Relative antioxidant activities of quercetin and its structurally related substances and their effects on NF-κB/CRE/AP-1 signaling in murine macrophages

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by the oxidative burst in activated macrophages and neutrophils cause oxidative stressimplicated diseases. Quercetin is flavonoid that occurs naturally in plants and is widely used as a nutritional supplement due to its antioxidant and anti-inflammatory properties. In this study, we investigated antioxidant activities and mechanisms of action in zymosan-induced macrophages of quercetin and quercetin-related flavonoids such as quercitrin, isoquercitrin, quercetin 3-O-beta-(2aEuro(3)-galloyl)-rhamnopyranoside (QGR) and quercetin 3-O-beta-(2aEuro(3)-galloyl)-glucopyranoside (QGG) as well as gallic acid, a building moiety of QGR and QGG. QGR and QGG exhibited stronger antioxidant activities compared with quercetin, whereas quercitrin, isoquercitrin and gallic acid exhibited weak-tono antioxidant activities, assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, superoxide production, superoxide scavenging, nitric oxide (NO) production, peroxynitrite (ONOO-) scavenging and myeloperoxidase (MPO) activity. Regarding mechanisms, the quercetincontaining flavonoids QGR and QGG differentially targeted compared with quercetin in the NF-kappa B signaling pathway that inhibited the DNA binding activity of the NF-kappa B complex without affecting the degradation and phosphorylation of I kappa B alpha and NF-kappa B phosphorylation. In addition, QGR and QGG inhibited CRE and activator protein (AP-1) transcriptional activity and JNK phosphorylation by inhibiting the cAMP/protein kinase A (PKA) and protein kinase C (PKC) signaling in a different manner than quercetin. Our results showed that although QGR and QGG exhibited stronger antioxidant activities than querce-tin in macrophages, their mechanisms of action in terms of the NF-kappa B, PKA and PKC signaling pathways were different.