title: Inhibition of NO-induced β-cell death by novel NF-κB inhibitor (-)-DHMEQ via activation of Nrf2-ARE pathway.
abstract: Excessive nitric oxide (NO) plays a pivotal role in the progression of β-cell apoptosis in type 1 diabetes mellitus. We used mouse insulinoma Min6 cells as a model of β cells in this research. We found that (-)-DHMEQ, an NF-κB inhibitor, rescued β cells from NO-induced apoptosis, and then studied the mechanism of apoptosis inhibition. (-)-DHMEQ activated Nrf2 and induced transcription of Nrf2-target genes following the increase of antioxidant response element (ARE) reporter activity. Similarly, tert-butyl hydroquinone (tBHQ), a known activator of Nrf2, inhibited NO-induced cell death along with the transcriptional activation of ARE. RNAi-mediated knockdown of Nrf2 lowered the cytoprotective effect of (-)-DHMEQ against NO, suggesting that (-)-DHMEQ inhibited NO-induced cell death via Nrf2 activation. Furthermore, overexpression of Nrf2 rendered cells to be more resistant to NO, indicating that Nrf2 activation provides critical defense function against NO in Min6 cells. Taken together, we conclude that (-)-DHMEQ may be a useful therapeutic agent for type 1 diabetes mellitus in the onset of disease by protecting β cells from apoptosis.
authors: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan.
authors: Akira
authors: A
authors: Ogasawara
authors: Siro
authors: S
authors: Simizu
authors: Ayumi
authors: A
authors: Ito
authors: Toshihide
authors: T
authors: Kawai
authors: Yoshifumi
authors: Y
authors: Saisho
authors: Izumi
authors: I
authors: Takei
authors: Kazuo
authors: K
authors: Umezawa
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007340:Insulinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; C464444:dehydroxymethylepoxyquinomicin; D009569:Nitric Oxide