Study of Retinoic Acid-Induced Osteoarthritis: Integrating RNA-sequencing, Network Pharmacology, Molecular Docking, and Experimental Validation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1269950 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33761988_1.fastq.gz | Fastqsanger.gz | |||
| SRR33761988_2.fastq.gz | Fastqsanger.gz | |||
| SRR33761989_1.fastq.gz | Fastqsanger.gz | |||
| SRR33761989_2.fastq.gz | Fastqsanger.gz | |||
| SRR33761990_1.fastq.gz | Fastqsanger.gz |
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Project description:Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and chondrocyte homeostasis disruption. Although retinoic acid (RA) has been applied in the model preparation of OA, its target of action and signaling pathway are not clear. Leveraging a translational framework that integrates RNA-sequencing transcriptomics, network pharmacology prediction, computational ligand-receptor molecular docking, and biological experimental validation, this study systematically deciphers RA's disease-modifying targets and associated signaling circuitry in OA pathogenesis. RNA-sequencing of RA-treated chondrocytes revealed 656 differentially expressed genes (DEGs). Protein-protein interaction (PPI) network analysis and functional enrichment (GO/KEGG) highlighted key pathways, including extracellular matrix reorganization and PI3K-Akt-mediated mechanotransduction and others. Additionally, molecular docking results ranked binding affinities in descending order as follows: ACAN > SFRP2 > KANSL2 (NSL2), and so on. Network pharmacology identified 42 RA-OA shared targets, with protein-protein interaction (PPI) analysis and functionally enriched (GO/KEGG) including the Renin-angiotensin system, Neuroactive ligand-receptor interaction, and others. The molecular docking results showed a total score in descending order of MAPK14(p38α), PTGER3(PGE2-R), CA2(CACNA2D2), and so on. Five intersecting targets (CA2, ACE, PTGS1(COX-1), PGR, and EDNRA(ETAR) ) from RNA-sequencing and network pharmacology were obtained, and molecular docking was used to dock the intersecting targets to RA. The docking results demonstrated strong binding affinities, which were further validated through western blot and RT-qPCR experiments, confirming the RA-induced upregulation of the intersecting targets. These findings were accompanied by immunofluorescent evidence showing elevated levels of MMP13 and suppressed expression of COL2A1, collectively reflecting the phenotypic characteristics of OA. Our findings position CA2 and ACE as key hubs for multi-targeting. This study not only reveals possible mechanistic studies of RA in OA but also provides a drug reference for the development of drugs against OA.
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Project description:Risperidone is an atypical antipsychotic that can cause substantial weight gain. The pharmacological targets and molecular mechanisms related to risperidone-induced lipogenesis (RIL) remain to be elucidated. Therefore, network pharmacology and further experimental validation were undertaken to explore the action mechanisms of RIL. In this study, RIL was systematically analyzed using integrating multiple databases through integrated network pharmacology, transcriptomics, molecular docking, and molecular experiment analysis. The potential signaling pathways for RIL were identified and experimentally validated using Gene Ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Our experimental data showed that Risperidone promotes adipocyte differentiate and lipid accumulation. And network pharmacology and GO analyses showed that risperidone induced adipocyte metabolism, differentiation, and lipid accumulation related functions. Intersecting analysis, molecular docking, and pathway validation analysis indicated that risperidone activated adipocytokine signaling pathway related genes by targeting MAPK14 (Mitogen-activated protein kinase 14), MAPK8 (Mitogen-activated protein kinase 8), and RXRA (Retinoic acid receptor RXR-alpha), thereby inhibiting long-chain fatty acid beta-oxidation by suppressing STAT3 (Signal transducer and activator of transcription 3) expression and phosphorylation. This study suggested that Risperidone increases adipocyte lipid accumulation by plausible inhibiting long-chain fatty acid beta-oxidation through targeting MAPK14, MAPK8, and RXRA.
2022-05-11 | GSE198053 | GEO
Project description:Condyloma acuminatum is a sexually transmitted disease characterized by the anomalous proliferation of keratinocytes caused by human papillomavirus (HPV) infection. Fu Fang Gang Liu liquid (FFGL) is an effective external prescription to treat condyloma acuminatum, but its potential molecular mechanism is still unclear. This study aimed to identify the major active ingredients and prospective targets of FFGL by using network pharmacology, molecular docking, and transcriptomics, and validating it experimentally. Network pharmacology analysis found that FFGL contains a total of 78 active compounds, from which 610 compound-related targets were screened. Among them, 59 compound-related targets overlapped with CA targets and were considered as targets with potential therapeutic effects. Protein-protein network analysis showed that AKT serine/threonine kinase 1 was the potential therapeutic target. To further confirm this result we performed RNA-seq assays on HPV18+ cells after FFGL intervention, and conducted enrichment analyses on the screened differentially expressed genes. Enrichment analyses results indicated that the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway may be a key pathway for FFGL to function. Further in vitro experiments revealed that FFGL significantly inhibited the activity of HPV18+ cells and reduced PI3K and Akt protein levels. Rescue experiment indicated that the reduction in cell viability caused by FFGL was partially restored after the use of activators of the PI3K/Akt pathway. We further explored the active components of FFCL for the treatment of condyloma acuminatum and screened two active compounds, periplogenin and periplocymarin. Molecular docking showed that these two compounds have good binding activity to AKT1.
2023-04-26 | GSE223380 | GEO
Project description:To investigate the mode of action of ccc_R08, a first-in-class orally available HBV cccDNA inhibitor, we designed and implemented two orthogonal and complementary approaches: a forward pharmacology approach and a reverse pharmacology approach. Bioinformatics analysis integrating biological knowledge with the observations from both approaches offered us preliminary insights into the mode of action of ccc_R08.
2022-12-30 | GSE214515 | GEO
Project description:Fibroblast growth factors and their receptors (FGFRs) play important roles in multiple cellular processes. FGFR genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in various cancer types, contributing to the initiation and progression of tumors by enhancing FGFR signaling. Identifying effective small molecule inhibitors that selectively target FGFR can advance cancers therapy driven by FGFR abnormalities. Here, we conducted molecular docking and dynamics simulations to discover new small compounds targeting FGFRs. By docking with 2.8 million small molecules, we identified three promising FGFR inhibitors ranked in the top average absolute difference in free energy. By evaluating the binding stability of the docking pose of these three compounds, we found that ZINC000101867325 formed the most stable binding interactions with FGFRs. After treatment with ZINC000101867325, colorectal cancer cell lines showed a decrease in FGFR phosphorylation and early apoptosis. In addition, ZINC000101867325 is also predicted to interact with FGFR2 mutations in colorectal cancer (CRC) patients. This study provides the novel FGFR inhibitors, and enriches treatment strategies for cancers.
2024-06-30 | GSE267868 | GEO
Project description:Integrating network pharmacology, transcriptomics to reveal neuroprotective of curcumin activate PI3K / AKT pathway in Parkinson’s disease
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Project description:Background: Parkinson’s disease (PD), a severe threat in aging society, is a significant cause of disable. Curcumin, a polyphenol with hydrophobic properties, has been proved to against Parkinson. Our previous study provides an initial understanding of the neuroprotective mechanisms of curcumin in treating Parkinson’s disease. However, further exploration in this area is needed. The present study was designed to investigate the potential mechanism of curcumin for treating PD. Methods: The therapeutic efficacy of curcumin was evaluated using behavioral tests, immunofluorescence of tyrosine hydroxylase (TH). Network pharmacology and transcriptomics predicted the active pathway and bioprocess of curcumin in PD. Activation of the PI3K / AKT signaling pathway was confirmed by quantitative real-time PCR and immunofluorescence. Result: Curcumin restored the dyskinesia and dopaminergic neurons damage of MPTP-induced mice. The results of network pharmacology and transcriptomics showed that curcumin against Parkinson's disease by regulating inflammation, oxidative stress, and aging. The mechanisms of these were associated with activation of PI3K / AKT pathway. Conclusion: In conclusion, the mechanism of curcumin against PD was revealed by our study which lays a foundation for the application of curcumin in treating.
2023-10-19 | GSE243886 | GEO
Project description:BACKGROUND Lung adenocarcinoma (LUAD) is the most common type of lung cancer, which poses a serious threat to human life and health. -(-)Guaiol, an effective ingredient of many medicinal herbs, has been shown to have a high potential for tumor interference and suppression. However, knowledge of pharmacological mechanisms is still lacking adequate identification or interpretation. MATERIAL AND METHODS The genes of LUAD patients collected from TCGA were analyzed using limma and WGCNA. In addition, targets of (-)-Guaiol treating LUAD were selected through a prediction network. Venn analysis was then used to visualize the overlapping genes, which were further condensed using the PPI network. GO and KEGG analyses were performed sequentially, and the essential targets were evaluated and validated using molecular docking. In addition, cell-based verification, including the CCK-8 assay, cell death assessment, apoptosis analysis, and western blot, was performed to determine the mechanism of action of (-)-Guaiol. RESULTS The genes included 959 differentially-expressed genes, 6075 highly-correlated genes, and 480 drug-target genes. Through multivariate analysis, 23 hub genes were identified and functional enrichment analyses revealed that the PI3K/Akt signaling pathway was the most significant. Experiment results showed that -(-)Guaiol can inhibit LUAD cell growth and induce apoptosis. Additional evidence suggested that the PI3K/Akt signaling pathway established an inseparable role in the antitumor processes of -(-)Guaiol, which is consistent with network pharmacology results. CONCLUSIONS Our results show that the effect of (-)-Guaiol in LUAD treatment involves the PI3K/Akt signaling pathway, providing a useful reference and medicinal value in the treatment of LUAD.
| S-EPMC9336205 | biostudies-literature
Project description:Deciphering risperidone-induced lipogenesis by network pharmacology and molecular validation
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Project description:<p>Cardiovascular adverse effects caused by high-intensity exercise (HIE) have become a public health problem of widespread concern. As a phytochemical with potential therapeutic effects, the therapeutic effect and metabolic regulation mechanism of myricetin have rarely been studied. In this study, we established different doses of myricetin intervention with 1 week of HIE after intervention. Cardiac function tests, serology and pathological examinations were used to evaluate the protective effect of myricetin on the myocardium. The possible therapeutic targets of myricetin were obtained using integrated analysis of metabolomics and network pharmacology and verified using molecular docking and RT-qPCR experiments. Different concentrations of myricetin improved cardiac function, significantly reduced the levels of myocardial injury markers, alleviated myocardial ultrastructural damage, reduced the area of ischemia/hypoxia, and increased the content of CX43. Through combined analysis with metabolomics and network pharmacology and then verification with molecular docking and RT-qPCR, we found that PTGS2, MAOB, EGFR, MAP2K1 were the key targets for injury protection. Arachidonic acid metabolism, glycine-serine-threonine acid metabolism and FoxO metabolism may be the key metabolic pathways affected by myricetin intervention. In summary, our findings suggest that myricetin exert cardiac protective effects of HIE by regulating myocardial metabolic network.</p>
2023-03-06 | MTBLS5608 | MetaboLights