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海洋来源的三萜皂苷 Frondoside A 抑制血栓形成。

The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation.

机构信息

Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany.

出版信息

Mar Drugs. 2020 Feb 14;18(2):111. doi: 10.3390/md18020111.

DOI:10.3390/md18020111
PMID:32074969
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7074411/
Abstract

BACKGROUND

The marine-derived triterpenoid frondoside A inhibits the phosphatidylinositol-3-kinase (PI3K) pathway in cancer cells. Because this pathway is also crucially involved in platelet activation, we studied the effect of frondoside A on thrombus formation.

METHODS

Frondoside A effects on platelet viability, surface adhesion molecule expression, and intracellular signaling were analyzed by flow cytometry and Western blot. The effect of frondoside A was analyzed by photochemically induced thrombus formation in the mouse dorsal skinfold chamber model and by tail vein bleeding.

RESULTS

Concentrations of up to 15 µM frondoside A did not affect the viability of platelets, but reduced their surface expression of P-selectin (CD62P) and the activation of glycoprotein (GP)IIb/IIIa after agonist stimulation. Additional mechanistic analyses revealed that this was mediated by downregulation of PI3K-dependent Akt and extracellular-stimuli-responsive kinase (ERK) phosphorylation. Frondoside A significantly prolonged the complete vessel occlusion time in the mouse dorsal skinfold chamber model of photochemically induced thrombus formation and also the tail vein bleeding time when compared to vehicle-treated controls.

CONCLUSION

Our findings demonstrated that frondoside A inhibits agonist-induced CD62P expression and activation of GPIIb/IIIa. Moreover, frondoside A suppresses thrombus formation. Therefore, this marine-derived triterpenoid may serve as a lead compound for the development of novel antithrombotic drugs.

摘要

背景

海洋来源的三萜类化合物 frondoside A 抑制癌细胞中的磷脂酰肌醇-3-激酶 (PI3K) 途径。由于该途径在血小板激活中也起着至关重要的作用，我们研究了 frondoside A 对血栓形成的影响。

方法

通过流式细胞术和 Western blot 分析 frondoside A 对血小板活力、表面黏附分子表达和细胞内信号的影响。通过在小鼠背部皮肤囊模型中的光化学诱导血栓形成和尾静脉出血分析 frondoside A 的作用。

结果

高达 15µM 的 frondoside A 浓度不会影响血小板的活力，但会减少其在激动剂刺激后的 P-选择素（CD62P）表面表达和糖蛋白 (GP)IIb/IIIa 的激活。进一步的机制分析表明，这是通过下调 PI3K 依赖性 Akt 和细胞外刺激反应激酶 (ERK) 磷酸化介导的。与载体处理对照组相比，frondoside A 显著延长了小鼠背部皮肤囊模型中光化学诱导血栓形成的完全血管闭塞时间和尾静脉出血时间。

结论

我们的研究结果表明，frondoside A 抑制激动剂诱导的 CD62P 表达和 GPIIb/IIIa 的激活。此外，frondoside A 抑制血栓形成。因此，这种海洋来源的三萜类化合物可能作为开发新型抗血栓药物的先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/d92536ac98d6/marinedrugs-18-00111-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/6649e9e301b4/marinedrugs-18-00111-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/4e0ff0232ead/marinedrugs-18-00111-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/28e77cab4fa1/marinedrugs-18-00111-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/d92536ac98d6/marinedrugs-18-00111-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/6649e9e301b4/marinedrugs-18-00111-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/4e0ff0232ead/marinedrugs-18-00111-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/28e77cab4fa1/marinedrugs-18-00111-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e28/7074411/d92536ac98d6/marinedrugs-18-00111-g004.jpg

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