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Evidence-Based Complementary and Alternative Medicine
Volume 2017, Article ID 7898973, 12 pages
Research Article

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

1College of Science and Technology, Nihon University, Chiyoda, Tokyo 101-0062, Japan
2Department of Chemistry and Biomolecular Sciences, Faculty of Engineering, Gifu University, Gifu 501-1112, Japan
3Department of Biomedical Information Engineering, Graduate School of Medical Science, Yamagata University, Yamagata 990-2332, Japan
4School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan
5Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan
6National Institute of Infectious Diseases, Musashimurayama, Tokyo 208-0011, Japan

Correspondence should be addressed to Atsuyoshi Nishina;

Received 10 October 2016; Revised 3 February 2017; Accepted 13 February 2017; Published 30 April 2017

Academic Editor: Darren R. Williams

Copyright © 2017 Atsuyoshi Nishina et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


We studied the anti-inflammatory activity of twelve 5,7-dihydroxyflavone analogues in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. We found that chrysin (1) and 4′-methoxytricetin (9) showed relatively significant anti-inflammatory activity and low cytotoxicity. Moreover, 1 and 9 recovered the expression levels of iNOS and COX2, as well as those of the intracellular inflammatory mediators IL-1β and IL-6, which were upregulated by LPS stimulation. In addition, 1 and 9 actively regulated the phosphorylation of IκBα, leading to the activation of NFκB. Phosphorylation of Akt and ERK5 (upstream of NFκB) by LPS stimulation was significantly regulated by 1 and 9, as well as by BIX 02189 and LY 294002, which are phosphorylation inhibitors of ERK5 and Akt, respectively. The results suggest that compounds 1 and 9 may suppress the levels of iNOS and COX2 by regulating phosphorylation of Akt, ERK5, and IκBα and thus NFκB-related signaling pathways, resulting in anti-inflammatory effects in the cells. Because 1 and 9 showed low cytotoxicity and regulated both PGE2 and NO production caused by inflammatory responses, they may hold promise as natural anti-inflammatory agents.