Huang Wei-Chieh, Jayakumar Thanasekaran, Sheu Joen-Rong, Hsia Chih-Wei, Hsia Chih-Hsuan, Yen Ting-Lin, Chang Chao-Chien
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
Department of Ecology and Environmental Sciences, Pondicherry University, Puducherry, 605014, India.
Chin Med. 2023 Jun 10;18(1):71. doi: 10.1186/s13020-023-00779-9.
Platelets play a crucial role in cardiovascular diseases (CVDs) and are activated by endogenous agonists like collagen. These agonists initiate signal transduction through specific platelet receptors, resulting in platelet aggregation. Glabridin, a prenylated isoflavonoid found in licorice root, is known for its significance in metabolic abnormalities. Glabridin has been observed to inhibit collagen-induced platelet aggregation, but the precise mechanisms, specifically concerning NF-κB activation and integrin αβ signaling, are not yet fully understood.
In this study, platelet suspensions were prepared from healthy human blood donors, and the aggregation ability was observed using a lumi-aggregometer. The inhibitory mechanisms of glabridin in human platelets were evaluated through immunoblotting and confocal microscopy. The anti-thrombotic effects of glabridin were assessed by histological analysis of lung sections in acute pulmonary thromboembolism and by examining fluorescein-induced platelet plug formation in mesenteric microvessels in mice.
Glabridin inhibited integrin αβ inside-out signals such as Lyn, Fyn, Syk, and integrin β activation and NF-κB-mediated signal events, with similar potency to classical inhibitors BAY11-7082 and Ro106-9920. Glabridin and BAY11-7082 inhibited IKK, IκBα, and p65 phosphorylation and reversed IκBα degradation, while Ro106-9920 only reduced p65 phosphorylation and reversed IκBα degradation. BAY11-7082 reduced Lyn, Fyn, Syk, integrin β, phospholipase Cγ2 and protein kinase C activation. Glabridin reduced platelet plug formation in mesenteric microvessels and occluded vessels in thromboembolic lungs of mice.
Our study revealed a new pathway for activating integrin αβ inside-out signals and NF-κB, which contributes to the antiplatelet aggregation effect of glabridin. Glabridin could be a valuable prophylactic or clinical treatment option for CVDs.
血小板在心血管疾病（CVDs）中起关键作用，并被内源性激动剂如胶原蛋白激活。这些激动剂通过特定的血小板受体启动信号转导，导致血小板聚集。光甘草定是一种存在于甘草根中的异戊烯基化异黄酮，以其在代谢异常中的重要性而闻名。已观察到光甘草定可抑制胶原蛋白诱导的血小板聚集，但其确切机制，特别是关于NF-κB激活和整合素αβ信号传导的机制，尚未完全了解。
在本研究中，从健康人类献血者制备血小板悬浮液，并使用发光聚集仪观察其聚集能力。通过免疫印迹和共聚焦显微镜评估光甘草定在人血小板中的抑制机制。通过对急性肺血栓栓塞症患者肺组织切片进行组织学分析以及检测小鼠肠系膜微血管中荧光素诱导的血小板栓形成，评估光甘草定的抗血栓作用。
光甘草定抑制整合素αβ外向内信号，如Lyn、Fyn、Syk和整合素β激活以及NF-κB介导的信号事件，其效力与经典抑制剂BAY11-7082和Ro106-9920相似。光甘草定和BAY11-7082抑制IKK、IκBα和p65磷酸化，并逆转IκBα降解，而Ro106-9920仅降低p65磷酸化并逆转IκBα降解。BAY11-7082降低Lyn、Fyn、Syk、整合素β、磷脂酶Cγ2和蛋白激酶C的激活。光甘草定减少小鼠肠系膜微血管中的血小板栓形成以及血栓栓塞性肺中的血管阻塞。
我们的研究揭示了一种激活整合素αβ外向内信号和NF-κB的新途径，这有助于光甘草定的抗血小板聚集作用。光甘草定可能是心血管疾病的一种有价值的预防或临床治疗选择。
Zotero 插件
