The effects of resveratrol on cyclooxygenase-1 and -2, nuclear factor kappa beta, matrix metalloproteinase-9, and sirtuin 1 mRNA expression in hearts of streptozotocin-induced diabetic rats
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Resveratrol (RSV) has a beneficial role in the prevention of diabetes and alleviates some diabetic complications, such as cardiomyopathy.We investigated cyclooxygenase-1 (COX-1), COX-2, nuclear factor κB (NF-κB), matrix metalloproteinase-9 (MMP-9), and sirtuin 1 (SIRT1) mRNA expression levels in heart tissue after RSV treatment in streptozotocin (STZ)-induced diabetic rats.After induction of chronic diabetes with STZ, 10 mg RSV/kg per day was administered to DM and DM+RSV groups for four weeks.At the end of the experiment, all rats were sacrificed and heart tissues were stored at -80°C; mRNA expression levels of COX-1, COX-2, NF-κB, MMP-9, and SIRT1 genes were analyzed with quantitative real-time PCR.We did not find any significant effect of RSV on ©FUNPEC-RP www.funpecrp.com.Keywords:
Sirtuin 1
Diabetic Cardiomyopathy
Resveratrol (RSV) has a beneficial role in the prevention of diabetes and alleviates some diabetic complications, such as cardiomyopathy.We investigated cyclooxygenase-1 (COX-1), COX-2, nuclear factor κB (NF-κB), matrix metalloproteinase-9 (MMP-9), and sirtuin 1 (SIRT1) mRNA expression levels in heart tissue after RSV treatment in streptozotocin (STZ)-induced diabetic rats.After induction of chronic diabetes with STZ, 10 mg RSV/kg per day was administered to DM and DM+RSV groups for four weeks.At the end of the experiment, all rats were sacrificed and heart tissues were stored at -80°C; mRNA expression levels of COX-1, COX-2, NF-κB, MMP-9, and SIRT1 genes were analyzed with quantitative real-time PCR.We did not find any significant effect of RSV on ©FUNPEC-RP www.funpecrp.com.
Sirtuin 1
Diabetic Cardiomyopathy
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Resveratrol‐enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice
Abstract Autophagic dysfunction is observed in diabetes mellitus. Resveratrol has a beneficial effect on diabetic cardiomyopathy. Whether the resveratrol‐induced improvement in cardiac function in diabetes is via regulating autophagy remains unclear. We investigated the mechanisms underlying resveratrol‐mediated protection against heart failure in diabetic mice, with a focus on the role of sirtuin 1 ( SIRT 1) in regulating autophagic flux. Diabetic cardiomyopathy in mice was induced by streptozotocin ( STZ ). Long‐term resveratrol treatment improved cardiac function, ameliorated oxidative injury and reduced apoptosis in the diabetic mouse heart. Western blot analysis revealed that resveratrol decreased p62 protein expression and promoted SIRT 1 activity and Rab7 expression. Inhibiting autophagic flux with bafilomycin A1 increased diabetic mouse mortality and attenuated resveratrol‐induced down‐regulation of p62, but not SIRT 1 activity or Rab7 expression in diabetic mouse hearts. In cultured H9C2 cells, redundant or overactive H 2 O 2 increased p62 and cleaved caspase 3 expression as well as acetylated forkhead box protein O1 ( FOXO 1) and inhibited SIRT 1 expression. Sirtinol, SIRT 1 and Rab7 si RNA impaired the resveratrol amelioration of dysfunctional autophagic flux and reduced apoptosis under oxidative conditions. Furthermore, resveratrol enhanced FOXO 1 DNA binding at the Rab7 promoter region through a SIRT 1‐dependent pathway. These results highlight the role of the SIRT 1/ FOXO 1/Rab7 axis in the effect of resveratrol on autophagic flux in vivo and in vitro , which suggests a therapeutic strategy for diabetic cardiomyopathy.
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Sirtuin 1
Diabetic Cardiomyopathy
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Sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, has been connected to beneficial effects elicited by calorie restriction. Physiological adaptation to starvation requires higher activity of SIRT1 and also the suppression of thyroid hormone (TH) action to achieve energy conservation. Here, we tested the hypothesis that those two events are correlated and that TH may be a regulator of SIRT1 expression. Forty-eight-hour fasting mice exhibited reduced serum TH and increased SIRT1 protein content in liver and brown adipose tissue (BAT), and physiological thyroxine replacement prevented or attenuated the increment of SIRT1 in liver and BAT of fasted mice. Hypothyroid mice exhibited increased liver SIRT1 protein, while hyperthyroid ones showed decreased SIRT1 in liver and BAT. In the liver, decreased protein is accompanied by reduced SIRT1 activity and no alteration in its mRNA. Hyperthyroid and hypothyroid mice exhibited increases and decreases in food intake and body weight gain respectively. Food-restricted hyperthyroid animals (pair-fed to euthyroid group) exhibited liver and BAT SIRT1 protein levels intermediary between euthyroid and hyperthyroid mice fed ad libitum . Mice with TH resistance at the liver presented increased hepatic SIRT1 protein and activity, with no alteration in Sirt1 mRNA. These results suggest that TH decreases SIRT1 protein, directly and indirectly, via food ingestion control and, in the liver, this reduction involves TRβ. The SIRT1 reduction induced by TH has important implication to integrated metabolic responses to fasting, as the increase in SIRT1 protein requires the fasting-associated suppression of TH serum levels.
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Intermittent Fasting
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The effects of streptozotocin-induced diabetes mellitus on the hypothalamic-pituitarythyroid axis in rats were studied.Streptozotocin (60mg/kg) was injected ip. Rats were decapitated at two and four weeks after the streptozotocin treatment. Thyrotropin releasing hormone (TRH), thyrotropin (TSH), thyroxine (T4), 3, 3', 5-triiodothyronine (T3), 3, 3', 5'-triiodothyronine (rT3), 3, 3'-diiodothyronine (3, 3'-T2) and 3', 5'-diiodothyronine (3', 5'-T2) were measured by means of the specific radioimmunoassay for each.Immunoreactive TRH (ir-TRH) contents in the hypothalamus significantly decreased at four weeks (p<0.02). Basal TSH levels in plasma significantly decreased (p<0.005, p<0.001), and plasma ir-TRH and TSH responses to cold were significantly inhibited after the strepotozotocin treatment (p<0.001). The plasma TSH response to TRH was decreased, but not significantly. The plasma T4 and T3 levels fell significantly. RT3 did not change throughout the experiment. 3, 3'-T2 levels in plasma fell significantly, whereas 3', 5'-T2 increased. Blood glucose levels rose significantly after streptozotocin treatment, but insulin treatment led to partial restoration.The findings suggest that streptozotocin-induced diabetes mellitus affects various sites of the hypothalamic-pituitary-thyroid axis in rats.
Hypothalamic–pituitary–thyroid axis
Basal (medicine)
Reverse triiodothyronine
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This experiment was aimed at elucidating the protective effect of resveratrol against diabetes. Forty male Wistar albino rats were allocated into four groups: the control and streptozotocin (STZ)-induced diabetes groups were treated either with placebo (1 ml/kg, i.p.) or resveratrol (20 mg/kg, i.p.) for 8 weeks. Body weight, blood glucose and serum malondialdehyde (MDA) concentrations were monitored. At the end of the experimental period, expression levels of visfatin, sirtuin-1 (SIRT1) and glucose transporters (GLUTs, 2 and 4) were measured in skeletal muscle and pancreas by Western blotting. The resveratrol treatment partially compensated for body weight loss and alleviated hyperglycaemia and returned serum MDA concentrations to the control group levels. Data suggest that supplementation may reduce the severity of diabetes and its complications through suppressing oxidative stress and increasing potential to internalise glucose by extrahepatic tissues.
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To investigate the protective effect of ovarian sex steroids against streptozotocin diabetes, groups of ovariectomized streptozotocin diabetic female mice were treated orally with estradiol-17 beta (5 and 500 ug/kg/day) or progesterone (1 mg/kg/day) for 10 weeks. Streptozotocin produced a more severe hyperglycaemia and a greater fall in plasma insulin concentrations in ovariectomized mice than intact female mice. The estradiol-17 beta and progesterone treatments reduced both the severity of the hyperglycaemia and the fall in plasma insulin. Loss of pancreatic insulin after streptozotocin administration was reduced in intact mice and in mice treated with estradiol-17 beta. These observations suggest that ovarian sex steroids reduce the severity of streptozotocin diabetes at least partly by countering the cytotoxic effect of the drug on the islet B-cells, thereby reducing the fall in pancreatic and plasma insulin.
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The effects of streptozotocin-induced diabetes on pituitary growth hormone (GH) content and release from incubated pituitaries were investigated. Male rats were made diabetic by a single injection of streptozotocin (65 mg/kg) and sacrificed by decapitation 15 days later. Pituitary GH concentration was significantly reduced in streptozotocin diabetic rats as compared to that observed in control animals. The amount of GH released from hemipituitaries was also lower in diabetic rats than in controls. Kinetic characteristics of somatostatin (SRIF) inhibition of GH release were not affected by the treatment. These results suggest that the decrease in plasma GH observed by some investigators in streptozotocin diabetic rats is probably due to a deficiency in GH storage and/or synthesis rather than a change in the responsiveness of pituitary GH cells to SRIF.
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The sexually dimorphic GH secretory pattern is thought to be the major factor regulating constitutive expression of hepatic P450IIC11 (P-450h) and P450IIC12 (P-450i). In this study we investigated whether factors other than the diabetesinduced decrease in GH secretion contribute to alterations in P- 450 isozyme expression in streptozotocin (STZ)-diabetic rats. In male rats, hepatic P-450h apoprotein and mRNA decreased to 13% and 24% of control male levels, respectively, within 14 days of STZ injection. STZ-diabetes had little effect on expression of P-450i in females. Treatment of diabetic male rats with GH did not reverse the suppression of P-450h. STZ treatment also suppressed P-450h expression in GH-treated hypophysectomized (Hx) male rats, but incompletely. Thus, GH can partially reverse diabetic suppression of P-450h. However, in Hx male rats without GH supplementation, STZ treatment suppressed P-450h apoprotein and mRNA expression to 16% and 6% of nondiabetic Hx male levels, respectively, demonstrating the existence of GH-independent regulation of P-450h expression. In Hx female rats, P-450h apoprotein levels were 40% of those in intact control males and were not significantly decreased by STZ. Concomitantly, STZ produced a greater decrease in serum insulin levels and a greater increase in serum glucagon in Hx male rats than in Hx females. The results provide evidence for the existence of STZ-sensitive GH-independent expression of P-450h and further document the gender differences in STZ sensitivity. (Endocrinology128: 2065–2076, 1991)
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To investigate the effect of resveratrol (RSV) on the histopathology and leptin and sirtuin 2 expression levels of the kidneys in streptozotocin (STZ)-induced diabetic rats.The study was carried out with 33 young, healthy, female Wistar Albino rats. STZ was given (50 mg/kg, intraperitoneal, single dose) to the rats to induce and constitute a diabetes model. After 1 month of STZ, resveratrol (10 mg/kg) was given for 15 days. Then the kidneys were evaluated histopathologically and the leptin and sirtuin 2 expressions were analyzed immunohistochemically.High glucose and fewer weight levels were seen in the STZ-induced diabetes mellitus group. The glucose levels in the RSV-administered diabetic group showed a tendency to decrease but not significantly. Decreased signs of histopathologic kidney damage was seen in the RSV-administered diabetic group, and an increased expression of leptin was seen in the diabetic kidney tissues. There were no significant differences of sirtuin 2 expression levels among the groups.It was observed that resveratrol caused changes in the diabetic kidney histology and leptin expression level. Resveratrol may be effective, with its antioxidant and antidiabetic effects, in the prevention of kidney damage caused by long-term hyperglycemia.
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Histopathology
Intraperitoneal injection
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