phyllanthin and Liver-Cirrhosis

Hepatic fibrosis is an important outcome of chronic liver injury and results in excess synthesis and accumulation of extracellular matrix (ECM) components. Phyllanthin (PLN) isolated from Phyllanthus amarus exhibits strong antioxidative property and protects HepG2 cells from carbon tetrachloride (CCl4)-induced experimental toxicity. The present study reports the antifibrotic potential of PLN. The in vivo inhibitory effect of PLN on CCl4-mediated lipid peroxidation and important profibrotic mediator transforming growth factor β1 and on predominant ECM components collagen and fibronectin were also studied. The results show that PLN acts by suppressing the expression of inflammatory cytokine tumor necrosis factor-α and prevents activation of nuclear factor-κB in hepatic tissue. Our study highlights the molecular mechanism responsible for the antifibrotic efficacy of PLN.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Down-Regulation; Female; Hep G2 Cells; Humans; Lignans; Lipid Peroxidation; Liver; Liver Cirrhosis; Mice; NF-kappa B; Oxidative Stress; Phyllanthus; Plant Extracts; Protective Agents; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Chronic injury to liver triggers synthesis of extracellular matrix components resulting in progressive fibrosis and eventually cirrhosis. Transforming growth factor-β1 (TGF-β1) transduces its signal by binding to TGF-β type 1 receptor kinase or activin like kinase (ALK5) receptor and mediates hepatic fibrosis by increasing the transcription of downstream entities such as collagen via Smad2 and Smad3. The present study was carried out to investigate the mechanism by which phyllanthin, a hepatoprotective lignin isolated from the plant Phyllanthus amarus (P. amarus) exerts its anti-fibrotic effect. The inhibitory role of phyllanthin on ALK5 was first analyzed using molecular docking experiments. Phyllanthin was found to effectively bind to serine (Ser) 280 at the active site of ALK5 by forming hydrogen bonds. The in vivo protective effect of phyllanthin against carbon tetrachloride (CCl4)-induced hepatic fibrosis was established by studying the protein expressions of TGF-β1, ALK5 and Smad2 and 3 and by determining various biochemical and histopathological parameters. Phyllanthin was found to exert its anti-fibrotic effect by down-regulating TGF signaling pathway via ALK5 and Smad2 and 3 inhibition.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Collagen; Female; Lignans; Liver Cirrhosis; Liver Function Tests; Mice; Molecular Docking Simulation; Phyllanthus; Protective Agents; Protein Binding; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1