Resveratrol gene activation

The findings could help in the development of drugs to curtail some of the health problems that arise as we get older. Certain metabolic diseases, including type 2 diabetes and heart disease, tend to strike as we age. In animal studies, severely restricting calories can help prevent some of these diseases. Over a decade ago, researchers found that resveratrol can mimic calorie restriction in some ways and extend the lifespans of yeast, worms, flies and fish.

Resveratrol affects the activity of enzymes called sirtuins. Sirtuins control several biological pathways and are known to be involved in the aging process. This site is intended for informational purposes only and not to provide medical advice. Learn how to enable it here. About ConsumerLab. Contact Us Privacy Policy. Save to favorites This feature is restricted to active members. Join now to save favorites and get all member benefits, including over 1, reviews.

Join Now Already a member? Answer: Yes, resveratrol has been shown to cause activation of the SIRT1 gene note: there is some evidence this effect may be blunted by exercise. However, more research is needed to determine the benefits of activating this gene in humans. Join today to unlock all member benefits including full access to all CL Answers and over 1, reviews.

Join now at www. Although SIRT1 activation was independent of the acetylpeptide sequence, resveratrol activation was completely dependent on the presence of a covalently attached fluorophore. Substrate competition studies indicated that the fluorophore decreased the binding affinity of the peptide, and, in the presence of resveratrol, fluorophore-containing substrates bound more tightly to SIRT1. Many studies also provided evidence that resveratrol not only acts a chemopreventive agent, but also display chemotherapeutic properties linked to its anti-inflammatory, antioxidant, pro-apoptosis and anti-proliferative actions [ 50 , 52 ].

Indeed, Resveratrol is believed to target intracellular signaling pathway components such as regulators of cell survival and apoptosis, pro-inflammatory mediators, and tumor angiogenic and metastatic switches by modulating a distinct set of transcription factors, upstream kinases, and their regulators [ 53 ].

For instance, resveratrol have demonstrated apoptotic and anti-proliferative effects on human cervical carcinoma by inducing cell shrinkage in HeLa cells and apoptosis through the activation of caspase-3 and -9, upregulation of the expression of the pro-apoptotic B-cell lymphoma Bcl associated X protein and downregulation of the expression of the anti-apoptotic proteins Bcl-2 and Bcl-extra-large in HeLa cells, and increased expression of the p53, a protein that is essential for cell survival and cell cycle progression [ 54 ].

Cheng et al. Resveratrol is also an Histone deacetylase inhibitors that display its antiproliferative action by activating cell cycle arrest, inducing apoptosis and autophagy, angiogenesis inhibition, increasing reactive oxygen species generation causing oxidative stress, and mitotic cell death in cancer cells [ 56 ].

Enzymatic assays demonstrated that DNA synthesis inhibition was induced by a direct interaction of resveratrol with DNA polymerases [ 40 ]. When this factor is present, cancer cells become chemotherapy-resistant, which then allows them to multiply.

Resveratrol acts blocking this transcription factor, thereby enabling chemotherapeutics to act at their targeted sites [ 57 , 58 , 59 ]. These effects fall into two classes: i Well-documented anti-proliferative and pro-apoptotic effects on cancer cell lines; and ii slightly more hypothetical chemopreventive effects that corresponds to resveratrol effects on cancer initiation [ 57 , 58 , 59 ].

Besides, the phytoestrogen, resveratrolt has received great attention as an upcoming preventive and therapeutic agent against breast cancer [ 61 ]. Resveratrol has also shown promise as part of combination therapy, particularly in breast cancer [ 62 ]. This compound has been shown to reverse drug resistance in a wide variety of in vitro cell systems by sensitizing tumor cells to drug-mediated effects in combination with other chemotherapeutic agents [ 50 ].

Resveratrol demonstrates ability to enhance the sensitivity of pancreatic cancer cells to gemcitabine therapy [ 55 ]. Cisplatin, a cancer chemotherapy agent against ovarian, bladder, testicular, and many other cancers, high risk of nephrotoxicity is reduce by Resveratrol [ 63 ].

Globally, many in vitro and animal-based studies have demonstrated such preventive anticancer activity in colon, cervical, prostate, breast and lungs [ 50 , 64 , 65 , 66 , 67 , 68 , 69 ].

Resveratrol-loaded nanoparticles have also demonstrated antioxidant potential in cancer cells [ 37 ]. In addition, resveratrol beneficial effects are also present when adopted as a conventional treatment support to cancer, using chemotherapy and radiotherapy [ 70 , 71 , 72 ].

Based on previous experimental and clinical trials, and on molecular characteristics of resveratrol, it could be used as: i A neoadjuvant chemotherapy agent before surgery to decrease tumor volume, owing to its ability to inhibit cancer cell proliferation and to induce apoptosis; ii an adjuvant chemotherapy drug to inhibit early cancer invasion and metastasis after surgery; iii a radiotherapy or chemotherapy sensitization agent in combination with chemotherapy agents, like capsaicin, docetaxel, doxorubicin, gemcitabine and temozolomide, since resveratrol may improve their anticancer effects; iv in cancer prevention for people under high risk of cancer; v a radioprotective agent to reduce treatment adverse effects, including radiotherapy-induced xerostomia and mucositis.

Resveratrol showed beneficial effect in heart failure by improving left ventricle function, decreased cardiac hypertrophy, contractile dysfunction and remodeling, interstitial fibrosis, and the level of plasma BNP [ 75 ]. Yan et al. In addition, resveratrol significantly reduced inflammation factors and malondialdehyde levels, which is a marker of oxidative stress [ 77 ].

These results showed that resveratrol treatment can improve cardiovascular function by reducing myocardial ischemia-reperfusion injury, vasodilation and atherosclerosis [ 78 ]. Contrarily, at physiological concentrations, resveratrol induces vasodilation, and consequently decreases hypertension and cardiovascular diseases risk [ 79 ]. On the other hand, these results have also confirmed the uses of Polygonum cuspidatum as a resveratrol source to treat and to prevent hyperlipidemia and arteriosclerosis in traditional chinese medicine [ 80 , 81 , 82 ].

A meta-analysis showed that resveratrol significantly decreased Profile of Mood States POMS including vigor and fatigue but had no significant effect on memory and cognitive performance [ 89 ].

Among the isolated resveratrol oligomers, vitisin A and heyneanol A have been reported for better dose-dependent inhibitory potential compared with standard inhibitor galantamine on both acetylcholinesterase AChE and butyrylcholinesterase BChE activity [ 17 , 37 ]. Resveratrol is also able to improve rat motor abilities and to deactivate neuroinflammatory response following intracerebral hemorrhage.

It may be used as a novel therapeutic agent to treat intracerebral hemorrhage [ 90 , 91 ]. Stilbenoids including resveratrol are non-nitrogenous polyphenols with acidic and amphiphilic characters with anti-inflammatory activity.

Many of their targets are occurring on cyclooxygenase COX , 5-lipoxygenase 5-LOX and protein kinase B [ 92 ], which is associated with its ability to inhibit COX-1 and COX-2 activity along with transcription factors activity inhibition, directly involved in COX activity regulation [ 93 ]. Studies reported the ability of resveratrol to reduce the secretion and expression of inflammatory factors [ 94 ].

Chen et al. Taken together, these studies suggest that resveratrol can prevent inflammation and oxidative stress, reduce the risk of carcinogenesis and developed as anti-inflammatory agent to improve the quality of life of patients. Resveratrol, in addition to the above described biological activities, has been studied for its ability to inhibit the growth of some pathogenic microorganisms, such as Gram-positive and Gram-negative bacteria and fungi [ ].

Indeed, resveratrol has been shown to efficiently inhibit Candida albicans growth [ ]. Dimethoxy resveratrol derivatives exhibited antifungal activity against C. However, the putative candidacidal activity of resveratrol is a matter of controversy. In fact, a study indicates that resveratrol is not effective against both C.

In another study, resveratrol antifungal activity against C. Campylobacter jejuni and Campylobacter coli are the major causes of bacterial gastroenteritis, while Arcobacter species are also known to be human and animal pathogens. Furthermore, it inhibited biofilm formation and promoted biofilm dispersion even at sub-MIC concentrations and therefore could be developed as a new anti-biofilm agent to enhance foods shelf-life and safety [ ].

Resveratrol showed antibacterial activity against Gram-positive bacteria and time-kill assays showed that its effects were due to its bacteriostatic action [ ]. However, the mechanism underlying its antibacterial activity is not clearly understood [ ]. Resveratrol was also able to affect cells with changes in cell morphology and DNA contents [ ]. Hwang and Lim [ ] demonstrated that resveratrol led to DNA fragmentation in Escherichia coli , inducing an SOS response; nevertheless, resveratrol also induced cell elongation without an SOS response and thereby inhibits bacterial cell growth by suppressing FtsZ crucial for Z-ring formation expression and Z-ring formation in E.

From another point of view, reactive oxygen species ROS , superoxide, peroxide, and hydroxyl radicals are thought to contribute to the rapid bactericidal activity of diverse antimicrobial agents. Pseudorabies virus is one of the devastating pathogen of swine for which there is no treatment and that often result in economic losses. Resveratrol showed antiviral activity by inhibiting the Pseudorabies virus replication and effectively increase the growth performance and reduce the mortality of Pseudorabies virus-infected piglets [ ].

Pterostilbene anti-MRSA potency was related to bacterial membrane leakage, chaperone protein downregulation, and ribosomal protein upregulation and can be topically applied for treatment of skin MRSA infection bearing it less toxicity to mammalian cells [ 32 ].

Resveratrol is a potentially useful agent on Staphylococcus aureus pneumonia and S. Also, resveratrol could alleviate rotavirus infection-induced diarrhea [ ]. Besides the cardioprotective, antioxidant, anticancer, neuroprotective, anti-inflammatory, anti-dyslipidemia, and antidiabetic effects of resveratrol, it also exhibits antiproliferative and androgen-lowering effects on theca-interstitial cells of ovary.

Moreover, it exerts a cytostatic but not cytotoxic effect in granulosa cells, while inhibiting aromatization and vascular endothelial growth factor VEGF expression.

These actions may be of clinical relevance in conditions associated with theca-interstitial cell hyperplasia, androgen excess, and abnormal angiogenesis, such as polycystic ovary syndrome. In addition, resveratrol may increase ovarian follicular reserve and prolong ovarian life span, serving as a potential anti-aging agent [ ]. Resveratrol is also able to decrease histopathological and biochemical damages and to exert protective effects on ischemia-reperfusion injury induced ovarian damages.

Resveratrol has become to continue a hotspot in many fields, including respiratory system diseases. Indeed, research has demonstrated that resveratrol is helpful in relieving pulmonary function in general population and plays a protective role in respiratory system diseases. The main protective effects of resveratrol in respiratory system diseases, including its anti-inflammatory, antiapoptotic, antioxidant, antifibrotic, antihypertensive, and anticancer activities were also examined.

In resveratrol-treated patients, serum levels of certain biochemical markers i. Therefore, the use of resveratrol as an adjuvant to conventional antirheumatic agents seems to be an optimum approach. On the other hand, resveratrol could be useful to protect health against several pathologies and ageing problems [ 84 ].

However, the comparative evaluation of animal and human studies shows that resveratrol cannot protect against metabolic diseases and their relevant complications. Nonetheless, it is important to point out that the clinical findings are influenced by many factors, such as sample size and study objectives. Till now, small sample size and high dosage levels were used to conduct most of clinical trials to assess resveratrol significance in chronic diseases [ 84 ].

Consequently, it is not easy to determine the exact safety range and therapeutic effectiveness of specific resveratrol doses on specific populations.

In this sense, before prescribing resveratrol, patients should be properly advised for effective treatment with minimum side effects. Further evaluations are needed before declaring resveratrol as a beneficial compound for human health. Resveratrol is widely known for its renowned beneficial biological effects, namely involving its chemopreventive and antioxidant properties. However, some studies have documented that it may behave as a pro-oxidizing agent [ ]; thus, paradoxically, it may also have implication in pathology of several diseases.

Resveratrol antioxidant potential has been attributed to its ROS-scavenging capacity [ , ] and to an up regulation capacity on cells antioxidant defense [ ]. Studies have reported that resveratrol could act as a signaling molecule within tissues and cells in modulating genes and proteins expression through redox-sensitive intracellular pathways activation. Thus, cell tolerance against oxidative environment could be attributed to gene expression changes and to a raise in antioxidant defense systems action and synthesis, which eventually results in cell survival and adaptation [ , , ].

A study carried out by Martins et al. The authors documented that, although a dose-dependent resveratrol pro-oxidative effect leads to cells oxidative stress over lesser time exposure, at same dose but with an increase in exposure time, less expressive cytotoxicity was found.

This suggest that surviving cells seemed to be more resistant to resveratrol-induced damages, being its effects attenuated over treatment time [ ]. Additionally, low resveratrol doses 0. Diagrammatic representation of resveratrol biphasic activity and gene expression modulation.

In a very interesting study, dose-time dependency of acute resveratrol administration on lipoperoxidation levels in heart, liver and kidney of male rats synchronized with a h dark-light cycle was investigated. It was documented that resveratrol behaved as an antioxidant during dark span and as a pro-oxidant during light span, possibly reflecting the putative changing ratio between pro- and antioxidant activities in various organs during h cycle or postprandial oxidative burst that occurred after a meal [ ].

There is an interesting correlation among dietary polyphenols pro-oxidant and cytotoxic activities, such as to resveratrol. In this way, it has been proposed that such pro-oxidant action could be an important mechanism of action to resveratrol anti-cancer and apoptotic-inducing properties [ ]. It has already been reported that resveratrol can lead to DNA damages, as well as to a reversible or irreversible cell cycle interruption mediated by its pro-oxidant effect [ ].

Recently, Plauth et al. Also, it has been reported earlier that a critical balance between intracellular hydrogen peroxide H 2 O 2 and O 2 — decides cells fate to apoptotic stimuli. Thus, a shift towards H 2 O 2 favors apoptosis, whereas inclination towards O 2 - obstructs apoptosis.

Indeed, H 2 O 2 promotes apoptosis by reducing intracellular O 2 - concentration and triggering cytosolic pH drop. Ahmad et al. Fukuhara and Miyata, firstly reported resveratrol pro-oxidant activity in a plasmid-based DNA cleavage assay, in the presence of transition metal ions, such as copper, the most redox-active metal ions present in nucleus, serum and tissues [ , ].

Resveratrol is closely linked with DNA bases, particularly guanine [ ]. Copper ions from chromatin can be mobilized by metal-chelating agents, giving inter-nucleosomal DNA fragmentation rise, a property that is considered the hallmark of cells undergoing apoptosis.

In fact, since copper ions are known to be found in a nucleus bound to guanine bases in chromatin, the mobilization of such endogenous copper by resveratrol result in pro-oxidant DNA cleavage at the site. Moreover, copper concentration is reported to be raised in various malignancies; so, this study explains resveratrol anticancer activity [ ]. Based on its structural similarity to diethylstilbestrol, a synthetic estrogen, resveratrol can also acts as a phytoestrogen, exhibiting variable estrogen receptor agonist degrees in different systems [ ].

In some cell types, resveratrol acted as a super agonist, whereas in other ones, it produced an equal to or lesser activation than that of estradiol, and as an antagonist at higher concentrations. Such concentration-dependent agonist and antagonist behavior was employed to account for mechanisms underlying biphasic concentration response. At concentrations similar to those required for its other biological effects, resveratrol inhibited labelled estradiol binding to estrogen receptor and activated estrogen-responsive reporter genes transcription transfected into human breast cancer cells [ ].

In another report, it was demonstrated that resveratrol abolishes serum deprivation-induced elevated caspase 3 activity, suggesting its rescue effect via p38 MAPK signaling [ ]. Resveratrol also regulates mitochondrial respiratory chain function, with mitochondrial complex I CI as a direct target of this molecule. It was also in vivo demonstrated that, in young and old mice brain mitochondria, resveratrol increased CI, while in aged animals with low antioxidant defenses led to oxidative stress.

Therefore, not only dose, but also age at the time of treatment, can modulate intracellular and mitochondrial redox status, switching from resveratrol beneficial to deleterious effects, highlighting the importance of a balance between resveratrol pro- and antioxidant effects, that depends on its dose and age as well [ ].

Yang et al. All the above highlighted studies show the pivotal role of dose-dependency and aging in resveratrol-induced responses towards health benefits. Also, in another study, aiming to compare resveratrol effects on aging-induced and re-nutrition-induced insulin resistance and its consequences on arterial system, the authors found that resveratrol improved insulin sensitivity in old mice fed standard diet, while did not improve insulin resistance status in old mice receiving high-protein diets.

In contrast, resveratrol exhibited deleterious effects by increasing inflammation state and superoxide production and decreasing aortic distensibility. This data demonstrates that resveratrol seemed to be beneficial to malnourished state of physiological aging, whereas when associated with high protein diets in old mice, may increase atherogenesis-associated risk factors by triggering vascular alterations that could represent an additional risk factor for cardiovascular system [ ].

One of the most fascinating resveratrol aspects for its future development as a promising drug is that, it does not appear to have debilitating or toxic side effects. A wide range of resveratrol doses has been used in various in vivo and in vitro studies.

However, it is imperative to find out the most appropriate dose and administration route. Also, it was documented that resveratrol induces cell death in tumor tissues with relatively no effect in normal adjacent tissues [ 52 ]. Resveratrol cell uptake disparity between normal and tumor cells may be attributed to differences in available cellular targets and gene expression in cancer cells, which makes resveratrol tumor-specific.

Mukherjee et al. Resveratrol does not appear to have side effects at short-term doses 1. Otherwise, at doses of 2. Interestingly, no major side effects were stated in long-term clinical trials [ ]. However, it is imperative to mention that these studies were done in healthy populations, and that may vary in sick patients.

Our understanding of resveratrol dose-dependency and administration route is further complicated, since orally administrated resveratrol gets metabolized by gut microbiota [ ], which makes it difficult to determine which effects are solely due to resveratrol or both resveratrol and its metabolites. To investigate the assumption, whether resveratrol inhibit atherosclerotic development in hypercholesterolemic rabbits, Wilson et al. Plasma LDL electrophoretic mobility was not different between groups.

Atherosclerotic lesions staining in control and resveratrol-treated groups revealed that resveratrol-treated rabbits had significantly more aortic surface area covered by atherosclerotic lesions. Therefore, resveratrol promoted atherosclerotic development, rather than protect against it, by an independent mechanism of differences observed in gross animal health, liver function, plasma cholesterol concentrations, or LDL oxidative status [ ]. Ferry-Dumazet et al. It resulted in nephrotoxicity documented as elevated serum blood urea nitrogen and creatinine levels, increased kidney weights, gross renal pathology changes, and an increased incidence and severity of histopathological changes in kidneys.

Kidneys microscopic evaluation identified lesions whose pathogenesis could be increased by resveratrol concentration or its metabolite as a function of renal osmotic concentration gradients, resulting in toxic levels in renal pelvis. This would result in necrosis, renal tubules obstruction and thus tubules dilation behind obstructed region. Indeed, inflammation and pelvic epithelium hyperplasia are expected responses to the presence of necrotic tissues.

Similarly, organs evidencing weight change did not evidenced histological changes [ ]. Resveratrol has been reported to both reduce cell growth and induce apoptosis in normal cells, when administered at high doses, which confirm its biphasic effects over low to high concentrations spectrum [ ].

Resveratrol rapidly activate mitogen-activated protein kinase MAPK in a MEK-1, Src, matrix metalloproteinase, and epidermal growth factor receptor in a dependent manner. Additionally, resveratrol consumption at modest doses result in a life span increase in 1-year old mice.

Studies on steady-state pharmacokinetics and tolerability of mg trans -resveratrol, administered twice daily with food, quercetin and alcohol ethanol showed that trans -resveratrol was well-tolerated by healthy subjects, although diarrhea was frequently observed [ ].

The use of natural products is prevalent among patients who are taking conventional medicines, leading to a higher risk of natural product-drug interactions. Resveratrol may interact with several medications. It may lead to interactions with various cytochrome P CYP , especially when taken at high doses [ ]. Resveratrol has been reported to inhibit CYP3A4 activity, in vitro [ ] and in healthy volunteers [ ].

Therefore, high resveratrol intakes even in through form of supplements with additional medications could potentially reduce drugs metabolic clearance that undergo extensive first-pass CYP3A4 metabolism, hence increasing both bioavailability and toxicity risk of these drugs. Since this polyphenol has been reported to have significant interactions with phase I and II enzymes both in vitro and in vivo [ ], they may be beneficial or harmful as well. Indeed, individuals taking drugs, such as tamoxifen, whose efficacy is highly specific and CYP enzymes-dependent, could be particularly affected.

Therefore, caution should be taken when using supplemental resveratrol doses for health benefits, such as chemoprevention. Aside from drug metabolizing enzymes, it is now greatly acknowledged that transport function modifications are involved in these resveratrol-drug interactions. Nonetheless, resveratrol interactions with transporters are still not fully elucidated.

Furthermore, few clinical studies were conducted to determine transporter-mediated resveratrol-drug interaction. On the other hand, it is also speculated that higher resveratrol doses compete with other polyphenols for transporters, reducing both their uptake and potential synergistic effects.