The involvement of Nrf2 antioxidant signalling pathway in the protection of monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats by (+)-catechin hydrate |
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Authors: | Xiaoqi Jing Jiaqi Zhang Zhenlin Huang |
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Institution: | 1. MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China;2. Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China |
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Abstract: | Hepatic sinusoidal obstruction syndrome (HSOS) is a rare and life-threatening liver disease. (+)-Catechin is a natural dietary flavonol with high antioxidant capacity. This study aims to investigate the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signalling pathway in the protection of (+)-catechin hydrate (CAT) against monocrotaline (MCT)-induced HSOS. Results of serum alanine/aspartate aminotransferases (ALT/AST) activities, total bilirubin (TBil) and bile acids (TBA) amounts, liver histological observation, scanning electron microscope evaluation, and hepatic metalloproteinase-9 (MMP-9) expression all demonstrated the protection of CAT against MCT-induced HSOS in rats. CAT attenuated MCT-induced liver oxidative injury in rats and the formation of cellular reactive oxygen species (ROS) in human hepatic sinusoidal endothelial cells (HHSECs). CAT-enhanced Nrf2 nuclear translocation in livers from MCT-treated rats and in HHSECs treated with MCT, and further increased the expression of Nrf2-dependent genes including catalytic or modify subunit of glutamate-cysteine ligase (GCLC/GCLM), haem oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). Moreover, GCL inhibitor L-buthionine-(S, R)-sulfoximine (BSO), NQO1 inhibitor diminutol (Dim), and HO-1 inhibitor zinc protoporphyrin (ZnPP) all abrogated CAT-provided the protection against MCT-induced cytotoxicity in HHSECs. The results of molecular docking analysis indicated the potential interaction of CAT with the Nrf2-binding site in kelch-like ECH-associated protein-1 (Keap1) protein. In summary, this study demonstrated the critical involvement of Nrf2 antioxidant signalling pathway in CAT-provided the protection against MCT-induced HSOS. |
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Keywords: | (+)-Catechin hydrate monocrotaline HSOS Nrf2 Keap1 |
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