ABSTRACT Acetaminophen (APAP) is a widely-used analgesic, while toxic doses of which induce liver injury. Inducible cyclooxygenase-2 (COX-2) is derived prostaglandins which play an anti-inflammatory role in acetaminophen-induced hepatotoxicity. Selective activation of vascular endothelial growth factor (VEGFR1, flt -1) on endothelial cells increased mRNA levels of hepatocyte mitogens (IL-6) and hepatocyte growth factor leading to prosurvival effects on hepatocytes. The aim of this study was to compare the hepatoprotective effect of N-acetylcysteine (NAC; the antidote for APAP) with that of α-Lipoic acid (ALA) and/or Thymoquinone (THQ) either alone or in combination on liver injury induced by APAP. APAP administration elevated most of the previously measured parameters and decreased GSH, SOD, and total protein levels compared with the control group. Liver sections of H&E demonstrate liver injury characterized by centrilobular hepatocellular necrosis, COX-2, and flt-1 expressions were also increased. Treatment with all fore mentioned antioxidants ameliorated most of the altered parameters compared to APAP-treated group. Treatment with the combination of ALA and THQ was the most effective therapy in the attenuation of liver injury assessed by a decrease in ALT and ALP activities and down-regulation of COX-2 and flt-1 expression. Section of liver from rat received APAP, ALA and THQ shows a marked improvement of hepatic degeneration which restricted to few hepatocytes with mild vacuolation of their cytoplasm while the nuclei appear normal mimic to control cells. It was concluded that the natural antioxidants such as ALA and THQ, may be considered as a potential antidote in combating liver injury induced by APAP.
This study aimed to explore the effective role of carnosine and /or L- arginine in down regulation of the inflammatory molecule expression caused renal damage in response to sodium nitrite (NaNO2) induced hypoxia in rats . NaNO2 was administered subcutaneously (s.c.) to rats as a single dose (60 mg/kg body weight ). L-arginine (200mg/Kg body weight) and carnosine (250 mg/ Kg body weight ) were administered (i.p.) as a single dose , 24 h before NaNO2 injection. The results revealed that pre- administration of arginine and /or carnosine to NaNO2 hypoxic rats, significantly modulated the increases in serum markers of renal function (creatinine and urea) as well as the decrease in hemoglobin (Hb) level versus hypoxic rats. The two agents each alone or in a combination, markedly down regulated the serum pro-inflammatory molecules, including tumor necrosis factor-α (TNF- α) , C-reactive protein (CRP), vascular endothelial growth factor (VEGF) and heat shock protein -70 (HSP-70) as well as interleukin-6 (IL-6) in renal tissue compared to NaNO2 hypoxic rats . Also, the two agents successfully down modulated the alteration in the serum hypoxia inducible factor 1α (HIF 1α) . The present biochemical results were also supported by histopathological examination. In conclusion, the current data revealed that although the efficacy of arginine or carnosine each alone, their combination was more effective in ameliorating the renal damage induced by inflammatory molecules in response to NaNO2 hypoxia . This may support the use of this combination as an effective drug to treat hypoxic renal damage