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Hypoxia-Mediated Upregulation of Xanthine Oxidoreductase Causes DNA Damage of Colonic Epithelial Cells in Colitis

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Abstract

Xanthine oxidoreductase (XOR) serves as the primary source of hydrogen peroxide and superoxide anions in the intestinal mucosa. However, its specific contribution to the progression of colonic disease remains unclear. In this study, we investigated the role of XOR in ulcerative colitis (UC) and attempted to identify the underlying mechanisms. We used the dextran sulfate sodium (DSS)–induced mouse model to mimic UC and observed that XOR inhibitors, allopurinol and diphenyleneiodonium sulfate (DPI), significantly alleviated UC in mice. In addition, treatment with cobalt chloride (CoCl2) and 1% O2 increased the expression of XOR and induced DNA oxidative damage in colonic epithelial cells. Furthermore, we identified that XOR accumulation in the nucleus may directly cause DNA oxidative damage and regulates HIF1α protein levels. In addition, allopurinol effectively protected colon epithelial cells from CoCl2-induced DNA damage. Altogether, our data provided evidence that XOR could induce DNA damage under hypoxic conditions, indicating a significant role of XOR in the initiation and early development of colitis-associated colorectal cancer (CAC).

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work supported by the National Natural Science Foundation of China (81773064, 31972973 and 31530056), National Youth 1000 Talents Plan, the Jiangsu Specially-Appointed Professor Program, Jiangsu Province Recruitment Plan for High-level, Innovative and Entrepreneurial Talents (Innovative Research Team), and Collaborative innovation center of food safety and quality control in Jiangsu Province.

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  1. Hongling Li and Xiaojing Li contributed equally to this work.

Authors and Affiliations

  1. College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China

    Hongling Li & Qi Zhang

  2. State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China

    Hongling Li, Xiaojing Li & Haitao Li

  3. School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China

    Hongling Li, Xiaojing Li & Haitao Li

  4. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, China

    Yupeng Wang, Weiyu Han & Qi Zhang

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  1. Hongling Li
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Hongling Li, Qi Zhang, and Haitao Li designed and supervised the experiments. Hongling Li prepared the manuscript. Hongling Li, Weiyu Han, and Yupeng Wang performed experiments.

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Li, H., Li, X., Wang, Y. et al. Hypoxia-Mediated Upregulation of Xanthine Oxidoreductase Causes DNA Damage of Colonic Epithelial Cells in Colitis. Inflammation (2024). https://doi.org/10.1007/s10753-024-01966-y

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