期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 606, 期 1-3, 页码 215-224出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2008.12.034
关键词
Chalcone; Heme oxygenase-1; Inflammation; Lipopolysaccharide; Nitric oxide
资金
- Korea Research Foundation [KRF-2006-005 J03202]
- National Research Foundation of Korea [2006-005-J03202] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Chalcones, a subclass of the flavonoid family, are widely known for their anti-inflammatory and anti-oxidative Properties. In the present Study, we synthesized the chalcone derivative, KB-34 (3-Phenyl-1-(2,4,6-tris (methoxymethoxy)phenyl)prop-2-yn-1-one), and examined its effect on nitric oxide (NO) production. KB-34 potently inhibited nitrite production in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). KB-34 treatment also markedly inhibited inducible nitric oxide synthase (iNOS) expression as assessed by Western blot and quantitative RT-PCR analyses. Treatment of cells with KB-34 significantly inhibited LPS-induced transcriptional activation by activator protein-1 (AP-1) as determined by luciferase reporter gene assay, whereas nuclear factor-kappa B (NF-kappa B) activity was not affected by KB-34, indicating that down-regulation of iNOS gene expression by KB-34 is mainly attributed by blockade of AP-1 activation. We also demonstrated that KB-34 treatment led to an increase in heme oxygenase-1 (HO-1) mRNA and protein expression, mediated by stimulating the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2). Treatment with SnPP, a selective inhibitor of HO-1, reversed the KB-34-mediated inhibition of nitrite production, suggesting that HO-1 plays an important role in the suppression of NO production by KB-34. In contrast, SnPP treatment did not counteract the KB-34-mediated suppression of AM activity, suggesting that inhibition of AP-1 activation by KB-34 is independent of HO-1 induction. Taken together, these results indicate that KB-34 Suppresses NO production in LPS-stimulated RAW 264.7 macrophages via simultaneous induction of HO-1 expression and blockade of AP-1 activation. This study reveals that KB-34 would be a promising agent for the treatment of inflammation-associated disease. (C) 2009 Elsevier B.V. All rights reserved.
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