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Glutathione Might Attenuate Arsenic-Induced Liver Injury by Modulating the Foxa2-XIAP Axis to Reduce Oxidative Stress and Mitochondrial Apoptosis

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Abstract

Arsenic (AS) is a metalloid element that widely exists and can cause different degrees of liver damage. The molecular mechanism of arsenic-induced liver injury has yet to be fully elucidated. Clinically, glutathione (GSH) is often used as an antidote for heavy metal poisoning and hepatoprotective drugs. However, the hepatoprotective effect of glutathione remains unknown in arsenic-induced liver injury. The regulatory relationship between Foxa2 and XIAP may play an important role in mitochondrial survival and death. Therefore, we took Foxa2-XIAP as the axis to explore the protective mechanism of GSH. In this study, we first established a mouse model of chronic arsenic exposure and examined liver function as reflected by quantitative parameters such as aspartate aminotransferase and alanine aminotransferase. Also, redox parameters in the liver were measured, including malondialdehyde, superoxide dismutase, 8-hydroxy-2′-deoxyguanosin, and glutathione peroxidase. RT-qPCR and western-blotting were used to detect the levels of related genes and proteins, such as Foxa2, XIAP, Smac, Bax, Bcl2, Caspase9, and Caspase3. Subsequently, GSH was administered at the same time as high arsenic exposure, and changes in the above parameters were observed. After a comprehensive analysis of the above results, we demonstrate that GSH treatment alleviates arsenic-induced oxidative stress and inhibits the mitochondrial pathway of apoptosis, which can be regulated through the Foxa2 and XIAP axis. The present study would be helpful in elucidating the molecular mechanism of arsenic-induced liver injury and identifying a new potential therapeutic target. And we also provided new theoretical support for glutathione in the treatment of liver damage caused by arsenic.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (grant no. 81773367).

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Author notes

  1. Hua Zhang and Baiming Jin contributed equally to this work.

Authors and Affiliations

  1. Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China

    Hua Zhang, Baiming Jin, Lele Liu, Haonan Li, Xiujuan Zheng, Mingqi Li, Rui He & Kewei Wang

  2. National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University, (23618504)150081, Harbin, China

    Hua Zhang, Lele Liu, Haonan Li, Xiujuan Zheng, Mingqi Li, Rui He & Kewei Wang

  3. Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, 150081, China

    Hua Zhang, Lele Liu, Haonan Li, Xiujuan Zheng, Mingqi Li, Rui He & Kewei Wang

  4. Department of Preventive Medicine, Qiqihar Medical University, Qiqihar, 161006, China

    Baiming Jin

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  1. Hua Zhang
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Contributions

Hua Zhang, Baiming Jin, and Kewei Wang developed the hypothesis and study design. All authors contributed to the study concept, analysis, and interpretation of the data. All authors approved the final manuscript for submission.

Corresponding author

Correspondence to Kewei Wang.

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Ethics Approval and Consent to Participate Animal Ethics

All procedures were approved by the Animal Use Ethics Committee of the Chinese Center for Disease Control and Prevention, Harbin Medical University (approval ID: hrbmuecdc20170306).

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The authors declare no competing interests.

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Zhang, H., Jin, B., Liu, L. et al. Glutathione Might Attenuate Arsenic-Induced Liver Injury by Modulating the Foxa2-XIAP Axis to Reduce Oxidative Stress and Mitochondrial Apoptosis. Biol Trace Elem Res 201, 5201–5212 (2023). https://doi.org/10.1007/s12011-023-03577-4

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