Nashwa M Abu-Elsaad1, Marwa S Serrya2, Amr M El-Karef3, Tarek M Ibrahim4. 1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: nosha.samaa@gmail.com. 2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: marwa.sereya@hotmail.com. 3. Department of Pathology and Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt. Electronic address: aelkaref@yahoo.com. 4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: tarekmoss@yahoo.com.
Abstract
BACKGROUND: 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. METHODS: Four groups of Swiss albino male mice (CD-1 strain) were used as follows: control group; thioacetamide group (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks); thioacetamide plus 17-AAG groups (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks plus 25 or 50mg/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. RESULTS: 17-AAG (50mg/kg) significantly decreased fibrosis percentage significantly (p<0.001, 0.05) compared to thioaceatmide and 25mg/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 (50mg/kg) compared to other groups. CONCLUSION: The Hsp90 inhibitor, 17-AAG, can attenuate thioacetamide hepatotoxicity through oxidative stress counterbalance, reducing stellate cells activity and inducing apoptosis.
BACKGROUND: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. METHODS: Four groups of Swiss albino male mice (CD-1 strain) were used as follows: control group; thioacetamide group (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks); thioacetamide plus 17-AAG groups (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks plus 25 or 50mg/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. RESULTS: 17-AAG (50mg/kg) significantly decreased fibrosis percentage significantly (p<0.001, 0.05) compared to thioaceatmide and 25mg/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 (50mg/kg) compared to other groups. CONCLUSION: The Hsp90 inhibitor, 17-AAG, can attenuate thioacetamidehepatotoxicity through oxidative stress counterbalance, reducing stellate cells activity and inducing apoptosis.
Authors: Xiao Zhao; Kristin Lorent; Diana Escobar-Zarate; Ramakrishnan Rajagopalan; Kathleen M Loomes; Kevin Gillespie; Clementina Mesaros; Michelle A Estrada; Ian A Blair; Jeffrey D Winkler; Nancy B Spinner; Marcella Devoto; Michael Pack Journal: Gastroenterology Date: 2020-06-04 Impact factor: 22.682