Lee Wonhwa, Kim Mi-Ae, Park InWha, Hwang Jae Sam, Na MinKyun, Bae Jong-Sup
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea; Department of Agricultural Biology, The National Academy of Agricultural Science, RDA, Wanju-gun 55365, Republic of Korea.
Food Chem Toxicol. 2017 Nov;109(Pt 1):19-27. doi: 10.1016/j.fct.2017.08.026. Epub 2017 Aug 24.
Tenebrio molitor is an edible insect that has antimicrobial, anticancer, and antihypertensive effects. The aim of this study was to identify the unreported bioactive compounds from T. molitor larvae with inhibitory activities against factor Xa (FXa) and platelet aggregation. Isolated compounds were evaluated for their anti-FXa and anti-platelet aggregation properties by monitoring clotting time, platelet aggregation, FXa activity, and thrombus formation. A diketopiperazine (1, cyclo(-Pro--Tyr)) and a phenylethanoid (2, N-acetyltyramine) were isolated and inhibited the catalytic activity of FXa in a mixed inhibition model and inhibited platelet aggregation induced by adenosine diphosphate (ADP) and U46619. They inhibited ADP- and U46619-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) and the expression of P-selectin and PAC-1 in platelets. They also improved the production of nitric oxide and inhibited the oversecretion of endothelin-1 compared to that of the ADP- or U46619-treated group. In an animal model of arterial and pulmonary thrombosis, the isolated compounds showed enhanced antithrombotic effects. They also elicited anticoagulant effects in mice. Compounds 1-2 inhibited ADP-, collagen-, or U46619-induced platelet aggregation and showed similar anti-thrombotic efficacy to rivaroxaban, a positive control. Therefore, 1-2 could serve as candidates and provide scaffolds for the development of new anti-FXa and anti-platelet drugs.
黄粉虫是一种具有抗菌、抗癌和抗高血压作用的可食用昆虫。本研究的目的是从黄粉虫幼虫中鉴定出尚未报道的具有抑制凝血因子Xa（FXa）和血小板聚集活性的生物活性化合物。通过监测凝血时间、血小板聚集、FXa活性和血栓形成来评估分离出的化合物的抗FXa和抗血小板聚集特性。分离出一种二酮哌嗪（1，环（-脯氨酸-酪氨酸））和一种苯乙醇类化合物（2，N-乙酰酪胺），它们在混合抑制模型中抑制FXa的催化活性，并抑制二磷酸腺苷（ADP）和U46619诱导的血小板聚集。它们抑制ADP和U46619诱导的富含丙氨酸的肉豆蔻酰化C激酶底物（MARCKS）的磷酸化以及血小板中P-选择素和PAC-1的表达。与ADP或U46619处理组相比，它们还提高了一氧化氮的产生并抑制了内皮素-1的过度分泌。在动脉和肺血栓形成的动物模型中，分离出 的化合物显示出增强的抗血栓作用。它们在小鼠中也引发了抗凝作用。化合物1-2抑制ADP、胶原或U46619诱导的血小板聚集，并且显示出与阳性对照利伐沙班相似的抗血栓疗效。因此，1-2可作为候选物，并为开发新的抗FXa和抗血小板药物提供支架。
