Activation of the Nrf2-antioxidant system by a novel cyclooxygenase-2 inhibitor furan-2-yl-3-pyridin-2-yl-propenone: implication in anti-inflammatory function by Nrf2 activator

Abstract

Furan-2-yl-3-pyridin-2-yl-propenone (FPP-3) is a novel synthetic compound and has demonstrated anti-inflammatory activity by inhibiting cyclooxygenase-2 (COX-2). It is widely accepted that reactive oxygen species (ROS) generated by activated inflammatory cells can exacerbate inflammation. In this study, the potential antioxidative efficacy of FPP-3 has been investigated in murine cells. FPP-3 increased the expression of multiple antioxidative enzymes, including NAD(P)H:quinone oxidoreductase 1 (Nqo1), γ-glutamylcysteine ligase (GCL) and heme oxygenase-1 (HO-1), by facilitating the nuclear translocation of nuclear factor-erythroid 2-p45-related factor 2 (Nrf2). Inducibility of antioxidant proteins such as HO-1 were lost in nrf2-deficient murine fibroblasts. As a result of enhanced cellular antioxidative capacity, elevation of NF-κB-driven reporter gene expression by lipopolysaccharide was attenuated by FPP-3 treatment in murine fibroblasts. Furthermore, FPP-3 treatment inhibited UVA-mediated induction of COX-2 in murine keratinocytes. Our current study suggests that FPP-3, which has been developed as a novel COX-2 inhibitor, has antioxidative properties by activating the Nrf2-ARE pathway. The dual function of this compound may provide a better strategy to block/attenuate the inflammation process and to alleviate ROS-associated inflammatory complications.