دورية أكاديمية
NADPH oxidase (NOX) isoforms are inhibited by celastrol with a dual mode of action
| العنوان: | NADPH oxidase (NOX) isoforms are inhibited by celastrol with a dual mode of action |
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| المؤلفون: | Jaquet, Vincent, Marcoux, Julien, Forest, Eric, Leidal, Kevin, Mccormick, Sally, Westermaier, Yvonne, Perozzo, Remo, Plastre, Olivier, Fioraso‐cartier, Laetitia, Diebold, Becky, Scapozza, Leonardo, Nauseef, William, Fieschi, Franck, Krause, Karl‐heinz, Bedard, Karen |
| المساهمون: | Department of Pathology and Immunology, Geneva University Hospital (HUG), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes 2016-2019 (UGA 2016-2019 )-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) |
| المصدر: | ISSN: 0007-1188. |
| بيانات النشر: | HAL CCSD Wiley |
| سنة النشر: | 2011 |
| المجموعة: | HAL-CEA (Commissariat à l'énergie atomique et aux énergies alternatives) |
| مصطلحات موضوعية: | reactive oxygen species, celastrol, NADPH oxidase, NOX inhibitor, SH3 domain, Tripterygium wilfordii Hook F, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology |
| الوصف: | International audience ; BACKGROUND Celastrol is one of several bioactive compounds extracted from the medicinal plant Tripterygium wilfordii. Celastrol is used to treat inflammatory conditions, and shows benefits in models of neurodegenerative disease, cancer and arthritis, although its mechanism of action is incompletely understood. EXPERIMENTAL APPROACH Celastrol was tested on human NADPH oxidases (NOXs) using a panel of experiments: production of reactive oxygen species and oxygen consumption by NOX enzymes, xanthine oxidase activity, cell toxicity, phagocyte oxidase subunit translocation, and binding to cytosolic subunits of NOX enzymes. The effect of celastrol was compared with diphenyleneiodonium, an established inhibitor of flavoproteins. KEY RESULTS Low concentrations of celastrol completely inhibited NOX1, NOX2, NOX4 and NOX5 within minutes with concentration-response curves exhibiting higher Hill coefficients and lower IC50 values for NOX1 and NOX2 compared with NOX4 and NOX5, suggesting differences in their mode of action. In a cell-free system, celastrol had an IC50 of 1.24 and 8.4 mM for NOX2 and NOX5, respectively. Cytotoxicity, oxidant scavenging, and inhibition of p47 phox translocation could not account for NOX inhibition. Celastrol bound to a recombinant p47 phox and disrupted the binding of the proline rich region of p22 phox to the tandem SH3 domain of p47 phox and NOXO1, the cytosolic subunits of NOX2 and NOX1, respectively. CONCLUSIONS AND IMPLICATIONS These results demonstrate that celastrol is a potent inhibitor of NOX enzymes in general with increased potency against NOX1 and NOX2. Furthermore, inhibition of NOX1 and NOX2 was mediated via a novel mode of action, namely inhibition of a functional association between cytosolic subunits and the membrane flavocytochrome. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | hal-02335573; https://hal.science/hal-02335573Test; https://hal.science/hal-02335573/documentTest; https://hal.science/hal-02335573/file/j.1476-5381.2011.01439.x.pdfTest |
| DOI: | 10.1111/j.1476-5381.2011.01439.x |
| الإتاحة: | https://doi.org/10.1111/j.1476-5381.2011.01439.xTest https://hal.science/hal-02335573Test https://hal.science/hal-02335573/documentTest https://hal.science/hal-02335573/file/j.1476-5381.2011.01439.x.pdfTest |
| حقوق: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.1552A811 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1111/j.1476-5381.2011.01439.x |
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