{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T08:56:07Z","timestamp":1773046567260,"version":"3.50.1"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001448","name":"Alpha-1 Foundation","doi-asserted-by":"publisher","award":["#007319."],"award-info":[{"award-number":["#007319."]}],"id":[{"id":"10.13039\/100001448","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Alpha-1 antitrypsin deficiency (AATD) is an inherited disease, the common variant caused by a Pi*Z mutation in the SERPINA1 gene. Pi*Z AAT increases the risk of pulmonary emphysema and liver disease. Berberine (BBR) is a nature dietary supplement and herbal remedy. Emerging evidence revealed that BBR has remarkable liver-protective properties against various liver diseases. In the present study, we investigated the therapeutic effects and toxicities of BBR in Pi*Z hepatocytes and Pi*Z transgenic mice.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Huh7.5 and Huh7.5Z (which carries the Pi*Z mutation) cells were treated with different concentrations of BBR for 48 hours. MTT was performed for cell viability assay. Intracellular AAT levels were evaluated by western blot. In vivo studies were carried out in wild type, native phenotype AAT (Pi*M), and Pi*Z AAT transgenic mice. Mice were treated with 50 mg\/kg\/day of BBR or solvent only by oral administration for 30 days. Western blot and liver histopathological examinations were performed to evaluate therapeutic benefits and liver toxicity of BBR.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>BBR reduced intracellular AAT levels in Huh7.5Z cells, meanwhile, no Pi*Z-specific toxicity was observed. However, BBR did not reduce liver AAT load but significantly potentiated liver inflammation and fibrosis accompanying the activation of unfolded protein response and mTOR in Pi*Z mice, but not in wild type and Pi*M mice.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>BBR exacerbated liver inflammation and fibrosis specifically in Pi*Z mice. This adverse effect may be associated with the activation of unfolded protein response and mTOR. This study implicates that BBR should be avoided by AATD patients.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0310524","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T17:35:08Z","timestamp":1726767308000},"page":"e0310524","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Berberine potentiates liver inflammation and fibrosis in the PI*Z hAAT transgenic murine model"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8196-8918","authenticated-orcid":true,"given":"Yuanqing","family":"Lu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naweed S.","family":"Mohammad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jungnam","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alek M.","family":"Aranyos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karina A.","family":"Serban","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0189-1565","authenticated-orcid":true,"given":"Mark L.","family":"Brantly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,9,19]]},"reference":[{"key":"pone.0310524.ref001","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.ejphar.2015.05.068","article-title":"Current knowledge and pharmacological profile of berberine: An update","volume":"761","author":"A Kumar","year":"2015","journal-title":"Eur J Pharmacol"},{"issue":"3","key":"pone.0310524.ref002","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/19390211.2017.1347227","article-title":"Variability in Potency Among Commercial Preparations of Berberine","volume":"15","author":"RS Funk","year":"2018","journal-title":"J Diet Suppl"},{"key":"pone.0310524.ref003","article-title":"The Effect of Berberine Supplementation on Glycemic Control and Inflammatory Biomarkers in Metabolic Disorders: An Umbrella Meta-Analysis of Randomized Controlled Trials","author":"A Nazari","year":"2023","journal-title":"Clin Ther"},{"issue":"1","key":"pone.0310524.ref004","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/cbdd.14231","article-title":"Current understanding and future prospects on Berberine for anticancer therapy","volume":"102","author":"A. 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