Administration Of Resveratrol Research Articles

Reprogramming of ovarian aging epigenome by resveratrol.

Resveratrol is an antiaging, antioxidant, and anti-inflammatory natural polyphenolic compound. Growing evidence indicates that resveratrol has potential therapeutic effects for improving aging ovarian function. However, the mechanisms underlying prolonged reproductive longevity remain elusive. We found that resveratrol ameliorates ovarian aging transcriptome, some of which are associated with specific changes in methylome. In addition to known aging transcriptome of oocytes and granulosa cells such as decline in oxidoreductase activity, metabolism and mitochondria function, and elevated DNA damage and apoptosis, actin cytoskeleton are notably downregulated with age, and these defects are mostly rescued by resveratrol. Moreover, the aging-associated hypermethylation of actin cytoskeleton is decreased by resveratrol. In contrast, deletion of Tet2, involved in DNA demethylation, abrogates resveratrol-reprogrammed ovarian aging transcriptome. Consistently, Tet2 deficiency results in additional altered pathways as shown by increased mTOR and Wnt signaling, as well as reduced DNA repair and actin cytoskeleton with mouse age. Moreover, genes associated with oxidoreductase activity and oxidation-reduction process were hypermethylated in Tet2-deficient oocytes from middle-age mice treated with resveratrol, indicating that loss of Tet2 abolishes the antioxidant effect of resveratrol. Taking together, our finding provides a comprehensive landscape of transcriptome and epigenetic changes associated with ovarian aging that can be reprogrammed by resveratrol administration, and suggests that aberrantly increased DNA methylation by Tet2 deficiency promotes additional aging epigenome that cannot be effectively restored to younger state by resveratrol.

763 ACTIVATION OF SIRT1 ATTENUATES VASCULAR DYSFUNCTION AND THROMBOSIS IN MTHFR DEFICIENCY

Abstract Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/-) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/- mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.

Resveratrol against Cervical Cancer: Evidence from In Vitro and In Vivo Studies.

Cervical cancer affects many women worldwide, with more than 500,000 cases diagnosed and approximately 300,000 deaths each year. Resveratrol is a natural substance of the class of phytoalexins with a basic structure of stilbenes and has recently drawn scientific attention due to its anticancer properties. The purpose of this review is to examine the effectiveness of resveratrol against cervical cancer. All available in vitro and in vivo studies on cervical cancer were critically reviewed. Many studies utilizing cervical cancer cells in culture reported a reduction in proliferation, cell cycle arrest, and induction of apoptosis. Apart from apoptosis, induction of autophagy was seen in some studies. Importantly, many studies have shown a reduction in the HPV oncoproteins E6 and E7 and increased levels of the tumor suppressor p53 with resveratrol treatment. A few studies examined the effects of resveratrol administration in mice ectopic-xenografted with cervical cancer cells showing reduced tumor volume and weight. Overall, the scientific data show that resveratrol has the ability to target/inhibit certain signaling molecules (EGFR, VEGFR, PKC, JNK, ERK, NF-kB, and STAT3) involved in cervical cancer cell proliferation and survival. Further in vivo experiments and clinical studies are required to better understand the potential of resveratrol against cervical cancer.

Abstract A020: Exploring the effects of resveratrol on the gut microbiome in high fat diet-fed BRAFV600E mutant mice

Abstract The polyphenol resveratrol, widely known for its cancer protective activities has been shown to protect against the pro-tumorigenic effects induced by high-fat diets (HFD) in mouse models of colorectal cancer (CRC). Although, the mechanisms of actions of this compound in humans still remain elusive, recent studies suggest its effects may be mediated partly through its interaction with the gut microbiota. Here we sought to determine the changes induced by HFD on the intestinal microbiome and the impact of resveratrol supplementation on these alterations in a mouse model of BRAFV600E mutant CRC. BRAFV600E; BRAFWT (wild-type) mice were randomised into 8 groups and fed either a standard diet or HFD supplemented with low or high-dose of resveratrol (0.7mg/kg/day and 14mg/kg/day, respectively) for 6-weeks. The mouse faecal microbial profile was then assessed by targeting the V3-V4 area of the bacterial 16S rRNA gene. Consumption of HFD was associated with significant alternations in the gut microbiome composition in both BRAFV600E and BRAFWT based on beta-diversity analysis (PADONIS<0.05). HFD increased the Firmicutes and Clostridia abundance in BRAFWT compared to animals on a standard diet (P<0.01, P<0.008 respectively), while in BRAFV600E mice, alterations were observed in lower taxonomic levels including the enrichment of Faecalibaculum (P<0.02) and growth inhibition of Lactobacillus johnsonhii (P<0.05). High-dose resveratrol resulted in significant differences in the microbial composition compared to HFD-treated group in the BRAFV600E mice (PADONIS<0.05) but not in BRAFWT . Resveratrol administration did not counteract the HF-induced taxonomic changes but high-dose resveratrol changed Muribaculum, and UBA181 genera abundances in BRAFV600E mice (P<0.001 and P<0.05 respectively) compared to HF-treated mice. Low dose resveratrol had no significant effects on bacterial abundance in both BRAFV600E and BRAFWT mice. It was also observed that BRAFV600E mutation influenced the gut microbiome independently of diet based on beta and alpha-diversity (PADONIS<0.05, PChao1<0.05 respectively). Resveratrol administration modified the gut microbiota composition of BRAFV600E mice but did not completely reverse the HFD-induced changes indicating that alternative mechanisms may contribute to the protective effects of resveratrol in this mouse model. Citation Format: Despoina Theofanous, Hong Cai, Karen Brown. Exploring the effects of resveratrol on the gut microbiome in high fat diet-fed BRAFV600E mutant mice [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A020.

Protective effect of resveratrol against pembrolizumab-induced hepatotoxicity and neurotoxicity in male rats.

The present study investigates the effects of resveratrol (RSV) on brain and liver tissues in rats with pembrolizumab (PEMB)-induced toxicity. Obtained for the study were 28 male Sprague-Dawley rats (3-4 months old) which were divided into four groups: Group 1: Control. Group 2: Administered PEMB at 5 mg/kg/day i.p. for a week. Group 3: Administered RSV orally at the dose of 20 mg/kg/day for 30 days by gavage. Group 4: Administered PEMB and RSV at 20and 5 mg/kg/day RSV, respectively, for 30 days. The results of this study revealed that PEMB leads to a significant increase in thiobarbituric acid reactive substance (TBARS) levels and a significant decrease in glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) activities, and glutathione (GSH) levels in the liver and brain tissues. The decreased SOD, CAT, GPx activities, and GSH levels increased significantly following RSV treatment in Group 4. The PEMB treatment showed histopathological alterations associated with strong positive cysteinyl aspartic acid-protease-3 (caspase-3) immunoreactivity, while RSV treatment reduced both the expression of caspase-3 protein and the histopathological changes. RSV administration prevents the biochemical, immunological, and histological alterations induced by PEMB. It can be suggested that the lower caspase-3 immunoreactivity in the PEMB + RSV group than in the PEMB group led to an inhibition of RSV on apoptosis.

Determination of Metabolomics Profiling in BPA-Induced Impaired Metabolism.

Exposure to bisphenol A (BPA) is unavoidable and it has far-reaching negative effects on living systems. This study aimed to explore the toxic effects of BPA in an experimental animal model through a metabolomics approach that is useful in measuring small molecule perturbations. Beside this, we also examined the ameliorative effects of resveratrol (RSV) against BPA-induced disturbances in experimental mice. This study was conducted for 28 days, and the results showed that BPA indeed induced an impairment in amino acid metabolism, taking place in the mitochondria by significantly (p < 0.05) decreasing the levels of certain amino acids, i.e., taurine, threonine, asparagine, leucine, norleucine, and glutamic acid in the mice plasma. However, the administration of RSV did prove effective against the BPA-induced intoxication and significantly (p < 0.05) restored the level of free amino acids. Lipid metabolites, L-carnitine, sphinganine, phytosphingosine, and lysophosphatidylcholine were also determined in the mice serum. A significant (p < 0.05) decline in glutathione peroxidase (GPx), superoxide dismutase (SOD,) glutathione, and catalase levels and an elevation in malondialdehyde level in the BPA group confirmed the generation of oxidative stress and lipid peroxidation in experimental mice exposed to BPA. The expression of Carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II (CPT-II), lecithin-cholesterol acyltransferase (LCAT), carnitine O-octanoyltransferase (CROT), carnitine-acylcarnitine translocase (CACT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) genes was significantly upregulated in the liver tissue homogenates of experimental mice exposed to BPA, although RSV regulated the expression of these genes when compared with BPA treated experimental mice. CPT-I, CPT-II, and CACT genes are located in the mitochondria and are involved in the metabolism and transportation of carnitine. Hence, this study confirms that BPA exposure induced oxidative stress, upregulated gene expression, and impaired lipid and amino acid metabolism in experimental mice.

The role of Sirt3-induced autophagy in renal structural damage caused by periodontitis in rats.

This research aimed to explore the effect of periodontitis on renal tissues injury in rats and the role of Sirtuin3 (Sirt3) and its regulation of autophagy in this progression. Thirty Wistar rats were assigned into three groups: control, periodontitis (P), and periodontitis with gavage administration of Sirt3 activator resveratrol (P + RSV). To induce periodontitis, the wire ligature was placed around the cervical region of the rat maxillary first molar. After 8 weeks, micro-computed tomography (Micro-CT) and hematoxylin and eosin (HE) were used to evaluate the alveolar bone resorption and periodontal inflammation. Serum and urine biochemical indicators were measured to assess renal function. The pathological changes of the kidney were observed via HE and periodic acid Schiff (PAS) staining. Autophagosome was viewed by transmission electron microscopy (TEM). Real-time PCR and western blot were used to test expressions of Sirt3 and autophagy indicators in renal and periodontal tissues, including mammalian target of rapamycin (mTOR), phosphor-mTOR (p-mTOR), BECN1 (Beclin-1), and microtubule-associated protein 1 light chain 3 (LC3). Alveolar bone destruction, resorption, and periodontal inflammation were observed in the P group (compared with the control group), and the above indexes were significantly improved after RSV intervention; the obvious changes in renal tissue structure in the P group were partially recovered after RSV intervention, while renal functional status was not affected (among the three groups); in addition, the levels of Sirt3 and autophagy in kidney and periodontal tissues of P group were inhibited, manifested as a decrease in the number of autophagosomes (renal tissue) and expressions of autophagy marker Beclin-1 and LC3 conversion rate and an increase in the expression of p-mTOR. After Sirt3 activation (RSV), the above indicators were significantly improved. Periodontitis causes renal structural damage in rats, which may be connected to the effect of Sirt3-induced autophagy.

Pumpkin (Cucurbita pepo) Fruit Extract Attenuates Paraquat-induced Toxicity in Wister Rats

Introduction: Paraquat is a bipyridil herbicide commonly used in modern agriculture for weed and pest control. Paraquat poisoning usually occurs through direct ingestion for suicidal intent, causing mortality as a consequence to oxidative damage, inflammation and multi-organ failure.
 Objectives: In this study, we investigated the ameliorative potential of Cucurbita pepo fruit on paraqaut-induced oxidative damage, inflammation, hyperlipidemia, hepatotoxicity and nephrotoxicity in rats.
 Methods: Rats were orally administered paraquat (2 mg/kg b.w) with or without the fruit extract (500 mg/kg b.w) or resveratrol (3.57 mg/kg b.w) co-administration for 2 weeks.
 Results: We found C. pepo fruit extract significantly restored paraquat-induced oxidative damage, acute inflammation and hyperlipidemia. Reduced glutathione (GSH) concentration was significantly abridged in paraquat treated group, while the concentration of GSH increases substantially across groups administered fruit extract and resveratrol. Furthermore, paraquat induced concomitant reduction in the activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD), which was restored by the fruit extract and resveratrol. However, nitric oxide level demonstrated a substantial elevation in paraquat-treated group, but restored by both the fruit extract and resveratrol. Moreover, pumpkin fruit extract and resveratrol supplementation suppressed overproduction of total cholesterol, triglycerides, low density lipoproteins, high density lipoproteins and thus, alleviated paraquat-induced hyperlipidemia. In addition, administration of C. pepo fruit extract and resveratrol ameliorated the hepatotoxic and nephrotoxic effect caused by paraquat.
 Conclusion: We conclude that C. pepo fruit extract and resveratrol administration ameliorated oxidative damage, acute inflammation, hyperlipidemia, hepatotoxicity and nephrotoxicity caused by paraquat ingestion.

Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models

Sanfilippo disease, caused by mutations in the genes encoding heparan sulfate (HS) (a glycosaminoglycan; GAG) degradation enzymes, is a mucopolysaccharidosis (MPS), which is also known as MPS type III, and is characterized by subtypes A, B, C, and D, depending on identity of the dysfunctional enzyme. The lack of activity or low residual activity of an HS-degrading enzyme leads to excess HS in the cells, impairing the functions of different types of cells, including neurons. The disease usually leads to serious psychomotor dysfunction and death before adulthood. In this work, we show that the use of molecules known as dietary (poly)phenolic antioxidants and other natural compounds known as autophagy activators (genistein, capsaicin, curcumin, resveratrol, trehalose, and calcitriol) leads to accelerated degradation of accumulated HS in the fibroblasts of all subtypes of MPS III. Both the cytotoxicity tests we performed and the available literature data indicated that the use of selected autophagy inducers was safe. Since it showed the highest effectivity in cellular models, resveratrol efficacy was tested in experiments with a mouse model of MPS IIIB. Urinary GAG levels were normalized in MPS IIIB mice treated with 50 mg/kg/day resveratrol for 12 weeks or longer. Behavioral tests indicated complete correction of hyperactivity and anxiety in these animals. Biochemical analyses indicated that administration of resveratrol caused autophagy stimulation through an mTOR-independent pathway in the brains and livers of the MPS IIIB mice. These results indicate the potential use of resveratrol (and possibly other autophagy stimulators) in the treatment of Sanfilippo disease.

Healing effects of monomer and dimer resveratrol in a mouse periodontitis model

BackgroundThe antioxidant and anti-inflammatory effects of resveratrol have been reported previously. Particularly, monomeric trans-resveratrol has been demonstrated to produce positive effects in various pathological processes. We reported previously that resveratrol dimer-rich melinjo extract, among others, caused bone healing, decreased local oxidative damage, and activated antioxidants nuclear factor erythroid 2-related factor 2 (Nrf2) pathways in a mouse model of experimentally induced periodontitis (EP). This study aimed to compare the bone-healing effects of the resveratrol monomer to the resveratrol dimer (gnetin C found in melinjo seed extract) in a model of EP and investigate the involvement of Nrf2 for effects of either form of resveratrol.MethodsEP was induced experimentally in mice by placement of a 9 − 0 silk ligature around the left second molar. Mice received 10 mg/kg of either resveratrol monomer or dimer intraperitoneally on day 15 after induction of EP. The bone level around the ligated teeth was measured over time, and levels of proinflammatory cytokines and oxidative stress were measured in the periodontal tissues around the ligated teeth.ResultsResveratrol dimer induced greater periodontal bone healing as compared to that related to use of the resveratrol monomer. It appears that healing of periodontal bone in either group was likely related to master regulation of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) significantly. Downregulation of IL-1β, a proinflammatory cytokine was also demonstrated in the resveratrol dimer group.ConclusionOur results showed that administration of resveratrol in either dimer form or the monomeric form reduced periodontal bone loss with greater inhibition of bone loss being demonstrated in the dimer group as compared to the monomer group and that these effects were related in all likelihood to decreased oxidative stress and hence reduction in local inflammation.

Evaluation of curcumin or resveratrol administration on the gene expression of DNA-modifying enzymes in a doxorubicin-induced chemobrain model

Evaluation of curcumin or resveratrol administration on the gene expression of DNA-modifying enzymes in a doxorubicin-induced chemobrain model

Effect of Andrographolide and Resveratrol on OX1R and Prepro-orexin mRNA expression in CIPN-induced hypothalamus of mice with oxaliplatin

Chemotherapy-induced peripheral neuropathy (CIPN) is a one of side effect in cancer patients that receive antineoplastic agent, like oxaliplatin. Orexinergic system in the hypothalamus is the one of system that modulate nociceptive and neuropathy. Because there is flavonoids such as resveratrol and andrographolide that may prevent chemotherapy induced peripheral neuropathy, this study analyzed effects of andrographolide and resveratrol treatment on PPOrx and OX1R mRNA expression in hypothalamic oxaliplatin-induced mice. Materials and Methods This study was conducted for 22 days in mice. Mice injected with oxaliplatin followed by andrographolide or resveratrol. Chemotherapy induced peripheral neuropathic pain was assessed based on withdrawal threshold, mRNA PPOrx expression, and mRNA OX1R expression. Results The results showed that intraperitoneal injection of 100mg/kg resveratrol and 20mg/kg andrographolide increased the withdrawal threshold after oxaliplatin induction. Resveratrol administration also increased the relative expression of PPOrx mRNA significantly, but not the OX1R mRNA relative expression. On the other hand, administration of andrographolide did not cause a change in the expression of PPOrx and OX1R in the hypothalamus. Conclusions Intraperitoneal injection of andrographolide and resveratrol reduces the mechanical allodynia response in oxaliplatin-induced mice significantly. The mechanism of andrographolide increases the withdrawal threshold does not via the orexinergic system, but the mechanism of resveratrol via the orexinergic system.

Long-term administration of resveratrol and MitoQ stimulates cavernosum antioxidant gene expression in a mouse castration model of erectile dysfunction

AimsErectile dysfunction is a common complication within many pathological conditions associated with low testosterone. Testosterone deficiency increases oxidative stress in the penile tissue that contributes to endothelial dysfunction and subsequent erectile dysfunction. Current therapies do not ameliorate oxidative stress so targeting oxidative stress may improve erectile dysfunction. Resveratrol and MitoQ are two prospective drugs that have antioxidant-like properties and may be useful to improve erectile dysfunction induced by androgen deprivation. Materials and methodsWe castrated 12-week-old male C57BL/6 mice and performed an eight-week intervention with oral delivery of resveratrol or MitoQ at low and high doses. We assessed vascular reactivity of the corpus cavernosum and internal pudendal arteries (IPA) through dose-dependent responses to vasodilatory, vasocontractile, and neurogenic stimuli in a myograph system. We performed qRT-PCR to measure expression changes of 18 antioxidant genes in the corpus cavernosum. Key findingsCastration significantly impaired erectile function via impaired endothelial-dependent and-independent relaxation, and increased constriction of the corpus cavernosum, and induced severe endothelial dysfunction of the IPA. Castration decreased expression of 8 of the antioxidant genes investigated. Resveratrol and MitoQ were ineffective in reversing the effects of androgen deprivation on vascular reactivity, however high-dose resveratrol treatment upregulated several key antioxidant genes, including Cat, Sod1, Gstm1, and Prdx3. SignificanceOur findings suggest that oral resveratrol and MitoQ treatment may provide protection to the corpus cavernosum under androgen deprived conditions by stimulating endogenous antioxidant systems. However, they may need to be paired with vasoactive drugs to reverse erectile dysfunction under androgen deprived conditions.

Resveratrol therapy improves liver function via estrogen-receptors after hemorrhagic shock in rats.

BackgroundResveratrol may improve organ dysfunction after experimental hemorrhagic or septic shock, and some of these effects appear to be mediated by estrogen receptors. However, the influence of resveratrol on liver function and hepatic microcirculation after hemorrhagic shock is unknown, and a presumed mediation via estrogen receptors has not been investigated in this context.MethodsMale Sprague-Dawley rats (200-300g, n = 14/group) underwent hemorrhagic shock for 90 min (MAP 35±5 mmHg) and were resuscitated with shed blood and Ringer’s solution. Animals were treated intravenously with vehicle (1% EtOH), resveratrol (0.2 mg/kg), the unselective estrogen receptor antagonist ICI 182,780 (0.05 mg/kg) or resveratrol + ICI 182,780 prior to retransfusion. Sham-operated animals did not undergo hemorrhage but were treated likewise. After 2 hours of reperfusion, liver function was assessed either by plasma disappearance rate of indocyanine green (PDRICG) or evaluation of hepatic perfusion and hepatic integrity by intravital microscopy, serum enzyme as well as cytokine levels.ResultsCompared to vehicle controls, administration of resveratrol significantly improved PDRICG, hepatic perfusion index and hepatic integrity after hemorrhagic shock. The co-administration of ICI 182,780 completely abolished the protective effect only with regard to liver function.ConclusionsThis study shows that resveratrol may improve liver function and hepatocellular integrity after hemorrhagic shock in rats; estrogen receptors mediate these effects at least partially.

Morphological, ultrastructural, and biochemical changes induced by sodium fluoride in the tongue of adult male albino rat and the ameliorative effect of resveratrol.

Little knowledge is available about the effects of fluoride exposure on the tongue. This study evaluated the effects of sodium fluoride (NaF) on the tongue ultrastructure and detected the ameliorative effects of resveratrol. Forty adult albino rats were separated into 4 groups: the control group was given a balanced diet and purified water. The NaF treated group: received 10 mg/kg/d dissolved in 2.5 ml distilled water once daily for 30 days orally. The NaF+resveratrol group: received NaF 10 mg/kg/d orally together with resveratrol in a dose of 30 mg/kg daily for 30 days. The resveratrol group was subjected to resveratrol in a dose of 30 mg/kg/d by oral gavage for 30 days. Sections were stained with hematoxylin & eosin, and Masson's trichrome. Tumor necrosis factor α immunohistochemical study and electron microscopic examinations were done. The oxidative stress markers malondialdehyde, antioxidant reduced glutathione, and the total antioxidant capacity were measured. The NaF group revealed ulceration, necrotic muscle fibers, distorted papillae and a significant increase in malondialdehyde level, and a significant decrease in glutathione and the total antioxidant levels. In the NaF+resveratrol group, pathological changes were less, and the oxidant levels were decreased by the administration of resveratrol with NaF. In conclusion, NaF adversely affects the ultrastructure of the adult rat tongue and resveratrol can ameliorate this effect.

Resveratrol Treatment of Autism Spectrum Disorder-A Pilot Study.

Considering autism spectrum disorder (ASD) as a neurodevelopmental condition associated with immune system impairments, we aimed to evaluate the potential benefits, efficacy, tolerability, and safety of the anti-inflammatory, antioxidant, and neuroprotective trans -resveratrol (RSV) in behavioral impairments and in a set of 8 microRNAs (miR) related to the immune system in pediatric subjects with ASD. This is an open-label pilot trial over a 3 months (90 days) study follow-up period designed to assess the effect of 200 mg/d RSV on 5 boys aged 10 to 13 (11.8 ± 1.1) years diagnosed with ASD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition . The RSV treatment significantly reduced the Aberrant Behavior Checklist total score ( P = 0.042) and Irritability ( P = 0.041), with no alteration in Stereotypical Behavior ( P = 0.066), Hyperactivity ( P = 0.068), and Lethargy/Social Withdrawal ( P = 0.078) subscales. On the Clinical Global Impression scale, 3 individuals showed marked improvement in behavior; one showed mild improvement, and the other had no changes. The RSV treatment increased the miR-195-5p ( P = 0.043), an important modulator of targets related to inflammatory and immunological pathways. RSV administration did not present adverse effects and did not alter clinical laboratory results. RSV is a safe molecule for administrating in the pediatric population, able to modulate behavior alterations and molecules associated with the immune system, becoming a promising therapeutic strategy for large-scale studies in ASD, to investigate both behavioral and molecular approaches.

Effects of Resveratrol Against Induced Metabolic Syndrome in Rats: Role of Oxidative Stress, Inflammation, and Insulin Resistance.

Metabolic syndrome (MS) is a serious health problem associated with an increase in risk factors for hepatic steatosis, which is the most common liver disease today. The goal of this study was to investigate the protective effects of resveratrol against metabolic alterations associated with a high-fat high-fructose diet (HFFD). Thirty-two male rats were randomly divided into four equal groups: control (cont.), metabolic syndrome (MS), resveratrol (Res), and metabolic syndrome treated with resveratrol (MS + Res). Resveratrol was administrated orally at a dose of 30 mg/kg·bw, daily. After 10 weeks, body weight, serum biochemical parameters, hepatic oxidative stress, inflammatory markers, as well as mRNA levels of hepatic genes related to lipid metabolism and insulin signaling were measured. In addition, the liver was examined histopathologically to detect lipid deposition. Increased body weight, hepatic dysfunction, dyslipidemia, hepatic insulin resistance, hepatic oxidative and inflammatory stress conditions, upregulation of mRNA expression level of sterol regulatory element binding protein 1-c (SREBP1-c), and downregulation of mRNA expression levels of peroxisome proliferated activated receptor alpha (PPARα) and insulin receptor substrate-2 (IR-S2) were all observed in the MS rats. Hepatic steatosis was confirmed by hematoxylin and eosin and Oil Red O staining. Administration of resveratrol reduced liver steatosis, oxidative stress, and inflammatory state. Also, it improved lipid profile as well as insulin sensitivity and reverted alterations in hepatic mRNA expression levels of the tested genes. Based on these findings, resveratrol could be proposed as a therapeutic approach for MS prevention.

Effects of Resveratrol Administration in Liver Injury Prevention as Induced by an Obesogenic Diet: Role of Ruminococcaceae.

Gut microbiota dysbiosis has been described in several metabolic disruptions, such as non-alcoholic fatty liver disease (NAFLD). Administration of resveratrol has been claimed to elicit benefits against NAFLD along with modulating gut microbiota composition. This investigation aims to study the putative mediating role of gut microbiota in the potential hepato-protective effects of resveratrol in a diet-induced NAFLD rat model. The involvement of bacteria from the Ruminococcaceae family in such effects was also addressed. Resveratrol administration resulted in lowered liver weight and serum total and non-HDL cholesterol concentrations, as well as in increased serum HDL cholesterol levels. The administration of this polyphenol also prevented obesogenic diet-induced serum transaminase increases. In addition, histopathological analysis revealed that resveratrol administration ameliorated the dietary-induced liver steatosis and hepatic inflammation. Gut microbiota sequencing showed an inverse relationship between some bacteria from the Ruminococcaceae family and the screened hepatic markers, whereas in other cases the opposite relationship was also found. Interestingly, an interaction was found between UBA-1819 abundance and resveratrol induced liver weight decrease, suggesting that for this marker resveratrol induced effects were greater when the abundance of this bacteria was high, while no actions were found when UBA-1819 abundance was low.

Combined resveratrol and vitamin D treatment ameliorate inflammation-related liver fibrosis, ER stress, and apoptosis in a high-fructose diet/streptozotocin-induced T2DM model.

A high fructose diet is a major cause of diabetes and various metabolic disorders, including fatty liver. In this study, we investigated the effects of resveratrol and vitamin D (VitD) treatments on endoplasmic reticulum (ER) stress, oxidative stress, inflammation, apoptosis, and liver regeneration in a rat model of type 2 diabetes mellitus, namely, T2DM Sprague-Dawley rats. This T2DM rat model was created through a combination treatment of a 10% fructose diet and 40mg/kg streptozotocin (STZ). Resveratrol (1mg/kg/day) and VitD (170/IU/week) were administered alone and in combination to both the diabetic and control groups. Immunohistochemical staining was performed to evaluate PCNA, NF-κB, TNF-α, IL-6, IL-1β, GRP78, and active caspase-3 in liver tissue. The TUNEL method and Sirius red staining were used to determine apoptosis and fibrosis, respectively. G6PD, 6-PGD, GR, and GST activities were measured to determine oxidative stress status. We found that the expressions of cytokines (TNF-α, IL-6, and IL-1β) correlated with NF-κB activation and were significantly increased in the T2DM rats. Increased GRP78 expression, indicating ER stress, increased in apoptotic cells, enhanced caspase-3 activation, and collagen accumulation surrounding the central vein were observed in the T2DM group compared with the other groups. The combination VitD + resveratrol treatment improved antioxidant defense via increasing G6PD, 6-PGD, GR, and GST activities compared to the diabetic groups. We concluded that the combined administration of resveratrol with VitD ameliorates the adverse effects of T2DM by regulating blood glucose levels, increasing antioxidant defense mechanisms, controlling ER stress, enhancing tissue regeneration, improving inflammation, and reducing apoptosis in liver cells. In conclusion, this study indicates that the combination treatment of resveratrol + VitD can be a beneficial option for preventing liver damage in fructose-induced T2DM.

SIRT1 pharmacological activation rescues vascular dysfunction and prevents thrombosis in MTHFR deficiency

Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/–) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/– mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.