2025
Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice
Gaspar R, Macêdo A, Nakandakari S, Muñoz V, Abud G, Vieira R, de Sousa Neto I, Pavan I, da Silva L, Simabuco F, da Silva A, Salgado W, Marchini J, Nonino C, Cintra D, Ropelle E, Pajvani U, de Freitas E, Pauli J. Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice. Liver International 2025, 45: e70068. PMID: 40078075, DOI: 10.1111/liv.70068.Peer-Reviewed Original ResearchConceptsNotch1 signalingAerobic exerciseRegulation of hepatic glucoseObese miceImpact of aerobic exerciseEffects of Notch1 signalingAerobic exercise trainingMTORC1 pathway activationNotch1 pathwayObese individualsTissue of obese miceCross-sectional studyNotch1 mRNA levelsMitochondrial respirationExercise trainingLivers of obese individualsTreadmill runningGluconeogenic enzymesHepG2 cell lineLipid accumulationTraining groupHepatic glucoseHepatic metabolismNotch1 proteinPathway activation
2024
Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease
Srivastava S, Zhou H, Shenoi R, Morris M, Lainez-Mas B, Goedeke L, Rajendran B, Setia O, Aryal B, Kanasaki K, Koya D, Inoki K, Dardik A, Bell T, Fernández-Hernando C, Shulman G, Goodwin J. Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease. Science Advances 2024, 10: eadn6068. PMID: 39630889, PMCID: PMC11616692, DOI: 10.1126/sciadv.adn6068.Peer-Reviewed Original ResearchConceptsAngiopoietin-like 4Diabetic kidney diseaseIntegrin B1Fibrogenic moleculesMutant miceSTING pathway activationIncreased fatty acid oxidationProgressive diabetic kidney diseaseDiabetic kidneyKidney diseaseReduced epithelial-to-mesenchymal transitionEpithelial-to-mesenchymal transitionFatty acid oxidationExpression of pro-inflammatory cytokinesTargeted pharmacological therapiesGene expressionMitochondrial damageEndothelial-to-mesenchymal transitionPro-inflammatory cytokinesPathway activationPharmacological therapyControl miceIntegrinAcid oxidationFibrogenic phenotypeUsing Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia
Jones L, Rukhlenko O, Dias T, Carmody C, Wynne K, Kholodenko B, Bond J. Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia. Blood 2024, 144: 4161-4161. DOI: 10.1182/blood-2024-207308.Peer-Reviewed Original ResearchAcute myeloid leukemiaPatient-derived xenograftsCombination-treated miceInhibitor combinationsPeripheral bloodPhosphorylated ERKBone marrowRAS pathway activationSpleen weightMyeloid leukemiaAML patient-derived xenograftDrug combinationsVehicle controlSingle agentHuman CD45+ cellsPre-clinical mouse modelPediatric acute myeloid leukemiaAssociated with poor outcomesHigh-risk patient groupsMedian spleen weightSB-treated micePreclinical in vivo modelsCD45+ cellsLateral tail veinPathway activationThe pathogenesis of IgA nephropathy and implications for treatment
Cheung C, Alexander S, Reich H, Selvaskandan H, Zhang H, Barratt J. The pathogenesis of IgA nephropathy and implications for treatment. Nature Reviews Nephrology 2024, 21: 9-23. PMID: 39232245, PMCID: PMC7616674, DOI: 10.1038/s41581-024-00885-3.Peer-Reviewed Original ResearchIgA nephropathyComplement activationDisease pathogenesisB cell primingMucosal immune systemPathogenesis of IgA nephropathyChronic kidney diseaseTargeting different pathwaysPlasma cellsPrimary glomerulonephritisTreatment optionsIgA antibodiesKidney diseaseImmune complexesTriggering inflammationKidney damageGut mucosaObservational studyKidney failureImmune systemLong-term outlookPathway activationPathogenesisIgANNephropathymiR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression
Fernández-Tussy P, Cardelo M, Zhang H, Sun J, Price N, Boutagy N, Goedeke L, Cadena-Sandoval M, Xirouchaki C, Brown W, Yang X, Pastor-Rojo O, Haeusler R, Bennett A, Tiganis T, Suárez Y, Fernández-Hernando C. miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression. JCI Insight 2024, 9: e168476. PMID: 39190492, PMCID: PMC11466198, DOI: 10.1172/jci.insight.168476.Peer-Reviewed Original ResearchMiR-33Regulation of biological processesMitochondrial fatty acid oxidationRegulation of lipid metabolismNon-alcoholic fatty liver diseaseDevelopment of effective therapeuticsFatty acid oxidationLipid synthesisProgression of non-alcoholic fatty liver diseaseMitochondrial functionTarget genesBiological processesComplex diseasesNon-alcoholic steatohepatitisLipid accumulationDeletionDevelopment of non-alcoholic fatty liver diseasePathway activationLipid metabolismProgress to non-alcoholic steatohepatitisAcid oxidationHCC progressionEffective therapeuticsTherapeutic targetHepatocellular carcinomaSystems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation
Trogdon M, Abbott K, Arang N, Lande K, Kaur N, Tong M, Bakhoum M, Gutkind J, Stites E. Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation. Npj Systems Biology And Applications 2024, 10: 75. PMID: 39013872, PMCID: PMC11252164, DOI: 10.1038/s41540-024-00400-1.Peer-Reviewed Original ResearchConceptsSignaling networksMathematical models of biochemical reaction networksModels of biochemical reaction networksG-proteinCell signaling networksDisease-causing mutationsComputational systems biologyBiochemical reaction networksDownstream pathway activationSignaling phenotypeSystems biologyBioinformatics analysisGPCR signalingMutationsCo-occurring mutationsOncogenic mutationsPathway activationDiscovery toolPathwayReaction networkSignalCYSLTR2 mutationsDiscoveryPhenotypeMutually-exclusiveEnterococcus faecalis-derived adenine enhances enterohaemorrhagic Escherichia coli Type 3 Secretion System-dependent virulence
Martins F, Rosay T, Rajan A, Carter H, Turocy T, Mejia A, Crawford J, Maresso A, Sperandio V. Enterococcus faecalis-derived adenine enhances enterohaemorrhagic Escherichia coli Type 3 Secretion System-dependent virulence. Nature Microbiology 2024, 9: 2448-2461. PMID: 38965331, PMCID: PMC11585081, DOI: 10.1038/s41564-024-01747-1.Peer-Reviewed Original ResearchMeSH KeywordsAdenineAnimalsCoculture TechniquesEnterococcus faecalisEnterocytesEnterohemorrhagic Escherichia coliEscherichia coli InfectionsEscherichia coli ProteinsGastrointestinal MicrobiomeGene Expression Regulation, BacterialHemolysin ProteinsHost-Pathogen InteractionsHumansHypoxanthineMiceType III Secretion SystemsVirulenceVirulence FactorsXanthineConceptsT3SS gene expressionType 3 secretion systemGene expressionAE lesion formationPromote colonization resistanceE. faecalisAdenine biosynthesisEHEC virulenceEffector translocationBacterial geneticsColonization resistanceEnteric pathogensT3SSLesion formationEHECSupplementation experimentsVirulencePathway activationAdenineEnhanced pathogenesisHost responseCo-infectionExpressionCo-cultureTranscriptomeLung Transcriptomics Links Emphysema to Barrier Dysfunction and Macrophage Subpopulations.
Lu R, Gregory A, Suryadevara R, Xu Z, Jain D, Morrow J, Hobbs B, Yun J, Lichtblau N, Chase R, Curtis J, Sauler M, Bartholmai B, Silverman E, Hersh C, Castaldi P, Boueiz A. Lung Transcriptomics Links Emphysema to Barrier Dysfunction and Macrophage Subpopulations. American Journal Of Respiratory And Critical Care Medicine 2024, 211: 75-90. PMID: 38935868, PMCID: PMC11755365, DOI: 10.1164/rccm.202305-0793oc.Peer-Reviewed Original ResearchRNA sequencing dataAlternative splicingExpressed genesFunctional pathwaysCell typesBiological pathwaysGene expressionTranscriptomic featuresGene regulatory processesDysregulated pathwaysSingle-cell RNA sequencing dataRNA-seq analysisLung cell typesLung Tissue Research ConsortiumTranscriptome analysisGenesCell-typeDifferential expressionMultiple lung cell typesPathway activationTranscriptomic signaturesPathway dysregulationRegulatory processesSplicingPathwayNetwork-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis
Rosenberger G, Li W, Turunen M, He J, Subramaniam P, Pampou S, Griffin A, Karan C, Kerwin P, Murray D, Honig B, Liu Y, Califano A. Network-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis. Nature Communications 2024, 15: 3909. PMID: 38724493, PMCID: PMC11082183, DOI: 10.1038/s41467-024-47957-3.Peer-Reviewed Original ResearchConceptsMechanism of cell responseResistance mechanismsSignaling pathway responsesDrug resistance mechanismsEnzyme/substrate interactionsAdaptive resistance mechanismsNetwork rewiringPhosphorylation stateSignaling pathway activationDrug perturbationsProteomic technologiesSignaling crosstalkPathway responsesInhibitor designPathway activationCancer drug resistance mechanismsCell adaptive responsesAdaptive responsePhosphatase activityNetwork-based methodologyRewiringTherapeutic efficacyPhosphoproteome coverageCell responsesControl medium
2023
HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway by regulating MSK1 and PPP2R2B
Malvi P, Chava S, Cai G, Hu K, Zhu L, Edwards Y, Green M, Gupta R, Wajapeyee N. HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway by regulating MSK1 and PPP2R2B. Cell Reports Medicine 2023, 4: 101285. PMID: 37951219, PMCID: PMC10694669, DOI: 10.1016/j.xcrm.2023.101285.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaHomeobox C6PDAC growthInsulin-like growth factor 1 receptorGrowth factor 1 receptorKinase MSK1Factor 1 receptorTranscription factorsPancreatic cancer growthMSK1Tumor growthPDAC tumor growthMost pancreatic ductal adenocarcinomasMammalian targetIGF1R inhibitorsTherapeutic vulnerabilitiesRapamycin (mTOR) pathway activationMEK inhibitor trametinibMetastasis pathwaysPDAC mouse modelPDAC cellsMTOR inhibitionPharmacological inhibitionPathway activationInhibition blocksIncreased anti‐oxidative action compensates for collagen tissue degeneration in vitiligo dermis
Yokoi K, Yasumizu Y, Ohkura N, Shinzawa K, Okuzaki D, Shimoda N, Ando H, Yamada N, Fujimoto M, Tanemura A. Increased anti‐oxidative action compensates for collagen tissue degeneration in vitiligo dermis. Pigment Cell & Melanoma Research 2023, 36: 355-364. PMID: 37230937, DOI: 10.1111/pcmr.13094.Peer-Reviewed Original ResearchConceptsCollagen-related genesUninvolved perilesional skinOxidative stressSignaling pathway activationCollagen homeostasisVitiligo lesionsPathway activationPerilesional skinExpression levelsAnti-oxidant enzymesAnti-oxidative actionDegraded collagen fibersNrf2 signaling pathway activationDefense systemProduction of oxidative stress
2022
Nicotine dose-dependent epigenomic-wide DNA methylation changes in the mice with long-term electronic cigarette exposure.
Peng G, Xi Y, Bellini C, Pham K, Zhuang ZW, Yan Q, Jia M, Wang G, Lu L, Tang MS, Zhao H, Wang H. Nicotine dose-dependent epigenomic-wide DNA methylation changes in the mice with long-term electronic cigarette exposure. American Journal Of Cancer Research 2022, 12: 3679-3692. PMID: 36119846, PMCID: PMC9442002.Peer-Reviewed Original ResearchElectronic cigarette exposureCigarette exposureMale ApoE-/- miceApoE-/- miceCytokine mRNA expressionPoor health outcomesWhite blood cellsElectronic cigarette useDose-dependent mannerE-cigarette aerosolAerosol inhalationCigarette smokingActivation of MAPKHigher nicotine concentrationsMAPK pathway activationCell-damaging effectsCpG sitesHealth outcomesCigarette useMRNA expressionNicotine concentrationsPathway activationSignificant CpG sitesBlood cellsSignificant alterationsPseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis
Brereton CJ, Yao L, Davies ER, Zhou Y, Vukmirovic M, Bell JA, Wang S, Ridley RA, Dean L, Andriotis OG, Conforti F, Brewitz L, Mohammed S, Wallis T, Tavassoli A, Ewing RM, Alzetani A, Marshall BG, Fletcher SV, Thurner PJ, Fabre A, Kaminski N, Richeldi L, Bhaskar A, Schofield CJ, Loxham M, Davies DE, Wang Y, Jones MG. Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis. ELife 2022, 11: e69348. PMID: 35188460, PMCID: PMC8860444, DOI: 10.7554/elife.69348.Peer-Reviewed Original ResearchConceptsHIF pathway activationPathway activationLung fibrosisOxidative stressHuman lung fibrosisOxidative stress scoreFibrillar collagen synthesisHypoxia-inducible factor (HIF) pathway activationExtracellular matrixActive fibrogenesisFibrosisHuman fibrosisFibrosis tissueHIF activationStress scoresVivo studiesCollagen synthesisMesenchymal cellsCritical pathwaysDownstream activationNormal fibroblastsCritical regulatorHIFActivationHuman tissuesSex- and estrous-cycle dependent dorsal hippocampal phosphoproteomic changes induced by low-dose ketamine
Saland SK, Wilczak K, Voss E, Lam TT, Kabbaj M. Sex- and estrous-cycle dependent dorsal hippocampal phosphoproteomic changes induced by low-dose ketamine. Scientific Reports 2022, 12: 1820. PMID: 35110693, PMCID: PMC8810966, DOI: 10.1038/s41598-022-05937-x.Peer-Reviewed Original ResearchConceptsLow-dose ketamineFemale ratsMale ratsTherapeutic effectIntact adult male ratsNMDA receptor antagonist ketamineAcute low doseKetamine's therapeutic effectsRapid antidepressant actionsAdult male ratsKetamine-induced changesRapid actionAntidepressant actionAntidepressant ketamineHormonal milieuHormone-dependent modulationHormonal statusLow doseKetamineBrain regionsRatsSynaptic signalingPathway activationBi-directional effectsCritical modulator
2021
Management of hemolytic transfusion reactions
Hendrickson JE, Fasano RM. Management of hemolytic transfusion reactions. Hematology 2021, 2021: 704-709. PMID: 34889404, PMCID: PMC8791106, DOI: 10.1182/hematology.2021000308.Peer-Reviewed Original ResearchConceptsHemolytic transfusion reactionsRBC alloantibodiesSevere DHTRTransfusion reactionsRed blood cell transfusionDisease-specific risk factorsPathway activationMultiple RBC alloantibodiesBlood cell transfusionSymptoms of painStem cell transplantationSafety of transfusionSickle cell diseaseClassic pathway activationAlternative pathway activationTransfusion avoidanceCell transfusionCurative therapyCell transplantationPatient's hemoglobinRisk factorsTransfusion safetyCell diseaseDHTRHgb AComparison of open and a novel closed vitrification system with slow freezing for human ovarian tissue cryopreservation
Sugishita Y, Taylan E, Kawahara T, Shahmurzada B, Suzuki N, Oktay K. Comparison of open and a novel closed vitrification system with slow freezing for human ovarian tissue cryopreservation. Journal Of Assisted Reproduction And Genetics 2021, 38: 2723-2733. PMID: 34398400, PMCID: PMC8581089, DOI: 10.1007/s10815-021-02297-9.Peer-Reviewed Original ResearchConceptsFollicle survivalCortical piecesPrimary folliclesHuman ovarian tissue cryopreservationOvarian tissue cryopreservationCell death pathway activationOvarian cortical piecesPrimordial follicle survivalPrimordial follicle densityHuman ovarian tissueClosed vitrification systemTissue cryopreservationDNA damageOvarian tissueHistological analysisPathway activationApoptosis rateDevice groupSlow freezingEmerging agents and regimens for polycythemia vera and essential thrombocythemia
Shallis RM, Podoltsev NA. Emerging agents and regimens for polycythemia vera and essential thrombocythemia. Biomarker Research 2021, 9: 40. PMID: 34049597, PMCID: PMC8161993, DOI: 10.1186/s40364-021-00298-5.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsPolycythemia veraEssential thrombocythemiaPV/ETDisease progression controlEarly efficacy signalsThrombotic risk reductionOutcomes of patientsPhase 1/2 trialNew JAK inhibitorsRed blood cell precursorsJAK-STAT pathway activationBlood cell precursorsHepcidin mimeticsTherapeutic phlebotomyDisease courseSymptom burdenEfficacy signalsHematologic parametersNovel agentsNew agentsJAK inhibitorsET pathogenesisProgression controlPatientsPathway activationMicroenvironment controls inflammatory response in macrophages
Zhou X, Pope S, Medzhitov R. Microenvironment controls inflammatory response in macrophages. The Journal Of Immunology 2021, 206: 111.03-111.03. DOI: 10.4049/jimmunol.206.supp.111.03.Peer-Reviewed Original ResearchInflammatory gene expressionInflammatory responseInflammatory response to lipopolysaccharideGene expressionModulate immune functionResponse to lipopolysaccharideControlling inflammatory gene expressionControlling inflammatory responsesTissue environmentPH-sensing receptorImmune cellsInflammatory conditionsInflammatory programGene-specific mannerTissue dysfunctionImmune functionNF-kBTissue microenvironmentPathway activationNarrow homeostatic rangeChromatin landscapeGene classesTissue homeostasisTranscriptional circuitsChromatin remodelingRole of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates
Brady MV, Vaccarino FM. Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates. Cells 2021, 10: 914. PMID: 33923415, PMCID: PMC8073580, DOI: 10.3390/cells10040914.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsSonic hedgehogHuman neurodevelopmentHuman pluripotent cellsDiverse cellular compositionRole of SHHMaster regulatorPluripotent cellsCellular phenotypesVentral identityNeural organoidsExpression gradientsOrganoid systemsDisease modelingVitro systemPathway activationModel systemCellular compositionOrganoidsHuman developmentQuestions scientistsHedgehogBiologyPPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK
Cho E, Lou HJ, Kuruvilla L, Calderwood DA, Turk BE. PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK. Cell Reports 2021, 34: 108928. PMID: 33789117, PMCID: PMC8068315, DOI: 10.1016/j.celrep.2021.108928.Peer-Reviewed Original ResearchConceptsProtein kinase cascadeCore oncogenic pathwaysKey negative regulatorOncogenic ERKERK pathway activationCrosstalk regulationCentral kinaseKinase cascadePhosphorylation sitesRegulatory subunitRaf-MEKNegative regulatorERK pathwayDrug targetsOncogenic pathwaysMEKMEK inhibitorsDephosphorylationPathway activationPPP6CPhosphatasePathwayERKHyperphosphorylationCascade
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