Effect of Terpenes from Poria Cocos: Verification of Therapeutic Modes of Action for Alzheimer’s Disease using Molecular Docking, Drug-induced Transcriptomes and Diffusion Network [SW1783]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE232868 | GEO | 2024/04/23
REPOSITORIES: GEO
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Project description:This study aimed to identify the modes of action (MOA) of Poria Cocos water extract (PCW) in HT29 cell line.
2024-04-23 | GSE232862 | GEO
Project description:Deciphering the mode of action (MOA) of new antibiotics discovered through phenotypic screening is of increasing importance. Metabolomics offers a potentially rapid and cost-effective means of identifying modes of action of drugs whose effects are mediated through changes in metabolism. Metabolomics techniques also collect data on off-target effects and drug modifications. Here, we present data from an untargeted liquid chromatography-mass spectrometry approach to identify the modes of action of eight compounds: 1-[3-fluoro-4-(5-methyl-2,4-dioxo-pyrimidin-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea (AZ1), 2-(cyclobutylmethoxy)-5'-deoxyadenosine, triclosan, fosmidomycin, CHIR-090, carbonyl cyanidem-chlorophenylhydrazone (CCCP), 5-chloro-2-(methylsulfonyl)-N-(1,3-thiazol-2-yl)-4-pyrimidinecarboxamide (AZ7), and ceftazidime. Data analysts were blind to the compound identities but managed to identify the target as thymidylate kinase for AZ1, isoprenoid biosynthesis for fosmidomycin, acyl-transferase for CHIR-090, and DNA metabolism for 2-(cyclobutylmethoxy)-5'-deoxyadenosine. Changes to cell wall metabolites were seen in ceftazidime treatments, although other changes, presumably relating to off-target effects, dominated spectral outputs in the untargeted approach. Drugs which do not work through metabolic pathways, such as the proton carrier CCCP, have no discernible impact on the metabolome. The untargeted metabolomics approach also revealed modifications to two compounds, namely, fosmidomycin and AZ7. An untreated control was also analyzed, and changes to the metabolome were seen over 4 h, highlighting the necessity for careful controls in these types of studies. Metabolomics is a useful tool in the analysis of drug modes of action and can complement other technologies already in use.
2017-06-16 | MTBLS464 | MetaboLights
Project description:Under REACH, the European Community Regulation on chemicals, the testing strategy for carcinogenicity is generally based on in vitro and in vivo genotoxicity assays. Given that non-genotoxic carcinogens are negative for genotoxicity, this class of carcinogens will not be detected. Therefore, alternative test are urgently needed. Non-genotoxic carcinogens, however, act through different modes of action, which complicates the development of such an assay. The aim of this study was to investigate whether gene expression profiling in primary mouse hepatocytes can be used to distinguish different modes of action of non-genotoxic carcinogens. Primary mouse hepatocytes were exposed to 16 non-genotoxic carcinogens with diverse modes of action. Upon profiling, pathway analysis was performed to obtain insight into the biological relevance of the observed changes in gene expression. To recognize similarities in mode of action at the transcriptomic level, both a supervised and an unsupervised comparison approach was applied.
2012-06-25 | E-GEOD-35058 | biostudies-arrayexpress
Project description:Under REACH, the European Community Regulation on chemicals, the testing strategy for carcinogenicity is generally based on in vitro and in vivo genotoxicity assays. Given that non-genotoxic carcinogens are negative for genotoxicity, this class of carcinogens will not be detected. Therefore, alternative test are urgently needed. Non-genotoxic carcinogens, however, act through different modes of action, which complicates the development of such an assay. The aim of this study was to investigate whether gene expression profiling in primary mouse hepatocytes can be used to distinguish different modes of action of non-genotoxic carcinogens.
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Project description:Chinese medicine is a complex system guided by traditional Chinese medicine (TCM) theories, which has proven to be especially effective in treating chronic and complex diseases. However, the underlying modes of action (MOA) are not always systematically investigated. Herein, a systematic study was designed to elucidate the multi-compound, multi-target and multi-pathway MOA of a Chinese medicine ,QSYQ, on myocardial infarction. Male Sprague Dawley rat model of myocardial infarction were administered QSYQ intragastrically for 7 days while the control group was not treated. The differentially expressed genes (DEGs) were identified from myocardial infarction rat model treated with QSYQ, followed by constructing a cardiovascular disease (CVD)-related multilevel compound-target-pathway network connecting main compounds to those DEGs supported by literature evidences and the pathways that are functionally enriched.
2014-01-17 | GSE54134 | GEO
Project description:This study aimed to compare the mechanisms of action (MOA) of similar natural compounds and observed the changes when they are mixed and used.
2023-04-03 | GSE228524 | GEO
Project description:The current test strategy for carcinogenicity consists initially of in vivo and in vitro genotoxicity tests. Non-genotoxic carcinogens do not directly induce DNA damage and, as such, go undetected under this test strategy. In a previous study we setup a comparison approach to categorize chemicals having similar modes of action, according to similarity in gene expression. In the current study we will investigate whether this comparison approach can be improved by omptimizing the concentration selection procedure and by testing a concentration range per chemical.
2016-12-23 | GSE53634 | GEO
Project description:It is considered that read-across based on only structure similarity has a risk of error on risk assessment. Under this circumstances, considering biological similarity based on adverse outcome pathways (AOPs) using in vitro omics technologies is expected to enhance the accuracy and robustness of conclusions in read-across. However, because of a lack of practical case studies, it is not well discussed key considerations and how to use these technologies for data gap filling. In the present case study, we elucidated and compared the mode of action for structural analogs ; p-dialkoxy chlorobenzenes including 1,4-dichloro-2,5-dimethoxybenzene (DDMB), 2,5-dichloro-1,4-diethoxybenzene (DDEB), 2-chloro-1,4-dimethoxybenzene (CDMB), and 1-chloro-2,5-diethoxybenzene (CDEB) using in vitro omics technologies. To reveal the modes of action, we conducted microarray analysis with rat primary hepatocytes.
2020-04-01 | GSE137379 | GEO
Project description:Cells activate various stress response pathways when exposed to chemicals that can damage cellular macromolecules and organelles. Whether different chemical stressors activate common and/or stressor-specific pathways and to what extent is largely unclear. Here, we used quantitative phosphoproteomics to compare the phosphorylation signaling cascades induced by four stressors with different modes of action: the DNA damaging agent: cisplatin (CDDP), the topoisomerase II inhibitor: etoposide (ETO), the pro-oxidant: diethyl maleate (DEM) and the immunosuppressant: cyclosporine A (CsA). We show that equitoxic doses of these stressors induce distinctive and complex phosphorylation signaling cascades. Our results reveal stressor-specific kinase motifs and pathways. CDDP activates the DNA damage response (DDR) predominantly through the replication-stress related Atr kinase, whereas ETO triggers the DDR through Atr as well as the DNA double stranded break associated Atm kinase. CsA shares with ETO, a strong activation of CK2 kinase and significant Atm phosphorylation but lacks prominent activation of the DDR. Congruent with their known modes of action, CsA-mediated signaling is related to down-regulation of pathways that control hematopoietic differentiation and immunity whereas oxidative stress is the most prominent initiator of DEM-modulated stress signaling. This study presents an unprecedented molecular insight into the activated phosphorylation signaling cascades after various types of stressors.
2020-03-23 | PXD012559 | Pride
Project description:High-throughput screening and gene signature analyses frequently identify lead therapeutic compounds with unknown modes of action (MoAs), and the resulting uncertainties can lead to the failure of clinical trials. We developed a multi-omics approach for uncovering MoAs through an interpretable machine learning model of the effects of compounds on transcriptomic, epigenomic, metabolomic, and proteomic data. We applied this approach to examine compounds with beneficial effects in models of Huntington’s disease, finding common MoAs for previously unrelated compounds that were not predicted based on similarities in the compounds’ structures, connectivity scores, or binding targets. We experimentally validated two such disease-relevant MoAs, autophagy activation and bioenergetics manipulation. This interpretable machine learning approach can be used to find and evaluate MoAs in future drug development efforts.
2020-01-22 | GSE129143 | GEO