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Hypoxia-Mediated Upregulation of Xanthine Oxidoreductase Causes DNA Damage of Colonic Epithelial Cells in Colitis.
- Source :
-
Inflammation [Inflammation] 2024 Aug; Vol. 47 (4), pp. 1142-1155. Date of Electronic Publication: 2024 Jan 11. - Publication Year :
- 2024
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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 (CoCl <subscript>2</subscript> ) and 1% O <subscript>2</subscript> 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 CoCl <subscript>2</subscript> -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).<br /> (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Subjects :
- Animals
Mice
Cobalt toxicity
Cobalt pharmacology
Humans
Colitis chemically induced
Colitis metabolism
Colitis pathology
Colitis, Ulcerative chemically induced
Colitis, Ulcerative metabolism
Colitis, Ulcerative pathology
Allopurinol pharmacology
Intestinal Mucosa metabolism
Intestinal Mucosa pathology
Intestinal Mucosa drug effects
Dextran Sulfate toxicity
Cell Hypoxia physiology
Mice, Inbred C57BL
Hypoxia metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Xanthine Dehydrogenase metabolism
Xanthine Dehydrogenase antagonists & inhibitors
DNA Damage
Epithelial Cells metabolism
Epithelial Cells drug effects
Colon pathology
Colon metabolism
Colon drug effects
Up-Regulation
Subjects
Details
- Language :
- English
- ISSN :
- 1573-2576
- Volume :
- 47
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Inflammation
- Publication Type :
- Academic Journal
- Accession number :
- 38206514
- Full Text :
- https://doi.org/10.1007/s10753-024-01966-y