{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:20:44Z","timestamp":1793118044136,"version":"4.5.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T00:00:00Z","timestamp":1680307200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Alcohol-associated liver disease (ALD) is a syndrome of progressive inflammatory liver injury and vascular remodeling associated with long-term heavy intake of ethanol. Elevated miR-34a expression, macrophage activation, and liver angiogenesis in ALD and their correlation with the degree of inflammation and fibrosis have been reported. The current study aims to characterize the functional role of miR-34a-regulated macrophage- associated angiogenesis during ALD.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods &amp; Results:<\/jats:title>\n            <jats:p>We identified that knockout of miR-34a in 5 weeks of ethanol-fed mice significantly decreased the total liver histopathology score and miR-34a expression, along with the inhibited liver inflammation and angiogenesis by reduced macrophage infiltration and CD31\/VEGF-A expression. Treatment of murine macrophages (RAW 264.7) with lipopolysaccharide (20 ng\/mL) for 24 h significantly increased miR-34a expression, along with the enhanced M1\/M2 phenotype changes and reduced Sirt1 expression. Silencing of miR-34a significantly increased oxygen consumption rate (OCR) in ethanol treated macrophages, and decreased lipopolysaccharide-induced activation of M1 phenotypes in cultured macrophages by upregulation of Sirt1. Furthermore, the expressions of miR-34a and its target Sirt1, macrophage polarization, and angiogenic phenotypes were significantly altered in isolated macrophages from ethanol-fed mouse liver specimens compared to controls. TLR4\/miR-34a knockout mice and miR-34a Morpho\/AS treated mice displayed less sensitivity to alcohol-associated injury, along with the enhanced Sirt1 and M2 markers in isolated macrophages, as well as reduced angiogenesis and hepatic expressions of inflammation markers MPO, LY6G, CXCL1, and CXCL2.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion:<\/jats:title>\n            <jats:p>Our results show that miR-34a-mediated Sirt1 signaling in macrophages is essential for steatohepatitis and angiogenesis during alcohol-induced liver injury. These findings provide new insight into the function of microRNA-regulated liver inflammation and angiogenesis and the implications for reversing steatohepatitis with potential therapeutic benefits in human alcohol-associated liver diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/hc9.0000000000000089","type":"journal-article","created":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T13:08:22Z","timestamp":1680872902000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":32,"title":["miR-34a regulates macrophage-associated inflammation and angiogenesis in alcohol-induced liver injury"],"prefix":"10.1097","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5909-2892","authenticated-orcid":false,"given":"Ying","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Slevin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6886-1961","authenticated-orcid":false,"given":"Sachiko","family":"Koyama","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6331-7898","authenticated-orcid":false,"given":"Chiung-Kuei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5049-6671","authenticated-orcid":false,"given":"Ashok K","family":"Shetty","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuedong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4328-8844","authenticated-orcid":false,"given":"Kelly","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Transplant Surgery, Baylor Scott & White Memorial Hospital, Temple, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingru","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sugeily Ramos","family":"Lorenzo","sequence":"additional","affiliation":[{"name":"The Pennsylvania State University World Campus, University Park, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer Mata","family":"Salinas","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4736-2223","authenticated-orcid":false,"given":"James E.","family":"Klaunig","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Laboratory of Investigative Toxicology and Pathology, Indiana School of Public Health, Indiana University, Bloomington, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8569-8070","authenticated-orcid":false,"given":"Chaodong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6833-2998","authenticated-orcid":false,"given":"Hidekazu","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA"},{"name":"Greater Los Angeles VA Health care System, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7602-9091","authenticated-orcid":false,"given":"Fanyin","family":"Meng","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2023,4]]},"reference":[{"key":"R1-20240826","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jhep.2021.02.028","article-title":"Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease","volume":"75","author":"Yang","year":"2021","journal-title":"J Hepatol"},{"key":"R2-20240826","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","article-title":"Alcoholic liver disease: pathogenesis and new therapeutic targets","volume":"141","author":"Gao","year":"2011","journal-title":"Gastroenterology"},{"key":"R3-20240826","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1152\/physrev.00040.2012","article-title":"Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases","volume":"94","author":"Bhattacharyya","year":"2014","journal-title":"Physiol Rev"},{"key":"R4-20240826","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1002\/hep.29051","article-title":"An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization","volume":"65","author":"Park","year":"2017","journal-title":"Hepatology"},{"key":"R5-20240826","doi-asserted-by":"crossref","first-page":"16010","DOI":"10.3390\/ijms140816010","article-title":"Non-coding RNAs: multi-tasking molecules in the cell","volume":"14","author":"Gomes","year":"2013","journal-title":"Int J Mol Sci"},{"key":"R6-20240826","doi-asserted-by":"crossref","first-page":"e0132767","DOI":"10.1371\/journal.pone.0132767","article-title":"miR-34 and p53: New Insights into a Complex Functional Relationship","volume":"10","author":"Navarro","year":"2015","journal-title":"PLoS One"},{"key":"R7-20240826","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1111\/bph.14573","article-title":"Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a\/Sirt1\/p53 and TGF-beta1\/Smads signalling","volume":"176","author":"Song","year":"2019","journal-title":"Br J Pharmacol"},{"key":"R8-20240826","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.3389\/fimmu.2019.02882","article-title":"Interplay Between Macrophages and Angiogenesis: A Double-Edged Sword in Liver Disease","volume":"10","author":"Ramirez-Pedraza","year":"2019","journal-title":"Front Immunol"},{"key":"R9-20240826","doi-asserted-by":"crossref","first-page":"dev200104","DOI":"10.1242\/dev.200104","article-title":"Erythro-myeloid progenitor origin of Hofbauer cells in the early mouse placenta","volume":"149","author":"Freyer","year":"2022","journal-title":"Development"},{"key":"R10-20240826","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1172\/JCI123069","article-title":"Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation","volume":"129","author":"Pan","year":"2019","journal-title":"J Clin Invest"},{"key":"R11-20240826","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-1-59745-242-7_3","article-title":"Intragastric ethanol infusion model in rodents","volume":"447","author":"Tsukamoto","year":"2008","journal-title":"Methods Mol Biol"},{"key":"R12-20240826","doi-asserted-by":"crossref","first-page":"G512","DOI":"10.1152\/ajpgi.90327.2008","article-title":"Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis","volume":"295","author":"Xiong","year":"2008","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R13-20240826","doi-asserted-by":"crossref","first-page":"G385","DOI":"10.1152\/ajpgi.00111.2018","article-title":"Knockout of microRNA-21 attenuates alcoholic hepatitis through the VHL\/NF-kappaB signaling pathway in hepatic stellate cells","volume":"315","author":"Wu","year":"2018","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R14-20240826","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1016\/j.ajpath.2017.08.027","article-title":"Regulation of Cellular Senescence by miR-34a in Alcoholic Liver Injury","volume":"187","author":"Wan","year":"2017","journal-title":"Am J Pathol"},{"key":"R15-20240826","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.ajpath.2012.06.010","article-title":"Epigenetic regulation of miR-34a expression in alcoholic liver injury","volume":"181","author":"Meng","year":"2012","journal-title":"Am J Pathol"},{"key":"R16-20240826","doi-asserted-by":"crossref","first-page":"7888","DOI":"10.1074\/jbc.M117.779447","article-title":"AMP-activated protein kinase alpha1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation","volume":"292","author":"Zhang","year":"2017","journal-title":"J Biol Chem"},{"key":"R17-20240826","doi-asserted-by":"crossref","first-page":"101147","DOI":"10.1016\/j.redox.2019.101147","article-title":"Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis","volume":"22","author":"Vijayan","year":"2019","journal-title":"Redox Biol"},{"key":"R18-20240826","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1002\/hep.24599","article-title":"An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice","volume":"54","author":"Mandrekar","year":"2011","journal-title":"Hepatology"},{"key":"R19-20240826","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.alcohol.2019.07.005","article-title":"Chronic alcohol-induced liver injury correlates with memory deficits: Role for neuroinflammation","volume":"83","author":"King","year":"2020","journal-title":"Alcohol"},{"key":"R20-20240826","doi-asserted-by":"crossref","first-page":"11709","DOI":"10.1038\/s41598-021-91187-2","article-title":"Pirfenidone modifies hepatic miRNAs expression in a model of MAFLD\/NASH","volume":"11","author":"Escutia-Gutierrez","year":"2021","journal-title":"Sci Rep"},{"key":"R21-20240826","doi-asserted-by":"crossref","first-page":"C687","DOI":"10.1152\/ajpcell.00276.2017","article-title":"Alcohol-induced adipose tissue macrophage phenotypic switching is independent of myeloid Toll-like receptor 4 expression","volume":"317","author":"Fulham","year":"2019","journal-title":"Am J Physiol Cell Physiol"},{"key":"R22-20240826","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1042\/CS20110366","article-title":"Bias in macrophage activation pattern influences non-alcoholic steatohepatitis (NASH) in mice","volume":"122","author":"Maina","year":"2012","journal-title":"Clin Sci"},{"key":"R23-20240826","doi-asserted-by":"crossref","first-page":"4477","DOI":"10.1016\/j.biomaterials.2014.02.012","article-title":"The role of macrophage phenotype in vascularization of tissue engineering scaffolds","volume":"35","author":"Spiller","year":"2014","journal-title":"Biomaterials"},{"key":"R24-20240826","doi-asserted-by":"crossref","first-page":"4054","DOI":"10.1182\/blood-2013-05-501494","article-title":"Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9","volume":"122","author":"Zajac","year":"2013","journal-title":"Blood"},{"key":"R25-20240826","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.3389\/fimmu.2019.01084","article-title":"Macrophage polarization: Different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages","volume":"10","author":"Orecchioni","year":"2019","journal-title":"Front Immunol"},{"key":"R26-20240826","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.jhep.2010.04.037","article-title":"Characterization of two F4\/80-positive Kupffer cell subsets by their function and phenotype in mice","volume":"53","author":"Kinoshita","year":"2010","journal-title":"J Hepatol"},{"key":"R27-20240826","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3389\/fphys.2018.00419","article-title":"The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes","volume":"9","author":"Krzyszczyk","year":"2018","journal-title":"Front Physiol"},{"key":"R28-20240826","doi-asserted-by":"crossref","first-page":"11183","DOI":"10.1038\/s41598-017-10694-3","article-title":"The role of the secretin\/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles","volume":"7","author":"Sato","year":"2017","journal-title":"Sci Rep"},{"key":"R29-20240826","first-page":"457","article-title":"The dual roles of neutrophils and macrophages in inflammation: a critical balance between tissue damage and repair","volume":"41","author":"Butterfield","year":"2006","journal-title":"J Athl Train"},{"key":"R30-20240826","doi-asserted-by":"crossref","first-page":"844","DOI":"10.4049\/jimmunol.1101736","article-title":"Regulation of the inflammatory response: enhancing neutrophil infiltration under chronic inflammatory conditions","volume":"188","author":"Bian","year":"2012","journal-title":"J Immunol"},{"key":"R31-20240826","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/s41467-017-01349-y","article-title":"Hyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs","volume":"8","author":"Syed","year":"2017","journal-title":"Nat Commun"}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/HC9.0000000000000089","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T15:10:17Z","timestamp":1724685017000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/HC9.0000000000000089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023]]}},"URL":"https:\/\/doi.org\/10.1097\/hc9.0000000000000089","relation":{},"ISSN":["2471-254X"],"issn-type":[{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4]]},"assertion":[{"value":"2021-07-09","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-21","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}