title: Salvianolic acid A suppress lipopolysaccharide-induced NF-κB signaling pathway by targeting IKKβ.
abstract: Salvianolic acid A, an active compound present in Salvia miltiorrhiza, is a phenolic carboxylic acid derivative, ((2R)-3-(3,4-Dihydroxyphenyl)-2-[(E)-3-[2-[(E)-2-(3,4-dihydroxyphenyl) ethenyl]-3,4-dihydroxyphenyl] prop-2-enoyl]oxypropanoic acid). The present study was performed to investigate the underlying mechanisms of anti-inflammatory effects with salvianolic acid A, specially focused on nuclear factor κB (NF-κB) signaling pathway by targeting the IκB kinase β (IKKβ). The effect of salvianolic acid A for IKKβ activity was analyzed using an immobilized metal affinity for phosphochemicals (IMAP)-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The underlying mechanisms of salvianolic acid A were examined using lipopolysaccharide (LPS)-stimulated RAW264.7 cells. IKKβ studies based on IMAP-TR-FRET showed that salvianolic acid A possesses a potent IKKβ inhibitory activity with Ki value of 3.63 μM in an ATP-noncompetitive manner. Pretreatment with salvianolic acid A (10, 30 μM) decreased LPS-induced expression of iNOS and COX-2, thereby inhibiting production of nitric oxide and prostaglandin E(2), respectively. In addition, salvianolic acid A (10, 30 μM) also attenuated the LPS-induced IκBα phosphorylation and degradation, and NF-κB translocation. These results suggest that salvianolic acid A modulates NF-κB-dependent inflammatory pathways through IKKβ inhibition and these anti-inflammatory effects will aid in understanding the pharmacology and mode of action of salvianolic acid A.
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong, Daejeon 305-343, Republic of Korea.
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.forename: Byung Koo
authors.initials: BK
authors.lastname: Oh
authors.forename: Jihye
authors.initials: J
authors.lastname: Mun
authors.forename: Ho Won
authors.initials: HW
authors.lastname: Seo
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002109:Caffeic Acids / Q000493:pharmacokinetics*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D015151:Immunoblotting; D007773:Lactates / Q000493:pharmacokinetics*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002109:Caffeic Acids; D007773:Lactates; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; C066201:salvianolic acid A; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D015232:Dinoprostone