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Dihydroartemisinin abolishes cisplatin-induced nephrotoxicity in vivo

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Abstract

Dihydroartemisinin (DHA), a derivative of artemisinin which is primarily used to treat malaria in clinic, also confers protective effect on lipopolysaccharide-induced nephrotoxicity. While, the activities of DHA in cisplatin (CDDP)-caused nephrotoxicity are elusive. To investigate the role and underlying mechanism of DHA in CDDP-induced nephrotoxicity. Mice were randomly separated into four groups: normal, CDDP, and DHA (25 and 50 mg/kg were orally injected 1 h before CDDP for consecutive 10 days). All mice except the normal were single injected intraperitoneally with CDDP (22 mg/kg) for once on the 7th day. Combined with quantitative proteomics and bioinformatics analysis, the impact of DHA on renal cell apoptosis, oxidative stress, biochemical indexes, and inflammation in mice were investigated. Moreover, a human hepatocellular carcinoma cells xenograft model was established to elucidate the impact of DHA on tumor-related effects of CDDP. DHA reduced the levels of creatinine (CREA) (p < 0.01) and blood urea nitrogen (BUN) (p < 0.01), reversed CDDP-induced oxidative, inflammatory, and apoptosis indexes (p < 0.01). Mechanistically, DHA attenuated CDDP-induced inflammation by inhibiting nuclear factor κB p65 (NFκB p65) expression, and suppressed CDDP-induced renal cell apoptosis by inhibiting p63-mediated endogenous and exogenous apoptosis pathways. Additionally, DHA alone significantly decreased the tumor weight and did not destroy the antitumor effect of CDDP, and did not impact AST and ALT. In conclusion, DHA prevents CDDP-triggered nephrotoxicity via reducing inflammation, oxidative stress, and apoptosis. The mechanisms refer to inhibiting NFκB p65-regulated inflammation and alleviating p63-mediated mitochondrial endogenous and Fas death receptor exogenous apoptosis pathway.

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Acknowledgements

The authors would like to thank Dr. Haiyang Shu and Mr. Chunyu He for their guidance on bioinformatics analysis in this research.

Funding

This study was supported by National Natural Science Foundation of China (No. 82260793); China Postdoctoral Science Foundation funded project (No. 2020M680834); Jiangxi Provincial Natural Science Foundation (No. 20212BAB216002); The Key R & D Project of Ganzhou Science and Technology Plan Project (2022B-SF8897); The Start-up Fund of Gannan Medical University (No. QD201821); The Science and Technology Project of the Education Department of Jiangxi Province (No. GJJ211517).

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Author notes

  1. Yan Luo, Jiaxing Zhang, and Yue Jiao have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, School of Pharmacy, Scientific Research Center, Gannan Medical University, Ganzhou, 341000, China

    Yan Luo, Yunlei Song & Yumao Jiang

  2. Artemisinin Research Center, and Institute of Chinese Materia Medical, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Yumao Jiang

  3. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China

    Jiaxing Zhang

  4. Beijing Key Laboratory of Traditional Chinese Medicine Basic Research On Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China

    Yue Jiao

  5. National Engineering Research Center for Modernization of Traditional Chinese Medicine-Hakka Medical Resources Branch, Gannan Medical University, Jiangxi, China

    Hao Huang & Yanlong Niu

  6. Institute for Advanced Study, Jiangxi University of Chinese Medicine, Jiangxi, China

    Liangshan Ming

  7. Department of Human Anatomy, School of Basic Medical Science, Gannan Medical University, Jiangxi, China

    Xiaolu Tang

  8. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China

    Liwei Liu

  9. The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China

    Yi Li

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  1. Yan Luo
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Contributions

Conceptualization, YL, YL, and YJ; data curation, YN, XT, YL, and YJ; formal analysis, YJ, LM, YS, YN, XT, LL, YL, and YJ; funding acquisition, YL and YJ; investigation, JZ, YJ, LM, YS, and YJ; methodology, YL, JZ, YL, and YJ; software, YS and YJ; supervision, YL and YJ; validation, YL, JZ, and YJ; writing—original draft, YL, YL, and YJ; writing—review and editing, YL, JZ, YJ, HH, LM, YS, YN, XT, LL, YL, and YJ.

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Correspondence to Yi Li or Yumao Jiang.

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Luo, Y., Zhang, J., Jiao, Y. et al. Dihydroartemisinin abolishes cisplatin-induced nephrotoxicity in vivo. J Nat Med 78, 439–454 (2024). https://doi.org/10.1007/s11418-024-01783-5

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