Hesperidin decreased cisplatin-induced functional and histopathological liver damage in a dose-dependent manner without affecting its potential cytotoxic effect.

Oxidative and nitrosative stress-induced endothelial cell damage play an essential role in the pathogenesis of hepatic ischemia-reperfusion (IR) injury. IR is associated with reduced eNOS expression and exacerbated by superimposed stress. NOSTRIN induces intracellular endothelial nitric oxide synthase (eNOS) translocation and inducible nitric oxide synthase (iNOS) increases nitric oxide (NO) production. Our aim was to assess hepatic expression of iNOS, eNOS, and NOSTRIN in IR with or without N-acetylcysteine (NAC) or thymoquinone (TQ) pretreatment and to compare their hepatoprotective effects. Surgical induction of IR was performed by occlusion of hepatic pedicle for 30 min with mini-clamp and reperfused for 30 min. The effects of TQ (20 mg/kg/day) or NAC (300 mg/kg/day) administered orally for 10 days were evaluated by serum ALT and AST, oxidative stress parameters, NO production, and histopathological analysis. Also, localization and expression of iNOS, eNOS, and NOSTRIN were assessed by immunofluorescence. TQ or NAC pretreatment significantly decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and myeloperoxidase (MPO) activities, malondialdehyde (MDA) level, and NO production. In addition, they restored the depleted GSH content and alleviated histopathological changes. Furthermore, they up-regulated eNOS and down-regulated iNOS and NOSTRIN expressions. TQ exerts its hepatoprotective effect, at least in part, by nitric oxide signaling pathway through modulation of iNOS, eNOS, and NOSTRIN expressions as well as suppression of oxidative stress.

Hyperlipidemia Isoproterenol RosuvastatinEllagic acid a b s t r a c t Hyperlipidemia (HL) with subsequent coronary atherosclerosis is the major trigger of ischemia and hence, myocardial infarction (MI) occurs. The present study aimed to elucidate the effects of pretreatment with rosuvastatin and ellagic acid, as well as their combination on isoproterenol-induced MI in hyperlipidemic rats. Adult rats were fed with a cholesterol-rich diet for seven weeks and received rosuvastatin (10 mg/kg) and/or ellagic acid (30 mg/kg) by oral gavage daily starting from the fifth week then subcutaneously injected with two doses 24-h apart of 100 mg/kg isoproterenol in the last two days. ECG pattern was monitored and both cardiac biomarkers (cTnI, CK-MB, LDH and AST) and lipid profile (TC, TG, HDL-c and LDL-c) were measured in serum. MDA and GSH levels were quantified in cardiac homogenates and heart tissue damage was examined by histopathology. Furthermore, the expression levels of iNOS, eNOS, Bax and Bcl-2 in heart samples were assessed by western blotting. Three-week pretreatment with rosuvastatin and/or ellagic acid markedly ameliorated HL-and isoproterenol-induced alterations in ECG, cardiac markers, oxidation markers, lipid profile and heart architecture. Both drugs downregulated iNOS and upregulated eNOS, while only rosuvastatin and the combination downregulated Bax. This study provides evidence that rosuvastatin and ellagic acid possess cardioprotective effect on the hyperlipidemic-myocardial infarction rat model and the combination does not offer extra protection than monotherapy.

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