School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
Institution of Basic Theory, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Int J Biol Sci. 2019 Jul 25;15(10):2037-2050. doi: 10.7150/ijbs.35245. eCollection 2019.
A high concentration of homocysteine (Hcy) in plasma induces vascular endothelial dysfunction, and it may ultimately accelerate the development of cardiovascular diseases (CVDs). Although several B vitamins have been clinically applied for hyperhomocysteinemia (HHcy) treatment, the outcomes are not satisfied due to their limited therapeutic mechanism. Hence, in order to improve the curative effect, development of new effective therapeutic strategies should be put on the agenda. Total phenolic extracts of L. (TPE-CA) is a naturally obtained phenolic mixture, mainly containing flavones, flavanones and their glycosyl derivatives, flavonols, polymethoxyflavones and coumarins. Previous reports indicated that bioactive phenolic compounds possessed potent vascular protective effects and regarded as a protective agent against CVDs. Intriguingly, the exact mechanism underlying the suppressed effects of TPE-CA on HHcy could assist in revealing their therapy on CVDs. Here, the multi-targeted synergistic mechanism of TPE-CA on HHcy-induced vascular endothelial dysfunction was uncovered in a deduced manner. TPE-CA treatment exhibited an obvious superiority than that of B vitamins treatment. Network pharmacology was employed to identify the interrelationships among compounds, potential targets and putative pathways. Further experimental validation suggested that the treatment of TPE-CA for HHcy could not only effectively reduce the Hcy level in plasma through up-regulating transsulfuration pathway in Hcy metabolism, but also restore the HHcy-induced vascular endothelial dysfunction by activating cytochrome P450 enzymes (CYPs) epoxygenase signal cascades and inhibiting CYPs hydroxylase signal cascades in arachidonic acid (AA) metabolism.
血浆中高浓度的同型半胱氨酸（Hcy）会引起血管内皮功能障碍，最终可能加速心血管疾病（CVDs）的发展。尽管几种 B 族维生素已在临床上用于治疗高同型半胱氨酸血症（HHcy），但由于其治疗机制有限，治疗效果并不理想。因此，为了提高疗效，应将新的有效治疗策略的开发提上日程。
黄连总酚提取物（TPE-CA）是一种天然获得的酚类混合物，主要含有类黄酮、黄酮醇、黄烷酮及其糖苷衍生物、多甲氧基黄酮和香豆素。先前的报告表明，生物活性酚类化合物具有强大的血管保护作用，被认为是预防 CVDs 的保护剂。有趣的是，TPE-CA 抑制 HHcy 的确切机制有助于揭示其对 CVDs 的治疗作用。
此处，以推理的方式揭示了 TPE-CA 对 HHcy 诱导的血管内皮功能障碍的多靶点协同作用机制。TPE-CA 治疗的效果明显优于 B 族维生素治疗。网络药理学被用来识别化合物、潜在靶点和假定途径之间的相互关系。进一步的实验验证表明，TPE-CA 治疗 HHcy 不仅可以通过上调 Hcy 代谢中的转硫途径有效降低血浆中的 Hcy 水平，还可以通过激活细胞色素 P450 酶（CYPs）环氧合酶信号级联和抑制 AA 代谢中的 CYP 羟化酶信号级联来恢复 HHcy 诱导的血管内皮功能障碍。
