2021
Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy
McConnell MJ, Kawaguchi N, Kondo R, Sonzogni A, Licini L, Valle C, Bonaffini PA, Sironi S, Alessio MG, Previtali G, Seghezzi M, Zhang X, Lee A, Pine AB, Chun HJ, Zhang X, Fernandez-Hernando C, Qing H, Wang A, Price C, Sun Z, Utsumi T, Hwa J, Strazzabosco M, Iwakiri Y. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy. Journal Of Hepatology 2021, 75: 647-658. PMID: 33991637, PMCID: PMC8285256, DOI: 10.1016/j.jhep.2021.04.050.Peer-Reviewed Original ResearchConceptsLiver sinusoidal endothelial cellsLiver injuryInterleukin-6Sinusoidal endothelial cellsAlanine aminotransferaseLiver histologyD-dimerCOVID-19Primary human liver sinusoidal endothelial cellsSARS-CoV-2 infectionHuman liver sinusoidal endothelial cellsEndothelial cellsSoluble glycoprotein 130IL-6 levelsSmall-interfering RNA knockdownJAK inhibitor ruxolitinibFactor VIII activityProinflammatory factorsInflammatory signalsLarge cohortInhibitor ruxolitinibVWF antigenEndotheliopathyPatientsInjury
2019
Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases
Fabris L, Fiorotto R, Spirli C, Cadamuro M, Mariotti V, Perugorria MJ, Banales JM, Strazzabosco M. Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases. Nature Reviews Gastroenterology & Hepatology 2019, 16: 497-511. PMID: 31165788, PMCID: PMC6661007, DOI: 10.1038/s41575-019-0156-4.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCystic fibrosis-related liver diseaseFibropolycystic liver diseaseLiver diseasePolycystic liver diseaseBiliary repairAlagille syndromeEpithelial toll-like receptor 4Toll-like receptor 4Acquired liver diseasesGut-derived productsPrimary sclerosing cholangitisDuct epithelial cellsSclerosing cholangitisΒ-catenin signalingPortal fibrosisBiliary diseaseIL-1βUnknown etiologyDependent cytokinesReceptor 4Peribiliary inflammationRole of NotchCholangiopathyNovel treatmentsCyst growth
2018
β‐Catenin and interleukin‐1β–dependent chemokine (C‐X‐C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis
Kaffe E, Fiorotto R, Pellegrino F, Mariotti V, Amenduni M, Cadamuro M, Fabris L, Strazzabosco M, Spirli C. β‐Catenin and interleukin‐1β–dependent chemokine (C‐X‐C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis. Hepatology 2018, 67: 1903-1919. PMID: 29140564, PMCID: PMC5906178, DOI: 10.1002/hep.29652.Peer-Reviewed Original ResearchConceptsSignal transducerΒ-cateninJanus kinase/signal transducerKinase/signal transducerActivator of transcriptionProtein kinase ATranscription 3 (STAT3) phosphorylationHepatic disease 1 (PKHD1) geneNOD-like receptorsKinase ATranscription 3Novel therapeutic avenuesGenetic diseasesNuclear translocationCognate receptorsFamily 3Nuclear factorMouse modelPKHD1Activated B cellsPhosphorylationActivatorCyst growthTherapeutic avenuesAMG 487Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy
Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M. Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy. Hepatology 2018, 67: 972-988. PMID: 28836688, PMCID: PMC5783790, DOI: 10.1002/hep.29400.Peer-Reviewed Original ResearchMeSH KeywordsAminophenolsAminopyridinesAnimalsBenzodioxolesBiliary TractCell Culture TechniquesChloride Channel AgonistsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCytokinesCytoskeletonEpithelial CellsFluorescent Antibody TechniqueHumansInduced Pluripotent Stem CellsInflammationMiceMicroscopy, ConfocalPyrimidinesQuinolonesSignal TransductionSrc-Family KinasesConceptsBiliary epitheliumCystic fibrosisToll-like receptor 4Cystic fibrosis transmembrane conductance regulatorFluid secretionActivated B cells (NF-κB) activationClinical liver diseaseStrong translational potentialCause of deathB cell activationSrc kinase inhibitionFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorInflammatory changesPharmacological therapyProinflammatory changesProinflammatory chemokinesInflammation contributesLiver diseaseHuman cholangiopathiesReceptor 4Healthy controlsLiver patientsCF patientsVX-770
2017
Notch signaling and progenitor/ductular reaction in steatohepatitis
Morell CM, Fiorotto R, Meroni M, Raizner A, Torsello B, Cadamuro M, Spagnuolo G, Kaffe E, Sutti S, Albano E, Strazzabosco M. Notch signaling and progenitor/ductular reaction in steatohepatitis. PLOS ONE 2017, 12: e0187384. PMID: 29140985, PMCID: PMC5687773, DOI: 10.1371/journal.pone.0187384.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDietFatty LiverHepatocytesMaleMiceMice, Inbred C57BLReceptors, NotchSignal TransductionStem CellsConceptsHepatic stellate cellsDuctular reactionRole of NotchMCD diet-fed miceMethionine-choline deficient (MCD) dietHepatic progenitor cell activationPrimary hepatic stellate cellsChronic liver diseaseDiet-fed miceTGF-β1 expressionAlternative therapeutic targetsTGF-β1 treatmentProgenitor cell activationNotch-1 activationLiver injuryMCD dietLiver diseaseFibrosis progressionNotch signalingDR responseLiver repairBSEP expressionHepatocyte cell lineLiver cancerAAV8-TBGMolecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview
Brivio S, Cadamuro M, Fabris L, Strazzabosco M. Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview. Gene Expression 2017, 18: 31-50. PMID: 29070148, PMCID: PMC5860940, DOI: 10.3727/105221617x15088670121925.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBile Duct NeoplasmsCholangiocarcinomaHumansNeoplasm InvasivenessSignal TransductionTumor MicroenvironmentConceptsMajority of patientsPrimary liver cancerCancer-related deathPotential prognostic relevanceDevelopment of metastasesPro-oncogenic pathwaysNovel druggable targetsMechanism of actionCholangiocarcinoma invasivenessMesenchymal-like phenotypeDevastating malignancyCurative treatmentMolecular mechanismsPoor prognosisPrognostic relevancePrimary tumorBiliary epitheliumLiver cancerUseful biomarkerAbnormal activationCCA cell invasionMost carcinomasCCA cellsTumor microenvironmentCholangiocarcinomaThe deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma
Cadamuro M, Stecca T, Brivio S, Mariotti V, Fiorotto R, Spirli C, Strazzabosco M, Fabris L. The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1435-1443. PMID: 28757170, PMCID: PMC6386155, DOI: 10.1016/j.bbadis.2017.07.028.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsTumor reactive stromaReactive stromaMain cellular componentsDeleterious interplayCyto/chemokinesCellular componentsParacrine signalsPrognosis of cholangiocarcinomaTumor epithelial cellsCell interactionsEarly invasivenessJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenDifferent cell elementsEpithelial cellsEpithelial malignanciesTumor behaviorTumor epitheliumGrowth factorNeoplastic cellsTumor progressionCentral roleStromal componentsPathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium
Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, Scirpo R, Fabris L. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1374-1379. PMID: 28754453, PMCID: PMC5785585, DOI: 10.1016/j.bbadis.2017.07.023.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsToll-like receptorsLiver damageCystic fibrosis-related liver diseaseInnate immunityDamage-associated molecular patternsEpithelial innate immunityPro-inflammatory behaviorBiliary epithelial cellsNumber of receptorsJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenLiver injuryLiver diseaseBile flowInflammatory processBiliary epitheliumInflammatory responsePathophysiologic implicationsReparative processesNumber of evidencesFirst defense lineCholangiocytesMolecular patterns
2016
Adenylyl cyclase 5 links changes in calcium homeostasis to cAMP-dependent cyst growth in polycystic liver disease
Spirli C, Mariotti V, Villani A, Fabris L, Fiorotto R, Strazzabosco M. Adenylyl cyclase 5 links changes in calcium homeostasis to cAMP-dependent cyst growth in polycystic liver disease. Journal Of Hepatology 2016, 66: 571-580. PMID: 27826057, PMCID: PMC5316496, DOI: 10.1016/j.jhep.2016.10.032.Peer-Reviewed Original ResearchMeSH KeywordsAdenylyl Cyclase InhibitorsAdenylyl CyclasesAnimalsCalciumCell ProliferationCyclic AMPCystsDisease Models, AnimalHomeostasisHumansLiver DiseasesMAP Kinase Signaling SystemMiceMice, KnockoutPolycystic Kidney, Autosomal DominantRNA InterferenceSignal TransductionStromal Interaction Molecule 1TRPP Cation ChannelsVascular Endothelial Growth Factor AConceptsProgressive cyst growthPolycystic liver diseaseNovel therapeutic targetLiver diseaseKO miceCyst growthTherapeutic targetBiliary organoidsDouble conditional knockout miceCAMP productionAutosomal dominant polycystic kidney diseaseVascular endothelial growth factorCell proliferationDominant polycystic kidney diseaseEndothelial growth factorConditional knockout micePolycystic kidney diseaseLiver transplantationLevels of cAMPStore-operated CaCystic areasKidney diseaseCyst sizeVivo treatmentKnockout mice
2015
Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation
Morton SD, Cadamuro M, Brivio S, Vismara M, Stecca T, Massani M, Bassi N, Furlanetto A, Joplin RE, Floreani A, Fabris L, Strazzabosco M. Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation. Oncotarget 2015, 6: 26052-26064. PMID: 26296968, PMCID: PMC4694885, DOI: 10.18632/oncotarget.4482.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsApoptosisBile Duct NeoplasmsBlotting, WesternCell Line, TumorCholangiocarcinomaCisplatinDeoxycytidineGemcitabineGene Expression Regulation, NeoplasticHumansLeukemia Inhibitory FactorLeukemia Inhibitory Factor Receptor alpha SubunitMicroscopy, FluorescenceMyeloid Cell Leukemia Sequence 1 ProteinPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktReverse Transcriptase Polymerase Chain ReactionRNA InterferenceSignal TransductionConceptsLeukemia inhibitory factorDrug-induced apoptosisChemotherapy-induced apoptosisPI3K inhibitionLIF effectsLIFR expressionExpression of LIFInhibitory factorRole of LIFCholangiocarcinoma cellsK inhibitionPI3K/Akt-dependent pathwayTumor stromal cellsHuman cholangiocarcinoma cell linesCell-like phenotypeCholangiocarcinoma cell linesMcl-1Akt-dependent pathwayUp-regulating Mcl-1IL-6 family cytokinesLIF secretionLiver malignanciesCholangiocarcinoma cell proliferationAnti-apoptotic proteinsFamily cytokinesEmerging roles of Notch signaling in liver disease
Geisler F, Strazzabosco M. Emerging roles of Notch signaling in liver disease. Hepatology 2015, 61: 382-392. PMID: 24930574, PMCID: PMC4268103, DOI: 10.1002/hep.27268.Peer-Reviewed Original ResearchConceptsRole of NotchNotch signalingMammalian cell fateSpecific cellular contextCell fateCellular contextOrgan homeostasisStem cell featuresSignificance of NotchDistinct liver cell typesLiver developmentLiver cell typesCell typesLiver diseaseIntrahepatic cholangiocarcinomaLiver malignanciesHepatocellular carcinomaFurther cellHomeostasisLiver homeostasisLiver metabolismPersistent activationClinical practiceRepair processSignaling
2013
Notch signaling and new therapeutic options in liver disease
Morell CM, Strazzabosco M. Notch signaling and new therapeutic options in liver disease. Journal Of Hepatology 2013, 60: 885-890. PMID: 24308992, DOI: 10.1016/j.jhep.2013.11.028.Peer-Reviewed Original ResearchConceptsLiver diseaseTherapeutic agentsNew therapeutic optionsNotch signalingSpecific therapeutic agentsStem cell featuresTherapeutic optionsLiver malignanciesLiver metabolismTherapeutic relevanceAberrant activationLiver regenerationPersistent activationDiseaseAdult liverPossible targetsFurther studiesCell featuresNovel findingsRecent reportsNotch pathwayLiverCritical playersSignalingActivationProtein kinase a‐dependent pSer675‐β‐catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis
Spirli C, Locatelli L, Morell CM, Fiorotto R, Morton SD, Cadamuro M, Fabris L, Strazzabosco M. Protein kinase a‐dependent pSer675‐β‐catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 2013, 58: 1713-1723. PMID: 23744610, PMCID: PMC3800498, DOI: 10.1002/hep.26554.Peer-Reviewed Original ResearchConceptsAutosomal recessive polycystic kidney diseaseCongenital hepatic fibrosisCaroli's diseaseΒ-cateninHepatic fibrosisRac-1 inhibitionIntrahepatic bile ductsRecessive polycystic kidney diseasePotential therapeutic targetPolycystic kidney diseaseStimulation of cAMPRac-1 activityE-cadherin expressionBile ductKidney diseaseLiver pathologyCystic dysplasiaMouse modelTherapeutic targetTranscriptional activityNuclear translocationDiseasePKA blockerCholangiocytesFibrosisPlatelet‐derived growth factor‐D and Rho GTPases regulate recruitment of cancer‐associated fibroblasts in cholangiocarcinoma
Cadamuro M, Nardo G, Indraccolo S, Dall'Olmo L, Sambado L, Moserle L, Franceschet I, Colledan M, Massani M, Stecca T, Bassi N, Morton S, Spirli C, Fiorotto R, Fabris L, Strazzabosco M. Platelet‐derived growth factor‐D and Rho GTPases regulate recruitment of cancer‐associated fibroblasts in cholangiocarcinoma. Hepatology 2013, 58: 1042-1053. PMID: 23505219, PMCID: PMC3732815, DOI: 10.1002/hep.26384.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBenzamidesBile Duct NeoplasmsBile Ducts, IntrahepaticCell Line, TumorCell MovementCell ProliferationCells, CulturedCholangiocarcinomaEpithelial-Mesenchymal TransitionFibroblastsHeterograftsHumansImatinib MesylateIn Vitro TechniquesLymphokinesMaleMiceMice, SCIDPiperazinesPlatelet-Derived Growth FactorPyrimidinesRho GTP-Binding ProteinsSignal TransductionConceptsCancer-associated fibroblastsPlatelet-derived growth factorEpithelial-mesenchymal transitionCCA cellsSecretion of PDGFRole of PDGFGrowth factorAbundant stromal reactionAlpha-smooth muscle actinPDGF-D expressionNovel therapeutic approachesPotential therapeutic targetSmooth muscle actinCCA cell linesPDGF-D signalingFibroblast migrationC-Jun N-terminal kinaseEMT biomarkersImmunodeficient miceStromal reactionTherapeutic approachesStroma interactionsTherapeutic targetCholangiocarcinomaMesenchymal markersVascular biology of the biliary epithelium
Morell CM, Fabris L, Strazzabosco M. Vascular biology of the biliary epithelium. Journal Of Gastroenterology And Hepatology 2013, 28: 26-32. PMID: 23855292, PMCID: PMC3721432, DOI: 10.1111/jgh.12022.Peer-Reviewed Original ResearchMeSH KeywordsAngiopoietinsAnimalsAutocrine CommunicationBile Duct DiseasesBile Ducts, IntrahepaticEpithelial CellsEpitheliumHumansLiverLiver Diseases, AlcoholicLiver RegenerationNeovascularization, PathologicParacrine CommunicationPlatelet-Derived Growth FactorRatsSignal TransductionVascular Endothelial Growth Factor AConceptsBile ductIntrahepatic bile ductsHepatic arteryPeribiliary plexusUnderlying molecular mechanismsArterial supplyLiver repairNormal organ physiologyLiver pathophysiologyVascular cell typesPathophysiological settingsVascular structuresStrong associationVascular biologyDifferent vascular cell typesCholangiocytesAngiogenic signalsLiver developmentCell typesMolecular mechanismsOrgan physiologyDuctAssociationCross talkNotch signalling beyond liver development: Emerging concepts in liver repair and oncogenesis
Morell CM, Fiorotto R, Fabris L, Strazzabosco M. Notch signalling beyond liver development: Emerging concepts in liver repair and oncogenesis. Clinics And Research In Hepatology And Gastroenterology 2013, 37: 447-454. PMID: 23806629, DOI: 10.1016/j.clinre.2013.05.008.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsBile Duct NeoplasmsBiliary TractCalcium-Binding ProteinsCarcinogenesisCarcinoma, HepatocellularCholangiocarcinomaHepatocytesHumansIntercellular Signaling Peptides and ProteinsJagged-1 ProteinLiverLiver NeoplasmsLiver RegenerationMembrane ProteinsReceptor Cross-TalkReceptors, NotchSerrate-Jagged ProteinsSignal TransductionNotch signaling regulates tubular morphogenesis during repair from biliary damage in mice
Fiorotto R, Raizner A, Morell CM, Torsello B, Scirpo R, Fabris L, Spirli C, Strazzabosco M. Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. Journal Of Hepatology 2013, 59: 124-130. PMID: 23500150, PMCID: PMC3777645, DOI: 10.1016/j.jhep.2013.02.025.Peer-Reviewed Original ResearchMeSH Keywords1-NaphthylisothiocyanateAmyloid Precursor Protein SecretasesAnimalsBile Ducts, IntrahepaticCalcium-Binding ProteinsImmunoglobulin J Recombination Signal Sequence-Binding ProteinIntercellular Signaling Peptides and ProteinsJagged-1 ProteinLiver RegenerationMembrane ProteinsMiceMice, Inbred C57BLMice, KnockoutMorphogenesisPyridinesReceptor, Notch2RNA, Small InterferingSerrate-Jagged ProteinsSignal TransductionStem CellsConceptsWild-type miceHepatic progenitor cellsBiliary damageType miceProgenitor cellsDuctular reactionΓ-secretase inhibitor treatmentTubule formationNotch signalingNotch-2 receptorRBP-JkBiliary repairMature ductsLiver-specific defectCKO miceInhibitor treatmentAbstractTextMiceNotch inhibitionNotch-1Jagged-1Notch-2ANITAIMSSOX-9
2012
Notch Signaling in Hepatocellular Carcinoma: Guilty in Association!
Strazzabosco M, Fabris L. Notch Signaling in Hepatocellular Carcinoma: Guilty in Association! Gastroenterology 2012, 143: 1430-1434. PMID: 23099244, PMCID: PMC3583012, DOI: 10.1053/j.gastro.2012.10.025.Peer-Reviewed Original ResearchAltered store operated calcium entry increases cyclic 3′,5′‐adenosine monophosphate production and extracellular signal‐regulated kinases 1 and 2 phosphorylation in polycystin‐2‐defective cholangiocytes
Spirli C, Locatelli L, Fiorotto R, Morell CM, Fabris L, Pozzan T, Strazzabosco M. Altered store operated calcium entry increases cyclic 3′,5′‐adenosine monophosphate production and extracellular signal‐regulated kinases 1 and 2 phosphorylation in polycystin‐2‐defective cholangiocytes. Hepatology 2012, 55: 856-868. PMID: 21987453, PMCID: PMC3272110, DOI: 10.1002/hep.24723.Peer-Reviewed Original ResearchMeSH KeywordsAdenylyl CyclasesAnimalsBile DuctsCalciumCalcium ChannelsCalcium SignalingCells, CulturedCyclic AMPCyclic AMP-Dependent Protein KinasesHomeostasisMembrane GlycoproteinsMiceMice, KnockoutMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Models, AnimalPhosphorylationSignal TransductionStromal Interaction Molecule 1TRPP Cation ChannelsVascular Endothelial Growth Factor AConceptsSensor stromal interaction molecule 1Adenylyl cyclase type 6Extracellular signal-regulated kinases 1Signal-regulated kinases 1Overproduction of cAMPStromal interaction molecule 1Orai channelsWild-type miceSOCE activationCAMP productionRapamycin (mTOR) signalingKinase 1ERK pathwayERK1/2 activationHuman diseasesWT cellsMammalian targetDependent activationSTIM-1CAMP/Inappropriate activationCyst growthCystic cholangiocytesPolycystic liver diseaseActivation
2011
Polycystic Liver Diseases: Congenital Disorders of Cholangiocyte Signaling
Strazzabosco M, Somlo S. Polycystic Liver Diseases: Congenital Disorders of Cholangiocyte Signaling. Gastroenterology 2011, 140: 1855-1859.e1. PMID: 21515270, PMCID: PMC3109236, DOI: 10.1053/j.gastro.2011.04.030.Peer-Reviewed Original ResearchMeSH KeywordsBiliary TractCystsDisease ProgressionEpithelial CellsGenetic Predisposition to DiseaseHumansLiver DiseasesSignal TransductionConceptsPolycystic liver diseaseLiver cyst formationClinical featuresLiver diseaseMultiple cystsDisease progressionBiliary epitheliumLiver parenchymaProgressive enlargementCongenital diseaseCyst formationCholangiocyte physiologyCongenital disorderPotential targetGenetic defectsDiseaseProgressionDisordersInheritance patternSignalingIntracellular organellesDifferent entitiesTherapyKidneyPathway