α-Mangostin Suppresses TNF-α-Induced Biomarkers of Endothelial Dysfunction

Abstract

Sepsis is a condition of dysregulated response to infection. Endothelial dysfunction is a key event in the onset and progression of sepsis, marked by a heightened pro-inflammatory response. Tumour necrosis factor-alpha (TNF-α), a major cytokine elevated in sepsis, induces the expression of adhesion molecules and cytokines which leads to the leukocyte recruitment. With limited treatment options to counteract sepsis-induced inflammation, natural compounds offer promising alternatives. α-Mangostin, a xanthone from Garcinia mangostana, exhibits anti-inflammatory properties, but its effects on TNF-αactivated endothelial cells remain underexplored. Herein, this study aimed to investigate the potential of α-Mangostin in modulating the inflammatory response of TNF-α-stimulated endothelial cells. Firstly, the structure of isolated α-Mangostin was confirmed via NMR and FTIR and the optimal non-toxic concentration of α-Mangostin in endothelial cells was pre-determined. Subsequently, a range of concentrations of α-Mangostin between 0.1-10 µM was added into TNF-α- stimulated human umbilical vein endothelial cells (HUVECs). After 4 h of exposure to TNF-α, cell lysates and medium supernatants were collected, and the effect of α-Mangostin in attenuating adhesion molecules (E-selectin, VCAM-1, and ICAM-1) and pro-inflammatory cytokine (IL-6) expression was measured using Western blot and ELISA, respectively. Additionally, the effect of the therapeutic concentration of α-Mangostin relative to an NF-κB inhibitor, BAY-11-7082, at a similar concentration, was compared. Cell viability assay, CCK-8, showed the IC50 of HUVEC against α-Mangostin to be 10.69 µM. α-Mangostin downregulated E-selectin, VCAM-1, and ICAM-1, with 1 µM and 10 µM showing comparable efficacy. Additionally, α-Mangostin significantly reduced IL-6 secretion from TNF-α-induced endothelial cells from 0.1 µM to 10 µM. Suppression of anti-inflammatory molecules was higher than the positive control, BAY-11-7082, suggesting possible inhibitory action beyond NF-κB activation. These findings highlight the potential of α-Mangostin as a therapeutic candidate to counteract sepsis-related endothelial dysfunction.