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.
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), gamma-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-kappaB-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.
College of Pharmacy, Yeungnam University, 214-1 Dae-dong, Gyeongsan-si, Gyeongsangbuk-do 712-749, South Korea.
Sarala
S
Manandhar
Aram
A
You
Eung-Seok
ES
Lee
Jung-Ae
JA
Kim
Mi-Kyoung
MK
Kwak
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements
C508534:1-furan-2-yl-3-pyridin-2-yl-propenone; D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011725:Pyridines; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D011407:Propane