Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells.
Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells.
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DOI：
10.3945/jn.115.217943
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Kay CD
中科院分区：
文献类型：
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作者：
Warner EF;Zhang Q;Raheem KS;O'Hagan D;O'Connell MA;Kay CD
背景资料：黄酮类化合物已被牵连在预防心血管疾病，然而，其作用机制尚未阐明，可能是因为大多数以前的体外研究使用超生理浓度的未代谢的黄酮类化合物，忽略了他们的更多的生物可利用的酚类代谢物。 目的：我们的目的是探索酚类代谢物及其前体黄酮类化合物在生理上可达到的浓度，在隔离和组合，可溶性血管细胞粘附分子-1（sVCAM-1）的影响。方法：筛选了14种酚酸代谢物和6种黄酮类化合物（1 μM）对肿瘤坏死因子α（TNF-α）刺激的人脐静脉内皮细胞分泌sVCAM-1的相对影响。进一步研究了活性代谢产物在不同浓度（0.01 μM-100 μM）下的反应、构效关系以及对血管细胞粘附分子（VCAM）-1 mRNA表达的影响。此外，通过筛选累积等摩尔浓度为1 μM的25种独特混合物，研究了代谢产物和黄酮类化合物的相加活性。结果如下：在1 μM筛选的20种化合物中，4种酚类代谢物可抑制sVCAM-1分泌，其中原儿茶酸（PCA）活性最高（− 17.2%，P = 0.05）。在不同浓度下对它们的反应的研究表明，PCA在1和100 μM之间显著降低sVCAM-1 15.2-36.5%，原儿茶酸-3-硫酸酯和异香草酸在10和100 μM之间降低sVCAM-1 12.2-54.7%，仅在100 μM时，原儿茶酸-4-硫酸酯和异香草酸-3-葡萄糖醛酸苷分别使sVCAM-1分泌减少27.6%和42.8%。PCA表现出最强的蛋白反应，因此探索了其对VCAM-1 mRNA的影响，其中仅在用100 μM PCA处理后观察到78.4%的抑制。代谢产物的混合物显示对sVCAM-1无活性，表明在1 μM时无相加活性。结论：目前的研究结果表明，类黄酮的代谢增加其血管功效，导致在不同的生物活性在人内皮细胞的结构的多样性。
Background: Flavonoids have been implicated in the prevention of cardiovascular disease; however, their mechanisms of action have yet to be elucidated, possibly because most previous in vitro studies have used supraphysiological concentrations of unmetabolized flavonoids, overlooking their more bioavailable phenolic metabolites. Objective: We aimed to explore the effects of phenolic metabolites and their precursor flavonoids at physiologically achievable concentrations, in isolation and combination, on soluble vascular cellular adhesion molecule-1 (sVCAM-1). Method: Fourteen phenolic acid metabolites and 6 flavonoids were screened at 1 μM for their relative effects on sVCAM-1 secretion by human umbilical vein endothelial cells stimulated with tumor necrosis factor alpha (TNF-α). The active metabolites were further studied for their response at different concentrations (0.01 μM–100 μM), structure-activity relationships, and effect on vascular cellular adhesion molecule (VCAM)-1 mRNA expression. In addition, the additive activity of the metabolites and flavonoids was investigated by screening 25 unique mixtures at cumulative equimolar concentrations of 1 μM. Results: Of the 20 compounds screened at 1 μM, inhibition of sVCAM-1 secretion was elicited by 4 phenolic metabolites, of which protocatechuic acid (PCA) was the most active (−17.2%, P = 0.05). Investigations into their responses at different concentrations showed that PCA significantly reduced sVCAM-1 15.2–36.5% between 1 and 100 μM, protocatechuic acid-3-sulfate and isovanillic acid reduced sVCAM-1 levels 12.2–54.7% between 10 and 100 μM, and protocatechuic acid-4-sulfate and isovanillic acid-3-glucuronide reduced sVCAM-1 secretion 27.6% and 42.8%, respectively, only at 100 μM. PCA demonstrated the strongest protein response and was therefore explored for its effect on VCAM-1 mRNA, where 78.4% inhibition was observed only after treatment with 100 μM PCA. Mixtures of the metabolites showed no activity toward sVCAM-1, suggesting no additive activity at 1 μM. Conclusions: The present findings suggest that metabolism of flavonoids increases their vascular efficacy, resulting in a diversity of structures of varying bioactivity in human endothelial cells.