Concanavalin-A as a Model for Induction of Murine Autoimmune Hepatitis: Role of TNF-α and NF-κß During The Acute Phase.

Autoimmune hepatitis (AIH) is a heterogeneous immune-mediated chronic liver disease affecting children and adults. It is important to rely on a specific animal model to study the hepatic changes and to evaluate the roles played by pro-inflammatory cytokines such as tumor necrosis factor alpha "TNF-α" and transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells "NF-κß" in the pathogenesis and outcome of the disease. This will help to identify specific targets for treatment of AIH. This study aimed at evaluating Concanavalin-A (Con A) as a model for induction of AIH and assessing splenocytes' TNF-α and hepatocytes' NF-κß levels at comparable durations after induction of hepatitis with Con A to evaluate the relationship between both factors. Materials and methods: A total of 130 outbreed CD1 mice were divided into group (1) which included 100 mice with induced AIH and group (2) included 30 normal mice as negative controls. Intra-peritoneal injection of Concanavalin-A was used to induce hepatitis. Hepatic injury was evaluated by the levels of liver enzymes, histopathological evidence for hepatic inflammatory infiltrate and/or apoptosis. Splenocytes and hepatocytes were cultured for assessment of TNF-α and NF-κß levels, respectively. Results: Con A injection caused a significant elevation in ALT and AST levels, portal inflammatory infiltrate, remarkable hepatocytes degeneration and marked increase of TNF-α levels, particularly within 24 hours, but all returned to normal within 1 week. Administration of another dose of Con A resulted in sharp significant elevation of liver enzymes, inflammatory infiltrate and hepatocyte apoptosis after 24 hours and sustained till the end of the study. There was a significant increase in NF-κß throughout most of the study duration following Con A injection as compared to that of normal mice. In conclusions, intra-peritoneal administration of Con A, particularly two doses, represents an efficient approach for induction of immune-mediated hepatitis. T-cells play a major role in AIH through release of TNF-α. Coincidently, hepatitis seems to be associated with elevation of NF-κß to protect hepatocytes. Thus TNF-α and NF-κß can represent targets for treatment of AIH either through inhibition or augmentation, respectively.

The therapeutic effects of bee venom on some metabolic and antioxidant parameters associated with HFD-induced non-alcoholic fatty liver in rats.

The present study was designed to investigate the therapeutic effects of bee venom (BV) on high-fat diet (HFD)-induced non-alcoholic fatty liver (NAFL) in rats at different levels. Histological manifestations, hepatic lipid content, liver function tests, glucose homeostasis, lipid abnormalities, adipocytokines, lipid peroxidation, disturbed glutathione and antioxidant enzymes systems and dysregulation of Nrf2 transcription factor were assessed. In the present study, the NAFL rats were subcutaneously treated with BV with different doses (0.01, 0.05, 0.1 mg/kg). The results indicated that BV treatment completely normalized the lipid profile values of NAFL rats. Fasting blood sugar, insulin level and homeostatic model assessment of insulin resistance significantly decreased. BV treated rats showed a significantly lower level of all liver enzymes and bilirubin. Moreover, BV treatment significantly increased the levels of active nuclear erythroid factor 2 like 2, glutathione (GSH) (total and reduced), GSH/glutathione disulphide ratio and activities of glutathione reductase, glutathione-S-transferase and glutathione peroxidase (total and Se-dependent). The level of tumor necrosis factor-α was reduced. Treatment showed correction of adiponectin level, and significant downregulation of hepatic triglycerides and cholesterol. At the histological level, BV improved the architecture of liver cells showing normal sinusoids. It may be concluded that BV may represent an interesting therapeutic alternative for the treatment of NAFL disease.

Thymoquinone improves the kidney and liver changes induced by chronic cyclosporine A treatment and acute renal ischaemia/reperfusion in rats.

OBJECTIVES: This study was designed to evaluate the effects of chronic cyclosporine A (CsA) treatment and acute renal ischaemia/reperfusion (I/R) on the kidney and liver in thymoquinone (TQ)-treated rats. METHODS: In the CsA study, adult male rats were divided into control, CsA (25 mg/kg per day), TQ (10 mg/kg per day) and CsA + TQ groups, and rat treatment was for 28 days. In the I/R study, adult male rats were divided into sham-operated, I/R (renal ischaemia for 60 min followed by 60 min reperfusion) and TQ + I/R (TQ 10 mg/kg, 24 h and 1 h before ischaemia) groups. KEY FINDINGS: CsA treatment and renal I/R caused kidney and liver dysfunction as evaluated by histopathological changes and biochemical parameters. TQ treatment reduced elevated serum indices back to control levels and ameliorated CsA-induced kidney and liver histopathological changes. In renal and hepatic tissues, CsA and renal I/R induced significant increases in malondialdehyde levels with significant decreases in reduced glutathione levels and superoxide dismutase activities. Such changes in oxidative stress markers were counteracted by TQ treatment. CONCLUSIONS: Kidney and liver injury due to CsA or renal I/R can be significantly reduced by TQ, which resets the oxidant/antioxidant balance of the affected organs through scavenging free radicals and antilipoperoxidative effects.