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dc.contributor.author이지희*
dc.contributor.author김희선*
dc.date.accessioned2025-08-07T07:11:19Z-
dc.date.available2025-08-07T07:11:19Z-
dc.date.issued2025*
dc.identifier.issn1873-2968*
dc.identifier.otherOAK-37504*
dc.identifier.urihttps://dspace.ewha.ac.kr/handle/2015.oak/272187-
dc.description.abstractNecroptosis is involved in neuronal cell death and inflammation, with the receptor-interacting protein kinase (RIPK) 1-RIPK3-mixed lineage kinase domain-like protein (MLKL) necrosome complex playing a significant role. Although MLKL is considered the final executor of necroptosis, its role in neuroinflammation remains unclear. In the present study, we explored the role of MLKL in lipopolysaccharide (LPS)- or polyinosinic-polycytidylic acid (poly(I:C))-induced neuroinflammation using the MLKL-specific inhibitor necrosulfonamide (NSA). NSA or MLKL siRNA reduced nitric oxide and proinflammatory cytokine production under LPS- or poly(I:C)-induced inflammation and LPS/QVD/BV6- or poly(I:C)/QVD/BV6-induced necroptosis in BV2 microglial cells; QVD is a pan-caspase inhibitor, and BV6 antagonizes inhibitor of apoptosis protein. Additionally, NSA suppressed the phosphorylation of RIPK1-RIPK3-MLKL and reduced the expression of damage-associated molecular patterns, including high mobility group box 1, in inflammatory/necroptotic BV2 cells. Subsequent mechanistic studies revealed that NSA reduces inflammation by upregulating nuclear factor-erythroid 2 (NF-E2)-related factor (Nrf2) signaling pathways and blocking reactive oxygen species, mitogen-activated protein kinases, and nuclear factor-κB. The anti-inflammatory effects of NSA were confirmed in the brains of mice with systemic inflammation caused by LPS or poly(I:C) injection. NSA suppressed microglial activation, proinflammatory gene expression, and disruption of blood–brain barrier integrity while upregulating Nrf2-mediated antioxidant enzymes in the brains of LPS- or poly(I:C)-injected mice. Furthermore, NSA suppressed the phosphorylation and expression of RIPK1-RIPK3-MLKL, and p-MLKL expressed in activated microglia, indicating that MLKL plays a crucial role in microglial activation in mice with systemic inflammation. Therefore, modulating MLKL expression may be an effective treatment for necroptosis-related neuroinflammatory disorders. © 2025 Elsevier B.V., All rights reserved.*
dc.languageEnglish*
dc.publisherElsevier Inc.*
dc.subjectMicroglia*
dc.subjectMlkl*
dc.subjectNecroptosis*
dc.subjectNecrosulfonamide*
dc.subjectNeuroinflammation*
dc.subjectSystemic Inflammation*
dc.subjectCatalase*
dc.subjectGelatinase B*
dc.subjectInducible Nitric Oxide Synthase*
dc.subjectLactate Dehydrogenase*
dc.subjectLactate Dehydrogenase A*
dc.subjectMitogen Activated Protein Kinase*
dc.subjectNeutrophil Collagenase*
dc.subjectNitric Oxide*
dc.subjectOccludin*
dc.subjectPolyinosinic Polycytidylic Acid*
dc.subjectProtein Kinase*
dc.subjectProtein Serine Threonine Kinase*
dc.subjectStromelysin*
dc.subjectToll Like Receptor 2*
dc.subjectToll Like Receptor 4*
dc.subjectAcrylamides*
dc.subjectAnti-inflammatory Agents*
dc.subjectLipopolysaccharides*
dc.subjectMlkl Protein, Mouse*
dc.subjectN-(4-(n-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide*
dc.subjectPoly I-c*
dc.subjectProtein Kinases*
dc.subjectSulfonamides*
dc.subjectAntiinflammatory Agent*
dc.subjectClaudin 5*
dc.subjectCyclooxygenase 2*
dc.subjectGlycoprotein Gp 91*
dc.subjectHeme Oxygenase 1*
dc.subjectHigh Mobility Group B1 Protein*
dc.subjectImmunoglobulin Enhancer Binding Protein*
dc.subjectInterleukin 1alpha*
dc.subjectInterleukin 1beta*
dc.subjectInterleukin 33*
dc.subjectInterleukin 6*
dc.subjectMessenger Rna*
dc.subjectMitogen Activated Protein Kinase P38*
dc.subjectMixed Lineage Kinase Domain Like Protein*
dc.subjectProtein P22*
dc.subjectProtein P47*
dc.subjectProtein P67*
dc.subjectProtein Serine Threonine Kinase Inhibitor*
dc.subjectReactive Oxygen Metabolite*
dc.subjectReceptor Interacting Protein Kinase 1*
dc.subjectReceptor Interacting Protein Kinase 3*
dc.subjectSmall Interfering Rna*
dc.subjectToll Like Receptor 3*
dc.subjectTranscription Factor Nrf2*
dc.subjectTranscription Factor Rela*
dc.subjectUnclassified Drug*
dc.subjectAcrylamide Derivative*
dc.subjectLipopolysaccharide*
dc.subjectSulfonamide*
dc.subjectAnimal Cell*
dc.subjectAnimal Experiment*
dc.subjectAnimal Model*
dc.subjectAnimal Tissue*
dc.subjectAntiinflammatory Activity*
dc.subjectArticle*
dc.subjectBrain Tissue*
dc.subjectBv-2 Cell Line*
dc.subjectControlled Study*
dc.subjectCytokine Production*
dc.subjectEnzyme Phosphorylation*
dc.subjectFemale*
dc.subjectGel Mobility Shift Assay*
dc.subjectGene Expression*
dc.subjectImmunofluorescence*
dc.subjectImmunohistochemistry*
dc.subjectLipopolysaccharide-induced Neuroinflammation*
dc.subjectMale*
dc.subjectMouse*
dc.subjectNervous System Inflammation*
dc.subjectNonhuman*
dc.subjectNrf2 Signaling*
dc.subjectReal Time Polymerase Chain Reaction*
dc.subjectReverse Transcription Polymerase Chain Reaction*
dc.subjectSignal Transduction*
dc.subjectUpregulation*
dc.subjectWestern Blotting*
dc.subjectAnimal*
dc.subjectC57bl Mouse*
dc.subjectCell Line*
dc.subjectDose Response*
dc.subjectDrug Effect*
dc.subjectDrug Therapy*
dc.subjectGenetics*
dc.subjectMetabolism*
dc.subjectPhysiology*
dc.subjectAnimals*
dc.subjectDose-response Relationship, Drug*
dc.subjectMice*
dc.subjectMice, Inbred C57bl*
dc.subjectNeuroinflammatory Diseases*
dc.titleAnti-inflammatory mechanism of the MLKL inhibitor necrosulfonamide in LPS- or poly(I:C)-induced neuroinflammation and necroptosis*
dc.typeArticle*
dc.relation.volume239*
dc.relation.indexSCIE*
dc.relation.indexSCOPUS*
dc.relation.journaltitleBiochemical Pharmacology*
dc.identifier.doi10.1016/j.bcp.2025.117021*
dc.identifier.wosidWOS:001508976400002*
dc.identifier.scopusid2-s2.0-105007518087*
dc.author.googleKim D.*
dc.author.googleLeem Y.*
dc.author.googlePark J.S.*
dc.author.googleKim S.*
dc.author.googleChoi Y.*
dc.author.googleKang J.L.*
dc.author.googleKim H.*
dc.contributor.scopusid이지희(7404517577)*
dc.contributor.scopusid김희선(57191372551)*
dc.date.modifydate20261006122233*
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