基于网络药理学预测多种微量元素作用于早产低出生体重儿的药理作用机制

Predicting Pharmacological Mechanism of Multiple Trace Elements in Preterm Low Birth Weight Infants Based on Network Pharmacology

关键词:  网络药理学  微量元素  低出生体重  早产儿  药理作用

Key words:  network pharmacology  trace elements  low birth weight  preterm infants  pharmacological mechanism

摘要:

目的 利用网络药理学方法探究多种微量元素作用于早产低出生体重儿的药理作用机制。方法 通过Drugbank数据库和TTD数据库获取多种微量元素调控的靶点，在GeneCards数据库和DisGeNet数据库收集早产低出生体重儿相关的基因，筛选出两者共同的靶点作为多种微量元素作用于早产低出生体重儿相关靶点，运用STRING数据库构建其蛋白相互作用网络，利用Cytoscape 3.6.1软件筛选候选靶点，并确定关键靶点。通过构建“多种微量元素-候选靶点”综合性网络，定义主要微量元素。使用g:Profiler软件对候选靶点进行KEGG和GO富集通路分析，预测多种微量元素作用于早产低出生体重儿的相关信号通路和分子机制。结果 共确定微量元素作用于早产低出生体重儿的靶点211个、候选靶点26个；预测到关键靶点为ALB、GAPDH、FN1；主要微量元素是铜(Cu)和锌(Zn)，分别调控22和19个靶点；KEGG富集分析到主要3条通路为补体与凝血级联、胆固醇代谢、脂质和动脉粥样硬化。结论 主要微量元素Cu和Zn可通过调节GAPDH、CP和SOD1等靶点，引起早产儿神经元损伤以及降低氧化应激导致的早产儿相关疾病的风险；早产儿合适的Cu和Zn水平可调控胆固醇代谢等信号通路而降低早产儿及其成年后心血管疾病的风险。因此，有必要进一步深入研究多种微量元素对早产儿的药理作用机制，为早产儿的良好生长和发育提供更加充分的理论依据。

Abstract:

OBJECTIVE To explore the pharmacological mechanism of trace elements in preterm low birth weight infants through network pharmacology. METHODS Targets associated with trace elements were obtained from Drugbank database and TTD database. Genes related to preterm low birth weight infants were collected from GeneCards database and DisGeNET database. Two groups of data were intersected to get mapping targets. Protein-protein interaction network of mapping targets were constructed by STRING database. Candidate targets were screened by Cytoscape 3.6.1 and ranked to obtain key targets. The major trace elements were defined by establishing network of “trace elements-candidate targets”. Kyoto Encyclopedia of Genes and Genomes(KEGG) and Gene Ontology(GO) term enrichment analysis was performed via g:Profiler software to predict the molecular mechanisms and related pathways of trace elements on preterm low birth weight infants. RESULTS A sum of 211 targets of trace elements in preterm low birth weight infants were screened, including 26 candidate targets and three key targets: albumin(ALB), glyceraldehyde-3-phosphate dehydrogenase(GAPDH) and fibronectin 1(FN1). The major trace elements were copper(Cu) and zinc(Zn), regulating 22 and 19 targets respectively. KEGG pathway enrichment analysis predicted that three major pathways were complement and coagulation cascades, cholesterol metabolism as well as lipid and atherosclerosis. CONCLUSION The major trace elements Cu and Zn may cause neuronal damage and reduce the risk of oxidative stress-related diseases in premature infants through the regulation of GAPDH, ceruloplasmin(CP), superoxide dismutase 1(SOD1), etc. The appropriate levels of Cu and Zn for preterm infants may regulate cholesterol metabolism and other signaling pathways and therefore reduce the risk of cardiovascular diseases in premature infants and adult. Further investigation of the pharmacological mechanism of trace elements in preterm infants is necessary to provide a more sufficient theoretical basis for the good growth and development of preterm infants.