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Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2\u2013knockout (Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR\u2010200b expression were evaluated in wild\u2010type and Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice were also treated with miR\u2010200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR\u2010200b in cholangiocytes and hepatic stellate cells\n                    <jats:italic>in vitro,<\/jats:italic>\n                    we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR\u2010200b expression increased in Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice and patients with PSC compared with controls and decreased in Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice subjected to dark exposure or melatonin treatment. Inhibition of miR\u2010200b in Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ablates biliary proliferation, liver fibrosis, and angiogenesis.\n                    <jats:italic>In vitro,<\/jats:italic>\n                    overexpression of AANAT or inhibition of miR\u2010200b in cholangiocytes and hepatic stellate cells decreased the expression of miR\u2010200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin\/miR\u2010200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.\u2014Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR\u2010200b down\u2010regulation. FASEB J. 31, 4305\u20134324 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700097r","type":"journal-article","created":{"date-parts":[[2017,6,20]],"date-time":"2017-06-20T21:05:23Z","timestamp":1497992723000},"page":"4305-4324","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR\u2010200b down\u2010regulation"],"prefix":"10.1096","volume":"31","author":[{"given":"Nan","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyin","family":"Meng","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"},{"name":"Digestive Research Center Baylor Scott &amp; White Temple Texas USA"},{"name":"Research Service Central Texas Veterans Health Care System Temple Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyan","family":"Han","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Venter","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"},{"name":"Digestive Research Center Baylor Scott &amp; White Temple Texas USA"},{"name":"Research Service Central Texas Veterans Health Care System Temple Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"DeMorrow","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"},{"name":"Digestive Research Center Baylor Scott &amp; White Temple Texas USA"},{"name":"Research Service Central Texas Veterans Health Care System Temple Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Onori","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, and Forensic Medicine and Orthopedic Sciences La Sapienza Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Invernizzi","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Liver Diseases Humanitas Clinical and Research Center Rozzano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bernuzzi","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Liver Diseases Humanitas Clinical and Research Center Rozzano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Mancinelli","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, and Forensic Medicine and Orthopedic Sciences La Sapienza Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Gaudio","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, and Forensic Medicine and Orthopedic Sciences La Sapienza Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Franchitto","sequence":"additional","affiliation":[{"name":"Eleonora Lorillard Spencer Cenci Foundation Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Glaser","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Texas A&amp;M University Health Science Center Temple Texas USA"},{"name":"Digestive Research Center Baylor Scott &amp; 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