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Hepatoprotective Effect of Apigenin Against Liver Injury via the Non-canonical NF-κB Pathway In Vivo and In Vitro

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Abstract

Apigenin, a flavonoid found in many plants, has various biological properties. We aimed to investigate the anti-inflammatory and anti-oxidative activity of apigenin against carbon tetrachloride (CCl4)-induced acute liver injury in mice and hydrogen peroxide (H2O2)-induced oxidative stress in HepG2 cells and possible mechanism. In vivo, apigenin significantly reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in serum of mice challenged by CCl4 and markedly alleviated the lipid peroxidation as indicated by the increased level of superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidases (GSH-Px) and catalase (CAT), and the decreased malondialdehyde (MDA) in liver tissue. Apigenin also ameliorated inflammation by downregulating tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and upregulating IL-10. Consistently, the elevated ALT and AST level; the impaired balance between SOD, GSH activity, and excessive ROS; and the increased gene expression of TNF-α and IL-6 resulting from H2O2-induced oxidative stress were restored by apigenin. Moreover, the results from Western blot, real-time qPCR, and immunofluorescence assay indicated that apigenin enhanced the activity of TNF receptor-associated factor (TRAF) 2/3 and cellular inhibitor of apoptosis protein (c-IAP) 1, ameliorated NF-κB-inducing kinase (NIK), and mediated the nuclear translocation of NF-κB2, therefore had an inhibitory effect on the non-canonical NF-κB pathway which was activated in both models. siNIK canceled the protective effect of apigenin on H2O2-induced HepG2 cells. Altogether, our results demonstrated that apigenin mitigated liver injury by ameliorating inflammation and oxidative stress through suppression of the non-canonical NF-κB pathway, indicating the potential of apigenin for treatment of the liver injury.

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Acknowledgments

This study was conceived by XW. XW and SWY designed the study. SWY performed all experiments in the current study. NX and HLL provided experimental assistance. SWY wrote the original draft. BSH, ZC, and XW reviewed the manuscript.

Funding

This work was supported by the Natural Science Foundation of Jiangsu Province (BK20180574, BK20171064), the Technology Incubator Scheme (Social Programs) of Jiangning District (2018Ca12), the Research Foundation of Jiangsu Provincial Medical Youth Talent, the Project of Inviogorating Health Care through Science, Technology and Education (QNRC2016858), the Nanjing Medical University Science Research and Development Foundation (2016NJMU013), the Natural Science Research Fund (General Program) for the Higher Education of Jiangsu Province of China (18KJB350005), and the Zhenjiang City 2017 Science and Technology Innovation Fund (SH2017043).

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  1. Shuwen Yue and Ning Xue contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China

    Shuwen Yue, Zhen Chen & Xing Wang

  2. Department of Acupuncture, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of China

    Ning Xue

  3. Department of Pharmacy, Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, People’s Republic of China

    Honglei Li

  4. Department of Neurosurgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China

    Baosheng Huang

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Yue, S., Xue, N., Li, H. et al. Hepatoprotective Effect of Apigenin Against Liver Injury via the Non-canonical NF-κB Pathway In Vivo and In Vitro. Inflammation 43, 1634–1648 (2020). https://doi.org/10.1007/s10753-020-01238-5

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