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Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.

dc.contributor.authorBlatt, Neal B
dc.contributor.authorBednarski, Jeffrey J
dc.contributor.authorWarner, Roscoe E
dc.contributor.authorLeonetti, Francesco
dc.contributor.authorJohnson, Kathryn M
dc.contributor.authorBoitano, Anthony
dc.contributor.authorYung, Raymond
dc.contributor.authorRichardson, Bruce C
dc.contributor.authorJohnson, Kent J
dc.contributor.authorEllman, Jonathan A
dc.contributor.authorOpipari, Anthony W
dc.contributor.authorGlick, Gary D
dc.coverage.spatialUnited States
dc.date.accessioned2024-05-03T17:17:07Z
dc.date.available2024-05-03T17:17:07Z
dc.date.issued2002-10
dc.identifier.issn0021-9738
dc.identifier.issn1558-8238
dc.identifier.urihttps://www.ncbi.nlm.nih.gov/pubmed/12393848
dc.identifier.urihttps://hdl.handle.net/2027.42/193028en
dc.description.abstractThe properties of a proapoptotic 1,4-benzodiazepine, Bz-423, identified through combinatorial chemistry and phenotype screening are described. Bz-423 rapidly generated superoxide (O(2)(-)) in transformed Ramos B cells. This O(2)(-) response originated from mitochondria prior to mitochondrial transmembrane gradient collapse and opening of the permeability transition pore. Bz-423-induced O(2)(-) functioned as an upstream signal that initiated an apoptotic program characterized by cytochrome c release, mitochondrial depolarization, and caspase activation. Pretreatment of cells with agents that either block the formation of Bz-423-induced O(2)(-) or scavenge free radicals attenuated the death cascade, which demonstrated that cell killing by Bz-423 depends on O(2)(-). Parallels between Ramos cells and germinal center B cells prompted experiments to determine whether Bz-423 had therapeutic activity in vivo. This possibility was tested using the (NZB x NZW)F(1) murine model of lupus, in which the pathologically enhanced survival and expansion of germinal center B cells mediate disease. Administration of Bz-423 for 12 weeks specifically controlled germinal center hyperplasia and reduced the histological evidence of glomerulonephritis. Collectively, these studies define a new structure-function relationship for benzodiazepines and point to a new target and mechanism that could be of value for developing improved drugs to manage systemic lupus erythematosus and related disorders.
dc.format.mediumPrint
dc.languageeng
dc.publisherAmerican Society for Clinical Investigation
dc.subjectAnimals
dc.subjectAntibodies, Antinuclear
dc.subjectApoptosis
dc.subjectB-Lymphocytes
dc.subjectBenzodiazepines
dc.subjectCell Line, Transformed
dc.subjectFemale
dc.subjectHumans
dc.subjectIn Vitro Techniques
dc.subjectLupus Erythematosus, Systemic
dc.subjectMice
dc.subjectMice, Inbred NZB
dc.subjectModels, Biological
dc.subjectReactive Oxygen Species
dc.subjectSignal Transduction
dc.subjectSuperoxides
dc.titleBenzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.
dc.typeArticle
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/193028/2/JCI0216029.pdf
dc.identifier.doi10.1172/JCI16029
dc.identifier.doihttps://dx.doi.org/10.7302/22673
dc.identifier.sourceJ Clin Invest
dc.description.versionPublished version
dc.date.updated2024-05-03T17:16:58Z
dc.identifier.orcid0000-0002-8181-027X
dc.identifier.volume110
dc.identifier.issue8
dc.identifier.startpage1123
dc.identifier.endpage1132
dc.identifier.name-orcidBlatt, Neal B
dc.identifier.name-orcidBednarski, Jeffrey J
dc.identifier.name-orcidWarner, Roscoe E
dc.identifier.name-orcidLeonetti, Francesco
dc.identifier.name-orcidJohnson, Kathryn M
dc.identifier.name-orcidBoitano, Anthony
dc.identifier.name-orcidYung, Raymond; 0000-0002-8181-027X
dc.identifier.name-orcidRichardson, Bruce C
dc.identifier.name-orcidJohnson, Kent J
dc.identifier.name-orcidEllman, Jonathan A
dc.identifier.name-orcidOpipari, Anthony W
dc.identifier.name-orcidGlick, Gary D
dc.working.doi10.7302/22673en
dc.owningcollnameInternal Medicine, Department of


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