Comprehensive Reviews in Food Science and Food Safety

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1 Comprehensive Reviews in Food Science and Food Safety Bioactivity of Resveratrol Robert E. King, Joshua A. Bomser, and David B. Min ABSTRACT: Resveratrol (3,5,4 -trihydroxystilbene) is a natural polyphenolic phytochemical with a variety of bioactivities associated with health promotion. Resveratrol is readily absorbed with the other absorbable digestion products of its main human dietary sources (peanuts, peanut butter, grapes, and red wine). The polyphenolic structure of resveratrol confers antioxidant activity and may reduce oxidant-induced apoptosis and low-density lipoprotein (LDL) oxidation. Resveratrol may be responsible, in part, for the correlation between increased wine consumption and decreased risk of coronary heart disease. The cardioprotective activity of resveratrol is associated with the inhibition of platelet aggregation and LDL oxidation and the promotion of artery vasorelaxation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression, as well as inhibit the growth of cancerous cells through increased apoptosis and/or cell cycle blockage. Inflammatory processes are associated in the pathogenesis of many chronic diseases including heart disease and cancer. Resveratrol has been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-b activity. In addition, the estrogenic activity of resveratrol may help prevent post-menopausal bone loss. Modulation of cellular signal transduction pathways (such as mitogen-activated protein kinases) may explain, in part, the diverse bioactivities associated with resveratrol. Scientific information summarized in this review supports the many potential health benefits of resveratrol; however, further understanding of the bioavailability, metabolism, and cellular effects of resveratrol is necessary. Introduction Interest in the potential health benefits associated with dietary consumption of resveratrol (3,5,4 -trihydrostilbene) has increased significantly in the past decade. Resveratrol is a member of the stilbene family, a group of compounds that consist of 2 aromatic rings joined by a methylene bridge. ver 30 stilbenes and stilbene glycosides have been identified in the plant kingdom (Soleas and others 1997). Resveratrol is the parent molecule of viniferins, a family of phytoalexin polymers that prevent the progression of fungal infections. Increased consumption of monomeric resveratrol and/or resveratrol-containing foods may be associated with improved health. These health benefits are related to a diverse range of biological activities. This review will discuss several aspects of resveratrol including bioavailability, antioxidant capacity, cardioprotection, anticancer activity, anti-inflammatory effects, estrogenic/anti-estrogenic properties, and modulation of cellular signal transduction pathways. MS Submitted 1/3/2006, Accepted 4/5/2006. Authors King and Min are with Dept. of Food Science and Technology, The hio State Univ., 2015 Fyffe Court, Columbus, Author Bomser is with Dept. of uman Nutrition, The hio State Univ., 1787 Neil Avenue, Columbus, Direct inquiries to Min ( min.2@osu.edu). ccurrence Resveratrol is found in at least 72 plant species (Dercks and Creasy 1989) and is formed via a condensation reaction between 3 molecules of malonyl CoA and 1 molecule of 4- coumaroyl CoA (Figure 1) (Soleas and others 1997). Resveratrol synthase facilitates this condensation reaction, which also produces 4 molecules of C 2. Resveratrol exists in 2 structural isomeric forms, cis and trans (Figure 2), with the trans form being more common and possessing greater biological activity. ne of the richest sources of this compound is Polygonum cuspidatum,a weed that is used in traditional Chinese and Japanese medicines. Trees such as eucalyptus and spruce have also been found to contain resveratrol (illis and others 1974; Rolfs and Kindl 1984); however, its presence in edible plants is rare. The primary dietary sources in the human diet are peanuts, peanut butter, grapes, and wine. The concentration of resveratrol present in peanuts is dependent upon many different factors. Cultivar, growing season, weather conditions, and peanut maturity have been shown to affect resveratrol concentrations (Sobolev and Cole 1999; Sanders and others 2000; Chen and others 2002). Resveratrol concentration appears to vary among the different components of a peanut, with higher concentrations found in the seed coat and shell than the embryos and kernels (Sanders and others 2000; Sobolev and Cole 1999). Processed peanuts and peanut products also display variability in resveratrol concentration. Boiled peanuts were found to contain the highest concentration, followed by peanut C 2006 Institute of Food Technologists Vol. 5, 2006 CMPREENSIVE REVIEWS IN FD SCIENCE AND FD SAFETY 65

2 CRFSFS: Comprehensive Reviews in Food Science and Food Safety butter and roasted peanuts (Sobolev and Cole 1999). The higher concentration in boiled peanuts was thought to be due to the greater use of immature kernels, which contain greater amounts of resveratrol than mature kernels. Resveratrol was first identified in grapevines (Vitis vinifera) in 1976 (Langcake and Pryce 1976). Leaf tissue was found to synthesize resveratrol in response to fungal infection or ultraviolet light exposure. Creasy and Coffee (1988) found resveratrol only in the skins of grapes, not the flesh, when its production was induced by ultraviolet light. Climate, wilting conditions, and amount of fungal (Botrytis cinerea) infection influence the concentration of resveratrol in grape skin. Grape variety also affects resveratrol concentration, with higher concentrations observed in red grape varieties compared to white grape varieties (Sieman and Creasy 1992). Due to its presence in grapes, it is no surprise that resveratrol is also found in wines. The resveratrol concentration in wine is variable, with grape variety and growing conditions having significant influence. Vinification, the conversion of fruit juice to wine through fermentation, is influential in resveratrol concentration. Mattivi and others (1995) followed the development of resveratrol through the vinification process and found that the resveratrol glucosides cis- and trans-resveratrol β-d-glycopyranoside Resveratrol synthase Resveratrol SCoA Coumaroyl CoA 3 [C-C -C-SCoA] 2 Figure Synthesis of resveratrol Malonyl CoA Figure Cis (top) and trans(bottom) piceid (cis- and trans-piceid) (Figure 3) were extracted from the grape before cis- and trans-resveratrol. As fermentation continued the concentrations of the piceid isomers decreased while the resveratrol isomers increased, with trans-resveratrol having the highest final concentration. The decrease in piceid isomers was explained as the hydrolysis of these isomers into resveratrol isomers. While hydrolysis of piceid isomers did increase the concentration of resveratrol, the extraction of resveratrol from the grapes was driven by increased ethanol production. The extraction of transresveratrol from wine is at a maximum concentration after approximately 10 days of fermentation (Soleas and Goldberg 1995; Gambuti and others 2004). In a comparison of wines from the north coast of California, red Pinot noir wines were found to contain the highest resveratrol concentrations, while white Bordeaux and Chardonnay wines contained the lowest concentrations (Lamuela-Raventós and Waterhouse 1993). Similar results were found by Sato and others (1997) in their comparison of wines made from grapes grown in Japan. The fermentation of grape flesh with the skin in red wine production allows red wines to have greater resveratrol concentrations than white wines, which are produced by fermentation of the flesh only. Figure Cis (top) and trans (bottom) isomers of resveratrol Absorption Bioavailability and Metabolism of Resveratrol The potential health benefits of resveratrol depend, in part, upon its absorption, bioavailability, and metabolism. Several in vitro and in vivo models have been utilized to characterize the absorption and bioavailability of resveratrol. Using the Caco-2 human intestinal cell model, Kaldas and others (2003) demonstrated that resveratrol uptake remained linear, for an hour, and transportation was nondirectional. Metabolites identified in the Caco-2 cells were resveratrol sulfate and resveratrol glucuronide, with resveratrol sulfate being predominant. The ease of absorption and accumulation of resveratrol suggests gastrointestinal cells as a possible biological target in vivo. enry and others (2005) also observed passive diffusion of resveratrol in Caco-2 cells; however, the transport of trans-piceid required the sodiumdependent glucose co-transporter SGLT1. Similar to Caco-2 cells 66 CMPREENSIVE REVIEWS IN FD SCIENCE AND FD SAFETY Vol. 5, 2006

3 Bioactivity... uptake, normal and tumor human hepatic cell lines utilize both passive diffusion and active transport for resveratrol uptake (Lançon and others 2004). In the rat small intestine model, resveratrol was absorbed on the serosal side of the jejunum, with the majority being metabolized to resveratrol glucuronide (Kuhnle and others 2000). Recently, several studies have examined resveratrol absorption in vivo. igh absorption of resveratrol, at least 70%, has been observed in human subjects after oral doses; however, only trace amounts of the parent compound were found in subjects plasma. Resveratrol sulfate was the major metabolite found in human plasma (Walle and others 2004). Sulfation may be the primary limiting factor in the bioavailability of resveratrol. Vitaglione and others (2005) found resveratrol was absorbed by human subjects after moderate wine consumption, though only trace amounts of the parent compound were identified in some of the blood serum samples. Resveratrol absorption and bioavailability varied between subjects, but was not affected by meal type or quantity of lipids in the meal. The food matrix in which resveratrol is consumed may have an effect on absorption and bioavailability. Following oral administration of pure resveratrol to human subjects, resveratrol glucuronide was the major metabolite detected in the plasma and urine. igh oral doses of grape juice resulted in the detection of the glucuronide and sulfate conjugates in subjects plasma and urine (Meng and others 2004). Grape juice consists of mostly resveratrol glucosides, cis- and trans-piceid, with low amounts of the free resveratrol, suggesting a lower bioavailability of the glucosides compared to the pure compound. The administration of polyphenols through different matrices (aqueous, ethanol, and vegetable suspension) has been shown to have no effect on human absorption of total resveratrol (free and conjugated forms) (Goldberg and others 2003). Antioxidant Activity of Resveratrol Many compounds with aromatic groups are able to function as antioxidants by forming stable radicals via resonance structures, thereby preventing continued oxidation. Resveratrol contains 2 aromatic groups and has been shown to have a higher 2,2 - azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), 1,1- diphenyl-2-picrylhydrazyl (DPP), and hydroxyl radicalscavenging capacity than propyl gallate, vitamin C, and vitamin E (Soares and others 2003). A positive correlation has been established between the antioxidant power of wine and resveratrol content (Alonso and others 2002). As an antioxidant, resveratrol may delay and/or prevent oxidative stress-induced cellular damage and disease. Excessive damage induced by oxidative stress can induce cells to undergo apoptosis. Resveratrol has been shown to inhibit oxidative-induced apoptosis in a variety of cell lines including Swiss 3T3 mouse fibroblasts, rat pheochromocytoma (PC12), human peripheral blood mononuclear (PBM), and human retinal pigment epithelium (RPE) cells (Jang and Surh 2001; Losa 2003; Kutuk and others 2004; King and others 2005). Reduced oxidative stress in RPE cells by resveratrol may be associated with reduced incidence of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. The antioxidant activity of resveratrol may also be associated with protection against the progression of atherosclerosis. The oxidation of low-density lipoproteins (LDL) is an important event in the development of this disease. Resveratrol has been shown to inhibit copper-initiated and, to a lesser extent, 2,2 -azobis (2-amidinopropane) dihydrochloride (AAP)-initiated oxidation of porcine LDL (Belguendouz and others 1997; Frémont and others 1999). In vivo, resveratrol inhibited copper-catalyzed LDL oxidation in 2 healthy human subjects by 81% and 70%, respectively (Frankel and others 1993). At the site of early atherosclerosis lesions, blood platelets can also be found. When activated, these platelets can generate reactive oxygen species (RS). Resveratrol was found to inhibit RS production and lower lipid peroxidation, though not to the extent achieved by vitamin C, in blood platelets (las and Wachowicz 2002). While there was no synergism between resveratrol and vitamin C, resveratrol was able to reduce the prooxidant effects of vitamin C. Cardiovascular ealth and Resveratrol The incidence of coronary heart disease in the French population is low despite their high fat consumption and the heavy use of tobacco products. This observation is referred to as the French paradox, and may be associated with increased dietary consumption of red wine. Red wine is one of the few dietary sources of resveratrol and it is believed that this compound is responsible, in part, for the positive cardiovascular effects associated with moderate wine consumption (Constant 1997). The most accepted mechanism of cardioprotection by resveratrol is the inhibition of platelet aggregation (Bhat and others 2001a). Platelets are cells without nuclei that are made in the bone marrow and function to stop bleeding via aggregation at the wound site. Platelets can be activated by several different factors, including adenosine diphosphate (ADP), collagen, and thrombin. When activated platelets change morphology they aggregate and seal damaged blood vessels. Excessive aggregation can lead to the development of cardiovascular disease. Pretreatment of platelets with resveratrol has been shown to inhibit lipopolysaccharide (LPS) and LPS + thrombin-stimulated platelet adhesion to collagen and fibrinogen in a non-dose-dependent manner (las and others 2002). Using in vitro and in vivo models, Wang and others (2002) have demonstrated that resveratrol inhibits ADP, collagen, and thrombin-stimulated human platelet aggregation in vitro. Furthermore, rabbits receiving resveratrol supplementation had reduced rates of platelet aggregation when fed a high cholesterol diet. The prevention of calcium influx through the stored operated calcium channels has been suggested as a target for resveratrol in the inhibition of thrombin-induced platelet aggregation (Dobrydneva and others 1999). The cardioprotective effects of resveratrol may also be due, in part, to its vasorelaxation properties. Chen and Pace-Asciak (1996) examined the vasorelaxation effect of resveratrol on rat aortic rings with and without intact endothelium. Pretreatment with resveratrol resulted in a dose-related decrease in noradrenaline (NA)- and phenylephrine (PE)-induced contraction in endothelium-intact rat aortic rings. Endothelium-independent rings required higher concentrations of resveratrol before relaxation was observed. The authors concluded that resveratrol mediates vasorelaxation in endothelium-intact and endotheliumindependent aortic rings via nitric oxide-dependent and -independent mechanisms, respectively. In a similar study, resveratrol relaxed endothelium intact rat aortic rings constricted by PE and potassium chloride (KCl) via N release; however, there was no vasorelaxation effect with endothelium-independent rings (rallo and others 2002). The release of N has also been suggested as a mechanism for the reduction of ischemia-reperfusion injury experienced by rat hearts after resveratrol treatments (ung and others 2000; Bradamante and others 2003). ther methods of resveratrol cardioprotection include the prevention of LDL oxidation (Frankel and others 1993; Frémont and others 1999). LDL oxidation can cause the formation of fatty streaks in arteries and lead to the development of atherosclerosis. Resveratrol also interacts with signal transduction pathways within vascular tissue affecting cellular gene expression, proliferation, and differentiation. Vol. 5, 2006 CMPREENSIVE REVIEWS IN FD SCIENCE AND FD SAFETY 67

4 CRFSFS: Comprehensive Reviews in Food Science and Food Safety Anticancer Activity of Resveratrol Resveratrol has been found to inhibit tumor initiation, promotion, and progression in vitro, as well as reduce skin tumor incidence and multiplicity via topical application to mice in vivo (Jang and others 1997). The anti-proliferative activity of resveratrol has been observed in a number of cancer cell lines and may be due, in part, to the induction of apoptosis (Surh and others 1999; Ding and Adrian 2002; Joe and others 2002). Proliferation inhibition may also be caused by the arrest of the cell cycle (Joe and others 2002; Castello and Tessitore 2005). Piceatannol (Figure 4), a naturally occurring analog of resveratrol, has been observed to inhibit the proliferation of cancer cell lines via apoptosis and cell cycle arrest (Wolter and others 2002; Larrosa and others 2004). Potter and others (2002) suggested that the anti-proliferative effects of resveratrol on cancer cells is the result of a metabolic conversion of resveratrol to piceatannol by cytochrome P450 1B1 (CYP1B1). CYP1B1 is highly expressed in cancerous tissue of the breast, colon, lung, esophagus, skin, lymph node, brain, and testis, but not in the normal tissue (Murray and others 1997). The molecular mechanisms associated with the anti-proliferative effects in cancer cells involve the activation of p53 and the suppression of nuclear factor-κb (NF-κB) and activator protein-1 (AP-1) (uang and others 1999; Banerjee and others 2002; Kundu and others 2004). Resveratrol and Inflammation Inflammatory processes are mediated by prostaglandins (PGs). Inhibition of PG activity may be partially responsible for the chemopreventative and cardioprotective effects of resveratrol. Resveratrol has been shown to dose-dependently inhibit induced production of PGE 2 in human peripheral blood leukocytes (Richard and others 2005), while in vivo resveratrol significantly decreased elevated levels of rat PGD 2 (Martín and others 2004). In the in vitro and in vivo model, resveratrol decreased the expression of cyclooxygenase-2 (CX-2), an enzyme that catalyzes PG synthesis and is induced by inflammation (Martín and others 2004; Richard and others 2005). Resveratrol has been observed to decrease induced CX-2 activity by inhibiting the expression of the enzyme via signal transduction pathways (Subbaramaiah and others 1998; Kundu and others 2004). Resveratrol also inhibits the inflammatory actions of cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) (Pendurthi and others 1999; Culpitt and others 2003). Nuclear factor-κb (NF-κB), a transcription factor, regulates genes involved in inflammation and tumorigenesis (Baeuerle and Baichwal 1997). Inhibition of NF-κB activity is a possible mechanism by which resveratrol exerts its anti-inflammatory activity. Inhibition of TNF-induced NF-κB activation by resveratrol has been observed in several cell lines (olmes-mcnary and Baldwin 2000; Manna and others 2000). A recent study found resveratrol decreased induced mammary tumor incidence, number of tumors, and extended cancer latency in female Sprague- Dawley rats by suppressing the expression of NF-κB and 2 en- Figure Chemical structure of piceatannol 68 CMPREENSIVE REVIEWS IN FD SCIENCE AND FD SAFETY Vol. 5, 2006 C 3 C 3 Figure Chemical structural comparison between diethylstilbestrol (top) and resveratrol (bottom) zymes regulated by NF-κB: CX-2 and matrix metalloprotease 9 (Banerjee and others 2002). The exact mechanism by which resveratrol inhibits NF-κB activation remains uncertain. Manna and others (2000) determined that resveratrol inhibited TNFinduced NF-κB activation by preventing phosphorylation and nuclear translocation of the NF-κB subunit p65. Resveratrol has also been shown to prevent NF-κB activity by blocking NF-κB DNA binding and inhibiting IκB kinase (IKK) activity (olmes-mcnary and Baldwin 2000). IκB is an inhibitory protein that is bound to inactive NF-κB. Upon activation, IKK phosphorylates IκB, degrading it and allowing NF-κB to translocate to the nucleus. IKK activity is not directly inhibited; resveratrol inhibits an upstream signaling component (olmes-mcnary and Baldwin 2000). Phytoestrogenic Activity of Resveratrol Phytoestrogens are nonsteroidal dietary compounds that, like estrogen, are able to bind to estrogen receptors resulting in the transcription of estrogen-responsive genes. The structural similarity of resveratrol to the synthetic estrogen diethylstilbestrol (DES) (Figure 5) suggests that it may have estrogenic activity. The estrogenic activity of resveratrol has been proposed as a mechanism for cardioprotection and prevention of estrogen-dependent cancers. In the vascular smooth muscle cells of stroke-prone spontaneously hypertensive rats, resveratrol inhibited advanced glycation end products (AGEs) induced cellular events (Mitzutani and others 2000). AGEs are involved in a variety of vascular complications. ICI , an estrogen receptor antagonist, partially reversed the inhibition of the AGEs-induced events, suggesting that the inhibitory effects of resveratrol were partially facilitated by estrogen receptors (Mitzutani and others 2000). In the human breast carcinoma MCF-7 cell line, the estrogenic properties of resveratrol vary. Stimulation of estrogen-regulated progesterone receptor (PR) expression in MCF-7 cells by resveratrol has been observed in several studies (Gehm and others 1997; Lu and Serrero 1999; Bhat and others 2001b). Though not as potent as the natural estrogenic hormone, estradiol, Gehm and others (1997) found that resveratrol exhibited a superagonist property by inducing reporter gene activity 2- to 3-fold greater than estradiol. Cis- and trans-resveratrol were both observed to have superagonist activity in MVLN cells, estrogen-dependent MCF-7 cell line (Basly and others 2000). In contrast, resveratrol has been shown to have no superagonist activity (Bhat and others, 2001b) and demonstrated anti-estrogenic activity, via estradiolinduced gene expression inhibition, in the MCF-7 cell line (Lu and Serrero 1999; Bhat and others 2001b). The estrogenic properties

5 Bioactivity... of resveratrol also appear to vary among different cell lines. In a comparison of 4 mammary cancer cell lines (MCF-7, T47D, LY2, and S30), resveratrol acted as an agonist in the MCF-7 and the S30 cell lines, while antagonizing estrogen activity in T47D and LY2 cells. The anti-estrogenic activity of resveratrol was also observed in human endometrial adenocarcinoma (Ishikawa) via the inhibition of estradiol-induced alkaline phosphatase activity, PR expression, and estrogen receptor-mediated reporter gene (Bhat and Pezzuto 2001). The estrogenic activity of resveratrol may also help prevent bone loss in post-menopausal women. Resveratrol was shown to increase the proliferation of osteoblastic MC3T3-E1 cells and induce alkaline phosphatase activity, an enzyme believed to be involved in bone mineralization (Mizutani and others 1998). The anti-estrogen tamoxifen blocked these effects, suggesting an estrogen-dependent mechanism. Resveratrol-treated ovariectomized rats have been found to have significantly greater femur bone length, epiphysis bone mineral density, and bone calcium content than ovariectomized rats without treatment (Liu and others 2005). Resveratrol as Signal Transduction Modulator Mitogen-activated protein kinase (MAPK) pathways are wellcharacterized mammalian signal transduction pathways and include p38, c-jun N-terminal protein kinase (JNK), and extracellular signal-regulated kinase (ERK). MAPK pathways consist of several kinases, which activate one another via a phosphorylation cascade in the cell cytoplasm and end with the activation of various transcription factors. The JNK and p38 pathways are associated with cellular apoptosis, while ERK is linked to cell proliferation and differentiation. The interaction between resveratrol and MAPK pathways provides possible explanations for many of the beneficial effects of resveratrol. Several studies have suggested the cardioprotection offered by resveratrol is due to the modulation of MAPK pathways. In porcine coronary arteries resveratrol was found to inhibit the induced activation of p38, JNK1, and ERK1/2 by endothelin-1 (ET-1), a cardiovascular disease mediator (El-Mowafy and White 1999). Resveratrol was also able to prevent ET-1-induced translocation of phosphorylated ERK1/2 to the nucleus. The modulation of ERK signaling by resveratrol has been shown to play an important role in angiotensin II (Ang II) induced proliferation and ET-1 gene expression in rat aortic smooth muscle cells (aider and others 2002; Chao and others 2005). Excessive secretion of extracellular matrix (ECM) proteins by cardiac fibroblasts and myofibroblast and differentiated cardiac fibroblasts can lead to the development of cardiac fibrosis. Resveratrol has been found to target MEK, an ERK pathway kinase, and ERK activation in the inhibition of cardiac fibroblast mitogenic signaling, proliferation, and differentiation into myofibroblasts (lson and other 2005). The anticancer properties of resveratrol are due, in part, to the activation of the p53 protein and the suppression NF-κB and AP-1 through the inhibition of signaling cascades. The p53 protein is a transcription factor and an important tumor suppressor. It has been postulated that over half of human cancers are related to the loss or mutation of this protein (Dong 2003). In JB6 mouse epidermal cells resveratrol inhibited 12--tetradecanoylphorbol- 13-acetate (TPA) and epidermal growth factor (EGF)-induced cell transformation while inducing apoptosis, activating p53 transcription activity, and increasing p53 levels (uang and others 1999). Resveratrol was able to induce apoptosis in mouse fibroblast cells with wild-type p53, but could not induce apoptosis in p53-deficient fibroblast cells (uang and others 1999). Studies have shown resveratrol-induced apoptosis and p53 activation (via phosphorylation) are mediated by the ERK and p38 pathways (She and others 2001; Lin and others 2002). Activator protein-1 (AP-1) is a dimeric transcription factor and is responsible for the modulating expression of several tumorpromoting genes (Kundu and Surh 2004). For this reason, AP-1 has been offered as a potential target for resveratrol. Yu and others (2001) induced AP-1 activity in human cervical squamous carcinoma (ela) cells using 12-myristate 13-acetate (PMA), a tumor promoter, and ultraviolet light-c (UV-C), a tumor promoter/initiator. PMA was a strong activator of the ERK1/2 pathway, while UV-C activated all 3 of the MAPK pathways. Resveratrol inhibited both PMA-induced and UV-C-induced AP-1 activity. Suppression of PMA-induced activity was associated with the inhibition of the ERK1/2 pathway. Similarly, UV-C-induced AP-1 activity suppression was associated with the inhibition of all 3 MAPK pathways. In vivo, topical application of resveratrol to mouse skin inhibited TPA-induced expression CX-2 via the inhibition of AP-1 activity and ERK phosphorylation (Kundu and others 2004). In human breast epithelial cells, Subbaramaiah and others (1998) found that resveratrol suppressed induced CX-2 activity. owever, in these cells, resveratrol targeted the protein kinase C (PKC) signal transduction pathway, preventing the translocation of PKC into the membrane. Resveratrol also suppressed the expression of the c-jun, part of the AP-1 dimer. Conclusion Resveratrol is a polyphenol produced in plants as a response to fungal infection and exists in cis and trans form, with the trans form being more biologically active. Peanuts, peanut butter, grapes, and red wine are the primary dietary sources of this compound. Easily absorbed in both in vitro and in vivo models, resveratrol has exhibited antioxidant, cardioprotective, chemopreventative, anti-inflammatory, and estrogenic properties, as well as interaction with signal transduction pathways. Future research should focus on translating in vitro findings regarding potential health benefits into in vivo models. In addition, further understanding of the potential toxicity, health effects, bioavailability, and metabolism of resveratrol is necessary before dietary and supplement recommendations can be made. References Alonso ÁM, Domínguez C, Guillén DA, Barroso CG Determination of antioxidant power of red and white wines by a new electrochemical method and its correlation with polyphenolic content. J Agric Food Chem 50(11): Baeuerle PA, Baichwal VR NF-κB as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol 65: Banerjee S, Bueso-Ramos C, Aggarwal BB Suppression of 7,12-dimethylbenz(a) anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factorκb, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res 62(17): Basly J-P, Marre-Fournier F, Le Bail J-C, abrioux G, Chulia AJ Estrogenic/ antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol. Life Sci 66(9): Bradamante S, Barenghi L, Piccinini F, Bertelli AAE, De Jonge R, Beemster P, De Jong JM Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Eur J Pharmacol 465(1-2): Belguendouz L, Fremont L, Linard A Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins. Biochem Pharmacol 53(9): Bhat KPL, Kosmeder JW II, Pezzuto JM. 2001a. Biological effects of resveratrol. Antioxid Redox Signal 3(6): Bhat KPL, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM. 2001b. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res 61(20): Bhat KPL, Pezzuto JM Resveratrol exhibits cytostatic and antiestrogenic properties with human endometrial adenocarcinoma (Ishikawa) cells. Cancer Res 61(16): Castello L, Tessitore L Resveratrol inhibits cell cycle progression in U937 cells. ncol Rep 13(1): Chao -, Juan S-, Liu J-C, Yang -Y, Yang E, Cheng T-, Shyu K-G Resveratrol inhibits angiotensin II-induced endothelin-1 gene expression and subsequent proliferation in rat aortic smooth muscle cells. Eur J Pharmcol 515(1-3):1 9. Chen C, Pace-Asciak Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta. Gen Pharmacol 27(2): Chen R-S, Wu P-L, Chiou RY-Y Peanut roots as a source of resveratrol. J Agric Food Chem 50(6): Vol. 5, 2006 CMPREENSIVE REVIEWS IN FD SCIENCE AND FD SAFETY 69

6 CRFSFS: Comprehensive Reviews in Food Science and Food Safety Constant J Alcohol, ischemic heart disease, and the French paradox. Coron Artery Dis 8(10): Creasy LL, Coffee M Phytoalexin production potential of grape berries. J Am Soc ortic Sci 113: Culpitt SV, Rogers DF, Fenwick PS, Shah P, De Matos C, Russell REK, Barnes PJ, Donnelly LE Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in CPD. Thorax 58(11): Dercks W, Creasy LL Influence of fosetyl-a1 on phytoalexin accumulation in the Plasmopara viticola-grapevine interaction. Physiol Mol Plant Pathol 34: Ding XZ, Adrian TE Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Pancreas 25(4):71 6. Dobrydneva Y, Williams RL, Blackmore PF trans-resveratrol inhibits calcium influx in thrombin-stimulated human platelets. Br J Pharmacol 128(1): Dong Z Molecular mechanism of the chemopreventive effects of resveratrol. Mut Res : El-Mowafy AM, White RE Resveratrol inhibits MAPK activity and nuclear translocation in coronary artery smooth muscle: reversal of endothelin-1 stimulatory effects. FEBS Lett 451(1):63 7. Frankel EN, Waterhouse AL, Kinsella JE Inhibition of human LDL by resveratrol. Lancet 341(8852): Frémont L, Belguendouz L, Delpal S Antioxidant activity of resveratrol and alcoholfree wine polyphenols related to LDL oxidation and polyunsaturated fatty acids. Life Sci 64(26): Gambuti A, Strollo D, Ugliano M, Lecce L, Moio L Trans-resveratrol, quercetin, (+)-cathechin, and (-)-epicathechin content in south Italian monvarietal wines: relationship with maceration time and marc pressing during winemaking. J Agric Food Chem 52(18): Gehm BD, McAndrews JM, Chien P-Y, Jameson JL Resveratrol, a polyphenolic compound found in grapes and wine, is agonist for the estrogen receptor. Proc Natl Acad Sci (USA) 94(25): Goldberg DM, Yan J, Soleas GJ Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin Biochem 36(1): aider UGB, Sorescu D, Griendling KK, Vollmar AM, Dirsch VM Resveratrol suppresses angiotensin II-induced Akt/Protein Kinase B and p70 s6 kinase phosphorylation and subsequent hypertrophy in rat aortic smooth muscle cells. Mol Pharmacol 62(4): enry C, Vitrac X, Decendit A, Ennamany R, Krisa S, Mérillon J-M Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells. J Agric Food Chem 53(3): illis WE, art J, Yazaki Y Polyphenols of Eucalyptus sideroxylon wood. Phytochemistry 13: olmes-mcnary M, Baldwin AS Jr Chemopreventative properties of trans-resveratrol are associated with inhibition activation of the IκB kinase. Cancer Res 60(13): uang C, Ma W-Y, Goranson A, Dong Z Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. Carcinogenesis 20(2): ung L-M, Chen J-K, uang S-S, Lee R-S, Su M-J Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res 47(3): Jang J-, Surh Y-J Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat phenochromocytoma. Mutat Res 496(1-2): Jang M, Cai L, Udeani G, Slowing KV, Thomas CF, Bleecher CWW, Fong S, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Sci 275(5297): Joe AK, Liu, Suzui M, Vural ME, Xiao D, Weinstein IB Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Cancer Res 8(3): Kaldas MI, Walle UK, Walle T Resveratrol transport and metabolism by human intestinal CaCo-2 cells. J Pharm Pharmacol 55(3): King RE, Kent KD, Bomser JA Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition. Chem Biol Interact 151(2): Kuhnle G, Spencer JPE, Chowrimootoo G, Schroeter, Debnam ES, Srai SKS, Rice-Evans C, ahn U Resveratrol is absorbed in the small intestine as resveratrol glucuronide. Biochem Biophys Res Commun 272(1): Kundu JK, Chun K-S, Kim S, Surh Y-J Resveratrol inhibits phorbol ester-induced cyclooxygenase-2 expression in mouse skin: MAPKs and AP-1 as potential molecular targets. BioFactors 21(1-4):33 9. Kundu JK, Surh Y-J Molecular basis of chemoprevention by resveratrol: NF-κB and AP-1 as potential targets. Mutat Res 555(1-2): Kutuk, Adli M, Poli G, Basaga Resveratrol protects against 4-NE induced oxidative stress and apoptosis in Swiss 3T3 fibroblasts. BioFactors 20(1):1 10. Lançon A, Delmas D, sman, Thénot J-P, Jannin B, Latruffe N uman hepatic cell uptake of resveratrol: involvement of both passive diffusion and carrier-mediated process. Biochem Biophys Res Commun 316(4): Langcake P, Pryce RJ The production of resveratrol by Vitis vinifera and other members of the Vitaceae as a response to infection or injury. Physiol Plant Pathol 9: Lamuela-Raventós RM, Waterhouse AL ccurrence of resveratrol in selected California wines by a new PLC method. J Agri Food Chem 41(4): Larrosa M, Tomás-Barberán FA, Espín JC The grape and wine polyphenol piceatannol is a potent inducer of apoptosis in human SK-Mel-28 melanoma cells. Eur J Nutr 43(5): Lin -Y, Shih A, Davis FB, Tang -Y, Martino LJ, Bennett JA, Davis PJ Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line. J Urol 168(2): Liu ZP, Li WX, Yu B, uang J, Sun J, uo JS, Liu CX Effects of trans-resveratrol from Polygonum cuspidatum on bone loss using the ovariectomized rat model. J Med Food 8(1):14 9. Losa GA Resveratrol modulates apoptosis and oxidation in human blood mononuclear cells. Eur J Clin Invest 33(9): Lu R, Serrero G Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J Cell Physiol 179(3): Manna SK, Mukhopadhyay A, Aggarwal BB Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-κB, Activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 164(12): Martín AR, Villegas I, La Casa C, de la Lastra CA Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats. Biochem Pharmacol 67(7): Mattivi F, Reniero F, Korhammer S Isolation, characterization, and evolution in red vinification of resveratrol monomers. J Agric Food Chem 43(7): Meng X, Maliakal P, Lu, Lee M-J, Yang CS Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J Agric Food Chem 52(4): Mizutani K, Ikeda K, Kawai Y, Yamori Y Resveratrol stimulates the proliferation and differentiation of osteoblastic MC3T3-E1 cells. Biochem Biophy Res Commun 253(3): Mizutani K, Ikeda K, Yamori Y Resveratrol inhibits AGEs-induced proliferation and collagen synthesis activity in vascular smooth muscle cells from stroke-prone spontaneous hypertensive rats. Biochem Biophy Res Commun 274(1):61 7. Murray GI, Taylor MC, McFadyen MC, Mckay JA, Greenlee WF, Burke MD, Melvin MF Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res 57(14): las B, Wachowicz B Resveratrol and vitamin C as antioxidants in blood platelets. Thromb Res 106(2): las B, Wachowicz B, Saluk-Juszczak J, Zieliński T Effect of resveratrol, a natural polyphenolic compound, on platelet activation induced by endotoxin or thrombin. Thromb Res 107(3-4): lson ER, Naugle JE, Zhang X, Bomser JA, Meszaros JG Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol. Am J Physiol eart Cir Physiol 288(3): rallo F, Álvarez E, Camiña M, Leiro JM, Gómez E, Fernández P The possible implication of trans-resveratrol in the cardioprotective effects of long-term moderate wine consumption. Mol Pharmacol 61(2): Pendurthi UR, Williams JT, Rao LVM Resveratrol, a polyphenolic compound found in wine, inhibits tissue factor expression in vascular cells: a possible mechanism for the cardiovascular benefits associated with moderate wine consumption. Arterioscler Thromb Vasc Biol 19(2): Potter GA, Patterson L, Wanogho E, Perry PJ, Butler PC, Ijaz T, Ruparelia KC, Lamb J, Farmer PB, Stanley LA, Burke MD The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYPIBI. Br J Cancer 86: Richard N, Porath D, Radspieler A, Schwager J Effects of resveratrol, piceatannol, triacetoxystilbene, and genistein on the inflammatory response of human peripheral blood leukocytes. Mol Nutr Food Res 49(5): Rolfs C-, Kindl Stilbene synthase and chalcone synthase. Two different constitutive enzymes in cultured cells of Picea exelsa. Plant Physiol 75: Sanders T, McMichael RW, endrix KW ccurrence of resveratrol in edible peanuts. J Agric Food Chem 48(4): Sato M, Suzuki Y, kuda T, Yokotsuka K Contents of resveratrol, piceid, and their isomers in commercially available wines made from grapes cultivated in Japan. Biosci Biotechnol Biochem 61(11): She Q-B, Bode AM, Ma W-Y, Chen N-Y, Dong Z Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res 61(4): Sieman E, Creasy LL Concentration of phytoalexin resveratrol in wine. Am J Enol Vitic 43: Soares DG, Andreazza AC, Salvador M Sequestering ability of butylated hydrooxytoluene, propyl gallate, resveratrol, and vitamin C and E against ABTS, DPP, and hydroxyl free radicals in chemical and biological systems. J Agric Food Chem 51(4): Sobolev VS, Cole RJ trans-resveratrol content in commercial peanuts and peanut products. J Agric Food Chem 47(4): Soleas GJ, Diamandis EP, Goldberg DM Resveratrol: a molecule whose time has come? And gone? Clin Biochem 30(2): Soleas GJ, Goldberg DM Influences of viticultural and oenological factors on changes in cis- and trans-resveratrol in commercial wines. J Wine Res 6(2): Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue, Jang M, Pezzuto JM, Dannenberg AJ Resveratrol inhibits cyclooxgenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Bio Chem 273(34): Surh YJ, urh YJ, Kang J-Y, Lee E, Kong G, Lee SJ Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (L-60) cells. Cancer Lett 140(1-2):1 10. Vitaglione P, Sforza S, Galaverna G, Ghidini C, Caporaso N, Ve4scovi PP, Fogliano V, Marchelli R Bioavailability of trans-resveratrol from red wine in humans. Mol Nutr Food Res 49(5): Walle T, sieh F, DeLegge M, atis JE, Walle UK igh absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 32(12): Wang Z, uang Y, Zou J, Cao K, Xu Y, Wu JM Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. Int J Mol Med 9(1):77 9. Wolter F, Clausnitzer A, Akoglu B, Stein J Piceatannol, a natural analog of resveratrol, inhibits progression through the Sphase of the cell cycle in colorectal cancer cell lines. J Nutr 132(2): Yu R, ebbar V, Kim DW, Mandlekar S, Pezzuto JM, Kong A-NT Resveratrol inhibits phorbol ester and UV-induced activator protein 1 activation by interfering with mitogenactivated protein kinase pathways. Mol Pharmacol 60(1): CMPREENSIVE REVIEWS IN FD SCIENCE AND FD SAFETY Vol. 5, 2006