Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.
dc.contributor.author | Blatt, Neal B | |
dc.contributor.author | Bednarski, Jeffrey J | |
dc.contributor.author | Warner, Roscoe E | |
dc.contributor.author | Leonetti, Francesco | |
dc.contributor.author | Johnson, Kathryn M | |
dc.contributor.author | Boitano, Anthony | |
dc.contributor.author | Yung, Raymond | |
dc.contributor.author | Richardson, Bruce C | |
dc.contributor.author | Johnson, Kent J | |
dc.contributor.author | Ellman, Jonathan A | |
dc.contributor.author | Opipari, Anthony W | |
dc.contributor.author | Glick, Gary D | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-05-03T17:17:07Z | |
dc.date.available | 2024-05-03T17:17:07Z | |
dc.date.issued | 2002-10 | |
dc.identifier.issn | 0021-9738 | |
dc.identifier.issn | 1558-8238 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/12393848 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/193028 | en |
dc.description.abstract | The 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.medium | ||
dc.language | eng | |
dc.publisher | American Society for Clinical Investigation | |
dc.subject | Animals | |
dc.subject | Antibodies, Antinuclear | |
dc.subject | Apoptosis | |
dc.subject | B-Lymphocytes | |
dc.subject | Benzodiazepines | |
dc.subject | Cell Line, Transformed | |
dc.subject | Female | |
dc.subject | Humans | |
dc.subject | In Vitro Techniques | |
dc.subject | Lupus Erythematosus, Systemic | |
dc.subject | Mice | |
dc.subject | Mice, Inbred NZB | |
dc.subject | Models, Biological | |
dc.subject | Reactive Oxygen Species | |
dc.subject | Signal Transduction | |
dc.subject | Superoxides | |
dc.title | Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility. | |
dc.type | Article | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/193028/2/JCI0216029.pdf | |
dc.identifier.doi | 10.1172/JCI16029 | |
dc.identifier.doi | https://dx.doi.org/10.7302/22673 | |
dc.identifier.source | J Clin Invest | |
dc.description.version | Published version | |
dc.date.updated | 2024-05-03T17:16:58Z | |
dc.identifier.orcid | 0000-0002-8181-027X | |
dc.identifier.volume | 110 | |
dc.identifier.issue | 8 | |
dc.identifier.startpage | 1123 | |
dc.identifier.endpage | 1132 | |
dc.identifier.name-orcid | Blatt, Neal B | |
dc.identifier.name-orcid | Bednarski, Jeffrey J | |
dc.identifier.name-orcid | Warner, Roscoe E | |
dc.identifier.name-orcid | Leonetti, Francesco | |
dc.identifier.name-orcid | Johnson, Kathryn M | |
dc.identifier.name-orcid | Boitano, Anthony | |
dc.identifier.name-orcid | Yung, Raymond; 0000-0002-8181-027X | |
dc.identifier.name-orcid | Richardson, Bruce C | |
dc.identifier.name-orcid | Johnson, Kent J | |
dc.identifier.name-orcid | Ellman, Jonathan A | |
dc.identifier.name-orcid | Opipari, Anthony W | |
dc.identifier.name-orcid | Glick, Gary D | |
dc.working.doi | 10.7302/22673 | en |
dc.owningcollname | Internal Medicine, Department of |
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