Systems pharmacology for traditional Chinese medicine with application to cardio-cerebrovascular diseases

Identified as a treasure of natural herbal products,traditional Chinese medicine(TCM)has attracted extensive attention for their moderate treatment effect and lower side effect.Cardio-cerebrovascular diseases(CCVD)are a leading cause of death.TCM is used in China to prevent and treat CCVD.However,the complexity of TCM poses challenges in understanding the mechanisms of herbs at a systems-level,thus hampering the modernization and globalization of TCM.A novel model,termed traditional Chinese medicine systems pharmacology(TCMSP)analysis platform,which relies on the theory of systems pharmacology and integrates absorption,distribution,metabolism,excretion and toxicity(ADME/T)evaluation,target prediction and network/pathway analysis,was proposed to address these problems.Here,we review the development of systems pharmacology,the TCMSP approach and its applications in the investigations of CCVD and compare it with other methods.TCMSP assists in uncovering the mechanisms of action of herbal formulas used in treating CCVD.It can also be applied in ascertaining the different syndrome patterns of coronary artery disease,decoding the multi-scale mechanisms of herbs,and in understanding the mechanisms of herbal synergism.

Uncovering the multi-target pharmacological mechanism of Xuebijing injection against sepsis by a systems pharmacology approach

Sepsis is a life-threatening organ dysfunction that is associated with a high risk of death.Xuebijing(XBJ)injection,a Chinese herbal compound preparation,has been widely used for the treatment of sepsis in China.The purpose of this research is to decipher the underlying multi-target pharmacological mechanism of XBJ in the treatment of sepsis using a systems pharmacology approach.Compounds in XBJ were collected by literature retrieval.The corresponding putative targets of XBJ were screened from the Traditional Chinese Medicine Systems Pharmacology(TCMSP),Swiss Target Prediction(STP),and Search Tool for Interacting Chemicals(STITCH)databases.Sepsis-related targets were summarized using the Genecards,DrugBank,and Online Mendelian Inheritance in Man(OMIM)databases.The intersection targets were obtained with Venny 2.1.Subsequently,protein-protein interaction(PPI)networks were constructed with the STRING database and Cytoscape 3.7.1.Then,degree,betweenness,and closeness were calculated to recognize the core targets in the PPI network.Moreover,the pharmacological mechanism of XBJ against sepsis was predicted via gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.After the literature review,the 33 most commonly cited chemical ingredients,were screened out as major compounds.Bioinformatics analysis revealed that the major compounds of XBJ modulated 218 common targets associated with sepsis.Through PPI network analysis,41 genes,including IL-6,AKT1,STAT3,TP53,and MAPK1,were identified as core targets.The results of GO and KEGG enrichment revealed that the potential biological functions of XBJ against sepsis were mainly involved in cytokine receptor binding,cytokine activity,growth factor receptor binding,growth factor activity,and chemokine activity.The crucial pathways were closely associated with initial immune activation(CLR/TLR4-NF-κB/MAPK pathway),the acute inflammatory response(TNFMAPK/caspase and IL-MAPK/STAT pathways),and the late inflammation and coagulation process(HMGB1-RAGE and HIF-1 signaling pathways).This study revealed that the multiple components of XBJ exert multitarget effects against sepsis by regulating initial immune activation,the acute inflammatory response,and the late inflammation and coagulation process.

Systems Pharmacology Uncovers Multiple Mechanisms of Erxian Decoction (二仙汤) for Treatment of Premature Ovarian Failure

Objective:To predict the chemical compositions and drug targets and to systematically dissect the pharmacological mechanism of Erxian Decoction(二仙汤,EXD)as a treatment for premature ovarian failure(POF)using a systems pharmacology approach.Methods:The compounds present in EXD were obtained from three databases.The active ingredient was identified by analyzing the values of oral bioavailability(OB),drug-like ness(DL),and Lipin ski's rule(LR).The active in gredients were further searched in research articles,drug targets in the DrugBank database,and the C-T and T-P networks,as well as by pathway analysis using the Cytoscape platform.Results:A total of 728 compounds were identified in EXD.Of these,59 were identified as active compounds that conformed to the criteria with OB>30%and DL>0.18.By further searches in the literature,126 related targets were ide ntified that could in teract with the active compounds.Additi on ally,it was found that the beneficial effects of EXD in POF are probably exerted via regulation of the immline system,modulation of estrogen levels,and anti-oxidative activities,and that it may act in a synergistic or cooperative manner with other therapeutic agents.Conclusions:The systems pharmacology approach is a comprehensive system that was used to elucidate the pharmacological mechanism of EXD as a treatment for POF.The results of this study will also facilitate the application of traditional medicine in modern treatment strategies.

A SYSTEMS PHARMACOLOGY VIEW OF THE BIOACTIVITY OF THE EXTRACT FROM RHIZOME DIOSCOREA NIPPONICA MANKINO

Key for worldwide acceptance of Traditional Chinese Medicine(TCM)is the ability to provide scientific evidence combined with a quality control system based on the bioactive ingredients.Modern scientific technology tools are now available to accomplish standardization of TCM products in order to achieve a high level of efficacy and safety,enhancing the introduction into the

Exploring the compatibility theory of traditional Chinese medicine formulae:the disassembled prescriptions study

Traditional Chinese medicine(TCM)has become very popular in the treatment of complex diseases worldwide in recent decades.Despite the promising performance of TCM,how herbs work synergistically in a formula and their therapeutic targets remain ambiguous.This largely limits the correct use and modernization of TCM formulas clinically.The study of disassembled prescriptions is important for investigating the compatibility theory of Chinese medicines.By dissecting the mechanisms of TCM formulae,the compatibility principles of some well-known formulae,such as Realgar-Indigo naturalis,have been elucidated to a certain extent.In this review,several common methods of disassembled prescription studies are summarized,including those of single herb or mineral,sub-prescription,active ingredients or effective parts,large formulae,and systems pharmacology studies,as well as the methods of grouping based on the properties or efficacy of Chinese medicines,in order to provide evidence for formulae study.Moreover,some challenges to be addressed in disassembled prescriptions studies have been identified in this review.

Screening and analysis of key active constituents in Guanxinshutong capsule using mass spectrum and integrative network pharmacology

Guanxinshutong capsule(GXSTC) is an effective and safe traditional Chinese medicine used in the treatment of cardiovascular diseases(CVDs) for many years. However, the targets of this herbal formula and the underlying molecular mechanisms of action involved in the treatment of CVDs are still unclear. In the present study, we used a systems pharmacology approach to identify the active ingredients of GXSTC and their corresponding targets in the calcium signaling pathway with respect to the treatment of CVDs. This method integrated chromatographic techniques, prediction of absorption, distribution, metabolism, and excretion, analysis using Kyoto Encyclopedia of Genes and Genomes, network construction, and pharmacological experiments. 12 active compounds and 33 targets were found to have a role in the treatment of CVDs, and four main active ingredients, including protocatechuic acid, cryptotanshinone, eugenol, and borneol were selected to verify the effect of(GXSTC) on calcium signaling system in cardiomyocyte injury induced by hypoxia and reoxygenation. The results from the present study revealed the active components and targets of GXSTC in the treatment of CVDs, providing a new perspective to enhance the understanding of the role of the calcium signaling pathway in the therapeutic effect of GXSTC.

Pharmacometrics of nutraceutical sulforaphane and its implications in prostate cancer prevention

Sulforaphane(SFN), found in broccoli and other cruciferous vegetables, has a beneficial effect in chemoprevention of prostate cancer, whose incidence and associated mortality have gradually increased worldwide. There is great enthusiasm for bench-to-bedside development of SFN as a potent chemopreventive agent, possibly alone or as an adjunct to existing chemotherapy regimens, in the oncology care setting to reduce toxicity of chemotherapeutics and potentially enhance their cancer cell-kill efficacy. In this review, we appreciate existing knowledge on SFN using a pharmacometrics approach, which is fast becoming a gold standard in discovery research and validation of New Chemical Entities and New Biological Entities in pharmaceutical industry. We discuss the epistemology of SFN target engagement and quantitative systems pharmacology with due emphasis on mechanistic pharmacology, pharmacodynamics, pharmacogenomics and metabolism of SFN. In addition, we explore the quantitative freeway to SFN translational medicine by assessing the preclinical and clinical PK/metabolism aspects of SFN that form the cornerstone of SFN pharmacometric evaluation, as well as the promise of SFN in prostate cancer. Taken together, we share perspectives on the exciting developments in translational cancer chemoprevention, with emphasis on the pharmacometric aspects, of the nutraceutical SFN which is currently in clinical trials, and suggest that the pharmacometric approach holds great promise in the SFN translational pharmacology paradigm for prostate cancer.

NOGEA: A Network-oriented Gene Entropy Approach for Dissecting Disease Comorbidity and Drug Repositioning

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes(DAGs),which are important for understanding disease initiation and developing precision therapeutics.However,DAGs often contain large amounts of redundant or false positive information,leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases.In this study,a networkoriented gene entropy approach(NOGEA)is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks.In addition,we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk.Master genes may also be used to extract the underlying information of different diseases,thus revealing mechanisms of disease comorbidity.More importantly,approved therapeutic targets are topologically localized in a small neighborhood of master genes in the interactome network,which provides a new way for predicting drug-disease associations.Through this method,11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments.Collectively,the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence,thus providing a valuable strategy for drug efficacy screening and repositioning.NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.