{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:27:51Z","timestamp":1770834471598,"version":"3.50.1"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T00:00:00Z","timestamp":1510704000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T00:00:00Z","timestamp":1510704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>TLR4 signaling in hepatic macrophages is increased after chronic ethanol feeding. Treatment of hepatic macrophages after chronic ethanol feeding with small-specific sized hyaluronic acid 35 (HA35) normalizes TLR4 signaling; however, the mechanisms for HA35 action are not completely understood. Here we used Next Generation Sequencing of microRNAs to identify negative regulators of TLR4 signaling reciprocally modulated by ethanol and HA35 in hepatic macrophages. Eleven microRNAs were up-regulated by ethanol; only 4 microRNAs, including miR291b, were decreased by HA35. Bioinformatics analysis identified Tollip, a negative regulator of TLR4, as a target of miR291b. Tollip expression was decreased in hepatic macrophages from ethanol-fed rats, but treatment with HA35 or transfection with a miR291b hairpin inhibitor restored Tollip expression and normalized TLR4-stimulated TNF\u03b1 expression. In peripheral blood monocytes isolated from patients with alcoholic hepatitis, expression of TNF\u03b1 mRNA was robustly increased in response to challenge with lipopolysaccharide. Importantly, pre-treatment with HA35 reduced TNF\u03b1 expression by more than 50%. Taken together, we have identified miR291b as a critical miRNA up-regulated by ethanol. Normalization of the miR291b\u2009\u2192\u2009Tollip pathway by HA35 ameliorated ethanol-induced sensitization of TLR4 signaling in macrophages\/monocytes, suggesting that HA35 may be a novel therapeutic agent in the treatment of ALD.<\/jats:p>","DOI":"10.1038\/s41598-017-15760-4","type":"journal-article","created":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T15:21:22Z","timestamp":1510240882000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip"],"prefix":"10.1038","volume":"7","author":[{"given":"Paramananda","family":"Saikia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjoy","family":"Roychowdhury","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damien","family":"Bellos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine A.","family":"Pollard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan R.","family":"McMullen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca L.","family":"McCullough","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur J.","family":"McCullough","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Gholam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"de la Motte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0580-2809","authenticated-orcid":false,"given":"Laura E.","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,11,15]]},"reference":[{"key":"15760_CR1","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1111\/acer.12887","volume":"39","author":"J Guirguis","year":"2015","unstructured":"Guirguis, J. et al. Clinical impact of alcohol-related cirrhosis in the next decade: estimates based on current epidemiological trends in the United States. Alcohol Clin Exp Res \n39, 2085\u20132094, https:\/\/doi.org\/10.1111\/acer.12887 (2015).","journal-title":"Alcohol Clin Exp Res"},{"key":"15760_CR2","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1053\/j.gastro.2016.02.035","volume":"150","author":"LE Nagy","year":"2016","unstructured":"Nagy, L. E., Ding, W. X., Cresci, G., Saikia, P. & Shah, V. H. Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes. Gastroenterology \n150, 1756\u20131768, https:\/\/doi.org\/10.1053\/j.gastro.2016.02.035 (2016).","journal-title":"Gastroenterology"},{"key":"15760_CR3","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1111\/acer.12704","volume":"39","author":"P Hartmann","year":"2015","unstructured":"Hartmann, P., Seebauer, C. T. & Schnabl, B. Alcoholic liver disease: the gut microbiome and liver cross talk. 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