title: Conophylline suppresses hepatic stellate cells and attenuates thioacetamide-induced liver fibrosis in rats.
abstract: OBJECTIVE
  Conophylline (CnP) is a vinca alkaloid purified from a tropical plant and inhibits activation of pancreatic stellate cells. We investigated the effect of CnP on hepatic stellate cells (HSC) in vitro. We also examined whether CnP attenuates hepatic fibrosis in vivo.
  
  
  METHODS
  We examined the effect of CnP on the expression of α-smooth muscle actin (α-SMA) and collagen-1, DNA synthesis and apoptosis in rat HSC and Lx-2 cells. We also examined the effect of CnP on hepatic fibrosis induced by thioacetamide (TAA).
  
  
  RESULTS
  In rat HSC and Lx-2 cells, CnP reduced the expression of α-SMA and collagen-1. CnP inhibited DNA synthesis induced by serum. CnP also promoted activation of caspase-3 and induced apoptosis as assessed by DNA ladder formation and TUNEL assay. In contrast, CnP did not induce apoptosis in AML12 cells. We then examined the effect of CnP on TAA-induced cirrhosis. In TAA-treated rats, the surface of the liver was irregular and multiple nodules were observed. Histologically, formation of pseudolobules surrounded by massive fibrous tissues was observed. When CnP was administered together with TAA, the surface of the liver was smooth and liver fibrosis was markedly inhibited. Collagen content was significantly reduced in CnP-treated liver.
  
  
  CONCLUSIONS
  Conophylline suppresses HSC and induces apoptosis in vitro. CnP also attenuates formation of the liver fibrosis induced by TAA in vivo.
authors.affiliation: Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan; Department of General Surgical Science (Surgery I), Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Kubo
authors.forename: Rie
authors.initials: R
authors.lastname: Saito
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Hamano
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Aoki
authors.forename: Izumi
authors.initials: I
authors.lastname: Takei
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
authors.forename: Itaru
authors.initials: I
authors.lastname: Kojima
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000188:drug therapy*; D051381:Rats; D013853:Thioacetamide / Q000009:adverse effects*; D014748:Vinca Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000199:Actins; D024042:Collagen Type I; D014748:Vinca Alkaloids; C099167:conophylline; D013853:Thioacetamide; D053148:Caspase 3
keywords: apoptosis; cirrhosis; collagen; fibrosis; stellate cell