Modular Network Screening Of Core Chinese Prescriptions For Urinary Tract Infection With Bladder Damp-heat Syndrome

1 BackgroundThe screening of the core Chinese medicine prescriptions is the use of relatively suitable methods or techniques for the Chinese medicines or their components that may treat diseases,discovering the possible medicinal or pharmacological activities of the Chinese medicines or their components,and guiding the effective treatment of diseases and new drugs.The development provides an effective theoretical basis.At present,there are two main methods for screening traditional Chinese medicine prescriptions for the treatment of diseases:First,the traditional model:guidance based on traditional Chinese medicine theory and clinical experience,but limiting the discovery of new drugs;second,high-throughput drug screening technology:rapid,Minor,convenient features,but did not consider the process of traditional Chinese medicine in the treatment of diseases such as the patient's body integrity and syndrome differentiation and other factors.And based on the pathological mechanism of the disease and the complexity of the pharmacological mechanism of the drug,the limitations of disease treatment and drug development models targeting a single target have become increasingly prominent.The rise of systems biology and network pharmacology has led to the development of pharmacological mechanisms and new drug development from the traditional"one-component,single-target" research model to "multi-component,multi-target"development.Faced with the massive data generated by multidisciplinary studies,network analysis as a new tool can integrate the relationship between drugs,targets,and diseases,and the combination of biological networks and Chinese medicine is a combination of traditional Chinese medicine pharmacology Research has brought new ideas and is also a hot spot for new drug development.However,due to the complexity of the network structure,it has brought great challenges to the exploration of laws.Therefore,the modular deconstruction and analysis of complex biological networks has become a new research direction of network pharmacology and systems biology.The module pharmacology believes that based on the modular analysis of complex biological networks and the balancing of disease networks through the adjustment of multi-target interaction modules,disease treatment goals can be achieved.And in the field of disease and drug research,the identification of target modules is an important part of revealing the multi-target synergy mechanism of Chinese medicine under the system and network level.This technology based on modular pharmacology for Chinese herbal compound discovery will provide new opportunities for drug development and disease treatment.Therefore,this study aims at the difficulties faced by Chinese medicine in the treatment of diseases and drug development models and the characteristics of multi-omics and multi-target network analysis based on module pharmacology.The establishment of a network was established using urinary tract infection bladder heat and heat syndrome as an example.The identification model of the network module,the judgment system of the core module,,and the screening model of the Chinese medicine prescription based on the core module provide a new idea and research method for the research and development of traditional Chinese medicine for the treatment of diseases and new Chinese medicines.2 ObjectiveExplore the correlation between different factors and overweight or obesity through health survey data analysis to the urban communities,rural communities and upper nursing institution based on the KAPC view.This can provide health management intervention strategy for the community elderly overweight people.3 Methods3.1 Acquisition of data3.1.1 Acquisition of traditional Chinese medicine for the treatment of urinary tract infection with bladder damp-heat syndrome.Inquiring the listed Chinese medicines through the Database for Value Evaluation of Chinese Medicine(http://crds.release.daodikeji.com)and removing the duplication,unifying the non-unified names,then the Chinese medicines to treat urinary tract infection with bladder damp-heat syndrome were obtained.3.1.2 Access to preferred genes associated with main symptoms of urinary tract infectionThe genes associated with the main symptoms of urinary tract infection with bladder heat syndrome were obtained through the HPO database(http://human-phenotype-ontology.github.io/)and the Disease Ontology database(http://www.disease-ontology.org/),and they were treated for de-duplication and unified name.The gained genes associated with the main symptoms of urinary tract infection with bladder heat syndrome were analyzed by Fisher's exact test and finally selected the preferred genes associated with main symptoms of urinary tract infection with bladder heat syndrome(P<0.05).3.2 Network Construction3.2.1 Construction of disease-Chinese medicine networkFirstly,using the Apriori algorithm to analyse the associated Chinese medicines for the treatment of urinary tract infection with bladder damp-heat syndrome and get the correlation between the Chinese medicines.Then inputing the relationship into Cytoscape 3.6.0 software to construct a disease-Chinese medicine network and visualize it.3.2.2 Construction of main symptom of disease genes networkWe submitted the preferred genes associated with the main symptoms of urinary tract infections to the String database and chosen humans as the background.The website automatically constructed a gene network associated with the main symptoms of urinary tract infection with bladder damp-heat syndrome.3.3 Network module divisionAfter the gene network data were acquired,using the three algorithms MCODE,MCL and Cytocluster in the Cytoscape 3.6.0 software to build the respective disease-Chinese medicine network and the main symptom of disease-gene networkand visualize it.3.4 Calculation of EntropyApplying the entropy algorithm as a criterion to determine the degree of dispersion of the module,the module identification results of different methods can be compared according to the dimension of the module entropy.The smaller the entropy value is,the smaller the degree of dispersion of the module is,and the higher the stability is.Based on the entropy of the module network,we determine the network module recognition effect from three different methods of MCODE,MCL,and Cytocluster;the smaller entropy value means the higher stability of the module network.Then we chosen the method to identify the network module with the smallest entropy.3.5 Identification of Network Core ModulesAfter selecting the preferred module division method based on the entropy value,we sort the primary and secondary relationships of each group of modules according to the three methods of node strength,center of intensity and page rank,and finally obtain the ranking in each group.A module is a candidate core module according to the ranking in each group.3.6 Screening core prescription3.6.1 Selection of core Chinese medicine prescriptions based on disease-Chinese medicine networkThe Chinese medicine network for the treatment of urinary tract infection with bladder heat syndrome,we have selected the core modules for the treatment of urinary tract bladder heat syndrome,we believe that the Chinese medicine nodes contained in the module are the core Chinese medicine prescriptions for the treatment of urinary tract infection with bladder damp-heat syndrome.3.6.2 Screening of core Chinese medicine prescriptions based on the major disease-gene networkWe identified the main symptom-gene network of the urinary tract infection bladder heat and heat syndrome card,identified the network core module,analyzed the protein components of the genes contained in the core network module,and established"gene-protein" based on the TCMSP and CTD databases.Ingredient-Chinese medicine is related,and the Chinese medicines associated with the core module are found,and statistical analysis is performed on the obtained Chinese medicine,and finally the core Chinese medicine prescription screened based on the main symptom-gene network of the urinary tract infection bladder heat-heat syndrome is obtained.3.7 Verification of resultsBased on the above-mentioned two types of core prescriptions based on the network core module for the treatment of urinary tract infection bladder heat syndrome for verification.We mainly use literature verification or cell experiment verification to verify the results.4 Results4.1 The Results of Data AcquisitionBased on the database of Chinese patent medicines value assessment information,we have searched for 27 proprietary Chinese medicines that contained 108 Chinese herbal medicines,which mainly were used for the treatment of urinary tract infection with bladder dampness and heat syndrome.By downloading the data associated with the disease symptoms in HPO and Disease Ontology databases,the genes associated with the main symptoms of urinary tract infections were screened.A total of 573 preferred genes were associated with the main symptoms were obtained(P<0.05).4.2 Construction of the NetworksFirstly,Apriori correlation algorithm was used to construct the connection between the two herbs in each Chinese patent medicine,and then Cytoscape software was used to construct a Chinese medicine network for the treatment of urinary tract infection bladder heat syndrome.The network consists of 107 nodes and 744 sides.The main symptom-gene network of urinary tract infection bladder heat and heat syndrome was constructed using the String(https://string-db.org/)database(Background:Homo sapiens).The network consisted of 522 nodes and 4411 edges.4.3 Division of Molecular Network Modules and Calculation of Entropy ValuesBy using MCODE,MCL,and Cytocluster to divide the modules of the two networks,it can be seen that using the MCODE method,the entropy value of the modules for the network partition is the smallest.Therefore,we finally decided to use the MCODE method to divide the three networks into modules.4.4 Identification of Network Core ModulesWe use the MCODE method to divide the modules of the two networks,and calculate the node strength,the center of the intensity,and the page rank of the divided modules in the entire network,sort the primary and secondary relationships of each module,and finally find out No.5 module is the core module in the disease-Chinese medicine network;and No.1 module is the core module of the network in the disease main symptom-gene network.4.5 Two Traditional Chinese Medicine Prescriptions for Treatment of Urinary Tract Infection Bladder Damp-heat SyndromeBased on the Chinese medicine network for the treatment of urinary tract infection bladder heat syndrome,we have selected the core modules for the treatment of urinary tract infection bladder heat syndrome,and obtained the core Chinese medicine prescriptions:Sansha,Bupleurum,Schisandra,continued Broken,white peony,mallow fruit,Scutellaria barbata,shiwei,honeysuckle,red peony,diffusa,agrimony.Based on the urinary tract infection-associated gene network of the main symptoms of bladder heat syndrome,the core Chinese medicine prescriptions for the treatment of urinary tract infection bladder heat syndrome were:Salvia miltiorrhiza,Glycyrrhiza uralensis,Schisandra chinensis,Caoguo,Ephedra,Epimedium,Bupleurum,Ginkgo biloba,Corydalis,Morinda and Sophora.5 ConclusionTaking the urinary tract infection bladder heat and heat syndrome as an example,we established the Chinese medicine network and the main symptom-gene network of the urinary tract infection bladder heat syndrome respectively.We used three different methods of module division to divide the network into modules,and finally discovered The MCODE method is most suitable for the division of network modules,and identifies the core modules of two different networks according to the three calculation methods,and combines the "multi-target,multi-component" model in the Chinese herbal compound and module network analysis,and establishes Two kinds of prescription prescriptions based on core modules were formulated.From two different perspectives,the core Chinese medicine prescriptions for the treatment of urinary tract infections with bladder dampness and heat syndrome were discovered:Sansha,Bupleurum,Schisandra,Dipsacus,Angelica,Mallow,Scutellaria barbata,Shiwei,honeysuckle,red peony root,Hedyotis diffusa,agrimony and salvia miltiorrhiza,licorice,schisandra,grass,ephedra,epimedium,bupleurum,ginkgo biloba,corydalis,Morinda officinalis and Sophora flavescens.And we verified through literature verification and cell test that these two Chinese medicine prescriptions have certain therapeutic effects on urinary tract infection bladder heat syndrome.This provides a new idea and research method for the discovery of core Chinese medicines for the treatment of diseases and the mode of research and development of new drugs.