Study On The Correlation Between The High Risk Factors Of Multiple Myeloma And The Syndrome Types Of Traditional Chinese Medicine And The Analysis Of The Network Pharmacological Mechanism Of Bushen HuoxueTongluo Prescription

Objective:Retrospectively study the distribution of TCM syndrome types in patients with multiple myeloma(MM),explore the correlation between the common high-risk prognostic factors of myeloma(creatinine elevation,extramedullary lesions,ISS Ⅲ,high-risk cytogenetic abnormalities)and TCM syndrome types,and based on the statistical results of the syndrome type factors with strong correlation with the high-risk prognostic factors of MM,Using the relevant database and methods of network pharmacology,the potential mechanism of tonifying kidney,activating blood circulation and dredging collaterals prescription in treating MM in hematology department was further explored.Methods:1.Retrospective collection of clinical data of MM patients,in line with the diagnostic criteria of MM in the Guidelines for the Diagnosis and Treatment of Multiple Myeloma in China(Revised 2022)and the TCM syndrome criteria of MM in the Guidelines for the Clinical Diagnosis and Treatment of Oncology in Traditional Chinese Medicine of the Chinese Society of Traditional Chinese Medicine.2.Analysis of the gender The correlation between general clinical characteristics such as age and common high-risk prognostic factors(creatinine,extramedullary lesions,ISS stage Ⅲ,high-risk cytogenetic abnormalities)and TCM syndrome types.3.Obtain the active ingredients and targets of the traditional Chinese medicine contained in the tonifying kidney,activating blood circulation and dredging collaterals prescription through the systematic pharmacology database and analysis platform of traditional Chinese medicine(TCMSP)and the comprehensive database of traditional Chinese medicine(TCMID)for molecular mechanism analysis of traditional Chinese medicine;Acquire MM disease targets through TTD database,GeneCards database and OMIM database;Construct the network diagram of "drug component disease target" with the help of Cytascape 3.7.2;Through Venny2.1.0 platform,the intersection of traditional Chinese medicine drug target and disease target is obtained and Wayne diagram is drawn;The obtained common gene targets are applied to the STRING 11.0 platform to establish protein interaction(PPI)network;Use CytoNCA to analyze the topology of PPI network,and screen the core target of Bushen Huoxue Tongluo Formula in the treatment of multiple myeloma;The R language is used to enrich and analyze the pathway of potential gene ontology biological process(GO)of the core target,and the GOplot software package is used to visualize the enrichment results.The metascape website is used to enrich and analyze the pathway of Kyoto Encyclopedia of Genes and Genome(KEGG),and the online network platform of Microbioinformatics is used to visualize the KEGG enrichment pathway,and analyze the potential pathway and biological process involved in the treatment of MM by Bushen Huoxue Tongluo Formula.Results:1.The basic characteristics of TCM syndrome type distribution in MM patients:among 121 newly diagnosed MM patients,28(23.1%)had deficiency of qi and blood;11 patients(9.1%)with yin deficiency of liver and kidney;30 cases(24.8%)of spleen and kidney yang deficiency;52 patients(43.0%)with phlegm-stasis obstruction syndrome;64 males(52.9%)and 57 females(47.1%);The age distribution of the population is the most among the people over 60 years old,92(76.03%),with the median age of 67 years.2.According to Kruskal-Wallis H rank sum test,the creatinine level is correlated with the distribution of TCM syndrome types(H=45.510,P<0.001).The creatinine level of spleen and kidney yang deficiency syndrome is significantly higher than that of other syndrome types(P<0.001).3.According to Fisher’s accurate test,extramedullary lesions have no correlation with TCM syndrome types(2=5.866,P>0.05).4.According to Kruskal-Wallis H rank sum test,the ISS stage is correlated with the syndrome types of traditional Chinese medicine(H=18.460,P<0.001).Further comparison between the two groups shows that there are statistical differences between the ISS stages of liver and kidney yin deficiency and deficiency of qi and blood,liver and kidney yin deficiency and deficiency of spleen and kidney yang,phlegm stasis obstruction and deficiency of spleen and kidney yang(P<0.05),and there is no statistical difference between other syndrome types.The patients with spleen and kidney yang deficiency were the highest in ISS Ⅲ,significantly higher than those with liver and kidney yin deficiency and phlegm stasis obstruction.Through frequency comparison,according to Statistics of Frequencies,the distribution of TCM syndrome types in ISS Ⅲ is from more to less,with phlegm stasis obstruction>spleen and kidney yang deficiency>qi deficiency deficiency>liver and kidney yin deficiency,accounting for 39%,30%,29%and 2%respectively.5.Fisher’s precise test showed that there was no correlation between high-risk cytogenetic abnormalities and TCM syndrome types(2=5.273,P>0.05).According to the statistics of Frequencies,the syndrome type of 1q amplification is phlegm stasis obstruction syndrome,followed by spleen and kidney yang deficiency syndrome,accounting for 34.8%and 30.4%respectively;The most common type of high risk cytogenetic abnormality associated with IgH translocation is phlegm-stasis obstruction syndrome,followed by spleen and kidney yang deficiency syndrome,accounting for 38.9%and 27.8%respectively;The syndrome types with the most mutation of del(1 7p)/TP53 are phlegm-stasis obstruction and deficiency of qi and blood,accounting for 29.6%respectively;The syndrome type with the highest incidence of cytogenetic abnormality of "double strikes" is the deficiency of qi and blood,followed by the obstruction of phlegm and blood stasis and the deficiency of spleen and kidney yang;The syndrome type with the highest incidence of "three strikes" cytogenetic abnormality is phlegm-stasis obstruction syndrome.6.According to the statistics of Frequencies,one patient has four high-risk factors at the same time,and its syndrome type is spleen and kidney yang deficiency;At the same time,MM patients with three high risk factors have their syndrome types from high to low:spleen and kidney yang deficiency>phlegm and blood stasis obstruction>qi and blood deficiency>liver and kidney yin deficiency,accounting for 46.1%,30.7%,23,2%and 0%respectively;The distribution of syndrome types of MM patients with two high-risk factors at the same time is from high to low;spleen and kidney yang deficiency>phlegm stasis obstruction>qi and blood deficiency>liver and kidney yin deficiency,accounting for 42.9%,35.7%,17.9%and 3.5%respectively;The syndrome type with the most high risk factors is spleen and kidney yang deficiency syndrome,which is the most distributed in MM patients with four,three and two high risk factors at the same time;The second is phlegm-stasis obstruction syndrome,which is second only to spleen-kidney yang deficiency syndrome in the distribution of MM patients with four and three high-risk factors at the same time.7.In terms of network pharmacology research,342 kinds of active ingredients of Bushen Huoxue Tongluo recipe were obtained,with a total of 315 targets.A total of 3341 targets were obtained by MM;Obtain 306 drug disease intersection targets,and according to the data of DC,BC,EC and CC values calculated by the CytoNCA plug-in,screen 42 core targets,involving TP53,VEGFA,AKT1,PIK3CA,HSP90AA1,IL1B,etc.The KEGG pathway analysis shows that the Kidney Tonifying Active Tongluo Formula mainly involves PI3K-Akt,JAK-STAT,TGF-β、Multiple signal pathways such as IL-17 treat MM.Conclusion:2.This study showed that there was correlation between creatinine and ISS stage and TCM syndrome type among MM prognostic risk factors,but there was no correlation between extramedullary disease and high-risk cytogenetic abnormality and TCM syndrome type.The TCM syndrome with the most risk factors for MM prognosis is spleen-kidney Yang deficiency syndrome,followed by phlegm-stasis obstruction syndrome.Through the application of network pharmacology,it has been found that the Bishen Huoxuetongluo prescription for the treatment of MM can regulate the targets of TP53,VEGFA,AKTI,PIK3CA,HSP90AA1,IL1B,and act on several signaling pathways such as PI3K-Akt,YAK-STAT,TGF-β,and IL-17.It is involved in cell proliferation,differentiation,apoptosis,immune regulation,tumor immune microenvironment regulation mediating inflammatory response.In this study,the potential targets and critical pathways of Bushenhuoxuetongluo prescription were studied by network pharmacology,but due to time constraints and other factors,clinical trial verification and target and pathway verification were not performed on patients.Clinical RCT studies on Bushenhuoxuetongluo prescription were expected to be carried out in the next step,and clinical verification and efficacy evaluation were carried out on MM patients.In addition,the differential expression of related key targets,pathways and genes before and after Bushen Huoxuetongluo prescription treated MM patients was studied,and the mechanism of action of Bushen Huoxuetongluo prescription treated MM patients was further studied,so as to improve the disease curative effect,prolong the survival of MM patients and improve the quality of life.