{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T07:05:24Z","timestamp":1758265524602,"version":"3.40.5"},"reference-count":25,"publisher":"S. Karger AG","issue":"7-8","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacology"],"published-print":{"date-parts":[[2022]]},"abstract":"<b><i>Introduction:<\/i><\/b> Alcohol-induced thickening of the gut mucosal layer and increased expression of goblet cell gel-forming mucins, such as mucin-2 (<i>MUC2<\/i>) are associated with disruptions to the gut barrier in alcoholic liver disease (ALD). Interest in drugs that can target gut mucins in ALD has grown; however to date, no studies have examined the properties of drugs on expression of gut mucins in models of ALD. We previously demonstrated that at 10 mg\/kg\/day, the drug fenretinide (N-[4-hydroxyphenyl] retinamide [Fen]), a synthetic retinoid, mitigates alcohol-associated damage to the gut barrier and liver injury in a murine model of ALD. <b><i>Methods:<\/i><\/b> In this study, we specifically sought to examine the effects of Fen on gut goblet cells, and expression of mucins, including <i>MUC2<\/i> using a 25-day Lieber-DeCarli model of chronic alcohol intake. <b><i>Results:<\/i><\/b> Our results show that chronic alcohol intake increased gut-mucosal thickening, goblet cell numbers, and mRNA and protein expression of <i>MUC2<\/i> in both the ileum and colon. Alcohol intake was associated with marked decreases in ileal and colonic Notch signaling, levels of Notch ligands <i>Dll1<\/i> and <i>Dll4<\/i>, and increases in the expression of Notch-associated genes indispensable for goblet cell specification, including Math1 and Spdef. Interestingly, ileal and colonic expression of <i>KLF4<\/i>, which is involved in terminal differentiation of goblet cells, was reduced in mice chronically fed alcohol. Coadministration of alcohol with Fen at 10 mg\/kg\/day significantly reduced alcohol-associated increases in ileal and colonic mucosal thickening, ileal <i>Muc2<\/i>, colonic <i>Muc2<\/i>, <i>Muc5ac<\/i> and <i>Muc6<\/i> mRNAs, and goblet cell numbers. We also found that Fen strongly prevented alcohol-mediated suppression of the Notch ligand <i>Dll1<\/i>, Notch signaling, and alcohol-induced increases in expression of Notch-associated goblet cell specification genes in both the ileum and colon. In the absence of alcohol, Fen treatments alone at 10 mg\/kg\/day had no effects on any of the goblet cell-related endpoints. <b><i>Conclusion:<\/i><\/b> These data show for the first time that the drug Fen possesses mucosal layer-modulating properties in response to chronic alcohol abuse. These data warrant further preclinical examination of Fen given the need for anti-ALD drugs and emerging evidence of a role for intestinal goblet cell mucins in the progression of ALD. <\/jats:p>","DOI":"10.1159\/000524386","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T21:00:34Z","timestamp":1652389234000},"page":"406-416","source":"Crossref","is-referenced-by-count":6,"title":["Fenretinide Reduces Intestinal Mucin-2-Positive Goblet Cells in Chronic Alcohol Abuse"],"prefix":"10.1159","volume":"107","author":[{"given":"Marta","family":"Melis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Han","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Mai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3115-4777","authenticated-orcid":false,"given":"Lorraine J.","family":"Gudas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven E.","family":"Trasino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"127","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1016\/s1521-6918(03)00034-9"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23009"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.4161\/21688370.2014.982426"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1159\/000046751"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2761"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1016\/j.livres.2017.12.004"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1177\/1535370217706952"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00362.2009"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.630557"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1113\/JP271667"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.010908.163145"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080758"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0034408"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2009.09.020"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2010.11.001"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e03-02-0059"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1016\/j.diff.2018.07.003"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.127308"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2931-8"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.007153"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.12.9.17715"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2011.08.002"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0261675"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222312687"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02054"}],"container-title":["Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/524386","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/524386","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T16:01:48Z","timestamp":1745424108000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000524386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022]]},"references-count":25,"journal-issue":{"issue":"7-8","published-online":{"date-parts":[[2022,7,1]]},"published-print":{"date-parts":[[2022,7,5]]}},"URL":"https:\/\/doi.org\/10.1159\/000524386","archive":["Portico"],"relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.6084\/m9.figshare.19753477","asserted-by":"subject"}]},"ISSN":["0031-7012","1423-0313"],"issn-type":[{"type":"print","value":"0031-7012"},{"type":"electronic","value":"1423-0313"}],"subject":[],"published":{"date-parts":[[2022]]}}}