Featured Publications
Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine
Cotero V, Graf J, Miwa H, Hirschstein Z, Qanud K, Huerta TS, Tai N, Ding Y, Jimenez-Cowell K, Tomaio JN, Song W, Devarajan A, Tsaava T, Madhavan R, Wallace K, Loghin E, Morton C, Fan Y, Kao TJ, Akhtar K, Damaraju M, Barenboim L, Maietta T, Ashe J, Tracey KJ, Coleman TR, Di Carlo D, Shin D, Zanos S, Chavan SS, Herzog RI, Puleo C. Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine. Nature Biomedical Engineering 2022, 6: 683-705. PMID: 35361935, PMCID: PMC10127248, DOI: 10.1038/s41551-022-00870-w.Peer-Reviewed Original ResearchConceptsGlucose homeostasisGlucose toleranceNerve plexusAfferent autonomic nervesHyperinsulinemic euglycaemic clampNon-pharmacologic therapiesType 2 diabetesInsulin-resistant diabetesHepatic portal systemAutonomic nervesNerve pathwaysDiabetic miceFocused ultrasound stimulationPeripheral neuronsSensory projectionsIntestinal tissueMetabolic diseasesMulti-omics profilingPortal systemMetabolic tissuesGlucose availabilityDiabetesSelective activationPlexusUltrasound stimulation
2020
Glutamate–Serine–Glycine Index: A Novel Potential Biomarker in Pediatric Non-Alcoholic Fatty Liver Disease
Leonetti S, Herzog RI, Caprio S, Santoro N, Tricò D. Glutamate–Serine–Glycine Index: A Novel Potential Biomarker in Pediatric Non-Alcoholic Fatty Liver Disease. Children 2020, 7: 270. PMID: 33291552, PMCID: PMC7761842, DOI: 10.3390/children7120270.Peer-Reviewed Original ResearchNon-alcoholic fatty liver diseaseAbdominal fat distributionFatty liver diseaseMagnetic resonance imagingGlycine indexLiver diseaseRisk factorsFat distributionPediatric non-alcoholic fatty liver diseasePotential biomarkersIntrahepatic fat accumulationIntrahepatic fat contentTraditional risk factorsRisk pediatric populationsBody mass indexLiver insulin resistanceTwofold higher prevalencePlasma amino acidsNovel potential biomarkersRace/ethnicityNAFLD prevalenceNAFLD patientsMass indexPediatric populationInsulin resistance
2019
O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth
Singh JP, Qian K, Lee JS, Zhou J, Han X, Zhang B, Ong Q, Ni W, Jiang M, Ruan HB, Li MD, Zhang K, Ding Z, Lee P, Singh K, Wu J, Herzog RI, Kaech S, Wendel HG, Yates JR, Han W, Sherwin RS, Nie Y, Yang X. O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth. Oncogene 2019, 39: 560-573. PMID: 31501520, PMCID: PMC7107572, DOI: 10.1038/s41388-019-0975-3.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAcetylglucosamineAnimalsAntigens, NeoplasmCarrier ProteinsCell Line, TumorDatasets as TopicDisease ProgressionFemaleGene Expression ProfilingGlycolysisHEK293 CellsHistone AcetyltransferasesHumansHyaluronoglucosaminidaseMaleMembrane ProteinsMiceN-AcetylglucosaminyltransferasesNeoplasm GradingNeoplasm StagingNeoplasmsProtein Processing, Post-TranslationalThyroid HormonesTissue Array AnalysisUp-RegulationXenograft Model Antitumor AssaysConceptsPyruvate kinase M2O-GlcNAcaseAerobic glycolysisO-GlcNAcylationKinase M2Lysine acetyltransferase activityTumor growthMetabolic rheostatAcetyltransferase activityGlcNAc transferaseMolecular basisMetabolic shiftHuman cancersGlycolysisCancer cellsHigh glucose conditionsGlucose availabilityTumor progressionGlucose conditionsExquisite controlGrowthRheostatCausative roleTargetEnzymeMitochondrial MsrB2 serves as a switch and transducer for mitophagy
Lee SH, Lee S, Du J, Jain K, Ding M, Kadado AJ, Atteya G, Jaji Z, Tyagi T, Kim W, Herzog RI, Patel A, Ionescu CN, Martin KA, Hwa J. Mitochondrial MsrB2 serves as a switch and transducer for mitophagy. EMBO Molecular Medicine 2019, 11: emmm201910409. PMID: 31282614, PMCID: PMC6685081, DOI: 10.15252/emmm.201910409.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood PlateletsCell LineDiabetes MellitusFemaleHumansMethionine Sulfoxide ReductasesMice, Inbred C57BLMice, KnockoutMicrofilament ProteinsMicrotubule-Associated ProteinsMitochondriaMitochondrial Membrane Transport ProteinsMitochondrial Permeability Transition PoreMitophagyMutationOxidation-ReductionOxidative StressParkinson DiseaseSignal TransductionUbiquitin-Protein LigasesUbiquitinationConceptsReduced mitophagyOxidative stress-induced mitophagyNovel regulatory mechanismStress-induced mitophagyLC3 interactionMitochondrial matrixDamaged mitochondriaMsrB2Reactive oxygen speciesRegulatory mechanismsMethionine oxidationMitophagyMitochondriaPlatelet apoptosisOxygen speciesPlatelet-specific knockoutApoptosisPathophysiological importanceExpressionImportant roleUbiquitinationParkin mutationsParkinSpeciesLC3
2018
Diabetes Exacerbates Myocardial Ischemia/Reperfusion Injury by Down-Regulation of MicroRNA and Up-Regulation of O-GlcNAcylation
Wang D, Hu X, Lee SH, Chen F, Jiang K, Tu Z, Liu Z, Du J, Wang L, Yin C, Liao Y, Shang H, Martin KA, Herzog RI, Young LH, Qian L, Hwa J, Xiang Y. Diabetes Exacerbates Myocardial Ischemia/Reperfusion Injury by Down-Regulation of MicroRNA and Up-Regulation of O-GlcNAcylation. JACC Basic To Translational Science 2018, 3: 350-362. PMID: 30062222, PMCID: PMC6058960, DOI: 10.1016/j.jacbts.2018.01.005.Peer-Reviewed Original ResearchR injuryInfarct sizeMyocardial ischemia/reperfusion injuryIschemia/reperfusion injuryMyocardial ischemia/reperfusionMiR-24Ischemia/reperfusionMyocardial infarct sizePromising therapeutic candidateReperfusion injuryDiabetic heartMyocardial infarctionPoor survivalMouse modelTherapeutic candidateO-GlcNAcylationGenetic overexpressionUp-RegulationInjuryDown regulationMultiple key proteinsKey proteinsHeartReperfusionHyperglycemia
2017
Nanopatterned Bulk Metallic Glass Biosensors
Kinser ER, Padmanabhan J, Yu R, Corona SL, Li J, Vaddiraju S, Legassey A, Loye A, Balestrini J, Solly DA, Schroers J, Taylor A, Papadimitrakopoulos F, Herzog RI, Kyriakides TR. Nanopatterned Bulk Metallic Glass Biosensors. ACS Sensors 2017, 2: 1779-1787. PMID: 29115132, DOI: 10.1021/acssensors.7b00455.Peer-Reviewed Original ResearchConceptsCyclic voltammetrySensitivity of biosensorsGlucose oxidase enzymeGlucose biosensor performanceBiocompatible biosensorSurface area enhancementBiosensor performanceElectrochemical measurementsElectrode sensitivityPt-BMGElectrode applicationsBiosensorOxidase enzymeVoltammetryBiocompatible materialsElectrodeΜA/Flat electrodesPlatinum-based bulk metallic glassArea enhancementControl electrodesBulk metallic glassOrders of magnitudeElectrical propertiesLow temperatureSelective proton‐observed, carbon‐edited (selPOCE) MRS method for measurement of glutamate and glutamine 13C‐labeling in the human frontal cortex
De Feyter H, Herzog RI, Steensma BR, Klomp DWJ, Brown PB, Mason GF, Rothman DL, de Graaf R. Selective proton‐observed, carbon‐edited (selPOCE) MRS method for measurement of glutamate and glutamine 13C‐labeling in the human frontal cortex. Magnetic Resonance In Medicine 2017, 80: 11-20. PMID: 29134686, PMCID: PMC5876108, DOI: 10.1002/mrm.27003.Peer-Reviewed Original ResearchExtracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis
Ryu C, Sun H, Gulati M, Herazo-Maya J, Chen Y, Osafo-Addo A, Brandsdorfer C, Winkler J, Blaul C, Faunce J, Pan H, Woolard T, Tzouvelekis A, Antin-Ozerkis DE, Puchalski JT, Slade M, Gonzalez AL, Bogenhagen DF, Kirillov V, Feghali-Bostwick C, Gibson K, Lindell K, Herzog RI, Dela Cruz CS, Mehal W, Kaminski N, Herzog EL, Trujillo G. Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2017, 196: 1571-1581. PMID: 28783377, PMCID: PMC5754440, DOI: 10.1164/rccm.201612-2480oc.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisNormal human lung fibroblastsExtracellular mitochondrial DNABronchoalveolar lavageIPF fibroblastsPulmonary fibrosisInnate immune ligandsEvent-free survivalSmooth muscle actin expressionMtDNA concentrationsSmooth muscle actin-expressing myofibroblastsGrowth factor-β1Muscle actin expressionHuman lung fibroblastsTGF-β1 stimulationExtracellular mtDNAIPF cohortClinical outcomesControl subjectsDisease progressionGlycolytic reprogrammingSoluble mediatorsTGF-β1Factor-β1Immune ligandsA Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease
Goffredo M, Santoro N, Tricò D, Giannini C, D’Adamo E, Zhao H, Peng G, Yu X, Lam TT, Pierpont B, Caprio S, Herzog RI. A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease. Nutrients 2017, 9: 642. PMID: 28640216, PMCID: PMC5537762, DOI: 10.3390/nu9070642.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseMagnetic resonance imagingBranched-chain amino acidsFatty liver diseaseHepatic fat contentObese adolescentsInsulin resistanceLiver diseaseTwo-step hyperinsulinemic-euglycemic clampOral glucose tolerance testSecond magnetic resonance imagingSubset of patientsGlucose tolerance testHyperinsulinemic-euglycemic clampHigher plasma levelsHepatic insulin sensitivityChain amino acidsPlasma levelsTolerance testInsulin sensitivityMetabolomic signaturePlasma metabolitesResonance imagingValine levelsLipid metabolismElevated α-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents
Tricò D, Prinsen H, Giannini C, de Graaf R, Juchem C, Li F, Caprio S, Santoro N, Herzog RI. Elevated α-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents. The Journal Of Clinical Endocrinology & Metabolism 2017, 102: 2473-2481. PMID: 28482070, PMCID: PMC5505187, DOI: 10.1210/jc.2017-00475.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAmino Acids, Branched-ChainBiomarkersBlood GlucoseChildCross-Sectional StudiesDiabetes Mellitus, Type 2FemaleGlucose Tolerance TestGlycemic IndexHumansHydroxybutyratesInsulin ResistanceLinear ModelsLongitudinal StudiesMaleMultivariate AnalysisObesityPredictive Value of TestsReference ValuesRisk AssessmentConceptsOral glucose tolerance testBranched-chain amino acidsGlycemic controlInsulin resistanceΑ-hydroxybutyrateGlucose toleranceInsulin sensitivityParameters of IRBody mass index z-scoreType 2 diabetes mellitusEarly metabolic featuresChain amino acid levelsTraditional risk factorsPediatric obesity clinicGlucose tolerance testElevated baseline concentrationsIndex z-scoreType 2 diabetesReduced insulin sensitivityDiabetes mellitusObesity clinicNondiabetic adolescentsProgressive worseningDisposition indexGlucose controlβ-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares
Goldberg E, Asher J, Molony R, Shaw A, Zeiss C, Wang C, Morozova-Roche L, Herzog R, Iwasaki A, Dixit V. β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. The Journal Of Immunology 2017, 198: 206.18-206.18. DOI: 10.4049/jimmunol.198.supp.206.18.Peer-Reviewed Original ResearchKetogenic dietGouty flaresNLRP3 inflammasomeSmall clinical trialsCurrent treatment strategiesMajor risk factorNLRP3-dependent ILAnti-inflammatory moleculesIL-1R antagonistAlternate metabolic fuelsGout flaresJoint destructionGout patientsIL-1βIntense painRisk factorsClinical trialsInflammatory neutrophilsTreatment strategiesImmune responseUrate crystalsBacterial infectionsNeutrophilsGoutNLRP3Oxidized Derivatives of Linoleic Acid in Pediatric Metabolic Syndrome: Is Their Pathogenic Role Modulated by the Genetic Background and the Gut Microbiota?
Tricò D, Di Sessa A, Caprio S, Chalasani N, Liu W, Liang T, Graf J, Herzog R, Johnson CD, Umano GR, Feldstein AE, Santoro N. Oxidized Derivatives of Linoleic Acid in Pediatric Metabolic Syndrome: Is Their Pathogenic Role Modulated by the Genetic Background and the Gut Microbiota? Antioxidants & Redox Signaling 2017, 30: 241-250. PMID: 28279074, PMCID: PMC6277079, DOI: 10.1089/ars.2017.7049.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAge FactorsBiomarkersChildDelta-5 Fatty Acid DesaturaseDisease SusceptibilityFatty Acid DesaturasesFemaleGastrointestinal MicrobiomeGenetic BackgroundGenetic Predisposition to DiseaseHaplotypesHumansLinoleic AcidLipid MetabolismLipoproteinsMaleMetabolic SyndromeMetabolomeObesityOxidation-ReductionConceptsProatherogenic lipoprotein profilePediatric metabolic syndromeLipoprotein profileGut microbiotaGut bacterial loadMetabolic syndromeObese adolescentsSmall dense low-density lipoproteinBacterial loadAdverse lipoprotein profileLow-density lipoprotein particlesHigher plasma concentrationsLow-density lipoproteinLinoleic acid metabolitesPlasma 9Haplotype AAPathogenic rolePlasma concentrationsGenetic predispositionAcid metabolitesGenetic backgroundLipoprotein particlesMetSSyndromeMicrobiotaMetabolic brain adaptations to recurrent hypoglycaemia may explain the link between type 1 diabetes mellitus and epilepsy and point towards future study and treatment options
Tricò D, Herzog RI. Metabolic brain adaptations to recurrent hypoglycaemia may explain the link between type 1 diabetes mellitus and epilepsy and point towards future study and treatment options. Diabetologia 2017, 60: 938-939. PMID: 28236055, PMCID: PMC5395303, DOI: 10.1007/s00125-017-4231-5.Peer-Reviewed Original Researchβ-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares
Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova-Roche LA, Herzog RI, Iwasaki A, Dixit VD. β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Reports 2017, 18: 2077-2087. PMID: 28249154, PMCID: PMC5527297, DOI: 10.1016/j.celrep.2017.02.004.Peer-Reviewed Original ResearchConceptsKetogenic dietGouty flaresΒ-hydroxybutyrateMajor risk factorAnti-inflammatory moleculesNLRP3-dependent mannerAlternate metabolic fuelsGout flaresJoint destructionIL-1βIntense painInterleukin-1βNLRP3 inflammasomeRisk factorsInflammatory neutrophilsBacterial infectionsNeutrophilsNLRP3Immune defenseGoutMetabolic fuelsBHBS100A9 fibrilsDietPain
2016
Pigment epithelium‐derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade
Belinsky GS, Sreekumar B, Andrejecsk JW, Saltzman WM, Gong J, Herzog RI, Lin S, Horsley V, Carpenter TO, Chung C. Pigment epithelium‐derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade. The FASEB Journal 2016, 30: 2837-2848. PMID: 27127101, PMCID: PMC4970601, DOI: 10.1096/fj.201500027r.Peer-Reviewed Original ResearchConceptsPigment epithelium-derived factorOsteogenesis imperfecta type VIWnt/β-catenin signalingBone massOI type VIΒ-catenin signalingAbility of PEDFTrabecular bone volume/total volumeType VIBone volume/total volumeWild-type miceEpithelium-derived factorBone plasticityPEDF-knockout miceMesenchymal stem cell commitmentBone volume fractionKO micePEDF peptidesStem cell commitmentFluorescent protein reporterCombination of Wnt3aMouse modelWnt modulatorsBone mineralizationMice
2015
Quantification of 1H NMR spectra from human plasma
de Graaf RA, Prinsen H, Giannini C, Caprio S, Herzog RI. Quantification of 1H NMR spectra from human plasma. Metabolomics 2015, 11: 1702-1707. PMID: 26526515, PMCID: PMC4624446, DOI: 10.1007/s11306-015-0828-1.Peer-Reviewed Original ResearchHyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor
Xiang Y, Cheng J, Wang D, Hu X, Xie Y, Stitham J, Atteya G, Du J, Tang WH, Lee SH, Leslie K, Spollett G, Liu Z, Herzog E, Herzog RI, Lu J, Martin KA, Hwa J. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood 2015, 125: 3377-3387. PMID: 25814526, PMCID: PMC4447857, DOI: 10.1182/blood-2015-01-620278.Peer-Reviewed Original ResearchConceptsVon Willebrand factorDiabetes mellitusMiR-24Diabetic patientsAdverse thrombotic eventsThrombotic cardiovascular eventsVWF expressionWillebrand factorDiabetic mouse modelNovel therapeutic targetHistamine H1 receptorsEndothelial cell expressionHyperglycemia-induced activationCardiovascular eventsThrombotic eventsH1 receptorsMouse modelVWF levelsTherapeutic targetCell expressionMellitusPatientsEndothelial cellsElevated levelsReactive oxygen species
2013
Vaccination with Single Chain Antigen Receptors for Islet-Derived Peptides Presented on I-Ag7 Delays Diabetes in NOD Mice by Inducing Anergy in Self-Reactive T-Cells
Gurr W, Shaw M, Herzog RI, Li Y, Sherwin R. Vaccination with Single Chain Antigen Receptors for Islet-Derived Peptides Presented on I-Ag7 Delays Diabetes in NOD Mice by Inducing Anergy in Self-Reactive T-Cells. PLOS ONE 2013, 8: e69464. PMID: 23894487, PMCID: PMC3722102, DOI: 10.1371/journal.pone.0069464.Peer-Reviewed Original ResearchConceptsSelf-reactive T cellsSingle chain receptorT cellsNOD miceB cellsReceptor repertoireSelf-reactive T cell clonesT cell receptor repertoireAnti-idiotypic vaccinationNormal NOD micePancreatic lymph nodesOnset of T1D.NOD-scid recipientsB cell receptor repertoireType 1 diabetesT cell clonesBDC2.5 TCRNOD recipientsProfound anergyLymph nodesSpecific autoantigensInducer cellsVaccination approachesMHC IVaccinationLactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia
Herzog RI, Jiang L, Herman P, Zhao C, Sanganahalli BG, Mason GF, Hyder F, Rothman DL, Sherwin RS, Behar KL. Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. Journal Of Clinical Investigation 2013, 123: 1988-1998. PMID: 23543056, PMCID: PMC3638906, DOI: 10.1172/jci65105.Peer-Reviewed Original ResearchConceptsAntecedent recurrent hypoglycemiaRecurrent hypoglycemiaHypoglycemic conditionsIntensive insulin therapyTight glycemic controlType 2 diabetesInsulin therapyGlycemic controlBrain metabolismElevated lactateNeuronal metabolismRodent modelsNeuronal activityGlucose metabolismHypoglycemiaLactate uptakeNeuronal functionType 1Metabolic regulatorOxidative capacityModest incrementLactateMetabolismUnexpected findingBrain
2012
Can tight glycemic control in diabetes benefit cognition?
Herzog RI, Sherwin RS. Can tight glycemic control in diabetes benefit cognition? Nature Reviews Neurology 2012, 8: 124-126. PMID: 22290574, PMCID: PMC5515668, DOI: 10.1038/nrneurol.2012.10.Peer-Reviewed Original Research