Traditional Chinese patent medicine Zhixiong Capsule (ZXC) alleviated formed atherosclerotic plaque in rat thoracic artery and the mechanism investigation including blood-dissolved-component-based network pharmacology analysis and biochemical validation
Traditional Chinese patent medicine Zhixiong Capsule (ZXC) alleviated formed atherosclerotic plaque in rat thoracic artery and the mechanism investigation including blood-dissolved-component-based network pharmacology analysis and biochemical validation
复制标题
中成药止芎胶囊（ZXC）缓解大鼠胸动脉粥样硬化斑块形成及基于血溶成分的网络药理学分析和生化验证的机制研究
DOI：
10.1016/j.jep.2019.112523
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发表时间：
2020-05-23
影响因子：
5.4
通讯作者：
Yin，Jun
中科院分区：
文献类型：
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作者：
Zhai，Jianxiu;Ren，Zhaohui;Yin，Jun
民族药理学相关性中成药治胸胶囊（ZXC）是由水蛭、川芎提取物、甘草提取物等组成。丹参，益母草，和葛根素（Puerarialobate（Willd.）Ohwi，长期用于抗炎，高血脂或血瘀。在我们之前的研究中，ZXC在预防兔动脉粥样硬化（AS）斑块形成方面表现出良好的疗效。研究目的在实际临床实践中，患者更有可能在AS斑块形成后接受治疗。材料与方法大鼠长期高脂饮食（12周）后，分别给予辛伐他汀（阳性对照）和ZXC（420 mg/kg和840 mg/kg）。在整个实验过程中监测大鼠的血脂变化，并在实验结束时（第18周）收集胸动脉进行AS评估。采用UPLC-QTOF-MS法对ZXC血溶组分进行分析，并对所得组分进行网络药理学分析，预测ZXC的关键成分和作用靶点。结果脂心胶囊能显著降低大鼠LDL-C和TC水平，升高HDL-C水平，具有良好的降血脂作用。与模型组比较，辛伐他汀、脂心胶囊低、高剂量组大鼠动脉内膜面积与中膜面积比值分别降低81.1%、71.1%和71.4%（p < 0.01），胶原沉积和矿化明显减轻。通过网络药理学分析发现，水蛭和4种成分（大豆苷元、4-亚甲基米替酮、异鼠李素和2-异丙基-8-甲基菲-3，4-二酮）是ZXC抗AS作用的关键成分。结合生化验证结果，确定ZXC的主要作用靶点为IL-4、IL-13、MAPK 1、MAPK 14、JUN和P53。结论ZXC在目前的应用剂量下具有抗AS斑块形成的临床应用价值。
Ethnopharmacological relevanceChinese patent medicine Zhixiong Capsule (ZXC) is the equal mixture of the extract of leech,Ligusticum chuanxiongHort.,Salvia miltiorrhizaBunge,LeonurusjaponicusHoutt., andPuerarialobate(Willd.) Ohwi, which have been long used against inflammation, hyperlipidemia or blood stasis. In our previous study, ZXC showed good efficacy in preventing atherosclerosis (AS) plaque formation in rabbits.Aim of the studyIn actual clinic practice, patients are more likely to receive treatments after AS plaque formation. Therefore, the efficacy of ZXC onformedAS plaques and the underlying mechanisms were further investigated in this study.Materials and methodsSimvastatin (positive control) and ZXC (420 mg/kg and 840 mg/kg) were administrated to rats which first received long-term high fat diet administration (12 weeks). The blood lipid profiles of rats were monitored during the whole experiment, and the thoracic arteries were collected at the end of experiment for AS assessment (18th week). The blood-dissolved ZXC components were determined using an UPLC-QTOF-MS method, and the attained components were then used for network pharmacology analysis to predict the key ZXC components and targets. At last, the predicted targets were validated by ELISA and western blot methods.ResultsZXC administration showed good blood lipid-lowering effect by significantly reduced LDL-C and TC levels in rats while significantly increased HDL-C level. Compared with model group, simvastatin, low- and high-dose of ZXC administration decreased the ratio of intimal area and medial area by 81.1%, 71.1% and 71.4%, respectively (p < 0.01), and significantly alleviated collagen deposition and mineralization in rat arteries. It was found by network pharmacology analysis that leech and four components (namely daidzein, 4-methylenemiltirone, isorhamnetin and 2-isopropyl-8-methylphenanthrene-3,4-dione) are vital components for the anti-AS efficacy of ZXC. Combing the results from biochemical validation, IL-4, IL-13, MAPK1, MAPK14, JUN and P53 were confirmed as key targets of ZXC.ConclusionIt could be concluded that ZXC has value as an anti-AS agent in clinical treatment against formed AS plaque at the current application dosage.