Combinatorial Action of Triterpenoid, Flavonoid, and Alkaloid on Inflammation

Abstract

In the present study, the synergistic effects of BASk, a combination of betulinic acid (B), apigenin (A), and skimmianine (Sk) in the ratio of 1:1:1, were studied to construct a novel drug mixture against inflammation via the TLR4-nuclear factor Kappa light chain enhancer of activated B cells (NFκB) signaling pathway. In silico drug likeness and docking studies recommended 3 bioactive compounds as suitable ligands for drug development. BASk inhibited TLR4 from its dimerization with MD2 and blocked the TLR4 signaling cascade. Reduced nuclear translocation of NFκB inhibited the release of pro-inflammatory mediators (IL-1β and TNF-α), COX-2 expression, and PGE2. Similarly, BASk exerted its protective role by reducing pro-inflammatory mediators and elevating anti-inflammatory cytokine, IL-10. This confirms the inhibiting potential of BASk in the activation of the TLR4-NFκB signaling cascade. Thus, BASk was superior in its anti-inflammatory effect on oxidized low density lipoprotein (ox-LDL) induced human peripheral blood mononuclear cells than its individual components synergistically. Since BASk inhibited COX-2 expression and further release of PGE2, it is a potent therapeutic agent with better efficacy against inflammation because COX-2 is the target site for treating inflammatory diseases. Thus, it can be clearly stated that this innovation will be a breakthrough in the treatment of inflammatory diseases.