2025
Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates
Strober J, Siebel S, Murray S, Rodríguez M, Rodriguez-Navas Gonzalez C, Vatner D. Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates. Journal Of Lipid Research 2025, 66: 100838. PMID: 40499904, DOI: 10.1016/j.jlr.2025.100838.Peer-Reviewed Original ResearchCarbon entryAntisense oligonucleotidesIncreased hepatic TG contentGlutamic-pyruvic transaminase 2Amino acidsChronic overnutritionDevelopment of novel therapiesDecreased hepatic triglyceride contentTCA cycle metabolitesInsulin-resistant subjectsIncreased de novo lipogenesisMultiple amino acidsAntisense oligonucleotide treatmentPrevention of dyslipidemiaHepatic triglyceride contentOverfed miceTG contentHepatic de novo lipogenesisHepatic TG contentC57BL6/J miceLactate dehydrogenase ANovel therapiesMultiple substratesMetabolic syndromeCarbon sourceLiver 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 formOlezarsen in patients with hypertriglyceridemia at high cardiovascular risk: Rationale and design of the Essence–TIMI 73b trial
Bergmark B, Marston N, Prohaska T, Alexander V, Zimerman A, Moura F, Kang Y, Murphy S, Zhang S, Lu M, Karwatowska-Prokopczuk E, Tsimikas S, Giugliano R, Sabatine M. Olezarsen in patients with hypertriglyceridemia at high cardiovascular risk: Rationale and design of the Essence–TIMI 73b trial. American Heart Journal 2025, 286: 116-124. PMID: 40081744, PMCID: PMC12065083, DOI: 10.1016/j.ahj.2025.02.022.Peer-Reviewed Original ResearchMeSH KeywordsAgedApolipoprotein C-IIICardiovascular DiseasesClinical Trials, Phase III as TopicComputed Tomography AngiographyCoronary AngiographyDouble-Blind MethodFemaleHeart Disease Risk FactorsHumansHypertriglyceridemiaMaleMiddle AgedOligonucleotidesOligonucleotides, AntisenseRandomized Controlled Trials as TopicTriglyceridesConceptsCoronary computed tomography angiographyCardiovascular riskTriglyceride levelsModerate hypertriglyceridemiaBaseline coronary computed tomography angiographyPlacebo-controlled phase 3 trialClearance of triglyceride-rich lipoproteinsApoC-IIIBaseline triglyceride levelsBaseline to 6 monthsLipid-lowering therapyAntisense oligonucleotidesNoncalcified coronary plaquesPhase 3 trialComputed tomography angiographyLowering triglyceride levelsIncreased cardiovascular riskElevated cardiovascular riskReduce cardiovascular riskAtherosclerotic cardiovascular diseaseTriglyceride-rich lipoproteinsPotential therapeutic strategyPooled placeboApolipoprotein C-IIIDouble-blindDesign and rationale of the CORE-TIMI 72a and CORE2-TIMI 72b trials of olezarsen in patients with severe hypertriglyceridemia
Marston N, Bergmark B, Alexander V, Karwatowska-Prokopczuk E, Kang Y, Moura F, Prohaska T, Zimerman A, Zhang S, Murphy S, Tsimikas S, Giugliano R, Sabatine M. Design and rationale of the CORE-TIMI 72a and CORE2-TIMI 72b trials of olezarsen in patients with severe hypertriglyceridemia. American Heart Journal 2025, 286: 125-135. PMID: 40064331, PMCID: PMC12065585, DOI: 10.1016/j.ahj.2025.03.003.Peer-Reviewed Original ResearchConceptsSevere hypertriglyceridemiaAcute pancreatitis eventInvestigated antisense oligonucleotidesBaseline to 6 monthsPhase 3 trialTriglyceride-rich remnantsBaseline triglyceridesMatching placeboApolipoprotein C-IIIPancreatitis eventsMedian ageInhibit lipoprotein lipasePooled analysisClinical consequencesMRI substudyHypertriglyceridemiaSerum triglyceridesTG clearanceLife-threateningPatientsStudy populationApoC-IIIHepatic uptakeAntisense oligonucleotidesDedicated trials
2024
Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment
Sun F, Wang H, Wu J, Quraishi I, Zhang Y, Pedram M, Gao B, Jonas E, Nguyen V, Wu S, Mabrouk O, Jafar-nejad P, Kaczmarek L. Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment. Biomolecules 2024, 14: 1397. PMID: 39595574, PMCID: PMC11591899, DOI: 10.3390/biom14111397.Peer-Reviewed Original ResearchWild-type miceKO miceSpectrum of epilepsy syndromesAntisense oligonucleotidesGain-of-function variantsAntisense oligonucleotide treatmentEpileptic phenotypePotassium channelsKCNT1Molecular profilingOligonucleotide treatmentAnimal modelsEpilepsy syndromesC-terminal mutationsIncreased expressionCerebral cortexMiceExpression of multiple proteinsComprehensive proteomic analysisDisease modelsCortical mitochondriaMolecular differencesDensity of mitochondrial cristaeMitochondrial membraneTreatmentAntisense oligonucleotides and their applications in rare neurological diseases
McDowall S, Aung-Htut M, Wilton S, Li D. Antisense oligonucleotides and their applications in rare neurological diseases. Frontiers In Neuroscience 2024, 18: 1414658. PMID: 39376536, PMCID: PMC11456401, DOI: 10.3389/fnins.2024.1414658.Peer-Reviewed Original ResearchAntisense oligonucleotidesRare diseaseImpaired quality of lifeDuchenne muscular dystrophyRare neurological diseasesNeurological diseasesClinical trial designSpinal muscular atrophyRare conditionApplication of antisense oligonucleotidesHigh treatment costsTherapeutic antisense oligonucleotidesClinical trialsAnimal modelsMuscular dystrophyEffective treatmentQuality of lifeImpaired qualityMuscular atrophyAntisense oligomersTrial designTherapeutic validityTarget gene expressionDiseaseTreatment costsCeramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway
Xu W, Zhang D, Ma Y, Gaspar R, Kahn M, Nasiri A, Murray S, Samuel V, Shulman G. Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway. Cell Reports 2024, 43: 114746. PMID: 39302831, DOI: 10.1016/j.celrep.2024.114746.Peer-Reviewed Original ResearchLipid-induced hepatic insulin resistanceHepatic insulin resistancePhosphorylation pathwayAntisense oligonucleotidesCeramide synthesis inhibitorsLipid-induced insulin resistanceMyriocin treatmentCeramide synthesisDihydroceramide desaturaseInsulin resistanceHepatic ceramideMyriocinCeramideCeramide contentInsulin-sensitizing effectsPhosphorylationHepatic insulin sensitivityPathwaySynthetic pathwayDES1Glucose productionSynthesis inhibitorDGAT2DesaturaseInhibition1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis
SAKUMA I, GASPAR R, NASIRI A, KAHN M, ZHENG J, GUERRA M, YIMLAMAI D, MURRAY S, PERELIS M, BARNES W, VATNER D, PETERSEN K, SAMUEL V, SHULMAN G. 1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis. Diabetes 2024, 73 DOI: 10.2337/db24-1571-p.Peer-Reviewed Original ResearchLipid droplet sizeCGI-58Choline-deficient l-amino acid-defined high-fat dietGlycerol-3-phosphate acyltransferaseAntisense oligonucleotidesComparative gene identification-58Glycerol-3-phosphateLoss of function mutationsLipid droplet morphologyExpression of CGI-58Liver inflammationCidebCholesterol contentFunction mutationsL-amino acid-defined high-fat dietComplications of type 2 diabetesMolecular mechanismsDevelopment of liver inflammationMacrophage crown-like structuresType 2 diabetesHigh-fat dietCrown-like structuresASO treatmentGPAMKnockdownGlis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease
Zhang C, Rehman M, Tian X, Pei S, Gu J, Bell T, Dong K, Tham M, Cai Y, Wei Z, Behrens F, Jetten A, Zhao H, Lek M, Somlo S. Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease. Nature Communications 2024, 15: 3698. PMID: 38693102, PMCID: PMC11063051, DOI: 10.1038/s41467-024-48025-6.Peer-Reviewed Original ResearchConceptsMouse models of autosomal dominant polycystic kidney diseaseModel of autosomal dominant polycystic kidney diseasePolycystin signalingAutosomal dominant polycystic kidney diseasePolycystin-1Polycystic kidney diseaseTreat autosomal dominant polycystic kidney diseaseGlis2Primary ciliaKidney tubule cellsSignaling pathwayMouse modelDominant polycystic kidney diseasePotential therapeutic targetTranslatomeAntisense oligonucleotidesKidney diseasePolycystinMouse kidneyFunctional effectorsCyst formationTherapeutic targetInactivationFunctional targetPharmacological targets
2021
Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion
Harada A, Matsumoto S, Yasumizu Y, Shojima K, Akama T, Eguchi H, Kikuchi A. Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion. ELife 2021, 10: e66721. PMID: 34590580, PMCID: PMC8598236, DOI: 10.7554/elife.66721.Peer-Reviewed Original ResearchConceptsDownstream effectorsEGF-Ras pathwayCancer cell invasionPancreatic cancer patientsPancreatic cancer cellsIQGAP1ARL4CCell invasionPancreatic cancerSite of invasionCancer cellsCancer patientsExtracellular matrixPseudopodsAntisense oligonucleotidesInvasive pancreatic cancerMetastasis of pancreatic cancerActive siteInduced degradationEffectorMMP14InvasionMortality rateLocalizationOligonucleotidesNeurodegenerative diseases: a hotbed for splicing defects and the potential therapies
Li D, McIntosh C, Mastaglia F, Wilton S, Aung-Htut M. Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies. Translational Neurodegeneration 2021, 10: 16. PMID: 34016162, PMCID: PMC8136212, DOI: 10.1186/s40035-021-00240-7.Peer-Reviewed Original ResearchConceptsAlternative splicingSplicing patternsSplicing defectsNeurodegenerative diseasesTrans-splicing factorsEukaryotic gene expressionDiversity of proteomesNon-coding regionsPrecursor messenger RNAAntisense oligonucleotide therapeuticsSplice-switching antisense oligonucleotidesRNA splicingMature mRNAGenetic plasticityCellular homeostasisSplicingGene expressionNeuronal differentiationNeuronal migrationNeuronal cellsNeurodegenerative disordersAlzheimer's diseaseSynaptic functionMessenger RNAAntisense oligonucleotides
2018
Precision Medicine through Antisense Oligonucleotide-Mediated Exon Skipping
Li D, Mastaglia F, Fletcher S, Wilton S. Precision Medicine through Antisense Oligonucleotide-Mediated Exon Skipping. Trends In Pharmacological Sciences 2018, 39: 982-994. PMID: 30282590, DOI: 10.1016/j.tips.2018.09.001.Peer-Reviewed Original ResearchConceptsSpinal muscular atrophyAntisense oligonucleotidesAntisense oligonucleotide-mediated exon skippingDuchenne MDTreat Duchenne muscular dystrophyExon skippingTherapeutic potential of antisense oligonucleotidesTargeted exon skippingPotential of antisense oligonucleotidesDuchenne muscular dystrophyPrecision medicineInherited rare diseaseClinical benefitRare diseaseMuscular dystrophyClinical implementationTherapeutic potentialMuscular atrophyAffected individualsAlternative splicingLethal mutationsDuchenneBecker casesExonMutations
2015
Splicing of human chloride channel 1
Nakamura T, Ohsawa-Yoshida N, Zhao Y, Koebis M, Oana K, Mitsuhashi H, Ishiura S. Splicing of human chloride channel 1. Biochemistry And Biophysics Reports 2015, 5: 63-69. PMID: 28955807, PMCID: PMC5600464, DOI: 10.1016/j.bbrep.2015.11.006.Peer-Reviewed Original ResearchAlternative splicingSplicing patternsRNA-binding protein familyTAG stop codonSplice variant expressionReal-time RT-PCRAbnormal splicing variantsProtein familyExon 6BInactive proteinStop codonAberrant splicingExon 5SplicingSplice variantsCCTG repeatsExon 7Variant expressionGenetic disordersExonMyotonic dystrophyAntisense oligonucleotidesRT-PCRSkeletal muscleAssay system
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