The heat shock protein 90 inhibitor, 17-AAG, attenuates thioacetamide induced liver fibrosis in mice
Tóm tắt
Heat shock protein 90 (Hsp90) is proposed to be involved in liver disorders. This study was conducted to test effect of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90, on attenuating thioacetamide induced liver fibrosis in vivo. Four groups of Swiss albino male mice (CD-1 strain) were used as follows: control group; thioacetamide group (received 100 mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks); thioacetamide plus 17-AAG groups (received 100 mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks plus 25 or 50 mg/kg 17-AAG, ip injection, 5 days/week along the last 4 weeks). Fibrosis was quantified by measuring hydroxyproline level and by morphometry and oxidative stress biomarkers were assigned. Relative hepatic mRNA expressions of α-smooth muscle actin (α-SMA), collagen-1-alpha-1 (Col1A1) and tissue inhibitor metalloproteinase-1 (TIMP-1) mRNAs were measured by RT-PCR. Levels of the apoptotic markers caspase-3, factor related apoptosis (Fas) and Hsp-90 were assigned in tissue homogenate. 17-AAG (50 mg/kg) significantly decreased fibrosis percentage significantly (p < 0.001, 0.05) compared to thioaceatmide and 25 mg/kg, respectively. Malondialdehyde, Hsp90, α-SMA, Col1A1 and TIMP-1 expression levels were significantly reduced (p < 0.05) by the inhibitor large dose. Levels of GSH, caspase-3 and Fas were markedly (p < 0.001) increased in the group received 17-AAG (50 mg/kg) compared to other groups. The Hsp90 inhibitor, 17-AAG, can attenuate thioacetamide hepatotoxicity through oxidative stress counterbalance, reducing stellate cells activity and inducing apoptosis.
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