Vaiyapuri Sakthivel, Roweth Harvey, Ali Marfoua S, Unsworth Amanda J, Stainer Alexander R, Flora Gagan D, Crescente Marilena, Jones Chris I, Moraes Leonardo A, Gibbins Jonathan M
Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
School of Pharmacy, University of Reading, Reading, UK.
Br J Pharmacol. 2015 Aug;172(16):4133-45. doi: 10.1111/bph.13191. Epub 2015 Jun 26.
The discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin, in the modulation of platelet function.
The ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. Fibrinogen binding, α-granule secretion and calcium mobilization assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice.
Nobiletin was shown to suppress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilization and thrombus formation. Nobiletin extended bleeding time in mice and reduced the phosphorylation of PKB (Akt) and PLCγ2 within the collagen receptor (glycoprotein VI)-stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of vasodilator-stimulated phosphoprotein, a protein whose activity is associated with inhibitory cyclic nucleotide signalling.
This study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore, nobiletin may represent a potential antithrombotic agent of dietary origins.
黄酮类化合物能够抑制血小板功能这一发现，促使人们将其作为潜在的抗血栓药物进行研究。然而，尽管对黄酮类化合物的抗血小板特性开展了一系列研究，但对于黄酮类化合物抑制血小板功能的机制却知之甚少。在本研究中，我们旨在探讨一种多甲氧基黄酮——橙皮素在调节血小板功能方面的药理作用。
采用一系列体外和体内实验方法，探究橙皮素调节血小板功能的能力。使用洗涤后的血小板进行聚集、致密颗粒分泌和铺展试验。使用富含血小板的血浆进行纤维蛋白原结合、α颗粒分泌和钙动员试验，并在阻抗聚集试验和血栓形成实验中使用全血。通过测量C57BL/6小鼠的尾部出血时间，评估橙皮素在体内的作用。
结果表明，橙皮素可抑制一系列已明确的激活机制，包括血小板聚集、颗粒分泌、整合素调节、钙动员和血栓形成。橙皮素可延长小鼠的出血时间，并降低胶原受体（糖蛋白VI）刺激途径中蛋白激酶B（Akt）和磷脂酶Cγ2的磷酸化水平，此外还可提高环磷酸鸟苷（cGMP）水平以及血管舒张刺激磷蛋白的磷酸化水平，该蛋白的活性与抑制性环核苷酸信号传导相关。
本研究深入探讨了橙皮素调节止血和血栓形成的潜在分子机制。因此，橙皮素可能是一种具有饮食来源的潜在抗血栓药物。
