title: Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism.
abstract: OBJECTIVE
  Dasatinib, a potent and broad-spectrum tyrosine kinase inhibitor, is approved for the treatment of imatinib-resistant chronic myelogenous leukemia. The aim of this study was to evaluate the anti-fibrotic, anti-inflammatory and antioxidant effects of this agent against CCl4-induced hepatic fibrosis and oxidative status.
  
  
  METHODS
  Experimental fibrosis was induced in Wistar male rats by 12 weeks of CCl4administration (i.p.). During the last 8 weeks of injection, rats were gavaged daily with Dasatinib (10 mg/kg). To evaluate anti-inflammatory and anti-fibrotic effects of Dasatinib, histopathological examination of liver tissue was performed and serum ALT and AST activities, oxidant, antioxidant parameters and hepatic tumor necrosis factor alpha (TNF-α) were examined. Moreover, transforming growth factor (TGF-β1), platelet derived growth factor (PDGF) and TNF-α mRNA expressions were also evaluated by real time polymerase chain reaction.
  
  
  RESULTS
  Dasatinib administration induced a significant reduction of ALT and AST activities (p < .001) and Malondialdehyde (MDA) content in CCl4injected rats (p < .05). Concomitantly hepatic protein and mRNA expression of TNF-α, mRNA expression of TGF-β1and PDGF were increased due to CCl4intoxication (p < .001), but Dasatinib treatment could significantly ameliorate these mediators at the level of gene expression (p < .01) and protein level of TNF-α (p < .001). The necro-inflammatory changes in histopathological finding, nitric oxide and hydroxyproline level were also increased during 12 weeks of CCl4administration which was significantly attenuated by Dasatinib (p < .01).
  
  
  CONCLUSIONS
  Our findings indicate that Dasatinib can be cautiously an anti-fibrotic, anti-inflammatory and anti-oxidative agent in clinical setting.
authors.affiliation: a Department of Biochemistry, School of Medicine , Hamadan University of Medical Sciences , Hamadan , Iran.
authors.forename: Adel
authors.initials: A
authors.lastname: Mohammadalipour
authors.affiliation: a Department of Biochemistry, School of Medicine , Hamadan University of Medical Sciences , Hamadan , Iran.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Karimi
authors.affiliation: a Department of Biochemistry, School of Medicine , Hamadan University of Medical Sciences , Hamadan , Iran.
authors.forename: Iraj
authors.initials: I
authors.lastname: Khodadadi
authors.affiliation: b Department of Immunology, School of Medicine , Hamadan University of Medical Sciences , Hamadan , Iran.
authors.forename: Ghasem
authors.initials: G
authors.lastname: Solgi
authors.affiliation: c Department of Pathobiology, Veterinary Medicine Faculty , Razi University , Kermanshah , Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hashemnia
authors.affiliation: a Department of Biochemistry, School of Medicine , Hamadan University of Medical Sciences , Hamadan , Iran.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Sheikh
authors.affiliation: a Department of Biochemistry, School of Medicine , Hamadan University of Medical Sciences , Hamadan , Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Bahabadi
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy* / Q000276:immunology; D000069439:Dasatinib / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000890:Anti-Infective Agents; D000975:Antioxidants; D000069439:Dasatinib
keywords: Carbon tetrachloride; Dasatinib; TGF-β1; TNF-α; liver fibrosis