Abstract
Traditional Chinese medicine (TCM) formulas treat complex diseases through combined botanical drugs which follow specific compatibility rules to reduce toxicity and increase efficiency. “Jun, Chen, Zuo and Shi” is one of most used compatibility rules in the combination of botanical drugs. However, due to the deficiency of traditional research methods, the quantified theoretical basis of herbal compatibility including principles of “Jun, Chen, Zuo and Shi” are still unclear. Network pharmacology is a new strategy based on system biology and multi-disciplines, which can systematically and comprehensively observe the intervention of drugs on disease networks, and is especially suitable for the research of TCM in the treatment of complex diseases. In this study, we systematically decoded the “Jun, Chen, Zuo and Shi” rules of Huanglian Jiedu Decoction (HJD) in the treatment of diseases for the first time. This interpretation method considered three levels of data. The data in the first level mainly depicts the characteristics of each component in single botanical drug of HJD, include the physical and chemical properties of component, ADME properties and functional enrichment analysis of component targets. The second level data is the characterization of component-target-protein (C-T-P) network in the whole protein-protein interaction (PPI) network, mainly include the characterization of degree and key communities in C-T-P network. The third level data is the characterization of intervention propagation properties of HJD in the treatment of different complex diseases, mainly include target coverage of pathogenic genes and propagation coefficient of intervention effect between target proteins and pathogenic genes. Finally, our method was validated by metabolic data, which could be used to detect the components absorbed into blood. This research shows the scientific basis of “Jun-Chen-Zuo-Shi” from a multi-dimensional perspective, and provides a good methodological reference for the subsequent interpretation of key components and speculation mechanism of the formula.
Highlights
After thousands of years of experience in the treatment of diseases, the effectiveness of traditional Chinese medicine (TCM) is indisputable (Liang et al, 2015)
We construct the C-T-P network by integrating C-T network of Huanglian Jiedu Decoction (HJD) and protein-protein interaction (PPI) network. This extremely complex C-T-P network with 12,324 nodes and 84,138 interactions is difficult to clarify drug mechanism of action (MOA), so discovery of functional communities in the C-T-P network is very important for understanding the organization and function units of the HJD under the concept of the compatibility principle “Jun-Chen-ZuoShi”. The extraction of these community structures can reduce the dimension of complex networks and could be considered as the key factor for further clarify the compatibility principle of HJD’s “Jun-Chen-Zuo-Shi”, we identify the functional communities in the C-T-P network based on the information graph algorithm combining random walk theory and huffman encoding
Huanglian has highest propagation coefficient both in diabetes mellitus (DM) and Alzheimer’s disease (AD), the propagation coefficient of Haungqin and Huangbo is lower than Huanglian and Zhizi has the lowest propagation coefficient, which indicate that Huanglian plays a major role in disease treatment by spreading the intervention effect at a more powerful level, and Chen botanical drugs and Zuo botanical drugs play a role in assisting Huanglian
Summary
After thousands of years of experience in the treatment of diseases, the effectiveness of traditional Chinese medicine (TCM) is indisputable (Liang et al, 2015). How to detect the action pattern and underlying mechanisms of “Jun, Chen, Zuo and Shi” at a systematic and global perspective is the key to understand the mechanisms of formulas in the treatment of complex diseases in TCM. Our new system pharmacology strategy integrated three levels of data including the characteristics of each component in HJD single botanical drug, the characterization of component-target-protein (C-TP) network in the whole protein-protein interaction (PPI) network and the characterization of intervention propagation properties of HJD in the treatment of different complex diseases. Our study provides a comprehensive systems pharmacology framework to decode the principles of “JunChen-Zuo-Shi” from multi-level perspective, which may give some enlightenment for the subsequent interpretation of key components and hidden mechanism of the formula. The PPI data were derived from public databases BioGRID, STRING, Dip, HPRD, Intact, Mint and Reactome (Guan et al, 2014)
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