| OBJECTIVE:(1)We Systematically summarize the current oral Chinese patent medicine used as the adjuvant therapy for breast cancer and its clinical evidence.Bayesian network Meta analysis was used to evaluate the efficacy and safety of oral Chinese patent medicine in adjuvant treatment of breast cancer.In order to provide reference for clinical practice,the information of Chinese patent medicine with the best curative effect was selected,based on different outcome assessment indicators.(2)Network pharmacology was used to systematically predict and summarize the mechanism of Xi Huang pill in treating cancer-related fatigue of breast cancer.At the same time,a mouse model of cancer-related fatigue of breast cancer induced by xenografted tumors.The efficacy and mechanism of Xi Huang pill in preventing and treating the cancer-related fatigue of breast cancer were investigated.METHODS:(1)Evidence based evaluation of oral Chinese patent medicine as the adjuvant treatment for breast cancer.Bibliometric method was used to systematically summarize the current oral Chinese patent medicine used as the adjuvant therapy for breast cancer,drug composition,and efficacy classification,etc.Taking the oral Chinese patent medicine for anti-tumor in the national medical insurance catalogue in recent three years as the research object,both the Chinese database and English database(including CNKI,Wanfang,VIP,SinoMed,PubMed,Embase,Web of Science and Cochrane Library database)were searched from inception to March 1,2022.This paper systematically summarizes the characteristics of various clinical research literatures,including the publication time,study types and types of intervention.The software of Revman5 3、Stata14.0、Gemtc14.3 were used for data analysis.To evaluate the efficacy and safety of oral Chinese patent medicine combined with chemotherapy in the treatment of breast cancer.Then we select the information of Chinese patent medicine with the best curative effect under different evaluation indexes,sort the curative effect probability,and summarize the clinical characteristics of different drugs.(2)Mechanism of Xi Huang pill in treatment of cancer-related fatigue of breast cancer based on network pharmacology.Active components and corresponding targets of Xi Huang pill were obtained through Traditional Chinese Medicine Systems Pharmacology Database(TCMSP),database of traditional Chinese medicine and chemical constituents,and database of HERB.Active components of traditional Chinese medicine were acquired according to ADME platform.Related targets of cancer-related fatigue of breast cancer were obtained through Gene Cards and OMIM databases.The "drugs-component-target" network was constructed by Cytoscape3.7.1 software.The protein-protein interaction(PPI)network was drawn using STRING platform.Gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were carried out using R3.6.1 software.(3)Experimental study on the mechanism of Xi Huang pill in preventing and treating cancer-related fatigue of breast cancer.The mice model of cancer-related fatigue of breast cancer was established.The experiment was divided into blank control group,high dose of Xi Huang pill,middle dose of Xi Huang pill,low dose of Xi Huang pill,and Capecitabine Tablets group,10 mice in each group.All of them were given intragastric administration,once a day,for 3 weeks,and two batches of mice were fed.In the first batch of 60 mice.The first batch of 60 mice were mainly used to investigate the mechanism of Xi Huang Pill on the cancer-related fatigue of breast cancer.The observation time was 0 days,14 days and 20 days of intervention.The second batch of 60 mice were selected to record and compare the general conditions of mice in the all groups,and to observe the effect of Xihuang Pill on the survival time of transplanted tumor induced model mice.(1)the mechanism of Xi Huang Wan on the cancer-related fatigue of breast cancer:①We compared the body weight,tail swing time of tail suspension experiment and the first residence time of rotating rod experiment on day 0,day 14 and day 20 of intervention.Then we determine whether there is fatigue like behavior in transplanted tumor mice and the change law of fatigue like behavior with time.② Comparison of survival time of mice in each group.③ After the experiment of the first batch of mice,relevant samples were obtained.Fiest,the contents of ATP and glycogen in skeletal muscle and routine blood indexes was test.④ The contents of myeloid derived suppressor cell(MDSC)and its subsets in tumor tissues of mice in each group were detected by flow cytometry.The protein expressions of Arg-1 and iNOS in tumor tissues of mice in each group were detected.⑤The inflammatory factors(such as the level of IL-6 and TNF-α)in tumor tissue and peripheral blood were detected by immunohistochemistry and ELISA.⑥The mRNA expression level of TNF-α,NF-κB p65 and IκB-α was detected by PCR test.The Protein expression level of TNF-α,NF-κB p65 and IκB-α was detected by Western blot test.(2)The observation on inhibition effect of Xi Huang Pill on breast cancer:① We compared the tumor volume,on day 0,day 14 and day 20 of intervention.② The morphological changes of transplanted tumor tissues in each group were observed by HE staining.CD31(platelet endothelial cell adhesion molecule)was labeled,and then the effect of Xihuang Pill on angiogenesis in tumor was observed by immunofluorescence.③ The expressions of apoptosis related proteins Bcl-2,Bax and caspase8 were detected by immunohistochemistry.RESULTS:(1)Evidence based evaluation of oral Chinese patent medicine as the adjuvant treatment for breast cancer.Most of the clinical trial types of oral Chinese patent medicine as adjuvant treatment in treatind breast cancer were randomized controlled trials(RCTs)(about 65.69%).The published time span of the literature was 1998-2021.The number of published papers showed a overall growth of literature.The literatures were published in 102 journals.Most of the articles were published in the Journal of《Journal of Modern Oncology》and《Drugs&Clinic》.There are 35 oral Chinese patent medicines for the treatment of malignant tumors in the medical insurance catalogue,of which 19 Chinese patent medicines had the clinical evidence of treating breast cancer.The top five Chinese patent medicines in terms of the number of published literature evidence are Huaier granule,Xihuang Pill/capsule.Pingxiao capsule,Shenyi capsule and Huachansu capsule.The Network Meta-analysis included 68 RCTs for data analysis,with a total of 6082 patients,studies were published from 2004 to 2021,involving 13 oral Chinese patent medicines.The results of network Meta-analysis shown that in terms of improving ORR(Ⅰ～Ⅲ stage),the order of efficacy was Shenyi capsule>Jinlong capsule>Xihuang Pill/capsule>Pingxiao capsule>compound cantharidin capsule>Huaier Granule>cinobufagin capsule>compound Taxus capsule.In terms of improving DCR(Ⅰ～Ⅲ stage).the order of efficacy was Jinlong capsule>compound Taxus capsule>Xihuang Pill/capsule>compound cantharidin capsule>Pingxiao capsule>cinobufagin capsule>Huaier Granule.In terms of improving ORR(Ⅲ～Ⅳ stage),the order of efficacy was Huaier Granule>Pingxiao capsule>Xihuang Pill/capsule>Shenyi capsule>cinobufagin capsule.In terms of improving DCR(Ⅲ～Ⅳ stage),the order of efficacy was Pingxiao capsule>Shenyi capsule>Xihuang Pill/capsule>Huachansu capsule>Huaier Granule.In terms of improving QOL.the order of efficacy was Xihuang Pill/capsule>Huaier Granule>Shenyi capsule>cinobufagin capsule>Jinlong capsule>compound cantharidin capsule>Pingxiao capsule.Xihuang pill/capsule was beneficial in improving PFS and OS of breast cancer patients.Pingxiao capsule was beneficial in improving OS of breast cancer patients.In terms of reducing the incidence rate of leukocyte decline,the order of efficacy was Aiyu capsule>Zhenqi Fuzheng granule>Shenyi capsule>Huaier Granule>Huachansu capsule>Xihuang Pill/capsule>Qizhen capsule>Pingxiao capsule>compound cantharidin capsule.In terms of alleviating the incidence of gastrointestinal reactions,the order of efficacy was Zhenqi Fuzheng granule>Qizhen capsule>Huachansu capsule>Xihuang Pill/capsule>Huaier Granule>Shenyi capsule>Pingxiao capsule>compound cantharidin capsule.In terms of improving the level of CD4+/CD8+,the order of efficacy was Pingxiao capsule>Qizhen capsule>YangZheng Xiaoji capsule>Huaier Granule>Jinlong capsule>Xihuang Pill/capsule>compound cantharidin capsule.Sensitivity analysis and publication bias suggest that the current results are basically stable and less affected by publication bias.(2)Mechanism of Xi Huang pill in treatment of cancer-related fatigue of breast cancer based on network pharmacology.A total of 106 compounds and 47 active components were screened out.Finally,77 drug and disease intersection targets were obtained.Quercetin,Petunidin,Morin,Beta-Sitosterol and Ellagic acid are the important components of Xi Huang pill for cancer-related fatigue of breast cancer.PPI network shown degree value of the top twenty target genes of CASP3、ESR1、MYC、EGFR、HIF1A、IL6、VEGFA,CCND1,PPARG,NF-κB,etc.Totally 1241 biological process terms.81 molecular functional terms,and 39 cellular component terms were obtained from GO enrichment analysis.A total of 117 related signal pathways were obtained by KEGG.From KEGG pathway analysis.PI3K-Akt signaling pathway,MAPK signaling pathway,Apoptosis signaling pathway,HIF-1 signaling pathway.TNF signaling pathway,and other related pathways were obtained.The target pathway network of cancer related fatigue of breast cancer indicates that EGFR,BCL2.CASP3,VEGFA.CASP8,MYC.IL6 and NFκB are important targets etither.(3)Experimental study on the mechanism of Xi Huang pill in preventing and treating cancer-related fatigue of breast cancer.1.The study of Xi Huang Pill on cancer related fatigue of breast cancer:(1)Effects of drugs on CRF behavior:During the experiment,compared with the blank group,all the transplanted tumor mice in each group showed different degrees of weight loss,sparse hair,slow movement,reduced eating,reduced grasping resistance,arched back and so on.Compared with the blank group,on the 14th and 20th days during intervening process,the swing immobility time of tail suspension test was gradually prolonged,and the first residence time of rotating rod test was gradually shortened,the difference was statistically significant(P<0.05).It indicates that the model mice have CRF characteristics.Compared with the model group,the rocking immobility time of mice in the high,medium and low dose groups of Xihuang Pill was significantly shorter(P<0.05).The first residence time of rotating rod experiment was longer than that of model group(P<0.05).There was no significant difference in the rocking immobility time and the first residence time of the rotating rod experiment in the capecitabine group and the model group.(2)Survival time:Compared with the model group,each drug group has the trend of prolonging the average survival time of mice,but there is no significant difference in prolongation time.In terms of median survival time,all the drug groups did not show the effect of prolonging the median survival time.(3)Muscle glycogen and muscle ATP content:Compared with the blank group,the ATP content of skeletal muscle in the model group decreased,while the muscle glycogen content increased after the intervention;Compared with the model group,the ATP content of skeletal muscle in each treatment group increased and the glycogen content of skeletal muscle decreased,but the difference was not statistically significant.There was no significant difference in the contents of the liver ATP and glycogen in of each group.(4)The level of MDSC:The level of MDSC in the model group increased significantly,compared with the model group,the level of MDSC in Xihuang Pill high and medium dose groups decreased significantly(P<0.05).Compared with the model group,the level of granulocyte like phenotype MDSC and the expression of iNOS and Arg-1 in Xihuang Pill high,medium and low groups were decreased,but the difference was not statistically significant.(5)Effect of drugs on TNF-α and IL-6:①The results of ELISA:Compared with the blank group,the level of TNF and IL-6 in peripheral blood of model group increased significant(P<0.05).Compared with the model group,the level of TNF and IL-6 in peripheral blood of each dose group of Xihuang Pill and capecitabine groups increased significant(P<0.05).② Immunohistochemical results:TNF-α in model group decreased significantly.Compared with the model group,the expression of TNF-α in capecitabine group and Xihuang Pill high and medium dose groups was increased(P<0.05).The expression of IL-6 in the model group was the highest.Compared with the model group,the expression of IL-6 in capecitabine group and Xihuang Pill high and medium dose groups decreased(P<0.05).(6)Effect of Xihuang Pill on TNF-αand NF-κB signaling pathway:① Real time PCR and Western blot results:Compared with the model group.The expression level of TNF-α and NF-κBp65 in each dose group of Xihuang Pill and capecitabine tablet group and decreased significantly.The effect of capecitabine tablets was more obviously better than that of Xihuang Pill group(P<0.05).2.Inhibitory effect of Xi Huang Pill on breast cancer xenografts:(1)During the experiment,the changes of tumor appearance volume in the model group and each drug group were positively correlated with time,and the growth trend of tumor volume in each drug group was lower than that in the model group.The result of tumor inhibition rate was capecitabine tablets>Xihuang Pill medium dose group>Xihuang Pill high dose group>Xihuang Pill low dose group(P<0.05).(2)HE staining results:compared with the model group,the tumor tissues of each dose group of Xihuang Pill had different degrees of necrosis.(3)Immunohistochemical results:Compared with the model group,Xihuang Pill groups and capecitabine group could up regulate the expression of Bax and caspase8 and down regulate the expression of Bcl2(P<0.05).(4)CD31 labeling results of immunofluorescence staining:compared with the model group,the number of neovascularization in tumor tissue in capecitabine group and Xihuang Pill group decreased significantly after drug intervention.CONCLUSIONS:(1)There were 19 related Chinese patent medicines in national medical insurance drug catalogue as adjuvant treatment for breast cancer and it has some clinical documentary evidence.The number of clinical evidence published in the top five Chinese patent medicines is in the following order:Huaier granule,Xihuang Pill/capsule,Pingxiao capsule,Shenyi capsule,Huachansu capsule.The curative effect of oral Chinese patent medicine combined with chemotherapy in treatment of breast cancer is generally better than chemotherapy alone.Xihuang Pill/capsule can improve the QOL of patients with breast cancer more significantly than other medicines and it was beneficial to improve the long-term efficacy of patients with breast cancer.Aiyu capsule and Zhenqi Fuzheng granule could reduce the incidence of leukocyte decline.Zhenqi Fuzheng granule can alleviate the incidence of gastrointestinal reactions.Considering the low quality of the study and the lack of evidence of direct comparison of Chinese patent medicines,the above conclusions need to be further verified by large samples and high-quality studies.(2)The important ingredients of Xi Huang pill in the treatment of cancer-related fatigue of breast cancer includes Quercetin,Petunidin,Morin,Beta-Sitosterol and Ellagic acid,etc.Xi Huang pill may treat cancer-related fatigue of breast cancer through regulating immune,inflammatory response,inhibiting cell proliferation and migration,and promoting cell apoptosis.(3)A mouse model of cancer related fatigue of breast cancer induced by xenograft tumor can be established and it has substantial CRF characteristics.Xi Huang pill has inhibitory effect on breast cancer.Xi Huang pill has the effect of alleviating the cancer related fatigue of breast cancer.Its therapeutic effect may be related to the following biological processes:Xihuang Pill can regulate the level of inflammatory cytokines in peripheral blood and tumor tissue of mice and reduce the content of MDSC in tumor tissue.The regulation of inflammatory environment is related to the expression of TNF-α、NF-κB p65 in TNF-α and NF-κB signaling pathway. |
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