High-Throughput Screen Identifies Non-Inflammatory Small Molecule Inducers of Trained Immunity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1127561 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29533111_1.fastq.gz | Fastqsanger.gz | |||
| SRR29533111_2.fastq.gz | Fastqsanger.gz | |||
| SRR29533112_1.fastq.gz | Fastqsanger.gz | |||
| SRR29533112_2.fastq.gz | Fastqsanger.gz | |||
| SRR29533113_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 112 |
Similar Datasets
Project description:Trained immunity is a form of innate immune memory characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenge, providing non-specific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite the promise of training for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the BCG vaccine. This limited collection of training compounds also limits study of the genes most involved in training responses as each molecule has both training and non-training effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future application for therapeutics. To identify novel small molecule inducers of trained immunity, we screened a library of 2000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over 2 dozen small molecules in several chemical classes, including the traditionally immunosuppressive glucocorticoids, that induce a training phenotype in the absence of initial immune activation – a current limitation of reported inducers of training. We chose 7 of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating new avenues for the study and application of innate immune training.
2024-07-08 | GSE270608 | GEO
Project description:Identification of Cytoprotective Small Molecule Inducers of Heme Oxygenase-1
| PRJNA869065 | ENA
Project description:MicroRNAs (miRNAs) are short RNAs that regulate fundamental biological processes. miR-132, a key miRNA with established functions in Tau homeostasis and neuroprotection, is consistently downregulated in Alzheimer’s disease (AD) and other tauopathies. miR-132 overexpression rescues neurodegenerative phenotypes in several AD models. To complement research on miRNA-mimicking oligonucleotides targeting the central nervous system, we developed a high-throughput-screen coupled high-throughput-sequencing (HTS-HTS) in human induced pluripotent stem cell (iPSC)-derived neurons to identify small molecule inducers of miR-132. We discovered that cardiac glycosides, which are canonical sodium-potassium ATPase inhibitors, selectively upregulated miR-132 in the sub-μM range. Coordinately, cardiac glycoside treatment downregulated total and phosphorylated Tau in rodent and human neurons and protected against toxicity by glutamate, N-methyl-D-aspartate, rotenone, and Aβ oligomers. In conclusion, we identified small-molecule drugs that upregulated the neuroprotective miR-132 and ameliorated neurodegenerative phenotypes. Our dataset also represents a comprehensive resource for discovering small molecules that modulate specific miRNAs for therapeutic purposes.
2023-10-19 | GSE216991 | GEO
Project description:Acute kidney injury (AKI) is a major public health concern with significant attributable morbidity and mortality with no current FDA approved treatments other than supportive care through dialysis. Several pre-clinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase 1/2 level. We have identified small molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and as-yet-undefined effects of the enzyme system. Through cell-based, high throughput screens for induction of HO-1 through the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine, an FDA approved antiprotozoal, for further consideration as candidate compounds exhibiting Emax ≥ 70% of 5 µM hemin and EC50<10 µM. RNA sequencing identified shared binding motifs to NRF-2, a transcription factor known to regulate antioxidant genes, including HO-1. siRNA knockdown of NRF-2 confirmed the role of NRF-2 in induction of HO-1. In vitro, cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of candidate compounds induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI.
2022-10-07 | GSE211130 | GEO
Project description:Hydroxychloroquine inhibits trained immunity
| PRJNA670179 | ENA
Project description:scRNAseq of monocytes from in vitro Trained immunity experiments stimulated by β-glucan (BG), uric acid (UA), muramyl dipeptide (MDP), oxidized low-density lipoprotein (oxLDL), or RPMI-Control, and respective samples restimulated with Lipopolysaccharide (LPS).
2021-09-30 | E-MTAB-9702 | biostudies-arrayexpress
Project description:We demonstrate that hydroxychloroquine inhibits trained immunity at the functional and epigenetic level and is accompanied by reduced expression of interferon-stimulated genes. Trained immunity comprises a functional adaptation induced by epigenetic reprogramming which facilitates the anti-viral innate immune response.
2020-10-21 | GSE159678 | GEO
Project description:Zebrafish chemical compound screen uncovers inducers of skeletal muscle engraftment across species
| PRJNA601746 | ENA
Project description:An essential function of the human epidermis is the maintenance of a protective barrier against the environment. As a consequence, keratinocytes, which make up this layer of the skin, undergo an elaborate process of self-renewal, terminal differentiation and cell death. Misregulation of these processes can lead to several human diseases including psoriasis and basal cell and squamous cell carcinomas. To identify novel regulators of keratinocyte differentiation, a cell-based screen of small molecule libraries was carried out for molecules that induce terminal differentiation of normal human epidermal keratinocytes (NHEKs). One class of molecules was identified, the 2-(3,4,5-trimethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidines, which were shown to induce differentiation of epidermal progenitor cells to terminally differentiated keratinocytes. These molecules serve as useful mechanistic probes of the cellular differentiation programs that regulate the formation and homeostasis of the epidermis, and may lead to novel therapeutic approaches for the treatment of skin hyperproliferative disorders. Experiment Overall Design: samples were taken from duplicate treatments of cells with DMSO or PP-2 (compound 9) at various time points
2009-04-10 | E-GEOD-6932 | biostudies-arrayexpress
Project description:Venous thromboembolism is common in individuals with chronic inflammatory diseases, but the pathogenic basis for this increased thrombotic risk remains poorly understood. Myeloid cell ‘trained immunity’ describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a novel maladaptive consequence of trained immunity. LPS stimulation of murine bone marrow-derived macrophages trained previously with either β-glucan or free haem exhibited significantly enhanced procoagulant and antifibrinolytic gene expression and activity compared to macrophages stimulated with LPS alone. The β-glucan training-mediated increase in activated myeloid cell procoagulant activity was mediated by enhanced acid sphingomyelinase-mediated tissue factor (TF) functional decryption. Furthermore, pre-treatment with methyltransferase and acetyltransferase inhibitors to erase epigenetic marks associated with innate immune memory diminished trained macrophage TF gene expression in β-glucan-trained macrophages. Functional analysis of splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Remarkably, monocyte procoagulant activity increased proportionately with time since β-glucan administration, before plateauing at 4 weeks. Furthermore, haematopoietic progenitor cells and bone marrow interstitial fluid isolated from β-glucan-trained mice possessed enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent novel therapeutic vulnerabilities in immunothrombotic disease development, opening new avenues for targeted intervention.
2025-03-07 | GSE273173 | GEO