title: Hepatoprotective effects of cathepsin B inhibitor on acute hepatic failure induced by lipopolysaccharide/D-galactosamine in mice.
abstract: BACKGROUND
  Increasing evidence suggests that the inactivation of cathepsin B attenuates hepatocyte apoptosis and liver damage. This study aimed to investigate the protective effects of a cathepsin B inhibitor (CA-074me) on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute hepatic failure (AHF) in mice.
  
  
  METHODS
  Mice were intraperitoneally injected with a combination of LPS/D-GalN to induce AHF with or without CA-074me pretreatment. The cumulative survival rates were calculated 48 hours after the induction of AHF. As well as changes in biochemical indicators and liver histology, hepatocyte apoptosis was assessed using a TUNEL method. Serum tumor necrosis factor-alpha (TNF-alpha) production, caspase-3, caspase-8, and caspase-9 activity was evaluated. Cytosolic cytochrome c and Bcl-2 expression were measured by Western blotting.
  
  
  RESULTS
  The marked elevation in serum aminotransferase activity and prothrombin time found in LPS/D-GalN-treated mice was significantly improved by pretreatment with CA-074me. The efficacy of CA-074me was also confirmed by histological analysis and TUNEL assay. The survival rate significantly improved in LPS/D-GalN-induced mice given CA-074me compared with untreated mice. LPS/D-GalN-induced caspase-3 and caspase-9 activation was remarkably suppressed by CA-074me. However, the increased levels of serum TNF-alpha and elevated caspase-8 activity in AHF mice were not significantly reduced by CA-074me. Moreover, CA-074me sharply reduced the increased expression of cytosolic cytochrome c and markedly augmented Bcl-2 expression.
  
  
  CONCLUSIONS
  These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.
authors: Department of Infectious Diseases, Second Clinical Hospital, Harbin Medical University, Harbin 150086, China.
authors: Bing-Zhu
authors: BZ
authors: Yan
authors: Li-Yan
authors: LY
authors: Chen
authors: Lan
authors: L
authors: Kang
authors: Xiao-Ren
authors: XR
authors: Wang
authors: Man-Ru
authors: MR
authors: Bi
authors: Wei
authors: W
authors: Wang
authors: Bao-Shan
authors: BS
authors: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D005688:Galactosamine / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011897:Random Allocation; D015996:Survival Rate; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; C052617:Bcl2 protein, mouse; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D005688:Galactosamine; D045304:Cytochromes c; D000637:Transaminases; D020169:Caspases; D002401:Cathepsin B; C533915:Ctsb protein, mouse