Prolonged Administration of Melatonin Ameliorates Liver Phenotypes in Cholestatic Murine Model
Ludovica Ceci, Lixian Chen, Leonardo Baiocchi, Nan Wu, Lindsey Kennedy, Guido Carpino, Konstantina Kyritsi, Tianhao Zhou, Travis Owen, Debjyoti Kundu, Amelia Sybenga, Abdulkadir Isidan, Burcin Ekser, Antonio Franchitto, Paolo Onori, Eugenio Gaudio, Romina Mancinelli, Heather Francis, Gianfranco Alpini, Shannon Glaser
Abstract
BACKGROUND & AIMS: ) mice by decreased miR200b-dependent angiogenesis. We aimed to evaluate the long-term effects of melatonin on liver phenotype that may be mediated by changes in MT1/clock genes/miR200b/maspin/glutathione-S transferase (GST) signaling. METHODS: mice had access to drinking water with/without melatonin for 3 months. Liver damage, biliary proliferation/senescence, liver fibrosis, peribiliary inflammation, and angiogenesis were measured by staining in liver sections, and by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay in liver samples. We confirmed a link between MT1/clock genes/miR200b/maspin/GST/angiogenesis signaling by Ingenuity Pathway Analysis software and measured liver phenotypes and the aforementioned signaling pathway in liver samples from the mouse groups, healthy controls, and PSC patients and immortalized human PSC cholangiocytes. RESULTS: mice ameliorates liver phenotypes, which were associated with decreased MT1 and clock gene expression. CONCLUSIONS: Melatonin improves liver histology and restores the circadian rhythm by interaction with MT1 through decreased angiogenesis and increased maspin/GST activity.