For instance, RE treatment can enhance the oral bioavailability of nicardipine, and this was associated with a decrease of P-glycoprotein-mediated efflux, with P-glycoprotein being a major drug transporter [142]. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. The ability of RE to induce DNA breaks has a potential therapeutic use that can be harnessed when RE is used against cancerous cells. HHS Vulnerability Disclosure, Help Synergistic effects of combined phytochemicals and skin cancer prevention in SENCAR mice. ROS decreases NO production and bioavailability [124], while RE increases them [125,126]. Pezzuto JM. Symington B., Mapanga R.F., Norton G.R., Essop M.F. Although other targets such as SIRT have garnered great publicity, even though the response remains a polemic, it appears that anti-inflammation is the common denominator responsible for amelioration of a host of disease states and other beneficial effects. Cho KS, Lee EJ, Kwon KJ, Gonzales EL, Kim YB, Cheong JH, Bahn GH, Lee J, Han SH, Kim YT, Shin CY. Resveratrol promotes foot ulcer size reduction in type 2 diabetes patients. Yusuf Y, Nasti TH, Meleth S, Elmets CA. For instance, piceatannol enhances the expression of the antioxidant enzyme hemeoxygenase-1 (HO-1) in human mammary epithelial cells by induction of Nrf2 [85]. Liu Y, Liu C, Kou X, Wang Y, Yu Y, Zhen N, Jiang J, Zhaxi P, Xue Z. In this context, the compound is overtly promiscuous. RE is found in over 70 plant species but is highly concentrated in the skin of red grapes. As such, further studies are needed to assert the safety of RE against normal healthy cell lines, especially before promoting RE as an anti-cancer agent. 2022 Sep 9;11(18):2774. doi: 10.3390/foods11182774. In 2003, he published research on yeast in the journal Nature that said - "We show that the potent activator resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%." Heart Fail Rev. Biol. NADPH oxidases 1 and 4 mediate cellular senescence induced by resveratrol in human endothelial cells. Resveratrol is rapidly metabolized in athymic (nu/nu) mice and does not inhibit human melanoma xenograft tumor growth. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Another reason could be the metabolism of RE into RE sulfate and glucuronide conjugates [66,193,194]. . Biochim Biophys Acta. Resveratrol appears to have a di erent e ective dosage range in . Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and COX-2, are heavily used in the management of inflammatory conditions, but they are not without adverse gastrointestinal side effects. Indeed, RE was reported to be able to maintain or enhance human cerebrovascular functions [14], modulate in vitro angiogenesis through the expression of vascular endothelial growth factor (VEGF) and the formation of new vascular networks [15], stimulate human immune cell functions [16], promote rat cell viability and proliferation [17], ameliorate mitochondrial respiratory dysfunction, and enhance cellular reprogramming in human fibroblasts derived from patients with a mitochondrial disease [18], a phenomenon potentially mediated by the activation of Sirtuins [19]. RE is very well tolerated by experimental models with no major adverse effects. Alteration of the redox state of endothelial cells is a critical step in the onset and progression of CVD [158]. Sharma S, Kulkarni SK, Chopra K. Effect of resveratrol, a polyphenolic phytoalexin, on thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Indeed, RE can lead to apoptosis and cell-cycle arrest of malignant melanoma cells [131]. In addition, piceatannol could inhibit the phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK), leading to a decrease in the deposition of extracellular matrix proteins and amelioration of fibrosis in a mouse model of renal fibrosis [90]. In this regard, half-life and plasma concentrations of RE metabolites in the blood were found to be 10 times higher than that of the native RE compound [58], suggesting that free RE may be locally released from these metabolites. Frequency distribution of resveratrol intervention studies based on the health status of participants. Given the ongoing history of resveratrol, it is reasonable to advocate for additional development and further clinical investigation. Penumathsa SV, Koneru S, Samuel SM, Maulik G, Bagchi D, Yet SF, Menon VP, Maulik N. Strategic targets to induce neovascularization by resveratrol in hypercholesterolemic rat myocardium: role of caveolin-1, endothelial nitric oxide synthase, hemeoxygenase-1, and vascular endothelial growth factor. Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress. Biphasic activity of resveratrol on indomethacin-induced gastric ulcers. The publications were, Protein-protein interactions and plausible target, Protein-protein interactions and plausible target pathways (see text) of resveratrol. In the case of RE metabolism, o-quinones are formed through a hydroxylation reaction by cytochrome P450 (Figure 2), leading to the formation of piceatannol, followed by catechol oxidation to form an o-quinone product. Dr David Sinclair reveals about what are the current projects in his lab and comments on resveratrol controversy in this clip.David Sinclair is a professor i. Leon-Galicia I., Diaz-Chavez J., Garcia-Villa E., Uribe-Figueroa L., Hidalgo-Miranda A., Herrera L.A., Alvarez-Rios E., Garcia-Mena J., Gariglio P. Resveratrol induces downregulation of DNA repair genes in MCF-7 human breast cancer cells. Westerhof W., Manini P., Napolitano A., dIschia M. The haptenation theory of vitiligo and melanoma rejection: A close-up. Ito S., Fujiki Y., Matsui N., Ojika M., Wakamatsu K. Tyrosinase-catalyzed oxidation of resveratrol produces a highly reactive ortho-quinone: Implications for melanocyte toxicity. Resveratrol as Add-on Therapy in Subjects With Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial. Europe PMC is an archive of life sciences journal literature. Sirt1-nullmice develop tumors at normal rates but are poorly protected by resveratrol. Further advancements in RE carrier delivery should help alleviate the harmful effects of high doses of RE, not only in cancer treatment but also in other diseases where RE showed therapeutic effects. Akaberi M., Hosseinzadeh H. Grapes (Vitis vinifera) as a Potential Candidate for the Therapy of the Metabolic Syndrome. Wan D, Zhou Y, Wang K, Hou Y, Hou R, Ye X. Resveratrol provides neuroprotection by inhibiting phosphodiesterases and regulating the cAMP/AMPK/SIRT1 pathway after stroke in rats. Accessibility Huang W, Chen Z, Wang O, Lin M, Wu S, Yan Q, Wu F, Yu X, Xie X, Li G, Xu Y, Pan J. Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system. Reagan-Shaw S, Afaq F, Aziz MH, Ahmad N. Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hair-less mouse skin. Antioxidants (Basel). Guha P., Dey A., Chatterjee A., Chattopadhyay S., Bandyopadhyay S.K. They also demonstrated that RE exhibited a biphasic concentration-dependent effect on endothelial cells. Resveratrol: Twenty Years of Growth, Development and Controversy. The author is grateful to Dr. Eun-Jung Park for her invaluable help in accumulating some of the data given in this report, as well as exceptional assistance with the graphics. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. Thus, it is of utmost importance to homogenize the results of animal testing by conducting experiments with similar study designs prior to even attempting to study the effects of RE in humans. Ponzo V., Soldati L., Bo S. Resveratrol: A supplementation for men or for mice? Lee TH, Seo JO, Baek SH, Kim SY. Accessibility To a large extent, this is based on animal models investigating conditions such as neuropathic pain [thermal hyperalgesia (Sharma et al., 2006, 2007; Kumar et al., 2007), cold allodynia (Sharma et al., 2006)], sensory neuropathy [e.g., thermal hypoalgesia with an increase in intraepidermal nerve fiber loss and the mean axonal diameter of myelinated axons of the tibial nerve (Chowdhury et al., 2012], cerebral infarction upon I/R exposure (Prabhakar, 2013), neurodegeneration (Jing et al., 2013), the reduction in motor nerve conduction velocity (Kumar et al., 2007), nerve blood flow (Kumar et al., 2007), DNA damage and apoptosis in sciatic nerve sections (Kumar et al., 2007), memory impairment (Schmatz et al., 2009), anxiety (Damin et al., 2014), and neuroinflammation (astrocytic activation) (Jing et al., 2013). sharing sensitive information, make sure youre on a federal Resveratrol protects vascular endothelial cells from high glucose-induced apoptosis through inhibition of NADPH oxidase activation-driven oxidative stress. The ROS/RNS molecules usually have dual roles in both health and disease; ROS/RNS at low or moderate concentrations contribute to basic physiology such as blood pressure regulation, neurotransmission, and immune responses. Resveratrol and cancer: Focus on in vivo evidence. An official website of the United States government. Smoliga JM, Baur JA, Hausenblas HA. Carboni L. Peripheral biomarkers in animal models of major depressive disorder. Jang M, Pezzuto JM. Furthermore, it was suggested that plasma proteins may act as in vivo natural reservoirs for antioxidants. 1) was . Unauthorized use of these marks is strictly prohibited. The first phase I clinical trial looking at RE as a therapy in human cancer patients was published in 2009 [200]. Therefore, orally administered high doses (more than 1000 mg/day) of RE indicate differences in pharmacokinetics of concomitantly administered drugs. In this regard, low doses of RE have diverse beneficial actions, such as protecting cells and tissues against neurodegeneration, cardiovascular disease, cancer, diabetes, and obesity-related disorders and extending the lifespan of organisms [119,120]. Systematic review and recommendations on the use of resveratrol. Fabbrocini G, Staibano S, De Rosa G, Battimiello V, Fardella N, Ilardi G, La Rotonda MI, Longobardi A, Mazzella M, Siano M, Pastore F, De Vita V, Vecchione ML, Ayala F. Resveratrol-containing gel for the treatment of acne vulgaris: a single-blind, vehicle-controlled, pilot study. A combination of RE and vitamin D3 was shown to effectively reduce TNF- and IL-6 expression when compared to individual drug treatments [218]. Interestingly, even chronobiology was shown to play a role in RE varying effects; when administered during the dark span, RE exerted an antioxidant effect by decreasing lipid peroxidation, whereas, during the light span, RE increased lipid peroxidation [39]. Synergistic Hypolipidemic Effects and Mechanisms of Phytochemicals: A Review. Biofactors. Perhaps of equal importance, resveratrol has become a household word in the context of a natural product that has the potential of promoting good health. Even at very high daily doses with human beings, e.g., 5 g/day, side effects are mild (Brown et al., 2010). Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Four-week administration of RE at 0, 300, 1000, and 3000 mg/kg/day failed to induce adverse effects up to 300 mg/kg/day, while dosage of 1000 and 3000 mg/kg/day induced renal toxicity [35]. This may be due to factors such as disparate doses (ca. Given that evidence-based responses are sparse and controversial, such claims, innuendo and hyperbole are atrocious. Duenas-Garcia I.E., Heres-Pulido M.E., Arellano-Llamas M.R., De la Cruz-Nunez J., Cisneros-Carrillo V., Palacios-Lopez C.S., Acosta-Anaya L., Santos-Cruz L.F., Castaneda-Partida L., Duran-Diaz A. Lycopene, resveratrol, vitamin C and FeSO4 increase damage produced by pro-oxidant carcinogen 4-nitroquinoline-1-oxide in Drosophila melanogaster: Xenobiotic metabolism implications. Mokni M., Hamlaoui S., Karkouch I., Amri M., Marzouki L., Limam F., Aouani E. Resveratrol Provides Cardioprotection after Ischemia/reperfusion Injury via Modulation of Antioxidant Enzyme Activities. Topical preparations seem especially promising, as do conditions that can respond to anti-inflammatory action and/or direct exposure, such as colon cancer prevention. RNS include an unreactive species, nitric oxide (NO), and its derivative, peroxynitrite (ONOO), a powerful oxidant which can destroy many biomolecules [117]. These include nanoparticles, liposomes, and emulsions [207,208]. Topical application of resveratrol is the most commonly used route of treatment in skin cancer models. Crowell J.A., Korytko P.J., Morrissey R.L., Booth T.D., Levine B.S. Hence, RE can be used to prevent cancer formation at its early stages or halt the progression and subsequent metastasis by acting as a cytotoxic agent [202,203,204,205,206]. Resveratrol mobilizes endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage: a putative mechanism for chemoprevention of cancer. In line, RE promoted the rapid increase in ROS levels, which resulted in a significant pro-oxidant activity [40] and apoptosis of endothelial cells [41]. Resveratrol modification can also occur via intestinal and hepatic conjugation reactions. 2018 Jan;44(1):69-82. doi: 10.1002/biof.1400. When published, the results of such trials are expected to unravel more data into the use of RE in humans [187,188,189,190]. However, low concentrations of RE (5 M) stimulated the proliferation of these cells. Metabolic effects of resveratrol: addressing the controversies Resveratrol: Twenty Years of Growth, Development and Controversy Biomol Ther (Seoul). Resveratrols health benefits were first highlighted in the early 1990s in the French paradox study, which opened extensive research activity into this compound. A 450 mg/day dose of RE was reported to be a safe dose for a 60-kg person [184]. This offers a window of opportunity, which can be harnessed as a potential chemotherapy against several cancers (Figure 1 and Figure 3). Howells L.M., Berry D.P., Elliott P.J., Jacobson E.W., Hoffmann E., Hegarty B., Brown K., Steward W.P., Gescher A.J. Mitochondrial biogenesis: pharmacological approaches. Biochim Biophys Acta. Bookshelf As noted above, based on a survey of the literature, there appears to be a high probability of resveratrol being of some value for neuronal diseases (FDR, 5.64e-47). Disclaimer. Interestingly, it was proposed that the pro-oxidant action of plant polyphenols, such as RE, could be a common mechanism for their cytotoxic properties that may inhibit the malignant phenotype of cancer cells [130,131]. Extremely rapid sulfate conjugation of RE in the intestine/liver looks to be the rate-limiting factor in determining the bioavailability of RE [66]. The finding should dispel much of and controversy about how resveratrol really works. Camont L., Cottart C.H., Rhayem Y., Nivet-Antoine V., Djelidi R., Collin F., Beaudeux J.L., Bonnefont-Rousselot D. Simple spectrophotometric assessment of the trans-/cis-resveratrol ratio in aqueous solutions. Anyone have insight into controversy about David Sinclair? Isomerization to the cis form can occur when the trans form is exposed to heat, light, or ultraviolet radiation [7,8]. Resveratrol-mediated downregulation of Rictor attenuates autophagic process and suppresses UV-induced skin carcinogenesis. Lifespan News - Update on Resveratrol Controversy above 25 M) from what may be the RE toxic dose in vivo. Pierce E.N., Piyankarage S.C., Dunlap T., Litosh V., Siklos M.I., Wang Y.T., Thatcher G.R. Takaoka M. Resveratrol, a new phenolic compound, from Veratrum grandiflorum. HHS Vulnerability Disclosure, Help Resveratrolthe hype continues - Harvard Health Levels of selenium, zinc, copper, and antioxidant enzyme activity in patients with leukemia. COVID-19 Get the latest information from the CDC about COVID-19. Resveratrol potential activates multiple targets, converging on pathways that lead to mitochondrial biogenesis and fatty acid oxidation. Fox J.T., Sakamuru S., Huang R., Teneva N., Simmons S.O., Xia M., Tice R.R., Austin C.P., Myung K. High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death. In the gut (right), where resveratrol concentrations are likely higher than plasma in animals, resveratrol leads to secretion of GLP-1 and an improvement in glucose tolerance. PGC-1 Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response. Pezzuto JM. Park DW, Baek K, Kim JR, Lee JJ, Ryu SH, Chin BR, Baek SH. The study also provides insight into another important aspect of the resveratrol controversy. Carter L.G., DOrazio J.A., Pearson K.J. The polyphenol mixture was able to significantly inhibit cell proliferation cell migration and matrix metalloproteinases (MMP) secretion [217]. Cragg GM, Pezzuto JM. Sun Y., Zhou Q.M., Lu Y.Y., Zhang H., Chen Q.L., Zhao M., Su S.B. Fontecave M., Lepoivre M., Elleingand E., Gerez C., Guittet O. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. While the actual levels of RE in organs and tissue of humans remain under investigation, multiple lines of evidence indicate that, in rodents, RE can accumulate in specific tissues or organs at relatively high concentrations, that are comparable to those used in many in vitro experiments. Ranawat P., Khanduja K.L., Pathak C.M. Sergi D., Naumovski N., Heilbronn L.K., Abeywardena M., OCallaghan N., Lionetti L., Luscombe-Marsh N. Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet. Ndiaye M, Philippe C, Mukhtar H, Nihal Ahmad N. The grape antioxidant resveratrol for skin disorders: promise, prospects, and challenges. One such supplement is resveratrol. The inhibition of resveratrol to human skin squamous cell carcinoma A431 xenografts in nude mice. Baxter RA. Green arrows represent activation and red bars represent inhibition. Zhang J., Chen J., Yang J., Xu C.W., Pu P., Ding J.W., Jiang H. Resveratrol attenuates oxidative stress induced by balloon injury in the rat carotid artery through actions on the ERK1/2 and NF-kappa B pathway. . Ozturk Y., Gunaydin C., Yalcin F., Naziroglu M., Braidy N. Resveratrol Enhances Apoptotic and Oxidant Effects of Paclitaxel through TRPM2 Channel Activation in DBTRG Glioblastoma Cells. However, as highlighted in the introduction, under certain conditions, an antioxidant may act as a pro-oxidant, leading to acceleration of lipid peroxidation and/or induction of DNA damage. Furthermore, data on the interactions of RE when combined with other therapies are still lacking, as well as results related to its absorption and bioavailability in the human body. In addition, RE was shown to interact with several drugs. In this process, we analyze in vitro and in vivo studies that have addressed this stilbenoid. doi: 10.2165/11530630-000000000-00000. Soleas GJ, Grass L, Josephy PD, Goldberg DM, Diamandis EP. In silico and in vitro inhibition of cytochrome P450 3A by synthetic stilbenoids. DAngelo S., Martino E., Ilisso C.P., Bagarolo M.L., Porcelli M., Cacciapuoti G. Pro-oxidant and pro-apoptotic activity of polyphenol extract from Annurca apple and its underlying mechanisms in human breast cancer cells. Inhibition of yet another high affinity target, QR2, may also contribute to an anti-inflammatory effect. Bhat KP, Pezzuto JM. TriCurin, a novel formulation of curcumin, epicatechin gallate, and resveratrol, inhibits the tumorigenicity of human papillomavirus-positive head and neck squamous cell carcinoma. Further, molecular targets are numerous and a dominant mechanism is elusive or nonexistent. There's been some controversy recently regarding resveratrol and the work of Dr. David Sinclair. Anton S.D., Ebner N., Dzierzewski J.M., Zlatar Z.Z., Gurka M.J., Dotson V.M., Kirton J., Mankowski R.T., Marsiske M., Manini T.M. It was shown that RE can act as a substrate of tyrosinase, a key enzyme in the production of melanin, to produce reactive o-quinones [92,95].
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