Natarajan Ashokkumar

Protective effect of esculetin on hyperglycemia-mediated oxidative damage in the hepatic and renal tissues of experimental diabetic rats

Diabetes mellitus is the most common serious metabolic disorder and it is considered to be one of the five leading causes of death in the world. Hyperglycemia-mediated oxidative stress plays a crucial role in diabetic complications. Hence, this study was undertaken to evaluate the protective effect of esculetin on the plasma glucose, insulin levels, tissue antioxidant defense system and lipid peroxidative status in streptozotocin-induced diabetic rats. Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. Extent of oxidative stress was assessed by the elevation in the levels of lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (HP) and conjugated dienes (CD); reduction in the enzymic antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST); nonenzymic antioxidants Vitamin C, E and reduced glutathione (GSH) were observed in the liver and kidney tissues of diabetic control rats as compared to control rats. Oral supplementation of esculetin to diabetic rats for 45 days significantly brought back lipid peroxidation markers, enzymic and nonenzymic antioxidants to near normalcy. Moreover, the histological observations evidenced that esculetin effectively rescues the hepatocytes and kidney from hyperglycemia mediated oxidative damage without affecting its cellular function and structural integrity. These findings suggest that esculetin (40 mg/kg BW) treatment exerts a protective effect in diabetes by attenuating hyperglycemia-mediated oxidative stress and antioxidant competence in hepatic and renal tissues. Further, detailed studies are in progress to elucidate the molecular mechanism by which esculetin elicits its modulatory effects in insulin signaling pathway.

MODULATION OF IMPAIRED CHOLINESTERASE ACTIVITY IN EXPERIMENTAL DIABETES: EFFECT OF Gymnema montanum LEAF EXTRACT

We reported that a leaf extract (GLEt) obtained from an anti-diabetic plant, Gymnema montanum, an endangered species endemic to India, has anti-peroxidative and antioxidant effects on diabetic brain tissue in rats. Here we examined the effect of the extract on the activity of reduced brain and retinal acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in streptozotocin (STZ)-induced diabetic male Wistar rats. Diabetic rats received GLEt orally (200 mg/kg bwt/d) for 12 wk, and changes in blood glucose, plasma insulin, the lipid peroxidation marker thiobarbituric acid-reactive substance (TBARS), and AChE and BChE activity were measured. The results confirmed prior reports that hyperglycemia significantly enhances TBARS levels in brain and retinal tissue and decreases AChE and BChE activity. Treatment with GLEt significantly reversed the impairment in enzymatic activity in addition to reducing the level of TBARS, suggesting that GLEt protects against the adverse effect of lipid peroxidation on brain and retinal cholinesterases. We suggest that GLEt could be useful for preventing the cholinergic neural and retinal complications of hyperglycemia in diabetes.

Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)-cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ-Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ-Cd induced diabetic nephrotoxic rats.

Antihyperglycemic effect of fraxetin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats.

Epidemiological studies have demonstrated that the diabetes mellitus is a serious health burden for both governments and healthcare providers. The present study was hypothesized to evaluate the antihyperglycemic potential of fraxetin by determining the activities of key enzymes of carbohydrate metabolism in streptozotocin (STZ) - induced diabetic rats. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg b.w). Fraxetin was administered to diabetic rats intra gastrically at 20, 40, 80 mg/kg b.w for 30 days. The dose 80 mg/kg b.w, significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as glucokinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and hepatic enzymes (aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)) in the liver tissues of diabetic rats were significantly reverted to near normal levels by the administration of fraxetin. Further, fraxetin administration to diabetic rats improved body weight and hepatic glycogen content demonstrated its antihyperglycemic potential. The present findings suggest that fraxetin may be useful in the treatment of diabetes even though clinical studies to evaluate this possibility may be warranted.

Antihyperglycemic, antihyperlipidemic, and renoprotective effects of Chlorella pyrenoidosa in diabetic rats exposed to cadmium.

Objective: The objective of the present study is to evaluate the antihyperlipidemic effect of Chlorella pyrenoidosa in diabetic rats exposed to cadmium (Cd). Materials and methods: Group 1 and 2 rats were treated as control and C. pyrenoidosa control. Group 3 and 4 rats were given single injection of streptozotocin (40u2009mg/kg b.w; i.p) followed by Cd (0.6u2009mg/kg b.w; s.c) for 5 days per week for a total period of 90 days. In addition, group 4 rats alone were treated with C. pyrenoidosa throughout the study period of 90 days. Assessments of plasma glucose, insulin, lipid profile and renal function markers were performed in control and experimental rats along with histological examination of kidney tissues. Results: Diabetic rats exposed to Cd showed increased levels of plasma glucose and decreased levels of plasma insulin accompanied by the significantly elevated levels of tissue lipids viz., total cholesterol, triglyceride, free fatty acid, and phospholipids compared with control rats. Alterations in lipoproteins (low density lipoprotein-C, very low density lipoprotein-C, and high density lipoprotein-C) levels were also observed. Discussion: Elevated levels of urinary albumin, creatinine, and blood urea nitrogen confirmed the onset of renal dysfunction in unsupplemented diabetic rats exposed to Cd. Conclusion: C. pyrenoidosa (100u2009mg/kg body weight) supplemented diabetic nephropathic rats showed near normal biochemical profile and well preserved renal histology that substantiate the antihyperglycemic, antihyperlipidemic, and renoprotective effects of C. pyrenoidosa in diabetic rats exposed to Cd.

Effect of N-benzoyl-D-phenylalanine on streptozotocin-induced changes in the lipid and lipoprotein profile in rats.

The effect of N‐benzoyl‐d‐phenylalanine (NBDP) and metformin combination treatment on circulatory lipids, lipoproteins and lipid peroxidation markers were studied in neonatal streptozotocin (nSTZ) non‐insulin dependent diabetic rats. Non‐insulin dependent diabetes mellitus (NIDDM) was induced by a single dose injection of streptozotocin (100 mg kg−1, i.p.) to two‐day‐old rats. After 10–12 weeks, rats weighing above 150g were selected for screening for the NIDDM model. The rats were checked for fasting blood glucose levels to confirm the status of NIDDM. NBDP (50,100 or 200 mg kg−1) was administered orally for six weeks to the confirmed diabetic rats (to evaluate the effective dose). The levels of serum lipids and lipid peroxidation markers were significantly increased, whilst the activity of glucose‐6‐phosphate dehydrogenase was significantly decreased in nSTZ diabetic rats. NBDP and metformin were able to restore the altered serum lipids, lipoproteins, lipid peroxidation marker levels and glucose‐6‐phosphate dehydrogenase activity to almost control levels. The results showed the antihyperlipidaemic properties of NBDP and metformin in addition to its antidiabetic action. Combination treatment was more effective then either drug alone. The results indicated that the coadministration of NBDP with metformin to nSTZ diabetic rats normalized blood glucose and caused marked improvement in altered serum lipids, lipoproteins and lipid peroxidation markers during diabetes. The data indicated that NBDP represented an effective antihyperglycaemic and antihyperlipidaemic adjunct for the treatment of diabetes, and may be a potential source of new orally active agents for future therapy.

Effect of N-benzoyl-d-phenylalanine on lipid profile in liver of neonatal streptozotocin diabetic rats.

The effect of N‐benzoyl‐d‐phenylalanine (NBDP) and metformin combination treatment on liver lipids and lipid peroxidation markers was studied in neonatal streptozotocin (nSTZ) diabetic rats. Oral administration of NBDP (50, 100 and 200u2003mg/kg body weight) and metformin (500u2003mg/kg body weight) for 6u2003weeks significantly reduced the elevated blood glucose, liver cholesterol, triglycerides, free fatty acids and phospholipids. The combination treatment also caused a significant decrease in hepatic hydroxymethyl glutaryl‐coenzyme A reductase, Thiobarbituric Acid Reactive Substances (TBARS) and significant increase in reduced glutathione levels. The results show that NBDP and metformin improve the hepatic lipid profile and antioxidant status in nSTZ diabetic rats. Combination treatment was more effective than either drug alone.

Combination of carvacrol and rosiglitazone ameliorates high fat diet induced changes in lipids and inflammatory markers in C57BL/6J mice

Type 2 diabetes mellitus is a chronic metabolic disease with the highest rates of prevalence and mortality worldwide. Hyperlipidemia has been ranked as one of the greatest risk factors. This study was undertaken to evaluate the antihyperlipidemic and anti-inflammatory effect of carvacrol (CVL) and rosiglitazone (RSG) combination on diabetic mice. HFD-induced C57BL/6J diabetic mice showed an elevation in total cholesterol (TC), triglycerides (TG), phospholipids (PL) and free fatty acids (FFA) in plasma and tissues. Further, increased levels of very low density lipoproteins-cholesterol (VLDL-C), low density lipoproteins-cholesterol (LDL-C) and decreased level of high density lipoproteins-cholesterol (HDL-C) were observed in the plasma of diabetic mice. Diabetic mice treated with CVL and RSG significantly modulates all these parameters towards normality. Histopathological analysis of adipose tissues and immunohistochemical analysis of liver tissue for inflammatory cytokines (TNF-α and IL-6) were in agreement with the biochemical parameters. These findings suggest that combination of CVL and RSG has better antihyperlipidemic and anti-inflammatory effect than treatment with individual compound.

Renoprotective effect of myricetin restrains dyslipidemia and renal mesangial cell proliferation by the suppression of sterol regulatory element binding proteins in an experimental model of diabetic nephropathy.

Myricetin is a natural flavonoid used in various health management systems. In this present study myricetin tested to evaluate the effect on lipids and lipid metabolism enzymes in normal and streptozotocin (STZ) with cadmium (Cd) induced diabetic nephrotoxic rats. Diabetic nephrotoxic rats were significantly (P<0.05) increased the levels of urinary albumin and lipid profiles: total cholesterol (TC), triglycerides (TGs), free fatty acids (FFAs), phospholipids (PLs), low density lipoprotein (LDL), very low-density lipoproteins (VLDL), and decreased in the levels of high-density lipoproteins (HDL). In addition, the activity of lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) were decreased significantly, whereas the 3-hydroxy 3-methylglutaryl coenzyme A (HmgCoA) reductase activity was increased. The upregulation of sterol regulatory element binding protein-1a (SREBP-1a), SREBP-1c, SREBP-2, transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF) and downregulation peroxisome proliferator-activated receptor alpha (PPAR-α) proteins expression levels were noticed. An administration of myricetin (1.0 mg/kg body weight (b/w)) for 12 weeks was brought the above parameters towards normal level. Histopathological study of kidney samples showed that extracellular mesangial matrix expansion, glomerulosclerosis and interstitial fibrosis in diabetic nephrotoxic rats was suppressed by myricetin treatment. Further our results indicate that administration of myricetin afforded remarkable protection against STZ-Cd induced alterations in lipid metabolism and thereby reduced the diabetic nephropathy in experimental rats.

Modulatory effect of vanillic acid on antioxidant status in high fat diet-induced changes in diabetic hypertensive rats

The worldwide incidence of diabetes has increased dramatically along with widespread lifestyle and dietary changes. Diets high in fat are strongly associated with the development of obesity and can induce insulin resistance in humans and animals. It is clear that obesity constitutes a risk factor for contributing to the development of type 2 diabetes. In the present study, we investigated the therapeutic potential action of vanillic acid on diabetes associated complications using a rat model. Rats were made diabetic hypertensive by high fat diet (HFD) for 20 weeks and were treated with vanillic acid (50mg/kg bw) for last 8 weeks. The effects of vanillic acid on glucose, plasma insulin, systolic and diastolic blood pressure, thiobarbituric acid reactive substances (TBARS), hydroperoxides as a lipid peroxidation marker, and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), vitamin C and vitamin E as an antioxidant marker, AST and ALT as a liver function marker, urea, uric acid and creatinine as a kidney function marker were investigated. Histopathology of liver and kidney was also investigated as part of the pathology of diabetes. Treatment of diabetic rats with oral administration of vanillic acid at a dose of 50mgkg/body weight for 8 weeks resulted in a significant decrease in fasting plasma glucose, insulin and blood pressure levels in comparison with diabetic control group. The antioxidant activities were significantly increased and the levels of lipid peroxidation markers were significantly decreased in diabetic hypertensive rats treated with vanillic acid. These results suggest that vanillic acid offer a modulatory effect on control of diabetic hypertension by reduction of blood glucose, insulin and blood pressure, combating oxidative stress by activation of tissue antioxidants.