ABSTRACT
Oxomollugin is a degraded product of mollugin and was found to be an active compound that inhibits LPS-induced NF-κB activation. In this study, we investigated the inhibitory activity of oxomollugin, focusing on TLR4 signaling pathway, resulting in NF-κB activation. Oxomollugin inhibited the LPS-induced association of essential factors for initial activation of TLR4 signaling, MyD88, IRAK4 and TRAF6. Furthermore, oxomollugin showed suppressive effects on LPS-induced modification of IRAK1, IRAK2 and TRAF6, LPS-induced association of TRAF6-TAK1/TAB2, and followed by IKKα/ß phosphorylation, which critical in signal transduction leading to LPS-induced NF-κB activation. The consistent results suggested that oxomollugin inhibits LPS-induced NF-κB activation via the suppression against signal transduction in TLR4 signaling pathway.The activities of oxomollugin reported in this study provides a deeper understanding on biological activity of mollugin derivatives as anti-inflammatory compounds.
Subject(s)
Lipopolysaccharides , NF-kappa B , Signal Transduction , Toll-Like Receptor 4 , Toll-Like Receptor 4/metabolism , NF-kappa B/metabolism , Lipopolysaccharides/pharmacology , Signal Transduction/drug effects , Animals , Mice , Humans , RAW 264.7 Cells , Phosphorylation/drug effects , Myeloid Differentiation Factor 88/metabolism , Lactones , Resorcinols , Zearalenone/administration & dosageABSTRACT
Oxomollugin (2) is a degradation product of mollugin (1) and a potent inhibitor of NO-production including nuclear factor kappa B signals. In our endeavor to develop a potent anti-inflammatory compound, we synthesized several aza-derivatives of oxomollugin (2) and evaluated their NO-production inhibitory activity. Azamollugin (3) showed a potent inhibitory activity, and its activity (IC50 0.34µM) was proved to be more potent than that of oxomollugin (2, IC50 1.3µM).
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Nitric Oxide/antagonists & inhibitors , Quinolones/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Cell Line , Lipopolysaccharides/pharmacology , Mice , Quinolones/chemical synthesisABSTRACT
Mollugin, a naphthoquinone derivative, was reported to possess various biological activities such as anti-inflammatory and anti-tumor activity. Mollugin isolated from Rubia tinctorum roots inhibited lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 macrophages. However, mollugin synthesized for further investigation of its anti-inflammatory mechanism showed weak activity in addition to unstable assay results. From the result of analysis on a degradation product of mollugin, oxomollugin was found to be the main active substance of mollugin degradation, showing a potent inhibitory activity on NO-production including nuclear factor kappa B signals.