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- W1983225030 abstract "This study characterizes a neuroprotective pathway responsible for coordinated enhancement of astrocyte glutathione (GSH)-homeostatic machinery. Injuries in fetal rat cortical neurons associated with Fetal Alcohol Syndrome are correlated to ethanol (E) exposure leading to increased oxidative stress, GSH depletion, and ultimately neuroapoptosis. Our lab has previously published that astrocytes protect neurons from E mediated apoptosis, via maintenance of GSH homeostasis. We hypothesize that neuroprotection is regulated by the activation of the anti-oxidant response elements (ARE) contained in the 5’ regions of cytoprotective genes, via the master transcription factor Nrf2. To identify the role of E in astrocyte anti-oxidant defense induction, we first employed an E time course to investigate Nrf2 protein expression. Primary cultured rat neonatal astrocytes were treated with 4mg/ml E at various time points. There was increased nuclear Nrf2 expression within 15 minutes after E treatment, and lasted up to 4 hours. Immunohistochemical studies corroborate cytoplasmic to nuclear translocation. Enhanced nuclear Nrf2 expression was further augmented by BSO pre-treatment. In addition, the transcription factor Maf, which obligatorily dimerizes with Nrf2 to activate gene transcription, was increased by E or BSO. Known ARE inducers and oxidative stress mimicked the cytoplasmic to nuclear translocation seen in E treatment. To determine whether E increased GSH-homeostatic machinery at the transcriptional level, cells were pre-incubated with Actinomycin D, and subsequently treated with E. Nrf2 expression induced by E was abolished in the presence of AD suggesting that E increases Nrf2 by stimulating gene transcription. Transfection of Nrf2 siRNA completely ablated Nrf2 expression, and furthermore blocks the tert-butyl hydroquinone induced Nrf2, GGT, and Mrp1 expression. Finally, we examined E's effect on Nrf2 ubiquitination. E decreased Nrf2 ubiquitination at 4 and 24 hours while not effecting overall ubiquitin levels in the cell suggesting another possible mechanism for Nrf2 protein level increase and subsequent nuclear translocation to activate ARE. Taken together, this suggests that Nrf2 is required for activation of ARE. The role of E in Nrf2-ARE control of astrocyte neuroprotection needs to be further investigated. These points of regulation may allow for pharmacological augmentation of this crucial neuroprotective mechanism." @default.
- W1983225030 created "2016-06-24" @default.
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- W1983225030 date "2008-06-01" @default.
- W1983225030 modified "2023-10-06" @default.
- W1983225030 title "NEUROPROTECTION AGAINST ETHANOL MEDIATED OXIDATIVE STRESS AND APOPTOSIS VIA NRF2/ARE." @default.
- W1983225030 doi "https://doi.org/10.1111/j.1530-0277.2008.00689_17.x" @default.
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