Post-marketing effectiveness evaluation of traditional Chinese medicine in paradigm based on "proving efficacy, conforming standard, and exploring mechanism":a case study of Danhong Injection / 中国中药杂志

At present, new concepts, new technologies, and new methods are emerging in the field of medical research, breaking through the inherent thinking patterns and research models, and promoting the transformation of the research paradigm of traditional Chinese medicine(TCM). This paper gave a case study of clinical research in Danhong Injection in the treatment of chronic stable angina, and based on the background of the study, index evaluation model, experimental design method, blind implementation of placebo, data management system, and exploration of clinical efficacy mechanism of traditional Chinese medicine compounds under the framework of modular pharmacology, the scientific idea of "proving efficacy, conforming standard, and exploring mechanism" was used as the guideline to discuss the research model of reevaluation of the effectiveness of post-marketing TCM varieties. This paper drew a target network map of Danhong Injection in the treatment of chronic stable angina for the first time, which was composed of targeted functional modules. By combining evidence-based clinical research with modular pharmacology framework, changes in the pharmacolo-gical mechanism were finally associated with changes in clinical efficacy, and the advantages of phenotypic correlation of efficacy were explored. This study is expected to provide references for the post-marketing effectiveness evaluation and new ideas for the phenotypic pharmacological mechanism study of multi-target TCM compounds and precise treatment, thereby promoting the innovative development of TCM.

Distribution Mechanism of Network Modules in Combined Treatment of Liver Cancer with Jiuwei Zhengxiao Granules / 中国实验方剂学杂志

ObjectiveTo explore the distribution mechanism of network modules in the combined treatment of liver cancer with Jiuwei Zhengxiao granules （JWZX） based on the analysis framework of module pharmacology. MethodThe cell experiment and the animal experiment were carried out to investigate the in vitro anti-liver cancer efficacy of JWZX of different concentrations and the effect on the survival time of H22 ascites tumor mice. By virtue of the analysis strategy of modular pharmacology，the distribution characteristics of nine Chinese drugs in the liver cancer disease network modules were investigated based on the constructed liver cancer disease network and module division by MCODE. In this study，the average degree （AD） of the nodes in the modules was used as an index to screen the main modules of the disease，and the intervention of the sovereign drugs，minister drugs，and assistant drugs on the main modules was explored. Finally，the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis was performed on the drug-acted modules by Metascape. ResultAs revealed by the cell experiment，JWZX could significantly inhibit the proliferation of H22 cells. The animal experiment demonstrated that the medium- and high-dose JWZX could significantly prolong the survival time of mice with H22 ascites tumor （P<0.05，P<0.01）. The distribution of targets of JWZX in the liver cancer disease network modules showed that JWZX interfered with tumor necrosis factor （TNF），epidermal growth factor receptor （EGFR），vascular endothelial growth factor A （VEGFA），transcription factor （JUN），tumor protein p53 （TP53），and other 26 targets and 8 modules. The sovereign drug Ginkgo Semen mainly intervened in modules 3 and 8，and the minister drugs such as Centipeda Herba jointly intervened in modules 1，3，5，8，10，and 12. Centipeda Herba and Phyllanthi Fructus intervened in module 7 and module 19 individually. Artemisiae Annuae Herba and other assistant drugs jointly intervened in modules 3，5，10，and 12. KEGG pathway enrichment analysis found that 135 pathways were enriched in 8 modules，and the pathway functions involved 12 categories including cancer，signal transduction，immune system，endocrine system，and amino acid metabolism. The functions of the four major modules involved cancer，signal transduction，and immune system. According to the results of literature verification，the key links of JWZX on the liver cancer disease network and the core mechanism were presumedly related to the inhibition of phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt） and hypoxia-inducible factor-1 （HIF-1） signaling pathways，reduction of the immunosuppressive effect in the tumor microenvironment，and improvement of the anti-tumor immune response. ConclusionJWZX possesses pharmacological activity against liver cancer，and the therapeutic efficacy was achieved through the multiple targets，multiple modules，and multiple functions of drugs alone or in combination to intervene in the disease. The present study reduced the complexity of drug-disease target network analysis with module analysis strategy and explored the network module distribution mechanism of JWZX in the treatment of liver cancer，which provides a new idea for interpreting the complex mechanism of prescription compatibility.

Analysis of Modular Network Mechanism of Danhong Injection in Treatment of Coronary Angina Pectoris / 中国实验方剂学杂志

Objective:To explore the pharmacological mechanism of Danhong injection (DHI) in the treatment of coronary heart disease with angina pectoris from the level of functional modules by modular pharmacological analysis framework. Method:The targets of drug components in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the angina-related genes in DisGeNET, OMIM and CTD databases were combined to construct the target network of DHI for the treatment of coronary angina pectoris by STRING version 11.0. Functional modules were identified by the molecular complex detection (MCODE), Markov cluster (MCL) and GLay algorithms, and the results were optimized by the minimum network structure entropy algorithm. The Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis was performed on the modules by DAVID version 6.8 bioinformatics analysis platform. Result:By integrating 262 genes related to DHI and 192 genes related to angina pectoris, the target network of DHI for angina pectoris was constructed, including 414 nodes and 6 621 edges. After optimization of the minimum network structure entropy, 12 functional modules (number of nodes>3) were identified by MCODE algorithm, of which the largest module (module 1) has 47 nodes and 962 edges, MCODE score=41.826. KEGG pathway enrichment analysis was conducted on the gene network of DHI for angina pectoris and the modules divided by MCODE, and 37 and 58 KEGG signaling pathways were obtained respectively, with the coverage rate of 86.5%. The pathways enriched by the modules could be roughly divided into 11 categories, among which human diseases (45%), signal transduction (17%), and amino acid metabolism (14%) were involved in a large proportion. Module 1 was enriched into 39 pathways, which was signal transduction-related module. Module 3 was amino acid metabolism-related module. Conclusion:The therapeutic effect of DHI on coronary heart disease with angina pectoris is achieved through multiple modules, multiple pathways and multiple functions, mainly by regulating modules related to signal transduction, amino acid metabolism, neuroactive ligand-receptor interaction, Ca2+ and p53 signaling.