The saponin DT-13 Attenuates Tumor Necrosis Factor-α-induced Vascular Inflammation Associated with Src/NF-κB/MAPK Pathway Modulation

This study aimed to explore the effect of DT-13 (25(R,S)-ruscogenin- 1-O-[beta-d-glucopyranosyl-(1 -> 2)][beta-d-xylopyranosyl-(1. 3)]-beta -d- fucopyranoside) on tumor necrosis factor (TNF)-alpha-induced vascular inflammation and the potential molecular mechanisms. In vitro, DT-13 suppressed TNF-alpha-induced adhesion and migration of human umbilical vein endothelial cells (HUVECs) by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). DT-13 markedly suppressed NF-kappa B p65 phosphorylation, and when NF-kappa B p65 was over-expressed, the inhibitory effect of DT-13 on adhesion molecular decreased. DT-13 also suppressed TNF-alpha induced luciferase activities of ICAM-1 and VCAM-1 promoter containing NF-kappa B binding sites. Furthermore, DT-13 markedly suppressed p38 phosphorylation and Src degradation induced by TNF-alpha, whereas had no significant effect on ERK and JNK activation. In vivo, DT-13 at 4 mg/kg prevented vascular inflammation and the expression of adhesion molecules induced by TNF-alpha in mice. These findings suggest that DT-13 abrogates vascular inflammation by down-regulating adhesion molecules associated with modulating the NF-kappa B, p38MAPK, Src signaling pathways, and NF-kappa B binding site is at least one of the targets of DT-13. This study provides novel information regarding the mechanism by which DT-13 exerts its effects on vascular inflammation, which is important for the onset and progression of various diseases.