5,7-Dihydroxyflavone Analogues May Regulate Lipopolysaccharide-Induced Inflammatory Responses by Suppressing IB-Linked Akt and ERK5 Phosphorylation in RAW 264.7 Macrophages.

We studied the anti-inflammatory activity of twelve 5,7-dihydroxyflavone analogues in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. We found that chrysin () and 4'-methoxytricetin () showed relatively significant anti-inflammatory activity and low cytotoxicity. Moreover, and recovered the expression levels of iNOS and COX2, as well as those of the intracellular inflammatory mediators IL-1 and IL-6, which were upregulated by LPS stimulation. In addition, and actively regulated the phosphorylation of IB, leading to the activation of NFB. Phosphorylation of Akt and ERK5 (upstream of NFB) by LPS stimulation was significantly regulated by and , as well as by BIX 02189 and LY 294002, which are phosphorylation inhibitors of ERK5 and Akt, respectively. The results suggest that compounds and may suppress the levels of iNOS and COX2 by regulating phosphorylation of Akt, ERK5, and IB and thus NFB-related signaling pathways, resulting in anti-inflammatory effects in the cells. Because and showed low cytotoxicity and regulated both PGE and NO production caused by inflammatory responses, they may hold promise as natural anti-inflammatory agents.