Suppression of Cisplatin-Induced Hepatic Injury in Rats Through Alarmin High-Mobility Group Box-1 Pathway by Ganoderma lucidum: Theoretical and Experimental Study

Purpose: Drug-induced liver injury (DILI) is the most common cause of acute liver failure. The aim of this study was to investigate the molecular mechanisms by which Ganoderma lucidum mushroom (GLM) may ameliorate cisplatin (CP)-induced hepatotoxicity theoretically and experimentally. Materials and Methods: Thirty-six male Sprague-Dawley (SD) rats were divided into six groups, two of them are normal and Ganoderma lucidum control groups. Liver injury was induced by a single dose of CP (12 mg/kg i.p) in four groups, one of them is CP control group. Besides cisplatin injection in day 1, rats in groups (4-6) were subjected to GLM (500 mg/kg/day) either every other day or daily oral dose or via i.p injection for 10 consecutive days. Results: In this study, GLM supplementation caused significant reduction of elevated highmobility group box-1 (HMGB-1) with a concurrent decline in TNF-alpha and upregulation of IL-10 compared to the CP group (P<0.05). The histopathological and fibrosis evaluation significantly confirmed the improvement upon simultaneous treatment with GLM. Moreover, immunohistochemical examination also confirmed the recovery following GLM treatment indicated by downregulation of NF-kappa B, p53 and caspase-3 along with upsurge of B-cell lymphoma 2 (Bcl-2) expression (P<0.05). GLM treatment significantly decreased serum levels of hepatic injury markers; ALT, AST, T. bilirubin as well as oxidative stress markers; MDA and H2O2 with a concomitant increase in hepatic GSH and SOD. Also, the performed docking simulation of ganoderic acid exhibited good fitting and binding with HMGB-1 through hydrogen bond formation with conservative amino acids which gives a strong evidence for its hepatoprotective effect and may interpret the effect of Ganoderma lucidum. Conclusion: GLM attenuated hepatic injury through downregulation of HMGB-1/NF-kappa B and caspase-3 resulted in modulation of the induced oxidative stress and the subsequent cross-talk between the inflammatory and apoptotic cascade indicating its promising role in DILI.