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Objective:To analyze the mechanism of Kaixin San in treating Alzheimer disease (AD) based on the TCM integrated pharmacology platform combined with GEO chip differential gene analysis method.Methods:By searching TCMIP and Drugbank database, the active components and related molecular targets of Kaixin San were obtained. GSE4757 chip data was obtained through GEO database, and its differential genes were obtained using R language to draw heat map and volcano map. Molecular target map of differentially expressed genes between Kaixin San and AD was constructed through Cytoscape 3.7.2. Bisogenet and CytoNCA were used to draw the target topological network, and GO enrichment analysis and KEGG enrichment analysis of Kaixin San and AD gene were carried out.Results:86 active components of Kaixin San were obtained to treat AD, and 29 differential genes shared with GEO were obtained. PPI topological network was constructed. 6 core candidate genes were screened, and were merged with KEGG pathway enriched genes to obtain important genes for disease treatment, such as CHRM1, CHRM2, ACHE, CHRM3, CASP8, PTGS2, DRD1, CACN1S, ADRB1. 375 GO entries were obtained, mainly involving biological processes such as vasoconstriction, postsynaptic membrane plasticity, neurotransmitter transmission, etc. KEGG enrichment analysis mainly involved cholinergic synaptic signal pathway, cAMP signal pathway, calcium signal pathway, nerve ligand receptor interaction signal pathway, etc.Conclusions:Kaixin San shows the features of multi-component, multi-target and multi-channel in treating AD. It can play a role in the treatment of AD by inhibiting inflammatory reaction, reducing the activity of acetylcholinesterase and regulating the concentration of calciumion.
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Objective:To identify the transdermal constituents of Euodiae Fructus and predict its molecular mechanism in treating diarrhea by transdermal drug delivery. Method:Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS） and integrated pharmacology methods were used. The rapid identification of transdermal constituents of Euodiae Fructus was realized by the means of comparison of reference substances， analysis of UNIFI system and mass spectrometry. On this basis， Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine （TCMIP） v2.0， SymMap， DisGeNET databases and literature were used to collected potential targets of transdermal constituents of Euodiae Fructus and targets for diarrhea-related diseases. The disease targets and drug targets were topologically analyzed to obtain the core targets， which were used for the Gene Ontology （GO） function and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis. Finally， Cytoscape 3.6.0 was used to build up a network of transdermal constituents-core targets-key pathways. Result:A total of 19 chemical constituents were speculatively identified from Euodiae Fructus extract， including quinolone alkaloids， limonins， indole alkaloids， organic acids and sterols. A total of 174 core targets of Euodiae Fructus for treating diarrhea were obtained by a topology analysis， signaling pathways of inflammatory response， cell proliferation， nutrient regulation and energy metabolism， signal transduction， bacterial infection were obtained through the analysis of KEGG enrichment. Conclusion:In this study， the transdermal constituents of Euodiae Fructus are identified for the first time， they can participate in the regulation of intestinal inflammation， maintain the integrity of intestinal mucosa， repaire and adjust the metabolism of the body by acting on Rac protein family， phosphatidylinositol 3-kinase， cytochrome P450 enzymes and aldo-keto reductase， respectively. In general， the molecular mechanism of Euodiae Fructus in the treatment of diarrhea is preliminarily elucidated.
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Objective:To predict the potential molecular mechanism of Yangxue Antai Fang in treating prethrombolic state of recurrent spontaneous abortion （RSA-PTS）. Method:The chemical constituents and drug targets of Yangxue Antai Fang were collected by Integrated Pharmacology-based Research Platform of Traditional Chinese Medicine （TCMIP V2.0）. RSA-PTS disease target information was collected by TCMIP V2.0 and improved by Online Mendelian Inheritance in Man （OMIM） database. The interaction of these targets was analyzed and key target network was constructed. Gene ontology （GO） function and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis were further performed. Finally， Cytoscape 3.5.1 was used to build up a multidimensional network of TCM-ingredient-target-pathway. The levels of absorption， distribution， metabolism， excretion and toxicity （ADMET） of the main components in the network were analyzed. Result:A total of 310 chemical constituents and 975 targets were collected from 8 TCMs in Yangxue Antai Fang. A total of 143 targets of RSA-PTS were obtained. A total of 243 core targets were obtained by the interrelationship analysis of drug and disease targets. The analysis of the top 100 core targets showed that these targets might participate in treating RSA-PTS by affecting biological processes related to thrombosis， such as blood coagulation， platelet activation， positive regulation of angiogenesis and so on. Pathway analysis showed that these targets were mainly concentrated in complement and coagulation cascades， platelet activation， estrogen signaling pathway， thyroid hormone signaling pathway， etc. Multidimensional network analysis in combination with ADMET level showed that 14 components （leonurine， paeonol， vanillin， and so on） may play a therapeutic role in RSA-PTS by affecting coagulation factors Ⅱ （F2）， plasminogen （PLG） and estrogen receptor 1 （ESR1） proteins involved in complement and coagulation cascades， platelet activation， thyroid hormone signaling pathway and others. Conclusion:The main chemical constituents in Yangxue Antai Fang may improve RSA-PTS by regulating complement and coagulation cascades， blood coagulation， platelet activation and other biological processes.
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Objective: To investigate the effective substance basis and possible mechanism of Huangliantang in treatment of gastritis. Method: Integrated pharmacology platform of traditional Chinese medicine was employed to predict the main active ingredients and functional targets of Huangliantang in treatment of gastritis, network of composition target-disease target of Huangliantang was constructed, key nodes were screened for enrichment analysis of pathways, and the possible mechanism of Huangliantang in treatment of gastritis with multiple ingredients-multiple targets-multiple pathways was explored. Result: A total of 175 predicted active ingredients of Huangliantang interacted with 538 key targets about gastritis, the regulation and treatment of gastritis during its different pathological stages, such as Helicobacter pylori infection, gastric mucosal damage and gastric mucosal atrophy, were involved through chemokine, T cell receptor, estrogen and other signaling pathways. Conclusion: This research may reveal the potential active ingredients of Huangliantang in treatment of gastritis and its possible mechanism, and it also provides a theoretical basis for further experimental research of pharmacodynamic substance basis and mechanism of action.
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Objective: To study on the molecular mechanism of anti-platelet aggregation and anti-thrombosis of Sparganii Rhizoma. Method: Based on the data information and analysis functions of traditional Chinese medicine(TCM) database,TCM composition database and target database in TCM platform for integration of pharmacology,information of chemical compositions in Sparganii Rhizoma was retrieved,interaction network between potential targets of Sparganii Rhizoma and disease targets was built,and the key targets were enriched and calculated,the gene functions and pathways were analyzed,multidimensional relationship network of " herbal medicines-chemical components-key targets-key pathways" was built. Result: Active ingredients of Sparganii Rhizoma mainly included flavonoids and phenolic acids,such as mountain kaempferol,sanleng acid,linoleic acid,etc.Anti-thrombosis involved 202 key targets,including protein kinase Cδ(PRKCD),glucose kinase(GCK),(PRKAA2),adenosine ribonucleotide activated protein kinase α-2 catalytic subunit,etc;and it was related to the endocrine system,circulatory system,neurodegenerative diseases and other related biological processes and signal pathways.Anti-platelet aggregation involved 136 key targets,including PRKCD,cytochrome C oxidase protein 7C(COX7C),GCK,etc;and it was involved in Parkinson's disease,circulatory system,neurodegenerative diseases and other related biological processes and signal pathways. Conclusion: Sparganii Rhizoma regulates vascular endothelial cell adhesion molecule expression and platelet mitochondrial function mediated apoptosis of platelets mainly through regulating neurotransmitter activity in the central nervous system,in order to exert antithrombotic effect and anti-platelet aggregation effect.
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Integrated pharmacological approach was used to predict the target genes and signal pathways of Xiaoer Fupi granules in the treatment of functional dyspepsia(FD), and the possible mechanism was discussed. The disease target information was collected by the DISEASES and UniProt databases, integrated pharmacological platform of traditional Chinese medicine(TCM-IP) was used to predict chemical composition, target, protein gene ontology(GO) function and Kyoto encyclopedia of genes and genomes(KEGG) pathway, and the networks of candidate target and TCMs-chemical components-core targets-key pathways were constructed. A total of 2 882 potential targets and 96 candidate target pathways were predicted, and β-1,4-galactosyltransferase(β-1,4-GalT) subtypes(B4GALT4, B4GALT2, B4GALT1) and phosphorylated protein kinase C subtype D(PRKCD), adenylate cyclase 2(ADCY2) and other targets were predicted. Some pathways were enriched, such as nervous system, endocrine system, thyroid hormone signaling pathway, long-term depression and other pathways related to FD. It was predicted that Xiaoer Fupi granules for treating FD by regulating gastrointestinal hormones, anti-depression, and regulating nerves and endocrine system. This study provides a basis for the precise clinical application and positioning of Xiaoer Fupi granules, and helps to clarify the mechanism of this drug.
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Quality marker(Q-marker) is a new concept and pattern for quality control of traditional Chinese medicine(TCM),which will lead the development direction for quality control of TCM.Among them,how to characterize the overall quality attribute of TCM and its biological effect,is a critical scientific problem in the study of Q-marker.In this paper,integrated pharmacology is utilized to screen out and confirm the Q-marker from the complex system of TCM,so as to solve the critical scientific problem.System biology in vivo is firstly applied to establish the correlation of chemical fingerprints of TCM,their metabolic fingerprints,network targets,biological effects and efficacy of TCM,which is used to preliminary screen out Q-marker of TCM.Following that,a pharmacological method in vitro,including intestinal absorption in vitro coupled with bioactivity assessment,is employed to simultaneously determine the absorbed doses of TCM and evaluate their biological activity.Furthermore,data mining is utilized to establish the exact quantitative mathematic model between Q-marker of TCM and bioactivity.Meanwhile,two representative examples,including Yuanhu Zhitong tablets,Xinsuning capsules,are introduced to identify Q-marker of TCM and establish their quality standards related with bioactivity,which will be beneficial to improve the level of quality control of TCM and ensure the effectiveness and safety of clinical applications.
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Objective:To explore the molecular mechanism of Banxia Baizhu Tianma Tang in treating hypertension. Method:Based on an internet-based computation platform for integrated pharmacology of traditional Chinese medicine(TCM),TCM prescription database,TCM database,TCM component database and disease/symptoms target database,information on the chemical compositions contained in TCM was retrieved,an interaction network between potential targets and disease targets of Banxia Baizhu Tianma Tang was built,then core target was enriched and calculated,gene function and pathway analysis was carried out,the multi-dimensional relationship network of "Chinese herbs-ingredients-critical targets-key pathways" of Banxia Baizhu Tianma Tang was further constructed. Result:A total of 90 active ingredients in Banxia Baizhu Tianma Tang were obtained,including alkaloids,nucleosides,flavonoids,saponins,organic acids and other ingredients;they involved 287 core targets,including 13 direct targets,such as adenylate cyclase,G protein coupled with β1 receptor,glucose kinase,etc;they also involved nervous system,endocrine system,circulatory system,estrogen signaling pathway,chemokine signaling pathway and other related biological processes and signaling pathways. Conclusion:Banxia Baizhu Tianma Tang can regulate neurotransmitter concentration and activity abnormalities,improve the protective effect of vascular endothelial cells by improving insulin resistance,regulating the production of inflammatory factors,and inhibiting inflammatory reactions,thereby exerting pharmacological effects on the treatment of hypertension.This study can provide a scientific basis for comprehensive interpretation of mechanism of Banxia Baizhu Tianma Tang.
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Objective: The classical formula of Dingxiang Shiditang can be used for hiccup and vomit which caused by many reasons,its molecular mechanism of this formula was investigated.Method: Based on the integrated pharmacology platform of traditional Chinese medicine,the potential molecular mechanism of Dingxiang Shiditang was revealed from the dimensions of multi-components and multi-targets.Result: There were 89 compounds related to hiccup and vomit of Dingxiang Shiditang,and there was 1 common target[cannabinoid receptor 1(CNR1)].On the one hand,CNR1 could inhibit the occurrence of hiccup and vomit by inhibiting the release of γ-aminobutyric acid(GABA),dopamine,5-hydroxytryptamine(5-HT);on the other hand,CNR1 could inhibit gastrointestinal motility and delay gastric emptying,and it was speculated that CNR1 may play a role in regulating gastrointestinal motility through brain-gut axis.Meanwhile,the mechanism of Dingxiang Shiditang may be related to nucleotide metabolism and nervous system.Conclusion: Dingxiang Shiditang may regulate gastrointestinal motility by affecting the release of neurotransmitters,mitochondrial energy metabolism,and achieve its effect on hiccup and vomit based on the joint intervention of multiple targets and multiple pathways.
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Objective: To explore the mechanism of the intervention of Xinkeshu Tablets (XKST) on atherosclerosis (AS) and provide reference for the secondary development and clinical application of XKST. Methods: The integrated pharmacology platform was used to predict the key targets and pathways of the intervention of XKST on AS and its molecular mechanism was also explored. Results: In the integrative analysis of heterogeneous network of “TCM-component-target-pathway”, 80 relevant effective ingredients were found, including B4GALT4, B4GALT2, PRKCD, GCK, GNB1, and other key targets; Endocrine system, thyroid hormone signaling pathway, nervous system, estrogen signaling pathway, and chemokine signaling pathway were key pathways related with its anti-atherosclerosis. Conclusion: According to the analysis and prediction of the enrichment information, the effect of XKST on common regulating PI3K/Akt/eNOS and Raf/MEK/ERK signaling pathway and protecting vascular endothelial cells is first prompted, thus achieving the intervention in AS.
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Objective To analyze the material basis and molecular mechanisms of Danggui Beimu Kushen (DBK) Pills in treating prostatic diseases based on the method of integrated pharmacology. Method The platform of Integrative Pharmacology of Traditional Chinese Medicine (TCM-IP, www.tcmip.cn) was utilized to predict the main active ingredients and functional targets of DBK Pills in treating prostatic disease, key targets were screened for enrichment analysis of pathways, and the network of “herb-core component-key target-main pathway” was constructed, and the possible mechanisms of DBK Pills in treating prostatic diseases were explored. Results A total of 532 candidate key targets for the treatment of prostatic diseases by DBK Pills were predicted, and 1 840 terms of gene function and 194 signal pathways were analyzed by gene ontology (GO) and KEGG, respectively. The network analysis of “herb-core component-key target-main pathway” showed that 65 core components were predicted, including 29 ingredients from Angelica sinensis, 11 from Fritillaria thunbergii and 26 from Sophora flavescens. Those predicted components acted on the key targets of prostatic diseases, such as transcription factor binding, negative regulation of apoptosis, et al, through the estrogen, apoptosis, chemokines and other signal pathways, and thus played a role in the regulation of cell cycle, apoptosis and proliferation imbalance, which might be the molecular mechanisms of DBK Pills for the treatment of prostatic disease. Conclusion DBK Pills regulate the development of BPH, prostate cancer and other diseases through multiple pathways with multi-component interacting with multiple targets.
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The medication rules of high frequency herb-pairs containing Codonopsis pilosula (Dangshen) were analyzed with data mining tools, and the molecular mechanisms of these herb-pairs on the gastrointestinal diseases were predicted with the network pharmacology. The R language association rules were used to mine the high frequency herb-pairs from TCM formulae containing Dangshen, and these herb-pairs would be screened out, which satisfied the following requirements with support ≥ 0.3 and confidence ≥ 0.9 at the same time. Using the Integrated Pharmacology Platform of Traditional Chinese Medicine (TCMIP) to predict the key core targets of the high frequency herb-pairs, the network of Chinese medicine-compound-target-pathway related to Dangshen were built to explore the preventing and treating molecular mechanism on gastrointestinal diseases. At last, the relation of the main active components from Dangshen and its herbal pairs with target proteins were validated by Systems Dock Web Site. The 185 formulae were selected from 543 formulae containing Dangshen, and 6 herbal pairs with Dangshen, which includes Angelica (Danggui), Licorice (Gancao), Atractylodes macrocephala (Baizhu), Poria cocos (Fuling), dried tangerine peel (Chenpi) and Astragalus membranaceus (Huangqi), were discovered with Apriori algorithm. The combination of 6 herbal pairs is similar to Bu Zhong Yi Qi Decoction; 6 herbal pairs with Dangshen were related to the target of POMC, OPRM1, CCR9 and HTR2C in TCMIP. The known targets (HTR2C, POMC, OPRM1, CCR9, OPRD1) and potential drug-targets (GNB1, GCK, SDHD, SLC25A2, DHRS4) for gastrointestinal diseases were predicted about the high frequency pairs with Dangshen. The results of GO enrichment analysis showed that the biological function was mainly located in the mitochondria and myelin sheath, and involved in the biological processes of three carboxylic acid cycle, platelet activation, and aspartic acid metabolism. KEGG pathway enrichment analysis showed that the main metabolic pathways related with Dangshen pairs involved amino acid metabolism, energy metabolism and endocrine metabolism. The prediction results showed many targets of the frequency herbal pairs with Dangshen preventing and treating gastrointestinal diseases were related with nerve cells. These herbal pairs could prevent and treat the gastrointestinal diseases through the neuroendocrine system and the brain gut axis.
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Objective: To explore the potential genetic target of Stephania terandra in the therapy for hypertension based on inte-grated pharmacology platform to study the molecular mechanism of Chinese medicines in treating hypertension. Methods: Using the functional prediction modules of integrated pharmacology platform and the functional modules of network construction, the component-target network of Stephania terandra was calculated, and the target network of anti-hypertension was further calculated, and the target molecules related to hypertension were explored. Results: A total of 198 targets related to hypertension were obtained from the hyper-tension prevention. Among them, there were 59 potential action nodes and 20 known action nodes. The nodes with direct action were type-2 angiotensin Ⅱ receptor ( AGTR2), type-1 angiotensin Ⅱ receptor ( AGTR1), prostacyclin receptor ( PTGIR), solute carrier family 12 member 3 (SLC12A3) and endothelin-1 (EDN1). The GO enrichment and KEGG pathway enrichment of Stephania terandra chemical components showed a close correlation with hypertension, and the molecular mechanism of the target was clear. Conclusion:Through the integration of pharmacology platform, the targets of Stephania terandra-disease are deeply explored, and its potential mo-lecular mechanism as well as potential factors is studied.
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To investigate the material foundation and mechanism of Zi Bu Pi Yin Recipe in the prevention and treatment of mild cognitive impairment. The integrated pharmacology platform was used to study the active ingredients, drug targets, and disease targets of 12 Chinese traditional medicines of Zi Bu Pi Yin Recipe, and to construct the target of"Zi Bu Pi Yin Recipe-Chinese herbal medicine-chemical composition-core Target-the key path "of the visual network and network analysis. Results:The platform screened 687 kinds of active ingredients of Zi Bu Pi Yin Recipe including glycosides, sugars and alcohols. and 595 key targets for treating mild cognitive impairment, Including HADHA, HADH, NAD (P) -dependent steroid dehydrogenase-like (NSDHL), and et al. The enrichment analysis of GO and KEGG showed that these key targets were mainly localized in the cytoplasm and mitochondria. The most common molecular functions were ATP binding and protein binding, and participated in purine metabolism, nucleotide metabolism, carbon metabolism pathway, Carbohydrate metabolism and so on. The platform could predict the key target of Zi Bu Pi Yin Recipe in preventing and treating Mild Cognitive Impairment and its related pathways, which lay a good foundation for further revealing its mechanism.
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To explore the medication regularity of Tibetan medicine in the treatment of spleen and stomach diseases, analyze the potential drug targets and interactions of the prescriptions, and reveal the mechanism of Tibetan medicine in the treatment of spleen and stomach diseases. The prescriptions in Tibetan medicine for treatment of spleen and stomach diseases were collected, and Traditional Chinese Medicine Inheritance Support System (TCMISS) was used to analyze the association rules between the herbs and discover the core herbs and new prescriptions. The integrated pharmacology platform V1.0 software was used to construct "herb-compound-target" network and investigate the interactions between various herbs and related pathways of Tibetan medicine Wuwei Shiliu powder in the treatment of spleen and stomach diseases. Among the 216 prescriptions of Tibetan medicine in the treatment of spleen and stomach diseases, pomegranate seed was used at a highest frequency (118 times), followed by white cardamom (107 times) and comatose (107 times). 12 new prescriptions were evolved by using the association rules (support>=34%, confidence>=0.85). 5 242 related drug targets and 20 related pathways were obtained from classic formula Wuwei Shiliu Powder (FDR<0.01). It was proposed that Tibetan medicine treatment for spleen and stomach diseases was mainly based on proliferation of "stomach fire" and the main drugs were for regulating Qi-flowing for strengthening spleen. The mechanism may be associated with regulation of digestive juice secretion, proton pump, mitochondria, regulation of intestinal digestion and immunity, the body's immunity to microorganisms function and other multiple targets and pathways to achieve the joint intervention.