Coenzyme Q0 regulates NFκB/AP-1 activation and enhances Nrf2 stabilization in attenuation of LPS-induced inflammation and redox imbalance: Evidence from in vitro and in vivo studies

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 CoQ(0) (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 CoQ(0) (2.5-10 mu M) inhibited iNOS/COX-2 protein expressions with subsequent reductions of NO, PGE(2), TNF-alpha and IL-1 beta secretions. This inhibition was reasoned by suppression of NF kappa B (p65) activation, and inhibition of AP-1 (c-Jun., c-Fos, ATF2) translocation. Our findings indicated that IKK alpha-mediated I-epsilon B degradation and MAPK-signaling are involved in regulation of NFKB/AP-1 activation. Furthermore, CoQ(0) triggered HO-1 and NQO-1 genes through increased Nrf2 nuclear translocation and Nrf2/ARE-signaling. This phenomenon was confirmed by diminished CoQ(0) protective effects in Nrf2 knockdown cells, where LPS-induced NO, PGE(2), TNF-alpha and IL-1 beta productions remained high. Molecular evidence revealed that CoQ(0) enhanced Nrf2 steady-state level at both transcriptional and translational levels. CoQ(0)-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 CoQ(0) (5 mg/kg) suppressed LPS-induced (1 mg/kg) induction of iNOS/COX-2 and TNF-(0)/IL-1 beta through tight regulation of NF kappa B/Nrf2 signaling in mice liver and spleen. Our findings conclude that pharmacological actions of CoQ(0) are mediated via inhibition of NFKB/AP-1 activation and induction of Nrf2/ARE-signaling. Owing to its potent anti-inflammatory and antioxidant properties, CoQ(0) could be a promising candidate to treat inflammatory disorders. (C) 2015 Elsevier B.V. All rights reserved.