| Material basis and modes of action (MOA) of traditional Chinese medicine formula (TCMF) belong to the key issues of the TCM modernization. Under the guidance of holism concept, TCMF are established to treat diseases. Due to non-linear "system to system" interactions between TCMF and disease, traditional methods are not suitable to uncover these multi-complexed interactions. Emerging new concepts, such as systems biology and network pharmacology, offer new opportunity to investigate drug effects on a biological network from a perspective of holistic regulation, which provide novel rationale and techniques for TCMF study. QiShenYiQi formula (QSYQ) is commonly used in treatment of ischemic heart disease (IHD) in clinic and its efficacy has been confirmed by evidence-based medicine study. Despite previous studies on QSYQ, a systematic research is required to understand the integrated effect of QSYQ against myocardial ischemia, which would accelerate its approval and acceptance in the international pharmaceutical industry. Based on network pharmacology, this thesis was designed to investigate anti-myocardial ischemia action of QSYQ, elucidate the integrative and synergistic mode of action in a multi-component-multi-target-multi-pathway manner through an integrative study at molecular, cellular and in vivo levels. The main contents of this thesis are summarized as follows:1. A platform for coronary heart disease (CHD) network, namely CHD@ZJU V2.0, was constructed and further network analysis was carried out according to information in this database. Through integrated resources from published articles, available databases and protein-protein interaction (PPI), CHD disease network was established. Network analysis (including network topology, clustering classes and biological function Gene Ontology analysis) results showed that the biological pathways associated with the pathogenesis of CHD mainly include:immune and inflammation, angiogenesis, hypoxia and oxidative stress, energy metabolism, etc.2. Regulatory effects on disease network were studied for main components from QSYQ. Through text mining, targets information of ten main compounds from QSYQ was obtained and drug-disease network was constructed. Network analysis showed that the common targets of ginsenoside Rg1 (Rg1) and danshensu (DSS) were JUN, MAPK8 and MAPK3. Pharmacological effects of astragaloside IV (Ast) on The cardiovascular system were associated with immune and inflammation, cell migration, adhesion and blood circulation, etc.3. As the main active components Ast, DSS, Rgi and trans-nerolidol (ENL) were chosen and their protective effects against acute myocardial infarction (AMI) individually or in combinations were investigated on rats. The infarct size was obviously decreased after Ast and DSS administration (i.g.), while more significant reduction was observed with four compounds combination group. Using gene chip technology, transcriptomics study was performed to reveal the integrated and synergetic effects of four compounds in a multi-target-multi-pathway manner. Results showed that the critical biological pathways related with their anti-AMI activity may relate to immune and inflammation, angiogenesis, ventricular remodeling and myocardium repair, energy metabolism, etc.4. Synergetic effects of four compounds were then evaluated against hypoxia injury and oxidative stress injury in vitro. Results indicated that Ast, DSS and Rgi showed cardioprotective effects against injury, four compounds combination Synergistic effects against hypoxia injury were exhibited for four-compound combination.5. The LPS induced RAW264.7 inflammation model was used to investigate the synergistic anti-inflammatory effects of the four components. Three sesquiterpene components, ENL, SDL and RDL, inhibited LPS stimulated NO secretion at various concentrations. Enhanced inhibitoryactivity against LPS induced NO secretion was observed on the combination of DSS and Rgi, which could be alleviated or even abrogated by HO-1 specific antagonist ZnPPIX. Four components combination can significantly enhance the inhibitory effect against LPS stimulated NO secretion. |
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