Network Pharmacology-based Analysis Research Articles

Effects of estrogen inhibition formula herbal mixture for danazol-induced precocious puberty in female rats: An experimental study with network pharmacology

BackgroundThis study aimed at determining the effect of the herbal mixture estrogen inhibition formula (EIF) and its possible mechanisms by precocious puberty animal models and network pharmacology-based analysis. MethodsPrecocious puberty animal models were established by a single injection of 300 μg danazol, then female rats were administered EIF, vaginal openings were monitored, uterus and pituitary indices were determined. The levels of ALP, E2, LH, and FSH were measured using ELISA kits. Real-time PCR was performed to evaluate the mRNA expression of GnRH, UNC5C, and netrin-1 in hypothalamic tissues. We applied network pharmacological analysis to predict potential targets and pathways of EIF. ResultsEIF delayed danazol-induced early vaginal opening. In the onset model, EIF reduced the increased levels of serum ALP, E2, LH, and FSH; as well as mRNA expressions of GnRH, Netrin-1, and UNC5C. Moreover, long-term administration of EIF not only diminished all impaired factors but also had no effect on the normal development of the animals. The gene set enrichment analysis showed that the targets of EIF are mainly associated with the GnRH signaling and ovarian steroidogenesis pathways. ConclusionEIF could be used in preclinical research for the treatment of precocious puberty by the inhibition of HPGA pre-maturation.

Experimental evidence and network pharmacology-based analysis reveal the molecular mechanism of Tongxinluo capsule administered in coronary heart diseases.

Background: Tongxinluo (TXL) capsule, a polypharmacy derived from traditional Chinese medicine (TCM), has been widely used in coronary heart disease (CHD), while the underlying mechanism of TXL capsule is still unclear. The present study aimed at investigating the underlying mechanism of TXL acting on CHD patients and providing substantial evidence in molecular evidence by means of a network pharmacological analysis.Method: Active compounds and targeted genes of TXL were retrieved from TCM systems pharmacology (TCMSP) and TCM integrative database (TCMID). CHD and coronary artery disease were treated as search queries in GeneCards and Online Mendelian Inheritance in Man (OMIM) databases to obtain disease-related genes. Visualization of disease–targets network was performed under administration of Cytoscape software. Besides, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were administered. H9c2 cells were used to validate the predicted results in cardiomyocytes/reoxygenation model, and anti-inflammatory ability was examined.Results: A network of a total of 212 nodes and 1016 edges was obtained. Peptide and ubiquitin-like protein ligase binding occupied a leading position of GO enrichment. For KEGG analysis, fluid shear stress and atherosclerosis, as well as inflammation-related pathways were enriched. Cellular validation revealed the anti-inflammatory effect of β-sitosterol, eriodictyol, odoricarpin, and tirucallol as active compounds of TXL.Conclusion: Our study provided substantial molecular evidence that TXL capsule possessed the characteristics of multitargets with safe profile, and the main component is capable of regulating cytokine level in CHD patients.

Network pharmacology-based analysis: Fufang Xiongdan Diyanye—clinical response and mechanism of action in the treatment of acute bacterial conjunctivitis

Network pharmacology-based analysis: Fufang Xiongdan Diyanye—clinical response and mechanism of action in the treatment of acute bacterial conjunctivitis

Systematic Investigation of the Efficacy of Sinitang Decoction Against Ulcerative Colitis.

The aim of this study was to investigate the precise clinical use of Sinitang decoction (SNT) in ulcerative colitis (UC). Network pharmacology-based analysis of the drug components–targets–diseases–pathways was used to predict the possible clinical applications of SNT. Next, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used to establish a rat model of UC, and the efficacy of SNT against UC was tested, followed by a proteomic analysis of the specific signatures regulated by SNT against UC. SNT was predicted to be effective in inflammatory bowel disease, UC, and several other diseases. In the rats with UC, SNT decreased the disease activity index and colon mucosal damage index compared to the untreated UC model rats. Additionally, SNT reversed the upregulated levels of serum tumor necrosis factor (TNF)-α, prostaglandin E2 (PGE2), interleukin (IL)-6, and nitric oxide (NO) in UC model rats. The proteomic analysis identified 78 proteins that were differentially regulated by SNT in the rats with UC, which were associated with the Gene Ontology terms sulfur compound binding, calcium ion binding, and Toll-like receptor (TLR)-4 binding. Among these differentially regulated proteins, C-reactive protein (CRP) and collagen alpha-1(XII) chain (COL12A1) were found to be signature proteins associated with the efficacy of SNT against UC. This study represents the first precise investigation of the efficacy and mechanisms of SNT against UC, and shows that SNT is a promising candidate for personalized management of UC.

Network pharmacology-based identification for therapeutic mechanisms of Dangguikushen pill in acne vulgaris.

The Dangguikushen (DGKS) pill is a proprietary traditional Chinese medicine that has shown superior efficacy in the treatment of acne vulgaris for many years. A network pharmacology-based analysis was performed to explore the potential anti-acne compounds, core therapeutic targets, and the main pathways, involved in the DGKS pill bioactivity. The matching results between the predicted targets of the DGKS pill and the well-known targets of acne vulgaris were collected, followed by network establishment using protein-protein interaction (PPI) data. Cytoscape was utilized to analyze the network and screen the core targets. Furthermore, the Database for Annotation, Visualization and Integrated Discovery (DAVID), and ClueGO were used for the enrichment analysis of the Kyoto Encyclopedia of Genes and Genomics (KEGG) pathways and Gene Ontology biological processes (GO-BP). Finally, the "compound-target-pathway" network was constructed. This approach identified 19 active compounds, 46 therapeutic targets, and 12 core therapeutic targets of the DGKS pill. The biological processes were primarily related to reactive oxygen species (ROS) metabolic process, gland morphogenesis, and female gonad development. The DGKS pill was significantly associated with eight pathways including the PI3K-Akt, TNF, NF-kappa B, and p53 signaling pathways. DGKS pill might have a synergistic effect on the inhibition of excessive sebaceous lipogenesis and sebocyte differentiation, and likewise, anti-inflammatory effects via the different signaling pathways (PI3K-Akt, TNF, NF-kappa B, and p53).

Comprehensive chemical profiling of Jia-Wei-Qi-Fu-Yin and its network pharmacology-based analysis on Alzheimer's disease

Jia-Wei-Qi-Fu-Yin (JWQFY) is a newly developed anti-Alzheimer's disease (AD) prescription modified from a classical traditional Chinese medicine formula, Qi-Fu-Yin (QFY). However, a systematic understanding of its chemical constituents and molecular mechanisms is still elusive. To address this problem, comprehensive chemical profiling followed by network pharmacology-based analysis of JWQFY was performed. Firstly, a total of 136 compounds were characterized by high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF MS), 17 of them were specifically identified in JWQFY comparing with QFY. Seventy compounds were further quantified via a validated HPLC coupled with triple quadrupole tandem mass spectrometry (QQQ MS) method. Then the protein targets of the seventy compounds were gathered from public databases for network construction. As a result, fifty-seven compounds were filtered, which interacted with 655 targets. Thirty-four of them were mapped into the KEGG pathway of AD, indicating JWQFY might exert anti-AD effects by anti-inflammation, neuronal apoptosis intervening, Aβ production inhibition and phosphorylating tau protein moderating. Furthermore, in the compound-target-AD network, a list of hub compounds and hub targets was identified based on their topological features, including the degree, node betweenness and closeness. Four of the hub compounds were specifically originated from JWQFY, supporting the modification rationality of this formula. This study provided a scientific basis for understanding the bioactive compounds and the multi-target mechanism of JWQFY.

Hair Growth Effect of Emulsion Extracted Brevilin A, a JAK3 Inhibitor, from Centipeda minima

Janus kinase 3 (JAK3) inhibitors have been used effectively in the treatment of several cases of alopecia universalis and its variants. Our study aims to evaluate whether the emulsion extract of brevilin A from Centipeda minima (CMX) stimulates hair regrowth in a clinical trial, as a JAK3 inhibitor, combined with network pharmacology-based analysis. CMX showed potent inhibition of JAK3 in a concentration-dependent manner. Significant differences in total hair count, terminal hair count, and anagen hair count from the baseline to 24 weeks were observed between the placebo and CMX subjects. The gene set enrichment analysis showed that the targets of CMX are mainly associated with the JAK-STAT signaling pathway, cytokine–cytokine receptor interactions, and the MAPK signaling pathway. This study suggests that the medicinal herbal extract CMX is useful in the treatment of mild to moderate vertex balding that contribute to the visible improvements in hair growth observed in treated patients.

Network pharmacology-based analysis of the role of traditional Chinese herbal medicines in the treatment of COVID-19.

The novel coronavirus named COVID-19, which originated in Wuhan, China, has spread to many countries around the world. Currently, no effective medical treatment exists to combat this disease. Traditional Chinese herbal medicines (CHM) have unique roles in the treatment of viral infections. In this article we analyzed the effectiveness and possible molecular mechanisms of CHM formulas for the prevention of COVID-19. The active ingredients and action targets of CHM formulas were obtained from the TCMSP database. Genes related to severe acute respiratory syndromes (SARS) and Middle East respiratory syndrome (MERS) were queried on the GeneCards database. The action mechanisms of these genes were predicted using a Gene Ontology (GO)-based functional enrichment and annotation tool and the Kyoto Encyclopedia of Genes and Genomes (KEGG). CHM formulas played a positive role in preventing COVID-19 and warrant further application. Our research provides new evidence to support the possible value of CHM formulas for the prevention of COVID-19. However, further clinical studies with large sample sizes are required to verify their effectiveness.

Identification of the Active Constituents and Significant Pathways of Cangfu Daotan Decoction for the Treatment of PCOS Based on Network Pharmacology.

Background Polycystic ovary syndrome (PCOS) is the most common female endocrine disease. Cangfu Daotan Decoction (CDD) can effectively relieve the clinical symptoms of PCOS patients. Methods To explore the active ingredients and related pathways of CDD for treating PCOS, a network pharmacology-based analysis was carried out. The active ingredients of CDD and their potential targets were obtained from the TCM system pharmacology analysis platform. The obtained PCOS-related genes from OMIM and GeneCards were imported to establish protein-protein interaction networks in STRING. Finally, GO analysis and significant pathway analysis were conducted with the RStudio (Bioconductor) database. Results A total of 111 active compounds were obtained from 1433 ingredients present in the CDD, related to 118 protein targets. In addition, 736 genes were found to be closely related to PCOS, of which 44 overlapped with CDD and were thus considered therapeutically relevant. Pathway enrichment analysis identified the AGE-RAGE signalling pathway in diabetic complications, endocrine resistance, the IL-17 signalling pathway, the prolactin signalling pathway, and the HIF-1 signalling pathway. Moreover, PI3K-Akt, insulin resistance, Toll-like receptor, MAPK, and AGE-RAGE were related to PCOS and treatment. Conclusions CDD can effectively improve the symptoms of PCOS, and our network pharmacological analysis lays the foundation for future clinical research.

Network Pharmacology-Based Analysis of the Pharmacological Mechanisms of Aloperine on Cardiovascular Disease.

Background Aloperine is an active component of Sophora alopecuroides Linn, which has been extensively applied for the treatment of cardiovascular disease (CVD). However, our current understanding of the molecular mechanisms supporting the effects of aloperine on CVD remains unclear. Methods Systematic network pharmacology was conducted to provide testable hypotheses about pharmacological mechanisms of the protective effects of aloperine against CVD. Detailed structure was obtained from Traditional Chinese Medicines Integrated Database (TCMID). Target genes of aloperine against CVD were collected from SwissTargetPrediction, DrugBank database, and Online Mendelian Inheritance in Man (OMIM) database. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway performance, and network construction were adopted to explore common target genes. Results Our findings showed that 25 candidate targets were the interacting genes between aloperine and CVD. GO analysis revealed biological process, cellular component, and molecular function of these target genes. More importantly, the majority of enrichment pathways was found to be highly associated with the nitrogen metabolism by KEGG analysis. Core genes particularly in nitrogen metabolism pathway including carbonic anhydrase (CA) III, CA IV, CA VA, CA VB, CA VI, CA VII, CA IX, CA XII, and CA XIV can be modulated by aloperine in the nitrogen metabolism. Conclusion Our work revealed the pharmacological and molecular mechanisms of aloperine against CVD and provided a feasible tool to identify the pharmacological mechanisms of single active ingredient of traditional Chinese medicines.

Network Pharmacology-based Analysis of the Mechanism of Action of the Herb Pair Chai Hu - Bai Shao

Objective To analyze the mechanism of action and compatibility of the active compounds of the traditional herb pair Bupleuri Radix (Chai Hu, CH, 柴胡) - Paeoniae Radix Alba (Bai Shao, BS, 白芍). Methods All chemical compounds related to CH and BS were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Traditional Chinese Medicine Integrated Database (TCMID), Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (Batman-TCM), Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan), and the literature. Relevant compounds were screened for oral bioavailability (OB), drug-likeness (DL), and the Caco-2 cell model. The Uniprot, Genecard, and CTD databases were used to obtain information on potential targets and diseases of associated compounds. Based on this, Cytoscape 3.2.1 software, GO enrichment analysis, and KEGG pathway enrichment were used to analyze the potential mechanism of action and pathways of the CH - BS drug combination. Results A total of 23 active compounds of CH and BS were indentified after meeting specific criteria by network pharmacology, showing 79 predicted targets of active compounds. Among them, all targets were associated with 344 diseases, and the compounds in CH and BS were connected to 94 pathways and biological, such as calcium signaling pathway, neuroactive ligand-receptor interaction and TNF signaling pathway. Conclusions Our results preliminarily validated the main compounds in CH - BS herb pair interacted with multiple targets in different diseases, and the molecular mechanism of these compounds involves multiple pathways, thereby establishing a good foundation for further studies.

Identifying cancer-related molecular targets of Nandina domestica Thunb. by network pharmacology-based analysis in combination with chemical profiling and molecular docking studies.

The fruits of Nandina domestica Thunb. have served as folk medicines in Chinese and Japanese tradition for treatment of several tumors including pharynx tumor and tooth abscess for many years, yet its exact mechanism of action is not yet known. The study targets the identification of the main constituents of the fruits extracts and investigation of their mode of action in cancer therapy via pharmacology-based analysis and molecular docking. The different extracts of N. domestica Thunb. were analyzed via UPLC-MS/MS for identification of their active constituents. STITCH, DAVID, KEGG and STRING database were utilized for construction of compound-target and compound-target-pathway networks using Cytoscape 3.2.1. Molecular docking analysis of the top hit compounds was performed against the identified top hit molecular targets in the constructed networks. In vitro-testing of Nandina domestica Thunb. against colorectal cancer cell lines was carried out and correlated to the chemical profile of the extract to identify important biomarkers. The ADME properties of the active compounds were also evaluated. 22 compounds were identified by UPLC-MS/MS analysis and were forwarded to network pharmacology-based analysis. Results showed the enrichment of 5 compounds and 4 molecular targets in the network namely; AKT1, CASP3, MAPK1 and TP53. The pathway analysis of the identified targets revealed that 15 cancer-related pathways were enriched including colorectal cancer, endometrial cancer and small-cell lung cancer. In-vitro testing of the extracts against colo-rectal cancer cell lines revealed the fractions enriched in the identified hit compounds were indeed the most active as revealed from the HCA-heat-map. ADME results showed that all compounds were drug-like candidates showing acceptable values according to Lipinski's rule. Network pharmacology analysis revealed that the compounds isoquercitrin, quercitrin, berberine, chlorogenic acid and caffeic acid showed strong synergistic interactions with the cancer-related targets and pathways. It could be concluded that N. domestica Thunb. constituents affect both apoptosis and Akt-signaling pathways during the stages of early and intermediate adenoma through interaction with the targets CASP3 and MAPK1 (ErC2) while during the stages of late adenoma and carcinoma, the compounds acts through the p53 and ErbB signaling pathways.

The Inhibitory Effect of Cordycepin on the Proliferation of MCF-7 Breast Cancer Cells, and its Mechanism: An Investigation Using Network Pharmacology-Based Analysis.

Cordyceps militaris is a well-known medicinal mushroom. It is non-toxic and has clinical health benefits including cancer inhibition. However, the anticancer effects of C. militaris cultured in brown rice on breast cancer have not yet been reported. In this study, we simultaneously investigated the anticancer effects of cordycepin and an extract of C. militaris cultured in brown rice on MCF-7 human breast cancer cells using a cell viability assay, cell staining with Hoechst 33342, and an image-based cytometric assay. The C. militaris concentrate exhibited significant MCF-7 cell inhibitory effects, and its IC50 value was 73.48 µg/mL. Cordycepin also exhibited significant MCF-7 cell inhibitory effects, and its IC50 value was 9.58 µM. We applied network pharmacological analysis to predict potential targets and pathways of cordycepin. The gene set enrichment analysis showed that the targets of cordycepin are mainly associated with the hedgehog signaling, apoptosis, p53 signaling, and estrogen signaling pathways. We further verified the predicted targets related to the apoptosis pathway using western blot analysis. The C. militaris concentrate and cordycepin exhibited the ability to induce apoptotic cell death by increasing the cleavage of caspase-7 -8, and -9, increasing the Bcl-2-associated X protein/ B-cell lymphoma 2 (Bax/Bcl-2) protein expression ratio, and decreasing the protein expression of X-linked inhibitor of apoptosis protein (XIAP) in MCF-7 cells. Consequently, the C. militaris concentrate and cordycepin exhibited significant anticancer effects through their ability to induce apoptosis in breast cancer cells.

The Inhibitory Effect of Cordycepin on the Proliferation of MCF-7 Breast Cancer Cells, and its Mechanism: An Investigation Using Network Pharmacology-Based Analysis.

We determined the lipid-lowering effect of a new strain of the lactic acid bacteria Lactobacillus plantarum CQPC02 (LP-CQPC02), from Sichuan pickled cabbages, using an in vivo animal model. A high-fat diet was used to generate obese mice. The effect of LP-CQPC02 was measured using serum parameters and tissues collected from the mice. Obese mice treated with LP-CQPC02 had a lower organ index for liver, epididymal fat, and perirenal fat, and lower levels of aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), and total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C) but higher levels of high density lipoprotein cholesterol (HDL-C) in the serum and liver. LP-CQPC02-treated obese mice also had lower serum levels of the cytokines tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin 6 (IL-6), and interleukin 1 beta (IL-1β), and higher levels of interleukin 4 (IL-4) and interleukin 10 (IL-10). LP-CQPC02 treatment lessened the obesity-associated pathological changes in the liver and epididymal adipose tissue and reduced adipocyte enlargement. The quantitative PCR (qPCR) and Western blot results showed that LP-CQPC02 treatment up-regulated mRNA and protein expression of lipoprotein lipase (LPL), peroxisome proliferator-activated receptor-alpha (PPAR-α), cholesterol 7 alpha-hydroxylase (CYP7A1), and carnitine palmitoyltransferase 1 (CPT1), but down-regulated peroxisome proliferator-activated receptor-gamma (PPAR-γ) and CCAAT enhancer-binding protein alpha (C/EBP-α) expression in the liver and epididymal adipose tissue. LP-CQPC02 effectively inhibited high-fat diet-induced obesity. The effects of LP-CQPC02 are comparable to the drug l-carnitine but superior to Lactobacillus delbruechii subsp. bulgaricus (LDSB), which is commonly used in the dairy industry. LP-CQPC02 is a potentially useful, high-quality probiotic strain.

Network Pharmacology-based Analysis on the Molecular Biological Mechanisms of Xin Hui Tong Formula in Coronary Heart Disease Treatment

ObjectiveTo investigate the potential molecular mechanism of Xin Hui Tong Formula (XHTF) in the treatment of coronary heart disease (CHD) by using network pharmacology and bioinformatics. MethodsThe targets network of CHD was constructed through Therapeutic Targets Database (TTD) and Drugbank database; The XHTF pharmacodynamic molecule-targets network and the XHTF pharmacodynamic molecule-CHD targets network were explored by the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). And the multi-targets mechanism and molecular regulation network of XHTF in the treatment of CHD were explored from multiple perspectives by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) database pathway enrichment analysis. ResultsA total of 88 CHD targets were screened out through the Therapeutic Targets and the Drugbank database. 393 compounds and corresponding 205 drug targets of XHTF were retrieved from TCMSP. A total of 13 known targets directly related to the development of CHD were retrieved from the disease-related databases: TP53, MAPK14, NFKB1, HSPA5, PLG, PTGS2, ADRB1, NOS2, CYP3A4, GRIA2, CYP2A6, GRIA1, PTGS1. XHTF also contained 118 drug targets that directly interact with CHD targets. GO enrichment analysis showed that the biological processes of 13 direct targets proteins were found to be mainly enriched in response to drug, cellular response to biotic stimulus, long-chain fatty acid metabolic process, fatty acid metabolic process and regulation of blood pressure. KEGG pathway enrichment analysis found that XHTF participated in the CHD pathological process mainly through retrograde endocannabinoid signaling, regulation of lipolysis in adipocytes, cAMP signaling pathway, chemical carcinogenesis and other pathways. ConclusionsXHTF plays a role in the treatment of CHD through multiple targets and multiple pathways, and provides a scientific basis for the theory of “virtual standard” in the treatment of CHD.

Network pharmacology-based identification for therapeutic mechanism of Ling-Gui-Zhu-Gan decoction in the metabolic syndrome induced by antipsychotic drugs

BackgroundThe metabolic syndrome (MetS) is a common side effect of second-generation antipsychotic drugs (SGAs), leading to poor prognosis in patients with mental illness. The traditional Chinese herbal formula Ling-Gui-Zhu-Gan decoction (LGZGD) is a clinically validated remedy for SGAs-induced MetS, but its underlying mechanism remains unclear. MethodsA network pharmacology-based analysis was performed to explore predicted plasma-absorbed components, putative therapeutic targets, and main pathways involved in LGZGD bioactivity. We constructed a target interaction network between the predicted targets of LGZGD and the known targets of MetS, after which we extracted major hubs using topological analysis. Thereafter, the maximum value of “edge betweenness” of all interactions was defined as a bottleneck, which suggested its importance in connecting all targets in the network. Finally, a pathway enrichment analysis of major hubs was used to reveal the biological functions of LGZGD. ResultsThis approach identified 120 compounds and 361 candidate targets of LGZGD. According to the data generated in this study, the interaction between JUN and APOA1 plays a vital role in the treatment of SGAs-induced MetS using LGZGD. Interestingly, JUN was a putative target of LGZGD and APOA1 is one of the known targets of both MetS and SGAs (olanzapine and clozapine). LGZGD was significantly associated with several pathways including PI3K-Akt signaling, insulin resistance, and MAPK signaling pathway. ConclusionsLGZGD might inhibit JUN and thereby increases the expression of APOA1 to maintain metabolic homeostasis via some vital pathways.

Network pharmacology-based analysis on bioactive anti-diabetic compounds in Potentilla discolor bunge

Ethnopharmacological relevancePotentilla discolor Bunge (PDB) is a commonly used herbal for alleviating diabetes mellitus and its complications. Although accumulating evidences show the anti-diabetic efficacy of PDB, the vital anti-diabetic compounds and their functional targets remain elusive. Aim of the studyTo investigate the anti-diabetic ingredients and their functional mechanisms in PDB, gas chromatograph-mass spectrometry analysis was performed on PDB extract and 21 were testified as anti-diabetic compounds. Materials and methodsSubsequently their potential protein targets were also identified. The bioinformatics analysis was implemented by network pharmacology-based approaches. STRING analysis was performed to reveal enrichment of these target proteins, protein-protein interactions, pathways and related diseases. Cytoscape was used to determine the potential protein targets for these components in PDB, indicating that 21 anti-diabetic compounds in PDB regulate 33 diabetes-related proteins in 28 signal pathways and involve 21 kinds of diabetes-related diseases. Among the 21 potential anti-diabetic components predicted by network analysis, tricetin was firstly experimentally validated at the molecular and cellular level. ResultsResults indicated that this active small-molecule compound may have beneficial effects on improving glucose uptake. ConclusionsWe envisage that network analysis will be useful in screening bioactive compounds of medicinal plants.

Prediction of potential cancer-related molecular targets of North African plants constituents using network pharmacology-based analysis

Ethnopharmacological relevanceNowadays, cancer is considered one of the leading causes of death in developing countries. Due to mediocre socioeconomic status of many of the North African countries, people resort to traditional medicine from natural products for cancer therapy which are of great chemical complexity, interacting with several protein targets leading to synergistic effects. A holistic network pharmacology approach is needed for understanding the molecular mechanism of North African plants constituents in the different cancer-related pathways. Aim of the studyThe aim of this study is the implementation of network pharmacology for identification of the main active constituents of North African plants against cancer molecular targets and to explore their therapeutic mechanism. Materials and methodsConstituents of North African plants were retrieved from public database and ADME screening was implemented for filtration of constituents using Qikprop software.STITCH database was used for predicting the plant constituents target proteins/genes, TDD DB and Uniprot databases were used for identifying genes related to cancer. Constituent-target gene (C-T), constituent-pathway (C-P) and plant-constituent-target gene (P-C-T) networks were constructed using Cytoscape to decipher the anti-cancer mechanism of action of the plants. KEGG pathway and GO enrichment analysis were performed to investigate the molecular mechanisms and pathways related to cancer. Results6844 constituent were subjected to ADME filtration resulting in 3194 constituent which were forwarded to target prediction. 53 constituents and 36 targets were linked through 329 edges which constituted the main pathways related to cancer. Luteolin, alternariol, apigenin, aloe-emodin and myricetin had the highest combined score in the C-T network, while the genes CASP3, CYP1A1, CYP1B1, PTGS2, MAPK8, AKT1 and EGFR were the most enriched by the constituents in this network. Euphorbia spp., Hyphaene thebaica, Artemisia herba-alba, bee propolis and Marrubium vulgare possessed the largest number of P-C-T interactions. The identified targets were mainly associated with cell cycle arrest and apoptosis in addition to inhibition of cellular proliferation by revealing a striking functional association with various signal and cancer related pathways ConclusionsAnalysis of the constructed pharmacological networks results allowed for the prediction and interpretation of the multi-constituent, multi-target, and multi-pathway mechanisms of North African plants as potential source for supportive treatment of cancer where their potential molecular mechanism towards cancer-associated targets, biological processes and pathways were revealed.

A Network Pharmacology-Based Analysis of Multi-Target, Multi-Pathway, Multi-Compound Treatment for Ovarian Serous Cystadenocarcinoma.

Pharmacological control against ovarian serous cystadenocarcinoma has received increasing attention. The purpose of this study was to investigate multi-drug treatments as synergetic therapy for ovarian serous cystadenocarcinoma and to explore their mechanisms of action by the network pharmacology method. Genes acting on ovarian serous cystadenocarcinoma were first collected from GEPIA and DisGeNET. Gene Ontology annotation, Kyoto Encyclopedia of Genes and Genomes pathway, Reactome pathway, and Disease Ontology analyses were then conducted. A connectivity map analysis was employed to identify compounds as treatment options for ovarian serous cystadenocarcinoma. Targets of these compounds were obtained from the Search Tool for Interacting Chemicals (STITCH). The intersections between the ovarian serous cystadenocarcinoma-related genes and the compound targets were identified. Finally, the Kyoto Encyclopedia of Genes and Genomes and Reactome pathways in which the overlapped genes participated were selected, and a correspondence compound-target pathway network was constructed. A total of 541 ovarian serous cystadenocarcinoma-related genes were identified. The functional enrichment and pathway analyses indicated that these genes were associated with critical tumor-related pathways. Based on the connectivity map analysis, five compounds (resveratrol, MG-132, puromycin, 15-delta prostaglandin J2, and valproic acid) were determined as treatment agents for ovarian serous cystadenocarcinoma. Next, 48 targets of the five compounds were collected. Following mapping of the 48 targets to the 541 ovarian serous cystadenocarcinoma-related genes, we identified six targets (PTGS1, FOS, HMOX1, CASP9, PPARG, and ABCB1) as therapeutic targets for ovarian serous cystadenocarcinoma by the five compounds. By analysis of the compound-target pathway network, we found the synergistic anti-ovarian serous cystadenocarcinoma potential and the underlying mechanisms of action of the five compounds. In summary, latent drugs against ovarian serous cystadenocarcinoma were acquired and their target actions and pathways were determined by the network pharmacology strategy, which provides a new prospect for medicamentous therapy for ovarian serous cystadenocarcinoma. However, further in-depth studies are indispensable to increase the validity of this study.

A Network Pharmacology-Based Approach to Investigate the Novel TCM Formula against Huntington's Disease and Validated by Support Vector Machine Model.

Several pathways are crucial in Huntington's disease (HD). Based on the concept of multitargets, network pharmacology-based analysis was employed to find out related proteins in disease network. The network target method aims to find out related mechanism of efficacy substances in rational design way. Traditional Chinese medicine prescriptions would be used for research and development against HD. Virtual screening was performed to obtain drug molecules with high binding capacity from traditional Chinese medicine (TCM) database@Taiwan. Quantitative structure-activity relationship (QSAR) models were conducted by MLR, SVM, CoMFA, and CoMSIA, constructed to predict the bioactivities of candidates. The compounds with high-dock score were further analyzed compared with control. Traditional Chinese medicine reported in the literature could be the training set provided for constructing novel formula by SVM model. We tried to find a novel formula that can bind well with these targets at the same time, which indicates our design could be highly related to the HD. Additionally, the candidates would validate by a long-term molecular dynamics (MD) simulation, 5 microseconds. Thus, we suggested the herbs Brucea javanica, Holarrhena antidysenterica, Dichroa febrifuga, Erythrophleum guineense, etc. which contained active compounds might be a novel medicine formula toward Huntington's disease.