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Eurycomalactone Inhibits Expression of Endothelial Adhesion Molecules at a Post-Transcriptional Level
Journal of Natural Products ( IF 5.1 ) Pub Date : 2017-11-17 00:00:00 , DOI: 10.1021/acs.jnatprod.7b00503
Clemens Malainer 1 , Daniel Schachner 1 , Enrico Sangiovanni 1, 2 , Atanas G. Atanasov 1, 3 , Stefan Schwaiger 4 , Hermann Stuppner 4 , Elke H. Heiss 1 , Verena M. Dirsch 1
Affiliation  

The C-19 quassinoid eurycomalactone (1) has recently been shown to be a potent (IC50 = 0.5 μM) NF-κB inhibitor in a luciferase reporter model. In this study, we show that 1 with similar potency inhibited the expression of the NF-κB-dependent target genes ICAM-1, VCAM-1, and E-selectin in TNFα-activated human endothelial cells (HUVECtert) by flow cytometry experiments. Surprisingly, 1 (2 μM) did not inhibit TNFα-induced IKKα/β or IκBα phosphorylation significantly. Also, the TNFα-induced degradation of IκBα remained unchanged in response to 1 (2 μM). In addition, pretreatment of HUVECtert with 1 (2 μM) had no statistically significant effect on TNFα-mediated nuclear translocation of the NF-κB subunit p65 (RelA). Quantitative RT-PCR revealed that 1 (0.5–5 μM) exhibited diverse effects on the TNFα-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 μM 1), was reduced (VCAM-1 at 5 μM 1), or even increased (E-selectin at 5 μM 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 μM) suggested that 1 might act as a protein synthesis inhibitor rather than an inhibitor of early NF-κB signaling.

中文翻译:

杜仲内酯在转录后水平上抑制内皮粘附分子的表达。

最近,在萤光素酶报告基因模型中,C-19 quassinoid eurycomalactone(1)是有效的(IC 50 = 0.5μM)NF-κB抑制剂。在这项研究中,我们通过流式细胞术实验显示,具有类似效力的1抑制TNF-α激活的人内皮细胞(HUVECtert)中NF-κB依赖性靶基因ICAM-1,VCAM-1和E-选择素的表达。令人惊讶地,1(2μM)没有明显抑制TNFα诱导的IKKα/β或IκBα磷酸化。此外,响应1(2μM),TNFα诱导的IκBα降解保持不变。此外,用1预处理HUVECtert(2μM)对TNF-α介导的NF-κB亚基p65(RelA)的核易位没有统计学意义。定量RT-PCR结果显示,1(0.5-5μM)上表现出的TNFα诱导的转录不同的影响ICAM-1 VCAM-1 ,和SELE基因由于在mRNA水平或者保持不变(ICAM-1,E-选择素,和1 VCAM-0.5μM 1),减少(VCAM-1在5μM 1),或甚至增加(E-选择在5μM 1)。最后,存在时间短的蛋白质(周期蛋白D1)的时间依赖性消耗以及在1(2–5μM)存在下从头蛋白质合成的测定表明:1可能起蛋白质合成抑制剂的作用,而不是早期NF-κB信号传导的抑制剂。
更新日期:2017-11-17
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