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Pharmacological actions of miltirone in the modulation of platelet function.
Acta Pharmacologica Sinica ( IF 8.2 ) Pub Date : 2018-05-23 , DOI: 10.1038/s41401-018-0010-1 Wei Song 1, 2 , Yuan-Yuan Ma 1, 2 , Shuo Miao 1, 2 , Ru-Ping Yang 1, 2 , Ying Zhu 1, 2 , Dan Shu 1, 2 , Meng Lu 1, 2 , Rong Ma 1, 2 , Zhang-Yin Ming 1, 2, 3
Acta Pharmacologica Sinica ( IF 8.2 ) Pub Date : 2018-05-23 , DOI: 10.1038/s41401-018-0010-1 Wei Song 1, 2 , Yuan-Yuan Ma 1, 2 , Shuo Miao 1, 2 , Ru-Ping Yang 1, 2 , Ying Zhu 1, 2 , Dan Shu 1, 2 , Meng Lu 1, 2 , Rong Ma 1, 2 , Zhang-Yin Ming 1, 2, 3
Affiliation
Salvia miltiorrhiza Bunge contains various active constituents, some of which have been developed as commercially available medicine. Moreover, some other ingredients in Salvia miltiorrhiza play roles in anti-platelet activity. The aim of the present study was to investigate the effects and the underlying mechanism of miltirone, a lipophilic compound of Salvia miltiorrhiza Bunge. The ability of miltirone to modulate platelet function was investigated by a variety of in vitro and in vivo experiments. Platelet aggregation and dense granule secretion induced by various agonists were measured with platelet aggregometer. Clot retraction and spreading were imaged by digital camera and fluorescence microscope. Ferric chloride-induced carotid injury model and pulmonary thromboembolism model were used to check miltirone antithrombotic effect in vivo. To elucidate the mechanisms of anti-platelet activity of miltirone, flow cytometry and western blotting were performed. Miltirone (2, 4, 8 µM) was shown to suppress platelet aggregation, dense granule, and α granule secretion in a dose-dependent manner. Meanwhile, miltirone inhibited the clot retraction and spreading of washed platelets. It reduced the phosphorylation of PLCγ2, PKC, Akt, GSK3β and ERK1/2 in the downstream signal pathway of collagen receptor. It also reduced the phosphorylation of Src and FAK in the integrin αIIbβ3-mediated "outside-in" signaling, while it did not suppress the phosphorylation of β3. In addition, miltirone prolonged the occlusion time and reduced collagen/epinephrine-induced pulmonary thrombi. Miltirone suppresses platelet "inside-out" and "outside-in" signaling by affecting PLCγ2/PKC/ERK1/2, PI3K/Akt, and Src/FAK signaling. Therefore, miltirone might represent a potential anti-platelet candidate for the prevention of thrombotic disorders.
中文翻译:
米替龙在调节血小板功能中的药理作用。
丹参丹参含有多种活性成分,其中一些已被开发为可商购的药物。此外,丹参中的其他一些成分在抗血小板活性中也起作用。本研究的目的是研究丹参丹脂中一种亲脂性化合物米替农的作用及其潜在机理。通过各种体外和体内实验研究了米替农调节血小板功能的能力。用血小板凝集仪测定各种激动剂引起的血小板聚集和致密颗粒分泌。通过数码相机和荧光显微镜对凝块回缩和扩散进行成像。用氯化铁诱导的颈动脉损伤模型和肺血栓栓塞模型检查米替隆的体内抗血栓形成作用。为了阐明米替隆的抗血小板活性的机制,进行了流式细胞术和蛋白质印迹。已显示Miltirone(2、4、8 µM)以剂量依赖的方式抑制血小板聚集,致密颗粒和α颗粒分泌。同时,米替龙抑制了凝结的回缩和洗涤后血小板的扩散。它减少了胶原蛋白受体下游信号通路中PLCγ2,PKC,Akt,GSK3β和ERK1 / 2的磷酸化。它也减少了整联蛋白αIIbβ3介导的“由内而外”信号转导中Src和FAK的磷酸化,而没有抑制β3的磷酸化。此外,米替龙延长了阻塞时间并减少了胶原蛋白/肾上腺素引起的肺血栓形成。Miltirone抑制血小板“由内而外”和“由外而内” 通过影响PLCγ2/ PKC / ERK1 / 2,PI3K / Akt和Src / FAK信号来发出信号。因此,米替龙可能是预防血栓形成疾病的潜在抗血小板候选药物。
更新日期:2018-05-23
中文翻译:
米替龙在调节血小板功能中的药理作用。
丹参丹参含有多种活性成分,其中一些已被开发为可商购的药物。此外,丹参中的其他一些成分在抗血小板活性中也起作用。本研究的目的是研究丹参丹脂中一种亲脂性化合物米替农的作用及其潜在机理。通过各种体外和体内实验研究了米替农调节血小板功能的能力。用血小板凝集仪测定各种激动剂引起的血小板聚集和致密颗粒分泌。通过数码相机和荧光显微镜对凝块回缩和扩散进行成像。用氯化铁诱导的颈动脉损伤模型和肺血栓栓塞模型检查米替隆的体内抗血栓形成作用。为了阐明米替隆的抗血小板活性的机制,进行了流式细胞术和蛋白质印迹。已显示Miltirone(2、4、8 µM)以剂量依赖的方式抑制血小板聚集,致密颗粒和α颗粒分泌。同时,米替龙抑制了凝结的回缩和洗涤后血小板的扩散。它减少了胶原蛋白受体下游信号通路中PLCγ2,PKC,Akt,GSK3β和ERK1 / 2的磷酸化。它也减少了整联蛋白αIIbβ3介导的“由内而外”信号转导中Src和FAK的磷酸化,而没有抑制β3的磷酸化。此外,米替龙延长了阻塞时间并减少了胶原蛋白/肾上腺素引起的肺血栓形成。Miltirone抑制血小板“由内而外”和“由外而内” 通过影响PLCγ2/ PKC / ERK1 / 2,PI3K / Akt和Src / FAK信号来发出信号。因此,米替龙可能是预防血栓形成疾病的潜在抗血小板候选药物。