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Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress

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Abstract

Hepatic stellate cell (HSC) activation plays an indispensable role in hepatic fibrosis. Inducing apoptosis of activated HSCs can attenuate or reverse fibrogenesis. In this study, we initially found that oroxylin A (OA) protected CCl4-induced liver injury accompanied by endoplasmic reticulum stress (ERS) activation of HSCs in mice. In vitro, OA treatment markedly reduced fibrogenesis by modulating extracellular matrix synthesis and degradation. OA inhibited cell proliferation and induced cell cycle arrest of HSCs at S phase. Further, OA was observed to induce HSC apoptosis, as indicated by caspase activation. Using the eIF2α dephosphorylation inhibitor salubrinal, we found that ERS pathway activation was required for OA to induce HSC apoptosis. ERS-related proteins were significantly upregulated by OA treatment, and salubrinal abrogated the effects of OA on HSCs. Thus, we inferred that OA attenuated HSC activation by promoting ERS. In vivo, inhibition of ERS by salubrinal partly abrogated the hepatoprotective effect of OA in CCl4-treated mice. In conclusion, our findings suggest a role for ERS in the mechanism underlying amelioration of hepatic fibrosis by OA.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81270514, 31401210, 31571455), Science and Technology Plan Program of Fujian Province (2017Y0061), Scientific Research Foundation of Third Institute of Oceanography, the Ministry of Natural Resources (2018020),Youth Natural Science Foundation of Jiangsu Province (BK20140955), Priority Academic Program Development of Jiangsu Higher Education Institutions, 2013 Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education, Natural Science Research General Program of Jiangsu Higher Education Institutions (14KJB310011), Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (TAPPPPZY2015A070), and Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (JKLPSE201502).

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  1. Mianli Bian and Jianlin He contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, Jiangsu, China

    Mianli Bian, Jianlin He, Huanhuan Jin, Naqi Lian, Jiangjuan Shao, Feng Zhang & Shizhong Zheng

  2. Third Institute of Oceanography, Ministry of Natural Resources, 361005, Xiamen, China

    Jianlin He

  3. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

    Mianli Bian, Naqi Lian, Jiangjuan Shao, Feng Zhang & Shizhong Zheng

  4. Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

    Mianli Bian, Naqi Lian, Jiangjuan Shao, Feng Zhang & Shizhong Zheng

  5. Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, 241000, China

    Huanhuan Jin

  6. Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China

    Qinglong Guo

  7. Shandong Co-innovation Center of TCM Formula, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, Jiangsu, China

    Shijun Wang

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  1. Mianli Bian
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Bian, M., He, J., Jin, H. et al. Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress. Apoptosis 24, 905–920 (2019). https://doi.org/10.1007/s10495-019-01568-2

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