title: Anti-inflammatory activity of rhamnetin and a model of its binding to c-Jun NH2-terminal kinase 1 and p38 MAPK.
abstract: Rhamnetin (1), a commonly occurring plant O-methylated flavonoid, possesses antioxidant properties. To address the potential therapeutic efficacy of 1, its anti-inflammatory activity and mode of action in mouse macrophage-derived RAW264.7 cells stimulated with lipopolysaccharide (LPS) or interferon (IFN)-γ were investigated. Rhamnetin (1) suppressed mouse tumor necrosis factor (mTNF)-α, mouse macrophage inflammatory protein (mMIP)-1, and mMIP-2 cytokine production in LPS-stimulated macrophages. A nontoxic dose of 1 suppressed nitric oxide production. It was found that the anti-inflammatory effects of 1 are mediated by actions on the p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and cyclooxygenase (COX)-2 pathways in LPS- or IFN-γ-stimulated RAW264.7 cells. It was determined that 1 binds to human JNK1 (9.7 × 10(8) M(-1)) and p38 MAPK (2.31 × 10(7) M(-1)) with good affinity. The binding model showed interactions with the 3'- and 4'-hydroxy groups of the B-ring and the 5-hydroxy group of the A-ring of 1. Further, 1 exerted an anti-inflammatory effect, reducing the levels of pro-inflammatory cytokines and mediators.
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Konkuk University , Seoul 143-701, South Korea.
authors.forename: Hum Nath
authors.initials: HN
authors.lastname: Jnawali
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.forename: Ki-Woong
authors.initials: KW
authors.lastname: Jeong
authors.forename: Areum
authors.initials: A
authors.lastname: Shin
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Yangmee
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C063423:rhamnetin; D007371:Interferon-gamma; D011794:Quercetin; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases