scholarly journals Systems Pharmacology-Based Approach of Connecting Disease Genes in Genome-Wide Association Studies with Traditional Chinese Medicine

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Jihye Kim ◽  
Minjae Yoo ◽  
Jimin Shin ◽  
Hyunmin Kim ◽  
Jaewoo Kang ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Target Gene ◽  
Target Genes ◽  
Disease Gene ◽  
Drug Repurposing ◽  
Genome Wide Association Studies ◽  
Systems Pharmacology ◽  
Potential Drug ◽  
Gene Pairs

Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies. We applied a systems pharmacology approach to prioritize disease-target genes. Using this bioinformatics approach, we analyzed 14,713 GWAS disease-TCM-target gene pairs and identified 115 disease-gene pairs with q value < 0.2. We validated several of these GWAS disease-TCM-target gene pairs with literature evidence, demonstrating that this computational approach could reveal novel indications for TCM. We also develop TCM-Disease web application to facilitate the traditional Chinese medicine drug repurposing efforts. Systems pharmacology is a promising approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. The computational approaches described in this study could be easily expandable to other disease-gene network analysis.

scholarly journals Molecular Targets and Pathways Contributing to the Effects of Wenxin Keli on Atrial Fibrillation Based on a Network Pharmacology Approach

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yujie Zhang ◽  
Xiaolin Zhang ◽  
Xi Zhang ◽  
Yi Cai ◽  
Minghui Cheng ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Clinical Symptoms ◽  
Chemical Constituents ◽  
Molecular Targets ◽  
Network Pharmacology ◽  
Systems Pharmacology

Background. Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with high rates of mortality and morbidity. The traditional Chinese medicine Wenxin Keli (WXKL) can effectively improve clinical symptoms and is safe for the treatment of AF. However, the active substances in WXKL and the molecular mechanisms underlying its effects on AF remain unclear. In this study, the bioactive compounds in WXKL, as well as their molecular targets and associated pathways, were evaluated by systems pharmacology. Materials and Methods. Chemical constituents and potential targets of WXKL were obtained via the Traditional Chinese Medicine Systems Pharmacology (TCMSP). The TTD, DrugBank, DisGeNET, and GeneCards databases were used to collect AF-related target genes. Based on common targets related to both AF and WXKL, a protein interaction network was generated using the STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGGs) pathway enrichment analyses were performed. Network diagrams of the active component-target and protein-protein interactions (PPIs) were constructed using Cytoscape. Results. A total of 30 active ingredients in WXKL and 219 putative target genes were screened, including 83 genes identified as therapeutic targets in AF; these overlapping genes were considered candidate targets for subsequent analyses. The effect of treating AF was mainly correlated with the regulation of target proteins, such as IL-6, TNF, AKT1, VEGFA, CXCL8, TP53, CCL2, MMP9, CASP3, and NOS3. GO and KEGG analyses revealed that these targets are associated with the inflammatory response, oxidative stress reaction, immune regulation, cardiac energy metabolism, serotonergic synapse, and other pathways. Conclusions. This study demonstrated the multicomponent, multitarget, and multichannel characteristics of WXKL, providing a basis for further studies of the mechanism underlying the beneficial effects of WXKL in AF.

scholarly journals A Network Pharmacology-Based Study on the Anti-Lung Cancer Effect of Dipsaci Radix

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Jiayan Wu ◽  
Shengkun Hong ◽  
Xiankuan Xie ◽  
Wangmi Liu
Keyword(s):  
Lung Cancer ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Interaction Network ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Hub Genes ◽  
Active Compounds

Objective. Dipsaci Radix (DR) has been used to treat fracture and osteoporosis. Recent reports have shown that myeloid cells from bone marrow can promote the proliferation of lung cancer. However, the action and mechanism of DR has not been well defined in lung cancer. The aim of the present study was to define molecular mechanisms of DR as a potential therapeutic approach to treat lung cancer. Methods. Active compounds of DR with oral bioavailability ≥30% and drug-likeness index ≥0.18 were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform. The potential target genes of the active compounds and bone were identified by PharmMapper and GeneCards, respectively. The compound-target network and protein-protein interaction network were built by Cytoscape software and Search Tool for the Retrieval of Interacting Genes webserver, respectively. GO analysis and pathway enrichment analysis were performed using R software. Results. Our study demonstrated that DR had 6 active compounds, including gentisin, sitosterol, Sylvestroside III, 3,5-Di-O-caffeoylquinic acid, cauloside A, and japonine. There were 254 target genes related to these active compounds as well as to bone. SRC, AKT1, and GRB2 were the top 3 hub genes. Metabolisms and signaling pathways associated with these hub genes were significantly enriched. Conclusions. This study indicated that DR could exhibit the anti-lung cancer effect by affecting multiple targets and multiple pathways. It reflects the traditional Chinese medicine characterized by multicomponents and multitargets. DR could be considered as a candidate for clinical anticancer therapy by regulating bone physiological functions.

scholarly journals Identification of atrial fibrillation associated genes and functional non-coding variants

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Antoinette F. van Ouwerkerk ◽  
Fernanda M. Bosada ◽  
Karel van Duijvenboden ◽  
Matthew C. Hill ◽  
Lindsey E. Montefiori ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Variants ◽  
Target Gene ◽  
Target Genes ◽  
Association Studies ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Cx43 Expression

Abstract Disease-associated genetic variants that lie in non-coding regions found by genome-wide association studies are thought to alter the functionality of transcription regulatory elements and target gene expression. To uncover causal genetic variants, variant regulatory elements and their target genes, here we cross-reference human transcriptomic, epigenomic and chromatin conformation datasets. Of 104 genetic variant regions associated with atrial fibrillation candidate target genes are prioritized. We optimize EMERGE enhancer prediction and use accessible chromatin profiles of human atrial cardiomyocytes to more accurately predict cardiac regulatory elements and identify hundreds of sub-threshold variants that co-localize with regulatory elements. Removal of mouse homologues of atrial fibrillation-associated regions in vivo uncovers a distal regulatory region involved in Gja1 (Cx43) expression. Our analyses provide a shortlist of genes likely affected by atrial fibrillation-associated variants and provide variant regulatory elements in each region that link genetic variation and target gene regulation, helping to focus future investigations.

scholarly journals Integrated Analysis of MicroRNA (miRNA) and mRNA Profiles Reveals Reduced Correlation between MicroRNA and Target Gene in Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Xingsong Li ◽  
Xiaokang Yu ◽  
Yuting He ◽  
Yuhuan Meng ◽  
Jinsheng Liang ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Mirna Target ◽  
Target Gene ◽  
Target Genes ◽  
Integrated Analysis ◽  
Cancer Type ◽  
Gene Pairs ◽  
Cancer Types

Background. Accumulating evidences demonstrated that microRNA-target gene pairs were closely related to tumorigenesis and development. However, the correlation between miRNA and target gene was insufficiently understood, especially its changes between tumor and normal tissues. Objectives. The aim of this study was to evaluate the changes of correlation of miRNAs-target pairs between normal and tumor. Materials and Methods. 5680 mRNA and 5740 miRNA expression profiles of 11 major human cancers were downloaded from the Cancer Genome Atlas (TCGA). The 11 cancer types were bladder urothelial carcinoma, breast invasive carcinoma, head and neck squamous cell carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and thyroid carcinoma. For each cancer type, we firstly obtained differentially expressed miRNAs (DEMs) and genes (DEGs) in tumor and then acquired critical miRNA-target gene pairs by combining DEMs, DEGs and two experimentally validated miRNA-target interaction databases, miRTarBase and miRecords. We collected samples with both miRNA and mRNA expression values and performed a correlation analysis by Pearson method for miRNA-target pairs in normal and tumor, respectively. Results. We totally got 4743 critical miRNA-target pairs across 11 cancer types, and 4572 of them showed weaker correlation in tumor than in normal. The average correlation coefficients of miRNA-target pairs were different greatly between normal (-0.38 ~ -0.61) and tumor (-0.04 ~ -0.26) for 11 cancer type. The pan-cancer network, which consisted of 108 edges connecting 35 miRNAs and 89 target genes, showed the interactions of pairs appeared in multicancers. Conclusions. This comprehensive analysis revealed that correlation between miRNAs and target genes was greatly reduced in tumor and these critical pairs we got were involved in cellular adhesion, proliferation, and migration. Our research could provide opportunities for investigating cancer molecular regulatory mechanism and seeking therapeutic targets.

scholarly journals A Network Pharmacology Approach to Explore the Mechanisms of Shugan Jianpi Formula in Liver Fibrosis

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Chang Fan ◽  
Fu Rong Wu ◽  
Jia Fu Zhang ◽  
Hui Jiang
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Liver Fibrosis ◽  
Signaling Pathways ◽  
Target Genes ◽  
Janus Kinase ◽  
Target Proteins ◽  
Effective Components ◽  
Search Tool ◽  
Common Target

Purpose. We explored the mechanism of Shugan Jianpi Formula (SGJPF) and its effective components for the treatment of liver fibrosis (LF). Materials and Methods. We collected the active ingredients in SGJPF through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and screened the effective components by absorption, distribution, metabolism, and excretion. Herb-associated target proteins were predicted and screened based on the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine and Search Tool for Interactions of Chemicals databases. LF-associated target proteins were predicted and screened based on the Online Mendelian Inheritance in Man® Database and Comparative Toxicogenomics Database. Common genes with LF and herbs were selected, and Cytoscape 3.5.1 software was used to construct an herb pathway and component-LF common target network. The Search Tool for the Retrieval of Interacting Genes/Proteins was used to build a protein-protein interaction, and quantitative PCR was used to verify the related target genes. Finally, clusterProfiler was applied for the analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways. Results. The pharmacological network contained 252 active compounds (e.g., Astragaloside A, saikosaponin, linoleic acid, and Poria acid A), 84 common target genes, and 94 significant signaling pathways. Among them, interleukin 6 (IL-6), tumor protein 53 p53 (TP53), prostaglandin-endoperoxide synthase 2 (PTGS2), AKT1, IL-1β, and the nucleotide-binding and oligomerization domain-like receptor and Janus kinase-signal transducer and activator of transcription signaling pathways were selected as the critical target gene and critical signal pathway, respectively. Conclusion. The mechanisms of SGJPF in protecting against LF include the regulation of multiple targets such as IL-6, TP53, PTGS2, and AKT1. These target proteins affect LF through various signal transduction pathways.

scholarly journals Exploring the mechanism of Astragalus membranaceus against uterine fibroids based on network pharmacology

2021 ◽  
Author(s):  
qiu tiantian ◽  
Li DongHua ◽  
Liu Yu ◽  
Gao LiFang ◽  
Wei Chao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Mechanism Of Action ◽  
Regulatory Network ◽  
Drug Targets ◽  
Target Genes ◽  
Uterine Fibroids ◽  
Network Pharmacology ◽  
Ppi Network

Abstract Backgroud: Uterine fibroids (ULs) are the most common benign tumors of the reproductive tract in gynecology and their clinical presentations include menorrhagia, pelvic pressure, dysmenorrhea, and anemia. Surgical resection and the hormonal drug administration are the primary treatment. The plant Astragalus membranaceus (astragalus) has a long history of use in traditional Chinese medicine and studies have shown that it has antitumor effects. However, the role and mechanism of astragalus in ULs are not completely clear. The present study aimed to investigate the astragalus mechanism of action against ULs based on network pharmacology approach, in order to provid insights for the development of a safe and effective drug for the ULs treatment.Methods: The astragalus active ingredients and the potential drug targets were screened by the Traditional Chinese Medicine System Pharmacology Database and Analytical Platform (TCMSP). The gene expression profiles of ULs were obtained from Gene Expression Omnibus (GEO). The intersection of astragalus components target genes and differentially expressed genes between UL and normal patients were obtained using Perl software to provide the astragalus-ULs drug regulatory network. The protein–protein interaction (PPI) network was established using the STRING online database and Cytoscape software, followed by the topological properties analysis of the PPI networks. GO (Gene ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses were conducted by R software. The KEGG relational network was constructed using Cytoscape software. Results: A total of 21 astragalus active ingredients and 406 drug targets were obtained from the TCMSP. Seventeen of these targets overlap with ULs disease targets and were considered potential targets for the ULs treatment by astragalus. The analysis of the regulatory network showed that the astragalus active components with the most targets are quercetin, kaempferol, mangiferin, tetrodotoxin and isorhamnetin. Target genes with the highest Dgree values obtained from the PPI network analysis are estrogen receptor 1 (ESR1), tumor suppressor factor p53 (TP53), neurotrophic tyrosine kinase receptor 1 (NTRK1) and E3 ubiquitin ligase protein (CUL3). GO and KEGG enrichment analyses indicate that these targets are mainly involved in biological processes related to cellular response to reactive oxygen species, oxidative stress and response to lipopolysaccharides. The main signal transduction pathways involved include the IL-17 and TNF signaling pathways, the AGE-RAGE signaling pathway in diabetic complications and proteoglycans in cancer.Conclusions: The present study demonstrates that the astragalus therapeutic use against ULs have multicomponent and multi-target properties, providing a novel approach to further investigate the astragalus mechanism of action in the treatment of ULs.

scholarly journals Chromatin-based techniques map DNA interaction landscapes in psoriasis susceptibility loci and highlight KLF4 as a target gene in 9q31

2019 ◽  
Author(s):  
Helen Ray-Jones ◽  
Kate Duffus ◽  
Amanda McGovern ◽  
Paul Martin ◽  
Chenfu Shi ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Association Studies ◽  
Dna Interaction ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Rna Seq ◽  
Causal Gene ◽  
Genome Wide ◽  
Crispr Activation

AbstractGenome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. Here, we use a disease-focused Capture Hi-C experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. In the 9q31 risk locus we combine further epigenomic evidence to demonstrate how the psoriasis association forms a functional interaction with the distant (>500 kb) KLF4 gene. We use CRISPR activation coupled with RNA-seq to demonstrate how activation of psoriasis-associated enhancers upregulates KLF4 in HaCaT cells. Our study design provides a robust pipeline for following up on GWAS disease-associated variants, paving the way for functional translation of genetic findings into clinical benefit.

scholarly journals CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci

2022 ◽  
Author(s):  
Joseph Rosenbluh ◽  
Natasha Tuano ◽  
Jonathan Beesley ◽  
Murray Manning ◽  
Wei Shi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Target Genes ◽  
Drug Repositioning ◽  
Association Studies ◽  
Drug Repurposing ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Breast Cells ◽  
Cancer Phenotypes

Abstract Genome-wide association studies (GWAS) have identified >200 loci associated with breast cancer (BC) risk. The majority of candidate causal variants (CCVs) are in non-coding regions and likely modulate cancer risk by regulating gene expression. However, pinpointing the exact target of the association and identifying the phenotype it mediates is a major challenge in the interpretation and translation of GWAS. Here, we used pooled CRISPR activation and suppression screens to evaluate predicted GWAS target genes, and to define the cancer phenotypes they mediate. We measured proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We performed 60 CRISPR screens and identified 21 genes predicted with high confidence to be GWAS targets that drive a cancer phenotype by driving a proliferation or DNA damage response in breast cells. We validated the regulation of a subset of these genes by BC-risk variants, and show the utility of expression profiling for drug repurposing. We provide a platform for identifying gene targets of risk variants, and present a blueprint of interventions for BC risk reduction and treatment.

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