Research On Medication Rule And Mechanism Prediction Of Treating Non-small Cell Lung Cancer From Stasis Based On Data Mining And Network Pharmacology

1.Data mining of traditional Chinese medicine for non-small cell lung cancer from stasisObjective: The study based on data mining,aims to sum up,study and analyze the medication characteristics,prescription rules and core medicine components of the Traditional Chinese Medicine(TCM)since when the database was established in the treatment of non-small cell lung cancer from stasis.Methods: The VIP,CNKI,WF,Pub Med,Web of Science and EMbase databases were searched from the establishment of the database to November 2022.All the literature concerning TCM treatment of non-small cell lung cancer from stasis were imported into Note Express software and screened according to the inclusion and exclusion criteria.Followed by extracting and standardizing the related data from the literature,a database was established via Excel,and the data were subjected to statistical analysis,prescription analysis and clustering analysis through the inheritance and calculation platform of Traditional Chinese Medicine(V3.0)software.Consequently,the most representative core medicine combination was selected from the comprehensive analysis results.Results:(1)140 articles were introduced in this study,including 186 traditional Chinese medicines.The medicines used over 40 times were listed as high-frequency medicines,14 medicines in total,in terms of Astragalus membranaceus,Radix Paeoniae Rubra,Radix Angelicae Sinensis,Curcuma zedoaria,Hedyotis diffusa Willd,peach kernel,Salvia miltiorrhiza,Ligusticum chuanxiong,licorice,Atractylodes Macrocephala,codonopsis pilosula,Poria cocos,Carthamus tinctorius,Rehmannia.Eleven Chinese medicines,used over20 times,with the efficacy of promoting blood circulation and removing blood stasis,were extracted,including Radix Paeoniae Rubra,Radix Angelicae Sinensis,Curcuma zedoaria,peach kernel,Salvia miltiorrhiza,Ligusticum chuanxiong,Carthamus tinctorius,Sparganii Rhizoma,Scutellaria barbata,Panax notoginseng,and Achyranthes bidentata.(2)The top five syndromes were : qi deficiency and blood stasis type,qi stagnation and blood stasis type,qi deficiency and blood stasis type,qi and yin deficiency and blood stasis type,blood stasis and toxin type.The statistical results of the efficacy frequency of Chinese medicines were as follows: tonifying medicine(especially qi-tonifying medicine and blood-tonifying medicine),promoting blood circulation and removing blood stasis medicine,clearing heat medicine(especially heat-clearing and blood-cooling medicine and heat-clearing and detoxicating medicine),resolving phlegm and relieving cough and asthma medicine,pacifying liver and wind medicine,draining water and dampness medicine,regulating qi medicine,hemostasis medicine,relieving exterior syndrome medicine and promoting digestion medicine.Based on the analysis of the four qi and five flavors of the medicines in the prescription,the medicine was featuring more to be warm,cold and mild,and the medicine taste was more often bitter,sweet and pungent.The statistical results of medicine meridian tropism suggested that medicine that entered liver meridian had the highest frequency,followed by spleen meridian and lung meridian.(3)The results of medicine association rule analysis stated that when the number of support degrees was set to 30 and the confidence level was set to 0.8,25 groups were combined into the core group of medication pattern,and 14 groups were combined into the association rule analysis group.(4)Based on K-means algorithm and clustering analysis of regression simulation,the samples were divided into the following three groups: the first group “Radix Paeoniae Rubra,Radix Angelicae Sinensis,peach kernel,Carthamus tinctorius,and Ligusticum chuanxiong”,the second group “Astragalus membranaceus,Poria cocos,Hedyotis diffusa Willd,Curcuma zedoaria and Salvia miltiorrhiza”,and the third group “Astragalus membranaceus,Atractylodes Macrocephala,Curcuma zedoaria,centipede,and licorice”.(5)The first group of medicine combinations,on the grounds of clustering analysis,were promoting blood circulation and removing blood stasis medicine,which suggested that they were representative.By the comparison between the other two groups,the core combination was closer to the regression curve,illustrating that the clustering effect of the core combination was better than that of the other two groups.Furthermore,the highest correlation could be seen visually from network topology analysis in this medicine group.Consequently,under the basis of the comprehensive utilization frequency,medicine pair frequency,association rules and clinical medication experience,Radix Paeoniae Rubra,Radix Angelicae Sinensis,peach kernel,Carthamus tinctorius,and Ligusticum chuanxiong were identified as the core medicine groups for the TCM treatment of non-small cell lung cancer from stasis.Conclusion:(1)Seeing blood stasis is not limited to promoting blood circulation,removing blood stasis focuses on syndrome differentiation.The etiology and pathogenesis of NSCLC are complex,which is the syndrome of deficiency in origin and excess in superficiality.The clinical medication of NSCLC from stasis cannot simply use large doses of blood-activating and stasis-resolving drugs.Under the principle of syndrome differentiation and treatment of traditional Chinese medicine,the relationship between qi and blood,deficiency and excess,cold and heat,as well as the severity of blood stasis should be distinguished,and the use of meridian guiding drugs should be emphasized.The treatment is centered on the method of promoting blood circulation and removing blood stasis,and attaches importance to the compatibility of drugs,so as to achieve the function of strengthening the body and eliminating the evil.In clinical practice,attention should be paid to qi deficiency and blood stasis when replenishing qi and activating blood,blood deficiency and blood stasis when tonifying blood and activating blood,blood heat and blood stasis when cooling blood and removing blood stasis,qi stagnation and blood stasis when promoting qi and activating blood,blood stasis and toxin internal knot when clearing heat and detoxifying,promoting blood circulation and removing blood stasis.(2)Among them,the frequency of use of Astragalus is the highest,Astragalus can strengthen the righting and anti-evil,tonic but not stagnation,and the use of drugs for promoting blood circulation and removing blood stasis can enhance the efficacy,so that ’removing blood stasis and breaking accumulation does not hurt the righting ’.It is suggested that in clinical practice,attention should be paid to the use of Yiqi Buxu and Huoxue Huayu methods for treatment,which reflects the importance of Yiqi and Huoxue simultaneously,and for patients with lung qi deficiency,special attention should be paid to their blood stasis in diagnosis.(3)The four qi of medicines largely concern warming,cold and Ping,and five flavors care more on bitter,sweet and pungent,at large extent,both of which are adopted in the treatment of liver,spleen,lung,heart and other visceral organs.(4)As a result,the medicine groups of Radix Paeoniae Rubra,Radix Angelicae Sinensis,peach kernel,Carthamus tinctorius,and Ligusticum chuanxiong were identified as the core medicine group for the treatment of NSCLC from blood stasis.2.Study on the mechanism of core drug combination based on network pharmacologyObjective: This study,basing on network pharmacology research,aims to analyze the core targets and action mechanisms of the core medicine groups(Radix Paeoniae Rubra,Radix Angelicae Sinensis,peach kernel,Carthamus tinctorius,and Ligusticum chuanxiong)in the treatment of non-small cell lung cancer from stasis in Traditional Chinese Medicine(TCM).Methods:(1)The effective components and target predictions of the core medicine groups were obtained via the TCM System Pharmacology Analysis Platform Database(TCMSP).(2)The targets of NSCLC were collected by Gene Expression Omnibus.(3)Venny2.1.0 software was chosen to select the intersection targets of the core medicine groups and diseases.(4)The network diagram of “drug-component-target-disease” was constructed through Cytoscape 3.9.0 software to explore the key active components and targets.(5)A protein-protein interaction network(PPI network)of intersecting targets was constructed using STRING11.0 database for visual analysis.(6)GO enrichment analysis and KEGG pathway enrichment analysis of the target gene were performed by R software and related installation packages.(7)Kaplan-Meier survival curve was drawn by Kaplan-Meier plotter..(8)Key target proteins were verified through the GEPIA database.(9)Simulation of molecular docking technology is introduced to verify the binding affinity between the core medicine group and potential targets of non-small cell lung cancer.Results: 49 effective components of medicines and 184 corresponding targets in all,by screening,were identified,and 1938 disease-related action targets were identified,of which44 were the common targets of medicines and diseases.The active components of medicine combination in the treatment of NSCLC may be quercetin,β-sitosterol,stigmasterol,luteolin,baicalein,kaempferol,and β-carotene,and the effective targets may be IL6,IL1 B,PTGS2,MMP9,JUN,CASP3,CCL2,FOS,PPARG,and BCL2L1.GO and KEGG analyses were performed,and the results suggested that the biological processes possibly involved in the treatment of NSCLC by the core medicine group included response to reactive oxygen species,cellular response to chemical stress,response to oxidative stress,response to radiation and response to xenobiotic stimulus,etc.It may have the relations with a variety of ways,including regulating lipid and atherosclerosis,TNF signaling pathway,fluid shear stress and atherosclerosis,IL-17 signaling pathway,AGE-RAGE signaling pathway in diabetic complications,rheumatoid arthritis,hepatitis B,transcriptional mis-regulation in cancer,Kaposi’s sarcoma-related herpesvirus infection,P53 signaling pathway,NOD-like receptor pathway,NF-κB signaling pathway,and apoptosis.The results of molecular docking indicated that all of them had good binding activity.Conclusion: Network pharmacology is introduced to predict the functional mechanism of the core medicine groups in the treatment of NSCLC,which possibly because of the participation of multiple medicine components,such as quercetin,β-sitosterol,stigmasterol,and luteolin in multiple biological processes and signaling pathways.These could be lipid and atherosclerosis,TNF signaling pathway,IL-17 signaling pathway,AGE-RAGE signaling pathway,transcriptional imbalance in cancer,participation in tumor cell apoptosis,etc.It may play a role in treating NSCLC by inhibiting platelet activation and aggregation,anti-thrombosis,inhibiting tumor cell growth and metastasis,inducing tumor cell apoptosis and inhibiting angiogenesis.