title: Attenuation of hepatic fibrosis by an imidazolium salt in thioacetamide-induced mouse model.
abstract: OBJECTIVE
  Hepatic fibrosis is a worldwide healthy burden associated with significant morbidity and mortality. It is caused by a variety of chronic liver injuries. There is currently no effective treatment for liver fibrosis. In this report, we tested an imidazolium salt, 1,3-diisopropylimidazolium tetrafluoroborate (DPIM), for its anti-fibrotic properties in the thioacetamide-induced mouse model.
  
  
  METHODS
  DPIM was orally delivered to the thioacetamide-treated mice via drinking water for 12 weeks at the onset of thioacetamide treatment at a concentration of 0.1% (prevention group), and for 4 weeks starting at the 8(th)  week at a concentration of 0.1% or 0.2% (attenuation group), respectively. Messenger RNA and protein were determined by real-time polymerase chain reaction and Western blotting, matrix metalloproteinase (MMP) activities were measured by fluorogenic peptide substrate and zymography. Mitogen-activated protein kinase (MAPK) and PI3K inhibitors were applied in HSC-T6 cells in combination of DPIM to probe possible signal pathways underlying the compound's action.
  
  
  RESULTS
  We observed a significant reduction in collagen deposition in both prevention and attenuation groups. The α-smooth muscle actin (SMA) and transforming growth factor (TGF)-β gene expressions were also reduced in both groups. The reduction of collagen deposition could be in part attributed to the suppression of CCR-2 expression and the enhanced matrix protein remodeling by metalloproteinases, especially MMP-3. MAPK and PI3K signaling pathways may be partially participated in DPIM's molecular action.
  
  
  CONCLUSIONS
  DPIM reduced fibrosis in the thioacetamide-induced mouse liver fibrosis model, and warranted further studies for possible clinical application in the future.
authors.affiliation: Institute of Bioengineering and Nanotechnology, Singapore.
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Ding
authors.forename: Lang
authors.initials: L
authors.lastname: Zhuo
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000201:enzymology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D020935:MAP Kinase Signaling System; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D013853:Thioacetamide; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: C558958:1,3-diisopropylimidazolium tetrafluoroborate; D000199:Actins; C515335:Ccr2 protein, mouse; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D054390:Receptors, CCR2; D016212:Transforming Growth Factor beta; D013853:Thioacetamide; D003094:Collagen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3