1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one alleviates lipopolysaccharide-induced inflammation by targeting NF-κB translocation in murine macrophages and it interacts with MD2 in silico

Abstract

Trienones are curcuminoid analogues and are minor constituents in the rhizomes of numerous Curcuma plant species. Studies investigating the biological activities of trienones, particularly their anti-inflammatory activities, are limited. In the present study, the trienone 1,7-bis(4-hydroxy-3- methoxyphenyl)-1,4,6-heptatrien-3-one (HMPH) was struc- turally modified from curcumin using a novel and concise method. HMPH was shown to exhibit potential anti-inflamma- tory effects on lipopolysaccharide (LPS)-activated RAW264.7 macrophages. Furthermore, LPS-induced nitric oxide secre- tion in RAW264.7 cells was markedly and dose-dependently inhibited by HMPH; in addition, HMPH had a greater efficacy compared with curcumin. This inhibition was accompanied by the suppression of inducible nitric oxide synthase and cyclo- oxygenase-2 expression, as well as pro-inflammatory cytokine secretion. To elucidate the molecular mechanism underlying the anti-inflammatory effects of HMPH, the effects of this compound on nuclear factor-κB (NF-κB) translocation were assessed. HMPH significantly inhibited the translocation of p65 NF-κB into the nucleus to a greater extent than curcumin, thus indicating that HMPH has more potent anti-inflammatory activity than curcumin. In addition, an in silico modelling study revealed that HMPH possessed stronger binding energy to myeloid differentiation factor 2 (MD2) compared with that of curcumin, and indicated that the anti-inflammatory effects of HMPH may be through upstream inhibition of the inflam- matory pathway. In conclusion, HMPH may be considered a promising compound for reducing inflammation via targeting p65 NF-κB translocation and interfering with MD2 binding.