Comparative study of the mechanism of natural compounds with similar structures using docking and transcriptome data
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228524 | GEO | 2023/04/03
REPOSITORIES: GEO
Similar Datasets
Project description:Comparative study of the mechanism of natural compounds with similar structures using docking and transcriptome data
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Project description:Natural products have successfully treated several diseases using a multi-component, multi-target mechanism. However, a precise mechanism of action (MOA) has not been identified. Systems pharmacology methods have been used to overcome these challenges. However, there is a limitation as those similar mechanisms of similar components cannot be identified. In this study, comparisons of physicochemical descriptors, molecular docking analysis and RNA-seq analysis were performed to compare the MOA of similar compounds and to confirm the changes observed when similar compounds were mixed and used. Various analyses have confirmed that compounds with similar structures share similar MOA. We propose an advanced method for in silico experiments in herbal medicine research based on the results. Our study has three novel findings. First, an advanced network pharmacology research method was suggested by partially presenting a solution to the difficulty in identifying multi-component mechanisms. Second, a new natural product analysis method was proposed using large-scale molecular docking analysis. Finally, various biological data and analysis methods were used, such as in silico system pharmacology, docking analysis and drug response RNA-seq. The results of this study are meaningful in that they suggest an analysis strategy that can improve existing systems pharmacology research analysis methods by showing that natural product-derived compounds with the same scaffold have the same mechanism.
| S-EPMC10555731 | biostudies-literature
Project description:We are presenting here the application of toxicogenomics in the evaluation of the toxic effects of three dioxin-like compounds, two Polycyclic aromatic hydrocarbons (PAHs), Benzo(a)pyrene, Benzo(k) fluoranthene and b-naphthoflavone on the developing zebrafish embryo. The main goal is to distinguish the pattern of action of the chemical compounds and their needs varying the times of exposure. The results suggest a variety of MoA for different dioxin-like compounds, probably related to the nature and number of benzene rings. About 5% genes were affected by the treatment. Gene ontology (GO) analyses show that these genes are involved in the oxidation-reduction process. Representatives of each GO functional groups were selected and quantified by real-time PCR to validate the microarray data and to differentiate the action of dioxin-like compounds studied.
2015-12-31 | GSE41334 | GEO
Project description:Exploring the therapeutic effects of bioactive compounds has been traditionally approaching by phenotypic screenings followed by functional validation by in vitro assays. The thermal proteome profiling (TPP) has been successfully applied to study drug targets and off-target. We applied a modified protocol based on TPP to elucidate the mechanism of actions (MOA)s of novel bioactives compounds from marine biodiscovery. We have modified the method to gain the specificity for its application to compounds with limited chemical or structural characterization. Method implementation includes increasing the centrifugation force to precipitate the microsomal fraction previous to the thermal shift assay. The range of temperatures has been reduced to optimize the analysis without compromising resolution. Finally, the mass spectrometry analysis was based on label-free quantitative proteomics. Comparison of the targets among methodologies confirmed that the precipitation of the microsomal membranes before TPP is an essential step to discriminate between true targets from proteins precipitates after subcellular fractionation by centrifugation force. As a probe of concept, a novel marine bioactive compound has been analyzed on the hepatic cell line HepG2. We found that 2 targets proteins, aldehyde dehydrogenase and isocitrate dehydoregenase, can be related with beneficial properties towards obesity and obesity-related comorbidities. Identification of targets is key to decipher the MOAs of bioactive compound, predict the mode of action as well as possible harmful effects.
2019-06-28 | PXD013227 | Pride
Project description:The inhibition of ?-glucosidase and ?-amylase is a clinical strategy for the treatment of type II diabetes, and herbal medicines have been reported to credibly alleviate hyperglycemia. Our previous study has reported some constituents from plant or herbal sources targeted to ?-glucosidase and ?-amylase via molecular docking and enzymatic measurement, but the hypoglycemic potencies in cell system and mice have not been validated yet. This study was aimed to elucidate the hypoglycemic efficacy of docking selected compounds in cell assay and oral glucose and starch tolerance tests of mice. All test compounds showed the inhibition of ?-glucosidase activity in Caco-2 cells. The decrease of blood sugar levels of test compounds in 30 min and 60 min of mice after OGTT and OSTT, respectively and the decreased glucose levels of test compounds were significantly varied in acarbose. Taken altogether, in vitro and in vivo experiments suggest that selected natural compounds (curcumin, antroquinonol, HCD, docosanol, tetracosanol, rutin, and actinodaphnine) via molecular docking were confirmed as potential candidates of ?-glucosidase and ?-amylase inhibitors for treating diabetes.
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Project description:The conventional battery for genotoxicity testing is not well suited to assessing the large number of chemicals needing evaluation. Traditional in vitro tests lack throughput, provide little mechanistic information, and have poor specificity in predicting in vivo genotoxicity. New Approach Methodologies (NAMs) aim to accelerate the pace of hazard assessment and reduce reliance on in vivo tests that are time-consuming and resource-intensive. As such, high-throughput transcriptomic and flow cytometry-based assays have been developed for modernized in vitro genotoxicity assessment. This includes: the TGx-DDI transcriptomic biomarker (i.e., 64-gene expression signature to identify DNA damage-inducing (DDI) substances), the MicroFlow® assay (i.e., a flow cytometry-based micronucleus (MN) test), and the MultiFlow® assay (i.e., a multiplexed flow cytometry-based reporter assay that yields mode-of-action (MoA) information). The objective of this study was to investigate the utility of the TGx-DDI transcriptomic biomarker, multiplexed with the MicroFlow® and MultiFlow® assays, as an integrated NAM-based testing strategy for screening data-poor compounds prioritized by Health Canada’s New Substances Assessment and Control Bureau. Human lymphoblastoid TK6 cells were exposed to 3 control and 10 data-poor substances, using a 6-point concentration range. Gene expression profiling was conducted using the targeted TempO-SeqTM assay, and the TGx-DDI classifier was applied to the dataset. Classifications were compared with those based on the MicroFlow® and MultiFlow® assays. Benchmark Concentration (BMC) modeling was used for potency ranking. The results of the integrated hazard calls indicate that five of the data-poor compounds were genotoxic in vitro, causing DNA damage via a clastogenic MoA, and one via a pan-genotoxic MoA. Two compounds were likely irrelevant positives in the MN test; two are considered possibly genotoxic causing DNA damage via an ambiguous MoA. BMC modeling revealed nearly identical potency rankings for each assay. This ranking was maintained when all endpoint BMCs were converted into a single score using the Toxicological Prioritization (ToxPi) approach. Overall, this study contributes to the establishment of a modernized approach for effective genotoxicity assessment and chemical prioritization for further regulatory scrutiny. We conclude that the integration of TGx-DDI, MicroFlow®, and MultiFlow® endpoints is an effective NAM-based strategy for genotoxicity assessment of data-poor compounds.
2022-11-15 | GSE213454 | GEO
Project description:Active natural compounds perturb the melanoma risk-gene network
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Project description:Natural compounds ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have been at clinical trials for treatment of different cancers including prostate cancer, pancreatic cancer and breast cancer. However, they displayed limited benefit to patients. Currently, a poor understanding of their direct targets and mechanisms of action (MOA) severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target for castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) and demonstrated that tumor cell RORγ directly activates gene programs such as androgen receptor (AR) signaling and cholesterol metabolism. Previous studies also demonstrated that UA and digoxin are potential RORγt antagonists in modulating the functions of immune cells such as Th17 cells. Here we showed that UA displays a strong activity in inhibition of RORγ-dependent transactivation function in cancer cells, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA down-regulates RORγ-stimulated AR expression and AR signaling, whereas digoxin up-regulates AR signaling pathway. In TNBC cells, UA but not digoxin alters RORγ-controlled gene programs of cell proliferation, apoptosis and cholesterol-biosynthesis.Together, our study reveals for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in the cancer cells. Our finding that RORγ is a direct target of UA in cancer cells will help select patients with tumors that likely respond to UA treatment.
2023-05-17 | GSE230039 | GEO
Project description:Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. The study aimed at providing an in-silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association studies (GWAS) signals (collectively melanoma risk genes). A protein-protein interaction network (melanoma risk network) was constructed using the melanoma risk genes to describe the functional landscape in which the melanoma genes operate within the cellular milieu. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride reinforcing the hypothesis that network modelling may represent an alternative screening approach to prioritize potentially active compounds.
2023-11-01 | GSE246383 | GEO
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