2025
Intratumoral IL12 mRNA administration activates innate and adaptive pathways in checkpoint inhibitor-resistant tumors resulting in complete responses
Lakshmipathi J, Santha S, Li M, Qian Y, Roy S, Luheshi N, Politi K, Bosenberg M, Eyles J, Muthusamy V. Intratumoral IL12 mRNA administration activates innate and adaptive pathways in checkpoint inhibitor-resistant tumors resulting in complete responses. Cancer Immunology, Immunotherapy 2025, 74: 250. PMID: 40560386, PMCID: PMC12198101, DOI: 10.1007/s00262-025-04105-0.Peer-Reviewed Original ResearchConceptsAnti-tumor immune responseTumor-associated macrophagesCytotoxic T cellsImmune responseActivity of checkpoint inhibitorsAnti-PD-L1 antibodyPhagocytosis of tumor cellsAnti-PD-L1Enhanced anti-tumorAntigen presentation machineryCell-based immune responsesMurine tumor modelsTh1-type cytokinesColorectal carcinoma tumorsICI resistanceMurine IL12Checkpoint inhibitorsPresentation machineryIntratumoral deliveryResistant tumorsAdvanced diseaseCarcinoma tumorsTumor microenvironmentMurine tumorsT cellsVisceral pain-related acute actions of cerulein on mouse and human sensory neurons.
Goyal S, Zurek N, Ehsanian R, Goyal S, Jones D, Shilling M, Desir G, Gorelick F, Westlund K, Alles S. Visceral pain-related acute actions of cerulein on mouse and human sensory neurons. Molecular Pain 2025, 21: 17448069251353346. PMID: 40524328, DOI: 10.1177/17448069251353346.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCeruletideFemaleGanglia, SpinalHumansHyperalgesiaMaleMiceMice, Inbred C57BLSensory Receptor CellsVisceral PainConceptsDorsal root gangliaDRG neuronsPain behaviorCCK-AAcute pancreatitisHuman DRGWhole-cell patch-clamp electrophysiologyIncreased excitabilityHuman dorsal root gangliaDorsal root ganglia neuronsHuman sensory neuronsThoracic DRG neuronsVon Frey testAssess pain behaviorCCK-A receptorsInduce acute pancreatitisPatch-clamp electrophysiologyCCK-B receptorsPre-clinical studiesResponse to ceruleinComplaints of patientsAntagonist of cholecystokininMechanical hypersensitivityPancreatic painCholecystokinin systemsEndothelial CLEC5A drives barrier dysfunction and vascular leakage responsible for lung injury in bacterial pneumonia and sepsis
Zhang T, Huang X, Goodwin J, Wen R, Liu Y, Yang Y, Zhang T, Zheng Y, Chen A, Hao P, Tong X, Yang N, Liu C. Endothelial CLEC5A drives barrier dysfunction and vascular leakage responsible for lung injury in bacterial pneumonia and sepsis. Science Advances 2025, 11: eadt7589. PMID: 40498836, PMCID: PMC12154197, DOI: 10.1126/sciadv.adt7589.Peer-Reviewed Original ResearchConceptsVascular leakagePuncture (CLP)-induced polymicrobial sepsisRegulating endothelial barrier functionCLP-challenged miceEndothelial barrier dysfunctionTrans-endothelial electrical resistanceEndothelial barrier functionLipopolysaccharide (LPS)-induced endotoxemiaVascular endothelial cellsPattern recognition receptorsSurvival benefitMultiorgan failurePolymicrobial sepsisTrans-endothelial migrationCecal ligationBacterial pneumoniaLung injuryBarrier dysfunctionVascular injurySingle-cell RNA sequencingDecreased mortalityInflammatory stormBacterial infectionsHeterogeneity of vascular endothelial cellsSepsisNeuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer
Delanne-Cuménal M, Defaye M, Delanne-Cuménal A, Ahmed M, Ho V, Abdullah N, Alhassoun M, Svendsen K, Mager L, Schlessinger J, Hirota S, Altier C. Neuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2500632122. PMID: 40493183, PMCID: PMC12184428, DOI: 10.1073/pnas.2500632122.Peer-Reviewed Original ResearchConceptsColitis-associated colorectal cancerAnaplastic lymphoma kinaseColorectal cancerAnaplastic lymphoma kinase activityColitis-associated colorectal cancer progressionAnaplastic lymphoma kinase receptorTRPV1+ nociceptorsDevelopment of colitis-associated colorectal cancerMouse colonic organoidsALK signalingInflammatory painTumor burdenTreatment resistanceSensory neuronsTumor growthColonic organoidsALKAL2Colonic mucosaOverall inflammationCancer progressionCancerIn vivoTRPV1NeuronsInflammationLKB1 regulates ILC3 postnatal development and effector function through metabolic programming
Zhang H, Zhao L, Zhang Q, Hu L, Su X, Sun J, Shen L. LKB1 regulates ILC3 postnatal development and effector function through metabolic programming. Frontiers In Immunology 2025, 16: 1587256. PMID: 40539052, PMCID: PMC12176730, DOI: 10.3389/fimmu.2025.1587256.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsCitrobacter rodentiumEnterobacteriaceae InfectionsImmunity, InnateInterleukin-22InterleukinsIntestinal MucosaIntestinesLymphocytesMetabolic ReprogrammingMiceMice, Inbred C57BLMice, KnockoutProtein Serine-Threonine KinasesConceptsLiver kinase B1Intestinal immune homeostasisEffector functionsPostnatal developmentImmune homeostasisFlow cytometryGroup 3 innate lymphoid cellsMetabolic regulationIntestinal immunityLKB1 deficiencyIL-22 productionLKB1-deficient miceConditional knockout miceIntestinal inflammatory responsePotential therapeutic implicationsImpaired cell metabolismILC3 numbersIntestinal ILC3sLymphoid cellsILC3 functionCytokine productionILC3sKnockout miceMitochondrial massILC3 activationCysteine depletion triggers adipose tissue thermogenesis and weight loss
Lee A, Orliaguet L, Youm Y, Maeda R, Dlugos T, Lei Y, Coman D, Shchukina I, Andhey P, Smith S, Ravussin E, Stadler K, Chen B, Artyomov M, Hyder F, Horvath T, Schneeberger M, Sugiura Y, Dixit V. Cysteine depletion triggers adipose tissue thermogenesis and weight loss. Nature Metabolism 2025, 7: 1204-1222. PMID: 40461845, PMCID: PMC12198010, DOI: 10.1038/s42255-025-01297-8.Peer-Reviewed Original ResearchConceptsWeight lossWhite adipose tissueAdipose browningCaloric restrictionAdipose tissueDietary amino acidsCysteine depletionSulphur amino acids cysteineIncreased energy expenditureAdipose tissue thermogenesisIncreased fat utilizationMetabolic inflammationNoradrenaline signalingOrganismal metabolismAdipose thermogenesisObese miceBrowning of adipocytesIncreased heat productionBrownRemoval of cysteineCore body temperatureAmino acidsEnergy expenditureAmino acid cysteineFat utilizationTargeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease
Yang Y, Duan Y, Lang S, Fondevila M, Schöler D, Harberts A, Cabré N, Chen S, Shao Y, Vervier K, Miyamoto Y, Zhang X, Chu H, Yang L, Tan C, Eckmann L, Bosques-Padilla F, Verna E, Abraldes J, Brown R, Vargas V, Altamirano J, Caballería J, Shawcross D, Louvet A, Lucey M, Mathurin P, Garcia-Tsao G, Bataller R, Stärkel P, Lawley T, Schnabl B. Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease. Cell Host & Microbe 2025, 33: 957-972.e6. PMID: 40441146, PMCID: PMC12162233, DOI: 10.1016/j.chom.2025.05.003.Peer-Reviewed Original ResearchConceptsEthanol-induced liver diseaseAlcohol-associated liver diseaseAlcohol-associated hepatitisLiver diseaseGenome of Escherichia coliE. coliMetagenomic sequencing of fecal samplesInternational cohort of patientsGenetic manipulation of bacteriaGnotobiotic mouse modelOutcomes of patientsManipulation of bacteriaCohort of patientsScavenger receptor MARCOGlobal health burdenVirulence factorsMetagenomic sequencingGut microbiotaGenetic manipulationDisease progressionMouse modelKupffer cellsKpsMBacterial spreadInternational cohortIL‐6 signaling regulates the inflammatory response without impacting pathogen burden during influenza‐associated pulmonary aspergillosis
Sharma L, Singh R, Tolman N, Ngeow C, Duray A, Naghshtabrizi N, Ahmad A, Bain W, Robinson K. IL‐6 signaling regulates the inflammatory response without impacting pathogen burden during influenza‐associated pulmonary aspergillosis. Physiological Reports 2025, 13: e70372. PMID: 40420617, PMCID: PMC12106949, DOI: 10.14814/phy2.70372.Peer-Reviewed Original ResearchConceptsAF infectionAspergillus fumigatusInterleukin-6IL-6 signalingLung inflammationInfluenza-associated pulmonary aspergillosisInterleukin-6 knockout miceNeutrophilic lung inflammationBronchoalveolar lavage fluidEpithelial cell damageLung capillary permeabilitySusceptibility to opportunistic pathogensPulmonary aspergillosisClinical courseLavage fluidKnockout miceOpportunistic pathogenRAGE levelsEpithelial integrityMouse modelIL-6Pathological inflammationTissue injuryInflammatory responseViral infectionGly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice
Hasan M, Wang H, Luo W, Du Y, Li T. Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice. AJP Gastrointestinal And Liver Physiology 2025, 329: g45-g57. PMID: 40418643, PMCID: PMC12178242, DOI: 10.1152/ajpgi.00044.2025.Peer-Reviewed Original ResearchConceptsKO miceBile acid compositionBile acid pool sizeBile acid poolBile acid hydrophobicityHepatic bile acidsHepatobiliary toxicityBile acid metabolismMale miceTherapeutic benefitCholestasis modelMdr2-KO miceDecreased liver injuryBile acidsSerum alkaline phosphataseBile acid absorptionAlkaline phosphataseFecal bile acid excretionAcid compositionDiminished therapeutic efficacyImpaired bile flowAcid metabolismHepatobiliary injuryUnique pharmacokineticsBiliary injuryActin organizes chromosomes and microtubules to ensure mitotic fidelity in the preimplantation embryo
Hernandez B, Tetlak P, Domingo-Muelas A, Akizawa H, Skory R, Ardestani G, Biro M, Liu X, Bissiere S, Sakkas D, Plachta N. Actin organizes chromosomes and microtubules to ensure mitotic fidelity in the preimplantation embryo. Science 2025, 388: eads1234. PMID: 40403077, DOI: 10.1126/science.ads1234.Peer-Reviewed Original ResearchConceptsMitotic fidelityError-free chromosome segregationBranched actin filamentsPreimplantation embryosNuclear envelope breakdownRounds of cell divisionNuclear actinFilament disassemblyActin cablesActin filamentsChromosome segregationNuclear peripherySpindle elongationMammalian developmentCell divisionProphase chromosomesSpindle assembly mechanismsEnvelope breakdownAssembly mechanismsGenetic materialActinChromosomeMammalian embryosMouse embryosHuman embryosSecretory leukocyte protease inhibitor influences periarticular joint inflammation in Borrelia burgdorferi-infected mice
Yu Q, Tang X, Hart T, Homer R, Belperron A, Bockenstedt L, Ring A, Nakamura A, Fikrig E. Secretory leukocyte protease inhibitor influences periarticular joint inflammation in Borrelia burgdorferi-infected mice. ELife 2025, 14: rp104913. PMID: 40392222, PMCID: PMC12092001, DOI: 10.7554/elife.104913.Peer-Reviewed Original ResearchConceptsSecretory leukocyte protease inhibitorJoint inflammationC57BL/6 miceHigher infection loadTick-borne infectionsWild-type control miceClinical manifestations of infectionDevelopment of Lyme arthritisElevated serum levelsExcessive pro-inflammatory responsesManifestations of infectionProtease inhibitorsPro-inflammatory responseAnkle joint tissueInfection loadPromote tissue repairAnti-inflammatory effectsSerum levelsPeriarticular swellingClinical manifestationsControl miceTibiotarsal jointMMP-8Lyme diseaseIL-6Mineralocorticoid receptor phase separation modulates cardiac preservation
Lei I, Sicim H, Gao W, Huang W, Noly P, Pergande M, Wilson M, Lee A, Liu L, Abou El Ela A, Jiang M, Saddoughi S, Pober J, Platt J, Cascalho M, Pagani F, Chen Y, Pitt B, Wang Z, Mortensen R, Ge Y, Tang P. Mineralocorticoid receptor phase separation modulates cardiac preservation. Nature Cardiovascular Research 2025, 4: 710-726. PMID: 40389663, DOI: 10.1038/s44161-025-00653-x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Cycle ProteinsCold IschemiaHeart TransplantationHistone Deacetylase 1HumansKidneyLiverLungMaleMiceMice, Inbred C57BLMineralocorticoid Receptor AntagonistsMyocytes, CardiacNuclear ProteinsOrgan PreservationPhase SeparationReceptors, MineralocorticoidTissue DonorsTranscription FactorsConceptsMineralocorticoid receptorDonor heartsHistone deacetylase 1Bromodomain-containing 4Gold standard treatmentEnd-stage heart failureCold ischemic timeShortage of donor heartsExpressed MRDonor cardiomyocytesHuman donor heartsHeart transplantationStandard treatmentIschemic timeHeart failureCardiac preservationSolid organsPharmacological inhibitionCold preservationPreserving biologyHeartGDF8 and activin A blockade protects against GLP-1–induced muscle loss while enhancing fat loss in obese male mice and non-human primates
Mastaitis J, Gomez D, Raya J, Li D, Min S, Stec M, Kleiner S, McWilliams T, Altarejos J, Murphy A, Yancopoulos G, Sleeman M. GDF8 and activin A blockade protects against GLP-1–induced muscle loss while enhancing fat loss in obese male mice and non-human primates. Nature Communications 2025, 16: 4377. PMID: 40360507, PMCID: PMC12075787, DOI: 10.1038/s41467-025-59485-9.Peer-Reviewed Original ResearchConceptsGlucagon-like peptide-1 receptor agonistsPeptide-1 receptor agonistsReceptor agonistsA blockadeGlucagon-like peptide-1 receptor agonist treatmentMuscle lossMuscle massFat lossObese male miceNon-human primatesType II activin receptorTreatment of obesityQuality of weight lossSignificant muscle lossIncrease muscle massEnhanced fat lossAgonist treatmentMale miceMuscle preservationAppetite suppressionActivin AActivin receptorsObese miceCaloric restrictionWeight lossSex Differences in Histamine Regulation of Striatal Dopamine
Van Zandt M, Pittenger C. Sex Differences in Histamine Regulation of Striatal Dopamine. Journal Of Neuroscience 2025, 45: e2182242025. PMID: 40355265, PMCID: PMC12160404, DOI: 10.1523/jneurosci.2182-24.2025.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCorpus StriatumDopamineFemaleHistamineMaleMiceMice, Inbred C57BLMicrodialysisReceptors, Histamine H2Sex CharacteristicsConceptsSubstantia nigra pars compactaAttention deficit hyperactivity disorderStriatal dopamineTourette syndromeSex differencesNeuropsychiatric conditionsModulation of striatal dopamineDysregulation of dopamineRegulation of dopamineReplicating previous workDeficit hyperactivity disorderInfusion of agonistsStriatal circuitryDopamine modulationHyperactivity disorderDopamineHistamine regulationBasal gangliaH3R agonistTargeted infusionGABAergic neuronsIntracerebroventricularMale miceEffect of histamineHistamine receptorsMapping pesticide-induced metabolic alterations in human gut bacteria
Chen L, Yan H, Di S, Guo C, Zhang H, Zhang S, Gold A, Wang Y, Hu M, Wu D, Johnson C, Wang X, Zhu J. Mapping pesticide-induced metabolic alterations in human gut bacteria. Nature Communications 2025, 16: 4355. PMID: 40348778, PMCID: PMC12065874, DOI: 10.1038/s41467-025-59747-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBacteriaFemaleGastrointestinal MicrobiomeHumansLipid MetabolismMaleMiceMice, Inbred C57BLPesticidesConceptsModulating gut microbiota compositionGut bacteria speciesGut microbial speciesHuman gut bacteriaGut microbiota compositionGut bacterial metabolismPesticide exposureHost healthGut bacteriaMicrobiota compositionMicrobial speciesBacterial metabolismBacteria speciesMolecular mechanismsComprehensive atlasLipid metabolismGutIn vivo mouse modelPesticidesHostMetabolismSpeciesInteractive atlasMouse modelMetabolic changesEndoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior
Jin S, Yoon N, Wei M, Worgall T, Rubinelli L, Horvath T, Min W, Diano N, di Lorenzo A, Diano S. Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior. Cell Metabolism 2025, 37: 1400-1412.e8. PMID: 40334659, PMCID: PMC12136989, DOI: 10.1016/j.cmet.2025.04.005.Peer-Reviewed Original ResearchConceptsAgRP neuron activityNogo-AAgRP neuronsNeuronal activityCeramide levelsNogo-A expressionCellular lipid metabolismIntracellular lipid transportSphingolipid de novo biosynthesisDownregulation of enzymesIncreased ceramide levelsLipid metabolismHigh-fat diet-induced obesityFeeding behaviorAgouti-related proteinControl of feedingControlling lipid metabolismAssociated with brain developmentWhole-body metabolismFatty acid oxidationReticulon 4Food intakeMitochondrial functionSynaptic plasticityLipid transportLiver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis
Sakuma I, Gaspar R, Nasiri A, Dufour S, Kahn M, Zheng J, LaMoia T, Guerra M, Taki Y, Kawashima Y, Yimlamai D, Perelis M, Vatner D, Petersen K, Huttasch M, Knebel B, Kahl S, Roden M, Samuel V, Tanaka T, Shulman G. Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2502978122. PMID: 40310463, PMCID: PMC12067271, DOI: 10.1073/pnas.2502978122.Peer-Reviewed Original ResearchConceptsCholine-deficient l-amino acid-defined high-fat dietBempedoic acidLiver fibrosisLiver diseaseL-amino acid-defined high-fat dietAdvanced liver diseaseCholesterol contentHSD17B13 variantsHigh-fat dietTotal liver cholesterol contentTreated miceActivate signaling pathwaysVariant rs738409Liver cholesterol contentLiver lipidsFibrotic responsePromote inflammationTherapeutic approachesSteatotic liver diseaseDietary cholesterol supplementationFibrosisHuman liver samplesI148MAntisense oligonucleotidesProgressive formBlocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors
Srivastava J, Yadav V, Jimenez R, Phadatare P, Inamdar N, Young M, Bacchiocchi A, Halaban R, Fang B, de Mingo Pulido A, Tsai K, Smalley K, Koomen J, Rodriguez P, Premi S. Blocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors. Cancer Research 2025, 85: 2268-2287. PMID: 40287947, PMCID: PMC12167936, DOI: 10.1158/0008-5472.can-24-0693.Peer-Reviewed Original ResearchConceptsInduce immunogenic cell deathNRAS-mutant melanomaDamage-associated molecular patternsImmunogenic cell deathMEK inhibitorsDendritic cellsRepertoire of CD8+ T cellsCocultures of dendritic cellsCD8+ T cellsCell deathActivating NRAS mutationsAntimelanoma immune responsesImmunocompetent mouse modelInnovative treatment strategiesMEK-ERK signalingAntitumor immunityNRAS mutationsMelanoma subtypesERK MAPK pathwayTargeted therapyTumor microenvironmentT cellsT lymphocytesMelanoma growthTherapeutic resistanceMultimodal identification of the mouse brain using simultaneous Ca2+ imaging and fMRI
Mandino F, Horien C, Shen X, Desrosiers-Grégoire G, Luo W, Markicevic M, Constable R, Papademetris X, Chakravarty M, Betzel R, Lake E. Multimodal identification of the mouse brain using simultaneous Ca2+ imaging and fMRI. Communications Biology 2025, 8: 665. PMID: 40287579, PMCID: PMC12033268, DOI: 10.1038/s42003-025-08037-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCalciumConnectomeMagnetic Resonance ImagingMaleMiceMice, Inbred C57BLMultimodal ImagingConceptsBOLD fMRIBOLD fMRI dataConnectome-based identificationCognitive neuroscientistsFMRI literatureHeterogeneous neurological conditionsWhole cortexFMRIMouse brainSimultaneous Ca2+ imagingCa2+ imagingAnimal modelsFluorescence calcium imagingCalcium imagingNeurological conditionsPersonalized treatmentNeuroimagingBOLDCortexNeuroscientistsBrainMiceMultimodal identificationCell-type specific signalsCardiomyocyte-specific NHE1 overexpression confers protection against myocardial infarction during hyperglycemia
Jiang K, Su F, Deng R, Xu Y, Qin A, Yuan X, Xing D, Chen Y, Wang D, Shen L, Hwa J, Hou L, Xiang Y. Cardiomyocyte-specific NHE1 overexpression confers protection against myocardial infarction during hyperglycemia. Cardiovascular Diabetology 2025, 24: 184. PMID: 40287728, PMCID: PMC12034198, DOI: 10.1186/s12933-025-02743-3.Peer-Reviewed Original ResearchConceptsNa+/H+ exchanger 1Na+/H+ exchanger 1 activationAcute hyperglycemiaMyocardial infarctionNHE1 overexpressionNHE1 activityTherapeutic strategiesCardiomyocyte necroptosisHistory of diabetes mellitusReduced extracellular Na+Worsened cardiac dysfunctionRetrospective cohort studyDouble knockout miceIschemia-reperfusion modelNon-diabetic individualsPost-MI patientsReduced infarct sizePathophysiology of MIBackgroundAcute hyperglycemiaElevated BNPMLKL knockoutReduced cardiomyocyte deathAcute myocardial infarctionExtracellular Na+Intracellular Na+
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