中药复方地黄饮子治疗脑卒中及后遗症的作用机制研究

发布时间：2018-08-07 21:10

【摘要】：脑卒中是一种急性脑血管疾病,主要由于脑部血管突然破裂或因血管阻塞导致血液不能流入大脑而引起脑组织损伤。脑卒中人口数量不断攀升,据统计,全球有数千万人口患有脑卒中。中国传统医学对脑卒中及其后遗症的治疗效果显著,其中中药复方地黄饮子已被广泛应用于临床中。然而,由于复方地黄饮子成分众多,其治疗脑卒中及后遗症的分子机制目前尚未明确。本研究中,我们采用系统药理学方法对中药复方地黄饮子进行系统分析,探究其治疗脑卒中及其后遗症的作用机制。研究结果如下:首先,我们通过数据库检索和文献挖掘收集了地黄饮子的15味中药中所包含的1117个化合物分子。然后通过计算分子的生物口服利用度和类药性并根据一定标准进行筛选,获得地黄饮子中的潜在活性分子92个,如山柰酚、黄芩苷、小檗碱等,这些分子已经被证实都是与脑卒中及后遗症相关的治疗分子。接下来通过加权系综相似度模型(WES)预测出活性分子的作用靶标,对92个分子的预测共得到了 203个潜在靶标蛋白,例如细胞色素P450(cytochromeP450CYP)、乙酰胆碱酯酶(ACHE)、基质金属蛋白酶9(MMP9)等等。这些分子和蛋白间的相互作用关系一共有1056对,大多数分子都能够与多个靶标产生联系,例如,槲皮素能够同时作用于75个靶标蛋白从而发挥生理活性。之后,根据GO通路富集结果,基于与脑卒中及后遗症相关的三个通路:ERBB信号通路、血管平滑肌收缩通路和MAPK信号通路构建了整合通路。通过靶标与疾病基因的关联、通路网络分析,发现地黄饮子中的潜在靶标与PPI网络中脑卒中及其后遗症相关的蛋白分子的相关性显著高于随机基因组。此外,我们将这些潜在靶标映射到作用通路中,并分析了其在通路中的协同拮抗作用,发现靶点间协同拮抗关系分别为138和41对,关系网络复杂。最终综合所有数据,我们构建了分子-靶点网络、靶点-通路网络以及靶点间协同拮抗网络,本研究通过系统药理学方法对复方地黄饮子的进行系统分析,解析了中药治疗脑卒中及其后遗症可能的分子机制,为脑卒中的中药治疗提供了新的依据,进一步促进了中药在现代医学中的应用。
[Abstract]:Stroke is an acute cerebrovascular disease, which is mainly caused by the sudden rupture of cerebral blood vessels or the failure of blood to flow into the brain due to the blockage of blood vessels. The number of people suffering from stroke is rising. According to statistics, tens of millions of people worldwide suffer from stroke. Traditional Chinese medicine has a remarkable effect on stroke and its sequelae, and its compound Dihuang decoction has been widely used in clinical practice. However, the molecular mechanism for the treatment of stroke and its sequelae has not yet been clarified due to the numerous components of compound Rehmannia glutinosa. In this study, we used the systematic pharmacological method to study the mechanism of the treatment of stroke and its sequelae by systematic analysis of the compound Rehmannia glutinosa (Rhizoma Rehmanniae) (Rhizoma Rehmanniae). The results are as follows: firstly, we collected 1117 compounds in 15 Chinese herbs of Rehmannia glutinosa by database retrieval and literature mining. Then by calculating the bioavailability of molecules and drug-like properties and screening according to certain criteria 92 potentially active molecules such as kaempferol baicalin berberine and so on were obtained in Radix Rehmanniae. These molecules have been identified as therapeutic molecules associated with stroke and sequelae. Then the target of active molecules was predicted by weighted ensemble similarity model (WES) and 203 potential target proteins such as cytochrome P450 (cytochromeP450CYP) and acetylcholinesterase (ACHE), matrix metalloproteinase 9 (MMP9) were obtained by predicting 92 molecules. There are 1056 pairs of interaction between these molecules and proteins, most of which can be associated with multiple targets. For example, quercetin can act on 75 target proteins simultaneously to perform physiological activities. Then, according to the enrichment results of go pathway, the integrated pathway was constructed based on three pathways: ERBB signal pathway, vascular smooth muscle contraction pathway and MAPK signal pathway. The association between target and disease gene and the analysis of pathway network showed that the correlation between the potential target in Rehmannia glutinosa and stroke and its sequelae in PPI network was significantly higher than that in random genome. In addition, we map these potential targets to the action pathway and analyze their synergistic antagonism in the pathway. We find that the cooperative antagonistic relationships among the targets are 138 and 41 pairs respectively, and the relationship network is complex. Finally, by synthesizing all the data, we constructed the molecular target network, the target pathway network and the cooperative antagonistic network among the targets. In this study, we systematically analyzed the compound Radix Rehmanniae by systematic pharmacological method. The possible molecular mechanism of traditional Chinese medicine in the treatment of stroke and its sequelae is analyzed, which provides a new basis for the treatment of stroke and promotes the application of traditional Chinese medicine in modern medicine.
【学位授予单位】：西北农林科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R277.7

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