose tissue is altered in obesity, which varies from one region to another (subcutaneous to intra-abdominal adipose tissue). Zn status modulates obesity and metabolic syndrome. In a large clinical study, both low consumption of dietary Zn and low serum Zn levels were associated with an increased prevalence of diabetes, hypertension, hypercholesterolemia and coronary artery disease. Animal studies have demonstrated potential mechanisms and implied a plausible therapeutic role for Zn in obesity. In rats fed with high fructose diet along with zinc supplementation showed improved insulin sensitivity and antioxidant status. Also, due to its antioxidant action, it provides a protective effect against ischemia/reperfusion injury, which could be relevant for critically ill obese patients (Cave et al. 2008). Low Zn status had been observed in several obese and diabetic patients (Suliburska et al. 2012). Another study in 2009 suggested that 20 mg Zn given daily to 60 obese children in a randomized, blinded, crossover trial resulted in significant reductions in fasting plasma glucose levels and fasting insulin levels. The authors concluded that, in addition to lifestyle modifications, Zn supplementation might be a useful and safe additional intervention for improving cardio metabolic risk factors related to childhood obesity (Bruney 2011). Vitamin A: Retinoic acid decreases lipid accumulation, glycerol 3-phosphate dehydrogenase (GPDH) activity and peroxisome proliferator-activated receptor (PPAR)γ expression. In one study, feeding a high dose of retinol (129 mg/kg a day) to obese rats reduced adipose tissue mass and body weight. The anti-adipogenic effects are exerted through a number of mechanisms; retinoic acid blocks C/EBPβ (CCAAT-enhancer-binding protein) mediated induction of downstream genes, notably PPARγ, prevents entry of the preadipocytes into the growth-arrested phase and interacts with activators of PPARγ through retinoic acid receptors (Bonet et al. 2003). Vitamin D: The status of vitamin D is strongly associated with variation in subcutaneous and visceral adiposity. In mouse epididymal fat tissue cultures, 1,25(OH)2D3 markedly suppressed the expression of PPARγ and C/EBPβ and in 3T3-L1 preadipocytes, ≥0.5 nM Complimentary Contributor Copy Use of Antioxidants to Control Obesity and Promote Weight Loss 151 1,25(OH)2D3 decreased viability and lipid accumulation and induced apoptosis (Andersen et al. 2010). Multivitamins and multiminerals: The effects of supplementation with multivitamin and multimineral on adiposity, energy expenditure and lipid profiles in obese Chinese women have been evaluated. In a 26-week, randomized, double-blind, placebo-controlled intervention study, 96 obese Chinese women (average BMI = 28 kg m2) participated. The trial was randomized into three groups, receiving either one tablet of multivitamin and mineral supplement (MMS), or Ca 162 mg or identical placebo daily during the study period. A total of 87 participants completed the study. After 26 weeks, results suggested that, in obese individuals, multivitamin and mineral supplementation could reduce body weight and fatness and improve serum lipid profiles which may be through increased energy expenditure and fat oxidation (Li et al. 2010). Arginine: Arginine is a non-essential amino acid mainly required for cell division, immune defence and removing ammonia from the body. It also regulates gene expression, mitochondrial biogenesis, brown adipose tissue (BAT) development and cellular signalling transduction pathways (Jobgen et al. 2009). A 21 day, randomized placebo-controlled trial on 33 hospitalized middle-aged, obese (BMI = 39.1 ± 0.5 kg/m2) participants with dietcontrolled Type-2 diabetes mellitus was conducted. Each patient received a low-calorie diet (1,000 kcal/day) and a regular exercise-training program (45 min twice a day for 5 days/week) during the study. They were randomized to 8.3 g arginine/day (approximately 80 mg/kg body weight per day) or placebo. Both groups of participants exhibited reductions in body weight, fat mass, waist circumference and circulating levels of glucose, fructosamine and insulin. Moreover, increases in antioxidant capacity and circulating levels of adiponectin were observed. Over the 3-week period of study, fat-free mass was maintained in the arginine group but reduced by 1.6 kg in the placebo group. Also, arginine supplementation to obese participants promoted fat reduction and spared lean body mass during weight loss (McKnight et al. 2010). Other studies with both animals and humans have also indicated that arginine supplementation may be a novel therapy for obesity and metabolic syndrome, acting via decreased plasma levels of glucose, homocysteine, fatty acids, dimethyl-arginines, triglycerides with concurrent improvement in insulin sensitivity. Alpha lipoic acid (ALA): Lipoic acid is an organo-sulfur compound with good antioxidant activity. 1127 obese and pre-obese people (445 men and 682 women, 18-60 years old) were screened in a study. According to the BMI, 53% were obese, and 43% were preobese. All were treated for 4 months with 800 mg/day of lipoic acid (ALA). In the pre-obese group, significant reductions of weight (8%, in both genders), BMI (2 points), blood pressure and abdominal circumference (female 6 cm, male 7 cm) were observed. In the obese group, significant reductions of weight (9%, in both gender), BMI (female 3 point, male 4 point), blood pressure and abdominal circumference (female 9 cm, male 11 cm) were seen (Carbonelli et al. 2010). Conjugated linoleic Acid (CLA): The potential mechanisms responsible for the antiobesity properties of CLA isomer in rodent models include decreased energy intake by suppressing appetite, increased energy expenditure, decreased lipogenesis and adipogenesis, increased lipolysis and apoptosis. Several studies have also shown that CLA regulates both leptin and adiponectin (Prieto-Hontoria et al. 2011). Complimentary Contributor Copy 152 Vandana Gulati, Pankaj Gulati and Enzo A. Palombo Omega-3 fatty acids: Omega-3 poly-unsaturated fatty acids (PUFAs), specifically the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) components, are very helpful in management of obesity as they reduce the inflammatory response through numerous distinct mechanisms. Studies have shown that they decrease activation and release of TNF-α, activate PPAR-γ and PPAR-α, decrease serum triglycerides levels and inflammatory prostaglandins and alter adiponectin levels. In a prospective randomized trial, participants with non-alcoholic fatty liver disease (NAFLD) who received 1 g/d of omega-3 PUFA for 12 months had significantly decreased serum levels of alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase and triglycerides compared with placebo controls (Cave et al. 2008). Role of Plants and Bioactive Compounds in Weight Loss Grape seed extract: Grape seed extract from Vitis vinifera was administered to obese rats (induced by high fat diet) for 45 days and the findings suggested that grape seed extract was a safe anti-obesity and cardio protective agent. It may also play a role in inflammatory damaging conditions such as stroke (Charradi et al. 2011). Curcumin and resveratrol combination: Curcumin (Figure 3) exhibits multiple anticarcinogenic effects and its role in chemoprevention is being assessed in clinical trials. It has also been shown to be protective in rat models of diverse diseases such as atherosclerosis, ischemia reperfusion injury, cystic fibrosis and diabetes mellitus (Sharma et al. 2006). Curcumin, resveratrol and their combination (3% suspended solution) were found to significantly suppress increased body weight, showing anti-obesity action in rats fed with a high fat diet for eight weeks. Decreases in plasma glucose and insulin levels were observed. This combination also lowered fat accumulation, suppressed triacylglycerol, total cholesterol, free fatty acids and normalized the activity of antioxidant enzymes in the liver (Hussein et al. 2013). O O HO OH OCH3 OCH3 Figure 3. Curcumin. Resveratrol: Resveratrol is a naturally occurring phytoalexin derived from red wines and grape juice (Figure 4) induces cell apoptosis in 3T3-L1 adipocytes by increasing the expression of Sirt1, Cytochrome c, cleaved Caspase 9 and cleaved Caspase 3. A combined Complimentary Contributor Copy HCA also inhibits adenosine triphosphate citrate lyase and has been used in the treatment of obesity. Hydroxycitric acid (HCA): The bioactive compound HCA. 1995). At 16 weeks. adipogenesis and lipolysis of 3T3-L1 cells. Guggulsterone.53. OH HO OH Figure 4. All participants were on a restricted diet (1200-1600 cals/day) and completed a brisk walk for 30 minutes daily. subcutaneous and Complimentary Contributor Copy .0 g/day Guggulu (Medohar) for 30 days or no drug.Use of Antioxidants to Control Obesity and Promote Weight Loss 153 treatment of resveratrol. (Figure 6) isolated from the dried fruit rind of Garcinia cambogia. A trial was conducted with 58 adult obese participants given either 1. genistein and quercetin enhanced apoptosis in pre. The participants included were aged 20-65 years with a visceral fat area > 90 cm2.and lipid-filled mature murine adipocytes. Further. A double-blind. The mean weight reduction in participants was higher in the Guggulu group without any adverse effects (Bhatt et al. randomized. cambogia extract (containing 100 mg HCA/day) on visceral fat. Resveratrol. 2012). The effect of guggulsterone has been determined on apoptosis. along with the micronutrient niacin-bound chromium provided safe weight loss in adults (Bruney 2011). Forty-four participants were randomized at baseline and 39 completed the study. a combination of resveratrol and genistein has a stronger effect on induction of adipocyte apoptosis (Zhang et al. Guggulsterones: Guugulsterones (Figure 5) are steroidal compounds extracted from Commiphora myrrh. H O O Figure 5. Results showed that guggulsterone isomers exert anti-obesity effects by inducing apoptosis and lipolysis in mature adipocytes (Shah et al. the Garcinia group had significantly reduced visceral. placebo-controlled study has investigated the effects of G. 2012). Therefore. Saper 2004). Based on this. Fifty men and women ingested 1 gm of Caralluma extract per day for 60 days. Pankaj Gulati and Enzo A. glucose. Compared to placebo. triglyceride. products containing the French white bean. improved glucose intolerance. have been widely marketed as weight loss aids. extracted from Hoodia pilifera and Hoodia gordonii was also tested clinically where it showed positive results in suppressing appetite and reduced body weight in obese individuals. guarana. placebo-controlled clinical study in 2007 included 60 slightly overweight people. identified as P57. 2012).25–50 mg/kg) resulted in decreased food consumption as compared to control (fenfluramine) and the reduction in food intake induced by Hoodia compounds was greater (Gooda Sahib et al. has shown be anti-obesity activity. yerba maté) for weight loss. An oral dose (6. the results indicated that Phaseolus treatment led to a significantly greater reduction of body weight and improvement of lean/fat ratio as compared to placebo (Obiro et al. No severe adverse or rebound effects were observed at any time in the test period.g. Phaseolus vulgaris: White kidney beans inhibit carbohydrate hydrolysing enzymes. The participants were given either placebo or a Phaseolus extract once daily 30 minutes prior to a main meal rich in carbohydrates. Over the next 30 days of the study. resulting in flatulence. decreased triglycerides and increased high-density lipoprotein cholesterol in high fat diet fed mice. Ephedra sinica reduced weight gain and epididymal fat accumulation. The compound.. this study suggested that Garcinia may be useful for the prevention and reduction of accumulation of visceral fat (Hayamizu et al. Hydroxycitric acid. Palombo total fat areas compared with the placebo group. Ephedra alkaloids are commonly combined with caffeine or botanical sources of caffeine (e. O HO OH O O OH HO OH Figure 6. Caralluma fimbriata: Caralluma. 2012). A double-blind. 2008). Gene expression Complimentary Contributor Copy . Hoodia pilifera: A novel compound from South African succulent plants of the Hoodia family has been reported to reduce appetite in animals. 2003). Feeding of the extract also resulted in a decrease in body weight.154 Vandana Gulati. hip circumference and body fat in overweight individuals (Gooda Sahib et al. A recent meta-analysis of clinical trials showed a weight loss of 0. 2006). an edible cactus used by tribal Indians to suppress hunger and increase endurance. BMI.9 kg per month for Ephedra-containing supplements compared with placebo (Robert B. fasting insulin and leptin levels in obese and overweight women (Hackman et al. the extract appeared to suppress appetite and significantly reduce waist circumference. Phaseolus vulgaris. Ephedra sinica: Ephedra extract induced significant decrease in serum cholesterol. placebocontrolled trial on 72 obese or overweight participants. both the saponin compounds were significantly able to suppress blood triacylglycerols. dikanut or African mango. triglycerides and glucose concentrations. RK stimulated the metabolism of white and brown adipose tissues and inhibited small intestinal absorption of dietary fat by suppressing pancreatic lipase activity. LDL cholesterol and fasting blood glucose level) were taken at baseline and at 4. RK might exert its anti-obesity effect via an increase of norepinephrine-induced lipolysis in white adipocytes and by enhancement of thermogenesis in brown adipose tissue (Morimoto et al. Capsules containing the placebo or active formulations were administered twice daily before meals without the involvement of major dietary changes or exercises. total plasma cholesterol. Raspberry ketones (RK): These major aromatic compounds of raspberries (Figure 7) were tested to investigate their effect on obesity using in vivo experiments. thereby providing a mechanism for weight loss via reduced oxidative stress. or 2% RK for 10 weeks. RK prevented and improved obesity and fatty liver. Liver triglyceride content was also reduced by more than 40% in the banaba water extract-treated mice (Klein et al. Due to the presence of various bioactive compounds such as flavonoids. As an agent effective in preventing both fat. When Sprague-Dawley rats were fed with high fat diet. Irvingia gabonensis: This plant is commonly known as bush mango. suggesting it may be useful in the management of obesity and its related complications (Oben et al. Therefore. 2012). also known as banaba water extract. this plant possesses strong antioxidant. 2005). dietary fat and carbohydrate blocking (Mishra et al. Lagerstroemia speciosa: Food containing 5% Lagerstroemia.and sugar-induced obesity. Therefore. 2008). Dioscorea nipponica: Methanol extract of Dioscorea nipponica showed potent inhibitory activity against pancreatic lipase enzyme due to the saponins dioscine and diosgenin present in this plant. steroidal saponins and polysaccharides. 2003). was used to feed female obese mice and a significant reduction in body weight was observed as compared with control mice fed with a regular diet. it may reduce obesity and hyperglycemia (Song et al. 2007).5. Complimentary Contributor Copy . 8 and 10 weeks.Use of Antioxidants to Control Obesity and Promote Weight Loss 155 analysis revealed that Ephedra sinica upregulated the expression of adiponectin and PPAR-α and downregulated the expression of TNF-α. double-blind. Mice were fed a high fat diet including 0. The high soluble fibre content lowers plasma cholesterol. gained less body weight and adipose tissue compared to controls in an eight week experimental study (Kwon et al. The combination resulted in larger reductions in these measurements. Anthropomorphic and serological measurements (body weight. Cissus quadrangularis: This plant helps in fighting obesity and symptoms of metabolic syndrome due to the presence of flavonoids and indanes. 1. as well as phytosterols and ketosteroids which have shown promise as powerful and efficient antioxidants. waist size. Asparagus officinalis: Asparagus is consumed as a healthy and nutritious vegetable in many parts of the world. body fat. The results indicated that RK prevented the high fat diet-induced elevations in body weight and the weights of the liver and visceral adipose tissues. 2010). The glycoproteins in the seeds seem to inhibit hydrolase enzymes by blocking the active sites or altering enzyme configuration. they also significantly increased norepinephrine-induced lipolysis associated with the translocation of hormone-sensitive lipase from the cytosol to lipid droplets in rat epididymal fat cells. A combination of Irvingia gabonensis and Cissus quadrangularis was studied for 10 weeks in a randomized. They also appear efficient for lipase and amylase inhibition. O HO Figure 7. furanocoumarins. antitumour. anthelmintic. Murraya koenigii: Murraya koenigii. serum high-density lipoprotein cholesterol levels were evidently increased. hepatoprotective. hypolipidaemic and hypoglycaemic activity (Gautam et al. extracts of Nigella sativa seeds showed significant reduction in body weight. fasting blood sugar and serum lipids were observed (Qidwai et al. Ethanolic and aqueous extracts of Asparagus officinalis significantly decreased body weight gain. Plerin. 2010).a novel extract of saffron stigma) supplementation on body weight changes over an eight week period in healthy. antifungal. The dichloromethane and ethyl acetate extracts of Murraya koenigii leaves significantly reduced the body weight gain. anti-inflammatory. The enrolled subjects consumed 1 capsule of Satiereal (containing 176. Satiereal caused a Complimentary Contributor Copy . Saffron reduced snacking and enhanced satiety through its moodimproving effect. 2013). both extracts dramatically decreased the activities of alanine and aspartate transaminases in serum with improvements in superoxide dismutase and total antioxidant capacity. digestive. plasma total cholesterol and triglyceride levels when given orally at a dose of 300 mg/kg/day to the high fat diet induced obese rats for two weeks. flavonoids. Asparagus has strong hypolipidaemic and hepatoprotective actions and would be a helpful supplement for weight loss (Zhu et al. 2009). The aromatic leaves are considered as a tonic. Reductions in body–mass index. commonly known as ‘Curry leaves’ is native to India and traditionally used as a spice for its characteristic flavour and aroma. analgesic. Moreover.156 Vandana Gulati. mahanimbine (Birari et al. The leaves contain carbazole alkaloids. Favourable results were reported in another randomized double blind clinical trial using Nigella sativa seeds in capsules. mildly overweight women. 2004). blood pressure. France . Raspberry ketone.5 mg of extract) per day (n = 31) or a matching placebo (n = 29) with no restrictions on the caloric intake during the study. Nigella sativa: In a randomized double blind clinical trial in fifty male obese subjects. and appetizer. Crocus sativa: A randomized. serum total cholesterol and serum low-density lipoprotein cholesterol in hyperlipidaemic mice when administered at a daily dose of 200 mg/kg for eight weeks. Pankaj Gulati and Enzo A. double-blind study evaluated the efficacy of Satiereal (Inoreal Ltd. waist–hip ratio. being widely used in Indian cookery for flavouring food stuffs. 2010). terpenoids and tannins and have shown strong hypolipidemic activity and have been indicated for the treatment of the mild form of diabetes. placebo-controlled. The observed antiobesity and antihyperlipidemic activities of these extracts are correlated with the carbazole alkaloids and a bioactive compound. Therefore. and thus contributed to weight loss. Palombo immunoprotective. waist circumference and triglycerides (Ranjbar et al. Also. or 50 mg/kg was given orally for ten weeks.Use of Antioxidants to Control Obesity and Promote Weight Loss 157 significantly greater body weight reduction than placebo and the mean snacking frequency was also significantly decreased. 60. in overweight subjects for twelve weeks.4 g/day). filtration. sinensis). 2011). and increased high-density lipoprotein (HDL). liver. 25.1% and 0. spray drying) of specific varieties of red orange (Citrus sinensis L. grapefruit (citrus paradise) and guarana (Paulinia cupanna). var. centrifugation. Citrus aurantium: The study investigated the lipolytic effect of a citrus-based polyphenolic dietary supplement. placebo-controlled. SINETROL stimulated lipolytic activity and significantly decreased body fat and body weight. Complimentary Contributor Copy . Therefore. GoChi. Therefore. 2013).amara). 2011). In the liver. Glycyrrhiza glabra: Licorice (Glycyrrhiza glabra Linn) is a well-known medicinal plant and glabridin is an isoflavan isolated from licorice. 2012). Therefore.25% licorice supercritical extract for eight weeks. it also decreased plasma leptin and fatty acid synthase (FAS) activity and enhanced the efficiency of the antioxidant defense system. Mice were fed with high fat diet containing 0. sweet orange (Citrus aurantium L. suggesting its lipolytic effect is mediated by cAMP-PDE inhibition. with the concomitant reduction of body weight. it effectively inhibited high fat diet-induced hepatic steatosis through downregulation of gluconeogenesis-related phosphoenolpyruvate carboxykinase and glucose 6-phosphatase and upregulation of the β-oxidation-related carnitine palmitoyl transferase. barbarum fruit juice. A standardized L. small clinical studies were conducted in healthy human adults for fourteen days to investigate the effect of L. bitter orange (Citrus aurantium L. low density lipoprotein (LDL). The effects were linked to polyphenolic composition of this supplement and its resulting synergistic activity. The obesity was induced via high fat diet and tamarind extract at 5. extraction. combination of an adequate diet with Satiereal supplementation might help people to achieve weight loss (Gout et al. The extract significantly reduced weight gain. 0. 2010). barbarum fruit juice on caloric expenditure and waist circumference. relative to placebo-treated control subjects (Amagase et al. possibly by regulating lipid metabolism and lowering plasma leptin and FAS levels in rat model (Azman et al. white adipose tissue and fat cell size in a dose-dependent manner. Tamarindus indicus: The antiobesity effect of aqueous extract of tamarind pulp was investigated in diet-induced obese Sprague–Dawley rats. double-blind. Moreover. cold pressure of juice. Lycium barbarum: Two separate randomized. it may prevent obesity by decreasing BMI (Dallas et al. The anti-obesity effect of glabridin and glabridin-rich supercritical fluid extract of licorice was investigated. the results suggested that glabridin and glabridin-rich licorice extract would be effective anti-obesity agents (Ahn et al. SINETROL is a potent inhibitor of cAMPphosphodiesterase (PDE). The study indicated that due to enhanced satiety effect. SINETROL is extracted by physical treatment (crushing of fruits. Osbeck (Blood group). and triglyceride. The inhibitory effect resulted from inhibiting the induction of the transcriptional factors CCAAT enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma. SINETROL (1. It was observed that the extract decreased the levels of plasma total cholesterol. and adipose tissue and suppressed obesity induced by a high fat diet. and 120 ml) and found to significantly decrease waist circumference and increase metabolic rate. was administered in three doses (30. The other flavonoid compounds of licorice have also shown strong antioxidant and antiobesity activity (Birari et al. Glabridin effectively inhibited adipogenesis in 3T3-L1 cells. 2008). var. tamarind improved obesity-related parameters in blood. 2007). Meju (fermented soybean blocks). energy intake. Therefore. In another study. 2006). increases lipid metabolism. The extract inhibited the development of obesity and hyperlipidemia in high fat diet-induced obese mice by inhibiting the pancreatic lipase activity and suppressing energy intake. 2012).) powder and is fermented for several months. (-)-epigallocatechin (EGC). These decrease lipid and carbohydrate absorption. mean BMI. The effect of thiacremonone. The extract-treated groups showed a significant decrease in body weight. However. 2004). Many studies have suggested that tea and tea polyphenols have beneficial effects on weight loss and prevention of obesity. It is one of the best known traditional foods in Korea has been recognised for its antiobesity activity by decreasing body weight and lipid levels rats fed with high fat diet (Rhee et al. reduction of lipid synthesis and increases in fatty acid oxidation therefore it may be a promising compound for the treatment of obesity (Kim et al. (-)-epicatechin. 2011). (-)Epicatechin (EC). adipose tissue and serum. total cholesterol. body fat percentage. resulted in the suppression of intracellular lipid droplet levels. pomegranate and avocado have been shown to decrease body weight. glucose levels and high density lipoprotein after 5 weeks treatment. 2010). The animals were treated with 400 or 800 mg/kg/day of pomegranate extract for five weeks. antioxidant. 2003). 2011). Marked cholesterol modulation was observed in the fermented red pepper paste-treated group with low levels of urinary hypoxanthine (Kim et al.3-gallate (ECG) and (-)epigallocatechin-3-gallate (EGCG) (Grove et al. and red pepper (Capsicum annuum L. 28 female volunteers (BMI more than 23 kg/m2) aged 19 to 60 years were treated with fermented red pepper paste for twelve weeks. 2010). salt. waist-hip-ratio and significant increase for fat free mass after the ten week period was observed. Complimentary Contributor Copy . Palombo Capsicum annum: Fermented red pepper paste is made with glutinous rice. the effect of ginger supplementation was investigated in obese men and a significant decrease in total cholesterol. Acai. inhibit de novo lipogenesis and increases carbohydrate utilization. antimicrobial. triglycerides. antiobesity and anti-inflammatory effects (Banerjee et al. 2003. Allium sativum: Garlic extracts exert anti-cancer. Thiacremonone resulted in AMPK activation. goji berries. It is also reported to inhibit lipid accumulation and stimulated lipolysis in 3T3-L1 adipocytes (Ahn et al. fat mass and adipocity in a number of studies which may be due to presence of various bioactive constituents (Devalaraja et al. a sulfur compound isolated from garlic significantly inhibited 3T3-L1 differentiation via down-regulation of adipogenesis-related transcription factors and adipogenic markers without any cytotoxic effect. HDL.158 Vandana Gulati. Pankaj Gulati and Enzo A. Punica granatum: The anti-obesity effect of the pomegranate leaf extract was investigated in a mouse model of high fat diet-induced obesity and hyperlipidemia. Zingiber officinale: Two grams of powdered ginger dissolved in hot water induced significant increase in thermogenic effect in healthy overweight men and influenced feelings of satiety without any adverse effects (Mansour et al. mangosteen. Other plant compounds: Exotic fruits such as litchi. fat mass. waist circumference. the results suggested that resistance training along with ginger supplementation may be an effective therapeutic strategy to induce favourable changes in lipid profiles and body composition in obese individuals (Atashak et al. It may be a novel appetite suppressant that only affects obesity resulting from a high fat diet (Lei et al. The main polyphenols present in tea are catechins. Kuda et al. In another study. 2012). LDL and triglyceride remained unchanged. 9: 15-21.. Antiobesity effect of Kochujang (Korean fermented red pepper paste) extract in 3T3-L1 adipocytes.-S. If not controlled.. S. 38: 1-10.-H. (2010). J. J.. Amagase. S. I. Ahn. which characterize metabolic syndrome. I. To.. Andersen. Food and Chemical Toxicology. H. N. atherosclerosis.-I. 51: 439-445. insulin resistance and diabetes mellitus. J.. Medicinal plants are gaining more credibility in the scientific community. Ha. A..-S. C. K. Kim... Obesity and the metabolic syndrome: role of different dietary macronutrient distribution patterns and specific nutritional components on weight loss and maintenance. H.. thus justifying the need for deeper research in this field. (2011)... Wang. metabolic syndrome.. (2010).A.A. Nutrition Reviews. References Abete. 30: 304-309... with the accompanying release of inflammatory cytokines (e.Use of Antioxidants to Control Obesity and Promote Weight Loss 159 Conclusion Obesity continues to be a major health challenge in the modern world. Kim. TNF-a. The excess fat deposits trigger low-grade inflammatory processes that recruit inflammatory cells. Achike. (2013)..-S.-O..M. 36: 415-422. Baile. Dietary phytochemicals might be employed as anti-obesity agents because they may suppress growth of adipose tissue. Complimentary Contributor Copy .-Y. Anti-obesity effects of glabridin-rich supercritical carbon dioxide extract of licorice in high-fat-fed obese mice..g. H. Park. H. There are thousands of unexplored plants across the world. 68: 214-231.. H. Jung. Various plants and natural products have been assessed for their potential anti-obesity effect. Journal of the American College of Nutrition.I. some of which have traditionally been used to maintain ideal body weight or as slimming agents.. Della-Fera.).... dyslipidaemia.. Y. thereby reducing adipose tissue mass.. M. D. Phytochemicals and adipogenesis. Clinical and Experimental Pharmacology and Physiology. Journal of Medicinal Food. BioFactors. M. it progresses to metabolic syndrome through a complex pathophysiological process. Obesity. (2011).A. Do. stimulate lipolysis and induce apoptosis of existing adipocytes.P. Ahn. Astrup. C. Thorsdottir. C. inhibit differentiation of preadipocytes. Lycium barbarum Increases Caloric Expenditure and Decreases Waist Circumference in Healthy Overweight Men and Women: Pilot Study.. Kim.-J.. (2006). Lee. Martínez. thus triggering a cascade of pathophysiological processes that lead to complications such as hypertension. Jang. T. The popularity of alternative medicine is increasing in demand of natural health products as drugs have failed to give desirable long-term results.-Y. IL-6 etc. Rayalam. I. or by suppressing appetite. There is increasing evidence that plants can exert anti-obesity effects through various mechanisms such as antilipase and anti-adipogenesis effects. in the viscera. Kim. Zulet. adipocytes and vascular function: A holistic viewpoint. 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Pankaj Gulati and Enzo A.. Complimentary Contributor Copy .. Qu. Zhao. The American Journal of Clinical Nutrition.164 Vandana Gulati. Zhu. 90: 1129-1135. M. Palombo Strychar. W. 2. Porto. we review the current knowledge regarding the use of medicinal plants as anti-hemolytic agents.3 and David M.4 Laboratory of Pharmacology and Experimental Therapeutics. Introduction Since ancient times. Although oxidative stress is not the primary etiology of diseases such as hemolytic anemias. the fundaments for the precise use of certain plants in the Complimentary Contributor Copy . Porto. it is believed to aggravate them. either as additives or as pharmaceutical supplements. the use of natural antioxidants. Chapter 6 Application of Antioxidant Plants as Anti-Hemolytic Agents 1 João C. have been in some cases further analyzed for a hypothetical anti-hemolytic potential. Department of Biological Sciences. as well as the mechanism of action is given. Inc. In this Chapter. Some of those plants with antioxidant activity. as well as their bioactive components. Porto. Portugal Abstract The use of medicinal plants represents the oldest and most common form of medication. Portugal 2 Institute for Molecular and Cellular Biology. University of Coimbra. medicinal plants were used in an intuitive and empirical way. Over time. Faculty of Medicine. Among the hundreds of studies published in the last two decades on medicinal plants research. Faculty of Pharmacy. University of Porto. IBILI. In earlier stages. Therefore. Particular emphasis in the compounds responsible for this activity. Portugal 4 Institute for Traditional Medicine. University of Porto. may prevent or at least slow down free radical reactions that are responsible for provoking damage to essential red blood cell molecules. humans have been looking for drugs in nature in order to prevent or heal a wide number of diseases.In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers. Portugal 3 Biochemistry Laboratory. Coimbra. the quest for new antioxidant drugs has a been pivotal. Pereira3. Fernandes1. phytochemicals. besides overall ageing. exerts various physiologic functions as a neuromediator. Among the various diseases that oxidative stress is believed to aggravate. In the last decades. Vitamin E. ulcers. a highly reactive radical that will immediately react with any biological molecule. cells are also protected by other non-enzymatic agents with endogenous and exogenous sources such as uric acid.g. regulator of immune functions. 2012). 2009). although required for certain enzymatic functions. glucose-6-phosphate dehydrogenase deficiency. thus keeping their free cellular concentration as low as possible (Marí et al. mainly in diseases originated by reactive oxygen species (ROS). it can react with superoxide to form peroxynitrite (ONOO-). unstable hemoglobin. carotenoids. Finally. congenital dyserythropoietic anemias. some Complimentary Contributor Copy . This search has been focusing primarily on plant metabolites (most of them are powerful antioxidants). As a result. notably lipids (O’Brien et al.. Fernandes and David M. Vitamin C.. cells can protect themselves against oxidative damage (Figure 1).. pollutants. Oxidative stress has been implicated in the beta-hemoglobinopathies (sickle cell anemia and thalassemia). are a few examples of human diseases and health conditions that may be instigated by free radicals (Morrell. environmental sources such as cigarette smoke. Moreover. The detrimental effect of transition metals is minimized through the action of proteins like ferritin. 2008). paroxysmal nocturnal hemoglobinuria and aging of red blood cells (RBCs) (Halliwell & Gutteridge... Countless studies have been performed and published upon the role of specific plant metabolites in disease prevention or treatment. as well as their ratio. Parkinson’s and Alzheimer’s). reflect the redox state of the cell and are crucial for an efficient ROS detoxification. ionizing radiation and xenobiotics also possess an important role on free radicals production (Beckman et al. Pereira treatment of specific diseases were being discovered and gradually the empiric use of those plant species was abandoned and started to be supported by evidences (Halberstein. 2009). lactoferrin that can store Fe2+ ions. among others (Marí et al. hemolytic anemias are given particular attention throughout this chapter (Huang et al. such damage to erythroid cells plays a crucial role in hemolysis due to ineffective erythropoiesis in the bone marrow and short survival of RBCs in the circulation. which is then converted to H2O by gluthatione peroxidase (GPx) or to O2 + H2O by catalase (CAT) (Miwa et al. However. 1984. polyphenols. 2005). 1990). 2011 ). Transition metals like Fe2+ or Cu2+. vitamins and fiber content. exacerbate oxidative damage by catalyzing the conversion of hydrogen peroxide into •OH. The enzyme superoxide dismutase (SOD) catalyzes the dismutation of superoxide to H2O2. an extremely potent cellular oxidant. hereditary spherocytosis. Another important free radical is nitric oxide (NO). ROS are metabolic byproducts of aerobic metabolism of cells resulting from normal physiological processes such as energy production. Sugamura & Keaney.. 2005). The reaction catalyzed by GPx requires gluthatione (GSH).166 João C. hydrogen peroxide (H2O2) or hydroxyl radical (•OH) (O’Brien et al. or vasodilator. platelets and polymorphonuclear (PMN) white cells are also exposed to oxidative stress.. Furthermore.. Although oxidative stress is not the primary etiology of these diseases. produced by the nitric oxide synthase (NOS) enzymes. 2012). 2008. which inevitably leads to the generation of oxidative molecules: superoxide (O2-•). The concentrations of GSH and GSSG. ultraviolet light. the scientific community has been trying to identify the specific molecules in herbs that account for their health promotion benefits. bilirubin. which is converted to reduced gluthatione (GSSG). This molecule. To a certain extent. 2005). transferrin. Huang et al. Coronary heart diseases. cancers and neurodegenerative diseases (e. with savory displaying the highest inhibition (>95%). Its main target in RBCs is hemoglobin. further suggesting that ingestion of medicinal plants with antioxidant capacity would strength the protection of RBCs membrane from free radical-induced oxidative damage. 1987).) were reported by Gião et al. eventually. Therefore. The authors hypothesize that these differences may be explained by the different profiles in phenolic content between the plants.). exposure of RBCs to H2O2 also results in changes of RBC membrane proteins. 2010). which occurs mainly due to lipid oxidation of erythrocyte membrane mediated by ROS as the ones generated by H2O2 or by 2. changes in cell deformability. used either as a whole or their individual constituents. The use of antioxidants may prevent or ameliorate free radical reactions in vivo. these endogenous defenses are not enough to protect RBCs whenever an unusual physical or chemical stress occurs. In addition. hence resulting in various pathologies as already described (Kruckeberg et al. at low concentrations [0. which will eventually lead to lysis. several studies have been focusing on medicinal plants regarding their capacity to prevent RBC membrane damage and. which become more pronounced with cell aging. peroxyredoxins and GPx) and non-enzymatic (GSSG and ascorbate) antioxidant systems. However. There are numerous evidences suggesting that several plants.00050.2'-azobisisobutyramidinium chloride (AAPH) (Pandey & Rizvi. thus reducing ROS into less reactive intermediates. hemolysis. drastic changes in RBC shape and membrane structure may occur. These include oxidation of hemoglobin. 2008.025-0. Mazor et al. thus suggesting that the higher anti-hemolytic activity is related with the amount of hydrogen donors and singlet oxygen quenchers. Serafini et al. The six extracts showed a hemolysis inhibition rate above 80%. Aqueous extracts of sage (Salvia sp. and ultimately from hemolysis. which is consequently converted to either met. As a consequence of these oxidative modifications.).. This natural oxidant is regularly used in vitro to initiate radical formation in intact cells. yarrow (Achillea millefolium L.) and walnut-tree (Juglans regia L. generation of high-molecular weight proteins or protein ionic shifts.). the circulating RBCs suffer and accumulate physical and chemical changes. as well as lipid peroxidation. which prevent or slow protein oxidation. myrtle leaf (Myrtus communis L. Hull) also displayed a dual effect: at low Complimentary Contributor Copy . There are numerous intracellular events that precede oxidant-induced cell hemolysis (Figure 2). mainly due to the limited biosynthesis capacity of these cells and their poor repair mechanisms.5% (w/v)]. agrimony (Agrimonia eupatoria L. RBCs have well known enzymatic (CAT.. thyme. SOD. In addition. savory (Satureja montana L. lipid peroxidation. Heath (Calluna vulgaris L. have substantial protective effects upon erythrocytes oxidative damage (Figure 3). 2001).).Application of Antioxidant Plants as Anti-Hemolytic Agents 167 patients develop thromboembolic phenomena and recurrent bacterial infections in addition to the chronic anemia (Halliwell & Gutteridge. Therefore. (2010) as to possess good capacity to inhibit H2O2-induced hemolysis in an in vitro system.or ferry-haemoglobin (its oxidized forms). (2002) showed that the ingestion of tea produced a significant increase in human plasma antioxidant capacity in vivo. thereby prevent some of the damage to essential erythrocyte molecules presented above. 1984).005% (w/v)]. phospholipid flip-flop processes within the lipid bilayer leaflet of the membrane and carbonylation – an irreversible post-translational amino acid residue modification (Fibach & Rachmilewitz. weet-amber and eucalyptus also showed a relevant protection although higher concentrations were requiresd [0. 100 µL of golden root aqueous extract (41. Moreover.) to scavenge peroxyl radicals generated by AAPH.). cumin (Cuminum cyminum L. hemolysis was inhibited by about 32.) Bullock & S. Atrooz (2013) analyzed two aromatic plants seeds. which in turn impairs the access of oxidants to the cell. Quince (Cydonia oblonga Mill) leaf extracts were analyzed by Costa el al. (2009) and showed a low capacity to inhibit AAPHinduced hemolysis. Sangkitikomol reported that the above-mentioned plants were also capable of inhibiting hemoglobin oxidation induced by Nacethylphenylhydrazine (APHZ) – source of free radical formation inside cytosol of RBCs.05% (w/v)] pro-hemolytic effect was found.) and caraway (Carum carvi L. aleppo oak (Quercus infectoria Oliv).. The golden root (Rhodiola rosea L. mainly hemoglobin. rose (Rosa domescena Mill). Both plants inhibited the lipid peroxidation of RBC membranes and •OH scavenging capacity. Sangkitikomol (2012) also assessed the effect of 30 plant extracts on delaying erythrocyte hemolysis induced by AAPH. Furthermore.6 mg/mL) was sufficient to reduce hemolysis in 50%. with proved medicinal properties and assessed their capacity to protect RBCs from FeSO4-induced Complimentary Contributor Copy . Using the same oxidative agent. Coulibaly et al.) is able to inhibit significantly the hemolysis induced by H2O2. the polyphenols protect the structure and function of RBC membranes by interacting with the surface of the membrane through hydrogen bonding. and eugenia (Syzygium gratum Wight) exhibited higher protection.05-0. Battistelli and co-workers have used hypochlorous acid as an oxidative agent.168 João C. Pereira concentrations is showed a protective effect. which is associated with oxidation of GSH and of -SH groups of membrane proteins.) and Indian fig tree (Ficus racemosa L. at concentrations around 1.) from both bark and root.Dahlgr. 200 µL completely inhibit hemolysis and RBC deformability (Battistelli et al. mainly due to its major phenolic compound constituent. clove [Eugenia caryophyllus (Spreng. This capacity to protect RBCs was attributed by Sangkitikomol to the plant polyphenols content: according to the author. Fernandes and David M. G. (2000) demonstrated that rooibos (Aspalathus linearis R. all the extracts tested delayed the hemolytic process to some extent. (2008) reported the high anti-hemolytic effect (about 70-80% hemolysis inhibition) of banyan tree (Ficus bengalensis L. leading to oxidation of proteins.5-92.5 mg/ mL.) has also been reported as possessing anti-hemolytic capacity. mexican marigold (Tagetes erecta L. against the 120 min seen for positive control. In general.5%. increasing the time required to achieve 50 % hemolysis above 210 min. At concentrations in the 0. Asghar & Masood (2008) reported the capacity of milk thistle (Silybum marinum L.). Manian et al. 2005). The extract with lower flavonol concentration exhibited the highest protection. lower than 40% at 50 µg/mL. the authors suggest that the anti-hemolytic capacity of this plant may also be associated to its capacity to increase both SOD and GPx. as well as with cross-linking of membrane proteins and extensive disruption of the membrane inducing lysis.5 mg/ml range. thus suggesting that the protective role of this plant against H2O2-mediated oxidation is not determined by the flavonol content. This oxidative agent can decompose to form carbon-centered radicals that can react with O2 to yield peroxyl radicals capable of removing hydrogen from membrane lipids and to stimulate lipid peroxidation. however at high concentrations [> 0. Nevertheless. (2011) concluded that goat weed (Scoparia dulcis L) may have therapeutic applications due to its antioxidant properties as it was able to prevent RBC lysis (56%-83%) at a concentration of 300 µg/mL. whether as decoct (more than 50%) or as an hot water extract (above 70%). Simon et al. Harrison]. 5-O-caffeoylquinic acid. which are commonly presented in several plants and fruit trees – myricetin (eg. Several other works have been published in the last years demonstrating the high capacity of other plant extracts. the authors also reported a strong inhibition against lipid peroxidation of RBC membranes in a tertbutylhydroperoxide (tBHP)/hemin oxidation system. quercetin (Ginkgo biloba. (2000) reported that all the polyphenols in green tea referred above were able to suppress erythrocyte hemolysis from AAPH-oxidation in the following sequence EGCG>EGC>ECG≈EC>GA. Furthermore.. In addition.3′.Ficus religiosa).5-trihydroxy-4′-methoxystilbene 3-β-D-glucoside.Aloe barbadensis).Fagopyrum esculentum.3′. however the compounds bearing ortho-dihydroxyl functionality (myricetin. Fava d'anta . This is to be expected as the ortho-hydroxyl would make the oxidation intermediate. It is an excellent source of polyphenol antioxidants including epicatechin (EC). quercetin rhamnopyranoside (Amur Maple Acer ginnala. Lam et al. 2000). rutin. Osage Orange leaf .Sambucus canadensis…). and kaempferol glucopyranoside (Sohanjana Moringa oleifera. 2006). more stable due to the intramolecular hydrogen bonding interaction. quercetin. Kuntze) is the most studied plant regarding the capacity to prevent erythrocyte lysis. Field Horsetail . quercetin rhamnopyranoside) possess remarkably higher activity than the ones bearing no such functionality (Dai et al.Dimorphandra mollis…). Small-leaved Lime . however cumin possessed higher capacity – over 60% inhibition at 100 µM against 45% by caraway at the same concentration. Old Fustic . ortho-hydroxyl phenoxyl radical.5-trihydroxy-4′-methoxystilbene 3-βD-glucoside showed higher protection (65%) than trolox (40%) in AAPH-induced hemolysis in RBC. epigallocatechin (EGC). Differently. kaempferol (Candle Bush . Ma et al. St. Peepal . Overall. the capacity of green tea polyphenols to act as chelators of catalytic cations involved in initiation of free radicals or to function synergistically with α-tocopherol (vitamin E) and L-ascorbic acid (vitamin C). Complimentary Contributor Copy . (2007) isolated 6-gingerol and 3. but also due to its ability to enhance the activity of endogenous antioxidant enzymes such as CAT. John's wort . At 50 µM. Dai and co-workers (2006) isolated several flavonols and their glycosides.. Aloe vera . respectively. The results demonstrated that all these flavonols (and their glycosides) are effective antioxidants. quercetin galactopyranoside (American saw-wort Saussurea americana.Ficus religiosa). quercetin galactopyranoside. and analyzed their effectiveness to protect RBCs from AAPHinduced hemolysis. concluded that phenolic compound from rhubarb is almost two times more potent than trolox while 6-gingerol was only about half as potent as trolox in this assay. Rhubarb . both plants showed anti-hemolytic activity. and/or glutathione antioxidant enzyme systems. Green tea (Camellia sinensis L. American Elderberry .Maclura pomifera.Cassia alata. it is already understood that its effects are not exclusively due to interruption of free-radical chain reaction (by trapping the free radicals). morin (Apple Guava . protects RBC membranes from oxidation (Basu et al. 6-gingerol only exerted some effect when at 100 µM. epicatechin gallate (ECG). 3.Application of Antioxidant Plants as Anti-Hemolytic Agents 169 hemolysis.).Tilia cordata. epigallocatechin gallate (EGCG) and gallic acid (GA) (Ma et al. Peepal . SOD. moringa .Maclura tinctoria…).Hypericum perforatum.Rheum rhabarbarum. Aloe vera).Acacia nilotica..Moringa oleifera. phenolic compounds from ginger (Zingiber officinale Roscoe) and rhubarb (Rheum rhabarbarum L. 2003). rutin (Buckwheat .Psidium guajava. gum tree .Equisetum arvense…). but mainly reporting the anti-hemolytic capacity of plant components in particular: Lam et al. Due to the high amount of studies on the antihemolytic effect by green tea. Figure 1. ROS generation in RBC and its defenses. Complimentary Contributor Copy . Figure 2. Complimentary Contributor Copy . Intracellular events that precede oxidant-induced cell hemolysis. 0025% (He et al. 2012) ++ 0.05% (Gião et al. 2010) Aleppo oak Quercus infectoria Oliv ND Aqueous/methanol extract (80:20) Human ++ <0.25% (Sangkitikomol..02% (Rajeshwari et al.0384% (Nabavi et al. 2013) Methanol extract Human ++ 100 µm (Atrooz. 2012) Avocado Persea Americana L Leaf Aqueous extract Human ++ 0. (+++) < 80% hemolysis inhibition. 2012) Aqueous/methanol extract (80:20) Human ++ <0. 2010) ++ <0. 2013) Banyan tree Ficus bengalensis L.25% (Sangkitikomol. 2012) ++ 0. Aerial root Acetone extract Cow ++ 0..1% (Sahaa et al. 2012) Chamberbitter Phyllanthus urinaria L Leaf Aqueous/methanol extract (80:20) Human ++ <0.05% (Marian et al. Seed Methanol extract Human ++ 100 µm (Atrooz. Summary of plants previously tested for their anti-hemolytic capacity Common name Botanical name Part used State RBC Activity* Concentration Ref Agrimony Agrimonia eupatoria L Leaf Aqueous extract Human +++ 0.. 2013) Black tea Camellia sinensis L.. 2013) Aqueous extract Human ++ 0.005% (Gião et al. (++) – 40% < hemolysis inhibition < 80%.1% (Gião et al..175% (Simon et al..< 40% hemolysis inhibition. Leaf Caraway Carum carvi L.05% (Marian et al. 2000) Acetone extract Human ++ 100 µm (Atrooz..01% (Sabuncuoğlu & Şöhretoğlu.25% (Sangkitikomol. 2010) Silk bananas Musa sapientum Leaf Methanol extract Human ++ 0. 2012) ++ 0.25% (Sangkitikomol..25% (Sangkitikomol.Table 1. 2012) ++ 0.. 2012) Clove Eugenia caryophyllusI Spreng Buds Human Coriander Coriandrum sativum Leaf & Seed Methanol extract Cumin Cuminum cyminum L Seed Acetone extract Human + 100 µm (Atrooz. 2008) Aqueous extract Quails ++ 0. 2013) Ceylon ironwood Mesua férrea L Flower Aqueous/methanol extract (80:20) Human ++ <0. Complimentary Contributor Copy .. 2008) Methanol extract Cow ++ 0. 2008) Eucalyptus Eucalyptus globules L Leaf Eugenia Syzygium gratum Wight Leaf Aqueous/methanol extract (80:20) Human Gamak Dorema aitchisonii Korovin Aerial parts Ethanol extract Rat Genarium Geranium tuberosum L Flower Methanol extract Ginkgo Ginkgo biloba L Leaf Aqueous extract Human Human *Activity classification: (+) . 084% Human Human ++ <0. (++) – 40% < hemolysis inhibition < 80%.0005% 0.03% +++ 0. 2008) (Gião et al.054% 0.05% ++ 0. 2008) (Asghar & Masood. Root Aqueous extract Green tea Camellia sinensis L. 2011) (Battistelli et al. 2012) (Asghar & Masood.005 Human Human Cow +++ ++ 0.. 1997) (Gião et al.. 2010) . 2008) (Costa et al.05% 0.005% <0.. 2012) (Nabavi et al.0025% 20µm 0.25% +++ 0..... Complimentary Contributor Copy Ref (Coulibaly et al.0071% Rat + N. Leaf Aqueous extract Heath Calluna vulgaris L Hyssopus angustifolius Leaf Flower Stem Leaf Indian fig tree Ficus racemosa L Stem bark Indian lotus Nelumbo Mucifera Gaertn Flower Aqueous extract Methanol extract Methanol extract Methanol extract Acetone extract Methanol extract Aqueous/methanol extract (80:20) Peppermint Mentha piperita L Aerial parts Ethanol extract Mexican marigold Tagetes erecta L Leaf Aqueous/methanol extract (80:20) Seed Aqueous extract Seed Aqueous extract Hyssop Milk thistle Silybum marinum L Myrtle Neem Myrtus communis L Azadirachta indica A Juss Leaf Leaf Aqueous extract Aqueous/methanol extract (80:20) Nilgiri barberry Berberis tinctoria Lesch Fruit Methanol extract Pale Cranesbill Biebersteinia multifida DC Roots Aqueous extract Activity* Concentration +++ 0. 2012) (Nabavi et al.D..0024% 0. 2012) (Ebrahimzadeh et al... 2010) (Nabavi et al.0065% 0... 2010) (Sangkitikomol. 2012) (Nabavi et al. 2011) (Coulibaly et al. 2005) (Battistelli et al.03% Human Human Rat Human Rat Rat Rat Cow Cow Human Rat +++ ++ +++ +++ ++ ++ ++ ++ +++ +++ 100µl of 41. 2012) (Marian et al. (+++) < 80% hemolysis inhibition.. 2010) (Sangkitikomol..6mg/ml 0. 2005) (Schmitz et al.. 2011) (Coulibaly et al. 2008) (Sangkitikomol.05% 0.. 2009) (Zhang et al.03% ++ 0.6mg/ml 200µl of 41.05 + 0.. 2012) (Sasikumar et al.25% ++ 0.Common name Botanical name Part used State Hexane Extract Goat weed Scoparia dulcis L Plant Chloroform extract Methanol extract RBC Rat Rat Rat Human Golden root Rhodiola rósea L.. Human Human ++ +++ *Activity classification: (+) .0026% 0. 2008) (Marian et al.< 40% hemolysis inhibition. 005% 0. 2010) (Sowndhararajan et al.0005% +++ 0.025% 3. 2012) (Gião et al. (+++) < 80% hemolysis inhibition. 2010) (Sangkitikomol. 2010) (Gião et al..05% *Activity classification: (+) .. Complimentary Contributor Copy Ref (Costa et al...1 g/1 kg 0.005% 0. 2000) (Simon et al.005% 0. 2009) (Gião et al. 2010) (Gião et al.< 40% hemolysis inhibition.15% <0. 2010) (Gião et al. 2010) .025% 0...Dahlgr Leaf Rose Sage Savory Screwpine Sweet-amber Thyme Walnut-tree Yarrow Rosa domescena Mill Salvia sp Satureja Montana L Pandanus amaryllifolius Roxb Hypericum androsaemum L Thymus vulgaris L Juglans regia L Achillea millefolium L Leaf Leaf Leaf Leaf Leaf Leaf Leaf Leaf State Methanol extract Aqueous extract Powder Aqueous extract Aqueous/methanol extract (80:20) Aqueous extract Aqueous extract Aqueous/methanol extract (80:20) Aqueous extract Aqueous extract Aqueous extract Aqueous extract Zombi pea Vigna vexillata L Seed Acetone extract RBC Human Human Quails Quails Human Human Human Human Human Human Human Human Human Activity* + ++ ++ ++ ++ +++ +++ ++ +++ +++ +++ +++ Concentration 0.25% 0. (Continued) Common name Quince Raspberry Botanical name Cydonia oblonga Mill Rubus idaeus L Part used Leaf Leaf Rooibos tea Aspalathus linearis R.0005% 0.. 2010) (Gião et al. (++) – 40% < hemolysis inhibition < 80%...Table 1.25% 0. 2000) (Sangkitikomol..005% <0. 2010) (Simon et al.. 2012) (Gião et al. C. in combination or separately. hence protecting these cells from hemolysis. The authors suggested that green tea polyphenols could be capable of trapping the initiating radicals of AAPH and inhibit RBC membrane lipid peroxidation. all the epicatechin isomers. sinensis presented one of the highest protection rates. nevertheless. EGC and EC were the only compounds found in blood after the ingestion of green tea polyphenols extracts. (2012) reported that among the 30 plants and fruits tested in their research.Application of Antioxidant Plants as Anti-Hemolytic Agents 175 Figure 3. over AAPH) than ECG or EC. (2008) results indicated that in a concentration of 0. with and without AAPH. (1997). Analysis to membrane lipid content revealed that all four epicatechin isomers significantly prevented loss of arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) compared to RBCs incubated with AAPH. In another study performed by Zhang et al. Schmitz et al. thus demonstrating to Complimentary Contributor Copy .54 mg/mL. green tea extracts inhibited 81. Optical microscopy images of RBCs population incubated with savory. suggesting that hemolysis was associated with a significant decrease in these polyunsaturated fatty acids. demonstrated to be effective antioxidants both in vitro and in vivo protecting RBC membrane to oxidation. it was demonstrated that EGCG and EGC possess a higher anti-hemolytic activity in vitro (above 85% inhibition at 20µM. Moreover.6% of AAPH-induced hemolysis. Sangkitikomol et al. The content of barbaloin in the juice of aloe leaves was reported to be 15-40%. as well as a protective effect over hemoglobin oxidation. taking 240 mg of dry extract of G. barbaloin and its aglycone aloe-emodin are the major constituents of leaves (Patel et al. The leaves of this tree have been used in Chinese medicine for thousands of years. biloba leaf extract increased the hypotonic resistance of red blood cells (decreasing hemolysis rate). C and J as well as bilobalide). Costa et al. He et al. hence suggesting that green tea may provide antioxidant protection to cells. further suggesting that polyphenols may be interacting with the membrane bilayer – decreasing its fluidity and therefore the diffusion of free radicals into the cell membranes and its consequent damaging effects. as well as the lack of conclusive results in some research works. (2008) reported a dual effect of G. vera constituents. as it also prevented the consumption of the cytosolic antioxidantGSH by AAPH. protecting the individual from oxidative stressderived diseases. such as reducing oxidative stress and. Among A. A. Complimentary Contributor Copy . the author also reported an increase in GSH. Fernandes and David M. Pereira possess an excellent anti-hemolytic capacity. Aloe vera L. biloba extracts. while terpenes didn’t seem to have any effect. as well as a decrease in membrane lipid peroxidation. the pro-oxidant effects found for certain concentrations. therefore. Both ginko extract and its flavonoids demonstrated to significantly inhibit hemolysis. 2012). He et al. vera (25-100 µM) not only prevented RBCs lysis – avoiding proteolytic degradation of band-3 anion exchanger membrane protein. Liu et al. which is compatible with lower RBC lysis. has also been subjected to several assays involving RBC hemolysis. In addition. (2012) demonstrated the antioxidant activity of this plant by maintaining RBCs membrane integrity when exposed to AAPH. biloba leaf extract. The authors found a significant reduction in the oxidative stress within the erythrocyte. as suggested by a significantly lower value of membrane binding hemoglobin (a parameter of oxidative stress within the RBCs) and by changes in band 3 profile towards a normal mean profile. namely an increase in the band 3 monomer (directly related with changes in RBC cytoskeleton and therefore in its shape). biloba leaf extracts and its main components – flavonoids (mainly quercetin. Basu et al. isorhamnetin and their glycosides) and terpenes (ginkgolides A.. B.176 João C. Singh et al. Today it has become one of the most popular and commonly used herbal remedies due to its wide spectrum of beneficial effects on health. also demonstrated that G. The results led the authors to conclude that drinking green tea has beneficial effects. (2009) tested the anti-hemolytic potential of G. Furthermore. biloba leaf extract on the amyloid peptide (Aβ25-35)-induced hemolysis. In other study published by Coimbra et al. (2009) also reported the antioxidant capacity of green tea extracts upon AAPH radicals. the hemolytic rate was inhibited by 70% at a dose of approximately 25 μg/ml. Conclusions suggested that there was an improvement in RBC deformability as well as in viscoelasticity. In the presence of G. (2006). 30 human subjects had their RBCs membrane analyzed after 4 weeks drinking 1L of green tea daily. Huang et al. Ginkgo biloba L. Mazzula et al. by inhibiting hemolysis in more than 50% at a concentration of 25 µg/mL. or decreased membrane fragility in the hypotonic environment. turns it necessary to have further studies on G. has been used as a traditional medicine and as an ingredient in many products due to its vast reported antioxidant properties. (2009) published the results of their research involving 25 type-2 diabetes patients with retinopathy. biloba leaves. Higher doses of G. biloba leaf extract increased the hemolytic rate significantly. However. kaempferol. (2003) reported that the obese participants of their study ingesting green tea (4 cups of 8oz boiled tea per day or 2 capsules) for 8 weeks had an increase in blood glutathione (1783 to 2395 μg/g). Paiva-Martins and colleagues have published a group of papers demonstrating that several olive polyphenols (hydroxytyrosol . Secoiridoids are the most representative class in olives with the glycoside oleuropein being present up to 14% of the dry weight. Pharmacological studies of garlic extracts and its components. barbaloin showed to possess higher effectiveness protecting RBCs from AAPH-induced hemolysis (trolox IC50 = 59. (2004) reported that shallot (Allium ascalonicum L. such as S-allylcysteine. protect vascular endothelial cells from oxidant injury or reduce plasma lipids. Paiva-Martins et al. secoiridoids. Leelarungrayub et al. The protective effects upon RBCs have also been studied upon fruit trees and some vegetables.14-0. 2009..) have also been accounted for beneficial effects upon RBCs (Jaiswal et al.) possess the capacity to inhibit RBC hemolysis induced by H2O2 (around 80% by hexane-extract shallot and only about 20% by water-extract shallot.2007). Lam et al. also. 2010. the authors stated that garlic significantly suppressed FeSO4-induced hemolysis. Moriguchi et al. results attained with garlic led to the publication of a group of papers on its anti-hemolytic activity (Moriguchi et al. additionally. 2013). The classes of phenols present in olives and olive tree leaves are phenolic alcohols (such as hydroxytyrosol). Morihara et al. (2007) demonstrated that barbaloin prevented several RBC membrane changes.2 µM. All the compounds showed capacity to significantly prevent hemolysis induced by AAPH and by H2O2. 2006).Application of Antioxidant Plants as Anti-Hemolytic Agents 177 (2000) also reported an increase of several cytosolic enzymes involved in RBC defences against oxidative damage – SOD. moreover. Jaiswal & Rizvi (2001) reported a significant protection of oxidative stress by onion outer layers extract on RBCs subjected to tert-butyl hydroperoxide treatment (hemolysis inhibition around 40%). 2001). as well as prevent hemoglobin oxidation and changes on RBC protein membrane profile induced by the same oxidative agents. compared with trolox. In summary.2001. as well as S-allylcysteine (1-10 mM dose-dependently) [56]. such as the stabilization of erythrocyte membranes. the hexane-extract shallot (200µg/mL) also reduced GSH oxidation and lipid peroxidation induced by AAPH.4´-O-diglucoside and quercetin-4´-O-monoglucoside. when mice were fed with fresh leaf pulp extract of Aloe vera (30 µl and 60 µl/day/mice daily for 14 days).. at 1. which in some cases do not fit the common designation of medicinal plants. barbaloin IC50 = 31..7µM) (Dai et al. Morihara et al.. the results are more pronounced for outer layers as compared to the inner layers due to variation in the quantities of quercetin according to layer position. (2007) demonstrated in his research that garlic extract [0.. Extracts of onions (Allium cepa L. protein crosslinking and sulfhydryl group oxidation induced by AAPH or by hemin (a trivalent ferric oxidant which also exists in vivo). The layers of onions are a rich source of flavonoids. such as lipid peroxidation. consisting mainly quercetin-3. Olive tree leaves have deserved in the last decade numerous studies upon its capacity to protect RBCs from oxidative stress (Garcia et al. the investigation on garlic led the researchers to conclude that it improves microcirculation Complimentary Contributor Copy . GPx and CAT. have revealed capacity to improve peripheral circulation.0 mg/mL).. flavonoids and lignans. as well as an increase in GSH levels. oleuropein and its hydrolysis products) can significantly protect RBCs from oxidative damage in a dosedependent manner (from 3 to 80 µM) (Paiva-Martins et al. 2013).57% (w/v)] was able to reduce peroxynitrite-induced hemolysis in a concentrationdependent manner. For this reason. Paiva-Martins et al. as well as significantly suppressed the hemolysis rate even without induction of peroxidation – this results led the author to suggest that garlic extracts may protect RBC membranes by mechanisms other than protection from lipid peroxidation. Furthermore. (2001) has reported that garlic extract prevents the decrease of erythrocyte deformability induced by lipid peroxidation in a dose-dependent manner. Lyonsb. M. Masood. Andrade.. Beckman. Valentão. the most active fraction or extracts have been discovered. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Nutr. Proc.. such as sickle cell anemia. Pharm.S. Costa. J.J. Dachà.. Therefore.. Nacoulma. Evaluation of antioxidant properties of silymarin and its potential to inhibit peroxyl radicals in vitro.A.M.A. Tonga. P. 5.. A... Kiendrebeogo.. Natl.. Z. Green tea supplementation increases glutathione and plasma antioxidant capacity in adults with the metabolic syndrome. R. J.M. Marshall. Sombie. Basu.B. 1990. M. Res. P. O. 49. 47. R.178 João C. 2005. 2011. 2013.. P. Rocha.. Pak. and congenital dyserythropoietic anemias.. Battistelli. P.. Rhodiola rosea as antioxidant in red blood cells: ultrastructural and hemolytic behaviour. Kehoe. 25. The effect of green tea in oxidative stress. seed extracts on human erythrocyte hemolysis. 1620-1624.. Biol. 249-254. Gobbi. Pereira. Rebelo. research in this area should be carried on until the agents responsible for the activity are determined or.Y. 2008. Santos-Silva. Fernandes and David M. Chen.. References Asghar.W.. Freeman.. M.. De Bellis.. Complimentary Contributor Copy .. 64-68. 2013.. 180-187. E. Magalhães. E. J. 1576-1582. and Carum carvi L. P. 243-254 Beckman. Nutr. However. Coulibaly. or even to retard red blood cells aging. 860-865. Antioxidant and anti-inflammatory effects of Scoparia dulcis L. S.. Cucchiarini. Med. when carefully applied. Sci.. B. O. Eur J Histochem. L.G. J. as well as perfectly defined the range of secure concentrations. Carvalho.M. B.. 33. J. Among the several therapeutic areas where medicinal plants may play an important role in the future.. Betts. The effects of Cuminum cyminum L. Pereira and rheological blood properties and conserves the structure and role of RBCs.. C.S. Acad. 790-796. A.E. Millogo. Toxicol...M.F. not only through an antioxidant process but also via the glycolysis pathway and membrane stabilization of RBCs. Silva. T. Food 14. P. Castro. Lamien. I. N. Clin..A. C. Int. De Sanctis. Atrooz.. J.G. USA 87. R.. M.... A.. as the case may be.A. Newmana. 2006.. Z. T. the use of several medicinal plants is often empiric and unreasonable due to lack of information. A.. 21... Mulugetaa. Sci. P. S. Coimbra. Evaluation of free radical-scavenging and antihemolytic activities of quince (Cydonia oblonga) leaf: a comparative study with green tea (Camellia sinensis). Rocha-Pereira.. A. Food Chem. 2009. glucose-6-phosphate dehydrogenase deficiency. the use of some of the plants with antioxidant activity mentioned in this chapter might be of great matter as support therapy against certain medical blood conditions. Conclusion Many common plants contain diverse therapeutic bioactive ingredients that may turn out to be valuable in the future as a primary or as supplemental therapies. J. . R. B.. J. Costa. 93. S. M.. 15..) O.. 78..I. Pintado.-M. Food Cont.. Gião. Lin. 615-621. 104..C.S. Comparison of the antioxidant activity amongst Gingko biloba extract and its main components. Improved haemorrheological properties by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with retinopathy... Prior. Toxicol. 29–50.J.. Garcia. Pinto. Zhong Yao Cai 32:736-740. Woo.. 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This chapter presents the most frequently used traditional plants from the Eastern Anatolia and describes their uses. poultice. Turkey 3 New South Wales University. Keywords: Eastern Anatolia. Many of the world’s contemporary staple foods originated here. Endemic plants are utilized daily in preparation of main meals. Kensington. The extensive daily use of local plants for foods and medicine in Eastern Anatolia continues today and traditionally used plants outnumber the conventional sources of plant-based foods. in salads and as herbal teas. North Ryde. They are used internally (e.au. decoction. is at the forefront of the world richest sources of plant species. The mountainous and strongly fragmentized area is a home to over 11.1. herbal tea) and externally (e.the westernmost protrusion of Asia. ethnobotanical. Van.000 plant species.g. Faculty of Science. rzekarega@hotmail.* Abdullah Dalar2 and Konrad A. Australia YüzüncüYıl University. Antioxidant Properties and Phytochemical Composition of Traditional Medicinal Plants from Eastern Anatolia Izabela Konczak. medicinal plant. phytochemical compositions and antioxidant capacities.Konczak@csiro. enzyme-inhibitory activity * Corresponding Author address: Email: Izabela. NSW. Inc. Complimentary Contributor Copy .g. antioxidant.com. Department of Biology. Australia Abstract Anatolia .In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers. NSW. traditional remedy. Konczak-Islam3 1 2 CSIRO Animal. Black Sea region (Fujita et al. Yesilada and E. In the 1990’s the research teams of E. In the developed world the interest in natural pharmaceuticals steadily increases and plant-based pharmaceuticals are seen as supportive medicine or an alternative to conventional medicine with fewer side effects... refer to medicinal products obtained from plant roots. botanical medicines or phytomedicines. Cubukcu and Ozhatay.. Mediterranean region (Yesilada et al. carried out the first. in collaboration with M. This exceeds the total number of endemic species found in Europe. to utilize the traditional knowledge in the development of plant based pharmaceuticals. Japan. In other studies the local uses of plants were reported primarily as a part of floristic studies (Tonbul and Altan. Eastern Anatolia. Konczak-Islam Introduction Traditional medicinal plants. With this exceptional diversity Turkey is the centre of genetic resources of many cultivated forms of annual and perennial. This invaluable contribution of both research centers resulted in a number of consecutive research papers listing traditional medicinal plants and methods of preparation and administration in the treatment of medical conditions in the following regions of Turkey: north-eastern Anatolia (Sezik et al. Kars.. 1993). stems. the number of studies capturing these uses are limited. to conventional medicine. These herbal materials are used directly in a prescription formulation or processed into various ready-to-use products (Tang and Halliwell. Traditional medicinal products constitute multi-billion-dollars industries worldwide and are becoming increasingly popular as a cost effective alternative. their efficacy and their safety has to be investigated. Western Anatolia (Honda et al. Eastern Anatolia. herbaceous and woody plants (Ağaoğlu et al. Southern Anatolia (Taurus Mountains region) (Yesilada et al. 2011). Traditional medicines have been and continue to be used in every country around the world in some capacity. 1996). 1991).. Early studies presented a list of plants used in various regions of Turkey and their application to cure health disorders (Başar. Iǧdir provinces (Sezik Complimentary Contributor Copy . leaves. Sezik of the Gazi University. However. 2010). Kastamonu province (Sezik et al. 1995). the identity of active components. However. 1987). Erzurum. Van and Bitlis provinces (Tabata et al. also known as herbal medicines. bark... The use of herbal products as a medicine. extensive.184 Izabela Konczak. based on a traditional knowledge generated over centuries.. Baytop. or complementary. 1972. Abdullah Dalar and Konrad A. 1995). 1989). systematic surveys with the objective of recording the local knowledge of medicinal plant uses across Turkey. Ankara. Aǧri. Turkey. 1994). Tabata’s team of Kyoto University.000 specific and intraspecific taxa of higher plants of which about 3000 are endemic. In the developing world. fruits and flowers that can be used to promote general health and treat diseases. Ethnobotanical Medicine in Turkey – Historical Perspective The use of wild plants for medical purposes in Turkey is a long tradition. The Turkish flora is estimated to contain more than 11. seeds. With regards to floristic diversity. 70-95% of the population depends on traditional medicine for primary health care needs (Robinson and Zhang. is still the dominant way of curing disease in the eastern part of Turkey. 1984. Turkey is one of the richest countries in the temperate world. 1992). Erzı̇ ncan. 1997). urens. 466 Complimentary Contributor Copy . The most commonly used medicinal herbs recorded by Yesilada (2001) were Plantago species (P. and north-west Anatolia (Yesilada et al. Antioxidant Properties and Phytochemical Composition … 185 et al. 601 for respiratory tract illnesses. which describes plantoriginated remedies obtained from 1011 plants belonging to 107 plant families (Yesialda. dioica and U. 1997).. Central Anatolia (Sezik et al. According to Yesilada (2001) the most frequently employed plant families in traditional Turkish ethnic medicine are the Lamiaceae. for example 1149 remedies were recorded for dermatological problems. montana. Rosaceae and Asteraceae families. The frequency of application of traditional medicinal species is presented in Figure 1. 2001). 1999). Rosa species (R. 2001). A vast number of remedies have been developed to treat similar health problems. The information obtained through these extensive field studies has been used to create the first comprehensive “Data Bank of Turkish Folk Medicine”... major and P. canina and R. 354 remedies) and Urtica species (U. 2001).Health Attributes. 2005). 327 remedies). A few years later the number of plant species used in Turkey as folk remedy has been estimated to be around 1500 (Yesilada. (According to Yesilada. lanceolata). applied in 371 remedies. The frequency of application of commonly used ethnobotanicals of Turkey in traditional remedies. Figure 1. Figure 2. The Eastern Anatolia region is regarded as one of the richest areas of plant biodiversity in Turkey with over 3. This knowledge was developed over centuries. the winters are cold and long. and hot and dry summers. They are followed by very short and rainy springs. Kemaliye. bordering Iraq. 360 for parasitic and microbial infections. it is included in the Irano-Turanian phytogeographical region. and Georgia (Figure 2). Armenia. 2011). Kesis Mountain. Özgőkçe and Özçelik. Complimentary Contributor Copy . Abdullah Dalar and Konrad A. Photograph licensed under the Creative Commonsa Attribution 3. covered with deciduous-mixed forests and deciduous tree steppes (Altundag and Ozturk.0 Unported license by The Emirr. 2001). Eastern Anatolia – A Pot of Gold for Medicinal Plants Eastern Anatolia is the largest (approximately 170 000 km2) of seven geographical divisions of Turkey with 14 provinces. Elbistan-Darende. The most important floral biodiversity centers in Eastern Anatolia are Munzur and Anti Taurus Mountains. 2011).000 vascular plant taxa. which protects it from the moderating effect of sea breezes. with snow lasting for several months.186 Izabela Konczak. which provided suitable conditions for the development of diverse flora (Tan. and Harput and Hazar Lake (Altundag and Ozturk. 278 for nervous system related conditions. The mountainous and strongly fragmentised area offers numerous microclimatic and ecological zones. (http://commons. 1998.wikimedia. Subsequently. Geographical location of the Eastern Anatolia region of Turkey (in black).org/wiki/File:Latrans-Turkey_location_Eastern_Anatolia_ Region. svg). Iran. 174 for immune system and neoplastic diseases. 176 for endocrine and metabolic diseases. The local population has a comprehensive knowledge of traditional herbal medicines which are commonly used to prevent or to treat disease. 425 for urological ailments. of which nearly 800 are endemic. Frequently the same plant or plant parts were used individually or in combination in the preparation of different remedies. Nakhichevan. and the same plant was often used to treat various conditions in different parts of the country. Konczak-Islam for skeleto-muscular problems. 120 for genital system problems and 36 remedies for the haematopoietic and lymphoid systems (Yesilada. 2004). The area is surrounded by coastal mountain ranges. presenting an overview of traditional medicinal plants from Eastern Anatolia (especially from the Van province). Bingöl. Senecio (groundsel or ragwort). Hakkari. Over many centuries a number of races and tribes originated from distant lands settled in Turkey. with 87 used as food and 87 used for medical purposes (Mükemre. Tunceli and Van. Assyrians and Akkadians. Erzincan. and a surgeon with the army of the Roman Emperor Nero. Erzı̇ ncan. grape hyacinth). The knowledge of herbal medicines in this region is still mostly passed on orally (with the exception of a few codices) from one generation of religious healers (referred to as‘şeyh’) and local healers (‘hekim’) to the next. Malatya. the majority of the described plants had originated from the Anatolian peninsula. Complimentary Contributor Copy . As established by Guenther (1934). In his book Pedanius described around 600 plants used for medical purposes by the Greeks. known phytochemical compositions and antioxidant capacities. Most of these plants are still in use by the local inhabitants of Anatolia (Yesilada and Sezik. Ardahan.. 2005). i. Muú. a number of plant remedies used currently in Turkey were described on clay tablets that have survived from the Mesopotamian civilizations. 1997). wrote the book “Materia Medica”. Romans and other ethnic groups. has contributed to an extensive use of plants in daily life as a food and medicine (Coşkun and Gençler Özkan. bringing knowledge of plants and their various uses. Elazig. 211 plant taxa are currently in use. Sumerians. recognised as the precursor to all modern pharmacopeias. Liliaceae (or Muscari type. This heritage. originally of Anazarbus in southern Anatolia. According to Solecki (1976) human fossils from the Middle Paleolithic age (about 60. Centaurea solstitialis (St. 1994).e. Antioxidant Properties and Phytochemical Composition … 187 when Anatolia served as a passageway between the continents of Europe. The continual use of the same medicinal plants for over two thousand years emphasizes the value of an empirical tradition based on trial and error. Barnaby’s thistle). Bitlis. In the Van and Bitlis provinces alone 40 medicinal plants belonging to 19 families are commonly used (Tabata et al. blue bottle. Kurdish Alps. Kars and Iǧdir provinces 87 plant species belonging to 38 families are used (Sezik et al. 2013).Health Attributes. were surrounded by an extraordinary amounts of plant pollen. later identified as Achillea (milfoil or yarrow).. Centaurea cyanus (cornflower. and Hettites. or blue bonnet).. A variety of flora. Kars. 2013). Dioscorides Pedanius (circa 40-90 AD). The utilization of local plants for medical purposes in Anatolia has a long history. while in the Erzurum. and on papyrus documents from the Egyptians. Ethnobotanical surveys undertaken by Tabata and collaborators in the 1990’s and data published by other authors have revealed that a large number of medicinal plants are found in the states of Agri. Igdir. Asia and Africa. Recent study by Tetik and collaborators reported the use of 123 medicinal plants with 15 being recorded for the first time in the Malatya province (Tetik et al.000 years ago) discovered in the Shanidar cave. citing it as evidence that the relationship between humans and plants in this area has developed over a prolonged period of time. fauna and cultures owe their geographical spread to this passageway. The author emphasize the importance of this finding. Erzurum. 2005). Their application in ethnopharmacology in light of scientifically proven physiological activities are also discussed. an ancient village of Eastern Anatolia.. This chapter aims to capture the historical and traditional knowledge in light of the most recent research reports and findings. According to Yesilada (2005). Zphedra altissima (joint pine or woody horsetail) and Althaea (hollyhocks). their uses. Aǧri. combined with the local flora. In Konalga (Êzdînan-Martanis). 2003) and it has been suggested that Materia Medica could be the oldest comprehensive document on Anatolian folk medicine (Yesilada. root sap and gum are utilized for the preparation of herbal remedies. which are used externally on skin (7. Some endemic plants grow in hardly accessible mountainous areas and can only be collected on dedicated trips. Honey and butter are the most frequent applied carriers of plant constituents. Most of the species are used in more than one form of preparation (e..g. including leaf. For example. drying enabled local people to use medicinal plants throughout the year. 1994). eczema. Fresh plants are gathered during summers. Tabata et al. From 182 traditional medicinal plants from Eastern Anatolia described in this chapter 68 plants (37. dried in the dark at room temperature and stored for winters. latex. fresh plants are available from spring to autumn. 2010). bud. branch.. seed.4%) are used externally.8%).6%) and decoctions. compress or bath). Traditionally. In one case. wounds. the decoction as drink. Today the herbs can also be purchased from local herbspice stores (aktars). asthma or even cancerous uterus (Plantago lanceolata and Plantago maritime).5%. Preservation and Application of Traditional Medicine in Eastern Anatolia The majority of traditional medicinal plants until now are collected from the wild. According to Tabata and collaborators 45% of medicinal preparations of Eastern Anatolia are used directly (Tabata et al. Tuzlacı and Doğan. honey. closely followed by application of a fresh plant (12. Abdullah Dalar and Konrad A. alum. This includes placing an intact plant or its parts (e. cortex. Complimentary Contributor Copy .3%). The simplest way of applying herbal remedies is a direct application of fresh or dried plant parts. Taking a medicated bath is especially practiced for the treatment of rheumatism and cold. different part of Juglans regia (seed. pounded and applied directly on skin.188 Izabela Konczak. filtered yoghurt. stem. leaf. The remedy can be also made by boiling herbs in a small amount of water and making a decoction. burns. Dry plant powder or macerated fresh plant material mixed with a carrier can also be used to prepare an ointment. whole leaf) on skin. plant (Eryngium billardieri) juice is used for sniffing to quit smoking. used to prepare an ointment.. Depending on the source. Tabata and co-workers reported earlier that applications of ointment can be made with Vaseline. stylus. bulb. Ointments have the lowest application rate of 5. 1994. Direct application includes an oral uptake and external use. or even flour mixed with soap (Tabata et al. fruit. bark and cortex) are eaten fresh. fungal infections. juice. which is applied on skin or used in a bath. The remedies are used externally to treat rheumatism. 2011. and used as poultice spread on cloth over the skin. Rarely.g. in a bath or as an ointment. bark. Frequently the same plant can be applied externally in various ways: pounded and placed directly on skin. flower.2%) or in bath (3. or used to prepare a poultice that is placed on a cloth and wrapped around the injured area (Kaval. placed fresh on the skin. decoction or ointment) and often the same preparation is utilised in different ways (for instance. the whole plant or its individual parts. Direct application of fresh plant material on the skin is the main external use of herbal remedies presented in this study. Konczak-Islam Collection. with poultice being the most frequent way of application (14. Özgökçe and Özçelik. tuber. butter. shoot. fruit. abscesses. or macerated prior to the use. and dried during winters. root. 1994). 2004. hemorrhoids. juice or latex (extracted by squeezing plant parts) is used externally (< 1%). Antioxidant Properties and Phytochemical Composition … 189 In an earlier study by Tabata and collaborators liquid preparations (decoctions or infusions) were reported to be the second most common way of medicine application in the Eastern Anatolia with a frequency of 39% (Tabata et al. as medicine and food. Dalar and Konczak (2013) reported that herbal infusions are especially common in the Eastern Anatolia and their consumption is an essential part of a lifestyle.7%. Asteraceae and Malva neglecta Wallr.5%) are used for two different ailments. Malvaceae with 11 species and Rosaceae with 8 species. Herbal infusions are prepared using predominantly leaves. aerial parts of Malva neglecta are used for preparation of salad. Malvaceae. is presented in Table 1. 1994). consumption of herbal teas is still preferred due to strong beliefs in their medicinal properties. which made the herbal teas the main dietary beverage. A quarter of the medicinal herbs (25. kidney disorders. The 182 plants listed represent 47 families. hypercholesterolemia. Urticaceae.2%) that are used to treat three ailments. ways of herbal remedy preparation.. flowers. both used for the treatment of 12 and Urtica dioica L. Apiaceae with 12 species.Health Attributes. Plants representing these five families make up 48. For example. Liquid preparations are used to treat a vast variety of conditions. including the plant parts used. 41 plants (22.3% of plants are applied to cure four or more ailments. Traditionally as much as 10 to 15 cups of various herbal infusions were consumed per day.. complete aerial parts and fruits.. hemorrhoids. from gastrointestinal problems.8%) identified in this study are consumed fresh. In the current study we have observed an increase of liquid preparations for internal use to 52. The most frequently represented plant family is the Asteraceae (formerly Compositaceae) with 36 species.. stomach ache. epilepsy and boosting the immune system. These plants are employed multi-contextually.. Half of the traditional medicinal plants listed (91 plants) are used to treat only one ailment. Lamiaceae. Some herbs are used as flavouring agents in cakes. through to treating diabetes. followed by the Lamiaceae (formerly Labiatae) with 21 species. followed by Cichorium intybus L. Traditional Medicinal Plants of Eastern Anatolia: Current Status The list of common examples of ethnobotanical medicines utilized daily in the Eastern Anatolia to cure common and minor ailments. with their primary function being to warm the body during long cold winters and cool summer’s days of the mountain climate. application and medical conditions treated.as ingredients of soups and omelets (Dalar et al. used to treat 10 ailments. The remaining 14. fresh leaves are mixed with yogurt and used as an appetizer or they are cooked and included in main meals . Complimentary Contributor Copy . and frequently there is no clear border between their use as food and as medicine. used to treat 15.3% of medicinal preparations are used as decoction and 16. stomach cancer and constipation. 2012). and there are 24 plants (13. Although currently the black tea of Camellia sinensis leaf is also used. and occasionally in liqueurs and in desserts (as spices).9% of all the plant sources utilized as traditional medicine presented in this chapter. including abdominal pain.6% are used as a fresh plant material. hypertension.. Recently Kaval (2011) reported that 43. with the most versatile being Mentha longifolia L. ) Kaval.. Heracleum antasiaticum Manden Heracleum persicum Desf.. 2013 decoction (int. Diplotaenia cachrydifolia Boiss. Eryngium bornmuelleri Ferula orientalis L. Tuzlacı and Doğan. 2010. diarrhoea Chewing Tuzlacı and Doğan.-ext.) Fresh (on wounds). Kermeğ Rizyane Rizyane RS SD AE wound healing Abdominal pain in children Stomach ache Hellis Soy LF AE Wound healing Diabetes Johrenia dichotoma DC. &Hausskn.. diuretic. Menegiç. Gezan. 2004 Kizvan.. 2013 Eaten fresh. infusion (int. Mükemre. Traditional application of medicinal plants in Eastern Anatolia Family/Species name AMARANTHACEAE Amaranthus retroflexus L. 2004. quit smoking. 1997 Mükemre. ex. abscesses. Cakilcioglu et al. Mill. stoma cancer Wormy wounds. 2011. bronchitis.) Eaten fresh. Kıngor. Sumak FR+SD. fungal infection. WP Ferula haussknechtii Wolff. Decoction (ext. sinusitis. stomach ache. antiseptic. Gımıgımi Siyabu Tüsü. Foeniculum vulgare R. decoction. decoction (int. 2010 Tabata et al. 2011 Kaval. 1994. 2011 Crushed (ext. Rech f. 2010. wound healing. sintenisii Bornm Serzer AE Wound healing Toothache.). Eryngium billardieri Delar. catarrh. gelenk Carminative Rheumatism. Tusi Heliz. 1994. Grammosciadium platycarpum Boiss. LX. 2011 Kaval. juice (sniffered) Infusion (int. BR.. Mükemre.) Tetik et al. FR(mature) APIACEAE Anethum graveolens L.) Fresh (on wounds) Powder Decoction Kaval. 2010 Pistacia khinjuk Stocks Pistacia terebinthus L. 2013 Kaval. Immunostimulant. 2011.. Cakilcioglu et al. stomach ache. FR (immature) GM FR Keratoma. 2011 Özgökçe and Özçelik. mouth diseases Stomach disorders Common colds.) Hoffm. Sıbıt AE Hypercholesterolemia Anthriscus slyvestris (L. çağşir. Cakilcioglu et al. 2011 Rhus coriaria L. diabetes Antifungal. eczema. FR RT RT. 2011 Complimentary Contributor Copy . urinary inflammations Burns. subsp. WP.) Fresh (on wounds).). çedene Eaten fresh Decoction (int. 2011 Kaval. 2013 Kaval. Local names Plant part Therapeutic effect/ailments treated Application References Horoz ibiği LF Sterility Infusion Özgökçe and Özçelik. infusion (int. Sezik et al. AE RS. wounds. 2011 Kaval.) Decoction (int.. poultice (ext.) Powder ( on wounds) Kaval. eaten fresh (after peeling). Tabata et al. 2011 Altundag and Ozturk.Table 1. ANACARDIACEAE Pistacia atlantica Desf. decoction Decoction (int. GM RT. nervend LX.). ) Arenes Arctium minus (Hill. astringent ASCLEPIDACEAE Vinetoxicum canescens (Wild.) colds Diuretic.) Pounded (ext. Anthemis tinctoria L.). Poultice (on wounds). 2011. canescens Vinetoxicum tmoleum Boiss. ointment (poultice mixed with honey) Kaval. expectorant. LF. erythematic. crushed (ext. subsp.) Özgökçe and Özçelik.. 2004 Decoction (int. Özçelik. AE FL. LF. 2011 Complimentary Contributor Copy . ARISTOLOCHIACEAE Aristolochia bottae Jaub. Decoction (int. bovijan Achillea millefolium L.) Boiled with milk Özgökçe and Özçelik. Ex Schott var. Dyspnoea and diabetes Anthemis austriaca Jacq.) Cakilcioglu et al. stomach ache Diabetes. Sezik et al. throat diseases Haemorrhoids. & Spach. 2013 Decoction Kaval. Mükemre. 2010 Tabata et al.. 2011 (ext. 2011 Infusion (int. 2011 Zilasur. subsp. antispasmodic. 2004. RT AE Swelling of stomach. minus Arctium tomentosum Miller var. colds. 2004. Zilasur Bevüjana kuvi Tuzlacı and Doğan. bovijan Papatya Papatya Sarı papatya Sarı papatya Nuserk. subsp. 2004.) Özgökçe and Özçelik. carminative. FL. Arı çiçeği.) Direct application Altundag and Ozturk.) Kaval. 2013 Özgökçe and Özçelik. 2011 Guhkıtık RT. ARACEAE Arum dentrucatum C. zehir otu BD.). FR. LF BD Scabies. inflammation.) Decne. menstrual pounded (ext. eye diseases. 2010. herezan Achillea vermicularis Trin Civan perçemi. glabrum (Körnicke) Arenes Artemisia absinthium L. stomach ache. 2004 (ext. colds. 2011 Decoction (int.) Bernh. Özgökçe and pounded. abscesses. antianemic.. infusion (int. Cakilcioglu et al. Tuzlacı and Doğan. var. sun stroke Loşlek LF Sunstroke Top telli. Özgökçe and Özçelik.). Infusion (int. 1997 (ext. Altundag and Ozturk. RT Swelling of stoma. top telli.A Mey. pubens (Bab. Anthemis nobilis L.. loşlek WP. Anthemis cotula L.) Özgökçe and Özçelik. abscesses.) Decoction (int. ASTERACEAE Achillea biebersteinii Afan. subsp. 2010. 2011 Karibel RT Diabetes Decoction (int.) disorders. stomach disorders Common cold Common cold Diuretic. 2011 Decoction Kaval.) Mükemre. 1994 FL. LF. 2004. Altundag and Ozturk. fungal infection Scabies Pounded (ext. 2010 Fresh (ext. boiled with milk 1994. AE AE AE FL FL LF. juice. red parts Kaval. AE Wound healing. swelling of stomach ache. vidensis. Tabata et al..). urinary antiseptic. millefolium Civan perçemi.Family/Species name Prangos pabularia Lindl.) Bernh.. 2004. kriz. Local names Kerkule Plant part RS Therapeutic effect/ailments treated Wound healing Application Fresh ( on wounds) References Kaval. 2011. tinctoria Arctium minus (Hill. Cakilcioglu et al. WP Stomach ache. ) Eaten fresh Decoction (int. depurative.) DC. 2004 . epilepsy. Centaurea glastifolia L.. vanensis Grierson Inula helenium L. cold. catarrh./int. 1994. 2011. cough.) Decoction (ext. 2011 SH. zerik AE Kaniş. FL Kidney stones AE Haemorrhoids Kaval. boiled long time (int.) Complimentary Contributor Copy Özgökçe and Özçelik.) Ointment ( mixed with Vaseline/cream) Infusion (int. ex Spreng. Altundag and Ozturk. ST Vitiligo. diabetes.) Decoction (then dry) (ext. 2004 Mükemre. 2011 Tuzlacı and Doğan. SH. 2011 Özgökçe and Özçelik. talişk. 2004. Cirsium pubigerum (Desf. infusion (int. spinosum Pet. hindiba. 2004 Kaval. kanej LX. diabetes Included in meals. 2011. 2011 Tabata et al. Koyun gözü. herdemtaze İngüz. Mükemre 2013 Tuzlacı and Doğan. hypercholesterolemia. Gundelia tournefortii L. decoction (int.. 2011. Kelembeşk Şermnik Şaladir LF LF WP Centaurea solstitialis L. subsp.) Powdered (ext.) Poultice (ext. peniruk AE. Cakilcioglu et al. 2011 Mükemre. 2010 Kaval.. Tetik et al.Koch. ash. asthma. armenium Helichrysum plicatum DC.). aphrodisiac. Tabata et al. internal diseases Swelling of the body Eaten Fresh (mixed with water). wound healing Haemorrhoids. + butter (ointment) Decoction (int. Özgökçe and Özçelik. Centaurea virgata Lam. cholesterol. Tabata et al. 2011 Kaval. coffee substitute. 2013 Kaval. Centaurea pterocaula Trautv.. Helichrysum armenium D. diarrhoea. LX.Table 1.) Eaten fresh Decoction (int.) Kaval. 1994.). stomach diseases Diarrhoea. prostate. antiallergic Malaria Infusion (int. Güya brinok Tahlisk FL WP AE Centaurea iberica Trev. 2011. direct application (ext. Altundag and Ozturk.) References Kaval. orexigenic Sevka ağı Guyazerk BB AE Diabetes Kidney stones.C. 2011 Kaval. . S ubsp. stomach ache. 2010. plicatum Inula helenium L. hypertension. subsp. kidney disorders. infusion (int. Centaurea karduchorum Boiss. subsp. RT. solstitialis Cichorium intybus L. SD. decoction (then dry).. 2013. purgative Wound healing Prostate Application Decoction (ext. wound healing. RT Circium sp. Altundag and Ozturk. Özgökçe and Özçelik. (Continued) Family/Species name Artemisia spicigera C. 2011 Kaval. Altundag and Ozturk. var. hepatic. 2011 Venom Diarrhoea Stomach ache.. AE. 2013 Gülülga zer. 2013. subsp.) Abdominal pain.). haemorrhoids.) Özgökçe and Özçelik. Belhok. Tetik et al. 1994. diuretic.) Decoction (int. tournefortii Kilindor Kivariavi RT RT Kenger Helianthus tuberosus L. var. 2004. 2011 Andız RT Chest pain Decoction. headache. Local names Giyabend Plant part AE Bellis perennis L. pseudohelenium Grierson Therapeutic effect/ailments treated Rheumatism. A.) Ointment (with butter. & C.. 2011 Özgökçe and Özçelik. asthma. (by licking) Eaten fresh Decoction (int. Tabata et al.) Poultice.) Ointment (with butter. Tanacetum chilliophyllum (Fisch.) Infusion (int. 2013 Özgökçe and Özçelik. 1994 Tuzlacı and Doğan. 2011 Diabetes Fresh ( as poultice ) Decoction LX Eye redness. RT RT ST RT Havaciva RT (bark) Wound healing. 2011 Tetik et al. balsamitoides (Schultz Bip. Özgökçe and Özçelik. 2010 and wax) Decoction Kaval. 1994 Mükemre. Karamuk Galatürpenk Kırkbaş otu FR.A. colds. hovacov Mıjmejok RT Wound healing FL Stomach ache. RT. Bevüjan AE Diabetes Gıyakeçk LF Wound healing Bevüjan AE Pıtot Zirinç Application Eaten fresh Infusion (int. 2011 Kaval. decoction (ext. Mükemre. chilliophyllum Taraxacum montanum (C. Arvent LX Wound healing Tanacetum argyrophyllum (C. AE LX. headache Scorzonera tomentosa L.) Eaten fresh. ext. argyrophyllum Tanacetum balsamita L. var. decoction (int. Local names Tehlişka geva Kaju Gurutik. 2011 Diabetes. ext.Family/Species name Lactuca saligna L. Lactuca serriola L. 2011.) Int.) Boiss. 2004.) Ointment (with butter and Pinus sp woodext. Deve dilli. var. Mey. colds Echium italicum L.Mey) Schultz Bip.) References Kaval. sinusitis Flatulence Pain. WP Therapeutic effect/ailments treated Hypertension Haemorrhoids. 2011 Özgökçe and Özçelik.. 1997 Berberis vulgaris L. nermend Plant part BD AE BR+FL. Leontice leontopetalum L. 2010 . haemorrhoids Altundag and Ozturk.) Infusion (int. 2011 Jaundince in animals Orexigenic Epilepsy Eaten fresh. gum (ext. 2004 Altundag and Ozturk.A. burns Alkanna orientalis (L. azurea Havacıva otu.) Sezik et al. sterility. orientalis Anchusa azurea Mill. 2004. Bostan otu BR+FL Cancer Complimentary Contributor Copy Kaval. Tabata et al. 2010 Kaval. BERBERIDACEAE Berberis crataegina DC. ewersmannii (Bunge) Coode BORAGINACEAE Alkanna megacarpa D. Mey.. 2013 Tuzlacı and Doğan. Bunias orientalis L.) Grierson. subsp. 2013 Ointment (with butter Tuzlacı and Doğan.) DC.Koch) Tvzel.) DC. kanok. var. Senecio vernalis Scorzonera latifolia (Fisch. subsp. 2004 Özgökçe and Özçelik.C. & C. wound healing Fresh on skin Kaval. 2004. var. goriz RT Wound healing Heliotropium circinatum Griseb.. 2004 RT Sterility Boiled (int.) Medik Cardamine uliginosa Bieb. buki LX Antiseptic Tabata et al. Özgökçe and Özçelik. Complimentary Contributor Copy Tabata et al. 1994 Gevrik LX Antiseptic for wounds and cuts Directly on skin (ext. Altundag and Ozturk.) Powder (ext. poultice (ext.. Munzur otu Nujdar AE AE LF Diabetes Kidney stones Wound healing. Nujdan AE. CUPRESSACEAE Juniperus oxycedrus L. RT Therapeutic effect/ailments treated Venom. 2010 Tuzlacı and Doğan. infusion (int. 2004 Puk. et Huet Cephalaria sparsipilosa Matthews EUPHORBIACEAE Euphorbia sp.) References Kaval. Local names Güzrik. vulnerary Decoction. CYPERACEAE Cyperus rotundus DIPSACACEAE Scabiosa sulfurea Boiss. WP LX Brassica oleracea L..) Ointment (with butter.) Kaval. 1997 Tabata et al.hypertension Decoction. powder (int.. 2004 Abdulselam... powdered (ext.) Özgökçe and Özçelik. Lepidium latifolum L.) Decoction (int. antiseptic Application Eaten fresh. pateri Asymnea rigidum Grosh. wound healing Wound healing. hoşil. 1994. Altundag and Ozturk. 2004 Topalak RT Diuretic Infusion (int. vulnerary Mayasıl otu LF Haemorrhoids Boiled (ext. juri ruvi. 2011.) As above Keringan.) DC.) Moistened. Sezik et al.) Infusion (int.). 2011 Keselmehmut. huşil LX Constipation Eaten fresh Tabata et al. 2011. 2011 BRASSICACEAE Alyssum pateri Nyár. (Continued) Family/Species name Nonea pulla (L. kidney pain.). mıjmıj Plant part LF.) Kaval. ğulik Heartache. daraling.) Özgökçe and Özçelik. orientale (Boiss) Nyman CRASSULACEA Umblicus erectus DC CUCURBITACEAE Bryonia multiflora Boiss. Lahana LF Abscesses Capsella bursa-pastoris (L. stomach disorders. 2010 Tabata et al.. burns. Mükemre. with sugar (ext. diarrhoea. constipation.Table 1.) Özgökçe and Özçelik. & Heldr. 1997 . Altundag and Ozturk. tırye ruvi FR Stomach disorders. bath) Özgökçe and Özçelik.. pounded (ext. 1994. subsp.1994 Tuzlacı and Doğan. 2011. 2004. 1994 CARYOPHYLACEAE Telephium imperati L. 2011 Sezik et al. 2013 Dikenli ardıç FR Rheumatism Decoction (ext. subsp. RT. fresh. Tetik et al. 2004. 2013 Kaval..) Boiss. 2011 Constipation Application Eaten fresh (with water) Eaten fresh LX For wound healing Fresh (ext. kidney pain Decoction. meyan. at kuyruğu AE. var. cough. 2004 Binbir delikotu. Trigonella foenum-graecum L. Özgökçe and Özçelik. 2010 Şilomali LX Constipation Directly on skin (ext. stomach ache. 2004 Kaval. heartache. subsp. & Kit Tan EQUISETACEAE Equisetum arvense L. HYPERICACEAE Hypericum perforatum JUNCACEAE Juncus inflexus L. Medicago sativa L. decoction (int. 2011 Mekik kökü. & Kit. 2004 Kaval. & Buhse Euphorbia macroclada Boiss. glandulifera (Waldst. 2011 Complimentary Contributor Copy . 2004. Local names Hekletis Plant part LX Therapeutic effect/ailments treated Abdominal pain.Family/Species name Euphorbia denticulata Lam.) Özgökçe and Özçelik. Özgökçe and Özçelik.) Özgökçe and Özçelik. var. kantaron WP. giganteum Lag-Foss. fungal infection Tuzlacı and Doğan. 2011 Sütleğen. WP Getgedok AE Urinary problems. bronchitis. diuretic Hypertension...& Spach Euphorbia macrocarpa Boiss. diarrhoea. 2011. 2011. Sezik et al.) Decoction Kaval.) Eaten fresh (with sugar) Özgökçe and Özçelik. sus. References Kaval. E.).) Özgökçe and Özçelik. sativa Trifolium repens L. digestive Decoction (int. yılan otu LX Eczema. Infusion (int. 2011 Kaval. FABACEAE Glycyrrhiza glabra L.) Kaval. fluviatile L. meyan kökü RT Diabetes. 2011 Ahu LF Parasites Infusion (int.) Hespıst Sebelk nefel WH AE Astringent Stomach disorders Poultice (ext. 2011 Pizak RT Kidney stones Decoction Kaval. 2004 Tolk RT Intestinal worm in children Decoction Kaval. 2011 Giyagezık. infusion (int. diarrhoea Euphorbia heteradena Jaub. GERANIACEAE Pelargonium quercetorum Agnew GLOBULARIACEAE Globularia trichosantha Fisch. Sütleğen LX Huşil Euphorbia virgata Waldst. Cakilcioglu et al. sedative Decoction (int. & Mey.) Decoction Kaval. 2011 Pıltan SH Hypoglycaemic Pounded. 1997. FL Stomach ache. . 1994 Prunella vulgaris L. Mükemre. tüylü nane. subsp. subsp. LF. 2010 LABIATEA Mentha longifolia (L. bronchitis. stomach ache. epilepsy.) Decoction (int. Cakilcioglu et al. Local names Plant part Therapeutic effect/ailments treated Application References Güz. (bath)]. LF. stomaache.. 2004. BR+FL WP Sedative. sunstroke. subsp. 2004. catarrh. stomach ache Wound healing. Cakilcioglu et al. punk. headache. Sezik et al. Origanum vulgare L. hypoglycaemic. (bath)] Eaten fresh Decoction (int.) Cough Cold Infusion (int. 2010 Origanum majorana L. bleeding. AE.Table 1. abscesses. longifolia Püng. asthma. LF Rheumatism. cantirik ST WP.) Kaval. WP Decoction [int. 2011 Tuzlacı and Doğan.).) 2011. 2010 Pünk. wounds. ceviz SD. 2010. 2011 Altundag and Ozturk. Tuzlacı and Doğan. 2010 Tabata et al.) Origanum acutidens (Hand-mazz) letswaart Mentha spicata L. Şalba Galabor AE WP. pounded. colds. yarpuz. 2011 Özgökçe and Özçelik. cough. 1994. Koch) letswaart Origanum vulgare L. colds. 2004.) Cakilcioglu et al. Özgökçe and Özçelik. FL WP LF Powdered. havşan. Tuzlacı and Doğan. 2004. CO Haemorrhoids. menstrual pain. flu Mercanköşk Catır.. kekik otu WP Wound healing Tabata et al. infusion (int. heart palpitations. 2011. 2013 Altundag and Ozturk.). Tuzlacı and Doğan. LF. poultice wrapped in a cloth (ext. Kaval. abdominal pains.. subsp. subsp.. Sosın Belgsesing Şalba. 2004. Salvia candidissima Vahl. Özgökçe and Özçelik.. (Continued) Family/Species name JUNGLADACEAE Juglans regia L./ext. antispasmodic./ext. FL BR+FL Common cold. kuş zemulu Cantir. gracile (C. çalba Abdominal pain Antipyretic. 2011 Mentha pulegium L. viride Origanum vulgare L. cold Stomach ache Decoction [(int. eczema Eaten fresh (int. infusion (int. BA...) Hud. Tuzlacı and Doğan. 1994. vulgare Complimentary Contributor Copy . Phlomis armeniaca Wild. 2010 Adaçayı AE Diabetes Decoction (int. 1997.) Infusion (int.) Decoction Infusion (int..) Tabata et al.. pünk AE. 1994. pune. antispasmodic Gall bladder disorders Abdominal pains Decoction (int. 2011. fungal infection. FR. asthma. ointment. 1994 Canter. nane WP. Özgökçe and Özçelik. Özgökçe and Özçelik. Tabata et al. Püjan. flu.) Tabata et al. internal diseases. with honey (int. nane Decoction (int. bronchitis Phlomis pungens Wild. Zemul WP. haemorrhoids. candidissima Salvia multicaulis Vahl. Tabata et al.) Kaval. (mixed with honey). 1994. cancer. & Hohen var.) Tuzlacı and Doğan.) Decoction (int. 2011. neman. diarrhoea.. eczema Gül falcı BD Rheumatism Eaten fresh Crushed with Plantago major leaves (ext.) Salvia sclarea L. LF BB Hypotensive . 2004. nausea Infusion (int. kotschyanus LEGUMINOSAE Trigonella foenum-graceum L. 2004. subsp. Allium macrochaetum Boiss. sinuatum (Cèlak) Rech. internal diseases. LF (juice) Diabetes. 1994. 2013 Dağ sarmısağı RT.) Antiseptic Dyspnoea. pounded (ext.) Eaten fresh Thymbra spicata L. 1997. GM Immunostimulant. Kaval. Local names Gemdaş Plant part WP Therapeutic effect/ailments treated Bleeding. ST bovijana şin Zahter WP Çatıra kuvi AE Immunostimulant Rheumatism. tenuiflora Eremurus spectabilis Bieb. Teucrium chamaedrys L.). LF. F. Tuzlacı and Doğan. Decoction (int.Family/Species name Salvia nemorosa L. crushed (ext.) Tuzlacı and Doğan. common colds. eaten fresh.) Crushed with honey Tuzlacı and Doğan. dağ kekiği BR+FL Keselmehmut.) Complimentary Contributor Copy References Sezik et al. ada çayı LF Catarrh. stomach disorders Eaten fresh Decoction (int. poison. Özgökçe and Özçelik. Tenuiflora E. . 2010 Tuzlacı and Doğan.) Bart.. cancer Medicago minima (L. 2011 Tuzlacı and Doğan. bleeding Included in foods Decoction (int... cancer Stoma disorders. fungal infection. 2010 Özgökçe and Özçelik. Tuzlacı var. 1994. 2010 Tabata et al.) Saturea hortensis L. 1997 Mükemre. kidney pain. Anıh. subsp..) Halbet SD Hypoglycaemic Astragalus brachycalyx Geven. 2010 (int. WP Keselmehmut. 2004 Kaval. stomach disorders. wounds Application Pounded (ext. derman AE.). AE.. Merendera trigyna (Steven ex Adam) Stapf. beyaz ot. 2010 Kaval. Dağ çayı BR+FL. keven SH. cold Salvia verticillata L. LF Respiratory system diseases. 2011. Sezik et al. ringworm Crushed (int. 1994 (int. 2004. haemorrhoids. Teucrium polium L. 2011 Tuzlacı and Doğan. merve. 2013 Özgökçe and Özçelik. 2010 Gulik RT.. 2011 Tuzlacı and Doğan. with lemon juice) Decoction (int. subsp. Özgökçe and Özçelik. 2010 Sirmuk Digestive.) Infusion (int. Gurnik FR Cardiac diseases Pounded or decoction Tabata et al. cancer. urinary inflammations Eaten fresh Tetik et al. Altundag and Ozturk. Hart. LILIACEAE Allium cepa L. Thymus kotschyanus Boiss. tuncelianum Allium sintenisii Freyn Asphodeline tenuior Ledeb. 2004 Tabata et al.). Özgökçe and Özçelik. 2010 Corin Yara otu LF RT Anaemia Wound healing Altundag and Ozturk. & Buhse. SH.. Altundag and Ozturk. stomach disorders Diuretic. Kaval. 2004 Tabata et al. 1997.. 2004. peptic ulcer.-ext. emollient Kidney pain. abscesses Alcea flavovirens (Boiss. common colds. cold Kidney stone.) Decoction (int. asthma References Özgökçe and Özçelik. & Huet ) Boiss. hayro Kidney stone Alcea dissecta (Baker) Zoh.). 2013 Expectorant. skin disorders. LF Kidney pain. arietina (Anders. Govik RT.) Hero Kidney ache. Tetik et al. 2011 (bath)].). 2011 Tuzlacı and Doğan. infertility. WP LF Infusion (int. 2010 Özgökçe and Özçelik. (bath)]. hiru Injury. 2004. stomach disorders. berberu. hiro. Sezik et al. urinary problems Infusion (int. vaginal candidiasis Infusion (int.Table 1. urinary problems. dolik. abscesses.) Cullen et Heywood PLANTAGINACEAE Plantago atrata Hoppe Hatmi Tolik. indigestion. 2011 Tuzlacı and Doğan. WP Tabata et al. korkut. LF RT Expectorant. Altundag and Ozturk. infusion (int. 2010 Sinir otu LF Wound healing Fresh (ext.) Alceae setosa Alef. asthma Decoction (int. Local names Plant part Therapeutic effect/ailments treated Application Huri Anti-inflammatory.) Tuzlacı and Doğan. 1994.. decoction (ext. 1994.) Decoction (int. kidney stones. WP RT. decoction [(int. 2004 Gulorç.) Poultice (ext. Kaval. infusion (int. stomach ache. wound healing. bronchitis.) Özgökçe and Özçelik. 2004 Complimentary Contributor Copy . (Continued) Family/Species name MALVACEAE Alcea apterocarpa (Fenzl) Boiss.. decoction (int. Altundag and Ozturk. kidney stone. antilithic Kidney and bladder stone. 2004 Kaval. Hıra çiçeği. LF LF LF.) Özgökçe and Özçelik. 2013 PAEONIACEAE Paeonia mascula (L.) Özgökçe and Özçelik. WP. Hatmi Hero RT. 2011. gülhorç AE Diabetes Infusion (int. Tolgaküvi.).).) Alcea excubita Iljin Alcea fasciculiflora Zohary Amervans Hatmi FL.) Decoction (int.) Poultice (ext. Althea officinalis Malva neglecta Wallr.) Boiss. Tolgabadinga. 2011 Infusion (int. hero RT.-ext. Alcea hohenackeri (Boiss. residue (ext. AE.) Miller subsp. cough Decoction [(int. ebegümeci. abdominal pain.) Alcea calvertii (Boiss. Özgökçe and Özçelik. 2010. RT WP LF. 2011 Mükemre.) Iljin Alcea kurdica Heru. diuretic. ST Diabetes.. subsp. diabetes. 2010. Nigella sativa RESEDACEA Reseda lutea L.) Decoction (int.& Hausskn. 2011 Kaval. horizontalis (Koch. PORTULACACEAE Portulaca oleracea Tırşoka kera LF Diabetes. SH. 2004. belgbirim. POLYGONACEAE Rheum ribes L. expectorant Powder (boiled in water). 2013 Cüngk Çörekotu LF SD Rheumatism Diabetes. 2011 Özgökçe and Özçelik.). 2011 Pırpar. LF belghavz. poultice (ext. 1994.) Boiss. belhevzar.Family/Species name Plantago lanceolata L. Mükemre. abscesses. ulcer. ilan dili.).). inflamed wounds. semiz otu. ribes.) Özgökçe and Özçelik. infusion (int. 2011. subsp. recovery of incisions. diarrhoea. SD. wound healing. POACEAE Zea mays L. constipation Decoction (int.. Local names Plant part Giyamambel. subsp. 2010. pirpirim AE Urethra infection. pimpirim. 2004. Sezik et al.. antirheumatic wound healing Kaval. rives RT. RANUNCULACEAE Ranunculus kotschyi Boiss. amin Therapeutic effect/ailments treated Stoma disorders. AE LF Chewing fresh Pounded (ext. 2004. 2013 Tabata et al. revas. haemorrhoids. decoction. Özgökçe and Özçelik. Tabata et al. cardiac disorders.) Kaval. diuretic. 2004 Gıyabirin Helhelok LF FR Astringent Prostate Poultice (ext. Mey.) References Kaval. tortuosa (Boiss. rimbez.) Rumex tuberosus L.).) Eaten fresh Kaval. Özgökçe and Özçelik.) Kaval. stomach disorders. Tabata et al. digestion problems. 2013 Tuzlacı and Doğan. 2004 Poultice (ext. 2010 Özgökçe and Özçelik.) Browicz Wound healing. stomach ache Haemorrhoids. diabetes. major L. parpar. ulcer Poultice (ext.. Rothm. decoction (int. 2004 Mısır SL Antilithic. major Plantago maritime L. LF. 2011 P. uşkun.. Tirşok Kuzu kulağı ST (juice). abscesses Application Eaten fresh. sinirotu.) Tuzlacı and Doğan.) Poultice (fresh). belghevizar. Tuzlacı and Doğan. 2004 Revas. Kaval. Cerasus microcarpa (C. Mükemre. 1994. ışgın. fresh on skin (ext. anti-inflammatory. var lutea ROSACEAE Alchemilla hessii. antiphlogistic. 1997 Özgökçe and Özçelik. cancerous uterus Yılan dili LF Cancer of uterus Decoction (ext.A.) Complimentary Contributor Copy . Rumex cripsus L. 2011. mambel. crushed (ext. powder (dry). Tetik et al. boğa yaprağı. 2011. 1994. Özgökçe and Özçelik. haemorrhoids Infusion (int. haemorrhoids. Tuzlacı and Doğan. fresh on skin (ext. 2010. LF giyabironug. zimanugmari Belhevzar. 2004 Muhabbet çiçeği RT Stomach pains Eaten fresh Özgökçe and Özçelik. anthelmintic.) Rech. eaten fresh Rumex acetosella L. 2004 . Salix alba L. mımirk.) Steam of brewed water applied directly (ext. söğüt LF LF LF Rheumatism Toothache Toothache..).) Decoction (int. 2013 Kaval. 1994. subsp. Sezik et al. stewed (int. Kaval.. infusion (int. rheumatism Masicark AE Rheumatism Tuzlacı and Doğan.) (ext. 2004 Tuzlacı and Doğan. haemorrhoids. 2011 Kaval. kidney stones Eaten fresh.) Rosa heckeliana Tratt.) Kaval.. subsp. Altundag and Ozturk.) Directly on skin (ext. 2010. Complimentary Contributor Copy References Cakilcioglu et al. burns Fresh (ext. 2010. domuzturpu Şilank Plant part FR FR FR FR. asthma. tütürk SD. glabrescens Ehrend SCROPHULARIACEAE Verbascum cheiranthifolium Boiss.. Nilsson Rubus caesius L. var. dırne. rheumatism Decoction (bath) Poultice Poultice. stomach ache Common cold. Özgökçe and Özçelik. 2011 Özgökçe and Özçelik. Tabata et al.) Ö. FR Tonsillitis. decoction (bath) Tabata et al.. stomach ache. 1994 Kaval.. 2010 Tabata et al. Crataegus monogyna Jacq.) FR Common cold and cough Decoction Düdırk.). vanheurckiana (Crĕp. Kenari BR Antifungal Fresh (on wounds then burned) Kaval. 2011 Özgökçe and Özçelik. Galium verum L. dry powder in water (gargle). RT. immunostimulant. Kavak Belgebi Belgibizeri. şilan.) Eaten fresh Infusion (int. 2004. Tabata et al. 2011 Süpürge out LF Inflammed wounds Crushed (with wheat flour).. antispasmodic Expectorant. Salix aegyptiaca L. bronchitis. var. 2011 RHAMNACEAE Paliurus spina-christi Mill. infusion (int. Mükemre. yanikotu AE FL Haemorrhoids All cancers. Local names Mahlep Alıç Şekok Şilank.) Powder (int. cheiranthifolium Verbascum speciosum Schrad. Scrophularia libanotica Boiss. syriaca Rosa canina L. strengthen of eyes. 2011. RUBIACEAE Galium consanguineum Boiss. 1994. urartuensis R. Özgökçe and Özçelik. Pyrus syriaca Boiss. Mill. 2011 Tabata et al. haemorrhoids. 2004. kuşburnu. var. (Continued) Family/Species name Cerasus mahalep L. 1994. 2011. sore throat. LF Therapeutic effect/ailments treated Diabetes Sedative. 2011 SALICACEAE Populus nigra L. cough. Kaval. 2011 Babelisk Yoğurt otu. Tuzlacı and Doğan. 1997 Kaval.Table 1. 1994 Masicerk BR+FL Arthralgia. Application Infusion (int. BD: bud.. SD: seed.. 2004. kidney pain Decoction (then dry).. Sezik et al. SH: shoot. Sedıdan. 1997. 1994 Tevri BR. decoction powder (ext. Sezik et al. rheumatism.. common cold.) Tabata et al. SD Haemorrhoids. Valeriana alliarifolia Adams ZYGOPHYLLACEAE Tribulus terrestris L. LF Cancer. BR: branch. FR RT. Int: internal. rheumatism VIOLACEAE Viola odorata L. Özgökçe and Özçelik.. roasted (int. CO: cortex. dırık SD.. tooth cavity Inhaled. 2010. diuretic. Kediotu AE RT Kidney stone Sedative. Bınevşok WH Stomach disorders. WP. THYMELAECEAE Daphne mucronata Royle ULMACEAE Celtis tournefortii Lam. 1994. Tabata et al. Local names Plant part Therapeutic effect/ailments treated Application References Hırdal.) Urtica urens L. Cakilcioglu et al. 1994. FR: fruit. batbat Dağdoğan SD Toothache. urinary incontinence. gezik. diarrhoea Decoction (int.) Kaval. 1994. 2011. dezink. prostatitis. cough Fresh.). 1997 Tabata et al.). decoction (int. çinçar. harundol.. 2004. pıtırak Kaval. ST: stem. 1994. Nicotiana tabacum L. RT: root. diabetes. yığınç. ban out. Kaval.. geznek. Özgökçe and Özçelik.). stomach ache. Tuzlacı and Doğan. GM: gum. directly on tooth (ext. 1997 Hyoscyamus reticulates L.-ext. antispasmodic Decoction (int. gezınk. diarrhoea. Kidney stone. LF: leaf. ısırgan otu. 2011. Özgökçe and Özçelik. 2010 Gezınk. 2004..). fresh (ext. FL: Flower.) RT+SD Intoxication Eaten fresh Tütün LF Wound healing Powder (ext.).Family/Species name SOLONACEAE Hyoscyamus niger L.. Isırgan otu. BA: bark. 2011 Tabata et al. losing weight Eaten fresh (mixed with honey).) Tabata et al.. poultice (ext.) Peganum harmala Üzerlik AE. WH: whole plant. fresh (ext. 2011 Derdoğan FR Diarrhoea Eaten fresh Tuzlacı and Doğan. çinçar LF. AE.. Özgökçe and Özçelik. rheumatism. RS: root sap. 2011 eaten fresh VALERIANACEAE Valeriana officinalis L. cough. 2013 Tea (int. kidney stone. 2010 Özgökçe and Özçelik. 1997 AE: aerial part. SL: stylus.) Tea (int. infusion (int. 2004. stomach ache Decoction (int.) Tuzlacı and Doğan. 2011. BK Toothache. 1994. Özgökçe and Özçelik. Tabata et al. Complimentary Contributor Copy . Sezik et al. URTICACEAE Urtica dioica L. ğıjırtken. Sezik et al. hargel. Cakilcioglu et al. LX: latex.) Kaval. joint pain. BK: bark. Ext: external. BB: bulb. WP Diarrhoea. Mükemre. 2004. 2004. Trigonella foenum-graceum.. Rheum ribes. Artemisia spicigera. Alcea kurdica. Tanacetum argyrophyllum. Echium italicum. Artemisia spicigera. Euphorbia heteradena. Teucrium polium. Viola odorata Helichrysum armenium. Glycyrrhiza glabra L. Teucrium chamaedrys. Verbascum cheiranthifolium. Valeriana officinalis. Telephium imperati . Rumex acetosella. Rumex tuberosus. Euphorbia virgata. Malva neglecta. Alkanna orientalis. Rheum ribes. Plantago lanceolata.. armenium. Arctium minus (Hill. Cerasus mahalep. Tanacetum balsamita. Inula helenium. Rubus caesius. Anchusa azurea Mill.. Nigella sativa. Selected ailments and their traditional remedies used in Eastern Anatolia Health condition Wounds. Urtica dioica Diplotaenia cachrydifolia. Portulaca oleracea. var. Mentha longifolia. Mentha spicata. Eremurus spectabilis Bieb. Aristolochia bottae. Ranunculus kotschyi. Zea mays. azurea. Alyssum pateri Nyár. pateri. Rumex cripsus. Tanacetum chilliophyllum. subsp. Allium cepa. Origanum vulgare. Helianthus tuberosus L. Alcea calvertii. Hypericum perforatum. Rosa canina. Paeonia mascula. Anthemis austriaca. Daphne mucronata. Grammosciadium platycarpum. Teucrium chamaedrys. var. Prunella vulgaris. Anthemis tinctoria L. Taraxacum montanum (eye redness) Urtica dioica. Portulaca oleracea. Rosa canina. Urtica dioica Achillea millefolium . Prangos pabularia Pistacia khinjuk. Galium consanguineum. Cichorium intybus. Teucrium polium. var lutea. Centaurea virgata. Heracleum persicum. Scorzonera tomentosa. Salvia sclarea. Plantago lanceolata. glandulifera. Euphorbia denticulata. pubens. Malva neglecta. Alcea hohenackeri. Lepidium latifolum. Origanum majorana. Berberis crataegina. Plantago major. Alcea calvertii. Asymnea rigidum. Arum dentrucatum. Anthemis cotula. Equisetum fluviatile. var. subsp. Salvia candidissima. Cardamine uliginosa. Alcea fasciculiflora. Achillea biebersteinii. Salix alba.. Allium cepa Alyssum pateri. Phlomis armeniaca. Juncus inflexus. Anchusa azurea Complimentary Contributor Copy . Urtica dioica. Bryonia multiflora. Salvia nemorosa. Pistacia atlantica. Capsella bursa-pastoris. Viola odorata. Cichorium intybus. Alcea flavovirens. injuries Stomach disorders Abdominal pain Carminative /flatulence Constipation Haemorrhoids Diabetes Rheumatism Diuretic Kidney pain Kidney stones Gallbladder disorders Urinary inflammation Cardiac disorders Eye problems Common cold Traditional remedy Nicotiana tabacum. Mentha longifolia. Helichrysum armenium D. Ferula haussknechtii. Achillea millefolium. Rubus caesius. Centaurea karduchorum. Achillea millefolium. Alyssum pateri. Anthemis nobilis . Origanum vulgare. Rheum ribes. Glycyrrhiza glabra L. Urtica dioica. Malva neglecta. var. Trifolium repens. Johrenia dichotoma. Medicago minima. Alcea apterocarpa.) Bernh. tournefortii. glandulifera. Verbascum speciosum. Cyperus rotundus. Asphodeline tenuior. Alkanna megacarpa. Glycyrrhiza glabra. Rosa heckeliana. Berberis crataegina.. tinctoria. Eryngium billardieri. Rumex acetosella. Alcea apterocarpa. Ferula orientalis. Juglans regia. Alcea hohenackeri. Salvia multicaulis. Achillea biebersteinii. Helichrysum armenium. Peganum harmala Foeniculum vulgare. Cichorium intybus. Alcea kurdica. Tribulus terrestris. subsp. Juniperus oxycedrus. Diplotaenia cachrydifolia Boiss. Urtica urens. Malva neglecta.C. Thymus kotschyanus. Alcea hohenackeri. Salvia verticillata.Table 2. Malva neglecta Pistacia terebinthus. Taraxacum montanum. Artemisia absinthium. Rubus caesius Mentha pulegium. Merendera trigyna. Origanum acutidens. Euphorbia macrocarpa. Mentha longifolia. Senecio vernalis Euphorbia sp. Rosa canina.. Tribulus terrestris. Ferula orientalis. Mentha spicata. Berberis crataegina. Teucrium polium. Reseda lutea L. Scrophularia libanotica. Plantago atrata. Pyrus syriaca. Circium sp. Plantago lanceolata. Arctium tomentosum. Achillea vermicularis. Peganum harmala. Gundelia tournefortii L. Heracleum antasiaticum. Valeriana officinalis. Alcea fasciculiflora. Arctium minus. Portulaca oleracea. Helichrysum plicatum. Plantago lanceolata. var. Bellis perennis. Juglans regia. Juncus inflexus. Malva neglecta Anthriscus slyvestris. Portulaca oleracea. Arctium minus. Populus nigra. Juglans regia. Anthemis nobilis. Cichorium intybus Equisetum fluviatile Rhus coriaria.C.Health condition Malaria Hypocholesterolemia Hypertension Burns Antiseptic Toothache Tonsilitis Parasites Venome poisoning Traditional remedy Centaurea solstitialis L. Galium verum Rhus coriaria L. Salix aegyptiaca Rubus caesius Pelargonium quercetorum. Allium macrochaetum Centaurea iberica. Cephalaria sparsipilosa Daphne mucronata.. Hyoscyamus niger. Nonea pulla Complimentary Contributor Copy . Asymnea rigidum. Scabiosa sulfurea. subsp. armenium. Alkanna megacarpa. solstitialis Anethum graveolens. Helichrysum armenium D. subsp.Globularia trichosantha. Salix alba. subsp. glabrescens Ehrend is used for the treatment of all types of cancers. These plants represent extremely valuable resources for future research aimed at identification of active constituents and possibly . Helichrysum armenium D. subsp.g.6% of the total number) have been identified for the treatment of wounds and 33 herbs (18. Konczak-Islam Table 2 presents the list of selected ailments and medicinal plants used in their treatment. and additional 13 plants (7. Contemporary research indicates that these compounds significantly influence the way a plant responds to stress.204 Izabela Konczak. 7. This table shows that frequently multiple herbs have been identified to treat the same health disorder. Traditional medicinal plants presented in this chapter may provide valuable leads for identification of physiologically active natural compounds for pharmaceutical uses.3%) by Kaval (2011). and hypocholesterolemia with Anethum graveolens. The percentages of herbs used to treat these two common health conditions listed in this chapter are higher than those cited by Kaval: 10.8% for stomach disorders (Kaval.1%) for the treatment of stomach disorders. The percentage of herbs to treat diabetes presented in this listing is double that reported earlier (7. tonsillitis.2%) utilized for the treatment of kidney disorders. A relatively high number of plants (12 plants. Twenty five herbs (13.7%) are in use to alleviate the symptoms of diabetes. 2011).1%) identified to cure specifically kidney stones. while Plantago lanceolata and Plantago maritime are used to treat the cancer of uterus. In the last group six plants belong to the Malvaceae family.development of new anti-diabetic or anti-cancer agents. Natural medicines to treat both conditions are in high demand. Galium verum L. Eryngium bornmuelleri is used specifically to cure stomach cancer. For example. and Cichorium intybus.7%) are used for the treatments of rheumatism. Complimentary Contributor Copy . Table 2 presents also 15 medicinal plants (8.1% for wound healing and 12. 32 herbs (17.6%) are applied in cancer treatment. and stomach cancer. such as gall bladder stones. Abdullah Dalar and Konrad A. hypertension with Equisetum fluviatile. 6. The application of herbal remedies from Eastern Anatolia listed in this chapter addresses common illnesses (e. In Eastern Anatolia a high number of plant sources have also been identified for their treatment.C. For example. abdominal pain or common cold) as well as specific conditions. the percentage of plants utilized to cure this condition is in agreement with earlier report by Kaval (2011). The Most Versatile Herbs: Phytochemical Composition and Pharmacological Activities The majority of original research papers and review publications dedicated to ethnobotanicals from Eastern Anatolia that have been published to date are aimed at providing information on the identity of the medicinal plants and their traditional uses. Two common chronic conditions related to the modern lifestyle are also treated. Physiological activities of plants and plant-originated products arise from the presence of secondary metabolites in the tissue used. Armenium. Relatively high number of plants (14. Alternative uses of a few members of the same plant family to cure one ailment may indicate a presence of the same active components. Diabetes and cancer are two prevailing health conditions of the contemporary society. . luteolin 7-O-rutinoside and luteolin 7-O-glucuronide in n-butanol extract of the aerial parts of M. These compounds are often highly efficient antioxidants. longifolia from Eastern Anatolia (Orhan et al.) Hudson subsp. apigenin 7-O-glucoside isolated from M. understood over generations of ‘trial and error’. 1990) and photooxidative injuries and subsequently produce more antioxidants to alleviate the harmful effects of free radicals. longifolia.47±7. including the reduction of oxidative stress. asthma. In order to clarify the reasons behind their efficacy. typhimurium TA1537: 0. Many parts of M. and are formed in pairs along a square-shaped stem. According to Kosar and co-workers. ultraviolet light (UV-B) and heavy metals.g. 2012). This quality contributes towards their physiological activities and numerous health benefits. lanceolate. are gathered to form spikes at the tip of the stems. The sources of this unique flavor are the Complimentary Contributor Copy . Mentha sp.. longifolia (L. which contains large amounts of phenolic acids and flavonoids in a variety of structural forms. longifolia is 107. four plants have an outstanding frequency of application .2% (S. Orhan and collaborators identified flavonoids luteolin 7-O-glucoside. hemorrhoids and sunstroke. 2003). cough. their phytochemical composition is discussed. are rich sources of tannins. dihydroflavonols and chalcones (Motamed and Naghibi. saponins. spreading through underground rootstock. can act as reducing agents. plants growing at high elevation are exposed to an increased flux of solar ultraviolet-B radiation (Blumthaler and Ambach. It is also used as an antispasmodic agent (Table 1). longifolia exerted strong antimutagenic activities (Ames test) with inhibition rates ranging from 27.1 m in height.97 mg QE (quercetin equivalent)/g DW. longifolia represents the Lamiaceae family. in case of photooxidative injury in leaves). flavonones. A high number of Eastern Anatolia’s herbal remedies are collected in mountainous areas. protection against coronary heart disease or cancer (Seelinger et al.4 μM/plate) to 91.7% (Gulluce et al. heart palpitations. including leaves. Flavonoids exhibit pronounced antioxidant capacity. (mint) is a very popular herb. as a decoction and herbal infusion.2 μM/plate) and inhibited yeast growth (yeast deletion assay) from 4% to 57.Health Attributes.5 .61% (Raj et al. white to mauve. represented by 20 to 30 species growing mostly in temperate regions. flu. Out of the 182 plant species listed in Table 1. M.1% (S. are used in herbal teas or as additives.2 mg GAE (gallic acid equivalent)/g DW (dry weight) and flavonoid content is 42. abdominal pains.they are used to cure 10 or more different health disorders. including flavones. 2010).. and externally. 2013). phenolic acids and flavonoids (Kosar et al. stomach ache. 2008). 2010). In the Eastern Anatolia the plant is used to treat common cold. Mentha is also used as a condiment in various foods such as beverages. which can reach 0. Antioxidant Properties and Phytochemical Composition … 205 anthocyanins are implicated in tolerance to environmental stress. The herb is collected from the wild and can be cultivated for its essential oils. Mentha longlifolia L. which mitigate injuries by scavenging free radicals and reactive oxygen species (e. bronchitis. The same authors reported pronounced antimutagenic activity of these flavonoids. It is a fast growing. ice creams.. The contribution of flavonoids to the total phenolics is high: 39. flowers and stems. menstrual pain. including drought. Similarly.21±34. It is used internally.. 2004). Accordingly. The total phenolic content of M. due to their aroma and flavor. catarrh. and also facilitate plant resistance to pathogens (bacteria and fungi) and herbivores (Gould. perennial plant. as a decoction in a bath. hydrogen-donating antioxidants and singlet oxygen quenchers (Hvattum and Ekeberg. 2004). flavonols. candies. cakes and in meats to adjust their taste and odor. internal diseases. Small flowers. headache. typhimurium TA1535: 0. The leaves are soft. d-cadinene.6%). β-caryophyllene (2. Nandagopal and Kumari (2007) named C. known locally as hindiba or kanej. colic. is an erect perennial herb 80-90 cm in height. belching. C. An interesting preparation has been developed for epilepsy treatment. antiulcerogenic. antiinflammatory. a reddish leaf and a fleshy taproot up to 75 cm in length.6%). 3octanol. thymol acetate. skin diseases. Basal leaves are shortly petiolate. asthma. pinocamphone. liver tonic. flatulence.. and alexeteric. intybus is an edible and a medicinal plant. and is used to prepare decoctions and infusions (Table 1). diuretic. leprosy. have medicinal value (Cowan. sativum). occasionally white or pink. C. salvial-4(14)-en-1-one. predominantly with bright blue flowers. heapatomegaly. hemorrhoids. intybus a ‘multipurpose medicinal plant’ used as: antihepatotoxic. C30. which are baked. It is also used in herbal mixtures in the symptomatic treatment of digestive disorders such as flatulence. It is cultivated in Europe for their roots (C. caryophyllene oxide. chronic and bilious fevers. humulene epoxide II) were present at levels of less than 1%.secondary metabolites that are highly enriched in compounds based on an isoprene structure. p-cymene. trans-piperitone epoxide (4. pulegone (15.9). terpinen-4-ol. prostate. Gulluce and collaborators identified 45 compounds comprising the essential oil of M. stomach ache. flowers and aerial parts. impotence. stomachic. epilepsy. it is also used to treat AIDS. limonene. present in M. β-copaene. indigenous to Europe. γ-terpinene. cancer. β-myrcene. Many terpens. are dried and ground into a fine powder for later use in a variety of herbal remedies. dysmenorrhoea. gout. inflammations. kidney disorders.0%). camphor (1. dihydro carvone.6%). hyperdipsia. All plant parts. 1994). intybus is one of the broadly used herbal medicines. and epigastric distension as well as to promote renal and digestive elimination functions. cardiotonic. (common chicory) of Asteracea family. It is useful in vitiated conditions of kapha and pitta. bicyclogermacrene. which occur as monoterpens. Konczak-Islam essential oils . cissabinene hydrate. strangury. sabinyl acetate. linalool. pharyngitis. C. depurative and cleansing agent. allergic conditions of skin. β-pinene. spathulenol. ground.1%). γ-cadinene. febrifuge. β-atlantol. longifolia and camphor. Cichorium intybus L. hypercholesterolemia. burning sensation.9%). depurative. leaves.6%). anorexia. such as menthol. diabetes. The dominating compounds of this mixture were: cis-piperitone epoxide (18. ophthalmia. cholagogue. and tetraterpenes (C10. 2007). The herb is also used as an animal feed. and piperitenone (1. slow digestion. α-terpineol. digestive. and C40). bornyl acetate. The flowers open early in the day and close soon after noon. hypertension. This chapter reports its use for abdominal pain.1%). carvone (4. piperitenone oxide (14. Western Asia. longifolia ssp. thymol (6. hepatic. emmenagogue. whereby a decoction prepared by boiling the pounded roots for 2-3 hours is taken on an empty stomach in the morning for 3 consecutive days (Tabata et al. insomnia. Stems are stiff and have length from 20 to 100 cm. αcaryophyllene. triterpenes. menthone (7. as well as hemiterpenes (C5) and sesquiterpenes (C15). Abdullah Dalar and Konrad A. β-bisabolene. γ-muurolene (1. C20. (Z)-β-ocimene. (E)-β-ocimene.5%). and used as a coffee substitute and an additive. wound healing as well as antiseptic. appetizer. diterpenes. vomiting. splenomegaly.7%). dyspepsia. An important component of essential oils are terpenes. jaundice. amenorrhoea. including roots. nepetalactone. inytbus is a typical Mediterranean plant. longifolia from the north-eastern part of Anatolia (Gulluce et al.206 Izabela Konczak. isomenthone (6. α-terpinene. β-bourbonene. Egypt and North America. cephalalgia. intybus var. The remaining 33 compounds (α-pinene. This medicinal plant is consumed fresh.4%).. oblanceolata. Aerial parts are used for preparation of meals or salad and roots are used as a chewing gum. 1999). splenitis and tachicardia Complimentary Contributor Copy . Antioxidant Properties and Phytochemical Composition … 207 (Nandagopal and Kumari. and lactucopicrin found in the roots and the heads of the plant and considered to be responsible for the bitter taste of chicory. In Turkey a number of Malva species are edible as leafy vegetables (known as tolık or ebegümeci) prepared in various forms. shallowly lobed leaves. 2003). lactucin. 8desoxylactucin. The leaves contain β-13-dihydrolactucin.. cyanidin 3-O-glucoside. bitter sesquiterpene lactones. 2007). external wounds. Complimentary Contributor Copy . chicoric acid (dicaffeoyltartaric acid). who reported that the main sesquiterpene lactones of C. 2012). 8 deoxylactucin. intybus also has been reported (Kim. present in roots and aerial parts. they are stuffed with bulgur wheat or rice or are boiled and used as a side dish (Dalar et al. it has been reported that chicory root extract decreased cholesterol absorption by 30% (p<0. lactucopicrin and its derivatives. The main phenolic compounds of leaf include monocaffeoyl tartaric acid. Malva neglecta Wallr. intybus revealed immunomodulatory and anticancer properties (Hazra et al. deoxylactupin. ixerisoside D and magnolialide. crepidiaside B. 2000.5-di-O-β-d-glucoside (Nørbæk et al. The sesquiterpene lactone chemistry of Cichorium species is dominated by lactucin-like guaianolides and their glycosides. For example. 2002). This information is in agreement with Bais and Ravishankar (2001). According to Varotto and collaborators numerous compounds such as inulin. abdominal pain. root of the C.Health Attributes. intybus roots lowered the serum and liver lipid concentration in rats (Kim and Shin.05) in the perfused ileum. common colds. intybus accumulates two major groups of physiologically active phytochemicals: phenolic compounds and sesquiterpene lactones.and eudesmane-type sesquiterpene lactones and their glycosides. 2000). flavonoids and vitamins present in the tuberous root of C.. containing delphinidin 3. Ahmed et al. although regarded elsewhere as a weed. intybus are lactucin. 2001). cyanidin 3-O-(6′′ malonyl) glucoside. Moreover. Moreover.5di-O-(6-O-malonyl-β-d-glucoside). intybus are of medical importance (Varotto et al. intybus plant produces a small number of germacrane.. as well as tentatively identified an acylated derivative of quercetin 3-O-glucoside. antihepatoxic effect (the ability to prevent liver damage) of C. delphinidin 3-O-β-d-glucoside-5-O-(6-O-malonyl-β-d-glucoside) and delphinidin 3. jacquinelin. including kidney and bladder stones. lactupin. and loliolide. Flower petals of C. while the root contains a mixture of methyl and ethyl esters of p-hydroxyphenylacetic acid... Kisiel and Zielinska (2001) reported that root and leaf samples of C. Flowers are borne in fascicles of the leaf axils. C.. intybus are a rich source of anthocyanins. indigestion and vaginal candidiasis (Table 1). quercetin 3-O-glucuronide and luteolin 7-Oglucuronide (Innocenti et al. bronchitis. cichorioside B and sonchuside A. Pharmacological investigation of the root extract of C. intybus contain sesquiterpenoid aglycones and glycosides. 1998). Laveli (2008) along with the above named phenolic compounds reported the presence of quercetin 3-O-glucoside. The plant is widespread in all regions of Turkey and. peptic ulcer. 2002). eudesmonolides and guanomanolides (Bais and Ravishankar. in Turkey it is used as food and folk medicine in a number of conditions. Further. Animal studies have revealed that preparations from C. delphinidin 3-O-(6′′ malonyl) glucoside. abscesses.05) in the jejunum and by 41% (p<0. The leaves and roots also contain trace amounts of other bitter sesquiterpene lactones such as guaianolides. which is in agreement with its traditional uses to reduce hypercholesterolemia. (common mallow) of Malvaceae family is an annual herb with orbicular. stomach disorders. infertility. chlorogenic acid (5-O-caffeoylquinic acid). coumarins. 2005). delphinidin 3-O-(6-O-malonyl-β-d-glucoside)-5-O-β-dglucoside. 19 mol Fe+2/g DW).45 mol Fe+2/g DW). fruit. stem and root (Dalar et al.3±6.2±0. neglecta plant their level ranged from 0.8 mol TE/g DW). Complimentary Contributor Copy . neglecta exhibited a similar total reducing capacity to Coptis ohinensis Franch (112. and FRAP on a single electron transfer (SET) mechanism. neglecta is limited. neglecta leaf extract had the highest total reducing capacity (FRAP assay) of 190.6 mol TE/g DW) of M. 4-Hydroxycinnamic acids made the second largest group of phenolic compounds and contributed approximately 10 to 18% of the total phenolics.8 mol TE/g DW) and fruit (448.208 Izabela Konczak.5% (leaf) of the total phenolics. The FRAP values of M.21±0.08±0. (common selfheal) (56. Alcohol-based (80% methanol and 1% HCl (v/v) in water) extracts of various plant parts exhibited comparable antioxidant capacity to that of traditional Chinese medicinal plants. represented 29.28 (leaf) mg RE (rutin equivalent)/g DW.. respectively.2±14.10±1.4±3. 2012). involving oxygen radical scavenging and reduction of oxidizing agents. 2012). neglecta compared favorably with 30 traditional Chinese medicinal plants evaluated by Wong and collaborators (Wong et al.22±3. 2012).12±0. which.8±1. and the leaf had a similar reducing capacity as Viola yedoensis Mak. These two assays are based on two different mechanisms of action: ORAC is based on a hydrogen electron transfer (HAT). In the different parts of M.51±6 mol TE/g DW) and parsley (529. stem (506.9±14.38±4. 2012). Antioxidant capacity of M. 2012). as well as various groups of phenolic compounds.8 mol TE/g DW) (Dalar et al. neglecta has been investigated using two reagent-based assys: oxygen radical absorbance capacity (ORAC) and ferric reducing antioxidant power (FRAP).3 mol Fe+2/g DW) and root (39. neglecta had similar ORAC values to those of basil (702±4 mol TE/g DW) and thyme (825±2.. respectively. The highest correlations were obtained for hydroxycinnamic acids and antioxidant capacities. The flower (795. may offer more efficient protection from oxidative stress. The distribution of flavonoids in various plant organs followed the order: root<stem <fruit<flower<leaf. Konczak-Islam Research data on the composition of phytochemicals in M.97±0. neglecta were comparable with those of the following Chinese medicinal plants: Portulaca oleracea (common purslane) (54. A strong positive correlation between the levels of total phenolics.2±1.56 mol Fe+2/g DW) and Taraxacum mongolicum Hand (dandelion) (54.. Abdullah Dalar and Konrad A. The leaf contained the highest level of phenolics and was followed by flower.5±1.07 (leaf) mg CAE (caffeic acid equivalent)/g DW.6 mol Fe+2/g DW). neglecta extracts indicates that phenolic compounds are the sources of antioxidant capacity (Dalar et al. Dalar and collaborators reported that the level of total phenolic compounds in different plant parts ranged from 3.91±2.56±0.2 mol Fe+2/g DW.6 mol TE/g DW) and leaf (898. The level of flavonoids ranged from 0.9 mol TE/g DW) of M. With regards to the distribution of 4-hydroxy-cinnamic acids in various plant organs the following order was observed: root˂stem˂fruit˂ flower˂leaf.. (199.7 mol Fe+2/g DW and was followed by flower (109. Prunella vulgaris L.. fruit (56.04 (root) to 2. This indicates that the distribution pattern of 4-hydroxycinnamic acids was identical to that of total phenolics and total flavonoids (Dalar et al.02 (root) to 7.28 mol Fe+2/g DW). Flowers of M.3% (root) and 14.7% (leaf) of the total phenolics. The levels of total phenolics in M. neglecta alcoholic extracts were similar to those of celery (419. Dalar et al..40.48±0.3±6.3 mol Fe+2/g DW). which represented 14. 2012).39 mol Fe+2/g DW) (Dalar et al. 2006).3 (root) to 17.1±1.40..7 mol TE (trolox equivalent)/g DW]. It can be expected that plants sources that exhibit potent antioxidant capacities in both assays. stem (51. and antioxidant capacities of the M.1% (root) and 41. The oxygen radical scavenging capacities (ORAC assay) of the root [425.3 (leaf) mg GAE /g DW. M. common colds. Pseudomonas aeruginosa. high in minerals (especially iron). 2006) and can therefore be used in the prevention and treatment of cardiovascular conditions. sylvestris on some bacterial and fungal contaminants of wound infections. kaempferol 3-O-rutinoside. Aspergillus fumigatus and Candida albicans (Zare et al. indigestion and vaginal candidiasis (Table 1). Fischer. Earlier studies have shown that U. sharply toothed leaves and white. 2003). and were especially effective against Streptococcus pyogenes. neglecta are the primary source for the preparation of decoctions used in the traditional medicine of Eastern Anatolia. peptic ulcers. herbaceous plant with opposite. anemia and allergic rhinitis (Bone and Mill. flavonols (rutin. 1988). dioica can be assigned mostly to the presence of 3 groups of phytochemicals: phenolic compounds. external wounds. are the potential sources of medicinal properties of this plant. 1999). U. dioica leaves (Riehemann et al. stinging trichomes. Other reports described the uses of U. dioica were a subject of multiple studies. 1980) and minerals (Weiss. kaempferol 3-Oglucoside. Seeds and aqueous extracts of the aerial parts of this herb have also been occasionally used in Turkey as herbal medicine by cancer patients (Akbay et al. 2008). dioica represents a very nutritious and easily digested food. U. In agreement.. Urtica dioica L.. and biodynamic agriculture. Decoction of M. and Proteus vulgaris. dioica leaf is a valuable source of vitamin C (Martınez-Para and Torija-Isasa. Riehemann and collaborators reported inhibition of proinflammatory transcription factor NFkB by a standardized extract of U. Leaves of M. neglecta. abscesses. especially flavonoids and hydroxycinnamic acids. which is in agreement with the finding that these two groups of phenolic compounds are the major contributors to the composition of phenolic compounds of M. stomach disorders.. The traditional medicinal uses of U. The stalk contains sclerenchymatic fibers. Zare and collaborators investigated the effect of chloroform. gout. which can be used in the textile industry (Pinelli et al. 2000. 1997). abdominal pain. dioica to treat eczema.Health Attributes. This herb grows in nitrogen-rich soils (nitrophilous herb) and is widely distributed throughout the temperate regions of the world. It has a long history of use as a traditional medicine and is utilized in cosmetics. 1993). Chrubasik et al. ethanol and water extracts of M. carotenoids and fatty acids. 1997). a clinical pilot study established that consumption of a stew made of U... Ethanol-based extracts exhibited the highest antibacterial activity. followed by Staphylococcus aureus. The physiological activities of U. (nettle) of Urticaceae family is a perennial. textiles.. Moreover. neglecta is commonly used in Eastern Anatolia to heal wounds (Table 1). dioica enhances the effectiveness of antirheumatic non-steroid anti-inflammatory drugs (NSAID. Antioxidant Properties and Phytochemical Composition … 209 followed by those for flavonoids and antioxidant capacities. quercetin p-coumaroyl-glucoside. dioica: hydroxycinnamic acid derivatives (main compounds being chlorogenic acid and 2-Ocaffeoyl-malic acid). bronchitis. Pinelli and collaborators reported the presence of three classes of phenolic compounds in the leaf and stalk of U. isorhamnetin 3-O-rutinoside) and anthocyanins Complimentary Contributor Copy . 2012). The exceptionally high ORAC value of the leaf extract supports their medicinal properties with suppression of oxidative stress as one of the potential mechanisms of action. vitamin C and provitamin A (Allardice. dioica in Eastern Anatolia include treatment of kidney and bladder stones. infertility. Aqueous and chloroform extracts had more pronounced antifungal activity against Aspergillus niger. However the physiological activities of U. neglecta and M. dioica leaf extract inhibits platelet aggregation (El Haouari et al. These results suggest that phenolic compounds. . Contemporary research revealed pronounced health-enhancing properties of the numerous phenolic compounds listed above. rosinidin 3-O-rutinoside. The major secondary metabolites of M.the dominating phenolic compound of U. Stalk extracts also contain chlorogenic acid. dioica accumulate diverse plant secondary metabolites: phenolic compounds and essential oils in M. Complimentary Contributor Copy . dioica leaf is among the most suitable plant sources of fatty acids for human nutrition with a high n-3 to n-6 acids ratio of 3. and a caffeic acid derivative as well as flavonols and anthocyanins (Pinelli et al. is the common quality of these broadly applied. C. enzymes activity and cholesterol and histamine metabolism. The dominating fatty acid in leaves was the α-linolenic acid.6%. Kroon and Williamson. dioica. They reduce coronary heart disease risk. 2005. 2009. 2010b). phenolic compounds and sesquiterpene lactones (terpens) in C. 2-Ocaffeoyl-malic acid. Chlorogenic and 2-O-caffeoylmalic acid are the main phenolic compounds (76. Guil-Guerrero and collaborators have concluded that young leaves of U. neglecta identified to date are phenolic compounds. longifolia. they are involved in immune function. carotenoids and fatty acids in U. with palmitic acid being the dominating compound (17. 2003). βcarotene and β-carotene isomers were the major carotenoids. exhibit antimutagenic. lutein isomers. Chlorogenic acid . This rich composition may be the key to their exceptional curing properties observed by many generations of traditional healers.is the active anti-diabetic agent of Nerium indicum leaf. Neoxanthin. anti-obesity and chemopreventative properties (Pandey and Rizvi. representing various groups and resulting in exceptionally rich composition of plant secondary metabolites. an Indian folk remedy for type II diabetes (Ishikawa et al. Kim et al. They have reported the presence of 9 carotenoids in the leaves of U. lutein.5%) and gadoleic acid (1. including modulation of gene expression.. they frequently possess potent antioxidant capacities and a wide array of biochemical functions resulting in promotion of good health. For all leaf maturity levels. antidiabetic. Guil-Guerrero and collaborators conducted a comprehensive evaluation of carotenoids and fatty acids in different parts of U. Flavonoids are especially widely researched due to their pleiotropic health beneficial effects.51. palmitoleic acid (2. For example. violaxanthin and lycopene were also important contributors in specific leaf maturity stages (Guil-Guerrero. The concurrent presence and high level of phytochemicals. also present in seeds.7%).2%) and in root: oleic acid (8. p-coumaric acid.210 Izabela Konczak. Kim et al. anti-viral. longifolia. dioica. dioica are a valuable source of fatty acids and carotenoids for human nutrition.4% in seeds) and little amounts of stearic acid. intybus and U. Konczak-Islam [peonidin 3-O-rutinoside.. dioica plant.. all-round traditional medicinal plants. intybus and phenolic acids. The same authors have established that U. et al.2%). Abdullah Dalar and Konrad A. 2007). peonidin 3-O-(6′′-O-p-coumaroylglucoside)]. however further in-depth studies are needed to investigate the secondary metabolites of this plant. 2010a. The saturated fatty acids were found in all plant parts..9% in mature leaves to 25.5% of total phenolics) of the leaf. dioica . 2008). The monounsaturated fatty acids were present in seeds: erucic acid (1. Three of the four plants described above: M. also present in stem at 0. which were approximately 1.1±19. especially dietary polyphenols. The ORAC values ranged from 905. Among these selected plants from the Van province V. heart problems or other chronic conditions as well as accelerated ageing (Halliwell. Maintaining the oxidative stress for a prolonged period of time leads to the damage of cell components.Health Attributes.. 1. cheiranthifolium were approximately 3-fold those of Centaurea karduchorum. 368. However. and iii) upregulate or protect the antioxidant defense system (Dai and Mumper. Defense against oxidative stress is therefore an important factor in preventing the development of many diseases. Verbascum cheiranthifolium exhibited superior antioxidant activity to all other plants. traditionally used for medical purposes by the local population.3 those of Dactylorhiza chuhensis. Phytochemicals. lipids and proteins. pollution. cheiranthifolium is among the most extensively used medical plants in the region.7 those of Eryngium bornmuelleri and 1. Antioxidants have the ability to neutralize free radicals. Table 3 presents the available data on antioxidant activities of methanol extracts of some herbs. cheiranthifolium leaf and flowers. hypertension. Among the extracts. Phenolic compounds i) scavenge radical species such as reactive oxygen/nitrogen species (ROS/RNS).reactive oxygen/nitrogen species (ROS. are potent antioxidants capable of scavenging and intercepting free radicals. formed as a part of natural metabolism as well as originating from external sources like smoking.45. V. thus preventing cellular molecule damage. ii) suppress ROS/RNS formation by inhibiting some enzymes or chelating trace metals involved in free radical production. Interestingly. The number of studies dedicated to antioxidant testing of traditional medicinal plants from the Van province of Eastern Anatolia are limited. as well as antioxidant capacities of herbal teas prepared from selected herbs. respectively). when an antioxidant neutralizes a free radical it becomes inactive.0 and 369. cheiranthifolium and Plantago lanceolata leaf exhibited comparable and the highest total reducing capacities (FRAP assay. 2009). The exceptionally high ORAC values of V. were comparable to those of the commonly used herbs Jasminum grandiflorum flower (Spanish jasmine) (2330±64 µmol TE/g DW) and Rosa damascena (Damascus rose) (2382±62 µmol TE/g DW) (Dudonné et al. karduchorum Complimentary Contributor Copy .3 (stem) to 2262. Antioxidant Properties and Phytochemical Composition … 211 Antioxidant Capacities and Enzyme-inhibitory Activities of Selected Medicinal Plants from the Van Province Oxidative stress is an imbalance in the redox status of a cell between the production of free radicals .4 µmol Fe+2/g DW. including DNA.0±5. radiation or exposure to chemicals. 2007). by receiving or donating an electron.6±8. which may result in potential mutations and ultimately the formation of cancer. 2010). diabetes. chuhensis leaves and 7-fold that of the C.5fold that of E. Flower extract exhibited the highest activity and was followed by leaf and stem (Dalar and Konczak. bornmuelleri and D. without becoming free radicals themselves as they are stable in both forms. RNS). The ORAC values of V. 2012). Free radicals are highly unstable molecules. Frequently. Therefore our body requires a continuous delivery of antioxidants from food. and antioxidant defense mechanisms. as evaluated in two reagent-based antioxidant capacity assays: ORAC and FRAP. a high antioxidant capacity is an indication of a plant’s health-enhancing properties.5 (flower) µmol TE/g DW (Table 3). 212 Izabela Konczak, Abdullah Dalar and Konrad A. Konczak-Islam leaf. The FRAP values of V. cheiranthifolium and P. lanceolata (Table 3) were comparable to those of the long and widely used medicinal trees Juniperus communis (common juniper) (240±9 µmol Fe+2/g DW) and Cananga odorata (cananga tree) (370±2 µmol Fe+2/g DW) (Dudonné et al., 2009). The results of both assays applied in this study have clearly shown that among all plant parts, leaves exhibited the highest antioxidant capacity. The utilization of aerial parts, especially leaves and flowers, have been the dominating ways of preparation of traditional medicines in the Eastern Anatolia region of Turkey for centuries. The antioxidant capacities of the leaves and flowers of these herbs were found to be relatively high and comparable or superior to antioxidant capacities of numerous Chinese and Ayurvedic medicinal plants and commonly used medicinal herbs, which may suggest that antioxidant capacities of these plants may be relevant to their physiological activities (Dalar and Konczak, 2012). The most common application of these selected plants in the Van province is preparation of herbal teas. Lyophilised hydrophilic extracts representing six herbal infusions (M. neglecta, P. lanceolata, Salvia limbata, Phlomis armeniaca, Anchonium elichrysifolium, and V. cheiranthifolium) also exhibited potent oxygen radical scavenging abilities and high total reducing capacities (Table 3). The high ORAC and FRAP values of these herbal teas indicate that the evaluated plant sources comprise a rich mixture of phytochemicals, able to donate a hydrogen cation (ORAC assay) or a free electron (FRAP assay), and could therefore offer comprehensive protection from reactive oxygen species and oxidants, which may effectively reduce oxidative stress. The level of total phenolics in the lyophilized herbal infusions, as evaluated using the Folin-Ciocalteu method, varied from 27.9±0.4 mg GAE/g DW (M. neglecta) to 80.4±1.8 mg GAE/g DW (P. lanceolata) (Table 3). P. lanceolata herbal tea had the highest total phenolic content (Table 3), which was similar to that of commercially available black tea (Camellia sinensis) Yellow Label (84.9±8.03 mg GAE/g DW). V. cheiranthifolium had a similar level of total phenolics to that of black tea Cameron Highlands trade (60.6±5.4 mg GAE/g DW); P. armeniaca and S. limbata had higher or comparable phenolics levels to that of oregano (58.6±3.7 mg GAE/g DW), while A. elichrysifolium and M. neglecta had similar phenolics levels to rosemary (28.1±0.8 mg GAE/g DW) (Dalar and Konczak, 2013). In another study Şahin and collaborators (2004) have identified exceptionally rich source of phenolic compounds in Origanum vulgare L. subsp. vulgare. The same herb exhibited very high radical scavenging activity towards the di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (DPPH) radicals (Table 3). The level of phenolic compounds of Heracleum persicum and Gundelia tournefortii was comparable to that of E. bornmuelleri leaf (Çoruh et al., 2007b). Antioxidant testing of selected plant sources conducted to date suggest that antioxidant capacities of these common herbs from the Van province of Eastern Anatolia are comparable to those of traditional medicinal plants used by other cultures, for example Chinese medicine (Dalar et al., 2012). Phenolic compounds, predominantly flavonoids and phenolic acids (Table 3, Table 4), were identified as the major sources of antioxidant capacities of hydrophilic extracts obtained from these plants. Complimentary Contributor Copy Table 3. Antioxidant capacities of traditional medicinal plants from Eastern Anatolia Antioxidant test Extraction ORAC (Oxygen radical absorbance capacity) assay Malva neglecta Aqueous methanol plant parts (root, stem, leaf, flower, fruit, whole plant) Plantago lanceolata Aqueous methanol plant parts (root, stem, leaf, flower, fruit, whole plant) Cichorium inytbus Aqueous methanol plant parts (root, stem, leaf, flower, whole plant) Eryngium bornmuelleri Aqueous methanol plant parts (root, stem, leaf, flower) Centaurea karduchorum Aqueous methanol plant parts (root, stem, leaf, flower) Verbascum cheiranthifolium Aqueous methanol plant parts (stem, leaf, flower) Malva neglecta tea Lyophilized ethanol Plantago lanceolata tea Salvia limbata tea Phlomis armeniaca tea Anchonium elichrysifolium tea Verbascum cheiranthifolium tea FRAP (Ferric reducing antioxidant power)assay Malva neglecta Aqueous methanol plant parts (root, stem, leaf, flower, fruit, whole plant) Plantago lanceolata Aqueous methanol plant parts (root, stem, leaf, flower, fruit, whole plant) Cichorium inytbus Aqueous methanol plant parts (root, stem, leaf, flower, whole plant) Results Compounds identified References 425.3±6.7 – 898.9±14.9 µmol Trolox eq./gDW Phenolics Dalar et al., 2012 920.8±3.0 – 1625.0±15.5 µmol Trolox eq./gDW Phenolics Dalar et al., 2012 823.9±10.6 – 1307.7±17.4 µmol Trolox eq./gDW Phenolics Dalar, unpublished result 406.6±3.1 – 1489.0±17.0 µmol Trolox eq./gDW 326.9±7.2 – 674.7±13.7 µmol Trolox eq./gDW 905.0±5.3 – 2262±8.5 µmol Trolox eq./gDW 1638.4±218.3 µmol Trolox eq./gDW Phenolics Dalar and Konczak, 2012 Dalar and Konczak, 2012 Dalar and Konczak, 2012 Dalar and Konczak, 2013 Phenolics Phenolics Phenolics 3343.9±215.2 µmol Trolox eq./gDW 3602.9±52.1 µmol Trolox eq./gDW 2978.9±74.6 µmol Trolox eq./gDW 2239.5±241.5 µmol Trolox eq./gDW 4265.9±132.9 µmol Trolox eq./gDW 39.2±1.2 – 190.3±6.7 µmol Fe2+/gDW Phenolics Dalar et al., 2012 130.4±11.5 – 369.1±19.4 µmol Fe2+/gDW Phenolics Dalar et al., 2012 90.1±9.5 – 251.6±9.7 µmol Fe2+/gDW Phenolics Dalar, unpublished result Complimentary Contributor Copy Table 3. (Continued) Antioxidant test Eryngium bornmuelleri plant parts (root, stem, leaf, flower) Centaurea karduchorum plant parts (root, stem, leaf, flower) Verbascum cheiranthifolium plant parts (stem, leaf, flower) Malva neglecta tea Plantago lanceolata tea Salvia limbata tea Phlomis armeniaca tea Anchonium elichrysifolium tea Verbascum cheiranthifolium tea Eryngium bornmuelleri leaf sequential fractions Extraction Aqueous methanol Results 55.2±5.9 – 250.3±2.2 µmol Fe2+/gDW Compounds identified Phenolics Aqueous methanol 42.1±1.6 – 67.7±1.4 µmol Fe2+/gDW Phenolics Aqueous methanol 223.8±3.6 – 368.4±5.0 µmol Fe2+/gDW Phenolics Lyophilized ethanol 390.8±13.5 µmol Fe2+/gDW Phenolics 1130.8±48.2 µmol Fe2+/gDW 930.4±18.8 µmol Fe2+/gDW 853.0±8.9 µmol Fe2+/gDW 402.8±7.9 µmol Fe2+/gDW 1123.5±52.4 µmol Fe2+/gDW 435.4±18.5 – 909.1±37.5 µmol Fe2+/gDW References Dalar and Konczak, 2012 Dalar and Konczak, 2012 Dalar and Konczak, 2012 Dalar and Konczak, 2013 Erygium bornmuelleri leaf Ethanol Acetone Pure water Lyophilized ethanol Centaurea karduchorum leaf Lyophilized ethanol 305.9±13.7 µmol Trolox eq./gDW Aqueous methanol 3.4±0.3 – 17.4±0.3 mg Gallic acid Eq./gDW Phenolics Dalar et al., 2012 Aqueous methanol 12.2±1.7 – 35.3±2.8 mg Gallic acid Eq./gDW Phenolics Dalar et al., 2012 Aqueous methanol 9.3±0.7 – 22.6±1.0 mg Gallic acid Eq./gDW Phenolics Dalar, unpublished result Aqueous methanol 3.6±0.3 – 25.8±0.2 mg Gallic acid Eq./gDW 4.4±0.1 – 7.4±0.1 mg Gallic acid Eq./gDW Phenolic compounds Dalar and Konczak, 2012 Dalar and Konczak, 2012 Total phenolics (Folin-Ciocalteu reducing) assay Malva neglecta plant parts (root, stem, leaf, flower, fruit, whole plant) Plantago lanceolata plant parts (root, stem, leaf, flower, fruit, whole plant) Cichorium inytbus plant parts (root, stem, leaf, flower, whole plant) Eryngium bornmuelleri plant parts (root, stem, leaf, flower) Centaurea karduchorum plant parts (root, stem, leaf, flower) Aqueous methanol 813.6±39.9 µmol Trolox eq./gDW Rutin, flavonoid glucosides, phenolic acids Dalar et al., 2013 Flavonoid glucosides, chlorogenic acid Flavonod glucosides Dalar, unpublished results Dalar, unpublished results Phenolic compounds Complimentary Contributor Copy Antioxidant test Verbascum cheiranthifolium plant parts (stem, leaf, flower) Malva neglecta tea Extraction Aqueous methanol Lyophilized ethanol Plantago lanceolata tea Salvia limbata tea Phlomis armeniaca tea Anchonium elichrysifolium tea Verbascum cheiranthifolium tea Eryngium bornmuelleri leaf sequential fractions Results 20.2±0.6 – 33.1±0.4 mg Gallic acid Eq./gDW 27.9±0.4 mg Gallic acid Eq./gDW 80.4±1.8 mg Gallic acid Eq./gDW 56.0±0.9 mg Gallic acid Eq./gDW 60.2±3.5 mg Gallic acid Eq./gDW 31.2±0.2 mg Gallic acid Eq./gDW 67.0±3.3 mg Gallic acid Eq./gDW 44.4±1.7 – 91.9±4.4 mg Gallic acid Eq./gDW Erygium bornmuelleri leaf Ethanol Acetone Pure water Lyophilized ethanol Centaurea karduchorum leaf Lyophilized ethanol 26.9±1.1 mg Gallic acid Eq./gDW Gundelia tournefortii L. seed and aerial parts Lyophilized methanol Heracleum persicum Prangos ferulacea Chaerophyllum macropodum Rheum ribes stem Lyophilized methanol Lyophilized methanol Lyophilized methanol Lyophilized chloroform Aerial parts: 64.4±4.8 mg Gallic acid Eq./gDW Seed: 105.1±8.7 mg Gallic acid Eq./gDW 65.1±6.4 mg Gallic acid Eq./gDW 34.0±7.0 mg Gallic acid Eq./gDW 59.6±2.8 mg Gallic acid Eq./gDW 22.68±1.10 mg Gallic acid Eq./gDW Rheum ribes stem Lyophilized methanol 35.71±1.23 mg Gallic acid Eq./gDW Rheum ribes root Lyophilized chloroform 48.66±1.23 mg Gallic acid Eq./gDW Rheum ribes root Lyophilized methanol 25.91±1.09 mg Gallic acid Eq./gDW Mentha longifolia L. subsp. longifolia Lyophilized methanol 45 mg Gallic acid Eq./gDW Origanum vulgare subsp. vulgare Lyophilized methanol 220 mg Gallic acid Eq./gDW 63.5±1.4 mg Gallic acid Eq./gDW Compounds identified Phenolic compounds Phenolic compounds References Dalar and Konczak, 2012 Dalar and Konczak, 2013 Rutin, flavonoid glucosides, phenolic acids Dalar et al., 2013 Flavonoid glucosides, chlorogenic acid Flavonod glucosides Dalar, unpublished results Dalar, unpublished results Çoruh et al., 2007a Phenolic compounds Phenolic compounds Phenolic compounds Phenolic compounds Phenolic compounds and essential oils Phenolic compounds and essential oils Phenolic compounds and essential oils Phenolic compounds and essential oils Phenolic compounds and essential oils Phenolic compounds and essential oils Complimentary Contributor Copy Çoruh et al., 2007b Çoruh et al., 2007b Çoruh et al., 2007b Öztürk et al., 2007 Öztürk et al., 2007 Öztürk et al., 2007 Öztürk et al., 2007 Gulluce et al., 2007 Şahin et al., 2004 Table 3. (Continued) Antioxidant test Extraction Results DPPH (di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium free radical scavenging activity) assay Gundelia tournefortii L. seed and aerial Lyophilized methanol High radical scavenging activities parts Aerial parts- IC50:0.442 mg/ml Seed- IC50: 0.073 mg/ml Heracleum persicum Lyophilized methanol High radical scavenging activities IC50:0.438 mg/ml Prangos ferulacea Lyophilized methanol High radical scavenging activities IC50:0.242 mg/ml Chaerophyllum macropodum Lyophilized methanol High radical scavenging activities IC50:0.623 mg/ml Rheum ribes stem Lyophilized methanol High radical scavenging activities 87.07±0.54 % at 100 µg concentration Rheum ribes root Lyophilized methanol High radical scavenging activities 60.60±0.86 % at 100 µg concentration Antioxidant test Extraction Results Rheum ribes root Lyophilized methanol High radical scavenging activities 50.87±0.30 % at 100 µg concentration Mentha longifolia L. subsp. longifolia Lyophilized methanol High radical scavenging activities IC50: 57.4 µg/ml Origanum vulgare subsp. vulgare Lyophilized methanol High radical scavenging activities IC50: 9.9 µg/ml Compounds identified References Phenolic compounds Çoruh et al., 2007 Phenolic compounds Çoruh et al., 2007 Phenolic compounds Çoruh et al., 2007 Phenolic compounds Çoruh et al., 2007 Phenolic compounds and essential oils Phenolics compounds and essential oils Compounds identified Phenolic compounds and essential oils Phenolic compounds and essential oils Phenolic compounds and essential oils Öztürk et al., 2007 Öztürk et al., 2007 References Öztürk et al., 2007 Gulluce et al., 2007 Şahin et al., 2004 Table 4. Enzyme inhibitory activities of traditional medicinal plants from Eastern Anatolia Enzyme inhibitory assay Alfa-amylase inhibitory activity Herbal Teas: Malva neglecta Plantago lanceolata, Salvia limbata, Phlomis armeniaca, Anchonium elichrysifolium, Verbascum cheiranthifolium Extraction Lyophilized ethanol Enzyme inhibitory activity Compounds identified References Inhibition (%) at concentration 4 mg/ml 23.6±0.5 32.3±0.4 28.3±1.0 13.5±0.4 22.4±0.9 67.8±1.1 Phenolic compounds Dalar and Konczak, 2013 Complimentary Contributor Copy 5±0.2 mg/ml IC50: 12.3 mg/ml IC50:19.08 IC50: 6.76±0.68±0. chlorogenic acid.28±0.10 IC50: 8. unpublished data Phenolic compounds Dalar and Konczak. phenolic acids Dalar et al.04 IC50: 8. flavonoid glucosides.9±0.5±0.21±0.4±0.83±0.6±0.03±0. Anchonium elichrysifolium.08 IC50: 4.10 IC50: 4. unpublished data Dalar.53±0. Verbascum cheiranthifolium Eryngium bornmuelleri leaf sequential fractions Malva neglecta whole plant Plantago lanceolata whole plant Extraction Ethanol Acetone Pure water Lyophilized ethanol Ethanol Acetone Pure water Lyophilized ethanol Lyophilized ethanol Lyophilized ethanol Lyophilized ethanol Ethanol Acetone Pure water Lyophilized ethanol Lyophilized ethanol Enzyme inhibitory activity IC50*: 8. flavonoid glucosides Dalar. 2013 Phenolic compounds Dalar.. Anchonium elichrysifolium. flavonoid glucosides. unpublished data IC50: 10.09 IC50: 8. 2013 Rutin. unpublished data Dalar.1 mg/ml IC50: 10.53±0.06 Flavonoid glucosides Complimentary Contributor Copy . Salvia limbata.21±0.4±0.. 2013 IC50: 13.05 Rutin.04 IC50: 3..28 IC50: 2.38 IC50: 6. 2013 Phenolic compounds IC50: 1.07 IC50: 5.1 mg/ml IC50: 5. Phlomis armeniaca.3±0.0±0.1 mg/ml IC50: 6.96±0.6 mg/ml IC50: 10.4 mg/ml Compounds identified Rutin.56±0. Phlomis armeniaca. Verbascum cheiranthifolium Eryngium bornmuelleri leaf sequential fractions Malva neglecta whole plant Plantago lanceolata whole plant Cichorium intybus whole plant Pancreatic lipase inhibitory activity Herbal Teas: Malva neglecta Plantago lanceolata.1 mg/ml IC50: 9.23 IC50: 2. Salvia limbata. flavonoid glucosides.02±0.17 Flavonoid glucosides IC50: 6. caftaric acid.72±0.17 IC50: 1.2 mg/ml IC50:19.54±0.02 IC50: 12. phenolic acids Dalar et al. phenolic acids References Dalar et al.1±0.05 Chicoric acid. 2013 Phenolic compounds Dalar and Konczak.Enzyme inhibitory assay Eryngium bornmuelleri leaf sequential fractions Alfa-glucosidase inhibitory activity Herbal Teas: Malva neglecta Plantago lanceolata.04±0. unpublished data Dalar.11±0.43±0. 0 21. flavonoid glucosides References Dalar. chlorogenic acid.0 35.0±2. unpublished data Inhibition (%) at concentration 0. Anchonium elichrysifolium. 2013 34.0 21.0 27. Phlomis armeniaca.97±0.Table 4.0±2.0±2.20 Compounds identified Chicoric acid. (Continued) Enzyme inhibitory assay Cichorium intybus whole plant Extraction Lyophilized ethanol Angiotensin converting enzyme (ACE) inhibitory activity Herbal Teas: Lyophilized Malva neglecta ethanol Plantago lanceolata. Salvia limbata.0±2.0 23. caftaric acid. Verbascum cheiranthifolium Enzyme inhibitory activity IC50: 3.0±2.0 *IC50 – half maximum inhibitory concentration.0±4. Complimentary Contributor Copy .6 mg/ml Phenolic compounds Dalar and Konczak. This chapter showed that herbs which are used to cure multiple health conditions. which may suggest their potential anti-diabetic properties. selected by traditional wisdom. flatulence. P. Galium verum. Until now our knowledge of both the phytochemical composition and mechanism of physiological actions of these traditional medicinal plants is limited. et al. Moreover.. lanceolata may be considered as a potential candidate for further studies towards identification of anti-diabetic and anti-obesity activities (Dalar and Konczak. attributed to the simultaneous inhibition of both enzymes. The rich composition of phytochemicals may hold the key to the efficacy of these commonly used traditional medicinal plants. Cichorium intybus and Urtica dioica. Teucrium polium. represent a vast and underutilized resource for the development of newer and more efficient pharmacological treatments. obesity. with the exception of V. Among the listed medicinal plants are those used for the treatment of various types of cancer. leading to abdominal distention. Their value should not be underestimated. Eryngium bornmuelleri. Anchonium elichrysifolium. Plantago lanceolata. including diabetes. limbata exhibited weak inhibitory activities against αamylase and pronounced inhibitory activities against α-glucosidase. P. are characterized by a concomitant presence of phytochemicals representing various groups: phenolic compounds. cheiranthifolium. Plantago maritime. which have a lower activity against α-amylase and a stronger activity against α-glucosidase. namely Mentha longifolia. Conclusion The uses of traditional medicinal plants are based on observations of their action and effectiveness arising from their application on humans over centuries. the majority of these sources have not been subjected to any studies. This chapter presents a number of plant sources. Natural α-amylase and α-glucosidase inhibitors from plant sources offer an attractive strategy to control postprandial hyperglycemia. to cure chronic health conditions associated with the contemporary fast-paced lifestyle. pancreatic lipase and the angiotensin I-converting enzyme (ACE) and. this result suggests that P. and a novel approach to curing the diseases of our age. Complimentary Contributor Copy . lanceolata. In fact. carotenoids. P. had a moderate to low inhibitory activity against α-amylase (Table 4). Traditional medicinal plants presented in this chapter may provide valuable leads for the identification of physiologically active natural compounds for pharmaceutical uses. These inhibitors in particular. 2006). and Heliotropium circinatum. 2013). fatty acids and terpenes. Antioxidant Properties and Phytochemical Composition … 219 The same extracts commonly consumed in the Van province as herbal teas successfully suppressed the activities of key enzymes involved in metabolic syndrome: α-glucosidase. 2006). including traditional Chinese and Ayurvedic systems. selected by generations of traditional healers. meteorism and even diarrhea (Apostolidis et al. can be used as an effective therapy for postprandial hyperglycemia with minimal side effects (Kwon.. which results in abnormal bacterial fermentation in the colon due to the presence of undigested carbohydrates. armeniaca and S. lanceolata was the most potent inhibitor of pancreatic lipase. hypertension or hypercholesterolemia. These plants. The majority of Eastern Anatolian medicinal plants evaluated to date exhibited an antioxidant capacity comparable to medicinal plants utilized by other cultures.Health Attributes. . 100. U. Science. J. A–Z of companion planting. 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Antioxidant Properties and Phytochemical Composition … 225 Yesilada.. (1995) Traditional medicine in Turkey. B. E. Houston.. T. E. 133-152.. 195-210. A. E.. Sezik. Govil. A. Honda. (1999). Tabata.. G. 6(29). Y. 4550-4552. Malva sylvestris and Malva neglecta on some bacterial and fungal contaminants of wound infections. LLC. Singh. Eds: Singh. Plants Res.. J.. Complimentary Contributor Copy . In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers. In particular. The study of substances that make up these plants and their possible mechanisms in health * Corresponding Author address: Email:elcoballase@yahoo. Mexico Abstract Hetherotheca inuloides (Mexican arnica) is a plant used in traditional medicine in different parts of the world. Inc. ointments) for therapeutic purposes due to its anti-inflammatory. UNAM. and how it can help protect the liver and brain. Keywords: Hetherotheca inuloides. José Luis Rodríguez-Chávez and Elvia Coballase-Urrutia* Laboratory of Neurochemistry. As an antioxidant. beverages. and antioxidant effects.com. it has attracted considerable interest because of the involvement of oxidative stress in various diseases affecting systemic and central levels. in experimental models affecting these organs. antioxidant. Complimentary Contributor Copy . National Institute of Pediatrics. the focus of this chapter is to describe the evidence that demonstrates the ability of Mexican arnica to be used as a potent antioxidant.mx. analgesic. Noemí Cárdenas-Rodríguez. Bernardino Huerta-Gertrudis. Chemistry Institute. antimicrobial. it is used in various presentations (tablets. neuroprotective and hepatoprotective effects Introduction The use of plants for medicinal purposes comes from the early history of civilization. Chapter 8 Hetherotheca inuloides (Mexican Arnica) a Potent Antioxidant Effect as Neuro and Hepato-Protective Liliana Carmona-Aparicio. oxidative stress. catalase (CAT). are aware of their potential and their possible adverse effects. 1990. 2004.. However. Valko et al. The functions that are attributed to natural phytochemicals include antioxidant. Huntington's. 2002. is the generation of free radicals (FR) and reactive oxygen species (ROS) (Segura et al. it is very important that users who consume or use the plants in therapy for various diseases. In certain situations antioxidant defenses may be overwhelmed by excessive ROS generation. Cárdenas-Rodríguez. Cárdenas-Rodríguez. antimutagen. There is evidence that might be helpful in diseases induced by oxidative stress caused by different harmful agents such as free radicals (FR) (Liu. 2001. B. 2006. vitamin C and vitamin E. with 3. Fang et al. Parkinson's. anticancerigen and antibacterial. Alzheimer's. Endogenous antioxidant systems such as superoxide dismutase (SOD). 2007). However. more than 5000 of them have been characterized in fruits. Wang et al. nitrogen-containing compounds and thiol groups (-SH). 2006). Matkowski and Piotrowska. Valko et al. etc. There also exist non-enzymatic systems. glutathione peroxidase (GPx) and antioxidants with thiol groups. together with the mechanisms underlying diseases that afflict humans. immune system enhancer. cancer. carotenoids. 2003 and 2004). This imbalance between oxidants and antioxidants species is known as oxidative stress. in vitro assays and physico-chemical nature can be extrapolated to potential in vivo protection (Cotelle. anti-inflammatory. While most reports are based on the determination of antioxidant capacity. In Mexico it is known that there are about 30.. as well as in aging processes and inflammation. 1997). such as glutathione (GSH). Generalities of Medicinal Plants Plants are a rich source of bioactive phytochemicals. epilepsy. ischemia reperfusion injury.. Halliwell and Whiteman. diabetes.Currently. vitamin C (ascorbic acid). It is necessary to continue studies to characterize the effect of these phytochemicals and get to know their potential applications in health benefits.228 L.. 2006. 2007). Albano. There is evidence suggesting that they are either involved or are a major source for the prevention of chronic diseases (Liu. the body has its own defense mechanisms to deal with the action of oxidizing species. vegetables and grains. such as proteins. These oxidizing species cause cumulative damage of molecules essential to body function. benefits is an area of broad interest.. Huerta-Gertrudis et al. phenols. liver cirrhosis. Carmona-Aparicio. 2007. bilirubin and uric acid that can be enhanced by incorporation into the diet (Matés and Sánchez-Jiménez 1999. there is still a large number unmarked. are the first defenses against FR.). vitamin E (tocopherol). It has now been determined that major biochemical mechanisms associated to pathologies affecting the peripheral nervous system (such as atherosclerosis. On the other hand. which is associated with many diseases as the ones mentioned above (Basaga. There are abundant scientific studies demonstrating that flavonoids.). may act by capturing these ROS.000 species of plants registered in 1997 by the National Indigenous Institute.and hepatoprotector effects of Hetheroteca inuloides (Mexican arnica). Valko et al. Matowski and Piotrowska. 2000. 2003 and 2004. N. the phytochemicals are mainly in carotenoids. 2006. In this chapter we will give detailed evidence on the neuro. alkaloids.000 documented uses in traditional medicine for Complimentary Contributor Copy . 2006).. lipids and DNA (Szabó and Ohshima. The production of ROS is a natural process. 2006. glutathione-S-transferase (GST) and gluthione reductase (GR) are the first defenses against FR (Matés and Sánchez-Jiménez. carotenoids. are permanently producing ROS (Valko. european specie widely used in folk medicine in Europe. 2006. vitamin E (tocopherol). This is considered evidence of their effectiveness (Almaguer. neurodegenerative diseases. the body has its own defense mechanisms to deal with the action of oxidizing species. vitamin C (ascorbic acid). Medicinal Plants and Oxidative Stress In the annals of medical history. Seifried et al. 2007).. Valko et al. regardless of their type. 2002. 2007). 2001. There are abundant scientific studies demonstrating that flavonoids. may act by capturing these ROS (Albano. Valko et al. 2007. ROS production and oxidative stress are associated with tissue injury and many pathological processes. All cells. 2007). catalase (CAT). In certain situations antioxidant defenses may be overwhelmed by excessive ROS generation. 1984 and 1989) .. diabetes. Valko. cancer.. which is associated with many diseases as the ones mentioned above. liver diseases and normal aging (Halliwell and Gutteridge. 2007). montana have similar characteristics and uses. Martínez. 2006. 2006. 2006. These oxidizing species cause cumulative damage in molecules essential to body function. There also exist non-enzymatic systems. 2007). However. including atherosclerosis.Hetherotheca inuloides (Mexican Arnica) a Potent Antioxidant Effect … 229 people living in rural and urban communities. Albano. In this chapter we will give detailed evidence on the neuro. 2010). Endogenous antioxidant systems such as superoxide dismutase (SOD). bilirubin and uric acid that can be enhanced by incorporation into the diet (Fang et al. Heterotheca inuloides Generalities In Mexico plant groups of different species share the common folk name "arnica" derived from Arnica montana. aimed to understand and regulate the production of FR and oxidative stress (Bayraktar et al. few events have had such a profound impact as the result of knowing about the existence of FR and reactive oxygen species (ROS) and their influence on living organisms. Halliwell and Gutteridge. Valko et al. This group of medicinal plants known as “arnica” and A. Valko et al. 1999. This imbalance between oxidants and antioxidants species known as oxidative stress. Complimentary Contributor Copy . such as glutathione (GSH). in vitro assays and physico-chemical nature can be extrapolated to potential in vivo protection. This has caused a lot of research. glutathione peroxidase (GPx).and hepato-protector effects of Hetheroteca inuloides (Mexican arnica). lipids and DNA (Halliwell and Gutteride. 2007). a consequence of life in an aerobic environment. such as proteins. unavoidable and constant. vitamin C and vitamin E. 2010. While most reports are based on the determination of antioxidant capacity. a continuous biological process. Goldibi and Laher. quercetin-3. inuloides became very popular because it was attributed medicinal properties. inuloides is also known as: arnica mexicana or Mexican arnica. H. as an ointment mixed with butter or poultices to heal wounds. arnika (Purepecha). H. Carmona-Aparicio. Veracruz. kaempferol. Huerta-Gertrudis et al. The foliage is used as an analgesic for chest pain. It can measure up to 1 m high. Guerrero (Coyuca de Catalan). The leaves are boiled to unswelland disinfect wounds and the water derived from this boiling is used to induce appetite. stomach. but no one has defined the part of the plant used. inuloides and H. which are used for skin infections. Jalisco Guadalajara. Puebla. inuloides Cass (with three varieties). Durango. Villaseñor Ríos and Espinosa García. Thitonia. 1998. grandiflora Nutt. H. heartburn. H. Therapheutics Effects of Diferents Mexican Arnica Extracts From the plant. Oaxaca.. bruises. B. The whole plant is used and consumed as decoct to ease the pain of lung. inuloides has elongated leaves and broad. San Luis Potosí. pimples. arnica the country. all of them are found in Mexico: H. dressing. rash. petal or stamens) in decoction is used to wash wounds. Distrito Federal. 1984). 7.It is distributed in Chihuahua.. results of research on the characterization of various components of the flower and its biological effects have been reported. gastritis. De Rzedowski and Rzedowski. 1998. In the market H. For inflammation and ovaries matrix compresses are applied. The aerial parts (flowers. plus it is readily available and inexpensive. Rusby. homeopathic tinctures. it is often grown in home gardens and harvesting is done at the time of flowering. Nuevo León. and is found in pine and oak forests. Hidalgo (Gangueo). 2001). Tlaxcala. 1998). Four species are recognized in Heterotheca sect. leptoglosa are endemic to Mexico. N. 1994. sores (Villaseñor Ríos and Espinosa García. cuateteco. kidney cancer. In recent years. Puebla. It has also been reported to be used for: bladder irritation. These plants are included in the genus Mentzelia. acahualli. 2001). its flowers are grouped and placed in a circle. Guanajuato. Trixis. Coalcoman Vazquez). 4'- Complimentary Contributor Copy . Helenium. Morelia (Ocampo).4'-trimethylether. De Rzedowski and Rzedowski. 3. It is also used as compresses. teas and ointments.7-dimethyl ether. Michoacán (Zitacuaro. 6-methoxykaempferol-3. acahua. De Rzedowski and Rzedowski. Medicinal Propierties In traditional medicine H. kaempferol-3. Colima. quercetin. Querétaro. 1998. field arnica. The H. Zacatecas. heart. the following pure compounds have been characterized: luteolin. For its widespread medicinal use. Verbesina. Nayarit and Estado de México (Argueta et al. Cárdenas-Rodríguez. nerves and eye bath in order to promote inflammatory states. Tacuaro. rheumatism. inuloides is found in different forms for example.3'-dimethylether.7-dimethyl-kaempferol. quercetin-3. mountain arnica. kidney and ulcers. It is usually found in cool and temperate climates. and Heterotheca (Villaseñor Ríos and Espinosa García. applied to bruises and welts. Heterotheca. and H. swollen bumps. Morelos. 2001). muscle. false arnica and tlályetl (Martínez. bumps and sores (Villaseñor Ríos and Espinosa García. and internal and external traumas. subaxilaris Britt.230 L. fevers. leptoglosa DC. sesquiterpenes and flavonoids with different biological properties (Table 1). Stigmasterol. Pharmacology propierties Antiinflammatory. support the use of this plant in skin infections since the use of antibiotics to combat them can induce long-term resistence (Kubo et al.4-dihydrocadalene and 7-hydroxycadalene in addition to the flavonoids quercetin and kaempferol. 7-(3.. These compounds showed potent radical scavenging activity of diphenyl-p-picrylhydrazyl (DPPH●) and radicalanion superoxide in an in vitro model using rat liver microsomes where the best scavengers are flavonoids (Haraguchi et al. COX-1 and COX-2 inhibitory effect. hydroxy-1(4H)-isocadalen-4-one. four sesquiterpenoids were isolated that exhibited antimicrobial activity against gram positive and two of these also showed anti-fungal activity... These results. Segura et al. quercetin-3. 7-hydroxy-4 α H-3. 2001. Antioxidant. 1997.7-oxide 5α-hydroxy-3. The sesquiterpenoid 7-hydroxy-3. Delgado et al. kaempferol-osophoroside. 3'. kaempferol-3-O-glucoside. Antioxidant. β-caryophyllene 4. nuclear magnetic resonance and mass spectra (Jerga et al. References Inhibition of Tyrosinase activity. β-sitosterol. Quercetin (0. In the Nineties. the 7-hydroxy-3. Haraguchi et al..4-dihydrocadalene isolated from H. 7-hydroxycadalene (0. 3-O-β-D-epinasterol glycoside. 1990). 1997).004). sterols. 1997. 7-hydroxy-4 α H-3..19). The sesquiterpenoid βcaryophyllene. were evaluated as antioxidants.7.3. Inhibition of lipid peroxidation. kaempferol..002). 1994.2.4'-trimethylether among others.4-dihydro-cadalene. Complimentary Contributor Copy . Delgado et al. 1α. Table 1. Kubo et al. quercetin-3 .. 2000.. cadinanes. quercetin-3.3-dimethylallyloxy)coumarin. Quercetin. Sereveral of the plant constituents are polyacetylenes. dicadalenol.7-dihydroxy-3(4H)-isocadalen-4-one. 1α-hydroxy-4αh-1. Caryolan-1. Epinasterol. triterpenes.3'trimethylether.9β-diol... 2009 (personal comunication) Haraguchi et al.7.4-dihydro-cadalene (0. D-chiro-inositol. 1996).. Inhibition of lipid peroxidation. 1996).4-dihydrocadalene and 7hydroxycadalene also showed cytotoxic activity against several lines of solid tumors (Kubo et al. Antiinflamatory. as well as investigations of their common use for nosocomial infections. 1994).4'-tetramethylether.4-tetrahydrocadalen15oic acid. inuloides was used against lipid peroxidation in an in vitro model using rat liver microsomes and human erythrocytes in conditions of oxidative stress (Haraguchi et al.7-dimethyl.Hetherotheca inuloides (Mexican Arnica) a Potent Antioxidant Effect … 231 dimethyl ether. 7-hydroxycadalene. Different pharmacological properties of the metabolites derived from acetone and methanol extracts of Heterotheca inuloides Extract Name Heterotheca inuloides Acetonic extract Heterotheca inuloides Methanolic extract Chemical composition (% extract ) Cadalen-15-oic acid. 3. Quercetin 3-O-glucoside. Likewise. The structures of these compounds were established by methodologies including UV spectroscopy. bruises and muscle aches and as an anti-inflamatory. et al. polyphenols and flavonoids are responsible for the antioxidant activity. Pharmaceutical. It is used in traditional medicine for the treatment of thrombophlebitis.. thymol. acne. inuloides is a plant widely used in Mexico for its recognized medicinal effects. 2007). and iii) the presence of hydroxyl groups at positions 3 and 5. Oxidative Stress and Mexican Arnica A large number of reports suggest that the use of antioxidant compounds can help to maintain human health. 1998. 2004). 2001). ii) a double bond at position 2 and 3 combined with the 4-oxo function. These features are important for their activity as scavengers of FR (Furuno et al. inuloides’s flavonoids are efficient scavengers of the two types of radicals. as well as edema of croton oil-induced in an animal model.. H. 2006. and herbs such as ginseng. vegetables.. 2001). detected by the inhibition of edema in the mouse ear induced by TPA (12-O-tetradecanoyl phorbol-13-acetate) (Delgado. Some of these individual terpenoids and flavonoids are reported to have anti-inflammatory activity and have been found in the acetonic extract. 2002. On the contrary. sodium ascorbate (AA1) (Elmore. It has further been reported that H. Complimentary Contributor Copy . grape. 2000. rosemary. Haraguchi determined that quercetin glycosides and kaempferol isolated from H. Several constituents of this plant have been previously identified (Table 1).. 2005).. 2001). Choi et al. 2006). Wang et al. ginkgo. therefore commonly used as reference compound. spices. 1997). studies are focused on the identification of extracts and naturally occurring metabolites as antioxidant supplements. The methanolic extract was mainly constituted by flavonoids and terpenes that were found in lower concentrations in the acetonic extract (Delgado et al. 2003).4-dihydrocadalene inhibited in vitro expression of COX-1 and COX-2 catalyzed biosynthesis of prostaglandins. inuloides sesquiterpenes have potent radical scavenging activity of DPPH●. predominantly in the methanolic extracts which have high antioxidant capacity (Rice-Evans and Miller. literature data suggests that structural characteristics of flavonoids include: i) a o-diphenol in the B ring. 7-hydroxy-3.232 L.. ginger and garlic (Rababah et al. Carmona-Aparicio. In particular. and quercetin dicadenol also possess anti-inflammatory effect with minimal side effects (Gené et al. 1997). Delgado et al. Ascorbic acid is an essential compound in plant tissues. food and cosmetic industries use synthetic or natural antioxidants such as vitamin C. 2001). Analgesic and anti-inflammatory effect in in vitro and in vivo models was evaluated with different bioactive compounds of Mexican arnica. In addition.. o-cymen (AA2) Drometrizole (AA3) in their preparations (Anderssen. et al. green tea. grains. Huerta-Gertrudis et al. Rice-Evans. B. Segura et al.. H. Moreover. it is reported that 1-9 cariolan-βdiol. This characterization is part of the bio-evaluation of its effectiveness as a traditional medicine and identification of potential drug molecules.. Cárdenas-Rodríguez. The polyphenol components of the plant are very important because they have hydroxyl groups that make them able to scavenge radicals and chelate transition metal ions (RiceEvans and Miller. N. Therefore. 1996 and 1997. with no activity against superoxide generated by enzymatic or non-enzymatic pathways (Haraguchi et al. Most of these natural antioxidants come from fruits.. it has been reported to act as an effective scavenger of DPPH● (Soares. turmeric. Furthermore.. 1997). 2010). At the same time it continues to support the importance of the hydroxyl group at position 3 on the C ring that interacts with the B ring by binding with the hidroxyl group in 6' and 2'. Halliwell and Gutteridge. 1998). 7. 1990. 4'). For instance.generated enzymatically or non-enzymatically (Haraguchi et al. it has been suggested that the flavonoids possessing a catechol-O-group with a double bond at position 2 and 3 on the B ring and bonded to an oxo group at position 4 in the C ring may be responsible for the trapping of DPPH● (Haraguchi et al. Furthermore.4-dihydrocadalene and 7-hidroxycadalene flavonoids isolated from the dried Complimentary Contributor Copy .. The stability of the resultant quinone structure supports an unpaired electron. Although Cos demonstrated the importance of the hydroxyl group in the 5 and 7 positions of the A ring and in the 3' and 4´ position of the B ring (Van Hoorn et al.. 2002). 1998). Recently.. due to the ease in which the hydrogen atom from the aromatic hydroxyl group can be donated to the radical species. 2010). Its chemical structure is associated to the scavenging of FR. 1997). These findings suggest that the reduction in superoxide concentration is associated with the presence of these metabolites isolated from H. with 5 or more hydroxyl groups in their substituents different structures. with IC50 of 90 mM.generated by xanthine/xanthine. it was demonstrated that the extra hydroxyl group in the basic structure of the flavonoids. 7 hidroxy-3. inuloides trap O2●.oxidase system (Coballase et al. which stabilizes and relocates the unpaired electron and for its ability to chelate transition metal ions (Cos et al. It has been proposed that inhibition of the xanthine/xanthine oxidase system for various flavonoids may be linked to the hydroxyl groups.. Quercetin is known to chelate iron and therefore directly inhibit lipoperoxidation (Mathew and Abraham. catechin (flavonol) and taxifolin (flavanone) with 5 hydroxyl groups (3. The OH● is generated by the reaction between the iron/EDTA with H2O2 in the presence of ascorbic acid. 5. 2005. and compounds having one hydroxyl group only take longer or may not react at the same time to reduce the ABTS (Panala et al. 2002). 1996). 1998. which can cause cell and DNA damage leading to various diseases (Basaga. Pannala et al. 1997). it was demonstrated in liver microsomes that flavonoids from H. Widmer et al. In particular this radical is scavenging by acetonic and methanolic extracts of H. 4') vary in a IC50 range of 3 to 9 mM. the ABTS [2-2´-azino-bis(3-ethylbenz-thiazoline-6-sulphonic acid)] assay. 7. this has been used for analysis of antioxidant activity of various flavonoids.. Superoxide (O2●-) is a ROS. 2006). These facts suggest that the B ring and the various substituent hydroxyl groups are important for the antioxidant activity of flavonoids.... or flavonoids with 3 hydroxyl groups (5. inuloides.. In particular.Hetherotheca inuloides (Mexican Arnica) a Potent Antioxidant Effect … 233 inuloides have a DPPH● scavenging activity because they contain a hydroxyl group attached to a methyl group which may contribute to this activity (Haraguchi et al. inuloides (Cos et al. There are reports that show the scavenging activity of short chain flavonoids. quercetin (flavone). Moreover. contribute to the inhibition of the xanthine/xanthine oxidase system and therefore influence the decrease of the IC50 (Coss et al. The results reported in our work group showed that quercetin and kaempferol inhibits the production of O2●. 3'. kaempferol. 2001). We showed that in all cases quercetin and kaempferol had a good radical scavenging capacity (Melidou et al. Haraguchi demonstrated that quercetine.. 2001).. the hydroxyl radical (OH●) is associated with various pathologies (Valentão et al.. Van Hoorn reported the hydroxyl substituents inhibiting decrease in the following order: 5> 7> 4'= 3'. Pannala reported that flavonoids with 3 hydroxyl in the B ring are better ABTS scavengers. Hirose et al.g. Binsack demonstrated that polyphenols react with HOCl and its chlorinated products.Fe3++OH●+OH The iron becomes unable to participate in Fenton reactions and the propagation phase of lipid peroxidation. In this sense. this data is consistent with previous reports in the literature (Melidou et al. 2005). mediated by a metal. proteins and lipids. However. the double bond at carbon 2 and 3 and the carbonyl group in position 4 of the C ring are strongly implicated in the antioxidant activity (Pollard et al. This measurement was done by HPLC and mass spectrometry. which results in the formation of OH● via Fenton reaction. The ability to react with various flavonoids ONOO− where observed indirectly by measuring the products formed by the nitration of tyrosine. 2001). and proved to be a powerful oxidant that reacts easily with many important molecules (Arouma et al. 2001). 2004). 1996 and 1997). 2009). which increases evidence of its antioxidant capacity (Binsack et al. flowers of H. Huerta-Gertrudis et al. These bioactive compounds are found in both extracts. HOCl is produced in the body by oxidation of Cl-ions by the enzyme neutrophil myeloperoxidase. this effect can be attributed mainly to the donation of hydrogen and electron transfer capability of hydroxyl groups as substituents (Coballase et al. These observations are Complimentary Contributor Copy . The blocking of this position in quercetin is associated to a diminishing scavenging activity (RiceEvans et al. as described below (Widmer et al. their main targets are side chains of proteins (Davies and Truscoot. these studies indicate the importance of a catechol group in the B structure and that perhaps the double bond at the C ring may be essential to scavenge the 1O2 (Huvaere et al. inuloides inhibited lipid peroxidation (Haraguchi et al. mainly by the presence of a hydroxyl group in position 3 and 4 of the C ring. the hydroxyl radical may come from multiple sources including peroxynitrous acid or peroxide acid decomposition. the efficiency of flavonoids to protect against ONOO− toxicity has been demonstrated in several studies (Heijnen et al. B.. 1989). UV or visible light). 2001). 2010).. Fe2++H2O2. Analysis by mass spectrometry indicated that the chlorination takes place at C6 and C8.234 L. 2002). Carmona-Aparicio.. this probably has a greater effect in the entrapment of HOCl. Peroxinitrite (ONOO−) is a compound formed by the reaction between the O2●. Hydrogen peroxide (H2O2) in vivo is commonly reduced by iron (II).. H2O2 is a weak oxidizing agent that inactivates the enzymes usually by the substantial oxidation of the thiol groups (-SH).and nitric oxide (NO●).. which confers greater activity against hypochlorous acid (Firuzi et al... Firuzi reported that the common structure feature of various flavonoids is the presence of a hydroxyl group at 5-position in the A ring and the presence of more than two hydroxyl groups. 2010). The authors conclude that the hydroxyl groups in 3' and 4' position of the B ring. it can easily cross the biological membrane and interact with target molecules such as DNA. 2006).. Therefore. Results reported in our work group suggest that flavonoids are able to bind to the iron.. Singlet oxygen (1O2) is generated in the biological systems by a number of endogenous processes (enzymatic and chemical reactions) and exogenous stimuli (e. the presence of an additional hydroxyl group in position 5 increases protection.. Cárdenas-Rodríguez. There are few reports in which the flavonoids have worked as scavengers. N. Moreover.. Melidou evaluated in Jurkat cells.. Another observation proposed is the presence of a hydroxyl group in position 3 of the C ring. 1996. the ability of flavonoids to protect DNA damage caused by H2O2. .. Weber et al.and NO● (Coballase et al. 2003).. inuloides antioxidant properties generated in vitro. The rise in MDA levels in liver may be caused by failure or decreased antioxidant defense mechanisms to prevent the formation of ROS. inuloides significantly reversed these changes. Ying-Shan et al. 2009). Lipid peroxidation derived FR from CCl4 (CCl3● and CCl3O2). 1999. 2006). supports the fact that both extracts effectively reduced the signal intensity of the adduct DMPO-OOH generated by the xanthine/xanthine oxidase system (Lun-Yi et al. inuloides (Coballase et al. 2010). The pretreatment of rats with acetonic or methanolic extracts clearly protected from CCl4-induced hepatotoxicity. A first hypothesis of liver damage induced by CCl4 administration was observed by the evaluation of liver injury marker enzymes such as AST and ALT. inuloides in a hepatotoxicity model where rats are poisoned with carbon tetrachloride (CCl4).can dismute to form H2O2 in the presence of transition metals through the Fenton reaction. In experiments conducted in our laboratory induced toxicity in the group treated with CCl4 caused an increased MDA level compared to the control groups. However. particularly the 3' and 4' of the B ring are essential. CCl3● can either interact with O2 to form a second radical (CCl3O●) or lose hydrogen atoms to form chloroform (Clawson. The administration of acetonic or methanolic extracts significantly prevented CCl4-induced elevation of AST and ALT. As mentioned above the O2●.. MDA (malondialdehyde) is a highly reactive aldehyde that appears during peroxidation of fatty acids of biological membranes. mentioning that the number and arrangement of hydroxyl groups.Hetherotheca inuloides (Mexican Arnica) a Potent Antioxidant Effect … 235 confirmed...by EPR method. These events occur in the membrane and cause liver damage. Protective Effects of H. The first radical (CCl3●) forms covalent bonds with lipids and proteins. Complimentary Contributor Copy .. It has been shown that scavenging of the O2●. the protection mechanism of these agents is the elimination of O2●-. The administration of this compound is one of the major mechanisms of injury induced in the liver. which is produced by the reaction between O2●. Therefore. in position 4 of the ring C and the oxo group also favors the activity (Huvaere et al. 3nitrotyrosine (3-NT) is thought to be a relatively specific marker of oxidative damage. CCl4 toxic effect was also confirmed by histological observations showed extensive perivenular macrovesicular steatosis with severe fibrosis and necrosis (Coballase et al. the polyphenols found in both extracts played an important role in cellular protection. 2010).. it was included in the experiments. Our results also showed that both extracts slightly affected the normal architecture creating some areas of discontinuity in the cords of hepatocytes. 2001. Hepatotoxicity induced by CCl4 is developed during the biotransformation of this by cytochrome P-450 forming two FR (Shimizu et al. Szymonik-Lesiuk et al. 1989. 2010). indicating hepatoprotective activity of the extracts of H. Our work group focus is to study the effects on oxidative profile of acetone and methanolic extracts of H. Considering that quercetin is known as a hepatoprotective agent and one of the main components present in the methanolic extract (Table 1). The transferases activity increases 48 hr after the final treatment. Treatment with acetonic and methanolic extracts of H.. 2003). inuloides Recent information regards the H. . SOD.. 2013). 2011). which can lead to apoptosis and necrosis. 2010). GR is a hepatic cytosolic enzyme involved in the detoxification of a range of xenobiotics by conjugation with GSH (Coballase et al. GPx and GR represent a protection against oxidative damage to various tissues (Coballase et al. GR. there is no noticeable increase that suggests an improvement of oxidative stress on these components (Coballase et al. probably due to inactivation of proteins by FR.236 L. Tyrosine residues of nitrated proteins give rise to the production of 3-NT. B. Cárdenas-Rodríguez. It has been shown that the scavenging ability of these agents makes them powerful antioxidant therapeutic agents for diseases that afflict all of our body systems. CAT is found in all cells and metabolizes H2O2 to oxygen and water. CAT. 2013).. SOD. GPx and GR.to H2O2. Huerta-Gertrudis et al. It is precisely this ability that gives us the possibility of using it as a therapeutic agent in other diseases in which it has not yet been used.. while not excluding those non-pathological physiological processes such as aging processes. NO● induces damage to proteins. due to the transformation of O2●. GPx plays an important role in detoxification of xenobiotics in the liver and catalyzes the reduction of H2O2 and hydroperoxides to nontoxic products. Carmona-Aparicio. Our data is consistent with increased staining of 4-HNE adducts in the group of animals treated with CCl4. 2010). 2003). Several studies have shown that the antioxidant enzymes such as SOD. Oxidative stress is generally defined as an excess ROS formation. which can become chronic and degenerative diseases. In particular. The results of our in vitro tests confirm the hypothesis that both quercetin and methanolic extracts have scavenging capacity against ONOO− and 1O2 (Coballase et al.. Another commonly used marker of the presence of lipid peroxidation is the 4-hydroxynonenal (4-HNE) (Zarkovic. The effect of antioxidants on oxidative stress is easily measured through certain biomarkers as CAT. this preventive effect could be reflected in the improved liver histology caused by the extract (Coballase et al. The capacity of the methanolic extract of H. The methanolic extracts and quercetin were able to prevent some of the decreased activity of the antioxidant enzymes. The results obtained by our work group clearly indicate that the accumulation of 3-NT in CCl4 treated group was significantly higher than in the groups treated with the methanolic extract and quercetin (Coballase et al. Complimentary Contributor Copy . inuloides toprevent protein damage has been evaluated by 3-NT immunostaining. N. In the liver samples from exposed groups to quercetin and methanolic extract. lipids and nucleic acids. Therapeutic Relevance The use of medicinal plants has been one of the major therapeutic tools to treat human diseases. 2010).. inuloides) has a potent antioxidant capacity that allows us to understand its use in more than one tratment for diseases. This knowledge has been systematized with increasing experimental approaches that allows us to elucidate the mechanisms of action by which these plants exert their therapeutic capacity. the evidence shows that Mexican arnica (H. CCl4 induced a significant decrease in the levels of activity of the antioxidant enzymes CAT. SOD has a very effective defense. GPx. Argueta A. J. Alcohol Clin Exp Res. Proc Nutr Soc. m-cresol. Bayraktar M. Cano L. Vol. The results described in this chapter support the biomedical properties attributed to this plant and warrant further research into its potential use as a preventive agent in human populations.. Lipid peroxidation and antioxidant enzyme activities in cancerous bladder tissue and their relation with bacterial infection: a controlled clinical study. Atlas de las plantas medicinales de la medicina tradicional mexicana. Clin. 12 pags. R. These metabolites have higher FR scavenging properties and protect the liver and brain against oxidative damage induced by CCl4. Basaga H. Almaguer G. inuloides are efficient FR scavengers. México. 278290. White C. 25-30. oxidative stress and free radical damage. Aksoy N. Halliwell B.. inuloides could confer protection against acute hepatotoxicity induced not only by CCl4. thymol.E. J. México. 25(3). Biochemical aspects of free radicals. inuloides described in this chapter. Alcohol..3. 1990. 2001. Zhou F.. Kilic S. Hoey B. 24.F. Final report on the safety assessment of sodium p-chloro-m-cresol. P. It is suggested that methanolic and acetonic extracts of H. 2006... Parks D. superoxide. Free Radic Biol Med. The antioxidant activity against some ROS resides mainly in the methanolic extract. Coordinación de Salud para los Pueblos Indígenas. o-cymen-5-ol. Biochem Cell Biol... Lab. but also by other environmental or biological agents capable of inducing FR. Darley-Usmar V. p-cresol. Barnes S. and carvacrol. 29-127.Hetherotheca inuloides (Mexican Arnica) a Potent Antioxidant Effect … 237 Conclusion The results reported in our work and the ones described in literature show that methanolic and acetonic extracts isolated from H.. 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Junshan Yang1 and Xudong Xu1. Chinese Academy of Medical Sciences and Peking Union Medical College.In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers.. Yao Li3.cn. Pharmacological activity Introduction Meconopsis Vig. China Abstract As the second-largest genus in the family Papaveraceae. Lisheng Ding4. Pharmacological activities include hepatoprotection and analgesic effects. The chemical constituents have been examined and the isolation of alkaloids. Chinese Academy of Sciences. Chemistry and Pharmacology 1 Haifeng Wu1. The phytochemical and pharmacological studies on medicinal plants of Meconopsis genus have been reviewed in this chapter. Beijing. China 4 Chengdu Institute of Biology. Xining. The plants of Meconopsis have been prescribed as popular Tibetan medicine for the treatment of tuberculosis and hepatitis. Xiaopo Zhang1. Xiaofeng Zhang2. Meconopsis comprises about 57 species among which 32 species are distributed in Qinghai-Tibet Plateau. Yan Zhou4. Keywords: Papaveraceae. Haikou. Chinese Academy of Sciences. Inc. Jingyi Zhang3. Hainan University.ac. Chapter 9 Meconopsis: Traditional Uses. the second largest genus in the family Papaveraceae. flavonoids and essential oils has been reported. China 2 Northwest Institute of Plateau Biology. comprises about 57 monocarpic or polycarpic species mainly distributed discontinuously in both East Asia and * Corresponding author: xdxu@implad. 1994). about 58 alkaloids belonging to ten different skeletal types (i. and others). protoberberines. dimeric bisbenzylisoquinolines) (Zenk. integrifolia. Ohba et al. punicea. rhoeadines.e. essential oils. A Complimentary Contributor Copy . Isoquinoline alkaloids with aromatic tetracyclic backbone are characteristic constituents of the genus Meconopsis. protopines. M. Herein. 2009. Alkaloids Alkaloids. annual or perennial poppy-like alpine herbs with attractive flowers.g. Yue Wang Yao Zhen. anti-inflammatory and analgesic activity. quintuplinervia. M. proaporphines. 1906. etc (Wang et al. hepatoprotection and analgesic effects. to alpine meadows. papaverine. The first reported isolations of alkaloids in Meconopsis date back to the first half of the 20th century. benzophenanthridines. M. Yan Zhou et al.244 Haifeng Wu. 2012. and M. Some plants have been individually used in Tibetan Sowa-Rigpa Medicine (commonly known as 'Amchi') and the Bhutanese traditional medicine as a chief ingredient of polyherbal formulations for the treatment of hepatitis. Prain. the isoquinoline alkaloids are of particular interest. aporphines. the rest being quarternary followed by secondary alkaloids. and other constituents. pavines and isopavines. essential oils. have attracted the interest of scientists in the chemical fields for a long time. e. 2012. have been obtained from plants of nineteen species. most species are commonly found in the region of the Himalayas and China. Wu and Zhuang. morphine and its chemical derivatives. Ireland. Most of these alkaloids are tertiary. flavonoids. 1. cambria indigenous to England. nitrogen-containing heterocycles. Si Bu Yi Dian. etc. About three fifths of these species is distributed in Qinghai–Tibet plateau area including seven endemic species (An et al. 1980. Until now. 1981). chemical investigation on the genus indicated the presence of flavonoids. Within the class of alkaloids. The medicinal application of Meconopsis was recorded in the traditional Tibetan pharmacopeia. triterpenoids and other constituents.. 2011. Zhuang. screes and nival zones up to 5500 m (Luo et al.. showing antimicrobial. headaches and fractures. 1996. and the fringes of Western Europe. Xiaopo Zhang.. The genus Meconopsis has been extensively investigated for the presence of alkaloids in its many species. 2009. The plants of the genus Meconopsis (Himalayan poppy). Besides. Egan.. tuberculosis. berberine. West Europe. steroids. are growing in a variety of habitats ranging from temperate forests and pastures below the tree line at around 2500 m.. and Jing Zhu Ben Cao. Sulaiman and Babu. Phytochemistry Previous phytochemical investigation on the genus Meconopis resulted in the isolation of alkaloids. Yoshida et al. owing to their tremendous potential chemical variations of the basic precursor molecules and on the other hand comprise some of the most important drugs for therapy and euphoria (e. racemosa were most commonly used Tibetan herbs. Li et al. horridula.g.. indoles. Pharmacological research demonstrated that extract of some Meconopsis exhibited significant antioxidant. M. 2003. Wales. Northwest Plateau Institute of Biology. benzylphenethylamines. 1991). 1984). the research reported over the past decades on the isolation and pharmacology is summarized in this chapter. Except M. Wang et al. and our group. Chemistry and Pharmacology 245 number of alkaloids from different species were isolated by Slavík and coworkers (Slavík. 1965. 1986. 2003a. 1983).. 2002b. Li. two new proaporphine alkaloids. Wang et al. Slavík and Slavíková. 2009). no rhoeadine alkaloids have been found with an oxygen substituent at C-9. However. Zhou et al. used response surface methodology (a statistic approach) for optimization of UHPLC–QTOF conditions to analyze the main alkaloids of Meconopsis species (Zhou et al. 1994. are cyclic acetals or hemiacetals having the (R) configuration at C-2 and are dextrorotatory. Wu et al. Structures of rhoeadine alkaloids (1–6). 1997.. 1996. 1976. 2009. respectively. 2001). 1996). 2009). Complimentary Contributor Copy .. 2007. 1960.Meconopsis: Traditional Uses. and C-13. a group of alkaloids with a unique pentacyclic skeleton composed of an indole ring and a polyphenolic moiety from M. R2 = OH NH H H3CO O O O 6 Figure 1. Most recently.. A series of alkaloids were discovered from eight species (Gao et al. bearing oxygen substituent at C-7. Six rhoeadine alkaloids are reported. O O 6 9 H B NCH3 1 H 10 O C 14 H3CO R1 O 4 A O H D O NCH3 H O H3CO O 1 HO H O O 2 H3CO NH H H O H3CO O O R2 H NH H O H3CO O 4 O 3 R1 + R2 = OCH2O 5 R1 = OCH3. isorhoeadine (2).. Allais et al. Tatsis et al. 1976. 2002a. and papaverrubine E (6) (Slavík and Slavíková. 1977.. 2007) and 8. 1. Shang. obtained a new alkaloid from M. Hemingway et al. were obtained by Li et al.1. Shang et al. C-12. papaverrubine C (4). cambrica (Tatsis et al. Recently. Liu and Wang. 2003b. C-8. (+)-Des-N-methylcryprochine (38) (Li. 2011. 1996) (Figure 1). Hemingway et al.. Wang and Ding. villosa (Allais. isolated a series of nudicaulins. 2007. Wang and Chen1995. Besides. The acid-catalyzed rearrangement and dehydration of rhoeadine alkaloids can result in a red irniniurn salt.. 1977.. 2013). 9dihydroprooxocryptochine (39) (Wu et al.. including rhoeadine (1). 1981). papaverrubine A (3). Xie et al. papaverrubine D (5). reported the isolation of several alkaloids from M. 1991. Rhoeadines Rhoeadine alkaloids that have only been found among the family Papaveraceae and are biosynthetic derivatives of protopines. cambrica in Europe (Hemingway and Phillipson. Chinese researchers started research into alkaloids in Meconopsis in 1980s. Subsequently. 1975. Yan Zhou et al. 1996. R9 = CH3 R1 = R6 = R7 = OCH3. Wang et al. Wang and Chen. and Ranunculaceae. Hemingway and Phillipson..3. Salminen et al. Ten alkaloids. R8 = CH2OH R1 = R4 = R7 = R8 = R9 = H. R8 = CH2OH R1 = R4 = R7 = R8 = R9 = H. karachine (17). Berberidaceae. 1995.. 1991. 1981... R2+R3 = R5+R6 = OCH2O.. 1991. Gertig. 1976. 1975.. Pavines and Isopavines Pavines and isopavine alkaloids are probably derived biosynthetically from the tetrahydrobenzylisoquinoline. N-oxide amurensinine B (22). R4 = R9 = H. 1994. 3). 2). Twelve protoberberines. and O-methylpallidine N-Oxide (28) (Hemingway et al.. Structures of protoberberine alkaloids (7–18). 1996. 2011). and valachine (18) were isolated (Slavík and Slavíková. Mecambridine showed antihistamine. R5 = H. 2009) were obtained (Fig.246 Haifeng Wu. R2+R3 = OCH2O. anti-inflammation effects. 1996. 1975. 1. Lauraceae. R3 N+ R2 R1 7 9 10 11 12 13 R4 R5 R9 R6 R8 R1 = R4 = R7 = R8 = R9 = H. Shang et al. R2 = OH. corysamine (9). R8 = CH2OH 15 R1 = R4 = R6= R7 = OCH3. Xiaopo Zhang.. O-methylflavinantine (25). 1977. (–)-flavinantine (24). 1981. Wang et al. R2 = R3 = OCH2O. R2 + R3= OCH2O. (–)-reframoline (19). R3 = OH. N-oxide amurensinine A (21). Wang et al. Complimentary Contributor Copy . R3 = OCH3. Wu et al. amurensinine methohydroxide (23). Wu et al. Liu and Wang. palmatine (13) (–)-mecambridine (14). meconoquintupline (27). Protoberberines Protoberberines present themselves as tetrahydroprotoberberines and protoberberine salts. mequinine (12). 2011) (Fig. Slavík and Slavíková. 1. (–)-Omethylmecambridine (15). 1986. R2=R3 = R5 = R6 = OCH3 R7 R4 R3 N R2 R1 H R5 R8 8 R1 = R4 = R7 = R8 = H. R8 = CH2OH R6 R7 O O O N+ O O O O N O N OCH3 OCH3 CH3 OH OCH3 16 OCH3 OCH3 17 OCH3 OCH3 18 Figure 2. frequently found in four plant families. namely the Papaveraceae. berberine (11). alborine (10). (–)-amurensinine (20). 2003b.2. R5 + R6 = OCH2O 14 R1 = R6= R7 = OCH3. R4 = R5 = H. (–)amurine (26). R5+ R6 =OCH3 R1 = R2 = R4 = R6 = R7 = OCH3. R2+R3 = R5+R6 = OCH2O R1= R4 = R7 = R8 = H. Hemingway et al. R2 = R3 = OCH2O. and inhibition of human drug metabolizing cytochrome P450 enzymes (Hemingway and Phillipson. cheilanthifoline (8). coptisine (7). R5 = R9 = H. (–)-N-methylmecambridinium (16). 1996. (+)-Des-N- Complimentary Contributor Copy . (+)-corytuberine (30). R3 + R4 = OCH3 NCH3 NCH3 H O R1 R2 OCH3 O OCH3 + R2 N OCH3 21 R1 = O. and glaziovine (37). sharing a characteristic tetracyclic motif with different levels of oxidation on both aromatic rings. derived from benzyltetrahydroisoquinolines.5. Hemingway and Phillipson. 4).Meconopsis: Traditional Uses. Slavík and Slavíková. R3+R4 = OCH2O 20 R1+R2= OCH2O. antiplatelet. Six proaporphine alkaloids. R2 = OH 33 R1 = R2 = H Figure 4. The dienone group in ring D was produced through oxidation of benzylisoquinoline. 1976. and (+)-roemerine (33). Five alkaloids. are a diverse family of isoquinoline alkaloids with more than 300 members. roemeroline (32). R2 = H 32 R1 = H. (–)-pronuciferine (36). 1996) (Fig. A range of interesting biological activities has been documented. 1996. R2 = OCH3. R2 = O 23 R1 = R2= CH3 O O OCH3 N O H3CO O OCH3 H3CO 27 24 R1 = OCH3. Chemistry and Pharmacology R1 NCH3 R2 R3 O R4 O R1 19 R1 = OH. H3CO HO HO H3CO O H3CO N+ CH3 H CH3 N CH3 H HO HO R1 H3CO 30 29 N CH3 H O R2 31 R1 = OH. anticancer.4. Aporphines Aporphines. 1975. 1. antimalarial and vasorelaxing activity. were reported (Gertig. (+)mecambroline (31). (+)-magnoflorine (29). (–)-mecambrine (34). (–)-Nmethylcrotonosine (35). R2 = OH 25 R1 = R2 = OCH3 26 R1 = R2 = OCH2O 247 28 Figure 3. Slavík et al. including serotonergic. 1977.. Structures of aporphine alkaloids (29–33). 1. 1965. R2 = CH3 22 R1 = CH3. Structures of pavine and isopavine alkaloids (19–28). Proaporphines Proaporphine alkaloids are probably intermediates in the conversion of benzylisoquinoline into aporphines. . R1 N R2 CH3 O R3 R5 R4 40 R1+R2 = R3+R4 = OCH2O. Five alkaloids. were obtained (Li. norsanguinarine (44). R3+R4= OCH2O. Shang et al. Complimentary Contributor Copy R CH3 46 R = H 47 R = Acetonyl . Structures of proaporphine alkaloids (34–39). 2003b. Benzophenanthridines Benzophenanthridine could be derived from proberberine by the cleavage of C-6–N bond and formation of C-6–C-13 bond. R1 H3CO NCH3 R2 H3CO NCH3 R H H3CO NH H3CO H H N HO O O O 34 R1+R2 = OCH2O 35 R1 = OH. Structures of protopine alkaloids (40–42). sanguinarine (43). 2009) (Fig. Hemingway et al. 1975. 2007. R5 = H 41 R1 = R2 = OCH3.. 7). were reported (Gao et al. consisting of four fused ring including aromatic rings A and D. 1997.6. Yan Zhou et al. 1981. 1960.. 1981. 6). O O O O O O O + O NCH3 O 43 O N O H3CO H3CO 44 N CH3 O O N O 45 Figure 7. cryptopine (41)..7. R5 = H Figure 6. methylcryprochine (38) and 8. dihydrosanguinarine (46). Wu et al. and 6-acetonyl-5. protopine (40).. 2007. 2011) (Fig. chelerthrine (45). Protopines The difference between protopines and proberberine is the cleavage of C–N into three rings system in protopine alkaloids. R2 = OCH3 HO HO 36 R = OCH3 37 R= OH 39 38 Figure 5.248 Haifeng Wu. and allocryptopine (42). Xiaopo Zhang. 1975. R3= R4 = OCH3. 9-dihydroprooxocryptochine (39). Three protopine alkaloids. Slavík. R5= H 42 R1+R2 = OCH2O. 1965. Shang et al. 1. Wu et al. Hemingway and Phillipson. 1975. 5).. 2003b) (Fig. Structures of benzophenanthridine alkaloids (43–47). 1. Hemingway and Phillipson.6-dihydrosanguinarine (47) were obtained (Hemingway et al. 1960. 2011) and anhydroberberillic acid (58) (Wu et al. 2007. villosa in the northern India (Allais et al. Others One new alkaloid.2-methyl-1.. 1965). punicea. R2= H Figure 8. 9). simplisifolia (Hemingway and Phillipson. Chemistry and Pharmacology 249 1. 1996) (Fig. 2013) (Fig. lycorine (55). 6-methoxy. Slavík and Slavíková. respectively (Fig. H3CO N N H HO HO O H OR2 HO HO OH HO HO HO HO OH O OH OR1 48 OR1 N OH O HMG O O O O COOH OH Mal OH 49 R1=R2= H 51 R1=Mal. R2= H OH O H OR2 COOH O O O HO HO OH HO HO N O O O O O OH OH 50 R1=R2= H 52 R1=Mal. Complimentary Contributor Copy .9. R2= H 54 R1=HMG.3.10. integrifolia and M.. 1975. Benzylphenethylamines A benzylphenethylamine.. 1. R2= H 53 R1=HMG. himalayamine (56) was isolated from M. 2011) was obtained from M. Structures of benzylphenethylamine alkaloid (55). Most recently. Oleracein E (57) (Wu et al. was isolated (Slavík. 1983). OH HO O O H H N 55 Figure 9. 10). 8). cambrica (Tatsis et al. was isolated from M.2. Indoles A indole alkaloid. a series of nudicaulins (49–54) were isolated from M. 1.Meconopsis: Traditional Uses.4-tetrahydro-β-carboline (48).8.. Structures of indole alkaloids (48–54). paniculata and M. quercetin (61). kaempferol 3-O-(6-O--D-glucopyranosyl)-D-galactopyranoside (66). tricin (78). 2011. 1996. 2010. have been isolated from thirteen species of Meconopsis (Fig. dihydroquercetin (74). quercetin3-O-[2′′′-O-acetyl-α-L-glucopyranosyl -(16)-D-glucopyranoside] (84). increase the levels of antioxidant enzymes. quintuplinervia (Yue et al. 2011). 2001. eriodictyol (73). Wang et al. isorhamnetin 3-O-[2′′′-O-acetyl--D-glucopyranosyl(16)--D-glucopyranoside] (83). 2006b. kaempferol-3-gentiobioside (64) and kaempferol 3-xylosylgentiobioside (65). herbacetin (60). 2.250 O O Haifeng Wu. kaempferol 3-O-[-D-glucopyranosyl-(12)]--D.. Wu et al.. 1991. suggested that flavonoids could be considered as the main characteristics for the quality control of Tibetan medicine M. Takeda et al. Shang.. Liu and Wang. hydnocarpin (80). as well as protective effects on cardiovascular systems. Till now. OH H CH3 N O 56 HO N HO O O O O H3CO O N O 57 O HO OCH3 O 58 Figure 10. 1986. Yue et al. 2002b. Structures of benzylphenethylamine alkaloid (56–58). apigenin (77). isorhamnetin 3-O-[-D-galactopyranosyl-(16)]--D glucopyranoside (68). quercetin 3-O-[2′′′-O-acetyl--D-glucopyranosyl(16)--D-glucopyranoside] (81). tricin 7-O--D-glucopyranoside (72). Yan Zhou et al. including isorhamnetin (59). 2010). kaempferol 3-Oβ-D-glucopyranoside (71). As antioxidants. quercetin 3-O--Dglucopyranoside (62).glucopyranoside] (69). quercetin 3-O-[-D-galactopyranosyl-(16)]-Dglucopyranoside (67).. and thus protect body systems against damage from free oxygen species (Sandhar et al. luteolin (76). as well as flavonoid glycosides. 11). chrysoeriol (75). quercetin 3-O--D-galacopyranoside (63).. isorhamnetin 3-O-[-D-glucopyranosyl-(16)]--D-galactoside (70). 2006). Flavonoids Flavonoids are a diverse group of polyphenolic compounds widely distributed in the plant kingdom.6′′′-O-diacetyl--D-glucopyranosyl(16)--D-glucopyranoside] (82). twenty-eight flavonoids divided into flavonols... Shang et al. Yoshida et al. Xiaopo Zhang. quercetin 3-O-[2′′′. Tanaka et al. huazhongilexone (79). 2002a.. flavones. possessing a wide range of bioactive capacities which includes antioxidant and antibacterial properties.. and anthocyanidin. flavonoids can scavenge free radicals. cyanidin 3-O-(6-O-malonyl-β-sambubioside) -7-O--Dglucopyranoside (85) and 3-O-(2-O--D-xylopyranosyl)--D-glucopyranosyl-7-O--Dglucopyranosyl-cyanidin (86) (Fu et al. Complimentary Contributor Copy . R2 = Ac.653%) and 6. R2 = OCH3 R1 = OH. 3. 1989. R3 = -gal-glc R1 = R2 = R4= R5 =H. and agricultural and food industries for bactericidal. R2 = R3 =R4= R5 = H R1 = R3 =R4= R5 = H. R3= -glc-gal 2 = -glc glc R1 = R2 =R4= R5 = H. Most of chemical constituents of essential oils are aliphatic components. R2 =OH 74 R1 = R2 = OH. R3 = -glc-glc-xyl R1 = R2 =R4= R5 = H. 2013. 2003). R3 = OH. Essential Oils Essential oils have been popularly used in pharmaceutical... Analysis on essential oils of several species of Meconopsis has been conducted using GC–MS (Chen and Zhang. R3= OH 75 76 77 78 O HO O R1 = OCH3. R3 = OH. R3 = -glc-glc R1 = R2 =R4= R5 = H. Usually obtained by steam distillation from aromatic plants. R2 = H R1 = OH. Chemistry and Pharmacology R1 R5O R2 O OH O 59 60 61 62 63 64 65 66 67 68 69 70 71 72 HO R4 O OH O R1 = R3 = R4= R5 =H. R2 = OH R1 = R4= R5 =H. R5 = glc R2 R1 O OH O O R4R5 R3 HO 81 82 83 84 O O HOHO OR2 HO OH O R2 R3 OH O 73 R1 = R3= H. R2 = Ac. Wu et al. R3 = glc R1 = R2 = H. phenol-derived aromatic components and aliphatic components.. R4 = OH. sanitary.. cosmetic. R5 = CH2OH R1 = R3 = H. R2 = OH. they contain a variety of volatile constituents such as terpenoids. R3= H 79 R1 = R2 = H. n-hexadecanoic acid (27. R3 = glc. R3 = glc R1 = R4= R5 =H. virucidal. antiparasitic and insecticidal properties. Complimentary Contributor Copy .14-trimethyl-2-pentadecanone (16. R2 = OCH3.330%) were the main components in M. 2006. 2013). Structures of flavonoids (59–86). R4=OCH3. R2 = Ac. R2 = OCH3. Gao et al. R3 = OH. R5 = CH2OH R1 = R4 = H. R3 = gal R1 = R2 =R4= R5 = H. fungicidal.Meconopsis: Traditional Uses. R2 = Ac. R5 = CH2OH R1 = CH3. oliverana essential oils that showed strong antioxidant activity (Gao et al.10. R2 = OH. 2007. R2 = OH. R3 = -glc-gal R1 =R4= R5 = H. Yuan et al. For example. R 3 R1 = R4= R5 =H. R2 = H R1 = R2 = H R1 = R2 = OCH3 CH2OH OCH3 O OH OH O 80 OH HO R1 OH OH OR3 251 OR1 O OH R1 = R4 = H. R5 = H OH O HO HO OH O O+ OH OH OH RO O O HO O HO HO O OH OH 85 R = malonyl 86 R = OH Figure 11.. R4 = H. R3 = -glc-gal R1 = R4= R5 =H. Guan et al. 12). R4 = COOH R1 = R3 = H.furanaldehyde (104). 4. R2 = H. p-hydroxybenzoyl. 2010. 5. 1998.. 2-(3. and 2-methoxyphenyl-β-D-glucopyranoside (107) are also Complimentary Contributor Copy . Xiaopo Zhang. 13). Steroids Three steroids.4-dihydroxyphenyl)-ethyl-O-β-Dglucopyranoside (99). coumaric acid (98). stigmasterol (88). 3-hydroxypropyl myristate (105). Guo et al.. 6. 1998. β-sitosterol (87). Structures of steroids (87–89). protocatechuic acid (97). Zhang et al.. 2006b. Triterpenoids Four triterpenoids.. R2 = R4 = CH3 R1 = CH3. R2 = COOH. were reported (Guo et al. R4 = CH3 Figure 13. 1997) (Fig. 21α-hydroxy ursolic acid (90). and daucosterol (89).. 2006b.. R2 = R3 = H. Miscellaneous Constituents In addition. Pan. Shang et al. and 3hydroxyolean-12(13)-en-24-oic acid (93) were reported (Fu et al. 7-dihydroxy-4H-4-chromenone (102).. R2 = R3 = H 87 Figure 12. R3 = OH. β-amyrin (91). and 2. ursolic acid (92). 2011. 2003. Wu et al. Pan.252 Haifeng Wu. uracil (106).β-D-glucopyranoside (100). 4-O-β-Dglucopyranosyl-(Z)-p-coumaric acid (101). Zhang et al. 2003. Yan Zhou et al. caffeic acid (95). Structures of triterpenoids (90–93). 5. 2hydroxyacetylfuran (103). 5′-bis(oxymethyl). p-hydroxycinnamic acid (96).. 5. cinnamic acid (94). Shang et al. 1997) (Fig. R4 = COOH R1 = R3 = H. R2 R3 R1O HO 88 R1 = R2 = R3 = H 89 R1 = glc. R1 R2 R4 HO R3 90 91 92 93 R1 = CH3. Guo et al. 2007.. 2013). Shang. quintuplinervia using various established systems (He et al. 14) . enteritis and diarrhea by Tibetan medical practitioner. Zhou et al. 1997.. anti-inflammatory. R2 = OH O HO NH O O N H 105 O HOH2C HO HO 106 H3CO O O OH 107 Figure 14. Guo et al. 2002a. Zhang et al. analgesic. He et al. Pan. 2010. and glutathione (GSH) levels and a significant increase in the malondialdehyde (MDA) level. MIE exhibited strong antioxidant ability in vitro.. 2011. Shang et al.. 2011) (Fig.. Some Meconopsis herbs reportedly exhibited significant antioxidant. Wu et al. Antioxidants extracted from plants could play an important role in liver protection (Akanitapichat et al. In the rats with CCl4-induced liver injury. Biological Activity Although some Meconopsis species are in clinically prescribed in form of complex preparations for the treatment of hepatitis. Recently. Wang et al. two reports focused on antioxidant properties of Meconopsis species. catalase (CAT). evaluated the antioxidant potential of ethanolic extract of M. Zhou et al. 2003.Meconopsis: Traditional Uses. investigated the hepatoprotective and antioxidant effects of ethanolic extract of M. alkaline phosphatase (ALP). integrifolia (MIE) in vitro and in vivo (Zhou et al. 2010). aspartate aminotransferase (AST). R1 COOH COOH R2 97 R = OH 98 R = OCH3 O CHO O 100 HO HO O Oglc O OH O 101 102 104 103 O OH HO Oglc Oglc 99 OH H3CO H3CO COCH2OH HO HO R 94 R1 = R2 = H 95 R1 = R2 = OH 96 R1 = H. 2013. 2003. most of which were significantly reversed (except for SOD in the liver) by treatment with the extract and standard Vitamin E. Miscellaneous compounds (94–107). the groups treated with MIE and silymarin showed significantly lower levels of glutamate pyruvate transaminase (ALT). Chemistry and Pharmacology 253 obtained (Fu et al. The extract showed strong in vitro antioxidant ability. 2013.. 2006b. In the in vivo study. CCl4-induced oxidative stress caused significant decreases in the superoxide dismutase (SOD). antidiarrheal and hepatoprotective effects (Ding and Li. Wangchuk et al. pharmacological activities of Meconopsis were rarely investigated... and total bilirubin Complimentary Contributor Copy .. 2012). 2002b... 2011. In another study. 2013).. 1998. horridula as well as their photosynthetic responses to light and temperature in the nursery at an altitude of 3260 m. phytochemical investigation. simplicifolia used as Bhutanese showed strong antiplasmodial activity with IC50 values of 0. horridula could be easier due to its wider physiological adaptation (Zhang and Hu. Biological/ecological role of these alkaloids in the life cycle of the plant should also be paid much more attentions. In addition. Wangchuk and colleagues found that M.2 strain (a wild type chloroquine and antifolate sensitive strain) and 6. In another study. The increasing use has exerted much more pressure on the wild plant population through persistent collection practices. MIE demonstrated good antioxidant activities in both the liver and kidney of the rats in vivo.254 Haifeng Wu. it was deduced that the poor photosynthetic performance at high temperature be what limits M. Zhang et al. (TB). In another study. pharmacological evaluation. however. most species of which inhabit open alpine slopes (Dar et al. Conclusion The scientific validation and the quality assurance of the ethno-medicinal plants requires an integrated multidisciplinary approaches including the ethno-medical assessment. So far. The biological activities of alkaloids in Meconopsis should be extensively investigated.40 μg/ml against TM4/8. found that at lower altitudes. 2013).. 2010). it is difficult for cultivation of Meconopsis at lower altitudes owing to its intolerance to hot summers. The indepth phytochemical and pharmacological investigations are required toward quest to unearth the scientific basis for medicinal use of Meconopsis. Yan Zhou et al. simplicifolia exhibited good inhibition of TNF-α production in LPS-activated THP-1 monocytic cells (Wangchuk et al. plants of the genus Meconopsis produce the structurally diverse and complex alkaloids. introduction and cultivation of M. Discovery of new species are ongoing. Meconopsis is an endangered genus of ornamental and medicinal value. It is imperative to cultivate Meconopsis. 2010). and the verification of ethnopharmacological uses of both the ingredient and the multi-herbs formulations. which should play a vital role for the plant itself from the evolutionary perspective. horridula cultivation at low altitude (Zhang. Complimentary Contributor Copy .. have sharply declined in the last few decades as a result of habitat destruction. It is highly likely that further phytochemical investigations on the other species will result in much more isolations of bioactive constituents. By comparison of the photosynthetic capacity of M.39 μg/ml against K1CB1 (multidrug resistant strain) (Wangchuk et al. particularly threatened endemic taxa. integrifolia and M. Xiaopo Zhang.. more than 107 compounds have been reported from nineteen species of Meconopsis genus. crude extracts of M. deforestation and overexploitation. 2011). 2008). botanical identification. Conservation Strategies Populations of many medicinal plant species. manasluensis (Papaveraceae). J. S. Ganguli. Pharm.M. Y.. S.. Zheng. Hemingway. Zhang. K. L.. 42. 27 (Suppl).F. Dawa.L... J. Nuchklang. Chemical constituenst from Meconopsis integravia. Zhao.L..). Sci. Shamma. Chemical components of essential oils from Meconopsis oliverana and their antioxidant activity.. B. X. Pharm. Yao.. B. 490-498.. 2013.. Thoms.. India. S. Chen. 81102770) is gratefully acknowledged.Z.Meconopsis: Traditional Uses. 2007.. Ann. recemosa.. Mat. Study on essential oil from Flowers of Meconopsis integrifolia. Pharm. Phraibung. Dar. Chin. Biol. G. Sci.. H. 286-288. Y.. Cui. K. 2007... 25-26. Guan.R. Food Chem. Xinjiang Univ. 7-8. A.D. 539-540. Northwest Normal Univ. (Nat. 1983. Talapatra. Z. 2011. Ni. Vet.. H.. Z. A.. Chin. S. Zhu. He.Z.R. Bianba..R. Wang. S. Ding.M..J.. Li.. An..R. Med. Talapatra. China. Guinaudeau. Freyer. B. J.X. In vitro and in vivo antioxidant activity of the ethanolic extract from Meconopsis quintuplinervia.. Preliminary studies on Meconopsis Horridula Hook.) 6. Peng. Antioxidant and hepatoprotective activities of five eggplant varieties. 24. J.P. Minorities 2. B. Ed. Shen. Zhu. X. Sci. Mat. D.. Chin.. Gao. (Poznan). Y.. Chemical constituents of Meconopsis integrifolid as a Tibetan medicinal herb(Ⅰ).Y.G.. Z. Study on protective effect of Meconopsis quintuplinervia Regel on experimental hepatic injury in Micl. 111-115.. Toxicol. P. Gertig. J. A. Complimentary Contributor Copy . 2010..R. 38. H. Allais..Q.P. Wang.S. 49-52. Yunan J. (Nat. two new species of Himalayan poppy endemic to central Nepal with sympatric congeners. Chemistry and Pharmacology 255 Acknowledgments Financial support from the National Natural Science Foundation of China (No. J. Tetrahedron Lett. 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An experimental design approach using response surface techniques to obtain optimal liquid chromatography and mass spectrometry conditions to determinethe alkaloids in Meconopsis species.F. Liu. X. Li. Shi.. Zhou.. 1994. Meconopsis grandis... C. Song. Photosynthetic adaptation of Meconopsis integrifolia Franch. C 58. Hu. 1053-1058. 66.R....F. Chen.. and M. diabetes. Inc.In: Medicinal Plants Editor: David Alexandre Micael Pereira ISBN: 978-1-62948-219-4 © 2014 Nova Science Publishers. tinctures or by cooking. hypertension among others. Chapter 10 A Case Study of Indigenous Medicinal Plants: Antioxidant Properties. infusion. infusions. Jamaica Abstract Jamaica’s flora has a rich source of medicinal plants. which are all alleviated by antioxidant compounds. It provides an alternative method for the management of various diseases. Herbal medicine has been the source for many pharmaceutical and nutraceutical products based on wellresearched and developed ethno-medicinal practices worldwide. Hibiscus sabdariffa (Jamaican sorrel). Complimentary Contributor Copy . Antioxidant activity is often times found in those plants that are edible and as such is able to alleviate oxidative stress when eaten. the Eupatorium odoratum (jack in the bush) and Momordica charantia (cerasee) are among the common plants used on the island to promote oxidative relief. of these 51 possessing antioxidant properties. such as cancer. 1788 plants have been identified to contain two or more bioactive compounds. Traditional Uses and Conservation Strategies Henry Lowe and Joseph Bryant Bio-Tech R&D Institute. The Petiveria alliacea (guinea hen weed). the green coffee beans decoction (Coffee arabica). These plants are often administered in many different ways. including decoctions. with over 2900 species of identified flowering plants. Due to their usefulness as medicinal plants tissue culture has been used as a part of the conservation strategies that have been employed in preserving and maintaining the island’s flora. macerations. especially those in the diet. These include garlic (Allium sativa). diabetes. and Jamaican sorrel (Hibiscus sabdariffa) as shown in Figure 1 below along with the known antioxidant portion of the plant. chocho (Sechium edule). this would again prevent further deterioration of cells. cinnamon (Cinnamomun verum). some of which are common and more frequently studied. Plants within the Jamaican flora with such properties have been in use for decades from generation to generation. terpenes. in vitro studies showed that the polyunsaturated fatty acids (PUFAs) had significant antioxidant activity as the PUFAs were able to stimulate the production of reactive oxygen/nitrogen species (ROS/RNS) from free radical within human aortic endothelial cells. as inflammation is reduced and subsequently the prevention of cardiovascular diseases such as atherosclerosis. hypertension. Azadirachta indica (neem plant) has been known to have Complimentary Contributor Copy . flavonoids. Other phytochemicals with antioxidant activity are the terpenes. cashew (Anarcardium occidentale). (2008). According to Richard et al. Spanish needle (Bidens pilosa). green coffee (Coffea arabica) beans. The incorporation of science has now been able to validate the uses of these plants in treating these ailments. tocopherols. ascorbic acid and polyunsaturated fatty acids present. guinea hen weed (Petiveria alliacea). Antioxidant Compounds in Medicinal Plants The active compounds that contribute to the antioxidant effect are usually due to the polyphenols. Jack-in-thebush (Euphorium odoratum).. Terpenes have been shown to protect the cells from oxidative stress using different mechanisms by scavenging for free radicals or by increasing the enzymatic and non-enzymatic antioxidant status within the cell (Gonzalez-Burgos et al. As a result. Antioxidant compounds are those inhibitory molecules that are able to bind to free radicals and thus prevent physiological damage which also inhibits interference of biochemical reactions within the body. There are over 4000 known polyphenols that have been extracted from various plants. Fruits are usually rich in polyphenols and therefore are usually included in fruit drinks or as dietary supplement. These phytochemical compounds have been shown to reduce oxidative stress and thus retards the progression of chronic diseases such cancer.260 Henry Lowe and Joseph Bryant Indigenous Plants with Antioxidant Activity The antioxidant effect of plants provides a wide array of medicinal uses that aids in the combating of various diseases. The elimination of free radicals from the body is imperative in maintaining health from the cellular level which will thus be reflected throughout the body. Aloe vera. pignut (Hyptis suaveolens). Approximately 51 plants have been known to contain antioxidant properties. soursop (Annona muricata). Polyphenol extracted from green coffee beans also show significant antioxidant activity. Spiny pigweed (Amaranthus spinosus). watermelon (citrillus lanatus). Plant Compounds As Antioxidants Polyphenols are natural phenolic compounds that possess antioxidant properties and are common among many plants. 2012). thus initiating their removal from the body. and Penisetum pupureum. The antioxidant activity of S. Williams et al.. The results showed that the bark had a higher quantity of total polyphenols present (23. Petiveria alliacea (guineahen weed) is a potential anticancer drug as research has shown the anti-tumour effect on various cancer cell lines (Uruena.. and has subsequently being added to juices which increase their antioxidant properties. 2009. They aid in pigmentation and act as a chemical messenger throughout the plant and have been known to reduce free radicals present and therefore have contributed to the antioxidant activity of many plants (Hernandez et al. It is an antidiabetic agent in that the oral administration of extract was able to significantly reduce the blood glucose and lipid levels in diabetic and hyperlipidaemia patients (Vogler and Ernst.. 2009). 2001. edule is due to the compound alpha rho. 2009). ethanol.04 µg/mg (tannic acid equivalents). as a three (3) year old aloe vera plant had more antioxidant activity when compared with the two and four years old plants (Hu et al.. Other commonly used plants with antioxidant properties include the Jamaican sorrel (Hibiscus sabdariffa) which has been shown to reduce the free radical content. It also acts as an immune system booster.. 1994). 2006). The antioxidant property of the seed. et al. 2003). that is the root. bark. 2000. especially herbs. Hibiscus sabdariffa (roselle/sorrel) exhibits significant antioxidative properties as the crude methanol extract of the calyx had a better effect in linoleic acid model system. which showed that the leaves contained more flavonoids contributing to the overall antioxidant property of the plant (Ghimeray. The type of polar solvent used is dependent on the type of plant. leaves. Its antioxidant activity is one such reason for its effectiveness against many diseases. This Complimentary Contributor Copy . which has been shown to contribute to significantly increase antioxidant activity the plant exhibits and the growth stage also played an important role in the level of antioxidant activity. The total flavonoids content was also assessed and expressed in equivalents to quercetine. edule showed significant hydrogen donating properties when reacted with DDPH stable radicals.. 2005). (Ordonez et al. Pietta. while the leaves contain between 66. Plant Extractions of Antioxidant Compounds Antioxidant compounds are found in the polar extractions that are usually done using methanol.63 – 629. They are able to remove free radicals from the body and have been prospective treatment for many ailments (Grassmann. 1-diphenyl-2-picrylhyazyl (DPPH) method (Ghimeray. No. 11. The crude ethanol extract of the leaves and the water extract of both the leaves and seeds of S.). et al. 1999). Pannala et al. One such plant is the Aloe vera which is known for its numerous medicinal properties. These effects may also be as a result of the high flavonoid and polysaccharide content. a bio-catalyser that can also extracted from the fermentation of Carica papaya Linn. Terpenoids such as monoterpenes and diterpenes contribute the unique flavours found in plants.00 µg/mg).. leaves and bark were found to contain high quantities of polyphenols and flavonoids when tested using the 1. Jovanovic et al. fruit or inflourescent. 2008.85 – 237. the region of the plant that the isolation will be done. acetone or water.. Flavonoids are another type secondary metabolite in plants with over 8000 already identified (Pietta. 2000).A Case Study of Indigenous Medicinal Plants 261 many medicinal advantages which may be attributed to the active compounds azadirachtin and nimbin. cavaliers A. vanillic acid. The leaves in particular are usually harvested for their antiinflammatory. antiinflammatory and antiandrogenic effects when the aqueous extract of the leaves were tested (Sofowora.antidiabetic. 2002). analgesic among other properties such as antifungal. Table 1 below lists other plants with antioxidant properties that are commonly used in ethnomedicinal therapy for various ailments. nitric oxide and hydroxyl) and showed that there was significant antioxidant activity (Chakraborty et al. phenolics and ascorbic acid Alkaloids. Eupatorium odoratum (jack in the bush) is a member of the Asteraceae family and have been used for various ailments. oleifera H. jackin-the-bush Horseradish tree(moringa) pignut M. 2010) and therefore confirms the use of this plant as an antioxidant. flavanol. spinosus A. Table 1. glucose. et al. terpenes leaves methanol root methanol bark methanol calyx Leaves and roots methanol methanol flavonoids Thiosulfate derivative leaves Crude Extract Complimentary Contributor Copy . The crude methanol extract of the bark of Swietenia mahagoni (West Indian mahogany) was able to significantly lower the thiobarbituric acid reactive substances (TBARS) while increasing the glutathione and catalase levels in STZ-induced diabetic rats(Prasa d Panda. 2010). 2002). alkaloids Cultivation for antioxidant activity Entire fern Bulb leaves shoot leaves Pulp and seeds ethanol methanol methanol methanol Ethanol n-butanol ethyl acetate Phenolics Ascorbic acid and other vitamins phenolics Aerial water Phosphate buffer Methanol NA leaves ethanol Flavonoid. mahagoni H. papaya Maiden fern Garlic Spiny pigweed Cashew Gungo papaw C. roselle Guineahen weed Class of Antioxidant Compound Flavonoids phenolics phenolics Flavonoid Vitamin C. sativum A.262 Henry Lowe and Joseph Bryant was as a result of the formation of conjugated diene compounds and the TBARS (thiobarbituric acid) when the extract was administered. occidentalis C cajan C. lanatus C. roseous periwinkle C. p-hydroxybenzoic Phenolics. nucifera watermelon coconut E. antihypertensive. mallic and citric acids. This level of antioxidant activity was also significantly more than grapes when tested similarly (Tee et. Some indigenous plants with antioxidant properties obtained from polar extractions Plant Common Names A.antibacterial. This was compared with two known antioxidant compounds (α-tocopherol and butylated hydroxyl-anisole.. It was investigated and thus authenticated its use as an antioxidant. suaveolens S. BHA) which had an increased antioxidant property. The crude extracts of the leaves obtained from ethanol and water were assessed using various in vitro radical induced assays (DPPH.. alliacea West Indian Mahogany Sorrel. odoratum Bitter bush. 1993). sabdariffa P. odoratum was said to be attributed to the phenolic content with in the leaves (Luximon-Ramma et al. The antioxidant activity of E.. al. This type of conservation is carried out by monitoring the forest cover and reducing deforestation for wood. Aloe vera and P. Conservation Strategies The use of plants as medicine has significantly impacted the pharmaceutical society as they form the basis for many medicines used in modern medicine and traditional treatment. For example. Research done by Richard et al found that teas were able to significantly promote the release of insulin when epididymal fat cells were assessed. However. alliacea are two such plants that also contain antioxidant activity. 2004). al. pilosa which showed the health benefits of infusion as the extract which showed significant antioxidant activity due to the flavonoids (Abajo et al. ex situ or in vitro. An infusion of aqueous B. Biotech R&D Institute Ltd. et. Jamaica has capsulated a number of plants with medicinal properties. Based on HPLC and other chromatographic analysis. These plants are traditional prepared in various ways. including cancer. which salso confirmed its antioxidant activity coupled with an increased antihyperglycaemic effect (Sitasawad et. The crude extract of the fruit was prepared via an aqueous extraction and was subsequently tested on STZ-induced diabetic rats. in 2010. Plants with bioactivity are screened for their active components. Eupatorium odoratum also showed marked antioxidant activity in lab tests using a variety of methods. macerations and cooking are not commonly used to extract and obtain an antioxidant effect from medicinal plants.A Case Study of Indigenous Medicinal Plants 263 Traditional Uses and Preparations These would include examples of endemic plants with antioxidant properties commonly used to treat various ailments. for example by heat during the cooking of fruits and vegetables. 2002). 1993). 2000). al. charcoal Complimentary Contributor Copy . Research done showed that cerasee significantly reduced oxidative stress when compared to the control.. these include: In decoctions the plants are either dried or placed as fresh samples in warm water. these plants can then be culture and modified to increase the percentage yield of the active compounds. the compounds are still able to elicit some effect if not destroyed... and thus further isolations can be done. The antioxidant activity of the teas was mainly due to the polyphenol content which reduces oxidative damage (Anderson. the antioxidant effect would be similar to that done experimentally with the ethanol and water as shown by Chakraborty et al. Tinctures. ). farming. The conservation of medicinal plants is imperative to the development of products and improved scientific research and as such protection includes the implementation of various types of gene banks whether they are in situ. Many plants show antioxidant properties when administered via decoction. As such. This plant is traditionally prepared as an infusion of the leaves and therefore. In situ conservation carried out in Jamaica and other regions of the Caribbean involves the protection these folkloric medicinal and agricultural plants within high conservation areas such as their natural habitats (Prendergast et al. it is imperative to implement various strategic methods that will always provide the necessary compounds with antioxidant properties that will reduce the free radicals within the body that often times interrupt the normal functioning of the organs which eventually leads to physiological diseases. The cerasee plant has long been used for various ailments via infusion. re-planting or for modification and extraction of phytochemicals.. Biotech R&D Institute can then be done to preserve the use of the plant products.264 Henry Lowe and Joseph Bryant etc… and by promoting the growth and sustainability of our Jamaican forests which houses many of our endemic species. 2009). 2009. and as an anticancer due to its antioxidant properties (Hu et al.. Vasquez et al. For example. Complimentary Contributor Copy . Fencing is also a common method used in other areas to prevent the continuous grazing and thus the loss of some of our valued ethnomedicinal plants. Psidium guajava (guava). 2003). sultana et al.. as a result. The conservation and sustainment of the rich medicinal source from nature can also be further creates medicines to alleviate various diseases. Some of medicinal plants are stored in seed banks. These prevent species from becoming extinct as they are constantly being regenerated and provides for continuous research can be done. 2007. germplasm banks and other in vitro methods. where plants with medicinal properties are replanted in mined out lands as a method of reforestation and as such increasing the quantity of these plants found in different parts of the island with improved technological. The active compounds towards these diseases are found in the succulent leaves of the plant. soil erosion. The Ministry of Agriculture via the Forestry Department ensures the conservation of these plants and constantly replants any species that has become endangered after continuous research. These leaves are often regenerated by tissue culture for research. This prevents extinction of species. Periodical testing of the stored seed are done to ensure viability and thus sustainability of medicinal plants. 2003). a seed bank helps to alleviate this. The neem and Cassia plants are commonly planted. Subsequent implementation of products to the market by nutraceutical companies e. odoratum are among some of the trees that can be found in our island’s forests containing antioxidant properties (Dudonne et al. Tissue culture creates the avenue for species regeneration especially with the tropical climatic conditions. Anarcardium occidentale (cashew) and E..g. The protection of the medicinal plant species can also be done by placing them in a new location with additional benefits which will enhance their survival is referred to as ex situ conservation (Heywoods et al. These medicinal plants may have been lost due to natural disasters such as hurricane. Tissue culture technique is often employed as one of the main measures in preserving these plants. fire and as such research is conducted in order to monitor the flora and its numerous natural products they contain. these parts of the plants are also stored for further regeneration of plantlets. Medicinal plant research also creates the avenue for conservation as knowledge of the usefulness of these plants are then published and thus increase knowledge of the uses of these plants as well as creates the avenue for additional study. hypertension. Aloe vera has numerous medicinal properties and is often used for diabetes. The smaller medicinal plants are often replanted in botanical gardens or in horticultural greenhouses. Eucalyptus globulus (eucalyptus).. Medicinal plants can be harvested in small quantities and the regeneration of plantlets is done using various parts of the plant depending on the species and the media being used.. This can be done colony relocation. The Azadirachta indica (neem tree). Various parts of the plant contain activity and thus. Eugenia spp. (2009)... I. Mendez. S..K. Heywood. S. and Imam. S. J. (2009).Hernandez. Agric. J.M. (2005). Gonzalez-Burgos.. Vitamins & Hormones. Chem. S.Medicinal Plants of Jamaica Parts 1-4 .. J. 8(13): 3084 – 3091. 57 (5): 1768 – 1774 Ghimeray. I. A. and Gomez-Serranillos.. Gonzalez. S.M.. 2 (4):77 – 79. and Merillon.P. M. and Breusegem. A.Food Chem.. Tosic.A Case Study of Indigenous Medicinal Plants 265 References Abajo. Steenken. Woillez. Antioxidant Activities of Phenolic. (2012).A. M.I. Ghimirez. Ahmad. Alegre. Journal of Pharmacology and Toxicology 6 (6): 580–588.. and Bastia. L.1021/jf020514c Asprey. Kaur. Boffill. DOI: 10. (1994). 14 (3): 125 – 132. 116 : 4846 – 4851. Terpene compounds in nature: A Review of their potential Antioxidant Activity. In vitro Antioxidant and Antimicrobial Activity of Methanolic Root Extracts of Hyptis suaveolens. and Ha Cho. J. (2004). (2002). ABTS. 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Trees. 33. 219 age-related diseases. 96. 158. 131. 46. 151. 155. 256. 205 adenine. 2. 86 adipocyte. xi. 26. 163 adiposity. 131. 228 aflatoxin. 150. 19. 146. 78. 121 aging process. 145. 59. 113. 52. 4. 130. 100. 158. 45. 135. vii. 221 aloe. 68. 155. 129. 236 agriculture. 149. 149. 65. 15. 160. 167 ammonia. 209. 247. 261. 130. 2.Index A ABA. 163. 153 adhesion. 235. 46 aggression. 149. 159. 59. 255. 33 acetaminophen. 69 adenosine. 39. 45. 235. 164 adiponectin. 187. 4. 151. 159. 1. 111. 84 active site. 266 age. ix. 44. 151 ammonium. 177 aldehydes. 135 adrenaline. 15. 49. 91. 149. 176. 89. 154 adipose. 120. 144. 80. 157. 167 amino acid(s). 15. 149. 145. 74 acne. 232 active compound. viii. 206 alanine. 26. 59. 62 acetone. 187. 117 adverse effects. 117 alfalfa. 262 alkylation. 21. 254. 243. 144. 245. 83 ALT. 152. 150. x. 264 active oxygen. 129. 108 amines. 153. 102. 109. 82 acetic acid. 152 albumin. 147. 144. 45. 92. 3. 132. 102. 254. 1. 114 amylase. 44. 261 acetonitrile. 163. 153. 102. 165. 86. 152. vii. 110 accounting. 44. 129. ix. 143. 153 adenosine triphosphate. 75. 248. 228. 260. 38 alkaloids. 146. 3 acute lymphob adaptation. 4. 233. 48. 258. 101. 155. 65. 69. 244. 151. 139 alcohols. 29 access. 6 allergic rhinitis. 15. vii. 60. 89. 88. 105. 258 additives. 19 acidic. 9. 87. 129. 128. 151. 153. 154. 59. 145. 2. 159 alters. 162 ADP. 131. 156 alanine aminotransferase. 99. 128 adenocarcinoma. 64. 147. 158. 168 accessions. 101. 148 adsorption. 45 Complimentary Contributor Copy . 58. 64. 151. 9. 155 acupuncture. 66. 128. 45. 109. 144. 216. 157. 80. 30 acidity. 31. 77 Africa. 257. 131. 32 amino. 15. 249. 44. 246. 261 alpha-tocopherol. 134. ix. 151. 75. 163. 2. 60. 49. 65. 26. 239 abstraction. 1. 231. 85. 219 amyotrophic lateral sclerosis. 209 AIDS. 110 Abraham. 253 alternative medicine. 156. 5 acetogenins. 17. viii. xi. 228. 131. 109. 12. 135 aldose reductase pathway. 178 advanced glycation end product (AGE). 163 adipose tissue. 137. 263. 157. 39 adults. 137. 150. 94. 80. 237 bacteriophage. 33. 227. 97 antiinflammatory drugs. 176. 81. 45 automation. 205 bacterial fermentation. 22. 62. 37. 167. 228. 66. xi. 81. 95. 132. 64. 37. 131 biochemical processes. 204. 177. 228. 121 birds. 87. 41. 262 aseptic. 76 angiotensin II. 159. 210 benefits. 129. 76 arthritis. 45. 132. 228. 96 biotechnology. 21 Armenia. 149. 126. 16 atmospheric pressure. 112. 92. 43. 13. 180. 56 artery. 50. 146. 230. 149. 162 argon. 13 anthocyanin. 14. 122. 257 biological activity. 55 awareness. 137 atherosclerosis. 138. 59. 135 beef. 65 bilirubin.268 Index analgesic. 127. 55. 102. 74. 42. 29. 136 biological activities. 70. 35 ATP. 105. 205. 220 biotic. 264 base. 60. 102. xi. 87. 69. 261. 69 apoptosis. 163. 232 biosynthetic pathways. 238. 71. 234. 192. 153. 109. 51. 3. 61. 254. 119. 56. 79. 240 Complimentary Contributor Copy . 126 antitumor. 128. 247. 159. 137. 16 autooxidation. 164. 92. 147. 184 black tea. 99. 49. 20. 2. 257 antibiotic. 16 benzene. 220 ascites. 53. 3. 209 antioxidative activity. 159. 54. 50. 158. 36. 122. 239. 95. 39. 38. 253 assessment. 71. 104. 3 autism. 189. 78. 63. 123 arginine. 42. 151. 3. 229. 186 aromatic compounds. 59. 111 biomarkers. 98. 66. 58. 104. 253 bioactive secondary metabolite. 79. 65. 97 Asia. 151. 54. 152. 27 biological systems. 142. 11. 57. 230 apples. 212. 260 atherosclerotic plaque. 28. 91. 118 azadirachtin. 44. 56. 41. 57. 93. 162 beer. 32. 58. 69. 62. 237. 146. 166. 131. 121 Beijing. 64. 236 appetite. 188. 108. 90. 105. 183. 206 ANS. 193. 67. 92 Black Sea region. 262 anemia. viii. 152. 261. 102 asthma. 209 angiogenesis. 219 bacterial infection. 228. 59. 53. 179 ban. 264 anticancer activity. 58. 156. 198. 82. 75 beta-carotene. 220. 155 aromatic rings. 78 arteries. 96. 201 banks. 60. 115 biomolecules. 26. 263. 34. 55. 167. 71. ix. 233. 90 antioxidative potential. ix. 263. 152. 132 anorexia. 118 biochemistry. 100 bioavailability. 123 benzo(a)pyrene. 108. 244. 83. 50. 57. 229. 59. 87 antispasmodic. 75 anticancer drug. 247. x. 102. 73. 104. 143. 9. 57. 150. 106. 48. 45. 107. viii. 65. 56. 139. 9. 14. 131 atmosphere. 92. 79. x. 37. 229. 156. 70 authorities. 205. 121. 87 biological samples. 187. 41. viii. 100. 132. 74. 130 atrophy. 10 anticancer. 151. viii. 200. 85. 186 bioflavonoids. viii. 33. 121. 145. 243 beneficial effect. 206 astringent. 205. 63. 78. 135 biosynthesis. 26. 136. 227 bile. 154. 109. 169. 136. 167. 161. 48. 191 atherogenesis. 63. 253. 146. 254 assimilation. 56. 222 aspartate. 15. 115. 54. 136. 166. 52. 12. 238. 64. 60. 236 biomass. 54 angiotensin converting enzyme. 158. xi. 264 benign. 44. 87 beverages. 126. 21. 180 biodiversity. 114. 73. 128 anhydrase. 97. 243. 206. 248 arres(s)t. 265 B bacteria. 196. 221 ascorbic acid. 158. 125. 143. 260. 240 biologically active compounds. 54. 79. 129. 67. 44. x. 83 cell death. 155. 33. 86. 80. 17 Central Europe. 47. 70. 77. 55. viii. 87 C-C. 64. 221. 67. 157 cellulose. 228. 70. 69. 196. 67. 87. 239. 228. 120. 160. 219 269 carbon. 48. 79. 83. 221. 45 blood. 168. 158 carbohydrate metabolism. 198. 207. 202 butadiene. 84. 195. 57. 57. 87. 152. 255. 69. 234. 65. 51. 25 carboxylic groups. 229. 177. 137. 58. 206 cardiovascular disease. 163 calibration. 71 breast cancer. 63. 54. 56 candidates. 204. 30. 229 cascades. 121. 81. 68. 155. 8. 15. 78. 62. 70. 39. 59. 43. 239 cell cycle. 67. 97. 56. 154. 238. 233. 37. 205. 52. 224. 83. 66. 33. 31 caloric intake. 261. 154. 87 cancer progression. xi. 261. 71. 97 by-products. 62. 178. 39. 26 buyers. 1. 42. 81. 132 challenges.Index bladder stones. 42. 23. 20. 87. 181. 150. 27 chemical structures. 222. 21. 157. 77. 261 blood pressure. 72. 219. 59. 152 chemotherapeutic agent. 64. viii. 100. 117. 54. 7. 34. 59. 68. 151 calyx. 45. 33. 48. 159. viii. 207. 144. 113. 88. 42. 23. 58 Complimentary Contributor Copy . 244. 261 chemical reactions. 147 cervix. 83. 58. 62. 76. 45. 72. 61. 157. 158. 146. 61. 206. 67. 263 cancer cells. 56 carcinoma. viii. 127. 84. viii. 212 cattle. 41 case study. viii. 92. 14. 149. 219. 90. 26. 95. 72. 134. 190. 111 central nervous system. 197. 169 bonds. 151. 154. 56. 57. 86. 87. 147. 69. 83. 61. 127 Catharanthus roseus. 27. 143. 154. 14 chemicals. 45. 200. 238 cell division. 58. 209 bursa. 119. 147. 205. 235. 154. 133 carbohydrates. 76. 148. 197 blindness. 77. 158. 259. 146. 50. 257. 68. 108. 4. 4. 168. 204. 79. 51. 44. 198. 143. 211. 234 chemical reactivity. 228. 51. 53. 102. 88. 78. 237 Brazil. 150. 70. 155. x. 143. 151. 190. 175. 56. 93. 144. 48. 157. 14. 110. 74. 144. 6. 134. 70. 115. 163. 118. xi. 129. 42. xi. 29. 161 calcium. 163 bonding. 209 bleeding. ix. 67. 17. 60. 43. 151. 141. 4 carbon dioxide. 47. 158 body composition. 132. 53. 18. 262 cancer. 42. 223 chemical. 82. 86. 156. 229. 2. 28. 51. 64. 55. 209. 67. 243. 151 cell line(s). 71. 119. ix. 96. 64. 88. 133. 151. 80. 181 carcinogenesis. 156 carbohydrate. 91. 75. 230. 181. 58. 89. 93. 166 bone resorption. 207. 23 butylated hydroxyanisole (BHA). 261 cell membranes. 55. 159. 145. 167. 71. 62. 49. 89. 57. 71. 58. 136 candidiasis. 211 chemoprevention. 196. 14. 78. 109. 209 capillary. 156. 135. 28. 58. 64. 35 capsule. 87. 57 brain. 111. 209. 176 cell size. 156. 57. 59. 240. 144. 22. 165. 33. 41. 2. 210. 2. 82 bronchitis. 157. 33. 78. 260. 62. 26 butylated hydroxytoluene (BHT). 84. 144. 64. 76. 118 cation. 118. 221 cardiotonic. 71. 154. 69. 79. 263 carotene. 128 cabbage. 166. 234. 26. 235. 114. 168 carboxyl. 74. 142. 156 calorie. 155. 240 carbon-centered radicals. 163. 163 BMI. 90. 8. 55 carcinogen. 55. 135. 189. 55. 62. 194. 160 breakdown. xi. 164 C Ca2+. 260 cardiovascular risk. 227. 79 cardiovascular system. 66. 133. 56 chain propagation. 240 carbon atoms. 158 body weight. 160 body fat. 132. 84 caffeine. 144. 238. 15. 148. 45. 29. 136 bone. 24 cell culture. 250 Caribbean. 159 carbon tetrachloride. x. vii. 145. 71. 251. 69. 49. 90 Britain. 35. 256. 15. 210 carotenoids. 56. 92. 48. 4. 109 cataract. 129. 30. 32. 6. 99. xi. 235 controlled trials. 25. 68. 70. 56. 238. 29 consumers. 177 civilization. 110. 34. xi. 65. 94. 7. 54. 103. 34. 21. 37. 102. 64. 99. 58. 101 correlations. 155. 144 chromatographic technique. 85. 159. 32. 258 condensation. 147. 102. 95. 238 cleavage. 82. 158. 32. 136. 58. 128. 121. 144. 28. 238. 111 cultivation. 251 cost. 87 cues. 94. 152. 258 Chinese medicine. 35. 220. 82. 95 consumption. 131. 229 community. 166 circulation. 96 control group. 113. 113. 79. 12. 154. 59. 76. 42. 25 cobalt. 47. 56. 8. 207. 131. 39 complications. 159 composition. 76. 56. 121. 29. 129 coffee. 111 crop production. 78. 2. 83. 199 constituents. ix. 108 contamination. 192. 189. 53. 129 CO2. 49. 95. 85. 20. 258 commercial. 190. 56. 162 chiral center. 263 coordination. 151. 146 CT. 7 chlorination. 66. 103. 25. 251. 54. 91. 52. 96. 72. 86. 36. 150. 6. 209. 210. 79. 94. 259. 71. 133. 140. 57. 219. 36. 69. 176. 221. vii. 6. viii. 98. 120. 232. 115 CRP. 90. 206. 209. 209 cortex. 12. 192. 135. 122. 51. 1. 100. 119. 4. 150 coronary heart disease. 59. 131 conjugation. 200. 41. 90. 111. 121. 63. 210. 86. 225. 108. 102. 48. 56. 208. 23. 140. 94. 166 comparative analysis. 67. 41. 27. x. 34. 146. 150. 222 colon cancer. 210 correlation. 91. 129. 57. 106. 16. 74. 174. 110. 34. 122 cultivars. 68. 44 copper. 222 color. 69. 188. 123 configuration. 70. 61. 90. 59. 125. 201 cortisol. 24 climate(s). 58. 74. 94. 60. 113. 67. 135. 58. 184 collagen. 18. 91. 205. 83. 98. 103. 64. 201. 54. 55. 79. 59. 172. 156. 4. 82. 26. 105. 53. 19. 68. 117. 205. 61. 16. 140. 115 compatibility. 60. 147 cosmetic(s). 37 chromatography. 44. 139 coenzyme. 149 cooking. 78. 82. 70. x. 58. 154. 24. 231. 19. 244. 108. 150. 57. 212 Chinese women. ix. 105. 181 crop. 71 cigarette smoke. 121. 144. 100. viii. 136. 72. 14. 17. 109. 95. 16. 256. 135 Croatia. 48. 113. 37. 154 clustering. 11. 78. vii. 111. 257 classification. 209. 257. 204. 219. 120. 150. 260 chronic illness. 230 clinical trials. 176. 188. 79. 111 crops. 232. 155. 44 colic. 149. 231. 155. 21. 150 children. 21 coronary artery disease. 153 chronic diseases. 194. 94. 95. 97. 60. 162. 16. 224. 97. 68 covalent bond. 264. 228. 108 China. 91. ix. 60. 69. 173. 54. 38. 100. 12. 243. 135. 50. 209 contaminant. 263. 198. 86. 244. 61. 234. 177. 266 constipation. 79. 135 corona discharge. 67. 62. 82. 189. 107 communities. 157. 72. 260 cognitive function. 176. 239. 19. 53. 254 Complimentary Contributor Copy . 2. 22. 195 Chile. 100. 71. 138. 88. 160. 256. 80. 88. 255. 103. 80. 120. 16 compilation. 48. 87. 97. 237 chloroform. 236 conservation. 192. 23. 56. 111. 196. 195. 115. 69. 90. 222 choline. 166.270 Index childhood. 235 chlorophyll. 245 conjugated dienes. 205 coumarins. 104. xi. 227 classes. 107. 101. 107. 184 cough. 144. 189. 266 colon. 206 collaboration. ix. 209. 98. 215. 115 cholesterol. 259. 97. 103. 71. 89. 96. 38. vii. 78. 110 Cuba. 248 cleavages. 106. vii. 158. 51. 259. 1. 53. 93. 56. 255. 1. 38 chromium. 16. 63. 45. 16. 258 construction. 134. 75. 89. 207 counterirritant. 254. xii. 90. 77. 109. 222. 61. 36. 94. 127. 80. 45. 243. 235 covalent bonding. 167. 62. 96. x. 118. 201. 254 detection. 159. 205. 204. 159 depression. x. 159 cytoskeleton. 43. 39. 224. 113 deforestation. 228. 131. 144 developing countries. 120. 178 deficit. 148. 18. 206 diversity. 85 Cydonia oblonga. 120. 136. 48.Index culture. 256 cytokines. 2. 219 CV. 159. 61. 120. 168. 119. 176. 127. 265 donors. 52. 234 defence. 235 deficiency. 45. 102. 207. 87. 41. 152. 132. 34 decomposition. 114. 35 distillation. 264 diabetic nephropathy. 70. 142.. 251 distribution. 83. 134. 119. 149. 118 Department of Agriculture. 94. viii. 81 decay. 229. 94. 149. 59. 62. 254. 73. 151. 47. 121. 94 database. 9. 146. 164. 147. 62. 125. 59. 106. 144 dietary intake. 223. 52. 156. 31. 17. 55. 128. 89. 167. 93. 176 cytotoxicity. 38. 33. 48. 146. xi. 94 DOI. 56. 119. 19. 118. 19. 177. 105. 56. 132 DNA strand breaks. 89. 112. 136 drug interaction. 20. 36. 3. 234. 199. vii. 160. 150. 45 deprivation. 18. 57 CWA. 75. 160. 141. 238 dehydration. 152. 119. 129. 204. 143. 198. 184. ix. 150. 45. 67. 70 diarrhea. 34. 199. 151. 184. 70. 167 double bonds. 118. 101 D damages. 28. 99. 2 drugs. 55. 33. 238. 20 destruction. 183. 133. 259. 112 drought. 48. 30. xi. 26. 154. 235. 93. 71 dietary supplementation. 158 drainage. 228. 75 danger. 93. 19. 229. 264 curcumin. 39. 33. 80. 201. 56. 74. 61. 80 dissociation. 118. 108. 65 cystic fibrosis. 134. 245 desiccation. 35. 178 cysteine. 204 dispersion. 210. 108. 131. 118 docosahexaenoic acid. 63 dietary habits. 253 diet. 240 DNA damage. 132. 161. 152. 160. 163. 89. 72. 121 depth. 100. 79. 95. 74. 153. 45. 56. 222. 211. 61. 34. 42 disorder. 101. 86. 109. 42. x. 53. 263 deformability. 155. 144. 140. 1. 138. 26. 192. 163 diabetic patients. 107 desorption. 195. 233. 234. 176. 85. 141 detoxification. 180 defense mechanisms. 31. 49. 245 deoxyribonucleic acid. 112. 98. 259. 80. 94. 175 doctors. 78. 2. 138. 21. 121. 162. 163. 63. 10. 93. viii. 111. 140. 44. 144 271 diabetes. 136. 9. 25 disease-reduction benefits. 36. 114. 174. 263. 159. 128. 82. 208. 156. 166. 6. 121. 168. 102. viii. 90. 50. 129. 81. 91. 77. 223. 258 diuretic. 176 digestion. 37. 72. 122. 42. 33 cure. 86. 52. 219. 133. 55. 103. 102. 94. 92 disposition. 91 deposition. 165. 114. 44. 235 discrimination. 76. 121 cyclophosphamide. 189. 65. 2. 100. 209. 228. 57. 109. ix. 139 cycles. 150. 71 down-regulation. 266 DNA. 155 dietary fiber. 244. 58. 126. 66. 233. 151. 107. 27. 94. 8. 211. 142. 104. 152 cytochrome. 190. 236 developed countries. 189. 61. 111. 136. 190. 228. 159 deposits. 75. 229. 38. 240 dietary fat. 191. 139. 49. 220. 51. 139. 199. 72. 219. 58. 239. 71. 158. 105. 93. viii. 240 DNA repair. 176. 56. 142 CVD. 82. 46. 17. 14. 81. 80. 14. 210. 3. 50. 260. 109. 120. 15 dipole moments. 135. 45. 64. 117. 140. 211. 147. 63. 157. 97. 37. 51. 149. 254 derivatives. 246. 150 diacylglycerol. 192. 206 dimethylformamide. 89. 93. 67. 166. 205 drug discovery. 140. 56 diffusion. 4. 16 discontinuity. 143. 44. 180 degradation. 239. 61. 87. 260 dietary antioxidants. 66. 19. 73. 50. xi. 244 Complimentary Contributor Copy . 15. 100. 229. 102. 95. 150. 70. 52. 206. 90 EPR. 210. 157. 110. 161. 18. 154. 266 eukaryotic. 228 epithelial cells. 254. 147. 253 entrapment. 3. 228. 152 epidemic. 2. 143. 151 expectorant. 150. 166 ESI. 145. 3. 151. 162 England. 167. 56. 92. 164. 43 euphoria. 36. 104. 231 erythroid cells. 88. 20. 22. 159. 95. 264 extracellular matrix. 149. 150. 82. 158. 93. 105 drying. 134 extraction. 244 Europe. 221. 206. 102 etiology. 29. 196. 176. 98. 111. 150 dyspepsia. 189. 180. 218. 205 EPA. 81. 130. 52. 17. 73. 97. 27. 107. 102. 68. 184. 177 erythrocytes. 115. viii. 45. 187. 91. 211. 20. 38. 260 endothelial dysfunction. 21. ix. 229. 258 expertise. 42. 29. 152 electric field. 162. 132 erythrocyte membranes. 189. 229. 212. 151. 144. ix. 217. 155. 147. 238 endothelial cells. 263 ethers. 146. 139 epidemiology. 149. 129. 34 electrophoretic separation. 264. 209. 131. 152. 206. 151. 131. 258 excitation. 21. 136 epidemiologic. 43. 208. 15.272 Index dry matter. 156. 158. 31 excretion. 109. 129. 147. 162. 21 evidence. 97. 122. 187. 131 endurance. 15. 147. 37. 159. 75. 263 fat reduction. 206 eicosapentaenoic acid. 66. 78. 69. 2. 225. 43. 153. 264 endocrine. 78. 23. 190. 244 enteritis. 57. 255 eczema. 114 FAD. 52. 177. 154. 129. 144. 94. 66. 213. 57. ix. 70. 146 endothelium. 219. 188 dyslipidemia. 128 families. 144. 266 fauna. 128. 121. 101 electron(s). 96. 9. 118. 157. 94. 165. 155. 151. 16. 235. viii. 232 editors. 167. 46 energy expenditure. 147 environmental issues. 211 extinction. 236 evolution. 15. 6. 75. 54. 126. 51. 137. 197. 9 ethanol. 235 equilibrium. 16. 234 electrophoresis. 118. 44. 38 ester. xi. 16. 214. 199 experimental condition. 115 evaporation. 152. 58 experimental design. 114. 112 endangered. 16. 135. 101. 43. 13 eucalyptus. 58. 156 fat. 233. 44. 131. 163. 216. 45. 87. 261. 95. 180 Egypt. 131. 47. 93. 246 FAS. 234 environment. 75. 102. 262. 107. 196. 167. 234. 145. 81. 116. 17. 18. 243 ecology. 148. 142 ethnic groups. 256. 46. 77. 160. 245 European Union. 262 ethylene. 75. 260. 94. x. 55. 227. 144. 2. 154 energy. 215. 129. 110. 58. 78. 209. 188. 14. 117. 3 exposure. 69. 141. 186. 149. 29. 181. 160. 222 exercise. 72. 187 FDA. 54. 206 E East Asia. 112. 97. 53. 84. 244. x. 166 energy density. 42. 112 environmental stress. 147. 20. 43 extracellular signal regulated kinases. 166 EU. 229 environmental conditions. 130. 21 electrical conductivity. 42. 64. 18. 263. 70 ester bonds. 25. 32. 23. 104 environmental impact. 43. 238 endocrine disorders. 179. 139. 18 emission. 108. 103. 151 fatty acids. 76. 38. 68. 28. 157. 34. 185. 150 epidemiologic studies. 3 Complimentary Contributor Copy . 192. 106 environmental influences. 15. 187 ethyl acetate. 128. 74. 50. 187. 147. 264 F factories. 109. 79 epilepsy. 82. 81. 91. 163. 31. 191. 17. 209 edema. 157 fasting. 157 Finland. 100. 162. 168. 51. 154. 120. 129. 196. 77. 131. 107 genus. 21 flooding. ix. 140. 15. 95. 21. 69 genes. viii. 61. 157 fluid extract. 65. 147. 144. 128 flora. 163. 144 fiber. 142. 103. 9. 24 France. 115 folic acid. 104. 96 fluid. 61. 58. 202. 178. 120. 42. 13. 29. 34. 205. 152. 82. 57. 155. 219 flavonol. 250. 157 fluorescence. 140. 98 ginger. 234. 14. 68. 169. 141. 79. 23. 86. 68. 54. 158. 148. 58. 49. 156 273 free radicals. 209. 65. 124. 121. 158. 257 field crops. 53. 32. 51. 24. 36. 236. 187. 72. 160. 69. 154. 263 fructose. 205 furan. 118. 166. 63. 76. ix. 211. 235. 228. 61. 135. 69. 122. 262 glucose tolerance. 27. 4. ix. 188. 53. 113 fertilizers. 81. 222. 3. 6. 261. 254. 65. 72. 85 fungal infection. 233. 186 Germany. 24. 92. 72. 54. 118. 42. 92. 57. 8. 90. xii. 157. 149 gene expression. 232 glasses. 132. 221. 176 fragments. 91. 33 gas diffusion. 166 fibrinogen. 230. 230 gastrointestinal tract. 51. 190. 244. 1. 131 fibroblasts. 168. x. 95. 266 fibrosis. 87. 140. 81. 142. 80. 151. 261. 205. 162 female rat. 127. 156. 34. 151. 248. 134. 137. 205. 244. 113 flammability. 68. 60. 48. 96 filtration. 96. 33. 63. 55. 48. 157 glucose. 186. 259. 235. 94. 239. 16. 261 ferritin. 46. 50. 37. 121. xi. 81 food.Index feelings. 122. 63. 65 gastritis. 230. 62. 103. 85. 102. 103. 31. 62. 154 food products. 124. 39. 211. 141. 6. 205 flight. 197 fungi. 139. 117. 149 gluconeogenesis. 18 formation. 73. 256. 121. 121. 134. 117. 187. 187 fractures. 251 Food and Drug Administration. 253 Complimentary Contributor Copy . 207. 69. 28. 20. 79. 136. 240. 161. 43. 243. 211. vii. 88. 232. 131. 133 glucose-induced insulin secretion. 127 glucagon. 64. 109. 60. 258. 184. 80. 150 glaucoma. 125. 137. 184. 8. 133 glucosidases. 156. 128. 117. 157. 150. 264 flour. 15. 231 glucosinolates. 55. 260. 127. 207. 64. 94. 189. 3 food intake. 15. 63. 42. 158. 150 fruits. 74 fermentation. 176. 244 fragility. 73. 212. 74. 44. 169. 135. 147 genetic marker. 2. 232. 88 force. 84. 133. 68. 210 gene regulation. 76. 120. 166. 134 glucoside. 150. 262 formula. 57. 93. 27. 240. 115 floods. 189. 96. 23. 45. 181. 82. 260. 206. 237. 81. 14. 150 genetic background. 184. 53. 128. 211. 10. 67. 21 fossils. 26. 11. 14. 121. 175. 256 flavo(u)r. 133. 16 flatulence. 240 ginseng. 64. 67. 232. 166 fiber content. 88. 90 genetic defect. 228. 120. ix. 44. 200 flowers. 191. 135. 75. 44. 87. 234. 51. 50. 47. 18. 75. 90. 41. 189. 34. 154. 195. 87. 19. 169. 133. 38. 127. 89 GLUT4. 62. 166 fertilization. 257 fluctuations. 263 functional food. 48. 21 Georgia. 148. 220. 158. 239. 52 germination. 136. 33 genetic factors. 117. 105 fever(s). 62 G gamma rays. 87. 61. 57. 188. 44. viii. 147 genotype. 60. 48. 257 geometry. 102 gastric ulcer. 39. 69 folklore. xi. 206. 51. 122. 74. 77. 134 glutamate. 209. 122. 58. 18. 66. 126. 106. 176 hybrid. 71. 80. 31. 262 glycerol. 127. 91. 264 growth. xi. 100. 108 guidance. 44. 94. 205 height. 230 HCC. 92. sabdariffa. 205. 205 harmonization. 205. 79. 220. 261. 186. 104. 166 heart rate. 4. 221 hereditary spherocytosis. 24 hormone(s). 108. 192. 48. 103. 240. viii. 98. 224 health care system. 237. 167. 14. 264 growth factor. 187 greenhouse. 42. 228. 179 hemorrhoids. 43. viii. 46. 74. 61. 59. 263 health care. 262 habitat. 201 health. 94. 147 hexane. 177. 114. 43. 199. 209 grass. 159. 129. 87. 205. xi. 129. 136. 188. 118. 193. 239. 56. 102. 176. 221 herbal teas. 196. 64. 84. 3. 101. 185. 55. 210. 108. 178 glycoproteins. viii. 208. 219. 55. 58. 166 hearing loss. 206. 255 hepatitis. 148. 79 headache. 61. 89. 239. 33 head and neck cancer. 109. 47. 212. 26. 8. 92. 133.274 Index glutathione. 109. 205. x. 166. 34. 128. 41. 162. 155 glycoside. 143. 29. 16. 126. 72. 106. 244. 237. 205. 108. 7. 162. 112. 206 hepatic injury. 131. 103. 114. 113 greenhouses. 224. 189. 26. 97. 99. 54. 67. 169. 11. 78 host. 56 heart disease. 58 hotspots. 211. 185 health promotion. 55. 143. viii. 50. 73. 176. 144 homeostasis. 42. 43. 165. 179. 166. 264 Greeks. 187. 143. 81. 41. 222. 150. 44. 71. 193. 33. 167. 184. 109. 266 House. 120. 184. 36. 2. 112. 147 growth rate. 111. 125. 105. 144. 60. 107. 132. 84. 166. 143 homocysteine. 158 high fat. 51. 5. 44. 198. 22. 244 harmful effects. 121. 235 hydrogen peroxide. 231 glycosylation. 229. 184. 142 health problems. 189. 219 health effects. 204. 166 heredity. 127. 41. 65. viii. 166. 95. 50. 238 herbal medicine. 178. 253 hepatocytes. 44 glycogen. 62. 111. 206. x. x. 160 Highlands. 113. 256 HPV. 142. 118. 147148 horticultural crops. 177 hemoglobinopathies. 94. 147. 21 heme. 99. 236 Complimentary Contributor Copy . 96. 192. 166 hemolytic anemia. 151 homolytic. 233. 77. 228. 41 growth hormone. 44. 37. 35. 234. 42. 86. 78. 154. 5. 97. 194. 56. 141. 73. 219. 3 harvesting. 150. 4. 227. 28. viii. ix. 129. 26. 54. 58. 91. 159. 41. 146. 25. 183. 166. 134 glycolysis. 42. 240 hydrolysis. 155. 243. viii. 131. 197. 69. 204. x. 196. 177 high density lipoprotein. 79. 156. 122 gout. 237. 24. 140. 41. 41. 191. 14. 26. 60. 115. 41. 180. 98. 235. 48. 99. 107. 44. 205. 44. 206 helium. 33. 103. 232 human subjects. 121. 224 health condition. 59. 2. 104. 98. 131. 62. 100. 113 human body. 128 hemoglobin. 205 healing. 65. 82. 177 hydroperoxides. 70. 87. 38 grazing. 26. vii. 212 hippocampus. 100. 176. 160. 14. 72. 254 habitats. 236 history. 45 heart attack. 158. 86 hydrazine. 209. 150 glycine. 2. 125. 157. 60 histamine. 190. ix. x. 50. 149. 97. 104. 127. 212. 94. 161 human health. 144. 121. 132. 6. 64. 101. 152. 230 heavy metals. 102. 56. 235 hepatotoxicity. 110. 101. 260. 41. vii. 137. 75. 148 heartburn. 50. 253. 29 hydrogen. 61. 92. 169. 92. 1. 261 hydrogen atoms. 223. viii. 210 histology. 81. 80. 44. 82. 140. 75. 3. viii. 95. 227 HIV. 63. x. 209. 84. 211. 220. 87. 166. 240. 34. 51. 82. 3 H H. 33 immune response. 24. 147. 86. 189. 100. 18. 219. 255 Indians. 26. 260 intervention. 154. 120. 166. 155. 150 ionization. 105. 232. 233. 86. 71. 129. 155. 90. 92. 163. 229. 207. 60 immunomodulatory. 83. 93 inflammatory mediators. 34. 207 images. 254 identity. 18 interference. 60. 22. 159. x. 141. 76 inositol. 30. 150. 238. 36. 58. 167. 138 hyperlipidemia. 72. 220. 204. 192. 126. 95 income. 233. 79 hypertrophy. 88 industries. 121. 33. 143. 249. 6. 134. 89. 133. 154 275 individuality. 22. 233. 53. 251 industry. 104. 20. 64. 23. 240 investment. 191. 260. 101. 166 ions. 157. 25. 219 hyperglycemia. 206. 148. 219 initiation. 41 infrastructure. 27. 96. 45. x. 122. 123. 104. 169. 96. 157. 236 hypothyroidism. 79. 55. 118. 261 immunomodulation. 150. x. 202. 47. 56. 167. 176 interface. 93. 136 integrity. 23. 72. 1. 235. 166. 189. 240. 144. 254 inhibitor. 97. 6. 136. 104. 56. 239 hypercholesterolemia. 103. 4. 181. 5. 81. 237. 229. 45. 144. 258. 64. 44 immune system. 115 hydroquinone. 143. 132. 74. 14. 207. 205. 120. 139. 222 ionizing radiation. 56. 129. 101. 239. 97 ingestion. 1. 23. 144. 76 intoxication. 151 insulin signaling. 59. 138. 70. 232. 146 hypotensive. viii. 144. 61. 129. 28. 82. 152. 174. 135. 92 immune function. 150. 156 in vivo. 234. 209 infection. 232. 59. 246. 206 insulin. 105. 4. 17. 38. 148. 118. 153. 235. 189. 159 inflammatory disease. 98 ion channels. 220 immunostimulant. 26 hydroxyacids. 62.Index hydrophobicity. 231 insects. 72. 88. 67. 76. 73. 157. ix. 149 hypothesis. 25. 178. 89. 184. 150. 228. 106. viii. 37. 222 hyperinsulinemia. 234. 144. 90 inflammation. 232. 101. 178. 199 infertility. 135. 127. vii. 184. 119. 111 hypoxia-inducible factor. 266 incidence. 232. 14. 202. 205 injury. 172. 34. 167. 79 hypoxia. 175 imbalances. 234. 131 inflammatory responses. 177. 50. 134. 64. 246. 89. 158 hypertension. 34. 166. 52. 35. 151. 144 India. 137. 97. 12. 142. 207. 3. 175 ingredients. 228. 260 inflammatory cells. 104. x. 4. 72. 204. 48. 200 impotence. 259. 92. 5. 71. 111. 55. 147. 186. 178. 240. 33. 51. 19. 117. 138. 17. 255 inhibition. 26. 21. 149. 144. 206. 198. 51. 175. 57. 264 hyperthyroidism. 70. 220. 97. 48. 223. 79. 44 I ideal. 109. 232. 159. 230. 71. 154. 129. 126. 235. vii. 45. 151 intestine. 151. 68. 219. 155. 94. 205. 53. 109. 206 improvements. 99. 50. 57. 222. 262 hydroxyl groups. 16. 119. 51. 133. 72. 42. 186. 159 identification. viii. 2. 148. 55. 175. 53. 35. vii. 57. 54. 235. 21. 228. 240. 89. 177. xi. 85. 150. 10 hydroxyl. 60. 156. 63. 145. 204 ileum. 194. 177. 4 individuals. 209. 92 insomnia. 192. 169. 239. 20. 109. 98. 36. 263 insulin resistance. 4. 83. 87. 76. 93. 102. 150. 149. 210 immune regulation. 158 induction. 234. 95. 219. 14. 169 injuries. 130. 62. 65. 91. 253 inner ear. 107. 159 insulin sensitivity. 67. 21. 136. 56. 68. 148. 23. 65. 240. 24. 63 hypothalamus. 70. 54. 110. 1. 141. 83. 258 Iowa. 51. 110. 142 hyperlipemia. 219. 114. 209 inflammasome. 19. 161. 43. 150. 90. 189. 44. 32. 150. 255. 15. 177 industrial processing. 14 intima. 222 Complimentary Contributor Copy . 84 Iran. 122. 253. 102. 18 hydroponics. 54. 173. 211. 117. 128. 100 lignans. 253. 36. 261 lipases. 244. 118. 230. 104 J Jamaica. 146. 233. 69. 54. 142. 61. 207 joint pain. xi. 115. 118. 139 K kaempferol. 166 L-arginine. 138. 72. 71. 265.276 Index Iraq. 146. 187. 97. 53. 14. 129. 254 lifestyle changes. 167. 83. 39 liver cells. 85. 61. 100. 71. 4. 53. 94 legume. 177. 79. 62. xi. 36. 233. 169. 59. 228 liver damage. 52. 231. 132. 63. 101. 235. 183. 33 irrigation. 136. 179 lung cancer. 51. 20. 156. 93 leukocytes. 86. 66. 52. 206. 176. 133. 222. 39. 67. 61 Luo. 15. 136. 118. 131. 207. 81. 135. 52. 207. 108. 126. 152. 177. ix. 67. 35. 126. 52. 135. 239 irradiation. 24. v isoflavone. 3. 148. 153. 89 Complimentary Contributor Copy . 91. 82. 147. xi. 82. 66. 87. 132. 52. 60. 75. 240. 234. 122. 156. 106 ischemia. 169. 49. 68. 86. 181 lens. 152. 158 L lactoferrin. 113 lead. 176. 189. 147. 102 low-density lipoprotein. 8. 106. 167 lipid peroxidation. 50. 157 lesions. 93 linoleic acid. 150. 245. 48. 64. 209. 166. 243. 150 kinetics. 131. 256 lutein. 158 lipid oxidation. 85. 234. 109. 42. 166. 43. 228. 13. 197. 16. 244 iron. 96. 62. 25. 234. 114. 236 lipolysis. 76. 200. 229. 93. 157. 152. 89. vii. 93. 4. 132. 135. 35 LDL. 158 leaching. 84. 205. 230. 206 issues. 131 lean body mass. 66. 59. 155 kidney. 132. 237. 55. 155. 78. 151. 72. 49. 76. 209. 207. 39. 144 light. 168. 132 lipid metabolism. 6. 71. 239 Korea. 200. 206 jejunum. 266 Japan. 236. 125 isolation. 256 jaundice. 143. 66. 167. 210 lymphatic system. 135. 258 liquid phase. 83 life cycle. 261 isomers. 79. 259. 54. 146 low risk. 184. 83. 210 lycopene. 11. 263. 209. 4. 134 leprosy. 10. 244. 234. 155. vii. 135 isoflavonoids. 44 low fat diet. 50. 236. 51. 110. 154. 201 Jordan. 118. 254 kidney stones. 32. 159. 43. 55. 132 LC-MS. 67. 144. 63. 65. 60. 250 ketones. 60. 52. 153. 16. 198. 4. 195. 84. 64. 151 legislation. 210 isoprene. 147. 67. 229. 77. 177 lignin. 228 ischemia reperfusion injury. 229 localization. 29. 211. 154. 101. 35. 134. 50. 131 liquid chromatography. 53. 120. 155. 88. 32 liver. 137. 239 lipid peroxides. 181. 65. vii. 186 Ireland. 79. 69. 48. 66 liver cirrhosis. 135. 180. 70. 136. 149. 162. 71. 204 kinase activity. 86. 123. 146. 56. 137. 19 low temperatures. 175. 140. 83. 206 leptin. 128. 78. 69. 1. vii. 157. 206. 70. 54. 51. 72 lymphocytes. 232. 76. 34. 198. 135 lipids. 58. 175. 9. 71. 158. 151. 194. 163. 72. 192. 71. 231. 24. 31. 235. 18 lithium. 49. 101. 56. 1. 149. 61. 76. 28. 131. 121. 93. 52. 62. 228. 45. 152. 55. 149. 15. 56. 50. 235 liver disease. 22. 159 lipoproteins. 66. 60. 231. 228 Islam. 51. 50. 204. 149. x. 201. 146. 147. 254 light conditions. 1 leakage. 91. 257 liver cancer. 33. 157. 233. 89. 227. 81. xi. 19. 236 lead molecules. 223 Italy. 1. 151 model system. 144 metabolic pathways. 37. 63. 3 mesangial cells. 35. 102. ix. 184. 163. 180. 102 metabolic syndrome. 165 medicine. 230. 68. 114. 152. 131 mitogen. 168. vii. 120. 55. 239 metabolized. 33. 149. 210. 207. 60 MMS. 187. 246. 107. 118. 155. 233 microwaves. 36. 136 microscopy. 176. 117. 107. 93. 163 metabolic changes. 60 MMP-2. 128. 42. 159. 151. 118. 39. 127. 243. 233 methylation. 263. 131 macromolecules. 238. 149. 183. 93. 133. 54 MMP-9. 213. 92. 2. 43. xi. 136. 126. 21 management. 181. 134 mellitus. 110. 119. 76. 117 microorganisms. 56. 45 meth. 185. 50. 181 lysozyme. 55. 231. 15. 112. 136. 189. 64. 175 microsomes. 187. 158. 5. 219. 86. 147. 6. 187. 137 mesophyll. 232. 138. 94. 43. 17. 264 medical. 142. 74. 116. 128. 207. 216. 256. 166. 16. 211. 57. xi. 135 majority. 43. 65. 11. 266 Mediterranean. 231. 180. 18. 93. 74. 259 manganese. 237. 233. 14. 245 methyl group(s). 22. 259. 144 metabolic dysfunction. 33. 117 277 meta-analysis. 121. 161. 48. 204. 34. 125. 91. 100. 208. 19. 8. 20. 120. 147. 104. 89. 4. 61 magnitude. 184. 65. 155. 76. 115 marketplace. 111. 232 mice. 114. 25. 229. 262 methodology. 179 membrane permeability. 60. 136 metabolizing. 229. 173. 235 memory. 89. 17. 46. 93 metals. 149. 84. 20. 224 Mediterranean climate. 36. 228. v. 180. 221. 1. 101 membranes. 83. 151. x. 76. 120. 30. 79. 223. 96. 227. 122. ix. 99. 106. 110. 261 models. 144. 35. 147. 162. 231. 131 macular degeneration. 59. 53. 15. 210. 83 Complimentary Contributor Copy . 225. 20. 227. 214. 130 mitochondrial DNA. 163. 110. 19. 5. 261. 222. 181. 155. 104. 96. 33. 256 metal ion(s). 222. 1. 234. 155. 221. 41. 86 MEK. 43. 178. 64. 224. 136. 100. 172. 151. 174. x. 189. 21. 230. 120. 116. 126 messengers. 234. 117. 54. 14. 67. 60 migration. 64. 108. 141 measurement(s). 63. 39 M machinery. 206. 258 mass spectrometry. 22. 176. 176. 34. 27. 54. 152. 53. 136. 167. 54. 211 metastasis. 96. 55. 219 MALDI. 18. 90. 45. 162.Index lymphoid. 79. 143. 138. 86. 101. 17. 101 macrophages. 134 mixing. 158. 61. 35. 97. 211 metabolites. viii. 59. 37. 59 magnesium. 82. 145. 244. 258 materials. 128. 90. 65. ix. 143. 215. 177 microemulsion. 76. 140. 151. 229 medication. 250. 99. 161. 144 metabolic disorder(s). ix. 136. 154. ix. 152. 228. 25. 159. 107 manufacturing. 132. x. 41. 179. 33. 160. 166. 180. 206. 121. 156. 232 modifications. 253. x. 102. 82 matrixes. 139. 79. 50. 45 mitochondria. 177. 258. vii. 65. 58. 188. 167 molasses. 50. 34. ix. 2 mass. 98. 104. 19. 231. 58. 96. 211. 48. 99. 184 matrix. 71 Maillard reaction. 56. 77 manipulation. 16 Middle East. 11. 223. 221 metabolism. 178. 150. 28. 234 media. 18 MMP. 46. 142. 144. 169. 113. 83 mental illness. 149. 27. 181. 17. 120. 94 methanol. 221 microcirculation. 54. 137. 150. 204. 186 lysis. 50. 17 Mexico. 21. 109. 159. 66. 166. 76. 178 MB. 119. 73. 54. 161. 3. 230 matrix metalloproteinase. 254 medical history. 91. 16 matter. 154 Metabolic. 229. 39. 209. 155. xi. viii. 117. 31. 156. 232. 36 micronutrients. 2. 86. 21. 150. 184. 164. 146. 222. 222. 95. 220. 76. 29. 169. 204. 234. 118. 92. 154. 26. 117. 150. 112 monomers. 118. 122. 21. 128. 104 mutation(s). 15. 102. 94. x. 163. 139. 135 NADH. 132 nutrient imbalance. 87. 219 natural disaster(s). 78. 128 nitric oxide. 118. 88. 128. 233. 90. 166 nitrogen. 81 non-enzymatic antioxidants. 98. 129 neuropathy. 107.278 Index molecular biology. 104. 183 niacin. 45. 4 nucleus. 54. 114. 229. 57. 264 nutrient. 121. 117. 47. 2. 37. 211. 11. 16. 39. 260 molybdenum. 247 mountain ranges. 155 normal aging. 117. 44 neuronal cells. 102. 206 Northeast Asia. xi. 160. 3. 103. xi. 11. 11 molecular mass. 18 molecular oxygen. 97. vii. 96. 1 nausea. 129. 105. 161. viii. 163. 150. 140 mutagen. 100. 142. x. 77 Nrf2. 24. ix. 106. 228. 138. 150. 111. 146. 128. 132 molecular structure. 151. 99. 186 MR. 167. 112. 159. 135. 129. ix. 21. 61. 50. 27. 108. 19. 81. 110. 91. 141 nucleic acid. 25. 111. 53. 133. 111 NAD. 80. 130. 153. 211 myoblasts. 122 molecular weight. 144. 210 oligomers. 60. 146. 57. 234 oil. 163. 262 nitric oxide synthase. 238 O obesity. 112. 49. 77. 101 NaCl. 186 Netherlands. 114 neurodegenerative diseases. 28. 210. 210 Montana. 116. 140. 149. ix. x. 34. 263 natural herbal products. 29. 129. 118 North America. 152. 211. 255 oil production. 145. 87. 99. 135 natural compound. 10. 48. 127 nervous system. 61. 166. 231 nuclei. 209. 229 neurodegenerative disorders. 260 NMR. 65. 75. 55 neutral. 164. 92. 148. 144. 136. 71. 236 nucleotides. 109. x. 118. 255. vii. 64. 84 neurons. 94. 101. 20. 45. 119. 236 negative effects. 112. 43. 63. 17 non-smokers. 131. 244. 45. 127 neurotoxicity. 143 mortality rate. 67. 104. 178. 113. 91. 75. 143 N Na+. 157. 93. 84 mortality risk. 32 MOM. 229 North Africa. 265 nephropathy. 105. 232. 44. 106. 166. 102. ix. 14 Nepal. 107. 126. 140. 25 New South Wales. 109. 118. 108. 18. 74 neuroendocrine system. 24. 103 mortality. 228. x. 22. 26. 64. 114. 110. 143 morphine. 19. 127. 53. 42. 80. 108. 114. 112. 1. 60 neuronal apoptosis. 50. 137. 43. 47. 54. 166. 150. 153 nicotinamide. 90. 179. 26. 174 Moon. 81 nuclear magnetic resonance. 4. 132 non-polar. 167 molecules. 20. 121. 21. 96. 48. 168. 47. 232. 117. 51. 244 morphology. 149 nutrition. 115. 147. 62. 66. x. 43. 97. 219 OH. 180 Complimentary Contributor Copy . 197 necrosis. 104. 47 motif. vii. 96. 132. 140 morbidity. 114. 100. 100. 77. 21. 55 olive oil. 45. 2. 235. 38. 165. 102. 44. 53. 64. 78. 21. 112 oleic acid. 95. 113. 158. 97 nutrients. 78. 155. 18. 118. 8. 143. 108. 210. 57. 69. 206. 65 norepinephrine. 121. 55. 147. vii. 264 natural habitats. 162. 108. 117. 86. 90. 35. 9. 126 Nuevo León. 84. 78. 146. 119. 93. 142. 56. 45. 128. 8 monounsaturated fatty acids. 1. 230 nutraceutical. ix. 101. 8. 259. 234. 118. 244. 145 myocardium. 109. 166. 147 neurological disease. 56. 59. 26. 67. 132. 55. 259. 111 pharmaceutical. 3. 4. 51. 204. 115 phosphorylation. 2. 53. 178. 122. 83. 33. 113 plaque. 239. x. 130 organelle(s). 29. 76. 110. 202. 153. 131. 234 peroxynitrite. 126. 138 plasma levels. 227. 103. 1. 2. 239 oxidative agents. 159. 166. 92. 176 partition. 152. 93. 141. 147 pesticide. 126 photosynthesis. 109. 97. 151. 45 pathogens. 178 phosphatidylcholine. 220 placebo. 192. 149. 167. 230 overlap. 143. 70 oxidation. 3 phytosterols. 13. 245. 26. 254 phycoerythrin. 160 ox. 168. 251. 135. 3. 48. 51. 102. 16. 111. 28. 57. 126. 87 osteoporosis. 154. 31. 143. 19. 251 phenylalanine. 155 phytotherapy. 198. 139. 27. 98. 169. 235. 153. 50. 11. 112. 127. 59 phosphate. 44. 55 phosphoenolpyruvate. 87 Physiological. 149.Index omega-3. 163 overweight adults. 100. 45. 50. 161. 144. 45. 135. 101. 95. 184 pharmacokinetics. 197. 156. 53. 177. 129. 31. 157. xi. 176. 205 279 pathophysiological. 194. 11. 162. 129. 12. 93. 117. 196. 165. 127. 66. 154. 96. 54. 198. 100. 147 physical properties. 102. 49. 104. 204. 240 personality. ix. 67. 232 pemphigus. 99. 71. 69. 70. vii. 138. 50. 205. 154. 101. 43. 100. 177 oxidative damage. 206 phenol. 209. 141. 239. 56. 220 PI3K. 50. 97. 77. 151. 52. 177. 160. 163. 166. 204 physiology. 234. 128. 140. x. 113 palpitations. 117. ix. 66. 41. 207. 177. 96. 34. 234. 86. 92 organs. 196. 126 P Pacific. 144. 121. 236. 157 phosphorus. 143 ozone. 108. 180. 74. ix. 237 peroxide. 180 pain. 92. 127. 28. 115. 15. 245 organ. 102. x. 162 optimization. 105. 92. 167. 61. 44. 93. 219 pharmacology. 105. 136 pharmacological treatment. 205 pancreas. 162 plant growth. 91. 91. 137. 230 Pakistan. 195. 128 overweight. 9. 97. 239. 131. 126. 63. 50. 106. x. 31. 64 organism. 168. 76. 117. 166. 157. 189. 244 pathogenesis. 128. 158. 43. 105. 177. ix. 110. 238. 236. 155. 244. 58. 147 personality characteristics. 70. 122. 46 organic compounds. 92. 60. 135. 131. vii. 176. 81 peripheral nervous system. 156. 44. 148. 90. 26. 158. 128. 142. 47. 241 pathways. 228 peroxidation. 92. 132. 55. 209 peptide. 101 osteoarthritis. 134. 81. 69. 148 overproduction. 55. 150 photobleaching. 121 pheochromocytoma. 176 peripheral blood. x. 11. 54. 137. 52. 134. 64. 150. 209. 120. 59 participants. 122. 101. 95. 162. 94. 129. 76. 115. 258 photosynthetic performance. 207. 146. 101. 152. viii. 93. 112. 4. 152 opportunities. 201. 143. 69. 161. 143. 219. 95. 235. 157. ix. 52. 68. 11. 148 parallel. 121 ovaries. 212. xi. 86. 109. 190. 42. 117. 45. 72. 41. 128. 151 Complimentary Contributor Copy . 65. 32 physical activity. 39. 114 osmotic stress. 250 oxygen consumption. 32. 28. 131. 121. 18 pastures. 26. 102. 103. 53. 131. viii. 155. 31 photooxidation. 3. 155. 149 parents. 78. 175. 149. 144. 134 pigmentation. 103. 166. 96. 104. 151. 60. 58. 98 pH. 263 pharmaceuticals. 148. 50. 167. 263 ornamental plants. 120 phytomedicine. 85. 135. 151. 256 pharyngitis. 237. viii. 32. 102. 208. 92. ix. 148. 149. 52. 74 peptic ulcer. 206. 181. 261 pilot study. 137. 180. 75. 63. 12. 205. 81. 208. 131. 118. 55. 247 oxidation products. 263 oxygen. 55. 108. 179. 228. 149. 56. 140 probability. 63. 131 protein kinase C(PKC). viii. 56. 45. 61 prostatitis. 131. 79. ix. vii. 57. 146 proliferation. 85. 152. 117. 136. 221 platelets. 175. 109 poison. 189. 209. 78. 261 rape. 145. 254 Portugal. 135. 71. 94 pulp. 96. 54. 261 polysaccharide(s). 121 pollinators. 166. 232 prostate cancer. 58. 49. 97. 232. 121. 184. 167 radical reactions. 78. 57. 54. 48. 166. 212. 169. 43. 94. 48. 118. 9. 211. 131. x. 28. 120 prevention. xi. 79. 260 pools. 250 questionnaire. 121 protective mechanisms. 263. 85. 42. 117. 79. 211. 69. 160. x. 34. 103. 2. viii. 58. 175. 234. 147 propagation. 85 propyl gallate (Pg). 33. 144. 146. 142. 138 Pseudomonas aeruginosa. 146. 33. 73. 78. 187 pollination. 11 pollutants. 17. 31. 166. 209. 51. 69. 2. 57. 167. 154. 19. 184. 253. 77. 167 radicals. 4. 123. 66. 46. 9. 23. 52. 260 primary function. 63. 139. 50. 43. 132. 45. 31. 36 quartile. 15. 21 pollen. 205. 120 polymorphism(s). 82. 80. 233 R radiation. 211. 39. 235. 180 protein folding. 54. 75. 260 polyunsaturated fatty acids. 97 polyunsaturated fat. 168. 92. 39 purity. 3. 147 preparation. 209. 98 playing. 60. 4. 68.280 Index plasma proteins. 175. 48. 236. 209 public health. 41. 30. 118. 60. 20. 8. 66. 38. 261 polystyrene. 82 plasminogen. x. 53. 129. 70. 4. 30. 55. 132. 166. 61. viii. 39 quinone. 168. 132. 179. 211 polymerization. 230 Complimentary Contributor Copy . 239. 234. 237. 144 quality standards. 143. 176 purification. 254 quality control. 129. 261. 230. 146. 260. ix. 74. 60. 26 prostaglandins. 112. 179. xi. 128. 205. 236. 1. 135. 67. 101. 176. 206. 155. 4. vii. 167 protein synthesis. 44. 186. 38. 118. 132. 231. 175. 39. 88. 197 polar. 205. 93. 121. 9. 205. 121. 167. 165. 212. 54 polymers. 11 proteins. 88 prostate specific antigen. 238. 26. 126. 157. 169. 169. 146. 122 production costs. 58. 238 proteolytic enzyme. 45. 131. 95. 260. 129. 63. vii. 149 quercetin. 211. 235. 42. 56. 88. 175. 93. 90 rash. 90. 16. 29. 120. 65. 65. 107 pro-inflammatory. 177. 83. 31. 233. 122. 75. 160 polyphenols. 211. 48. 152. 53. 47. 49. 66. 28 probe. 90. 42. 120. 33. 61. 33. 209. 81. 201 protection. 92. 188. 229. 235. 165 positive correlation. 143. 95. 177. 60. 186. 127. 179. 168. 59 pruning. 19. 84. 234 prophylactic. 177. 179. 51. 61. 51. 41. 250 quality of life. 49. 2. 232. 64. 232. 222. 222. 1. 169. 84. 28. 21. 97 profitability. 108 potassium persulfate. 150. 68. 32. 39. 262 polarity. viii. 180. 66. 183. 236. 133. 44. 54. 228. 34. 72. 208 potassium. 33. 117 protein oxidation. 129 platelet aggregation. 17. 58. 92 protective role. 72. 229. 146. 71. 212 preservative. 48. 158. viii. 69. 31. 14. 220 radical formation. 166 platform. 133. 34. 52. 166 pollution. 30 precipitation. 76. 234. 16. 228. 51. 34. 43 population. 223. 237. 175. 95. 1. 95 quantification. 178. 97 Q quality assurance. 58. 208. 52. 57. 58. 207. 158. 234. 189 principles. 31 pregnancy. 60 PM. 75. 264 protection of plants. 14. 235. 215. 56. 262 root growth. 129. 138. 29. 2. 65. 139. 55. 127. 3. 45 science. 31 reaction time. 61. 178. 28. 89. 181 red wine. ix. 97. 143. 48. 4. 58. 8. 30 reactions. 209 relevance. 56. 240 reticulum. 34. 120. 48. 43. 43. 121. 102. 147 shape. 188. 151. 48. 62 shoot. 70. 210. 114. 86. 55. 84. 90. 208. 163. 137 salt tolerance. 79. ix. 152. 117. 79. 166. 201. 4. 26. xi. 104. 149 researchers. 138 secondary metabolism. 166. 101 salts. 22. 57. 99. 101. 82. 115. 239 schizophrenia. 184. 105. 121. 147 security. 221. 122 sex. 152 reducing sugars. 56. 82. 89. 121. 109. 150 retinopathy. 106. 140. 6. 127. viii. 238. 33. 158. 149. 262 shoots. 231. 179 revenue. 28 room temperature. 112. 132. 17 recovery. 212. 122. 134. 102. 207. 234. 81. 55. x. viii. 178 sickle cell anemia. 160 residues. 102 response. 33 rings. 21 resources. 19. 150. 23. 146. 129. 108. 94. 42. 216. 87. 207. 125 retinol. 50. 51. 158. 255. 176. 42. 197 risk(s). 42. 57 redundancy. 102. 176. 122. 237. 50. 139. 57. 201. 104. 229. 105 root system. 91. 92. 177. 167. 240. 111. 45 repair. 92. 152. 103. 239. 11. 26. 181. 83. 102. 143. 73. 135. 128. 55. 261. 78. 100. 113. 115 saliva. 110. 50. 163. 83. 224 respiration. 95. 156 resveratrol. 246 saponin. 73. 38 relief. 149. 238 salinity. 71. 173. 264 regions of the world. 176. 216. 240. 33. 104. 161 ROOH. 101. 208 reaction mechanism. 236 resistance. 65. 88. 184. 150. 214. 231. 206. 237. 261. 11. 260 reactive oxygen. 140 receptors. 44. ix. 93 Royal Society. 75. 4. 98. 205 resolution. 48. 14. 258 restoration. 260 scope. 11. 3 sedative. 121. 18. 135. 115 sensitivity. 131. 33. 47. 61. 45. 75. 152. 149. 121. 161. 115. x. 222 sesquiterpenoid. 102. 206 sensing. 139. 179. 210 scavengers. 166. 45. 72. viii. 184. 213. 56. 59. 160. 90. 233. 124. 150. 248 ringworm. 129. 121. 215. 33. 207. 93. 67. 205. 61. 228. 48. 75. 102 serum. 63. 94. 91. 86. 100. 78. 41. 234. 10. 66 restrictions. 163. 108. 96. 50. 92 requirements. 232. 94. 17. 98. 178 Complimentary Contributor Copy . 27. 112. 104. 71. 150. 74. 211. 101. 244 sickle cell. 105 showing. 68. 105. 223. 101. 23. 166. 149 selenium. 74. 2 riboflavin. 120. 111. 222. 83. 83. 92. 8. 90. 56. 53. 145.Index RE. 44. 115. 97. 152. 147 sex steroid. 131. 4. 31 reaction medium. 63 secretion. 156. 2. 100. 188 281 root(s). 141. 201. 96. 4. 110 selectivity. 39. 85. 118. vii. 78. 84. 33. 144. 25. 220. 154. 245 reserves. 61. 26. 176 shelf life. 155 saturated fat. 60. 152. 76. 102. 168. 45 reagents. 245. 102 routes. 140. 260 reactivity. 70. 160 sensation. 148 regeneration. 118. 48. 99. 204. 92. 135. 72. 199 red blood cells. 146. 122. 47. 264 seedlings. 210 risk factors. 150 recognition. 259 renal cell carcinoma. 66. 172. 18. 146. 149. 210 saturated fatty acids. 102 secrete. 111. 64. 178. 188. 110 S safety. 195 seed. 87. 239 severe stress. x. 143. 26. 167 reproduction. 188. 149. 92. 231 stigma. 194. 129. 122. 117. 56. 53. 199. 158. 16. 234 side effects. 29. 147. 129. 54. 5. 161 society. 89. 27. 32. 15 solid tumors. 184. 64. 68 stimulation. 17. 155. 38. 104. 180. 77. 66. 151 signals. 28 spectroscopy. 83. 108. 118. 245 skin. 142. 4. 204. 229. 121. 55 splenitis. 94. 73. 166. 101. 29. 256. 91. 18. 191 structural changes. 33. 134 signaling pathway. 166. 239 solvents. 222. ix. 236 stress factors. 5. 122 substrate(s). 54. 209. 31. viii. 101. 96. 96. 7. 71. 180. 50. 91. 138. 3. 113. 45 smooth muscle cells. 63. 53. 70. 85. 4. 206 Sprague-Dawley rats. 48. 14. 120. 102. 44. 76. 101. 178 suppression. 21. 179. ix. 29. 232 structure. 148 smoking. 119. 102. 15. 71 Complimentary Contributor Copy . 60. 240 subgroups. 65. 232 signal transduction. 32 sulfur. 94 spectrophotometry. 47. 105. 121. 150. 150. 230 stem cells. 206 small intestine. 121. 97. 107. 88 squamous cell carcinoma. 190. 108 surfactants. 145 stress. 77. 2. 109 sustainability. 131. 231 skin cancer. 116. 177. 92. 59. 76. 21. 24. 264 Sustainable Development. 244. 70. 190. 18 surplus. 134. 33. 191 Switzerland. 65. 26. 196. 85. 154 soybeans. 79. 117. 86. 232. 177 stable radicals. 139. 13. 126 Sun. 231 solubility. 231 spleen. 119. 83. 167. 41. 81. 156 stimulant. 106. 144. 129. 83 syndrome. 263 sodium. 258 supplementation. 181. 15 sulfate. 197. 206. viii. 147. 104. 112. 195. 18. 30. 163. 68. 70. vii. 128. 90 symptomatic treatment. 60. 136. 150. 44. 121. 199. 194. 118 structural characteristics. 32. 187. 204 synaptic plasticity. 140. 83. 88 SS. 138 stroke. 193. 252 sterols. 86 squamous cell. 122. 230 storage. 233 stabilization. 19. 130. 7 specialty crop. 144 silica. 134 sucrose. 219. 12. 160. 93. 13. 176. 56. 264 soil particles. 230. 198. 151. 72. 148. 60 skin diseases. 155. 234. 195. 33. 10. 130. 17. x. 145 stenosis. 128. 37 South Africa. 261 stamens. 61. 61. 32 sulphur. 139. 188. 44. 125 solution. 68. 152. 130. 222 signalling. 80. 206 splenomegaly. 62. 113 swelling. 136 survival. 78. 162. 76. 148 skeleton. 105. vii. 96. 107. 149. 94. 264 susceptibility. 147. 122. 46. 201. 191. 237 sodium dodecyl sulfate (SDS). 132 stoma. 189. 89. 96 stress response. 193 skeletal muscle. 97. 37. 152. 102. 109 specifications. 162 sulfur dioxide. 200. 211 smooth muscle. 56. 190. 55. 128. 22. 204. 125 substitutions. 92. 191 stomach. 137. 86. 30. 166. 200. 88. 158. 233. 31. 159 synergistic effect. 2. 123. 204. ix. 158. 4. 115. 93. 211. 167. 81. 156. 6. 45 snacking. 190. 44. 8. 142 stability. 101. 156. 52. 44. 3. 25. 139. 110. 56. 206. 64. 59. 19. 15. 139. 45. 18 soil erosion. 5. 100. 209 surface area. 25. 50. 129. 9 substitution. 192. 80. 120. 162. 5. 32. 96. 188. 177. 206. 110. 6. 64. 98. 61. 205. 1. 3. 34. 207. 155 sprouting. 98. 151. 26. 45. 21. 230 standardization. 206 symptoms. 43. 198. 100 state(s). 96 starvation. 49. 129. 134 solid phase. 114. 47. 138. 48. 95 soleus. 221. 17 sinusitis. 76 steroids.282 Index side chain. 70. 257 TNF-α. 33. 93. 128 transportation. 11. 209. 56. 151. 94. 212. 184. 52. 184. 222. 37. 136 therapeutic effects. 243. 145. 12. 238 TPA. 159. 107. 150. 62. 44. 92 toxicity. 61 Turkey. 166. 212 training. 147 Tibet. 44. x. 9. 35. 122. 141. 178. 76. 62. 151 transferrin. 237. 86. 57. 108. 77 TNF. 150. 103. 234 taxa. 177. 184. 223. 219. 16. 120 tryptophan. 88 thalassemia. 236 transition metal. 61. 127 tricarboxylic acid cycle. 166. 150. 152. 158. 131 triglycerides. 107. 90. 243. 45 tumor necrosis factor. 151. 160 traits. 33. 142. 15. 163. 232 trace elements. 199 ultrasound. 186. 132 trade. 17. 56. 244. 42. 152. 115. 135. 47. 127. 129 tumorigenesis. 151. 158 transducer. 135. 69. viii. xi. 236 U UK. 236 therapeutic approaches. 22. 219. 131. x. 234 Tyrosine. 56. 83. 26. 257 Thailand. 157. 95. 70 tissue. 223. 184 technical assistance. 179. 264 textiles. 49. 130. 8. 119. 258 time periods. 219. 48. 176. 263 trial. 244. 206. 228. 162 toxic effect. 44. 206 tonsillitis. vii. 107 treatment. 59. xi. 153. 43. 201 total cholesterol. 156. 211. 48. 99. 93. 155.Index synthesis. 254. 220. 179. 232. 132. 253. 57 tumors. 53. 204 tooth. 56. 80. 108. 64 tuberculosis. 61. 115. 120. 113. 104. 237 techniques. 71 thrombophlebitis. 232. 109 transaminases. 115. 31. 15. 235. 258 technologies. 179 tyrosine. 158. 28. 155. 235. 127 triggers. 156. 257 tobacco. 261. 108. 183. 158 tropical rain forests. 149. viii. 151. 232 thyroid. 244 tumor. 90. 118. 62. 153. 42 therapeutic targets. 93. 205 target. 42. 17. 58. viii. 59. 156. 42. 82 transport. 87. 50. 254 terpenes. 88. 85. 50. 32. 111. 185. 20. 206. 129 tumor cells. 132. 223 transcription factors. 152. 205 tricarboxylic acid. 14. 142 tannins. xi. 152. 260. 156. 60. 92. 45. 204. 254. 238. 234. 56. viii. 111. 86. 45. 120. 120. 54. 209 texture. 132. 115. 132. 92. 229. 149. 159. 129. 126. 61. 158. 149. 156 transcription. 98. 262 tert-butyl hydroquinone (TBHQ). 134. 113 technology. 120. 233 translocation. 58. 156. 122. 244. 186. 2. 146. 101. 65 tocopherols. 145. 150. xi. 56. 117. 91. 67. 56. 2. 131. 167. 152. 235 283 toxic substances. 33. 65. 9. 161. 16. 235 transition metal ions. 129. 146. 225 type 2 diabetes. 187. 38. 101. 43. 154. 148. 207. 113 temperature. 57. 152. 16. 142 therapy. 11. 150. 209. 68 TGF. 232. 148. 59 tumor development. 212. 164. 154. 129. 158. 48. viii. 155. 76 T Taiwan. 155 transplantation. 65 tobacco smoke. 117. 65. 204. 262 thermal energy. 104. 136. 221. 100. 35 ulcer. 260 Tonga. 130. 56. 96. 95. 127. 111. 17. 108. 221. 3 therapeutics. 79. 156. 75. 121. 209. 157. ix. 101. 96. 158 systolic blood pressure. 44. 128. 104. 178 tonic. 61. 232. 101. 63. 160. 131. 166 therapeutic agents. 15 Complimentary Contributor Copy . 94. 101. 188. 54. 53. 259. 88 therapeutic use. 187. 54 tumor growth. 63. 224. 264 TLR. 46. 97. 155. 189. 128 transduction. 26 testing. 41. 101. 134. vii. 125. 254 teams. 72. 93. 243. 58. 166 transformation. 79 urban. 99. 178. 72. 17 vomiting. 54. 159 visceral adiposity. 266 Western Europe. 157. 65. 2. 42. 73. 3. 166 vegetables. 120. 49. 166. 48 weight control. 149. 66. 163 wild type. 22. 70. 263 Z Zimbabwe. 149. x. 79. 107. 232 Vitamin C. 11. 37. 36. 15. 82. 154. 80. 57 waste water. 209. 51. 8. 79. 107. 169. 244 varieties. 42. 60. 126 V valence. 17 UV radiation. 69. 190. 122. 158. 53. 70. 86 urine. 77. 44. 28. 64. 58. 47. 192. 60. 263 viral pathogens. 17. 14. 69. 4. 147 weight gain. 47. 65. 161. 96. 42 validation. 180 uterus. 20. 61. 168. 156 West Indies. 135. 143. 77 zinc. 21 vanadium. 82. 232. 68. 194. 75. 231. 168. 50. 151. 153. 146. 98. 94. 58. 166. 49. 10 viscera. 15 wavelengths. 188. 87. 228. 26. 108. 90. 103. 177.284 Index underlying mechanisms. 62. 90. 129. 53. 67. 57 Y yeast. 97. 229. 3. 49. 78. 121. 244 walking. 33 United States. 54. xi. 65. 97. 132. 159. 59. 121. 48. 254 valve. 150 Complimentary Contributor Copy . 44. 199. 48. 78. 254 wood. 162 USA. 57. 110. 163 vitamin E. 157 weight loss. 101. 15. 44. 205. 147 variations. 77. 184. 153. 19. 48. 64. 66. 55. 240 vitamins. 42. 112. 26 UV light. 46. 19. 44. 259 wound healing. 103. 244 WHO. 51. 204 UV. 225 X xanthones. 92. 2. 60. 98. 229 urinary tract. 101. 163 weight reduction. 229 uric acid. 18. 68. 150. 199. 228. 204. 11. 86. 230. viii. 162. 66. 209. 229. 39. 75. 262 vitamin D. 30 wealth. 193. 45. 255 vasculature. 228. 139. 239. 144. 141. 121. 3. 209 vitamin B6. 67. 163 weight management. 126. 156. 113. 97. 133. 48. 195. 228. 26. 80. 110. 92. 64. 144. 207. 160. 49. 108. 132. 65. 98. 62. 49. 126. 29. 94. 169. 166. 234 UV irradiation. 95. 149. 262 volatility. 70. 6. 155. 74. 198. 87. 110 waste. x. 25. 66. 240. 115. 144. 132. 33. 188. 207. 138 variables. 59. 62. 47. 66. 4. 38. 99. 146. 206 W Wales. 223 worldwide. 47 vitamin C. 169. 74. 81. 205 World Health Organization. viii. 64. 154. 68 yield. 181. 122. 132. 150 vitamin A. 81. 121. 205 yellow fever. 142 vasodilator. 26. 26. 86 urinary tract infection. 147 Washington. 43. 147. 113. 2. 263 workers. 148. 114. 206 wound infection. 58.