title: 2',4',6'-Tris(methoxymethoxy) chalcone attenuates hepatic stellate cell proliferation by a heme oxygenase-dependent pathway.
abstract: Proliferation of hepatic stellate cells (HSCs) is central for the development of fibrosis during liver injury. We have shown previously that butein (3,4,2',4'-tetrahydroxychalcone) suppresses myofibroblastic differentiation of rat HSCs. Our aim in this study was to determine whether a new synthetic chalcone derivative, 2',4',6'-tris(methoxymethoxy) chalcone (TMMC) inhibits HSC proliferation induced by serum- or platelet-derived growth factor (PDGF). TMMC significantly inhibited growth factor-induced HSC proliferation. The inhibition of PDGF-induced proliferation by TMMC was associated with the phosphatidylinositol 3-kinase-Akt-p70(S6K) pathways. TMMC induced the expression of heme oxygenase 1 (HO-1) in HSCs. Using the chemical inhibitor tin protoporphyrin, we also found that the inhibitory action of TMMC on PDGF-induced proliferation is mediated by HO-1. Glutathione (GSH) depletion produced by TMMC activated extracellular signal-regulated kinase (ERK), which led to c-Fos expression and transactivation of activator protein 1 (AP-1) and HO-1 gene expression in the HSCs. These results demonstrate that TMMC preferentially activates ERK and that this activation leads to the transcriptional activation of AP-1 and consequently to HO-1 expression. HO-1 expression might be responsible for the antiproliferative effect of TMMC on HSCs.
authors.affiliation: College of Pharmacy, Medicinal Resources Research Institute, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Geom Seog
authors.initials: GS
authors.lastname: Seo
authors.forename: Hak Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Sun Wook
authors.initials: SW
authors.lastname: Woo
authors.forename: Geonil
authors.initials: G
authors.lastname: Ko
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Sohn
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D016895:Culture Media, Serum-Free; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C510589:2',4',6'-tris(methoxymethoxy) chalcone; D047188:Chalcones; D016895:Culture Media, Serum-Free; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione