Simvastatin ameliorates diabetic nephropathy by attenuating oxidative stress and apoptosis in a rat model of streptozotocin-induced type 1 diabetes.

Statins are HMG-CoA reductase inhibitors with lipid-lowering effect and commonly used to reduce cardiovascular risk in diabetic patients. The present study investigates the ameliorative effect of simvastatin (SIM) on diabetic nephropathy in rats, pointing to its anti-apoptotic and anti-oxidative stress efficacies. Diabetes was induced by a single intraperitoneal injection of 55 mg/kg body weight streptozotocin (STZ) and both control and diabetic rats received 10 mg/kg SIM for 90 days. Treatment with SIM diminished the body weight loss, blood glucose and, serum creatinine, urea and uric acid in diabetic rats. SIM improved the creatinine clearance rate and urinary levels of creatinine, urea and albumin in STZ-induced rats. Lipid peroxidation and nitric oxide (NO) were significantly increased in the diabetic kidney whereas reduced glutathione, SOD and catalase were declined. Bax and caspase-3 showed a significant increase and Bcl-2 was decreased in the kidney of diabetic rats. SIM administration reduced lipid peroxidation and NO, and improved antioxidants and the expression of apoptotic markers. Diabetic rats showed increased collagen deposition in the kidney, atrophied irregular renal corpuscles with collapsed glomeruli and tubules with degenerated epithelial lining, an effect that was reversed following treatment with SIM. In conclusion, SIM can protect against diabetic nephropathy by attenuating oxidative stress and apoptosis.

Possible protective mechanisms exerted by metformin or metformin and vitamin E in isoproterenol-induced cardiac injury.

Several studies have reported that metformin is cardioprotective for diabetic and non-diabetic ischemic hearts through mechanisms that cannot be entirely attributed to its anti-hyperglycemic effect. This study was designed to investigate the cardioprotective effects of metformin with and without vitamin E after induction myocardial infarction (MI) in rats, using isoproterenol. Administration of metformin or vitamin E significantly reduced the cardiac mass index (P < 0.01), ameliorated the changes to cardiac biomarkers, and attenuated oxidative stress levels compared to the isoproterenol group. Interestingly, combination therapy showed a slight synergistic effect. Histopathological analysis suggested that metformin treatment reduced NF-κB expression and protected against isoproterenol-induced MI. Our results indicate that metformin mediates a cardioprotective effect against isoproterenol-induced MI via antioxidant activity and modulation of the NF-κB signaling pathway. This suggests that metformin would be beneficial in MI treatment.

Simvastatin Ameliorates Diabetic Cardiomyopathy by Attenuating Oxidative Stress and Inflammation in Rats.

Simvastatin is a lipid-lowering agent used to treat hypercholesterolemia and to reduce the risk of heart disease. This study scrutinized the beneficial effects of simvastatin on experimental diabetic cardiomyopathy (DCM), pointing to the role of hyperglycemia-induced oxidative stress and inflammation. Diabetes was induced by intraperitoneal injection of streptozotocin and both control and diabetic rats received simvastatin for 90 days. Diabetic rats showed significant cardiac hypertrophy, body weight loss, hyperglycemia, and hyperlipidemia. Serum creatine kinase MB (CK-MB) and troponin I showed a significant increase in diabetic rats. Simvastatin significantly improved body weight, attenuated hyperglycemia and hyperlipidemia, and ameliorated CK-MB and troponin I. Simvastatin prevented histological alterations and deposition of collagen in the heart of diabetic animals. Lipid peroxidation and nitric oxide were increased in the heart of diabetic rats whereas antioxidant defenses were decreased. These alterations were significantly reversed by simvastatin. In addition, simvastatin decreased serum inflammatory mediators and expression of NF-κB in the diabetic heart. Cardiac caspase-3 was increased in the diabetic heart and decreased following treatment with simvastatin. In conclusion, our results suggest that simvastatin alleviates DCM by attenuating hyperglycemia/hyperlipidemia-induced oxidative stress, inflammation, and apoptosis.

Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has been reported to promote cardioprotection in diabetic hearts by limiting hyperglycemia and hyperlipidemia. However, little is known about the involvement of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway modulation in the cardioprotective effects of sitagliptin. The current study aimed to investigate the protective effects of sitagliptin against diabetic cardiomyopathy (DCM), focusing on the modulation of the JAK/STAT pathway. Diabetes was induced by streptozotocin injection, and rats received sitagliptin orally and daily for 90 days. Diabetic rats exhibited hyperglycemia, hyperlipidemia, and a significant increase in heart-to-body weight (HW/BW) ratio. Serum troponin I and creatine kinase MB, cardiac interleukin-6 (IL-6), lipid peroxidation, and nitric oxide levels showed significant increase in diabetic rats. In contrast, both enzymatic and nonenzymatic antioxidant defenses were significantly declined in the heart of diabetic rats. Histopathological study revealed degenerations, increased collagen deposition in the heart of diabetic rats. Sitagliptin alleviated hyperglycemia, hyperlipidemia, HW/BW ratio, histological architecture, oxidative stress, and inflammation, and rejuvenated the antioxidant defenses. In addition, cardiac levels of pJAK2 and pSTAT3 were increased in diabetic rats, an effect which was remarkably decreased after sitagliptin treatment. In conclusion, these results confer an evidence that sitagliptin has great therapeutic potential on DCM through down-regulation of the JAK/STAT signaling pathway.

Vitamin D attenuates pro-inflammatory TNF-alfa cytokine expression by inhibiting NF-kB/p65 signaling in hypertrophied rat hearts

A growing body of evidence suggests that immune activation and inflammatory mediators may play a key role in the development and progression of left ventricle (LV) hypertrophy. The present study was designed to test the hypothesis that the cardioprotective effect of cholecalciferol (Vit-D3) is mediated via the regulation of messenger RNA (mRNA) expression of pro-inflammatory cytokines. Rats were randomly divided into four groups: control group received normal saline (0.9 % NaCl) i.p. for 14 days; Vit-D3 group received Vit-D3 at a dose of 12 μg/kg/day by gavage for 14 days; ISO group received saline for 7 days, and at day 7, ISO (5 mg/kg/day) was injected i.p. for 7 consecutive days to induce cardiac hypertrophy; and Vit-D3 + ISO group was treated with Vit-D3 for 14 days, and at day 7, ISO was administered for 7 consecutive days. Heart/body weight ratio, troponin-T, creatine kinase-MB, and tumor necrosis factor-alfa (TNF-alfa) levels of LV tissue were estimated. Levels of mRNA expression of NF-кB (NF-кB)/p65 and inhibitory kappa B (IкB)-alfa were determined by real-time PCR. Vit-D3 administration before and during induction of cardiac hypertrophy significantly reduced (P < 0.001) cardiac biomarkers. The histopathological examination further confirmed these results. In addition, Vit-D3 significantly decreased (P < 0.001) NF-кB-p65mRNA expression and increased (P < 0.01) IкB-alfa mRNA expression in LV tissues compared to ISO group. Based on these findings, it was concluded that the administration of cholecalciferol markedly attenuated the development of ISO-induced cardiac hypertrophy likely through downregulation ofTNF-alfa /NF-кb/p65 signaling pathways. However, it should be pointed out that other signaling pathways may contribute to the cardioprotective effect of Vit-D3 which requires further investigation

Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy.

This study was conducted to investigate whether the renoprotective effects of fenofibrate are mediated via attenuation of endothelial dysfunction and modulating the mRNA expression of adenosine monophosphate-activated protein kinase (AMPK) and its downstream kinase liver kinase B1 (LKB1) in rats with diabetic nephropathy (DN). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg kg(-1)). Fenofibrate (100 mg kg(-1), p.o.) was given to diabetic rats daily for 12 weeks. Treatment with fenofibrate significantly improved the renal function as revealed by the significant reductions in urinary albumin excretion and serum levels of creatinine and urea, in addition to the significant increase in creatinine clearance compared with the diabetic control group. Hyperglycemia-induced oxidative damage was ameliorated by treatment with fenofibrate as indicated by the significantly increased levels of glutathione and catalase together with the significant decrease in lipid peroxidation. Administration of fenofibrate caused significant increases in renal nitric oxide (NO) production and mRNA expression of endothelial NO synthase (eNOS), AMPK and LKB1, reflecting improvement of endothelial function. Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN via modulation of AMPK, LKB1 and eNOS mRNA expression.

Vitamin D attenuates pro-inflammatory TNF-α cytokine expression by inhibiting NF-кB/p65 signaling in hypertrophied rat hearts.

A growing body of evidence suggests that immune activation and inflammatory mediators may play a key role in the development and progression of left ventricle (LV) hypertrophy. The present study was designed to test the hypothesis that the cardioprotective effect of cholecalciferol (Vit-D3) is mediated via the regulation of messenger RNA (mRNA) expression of pro-inflammatory cytokines. Rats were randomly divided into four groups: control group received normal saline (0.9 % NaCl) i.p. for 14 days; Vit-D3 group received Vit-D3 at a dose of 12 µg/kg/day by gavage for 14 days; ISO group received saline for 7 days, and at day 7, ISO (5 mg/kg/day) was injected i.p. for 7 consecutive days to induce cardiac hypertrophy; and Vit-D3 + ISO group was treated with Vit-D3 for 14 days, and at day 7, ISO was administered for 7 consecutive days. Heart/body weight ratio, troponin-T, creatine kinase-MB, and tumor necrosis factor-α (TNF-α) levels of LV tissue were estimated. Levels of mRNA expression of NF-кB (NF-кB)/p65 and inhibitory kappa B (IкB)-α were determined by real-time PCR. Vit-D3 administration before and during induction of cardiac hypertrophy significantly reduced (P < 0.001) cardiac biomarkers. The histopathological examination further confirmed these results. In addition, Vit-D3 significantly decreased (P < 0.001) NF-кB-p65 mRNA expression and increased (P < 0.01) IкB-α mRNA expression in LV tissues compared to ISO group. Based on these findings, it was concluded that the administration of cholecalciferol markedly attenuated the development of ISO-induced cardiac hypertrophy likely through downregulation of TNF-α /NF-кb/p65 signaling pathways. However, it should be pointed out that other signaling pathways may contribute to the cardioprotective effect of Vit-D3 which requires further investigation.