Mehmet Bilgehan Pektaş

Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats

Dietary intake of fructose and sucrose can cause development of metabolic and cardiovascular disorders. The consequences of high-fructose corn syrup (HFCS), a commonly consumed form of fructose and glucose, have poorly been examined. Therefore, in this study, we investigated whether HFCS intake (10% and 20% beverages for 12 weeks) impacts vascular reactivity to insulin and endothelin-1 in conjunction with insulin receptor substrate-1(IRS-1), endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) mRNA/proteins levels in aorta of rats. At challenge, we tested the effectiveness of resveratrol (28-30 mg/kg body weight/day) on outcomes of HFCS feeding. HFCS (20%) diet feeding increased plasma triglyceride, VLDL, cholesterol, insulin and glucose levels, but not body weights of rats. Impaired nitric oxide-mediated relaxation to insulin (10⁻⁹ to 3×10⁻⁶ M), and enhanced contraction to endothelin-1 (10⁻¹¹ to 10⁻⁸ M) were associated with decreased expression of IRS-1 and eNOS mRNA and protein, but increased expression of iNOS, in aortas of rats fed with HFCS. Resveratrol supplementation restored many features of HFCS-induced disturbances, probably by regulating eNOS and iNOS production. In conclusion, dietary HFCS causes vascular insulin resistance and endothelial dysfunction through attenuating IRS-1 and eNOS expressions as well as increasing iNOS in rats. Resveratrol has capability to recover HFCS-induced disturbances.

Resveratrol improves hepatic insulin signaling and reduces the inflammatory response in streptozotocin-induced diabetes

Diabetes mellitus is a heterogeneous metabolic disorder essentially characterized by deficiency of insulin secretion, insulin receptor or post-receptor events. This study aims to investigate the effects of resveratrol administration on the metabolic characteristics, hepatic functions, histopathological features and insulin signaling pathway components in streptozotocin induced diabetes. Male Wistar rats were randomly divided into four groups: (1) control/vehicle; (2) control/20mg/kg resveratrol; (3) diabetic/vehicle; and (4) diabetic/20mg/kg resveratrol. Histopathological examinations were carried out to reveal hepatic tissue damage and inflammation. In addition to hepatic glucose, lipid, insulin, ALT, AST, resistin and XOD contents, gene and protein expressions of insulin signaling pathway components such as insulin Rβ, IRS-1, IRS-2, eNOS, PI3K, Akt, and FOXO3a were analyzed by qRT-PCR and Western blot. The rats in the diabetes group had significantly lower terminal body weight and hepatic insulin level, but significantly higher hepatic glucose, total cholesterol, triglyceride and resistin concentrations. Diabetes triggered the inflammatory process in the liver tissues that was evidenced by histopathological deformations and increase in the hepatic ALT and AST levels. Hepatic inflammation was considerably associated with insulin signaling pathway ever since a significant down-regulation of insulin signaling components; IRS-1, IRS-2, PI3K, Akt and mTOR have been identified in the diabetic group. To some extent, resveratrol treatment reversed the diabetes-induced changes in the liver tissues. Taken together, resveratrol partly improved hepatic dysfunction induced by diabetes. This may be due to the healing activity of resveratrol on insulin signaling pathway, resistin levels and hepatic glucose-lipid contents.

Differential Gene Expression in Liver Tissues of Streptozotocin-Induced Diabetic Rats in Response to Resveratrol Treatment

This study was conducted to elucidate the genome-wide gene expression profile in streptozotocin induced diabetic rat liver tissues in response to resveratrol treatment and to establish differentially expressed transcription regulation networks with microarray technology. In addition to measure the expression levels of several antioxidant and detoxification genes, real-time quantitative polymerase chain reaction (qRT-PCR) was also used to verify the microarray results. Moreover, gene and protein expressions as well as enzymatic activities of main antioxidant enzymes; superoxide dismutase (SOD-1 and SOD-2) and glutathione S-transferase (GST-Mu) were analyzed. Diabetes altered 273 genes significantly and 90 of which were categorized functionally which suggested that genes in cellular catalytic activities, oxidation-reduction reactions, co-enzyme binding and terpenoid biosynthesis were dominated by up-regulated expression in diabetes. Whereas; genes responsible from cellular carbohydrate metabolism, regulation of transcription, cell signal transduction, calcium independent cell-to-cell adhesion and lipid catabolism were down-regulated. Resveratrol increased the expression of 186 and decreased the expression of 494 genes in control groups. While cellular and extracellular components, positive regulation of biological processes, biological response to stress and biotic stimulants, and immune response genes were up-regulated, genes responsible from proteins present in nucleus and nucleolus were mainly down-regulated. The enzyme assays showed a significant decrease in diabetic SOD-1 and GST-Mu activities. The qRT-PCR and Western-blot results demonstrated that decrease in activity is regulated at gene expression level as both mRNA and protein expressions were also suppressed. Resveratrol treatment normalized the GST activities towards the control values reflecting a post-translational effect. As a conclusion, global gene expression in the liver tissues is affected by streptozotocin induced diabetes in several specific pathways. The present data suggest the presence of several processes which contribute and possibly interact to impair liver functions in type 1 diabetes, several of which are potentially amenable to therapeutic interventions with resveratrol.

Long-Term Dietary Fructose Causes Gender-Different Metabolic and Vascular Dysfunction in Rats: Modulatory Effects of Resveratrol

Background/Aims: There is limited knowledge on the gender differences in the effects of dietary fructose. In the current study, we investigated whether long-term fructose intake impacts metabolic parameters and vascular reactivity differently between male and female rats. Moreover, we tested whether resveratrol has a gender-specific effectiveness on the alterations. Methods: Male and female rats were divided into four groups as control; resveratrol; fructose and resveratrol plus fructose. Fructose was given to the rats as 10% solution in drinking water for 24 weeks. All rats were fed with the standard diet with or without resveratrol. Results: High-fructose diet increased plasma insulin, triglyceride and VLDL levels as well as omental weights in both genders. Long-term dietary fructose causes marked increase in body weight of males, but not females. Dietary fructose impaired endothelial relaxation to acetylcholine and intensified contraction to phenylephrine in the aortas of male and female rats, but differently it also reduced insulin-induced vasodilation in aortas of female rats. These changes were associated with decreased expression levels of endothelial nitric oxide synthase (eNOS) mRNA and protein, but increased in inducible NOS (iNOS), in aortas of male and female rats. Dietary fructose suppressed expression levels of sirtuin 1 (SIRT1) and insulin receptor substrate-2 (IRS-2) mRNA in aortas from female rats. Resveratrol supplementation efficiently restored fructose-induced metabolic and vascular dysfunction in both genders probably by regulating eNOS and iNOS production. Moreover, the augmentations in SIRT1 and IRS-2 mRNA in females and IRS-1 mRNA in males may possibly contribute to the beneficial effects of resveratrol as well. Conclusion: Long-term fructose intake may differently affect metabolic and vascular function between male and female rats, which are modified by resveratrol.

Dietary Fructose Activates Insulin Signaling and Inflammation in Adipose Tissue: Modulatory Role of Resveratrol

The effects of high-fructose diet on adipose tissue insulin signaling and inflammatory process have been poorly documented. In this study, we examined the influences of long-term fructose intake and resveratrol supplementation on the expression of genes involved in insulin signaling and the levels of inflammatory cytokines and sex hormones in the white adipose tissues of male and female rats. Consumption of high-fructose diet for 24 weeks increased the expression of genes involved in insulin signaling including IR, IRS-1, IRS-2, Akt, PI3K, eNOS, mTOR, and PPARγ, despite induction of proinflammatory markers, iNOS, TNFα, IL-1β, IL-18, MDA, and ALT, as well as anti-inflammatory factors, IL-10 and Nrf2 in adipose tissues from males and females. Total and free testosterone concentrations of adipose tissues were impaired in males but increased in females, although there were no changes in their blood levels. Resveratrol supplementation markedly restored the levels of MDA, IL6, IL-10, and IL-18, as well as iNOS, Nrf2, and PI3K mRNA, in adipose tissues of both genders. Dietary fructose activates both insulin signaling and inflammatory pathway in the adipose tissues of male and female rats proposing no correlation between the tissue insulin signaling and inflammation. Resveratrol has partly modulatory effects on fructose-induced changes.

Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin-Induced Diabetes.

Preclinical Research

Dietary Fructose-Induced Hepatic Injury in Male and Female Rats: Influence of Resveratrol.

Purpose: Relatively little is known about gender-dependent susceptibility to hepatic injury induced by nutritional factors. In the current study, we investigated dietary fructose-induced hepatic degeneration and roles of endothelial nitric oxide synthase (eNOS), insulin receptor (IRβ) and substrate-1 (IRS-1) expressions in association with inflammatory markers in male and female rats. Moreover, we examined potential effect of resveratrol on fructose-induced changes. Methods: Male and female rats were divided into 4 groups as control, resveratrol, fructose and resveratrol plus fructose. All rats were fed with a standard diet with or without resveratrol (500 mg/kg). Fructose was given as 10% in drinking waterfor 24 weeks. Results: Long-term dietary fructose caused parenchymal degeneration and hyperemia in association with impaired eNOS mRNA/protein expressions in liver of male and female rats. This dietary intervention also led to increases in hepatic triglyceride content, TNFα and IL-1β levels in both genders. Gender-related differences to consequence of fructose consumption were not obvious. Resveratrol supplementation markedly attenuated hepatic degeneration, hyperemia and triglyceride content in association with reduced TNFα and IL-1β levels, but enhanced IRβ mRNA and IRS-1 protein, in male and female rats upon fructose feeding. Conclusion: Long-term dietary fructose causes hepatic degeneration possibly via a decrease in eNOS, but increase in TNFα and IL-1β, in both genders. Resveratrol supplementation improved fructose-induced hepatic injury.

Nebivolol compared with metoprolol for erectile function in males undergoing coronary artery bypass graft

Objective: The aim of this study was to evaluate erectile function in males undergoing coronary artery bypass graft (CABG) while on two different adrenoceptor beta-blocker regimens, namely nebivolol and metoprolol. We hypothesize that the negative effects of cardiopulmonary bypass on erectile function may be possibly attenuated by preferring a vasodilating selective β1-blocker, nebivolol, to metoprolol as an anti-ischemic and antiarrhythmic agent in males undergoing CABG. Methods: This randomized, double-blind, prospective clinical study was conducted in patients scheduled for CABG surgery between February 2012 and June 2014. A total of 60 consecutive patients who met inclusion criteria were randomized and divided into the following two groups: N group, which received 5 mg of nebivolol orally for 2 weeks before surgery plus 12 weeks after surgery or M group, which received 50 mg of metoprolol orally for the same period. All patients were evaluated by the erectile function domain of the International Index of Erectile Function-5 (IIEF-5) at the time of admission (before starting the beta-blocker) and 3 months after surgery. Results: In the metoprolol group, the mean IIEF-5 score decreased significantly from a baseline of 15.2±5.8 to 12.9±5.8 (p<0.001), but in the nebivolol group, this difference was not significant (from a baseline 12.9±5.5 to 12.4±5.5, p=0.053). In all patients, the mean IIEF-5 score decreased significantly from a baseline of 14.0±5.7 to 12.6±5.6 (p<0.001). Conclusion: Although erectile function in males undergoing CABG surgery decreases when metoprolol is used, nebivolol exerts protective effects on erectile function against the disruptive effects of cardiopulmonary bypass in patients undergoing CABG.

Effects of resveratrol on diabetes-induced vascular tissue damage and inflammation in male rats

Abstract Objective: The present study aims to investigate the short-term effects of resveratrol on histopathological characteristics and inflammatory cytokines of the heart and thoracic aorta tissues in animal models of streptozotocin (STZ)-induced diabetes. Methods: Male Wistar rats were randomly divided into four groups; (1) control/vehicle, (2) control/20 mg/kg resveratrol, (3) diabetic/vehicle, (4) diabetic/20 mg/kg resveratrol. Heart and thoracic aorta were examined histopathologically and the levels of interleukin (IL)-1β, IL-18 and tissue necrosis factor (TNF)-α were analyzed by ELISA. Malondialdehyde (MDA) contents were determined with HPLC. Results: Diabetes group had significantly higher vascular MDA content (p<0.05) as compared with the control and resveratrol treated groups. Resveratrol significantly reduced vascular MDA level in diabetic animals (p<0.05). Significant elevation in IL-1β and TNF-α contents in thoracic aorta and IL-18 contents in cardiac and arterial tissues with diabetes were almost normalized with resveratrol treatment. Additionally, diabetic animals demonstrated significant endothelial damage, irregularities in smooth muscle fibers and degeneration of elastic fibers in thoracic aortas together with significant irregularities and hypertrophy in cardiac muscle fibers. Resveratrol significantly improved most of these histopathological alterations. Conclusion: Four-week-long intraperitoneal administration of resveratrol may restore the diabetes related inflammation and oxidative stress within the cardiovascular system. Özet Amaç: Bu çalışma, streptozotocin (STZ) ile oluşturulmuş diyabetin hayvan modellerinde resveratrolün kalp ve damar dokularında histopatolojik özellikler ve inflamatuar sitokinler üzerine kısa süreli etkilerini araştırmayı amaçlamıştır. Metod: Erkek Wistar sıçanları (1) kontrol, (2) kontrol/20 mg/kg resveratrol, (3) diyabetik, (4) diyabetik/20 mg/kg resveratrol olmak üzere dört gruba ayrılmıştır. Kalp ve damar dokuları histopatolojik olarak incelenmiştir. Buna ilave olarak, interleukin (IL)-1β, IL-18 ve doku nekroz faktör (TNF)-α düzeyleri ELISA yöntemiyle, malondialdehit (MDA) miktarı ise HPLC ile belirlenmiştir. Bulgular: Diyabet grubunda vasküler MDA miktarı kontrol ve resveratrol gruplarına göre anlamlı ölçüde (p<0,05) yükselmiştir. Diyabetik hayvanlarda resveratrol, vasküler MDA düzeylerini anlamlı derecede (p<0,05) düşürmüştür. Torasik aorta dokularındaki IL-1β ve TNF-α düzeylerinde meydana gelen anlamlı artış, kardiyak ve arterial dokularındaki IL-18 düzeylerindeki yükseliş, resveratrol uygulamasıyla büyük ölçüde normalize edilmiştir. Buna ilave olarak diyabetik hayvanların torasik aortlarında anlamlı ölçüde endotel hasar, düz kas liflerinde düzensizlikler ve elastik liflerinde dejenerasyon gösterilmiştir. Ayrıca kardiyak kas liflerinde belirginleşen düzensizlikler ve hipertropi gösterilmiştir. Diyabetik hayvanlara resveratrol tedavisi, bu olumsuz değişiklikleri kısmi olarak iyileştirmiştir. Sonuç: Dört hafta boyunca intraperitonal yoldan uygulanan resveratrol, kardiyovasküler sistemde diyabetle meydana gelen inflamasyon ve oksidatif stresi azaltacak potansiyele sahiptir.

An Epidemiological Study Of Pulmonary Hypertension In Turkish Adults

Objective: The present study aims to evaluate the nationwide epidemiological characteristics of adulthood pulmonary hypertension (PH) within whole Turkish population over a period of five years using the registry of the National Health Insurance System. Methods: All individuals aged more than 18 years who were admitted to a Turkish hospital for the first time between 2009 and 2013 with a discharge diagnosis of primary PH (ICD-10 code I27.0) and secondary PH (ICD-10 code I27.2) were identified. Results: The overall annual prevalence of primary PH during adulthood was 9.6 cases per million. When compared with other age groups, the number of individuals aged more than 45 years was significantly higher in adults affected by primary PH during the study period (p=0.001 for all years). The female to male ratio was 2.2:1 for adulthood primary PH throughout the study period. The number of patients settled in the Northwestern Anatolia was significantly higher in the primary PH group (p<0.05 for all years). The overall annual prevalence of secondary PH in adults was 6.0 cases per million. When compared with other age groups, the number of individuals aged more than 45 years was significantly higher in adults affected by secondary PH during the study period (p=0.001 for all years). Conclusion: The prevalence of adulthood PH in Turkey may be higher than that of adulthood PH in Western countries and adulthood PH usually affects Turkish individuals aged over 45 years. Keywords: Adult; epidemiology; pulmonary hypertension