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The beneficial properties of the phenolic compounds present in grapes and wine have been studied after the discovery of the “French Paradox.” This term refers to the fact that in north France there is a high intake of saturated fat but low mortality from coronary heart disease compared to other countries where the same high saturated fat intake exists, being the Paradox attributable to high wine consumption. In fact, there are more and more studies dealing with the ability of grape polyphenols and red wine to protect against different types of diseases. Resveratrol is one of the most studied red wine molecules and, in fact, there are more than 1000 references about its properties in the bibliography. Some of these studies in vivo and in vitro are described in. Because of its chemical and physical features, resveratrol can either cross passively cell membranes or interact with membrane receptors. Therefore, it may interact with extracellular and intracellular molecules. For this reason, its mechanism of action at the cellular level may be triggered by either activating signaling pathways when binding to cell membrane receptors, activating intracellular mechanisms, or even developing its effects inside the nucleus.
In fact, resveratrol is able to bind to estrogen receptors alpha and beta (ER-α and ER-β) with similar affinities, but this interaction is 7000 times less powerful than that of estradiol. Molecular studies have shown that the union of resveratrol to ER-α is stereoselective, that is, that the trans-isomer shows more affinity for this receptor than the cis-isomer. The chemical structure of resveratrol is similar to that of 17-β-estradiol or synthetic estrogens like diethylstilbestrol. Thus, several studies have been carried out in order to test its ability to act as a phytoestrogen.
Comparison of the chemical structures of trans-resveratrol and 17-β-estradiol.
Estrogens and phytoestrogens exert almost all of their effects through binding to estrogen receptors. When estrogen binds to its receptor, it activates the transcription of target genes. We found that antioxidant genes were upregulated by this mechanism. Resveratrol can bind to estrogen receptors and activate the transcription of such genes with similar concentrations to those required for its other biological effects. In this regard, Gehm et al. demonstrated in 1997 that resveratrol behaves as an estradiol analog. They used MCF-7 cells, which are rich in estrogenic receptors. Maximal efficiency binding was at 10 μM. This subsequently activated genes with estrogen responsive elements (ERE). Furthermore, to confirm that resveratrol starts ERE activation, they used estrogenic antagonists and the effect was inhibited. By contrast, it has also been shown that resveratrol, in its capacity of an estrogen receptor modulator, can also antagonize the effect of estradiol on increasing proliferation of MCF-7 cells, at higher doses.
Regarding its estrogenic activity, it has been shown that it does not have any effect on the growth and differentiation in the uterus of growing rats. In the same article, the authors did not find any effect of resveratrol on either radial bone growth, serum cholesterol levels, or animal body weight. This study concludes that resveratrol does not act as an agonist in rats at doses from 1 to 100 μg/day. Even with higher doses (1000 μg/day) the effect is insignificant and could also act as an estrogen antagonist.
Oxidative damage is involved in the pathogenesis of many important diseases, such as diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. It also plays an important role in the aging process. Therefore, a great deal of attention has been focused on finding natural antioxidants, which could help in the treatment of all these diseases and, consequently, potential antioxidant effects of resveratrol have been studied in depth. Its antioxidant activity has been determined in isolated rat brain mitochondria, which shows an inhibition of the mitochondrial respiration state when they are incubated with resveratrol. Furthermore, it inhibits the activity of complex III by competing with coenzyme Q. This fact is interesting because it determines its antioxidant activity in mitochondria, not only its activity in uptake capacity of unpaired electrons, but also by inhibiting a complex that generates free radicals.
Most published in vitro studies report using concentrations of resveratrol too high to be reached in the organism after red wine consumption. Therefore, it is very important to make sure that low plasma concentrations of free resveratrol are sufficient enough to be active as an antioxidant. In this regard, it has been shown that nutritionally relevant concentrations of resveratrol are able to decrease H2O2 levels in MCF-7 cells by inducing the expression of antioxidant genes, such as catalase and manganese superoxide dismutase (MnSOD), through a mechanism that involves phosphatase and tensin homolog (PTEN) and proteinkinase-B (PKB or Akt) signaling pathway. In the cardiovascular system it has been reported how this polyphenol, at a concentration of 20 μM, can reduce the malondialdehyde content in blood mononuclear cells isolated ex vivo from healthy individuals. Thus, resveratrol preincubation of bovine aortic smooth muscle cells was able to attenuate oxidized low-density lipoprotein- (oxLDL-) induced increases in reactive oxygen species (ROS) and H2O2 levels. In another study performed in human blood platelets treated with peroxynitrite, resveratrol inhibited protein carbonylation and nitration, as well as lipid peroxidation.
Regarding other physiological systems and tissues, resveratrol has also been shown to protect primary hepatocytes in culture against oxidative stress damage by increasing the activities of catalase, superoxide dismutase, glutathione peroxidase, NADPH quinone oxidoreductase, and glutathione-S-transferase. Furthermore, it increases the level of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and induces its translocation to the nucleus. This factor can activate genes with antioxidant responsive elements (ARE). In rat spinal cord, resveratrol was shown to protect it from secondary spinal cord injuries via improving the energy metabolism system and inhibiting the lipid peroxidation, at a dose between 50 and 100 mg/kg, reaching the maximal effect after 48 h of the spinal cord injury. In a related article, resveratrol protected rabbit spinal cord from ischemia-reperfusion injury by decreasing lipid peroxidation (at a dose of 10 mg/kg) and increasing nitric oxide (NO) release (at doses of 1 mg/kg and 10 mg/kg).
Regarding the musculoskeletal system, it has been described how, in young and old rats submitted to a 14-day muscle disuse by hindlimb suspension, resveratrol (at a dose of 12.5 mg/Kg) was able to diminish oxidative stress by increasing gastrocnemius catalase activity, MnSOD activity, and MnSOD protein content. Interestingly, resveratrol was also able to regain the muscle isometric force, but apoptotic markers were not modified. Another similar article also deals with the ability of resveratrol to protect against muscle and bone alterations after disuse and suggests resveratrol as a physical exercise mimetic. The ability of resveratrol to act as an antioxidant has also been found in a model of senescence-accelerated mice, where resveratrol at different dosages (25, 50, and 100 mg/Kg/day) for 8 weeks increased the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx), as well as diminishing malondialdehyde levels. Despite this antioxidant function, however, it can also suffer an autooxidation process, leading to the production of O2 ?−, H2O2, and a complex mixture of semiquinones and quinones, which can become cytotoxic. The oxidized resveratrol molecule can generate complexes with copper that can fragment DNA.
Resveratrol can interact with the αVβ3 integrin receptor in MCF-7 cells (a breast-cancer cell line) inducing apoptosis. Besides, it shows antagonist actions when binding to the aryl hydrocarbon receptor, which has immunosuppressive and carcinogenic activity in cells. Nevertheless, these studies conclude that resveratrol inhibits cellular proliferation at concentrations within 10–30 μM. In particular, the effect is locked in phase G/S2 of the cellular cycle, suggesting an inhibition in the enzymatic activities responsible for DNA duplication. These effects have been observed in a cell line of prostate cancer with a concentration of 25 μM but not with 2.5 μM.
Some studies show that it can exert its antitumor effects on the initiation, promotion, and progression of cancer in tumor cells. In this regard, it has been shown how resveratrol at 15 μM is able to inhibit cyclooxigenase 1 (COX-1), a very active enzyme involved in tumor progression. In addition, at 11 μM, it induces phenotypic nonproliferative markers, like the reduction of the nitroblue tetrazolium activity. In the initiation of tumor cells, it acts to inhibit the formation of free radicals at 27 μM on leukemia cells (HL-60). In hepatoma cells (Hepa LcLc7), it inhibits hepatic reductase activity, an enzyme which produces hepatic toxicity, at concentrations of 21 μM. In addition, at 18 μM, the incorporation of thymidine is inhibited, indicating the end of differentiation and thus the transformation to a nonproliferative phenotype. In MCF-7 cells, 10 μM resveratrol blocks the aryl hydrocarbon receptor obtaining beneficial effects against cancer, as it is reported that the activation of this receptor may be involved in some types of tumors [91]. The anticancer effect of resveratrol in MCF-7 has also been associated with BCL-2 and NF-kappaβ. Between 10 and 40 μM, it induces apoptosis via p53 activation in human lymphoblast cell lines. It can also inhibit ribonuclease reductase or COX-2 activity. For that reason, resveratrol has antitumor effects when administered in vitro.
In vivo studies show beneficial effects. For example, its preventive effect on the initiation of cancer has been determined in a skin cancer animal model, with a concentration between 1 and 25 μM of resveratrol, and administrated twice a week. Thus, in vivo studies support the antitumor beneficial effects previously seen in in vitro studies.
Platelet aggregation is inhibited by resveratrol both in vitro and in vivo. There are studies that suggest that resveratrol, at concentrations of 0.1, 1, and 10 μM binds to calcium channels producing 20, 30, and 50% inhibition of thrombin, respectively. This is very beneficial for the cardiovascular system, due to its interference in the formation of blood clots. Those effects on platelet aggregation showed in in vitro studies mentioned above have also been shown in an in vivo study in rabbits, when a dose of 4 mg/kg/day of resveratrol was administered.
Other cardiovascular effects attributed to resveratrol are the regulation of the accumulation of triglycerides and the regulation of the lipolysis in murine adipocytes. When human adipocyte cells (3T3-L1 and SGBS) are incubated with resveratrol at 100 μM, a decrease in triglycerides is observed by an induction of lipolysis, activating adipose triglyceride lipase, and by inducing lipid mobilization. Thus, authors suggest a possible treatment for obesity.
In a cellular model of leucocytes (RBL-2H3 cells), it has been observed that resveratrol at 15 μM has an antiallergenic effect by decreasing the β-hexosaminidase activity. In human mesenchymal stem cells, resveratrol promotes a spontaneous osteogenesis, activating genes such as osteocalcin and RUNX2. It also prevents adipogenesis by repressing the expression of some genes such as PPARγ2 and leptin, suggesting beneficial effects of resveratrol on bone regeneration. Resveratrol has been shown to have beneficial effects on experimental diabetes. It improves the health status of diabetic rats induced with streptozotocin, by enhancing the energy metabolism and reducing protein breakdown.
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