The C-19 quassinoid eurycomalactone (1) has recently been shown to be a potent (IC50 = 0.5 Î¼M) NF-ÎºB inhibitor in a luciferase reporter model. In this study, we show that 1 with similar potency inhibited the expression of the NF-ÎºB-dependent target genes ICAM-1, VCAM-1, and E-selectin in TNFÎ±-activated human endothelial cells (HUVECtert) by flow cytometry experiments. Surprisingly, 1 (2 Î¼M) did not inhibit TNFÎ±-induced IKKÎ±/Î² or IÎºBÎ± phosphorylation significantly. Also, the TNFÎ±-induced degradation of IÎºBÎ± remained unchanged in response to 1 (2 Î¼M). In addition, pretreatment of HUVECtert with 1 (2 Î¼M) had no statistically significant effect on TNFÎ±-mediated nuclear translocation of the NF-ÎºB subunit p65 (RelA). Quantitative RT-PCR revealed that 1 (0.5-5 Î¼M) exhibited diverse effects on the TNFÎ±-induced transcription of ICAM-1, VCAM-1, and SELE genes since the mRNA level either remained unchanged (ICAM-1, E-selectin, and VCAM-1 at 0.5 Î¼M 1), was reduced (VCAM-1 at 5 Î¼M 1), or even increased (E-selectin at 5 Î¼M 1). Finally, the time-dependent depletion of a short-lived protein (cyclin D1) as well as the measurement of de novo protein synthesis in the presence of 1 (2-5 Î¼M) suggested that 1 might act as a protein synthesis inhibitor rather than an inhibitor of early NF-ÎºB signaling.
|Titolo:||Eurycomalactone inhibits expression of endothelial adhesion molecules at a post-transcriptional level|
|Parole Chiave:||analytical chemistry; molecular medicine; pharmacology; drug discovery; pharmaceutical science; complementary and alternative medicine; dermatology; organic chemistry|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||22-dic-2017|
|Data ahead of print / Data di stampa:||17-nov-2017|
|Digital Object Identifier (DOI):||10.1021/acs.jnatprod.7b00503|
|Appare nelle tipologie:||01 - Articolo su periodico|