title: Reduction of Dimethylnitrosamine-Induced Liver Fibrosis by the Novel Gene Regulator PI Polyamide Targeting Transforming Growth Factor β1 Gene.
abstract: Pyrrole-imidazole (PI) polyamide is a novel gene regulating agent that competitively inhibits transcription factor binding to the promoter of the specific target gene. Liver fibrosis is an integral stage in the development of chronic liver disease, and transforming growth factor β (TGFβ) is known to play a central role in the progression of this entity. The aim of this study was to evaluate the effect of PI polyamide targeting TGFβ1 on rat liver fibrosis. PI polyamide was designed to inhibit activator protein 1 (AP-1) transcription factor binding to the TGFβ1 gene promoter. The effect of PI polyamide on hepatic stellate cells was evaluated by real time polymerase chain reaction (PCR) in RI-T cells. To determine the effect of PI polyamide in vivo, PI polyamide was intravenously administered at a dose of 3 mg/kg/week in dimethylnitrosamine (DMN)-induced rat model of liver fibrosis. Treatment of RI-T cells with 1.0 µM PI polyamide targeting TGFβ1 significantly inhibited TGFβ1 mRNA expression. Azan staining showed that DMN treatment significantly increased areas of fibrous materials compared with controls. PI polyamide targeting TGFβ1 significantly decreased the fibrous area compared with DMN group. mRNA expression levels of α-smooth muscle actin and matrix metalloproteinase-2 were significantly increased in DMN-treated group compared with control. Treatment with TGFβ1 PI polyamide significantly decreased mRNA expression of these genes compared with DMN group. The novel gene regulator PI polyamide targeting TGFβ1 may be a feasible therapeutic agent for the treatment of chronic liver disease.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine.
authors.forename: Makiko
authors.initials: M
authors.lastname: Inami
authors.forename: Akiko
authors.initials: A
authors.lastname: Fukushima
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueno
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yamada
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsunemi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Moriyama
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004128:Dimethylnitrosamine; D058625:End Stage Liver Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005355:Fibrosis; D020868:Gene Silencing; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D007093:Imidazoles; D011758:Pyrroles; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C029899:imidazole; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D004128:Dimethylnitrosamine