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. CONCLUSION: These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.
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. CONCLUSION: These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.
Authors: Álvaro de Mingo; Estefanía de Gregorio; Anna Moles; Núria Tarrats; Anna Tutusaus; Anna Colell; Jose C Fernandez-Checa; Albert Morales; Montserrat Marí Journal: Cell Death Dis Date: 2016-11-10 Impact factor: 8.469