Desmethylanhydroicaritin inhibits NF-kappaB-regulated inflammatory gene expression by modulating the redox-sensitive PI3K/PTEN/Akt pathway.
Eur J Pharmacol
; 602(2-3): 422-31, 2009 Jan 14.
Article
em En
| MEDLINE
| ID: mdl-19027002
ABSTRACT
We investigated the effect of desmethylanhydroicaritin (DMAI), a major compound of the Chinese herbal medicine Epimedium, on inflammatory gene expression and the NF-kappaB signaling pathway. We found that DMAI suppressed the expression of NF-kappaB-responsive genes, such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1beta, and tumor necrosis factor-alpha, in lipopolysaccharide (LPS)-stimulated macrophages and endotoxemic mice as well as protected mice against LPS-induced lethality. DMAI inhibited NF-kappaB activation through the inhibition of IkappaB kinase (IKK) activation, IkappaB phosphorylation and degradation, and NF-kappaB nuclear translocation in LPS-stimulated macrophages. This compound inhibited in vitro and in vivo LPS-induced phosphatidylinositol 3-kinase (PI3K) activation, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) oxidation, and Akt phosphorylation, which are upstream modulators of IKK activation. Moreover, treatment with DMAI was not observed to affect the interaction between the Toll-like receptor 4, MyD88, and TRAF6 as well as mitogen-activated protein kinase activation. DMAI also suppressed intracellular H(2)O(2) accumulation, hydroxyl radical production, and glutathione oxidation without affecting superoxide generation and accumulation by NADPH oxidase. Moreover, DMAI inhibited redox-sensitive activation of the PI3K/PTEN/Akt pathway and NF-kappaB activation in macrophages treated with H(2)O(2). These results indicate that DMAI negatively regulates canonical NF-kappaB-regulated inflammatory gene expression by functioning as an inhibitor of the NF-kappaB pathway through the suppression of redox-based PI3K activation and PTEN inactivation and therefore can be considered as a potential drug for inflammatory diseases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
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NF-kappa B
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Fosfatidilinositol 3-Quinases
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Flavonas
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PTEN Fosfo-Hidrolase
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Proteínas Proto-Oncogênicas c-akt
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Inflamação
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2009
Tipo de documento:
Article