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Mesenchymal stem cells ameliorate oxidative stress, inflammation, and hepatic fibrosis via Nrf2/HO-1 signaling pathway in rats

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Liver fibrosis occurs in most types of chronic liver diseases and can develop into cirrhosis and liver failure. Bone marrow-derived mesenchymal stem cells (BMSCs) showed promising effects in the treatment of fibrosis. This study evaluated the possible role of Nrf2/HO-1 signaling in the ameliorative effect of BMSCs against carbon tetrachloride (CCl4)-induced liver fibrosis, oxidative stress, and inflammation in rats. Hepatic fibrosis was induced by subcutaneous injection of CCl4 twice per week for 6 consecutive weeks and rat BMSCs were administered intravenously. After 4 weeks, the rats were sacrificed, and samples were collected for analysis. CCl4-intoxicated rats showed elevated serum transaminases, ALP, γGT, bilirubin and pro-inflammatory cytokines, and decreased albumin. Hepatic NF-κB p65 and malondialdehyde (MDA) were significantly increased, and cellular antioxidants were decreased in CCl4-intoxicated rats. BMSCs ameliorated liver function markers, suppressed MDA, NF-κB p65, and inflammatory cytokines, and enhanced antioxidants in the liver of CCl4-intoxicated rats. BMSCs were engrafted within the liver tissue and prevented histological alterations and collagen accumulation induced by CCl4. In addition, BMSCs upregulated hepatic Nrf2 and HO-1 expression in CCl4-intoxicated rats. In conclusion, this study provides evidence that BMSCs suppress oxidative stress, inflammation, and liver fibrosis through a mechanism involving activation of the Nrf2/HO-1 signaling.

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The authors extend their appreciation to Faculty of Science, Beni-Suef University for supporting this research.

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Conceptualization, methodology, data curation, investigation, and funding acquisition: A.M.M., S.M.K, and H.M.M. Original draft preparation: A.M.M. and S.M.K. Review and editing, validation and formal analysis: A.M.M. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Ayman M. Mahmoud.

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The experimental protocol and procedures were approved by the Institutional Research Ethics Committee of Beni-Suef University (2018/0728).

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The authors declare that they have no conflicts of interest.

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Responsible editor: Mohamed M. Abdel-Daim

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Khadrawy, S.M., Mohamed, H.M. & Mahmoud, A.M. Mesenchymal stem cells ameliorate oxidative stress, inflammation, and hepatic fibrosis via Nrf2/HO-1 signaling pathway in rats. Environ Sci Pollut Res 28, 2019–2030 (2021).

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