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Pharmacological inhibition of AMP-activated protein kinase reduced but did not prevent metformin-induced therapeutic effect as well as treatment of colitic mice with a pharmacological activator of AMP-activated protein kinase attenuated but did not resolve colitis. These data suggest that the anti-inflammatory effect of metformin relies on the control of additional pathways other than AMP-activated protein kinase. Indeed, metformin down-regulated p38 MAP kinase activation in colitic mice through an AMP-activated protein kinase-independent mechanism. Expression of active form of AMP-activated protein kinase was reduced in inflammatory bowel disease patients and treatment of mucosal cells of such patients with metformin enhanced AMP-activated protein kinase activation and reduced p38 MAP kinase activation, thereby inhibiting interleukin-6 expression. Our findings indicate that metformin is a good candidate for inhibiting pathological inflammation in the gut.<\/jats:p>","DOI":"10.1042\/cs20180167","type":"journal-article","created":{"date-parts":[[2018,3,14]],"date-time":"2018-03-14T17:50:33Z","timestamp":1521049833000},"page":"1155-1168","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation"],"prefix":"10.1042","volume":"132","author":[{"given":"Davide","family":"Di Fusco","sequence":"first","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Dinallo","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Monteleone","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Laudisi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Marafini","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Franz\u00e8","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Di Grazia","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Dwairi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"},{"name":"Department of Internal Medicine, Mutah University, Karak, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Colantoni","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Ortenzi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Stolfi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Monteleone","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of \u201cTor Vergata\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2018,6,9]]},"reference":[{"key":"2021113010581958100_B1","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1053\/j.gastro.2011.01.05510.1053\/j.gastro.2011.01.055","article-title":"Epidemiology and natural history of inflammatory bowel diseases","volume":"140","author":"Cosnes","year":"2011","journal-title":"Gastroenterology"},{"key":"2021113010581958100_B2","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/nri366110.1038\/nri3661","article-title":"Cytokines in inflammatory bowel disease","volume":"14","author":"Neurath","year":"2014","journal-title":"Nat. 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