Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GST micro-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.
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PMID:Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin. 1648 34

Ischemia and oxidative stress play crucial roles in the pathophysiology of sudden sensorineural hearing loss (SSNHL). Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and serves an important role in hearing function. The present study was designed to evaluate the effect of MIF on oxygen-glucose deprivation (OGD)-induced ototoxicity and to elucidate its molecular mechanism. In HEI-OC1 auditory cells, OGD reduced cell viability and increased supernatant lactate dehydrogenase (LDH) and MIF in a time-dependent manner. However, the reduced cell viability exerted by OGD was attenuated by antioxidant and MIF. Luciferase reporter assay demonstrated that MIF could activate NF-E2-related factor 2 (Nrf2), and real-time PCR showed increased mRNA expressions of Nrf2 and two Nrf2-responsive genes, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). MIF also suppressed oxidative stress induced by OGD, as demonstrated by decreased MDA and increased GSH in cellular supernatant. Inhibition of Nrf2 using siRNA suppressed HO-1 protein expression, the protective effect on OGD-induced injury and decrease in oxidative stress by MIF. Moreover, MIF prevented OGD-induced reduction of Akt1 phosphorylation at Ser473. LY294002, an inhibitor of PI3K/Akt signaling, attenuated the enhancement of Nrf2 protein and protective effect of MIF in OGD-treated cochlear cells. We demonstrate that MIF protects cochlear cells against OGD-induced injury through activation of Akt-Nrf2-HO-1 pathway.
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PMID:MIF protects against oxygen-glucose deprivation-induced ototoxicity in HEI-OC1 cochlear cells by enhancement of Akt-Nrf2-HO-1 pathway. 2990 83