"Bioactive compounds" are extranutritional constituents that typically occur in small quantities in foods. They are being intensively studied to evaluate their effects on health. The impetus sparking this scientific inquiry was the result of many epidemiologic studies that have shown protective effects of plant-based diets on cardiovascular disease (CVD) and cancer. Many bioactive compounds have been discovered. These compounds vary widely in chemical structure and function and are grouped accordingly. Phenolic compounds, including their subcategory, flavonoids, are present in all plants and have been studied extensively in cereals, legumes, nuts, olive oil, vegetables, fruits, tea, and red wine. Many phenolic compounds have antioxidant properties, and some studies have demonstrated favorable effects on thrombosis and tumorogenesis and promotion Although some epidemiologic studies have reported protective associations between flavonoids or other phenolics and CVD and cancer, other studies have not found these associations.

Various phytoestrogens are present in soy, but also in flaxseed oil, whole grains, fruits, and vegetables. They have antioxidant properties, and some studies demonstrated favorable effects on other CVD risk factors, and in animal and cell culture models of cancer. However, because phytoestrogens act both as partial estrogen agonists and antagonists, their effects on cancer are likely complex. Hydroxytyrosol, one of many phenolics in olives and olive oil, is a potent antioxidant. Resveratrol, found in nuts and red wine, has antioxidant, antithrombotic, and anti-inflammatory properties, and inhibits carcinogenesis. Lycopene, a potent antioxidant carotenoid in tomatoes and other fruits, is thought to protect against prostate and other cancers, and inhibits tumor cell growth in animals. Organosulfur compounds in garlic and onions, isothiocyanates in cruciferous vegetables, and monoterpenes in citrus fruits, cherries, and herbs have anticarcinogenic actions in experimental models, as well as cardioprotective effects. In summary, numerous bioactive compounds appear to have beneficial health effects. Much scientific research needs to be conducted before we can begin to make science-based dietary recommendations. Despite this, there is sufficient evidence to recommend consuming food sources rich in bioactive compounds. From a practical perspective, this translates to recommending a diet rich in a variety of fruits, vegetables, whole grains, legumes, oils, and nuts.

Grapes and wines are now known to constitute a rich source of phenolics such as stilbenes and flavonoids. These compounds have been shown to have cancer chemopreventive activity and potential beneficial effects on cardiovascular diseases thanks to their antioxidant and antiplatelet properties. However, because little is known about African wines and their phenolic compositions, we investigated wine samples from North Africa.

A three-step method was used for the fractionation of the Merlot variety wine: column chromatography followed by centrifugal partition chromatography and reversed-phase semipreparative high-performance liquid chromatography (HPLC). Six polyphenolic compounds of the Merlot variety (from Algeria) were isolated and identified by NMR spectroscopy, five of which are known (trans-resveratrol, trans-piceid,trans-epsilon-viniferin, pallidol, and astilbin) and one that is reported for the first time in wine, (+)-hopeaphenol, a stilbene tetramer. Furthermore, these molecules were quantified in 10 commercial wines from North Africa by means of an analytical HPLC system coupled with diode array detection. Differences in concentrations were found ranging in mg/L from 4.6 to 45 (trans-piceid), 0.66 to 3.45 (trans-resveratrol), 0.2 to 1.2 (trans-epsilon-viniferin), 0.2 to 9.2 (pallidol), 0.3 to 3.8 (hopeaphenol), and 10.8 to 24.22 (astilbin). Such a high level of pallidol and astilbin has never been recorded in wine. North African wines may contribute to a significant proportion of dietary intake of stilbene and astilbin, which may have health benefits.

BACKGROUND AND AIMS: Gene-environment interaction is behind the pathogenesis of most widespread diseases, and nutrition is among the environmental factors with the highest impact on human health. The mechanisms involved in the interaction between nutritional factors and the genetic background of individuals are still unclear. The aim of this study was to investigate whether resveratrol (RES), an antioxidant polyphenol of red wine, can influence the activity of PPARalpha in the rat hepatoma cell line McArdle-RH7777. PPARalpha is a transcriptional factor that regulates gene expression when activated by endogenous or exogenous long-chain fatty acids. Its activation results in significant protection from cardiovascular diseases in humans.

METHODS AND RESULTS: By means of the electromobility shift assay (EMSA), we observed that PPARalpha is redox-sensitive as it displays reduced DNA-binding activity following in vivo treatment of the cells with 1mmol/L diethylmaleate (DEM), a glutathione-depleting agent. This finding could be relevant considering the important role of redox balance in pathological and physiological processes. We also observed a dual effect of 100mumol/L RES on PPARalpha activity: it was able to prevent, to a large extent, the DEM-induced reduction of DNA-binding activity at earlier time points, when the effect of DEM was stronger, but it depressed PPARalpha activity at later time points, when the effect of DEM was greatly reduced.

CONCLUSION: A nutritional substance, such as RES, is able to influence the activity of gene-regulating factors, but the net effect is difficult to predict when the compound involved has multiple biological properties. Caution is therefore warranted before drawing conclusions about the potential benefits of RES for human health.

Chronic ethanol ingestion is known to cause oxidative damage to a number of organs including the brain. This is partly due to the ability of ethanol to enhance oxygen free radical production and lipid peroxidation. Increase in oxidative stress has been regarded as an important underlying factor for a number of human health problems including cardiovascular diseases, aging, as well as many age-related neurodegenerative diseases. The strikingly low incidences of coronary heart diseases (CHD) in France, despite intake of a high-fat diet, have been attributed to the consumption of red wine containing high levels of polyphenolic compounds.

In recent years, understanding the "French Paradox" has stimulated new research interest to investigate whether polyphenolic antioxidants may offer protective effects beyond the cardiovascular system, and whether polyphenols from other botanical sources may similarly offer beneficial effects to human health. Our studies with animal models have provided information clearly indicating the ability of grape polyphenols to ameliorate neuronal damages due to chronic ethanol consumption. Studies with resveratrol, an important component of grape polyphenols, also show protective effects on neuron cell death induced by ethanol and other oxidative agents. These studies demonstrate an urgent need to extend research beyond the "French Paradox" towards better understanding molecular mechanisms of action of polyphenolic compounds and their application to human health.

Plant phenolics present in fruit and vegetables, and that are particularly rich in red wine, have received considerable attention because of their potential antioxidant activity. Human consumption of antioxidants has many alleged health benefits, including protection against cardiovascular diseases, and, most recently, cancer. Red wines contain a variety of polyphenolic antioxidants. Five samples of commercial red wines from Spain and four phenolic compounds of red wine: gallic acid, trans-resveratrol, quercetin and rutin, have been studied.

The total phenolics content and the total antioxidant activity (TAA) of wines was determined. The total phenolic content, determined according to the Folin-Ciocalteu method, varied from 1800 to 2300 mg/L, expressed as gallic acid equivalents (GAE). The antioxidative effects of wine phenolics were determined using a system based on the inhibition by antioxidants of the absorbance of the radical cation. The relationship between antioxidant activity of phenolic comounds, as hydrogen donating free radical scavengers, and their chemical structures was studied. Furthermore, the total antioxidant activity of the wines investigated was well correlated with phenol content. Thus, the results confirm that red wine polyphenols are, in vitro, significant antioxidants.

trans-Resveratrol was reported to have health benefits including anticarcinogenic effects and protection against cardiovascular disease. One of the mechanisms by which it exerts its action is through modulating the estrogen response systems. Because estrogen is involved in male reproductive biology, we investigated the effect of trans-resveratrol on testis and spermatogenesis. Adult male rats were divided into 2 groups. The treated group was administered by gavage 20 mg/(kg .d) of trans-resveratrol suspended in 10 g/L of carboxymethylcellulose for 90 d, whereas the control group received only carboxymethylcellulose during the same period. The relative weight of testes did not differ between the groups.

However, the diameter of the seminiferous tubules was significantly reduced from 437.5 +/- 0.1 mum in the controls to 310.9 +/- 0.1 mum in the resveratrol-treated rats. This decrease was accompanied by a significant increase in tubular density, from 3.20 +/- 0.18 in controls to 6.58 +/- 0.18 tubules/mm(2) in the treated group. Moreover, sperm counts were significantly greater in the resveratrol-treated rats (24.8 +/- 3.30 x 10(7)) than in the control group (14.1 +/- 0.80 x 10(7)), but sperm quality did not differ. Serum concentrations of gonadotrophins and testosterone were significantly higher in the resveratrol-treated group. We identified a novel activity of trans-resveratrol. The daily oral administration of this phytochemical to adult male rats enhanced sperm production by stimulating the hypothalamic-pituitary-gonadal axis, without inducing adverse effects.

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a common phytoalexin that is found in a few edible materials, such as grape skins, peanuts, and red wine. It has been speculated that dietary resveratrol may act as an antioxidant, promote nitric oxide production, inhibit platelet aggregation, and increase high-density lipoprotein cholesterol, and thereby serve as a cardioprotective agent. Based on epidemiological data, carcinogenesis and coronary heart disease are linked to dietary lifestyle and share a number of common pathways.

Recently, it has been demonstrated that resveratrol can function as a cancer chemopreventive agent, and there has been a great deal of experimental effort directed toward defining this effect. Resveratrol has been reported to be estrogenic in transfected mammary cancer cells; however, there are conflicting results with respect to its actual estrogenic properties. In addition, resveratrol exhibits antiinflammatory, neuroprotective, and antiviral properties. In future work, some controversial in vitro biological effects need to be explored in animal models, and relevant physiological and pharmacological concentrations need to be used when assessing biological activities. This review focuses on various biological aspects of resveratrol and some issues that need to be addressed to gain a fuller appreciation of potential health benefits for human beings.

Resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, has shown to possess chemopreventive properties against several cancers, and cardiovascular diseases. Recently, resveratrol has been shown to have positive effects on age longevity, lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by up-regulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4 and TRAIL-R2/DR5 and simultaneously down-regulating the expression of Bcl-2, Bcl-XL, Mcl-1 and survivin. Resveratrol causes growth arrest at G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-kappaB activity.

Modulation of cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression. There is growing evidence that resveratrol can prevent or delay the onset of various cancers, heart diseases, ischemic and chemically induced injuries, pathological inflammation and viral infections. This review summarizes the molecular mechanisms of resveratrol and its clinical benefits for human diseases.

The last couple of decades have seen a tremendous increase in interest in the biological properties of natural products as a means to identify novel small compounds that could have potential in clinical medicine. To that end, flavonoids- and flavonoid-like compounds percolate to the top due to their presence in diet constituents and reported beneficial effects on diverse biological processes and disease conditions. As such, the plant polyphenolic antibiotic resveratrol, found in grapes, nuts and wines, has been the focus of many studies aimed at understanding its full range of health beneficial effects.

The interest in this compound stems from the earlier observations describing the therapeutic benefits of roots of the oriental medicinal plant from which resveratrol was first isolated. Being a constituent of grapes and wines, the initial work was focused on linking resveratrol to the beneficial cardiovascular effects of moderate wine intake, however, since its reported cancer chemopreventive activity in a murine model of carcinogenesis, there has been a heightened interest in understanding the anti-cancer activity of resveratrol. As a result, a substantial amount of data strongly suggests that resveratrol could affect the process of carcinogenesis through a variety of different mechanisms in different tumor cell types. However, a couple of recent reports provide evidence to the contrary. This critical review attempts to summarize some of these findings and discuss the clinical potential of this compound or its derivatives in the light of the recent conflicting reports.

Osteoporosis is a major public health problem and the most obvious preventive strategy, hormone replacement therapy, has lost favor due to recent findings of the Women's Health Initiative regarding increased risks of breast cancer and cardiovascular disease. Resveratrol, a naturally occurring compound possessing estrogenic activity, is thought to have considerable potential for therapy of osteoporosis. In the present study, resveratrol was found to exhibit bone-protective effects equivalent to those exerted by hormone replacement therapy and decrease the risk of breast cancer in the in vivo and in vitro models.

Forkhead proteins were found to be essential for both effects of resveratrol. The bone-protective effect was attributable to induction of bone morphogenetic protein-2 through Src kinase-dependent estrogen receptor activation and FOXA1 is required for resveratrol-induced estrogen receptor-dependent bone morphogenetic protein-2 expression. The tumor-suppressive effects of resveratrol were the consequence of Akt inactivation-mediated FOXO3a nuclear accumulation and activation. Resveratrol is therefore anticipated to be highly effective in management of postmenopausal osteoporosis without an increased risk of breast cancer.

Resveratrol has been associated with reduced cardiovascular disease and reduced cancer risk. This phytoalexin has been reported in a number of plant species, including grapes, and may be one of the compounds responsible for the health benefits of red wine. Analytical methods for measuring resveratrol in wine and peanuts were adapted to isolate, identify, and quantify resveratrol in several cultivars of peanuts. Aqueous ethanol (80% v/v) extracts from peanuts without seed coats were purified over alumina/silica gel columns and analyzed by reversed phase HPLC using a C-18 column.

Peanuts from each market type, Virginia, runner, and Spanish, produced in four different locations contained from 0.03 to 0.14 microg of resveratrol/g. Seed coats from runner and Virginia types contained approximately 0.65 microg/g of seed coat, which is equivalent to <0.04 microg/seed. Quantitative analysis of 15 cultivars representing 3 peanut market types, which had been cold stored for up to 3 years, indicated a range of 0.02-1.79 microg/g of peanut compared to 0.6-8.0 microg/mL in red wines.

Resveratrol, a natural polyphenol, has a variety of effects including protection against ischemia-reperfusion injury, and antitumor and chemopreventive action against malignant tumors. In recent years, resveratrol has been found to exert pro-and anti-angiogenic effects, depending on the situation. For example, pro-angiogenic effects are noted in the peri-infarct myocardium, whereas resveratrol inhibits angiogenesis in tumors. In this article, a review of the literature concerning both pro-angiogenic and anti-angiogenic effects of resveratrol and the underlying mechanisms of its effects on angiogenesis is presented.

Resveratrol (3,4',5 tri-hydroxystilbene) is a phytoalexin produced in hudge amount in grapevine skin in response to infection by Bothrytis cinerea. This production of resveratrol blocks the proliferation of the pathogen, thereby acting as a natural antibiotic. Numerous studies have reported interesting properties of trans-resveratrol as a preventive agent against important pathologies i.e. vascular diseases, cancers, viral infection or neurodegenerative processes. Moreover, several epidemiological studies have revealed that resveratrol is probably one of the main microcomponents of wine responsible for its health benefits such as prevention of vaso-coronary diseases and cancer.

Resveratrol acts on the process of carcinogenesis by affecting the three phases: tumor initiation, promotion and progression phases and suppresses the final steps of carcinogenesis, i.e. angiogenesis and metastasis. It is also able to activate apoptosis, to arrest the cell cycle or to inhibit kinase pathways. Interestingly, resveratrol does not present any cytotoxicity in animal models. Moreover, concentrations of resveratrol in blood seem to be sufficient for anti-invasive activity. The enterohepatic recirculation may contribute to a delayed elimination of the drug from the body and bring about a prolonged effect. By its binding to plasmatic proteins, resveratrol also exhibits a prolonged effect. Interestingly, low doses of resveratrol can sensitize to low doses of cytotoxic drugs and so provide an innovative strategy to enhance the efficacy of anticancer therapy in various human cancers. By these properties, resveratrol appears to be a good candidate in chemopreventive or chemotherapeutic strategies and is believed to be a novel weapon for new therapeutic strategies.

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

Low alcohol consumption seems to decrease total mortality and to have beneficial properties on cardiovascular disease; data for cancer are still inconclusive. There is evidence that wine consumption decreases the risk of cancer at several sites, including cancer of upper digestive tract, lung, colon, basal cell carcinoma, and non-Hodgkin lymphoma. The presence of resveratrol, a polyphenol specifically present in red wine, may contribute to these cancer preventive effects. Resveratrol in fact inhibits the metabolic activation of carcinogens, has antioxidant and anti-inflammatory properties, decreases cell proliferation and induces apoptosis. Data on the availability of resveratrol in vivo are however still lacking. Although regular consumption of one or two glasses of wine seems reasonably safe from the health point of view, a recommendation to the general population for low wine consumption is not justified.

Resveratrol (trans-3,4',5-trihydroxystilbene), a natural polyphenolic, non-flavonoid antioxidant, is a phytoalexin found in many plants including grapes, nuts and berries. Recent studies have documented that resveratrol has various health benefits, such as cardiovascular and cancer preventive properties. However, the experimental basis for such health benefit is not fully understood. One of the possible mechanisms for its protective activities is by down regulation of the inflammatory responses. That includes the inhibition of synthesis and release of pro-inflammatory mediators, modifications of eicosanoid synthesis, inhibition of some activated immune cells, or inhibiting the enzymes, such as cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2), which are responsible for the synthesis of pro-inflammatory mediators through the inhibitory effect of resveratrol on transcription factors like nuclear factor kappaB (NFkappaB) or activator protein-1 (AP-1). Being a phenolic compound, resveratrol certainly possesses a low bioavailability and most importantly, a rapid clearance from the plasma. Recent growing interest in varying protective nature of resveratrol may clinically also hold a respectable position as a better alternative for anti-inflammatory drugs. The purpose of this review is to provide evidence that resveratrol exhibits potent anti-inflammatory activity and also to explain the underling mechanism for both resveratrol- induced cardioprotective and anti-inflammatory properties. While it is true that the cardioprotective properties of resveratrol are likely attributable, at least in part, to its anti-inflammatory properties, the mechanisms discussed address foremost mechanisms for the anti-inflammatory activity which, in turn, is responsible for cardioprotection.

Resveratrol, which is present in grapes, wine and peanuts, is believed to possess chemoprotective properties such as anticarcinogenic effects and to provide protection against cardiovascular diseases. Little is known, however, about its intestinal absorption. We investigated the absorption and metabolism of resveratrol by using an isolated preparation of luminally and vascularly perfused rat small intestine. A synthetic perfusate free from blood components was used as vascular medium with a perfluorocarbon as oxygen carrier. Luminal media consisted of a bicarbonate buffered sodium chloride solution spiked with resveratrol in physiological, nutritionally relevant concentrations (28, 34 and 57 micromol/l, respectively). Viability was maintained during the entire perfusion and no significant differences between resveratrol and control perfusions for oxygen consumption, arterial pressure, lactate-pyruvate ratio and acid-base homeostasis were observed. Vascular uptake of luminally administered resveratrol was 20.5%.

The majority of the absorbed resveratrol was conjugated to yield resveratrol glucuronide (16.8%), which was also the main luminal metabolite (11.2%). Lesser amounts of resveratrol sulfate, 3.0% and 0.3%, were found on the luminal and vascular side, respectively, while only minute amounts of resveratrol and resveratrol conjugates (1.9%) were found in the intestinal tissue. The structures of the resveratrol conjugates were verified by liquid chromatography coupled with mass spectometry (LC-MS). The results demonstrate an ample uptake and metabolic conversion of resveratrol. The proposed perfusion model serves as a tool to evaluate intestinal absorption and metabolic handling of phytochemicals, a pertinent input to the ongoing discussion about their health benefits.

Resveratrol (3,4',5-trihydroxy-trans-stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that at low doses (such as consumed in the common diet) resveratrol may have cardioprotective activity. In this article we describe recent in vitro and in vivo studies in animal models. The results of these studies suggest that resveratrol modulates vascular cell function, inhibits LDL oxidation, suppresses platelet aggregation and reduces myocardial damage during ischemia-reperfusion. Although the reported biological data indicate that resveratrol is a highly promising cardiovascular protective agent, more studies are needed to establish its bioavailability and in vivo cardioprotective effects, particularly in humans.

The phytoantitoxin resveratrol is a plant-derived polyphenol with phytoestrogenic properties. Resveratrol protects the cardiovascular system by mechanisms that include defense against ischemic-reperfusion injury, promotion of vasorelaxation, protection and maintenance of intact endothelium, anti-atherosclerotic properties, inhibition of low-density lipoprotein oxidation, suppression of platelet aggregation, and estrogen-like actions. The purpose of this article is to review the mechanisms of these effects.

Phytoantitoxin resveratrol, which belongs to polyphenol, is a kind of phytoestrogen, and protects the cardiovascular system against ischemic-reperfusion injury and promotion of vasorelaxation, protects and maintains the intact endothelium, exhibits antiatherosclerotic properties inhibits the LDL oxidation, suppress the platelet aggregation and exhibits estrogen like action. The purpose of this article is to review the mechanisms of about mentioned effects. (Ref. 30.).

Cardiovascular diseases are the leading cause of death in developed countries where the common pathological substrate underlying this process is atherosclerosis. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of the vascular diseases and associated inflammatory effects. Recently, potential antioxidants (vitamin E, polyphenols) have received much attention as potential anti-atherosclerotic agents. Among the polyphenols with health benefic properties, resveratrol, a phytoalexin of grape, seem to be a good candidate protecting the vascular walls from oxidation, inflammation, platelet aggregation, and thrombus formation. In this review, we focus on the mechanism of resveratrol cardiovascular benefic effects.

We analyze, in relation with the different steps of atherosclerotic process, the resveratrol properties at multiple levels, such as cellular signaling, enzymatic pathways, apoptosis, and gene expression. We show and discuss the relationship with reactive oxygen species, regulation of pro-inflammatory genes including cycloxygenases and cytokines in molecular inflammatory and aging processes, and how the regulation of these activites by resveratrol can lead to a prevention of vascular diseases.

Cardiovascular diseases are the leading cause of death in developed countries where the common pathological substrate underlying this process is atherosclerosis. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of the vascular diseases and associated inflammatory effects. Recently, potential antioxidants (vitamin E, polyphenols) have received much attention as potential anti-atherosclerotic agents. Among the polyphenols with health benefic properties, resveratrol, a phytoalexin of grape, seem to be a good candidate protecting the vascular walls from oxidation, inflammation, platelet aggregation, and thrombus formation. In this review, we focus on the mechanism of resveratrol cardiovascular benefic effects.

We analyze, in relation with the different steps of atherosclerotic process, the resveratrol properties at multiple levels, such as cellular signaling, enzymatic pathways, apoptosis, and gene expression. We show and discuss the relationship with reactive oxygen species, regulation of pro-inflammatory genes including cycloxygenases and cytokines in molecular inflammatory and aging processes, and how the regulation of these activities by resveratrol can lead to a prevention of vascular diseases.

Hypercholesterolemia (HC) is a common health problem that significantly increases risk of cardiovascular disease. Both statin (S) and resveratrol (R) demonstrated cardioprotection through nitric oxide-dependent mechanism. Therefore, the present study was undertaken to determine whether combination therapy with statin and resveratrol is more cardioprotective than individual treatment groups in ischemic rat heart model. The rats were fed with 2% high cholesterol diet and after 8 weeks of high cholesterol diet the animals were treated with statin (1 mg/kg bw/day) and resveratrol (20 mg/kg bw/day) for 2 weeks. The rats were assigned to: (1) Control (C), (2) HC, (3) HCR, (4) HCS and (5) HCRS. The hearts, subjected to 30-min global ischemia followed by 120-min reperfusion were used as experimental model. The left ventricular functional recovery (+dp/dt(max)) was found to be significantly better in the HCRS (1926+/-43), HCR (1556+/-65) and HCS (1635+/-40) compared to HC group (1127+/-16). The infarct sizes in the HCRS, HCS and HCR groups were 37+/-3.6, 43+/-3.3 and 44+/-4.2 respectively compared to 53+/-4.6 in HC.

The lipid level was found to be decreased in all the treatment groups when compared to HC more significantly in HCS and HCRS groups when compared to HCR. Increased phosphorylation of Akt and eNOS was also observed in all the treatment groups resulting in decreased extent of cardiomyocyte apoptosis but the extent of reduction in apoptosis was more significant in HCRS group compared to all other groups. In vivo rat myocardial infarction (MI) model subjected to 1 week of permanent left descending coronary artery (LAD) occlusion documented increased capillary density in HCR and HCRS treated group when compared to HCS treatment group. We also documented increased beta-catenin translocation and increased VEGF mRNA expression in all treatment groups. Thus, we conclude that the acute as well as chronic protection afforded by combination treatment with statin and resveratrol may be due to pro-angiogenic, anti-hyperlipidemic and anti-apoptotic effects and long-term effects may be caused by increased neo-vascularization of the MI zone leading to less ventricular remodeling.

Prevention of cardiovascular disease through nutritional supplements is growing in popularity throughout the world. Multiple epidemiologic studies found that moderate consumption of alcohol, particularly red wine, lowers mortality rates from coronary heart diseases (CHD). Chronic inflammation and atherosclerosis associated with CHD culminate in aberrant intravascular expression of tissue factor (TF), which triggers blood coagulation leading to thrombosis, a major cause for heart attack. We showed earlier that two red wine phenolics, resveratrol and quercetin, suppressed TF induction in endothelial cells. In the present study, we investigated efficacy of seven resveratrol derivatives, which were shown to be effective in regulating cancer cell growth in vitro at much lower concentrations than the parent compound resveratrol, in inhibiting TF induction in peripheral blood mononuclear cells (PBMCs).

We also tested possible synergistic effects of resveratrol and quercetin with the other major red wine phenolics in suppression of lipopolysaccharide-induced TF expression in human PBMCs. We found that several resveratrol derivatives were 2- to 10-fold more efficient than resveratrol in inhibiting TF induction. Our study found no evidence for synergism among red wine polyphenolics. These data suggest that structural alterations of resveratrol can be effective in producing potent antithrombotic agents that will have therapeutic potential in the improvement of cardiovascular health and prevention of CHD. Among major red wine phenolics, quercetin appears to be the predominant suppressor of TF induction.

Epidemiological studies demonstrated that even in the absence of other risk factors (e.g. diabetes, hypertension, hyperhomocysteinemia, hypercholesterolemia), advanced age itself significantly increases cardiovascular morbidity by enhancing vascular oxidative stress and inflammation. Because the population in the Western world is rapidly aging, there is a substantial need for pharmacological interventions that delay the functional decline of the cardiovascular system.

Resveratrol is an atoxic phytoestrogen found in more than 70 plants including grapevine and berries. Recent data suggest that nutritional intake of resveratrol and other polyphenol compounds may contribute to the "French paradox", the unexpectedly low cardiovascular morbidity in the Mediterranean population. There is increasing evidence that resveratrol exerts multifaceted anti-oxidant and/or anti-inflammatory effects in various disease models. Importantly, resveratrol was reported to slow aging and increase lifespan in simple organisms and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to activate NAD-dependent histone deacetylases (sirtuins), which may contribute to its anti-aging effects. This review focuses on the role of oxidative stress and inflammation in cardiovascular dysfunction in aging, and on emerging anti-aging therapeutic strategies offered by resveratrol and other polyphenol compounds.

Resveratrol, (3,5,4'-trihydoxystilbene) a compound found in grapes, mulberries, and peanuts, has antimycotic, antiviral, and beneficial cardiovascular and cancer preventive activities. It is being developed for several clinical indications. To evaluate the potential toxicity of resveratrol, rats were administered by gavage 0, 300, 1000, and 3000 mg trans-resveratrol per kilogram body weight per day for 4 weeks. Most of the adverse events occurred in the rats administered 3000 mg per kilogram body weight per day. These included increased clinical signs of toxicity; reduced final body weights and food consumption; elevated BUN, creatinine, alkaline phosphatase, alanine aminotransferase, total bilirubin, and albumin; reduced hemoglobin, hematocrit, and red cell counts; and increased white cell counts. Increases in kidney weights and clinically significant renal lesions, including an increased incidence and severity of nephropathy, were observed.

Diffuse epithelial hyperplasia in the bladder was considered, equivocal and of limited biological significance. No histological effects on the liver were observed, despite the clinical chemistry changes and increased liver weights in the females. Effects seen in the group administered 1000 mg resveratrol per kilogram body weight per day included reduced body weight gain (females only) and elevated white blood cell count (males only). Plasma resveratrol concentrations in blood collected 1 h after dose administration during week 4 were dose related but were relatively low given the high dosage levels; conjugates were not measured. Under the conditions of this study, the no observed adverse effect level was 300 mg resveratrol per kilogram body weight per day in rats.

Trans-3,5,4'-Trihydroxystilbene (trans-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 trans-resveratrol have harmful effects on Sprague-Dawley rats. trans-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 trans-resveratrol/d. Body weight, and food and water consumption did not differ between rats treated with trans-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 trans-resveratrol at 20 mg/(kg x d) does not adversely affect the variables tested in rats.