On Key Genes Of Hypertension And Pharmacology Of Panax Notoginseng Based On Complex Networks

Complex network is an effective approach in the field of complex systems and has been widely used in many fields such as natural sciences,social sciences,and computer science.In particular,it has been applied to the studies of complex diseases such as tumors,AIDS,and asthma.Hypertension is a typical complex disease,one of the important risk factors that lead to cardiovascular disease and death.The main type of hypertension,salt-sensitive(SS)hypertension,accounts for about 51% of hypertensive patients worldwide.The occurrence of hypertension is closely related to many factors such as heredity,metabolism,environment,and life style;however,its pathogenesis is still not completely clear.Panax notoginseng(PN,i.e.Sanqi)is one of the famous traditional Chinese medicines for the treatment of hypertension.Since the effectiveness of drugs in the treatment of complex diseases is involved with a huge biological network of multiple components and multiple targets,this complexity makes the pharmacological mechanisms of PN in the treatment of hypertension unclear.The complex network theory collectively looks at the interactions between different components of a complex system and has become a new perspective for exploring the essential characteristics of the complex system.This theory therefore could help explain the pathological mechanisms of hypertension and the pharmacological mechanisms of PN in the treatment of hypertension.By combining the complex network approach with network pharmacology,firstly,this thesis constructs a pathway-based weighted network of hypertension-related genes and identifies its key hub genes;secondly,this thesis constructs a variety of complex networks of drug components,target proteins,biological pathways of PN,and targets of hypertension,and uses these networks to deeply analyze the pharmacological mechanisms of PN in regulating blood pressure.This study could provide a new approach for understanding the pathology of complex diseases and the pharmacological mechanisms of drugs.The main research results of this thesis include the following three aspects:1.Construction and analysis of the pathway-based weighted network of hypertension-related genes: The Dahl SS rat is a widely used genetic animal model of human hypertension.By combining its gene data with the information of biological pathways,this thesis constructs a pathway-based weighted network of hypertension-related genes.The analysis of the statistical and topological properties of the network shows that there is a significant correlation between node strengths and degree values in the network.The weight of each edge in the network is close to the unit weight;the edge weight distribution for the nodes with the same degree value is of approximately equal weights;furthermore,the edges with the larger weights tend to connect with the nodes with higher degree.By combining the node strength,node degree and number of pathways in which the node is involved,this thesis proposes a new integrated ranking index to comprehensively reflect the contribution of these three indices,and identifies eight key hub genes(Jun,Cdk4,Pdgfra,RT1-Da,Fn1,Actg1,Cycs,and Creb3l2).These key hub genes play important roles in the occurrence and treatment of hypertension,which have been confirmed by biological and medical research.They are further verified by two literature scores defined through the three popular search engines(Google Scholar,Pub Med,and Science Direct).This study has identified the key genes related to SS hypertension from a new perspective.2.Construction and analysis of the interaction networks of PN drug components,target proteins,and biological pathways: The information of the drug components(compounds),target proteins and biological pathways of PN are obtained from TCMSP,Drug Bank,and KEGG databases,respectively,and two interaction networks are constructed and analyzed.Here,the degree distribution of the PN drug component–target protein–biological pathway network conforms to a power-law;the network analysis shows that PN has the characteristics of multiple components and multiple targets: Quercetin,?-elemene,and farnesol are the main active components of PN,which act on the key target proteins such as MAPK1 and ADH1 C,thereby exerting pharmacological effects by activating MAPK signaling pathway,prostate cancer pathway,Toll-like receptor signaling pathway,and other pathways.The target protein-based PN drug component–biological pathway multiplex network includes three parts(three sub-networks),namely the two-mode component–pathway network,the component–component interaction network,and the pathway–pathway interaction network,with the small-world characteristics of short average path lengths and high clustering coefficients.The analysis results show that the efficacy of PN is achieved by the multiple drug components acting on the multiple target proteins involved in the multiple signaling pathways.The centrality analysis of network nodes shows that the active components such as ?-cedrene,quercetin,and1-methyl-5-isopropenylcyclohexene,as well as prostate cancer pathway and MAPK signaling pathway,are closely related to blood pressure regulation.This study has identified the main active components,key target proteins,and core biological pathways of PN,as well as the potential pathways involved in blood pressure regulation.3.Construction and analysis of the interaction networks of hub genes of hypertension,target proteins of disease,and target proteins of PN: By mapping the hub hypertension-related genes obtained from the SS rat model analysis to human-derived proteins,a pathway-based hub hypertension gene–disease target protein interaction network and a PN target protein–hypertensive disease target protein interaction network are constructed.The network analysis confirms that the hub genes,such as Creb3l2,Pdgfra,and Jun,are highly related to the occurrence and development of hypertension;and NOS3 and PGH2 may be the key PN target proteins for regulating blood pressure.This study integrates the data from the SS hypertensive rat model,hypertensive populations,and PN,and clarifies the relationships among the hub hypertension genes,hypertensive disease target proteins,and PN target proteins.This thesis uses the complex network approach to identify and clarify the key genes in the pathological mechanisms of hypertension,and the main active components,key target proteins,and core biological pathways in the pharmacological mechanisms of PN from a new systemic perspective.The findings of this thesis have important significance and reference value for the occurrence and prevention of hypertension,which can also provide new ideas for the mechanism research and related drug development of other complex diseases.