26DOI 10.1002/mnfr.200700389 Mol. Nutr. Food Res. 2008, 52, 26 – 42 Review Ursolic acid: An anti- and pro-inflammatory triterpenoid Yasutaka Ikeda*, Akira Murakami, and Hajime Ohigashi** Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan There is growing interest in the elucidation of the biological functions of triterpenoids, ubiquitously distributed throughout the plant kingdom, some of which are used as anticancer and anti-inflammatory agents in Asian countries. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, is the major component of some traditional medicine herbs and is well known to possess a wide range of biological functions, such as antioxidative, anti-inflammation, and anticancer activities, that are able to counteract endogenous and exogenous biological stimuli. In contrast to these beneficial properties, some laboratory studies have recently revealed that the effects of UA on normal cells and tissues are occasionally pro-inflammatory. Thus, UA may be designated as a double-edged sword with both positive and negative effects, and further evaluations of the effects of UA on the biological status of target cells or tissues are necessary. This review summarizes previous and current information regarding UA, and provides new insights into the underlying molecular mechanisms of its activities. Keywords: Anti-inflammation / CD36 / Pro-inflammation / Triterpene / Ursolic acid / Received: April 25, 2007; revised: June 16, 2007; accepted: June 18, 2007 1 Introduction Plants synthesize an enormous variety of metabolites classified as primary metabolites, that are synthesized for metabolic processes within the plant, as well as secondary metabolites that stimulate ecological interactions between plants and their environment [1]. Isoprenoids, more commonly called terpenoids, are the most functionally and structurally varied group of plant metabolites, and plantproduced terpenoids are essential components of the human diet. Correspondence: Dr. Hajime Ohigashi, Faculty of Biotechnology, Fukui Prefectural University, Fukui 910-1195, Japan E-mail:
[email protected] Fax: +81-77-661-6000 Abbreviations: B[a]P, benzo[a]pyrene; COX, cyclooxygenase; DMAPP, dimethylallyl diphosphate; DMBA, dimethylbenz[a]anthracene; EBV, Epstein-Barr virus; EGF, endothelial growth factor; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; FPP, farnesyl diphosphate; GA, glycyrrhetinic acid; GGPP, geranylgeranyl diphosphate; GM-CSF, granulocyte macrophage colony-stimulating factor; GPP, geranyl diphosphate; H2O2, hydrogen peroxide; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; IPP, isopentenyl diphosphate; JNK, c-Jun NH2-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; MEP, methylerythritol 4-phosphate; MIF, macrophage migra- Terpenoids are synthesized in a great number of organisms, and are especially abundant and diverse in plants, with tens of thousands of compounds reported to date [1 – 4]. Further, many are present in all types of plants, where they function as primary metabolites with roles in respiration, photosynthesis, and regulation of growth and development. For example, vitamin A acts as a photoreceptor in animals and is the chromophoric element of a light-driven proton pump in certain bacteria. Carotenoids, such as b-carotene, act as light-protecting pigments in plants and have tion inhibitory factor; MIP, macrophage-inflammatory protein; MMP, matrix metalloproteinase; MVA, mevalonic acid; MN, macrophages; NF-jB, nuclear factor-kappa B; NO, nitric oxide; NOX, NADPH oxidase; O2 – , superoxide anion; OA, oleanolic acid; 9OH, hydroxyl radical; ONOO-, peroxynitrite; oxLDL, oxidized low-density lipoprotein; PDGF, platelet-derived growth factor; PG, prostaglandin; pMN, peritoneal Mb; RA, retinoic acid; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; SR, scavenger receptor; TBARS, thiobarbituric acid reactive substances; TGF, transforming growth factor; TNF, tumor necrosis factor; TPA, 12-O-tetradecanoylphorbol-13-acetate; UA, ursolic acid * Current address: Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan ** Current address: Faculty of Biotechnology, Fukui Prefectural University, Fukui, Japan i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com fibers. 25] and skin [26]. Structure of UA. and the semi-synthetic Taxoterem have rapidly achieved a central position in chemotherapy for malignant tumors. 22]. 26 – 42 27 been claimed to have anticancer activities. In addition. only limited knowledge of the pathways involved in the biosynthesis of their precursors has been available until very recently. an interesting finding that UA activated NF-jB for releasing pro-inflammatory mediators in non-stimulated mouse Mb was recently reported [23]. while steroids.7 mouse macrophages (Mb) [21] and of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor promotion [16]. drugs. and an exponential increase in the number of reports regarding bioactive triterpenoids in the last decade reflects their growing importance as sources of medications and preventive medicines. Genetic engineering appears to be a powerful tool to direct the production of both primary and secondary terpenoids products in plants. UA attenuates the expression of LPS-induced inflammatory mediators through NF-jB abrogation in activated Mb. it has been speculated that isopentenyl diphosphate (IPP) is synthesized from acetylCoA and then isomerized to dimethylallyl diphosphate (DMAPP) (Fig. more than 80 different triterpenoid structures have been identified as being common in plants. many compounds that are secondary metabolites with a triterpenoid origin have important commercial value and are used as chemotherapeutic agents. 3). However. Nutr. 3) [3.com . 3). g. Paclitaxel (Taxolm). some are increasingly being used for medicinal purposes for a variety of clinical diseases in many Asian countries as antioxidant. we recently Figure 1. 12].Mol. 4].3-oxide (Fig. Different responses of RAW264. such as flavors. the MEP pathway synthesizes IPP and DMAPP from pyruvate and D-glyceraldehyde 3-phosphate (Fig.mnf-journal. 52. Figure 2. and have long been considered to have a number of biological effects [11]. are essential components of eukaryotic cell membranes. comprehensive in vitro and in vivo studies of the action mechanisms of UA are limited.7 cells to UA. Both in vitro and in vivo studies have demonstrated that UA has many important biological functions [11. 28]. and agrochemicals [5. Interestingly. 2). such as ovarian and mammary carcinomas [7]. polymers. In the MVA pathway. such as cholesterol. several experiments using labeled compounds have revealed that cytosolic IPP and DMAPP are preferential precursors for pentacyclic triterpenoids. however. 1). 6]. 3b-hydroxy-12-urs-12-en-28-oic acid.and pro-inflammatory activities that are dependent on the biological status of cells and tissues (Fig. terpenoids with the greatest variety are secondary metabolites that function to protect plants against herbivores and pathogens. e. as well as to attract pollinators and seed-dispersing animals. via mevalonic acid (MVA) and methylerythritol 4-phosphate (MEP) (Fig. anticancer. it is possible that UA has contrasting anti. In contrast. In addition. a natural pentacyclic triterpenoid carboxylic acid. Further. suppression of the expression of lipopolysaccharide (LPS)-induced pro-inflammatory mediators in RAW264. and provides new insights into its underlying molecular mechanisms. was long considered to be biologically inactive [12]. while they also act as allelochemicals that influence competition among plant species [1. Presently. The biosynthesis of triterpenoids and sterol exhibits a common route from IPP and DMAPP to the formation of the C30 units squalene and squalene 2. Weinheim www. Meanwhile. glues. found that UA has similar effects in non-stimulated mouse Mb [24. Biosynthesis of isoprene building units is the first step in the biosynthesis of terpenoids. KGaA. Fig. a taxane-type diterpene from the yew tree. pigments. waxes. Ursolic acid (UA. 3) [27. Food Res. In fact. 2].. 2008. 2 Biosynthesis Terpenoids are synthesized in all living organisms and recent experimental results have demonstrated two different pathways for them in plants. the compound also induces production of inflammatory mediators via NF-jB activation in resting Mb. i 2008 WILEY-VCH Verlag GmbH & Co. This review summarizes previous and current information regarding UA. types of triterpenoids [8 – 10]. Triterpenoids are ubiquitously distributed throughout the plant kingdom in the form of free acid or aglycones for saponins. however. 14 – 21]. such as UA. Thus. whereas in recent years it has attracted considerable interest because of its pharmacological effects combined with low toxicity [13]. and anti-inflammatory agents [11. although this step differs between the two pathways. It has been proposed that these functions are the result of inhibition of nuclear factor-kappa B (NFjB) activation [21. In addition. Further. Plantain (Plantago major L.1 Overview Increasing evidence suggests that certain phytochemicals have marked anti-inflammatory and cancer chemopreventive properties [65. with UA regarded to be one such compound. In contrast. and diseases of the liver [40] and kidney [38. thyme (Thymus) leaves are utilized as herbal traditional medicine for anti-inflammation in Morocco [42. 41]. C10) and geranylgeranyl diphosphate (GGPP. For example. Ikeda et al. Table 1 summarizes representative example of plants containing UA and its biological activities.28 Y. 19. Numbers in parentheses indicate the carbon chain number. 66]. C20). and anticancer biological functions [11. the MEP pathway synthesizes plastid IPP and DMAPP. Nutr. asthma [38]. 16. and sterol biosynthesis (Fig. thus providing the precursors geranyl diphosphate (GPP. Food Res. a number of therapeutic effects of plants containing UA have been confirmed by contemporary scientific research [15. it has been postulated that active biosynthesis of triterpenoids occurs when sterol formation has been satisfied. 2008. Of these. based on their remarkable antioxidative. Terpenoid skeleton biosynthesis within plant cells between cytosol (MVA pathway). and plastid (MEP pathway) and UA biosynthesis pathways. 4 Beneficial effects 4. crosstalk between these two different IPP biosynthetic pathways has been documented [33 – 36]. are used in Native American traditional medicine to treat several inflammatory pathologies such as inflammatory disease [37]. and hepato- i 2008 WILEY-VCH Verlag GmbH & Co. including skin diseases. and tetraterpenes (Fig. UA is naturally found in various plants such as fruits and herbs (Table 1) in the form of aglycones or glycosides [8 – 10]. although there is relatively little knowledge of their action mechanisms. and ultimately monoterpenes. diterpenes. 26 – 42 Figure 3. 12]. 18. respiratory organs illness. and cancer [44]. triterpenoids are compounds that have attracted considerable interest. Mol. and traditional uses of plants containing UA in folk medicine are abundant. anti-inflammatory. as it possesses many biological activities.com . KGaA. 3).mnf-journal. anti-inflammatory. anticancer. 3 Distribution Interestingly. Weinheim www. rheumatism [39]. an Ericaceae widely distributed throughout North America. herbal medicines derived from plant extracts are utilized to treat a wide variety of clinical diseases.) leaves have been used as a woundhealing remedy for centuries in nearly all parts of the world as well as for treatment of many other types of diseases. 52. Recently. 43]. such as antioxidative. Also. 42 – 64] and it is thought that some of these effects may contribute to the use of plants that contain it in folk medicine. 3) [29 – 32]. the leaves and twigs of the Labrador tea (Ledum groenlandicum Retzius). in sites of inflammation are phagocytes. tumor necrosis factor (TNF)-a. Weinheim www. immune activation. 2008. administration of UA (60 mg/kg) significantly reduced the lipid peroxides levels by scavenging free radicals in isoproterenol-induced myocardial ischemia. the antioxidative activities of UA against free radical-induced damage were studied [78. Nutr. Salvia officinalis L.com . nitric oxide (NO). 26 – 42 29 Table 1. and glutathione S-transferase]. lipid hydroperoxides. 4). UA remarkably reduced the lipid peroxidation by scavenging free radicals. Vaccinium macrocarpon Glechoma hederacea L. it is thought that the generation of O2– from xanthine oxidase. and conjugated dienes]. both ROS and RNS are capable of causing oxidative damage to macromolecules. and lipids. which increases free radical production and lipid i 2008 WILEY-VCH Verlag GmbH & Co. with NADPH oxidase (NOX) responsible for O2– generation [67]. KGaA. 52. and Mb. Thymus [55 – 57] [58. details of these desirable effects are described. is lower than that of NOX in inflammatory cells. 83. 54] Oregano Persimmon Plantain Rosemary Sage Thyme Origanum vulgare Diospyros leucomelas Plantago major L. and pretreatment with it prevented PC12 nerve cells from ROS toxicity by amyloid b. four standard systems. hydroxyl radical (9OH). Thus. Psidium guajava Calluna vulgaris Prunus serrulata var. In this section. 64] [42. as well as others.mnf-journal. ascorbic acid and a-tocopherol) [80. catalase. including neutrophils. and increasing the levels of non-enzymic antioxidants (reduced glutathione. 84]. as well as an ability to induce apoptosis. 16] [48] [18] [49] [50] Loquat Olive Eribotrya japonica Lindl. glutathione peroxidase. were used to induce lipid peroxidation in isolated rat liver and heart microsomes in vitro. and adriamycin. 52] [53.2 Oxidative stress The predominant sources of reactive oxygen species (ROS) and reactive nitrogen species (RNS). thereby decreasing TBARS and maintaining the activities of enzymic and non-enzymic antioxidants [82]. In other experiments. spontanea Ledum groenlandicum Retzius Biological activity Anti-proliferation Anti-cancer Antiviral Anti-cancer Anti-cancer Anti-cancer Unknown Anti-inflammatory Unknown Antioxidant Anti-inflammatory Anti-cancer Anti-mutagenic Antioxidant Anti-atherosclerotic Anti-hypertensive Anti-leukemic Antioxidant Antioxidant Anti-inflammatory Antioxidant Anti-inflammatory Anti-inflammatory Anti-cancer Anti-inflammatory Anti-inflammatory Reference [45] [46] [47] [47] [15. inflammatory bowel disease (IBD) [75]. they are potentially toxic. 62] [63. such as superoxide anion (O2– ). hydrogen peroxide (H2O2). 71]. Rosmarinus officinalis L. 4. Meanwhile. Further. asthma [76]. including interleukin (IL)-1b. administrations of UA to rats at a dose of 20 mg/kg controlled ethanol-induced oxidative stress in the liver and heart by decreasing lipid peroxidation products [thiobarbituric acid reactive substances (TBARS). In these experiments. Olea europaea [51. and granulocyte macrophage colony-stimulating factor (GM-CSF) through mechanisms that are dependent on NF-jB [70. Food Res. including DNA. Interestingly. carbon tetrachloride. 60] [19. In the early 1990s. Although ROS have been recognized to be important signal transduction mediators that regulate gene expression. Additionally. thereby amplifying the inflammatory response in diseases such as cancer [72. 43] protective activities. which is mainly expressed in epithelial cells. protein. Representative example of distribution of UA in folk medicines and its pharmacological activities Plant name Apple Basil Blueberry Cranberry Ground ivy Guava Heather flower Japanese cherry Labrador tea Botanical name Malus pumila Ocimum basilicum Vaccinium spp. 81]. monocytes. ADP/iron. 59] [44. UA was also reported to show neuroprotective effects by decreasing oxidative stress [57. vascular disease [74]. 61. and apoptosis [68]. increasing the activities of antioxidant enzymes [superoxide dismutase (SOD). inappropriate ROS production via NOX damages host tissue [69] and induces pro-inflammatory cytokines. cell differentiation.Mol. and rheumatism [77] (Fig. RNA. ascorbic acid. and peroxynitrite (ONOO – ). 79]. 73]. Food Res. Nutr. IL-12. EDF. Suh et al. plateletderived growth factor. and terminate inflammatory processes. NO. MCP-1.79-dichlorofluorescin-diacetate in murine fibrosarcoma L-929 cells [50]. inflammation can result in tissue destruction and lead to organ dysfunction. VIII. MIP-1 EGF. TNF. and autoimmune responses. IL-15. g.mnf-journal. [84] studied the protective effect of UA on the hippocampal neurons against kainate-induced excitotoxicity in rats and proved that free radical scavenging may account. Weinheim www. maintain. and pain. FGF. are essential for the host defense system. leading to apoptosis and cell death [57. [21] showed that pretreatment with UA attenuated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 via NF-jB repression in RAW264. while in pathologic situations. properdin) Coagulation factors (e.30 Y. IL-18. highly sequential series of events that is provoked by a variety of stimuli including pathogens. TNF-a. a regulated response protects against further injury and clears damaged tissue. Mb. they are considered to play a key role in chronic inflammatory diseases. for the protective effects of UA. inflammatory cytokines and chemokines. 90]. IL. Generation of ROS and RNS from activated monocytes/macrophages is pivotal in the pathogenesis of various diseases. such as IL-1b. resulting in cellular and tissue damages. MCP. MIF. swelling. [20] demonstrated that UA strongly inhibited NO production in the same cell lines.com . even though inflammatory mediators. Subbaramaiah et al. transforming growth factor. In physiologic conditions. at least partially. For example. TNF-a. RONS. including ROS. 4. Figure 4. Further. reactive oxygen and nitric species. KGaA. IL-6. noxious mechanical and chemical agents.3 Inflammation Inflammation is a complex. 85]. Mol. interleukin. Since Mb produce a wide range of biologically active molecules. peroxidation. when the positive and negative signals become imbalanced. matrix metalloproteinases (MMPs). granulocyte macrophage colony-stimulating factor. Next. RNS. tissue factor) Cytokines and chemokines IL-1. macrophageinflammatory protein. 26 – 42 Table 2. MIF. These results suggest that the pharmacological action of UA may offer a novel therapeutic strategy for treatment of oxidative stress-related diseases. TGF-b. In addition. C1 to C5. The neuroprotective effect of UA (10 mg/kg) against D-galactose-induced neurotoxicity in brain might be caused by the increase in the activity of antioxidant enzymes with a reduction in lipid peroxidation [83]. RNS Growth factor PDGF. tumor necrosis factor. endothelial growth factor. macrophage migration inhibitory factor. Similarly. it is well known that excessive production of these mediators in an inflammatory site may lead to chronic diseases such as cancer [86 – 88] and neoplasms [89. inflammation does not shut down. heat. The inflammatory process is usually tightly regulated and involves numerous signals that initiate. Shih et al. fibroblast growth factor. factor V. IL-6. macrophages. Ikeda et al. Products released by Mb Enzymes Neutral proteases Elastase Lysozyme Collagenase Plasminogen activator Acid hydrolases Phosphatases Lipases Lipid mediators Eicosanoids Reactive metabolites of oxygen ROS. monocyte chemoattractant protein. and Ryu et al. GM-CSF. TGF. However. IL-10. with the earliest report of potential anti-inflammatory effects of UA published in 1992. UA isolated from Ledum groenlandicum twigs showed antioxidative activity in vitro in ORAC assay results and inhibited tert-butylhydroperoxide-induced oxidation of 29. In a study conducted to i 2008 WILEY-VCH Verlag GmbH & Co. and others (Table 2). 52. in which it was isolated from heather flowers (Calluna vulgaris) as an inhibitor of arachidonate metabolism [18]. and prostaglandin (PG)E2. [91] indicated that treatment with UA suppressed TPA-mediated induction of COX-2 protein and synthesis of PGE2 in human mammary epithelial cells.7 mouse Mb. PDGF. The anti-inflammatory effects of UA on Mb have been investigated since the early 1990s. Inflammation is the primary process through which the body repairs tissue damage and defends itself against stimuli. FGF Plasma protein Complement components (e. g. which participate in both beneficial and detrimental outcomes of inflammation. eicosanoids. MIP. The subsequent cascade of events is characterized by such signs and symptoms as redness. 2008. GM-CSF IL-8. [105] performed screening of antitumor promotion suppressants in edible plants using TPA-induced Epstein-Barr virus (EBV)-associated activation of Raji cells. 4. promotion. in which dimethylbenz[a]anthracene (DMBA) and TPA were used as a tumor initiator and promoter. while RA was ineffective with the same treatment. while it induces differentiation of F9 teratocarcinoma stem cells into endoderm cells [111] and M1 cells into Mb-like cells [112]. we have concerns about the risks of UA in humans. Interestingly. c-Jun. teleocidin B-4 [15. [22] and Rhew et al. impaired apoptosis is associated with hyperpro- i 2008 WILEY-VCH Verlag GmbH & Co. it is well known that UA suppresses tumor promoterinduced inflammation [19. This fact suggests that the role of UA in inhibiting tumor promotion differs slightly from that of other triterpenoids. UA has been shown to inhibit ear edema production by TPA and croton oil [42.Mol. Although the action mechanisms underlying the anticancer activities of UA in the skin remain to be fully elucidated. and found that the activity levels were nearly equal to those of retinoic acid (RA) and glycyrrhetinic acid (GA). 109] and ornithine decarboxylase [5. and p38 mitogen-activated protein kinase (MAPK). to the best of our knowledge. Further. 52. KGaA. 26 – 42 31 determine its action mechanism. In addition. 99]. In a two-stage mouse carcinogenesis model. UA effectively reduced both the percentage of papilloma-bearing mice and the average number of papillomas per mouse and the activity was comparable to that of RA [16]. A methanol extract from Mallotus peltatus leaves. Nearly 20 years ago. However. 105.1 nmol) delayed the formation of papillomas in skin as compared with TPA alone [16]. UA may inhibit skin tumor formation by inhibiting the binding of B[a]P and DMBA to epidermal DNA [19]. Koshimizu et al. These findings are important for understanding the anti-inflammatory properties of UA. Food Res. cyclin D1. and production of NO and PGE2 [12. which will be discussed later in this review. elastase activity. and gasoline vapors). are now being utilized for the development of a useful new chemopreventive agent that may be useful for malignancy therapy. Shishodia et al. [107] indicated that UA inhibits the activation of NF-jB through suppression of the inhibitor of NF-jB and p65 phosphorylation. This multi-step process of carcinogenesis consists of three phases. It should be noted that the use of UA is recommended for skin cancer therapy. in which UA is the major compound. UA inhibited TPA-mediated activation of protein kinase C. UA inhibited mutagenicity produced by benzo[a]pyrene (B[a]P) in bacteria [103]. damaged. 100]. and TPA to the epidermal membrane [108]. extracellular signalregulated kinase 1/2 (ERK1/2). and continuous applications of UA might be harmful to mouse skin. Also. In fact. 97]. they identified UA as an active component of Glechoma hederacea L. or abnormal cells is important. its administration to mice at a dose of 80 mg/kg reduced the number of micro-nucleated polychromatic erythrocytes induced by the mutagen mitomycin C by 76% [104]. 115]. 20. industrial emissions. MMP-9. Weinheim www. thus apoptosis is necessary for the maintenance of normal tissue homeostasis. 2008. These antiinflammatory effects have been attributed to the inhibition of different events of inflammatory reactions. In addition. Extensive research has revealed that regular consumption of certain fruits and vegetables can reduce the risk of several cancers [102]. such as histamine release. and topical cosmetic preparations containing UA have been patented in Japan for the prevention of skin cancer [114. which have significant antioxidative and anti-inflammatory effects [116. it blocked the binding of activator protein-1 to the COX-2 promoter [91]. In addition. a single application of UA before initial TPA treatment enhanced the activity much more as compared with the case of multiple applications. It is evident that carrageenan-induced edema is commonly used as an experimental in vivo model for evaluating the anti-inflammatory potentials of plant extracts [92 – 94].com . 61. respectively. 63. inflammatory agents (such as TNF-a and H2O2). a series of novel derivatives of UA. Also. and progression phages. including tumor initiation. c-Jun NH2-terminal kinase 1/2 (JNK1/2). and c-Fos. 21. and by aflatoxin B1 in Salmonella typhimurium TA100 and TA98 assay systems [52]. there are no results from a human study regarding the effect of UA. Likewise. 106]. since its effects on normal cells and tissues have not been fully addressed. 110]. such as COX-2.4 Mutagenesis and carcinogenesis Tumorigenesis is a multi-step process [101] that is induced primarily by various environmental carcinogens (such as cigarette smoke. 60. however.mnf-journal. exhibited significant antiinflammatory activity against carrageenan-induced rat paw edema and its potency was comparable to that of the nonsteroidal anti-inflammatory drug indomethacin [95]. for inhibiting the tumor-promoting effects of TPA. In this process. 19. thereby causing down-regulation of the expression of certain oncogenes. UA-induced apoptosis of M4Beu melanoma cells may have some correlation to the suppression of tumorigenesis [113]. known inhibitors of tumor promotion [15]. Nutr. In addition. UA isolated from Nepeta sibthorpii Bentham and Verbena officinalis also inhibited carrageenan-induced paw edema in rats by scavenging free radicals [96. 4. 117]. topical application of UA (41 nmol) before TPA treatment (4.5 Apoptosis Establishment of a natural balance between cell death and cell renewal in mature animals by destruction of excess. and tumor promoters (such as TPA and okadaic acid). as well as another tumor promoter. Further. several plausible explanations have been reported. 5-lypooxygenase. 98. 59. UA has been demonstrated to induce apoptosis in many cell types. and ovarian [136] tissues. HT-29 human colon cancer [120].7 Mb. 120. MCF-7 human breast cancer [121. 121]. non-stimulated or stimulated. TNF-a. namely. On the other hand. 4. and NS-398 (COX-2 inhibitor) showed significant suppressive effects. it has been reported that UA attenuated the expression of iNOS and COX-2 [21. are the result of inhibition of NF-jB activation [21. These findings along with those of a previous report [23] led us to further study the potential pro-inflammatory effects of UA in vitro and in vivo. The beneficial effects of UA on the liver could be due to its antioxidative and anti-inflammatory effects. 5 Potentially harmful effects 5. indicating that these various disorders are triggered by cytokine release. In addition. as well as chronic liver fibrosis and cirrhosis [12. PC-3 human prostate cancer [125]. IFN-c-induced MIF protein production was enhanced by pretreatment with UA (Table 3). okadaic acid-. 91]. 2008. IL-6.com . Shishodia et al. and macrophage migration inhibitory factor (MIF) has been shown to be enhanced in patients with IBD [130.32 Y. 2). Although ( – )-epigallocatechin gallate (green tea polyphenol). colon [133]. 52. although it is not the sole mechanism for protection against chemically induced liver injury [128]. excessive production of these cytokines has been observed in many cancerous areas. such as skin [132]. benzylisothiocyanate (cruciferous isothiocyanate).7 Mb and then incubated for 12 h. which is caused by the release of ROS. 124]. we discuss the i 2008 WILEY-VCH Verlag GmbH & Co. gastric [135]. Five years ago. a distinct pro-inflammatory cytokine that functionally inactivates the tumor suppressor protein p53 [137. and cigarette smoke-induced NF-jB activation in various cell lines. Figure 5. H2O2-. 5). caspase-3. Weinheim www. Mol. 1400W (iNOS inhibitor). [22] reported that UA inhibited TNF-a-. 125]. induction of p53 [122]. including HL-60 and K562 human leukemia [118. KGaA. Nutr. a small cysteine-rich protein that functions like glutathione in defense against toxic insult in the human body. the release of IL-1b. as noted above. Induction of the hepatic metallothionein responsible for the detoxification of heavy metals is believed to be one of the hepatoprotective mechanisms of this triterpenoid. It has been proposed that these functions. conflicting experimental results that bring into question these general results were reported in 2001 [23]. A549 and H460 human lung cancer [123. Biological responses to cytokines.6 Hepatoprotection UA is well known for its hepatoprotective effects on acute chemically induced liver injury. both in vitro and in vivo experiments have demonstrated that UA has many important biological functions. 138]. as well as the possible underlying mechanisms. activation of JNK1/2 [119]. Ikeda et al. 5.1 Overview As noted in the previous sections. after which MIF protein in media was quantified using an ELISA kit. 119]. A total of 13 food factors and ten synthetic agents were separately added to interferon (IFN)-c -treated RAW264. 122]. 131]. up-regulation of MMP family gene expression [124]. which leads to activation of not only inflammatory cells but also transcriptional factors. in which treatment with UA caused enhancement of NO and TNF-a mRNA induction via transactivation of NF-jB in non-stimulated RAW264. It is believed that the action mechanisms of UA-induced apoptosis are dependent on inhibition of the initiation of DNA replication [126]. These findings imply that UA has dual effects on NF-jB activation that are dependent upon the biological status of the target Mb (Fig. In this section. and -9 [113. it is thought that chronic inflammatory diseases might be caused in part by the uncontrolled production of cytokines. Indeed.2 In vitro observations Prolonged inflammatory responses cause excessive production of cytokines.mnf-journal. -8. and PGs from cytokine-activated inflammatory cells (Fig. Thus. breast [134]. Further. and that topical application of UA to mouse skin delayed the formation of TPA-induced papillomas [16]. undesirable effects of UA both in vitro and in vivo. and decrease of the expression of bcl-2 family proteins [119. we screened agents that modify the production of MIF. at least in part. and has attracted attention as a key molecule involved with linking the processes of inflammation and carcinogenesis. 127 – 129]. anti-inflammatory. M4Beu melanoma [113]. and it is presently used alone or in combination with other hepatoprotective ingredients as oral medications. phorbol ester-. as well as the underlying molecular mechanisms. 26 – 42 liferation and tumorigenesis. Food Res. This triterpenoid is an effective inducer of metallothionein. 22]. such as antioxidative. and HepG2 human hepatoblastoma [126] cell lines. RNS. and anticancer activities. 123. inducible nitric oxide synthase.0 36.6 107 95. Interestingly. translational. members of the scavenger receptor (SR) family. and CD68. [144] suggested that oxLDL binding to SRs can generate intracellular ROS production through NOX activation. and MIF production was induced by ROS-activated ERK1/ 2 [141]. Further.9 35.0 23.5 32. 24]. and found that it decreased intracellular MIF protein levels and promoted the release of MIF into culture media in dose.9 54.7 87.7 mouse Mb. such as IL-1b.5 8.8 – 125 – 137 – 141 – 144 81.9 – 152 77. IFN. cyclooxygenase. Meanwhile. The mechanisms for MIF release by UA appear to be related to the activation of ERK1/2.1 2. because the proinflammatory effects of UA have only been demonstrated in resting RAW264.7 95. phosphodiesterase.9 41.2 37. After then.91 – 17.9 0. It is conceivable that the UA-triggered activation of ERK2 may also be associated with the activation of NF-jB and the resultant induction of pro-inflammatory mediators [24].2 23.5 27.0 36. UA was found to aggregate in culture media and the aggregates were suggested to be responsible for IL-1b production [25]. iNOS. Similarly. with action mechanisms that may be similar to those seen with IL-1b release. 143].0 106 87.3 85. TNF-a.7 cells. All compounds were tested at a concentration of 20 lM.7 RAW264. it is possible that aggregated UA is recognized by SRs.3 106 91.7 – 30. which resulted in activation of both the ERK1/2 and p38 MAPK pathways and caspase-1 activation [25]. to a lesser extent.0 86. while the involvement of ERK2 and.mnf-journal.9 72. such as oxidized low-density lipoprotein (oxLDL) and amyloid b [142. CD36. protein release.7 87. We initially attempted to investigate the effects of UA on the production of MIF in resting RAW264.5 31. in experiments using SR neutralization antibodies. 13-HOA.0 101 102 94. which are more appropriate for mimicking in vivo situations than established cell lines.5 33. JNK.5 – 34.6 46.7 37.0 73. c-Jun NH2-terminal kinase.7 cells Treatment DMSO IFN-c Natural compounds IFN-c + ( – )-Epigallocatechin-3-gallate (Green tea polyphenol) + Capsaicin (Chili peppers capsaicinoid) + Benzyl isothiocyanate (Cruciferous isothiocyanate) + Nobiletin (Citrus flavonoid) + ( – )-Catechin (Green tea polyphenol) + Silymarin (Milk Thistle flavonoid) + Glutathione (Antioxidant) + Sodium butyrate (histone deacetylase inhibitor) + Rutin (Quercetin-3-rutinoside) + Ferulic acid (Phenolic compound) + a-Tocopherol (Vitamin E) + 13-HOA (Corn fatty acid) + Ursolic acid (Pentacyclic triterpenoid) Synthetic compounds + Indomethacin (COX inhibitor) + NS-398 (COX-2 inhibitor) + 1400W (iNOS inhibitor) + SB202474 (Inactive analog of SB203580) + Acetylsalicylic acid (COX inhibitor) + PD98059 (MEK1 inhibitor) + Pentoxifilline (PDE inhibitor) + SB203580 (p38 inhibitor) + SP600125 (JNK1/2 inhibitor) + U0126 (MEK1/2 inhibitor) MIF (ng/ml) 11.Mol.4 93. 13-hydroxy-10-oxo-trans-11-octadecenoic acid. MEK.3 22.9 71.0 75. 140]. In fact.1 – 11.9 27. without affecting mRNA levels [24].7 19. From these results. and MIF.7 45.9 22.and time-dependent manners. this triterpenoid induced IL-6 and MIF.0 68. 52. presumably through intracellular ROS generation. an established cell line [23. thereby activating NF-jB. 2008.5 84. We also considered it worthwhile to examine the effects of this triterpenoid on the production of inflammatory cytokines.com . PDE.2 31. IL-6.5 86.1 Inhibition (%) – – Cell viability (%) 104 100 18. are known to recognize high-molecular weight substances. interferon. but not TNF-a.7 cells were pretreated with each compound for 30 min before exposure to IFN-c for 12 h.1 16.1 44. ERK1 following activation caused by the release of MIF was revealed in experiments using small interfering RNAs.4 98. Effects of natural and synthetic compounds on MIF protein releated from IFN-c-treated RAW264.3 32. Weinheim www. Nishimura et al.0 97. including SR-A. Food Res.9 – 29. and post-translational levels. in peritoneal Mb (pMb). 26 – 42 33 Table 3. p38 MAPK.2 28. MIF released into the media was evaluated using ELISA.2 73.6 40. because IL-6 was previously shown to be strongly induced by ROS generation. COX. as well as the ERK1/ 2. Nutr. and NF-jB signaling pathways [139. a surface plas- i 2008 WILEY-VCH Verlag GmbH & Co. mitogen-activated protein kinase/extracellular signalregulated kinase.5 107 96.6 37. KGaA. UA markedly amplified ATP binding cassette transportermediated IL-1b secretion from murine pMb at transcrip- tional.6 31. together with increased IL-1b production in pMb [25]. Ikeda et al.) has been used as an antidote. Several studies have shown that IL-1b production was enhanced in human IBD and dextran sulfate sodium-induced colitis murine models [146 – 149]. Mol.com . it is presumed that UA has the potential to trigger inflammation in the large intestine. Although these mediators have critical roles in the early stages of skin tumor formation and colon cancer. 26]. and antihepatotoxic [12. in resting Mb [23 – 25]. 6 Other functional triterpenoids 6. 19. and COX-2 expression may have a major role in potentiating the development of tumor formation in mouse skin. a high dose of UA dramatically reduced DMBA/ TPA-induced tumor formation over a period of 20 wk [26]. mediated by CD36 signaling. thereby abolishing papilloma genesis. [145]. gums. Together. supporting the in vitro observations [23 – 25]. UA-increased pro-inflammatory mediator production is known to contribute greatly to skin tumor promotion. 152. Although the precise reasons for these contrasting outcomes are not known. the effects of UA shown in experiments with RAW264. although there are also a number of reports showing its antitumor promoting activities [16. KGaA. and beer [5. Presently. we identified CD36 as one of the cell surface receptors [25]. cigarettes. chocolate candy. 26 – 42 mon resonance assay. [150] proposed that the major source of IL-1b in the large intestine was chronically activated Mb in the mucosal and submucosal layers in the site of colitis. In both Japan and the United States. 117 – 125]. liquors. continuous and high-dose applications of UA may induce apoptosis in DMBA-initiated cells. it should be emphasized that the dose and duration of UA treatment may be conditional determinants of its effects toward mRNA expression of pro-inflammatory mediators and TPA-induced tumor promotion in mouse skin. Second. in which this SR is expressed in a constitutive manner. 6]. 105]. because UA binds to the same cell lines [25]. GA (Fig. demulcent.3 In vivo observations As noted above. Weinheim www. Thus. is similar in structure to UA and OA. 3b-hydroxy-12-olea-12-en28-oic acid) OA (Fig. MIF. These results suggest that it is necessary to perform more comprehensive evaluations in vivo. including antioxidative [78. 103. there is ample evidence that UA induces several pro-inflammatory mediators. a UA isomer. 3b-hydroxy-11oxoolean-12-en-30-oic acid) Licorice (Glycyrrhiza glabra L. 6). anti-inflammatory [21. such as NO. 22]. repetitive. On the other hand. although the relationships between the short-term (2 wk) effects of UA and those over the long term (20 wk) are unclear. 24] may also be mediated by binding to CD36. skin-tumor development in TNF-a-deficient mice was delayed. thereby preventing TPA from reaching the target tissue. the aglycone of glycyrrhizin. IL-1b. intraperitoneal administration of UA at a high dose (200 mg/kg) induced IL-1b production and myeloperoxidase activity in colonic mucosa [25]. and has been shown to possess sev- i 2008 WILEY-VCH Verlag GmbH & Co. Nutr.2 Glycyrrhetinic acid (GA. it is used as a sweetening and flavoring agent in candy. For example. 2008. OA has been isolated from more than 120 different plant species [10]. Surprisingly. Food Res. Youngman et al. and COX-2 mRNA levels. indicating that Mbderived IL-1b may be closely and critically associated with disease pathology. 5. COX1. long-term high-dose applications of UA may lead to accumulation of non-absorbed UA on the skin. and genetically modified mice. First. who reported that homozygous COX-1 and COX-2 deficient-mice had tumor numbers reduced by 75% as compared with their wild-type counterparts. 79]. although UA-induced pro-inflammatory mediator production is known to contribute greatly to skin tumor promotion. Although we give no details of the biological activities of OA in this review. and plants that include OA have been used as a drug for longevity as well as a cure-all in East Asian countries since ancient times. 6).1 Oleanolic acid (OA. TNF-a. at least in part. Therefore.34 Y. Interestingly. widely exists in plants in the form of free acid or aglycones for saponins group of triterpenoids [8 – 10]. At this moment. Collectively. The importance of not only COX2 but also COX-1 in mouse-skin carcinogenesis was extensively investigated by Tiano et al. 16. and tumor multiplicity and diameter were dramatically reduced as compared with wild-type mice following its application [132]. Nonetheless. whereas 2 wk of applications may not have been enough to produce such a physical barrier. because the action mechanisms of UA in mouse skin are highly complex and may exhibit undesirable effects on colonic mucosa. increases in TNF-a. 6. a naturally occurring saponin triterpenoid and the major constituent of licorice. 153]. it is considered that the pro-inflammatory effects of UA are. anticancer [15. 52. they may be due to the following effects. Thus.mnf-journal.7 cells [23. 127 – 129] activities. and IL-6. topical UA applications to mouse skin at a high dose (1600 nmol) twice a week for 2 wk increased TNF-a. topical cosmetic preparations containing UA are now patented in Japan for the prevention of skin cancer [115]. the effects of UA on TPA-induced tumor promotion in mouse skin and mouse colonic mucosa were addressed [25. and elixir in folk medicine for generations in China. a pharmaceutical preparation containing OA has been patented for treatment of non-lymphatic leukemia [151] and OA has been shown to have virtually the same biological effects as UA. there is limited information on the effects of UA in vivo. which is supported by the above-mentioned results of several in vitro studies [112. COX-1. In addition. Latin America. Nutr. intracellular proteins are released and exhibit their biological functions. 6. CDDO has some important properties. CDDO has also been shown to have several mechanisms of actions including disrupting intracellular redox balance [177]. and antihepatotoxic [157] activities. and it induced apoptosis of human acute myeloid leukemia [172. Japan.12-dioxooleana-1.4 CDDO (2-cyano-3. This triterpenoid has exhibited strong antioxidative. 171]. and has been used by native people in North America. such as carrageenan and histamine.mnf-journal. breast cancer [174]. Weinheim www. This process triggers the activation of MAPK pathways and NF-jB for promoting transcription of pro-inflammatory mediator (such as iNOS. 2008. 26 – 42 35 found that it inhibited lipemic-oxidative stress in experimental hypercholesterolemia [169]. such as olive.Mol. and was also effective in inhibiting the covalent binding of B[a]P to epidermal DNA and tumor initiation by B[a]P and DMBA [5]. KGaA.3 Lupeol (Lup-20(29)-en-3b-ol) Lupeol (Fig. suggesting a plausible mechanism for the anti- Figure 6. up-regulating the expression of cyclin D1 and p21 [174]. Further. and chronic lymphocytic leukemia [178] cells. such as anti-inflammatory effects and antiproliferative. it potently prevented ileitis induced by Toxoplasma gondii infection [181] as well as activation of NF-jB by TNF-a and IL-1b [182. and a recent report linked the antioxidative activity of CDDO to increased expression of phase II response enzymes. activating p38 MAPK and JNK1/2 [179]. In fact. via activation of nuclear factor E2-related factor 2 signaling. 6. osteosarcoma [176]. GA inhibited paw edema induced by vasoactive agents. presumably by NOX. TNF-a. and fig. and antiarthritic activities in both in vitro and in vivo systems [163]. 170. lupeol induced apoptotic death of human pancreatic adenocarcinoma cells via inhibition of the Ras signaling pathway [165]. i 2008 WILEY-VCH Verlag GmbH & Co. while another study Figure 7. It was also shown that lupeol has a lowdensity lipoprotein (LDL) protective activity in LDL oxidation studies performed in in vivo [168]. 171]. Food Res. GA. Then. and has also induced Fasmediated apoptotic death of androgen-sensitive prostate cancer cells and inhibited tumor growth in a xenograft model [164]. mango. and CDDO. leading to the expression of pro-inflammatory mediators for intracellular protein production. and apoptosis-inducing activities. and IL-1b) genes. 52. 155]. Further. anticancer.com . Proposed molecular mechanisms by which UA induces pro-inflammatory cytokines in murine Mb. 173]. this compound inhibited the mutagenicity of B[a]P. eral beneficial pharmacological effects. 6). differentiating. 2-aminoflourene and aflatoxin B1 in Salmonella typhimurium TA100 and TA98 assay systems. anti-inflammatory. lupeol. and inducing apoptosis through both intrinsic and extrinsic pathways [173. strawberry. anticancer [16. in rats [159]. CDDO was 400-fold more potent than UA in suppressing the expression of iNOS and COX-2 [117. Aggregated UA is recognized by CD36 and then ROS are intracellularly generated. 180]. including CDDO (Fig. 183]. 156].9-dien-28oic acid) Since naturally occurring triterpenoids have relatively weak anti-inflammatory and anticancer activities. In previous studies. and the Caribbean islands [160 – 162]. such as antiinflammatory [154. as well as inhibition of the growth of melanomas in mice [158]. Structures of OA. such as heme oxygenase 1 and SOD. China. lung cancer [175]. 6) is a naturally occurring triterpene found in various edible plants. as well as medicinal plants. while it also inhibited paw edema induced by carrageenan in rats [166] and tumor promotion in two-stage mouse skin carcinogenesis by modulating the NF-jB and phosphatidylinositol 3-kinase/AKT pathways [167]. have been synthesized [116. It is noteworthy that several antioxidants that display anti-inflammatory activities also inhibit NF-jB signaling [184 – 186]. a series of novel derivatives of UA. Further. red grape. multiple myeloma [177]. In addition. interleukin. NF-jB Z [23] MIF Z. NO. z: suppressed COX. and anticancer activity agent (Table 4). tumor necrosis factor. there are no results from a human study regarding the effect of UA. IL. ERK1/2 Z. NF-jB z [21] COX-2 z.36 Y. 2008. a derivative of UA. ROS. the use of UA is recommended for skin cancer therapy. nuclear factor-kappa B. TPA. 63. undesirable effects of UA. although. TNF. However. Because comprehensive studies of the action mechanisms of UA in resting Mb and tissues are limited. 26 – 42 Table 4. 105. NF-jB. Myeloperoxidase Z [25] H f j f h Marcophages Burkitt's lymphoma cells Melanoma cells H f f f j f f f h Leukemic cells H j h Macrophages Mammary epithelial cells Paw & Ear Fibrosarcoma cells Nerve cells H j h Liver & Heart Brain Proposed mechanisms [Ref] Experimental systems Skin Skin Colonic mucosa Z: enhanced. cyclooxygenase. 59.mnf-journal. COX-2 z. MAPK. reactive oxygen species. 7. prostaglandin. PG. ERK2 Z [24] IL-1b Z. Epstein-Barr virus.com . Weinheim www. PGE2 z [91] Edema z [42. CDDO. Extensive research during the last quarter century has identified UA from several plants (Table 1) as an antioxidative. nitric oxide. MIF. 7 Conclusions and perspectives Fruits and vegetables are recommended for the prevention of cancer and other disease. MIF Z. Nutr. which may be partially mediated by CD36. 82] Non-enzymic antioxidants Z [80-82] Antioxidant enzymes Z [83. additional extensive investigations regarding the desirable or undesirable effect of UA on normal tissue and human are required to determine the risks and benefits of this triterpene. Table 4). Food Res. Antioxidant enzymes Z [57] Lipid peroxidation production z [80 – 82] Antioxidant enzymes Z [80. COX-1 Z. Therefore. 19. their action mechanisms are poorly understood. This compound is now being utilized in the development of a useful new chemopreventive agent that may be used in the future for malignancy therapy. although UA is able to counteract endogenous and exogenous inflammatory stimuli. KGaA. and topical cosmetic preparations containing UA have been patented in Japan for the prevention of skin cancer. mitogen-activated protein kinase. it is considered that the effects of UA on normal cells and tissues are occasionally pro-inflammatory. ROS Z. p38 MAPK Z [25] TNF-a Z. extracellular signal-regulated kinase. Representative biological effects of UA Effects Antioxidation ROS z [50] ROS z. COX-2 Z [26] IL-1b Z. iNOS. 95 – 99] Anti-cancer EBV activation z [15. EBV. 110] Pro-inflammation NO Z. TNF-a Z. are now emerging from both in vitro and in vivo experiments conducted over the past 5 years (Fig. Mol. to the best of our knowledge. anti-inflammatory. Such approaches will likely show the diversity of the physiological effects and underly- i 2008 WILEY-VCH Verlag GmbH & Co. IL-6 Z. macrophage migration inhibitory factor. 61.84] Anti-inflammation Lipoxygenase and COX z [18] NO z [20] iNOS z. However. Ikeda et al. Currently. is being utilized for the development of a useful new chemopreventive agent for malignancy. ERK. 107] DNA binding of tumor initiator z [19] Epidermal membrane binding of TPA z [108] Tumor promotion by TPA z [16] Inflammation by TPA z [19. 52. 109] Ornithine decarboxylase z [5. 106] Apoptosis Z [113] DNA binding of NF-jB z [22. 12-O-tetradechanoylphorbol-13-acetate inflammatory effects of this agent [187]. inducible nitric oxide synthase. . Cho.Mol. K. Oak.. [24] Ikeda. B. G.. 2367 – 2371. 40. K. J. Triterpenoid saponins. Majumdar.. R. Biotechnol. P. M.and tetraterpenes. 1988. Pharmacology of oleanolic acid and ursolic acid. H. Eliel.. Eur. Y. Slaga. [25] Ikeda. et al. H. 1033 – 1037.. Ursolic acid promotes the release of macrophage migration inhibitory factor via ERK2 activation in resting mouse macrophages.6-epoxyretinoic acid. Giner. [3] McGarvey. D. [5] Wang. Phytochemistry 1988. matrix metalloproteinase 9. J. J. I.. S. J. B.. Plant Cell 1995. Ned.. Ohigashi.. Takamura.. M. 502 – 504.. Agarwal. Ito. platelets and differentiated HL60 leukemic cells.. Rios. Biosci. 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