Preclinical Evidence for the Glucocorticoid-Sparing Potential of a Dual Toll-Like Receptor 7/8 Inhibitor in Autoimmune Diseases
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA988047 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25039251_1.fastq.gz | Fastqsanger.gz | |||
| SRR25039251_2.fastq.gz | Fastqsanger.gz | |||
| SRR25039252_1.fastq.gz | Fastqsanger.gz | |||
| SRR25039252_2.fastq.gz | Fastqsanger.gz | |||
| SRR25039253_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 48 |
Similar Datasets
Project description:Single cell RNA-seq analysis of PBMCs testing for a synergistic effect of TLR7/8 inhibition and the glucocorticoid dexamethasone
2023-09-01 | GSE235927 | GEO
Project description:Autoimmune disease is a systemic inflammatory response of immune blood cells caused by self-tolerance dysfunction, due to genetic or environmental factors or a combination thereof. Studies on autoimmune disease regarding the inhibition of toll-like receptor (TLR)7/9-MyD axis or the regulation of plasmacytoid dendritic cells (pDCs) and Th17 comprising an abundance of respective receptors have shown improvements in phenotypes or molecular markers, providing clues to the practicality of the inhibitors of endosomal TLRs. This study discovered several small-molecule compounds in endosomes exerting specific inhibitory effects on SITE1 shared among TLR 3, 7, 8, and 9, named endosomal TLR inhibitors (ETIs). The drug discovery process involved identifying lead compounds optimized to the receptors using a quantitative structure-activity relationship model and subsequent modification of the compounds to improve their binding affinity to target proteins. To propose a method of verifying the drug effects against side or placebo effect arising from false positives, the drug evaluation process converged from cellular response to signaling process to protein binding. Drug values on the inhibition of endosomal TLRs in autoimmune disease were assessed based on the onset of mild-to-life-threatening autoimmune disease including psoriasis, systemic lupus erythematosus, and multiple sclerosis. Complete healing was achieved for psoriasis through direct or indirect association with TLRs. Therapeutic potential of the novel ETIs for psoriasis was verified and is considered an effective drug for other autoimmune diseases associated with the TLR7/9-MyD axis.
2024-02-29 | GSE255890 | GEO
Project description:An endosomal toll-like receptor inhibitor drug with therapeutic effects in autoimmune diseases
| PRJNA1076919 | ENA
Project description:TNIP1 protein is increasingly being recognized as a key repressor of inflammatory signaling and a potential factor in multiple autoimmune diseases. In addition to earlier foundational reports of TNIP1 SNPs in human autoimmune diseases and TNIP1 protein-protein interaction with receptor regulating proteins, more recent studies have identified new potential interaction partners and signaling pathways likely modulated by TNIP1. Subdomains within the TNIP1 protein as well as how they interact with ubiquitin have not only been mapped but inflammatory cell- and tissue-specific consequences subsequent to their defective function are being recognized and related to human disease states such as lupus, scleroderma, and psoriasis. In this review, we emphasize receptor signaling complexes and regulation of cytoplasmic signaling steps downstream of TLR given their association with some of the same autoimmune diseases where TNIP1 has been implicated. TNIP1 dysfunction or deficiency may predispose healthy cells to the inflammatory response to otherwise innocuous TLR ligand exposure. The recognition of the anti-inflammatory roles of TNIP1 and improved integrated understanding of its physical and functional association with other signaling pathway proteins may position TNIP1 as a candidate target for the design and/or testing of next-generation anti-inflammatory therapeutics.
| S-EPMC6192141 | biostudies-other
Project description:HMGB1, a nucleoprotein, is expressed in almost all eukaryotic cells. During cell activation and cell death, HMGB1 can function as an alarm protein (alarmin) or damage-associated molecular pattern (DAMP) and mediate early inflammatory and immune response when it is translocated to the extracellular space. The binding of extracellular HMGB1 to Toll-like receptors (TLRs), such as TLR2 and TLR4 transforms HMGB1 into a pro-inflammatory cytokine, contributing to the occurrence and development of autoimmune diseases. TLRs, which are members of a family of pattern recognition receptors, can bind to endogenous DAMPs and activate the innate immune response. Additionally, TLRs are key signaling molecules mediating the immune response and play a critical role in the host defense against pathogens and the maintenance of immune balance. HMGB1 and TLRs are reported to be upregulated in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune thyroid disease. The expression levels of HMGB1 and some TLRs are upregulated in tissues of patients with autoimmune diseases and animal models of autoimmune diseases. The suppression of HMGB1 and TLRs inhibits the progression of inflammation in animal models. Thus, HMGB1 and TLRs are indispensable biomarkers and important therapeutic targets for autoimmune diseases. This review provides comprehensive strategies for treating or preventing autoimmune diseases discovered in recent years.
| S-EPMC10478470 | biostudies-literature
Project description:Activating mutations in ERBB receptors act as oncogenes in non-small cell lung cancer (NSCLC). Besides the more prevalent epidermal growth factor receptor (EGFR) activating mutations, oncogenic variants in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of NSCLC patients. HER2 oncogenic mutations in NSCLC predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinically approved and currently tested tyrosine kinase inhibitors are limited by either insufficient potency on exon 20 altered HER2 and/or their insufficient selectivity against EGFR wild type (EGFR WT) – a major cause of dose limiting toxicity. We report herein the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing EGFR WT. The new inhibitors presented in this study reduce tumor cell survival and proliferation in vitro, and result in regressions in in vivo preclinical xenograft models of HER2 exon 20 mutant NSCLC as well as inhibition of downstream signaling. Our results suggest that HER2 exon 20 insertion driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing EGFR WT. The new inhibitors described in this study pave the way for testing potent HER2 selective inhibitors in HER2 mutant NSCLC patients and may offer an additional therapeutic option for these patients.
2022-03-19 | GSE181673 | GEO
Project description:Current diagnostic methods for prion diseases in vivo only work in late stages of the disease when neurodegeneration is very advanced and irreversible. Therefore, the search for biomarkers that can detect the disease before the onset of clinical symptoms is necessary. For this purpose, high-throughput techniques are of great interest. Here we have used mass spectrometry for the study of the cerebrospinal fluid proteome in 30 animals: sheep affected with natural scrapie, both in preclinical and clinical stages, and healthy sheep as a control group. Interestingly, using DDA and SWATH proteomic assays, we found 46 proteins in the preclinical stage of the disease that were significantly altered (p<0.01) compared to healthy sheep, mainly associated with biological processes such as stress response and inflammatory response. Five of them were selected for validation by ELISA, having been found to be altered also in other human neurodegenerative diseases: synaptotagmin binding, cytoplasmic RNA interacting protein (SYNCRIP), involved in nucleic acid metabolism; phospholipase D3 (PLD3) and cathepsin D (CTSD), both related to lysosomal apoptosis; C4 complement, an element of the classical immune response; and osteopontin (SPP1), a proinflammatory cytokine. These proteins were found to be significantly increased in the preclinical stage of disease. All proteins maintained their levels in the clinical phase, except for CTSD, which concentration returned to basal levels in the clinical group. Further research is ongoing to explore their future potential as preclinical biomarkers of prion diseases.
2025-04-23 | PXD050656 | Pride
Project description:The aim of this study is to investigate the interaction between diet - primary meat and fiber - and polymorphisms in Toll-like receptors in relation to risk of colorectal cancer in a Danish prospective cohort.
| 2251863 | ecrin-mdr-crc
Project description:Tissue morphogenesis requires the spatial control over actomyosin contractility to drive cell shape changes. How developmental patterning information controls cell mechanics is poorly understood. In the Drosophila embryo ectoderm, Myosin-II is enriched at the interface between antero-posterior neighboring cells, leading to planar polarized cell intercalation. G protein-coupled receptors (GPCRs) are required for planar polarized Myosin-II activation at junctions and Toll receptors provide a positional code underlying this process. How Toll receptors polarize actomyosin contractility remains unknown. Here we report that cells expressing different levels of a single Toll receptor Toll-8 activate Myosin-II at their interface. Surprisingly, the Toll-8 intracellular domain is not required for signaling at cell interfaces suggesting signaling by proxy. We found that Toll-8 forms a molecular complex with the adhesion GPCR Cirl/Latrophilin that is required for Toll-8 dependent junctional Myosin-II activation. Strikingly, the interfaces between Cirl expressing and cirl mutant cells also activate Myosin-II suggesting that Toll-8 induces Cirl asymmetric signaling at cell interfaces. We further showed that Toll-8 recruits Cirl both in trans and in cis, inducing asymmetric Cirl localization at the boundary of the Toll-8 expression domain. Finally, we found that Toll-8 and Cirl exhibit dynamic interdependent planar polarization when neighboring cells express different levels of Toll-8. Through this feedback, Toll-8 and Cirl self-organize planar polarized signaling.
2021-04-22 | PXD017895 | Pride
Project description:Nanomaterials offer new opportunities to engineer immunomodulatory activity. In this work, we report the endosomal toll-like receptor agonist activity of a nanoscale adjuvant zeolitic imidazolate frameworks-8 (ZIF-8). The accumulation of ZIF-8 in endosomes and the pH-responsive release of its subunits enable selective engagement with endosomal TLRs, minimizing the risk of off-target activation. The intrinsic adjuvant properties of ZIF-8, along with the efficient delivery and biomimetic presentation of a SARS-CoV-2 spike protein receptor binding domain trimer, primed rapid humoral and cell mediated immunity in a dose sparing manner. Our study offers new insights for next-generation adjuvants that can potentially impact future vaccine development.
2024-03-13 | GSE246178 | GEO