Pathogenic Factors,Metastatic Factors And Chinese Medicine Treatment Of Prostate Cancer Based On The Theory Of "Preventive Treatment Of Disease" In Traditional Chinese Medicine

Objective:The theory of "preventive treatment of disease" in traditional Chinese medicine(TCM)has formed a theoretical system of "prevent disease before disease,prevent disease change,and prevent recurrence after recovery" through the enrichment,development and innovation of physicians in the past dynasties,which is also the essence of TCM theory.This theory has many commonalities with the theory of"tertiary prevention" of modern cancer prevention,which makes the theory of "preventive treatment of disease" have an irreplaceable role in the prevention and treatment of modern cancer.Prostate cancer is one of the health killers of men in China and even worldwide.Because its onset is insidious,prevention is difficult,the treatment is relatively single compared with other cancer types,the treatment side effects are greater,the condition is easier to change,and the prognosis is complex,so it brings a huge impact on the quality of life of patients and causes a great burden psychologically and economically,so it is of great significance to actively prevent the disease,timely prevent the change of the nature of the disease,and prevent recurrence and metastasis.Methods:Based on the theory of "preventive treatment of disease",this study flexibly uses bioinformatics,network pharmacology,clinical data statistical analysis and other methods of theory,research involved genes,active ingredients of traditional Chinese medicine,traditional Chinese medicine,disease risk prediction and other aspects,to provide theoretical support for better and more accurate prevention and treatment of prostate cancer by traditional Chinese medicine.This study is divided into two chapters and five parts,including literature research and practice research.Chapter 1 is literature research,mainly discusses the historical evolution and rich development history of the theory of "preventive treatment of disease",the understanding of the etiology,pathogenesis and syndrome types of prostate cancer in traditional Chinese medicine,and the correlation between the theory of "preventive treatment of disease" and the prevention and treatment of prostate cancer,providing theoretical possibilities for subsequent research.Chapter 2 is the practical research part,divided into four parts.The first part is to investigate the biomarkers of prostate cancer occurrence,development,diagnosis and prognosis based on the theory of "preventive treatment of disease" and bioinformatics analysis.In this part,R software was used to analyze the prostate cancer dataset in GEO database and obtain differential genes,and String and Cytoscape were used to screen core differential genes,which were further verified by GEPIA and HPA.DAVID performed GO analysis of differential genes and pathway enrichment by IPA analysis.Using miRTarBase,StarBase,lncBase and GEPIA databases,ceRNA networks were screened and constructed conditional on expression and prognostic value,and cytoscape was used to visualize ceRNA networks.Among them,subcellular localization of lncRNAs was performed using the lncLocator database.The second part is to investigate the risk factors of prostate cancer bone metastasis based on the theory of "preventive treatment of disease".In this part,a predictive model is developed based on a training dataset of 204 prostate cancer patients and a validation dataset containing 50 patients.Chi-square test and one-way t-test were used for univariate comparison of patients in the bone metastasis and non-bone metastasis groups.Univariate and multivariate logistic regression models were used for further screening of parameters for constructing nomogram models.ROC curve,c-index,calibration curve and benefit curve are used for the validation,calibration,clinical benefit assessment and external validation of nomogram model.R software was used for visualization of graphs.The third part is based on the theory of "preventive treatment of disease" and data mining methods to analyze and explore the clinical treatment of prostate cancer Chinese medicine medication rules.Candidate genes for prostate cancer treatment were screened based on the Expert Consensus on Genetic Testing in Chinese Prostate Cancer Patients(2020 Edition)and bioinformatics methods.Target-related active ingredients with DL>=0.18 and OB>=30%were obtained from TCMSP database.CytoScape software calculates the active ingredient degree value and imports the relevant active ingredients into TCMSP database to obtain candidate herbs for targeted therapy of prostate cancer.Based on the data mining method to obtain the clinical treatment of prostate cancer herbs,and targeted therapy prostate cancer candidate herbs intersection to obtain clinical targeted therapy prostate cancer candidate herbs.With the help of ancient and modern medical record cloud platform,the taste meridians of candidate herbs for clinical targeted therapy of prostate cancer were analyzed,as well as the herb drug pairs with the highest correlation and the highest degree of clustering.CytoScape analyzes the score of the drug on the relevant active ingredient,and the highest score is recorded as the key active ingredient.To analyze the pathway enrichment of drugs on relevant targets and relevant targets of key active ingredients.The fourth part is to investigate the mechanism of several common active ingredients of traditional Chinese medicine in the treatment of prostate cancer based on the theory of "preventive treatment of disease" and network pharmacology methods.Validated prostate cancer therapeutic targets were identified in the GeneCards,OMIM,and PharmGkb databases.DrugBank,TTD,BindingDB,PubChem,and ChEMBL databases were used to identify therapeutic targets for curcumin/paclitaxel/ursolic acid.After intersection,the targets of curcumin/paclitaxel/ursolic acid in the treatment of prostate cancer were obtained and GO and KEGG analysis of the targets were performed.Cytoscape was used to screen core targets.AutoDock was used for molecular docking of core targets to natural products.Results:The first chapter of literature research found that the theory of "preventive treatment of disease" has a long history,and with the progress of the times has been endowed with new connotation,and finally formed a theoretical system of "prevent disease before disease,prevent disease change,and prevent recurrence after recovery".It also plays an important role in the prevention and treatment of prostate cancer.First,we should pay attention to protecting vital qi,enhancing physical fitness,health regulation,and preventing the occurrence of prostate cancer,that is,the so-called "prevent disease before disease";second,we should pay attention to the transformation of precancerous lesions into malignant lesions,and the transformation of early cancer into advanced cancer,that is,the so-called "prevent disease change";finally,patients who achieve clinical cure after radical surgery and chemoradiotherapy should pay more attention to protecting vital qi and preventing the return of cancer virus,that is,the socalled "prevent recurrence after recovery".In the second chapter,based on the theory of "preventive treatment of disease",the three kernels "prevent disease before disease,prevent disease change,and prevent recurrence after recovery" were explored.In the first part,starting from "prevent disease before disease",after screening and verification,a total of 9 genes closely related to the diagnosis and prognosis of PCa were obtained,including 4 biomarkers validated by HPA,CENPF,TPX2,TK1 and CCNB1,as well as 5 novel PCa biomarkers RRM2,UBE2C,TOP2A,BIRC5 and ZWINT.Pathway analysis suggests that PCa carcinogenesis is highly associated with liver fibrosis pathways,ILK signaling,and NRF2-mediated oxidative stress responses.After a series of screens,we found that two ceRNA networks,BIRC5/hsa-miR-218-5p/NEAT 1 and UBE2C/hsa-miR-4833p/NEAT1,were novel biomarkers that could predict PCa development.QRT-PCR results confirmed upregulation of UBE2C,BIRC5 and NEAT1 and downregulation of hsa-miR-218-5p and hsa-miR-483-3p in human PCa cells compared to normal prostate epithelial cells,which is consistent with the bioinformatics results.The second part starts with "prevent disease change",and finally includes 7 factors:drinking history,prostate hardness by digital rectal examination,prostate nodules by digital rectal examination,fibrinogen,alkaline phosphatase,cTx,and Gleason Score in the nomogram model.The area under the ROC curve of the final model was 92.7%,and the c-index of the nomogram model was 0.937(95%CI:0.899-0.975),which had good predictive ability,and the calibration curve also indicated that the model had good calibration ability.The c-index of the external validation set was 0.929,which also illustrates the good predictive ability of the nomogram model.Decision curve analysis showed that the prostate cancer bone metastasis risk value map was clinically useful when the risk possible threshold of influencing factors was 0.02-0.92.The third part and the fourth part are taking into account "prevent disease before disease,prevent disease change,and prevent recurrence after recovery".In the third part,64 candidate targets for prostate cancer therapy were obtained,1584 target-related active ingredients,and 346 active component-related herbs with degree values>=3.Data mining yielded 115 prescriptions for clinical treatment of prostate cancer,involving 201 herbs.After the intersection of the two,102 herbs for clinical targeted therapy of prostate cancer were obtained.Ancient and modern medical record cloud platform analysis found that clinical targeted therapy of prostate cancer herbs in the four qi,to flat,cold,warm;five flavors,to sweet,bitter,pungent;meridians,to lung,liver,spleen.Drug cluster analysis and drug association analysis revealed that the drug pair Lobelia chinensis-Scutellaria barbata was the key drug pair.CytoScape analysis of the key drugs on the relevant active ingredients revealed that wogonin had the highest degree value and was the key active ingredient.Analysis of the enrichment of key drug pairs and key active component-related target pathways revealed that both of them were significantly enriched in cellular senescence pathways.In the fourth part,after CytoScape screening and molecular docking validation,three natural products were obtained to treat prostate cancer targets,including curcumin 4 targets(EP300,RELA,EGFR,NFKB1),paclitaxel 7 targets(PTEN,EGFR,ERBB2,TP53,KRAS,AR,AKT1)and ursolic acid 2 targets(GSK3B,RELA).Conclusion:Based on the theory of "prevent disease before disease,prevent disease change,and prevent recurrence after recovery",we find that the prevention and treatment of prostate cancer can be well combined with the theory of "preventive treatment of disease" and play a guiding role in the prevention and treatment of prostate cancer.(1)The nine genes and two groups of ceRNA networks discovered by bioinformatics methods can be used as effective biomarkers for the occurrence,development,and prognosis of prostate cancer and provide a theoretical basis for the diagnosis and treatment of prostate cancer.(2)The nomogram model constructed by combining seven factors including drinking history,digital rectal examination prostate stiffness,digital rectal examination prostate nodules,fibrinogen,alkaline phosphatase,cTx,and Gleason Score can effectively predict the risk of prostate cancer bone metastasis and provide a theoretical basis for early clinical prevention of prostate cancer bone metastasis.(3)Using network pharmacology and data mining methods,the regularity of clinical targeted therapy of prostate cancer herbs was found,and it was found that the key drug pair was Lobelia chinensis-Lobelia chinensis drug pair,and the key active component of the two was wogonin,and its key action pathway was the cellular senescence pathway.To provide some reference for clinical treatment of prostate cancer.(4)Combined with network pharmacology,we found and validated the key targets of curcumin,ursolic acid,and violacein against prostate cancer,and further revealed the mechanisms of the three in the treatment of prostate cancer,providing a theoretical reference for the development of subsequent molecular targeted drugs.Combined with network pharmacology,network pharmacology,data mining and other methods,our study reveals the molecular mechanism of the occurrence and development of prostate cancer,the clinical risk factors of prostate cancer bone metastasis,targeting the taste meridians of anti-prostate cancer herbs and their possible molecular mechanisms and the molecular mechanism of natural products against prostate cancer,providing a theoretical basis for the "prevent disease before disease,prevent disease change,and prevent recurrence after recovery" of prostate cancer.