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Circulating metabolites of Borneolum syntheticum (Bingpian) ameliorate atherosclerosis in ApoE-/- mice via inhibiting macrophage foam-cell formation

文献类型：期刊论文

作者He, Rong-rong5,6; Ma, Chuan-rui4; He, Xin3; Dong, Yan-xi3; Li, Hui5,6; Chu, Zi-xuan2,5; Yang, Xi-he2,5; Wang, Jia-qi2,5; Wang, Ting2,5; Wang, Feng-qing5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2024-10-29
页码18
关键词Borneolum syntheticum Bingpian borneol isoborneol metabolism atherosclerosis
ISSN号1671-4083
DOI10.1038/s41401-024-01406-5
通讯作者Fan, Guan-wei(guanwei.fan@tjutcm.edu.cn) ; Cheng, Chen(chengchen@simm.ac.cn) ; Li, Chuan(chli@simm.ac.cn)
英文摘要Translational pharmacological research on traditional medicines lays the foundation for precisely understanding how the medicines function in the body to deliver therapeutic benefits. Borneolum syntheticum (Bingpian) is commonly used in Chinese herbal medicines for coronary heart disease, but its specific cardiovascular impact remains poorly understood. Isoborneol, a constituent of Bingpian, has been found to reduce lipid accumulation in macrophages in vitro, but its oral bioavailability is limited. This investigation aimed to evaluate anti-atherosclerotic effects of Bingpian, based on understanding its first-pass metabolism. Human subjects orally received an herbal medicine containing Bingpian and their plasma samples were analyzed to identify the major circulating compounds of Bingpian, with the metabolism that was also characterized in vitro and in mice. The identified compounds were evaluated for their ability to inhibit macrophage foam-cell formation induced by oxidized low-density lipoprotein. Furthermore, the anti-atherosclerotic effect of repeatedly dosed Bingpian was assessed in ApoE-/- mice fed a high-fat diet. In human subjects, the major circulating compounds of Bingpian were metabolites, rather than their precursor constituents borneol and isoborneol. These constituents were efficiently absorbed in the intestinal tract but underwent significant first-pass metabolism, involving UGT2B7-mediated glucuronidation into borneol-2-O-glucuronide and isoborneol-2-O-glucuronide, respectively, and CYP2A6/2B6/3A-mediated oxidation both into camphor. Despite their poor membrane permeability, hepatic efflux of borneol-2-O-glucuronide and isoborneol-2-O-glucuronide into the systemic circulation was enhanced by MRP3/4. The circulating metabolites, particularly their combinations, markedly inhibited macrophage foam-cell formation induced by oxidized low-density lipoprotein in vitro. Sub-chronic administration of Bingpian (30 mgkg-1d-1, i.g.) for 12 weeks significantly decreased atherosclerotic lesion size and enhanced plaque stability in ApoE-/- mice. Systemic exposure to Bingpian metabolites in mice closely resembles that in humans, suggesting that the pharmacodynamic effects of Bingpian in mice are likely applicable to humans. Overall, the cardiovascular benefits of Bingpian involve reducing atherosclerosis by inhibiting foam-cell formation through its metabolites. This investigation supports that oral Bingpian could be a druggable agent for reducing atherosclerosis.
WOS关键词CHOLESTEROL EFFLUX ; TARGET ; ISOBORNEOL ; MECHANISMS ; POTENT
资助项目National Natural Science Foundation of China[82192912] ; National Engineering Research Center of TCM Standardization Technology[2023-ZYBZH-10] ; National Key R&D Program Strategic Scientific and Technological Innovation Cooperation Key Project[2022YFE0203600]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001344754000001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/314053]  
专题新药研究国家重点实验室
通讯作者Fan, Guan-wei; Cheng, Chen; Li, Chuan
作者单位1.Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharm, Shanghai 201203, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Tianjin Univ Tradit Chinese Med, Teaching Hosp 1, Tianjin 300073, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Tianjin Univ Tradit Chinese Med, Grad Sch, Tianjin 301617, Peoples R China
推荐引用方式
GB/T 7714		 He, Rong-rong,Ma, Chuan-rui,He, Xin,et al. Circulating metabolites of Borneolum syntheticum (Bingpian) ameliorate atherosclerosis in ApoE-/- mice via inhibiting macrophage foam-cell formation[J]. ACTA PHARMACOLOGICA SINICA,2024:18.
APA He, Rong-rong.,Ma, Chuan-rui.,He, Xin.,Dong, Yan-xi.,Li, Hui.,...&Li, Chuan.(2024).Circulating metabolites of Borneolum syntheticum (Bingpian) ameliorate atherosclerosis in ApoE-/- mice via inhibiting macrophage foam-cell formation.ACTA PHARMACOLOGICA SINICA,18.
MLA He, Rong-rong,et al."Circulating metabolites of Borneolum syntheticum (Bingpian) ameliorate atherosclerosis in ApoE-/- mice via inhibiting macrophage foam-cell formation".ACTA PHARMACOLOGICA SINICA (2024):18.

入库方式： OAI收割

来源：上海药物研究所

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