School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
Eur J Pharmacol. 2023 Jan 5;938:175436. doi: 10.1016/j.ejphar.2022.175436. Epub 2022 Dec 5.
Natural product berberine was reported to inhibit platelet activation and thrombosis by suppressing the class Ⅰ PI3Kβ/Rasa3/Rap1 pathway. This study aims to investigate the effects and mechanisms of berberrubine, a main metabolite of berberine, to inhibit thrombus formation.
Carrageenan-induced mouse tail thrombosis model was used to evaluate the effects of berberrubine hydrochloride (BBB) on thrombus formation in vivo. Non-targeted metabolomics was performed with UPLC-Q-TOF/MS to explore the potential mechanisms of BBB in inhibiting thrombosis. The effects of BBB on bleeding risk and prothrombin time were determined. And molecular docking was used to identify the possible target of BBB.
After oral administration, BBB significantly inhibited carrageenan-induced thrombosis in mice without prolonging bleeding time. The results of non-targeted metabolomics showed that oral BBB could regulate 'Phenylalanine, tyrosine and tryptophan biosynthesis' and 'Ubiquinone and other terpenoid-quinone biosynthesis', which is closely related to the vitamin K catalytic cycle. Molecular docking revealed BBB could combine and interact with vitamin K epoxide reductase (VKOR) and γ-Glutamyl carboxylase (GGCX), which was mutually confirmed with the experimental results that oral BBB could significantly prolong prothrombin time.
Integrated metabolomics and molecular docking reveal BBB inhibited thrombosis by regulating the vitamin K catalytic cycle. Our research is helpful in deeply understanding the antithrombotic material basis of oral berberine, and also could provide scientific evidence for developing new antithrombotic drugs based on BBB in the future.
已有研究报道天然产物小檗碱可通过抑制Ⅰ类 PI3Kβ/Rasa3/Rap1 通路来抑制血小板激活和血栓形成。本研究旨在探讨小檗碱的主要代谢产物小檗红碱抑制血栓形成的作用及其机制。
采用角叉菜胶诱导的小鼠尾血栓形成模型评价盐酸小檗红碱（BBB）对体内血栓形成的影响。采用 UPLC-Q-TOF/MS 进行非靶向代谢组学分析，以探讨 BBB 抑制血栓形成的潜在机制。测定 BBB 对出血风险和凝血酶原时间的影响。并采用分子对接技术鉴定 BBB 的可能作用靶点。
BBB 经口服给药后可显著抑制角叉菜胶诱导的小鼠血栓形成，且不延长出血时间。非靶向代谢组学结果表明，BBB 经口服给药可调节“苯丙氨酸、酪氨酸和色氨酸生物合成”和“泛醌和其他萜烯醌生物合成”，这与维生素 K 催化循环密切相关。分子对接结果显示，BBB 可与维生素 K 环氧化物还原酶（VKOR）和γ-谷氨酰羧化酶（GGCX）结合并相互作用，这与 BBB 可显著延长凝血酶原时间的实验结果相互印证。
整合代谢组学和分子对接结果表明，BBB 通过调节维生素 K 催化循环来抑制血栓形成。本研究有助于深入了解口服小檗碱的抗血栓物质基础，也可为未来基于 BBB 开发新型抗血栓药物提供科学依据。
