Resveratrol, <em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several <em>trans</em>cription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. At least some of these activities are mediated through the interaction of phytoestrogens with estrogen receptors alpha and beta (ERalpha and ERbeta). Resveratrol, <em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>, is a phytoestrogen in grapes that is present in red wine. Resveratrol was shown to bind ER in cytosolic extracts from MCF-7 and rat uteri. However, the contribution of ERalpha vs. ERbeta in this binding is unknown. Here we report that resveratrol binds ERbeta and ERalpha with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, resveratrol differs from other phytoestrogens that bind ERbeta with higher affinity than ERalpha. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ERalpha or ERbeta. The estrogen agonist activity of resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ERbeta has higher <em>trans</em>criptional activity than E2-liganded ERbeta at a single palindromic ERE. This indicates that those tissues that uniquely express ERbeta or that express higher levels of ERbeta than ERalpha may be more sensitive to resveratrol's estrogen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, resveratrol shows activity comparable to that induced by E2. We report that resveratrol exhibits E2 antagonist activity for ERalpha with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ERbeta. These data indicate that resveratrol differentially affects the <em>trans</em>criptional activity of ERalpha and ERbeta in an ERE sequence-dependent manner.

OBJECTIVE

Resveratrol (<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is the parent compound of a family of molecules, including glucosides and polymers, existing in cis and <em>trans</em> configurations in a narrow range of spermatophytes of which vines, peanuts and pines are the prime representatives. Its synthesis from p-coumaroyl CoA and malonyl CoA is induced by stress, injury, infection or UV-irradiation, and it is classified as a phytoalexin anti-fungicide conferring disease resistance in the plant kingdom.

RESULTS

In vitro, ex vivo and animal experiments have shown that it possesses many biological attributes that favour protection against atherosclerosis, including antioxidant activity, modulation of hepatic apolipoprotein and lipid synthesis, inhibition of platelet aggregation as well as the production of pro-atherogenic eicosanoids by human platelets and neutrophils. Red wine represents its main source in the human diet, and it has been proposed as a major constituent of the polyphenol fraction to which the health benefits of red wine consumption have been attributed.

CONCLUSIONS

The past several years have witnessed intense research devoted to its measurement in wine and the factors likely to promote its enrichment in this beverage. Up to the present, conclusive evidence for its absorption by human subjectsin biologically significant amounts is lacking, and it is questionable (but not yetexcluded) that its powerful and beneficial in vitro activities are reproduced as a consequence of sustained moderate red wine consumption.

Excessive oxidative stress has been implicated in the pathology and complications of diabetes, which leads to myocardial ischemia reperfusion injury. The present study was designed to examine whether resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), a polyphenolic compound present in red wine has a direct cardioprotective effect on diabetic myocardium. Resveratrol (2.5 mg/kg body wt/day) and L-NAME (25 mg/kg body wt/day) were administered orally for 15 days to streptozotocin (65 mg/kg)-induced diabetic rats. Sprague Dawley rats were divided into 5 groups: (i) control, (ii) diabetic, (iii) diabetic+resveratrol, (iv) diabetic+resveratrol+L-NAME (nitric oxide synthase inhibitor), and (v) diabetic+L-NAME. In our present study resveratrol demonstrated significant reduction in glucose level in diabetic rats. After the treatment, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Resveratrol-treated diabetic rats demonstrated significant reduction in glucose levels as compared to the nontreated diabetic animals, and improved left ventricular function throughout reperfusion compared to the diabetic or L-NAME-treated animals (dp/dt(max) 1457+/-51 vs 999+/-44 mm Hg/s at 120 min reperfusion). Cardioprotection from ischemic injury in resveratrol-treated diabetic rats showed decreased infarct size (42% vs 51%) and cardiomyocyte apoptosis (35% vs 40%) as compared with diabetic animals. Resveratrol produced significant induction of p-AKT, p-eNOS, Trx-1, HO-1, and VEGF in addition to increased activation of MnSOD activity in diabetic animals compared to nondiabetic animals. However treatment with L-NAME in resveratrol-treated and nontreated diabetic animals demonstrated significant downregulation of the above-noted protein expression profile and MnSOD activity. In the present study we found that the mechanism(s) responsible for the cardioprotective effect of resveratrol in the diabetic myocardium include upregulation of Trx-1, NO/HO-1, and VEGF in addition to increased MnSOD activity and reduced blood glucose level. Thus this study shows a novel mechanism of pharmacological preconditioning with resveratrol in the diabetic myocardium.

Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), a polyphenolic compound found in plant products, including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties. Using an animal model of multiple sclerosis (MS), we investigated the use of resveratrol for the treatment of autoimmune diseases. We observed that resveratrol treatment decreased the clinical symptoms and inflammatory responses in experimental allergic encephalomyelitis (EAE)-induced mice. Furthermore, we observed significant apoptosis in inflammatory cells in spinal cord of EAE-induced mice treated with resveratrol compared with the control mice. Resveratrol administration also led to significant down-regulation of certain cytokines and chemokines in EAE-induced mice including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-9, IL-12, IL-17, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), and Eotaxin. In vitro studies on the mechanism of action revealed that resveratrol triggered high levels of apoptosis in activated T cells and to a lesser extent in unactivated T cells. Moreover, resveratrol-induced apoptosis was mediated through activation of aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) and correlated with up-regulation of AhR, Fas, and FasL expression. In addition, resveratrol-induced apoptosis in primary T cells correlated with cleavage of caspase-8, caspase-9, caspase-3, poly(ADP-ribose) polymerase, and release of cytochrome c. Data from the present study demonstrate, for the first time, the ability of resveratrol to trigger apoptosis in activated T cells and its potential use in the treatment of inflammatory and autoimmune diseases including, MS.

<em>trans</em>-<em>3,5,4</em>'-<em>Trihydroxystilbene</em> (<em>trans</em>-resveratrol) is a phytochemical present in peanuts, grapes and wine with beneficial effects such as protection against cardiovascular disease and cancer prevention. The purpose of this study was to evaluate whether high doses of <em>trans</em>-resveratrol have harmful effects on Sprague-Dawley rats. <em>trans</em>-Resveratrol was administered orally to male rats for 28 d at a dose of 20 mg/(kg x d), 1000 times the amount consumed by a 70-kg person taking 1.4 g of <em>trans</em>-resveratrol/d. Body weight, and food and water consumption did not differ between rats treated with <em>trans</em>-resveratrol and the control group. Hematologic and biochemical variables were not affected by the treatment. Histopathologic examination of the organs obtained at autopsy did not reveal any alterations. These results support the view that repeated consumption of <em>trans</em>-resveratrol at 20 mg/(kg x d) does not adversely affect the variables tested in rats.

Inflammatory bowel disease is a chronic, relapsing, and tissue-destructive disease. Resveratrol (3,4,5-trihydroxy-trans-stilbene), a naturally occurring polyphenol that exhibits beneficial pleiotropic health effects, is recognized as one of the most promising natural molecules in the prevention and treatment of chronic inflammatory disease and autoimmune disorders. In the present study, we investigated the effect of resveratrol on dextran sodium sulfate (DSS)-induced colitis in mice and found that it effectively attenuated overall clinical scores as well as various pathological markers of colitis. Resveratrol reversed the colitis-associated decrease in body weight and increased levels of serum amyloid A, tumor necrosis factor-alpha, interleukin (IL-6), and IL-1beta. After resveratrol treatment, the percentage of CD4(+) T cells in mesenteric lymph nodes (MLN) of colitis mice was restored to normal levels, and there was a decrease in these cells in the colon lamina propria (LP). Likewise, the percentages of macrophages in MLN and the LP of mice with colitis were decreased after resveratrol treatment. Resveratrol also suppressed cyclooxygenase-2 (COX-2) expression induced in DSS-exposed mice. Colitis was associated with a decrease in silent mating type information regulation-1 (SIRT1) gene expression and an increase in p-inhibitory kappaB expression and nuclear transcription factor-kappaB (NF-kappaB) activation. Resveratrol treatment of mice with colitis significantly reversed these changes. This study demonstrates for the first time that SIRT1 is involved in colitis, functioning as an inverse regulator of NF-kappaB activation and inflammation. Furthermore, our results indicate that resveratrol may protect against colitis through up-regulation of SIRT1 in immune cells in the colon.

Micro RNAs (miRNAs), small and labile ~22 nucleotide-sized fragments of single stranded RNA, are important regulators of messenger (mRNA) complexity and in shaping the <em>trans</em>criptome of a cell. In this communication, we utilized amyloid beta 42 (Aβ42) peptides and interleukin-1beta (IL-1β) as a combinatorial, physiologically-relevant stress to induce miRNAs in human primary neural (HNG) cells (a co-culture of neurons and astroglia). Specific miRNA up-regulation was monitored using miRNA arrays, Northern micro-dot blots and RT-PCR. Selective NF-кB <em>trans</em>location and DNA binding inhibitors, including the chelator and anti-oxidant pyrollidine dithiocarbamate (PDTC) and the polyphenolic resveratrol analog CAY10512 (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), indicated the NF-кB sensitivity of several brain miRNAs, including miRNA-9, miRNA-125b and miRNA-146a. The inducible miRNA-125b and miRNA-146a, and their verified mRNA targets, including 15-lipoxygenase (15-LOX), synapsin-2 (SYN-2), complement factor H (CFH) and tetraspanin-12 (TSPAN12), suggests complex and highly interactive roles for NF-кB, miRNA-125b and miRNA-146a. These data further indicate that just two NF-кB-mediated miRNAs have tremendous potential to contribute to the regulation of neurotrophic support, synaptogenesis, neuroinflammation, innate immune signaling and amyloidogenesis in stressed primary neural cells of the human brain.

Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is a naturally occurring polyphenol with cancer chemopreventive properties in preclinical models of carcinogenesis, including those of colorectal cancer. Recently, a variety of analogues of resveratrol have been synthesised and investigated in in vitro assays. One analogue, 3,4,5,4'-tetramethoxystilbene (DMU 212), showed preferential growth-inhibitory and proapoptotic properties in <em>trans</em>formed cells, when compared with their un<em>trans</em>formed counterparts. As part of a chemoprevention drug development programme, the pharmacokinetic properties of DMU 212 were compared with those of resveratrol in the plasma, liver, kidney, lung, heart, brain and small intestinal and colonic mucosa of mice. DMU 212 or resveratrol (240 mg kg(-1)) were administered intragastrically, and drug concentrations were measured by HPLC. Metabolites were characterised by cochromatography with authentic reference compounds and were identified by mass spectrometry. The ratios of area of plasma or tissue concentration vs time curves of resveratrol over DMU 212 (AUC(res)/AUC(DMU212)) for the plasma, liver, small intestinal and colonic mucosa were 3.5, 5, 0.1 and 0.15, respectively. Thus, resveratrol afforded significantly higher levels than DMU 212 in the plasma and liver, while DMU 212 exhibited superior availability compared to resveratrol in the small intestine and colon. Resveratrol was metabolised to its sulphate or glucuronate conjugates, while DMU 212 underwent metabolic hydroxylation or single and double O-demethylation. DMU 212 and resveratrol inhibited the growth of human-derived colon cancer cells HCA-7 and HT-29 in vitro with IC(50) values of between 6 and 26 microM. In the light of the superior levels achieved in the gastrointestinal tract after the administration of DMU 212, when compared to resveratrol, the results provide a good rationale to evaluate DMU 212 as a colorectal cancer chemopreventive agent.

Stilbenes are phytochemicals present in grapes, berries, peanuts and red wine. A widely studied stilbene, resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), has been shown to exert antioxidant, anti-inflammatory, chemopreventive and antiaging effects in a number of biological systems. We reported earlier that pterostilbene (<em>trans</em>-3,5-dimethoxy-4'-hydroxystilbene), a structurally related stilbene found in blueberries, was effective in reducing the incidence and multiplicity of aberrant crypt foci formation in the colon of rats injected with azoxymethane (AOM). Our present study was to identify the chemopreventive potential of pterostilbene with colonic tumor formation as an end point and further to evaluate the mechanistic action of pterostilbene during colon carcinogenesis. F344 rats were given two AOM injections subcutaneously when they were 7 and 8 weeks old and continuously fed the control or 40 p.p.m. pterostilbene diet for 45 weeks. Overall analyses indicated that pterostilbene reduced colon tumor multiplicity of non-invasive adenocarcinomas, lowered proliferating cell nuclear antigen and downregulated the expression of beta-catenin and cyclin D1. Pterostilbene decreased mucosal levels of the proinflammatory cytokines, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-4. Colon tumors from pterostilbene-fed animals showed reduced expression of inflammatory markers as well as nuclear staining for phospho-p65, a key molecule in the nuclear factor-kappaB pathway. In HT-29 cells, pterostilbene reduced the protein levels of beta-catenin, cyclin D1 and c-MYC, altered the cellular localization of beta-catenin and inhibited the phosphorylation of p65. Our data with pterostilbene in suppressing colon tumorigenesis, cell proliferation as well as key inflammatory markers in vivo and in vitro suggest the potential use of pterostilbene for colon cancer prevention.

Inhibition of cancer growth by resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.

The content of selected phenolic compounds including resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) and its cis-isomer and glucosides (piceides) were monitored in grape (Vitis vinifera L. cv. Corvina) berry skin during ripening in the vineyard and in response to the post-harvest drying process (wilting). Four wilting conditions were compared (traditional, mixed, low-temperature, and high-temperature) to verify the eliciting effect of drying on resveratrol production. During fruit ripening the cis-piceid was the major stilbene found in berry skins, and a weak accumulation of stilbene synthase (STS) mRNA was observed, whereas UV-light irradiation greatly stimulated STS <em>trans</em>cript of unripe berries. A time-course experiment showed the highest STS mRNA accumulation and resveratrol content (34 microg/g fresh weight at 58 days) occurring in berry skins in a mixed wilting process.

Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), a compound found largely in the skins of red grapes and wines, possesses anti-cancer and anti-angiogenic properties and protects the cardiovascular system. However, the molecular mechanisms by which resveratrol inhibits angiogenesis are currently subjects of intense investigation. The purpose of this study was to examine whether FOXO <em>trans</em>cription factors mediate anti-angiogenic effects of resveratrol, and whether vascular endothelial growth factor (VEGF) neutralizing antibody can enhance these effects of resveratrol. Inhibition of PI3 kinase (PI3K)/AKT and MEK/ERK pathways synergistically inhibited migration and capillary tube formation of Human Umbilical Vein Endothelial Cells (HUVECs) and further enhanced the anti-angiogenic effects of resveratrol. Inhibitors of AKT and MEK kinase synergistically inhibited cytoplasmic FOXO3a phosphorylation, which was accompanied by its nuclear <em>trans</em>location in HUVECs. Interestingly, inhibition of PI3K/AKT and MEK/ERK pathways synergistically induced FOXO <em>trans</em>criptional activity and inhibited cell migration and capillary tube formation. Antiangiogenic effects of resveratrol were enhanced by inhibitors of AKT and MEK. Phosphorylation-deficient mutants of FOXOs induced FOXO <em>trans</em>criptional activity, inhibited HUVEC cell migration, and capillary tube formation, and also enhanced antiangiogenic effects of resveratrol. Finally, VEGF neutralizing antibody enhanced the anti-proliferative and anti-angiogenic effects of resveratrol. In conclusion, regulation of FOXO <em>trans</em>cription factors by resveratrol may play an important role in angiogenesis which is critical for cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, and cardiovascular disorders.

It remains presently unknown whether vascular reactivity is impaired and whether maladaptive cardiac remodeling occurs before the onset of overt obesity and in the absence of hyperlipidemia. Normal female rats were fed a high-fat diet for 8 weeks and were associated with a modest nonsignificant increase of body weight (standard diet, 300 +/- 10, versus high-fat diet, 329 +/- 14 g) and a normal plasma lipid profile. In rats fed a high-fat diet, systolic (171 +/- 7 mm Hg) and diastolic blood pressures (109 +/- 3) were increased compared to a standard diet (systolic blood pressure, 134 +/- 8; diastolic blood pressure, 96 +/- 5 mm Hg), and acetylcholine-dependent relaxation of isolated aortic rings (high-fat diet, 22 +/- 5%, versus standard diet, 53 +/- 8%) was significantly reduced. Furthermore, perivascular fibrosis was detected in the heart of rats fed a high-fat diet. The exogenous addition of resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) (0.1 microM) to aortic rings isolated from rats fed a high-fat diet restored acetylcholine-mediated relaxation (47 +/- 9%). The administration of resveratrol (20 mg/kg/day for 8 weeks) to rats fed a high-fat diet prevented the increase in blood pressure and preserved acetylcholine-dependent relaxation of isolated aortic rings. However, resveratrol therapy failed to attenuate the perivascular fibrotic response. These data have demonstrated that a high-fat diet fed to normal female rats can elicit a hypertensive response and induce perivascular fibrosis before the development of overt obesity and in the absence of hyperlipidemia. Resveratrol therapy can prevent the hypertensive response in female rats fed a high-fat diet but is without effect on the progression of perivascular fibrosis.

Liver ischemia-reperfusion (I/R) injury occurs in many clinical conditions, including liver surgery and <em>trans</em>plantation. Oxygen free radicals generated during I/R reduce endogenous antioxidant systems and contribute to hepatic injury. <em>trans</em>-Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is reported to have antioxidant properties. We investigated the effect of <em>trans</em>-resveratrol on liver injury induced by I/R. After 1 hour of ischemia, administered 5 minutes before 3 hours of reperfusion, <em>trans</em>-resveratrol was hepatoprotective at a low dose (0.02 mg/kg). It significantly decreased amino<em>trans</em>ferase levels by about 40% and improved sinusoidal dilatation. <em>trans</em>-Resveratrol preserved antioxidant defense by preventing total and reduced glutathione depletion caused by I/R. At 0.2 mg/kg, <em>trans</em>-resveratrol significantly increased glutathione reductase, Cu/Zn-superoxide dismutase, and catalase activities. However, at a high dose (20 mg/kg), <em>trans</em>-resveratrol became prooxidant with an aggravation of liver injury evaluated by amino<em>trans</em>ferase release and histological analysis and associated with a depletion of total and reduced glutathione levels and a decrease of antioxidant enzyme activities. In conclusion, a prereperfusion treatment by <em>trans</em>-resveratrol only at low doses decreases liver injury induced by I/R by protecting against antioxidant defense failure. This administration protocol could reduce liver damage during surgery or <em>trans</em>plantation.

<em>trans</em>-Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is a nonflavonoid polyphenol reported to exert different biological activities, among them inhibition of the lipid peroxidation, scavenging of the free radicals, inhibition of the platelet aggregation, and anticancer activity as the most important. In order to enlighten the radical-scavenging mechanism of <em>trans</em>-resveratrol, stationary gamma-radiolytic experiments in liposomes and pulse radiolytic experiments in aqueous solutions were performed. Applying the stationary gamma-radiolysis together with the subsequent product analysis, reactions of lipid peroxyl radicals, LOO*, with <em>trans</em>-resveratrol and other natural antioxidants were investigated. It was found that <em>trans</em>-resveratrol was a better radical scavenger than vitamins E and C but similar to the flavonoids epicatechin and quercetin. The comparison of the radical-scavenging effects of <em>trans</em>-resveratrol and its analogues <em>trans</em>-4-hydroxystilbene and <em>trans</em>-3,5-dihydroxystilbene revealed that <em>trans</em>-resveratrol and <em>trans</em>-4-hydroxystilbene showed almost the same effect and were more efficient than <em>trans</em>-3,5-dihydroxystilbene. These findings indicate greater radical-scavenging activity of <em>trans</em>-resveratrols para-hydroxyl group than its meta-hydroxyl groups. Using the pulse radiolysis, reactions of <em>trans</em>-resveratrol and its analogues with trichloromethylperoxyl radicals, CCl(3)OO*, were studied. Spectral and kinetic properties of the observed <em>trans</em>ients showed great similarity between <em>trans</em>-resveratrol and <em>trans</em>-4-hydroxystilbene which seems to confirm that para-hydroxyl group of <em>trans</em>-resveratrol scavenges free radicals more effectively than its meta-hydroxyl groups.

BACKGROUND

This study was designed to investigate the possible effectiveness of resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) administration on oxidative stress, nuclear factor κB (NF-κB) activity and apoptosis rate in streptozotocin-nicotinamide-induced diabetic retinopathy.

METHODS

Male Wistar rats were divided into four groups: normal control, diabetic control, normal rats treated with resveratrol, and diabetic rats treated with resveratrol. Diabetes was induced by injection of streptozotocin (50 mg/kg; ip), 15 min after the prescription of nicotinamide (110 mg/kg; ip) in 12 h fasted rats.

RESULTS

Four-month oral resveratrol administration (5 mg/kg/day) significantly alleviated hyperglycemia, weight loss, enhancement of oxidative markers (lipid peroxidation index and oxidized to reduced glutathione ratio) and superoxide dismutase activity in both blood and retinas of the diabetic rats. Moreover, resveratrol administration to diabetic rats improved the elevated levels of retinas NF-κB activity and apoptosis rate. On the other hand, four months resveratrol administration prevented from disarrangement and reduction in thickness of retinal layers.

CONCLUSIONS

These beneficial antidiabetic observations suggest that resveratrol may be considered as a therapeutic supplement to prevent from diabetic retinopathy.

Resveratrol (<em>3,5,4</em>'-<em>trans</em>-<em>trihydroxystilbene</em>) is a natural phytoalexin present in grapes and red wine, which possesses a variety of biological activities including antioxidative activity. To find more efficient antioxidants by structural modification, resveratrol analogues, that is, 3,4-dihydroxy-<em>trans</em>-stilbene (3,4-DHS), 4,4'-dihydroxy-<em>trans</em>-stilbene (4,4'-DHS), 4-hydroxy-<em>trans</em>-stilbene (4-HS) and 3,5-dihydroxy-<em>trans</em>-stilbene (3,5-DHS), were synthesized and their antioxidant activity studied for the free radical-induced peroxidation of rat liver microsomes in vitro. The peroxidation was initiated by either a water-soluble azo compound 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH) or Fe(2+)/ascorbate, and monitored by oxygen uptake and formation of thiobarbituric acid reactive substances (TBARS). It was found that all of these <em>trans</em>-stilbene derivatives are effective antioxidants against both AAPH- and iron-induced peroxidation of rat liver microsomes with an activity sequence of 3,4-DHS>4,4'-DHS>resveratrol>4-HS>3,5-DHS. The remarkably higher antioxidant activity of 3,4-DHS is discussed.

This study was aimed at identifying the isoform(s) of human liver cytochrome P450 (CYP) involved in the hepatic bio<em>trans</em>formation of <em>trans</em>-resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>). <em>Trans</em>-resveratrol metabolism was found to yield two major metabolites, piceatannol (3,5,3',4'-tetrahydroxystilbene) and another tetrahydroxystilbene named M1. <em>Trans</em>-resveratrol was hydroxylated to give piceatannol and M1 with apparent K(m) of 21 and 31 microM, respectively. Metabolic rates were in the range 14-101 pmol min(-1) mg(-1) protein for piceatannol and 29-161 pmol min(-1) mg(-1) protein for M1 in the 13 human liver microsomes tested. Using microsomal preparations from different human liver samples, piceatannol and M1 formation significantly correlated with ethoxy-resorufin-O-deethylation (r(2) = 0.84 and 0.88, respectively), phenacetin-O-deethylation (r(2) = 0.92 and 0.94) and immuno-quantified CYP1A2 (r(2) = 0.85 and 0.90). Formation of these metabolites was markedly inhibited by alpha-naphthoflavone and furafylline, two inhibitors of CYP1A2. Antibodies raised against CYP1A2 also inhibited the bio<em>trans</em>formation of <em>trans</em>-resveratrol. In addition, the metabolism of <em>trans</em>-resveratrol into these two metabolites was catalyzed by recombinant human CYP1A1, CYP1A2 and CYP1B1. Our results provide evidence that in human liver, CYP1A2 plays a major role in the metabolism of <em>trans</em>-resveratrol into piceatannol and tetrahydroxystilbene M1.

Abundant neurochemical, neuropathological, and genetic evidence suggests that a critical number of proinflammatory and innate immune system-associated factors are involved in the underlying pathological pathways that drive the sporadic Alzheimer's disease (AD) process. Most recently, a series of epigenetic factors - including a select family of inducible, proinflammatory, NF-κB-regulated small noncoding RNAs called miRNAs - have been shown to be significantly elevated in abundance in AD brain. These upregulated miRNAs appear to be instrumental in reshaping the human brain <em>trans</em>criptome. This reorganization of mRNA speciation and complexity in turn drives proinflammatory and pathogenic gene expression programs. The ensuing, progressively altered immune and inflammatory signaling patterns in AD brain support immunopathogenetic events and proinflammatory features of the AD phenotype. This report will briefly review what is known concerning NF-κB-inducible miRNAs that are significantly upregulated in AD-targeted anatomical regions of degenerating human brain cells and tissues. Quenching of NF-κB-sensitive inflammatory miRNA signaling using NF-κB-inhibitors such as the polyphenolic resveratrol analog <em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em> (CAY10512) may have some therapeutic value in reducing inflammatory neurodegeneration. Antagonism of NF-κB-inducing, and hence proinflammatory, epigenetic and environmental factors, such as the neurotrophic herpes simplex virus-1 and exposure to the potent neurotoxin aluminum, are briefly discussed. Early reports further indicate that miRNA neutralization employing anti-miRNA (antagomir) strategies may hold future promise in the clinical management of this insidious neurological disorder and expanding healthcare concern.

The antioxidant activities of <em>trans</em>-resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) and <em>trans</em>-piceid (<em>trans</em>-5,4'-dihydroxystilbene-3-O-beta-D-glucopyranoside), its more widespread glycosilate derivative, have been compared measuring their inhibitory action on peroxidation of linoleic acid (LA) and the radical scavenging ability towards different free radicals (such as DPPH) and radical initiators. It has been found that the two stilbenes have similar antioxidant capacity, while the comparison with BHT (2,6-di-tert-butyl-4-methylphenol) and alpha-tocopherol (vitamin E, vit. E), taken as reference, points out a slower but prolonged protective action against lipid peroxidation. Furthermore, piceid appears more efficacious than resveratrol as a consequence of the reaction of the latter with its radical form. The DSC profiles of phosphatidylcholine liposomes of various chain lengths, and EPR measurements of spin labelled liposomes demonstrated that the susceptible hydroxyl group of these compounds are located in the lipid region of the bilayer close to the double bonds of polyunsaturated fatty acids, making these stilbenes particularly suitable for the prevention and control of the lipid peroxidation of the membranes.

The phytoalexin resveratrol (<em>trans</em>-<em>3,5,4</em>'-trihydroxy-stilbene), a natural component of resistance to fungal diseases in many plants, is synthesized by the enzyme <em>trihydroxystilbene</em> synthase (stilbene synthase, EC 2.3.1.95), which appears to be deficient or lacking in susceptible plants. Earlier workers isolated a stilbene synthase gene (Vst1) from grapevine (Vitis vinifera L.), which has subsequently been introduced as a <em>trans</em>gene into a range of species to increase resistance of hosts to pathogens to which they were originally susceptible. Papaya (Carica papaya L.) is susceptible to a variety of fungal diseases, including root, stem, and fruit rot caused by the pathogen Phytophthora palmivora. Since resveratrol at 1.0 mM inhibited mycelium growth of P. palmivora in vitro, we hypothesized that papaya resistance to this pathogen might be increased by <em>trans</em>formation with the grapevine stilbene synthase construct pVst1, containing the Vst1 gene and its pathogen-inducible promoter. Multiple <em>trans</em>formed lines were produced, clonally propagated, and evaluated with a leaf disk bioassay and whole plant response to inoculation with P. palmivora. RNA <em>trans</em>cripts of stilbene synthase and resveratrol glycoside were induced in plant lines <em>trans</em>formed with the grapevine pVst1 construct shortly after pathogen inoculation, and the <em>trans</em>formed papaya lines exhibited increased resistance to P. palmivora. The immature <em>trans</em>formed plants appear normal and will be advanced to field trials to evaluate their utility.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of gram-negative bacteria inducing deleterious effects on several organs including the liver and eventually leading to septic shock and death. Endotoxemia-induced hepatotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation inducing DNA, proteins and membrane lipid damages. Resveratrol (<em>trans</em>-<em>3,5,4</em>' <em>trihydroxystilbene</em>) is a phytoalexin polyphenol exhibiting antioxidant and anti-inflammatory properties. In this study, we investigated the effect of subacute pre-treatment with this natural compound on LPS-induced hepatotoxicity in rat. Resveratrol counteracted LPS-induced lipoperoxidation and depletion of antioxidant enzyme activities as superoxide dismutase (SOD) and catalase (CAT) but slightly glutathione peroxidase (GPx) activity. The polyphenol also abrogated LPS-induced liver and plasma nitric oxide (NO) elevation and attenuated endotoxemia-induced hepatic tissue injury. Importantly resveratrol treatment abolished LPS-induced iron sequestration from plasma to liver compartment. Our data suggest that resveratrol is capable of alleviating LPS-induced hepatotoxicity and that its mode of action may involve differential iron compartmentalization via iron shuttling proteins.

Consumption of a high-fat diet (HFD) is correlated with increased oxidative stress and chronic inflammation in many organs. Regulatory T cells (Tregs) are essential negative regulators of inflammation. We hypothesized that resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) could protect against HFD-induced oxidative stress and inflammation. Therefore, we examined the effect of resveratrol on oxidative stress and the relevant peripheral immune-regulating mechanisms in HFD-induced obese (DIO) and diet-resistant mice. C57BL/6 mice were fed a normal diet and an HFD for 13 weeks. Then the experimental group was subdivided into DIO and diet-resistant groups according to their body weights, which were further supplemented with 0.03% resveratrol and 0.06% resveratrol, respectively, for an additional 13 weeks. Resveratrol prevented the accumulation of chronic oxidative stress and suppression of Tregs production in HFD mice, modulated changes of cytokines in the plasma and spleen, and decreased expressions of inflammatory mediators compared with those of the DIO group. Our results indicate that resveratrol, as a feasible effective supplement for HFD, can relieve oxidative stress, inhibit inflammatory genes expression, and increase Tregs number via aryl hydrocarbon receptor activation inhibited by HFD, especially in DIO mice.