Studies on the mechanism of anti-inflammatory action of swietenine, a tetranortriterpenoid isolated from <i>Swietenia macrophylla </i>seeds

Background: Swietenia macrophylla seeds possess diverse biological activities in which inflammation is the primary cause, and swietenine is the main tetranortriterpenoid present. Purpose: The purpose of the study is to investigate the molecular mechanisms involved in the anti-inflammatory activity of swietenine and its cytoprotective effect. Methods: The anti-inflammatory activity of swietenine and its molecular mechanisms were evaluated using LPSEc- stimulated RAW 264.7 cells. The cytoprotective effect of swietenine was evaluated via determining NRF2 inducing activity in Hepa-1c1c7 cells. The in vitro metabolic stability of swietenine was assessed using mouse, rat and human liver microsomes.Results: Swietenine showed dose-dependent effect in inhibiting NO production, downregulating pro-inflammatory cytokines (IL-1β, IFN-γ, TNF-α, and IL-6) and mediators (NF-κB and COX-2); and increasing the levels of NRF2, and HO-1 in LPSEc-stimulated RAW264.7 cells. Swietenine also induced NQO1 activity, a classical marker of NRF2 activation, in Hepa-1c1c7 cells. In addition, swietenine was metabolically stable in mouse, rat, and human liver microsomes. Conclusion: The results suggest that the anti-inflammatory effect of swietenine is mediated by the down-regulation of pro-inflammatory cytokines and mediators and the activation of cytoprotective NRF2/HO-1 pathway.