| First Author | Yang HL | Year | 2016 |
| Journal | Biochim Biophys Acta | Volume | 1859 |
| Issue | 2 | Pages | 246-61 |
| PubMed ID | 26548719 | Mgi Jnum | J:250883 |
| Mgi Id | MGI:6106352 | Doi | 10.1016/j.bbagrm.2015.11.001 |
| Citation | Yang HL, et al. (2016) Coenzyme Q0 regulates NFkappaB/AP-1 activation and enhances Nrf2 stabilization in attenuation of LPS-induced inflammation and redox imbalance: Evidence from in vitro and in vivo studies. Biochim Biophys Acta 1859(2):246-61 |
| abstractText | Coenzyme Q (CoQ) analogs with variable number of isoprenoid units have been demonstrated as anti-inflammatory and antioxidant/pro-oxidant molecules. In this study we used CoQ0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero isoprenoid side-chains), a novel quinone derivative, and investigated its molecular actions against LPS-induced inflammation and redox imbalance in murine RAW264.7 macrophages and mice. In LPS-stimulated macrophages, non-cytotoxic concentrations of CoQ0 (2.5-10 muM) inhibited iNOS/COX-2 protein expressions with subsequent reductions of NO, PGE2, TNF-alpha and IL-1beta secretions. This inhibition was reasoned by suppression of NFkappaB (p65) activation, and inhibition of AP-1 (c-Jun., c-Fos, ATF2) translocation. Our findings indicated that IKKalpha-mediated I-kappaB degradation and MAPK-signaling are involved in regulation of NFkappaB/AP-1 activation. Furthermore, CoQ0 triggered HO-1 and NQO-1 genes through increased Nrf2 nuclear translocation and Nrf2/ARE-signaling. This phenomenon was confirmed by diminished CoQ0 protective effects in Nrf2 knockdown cells, where LPS-induced NO, PGE2, TNF-alpha and IL-1beta productions remained high. Molecular evidence revealed that CoQ0 enhanced Nrf2 steady-state level at both transcriptional and translational levels. CoQ0-induced Nrf2 activation appears to be regulated by ROS-JNK-signaling cascades, as evidenced by suppressed Nrf2 activation upon treatment with pharmacological inhibitors of ROS (N-acetylcysteine) and JNK (SP600125). Besides, oral administration of CoQ0 (5 mg/kg) suppressed LPS-induced (1 mg/kg) induction of iNOS/COX-2 and TNF-alpha/IL-1beta through tight regulation of NFkappaB/Nrf2 signaling in mice liver and spleen. Our findings conclude that pharmacological actions of CoQ0 are mediated via inhibition of NFkappaB/AP-1 activation and induction of Nrf2/ARE-signaling. Owing to its potent anti-inflammatory and antioxidant properties, CoQ0 could be a promising candidate to treat inflammatory disorders. |
