Xia Kai-Rou, Zhang Xiao-Yu, Zhang Huang-Qin, Su Ke-Lei, Shang Er-Xin, Xiao Qing-Ling, Li Wei-Wen, Guo Sheng, Duan Jin-Ao, Liu Pei
Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210028, China.
J Ethnopharmacol. 2024 Jul 15;329:118158. doi: 10.1016/j.jep.2024.118158. Epub 2024 Apr 13.
Trichosanthis pericarpium (TP; Gualoupi, pericarps of Trichosanthes kirilowii Maxim) has been used in traditional Chinese medicine (TCM) to reduce heat, resolve phlegm, promote Qi, and clear chest congestion. It is also an essential herbal ingredient in the "Gualou Xiebai" formula first recorded by Zhang Zhongjing (from the Eastern Han Dynasty) in the famous TCM classic "Jin-Guì-Yào-Lüe" for treating chest impediments. According to its traditional description, Gualou Xiebai is indicated for symptoms of chest impediments, which correspond to coronary heart diseases (CHD).
This study aimed to identify the antithrombotic compounds in Gualoupi for the treatment of CHD.
A CHD rat model was established with a combination of high-fat diet and isoproterenol hydrochloride (ISO) administration via subcutaneous multi-point injection in the back of the neck. This model was used to evaluate the antithrombotic effect of two mainstream cultivars of TP ("HaiShi GuaLou" and "WanLou") by analyzing the main components and their effects. Network pharmacology, molecular docking-based studies, and a zebrafish (Danio rerio) thrombosis model induced by phenylhydrazine was used to validate the antithrombosis components of TP.
TP significantly reduced the body weight of the CHD rats, improved myocardial ischemia, and reduced collagen deposition and fibrosis around the infarcted tissue. It reduced thrombosis in a dose-dependent manner and significantly reduced inflammation and oxidative stress damage. Cynaroside, isoquercitrin, rutin, citrulline, and arginine were identified as candidate active TP compounds with antithrombotic effects. The key potential targets of TP in thrombosis treatment were initially identified by molecular docking-based analysis, which showed that the candidate active compounds have a strong binding affinity to the potential targets (protein kinase C alpha type [PKCα], protein kinase C beta type [PKCβ], von Willebrand factor [vWF], and prostaglandin-endoperoxide synthase 1 [PTGS1], fibrinogen alpha [Fga], fibrinogen beta [Fgb], fibrinogen gamma [Fgg], coagulation factor II [F2], and coagulation factor VII [F7]). In addition, the candidate active compounds reduced thrombosis, improved oxidative stress damage, and down-regulated the expression of thrombosis-related genes (PKCα, PKCβ, vWF, PTGS1, Fga, Fgb, Fgg, F2, and F7) in the zebrafish model.
Cynaroside, isoquercitrin, rutin, citrulline, and arginine were identified as the active antithrombotic compounds of TP used to treat CHD. Mechanistically, the active compounds were found to be involved in oxidative stress injury, platelet activation pathway, and complement and coagulation cascade pathways.
瓜蒌皮（TP；栝楼皮，即瓜蒌Trichosanthes kirilowii Maxim的果皮）在传统中医（TCM）中用于清热、化痰、理气和宽胸散结。它也是东汉张仲景在著名中医典籍《金匮要略》中首次记载的用于治疗胸痹的“瓜蒌薤白”方剂中的重要草药成分。根据其传统描述，瓜蒌薤白适用于胸痹症状，这与冠心病（CHD）相对应。
本研究旨在鉴定瓜蒌皮中用于治疗冠心病的抗血栓化合物。
通过高脂饮食联合颈部皮下多点注射盐酸异丙肾上腺素（ISO）建立冠心病大鼠模型。该模型用于评估两种主流栽培品种的瓜蒌皮（“海丝瓜蒌”和“皖蒌”）的抗血栓作用，通过分析其主要成分及其作用。采用网络药理学、基于分子对接的研究以及由苯肼诱导的斑马鱼（Danio rerio）血栓形成模型来验证瓜蒌皮的抗血栓成分。
瓜蒌皮显著降低了冠心病大鼠的体重，改善了心肌缺血，并减少了梗死组织周围的胶原沉积和纤维化。它以剂量依赖性方式减少血栓形成，并显著减轻炎症和氧化应激损伤。洋蓟素、异槲皮苷、芦丁、瓜氨酸和精氨酸被鉴定为具有抗血栓作用的瓜蒌皮候选活性化合物。通过基于分子对接的分析初步确定了瓜蒌皮在治疗血栓形成中的关键潜在靶点，结果显示候选活性化合物与潜在靶点（蛋白激酶Cα型[PKCα]、蛋白激酶Cβ型[PKCβ]、血管性血友病因子[vWF]、前列腺素内过氧化物合酶1[PTGS1]、纤维蛋白原α [Fga]、纤维蛋白原β [Fgb]、纤维蛋白原γ [Fgg]、凝血因子II [F2]和凝血因子VII [F7]）具有很强的结合亲和力。此外，候选活性化合物在斑马鱼模型中减少血栓形成，改善氧化应激损伤，并下调血栓形成相关基因（PKCα、PKCβ、vWF、PTGS1、Fga、Fgb、Fgg、F2和F7）的表达。
洋蓟素、异槲皮苷、芦丁、瓜氨酸和精氨酸被鉴定为瓜蒌皮用于治疗冠心病的活性抗血栓化合物。从机制上讲，发现这些活性化合物参与氧化应激损伤、血小板激活途径以及补体和凝血级联途径。
