Mechanism of protective effect of phyllanthin against carbon tetrachloride-induced hepatotoxicity and experimental liver fibrosis in mice.
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.
a Department of Zoology , University School of Sciences, Gujarat University , Ahmedabad , India .
Rajesh
R
Krithika
b Department of Medical Biochemistry , Dr. A.L.M.Post Graduate Institute of Basic Medical Sciences, University of Madras , Taramani , Chennai , India , and.
Vasavan
V
Jyothilakshmi
c Department of Biotechnology , PES Institute of Technology , BSK III Stage , Bangalore , India.
Karunakar
K
Prashantha
a Department of Zoology , University School of Sciences, Gujarat University , Ahmedabad , India .
Ramtej J
RJ
Verma
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000378:metabolism; D005260:Female; D017705:Lignans / Q000008:administration & dosage / Q000302:isolation & purification / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008111:Liver Function Tests; D051379:Mice; D062105:Molecular Docking Simulation; D029803:Phyllanthus / Q000737:chemistry; D020011:Protective Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000627:therapeutic use*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D017705:Lignans; D020011:Protective Agents; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; C517985:phyllanthin; D003094:Collagen; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse
ALK5; CCl4; Smad2; Smad3; TGF-β1; liver fibrosis; phyllanthin