Therapeutic efficacy of Ganoderma Lucidum on Thioacetamide-Induced Hepatic Fibrosis through Inhibition of TGF-β1 signaling in Male Rats.

Hanan Hassan,Sahar Elswefy

doi:10.21608/rpbs.2020.51148.1081

Abstract

The anti-fibrosis efficacy of Ganoderma lucidum (GL) was investigated on thioacetamide (TAA)-induced liver fibrosis. Experimental fibrosis was induced by (200 mg/kg TAA, i.p.) twice weekly for 6 weeks in male Sprague-Dawley rats. GL was administered to TAA rats, either as (250/500 mg/kg, i.p) daily for further 3 weeks. Repeated administration of TAA caused liver fibrosis evidenced by significant elevation of hepatic TGF-β1 accompanied by an increase in the hydroxyproline content, oxidative stress levels and liver biomarkers. Contrarily, GL treatment significantly reduced ALT, AST, total bilirubin, MDA, NO concentrations and restored SOD activity. H & E and Masson trichrome staining confirmed that GL suppressed liver fibrosis, inflammation and attenuated the histopathological alterations. GL also elicited a statistical decrease in TGF-β1 level and hydroxyproline content with a concomitant decline in NFk-B and α-SMA immunoexpression in the TAA treated rats. Furthermore, GL downregulated TNF-α and IL-1β levels in TAA-treated rats compared to the control group. Conclusion: GL possesses a pronounced protective activity against TAA-induced fibrosis in rats; It significantly inhibits oxidative stress, inflammation and diminishes fibrosis by: inhibiting NFk-B activation, reducing TGF-β mediated by PI3K-AKT pathway thus restoring the liver function, the effect was in a dose dependent manner.

Highlights

Liver fibrosis is a major global public health problem caused by several chronic liver diseases (Li et al, 2019)
Liver fibrosis may progress into more severe stages known as cirrhosis, when liver acini are substituted by nodules and further to hepatocellular carcinoma
Schyman et al (2018) and Sharma et al (2019) demonstrated that thioacetamide bioactivation is catalyzed by CYP450 isoenzymes, resulted in the formation of thioacetamide sulfur dioxide which may imply downregulation of enzymes involved in fatty acid β-oxidation, branched chain amino acids, methionine breakdown and upregulation of proteins related to lipid peroxidation and oxidative stress (Low et al, 2004)

Summary

Introduction

Liver fibrosis is a major global public health problem caused by several chronic liver diseases (Li et al, 2019). It is defined as the remodeling and excessive deposition of extracellular matrix (ECM) proteins in liver (Palmer et al, 2005). Oxidative stress is an important primary factor which was extensively investigated in number of liver diseases as hepatic fibrosis. The latter is associated with reactive oxygen species (ROS) production, which is known to aggravate inflammation and induce the pathogenesis of hepatic fibrosis (Wang et al, 2013). Reactive nitrogen species (RNS) play a major role in the pathogenesis of various liver diseases and inducible nitric oxide synthase (iNOS)-derived NO is closely related to this process (Iwakiri and Kim 2015)

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