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University","award":["1I01BX003031"],"award-info":[{"award-number":["1I01BX003031"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["1IK2BX005306"],"award-info":[{"award-number":["1IK2BX005306"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["DK108959"],"award-info":[{"award-number":["DK108959"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["DK119421"],"award-info":[{"award-number":["DK119421"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["DK054811"],"award-info":[{"award-number":["DK054811"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["DK115184"],"award-info":[{"award-number":["DK115184"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["DK076898"],"award-info":[{"award-number":["DK076898"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["DK107310"],"award-info":[{"award-number":["DK107310"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["DK110035"],"award-info":[{"award-number":["DK110035"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["DK062975"],"award-info":[{"award-number":["DK062975"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["AA028711"],"award-info":[{"award-number":["AA028711"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["CPRIT RP210213"],"award-info":[{"award-number":["CPRIT RP210213"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["#RM12117A7AF3C286"],"award-info":[{"award-number":["#RM12117A7AF3C286"]}]},{"name":"the PSC Partners Seeking a Cure (GA) and Sapienza University","award":["#RM12117A76FD45EB"],"award-info":[{"award-number":["#RM12117A76FD45EB"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Background &amp; aims: Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-\u03b21), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis. Taurocholic acid (TC) stimulates biliary hyperplasia by activation of 3\u2032,5\u2032-cyclic cyclic adenosine monophosphate (cAMP) signaling, thereby preventing biliary damage (caused by cholinergic\/adrenergic denervation) through enhanced liver angiogenesis. Also: (i) \u03b1-calcitonin gene-related peptide (\u03b1-CGRP, which activates the calcitonin receptor-like receptor, CRLR), stimulates biliary proliferation\/senescence and liver fibrosis by enhanced biliary secretion of SASPs; and (ii) knock-out of \u03b1-CGRP reduces these phenotypes by decreased cAMP levels in cholestatic models. We aimed to demonstrate that TC effects on liver phenotypes are dependent on changes in the \u03b1-CGRP\/CALCRL\/cAMP\/PKA\/ERK1\/2\/TGF-\u03b21\/VEGF axis. Methods: Wild-type and \u03b1-CGRP\u2212\/\u2212 mice were fed with a control (BAC) or TC diet for 1 or 2 wk. We measured: (i) CGRP levels by both ELISA kits in serum and by qPCR in isolated cholangiocytes (CALCA gene for \u03b1-CGRP); (ii) CALCRL immunoreactivity by immunohistochemistry (IHC) in liver sections; (iii) liver histology, intrahepatic biliary mass, biliary senescence (by \u03b2-GAL staining and double immunofluorescence (IF) for p16\/CK19), and liver fibrosis (by Red Sirius staining and double IF for collagen\/CK19 in liver sections), as well as by qPCR for senescence markers in isolated cholangiocytes; and (iv) phosphorylation of PKA\/ERK1\/2, immunoreactivity of TGF-\u03b21\/TGF- \u03b2RI and angiogenic factors by IHC\/immunofluorescence in liver sections and qPCR in isolated cholangiocytes. We measured changes in BA composition in total liver by liquid chromatography\/mass spectrometry. Results: TC feeding increased CALCA expression, biliary damage, and liver inflammation and fibrosis, as well as phenotypes that were associated with enhanced immunoreactivity of the PKA\/ERK1\/2\/TGF-\u03b21\/TGF-\u03b2RI\/VEGF axis compared to BAC-fed mice and phenotypes that were reversed in \u03b1-CGRP\u2212\/\u2212 mice fed TC coupled with changes in hepatic BA composition. Conclusion: Modulation of the TC\/ \u03b1-CGRP\/CALCRL\/PKA\/ERK1\/2\/TGF-\u03b21\/VEGF axis may be important in the management of cholangiopathies characterized by BA accumulation.<\/jats:p>","DOI":"10.3390\/cells11091591","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T21:23:27Z","timestamp":1652131407000},"page":"1591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["RETRACTED: The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2040-0581","authenticated-orcid":false,"given":"Romina","family":"Mancinelli","sequence":"first","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Ceci","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vik","family":"Meadows","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixian","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8570-2519","authenticated-orcid":false,"given":"Guido","family":"Carpino","sequence":"additional","affiliation":[{"name":"Department of Movement, Human and Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Kyritsi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5722-6954","authenticated-orcid":false,"given":"Tianhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5380-8001","authenticated-orcid":false,"given":"Keisaku","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Pannarale","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M University, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4869-3198","authenticated-orcid":false,"given":"Sanjukta","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M University, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6658-3021","authenticated-orcid":false,"given":"Gianfranco","family":"Alpini","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Gaudio","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Onori","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Franchitto","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,9]]},"reference":[{"key":"ref_1","first-page":"G612","article-title":"Regulation of cholangiocyte bicarbonate secretion","volume":"281","author":"Kanno","year":"2001","journal-title":"Am. 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