Ethanol and oxidative mechanisms in the brain

There is strong evidence showing that chronic and excessive ethanol consumption may enhance oxidative damage to neurons and result in cell death. Although not yet well understood, ethanol may enhance ROS production in brain through a number of pathways including increased generation of hydroxyethyl radicals, induction of CYP2E1, alteration of the cytokine signaling pathways for induction of iNOS and sPLA(2), and production of prostanoids through the PLA(2)/COX pathways. Since many neurodegenerative diseases are also associated with oxidative and inflammatory mechanisms in the brain, it would be important to find out whether chronic and excessive ethanol consumption may exacerbate the progression of these diseases. There is evidence that the polyphenolic antioxidants, especially those extracted from grape skin and seed, may protect the brain from neuronal damage due to chronic ethanol administration. Among the polyphenols from grapes, resveratrol seems to have unique antioxidant properties. The possible use of this compound as a therapeutic agent to ameliorate neurodegenerative processes should be further explored.     

Potential of phenolic compounds from pomegranate (Punica granatum L.) by-product with significant antioxidant and therapeutic effects: A narrative review

The wealth of epidemiological evidence in the scientific world underscores the possibility that a plant-based diet can reduce the prevalence of common diseases such as diabetes, cardiovascular disease, cancer, and stroke. The therapeutic effects of plant sources are partly explained by phenolic secondary metabolites or polyphenolic compounds. Therefore, polyphenolic compounds, which are widely distributed in plants, are of great interest for the development of effective specific drugs with antioxidant and anti-inflammatory effects. Moreover, polyphenol compounds have no harmful effects due to their natural biocompatibility and safety. Numerous studies have highlighted the potential of some industrial food wastes from plant material processing, including apple peels and mashed potatoes, grape skins, tomato and carrot peels, pomegranate peels and seeds, and many others. These byproducts are considered low-cost sources of natural biological compounds, including antioxidants, which have beneficial effects on human health.The polyphenol complex of pomegranate peel (Punica granatum L.), which makes up half of the pomegranate fruit, has more pronounced antioxidant and anti-inflammatory properties than other parts. And the most important active components of pomegranate peel, which are found only in this plant, are punicalagin, followed by ellagic acid and gallic acid. It is known that these polyphenolic compounds of pomegranate peel have the most pronounced therapeutic effect. Several studies have shown the protective effect of ellagic acid, punicalagin, against oxidative stress damage caused by free radicals. The potential of pomegranate peel as an antioxidant and therapeutic component in various biological systems is high, according to scientific sources.However, despite extensive research in recent years, a review of sources has shown that there is insufficient evidence to support the therapeutic effects of polyphenolic compounds from pomegranate peels. The role of pomegranate peel polyphenolic compounds, including flavonoids, as antioxidants in various biological systems also requires further research. Of particular importance are the mechanisms by which antioxidants influence the cellular response against oxidative stress. The purpose of this review was to report our current knowledge of plant polyphenolic compounds and their classification, and to evaluate the potential of phenolic compounds from pomegranate peels with significant antioxidant and therapeutic effects.     

Renal damage mediated by oxidative stress: a hypothesis of protective effects of red wine

Over the last decade, oxidative stress has been implicated in the pathogenesis of a wide variety of seemingly unrelated renal diseases. Epidemiological studies have documented an association of moderate wine consumption with a decreased risk of cardiovascular and neurological diseases; however, similar studies in the kidney are still lacking. The kidney is an organ highly vulnerable to damage caused by reactive oxygen species (ROS), likely due to the abundance of polyunsaturated fatty acids in the composition of renal lipids. ROS are involved in the pathogenic mechanism of conditions such as glomerulosclerosis and tubulointerstitial fibrosis. The health benefits of moderate consumption of red wine can be partly attributed to its antioxidant properties. Indeed, the kidney antioxidant defense system is enhanced after chronic exposure to moderate amounts of wine, a response arising from the combined effects of ethanol and the nonalcoholic components, mainly polyphenols. Polyphenols behave as potent ROS scavengers and metal chelators; ethanol, in turn, modulates the activity of antioxidant enzymes. Therefore, a hypothesis that red wine causes a decreased vulnerability of the kidney to the oxidative challenges could be proposed. This view is partly supported by direct evidences indicating that wine and antioxidants isolated from red wine, as well as other antioxidants, significantly attenuate or prevent the oxidative damage to the kidney. The present hypothesis paper provides a collective body of evidence suggesting a protective role of moderate wine consumption against the production and progression of renal diseases, based on the existing concepts on the pathophysiology of kidney injury mediated by oxidative stress.     

Malvidin,a red wine polyphenol,modulates mammalian myocardial and coronary performance and protects the heart against ischemia/reperfusion injury

A moderate red wine consumption and a colored fruit-rich diet protect the cardiovascular system, thanks to the presence of several polyphenols. Malvidin-3-0-glucoside (malvidin), an anthocyanidine belonging to polyphenols, is highly present in red grape skin and red wine. Its biological activity is poorly characterized, although a role in tumor cell inhibition has been found. To analyze whether and to which extent, like other food-derived polyphenols, malvidin affects the cardiovascular function, in this study, we have performed a quantitative analysis by high-performance liquid chromatography of polyphenolic content of red grape skins extract, showing that it contains a high malvidin amount (63.93±12.50 mg/g of fresh grape skin). By using the isolated and Langendorff perfused rat heart, we found that the increasing doses (1–1000 ng/ml) of the extract induced positive inotropic and negative lusitropic effects associated with coronary dilation. On the same cardiac preparations, we observed that malvidin (10^?10–10^?6 mol/L) elicited negative inotropism and lusitropism and coronary dilation. Analysis of mechanism of action revealed that malvidin-dependent cardiac effects require the activation of the phosphatidylinositol 3-kinase (PI3K)/nitric oxide (NO)/cGMP/PKG pathway and are associated with increased intracellular cGMP and the phosphorylation of endothelial NO synthase (eNOS), PI3K–AKT, ERK1/2, and GSK-3β. AKT and eNOS phosphorylation was confirmed in human umbilical vein endothelial cell. We also found that malvidin act as a postconditioning agent, being able to elicit cardioprotection against ischemia/reperfusion damages. Our results show the cardioactivity of polyphenols-rich red grape extracts and indicate malvidin as a new cardioprotective principle. This is of relevance not only for a better clarification of the beneficial cardiovascular effects of food-derived polyphenols but also for nutraceutical research.     

Polyphenols and prevention of cardiovascular diseases

PURPOSE OF REVIEW: Polyphenols are the most abundant dietary antioxidants and research on their role in the prevention of degenerative diseases has developed quickly over these last few years. This paper reviews the recent studies on the prevention of cardiovascular diseases by polyphenols, focusing on human studies. RECENT FINDINGS: A large number of recent intervention studies have shown that several biomarkers of cardiovascular risk are influenced by the consumption of polyphenol-rich foods. Effects on biomarkers of oxidative stress, lipemia and inflammation appear so far inconclusive. More consistent effects have been observed on endothelial function and haemostasis and support a reduction of risk by polyphenols in agreement with the few epidemiological studies already published. All clinical studies have used foods or beverages containing a mixture of different polyphenols and the exact nature of the most active compounds remains largely unknown. Absorption, metabolism and elimination vary widely between polyphenols. These data on bioavailability should be taken into account to improve the experimental design and the interpretation of the observed effects. SUMMARY: Future intervention studies should include a detailed assessment of the bioavailability of polyphenols. Beyond clinical trials carried out with polyphenol-rich foods, more studies with pure polyphenols will also be needed to establish their role in the prevention of cardiovascular diseases.     

Antioxidant effects of resveratrol and other stilbene derivatives on oxidative stress and *NO bioavailability: Potential benefits to cardiovascular diseases

Oxidative stress plays an important part in the appearance and development of cardiovascular diseases. In this context, overproduction of reactive oxygen species leads to deregulation of metabolic pathways, such as cell proliferation or inflammation, which interferes with the homeostasis of vascular endothelium. Oxidative stress can decrease the bioavailability of nitric oxide (*NO) in vessels. This decrease is highly associated with endothelial dysfunction. The "French paradox" is a phenomenon that associates a diet rich in saturated fatty acids and a moderate consumption of wine to a low prevalence of cardiovascular diseases. During the past 10 years, the beneficial effects of wine on cardiovascular diseases have been attributed to the actions of resveratrol and other polyphenols. One of the mechanisms involved in these beneficial effects is the capacity of resveratrol and some other stilbene derivatives to maintain sufficient *NO bioavailability in vascular endothelium. This review presents the latest findings on the molecular effects of resveratrol and other stilbene derivatives on the various actors that modulate *NO bioavailability during oxidative stress.     

Neuroprotective and anticonvulsant effects of organic and conventional purple grape juices on seizures in Wistar rats induced by pentylenetetrazole

Epilepsy is the most common neurological disorder worldwide. Studies have shown that recurrent seizures may increase the concentration of reactive oxygen species, which can lead to oxidative stress and neuronal damage. These seizures result in substantial deleterious effects on an individual's health. Organic and conventional grape juices are rich in polyphenols, compounds with important antioxidant activity. However, these juices could have differences in their polyphenol content. The aim of this study was to investigate the neuroprotective and anticonvulsant effects of organic and conventional grape juice treatments in Wistar rats against pentylenetetrazole (a convulsant drug)-induced damage. In addition, we evaluated potential behavioral changes in rats treated with the juices and the polyphenolic profile of those samples. Animals (n=16 in each group) received treatment with saline, organic or conventional grape juice for 17 days. On the eighteenth day, behavioral changes were evaluated by an open field test. Afterwards, half of the rats from each group received pentylenetetrazole and were observed for 30 min to evaluate possible seizure characteristics. The animals were subsequently killed by decapitation and their hippocampus, cerebellum and cerebral cortex tissues were isolated. The results of this study showed that neither organic nor conventional grape juice altered the behavior parameters, and no statistical differences were observed in the seizure characteristics of the groups. Nevertheless, both juice types were able to protect from lipid and protein oxidative damage, decrease nitric oxide content and increase enzymatic (superoxide dismutase and catalase) and non-enzymatic (sulfhydryl protein) antioxidant defenses in brain tissues following pentylenetetrazole-induced seizures. In general, organic juice showed superior results in each test, probably due to its higher polyphenol content relative to conventional juice. These results indicate that grape juices can provide further insight into natural neuroprotective compounds and may lead to the development of new therapeutic strategies for epileptic patients.     

Red wine polyphenols prevent endothelial damage induced by CCl4 administration

It became evident in the present study that carbon tetrachloride (CCl(4)), in addition to its known liver and renal toxicity, causes serious damage to endothelial cells. The preventive effect of red wine on cardiovascular diseases has been documented in a number of human population studies as well as in animal experimental models. In this study, the endothelium protective effect of polyphenolic compounds isolated from red wine was studied in rats administered 0.5 ml of CC(4)/kg body weight intraperitoneally twice a week for 8 weeks. Endothelemia (endothelial cells/10 microl of plasma) was used as the marker of endothelial cell injury in vivo. Chronic CCl(4) treatment for 8 weeks lead to a 3-fold increase of free endothelial cells circulating in the blood when compared to the baseline values (2.5+/-0.3). Parallel oral administration of polyphenols 40 mg/kg/day significantly decreased the endothelemia. Polyphenolic compounds alone did not produce significant changes. Three weeks of spontaneous recovery after the 8-week treatment with CCl(4) did not lead to a marked decrease of endothelemia, but the administration of red wine polyphenols during the 3-week period significantly decreased free endothelial cells in the blood. It can be concluded that long-term administration of CCl(4) may serve as a useful experimental model of endothelial damage. The red wine polyphenolic compounds exert a powerful protective effect on endothelial cells from the injury caused by CCl(4). This effect was documented by decreased endothelemia that corresponded to diminished endothelial cell swelling and detachment evaluated by histology of the vascular intima. The endothelium protective effect may be one of the key factors that contribute to the preventive action of red wine on cardiovascular diseases.     

Beneficial effects of Provinols: cardiovascular system and kidney

Red wine polyphenols have been reported to exert beneficial effects in preventing cardiovascular diseases but their molecular mechanisms of hemodynamic effects on functional cardiovascular and renal changes were studied much less. The review is focused on in vitro as well as in vivo effects of red wine extract containing polyphenolic compounds (Provinols) on cardiovascular systems and kidney in relation to the molecular and biochemical mechanisms of these compounds. This review provides the evidence that Provinols is able to produce ex vivo endothelium-dependent relaxation as a result of enhanced NO synthesis. Administration of Provinols partially prevents the development of hypertension during NO deficiency and accelerates the decrease of blood pressure in already established hypertension. The effects of Provinols include prevention and/or attenuation of myocardial fibrosis, reduction of aortic wall thickening and improvement of vascular functions. These functional and structural alterations are associated with significant augmentation of NO production, seen as the increase of NO synthase activity and eNOS protein expression. Moreover, it has been documented that Provinols decreased the oxidative stress within the cardiovascular system and kidney.     

Delphinidin attenuates stress injury induced by oxidized low-density lipoprotein in human umbilical vein endothelial cells

Moderate consumption of natural dietary polyphenolic compounds can reduce the risk of cardiovascular diseases. Here we investigated the protective effects of delphinidin against oxidized low-density lipoprotein (oxLDL)-induced damage in human umbilical vein endothelial cells (HUVECs). The MTT assay showed that 2 h pre-incubation with delphinidin markedly restored the oxLDL-induced viability loss in HUVECs in a concentration-dependent manner. This effect was accompanied by a significant decrease in intracellular reactive oxygen species. Moreover, delphinidin imposed preventive effects on suppressing the production of lipid peroxidation, restoring the activities of endogenous antioxidants, and increasing the level of nitric oxide. Pre-incubation of delphinidin with HUVECs led to the reduction of apoptosis. Finally, delphinidin can efficiently prevent the down-regulation of Bcl-2 protein and up-regulation of Bax protein. Together, our findings suggest that delphinidin can effectively protect HUVECs against oxidative stress induced by oxLDL, which may be important for preventing both plaque development and stability in atherosclerosis.     

Role of plant polyphenols in genomic stability

Polyphenols are a large and diverse class of compounds, many of which occur naturally in a range of food plants. The flavonoids are the largest and best-studied group of these. A range of plant polyphenols are either being actively developed or currently sold as dietary supplements and/or herbal remedies. Although, these compounds play no known role in nutrition (non-nutrients), many of them have properties including antioxidant, anti-mutagenic, anti-oestrogenic, anti-carcinogenic and anti-inflammatory effects that might potentially be beneficial in preventing disease and protecting the stability of the genome. However not all polyphenols and not all actions of individual polyphenols are necessarily beneficial. Some have mutagenic and/or pro-oxidant effects, as well as interfering with essential biochemical pathways including topoisomerase enzyme activities, prostanoid biosynthesis and signal transduction. There is a very large amount of in vitro data available, but far fewer animal studies, and these are not necessarily predictive of human effects because of differences in bacterial and hepatic metabolism of polyphenols between species. Epidemiological studies suggest that high green tea consumption in the Japanese population and moderate red wine consumption in the French population may be beneficial for heart disease and cancer, and these effects may relate to specific polyphenols. A small number of adequately controlled human intervention studies suggest that some, but not all polyphenol extracts or high polyphenol diets may lead to transitory changes in the antioxidative capacity of plasma in humans. However, none of these studies have adequately considered long-term effects on DNA or the chromosome and unequivocally associated these with polyphenol uptake. Furthermore, clinical trials have required intravenously administered polyphenols at concentrations around 1400mg/m(2) before effects are seen. These plasma concentrations are unlikely to be achieved using the dietary supplements currently available. More focused human studies are necessary before recommending specific polyphenolic supplements at specific doses in the human population.     

The effects of phenolic components of tea on the production of pro- and anti-inflammatory cytokines by human leukocytes in vitro

Epidemiological evidence suggests protective effects of dietary flavonoids against cardiovascular disease. Tea provides a major source of dietary flavonoids in many countries and its polyphenolic components have well-recognised antioxidant properties. However, scavenging of free radicals may not be the sole mechanism by which tea-derived polyphenols exert their protective effects. This study investigates the effects of four major tea-derived catechins and a black tea extract on the production of pro- and anti-inflammatory cytokines by human leukocytes in vitro. Epicatechin gallate, epigallocatechin and epigallocatechin gallate decreased the production of interleukin 1beta and enhanced the production of interleukin 10, but had no effect on the production of interleukin 6 or tumour necrosis factor-alpha. Although these effects suggest anti-inflammatory properties of the tea-derived catechins, they were observed at concentrations which were unlikely to be achievable in plasma in vivo and are therefore unlikely to contribute to the protective effects of tea-derived flavonoids in inflammatory diseases.     

Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans

The beneficial effects of polyphenol compounds in fruits and vegetables are mainly extrapolated from in vitro studies or short-term dietary supplementation studies. Due to cost and duration, relatively little is known about whether dietary polyphenols are beneficial in whole animals, particularly with respect to aging. To address this question, we examined the effects of blueberry polyphenols on lifespan and aging of the nematode, Caenorhabditis elegans, a useful organism for such a study. We report that a complex mixture of blueberry polyphenols increased lifespan and slowed aging-related declines in C. elegans. We also found that these benefits did not just reflect antioxidant activity in these compounds. For instance, blueberry treatment increased survival during acute heat stress, but was not protective against acute oxidative stress. The blueberry extract consists of three major fractions that all contain antioxidant activity. However, only one fraction, enriched in proanthocyanidin compounds, increased C. elegans lifespan and thermotolerance. To further determine how polyphenols prolonged C. elegans lifespan, we analyzed the genetic requirements for these effects. Prolonged lifespan from this treatment required the presence of a CaMKII pathway that mediates osmotic stress resistance, though not other pathways that affect stress resistance and longevity. In conclusion, polyphenolic compounds in blueberries had robust and reproducible benefits during aging that were separable from antioxidant effects.     

Fruit juice consumption modulates antioxidative status,immune status and DNA damage

Polyphenolic compounds exert a variety of physiological effects in vitro including antioxidative, immunomodulatory and antigenotoxic effects. In a randomized crossover study in healthy men on a low-polyphenol diet, we determined the effects of 2 polyphenol-rich juices (330 ml/d) supplemented for 2 weeks on bioavailability of polyphenols, markers of antioxidative and immune status, and reduction of DNA damage. Juices provided 236 mg (A) and 226 mg (B) polyphenols with cyanidin glycosides (A) and epigallocatechin gallate (B) as major polyphenolic ingredients. There was no accumulation of plasma polyphenols after two weeks of juice supplementation. In contrast, plasma malondialdehyde decreased with time during juice interventions. Moreover, juice consumption also increased lymphocyte proliferative responsiveness, with no difference between the two juices. Interleukin-2 secretion by activated lymphocytes and the lytic activity of natural killer cells were significantly increased by both juices. Juice intervention had no effect on single DNA strand breaks, but significantly reduced oxidative DNA damage in lymphocytes. A time-delay was observed between the intake of fruit juice and the reduction of oxidative DNA damage and the increase in interleukin-2 secretion. We conclude that consumption of either juice enhanced antioxidant status, reduced oxidative DNA damage and stimulated immune cell functions. However, fruit juice consumption for 2 weeks did not result in elevated plasma polyphenols in subjects after overnight fasting. Further studies should focus on the time-delay between juice intake and changes in measured physiological functions, as well as on active polyphenolic metabolites mediating the observed effects.     

Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols

Endothelial dysfunction is an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. In the present paper, we review the effects of flavonoids, especially quercetin and wine polyphenols, on endothelial function and dysfunction and its potential protective role in hypertension, ischemic heart disease and stroke. In vitro studies show that flavonoids may exert multiple actions on the NO-guanylyl cyclase pathway, endothelium-derived hyperpolarizing factor(s) and endothelin-1 and protect endothelial cells against apoptosis. In vivo, flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress and end-organ damage in hypertensive animals. Moreover, some clinical studies have shown that flavonoid-rich foods can improve endothelial function in patients with hypertension and ischemic heart disease. Altogether, the available evidence indicates that quercetin and wine polyphenols might be of therapeutic benefit in cardiovascular diseases even though prospective controlled clinical studies are still lacking.     

Endothelial function and cardiovascular disease: Effects of quercetin and wine polyphenols

Endothelial dysfunction is an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. In the present paper, we review the effects of flavonoids, especially quercetin and wine polyphenols, on endothelial function and dysfunction and its potential protective role in hypertension, ischemic heart disease and stroke. In vitro studies show that flavonoids may exert multiple actions on the NO-guanylyl cyclase pathway, endothelium-derived hyperpolarizing factor(s) and endothelin-1 and protect endothelial cells against apoptosis. In vivo, flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress and end-organ damage in hypertensive animals. Moreover, some clinical studies have shown that flavonoid-rich foods can improve endothelial function in patients with hypertension and ischemic heart disease. Altogether, the available evidence indicates that quercetin and wine polyphenols might be of therapeutic benefit in cardiovascular diseases even though prospective controlled clinical studies are still lacking.     

Neurological mechanisms of green tea polyphenols in Alzheimer's and Parkinson's diseases

Tea consumption is varying its status from a mere ancient beverage and a lifestyle habit, to a nutrient endowed with possible prospective neurobiological-pharmacological actions beneficial to human health. Accumulating evidence suggest that oxidative stress resulting in reactive oxygen species generation and inflammation play a pivotal role in neurodegenerative diseases, supporting the implementation of radical scavengers, transition metal (e.g., iron and copper) chelators, and nonvitamin natural antioxidant polyphenols in the clinic. These observations are in line with the current view that polyphenolic dietary supplementation may have an impact on cognitive deficits in individuals of advanced age. As a consequence, green tea polyphenols are now being considered as therapeutic agents in well controlled epidemiological studies, aimed to alter brain aging processes and to serve as possible neuroprotective agents in progressive neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In particular, literature on the putative novel neuroprotective mechanism of the major green tea polyphenol, (-)-epigallocatechin-3-gallate, are examined and discussed in this review.     

Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications

Can drinking several cups of green tea a day keep the doctor away? This certainly seems so, given the popularity of this practice in East Asian culture and the increased interest in green tea in the Western world. Several epidemiological studies have shown beneficial effects of green tea in cancer, cardiovascular, and neurological diseases. The health benefits associated with green tea consumption have also been corroborated in animal studies of cancer chemoprevention, hypercholesterolemia, artherosclerosis, Parkinson's disease, Alzheimer's disease, and other aging-related disorders. However, the use of green tea as a cancer chemopreventive or for other health benefits has been confounded by the low oral bioavailability of its active polyphenolic catechins, particularly epigallocatechin-3-gallate (EGCG), the most active catechin. This review summarizes the purported beneficial effects of green tea and EGCG in various animal models of human diseases. Dose-related differences in the effects of EGCG in cancer versus neurodegenerative and cardiovascular diseases, as well as discrepancies between doses used in in vitro studies and achievable plasma understanding of the in vivo effects of green tea catechins in humans, before the use of green tea is widely adopted as health-promoting measure.     

Carbon-14 biolabelling of wine polyphenols in Vitis vinifera cell suspension cultures

14C-L-phenylalanine is incorporated into a range of polyphenolic compounds when fed to grape cell cultures. Optimisation of several parameters such as the quantity of precursor applied and the duration of metabolism led to incorporation yields of 15% and to specific activities of 875 mu Ci g(-1) in stilbenes. Purification of the products by several chromatographic steps is reported. Both trans- and cis-resveratrols were easily obtained by enzymatic hydrolysis of their corresponding glucosides, with specific activity of 1200-1400 mu Ci g(-1). The specific radioactivity obtained for all the compounds is suitable for in vivo feeding trials to trace their metabolic fate when consumed by animals and for in vitro activity mechanism studies. Indeed, these polyphenols seem to be implicated in the health benefits associated with regular and moderate wine consumption but little is known about their pharmacokinetics and cellular uptake.