ABSTRACT
This study aims to explore the mechanism of Qingkailing(QKL) Oral Preparation's heat-clearing, detoxifying, mind-tranquilizing effects based on "component-target-efficacy" network. To be specific, the potential targets of the 23 major components in QKL Oral Preparation were predicted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The target genes were obtained based on UniProt. OmicsBean and STRING 10 were used for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment of the targets. Cytoscape 3.8.2 was employed for visualization and construction of "component-target-pathway-pharmacological effect-efficacy" network, followed by molecular docking between the 23 main active components and 15 key targets. Finally, the lipopolysaccharide(LPS)-induced RAW264.7 cells were adopted to verify the anti-inflammatory effect of six monomer components in QKL Oral Preparation. It was found that the 23 compounds affected 33 key signaling pathways through 236 related targets, such as arachidonic acid metabolism, tumor necrosis factor α(TNF-α) signaling pathway, inflammatory mediator regulation of TRP channels, cAMP signaling pathway, cGMP-PKG signaling pathway, Th17 cell differentiation, interleukin-17(IL-17) signaling pathway, neuroactive ligand-receptor intera-ction, calcium signaling pathway, and GABAergic synapse. They were involved in the anti-inflammation, immune regulation, antipyretic effect, and anti-convulsion of the prescription. The "component-target-pathway-pharmacological effect-efficacy" network of QKL Oral Preparation was constructed. Molecular docking showed that the main active components had high binding affinity to the key targets. In vitro cell experiment indicated that the six components in the prescription(hyodeoxycholic acid, baicalin, chlorogenic acid, isochlorogenic acid C, epigoitrin, geniposide) can reduce the expression of nitric oxide(NO), TNF-α, and interleukin-6(IL-6) in cell supernatant(P<0.05). Thus, the above six components may be the key pharmacodynamic substances of QKL Oral Preparation. The major components in QKL Oral Prescription, including hyodeoxycholic acid, baicalin, chlorogenic acid, isochlorogenic acid C, epigoitrin, geniposide, cholic acid, isochlorogenic acid A, and γ-aminobutyric acid, may interfere with multiple biological processes related to inflammation, immune regulation, fever, and convulsion by acting on the key protein targets such as IL-6, TNF, prostaglandin-endoperoxide synthase 2(PTGS2), arachidonate 5-lipoxygenase(ALOX5), vascular cell adhesion molecule 1(VCAM1), nitric oxide synthase 2(NOS2), prostaglandin E2 receptor EP2 subtype(PTGER2), gamma-aminobutyric acid receptor subunit alpha(GABRA), gamma-aminobutyric acid type B receptor subunit 1(GABBR1), and 4-aminobutyrate aminotransferase(ABAT). This study reveals the effective components and mechanism of QKL Oral Prescription.
Subject(s)
Animals , Mice , Chlorogenic Acid , Drugs, Chinese Herbal/pharmacology , gamma-Aminobutyric Acid , Interleukin-6 , Medicine, Chinese Traditional , Molecular Docking Simulation , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Objective: To investigate the anti-hepatoma active components of Rhei Radix et Rhizoma and their molecular mechanisms through GEO database, integrative pharmacology platform and molecular docking technology. Method: The active ingredients of Rhei Radix et Rhizoma were screened by TCMIP and the corresponding targets of these components were predicted through TCMIP and Swisstarget databases. The hepatoma gene chip database was downloaded from GEO databases, and the differentially expressed genes between hepatocellular carcinoma (HCC) and normal liver tissue were analyzed by GEO2R. Based on the matching results of potential targets of Rhei Radix et Rhizoma and the targets of hepatoma, the key targets of Rhei Radix et Rhizoma against hepatoma were screened, and GO function enrichment and KEGG pathway enrichment analysis of the key targets were performed. Main components and core targets of Rhei Radix et Rhizoma against hepatoma were analyzed and screened by constructing PPI network, component-target network and traditional Chinese medicine-component-target-pathway network. Furthermore, the molecular docking between the core targets and the main active components was performed by Schrodinger-Maestro software to virtually verify their binding ability and analyze their binding mode. Result: A total of 20 anti-hepatoma active components of Rhei Radix et Rhizoma were collected and related 86 targets were obtained, including CDK1, AKR1C3, PTGS2, AR and CCNB1, etc. The results of GO functional enrichment mainly focused on the cell cycle, G2/M transition of mitotic cell cycle, oxidation-reduction process, drug reactions and steroid metabolism processes, etc. The results of KEGG pathway enrichment mainly involved cell cycle, cell senescence, complement system, arachidonic acid metabolism and bile metabolism, and these metabolic pathways were related to cell apoptosis, metastasis, inflammation and immunity. The results of molecular docking showed that 92.2% of the active components had good binding ability with the 10 core proteins, and the main combination forms mainly were hydrogen bonds, hydrophobic bonds, π-π bonds and cation-π. Conclusion: The active components of Rhei Radix et Rhizoma including rhein, emodin, chrysophanol-8-O-β-D-glucopyranoside, chrysophanol-1-O-β-D-glucoside and rhapontigenin can act on multiple targets such as CDK1, CCNB1, CYP2C9, MMP9 and PTGS2, by regulating signaling pathways related to cell apoptosis, metastasis, inflammation and immunity to play an anti-hepatoma effect.
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Objective: To explore the potential Q-markers between crude Schisandrae Chinensis Fructus (SCF) and vinegar-processed Schisandrae Chinensis Fructus (VSCF) based on multivariate statistical analysis and network pharmacology. Methods: UPLC-Q/TOF-MS was used to analyze the main lignans in SCF and VSCF, and the potential differences of chemical components (Q-markers) between SCF and VSCF were screened out by using multiple statistical methods. Furthermore, through network pharmacology and bioinformatics, the main action targets and pathways related to significantly different components were analyzed to construct the “component-target-pathway” network relationship and predict the potential quality markers between SCF and VSCF. Results: In this study, 40 different constituents of Schisandra chinensis between SCF and VSCF were screened, among which eight chemical markers had significant differences between SCF and VSCF. Five chemical constituents were identified and confirmed, namely 5-HMF, deoxyschizandrin and its isomer, schisandrin B, and schisantherin D. The other three chemical markers were speculated to be lignans by analyzing the first-and second-order mass spectrometry information. The results of network pharmacological analysis showed that the five potential quality markers identified were highly related to the main pharmacological effects of SCF. Finally, schisandrin B and 5-hydroxymethyl furfural were identified as the most representative potential quality markers. Conclusion: The results showed that the chemical composition of SCF had a series of complex changes. It was determined that schisandrin B and 5-hydroxymethyl furfural could be used as representative potential quality markers between SCF and VSCF. It is speculated that lignans may be the basis of the important effect of VSCF on liver protection.
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To screen the active ingredients of Gardenia jasminoides and potential targets,and investigate the mechanisms against cholestasis based on network pharmacology technology. Twenty-one active components of G. jasminoides were retrieved and the target sites were screened by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform( TCMSP). Cytoscape3. 2. 1 was used to construct the component-target network. Two hundred and eight targets related to cholestasis were searched and screened through Dis Ge NET,KEGG and OMIM databases. The key targets of G. jasminoides components and cholestasis were integrated and screened,and the component-target-disease network was constructed with Cytoscape 3. 2. 1 software to screen out the core network whose freedom degree was greater than the average value. The Clue GO plug-in of Cytoscape 3. 2. 1 software was used to analyze the biological processes and pathway enrichment of G. jasminoides in regulation of cholestasis. GO biological process analysis revealed 17 biological processes,involving 3 signaling biological processes related to cholestasis,i.e. acute inflammatory response,positive regulation of reactive oxygen species metabolic process,and nitric oxide biosynthetic process. KEGG-KEEG-305 terms and REACTOME pathways analysis revealed 17 regulatory pathways,involving 4 signaling pathways related to cholestasis,i.e. metabolism of xenobiotics by cytochrome P450,nuclear receptor transcription pathway,GPVI-mediated activation cascade and platelet activation. It was found that aqueous extract of G. jasminoides could improve serum biochemical abnormalities in ANIT-induced cholestasis rats. Aqueous extract of G. jasminoides could decrease the protein and mRNA expression levels of ESR1 in liver tissues,and increase the protein and mRNA expression levels of PPARG,NOS2,F2 R,NOS3,and NR3 C1. To sum up,the possible mechanisms of G. jasminoides against cholestasis may be related with the above three processes and four pathways.
Subject(s)
Animals , Rats , Cholestasis , Drug Therapy , Drugs, Chinese Herbal , Pharmacology , Gardenia , Chemistry , Medicine, Chinese Traditional , Plant Extracts , Pharmacology , Signal TransductionABSTRACT
The aim of this paper was to find out the active components of Epimedium brevicornum using network pharmacology, and find the potential targets and mechanisms. The TCMSP database was used to screen the active ingredients, and TTD and DrugBank databases were used to predict the potential targets with the literature mining. The pathway annotation was used to enrich and analyze the active ingredients and potential targets of E. brevicornum. The results showed that E. brevicornum had34 potential target active ingredients, including 21 flavones components, such as icariin, epimedin A, epimedin B, epimedin C, Yinyanghuo A, Yinyanghuo C and so on, 2 lignans involved in (+)-cycloolivil and olivil, 3 sterols consisting of sitosterol, 24-epicampesterol and poriferast-5-en-3beta-ol. The main predicted targets included Ptgs2, NCOA6, RANK, OPG, WNT9B, PTH1R, BMPs, SMAD4A and so on. There were 88 signaling pathways involved in 10 signaling pathways which was related to inflammation, such as NF-kappa B signaling pathway, T cell receptor signaling pathway, IL-17 signaling pathway and 10 pathways which was related to cancer included breast cancer, bladder cancer, pancreatic cancer and so on, and estrogen related signaling pathways included estrogen signaling pathway. This laid the foundation for the discovery of the active components of Epimedium and the study on its mechanism of action.
Subject(s)
Epimedium , Classification , Metabolism , Estrogens , Flavonoids , Signal TransductionABSTRACT
OBJECTIVE: To investigate the regulation effects of main active components in Honghua Injection on cerebrovascular disease network. METHODS: Cerebrovascular disease network was constructed using genes from public database RGD based on the protein-protein interaction (PPI) relationship databases HPRD and BioGRID. Then targets of five main active components in Honghua injection was retrieved from PubMed. Component-target relationships were extracted and associated with PPI in cerebrovascular disease. Component-target network was constructed with Cytoscape 3.1.0. Network analysis technologies were applied to find critical targets, biological pathways and potential synergistic effects among components. RESULTS: The component-target network contains 940 nodes and 2360 edges. MCODE analysis extracted 28 clusters in which 18 clusters had at least 3 nodes. There were 6 clusters with score ≥3, and they were further investigated using BinGO analysis. The results showed that the main biological processes included regulation of macromolecule biosynthetic and metabolic processes, neurogenesis, apoptosis, angiogenesis, immune-inflammation reaction, response to hypoxia stress. Our study also indicated that Hydroxysafflor yellow A and Quercetin may show their cerebrovascular-protective potential based on their synergistic anti-apoptosis effects. CONCLUSION: From the view of molecular network, our study applied network pharmacology methods and technologies to reveal the multi-target, multi-pathway mode of action of Honghua injection on anti-cerebro-vascular disease effects, and the synergistic effects among Hydroxysafflor yellow A and quercetin.