{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:23:31Z","timestamp":1792034611319,"version":"4.4.0"},"reference-count":133,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK108959 DK119421 DK054811 DK115184 DK076898 DK107310 DK110035 DK062975 AA028711"],"award-info":[{"award-number":["DK108959 DK119421 DK054811 DK115184 DK076898 DK107310 DK110035 DK062975 AA028711"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["5I01BX000574 1I01BX003031 1IK2BX005306"],"award-info":[{"award-number":["5I01BX000574 1I01BX003031 1IK2BX005306"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease. As well, cells in a SASP state secrete a multitude of inflammatory and pro-fibrogenic factors that modulate the microenvironment. Cellular SASP and the associated, secreted factors have been implicated in the progression of liver diseases, such as cholestatic injury that target the biliary epithelial cells (i.e., cholangiocytes) lining the bile ducts. Indeed, cholangiocyte senescence\/SASP is proposed to be a driver of disease phenotypes in a variety of liver injuries. Within this review, we will discuss the impact of cholangiocyte senescence and SASP in the pathogenesis of cholestatic disorders.<\/jats:p>","DOI":"10.3389\/fmolb.2021.803098","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T05:54:35Z","timestamp":1640066075000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":34,"title":["Biliary Epithelial Senescence in Liver Disease: There Will Be SASP"],"prefix":"10.3389","volume":"8","author":[{"given":"Vik","family":"Meadows","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Baiocchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debjyoti","family":"Kundu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisaku","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yessenia","family":"Fuentes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaodong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjukta","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Glaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Alpini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2455","DOI":"10.1111\/liv.14569","article-title":"Senescent Cholangiocytes Release Extracellular Vesicles that Alter Target Cell Phenotype via the Epidermal Growth Factor Receptor","volume":"40","author":"Al Suraih","year":"2020","journal-title":"Liver Int."},{"key":"B2","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1172\/jci113355","article-title":"Biliary Physiology in Rats with Bile Ductular Cell Hyperplasia. Evidence for a Secretory Function of Proliferated Bile Ductules","volume":"81","author":"Alpini","year":"1988","journal-title":"J. Clin. Invest."},{"key":"B3","doi-asserted-by":"publisher","first-page":"100250","DOI":"10.1016\/j.jhepr.2021.100250","article-title":"Genetic or Pharmacological Reduction of Cholangiocyte Senescence Improves Inflammation and Fibrosis in the Mdr2 Mouse","volume":"3","author":"Alsuraih","year":"2021","journal-title":"JHEP Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/s0168-8278(00)80377-3","article-title":"Regulation and Deregulation of Cholangiocyte Proliferation","volume":"33","author":"Alvaro","year":"2000","journal-title":"J. Hepatol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1053\/j.gastro.2006.07.023","article-title":"Proliferating Cholangiocytes: A Neuroendocrine Compartment in the Diseased Liver","volume":"132","author":"Alvaro","year":"2007","journal-title":"Gastroenterology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/s41586-020-2403-9","article-title":"Senolytic CAR T Cells Reverse Senescence-Associated Pathologies","volume":"583","author":"Amor","year":"2020","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"S1018","DOI":"10.1016\/s0016-5085(15)33483-1","article-title":"Sa1715 Regulation of Cellular Senescence by the microRNA-34a\/p53 Axis During Alcoholic Liver Injury","volume":"148","author":"Annable","year":"2015","journal-title":"Gastroenterology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.jhepr.2019.05.006","article-title":"Promoter Hypermethylation of the AE2\/SLC4A2 Gene in PBC","volume":"1","author":"Arenas","year":"2019","journal-title":"JHEP Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.3390\/cells10071692","article-title":"Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment","volume":"10","author":"Baiocchi","year":"2021","journal-title":"Cells"},{"key":"B10","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/s41575-019-0125-y","article-title":"Cholangiocyte Pathobiology","volume":"16","author":"Banales","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1002\/hep.25691","article-title":"Up-regulation of microRNA 506 Leads to Decreased Cl\u2212\/HCO3\u2212 Anion Exchanger 2 Expression in Biliary Epithelium of Patients with Primary Biliary Cirrhosis","volume":"56","author":"Banales","year":"2012","journal-title":"Hepatology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1111\/j.1478-3231.2008.01921.x","article-title":"Cholangiocytes as Immune Modulators in Rotavirus-Induced Murine Biliary Atresia","volume":"29","author":"Barnes","year":"2009","journal-title":"Liver Int."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3269","DOI":"10.1002\/hep.32011","article-title":"The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis","volume":"74","author":"Barron-Millar","year":"2021","journal-title":"Hepatology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1002\/hep.29905","article-title":"Biliary Atresia: Clinical and Research Challenges for the Twenty-First Century","volume":"68","author":"Bezerra","year":"2018","journal-title":"Hepatology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1111\/j.1600-0676.1985.tb00254.x","article-title":"Deletion of Hyperplastic Biliary Epithelial Cells by Apoptosis Following Removal of the Proliferative Stimulus","volume":"5","author":"Bhathal","year":"1985","journal-title":"Liver"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.1042\/cs20190893","article-title":"Regulation of Cellular Senescence by Extracellular Matrix During Chronic Fibrotic Diseases","volume":"134","author":"Blokland","year":"2020","journal-title":"Clin. Sci. (Lond)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1146\/annurev-physiol-030212-183653","article-title":"Aging, Cellular Senescence, and Cancer","volume":"75","author":"Campisi","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/s41586-019-1365-2","article-title":"From Discoveries in Ageing Research to Therapeutics for Healthy Ageing","volume":"571","author":"Campisi","year":"2019","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2272","DOI":"10.4161\/cc.20717","article-title":"CTGF Drives Autophagy, Glycolysis and Senescence in Cancer-Associated Fibroblasts via HIF1 Activation, Metabolically Promoting Tumor Growth","volume":"11","author":"Capparelli","year":"2012","journal-title":"Cell Cycle"},{"key":"B20","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.ajpath.2017.11.010","article-title":"Hepatic Stem\/Progenitor Cell Activation Differs Between Primary Sclerosing and Primary Biliary Cholangitis","volume":"188","author":"Carpino","year":"2018","journal-title":"Am. J. Pathol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"100286","DOI":"10.1016\/j.jhepr.2021.100286","article-title":"Cholangiocyte Senescence in Primary Sclerosing Cholangitis Is Associated with Disease Severity and Prognosis","volume":"3","author":"Cazzagon","year":"2021","journal-title":"JHEP Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1055\/s-2007-1007153","article-title":"Dysregulation of Apoptosis in the Cholangiopathies and Cholangiocarcinoma","volume":"18","author":"Celli","year":"1998","journal-title":"Semin. Liver Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12929-017-0327-y","article-title":"ALDH2 Polymorphism and Alcohol-Related Cancers in Asians: A Public Health Perspective","volume":"24","author":"Chang","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/icb.2008.37","article-title":"The Immunobiology of Cholangiocytes","volume":"86","author":"Chen","year":"2008","journal-title":"Immunol. Cel Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1016\/j.bbadis.2017.06.024","article-title":"Pathobiology of Biliary Epithelia","volume":"1864","author":"Cheung","year":"2018","journal-title":"Biochim. Biophys. Acta (Bba) - Mol. Basis Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.15252\/embr.201439245","article-title":"Senescence and Apoptosis: Dueling or Complementary Cell Fates","volume":"15","author":"Childs","year":"2014","journal-title":"EMBO Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1007\/s00383-020-04765-2","article-title":"A Novel Model of Injured Liver Ductal Organoids to Investigate Cholangiocyte Apoptosis with Relevance to Biliary Atresia","volume":"36","author":"Chusilp","year":"2020","journal-title":"Pediatr. Surg. Int."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2853","DOI":"10.1371\/journal.pbio.0060301","article-title":"Senescence-associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the P53 Tumor Suppressor","volume":"6","author":"Copp\u00e9","year":"2008","journal-title":"Plos Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"5545","DOI":"10.1073\/pnas.92.12.5545","article-title":"Transforming Growth Factor Beta Induces the Cyclin-dependent Kinase Inhibitor P21 Through a P53-independent Mechanism","volume":"92","author":"Datto","year":"1995","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/j.jhep.2008.07.024","article-title":"A Rodent Model of NASH with Cirrhosis, Oval Cell Proliferation and Hepatocellular Carcinoma","volume":"49","author":"de Lima","year":"2008","journal-title":"J. Hepatol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1038\/s41467-018-03299-5","article-title":"Paracrine Cellular Senescence Exacerbates Biliary Injury and Impairs Regeneration","volume":"9","author":"Ferreira-Gonzalez","year":"2018","journal-title":"Nat. Commun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/s1081-1206(10)63176-6","article-title":"Apoptosis","volume":"78","author":"Fleisher","year":"1997","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1002\/hep.26099","article-title":"Aging Promotes the Development of Diet-Induced Murine Steatohepatitis but Not Steatosis","volume":"57","author":"Fontana","year":"2013","journal-title":"Hepatology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1093\/toxsci\/kfz055","article-title":"Nrf2 Ameliorates DDC-Induced Sclerosing Cholangitis and Biliary Fibrosis and Improves the Regenerative Capacity of the Liver","volume":"169","author":"Fragoulis","year":"2019","journal-title":"Toxicol. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"27","DOI":"10.3978\/j.issn.2305-5839.2012.10.03","article-title":"Recent Advances on the Mechanisms Regulating Cholangiocyte Proliferation and the Significance of the Neuroendocrine Regulation of Cholangiocyte Pathophysiology","volume":"1","author":"Franchitto","year":"2013","journal-title":"Ann. Transl Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"C499","DOI":"10.1152\/ajpcell.00369.2007","article-title":"Small Mouse Cholangiocytes Proliferate in Response to H1 Histamine Receptor Stimulation by Activation of the IP3\/CaMK I\/CREB Pathway","volume":"295","author":"Francis","year":"2008","journal-title":"Am. J. Physiology-Cell Physiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1016\/j.jhep.2004.06.009","article-title":"cAMP Stimulates the Secretory and Proliferative Capacity of the Rat Intrahepatic Biliary Epithelium Through Changes in the PKA\/Src\/MEK\/ERK1\/2 Pathway","volume":"41","author":"Francis","year":"2004","journal-title":"J. Hepatol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1038\/labinvest.2009.6","article-title":"Morphological and Functional Heterogeneity of the Mouse Intrahepatic Biliary Epithelium","volume":"89","author":"Glaser","year":"2009","journal-title":"Lab. Invest."},{"key":"B39","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/path.2697","article-title":"Autophagy: Cellular and Molecular Mechanisms","volume":"221","author":"Glick","year":"2010","journal-title":"J. Pathol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.jhep.2018.05.018","article-title":"Macrophages Contribute to the Pathogenesis of Sclerosing Cholangitis in Mice","volume":"69","author":"Guicciardi","year":"2018","journal-title":"J. Hepatol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"25974","DOI":"10.1073\/pnas.1908137116","article-title":"Targeting Liver Aldehyde Dehydrogenase-2 Prevents Heavy but Not Moderate Alcohol Drinking","volume":"116","author":"Guillot","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B42","doi-asserted-by":"publisher","first-page":"155","DOI":"10.3727\/105221616x692568","article-title":"Regulators of Cholangiocyte Proliferation","volume":"17","author":"Hall","year":"2017","journal-title":"Gene Expr."},{"key":"B43","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1177\/1535370213489926","article-title":"Recent Advances in the Morphological and Functional Heterogeneity of the Biliary Epithelium","volume":"238","author":"Han","year":"2013","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"B44","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.ebiom.2016.11.021","article-title":"Early Molecular Stratification of High-Risk Primary Biliary Cholangitis","volume":"14","author":"Hardie","year":"2016","journal-title":"EBioMedicine"},{"key":"B45","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.jaut.2016.08.006","article-title":"Hydrophobic Bile Acids Suppress Expression of AE2 in Biliary Epithelial Cells and Induce Bile Duct Inflammation in Primary Biliary Cholangitis","volume":"75","author":"Hisamoto","year":"2016","journal-title":"J. Autoimmun."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1809","article-title":"Induced Pluripotent Stem Cells from Subjects with Primary Sclerosing Cholangitis Develop a Senescence Phenotype Following Biliary Differentiation","author":"Jalan-Sakrikar","year":"2021","journal-title":"Hepatol. Commun."},{"key":"B47","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.freeradbiomed.2021.04.019","article-title":"Paricalcitol Inhibits Oxidative Stress-Induced Cell Senescence of the Bile Duct Epithelium Dependent on Modulating Sirt1 Pathway in Cholestatic Mice","volume":"169","author":"Jia","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.apsb.2015.01.009","article-title":"Bile Acid Signaling and Biliary Functions","volume":"5","author":"Jones","year":"2015","journal-title":"Acta Pharmaceutica Sinica B"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1002\/hep.28704","article-title":"Inhibition of Mast Cell-Secreted Histamine Decreases Biliary Proliferation and Fibrosis in Primary Sclerosing Cholangitis Mdr2\u2212\/\u2212mice","volume":"64","author":"Jones","year":"2016","journal-title":"Hepatology"},{"key":"B50","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1159\/000108341","article-title":"Histamine and the Regulation of Body Weight","volume":"86","author":"J\u00f8rgensen","year":"2007","journal-title":"Neuroendocrinology"},{"key":"B51","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1002\/hep.510310302","article-title":"Functional Heterogeneity of the Intrahepatic Biliary Epithelium","volume":"31","author":"Kanno","year":"2000","journal-title":"Hepatology"},{"key":"B52","doi-asserted-by":"publisher","first-page":"10269","DOI":"10.1096\/fj.201802606r","article-title":"Secretin\/secretin Receptor Signaling Mediates Biliary Damage and Liver Fibrosis in Early\u2010stage Primary Biliary Cholangitis","volume":"33","author":"Kennedy","year":"2019","journal-title":"FASEB j."},{"key":"B53","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.ajpath.2017.11.016","article-title":"Knockout of L-Histidine Decarboxylase Prevents Cholangiocyte Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via Disrupted Histamine\/Leptin Signaling","volume":"188","author":"Kennedy","year":"2018","journal-title":"Am. J. Pathol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1002\/hep.29898","article-title":"Blocking H1\/H2 Histamine Receptors Inhibits Damage\/fibrosis in Mdr2-\/- Mice and Human Cholangiocarcinoma Tumorigenesis","volume":"68","author":"Kennedy","year":"2018","journal-title":"Hepatology"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.ajpath.2020.01.013","article-title":"Amelioration of Large Bile Duct Damage by Histamine-2 Receptor Vivo-Morpholino Treatment","volume":"190","author":"Kennedy","year":"2020","journal-title":"Am. J. Pathol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/hep.31713","article-title":"Mast Cells Promote Nonalcoholic Fatty Liver Disease Phenotypes and Microvesicular Steatosis in Mice Fed a Western Diet","volume":"74","author":"Kennedy","year":"2021","journal-title":"Hepatology"},{"key":"B57","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/j.surg.2018.12.003","article-title":"Divergent Expression of Liver Transforming Growth Factor Superfamily Cytokines After Successful Portoenterostomy in Biliary Atresia","volume":"165","author":"Kerola","year":"2019","journal-title":"Surgery"},{"key":"B58","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.ajpath.2019.10.012","article-title":"Necroptosis in the Pathophysiology of Disease","volume":"190","author":"Khoury","year":"2020","journal-title":"Am. J. Pathol."},{"key":"B59","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.4049\/jimmunol.138.11.3684","article-title":"Selective Inhibition of the Generation of T Suppressor Cells of Contact Sensitivity In Vitro by Interferon","volume":"138","author":"Knop","year":"1987","journal-title":"J. Immunol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"77","DOI":"10.3727\/105221620x15960509906371","article-title":"The Dynamic Interplay Between Mast Cells, Aging\/Cellular Senescence, and Liver Disease","volume":"20","author":"Kundu","year":"2020","journal-title":"Gene Expr."},{"key":"B61","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3727\/105221620x15889714507961","article-title":"Downregulation of P16 Decreases Biliary Damage and Liver Fibrosis in the Mdr2\/ Mouse Model of Primary Sclerosing Cholangitis","volume":"20","author":"Kyritsi","year":"2020","journal-title":"Gene Expr."},{"key":"B62","doi-asserted-by":"publisher","first-page":"2397","DOI":"10.1002\/hep.31497","article-title":"Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell-Derived Transforming Growth Factor Beta 1 Signaling","volume":"73","author":"Kyritsi","year":"2021","journal-title":"Hepatology"},{"key":"B63","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1016\/j.mayocp.2015.03.017","article-title":"The Cholangiopathies","volume":"90","author":"Lazaridis","year":"2015","journal-title":"Mayo Clinic Proc."},{"key":"B64","doi-asserted-by":"publisher","first-page":"G182","DOI":"10.1152\/ajpgi.2001.281.1.g182","article-title":"Regression of Cholangiocyte Proliferation After Cessation of ANIT Feeding Is Coupled with Increased Apoptosis","volume":"281","author":"Lesage","year":"2001","journal-title":"Am. J. Physiology-Gastrointestinal Liver Physiol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.cyto.2019.01.013","article-title":"The Senescence-Associated Secretory Phenotype and its Regulation","volume":"117","author":"Lopes-Paciencia","year":"2019","journal-title":"Cytokine"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The Hallmarks of Aging","volume":"153","author":"L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"key":"B67","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1002\/hep.26308","article-title":"GABA Induces the Differentiation of Small into Large Cholangiocytes by Activation of Ca2+\/CaMK I-dependent Adenylyl Cyclase 8","volume":"58","author":"Mancinelli","year":"2013","journal-title":"Hepatology"},{"key":"B68","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1016\/j.dld.2020.09.013","article-title":"NAFLD, MAFLD and DAFLD","volume":"52","author":"Mantovani","year":"2020","journal-title":"Dig. Liver Dis."},{"key":"B69","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1002\/hep.30466","article-title":"Aging\u2010Related Expression of Twinfilin\u20101 Regulates Cholangiocyte Biological Response to Injury","volume":"70","author":"Maroni","year":"2019","journal-title":"Hepatology"},{"key":"B70","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1007\/s12199-016-0579-2","article-title":"Roles of Defective ALDH2 Polymorphism on Liver protection and Cancer Development","volume":"21","author":"Matsumoto","year":"2016","journal-title":"Environ. Health Prev. Med."},{"key":"B71","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1002\/hep.28831","article-title":"Forkhead Box A2 Regulates Biliary Heterogeneity and Senescence During Cholestatic Liver Injury in Mice\u2021","volume":"65","author":"McDaniel","year":"2017","journal-title":"Hepatology"},{"key":"B72","doi-asserted-by":"publisher","first-page":"2684","DOI":"10.1002\/hep.32028","article-title":"Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling","volume":"74","author":"Meadows","year":"2021","journal-title":"Hepatology"},{"key":"B73","doi-asserted-by":"publisher","first-page":"165557","DOI":"10.1016\/j.bbadis.2019.165557","article-title":"Downregulation of Hepatic Stem Cell Factor by Vivo-Morpholino Treatment Inhibits Mast Cell Migration and Decreases Biliary Damage\/senescence and Liver Fibrosis in Mdr2\u2212\/\u2212 Mice","volume":"1865","author":"Meadows","year":"2019","journal-title":"Biochim. Biophys. Acta (Bba) - Mol. Basis Dis."},{"key":"B74","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1111\/j.1478-3231.2006.01401.x","article-title":"Endocannabinoid Receptor CB2 in Nonalcoholic Fatty Liver Disease","volume":"27","author":"Mendez-Sanchez","year":"2007","journal-title":"Liver Int."},{"key":"B75","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1002\/hep.29464","article-title":"Targeting Senescent Cholangiocytes and Activated Fibroblasts with B-Cell Lymphoma-Extra Large Inhibitors Ameliorates Fibrosis in Multidrug Resistance 2 Gene Knockout (Mdr2\u2212\/\u2212 ) Mice","volume":"67","author":"Moncsek","year":"2018","journal-title":"Hepatology"},{"key":"B76","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/1476-4598-7-87","article-title":"ALDH Isozymes Downregulation Affects Cell Growth, Cell Motility and Gene Expression in Lung Cancer Cells","volume":"7","author":"Moreb","year":"2008","journal-title":"Mol. Cancer"},{"key":"B77","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.freeradbiomed.2011.11.033","article-title":"Aldehyde Dehydrogenases and Cell Proliferation","volume":"52","author":"Muzio","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"B78","doi-asserted-by":"publisher","first-page":"9765027","DOI":"10.1155\/2018\/9765027","article-title":"ALDH2 Activity Reduces Mitochondrial Oxygen Reserve Capacity in Endothelial Cells and Induces Senescence Properties","volume":"2018","author":"Nannelli","year":"2018","journal-title":"Oxid Med. Cel Longev"},{"key":"B79","doi-asserted-by":"publisher","first-page":"1942","DOI":"10.1002\/hep.27175","article-title":"Saturated Free Fatty Acids Induce Cholangiocyte Lipoapoptosis","volume":"60","author":"Natarajan","year":"2014","journal-title":"Hepatology"},{"key":"B80","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1194\/jlr.m071357","article-title":"FoxO3 Increases miR-34a to Cause Palmitate-Induced Cholangiocyte Lipoapoptosis","volume":"58","author":"Natarajan","year":"2017","journal-title":"J. Lipid Res."},{"key":"B81","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1002\/hep.1840140324","article-title":"Mechanisms and Regulation of Bile Secretion","volume":"14","author":"Nathanson","year":"1991","journal-title":"Hepatology"},{"key":"B82","doi-asserted-by":"publisher","first-page":"15691","DOI":"10.1038\/ncomms15691","article-title":"Cellular Senescence Drives Age-dependent Hepatic Steatosis","volume":"8","author":"Ogrodnik","year":"2017","journal-title":"Nat. Commun."},{"key":"B83","first-page":"347","article-title":"Gadolinium Chloride Suppresses Hepatic Oval Cell Proliferation in Rats with Biliary Obstruction","volume":"152","author":"Olynyk","year":"1998","journal-title":"Am. J. Pathol."},{"key":"B84","first-page":"145","article-title":"A Practical Review of Primary Biliary Cholangitis for the Gastroenterologist","volume":"15","author":"Onofrio","year":"2019","journal-title":"Gastroenterol. Hepatol. (N Y)"},{"key":"B85","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.cbi.2011.01.011","article-title":"Importance of Inverse Correlation Between ALDH3A1 and PPAR\u03b3 in Tumor Cells and Tissue Regeneration","volume":"191","author":"Oraldi","year":"2011","journal-title":"Chemico-Biological Interactions"},{"key":"B86","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s12964-021-00731-0","article-title":"Mild Exacerbation of Obesity- and Age-dependent Liver Disease Progression by Senolytic Cocktail Dasatinib + Quercetin","volume":"19","author":"Raffaele","year":"2021","journal-title":"Cell Commun Signal"},{"key":"B87","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.jhep.2016.11.004","article-title":"Aging Aggravates Alcoholic Liver Injury and Fibrosis in Mice by Downregulating Sirtuin 1 Expression","volume":"66","author":"Ramirez","year":"2017","journal-title":"J. Hepatol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.trecan.2016.10.001","article-title":"SASP: Tumor Suppressor or Promoter? Yes!","volume":"2","author":"Rao","year":"2016","journal-title":"Trends Cancer"},{"key":"B89","volume-title":"Primary Sclerosing Cholangitis","author":"Rawla","year":"2021"},{"key":"B90","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/s0962-8924(03)00147-8","article-title":"Id Proteins in Development, Cell Cycle and Cancer","volume":"13","author":"Ruzinova","year":"2003","journal-title":"Trends Cel Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1289\/ehp.919359","article-title":"Senescence as a Mode of Tumor Suppression","volume":"93","author":"Sager","year":"1991","journal-title":"Environ. Health Perspect."},{"key":"B92","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1007\/s00268-012-1453-z","article-title":"Hepatocellular Telomere Length in Biliary Atresia Measured by Q-FISH","volume":"36","author":"Sanada","year":"2012","journal-title":"World J. Surg."},{"key":"B93","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1111\/j.1478-3231.2011.02656.x","article-title":"A Possible Involvement of P62\/sequestosome-1 in the Process of Biliary Epithelial Autophagy and Senescence in Primary Biliary Cirrhosis","volume":"32","author":"Sasaki","year":"2012","journal-title":"Liver Int."},{"key":"B94","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1002\/path.1729","article-title":"Frequent Cellular Senescence in Small Bile Ducts in Primary Biliary Cirrhosis: A Possible Role in Bile Duct Loss","volume":"205","author":"Sasaki","year":"2005","journal-title":"J. Pathol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"831","DOI":"10.2353\/ajpath.2006.051237","article-title":"Decreased Expression of Bmi1 Is Closely Associated with Cellular Senescence in Small Bile Ducts in Primary Biliary Cirrhosis","volume":"169","author":"Sasaki","year":"2006","journal-title":"Am. J. Pathol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1002\/hep.22348","article-title":"Telomere Shortening in the Damaged Small Bile Ducts in Primary Biliary Cirrhosis Reflects Ongoing Cellular Senescence","volume":"48","author":"Sasaki","year":"2008","journal-title":"Hepatology"},{"key":"B97","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1111\/his.13476","article-title":"Increased Expression of Senescence-Associated Cell Cycle Regulators in the Progression of Biliary Atresia: An Immunohistochemical Study","volume":"72","author":"Sasaki","year":"2018","journal-title":"Histopathology"},{"key":"B98","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1007\/s10620-011-1929-y","article-title":"Autophagy May Precede Cellular Senescence of Bile Ductular Cells in Ductular Reaction in Primary Biliary Cirrhosis","volume":"57","author":"Sasaki","year":"2012","journal-title":"Dig. Dis. Sci."},{"key":"B99","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1038\/labinvest.2010.56","article-title":"Autophagy Mediates the Process of Cellular Senescence Characterizing Bile Duct Damages in Primary Biliary Cirrhosis","volume":"90","author":"Sasaki","year":"2010","journal-title":"Lab. Invest."},{"key":"B100","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.jhep.2010.03.008","article-title":"Modulation of the Microenvironment by Senescent Biliary Epithelial Cells May Be Involved in the Pathogenesis of Primary Biliary Cirrhosis","volume":"53","author":"Sasaki","year":"2010","journal-title":"J. Hepatol."},{"key":"B101","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/s41374-018-0045-4","article-title":"An Impaired Biliary Bicarbonate Umbrella May Be Involved in Dysregulated Autophagy in Primary Biliary Cholangitis","volume":"98","author":"Sasaki","year":"2018","journal-title":"Lab. Invest."},{"key":"B102","doi-asserted-by":"publisher","first-page":"102377","DOI":"10.1016\/j.jaut.2019.102377","article-title":"Increased p16INK4a-Expressing Senescent Bile Ductular Cells Are Associated with Inadequate Response to Ursodeoxycholic Acid in Primary Biliary Cholangitis","volume":"107","author":"Sasaki","year":"2020","journal-title":"J. Autoimmun."},{"key":"B103","doi-asserted-by":"publisher","first-page":"11413","DOI":"10.1038\/s41598-021-91016-6","article-title":"Interferon-induced Protein with Tetratricopeptide Repeats 3 May Be a Key Factor in Primary Biliary Cholangitis","volume":"11","author":"Sasaki","year":"2021","journal-title":"Sci. Rep."},{"key":"B104","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1007\/s00535-014-1033-0","article-title":"A Possible Involvement of Endoplasmic Reticulum Stress in Biliary Epithelial Autophagy and Senescence in Primary Biliary Cirrhosis","volume":"50","author":"Sasaki","year":"2015","journal-title":"J. Gastroenterol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"101781","DOI":"10.1016\/j.legalmed.2020.101781","article-title":"The Effect of Hepatic Steatosis and Fibrosis on Liver Weight and Dimensions","volume":"47","author":"Simon","year":"2020","journal-title":"Leg. Med."},{"key":"B106","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1007\/s10620-005-2719-1","article-title":"A Clinical-Morphological Study on Cholestatic Presentation of Nonalcoholic Fatty Liver Disease","volume":"50","author":"Sorrentino","year":"2005","journal-title":"Dig. Dis. Sci."},{"key":"B107","doi-asserted-by":"publisher","first-page":"2263","DOI":"10.1002\/hep.26993","article-title":"Cholangiocyte Senescence by Way of N-Ras Activation Is a Characteristic of Primary Sclerosing Cholangitis","volume":"59","author":"Tabibian","year":"2014","journal-title":"Hepatology"},{"key":"B108","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1002\/hep.27927","article-title":"Absence of the Intestinal Microbiota Exacerbates Hepatobiliary Disease in a Murine Model of Primary Sclerosing Cholangitis","volume":"63","author":"Tabibian","year":"2016","journal-title":"Hepatology"},{"key":"B109","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1038\/labinvest.2014.94","article-title":"Characterization of Cultured Cholangiocytes Isolated from Livers of Patients with Primary Sclerosing Cholangitis","volume":"94","author":"Tabibian","year":"2014","journal-title":"Lab. Invest."},{"key":"B110","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1016\/j.jhep.2010.11.021","article-title":"Presence and Significance of Microvesicular Steatosis in Nonalcoholic Fatty Liver Disease","volume":"55","author":"Tandra","year":"2011","journal-title":"J. Hepatol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1073\/pnas.0806196106","article-title":"Distinct Mechanisms Act in Concert to Mediate Cell Cycle Arrest","volume":"106","author":"Toettcher","year":"2009","journal-title":"Pnas"},{"key":"B112","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1002\/(sici)1096-9896(199912)189:4<609::aid-path474>3.0.co;2-2","article-title":"Aberrant Expression of Stem Cell Factor on Biliary Epithelial Cells and Peribiliary Infiltration of C-Kit-Expressing Mast Cells in Hepatolithiasis and Primary Sclerosing Cholangitis: A Possible Contribution to Bile Duct Fibrosis","volume":"189","author":"Tsuneyama","year":"1999","journal-title":"J. Pathol."},{"key":"B113","doi-asserted-by":"publisher","first-page":"e0134689","DOI":"10.1371\/journal.pone.0134689","article-title":"Telomere Length in Peripheral Blood Leukocytes Is Associated with Severity of Biliary Atresia","volume":"10","author":"Udomsinprasert","year":"2015","journal-title":"PLoS One"},{"key":"B114","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1007\/s00261-016-1002-6","article-title":"Imaging Patterns and Focal Lesions in Fatty Liver: A Pictorial Review","volume":"42","author":"Venkatesh","year":"2017","journal-title":"Abdom. Radiol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"S974","DOI":"10.1016\/s0016-5085(15)33327-8","article-title":"miR-34a Regulates Cellular Senescence in Activated Hepatic Stellate Cells During Alcohol Induced Hepatic Injury","volume":"148","author":"Wan","year":"2015","journal-title":"Gastroenterology"},{"key":"B116","doi-asserted-by":"publisher","first-page":"2788","DOI":"10.1016\/j.ajpath.2017.08.027","article-title":"Regulation of Cellular Senescence by miR-34a in Alcoholic Liver Injury","volume":"187","author":"Wan","year":"2017","journal-title":"Am. J. Pathol."},{"key":"B117","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/bf00548204","article-title":"Effects of Intracarotid Ionic and Non-ionic Contrast Material on the Blood-Brain Barrier in a Rabbit Model","volume":"28","author":"Wilcox","year":"1986","journal-title":"Neuroradiology"},{"key":"B118","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1111\/joim.12609","article-title":"Understanding Cell Cycle and Cell Death Regulation Provides Novel Weapons Against Human Diseases","volume":"281","author":"Wiman","year":"2017","journal-title":"J. Intern. Med."},{"key":"B119","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.jhep.2020.08.033","article-title":"Endothelial GATA4 Controls Liver Fibrosis and Regeneration by Preventing a Pathogenic Switch in Angiocrine Signaling","volume":"74","author":"Winkler","year":"2021","journal-title":"J. Hepatol."},{"key":"B120","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1002\/hep.31484","article-title":"Functional Role of the Secretin\/Secretin Receptor Signaling During Cholestatic Liver Injury","volume":"72","author":"Wu","year":"2020","journal-title":"Hepatology"},{"key":"B121","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1002\/hep.28622","article-title":"The Secretin\/secretin Receptor Axis Modulates Liver Fibrosis Through Changes in Transforming Growth Factor-\u03921 Biliary Secretion in Mice","volume":"64","author":"Wu","year":"2016","journal-title":"Hepatology"},{"key":"B122","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1016\/j.ajpath.2018.06.015","article-title":"The Secretin\/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis Through Changes in Transforming Growth Factor-\u03921-Mediated Biliary Senescence","volume":"188","author":"Wu","year":"2018","journal-title":"Am. J. Pathol."},{"key":"B123","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1002\/hep.30698","article-title":"Long Noncoding RNA H19 Contributes to Cholangiocyte Proliferation and Cholestatic Liver Fibrosis in Biliary Atresia","volume":"70","author":"Xiao","year":"2019","journal-title":"Hepatology"},{"key":"B124","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.bbrc.2018.08.081","article-title":"ALDH2 Mediates the Dose-Response Protection of Chronic Ethanol Against Endothelial Senescence Through SIRT1\/p53 Pathway","volume":"504","author":"Xue","year":"2018","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B125","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.bbrc.2019.03.037","article-title":"Appropriate Dose of Ethanol Exerts Anti-senescence and Anti-atherosclerosis Protective Effects by Activating ALDH2","volume":"512","author":"Xue","year":"2019","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B126","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.jpsychires.2018.11.007","article-title":"Telomere Shortening in Alcohol Dependence: Roles of Alcohol and Acetaldehyde","volume":"109","author":"Yamaki","year":"2019","journal-title":"J. Psychiatr. Res."},{"key":"B127","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1053\/j.gastro.2014.07.056","article-title":"Pathological Features of Fatty Liver Disease","volume":"147","author":"Yeh","year":"2014","journal-title":"Gastroenterology"},{"key":"B128","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.2337\/diabetes.48.12.2286","article-title":"Hypothalamic Neuronal Histamine as a Target of Leptin in Feeding Behavior","volume":"48","author":"Yoshimatsu","year":"1999","journal-title":"Diabetes"},{"key":"B129","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1002\/hep.31420","article-title":"From NAFLD to MAFLD: Implications of a Premature Change in Terminology","volume":"73","author":"Younossi","year":"2021","journal-title":"Hepatology"},{"key":"B130","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1016\/j.jhep.2014.12.022","article-title":"Pharmacological Activation of Aldehyde Dehydrogenase 2 by Alda-1 Reverses Alcohol-Induced Hepatic Steatosis and Cell Death in Mice","volume":"62","author":"Zhong","year":"2015","journal-title":"J. Hepatol."},{"key":"B131","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.3390\/cells10082072","article-title":"Feedback Signaling Between Cholangiopathies, Ductular Reaction, and Non-alcoholic Fatty Liver Disease","volume":"1010","author":"Zhou","year":"2021","journal-title":"Cells"},{"key":"B132","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1038\/s41374-018-0093-9","article-title":"Knockout of Secretin Receptor Reduces Biliary Damage and Liver Fibrosis in Mdr2\u2212\/\u2212 Mice by Diminishing Senescence of Cholangiocytes","volume":"98","author":"Zhou","year":"2018","journal-title":"Lab. Invest."},{"key":"B133","doi-asserted-by":"publisher","first-page":"117990","DOI":"10.1016\/j.lfs.2020.117990","article-title":"Combination of Luteolin and Lycopene Effectively Protect Against the \"Two-Hit\" in NAFLD Through Sirt1\/AMPK Signal Pathway","volume":"256","author":"Zhu","year":"2020","journal-title":"Life Sci."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.803098\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T16:30:08Z","timestamp":1674145808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.803098\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,21]]},"references-count":133,"alternative-id":["10.3389\/fmolb.2021.803098"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2021.803098","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,21]]},"article-number":"803098"}}