Summary Resveratrol (3,5,4'-trihydroxystilbene) has been subject to a lot of reasearch lately and a wide range of positive effects have been attributed to this plant phytoalexin. Effects like increased lifespan, cancer prevention, athletic performance enhancement, anti-oxidative, anti-viral, anti- bacterial, anti-inflammatory, cardio protective and neuronal protective effects has been proposed positive effects of resveratrol. The structure of resveratrol enables it to interact with many receptors and enzymes throughout the organism. It has been shown to activate sirtuins, inhibit lipid peroxidation, induce apoptosis in tumours, repress oxidative stress, act as an estrogen-receptor antagonist (and agonist in some tissues), increase testosterone levels without any adverse effects, promote vasorelaxation, inhibit platelet aggregation, protect against neuronal cell death, inhibit pro-inflammatory cytokines and suppress inflammation responses. However positive the outlooks seem there are still many issues to be raised regarding the effect in humans. Bioavailability and plasma concentrations required for desirable effect needs to be examined (re-examined). The research has not been equivocal on these issues and there must also be a thorough toxicity evaluation of resveratrol before any therapeutical treatments on humans can be executed. The lack of studies on human will force the researchers to extrapolate data from in-vitro or animal experiments to human systems.
Resveratrol is a substance produced by certain plants in response to stress conditions, such as fungi or bacteria infection (1). The plants have also several other molecules that protect them from toxins during such attacks resveratrol one among many. Resveratrol is a phytoalexin which are natural plant antibiotics. The current research is pointing towards many health benefits for this substance in humans. These benefits include: Increased lifespan, cancer prevention, athletic performance enhancement, anti-oxidative, anti-viral, anti-bacterial, anti- inflammatory, cardio protective and neuronal protective effects (1-20). However, there are still many questions to be answered regarding the relevance of the effects in humans. This report will try to elucidate some of the effects and controversies regarding this substance and explain the possible mechanisms that resveratrol acts through. The resveratrol molecule has a stilbene skeleton with 3 hydroxyl-groups attached on it (see Fig 1.). Resveratrol or 3,5,4'-trihydroxystilbene (C14H12O3) exicts in two geometric isomeres cis- and trans-. The trans form can undergo transformation to cis form if exposed to UV light and the cis form is the least common type (more unstable and stearically hindered)(2). Stilbenoids (stilbene derivate) like resveratrol is produced through the enzyme stilbene synthase in plants. It is lipophilic and is able to cross the blood-brain-barrier in humans (1). Resveratrol is found only a few of our dietary scourses: in white hellebore (julrosor), Japanese knotweed, grapes (in the skin and seeds), cranberries, peanuts, blueberries (Vaccinium corymbosum, amerikanskt blåbär), bilberries (Vaccinium myrtillus, blåbär) and mulberries (3). The highest concentrations are observed in matured red wine berries and red wine has therefore been of great interest in research lately. However, some in-vivo experiments exists, most studies on resveratrol are in-vitro, in yeast, worms, fruit flies, fish, mice, and rats. It’s currently also sold as nutritional supplement, however there are no research on long-term effect on humans. With the simple structure it can interact with many enzymes and receptors and thus inactivate or activate a number of pathways (1). Fig 1.Chemical structure of Trans-resveratrol. A stilbene is just the ethene with the two phenyl groups attached to it.
There are several other stilbenes produced by these plants which are involved in protecting the plant from toxins originating from fungi and bacteria. Resveratrol is related to Pterostilbene, a substacne in blueberries and grapes which is also believed to be a potent theraputic target (See Fig 2.).
Fig 2. Pterostilbene is very similar to resveratrol 2. Results
2.1 Can resveratrol increase lifespan? The main argument for life extending properties of resveratrol is based on the hypothesis that the stilbenes can activate sirtuins. SIRT1 activation by resveratrol: Sirtuins are closely related enzymes that aredependent ound inaome researchers believe that sitruins are an important factor in the organisms respons to stress situations including heat and starvation (4,5). The hypothesis is that the life extending effect of calorie restriction (such as lower blood cholesterol, nlevels) is due to the activity of sirtuins. The deacetylation process involves removal of acetyl groups from histone tails, which causes DNA to bind more tightly to the histones. This leads to an interferance with transcription of genes by blocking transcription factors. This results in a non specific reducti(4). SIRT1 have also been shown to repress PPARγ in yeast and mice (5), which results in a number of positive effects including attenuated adipogenesis. The same study demonstrated an upregulation of lipolysis and loss of fat. The sirtuin SIRT1 in humans are important in many biological processes including: gene silencing (transcription regulation i.e marker genes near telomeres are silenced), cell cykle regulation (i.e p53 dependent processes), adipogenesis, muscle differentiation, protection from axonal degeneration and life span extension (4). Reasearchers have demonstrated that resveratrol can activate the sirtuins; Sir2/SIRT1 (SIRT1 is thaught to be the human homologue of Sir2) in yeast, worms, fruit flies and mice by up to 8-fold increase in activity. The most apperant effects were extended lifespan despite the fact that they were put on a high calorie diet (6). However, the question whether this is a consequense of resveratrol alone have been challanged. In-vitro studies have shown that human SIRT1 requires a fluorophore (naturally occuring compound that are also flourecent) to be covalently bound in order to be activated (4,7). Moreover, the fluorophore-SIRT1 complex displays higher affinity when resveratrol is present. Of note is that one study showed no effect on lifespan in yeast experiments (7). 2.2 Resveratrol affects tumour initiation, promotion and progression There are a numerous ways of which resveratrol is proposed to act as a chemopreventive agent. Some of which are explained below. Most studies reviewed in this report show effects on breast cancer or prostate cancer, although intestinal and melanoma cancers have been reported to be affected by resveratrol (1, 16-21). Resveratrol has been shown to prevent metabolic activation of procarcinogens (such as polycyclic aromatic hydrocarbons (PAH’s)) by inhibition of phase I enzymes and competitive inhibition of the aryl hydrocarbon receptor; AhR. The AhR is believed to be involved in cell proliferation, differentiation, induction of P450 1A1 after xenobiotic exposure and is a major contributor to tumour initiation (17). Resveratrol has an antagonising effect on this receptor. However, this findings have been questioned by other reports showing an AhR independent inhibition of P450 1A1 by resveratrol (17). ROS from lipid peroxidation is believed to initiate tumour development through cell membrane damage. Resveratrol have been shown to protect cell membranes from lipid peroxidation, damage to our DNA caused by ROS and induction of phase II enzymes (12, 17). Resveratrol in capable of increasing the activity of the cell-cycle regulator, p53 (17). This highly important process can cause an arrest in the cell-cycle and make room form DNA repair systems or activate apoptotic signals to prevent the cell from becoming a tumour cell. However, studies on human breast cancer cell lines shows that the changes in p53 concentration are relatively small (and was not dose dependant). This lead to the conclusion that modulation of p53 gene expression by resveratrol (and other wine polyphenols) could not account for the anti-carcinogenic effects (19). Furthermore, resveratrol can affect the MAPK pathways by a number of mechanisms. It can inhibit the protein kinase C (and many of its isoenzymes) phosphorylation of arginin-rich substrates (proteins). This, by way of a non-competitive action (17). MAPK pathways are involved in many cellular processes such as gene expression, differentiation, survival/apoptosis and mitosis. This MAPK cascade inhibition by resveratrol hinders tumour formation (17). Although, as will be described below, resveratrol can also induce phosphorylation of MAPK family members ERK-1 and -2 (1). Moreover, prostaglandins (PG’s) are thought to play an important role in promoting cell proliferation, suppress immune responses and stimulate tumour formation (17). To synthesise PG’s, prostaglandin H synthase (PHS), cyclooxygenase (COX) and lipoxygenase pathways can convert for example arachidonic acid into PG’s. Indeed, resveratrol is a competitive inhibitor of COX and peroxidase activity of PHS in human erythroleukemia cells (17). The mechanism of this inhibition is yet to be elucidated. Yet another cancer preventive effect exhibited by resveratrol is the prevention of cells (in- vitro) from entering the S/G2/M phase during the cell cycle. This is accomplished by blocking cyklins, cdk’s pRB and other substances affecting the progression of the cell cycle (17). Finally, resveratrol can induce cell death by up-regulation, conformational changes and mitochondrial redistribution of Bax and Bak (both of which are pro apoptotic proteins from the Bcl-2 gene family) along with activation of caspase-3 and -9 (proteases in the apoptotic cascade) (17, 20). Resveratrol treated rats demonstrated a reduction in mammary tumour incidence by approximately 50% (low-dose <100 mg / kg) (16). The tumours on treated animals where examined and evidence of apoptotic cells within peripheral tumour areas where observed (16). This indicates that resveratrol could induce apoptosis in tumour cell lines and proposes a possible treatment target for breast cancer.
2.3 Resveratrol as an anti-oxidant? Resveratrol have been said to have various antioxidant activities, however when reviewing the research it seems that the interaction of resveratrol with other biomolecules that do the actual “antioxidative job” is contributing more to this observed effect. Therefore, resveratrol is thought to be a weak ROS (radical oxygen species) scavenger (9). But one study suggested three different mechanisms that resveratrol acts as a natural (direct) antioxidant: 1, Competition with CoenzymeQ (decreases the respiration chain formation of ROS). 2, Scavenge oxygen radicals formed in the mitochondria (debated in other studies). 3, Inhibition of lipidperoxidation induced by Fenton reaction products (12). It seems that resveratrol can lower the amount of oxidative damaged DNA; however the mechanism is currently unknown. MnSOD (mitochondrial superoxid dismutase, a member of iron/manganese superoxid dismutase family) converts the byproducts of oxidative phosphorylation into hydrogen peroxide and O2. This is a major process of our defence against oxidative stress since an overexpression of MnSOD itself can significantly reduce intracellular oxidative stress, extend life span and inhibit cancer cell growth (9). One study resulted in a 14-fold increase in MnSOD activity after two weeks of resveratrol (50µM) incubation in human lung fibroblasts (MRC-5) (9). The mechanism by which resveratrol stimulates MnSOD is not known to researchers. Interestingly, at higher concentrations than 50µM resveratrol, the effects (including MnSOD activity) on the cells did not increase further. This is suggests that lower concentrations will still have some effect on the cells. Since the concentrations in human tissues after ingestion of resveratrol rich food (typically red wine) ends up at low µM concentrations (1, 9). The research on resveratrol effects on other antioxidant enzymes has been equivocal. For example, several glutathione enzymes have been shown to be increased in some studies while in others no or adverse effect have been demonstrated (9, 12). Concentration levels were significantly higher in the study that showed an increase compared with the study that showed no or adverse effect (9, 12).
2.4 Resveratrol is estrogenic/anti-estrogenic Estrogen plays an important role in development of for example breast cancer. Current research is looking for ways to inhibit estrogen synthesis as a target for breast cancer treatment (21). The Cyt-P450 enzyme, aromatase, transforms androgens to become estrogens (like estradiol). Resveratrol have demonstrated an inhibition of aromatase at both enzyme and mRNA levels in-vitro (10, 11, 21). Resveratrol has been shown to bind to both estrogen-receptor-α and –β (ER- α / β) in-vitro (15, 16). The binding affinity is equally low for both receptors when compared with the potent estrogen; estradiol. It has been classified as a phytoestrogen due to its modulating effects of estrogenic pathways (1, 8). It exhibits agonistic/antagonistic effects depending on the cell type and gene promoter (as does the breast cancer preventive tamoxifen (TAM)) (15, 16). This makes resveratrol especially interesting in preventing for example breast cancer. An estradiol antagonistic effect is observed on resveratrol-liganded ER-α, but not ER-β (1, 15, 16). Interestingly, resveratrol-liganded ER-β has higher transcriptional activity than estradiol has on the same receptor. This means that tissues expressing more ER-β than ER-α may be more affected by resveratrols estrogen agonistic effects (15, 16). Resent studies also show lack of estrogenic activity in the uterus and mammary (and possibly even anti-estrogenic activity in these tissues by resveratrol). Moreover, there have been demonstrated estrogenic activities in bone and endothelial cells (1). All this taken into account it would seem relevant to administer resveratrol together with a selective ER-modulator in order to treat breast cancer. 2.5 Performance enhancement by resveratrol Athletes are constantly looking for natural ways to boost their testosterone levels without using illegal drugs such as androgenic-anabolic steroids. In one experiment on rats the researchers studied the serum concentration of LH (signals to Leydig cells to produce testosterone), FSH (stimulate spermatogenesis) and testosterone to determine weather the resveratrol treated group had any difference in these reproduction hormones. The results after 90 days treatment with orally administered resveratrol (20 mg/kg * d) were around 100% or more than 100% increase in concentrations of all the hormones including sperm count in the resveratrol treated group (8). No adverse effects or side effects (like sperm abnormalities) were seen in the treated group compared with the untreated group. Furthermore, the body weight and food/water consumption did not differ among the groups. Nor were there any estrogenic effects on the testes of the treated rats. These findings lead the researchers to conclude that resveratrol acts as a week estrogen antagonist/agonist without any estrogenic properties, which is in agreement with several other studies (8). One proposed mechanism resveratrol uses to accomplish this is through its aromatase inhibitory effects. This leaves the androgens to execute their masculine activity instead of converting it to estradiol (10, 11).
2.6 Resveratrol as a cardio-vascular protective agent
A possible important cardio protective effect of resveratrol is to inhibit peroxidation of LDL by chelating activity and oxygen radical scavenging (1). Resveratrol also seem to function as a vasorelaxation agent by nitric-oxide (NO) mediated way (NO is known to inhibit vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium). This has been demonstrated through administration of NO-synthase inhibitor to isolated rat aorta. The result was an antagonising pattern on resveratrols vasorelaxation effect (1). Another mechanism proposed for the vasorelaxation effect is that resveratrol stimulates Ca2+- activated K+-channels (BKCa) that exists in human vascular endothelial cells. This can lead to an increase in K+ concentration in myoendothelial space which then leads to hyperpolarisation of vascular monocytes. The result is dilated blood vessels (1). 2.7 Neuronal protective effects of resveratrol
Resveratrol, as described above can affect several MAPK pathways. One if these is induction of phosphorylation of MAPK family members, ERK1 and 2 in human neuroblastoma cells (konc. 1 pM). Epidemiological studies show inverse relation to dementia. It has also been showed that resveratrol can protect against neuronal cell death that could manifest Alzheimer’s disease, through inhibition of LDL peroxidation in treated PC-12 cells (1). 2.8 Anti-inflammatoryproperties of resveratrol Resveratrol demonstrated a dose-dependant inhibition of interleukin-6 (a pro-inflammatory cytokine released my macrophages and T-cells), by blockade of Ca2+ influx into cells. Another anti-inflammatory action by resveratrol is suppression of activation of NF-κB (key regulator of stress, immune, infection and inflammation responses) by LPS and inhibited phosphorylation of inhibitory κBα (1).
Indeed, resveratrol displays a wide and complex interaction with different tissues, cells and proteins throughout the human body. The main thing one comes across when reading the literature on resveratrol is that it is hard to prove or illustrate if resveratrol itself is responsible for the changes seen or if it is because of resveratrol derivates or even other compounds with similar structure and shape (when grape extract was administered to subjects). Some studies have demonstrated an up to 100 times greater growth inhibitory activity on cancer cells in synthesised resveratrol derivates (18). This should be the focus of future studies, to determine the effectiveness of resveratrol in therapeutical doses. As seen in some of the research, concentrations of resveratrol into subjects or cells are far greater than the normal diet could provide (5.9). However, many studies displays no toxic effects, there have been reports on pro-oxidative effects by resveratrol under certain conditions (12). This implicates that there should still be some cautiousness in recommending people daily use of resveratrol or resveratrol containing foods. Despite some problems and unanswered questions regarding mechanisms and interactions, resveratrol seem to be a promising target for more research. Taken into account that resveratrol-like molecules could be more effective in certain chemopreventive actions the question still remains weather it is efficient to use resveratrol as a research tool for possible effects. Indeed, numerous studies displays many positive actions including affecting pathways that control inflammation, lipidperoxidation, platelet aggregation, vasodilation, sex-hormone responses, detoxifying enzymes and longevity. Finally, the lack of studies on human is a problem and proves that the research have still many steps to go through before any certainties can be issued. The researchers need to extrapolate data from in-vitro or animal experiments to human systems in order to advance the knowledge of resveratrol further.
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