Network Perturbation-based Personalized Precision Prescription System For TCM And New Drug Discovery

Thousands of years of TCM clinical practice has fully demonstrated that Traditional Chinese Medicine(TCM)can effectively treat various diseases such as rheumatoid arthritis,tumors,and respiratory infections,thus effectively improving people's health status.However,the complexity of etiology,individual differences,and environmental changes have led to a high degree of heterogeneity and diversity in diseases,and have led to the fluctuations in the efficacy of traditional experience-based TCM.To precisely portray the potential association between herbs and complex diseases and construct disease-specific herbal medicine precision treatment protocols,we need to focus on the systematic description of complex diseases and herbal medicines.Hence,in this study,we propose the concept of network perturbation signatures based on the networked nature of organisms and apply it to the systematic portrayal of TCM and diseases,so as to elaborate the effects of disease occurrence,TCM treatment on the biological network of the organism and the potential connection between them.Firstly,we used an innovative technical solution represented by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)to construct the ingredients of 502 herbs and their target information,and constructed the global-scale perturbation signatures of TCM based on the perturbation diffusion of protein interaction network to simulate the effects of TCM on the biological network of the organism during the therapeutic process.Meanwhile,the comparative analysis based on the perturbation signatures also showed that the network perturbation of TCM showed a diversity features,indicating that each TCM has a unique therapeutic mechanism.Secondly,making full use of the large amount of disease information data accumulated during the development of the omic technology,we screened 460 disease transcriptomic data from 1,772 GEO human high-throughput datasets to construct a biological network perturbation signature after disease onset.Next,the analysis of disease classification based on network perturbation signatures further allowed us to understand the differences and commonalities in diseases.The above results suggest that network perturbation signatures can be used as a new method to quantitatively characterize the systematic effects of disease occurrence and TCM treatments on the biological network of organism,thus providing a basis for disease mechanism resolution and personalized treatment of TCM.To further explore the potential association between herbs and diseases,we further proposed a herb-disease mapping framework,HDmap-S,based on the network perturbation signatures of herbs and diseases.Based on this framework,we calculated the matching degree score between herbs and diseases and screen 15,035 potential herbal-disease relationship pairs.And the literature mining analysis of Pubmed database also proved that the prediction accuracy of herbal-disease association based on HDmap-S framework was 83.25%.In addition,comparative analysis of herb-disease pairs revealed that HDmap-S can provide consistent herbal treatment protocols for co-occurring diseases and diseases with similar mechanisms,such as rheumatoid arthritis,osteoarthritis,type 2 diabetes,and pulmonary hypertension.Also,the analysis of three pathological states of asthma(mild,severe,and allergic)has demonstrated that HDmap-S is able to provide differentiated herbal treatment protocols for different pathological states of the same disease.These results suggest that HDmap-S has a wide range of applications in the personalized treatment of TCM.However,the clinical application of TCM is often in the form of compound prescriptions,and the combination of multiple herbs leads to more challenging research on the individualized treatment and mechanism of compound prescriptions.Hence,we further explore the application of network perturbation signatures to the precision design and material basis research of compound prescriptions.To this end,based on HDmap-S,we further designed an herbal combination prediction framework(HDmap-M)to investigate the application of network perturbation signatures in new prescription development and therapeutic mechanism studies.And HDmap-M analysis for 189 diseases showed that the accumulation of herbal quantities did not increase the efficacy of the prescription,but rather led to a decrease in efficacy due to potential antagonism of the herbs.The prescription analysis based on the HDmap-M showed that a combination of up to 5 herbs would have the best efficacy for various diseases such as tumors,neurological diseases,digestive diseases,immune system diseases,and so on.At the same time,compared with the classical prescriptions of Minor Pinellia Decoction and Cimicifuga and Pueraria Decoction,we found that the prescriptions predicted by the HDmap-M also followed the compatibility theory of "Jun-Chen-Zuo-Shi".These results suggest that network perturbation signatures can not only reflect the basic characteristics of TCM and diseases,but also can be further used to characterize TCM combinations and develop new prescriptions for diseases,which is a powerful tool for practicing personalized TCM precision treatment strategies.Finally,to further validate the utility of the HDmap-M,a new prescription TNX-SMCCR was predicted in this study for rheumatoid arthritis: Arisaematis Rhizoma,Rhizoma Cimicifugae and Boschniakia Rossica.Meanwhile,literature research,GO enrichment analysis and network topology analysis revealed that TNX-SM-CCR treats rheumatoid arthritis by influencing biological processes such as steroid hormones,oxidation-reduction process,stem cell population maintenance and so on.In addition,we explored the synergistic therapeutic mechanism of Zhi-zhu Wan in the treatment of functional dyspepsia based on the network perturbation signatures and the systems pharmacology framework.The results showed that Zhi-zhu Wan exerted synergistic effects on the treatment of functional dyspepsia through the upstream and downstream targets of calcium signaling pathway,c AMP signaling pathway,MAPK signaling pathway and NF-?B pathway.In conclusion,the systematic analysis strategy of biological networks,based on the full consideration of individual differences,disease processes,and environmental signals,is of great significance in establishing a personalized,dynamic,and holistic diagnosis and treatment system for TCM.