{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:59:29Z","timestamp":1787068769180,"version":"build-2736575974"},"reference-count":51,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001721","name":"Rijksuniversiteit Groningen","doi-asserted-by":"publisher","award":["MD\/PhD funding"],"award-info":[{"award-number":["MD\/PhD funding"]}],"id":[{"id":"10.13039\/501100001721","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Liver fibrosis results from excessive proliferation of, and collagen production by hepatic stellate cells (HSCs) that is caused by chronic liver injury. No drugs are available to cure liver fibrosis. Hydroxyurea is an\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/en.wikipedia.org\/wiki\/Antineoplastic\">anti\u2010proliferative drug that is<\/jats:ext-link>\n                    used in benign and malignant disorders. Here, we studied the effect of hydroxyurea on primary HSCs and its anti\u2010fibrotic effect in the CCl\n                    <jats:sub>4<\/jats:sub>\n                    mouse model of liver fibrosis. Primary rat HSCs were cultured in the absence or presence of hydroxyurea (0.1\u20131.0\u2009mmol\/L). CCl\n                    <jats:sub>4<\/jats:sub>\n                    or vehicle was administered to C57BL\/6\/J mice for 4\u2009weeks, with or without hydroxyurea (100\u2009mg\/kg\/day) co\u2010treatment. We used real\u2010time cell proliferation analysis, Oil Red O (lipid droplet) staining, immunohistochemistry, Acridine Orange staining (apoptosis), Sytox green staining (necrosis), RT\u2010qPCR, ELISA, and Western Blotting for analysis. Hydroxyurea dose\u2010dependently suppressed lipid droplet\u2010loss and mRNA levels of\n                    <jats:italic>Col1\u03b11<\/jats:italic>\n                    and\n                    <jats:italic>Acta2<\/jats:italic>\n                    in transdifferentiating HSCs. In fully\u2010activated HSCs, hydroxyurea dose\u2010dependently attenuated PCNA protein levels and BrdU incorporation, but did not reverse\n                    <jats:italic>Col1\u03b11<\/jats:italic>\n                    and\n                    <jats:italic>Acta2<\/jats:italic>\n                    mRNA expression. Hydroxyurea did not induce apoptosis or necrosis in HSCs or hepatocytes. Hydroxyurea suppressed accumulation of desmin\u2010positive HSCs and hepatic collagen deposition after CCl\n                    <jats:sub>4<\/jats:sub>\n                    treatment. CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010induced regenerative hepatocyte proliferation,\n                    <jats:italic>Col1\u03b11<\/jats:italic>\n                    and\n                    <jats:italic>Acta2<\/jats:italic>\n                    mRNA expression and \u03b1\u2010SMA protein levels were not affected. This study demonstrates that hydroxyurea inhibits HSC proliferation in vitro and attenuates early development of liver fibrosis in vivo, while preserving hepatocyte regeneration after toxic insults by CCl\n                    <jats:sub>4.<\/jats:sub>\n                    Thus, hydroxyurea may have therapeutic value against liver fibrosis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202300920r","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T11:26:43Z","timestamp":1691494003000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hydroxyurea attenuates hepatic stellate cell proliferation in vitro and liver fibrogenesis in vivo"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2641-5170","authenticated-orcid":false,"given":"Floris","family":"Haijer","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology University Medical Center Groningen, University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiva","family":"Koets\u2010Shajari","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology University Medical Center Groningen, University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janette","family":"Heegsma","sequence":"additional","affiliation":[{"name":"Department Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases University Medical Center Groningen, University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Serna\u2010Salas","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology University Medical Center Groningen, University of Groningen  Groningen The 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