To Study The Rules And Mechanism Of TCM Syndrome Differentiation And Treatment Of Prostate Cancer Based On Literature Data Mining

Objective:1.Through the collection of clinical literature on the treatment of Prostate cancer(PCa)with traditional Chinese medicine,combined with the theory of modern traditional Chinese medicine,the distribution characteristics of TCM syndrome types,syndrome elements,symptoms/signs,and clinical prescription and medication rules of PCa were statistically excavated,so as to improve the overall process from syndrome differentiation to treatmentt.To provided reference for clinical syndrome differentiation and treatment of PCa.2.Data mining was used to screen out the core drug cluster of traditional Chinese medicine in the treatment of PCa,and network pharmacology and molecular docking technology were used to explore the effective components,targets and potential mechanisms of the core drug cluster in the treatment of PCa.Methods:1.Data mining: Search China National Knowledge Infrastructure(CNKI),Wanfang Database(Wanfang),VIP Database for Chinese Technical Periodicals(VIP)and China Biomedical Literature Database(CBM)included in the relevant clinical literature of traditional Chinese medicine and integrated traditional Chinese and Western medicine in the treatment of PCa,and the search date was January 01,1980 to March 31,2022.According to the inclusion and exclusion criteria,the literature was screened and the data were standardized.Microsoft Office Excel 2019 was used to establish the database of syndrome type,syndrome element,symptom/sign,prescription and traditional Chinese medicine,and the frequency analysis was conducted.IBM SPSS Modeler 18.0,IBM SPSS Statistics 26.0 and Gephi 0.9.2software were used for association rule analysis,cluster analysis,factor analysis and complex network analysis to summarize the TCM syndrome types,syndrome elements,symptoms/signs,prescriptions and medication rules of PCa.The core drug clusters of traditional Chinese medicine in the treatment of PCa were excavated.2.Network pharmacology and molecular docking: Search the active ingredients and targets of core drug groups through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP);PCa-related disease targets were obtained through Gene Cards,OMIM,Pharm Gkb,TTD and Drug Bank databases,and intersected with the corresponding targets of core drug group active ingredients.Import the intersecting targets into the Cytoscape 3.8.0 software to build an "active ingredient-key target" network to find the key active ingredients;The Protein-protein interaction(PPI)network diagram was constructed through the String database,and the core targets were screened out by Cytoscape3.8.0.GO and KEGG enrichment analysis was performed using R 4.2.1 software to predict the potential mechanism of action of core drug groups against PCa.Molecular docking of key active ingredients and core targets was performed using Auto Dock Vina 1.1.2 software,and results were presented using Pymol 2.5.4 software.Results:1.A total of 3518 literatures were retrieved,and 203 literatures were finally included.There were 83 syndrome types,32 of which were single syndrome type and 51 were complex syndrome type.The most common frequency distribution was dampness-heat in lower-jiao syndrome,followed by liver and kidney Yin deficiency syndrome,qi and Yin deficiency syndrome,qi deficiency and blood stasis syndrome,spleen and kidney Yang deficiency syndrome,qi stagnation and blood stasis syndrome,blood stasis internal stasis syndrome,spleen and kidney qi deficiency syndrome,kidney Yin deficiency syndrome,and phlegm and blood stasis syndrome.2.A total of 26 kinds of syndrome elements were proposed.There were 7 kinds of deficiency syndrome elements(mainly qi deficiency,Yin deficiency and Yang deficiency),8kinds of solid syndrome elements(mainly blood stasis,dampness,heat,poison and phlegm),and 11 kinds of disease location syndrome elements(mainly kidney,spleen,liver and lowerjiao).Cluster analysis showed that 7 types were reasonable,and the syndrome types were inferred as: kidney Yang deficiency syndrome,poison and blood stasis syndrome,spleen qi and blood deficiency syndrome,liver Yin deficiency syndrome,lower-jiao dampness and heat syndrome,phlegm turbidity internal obstruction syndrome,qi stagnation syndrome.3.Symptoms/signs include 124 general symptoms,45 tongue images,and 40 pulse images.The top ten statistics of general symptom frequency are: difficulty urinating,fatigue,anorexia,frequent and urgent urination,soreness of the waist and knees,abdominal pain,insomnia,nocturia,low back pain,and painful urination.The top five tongue images were red tongue,yellow greasy fur,little fur,petechial tongue,and light tongue.The top three pulse frequency statistics were fine pulse,weak pulse and sink fine pulse.Complex network analysis showed that the core symptoms/signs were frequent urination and urgency,difficulty urinating,fatigue,anorexia,waist and knee soreness,low back pain,insomnia,nocturia,red tongue,abdominal pain,dry stool,dry mouth and thirst,urination pain,emaciation and cold limbs.A total of 14 common factors were extracted by factor analysis,and the syndrome types were inferred as: F1,F2,F3: Yin deficiency of liver and kidney;F4,F7,F9,F12: kidney qi deficiency syndrome;F5: Kidney Yang deficiency syndrome;F6,F10,F11,F13: lowerjiao damp-heat syndrome;F8,F14: Qi deficiency and blood stasis syndrome.Cluster analysis finally identified 6 clusters,and inferred that the syndrome types were: liver-kidney Yin deficiency syndrome,spleen-kidney Yang deficiency syndrome,dampness and heat accumulation syndrome,qi and Yin deficiency syndrome,qi stagnation and blood stasis syndrome,and phlegm and blood stasis syndrome.4.92 prescriptions were extracted,of which 41 were self-made prescriptions.The frequency analysis showed that Qianlie Xiaozheng Decoction ranked first,followed by Liuwei Dihuang decoction and Zhibai Dihuang decoction.5.A total of 245 Chinese herbs were involved,with a total frequency of 2707 times.The top ten were: astragalus,licorice,spreading hedyotis herb,poria,atractylodis,radix rehmanniae preparata,barbed skullcap herb,yam,rhizoma alismatis,radix codonopsis.The245 Chinese herbs were mainly warm,cold and flat,with sweet,bitter and spicy flavors.The main meridians were liver,spleen,kidney and lung meridians,and the main drug effects were tonifying deficiency drugs,followed by clearing heat drugs,promoting blood circulation and removing stasis drugs and promoting water and wetting drugs.6.A total of 115 rules were produced in the analysis of the association rules of traditional Chinese medicines.Among them,the support of poria → rhizoma alismatis was the highest(25.00%),yam → peony peel + dogwood fruit + rhizoma alismatis + poria had the highest confidence(96.15%);and peony peel → dogwood fruit + yam + radix rehmanniae preparata had the highest gain(5.25).The network diagram of the association rules showed that the combination of yam,dogwood fruit,poria,rhizoma alismatis,peony peel,atractylodis,spreading hedyotis herb,astragalus,radix codonopsis,barbed skullcap herb and liquorice root was more likely.The frequency analysis of traditional Chinese medicine combined with the analysis of association rules determined that the core groups of traditional Chinese medicine for the treatment of PCa were poria,peony peel,yam,dogwood fruit and rhizoma alismatis.7.Cluster analysis of traditional Chinese medicine finally identified 7 clusters.Type 1:astragalus,turmeric,radix pseudostellariae,and common turmeric,which are beneficial to qi and spleen,promoting qi and blood circulation;Type 2:licorice root,Fructus Psoraleae,cassia twig,mankshood,with the effect of warming and tonifying kidney Yang;Type 3: spreading hedyotis herb,barbed skullcap herb,scorpion and salvia miltiorrhiza,which have the effects of clearing heat and dampness,removing blood stasis and detoxifying;Type 4: poria,radix rehmanniae preparata,yam,rhizoma alismatis,cornus officinalis,raw rehmanniae,peony peel,lycium barbarum,the root of bidentate achyranthes.This is Liuwei Dihuang decoction combined with lycium barbarum,the root of bidentate achyranthes and raw rehmanniae,which has the effect of nourishing liver and kidney,nourishing Yin and clearing heat;Type 5:white atractylodes rhizome,codonopsis pilosula,angelica,Tangerine Peel,white paeony root,Radix bupleurum,with the meaning of tonifying and invigorating qi decoction,with the effect of invigorating spleen and soothing liver;Type 6: coix seed,curcuma zedoary,fritillaria,rhizoma polygonati,polyporus umbellatus,with invigorating spleen and kidney,invigorating qi and nourishing Yin,clearing heat and dampness,promoting blood circulation and phlegm;Type 7: phellodendron,rhizoma anemarrhenae,rhizoma smilacis glabrae,with the effect of clearing heat and dampness.8.A total of 12 common factors were extracted by factor analysis of traditional Chinese medicine.Its functions are as follows: F1: tonifying spleen and kidney,clearing heat and dampness;F2: invigorating qi and spleen,promoting dampness and blood circulation;F3:Nourishing qi and spleen,nourishing Yin and tonifying kidney;F4,F8: promoting qi and blood circulation;F5,F6: clearing heat and dampness;F7,F10,F11: warm spleen and kidney;F8: promoting qi and blood circulation;F9: clearing heat,activating blood circulation and detoxifying;F12: Nourishing Yin and clearing heat.9.Network pharmacology research,72 active ingredients,465 targets,10692 disease targets,and 178 intersection targets were finally obtained.The "active ingredients-key targets" network was constructed in Cytoscape 3.8.0 to obtain the key active ingredients of core drug clusters: quercetin,kaempferol,stigmasterol,beta-sitosterol and kadsurenone.The protein interaction network map was formed by String database,and the topology analysis was performed by Cyto NCA,and 12 core targets were obtained: ESR1,MAPK1,TP53,HIF1 A,FOS,MYC,RELA,CCND1,RUNX2,NR3C1,AKT1 and EGFR.GO enrichment analysis showed that the biological process of PCa mainly involved the response to xenobiotic stimulus,response to me tal ion,and response to peptide,etc.The locations of potential targets were mainly distributed in membrane r aft,membrane microdomain,and caveola,etc.The molecular functions mainly include DNA-binding transcription factor binding,nuclear receptor activity,and ligand-activated transcription factor activity,etc.KEGG pathway enrichment results were mainly involved in Lipid and atherosclerosis,Chemical carcinogenesis-receptor activation,and PI3K-Akt signaling pathway,etc.10.The docking binding energies between the key active ingredients and the core target molecules were all ≤-6.0kcal/mol,and stable hydrogen bonds were formed between the small molecule ligands and the receptor proteins.The strongest binding capacity was stigmasterol and AKT1(-10.9kcal/mol),followed by β-sitosterol and AKT1(-10.4kcal/mol).Conclusion:1.PCa is characterized by a mixture of deficiency and excess,positive deficiency and excess factors.The main disease sites are kidney,spleen and liver.Qi deficiency,Yin deficiency and Yang deficiency are the main causes of positive deficiency,damp-heat and blood stasis are the most common causes of pathogenic excess,followed by qi stagnation,phlegm and poison.The common clinical syndrome types can be summarized as kidney qi deficiency syndrome,liver and kidney Yin deficiency syndrome,spleen and kidney Yang deficiency syndrome,lower jiao damp-heat syndrome,qi stagnation and blood stasis syndrome,and phlegm and blood stasis mutual syndrome.2.In clinical treatment,the main treatment principles are strengthening the health and eliminating pathogenic factors,strengthening the roots and clearing the source.The main combination of drugs is yam,cornus officinalis,poria,rhizoma alismatis,peony peel,Atractylodis,spreading hedyotis herb,astragalus,radix codonopsis,barbed skullcap herb,radix rehmanniae preparata,raw rehmanniae radix and liquorice root.The common treatment methods include tonifying spleen and kidney,tonifying liver and kidney,regulating Yin and Yang,invigorating qi and activating blood circulation,clearing heat and dampness,removing blood stasis and detoxifying.3.The main active ingredients of the core drug group,quercetin,kaempferol,stigmasterol,β-sitosterol,and kadsurenone,have good binding and stable structure with the key targets ESR1,MAPK1,TP53,AKT1,and EGFR.The core drug group plays an anti-PCa role by regulating the growth,proliferation,inflammation,apoptosis,tumor angiogenesis and drug resistance of tumor cells through key pathways such as PI3K-Akt signaling pathway,IL-17 signaling pathway,HIF-1 signaling pathway and TNF signaling pathway.It is suggested that the anti-PCa mechanism of the core drug group is the combined effect of multicomponent,multi-function,multi-pathway and multi-target.