Resveratrol Co-treatment Research Articles

The Possible Protective Role of Resveratrol against Zinc Oxide Nanoparticles Induced Hepatic Tissue Injury in Adult Albino Rat

Abstract Background Zinc oxide nanoparticles (ZnO NPs) are widely used in industries and medications. This may elevate the probability of their existence in the environment, which may have harmful side effects on different body organs, especially on the liver. So it became mandatory to search for natural hepatoprotective elements such as Resveratrol. Aim of the Work The aim of the present work was to determine the effect of zinc oxide nanoparticles on the histological structure and biochemical markers of the liver of adult male albino rats and to evaluate the possible protective role of Resveratrol. Material and Methods 40 adult male albino rats aged 3-6 months, were divided randomly into four groups; Group I (Control group), which consisted of 10 male albino rats with free access to food (rat chew) and water; Group II (ZnO NPs group), which included 10 male albino rats, which received a dose of 50 mg/kg body weight ZnO NPs through oral gavage daily for 4 weeks; Group III (Resveratrol group) was composed of 10 male albino rats which received a dose of 20 mg/kg body weight Resveratrol through oral gavage daily for 4 weeks, and Group IV (ZnO NPs + Resveratrol group) included 10 male albino rats which were co-administered with a combination of ZnO NPs at a dose of 50mg/kg body weight and Resveratrol at a dose of 20 mg/kg body weight dose through oral gavage daily for 4 weeks. At the end of the experiment, blood samples were collected for serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). All the animals were sacrificed, and the liver was extracted and processed into paraffin blocks for light microscopic examination. A morphometric study and a statistical analysis were done. Results The present work demonstrated that liver sections obtained from adult male albino rats that received ZnO NPs showed disorganized hepatic architecture, severe affection of the hepatocytes, which had small darkly stained nuclei, and deep acidophilic cytoplasm. The hepatocytes sometimes showed extensive cytoplasmic vacuolations. Most hepatocytes had small apoptotic nuclei and were surrounded by clear halos. While some hepatocytes lost their cell boundaries and coalesced together. Central veins were dilated, distorted, and congested with areas of epithelial lining detachment. Most of the blood sinusoids appeared congested with marked inflammatory cell infiltration. The portal tracts showed vascular congestion, dilatation, and proliferation of the bile ducts. There was a marked increase in the collagen deposition around the portal tracts, central veins, and in-between hepatocytes. Marked depletion of glycogen content with sporadic positive PAS reactions within the cytoplasm of the hepatocytes was also noticed. Hepatocyte apoptosis was evident by a significant increase in caspase-3 expression compared to the control group. On the other hand, ZnO NP +Resveratrol group showed the restoration of normal hepatic lobules with few areas of subcapsular haemorrhage. Most hepatocytes appeared polygonal in shape, with acidophilic cytoplasm and central rounded vesicular nuclei. While few hepatocytes appeared degenerated with dark stained pyknotic nuclei and cytoplasm showed hydropic degeneration. Most of the blood sinusoids returned to their normal sizes with flattened endothelial cells. However, sometimes they were congested, dilated, and contained Kupffer cells. Some central veins appeared congested. The portal tract also returned to its normal size with a marked decrease in inflammatory cell infiltration and showed apparent minimal collagen fiber deposition. Another finding in the present work was that Resveratrol restored the glycogen content of the hepatocytes which were depleted in ZnO NPs group. This was marked by a strong PAS positive reaction in the cytoplasm of most hepatocytes, with few hepatocytes with weak PAS reaction. Resveratrol co-treatment with ZnO NPs significantly reduced the degeneration and necrosis of hepatocytes. This was evident in our study by the apparent negative Caspase-3 reaction in the cytoplasm of most hepatocytes. Clear deterioration of liver function tests was observed in ZnO NPs group compared with the control, with marked improvement in the group treated with ZnO NPs and Resveratrol together. Conclusion The present study demonstrated the degenerative and hepatotoxic effects of ZnO NPs on the histological structure and function of the liver and the hepatoprotective role of Resveratrol against these effects.

The interlacing anticancer effect of pharmacologic ascorbate, chloroquine, and resveratrol.

Currently, a diagnosis with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) means a death warrant, so finding efficient therapeutic options is a pressing issue. Here, we presented that pharmacologic ascorbate, chloroquine and resveratrol co-treatment exerted a synergistic cytotoxic effect on PDAC cell lines. The observed synergistic cytotoxicity was a general feature in all investigated cancer cell lines independent of the KRAS mutational status and seems to be independent of the autophagy inhibitory effect of chloroquine. Furthermore, it seems that apoptosis and necroptosis are also not likely to play any role in the cytotoxicity of chloroquine. Both pharmacologic ascorbate and resveratrol caused double-strand DNA breaks accompanied by cell cycle arrest. It seems resveratrol-induced cytotoxicity is independent of reactive oxygen species (ROS) generation and accompanied by a significant elevation of caspase-3/7 activity, while pharmacologic ascorbate-induced cytotoxicity shows strong ROS dependence but proved to be caspase-independent. Our results are particularly important since ascorbate and resveratrol are natural compounds without significant harmful effects on normal cells, and chloroquine is a known antimalarial drug that can easily be repurposed.

Investigation of the Effects of Resveratrol on Paracetamol Toxicity Established in Hep3B Cells

Aim: We therefore wanted to investigate acetaminophen hepatotoxicity by using Hep3B human hepatoma cells exposed to acetaminophen and resveratrol, used as a protective agent. Specifically, we studied the role of some proinflammatory markers and oxidative damage as possible mechanisms of acetaminophen-associated cytotoxicity.
 Materials and Method: The Hep3B human hepatoma cell line was used for this study. In vitro studies (GSH, SOD, CAT, AST, ALT, TNF-alpha, IL-6 and cell viability) were performed by using different methods such as Biochemical analyzer, RT-PCR, ELISA and MTT. Acetaminophen and resveratrol were applied to cells in a different time and doses.
 Results: Only acetaminophen treatment decreased SOD, CAT and GSH levels in Hep3B cells whereas acetaminophen and resveratrol co-treatment increased these enzymes levels. On the other hand, acetaminophen and resveratrol co-treatment (especially 160 µM dose of resveratrol) lead a severe increase in TNF-alpha and IL-6 levels.
 Conclusion: It is shown that acetaminophen has caused hepatotoxicity but interestingly but resveratrol treatment effects the related parameters mentioned above. Only, acetaminophen administration may cause abnormal decreases and/or increases in antioxidant enzymes and proinflammatory cytokines levels. Additionally, acetaminophen and high dose resveratrol co-treatment triggered the inflammation and oxidative stress. These results showed that resveratrol have a potential to be an effective agent on the treatment and protection of hepatic damage.

Protective role of resveratrol against VCM-induced hepatotoxicity in male wistar rats.

Background: Vancomycin is a glycopeptide antibiotic with a high risk of acute liver injury. Resveratrol is believed to protect the liver against toxicity. Aim: To investigate the ability of resveratrol to attenuate vancomycin-induced liver toxicity in rats injected with vancomycin. Method: Twenty-four adult male Wistar rats were distributed into three groups. The control group received only a vehicle, while the treated group received either vancomycin 200 (mg/kg, i. p.) only or vancomycin (200mg/kg, i. p.) with resveratrol (20mg/kg, oral gavage). All groups received their dose once daily for 7days. Hepatic damage was assessed by measuring biochemical parameter levels in serum, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). Also, antioxidants and inflammation biomarkers such as Interleukin-6 (IL-6), malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) were measured. Furthermore, the vancomycin-induced pathological changes in the liver were evaluated by histopathological studies. Results: In the vancomycin-treated group, hepatic serum biomarkers such as AST, ALT, ALP, IL-6, and MDA were elevated, while NO and GSH were depleted. However, resveratrol co-treatment with vancomycin prevented the elevation of AST, ALT, ALP, IL-6, and MDA and it protected the liver from NO and GSH depletion. Also, regarding vancomycin-induced degeneration of hepatocytes, resveratrol co-treatment with vancomycin prevented such degeneration and improved mononuclear cells in the liver. Conclusion: The results showed that oral administration of resveratrol has a significant hepatoprotective effect against vancomycin-induced hepatotoxicity.

Resveratrol activates PI3K/AKT to reduce myocardial cell apoptosis and mitochondrial oxidative damage caused by myocardial ischemia/reperfusion injury

Resveratrol is a kind of iPolyphenols widely existing in herbal medicine. Here we aim to investigate whether resveratrol can reduce the degree of myocardial ischemia/reperfusion (IR) injury and inhibit the development of oxidative stress, and elucidate the molecular mechanism of resveratrol in protecting myocardial cells. The primary rat cardiomyocytes were used to establish an ischemia/reperfusion model in vitro, and a series of routine biochemical experiments were conducted to explore the antioxidant and anti-apoptotic effects of resveratrol in myocardial ischemia-reperfusion injury. Compared with that of the simulated ischemia-refusion (SIR) group, cell viability in the SIR and resveratrol co-treatment groups increased significantly (P < 0.001), the release of lactate dehydrogenase (LDH) and creatine kinase MB (CKMB) decreased, the positive rate of reactive oxygen species (ROS) in cardiomyocytes decreased, and the concentration of catalase and glutathione peroxidase increased significantly (P < 0.001). Besides, resveratrol can activate PI3K/AKT signaling pathway. PI3K siRNA can inhibit the PI3K/AKT signaling mediated by resveratrol. The addition of resveratrol can significantly increase the activity of mitochondrial superoxide dismutase (SOD) and reduce the malondialdehyde (MDA), which indicates that the oxidative damage of mitochondria induced by resveratrol was significantly weakened. The mitochondrial functional changes induced by resveratrol can be reversed by PI3K siRNA. In conclusion, our study shows that resveratrol can reduce ROS in cardiomyocytes by PI3K/AKT signaling pathway activation, and effectively inhibit the apoptosis of cardiomyocytes, thus having a direct protective effect on cardiomyocytes under SR.

Resveratrol counteracts IL-1β-mediated impairment of extracellular matrix deposition in 3D articular chondrocyte constructs.

When aiming at cell-based therapies in osteoarthritis (OA), proinflammatory conditions mediated by cytokines such as IL-1β need to be considered. In recent studies, the phytoalexin resveratrol (RSV) has exhibited potent anti-inflammatory properties. However, long-term effects on 3D cartilaginous constructs under inflammatory conditions with regard to tissue quality, especially extracellular matrix (ECM) composition, have remained unexplored. Therefore, we employed long-term model cultures for cell-based therapies in an in vitro OA environment and evaluated effects of RSV. Pellet constructs made from expanded porcine articular chondrocytes were cultured with either IL-1β (1-10 ng/ml) or RSV (50 μM) alone, or a cotreatment with both agents. Treatments were applied for 14 days, either directly after pellet formation or after a preculture period of 7 days. Culture with IL-1β (10 ng/ml) decreased pellet size and DNA amount and severely compromised glycosaminoglycan (GAG) and collagen content. Cotreatment with RSV distinctly counteracted the proinflammatory catabolism and led to partial rescue of the ECM composition in both culture systems, with especially strong effects on GAG. Marked MMP13 expression was detected in IL-1β-treated pellets, but none upon RSV cotreatment. Expression of collagen type I was increased upon IL-1β treatment and still observed when adding RSV, whereas collagen type X, indicating hypertrophy, was detected exclusively in pellets treated with RSV alone. In conclusion, RSV can counteract IL-1β-mediated degradation and distinctly improve cartilaginous ECM deposition in 3D long-term inflammatory cultures. Nevertheless, potential hypertrophic effects should be taken into account when considering RSV as cotreatment for articular cartilage repair techniques.

Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin-angiotensin system.

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system.

Mechanistic perspective of protective effects of resveratrol against cisplatin-induced ovarian injury in rats: emphasis on anti-inflammatory and anti-apoptotic effects.

Chemotherapeutic platinum-containing drugs are widely used to treat a variety of cancer types; however, they cause ovarian failure and infertility. The aim of this study is to investigate the molecular mechanism underlying the potential protective effect of resveratrol against cisplatin-induced ovarian damage in a rat model. Female rats were given either cisplatin (6mg/kg, i.p., once per week for two consecutive weeks) and/or resveratrol (10mg/kg, orally for 17days). Follicular development, ovarian function markers, as well as apoptotic and inflammatory markers were assessed 24h after the last resveratrol dose. Resveratrol ameliorated the marked follicular loss and the significant reduction in anti-Müllerian hormone (AMH) level triggered by cisplatin. Mechanistically, cisplatin elicited a potent inflammatory response in ovarian tissue as evidenced by the elevated expression of tumor necrosis factor, nuclear factor kappa-B, and proinflammatory enzymes. Co-treatment with resveratrol inhibited the elevation in inflammatory mediators induced by cisplatin. Further, cisplatin switched on the apoptotic machinery in ovarian tissues via increasing the expression of both cytochrome c and caspase-3 which was reversed upon resveratrol co-treatment. Resveratrol also counteracts the upregulating poly(ADP-ribose) polymerase expression which could attribute to the inflammatory and apoptotic effects of cisplatin. Resveratrol protects the ovary from cisplatin-induced toxicity through preventing the loss of the AMH-secreting granulosa cells, diminishing PARP-1 expression, and downregulating the inflammatory and apoptotic events implicated in cisplatin toxicity.

Resveratrol Co-Treatment Attenuates the Effects of HIV Protease Inhibitors on Rat Body Weight and Enhances Cardiac Mitochondrial Respiration.

Since the early 1990s human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) emerged as a global health pandemic, with sub-Saharan Africa the hardest hit. While the successful roll-out of antiretroviral (ARV) therapy provided significant relief to HIV-positive individuals, such treatment can also elicit damaging side-effects. Here especially HIV protease inhibitors (PIs) are implicated in the onset of cardio-metabolic complications such as type-2 diabetes and coronary heart disease. As there is a paucity of data regarding suitable co-treatments within this context, this preclinical study investigated whether resveratrol (RSV), aspirin (ASP) or vitamin C (VitC) co-treatment is able to blunt side-effects in a rat model of chronic PI exposure (Lopinavir/Ritonavir treatment for 4 months). Body weights and weight gain, blood metabolite levels (total cholesterol, HDL, LDL, triglycerides), echocardiography and cardiac mitochondrial respiration were assessed in PI-treated rats ± various co-treatments. Our data reveal that PI treatment significantly lowered body weight and cardiac respiratory function while no significant changes were found for heart function and blood metabolite levels. Moreover, all co-treatments ameliorated the PI-induced decrease in body weight after 4 months of PI treatment, while RSV co-treatment enhanced cardiac mitochondrial respiratory capacity in PI-treated rats. This pilot study therefore provides novel hypotheses regarding RSV co-treatment that should be further assessed in greater detail.

Resveratrol Ameliorates Contrast Induced Nephropathy Through the Activation of SIRT1-PGC-1α-Foxo1 Signaling in Mice

Background/Aims: SIRT1 activation promotes the resistance of renal tubular cells to oxidative stress, and resveratrol is known as a SIRT1 activator. Methods: Resveratrol was injected intraperitoneally with iohexol for 24 hours. NRK-52E cells were pretreated with resveratrol for 24 hours and then exposed to iohexol for 3 hours. Renal function was measured by serum creatinine and cell survival was assessed by MTT assay. We investigated whether resveratrol attenuates oxidative stress and apoptosis in contrast-induced nephropathy (CIN). Results: Serum creatinine and tubular injury increased significantly after iohexol treatment, and resveratrol co-treatment attenuated the renal injury. Cell survival decreased after iohexol exposure and resveratrol reduced cell death induced by iohexol. Resveratrol was accompanied with the activation of SIRT1 and PGC-1α and dephosphorylation of FoxO1 in mice with CIN. SIRT1 and PGC-1α expression were decreased by iohexol, and increased significantly in resveratrol-pretreated cells. These processes resulted in reduction of oxidative stress and apoptosis both in vivo and in vitro experiments. Resveratrol decreased inflammatory cell infiltration induced by iohexol in mice with CIN. SIRT1 inhibition using siRNA in tubular cells accentuated the decrease of cell viability by iohexol. Conclusion: Resveratrol attenuated CIN by modulating renal oxidative stress and apoptosis through activation of SIRT1-PGC-1α-FoxO1 signaling.

Resveratrol ameliorates benzo(a)pyrene-induced testicular dysfunction and apoptosis: involvement of p38 MAPK/ATF2/iNOS signaling

Benzo(a)pyrene [B(a)P] is an environmental toxicant that alters the steroidogenic profile of testis and induces testicular dysfunction. In the present study, we have investigated the molecular signaling of B(a)P and the ameliorative potential of the natural aryl hydrocarbon receptor (AhR) antagonist and antioxidant, resveratrol, on B(a)P-induced male reproductive toxicity. Studies showed that B(a)P treatment resulted in p38 MAPK activation and increased inducible nitric oxide synthase (iNOS) production along with testicular apoptosis and steroidogenic dysfunction. Resveratrol cotreatment maintained testicular redox potential, increased serum testosterone level and enhanced expression of major testicular steroidogenic proteins (CYPIIA1, StAR, 3βHSD, 17βHSD) and prevented subsequent onset of apoptosis. Resveratrol cotreatment resulted inhibition of testicular cytochrome P4501A1 (CYP1A1) expression, which is the major B(a)P metabolizing agent for BPDE-DNA adduct formation. Resveratrol also significantly decreased the B(a)P-induced AhR protein level, its nuclear translocation and subsequent promoter activation, thereby decreased the expression of CYP1A1. Resveratrol also down-regulated B(a)P-induced testicular iNOS production through suppressing the activation of p38 MAPK and ATF2, thus improved the oxidative status of the testis and prevented apoptosis. Our findings cumulatively suggest that resveratrol inhibits conversion of B(a)P into BPDE by modulating the transcriptional regulation of CYP1A1 and acting as an antioxidant thus prevents B(a)P-induced oxidative stress and testicular apoptosis.

Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats.

Objectives:To investigate the potential protective effect of resveratrol (RES) on aluminum chloride (AlCl3)-induced nephrotoxicity in rats.Methods:This experimental study was conducted from April to June 2015 at the Medical College of King Khalid University, Abha, Kingdom of Saudi Arabia. The experiments were performed on 24 male Wistar rats. The rats were randomly allocated into 4 groups; 1) group A: control rats received only normal saline, 2) group B: received RES dissolved in normal saline, 3) group C: model group and received AlCl3 dissolved in normal saline and 4) group D: RES treated group and received concomitant doses of RES+AlCl3. All treatments were administered for consecutive 40 days. After 40 days of treatments, kidney function tests, oxidative stress parameters and histopathological assay were evaluated.Results:all findings clearly showed significant deteriorations in kidney function and architectures after AlCl3 exposure. This was accompanied by increased renal oxidative stress and inflammation suggesting strong pro-oxidant activity of AlCl3 in spite of its non-redox status. Resveratrol co-treatment with AlCl3 to the rats showed significant improvement in all biochemical and histological parameters related to kidney function and structure.Conclusion:The findings of the current study showed that RES pre-administration to rats ameliorates renal damage and improves renal function in AlCl3 intoxicated rats in a mechanism related to its antioxidant potential.

Resveratrol protects PC12 cells from high glucose-induced neurotoxicity via PI3K/Akt/FoxO3a pathway.

Diabetes is known to be associated with neurodegenerative diseases. Resveratrol, a plant-derived polyphenolic compound found in red wine, possesses antioxidant properties. In this study, we aimed to investigate the effects of resveratrol on the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt)/FoxO3a pathway in mediating high glucose (HG)-induced injuries in neuronal PC12 cells. PC12 cells were exposed to HG to establish a model of HG neurotoxicity. Results showed that pre-treating PC12 cells with resveratrol before exposure to HG led to increased cell viability, decreased apoptotic cells, and reactive oxygen species generation. Western blot analysis showed that HG decreased the phosphorylation of Akt and FoxO3a and led to the nuclear localization of FoxO3a. These effects were significantly alleviated by resveratrol co-treatment. Furthermore, the protective effects of resveratrol were abolished by PI3K/Akt inhibitor LY294002. All these results demonstrate that resveratrol protected the PC12 cells from HG-induced oxidative stress and apoptosis via the activation of PI3K/Akt/FoxO3a signaling pathway.

Antichemosensitizing effect of resveratrol in cotreatment with oxaliplatin in HCT116 colon cancer cell.

PurposeAlthough oxaliplatin is one of the most widely used chemotherapeutic agents for the treatment of advanced stages of colorectal cancers in clinic, cancer cells often develop oxaliplatin drug resistance. Thus, overcoming oxaliplatin drug resistance is a major issue in the successful treatment for advanced stages of colorectal malignancy. In order to maximize oxaliplatin therapy, we examined whether resveratrol, a natural phytochemical known to have chemopreventive effects on cancers, can have a chemosensitizing effect upon cotreatment with oxaliplatin. Survivin, a small inhibitor of apoptosis protein (IAP), expression is examined using HCT116 colon cancer cells.MethodsIn order to examine resveratrol chemosensitizing effect upon oxaliplatin cotreatment, survivin transcripts and protein expression, cell proliferation, and apoptotic responses were evaluated using HCT116 cells. Reverse transcription polymerase chain reaction (RT-PCR), Western blot, crystal violet staining analyses were performed. For survivin specific inhibition, YM155 molecule was used.ResultsAlthough oxaliplatin significantly suppressed survivin transcripts and protein expression level in HCT116 cells, resveratrol cotreatment induced restoration of survivin expression level of both transcripts and protein. Apoptotic induction by oxaliplatin only treatment was nullified upon resveratrol cotreatment. Induction of survivin restoration upon resveratrol cotreatment also occurred when survivin specific inhibitor, YM155, was used. In addition to survivin restoration, resveratrol cotreatment also induced restoration of Bcl-2/caspase-3 expression suppressed by oxaliplatin only treatment.ConclusionResveratrol has an antichemosensitizing effect upon cotreatment with oxaliplatin in HCT colon cancer cells. This antichemosensitizing effect of resveratrol can be cell-type specific. However, clinical use of resveratrol cotreatment with oxaliplatin should be approached cautiously.

English

Statins are widely used besides their myopathic side effects, ranging from mild myalgia to fatal rhabdomyolysis. Resveratrol is one of the most popular over the counter products used for similar purposes with statins. The aim of this study was to elucidate the myopathic effects of atorvastatin and coadministered resveratrol in male rat skeletal muscle via morphological analyses and immunohistochemistry studies. Control group received 1.5 ml of drinking water by oral gavage and 1 ml 15% ethanol (vehicle of resveratrol) i.p. for 14 days daily; atorvastatin group was treated with 40 mg/kg atorvastatin by oral gavage and 1 ml 15% ethanol i.p. for 14 days daily. Resveratrol + atorvastatin group was treated with 40 mg/kg atorvastatin by oral gavage and 20 mg/kg i.p resveratrol for 14 days daily. Atorvastatin treatment resulted with a moderate inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) immunoreactivity in nucleus and strong immunoreactivity in fibers. Control group and resveratrol + atorvastatin group showed weak iNOS and eNOS immunoreactivity in nucleus and moderate immunoreactivity muscular fibers. Treatment with atorvastatin resulted in a significantly shortened fibrils, and resveratrol co-treatment reversed this effect. Resveratrol and atorvastatin co-treatment could be an alternative treatment to prevent the myositis adverse effects of atorvastatin on skeletal muscle. &nbsp; Key words:&nbsp;Atorvastatin, myositis, resveratrol.

Resveratrol Prevents Endothelial Cells Injury in High-Dose Interleukin-2 Therapy against Melanoma

Immunotherapy with high-dose interleukin-2 (HDIL-2) is an effective treatment for patients with metastatic melanoma and renal cell carcinoma. However, it is accompanied by severe toxicity involving endothelial cell injury and induction of vascular leak syndrome (VLS). In this study, we found that resveratrol, a plant polyphenol with anti-inflammatory and anti-cancer properties, was able to prevent the endothelial cell injury and inhibit the development of VLS while improving the efficacy of HDIL-2 therapy in the killing of metastasized melanoma. Specifically, C57BL/6 mice were injected with B16F10 cells followed by resveratrol by gavage the next day and continued treatment with resveratrol once a day. On day 9, mice received HDIL-2. On day 12, mice were evaluated for VLS and tumor metastasis. We found that resveratrol significantly inhibited the development of VLS in lung and liver by protecting endothelial cell integrity and preventing endothelial cells from undergoing apoptosis. The metastasis and growth of the tumor in lung were significantly inhibited by HDIL-2 and HDIL-2 + resveratrol treatment. Notably, HDIL-2 + resveratrol co-treatment was more effective in inhibiting tumor metastasis and growth than HDIL-2 treatment alone. We also analyzed the immune status of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) and FoxP3+CD4+ regulatory T cells (Treg). We found that resveratrol induced expansion and suppressive function of MDSC which inhibited the development of VLS after adoptive transfer. However, resveratrol suppressed the HDIL-2-induced expansion of Treg cells. We also found that resveratrol enhanced the susceptibility of melanoma to the cytotoxicity of IL-2-activated killer cells, and induced the expression of the tumor suppressor gene FoxO1. Our results suggested the potential use of resveratrol in HDIL-2 treatment against melanoma. We also demonstrated, for the first time, that MDSC is the dominant suppressor cell than regulatory T cell in the development of VLS.

Resveratrol potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse

A strong association between polymorphisms of the cytochrome P450 (CYP/Cyp) 2D6 gene and risk to Parkinson's disease (PD) is well established. The present study investigated the neuroprotective potential of Cyp2d22, a mouse ortholog of human CYP2D6, in maneb- and paraquat-induced parkinsonism and the mechanisms involved therein along with the effects of resveratrol on various parameters associated with Cyp2d22-mediated neuroprotection. The animals were treated intraperitoneally with resveratrol (10mg/kg, daily) and paraquat (10mg/kg) alone or in combination with maneb (30mg/kg), twice a week, for 9weeks, along with their respective controls. The subsets of animals were also treated intraperitoneally with a Cyp2d22 inhibitor, ketoconazole (100mg/kg, daily). Maneb and paraquat reduced Cyp2d22 and vesicular monoamine transporter type 2 (VMAT-2) expressions, the number of tyrosine hydroxylase-positive cells, and dopamine content and increased paraquat accumulation in the nigrostriatal tissues, oxidative stress, microglial activation, neuroinflammation, and apoptosis. Cyp2d22 inhibitor significantly exacerbated all these neurodegenerative indexes. Resveratrol cotreatment, partially but significantly, ameliorated the neurodegenerative changes by altering Cyp2d22 expression and paraquat accumulation. The results obtained in the study demonstrate that Cyp2d22 offers neuroprotection in maneb- and paraquat-induced dopaminergic neurodegeneration and resveratrol enhances its neuroprotective credentials by influencing Cyp2d22 expression and paraquat accumulation.

Resveratrol reduces vacuous chewing movements induced by acute treatment with fluphenazine

Treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the possible neuroprotective effects of resveratrol, a polyphenol compound contained in red grapes and red wine, in an animal model of orofacial dyskinesia (OD) induced by acute treatment with fluphenazine. Adult male rats were treated during 3weeks with fluphenazine enantate (25mg/kg, i.m., single administration) and/or resveratrol (1mg/kg, s.c., 3 times a week). Vacuous chewing movements (VCMs), locomotor and exploratory performance were evaluated. Fluphenazine treatment produced VCM in 70% of rats and the concomitant treatment with resveratrol decreased the prevalence to 30%, but did not modify the intensity of VCMs. Furthermore, the fluphenazine administration reduced the locomotor and exploratory activity of animals in the open field test. Resveratrol co-treatment was able to protect the reduction of both parameters. Taken together, our data suggest that resveratrol could be considered a potential neuroprotective agent by reducing motor disorders induced by fluphenazine treatment.

Resveratrol protects against a model of vacuous chewing movements induced by reserpine in mice

Reserpine treatment is a putative animal model of orofacial dyskinesia, tremor, and Parkinsonism. Here, we examined the effects of resveratrol, a polyphenol with neuroprotective properties primarily contained in red grapes and red wine, in an animal model of vacuous chewing movements (VCMs) induced by treatment with reserpine. Mice were treated with reserpine (1 mg/kg, subcutaneously on days 1 and 3) and/or resveratrol (5 mg/kg, intraperitoneally 3 consecutive days). VCM, locomotor, and exploratory performance were evaluated. Reserpine treatment produced an increase in VCM intensity, which was significantly reduced by resveratrol co-treatment. Reserpine also decreased locomotor and exploratory activity in the open field test. However, resveratrol co-treatment was not able to protect against these effects. The data suggest that resveratrol could be a promising pharmacological tool for studying VCM in rodents. However, further investigations are needed to understand the exact mechanisms involved in the neuroprotective effects of resveratrol.