| Systems pharmacology is an emerging field that integrates systems biology andpharmacology to advance the process of drug discovery, development and the understandingof therapeutic mechanisms. Systems pharmacology focus on the rapid screening of activeingredients and targets at a system level, as well as help in the understanding of theclassification of disease, regulating mechanism and toxicological evaluation based on theinteractions between multi-component, multi-target, multi-pathway of herbal medicines andorganisms at the molecular level. This method will be very valuable tools not only promotethe discovery of new drugs, the identification of targets and the new clinical strategies, butalso provide a base for the pharmacodynamics and theory of TCM from a systems perspective.Therefore, the present work aim to construct a systems pharmacology framework byintegrating pharmacokinetics and toxicological evaluation, multiple targeting technology andnetwork pharmacology, which can be used for the typing, treatment and toxicologicalevaluation of cardiovascular disease. The main findings of this work are summarized asfollows:(1) To clarify the underlying mechanisms of major types of coronary heart disease frommolecule to systems level, we take the known herbs as the probe to uncover the potentialmechanism between the major types (blood stasis and qi deficiency) and coronary heartdisease. First, we extract the available herbal medicines by the text mining approach, which iseffective for the blood stasis and qi deficiency types in coronary heart disease. And then wefocus on the exploration of the active ingredients by carrying out Oral Bioavailability anddrug-likeness analysis. Second, the herb feature mapping reveals the relationship between thephysicochemical properties and pharmacological activities of active compounds. Third, weattempt to decipher the underlying mechanisms of major types of coronary heart disease byconnecting the drugs, targets and diseases to obtain the compound-target-disease associationsfor reconstructing the biologically-meaningful networks based on systems pharmacologymethod. Finally, the mapping of these targets to the CVD signal pathway further facilitates our understanding of the blood stasis syndrome at the systems level. The results indicate thatthe herbs for eliminating blood stasis have pharmacological activity of dilating blood vessel,improving the microcirculation, reducing blood viscosity and regulating blood lipid, whileqi-enhancing herbs have the potential for enhancing energy metabolism andanti-inflammation.(2) Herb pair therapy has been widely used in Traditional Chinese medicine and tailoredto meet the specific needs of each individual. To explain why different herb pairs havecontributed to controlling various diseases at the molecular mechanism/system, a systemspharmacology approach, integrating pharmacokinetics, pharmacology and systems biology, isused to comprehensively identify the drug-target and drug-disease networks, exemplified bythree representative Danshen herb pairs. The primary findings of the study can besummarized as follows: First, the herb feature mapping reveals the differences in chemistryand pharmacological synergy between pairs. Second, the multiple targeting technologyidentifies the specific targets for each herb and pairs. Finally, the systems-comparison ofdifferent Danshen pairs by constructing the compound-target-disease network explains themechanisms of treatment for various diseases from a systematic level. Our work provides anovel strategy for revealing the mechanism of synergistic herb pairs, and also a rational wayfor developing novel drug combinations for treatments of complex diseases.(3) To get a systematic evaluation of toxicology for cardiovaculr disease, a systemstoxicology approach that integrates massive diverse chemical, genomic and toxicologicalinformation was developed for prediction of the toxin targets and their related networks. Theimportant findings were as follows:: first, by use of two powerful statistical methods, i.e.,support vector machine and random forest, a systemic model for prediction of multipletoxin-target interactions using the extracted chemical and genomic features has beendeveloped with its reliability and robustness estimated. Second, based on the predictedtoxin-target interactions, a genome-scale toxin-target-disease network exampled bycardiovascular disease is generated. Third, a topological analysis of the network is carried outto identify those targets that are most susceptible in human to topical agents including themost critical toxins, as well as to uncover both the toxin-specific mechanisms and pathways.The methodologies presented herein provide an effective tool for the prediction of new toxinsand corresponding targets, so as to facilitate the development of new drug.Taken togother, the present work has provided an integrated systems pharmacologyframework to shed light on the medicinal effectiveness and action mechanism of Chinesemedicine, drug synergetic mechanism, drug-disease associations, toxic and therapymechanism of diseases. The successful application of our method in typing, synergistic therapeutic effect and toxicological evaluation not only offers an effective way for the therapyof cardiovascular disease, but also helps in the understanding of the interactions betweenherbal medicines and organisms, the discovery of new drugs, the identification of targets, thenew clinical strategies and so on. The development of systems pharmacology will provide anew theoretical base of new drug discovery, as well as offer a new useful reference for thedevelopment of modernization of traditional Chinese medicine. |
PDF Full Text Request