Antihyperglycemic effect of a new thiazolidinedione analogue and its role in ameliorating oxidative stress in alloxan-induced diabetic rats
ABSTRACT Thiazolidinediones (TZDs) are a new class of antidiabetic drugs, having an insulin sensitizing effect in patients with type 2 diabetes. The contribution of oxidative stress from the standpoint of lipid and protein damage, alteration in endogenous antioxidant enzymes and effects of newly synthesized compounds, 5-[4-2-(6,7-Dimethyl-1,2,3,4-tetrahydro-2-oxo-4-quinoxalinyl)ethoxy]phenyl]methylene]thiazolid- ine-2,4-dione, (C(1)) in normal/alloxan-induced diabetic rats form the focus area of this study. Its effect was compared to two well-known TZDs, namely pioglitazone and rosiglitazone. It has been concluded from results that after thirty days of administration of C(1), Pg and Rg in alloxan-induced diabetic animal groups, the blood glucose level decreased, more remarkably in C(1) treated group. Also oxidative damage has been studied by estimating hepatic superoxide dismutase (SOD) activity, which was found to be increased (p<0.001 vs. control). An inverse change in SOD values between hepatic and pancreatic/kidney tissues were observed. Treatment with the test compounds lowered the activity of SOD in liver while increased its activity in kidney and pancreas. Similar normalizing effect of C(1) on liver, pancreatic and renal catalase (CAT)/ glutathione peroxidase (GPx) activities were pronounced in diabetic rats (p<0.001 vs. diabetic rats). Decreased reduced glutathione (GSH) content, found in diabetic animals, was significantly elevated to normal levels by C(1) treatment. The treatment with C(1) also decreased the levels of nitric oxide and increased the activities of glutathione-s-transferase and glutathione reductase, as compared to diabetic animals. Evidence of oxidative damage to lipids and proteins was shown through the quantification of protein carbonyl (in tissues) and malondialdehyde levels (both serum and tissues). It was observed that the protein/lipid damage in diabetic rats was improved by treatment with C(1). Total antioxidant activity (TAA) was found to be enhanced in C(1) treated rats (p>0.05 vs. group3, p<0.001 vs. group2, p<0.001 vs. group 4). These results suggest that the newly synthesized TZD derivative (C(1)) has a potential to act as antihyperglycemic and antioxidant agent. In addition, for all parameters checked, it has better efficacy than rosiglitazone and is as effective as pioglitazone.
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ABSTRACT: Diabetic nephropathy is a serious microvascular complication for patients associated with diabetes mellitus. Recent studies have suggested that NF-κB is the main transcription factor for the inflammatory response mediated progression of diabetic nephropathy. Hence, the present study is hypothesized to explore the renoprotective nature of BAY 11-7082 an IκB phosphorylation inhibitor on Streptozotocin (STZ) induced diabetic nephropathy in Sprague-Dawley (SD) rats. Male SD rats were divided into five groups, group I sham control, group II drug control, group III diabetic control (STZ 50mg/kg), group IV and V are test drug groups to which a single dose of STZ 50mg/kg was injected initially and later received BAY 11-7082 1mg/kg and 3mg/kg, respectively from 5th to 8th week. Eight weeks after STZ injection, diabetic rats exhibited significant renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, urea nitrogen and creatinine, which were reversed to near normal by BAY 11-7082. BAY 11-7082 treated rats showed significant improvement in the decreased enzymatic antioxidant SOD, non-enzymatic antioxidant GSH levels, and elevated lipid peroxidation and nitric oxide levels as observed in the diabetic rats. BAY 11-7082 treatment was found to significantly recover kidney histological architecture in the diabetic rats. Altered levels of inflammatory cytokines like TNF-α, IL-1β, IL-6 and nuclear transcriptional factor subunit NF-κB p65 were reverted to the normal level upon treatment with BAY 11-7082. Our results suggest that by limiting the activation of NF-κB, thereby reducing the expression of inflammatory cytokines and by inhibiting the oxidative damage BAY 11-7082 protect the rats against diabetic nephropathy. Copyright © 2015 Elsevier B.V. All rights reserved.Environmental Toxicology and Pharmacology 01/2015; DOI:10.1016/j.etap.2015.01.019 · 1.86 Impact Factor
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ABSTRACT: Grape seed proanthocyanidin extract (GSPE) has a broad spectrum of biologic properties against oxidative stress. This study aimed to investigate the effects of GSPE on biochemical factors and antioxidant enzymes of erythrocyte in diabetic rats. Diabetes was induced through single injection of streptozotocin (50 mg.Kg(-1), i.p). Forty Male Sprague-Dawley rats were divided into four Groups: Group 1, healthy control group; Group 2, healthy group treated with GSPE (200 mg.Kg(-1)); Group 3, diabetic control group; Group 4, diabetic group treated with GSPE (200 mg.Kg(-1)) for 4 weeks. At the end, the experimental animals were sacrificed and blood samples were collected and plasma parameters and erythrocytes antioxidant status were evaluated. The results show, treatment with GSPE significantly reduced (P<0.001) urine volume, proteinuria and biochemical factors such as blood urea nitrogen, creatinine, triglyceride, total cholesterol, low density lipoprotein and very low density lipoprotein as well as malondialdehyde. Also GSPE treatment significantly (P<0.005) increased high density lipoprotein, total protein and albumin. Moreover GSPE significantly increased antioxidant enzymes activity such as: superoxide dismutase, glutathione peroxidase and catalase. These results suggest that GSPE can ameliorate biochemical abnormalities and antioxidant system status in streptozotocin- induced diabetic rats probably by its potent antioxidant features.Iranian journal of pharmaceutical research (IJPR) 01/2015; 14(1):329-34. · 0.51 Impact Factor
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ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance, oxidative stress, and cytokine imbalance. Boswellic acids, a series of pentacyclic triterpene molecules that are produced by plants in the genus Boswellia, has been traditionally used for the treatment of a variety of diseases. This study aimed at evaluating the protective effect of boswellic acids in a model of diet-induced NAFLD in rats in comparison to the standard insulin sensitizer, pioglitazone. Rats were fed with a high-fat diet (HFD) for 12 weeks to induce NAFLD. Starting from week 5, rats received boswellic acids (125 or 250 mg/kg) or pioglitazone parallel to the HFD. Feeding with HFD induced hepatic steatosis and inflammation in rats. In addition, liver index, insulin resistance index, activities of liver enzymes, and serum lipids deviated from normal. Further, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cyclooxygenase 2 were elevated; this was associated with an increase in hepatic expression of inducible nitric oxide synthase (iNOS) and formation of 4-hydroxy-2-nonenal (HNE). Rats treated with boswellic acids (125 or 250 mg/kg) or pioglitazone showed improved insulin sensitivity and a reduction in liver index, activities of liver enzymes, serum TNF-α and IL-6 as well as hepatic iNOS expression and HNE formation compared to HFD group. Furthermore, at the cellular level, boswellic acids (250 mg/kg) ameliorated the expression of thermogenesis-related mitochondrial uncoupling protein-1 and carnitine palmitoyl transferase-1 in white adipose tissues. Data from this study indicated that boswellic acids might be a promising therapy in the clinical management of NAFLD if appropriate safety and efficacy data are available.Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; DOI:10.1007/s00210-015-1102-9 · 2.36 Impact Factor