Saurabh Bharti

Up-regulation of PPARγ, heat shock protein-27 and -72 by naringin attenuates insulin resistance, β-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes

Naringin, a bioflavonoid isolated from grapefruit, is well known to possess lipid-lowering and insulin-like properties. Therefore, we assessed whether naringin treatment ameliorates insulin resistance (IR), β-cell dysfunction, hepatic steatosis and kidney damage in high-fat diet (HFD)-streptozotocin (STZ)-induced type 2 diabetic rats. Wistar albino male rats were fed a HFD (55 % energy from fat and 2 % cholesterol) to develop IR and on the 10th day injected with a low dose of streptozotocin (40 mg/kg, intraperitoneal (ip)) to induce type 2 diabetes. After confirmation of hyperglycaemia (>13·89 mmol/l) on the 14th day, different doses of naringin (25, 50 and 100 mg/kg per d) and rosiglitazone (5 mg/kg per d) were administered orally for the next 28 d while being maintained on the HFD. Naringin significantly decreased IR, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, TNF-α, IL-6, C-reactive protein and concomitantly increased adiponectin and β-cell function in a dose-dependent manner. Increased thiobarbituric acid-reactive substances and decreased antioxidant enzyme activities in the serum and tissues of diabetic rats were also normalised. Moreover, naringin robustly increased PPARγ expression in liver and kidney; phosphorylated tyrosine insulin receptor substrate 1 in liver; and stress proteins heat shock protein (HSP)-27 and HSP-72 in pancreas, liver and kidney. In contrast, NF-κB expression in these tissues along with sterol regulatory element binding protein-1c and liver X receptor- expressions in liver were significantly diminished. In addition, microscopic observations validated that naringin effectively rescues β-cells, hepatocytes and kidney from HFD-STZ-mediated oxidative damage and pathological alterations. Thus, this seminal study provides cogent evidence that naringin ameliorates IR, dyslipidaemia, β-cell dysfunction, hepatic steatosis and kidney damage in type 2 diabetic rats by partly regulating oxidative stress, inflammation and dysregulated adipocytokines production through up-regulation of PPARγ, HSP-27 and HSP-72.

Telmisartan, a dual ARB/partial PPAR-γ agonist, protects myocardium from ischaemic reperfusion injury in experimental diabetes.

Aim: Apart from its angiotensin receptor blocker (ARB) activity, telmisartan is also a partial agonist of peroxisome proliferator‐activated receptor gamma (PPAR‐γ). Therefore, we assessed whether telmisartan treatment attenuates myocardial ischaemia/reperfusion (I/R) injury in diabetic rats through PPAR‐γ pathway.

Upregulation of PPARγ by Aegle marmelos ameliorates insulin resistance and β-cell dysfunction in high fat diet fed-streptozotocin induced type 2 diabetic rats.

The global epidemic of type 2 diabetes demands the rapid evaluation of new and accessible interventions. This study investigated whether Aegle marmelos fruit aqueous extract (AMF; 250, 500 and 1000 mg/kg) improves insulin resistance, dyslipidemia and β‐cell dysfunction in high fat diet fed‐streptozotocin (HFD‐STZ)‐induced diabetic rats by modulating peroxisome proliferator‐activated receptor‐γ (PPARγ) expression. The serum levels of glucose, insulin, homeostasis model assessment of insulin resistance (HOMA‐IR), homeostasis model assessment of β‐cell function (HOMA‐B), lipid profile, TNF‐α and IL‐6 were evaluated. Further, the TBARS level and SOD activity in pancreatic tissue and PPARγ protein expression in liver were assessed. In addition, histopathological and ultrastructural studies were performed to validate the effect of AMF on β‐cells. The HFD‐STZ treated rats showed a significant increase in the serum levels of glucose, insulin, HOMA‐IR, TNF‐α, IL‐6, dyslipidemia with a concomitant decrease in HOMA‐B and PPARγ expression. Treatment with AMF for 21 days in diabetic rats positively modulated the altered parameters in a dose‐dependent manner. Furthermore, AMF prevented inflammatory changes and β‐cell damage along with a reduction in mitochondrial and endoplasmic reticulum swelling. These findings suggest that the protective effect of AMF in type 2 diabetic rats is due to the preservation of β‐cell function and insulin‐sensitivity through increased PPARγ expression. Copyright

Chrysin, a PPAR-γ agonist improves myocardial injury in diabetic rats through inhibiting AGE-RAGE mediated oxidative stress and inflammation

AGE-RAGE interaction mediated oxidative stress and inflammation is the key mechanism involved in the pathogenesis of cardiovascular disease in diabetes. Inhibition of AGE-RAGE axis by several PPAR-γ agonists has shown positive results in ameliorating cardio-metabolic disease conditions. Chrysin, a natural flavonoid has shown to possess PPAR-γ agonist activity along with antioxidant and anti-inflammatory effect. Therefore, the present study was designed to evaluate the effect of chrysin in isoproterenol-induced myocardial injury in diabetic rats. In male albino Wistar rats, diabetes was induced by single injection of streptozotocin (70 mg/kg, i.p.). After confirmation of the diabetes, rats were treated with vehicle (1.5 mL/kg, p.o.), chrysin (60 mg/kg, p.o.) or PPAR-γ antagonist GW9662 (1 mg/kg, i.p.) for 28 days. Simultaneously, on 27th and 28th day myocardial injury was induced by isoproterenol (85 mg/kg, s.c.). Chrysin significantly ameliorated cardiac dysfunction as reflected by improved MAP, ±LVdP/dtmax and LVEDP in diabetic rats. This improvement was associated with increased PPAR-γ expression and reduced RAGE expression in diabetic rats. Chrysin significantly decreased inflammation through inhibiting NF-κBp65/IKK-β expression and TNF-α level. Additionally, chrysin significantly reduced apoptosis as indicated by augmented Bcl-2 expression and decreased Bax and caspase-3 expressions. Furthermore, chrysin inhibited nitro-oxidative stress by normalizing the alteration in 8-OHdG, GSH, TBARS, NO and CAT levels and Nox4, MnSOD, eNOS and NT expressions. Co-administration of GW9662 significantly blunted the chrysin mediated cardioprotective effect as there was increase in oxidative stress, inflammation and apoptosis markers. Chrysin significantly ameliorated isoproterenol-induced myocardial injury in diabetic rats via PPAR-γ activation and inhibition of AGE-RAGE mediated oxidative stress and inflammation.

Regulation of Heat Shock Proteins 27 and 70, p-Akt/p-eNOS and MAPKs by Naringin Dampens Myocardial Injury and Dysfunction In Vivo after Ischemia/Reperfusion

Naringin has antioxidant properties that could improve redox-sensitive myocardial ischemia reperfusion (IR) injury. This study was designed to investigate whether naringin restores the myocardial damage and dysfunction in vivo after IR and the mechanisms underlying its cardioprotective effects. Naringin (20–80 mg/kg/day, p.o.) or saline were administered to rats for 14 days and the myocardial IR injury was induced on 15th day by occluding the left anterior descending coronary artery for 45 min and subsequent reperfusion for 60 min. Post-IR rats exhibited pronounced cardiac dysfunction as evidenced by significantly decreased mean arterial pressure, heart rate, +LVdP/dt max (inotropic state), -LVdP/dt max (lusitropic state) and increased left ventricular end diastolic pressure as compared to sham group, which was improved by naringin. Further, on histopathological and ultrastructural assessments myocardium and myocytes appeared more normal in structure and the infarct size was reduced significantly in naringin 40 and 80 mg/kg/day group. This amelioration of post-IR-associated cardiac injury by naringin was accompanied by increased nitric oxide (NO) bioavailability, decreased NO inactivation to nitrotyrosine, amplified protein expressions of Hsp27, Hsp70, β-catenin and increased p-eNOS/eNOS, p-Akt/Akt, and p-ERK/ERK ratio. In addition, IR-induced TNF-α/IKK-β/NF-κB upregulation and JNK phosphorylation were significantly attenuated by naringin. Moreover, western blotting and immunohistochemistry analysis of apoptotic signaling pathway further established naringin cardioprotective potential as it upregulated Bcl-2 expression and downregulated Bax and Caspase-3 expression with reduced TUNEL positivity. Naringin also normalized the cardiac injury markers (lactate dehydrogenase and creatine kinase-MB), endogenous antioxidant activities (superoxide dismutase, reduced glutathione and glutathione peroxidase) and lipid peroxidation levels. Thus, naringin restored IR injury by preserving myocardial structural integrity and regulating Hsp27, Hsp70, p-eNOS/p-Akt/p-ERK signaling and inflammatory response.

Abresham ameliorates dyslipidemia, hepatic steatosis and hypertension in high-fat diet fed rats by repressing oxidative stress, TNF-α and normalizing NO production

This study was aimed to investigate whether standardized hydroalcoholic extract of abresham (AB) ameliorates dyslipidemia, hepatic steatosis and associated hypertension in rats fed with high-cholesterol/high-fat diet (HFD). HFD (55% calorie from fat and 2% cholesterol) were fed for 45 days to induce dyslipidemia, hepatic steatosis and associated hypertension. After confirmation of hypercholesterolemia (total cholesterol >150 mg/dl) on 30th day, different doses of AB (200-800 mg/kg/day) were administered for next 15 days. HFD administration for 45 days led to cardiometabolic syndrome characterized by significant increase in body weight, total cholesterol, triglyceride, low density lipoprotein cholesterol, TNF-α levels along with decrease in high density lipoprotein cholesterol and serum NO level. Furthermore, HFD resulted in significant increase in systolic arterial pressure, diastolic arterial pressure and mean arterial pressure. In addition, morphological studies revealed hepatic steatosis along with swelling of mitochondria and loss of cristae in hepatocyte and periarteritis in aorta. Treatment with AB for 15 days positively modulated the altered parameters in dose-dependent fashion, though maximum effect was seen at 800 mg/kg. These findings suggest that AB guard against cardiometabolic syndrome in HFD fed rats. It attenuates dyslipidemia, hepatic steatosis and associated hypertension by decreasing oxidative stress, TNF-α and normalizing NO production.

Sesamol alleviates diet-induced cardiometabolic syndrome in rats via up-regulating PPARγ, PPARα and e-NOS

Increased oxidative stress and inflammation in obesity are the central and causal components in the pathogenesis and progression of cardiometabolic syndrome (CMetS). The aim of the study was to determine the potential role of sesamol (a natural powerful antioxidant and anti-inflammatory phenol derivative of sesame oil) in chronic high-cholesterol/high-fat diet (HFD)-induced CMetS in rats and to explore the molecular mechanism driving this activity. Rats were fed with HFD (55% calorie from fat and 2% cholesterol) for 60 days to induce obesity, dyslipidemia, insulin resistance (IR), hepatic steatosis and hypertension. On the 30th day, rats with total cholesterol >150 mg/dl were considered hypercholesterolemic and administered sesamol 2, 4 and 8 mg/kg per day for the next 30 days. Sesamol treatment decreased IR, hyperinsulinemia, hyperglycemia, dyslipidemia, TNF-α, IL-6, leptin, resistin, highly sensitive C-reactive protein (hs-CRP), hepatic transaminases and alkaline phosphatase, along with normalization of adiponectin, nitric oxide and arterial pressures in a dose-dependent fashion. Increased TBARS, nitrotyrosine and decreased antioxidant enzyme activities were also amended in HFD rats. Similarly, sesamol normalized hepatic steatosis and ultrastructural pathological alteration in hepatocytes, although the effect was more pronounced at 8 mg/kg. Furthermore, hepatic PPARγ, PPARα and e-NOS protein expressions were increased, whereas LXRα, SERBP-1c, P-JNK and NF-κB expression were decreased by sesamol treatment. These results suggest that sesamol attenuates oxidative stress, inflammation, IR, hepatic steatosis and hypertension in HFD-fed rats via modulating PPARγ, NF-κB, P-JNK, PPARα, LXRα, SREBP-1c and e-NOS protein expressions, thereby preventing CMetS. Thus, the present study demonstrates the therapeutic potential of sesamol in alleviating CMetS.

In vivo cardioprotection by pitavastatin from ischemic-reperfusion injury through suppression of IKK/NF-κB and upregulation of pAkt-e-NOS.

Recent studies have uncovered the beneficial effects of statin in cardiovascular diseases; however, the role of pitavastatin in ischemia-reperfusion (IR)-induced apoptosis and myocardial damage is not established. Therefore, in this study, we aim to investigate whether pitavastatin treatment attenuates myocardial IR injury via regulating oxidative stress, inflammation, apoptosis, and phosphorylated protein kinase B (pAkt) endothelial nitric oxide synthase (e-NOS) pathways. After the 14-day treatment with pitavastatin (0.16-0.64 mg·kg−1·d−1, po) or saline, rats were subjected to 45 minutes of ischemia by occluding the left anterior descending coronary artery and to 60 minutes of reperfusion to induce myocardial damage. Pitavastatin at a dose of 0.32 and 0.64 mg/kg significantly improved cardiac function as evidenced by the normalization of the mean arterial pressure, heart rate, ±LVdP/dtmax, and left ventricular end-diastolic pressure as compared with the IR control. Additionally, pitavastatin dose-dependently normalized myocardial antioxidants, lactate dehydrogenase, and thiobarbituric acid reactive substances along with decreased serum tumor necrosis factor-α level and creatine kinase isoenzyme-MB activity. Furthermore, pitavastatin enhanced pAkt, (p) e-NOS, Bcl-2, and suppressed IκB kinase/nuclear factor-kappa B, nitrotyrosine (NO inactivation product), Bax, and capases-3 protein expression in the heart. Morphological assessments of the IR-challenged myocardium showed that 0.32 and 0.64 mg/kg of pitavastatin decrease myocardial necrosis and inflammatory changes. Thus, pitavastatin reduced IR-induced infarction and dysfunction via the augmentation of endogenous antioxidant, suppression of IκB kinase/nuclear factor-kappa B, activation of pAkt-e-NOS, and/or decreased NO inactivation and apoptosis.

Pharmacological Properties and Therapeutic Potential of Naringenin: A Citrus Flavonoid of Pharmaceutical Promise

Naringenin chemically known as 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one is a common dietary polyphenolic constituent of the citrus fruits. It has received considerable attention for pharmaceutical and nutritional development due to potent pharmacological activities and therapeutic potential. Accruing evidence from both in vitro and in vivo studies have unraveled numerous biological targets along with complex underlying mechanisms suggesting possible therapeutic applications of naringenin in various neurological, cardiovascular, gastrointestinal, rheumatological, metabolic and malignant disorders. Functionally, this ameliorative effect of naringenin is primarily attributed to its antiinflammatory (via inhibiting recruitment of cytokines and inflammatory transcription factors) and anti-oxidant (via scavenging of free radicals, bolstering of endogenous antioxidant defense system and metal ion chelation) effects. The present article provides a comprehensive review of the various studies that have evaluated the therapeutic potential of naringenin and its actions at the molecular level. It also summarizes the pharmacokinetic data and issues and challenges involved in pharmaceutical development and suggest that it may be a potential agent for further exploration as well as may be useful as a dietary adjunct in treatment of various human ailments.

Endothelin receptor antagonist BQ-123 ameliorates myocardial ischemic-reperfusion injury in rats: a hemodynamic, biochemical, histopathological and electron microscopic evidence.

We investigated the effect of BQ-123, a selective endothelin-A (ET(A)) receptor antagonist in ischemia-reperfusion (IR) induced myocardial infarction (MI) with and without endothelin-1 (ET-1) challenge. MI was produced in rats by occlusion of left anterior descending coronary artery for 40 min and reperfusion for 120 min. ET-1 was administered immediately prior to coronary occlusion whereas vehicle or BQ-123 was administered 20 min after the occlusion. IR control group exhibited marked hemodynamic changes along with significant impairment of left ventricular functions. In addition, oxidative stress was increased, as evidenced by marked reduction in the activities of antioxidants and cardiac injury markers in myocardium. Furthermore, light microscopic and ultrastructural changes revealed myocardial necrosis, edema and inflammation. Prior administration of ET-1 acts synergistically with IR injury and further aggravates the impairment of ventricular functions, increased percent infarct area and decreased antioxidant levels. However, treatment with BQ-123 (1 mg/kg, IV) with or without ET-1 caused significant improvement in cardiac functions, percent infarct area, decreased malonaldehyde level, restored myocardial enzymes activities and maintained the redox status of the myocardium as compared to IR control group. Further, histopathological and ultrastructural studies reconfirmed the protective action of BQ-123. The results of present study suggest that ET-1 acting via ET(A) receptor may exaggerate myocardial damage produced by IR injury and selective blockade of ET(A) receptor by BQ-123 might offer potential cardioprotective action.