eupatilin and Cholestasis

In cases of cholestasis, bile acids induce hepatocyte apoptosis by activating death receptor-mediated apoptotic signaling cascades. Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a pharmacologically active ingredient found in Artemisia asiatica and exhibits cytoprotective effects against experimentally induced gastrointestinal, pancreatic, and hepatic damage. This study was undertaken to examine if eupatilin modulates bile acid-induced hepatocyte apoptosis.. Huh-BAT cells, a human hepatocellular carcinoma cell line stably transfected with a bile acid transporter, were used in this study. Apoptosis was quantified using 4',6-diamidino-2-phenylindole dihydrochloride staining, and its signaling cascades were explored by immunoblot analysis. Kinase signaling was evaluated by immunoblotting and by using selective inhibitors. Eupatilin's in vivo effect on bile acid-induced hepatocyte apoptosis was explored in bile duct-ligated rats.. Eupatilin significantly reduced bile acid-mediated hepatocyte apoptosis by attenuating bile acid-induced caspase 8 cleavage. Eupatilin diminished the bile acid-induced activation of mitogen-activated protein kinases, including p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In particular, the eupatilin-mediated inhibition of bile acid-induced c-Jun N-terminal kinase activation was found to be responsible for attenuating caspase 8 cleavage. Moreover, eupatilin diminished hepatocyte apoptosis in bile duct-ligated rats.. Eupatilin attenuates bile acid-induced hepatocyte apoptosis by suppressing bile acid-induced kinase activation. Therefore, eupatilin might be therapeutically efficacious in a variety of human liver diseases associated with cholestasis.

Topics: Animals; Apoptosis; Caspase 8; Cell Line, Tumor; Cholestasis; Deoxycholic Acid; Flavonoids; Hepatocytes; Humans; Immunoblotting; In Situ Nick-End Labeling; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Microscopy, Fluorescence; Models, Animal; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley

Topics: Apoptosis; Cell Line, Tumor; Cholestasis; Flavonoids; Hepatocytes; Humans