title: 2',4',6'-Tris(methoxymethoxy) chalcone induces apoptosis by enhancing Fas-ligand in activated hepatic stellate cells.
abstract: Suppression of hepatic stellate cell (HSC) activation and proliferation, and induction of apoptosis in activated HSCs have been proposed as therapeutic strategies for the treatment and prevention of the hepatic fibrosis. We previously showed that 2',4',6'-tris(methoxymethoxy) chalcone (TMMC), a synthesized chalcone derivative, inhibits platelet-derived growth factor-induced HSC proliferation at 5-20 μM. Here, we showed that TMMC induces apoptosis in activated HSCs at higher concentrations (30-50 μM), but is not cytotoxic to primary hepatocytes. Moreover, TMMC induces hyperacetylation of histone by inhibiting histone deacetylase (HDAC) in activated HSCs. Interestingly, TMMC treatment remarkably increased Fas-ligand (FasL) mRNA expression in a dose-dependent manner. Cycloheximide treatment reversed the induction of TMMC on apoptosis, indicating that de novo protein synthesis was required for TMMC-induced apoptosis in activated HSCs. In addition, FasL synthesis by TMMC is closely associated with maximal procaspase-3 proteolytic processing. In vivo, TMMC reduced activated HSCs in CCl(4)-intoxicated rats during liver injury recovery, as demonstrated by α-smooth muscle actin expression in rat liver. TMMC treatment also resulted in apoptosis, as demonstrated by cleavage of poly(ADP-ribose) polymerase in rat liver. In conclusion, TMMC may have therapeutic potential by inducing HSC apoptosis for the treatment of hepatic fibrosis.
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Chonbuk, Republic of Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Yu-Zhe
authors.initials: YZ
authors.lastname: Zhao
authors.forename: Eun-Jeon
authors.initials: EJ
authors.lastname: Park
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Che
authors.forename: Geom Seog
authors.initials: GS
authors.lastname: Seo
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Sohn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002251:Carbon Tetrachloride / Q000633:toxicity; D047188:Chalcones / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D007267:Injections; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C510589:2',4',6'-tris(methoxymethoxy) chalcone; D047188:Chalcones; D053222:Fas Ligand Protein; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D002251:Carbon Tetrachloride