Research Progress in the Application of Network Pharmacology in Traditional Chin

Jiangcun WEI, Zujie QIN, Xiumei MA, Wen ZHONG, Zongxi SUN, Liping QIN, Yinghong HUANG, Xianyi SHI

Guangxi International Zhuang Medicine Hospital, Nanning 530201, China

Abstract Network pharmacology is a new discipline based on the theory of systems biology, mainly for network analysis of biological systems. It selects specific signal nodes for multi-target drug molecular design. This article summarizes the application of network pharmacology in traditional Chinese medicine and compound prescriptions in recent years from the research progress of network pharmacology, the current research status of single herbs, and the research and application of compound prescriptions.

Key words Network pharmacology, Traditional Chinese medicine, Compound prescription

1 Introduction

As new drugs continue to have low safety and poor effectiveness in the treatment of complex diseases[1], people have gradually realized the limitations of the drug development model. The role of compound prescriptions is characterized by the "multi-component, multi-path, multi-target" synergistic effect, which makes them play an advantage in the treatment of cardiovascular and cerebrovascular diseases, anti-tumor and other major diseases. However, the medicinal material basis and mechanism of action are unknown, and the quality of Chinese medicinal materials is difficult to effectively control. Systematic and comprehensive research from the overall level to the molecular level and then to the gene level appears to have great resistance[2]. Network pharmacology is an emerging discipline. It reveals the complex network relationship between "drug-gene-target-disease" by combining various technologies such as omics, high-throughput screening, molecular exchange verification, network visualization, and network analysis[3]. A new model of drug molecular design based on network pharmacology is an important way to develop and research innovative drugs. Therefore, this article describes the research progress of network pharmacology in the field of traditional Chinese medicine from the aspects of network pharmacology, its research status in single herbs, and its application in compound prescriptions.

2 Development status of network pharmacology

Network pharmacology was first proposed in 2007 by Professor Hopkins A L, a pharmacologist at the University of Dundee, UK. His idea is to combine pharmacology with network analysis, forming the concept of network pharmacology[4], which combines molecular pharmacology, network biology, computational biology, molecular dynamics and other disciplines together to construct and integrate "disease-phenotype-gene-drug" multi-level network technology and analyze the interaction between drugs and specific pathway nodes in the network. It is a new subject that explores the interaction between drugs and the body as a whole[5]. The main technologies of network pharmacology are database technology, analysis technology, modeling and experimental technology.

2.1 Database technologyThe content of database technology covers data retrieval, data extraction, data integration, calculation and literature retrieval[6]. Commonly used databases in network pharmacology include active ingredient databases (Ch EMBL and Pub Chem), drug information databases (Drug Bank and STITCH), phenotype and genotype association database (OMIM), biomolecular interaction databases (HPRD, BIND, DIP, HAPPI, MINT and String),etc.According to these databases and experimental studies and their clinical results, from the biological direction, based on the analysis of the "disease phenotype-gene-target-drug" interaction, through data processing, network pharmacology is to observe and research the intervention of drugs on pathology and make the medicines closer to the actual situation of human physiological diseases[7].

Through the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), the Traditional Chinese Medicine Potential Target Database (TCM-PTD) and the Traditional Chinese Medicine Integrated Database (TCMID), Chen Wennaetal.[8]found the main components of Erchen decoction. Using the ChemMapper database, targets were predicted, and component targets were screened. The TTD, Drugbank and DisGeNET databases were used for searching to obtain targets related to coronary heart disease. The disease targets were intersected with drug targets, and the disease-drug common target proteins were obtained through screening. The STRING platform was used to construct a protein-protein interaction (PPI) network model. Using Metabo Analyst database, the component metabolites screened above were analyzed to screen out the main metabolites. Using Cytoscape’s MetScape and ClueGO plug-ins, the main drug component-metabolite-target-signaling pathway topology network of Erchen decoction was constructed. The potential molecular mechanism of Erchen decoction in treating coronary heart disease from phlegm and blood stasis was explored from multiple angles. The pharmacological effect of Erchen decoction was revealed, providing a research direction for the screening of subsequent clinical efficacy evaluation indicators.

2.2 Modeling and analysis technologiesModeling and analysis technologies mainly include network construction, key node analysis, key module analysis and critical path analysis. Network analysis technology is the key technology of network pharmacology. It conducts multi-angle and multi-level information mining on the relevant molecular networks in network pharmacology research by combining multiple disciplines and technologies to accurately and objectively query the ingredients or combination of ingredients, drugs or drug combinations that can produce specific pharmacological effects, as well as key nodes and modules with specific physiological functions, providing valuable information for the discovery of drug mechanism of action, new drug development, biomarker specification and disease mechanism interpretation[9].

Zhu Yanfangetal.[10]used molecular docking and complex network analysis techniques to study the interaction between the active ingredients of Tiaopi Huxin Recipe and the target, and the results showed that the scale-free nature of the network and the nature of the network nodes can better explain the pharmacological effects of the active ingredients contained in Tiaopi Huxin Recipe. This research strategy provides a reference for the systematic research of compound prescriptions. Zhao Qinqinetal.[11]studied the regulatory effects of the main active ingredients of safflower injection on the cerebrovascular disease network through the concept of network pharmacology and network analysis technology, constructed a disease network using genes related to cerebrovascular diseases in the public database RGD, comprehensively collected the target information of the five main active ingredients of safflower injection in PubMed, extracted the component-target relationship and integrated the cerebrovascular disease network to build a component-target network. Using network topology attribute analysis, sub-cluster clustering algorithm and network GO enrichment analysis, the multi-target and multi-path mode of action of the main active ingredients of safflower injection against cerebrovascular diseases and the synergistic effect between the ingredients were revealed from the molecular network level.

2.3 Experimental technologyThe experimental technology contains experimental verification at the molecular level, cell level and overall animal level. Based on network pharmacology prediction and experimental verification of rat myocardial ischemia-reperfusion injury model, Zou Chuncaietal.[12]found that Gualou Xiebai dripping pill pretreatment can activate the PI3K-Akt signaling pathway, promote Akt protein phosphorylation and reduce caspase-3 protein expression, playing the role of inhibiting cell apoptosis and protecting myocardium, confirming the results of network pharmacology, and comprehensively clarifying the anti-heart failure mechanism of Semen Trichosanthis-Bulbus Allii Macrostemi compatibility.

Based on network pharmacology prediction and animal model verification, Pan Guofengetal.[13]studied the mechanism of Yangyin Qingfei Oral Liquid to protect lung from injury, predicted that Yangyin Qingfei Oral Liquid has 53 targets, plays a role through multi-targets of different active ingredients, shared target collaboration and independent targets, and also plays a role through anti-inflammatory and antioxidant pathways. Studies have found that Yangyin Qingfei Oral Liquid significantly reduces lung damage caused by fog combined with haze, and the mechanism of improving lung function is related to inhibiting the expression of inflammatory mediators, regulating oxidation/antioxidation, and down-regulating inflammation signal pathways.

3 Research status of single herbs

In recent years, network pharmacology has been widely used to mine and analyze the active ingredients of single herbs, search targets related to disease, and explore the mechanism of action of Chinese medicine, in order to provide theoretical basis for related experiments and clinical research, and achieve the effect of slowing down the occurrence and development of diseases. Wu Fangetal.[14]found that Radix Salviae Miltiorrhizae has a good effect on the treatment of diabetic nephropathy. The experiment used the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and analysis platform to mine the active components of single Radix Salviae Miltiorrhizae, searched the databases of DrugBank, TTD, GAD, OMIM and Pharm GKB for disease-related targets, screened out the targets of diabetic nephropathy, find the specific targets for preventing and treating diabetic nephropathy based on bioinformatics methods, and further analyzed the possible mechanism of action against key targets using ClueGO. Radix Salviae Miltiorrhizae has the characteristics of multiple components and multiple targets in the treatment of diabetic nephropathy. This may be related to cell proliferation, differentiation and apoptosis. It protects the glomerular filtration barrier and reduces kidney damage through the body’s glucose and lipid metabolism, inflammation,etc.

Based on network pharmacology research, Gao Yuanetal.[15]analyzed the anti-inflammatory targets and signal pathways of the effective components of Semen Astragali Complanati, imported the potential targets associated with inflammation into the KEGG Pathway database, and aligned drug targets and disease targets to verify the anti-inflammatory mechanism of Semen Astragali Complanati. Zhang Runtongetal.[16]integrated and analyzed the active components, potential targets and mechanism of Herba Epimedii for preventing and curing diseases through network pharmacology research. A total of 34 active ingredients with potential targets were screened out. In addition, 183 corresponding targets were screened, involving 84 signal-related pathways, which laid the foundation for the discovery of the active components of Herba Epimedii and the study of the mechanism of action.

4 Current status of research on compound prescriptions

Relevant scientific and technical personnel have used network pharmacology method to systematically study the mechanism of action of compound prescriptions to provide scientific theoretical basis. Zhai Yuanyuanetal.[17]found 39 major liver-protecting active ingredients through network pharmacology method. They may regulate 321 targets and 51 pathways to protect the liver. Tao Lingjiaetal.[18]studied the anti-tumor mechanism of Jianpi Bushen Compound with network pharmacology method. The results showed that it may be related to the effect of macrophage colony’s stimulating factor receptor and interleukin-2 receptor on the immune system and inhibiting angiogenesis. Wang Qianetal.[19]used the method of network pharmacology to make a preliminary study on the mechanism of action of Jiawei Huanglian Yinzi in the treatment of coronary heart disease, and found that the effective components of Jiawei Huanglian Yinzi can treat coronary heart disease through inflammation-related pathways, neuronutrition, hemodynamics regulation, calcium ion channel and other related mechanisms. It is verified that Jiawei Huanglian Yinzi can reduce serum inflammatory factors and brain-derived nutritional factors and regulate blood lipids.

Ma Yuncietal.[20]obtained relevant information of Chinese medicines, ingredients and targets from the TCMSP database, used Cytoscape software to screen Chinese medicines that can act on targets related to accelerated atherosclerosis in chronic renal failure, screened further and constructed compound prescription according to the theory and formulating principles of traditional Chinese medicine, and observed the effect of Yishen Jiangzhi Recipe on atherosclerosis through animal experiments. The changes in the blood lipids level, tissue morphology and serum biochemical indices were detected. It was found that Yishen Jiangzhi Recipe constructed using network pharmacology and traditional Chinese medicine theory has the effect of improving accelerated atherosclerosis in chronic renal failure.

5 Conclusions

Traditional Chinese medicine has a history of thousands of years. It is a summary of the rich experience of the Chinese people in fighting the disease for a long time[21]. Network pharmacology is combined with the holistic view of dialectical treatment of Chinese medicine. It has a relatively comprehensive analysis and research technology. At the same time, it is a methodology with dynamic analysis and holistic view[22]. In recent years, researchers have conducted related research on the use of network pharmacology in diseases treated with compound prescriptions, conducive to a new understanding of Chinese medicine from the levels of gene and protein[23]. Drug-gene-disease co-module analysis based on network pharmacology is helpful to clarify the compatibility mechanism of traditional Chinese medicine prescriptions and their network mechanism analysis[24]. However, the application of network pharmacology to the research of traditional Chinese medicine compound prescriptions is still in its infancy, and there are still many problems, such as incomplete data in the database, limited number of targets and ingredients of drugs, and incapability to fully reveal the mechanism of action and pathway targets.

Network pharmacology analyzes the effects of drugs on diseases from a comprehensive perspective and the characteristics of network through the connection of nodes in the network and their relationship, so as to further clarify the mechanism of action of drugs, including the mechanism of action of traditional Chinese medicine in the treatment of complex diseases. This will help promote the inheritance, development and innovation of Chinese medicine, accelerate the development process of the modernization and internationalization of Chinese medicine in China and contribute to the progress of Chinese medicine.

Acknowledgements

We would like to express our sincere thanks to the Zhuang Yao Medicine Research Laboratory of Guangxi International Zhuang Medicine Hospital for its support and help during the research process.