{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T21:03:38Z","timestamp":1774991018865,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T00:00:00Z","timestamp":1621468800000},"content-version":"vor","delay-in-days":139,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81670479"],"award-info":[{"award-number":["81670479"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p><jats:italic>Background<\/jats:italic>. Intestinal barrier injury is an important contributor to many diseases. We previously found that heme oxygenase\u20101 (HO\u20101) and carbon monoxide (CO) protect the intestinal barrier. This study is aimed at elucidating the molecular mechanisms of HO\u20101\/CO in barrier loss. <jats:italic>Materials and Methods<\/jats:italic>. We induced gut leakiness by injecting carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) to wildtype or intestinal HO\u20101\u2010deficient mice. In addition, we administrated tumor necrosis factor\u2010<jats:italic>\u03b1<\/jats:italic> (TNF\u2010<jats:italic>\u03b1<\/jats:italic>) to cells with gain\u2010 or loss\u2010of\u2010HO\u20101 function. The effects of HO\u20101\/CO maintaining intestinal barrier integrity were investigated <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. <jats:italic>Results<\/jats:italic>. Cobalt protoporphyrin and CO\u2010releasing molecule\u20102 alleviated colonic mucosal injury and TNF\u2010<jats:italic>\u03b1<\/jats:italic> levels; upregulated tight junction (TJ) expression; and inhibited epithelial I<jats:italic>\u03ba<\/jats:italic>B\u2010<jats:italic>\u03b1<\/jats:italic> degradation and phosphorylation, NF\u2010<jats:italic>\u03ba<\/jats:italic>B p65 phosphorylation, long MLCK expression, and MLC\u20102 phosphorylation after administration of CCl<jats:sub>4<\/jats:sub>. Zinc protoporphyrin completely reversed these effects. These findings were further confirmed <jats:italic>in vitro<\/jats:italic>, using Caco\u20102 cells with gain\u2010 or loss\u2010of\u2010HO\u20101\u2010function after TNF\u2010<jats:italic>\u03b1<\/jats:italic>. Pretreated with JSH\u201023 (NF\u2010<jats:italic>\u03ba<\/jats:italic>B inhibitor) or ML\u20107 (long MLCK inhibitor), HO\u20101 overexpression prevented TNF\u2010<jats:italic>\u03b1<\/jats:italic>\u2010induced TJ disruption, while HO\u20101 shRNA promoted TJ damage even in the presence of JSH\u201023 or ML\u20107, thus suggesting that HO\u20101 dependently protected intestinal barrier via the NF\u2010<jats:italic>\u03ba<\/jats:italic>B p65\/MLCK\/p\u2010MLC\u20102 pathway. Intestinal HO\u20101\u2010deficient mice further demonstrated the effects of HO\u20101 in maintaining intestinal barrier integrity and its relative mechanisms. Alleviated hepatic fibrogenesis and serum ALT levels finally confirmed the clinical significance of HO\u20101\/CO repairing barrier loss in liver injury. <jats:italic>Conclusion<\/jats:italic>. HO\u20101\/CO maintains intestinal barrier integrity through the NF\u2010<jats:italic>\u03ba<\/jats:italic>B\/MLCK pathway. Therefore, the intestinal HO\u20101\/CO\u2010NF\u2010<jats:italic>\u03ba<\/jats:italic>B\/MLCK system is a potential therapeutic target for diseases with a leaky gut.<\/jats:p>","DOI":"10.1155\/2021\/6620873","type":"journal-article","created":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T23:20:09Z","timestamp":1621552809000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["HO\u20101\/CO Maintains Intestinal Barrier Integrity through NF\u2010<i>\u03ba<\/i>B\/MLCK Pathway in Intestinal HO\u20101<sup>-\/-<\/sup> 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