Blockade of nuclear factor-κB signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analog from Alpinia conchigera

Nuclear factor-κB (NF-κB) and the signaling pathways that regulate its activity have become a focal point for intense drug discovery and development efforts. NF-κB regulates the transcription of a large number of genes, particularly those involved in immune, inflammatory, and antiapoptotic responses. In our search for NF-κB inhibitors from natural resources, we identified cardamomin, 2′,4′-dihydroxy-6′-methoxychalcone, as an inhibitor of NF-κB activation from Alpinia conchigera Griff (Zingiberaceae). In present study, we demonstrated the effect of cardamomin on NF-κB activation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and LPS-induced mortality. This compound significantly inhibited the induced expression of NF-κB reporter gene by LPS or tumor necrosis factor (TNF)-α in a dose-dependent manner. LPS-induced production of TNF-α and NO as well as expression of inducible nitric-oxide synthase and cyclooxygenase-2 was significantly suppressed by the treatment of cardamomin in RAW264.7 cells. Also, cardamomin inhibited not only LPS-induced degradation and phosphorylation of inhibitor κBα (IκBα) but also activation of inhibitor κB (IκB) kinases and nuclear translocation of NF-κB. Further analyses revealed that cardamomin did not directly inhibit IκB kinases, but it significantly suppressed LPS-induced activation of Akt. Moreover, cardamomin suppressed transcriptional activity and phosphorylation of Ser536 of RelA/p65 subunit of NF-κB. However, this compound did not inhibit LPS-induced activation of extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun NH ₂-terminal kinase, but significantly impaired activation of p38 mitogen-activated protein kinase. We also demonstrated that pretreatment of cardamomin rescued C57BL/6 mice from LPS-induced mortality in conjunction with decreased serum level of TNF-α. Together, cardamomin could be valuable candidate for the intervention of NF-κB-dependent pathological condition such as inflammation.