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Role of nuclear factor‐ κ B and heme oxygenase‐1 in the mechanism of action of an anti‐inflammatory chalcone derivative in RAW 264.7 cells
Author(s) -
Alcaraz María José,
Vicente Ana María,
Araico Amparo,
Dominguez José N,
Terencio María Carmen,
Ferrándiz María Luisa
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705821
Subject(s) - chalcone , heme oxygenase , heme , mechanism of action , chemistry , nitric oxide , nitric oxide synthase , biochemistry , chalcone synthase , lipopolysaccharide , nf κb , transcription factor , signal transduction , microbiology and biotechnology , pharmacology , antioxidant , biology , stereochemistry , flavonoid , enzyme , gene , in vitro , immunology , organic chemistry
The synthetic chalcone 3′,4′,5′,3,4,5‐hexamethoxy‐chalcone (CH) is an anti‐inflammatory compound able to reduce nitric oxide (NO) production by inhibition of inducible NO synthase protein synthesis. In this work, we have studied the mechanisms of action of this compound. CH (10–30 μ M ) prevents the overproduction of NO in RAW 264.7 macrophages stimulated with lipopolysaccharide (1 μ g ml −1 ) due to the inhibition of nuclear factor κ B (NF‐ κ B) activation. We have shown that treatment of cells with CH results in diminished degradation of the NF‐ κ B–I κ B complex leading to inhibition of NF‐ κ B translocation into the nucleus, DNA binding and transcriptional activity. We also demonstrate the ability of this compound to activate NfE2‐related factor (Nrf2) and induce heme oxygenase‐1 (HO‐1). Our results indicate that CH determines a rapid but nontoxic increase of intracellular oxidative species, which could be responsible for Nrf2 activation and HO‐1 induction by this chalcone derivative. This novel anti‐inflammatory agent simultaneously induces a cytoprotective response (HO‐1) and downregulates an inflammatory pathway (NF‐ κ B) with a mechanism of action different from antioxidant chalcones.British Journal of Pharmacology (2004) 142 , 1191–1199. doi: 10.1038/sj.bjp.0705821