Plasma exosomes transfer miR-885-3p targeting AKT/NFκB signaling pathway to improve the sensitivity of intravenous glucocorticoid therapy against Graves ophthalmopathy
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PROVIDER: PRJNA787441 | ENA |
REPOSITORIES: ENA
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Project description:Graves ophthalmopathy (GO), a manifestation of Graves' disease, is an organ-specific autoimmune disease. Intravenous glucocorticoid therapy (ivGCs) is the first-line treatment for moderate-to-severe and active GO. However, ivGCs is only effective in 70-80% of GO patients. Insensitive patients who choose 12 weeks ivGCs were not only delayed in treatment, but also took the risk of adverse reactions of glucocorticoids. At present, there is still a lack of effective indicators to predict the therapeutic effect of ivGCs. Therefore, the purpose of this study is to find biomarkers that can determine the sensitivity of ivGCs before the formulation of treatment, and to clarify the mechanism of its regulation of ivGCs sensitivity. This study first characterized the miRNA profiles of plasma exosomes by miRNA sequencing to identify miRNAs differentially expressed between GO patients with significant improvement (SI) and non-significant improvement (NSI) after ivGCs treatment. According to the function of the target genes, we screened 10 differentially expressed miRNAs. Results showed that compared with NSI patients, mir-885-3p was up-regulated and mir-4474-3p and mir-615-3p were down regulated in the exosomes of SI patients. Based on statistical difference and miRNA function, mir-885-3p was selected for follow-up study. In vitro functional analysis of exosomes mir-885-3p showed that exosomes from SI patients (SI-exo) could transfer mir-885-3p to orbital fibroblasts (OFs), up-regulate the GRE luciferase reporter gene plasmid activity and the level of glucocorticoid receptor (GR), down-regulate the level of inflammatory factors, and improve the glucocorticoid sensitivity of OFs. In addition, we found that high levels of mir-885-3p could inhibit AKT/NFκB signaling pathway, up‐regulate the GRE plasmid activity and GR level, and down‐regulate the level of inflammatory factors of OFs. Moreover, the improvement of glucocorticoid sensitivity by mir-885-3p transmitted by SI-exo can also be inhibited by AKT/NFκB agonist. Finally, through the in vivo experiment of GO mouse model, we further determined the relationship between exosomes mir‐885‐3p sequence, AKT/NFκB signaling pathway, and glucocorticoid sensitivity. As a conclusion, plasma exosomes deliver mir‐885‐3p and inhibit AKT/NFκB signaling pathway to improve the glucocorticoid sensitivity of OFs. Exosomes mir-885-3p can be used as a biomarker to determine the sensitivity of ivGCs in GO patients.
2022-02-19 | GSE190515 | GEO
Project description:Thyroid-associated ophthalmopathy (TAO) is a complex eye and orbital disorder that is uniquely linked to Graves’ hyperthyroidism (GH). A popular explanation for the development of orbital inflammation in these patients is autoimmunity against the TSH-receptor expressed in orbital preadipocytes. However, this has not been proven and alternative hypotheses should be entertained. We have shown recently that antibodies against highly purified rabbit skeletal muscle calsequestrin are sensitive and specific markers of eye muscle inflammation in patients with thyroid autoimmunity. Keywords: disease state comparison In the study presented here, RNA from thyroid tissue of hyperthyroid patients with (n=10) and without (n=8) symptoms of ophthalmopathy was compared across 20,589 genes.
2007-10-16 | E-GEOD-9340 | biostudies-arrayexpress
Project description:Thyroid-associated ophthalmopathy (TAO) is a complex eye and orbital disorder that is uniquely linked to Graves’ hyperthyroidism (GH). A popular explanation for the development of orbital inflammation in these patients is autoimmunity against the TSH-receptor expressed in orbital preadipocytes. However, this has not been proven and alternative hypotheses should be entertained. We have shown recently that antibodies against highly purified rabbit skeletal muscle calsequestrin are sensitive and specific markers of eye muscle inflammation in patients with thyroid autoimmunity. Keywords: disease state comparison
2007-10-16 | GSE9340 | GEO
Project description:Graves’ ophthalmopathy (GO) is a common orbital disease that threatens visual function and appearance. Orbital fibroblasts (OFs) are considered key target and effector cells in GO. In addition, hyaluronan (HA) production, inflammation, and orbital fibrosis are intimately linked to the pathogenesis of GO. In this study, we explored the therapeutic effects of dihydroartemisinin (DHA), an antimalarial drug, on GO-derived, primary OFs. RNA sequencing was conducted to identify differentially expressed genes (DEGs) in DHA-treated OFs, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs was performed to explore potential mechanisms mediating the antifibrotic effect of DHA on GO-derived OFs. Results showed that DHA dose-dependently inhibited OF proliferation and downregulated, at the mRNA and protein levels, TGF-β1-induced expression of fibrosis markers, including alpha smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF). Furthermore, DHA inhibited TGF-β1 induced phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3), which suggested that DHA exerted antifibrotic effects via suppression of the ERK and STAT3 signaling pathways.In conclusion, our study provides first-time evidence that DHA may significantly alleviate pathogenic manifestations of GO by inhibiting proliferation, fibrosis- and inflammation-related gene expression, and HA production in OFs. These data suggest that DHA may be a promising candidate drug for treatment of GO.
2022-04-05 | GSE199688 | GEO
Project description:Dihydroartemisinin Exerts Antifibrotic and Anti-inflammatory Effects in Graves’ Ophthalmopathy by Targeting Orbital Fibroblasts
| PRJNA821181 | ENA
Project description:As miR-885-5p is a microRNA downregulated in Cutaneous Lupus Erythematosus (CLE) and it is localted in the epidemis and its function is focused in keratinocytes, human Arrays to study the role of miR-885-5p in Cutaneous Lupus Erythematosius will be conducted.Gene expression in keratinocytes transfected with anti-miR-885-5p will be studied. We have included 24 Samples: Non-stimulated control (4), Non-stimulated anti-miR-885-5p (4), UVB-stimulated control (4), UVB-stimulated antimiR-885-5p (4), IFN alpha-stimulated control (4) and IFN alpha-stimulated anti-miR-885-5p
2022-07-19 | GSE193090 | GEO
Project description:Prevotella sp. 885 Genome sequencing and assembly
| PRJNA395537 | ENA
Project description: Not available
| S-EPMC3271309 | biostudies-literature
Project description:Graves’ ophthalmopathy (GO) is an extrathyroidal complication of Graves’ hyperthyroidism. Orbital fibroblast, an important cell in the pathogenesis of GO, is responsible for GO characteristics during active and inactive stages; however, information on the extensive profiles and the mechanistic regulations behind orbital fibroblast phenotypes are currently limited. The aim of this study was to compare the proteome profile of orbital fibroblasts isolated from inactive GO, active GO and healthy control. The proteome profile was further integrated with global DNA methylation data to identify this epigenetics regulation involved in the pathogenesis of GO. Methods Orbital fibroblasts culture isolated from five inactive GO, four active GO and five controls were cultured for total protein and DNA extraction. The labelled and fractionated proteins were analyzed with a liquid chromatography tandem-mass spectrometer (LC-MS/MS). On the other hand, the bisulphite-treated DNA was measured with the Illumina Infinium Human Methylation 450K beadchip. Proteome and methylation data were validated by real-time quantitative (RQ)-PCR. Network, pathway and functional analysis were performed by Ingenuity (Qiagen). Results Orbital fibroblasts from active GO displayed overexpression of proteins typically involved with inflammation, cellular proliferation, hyaluronan synthesis and adipogenesis, while several proteins linked to extracellular matrix (ECM) biology and fibrotic disease were overexpressed in orbital fibroblasts from inactive GO. The DNA methylation patterns were similar in healthy control and inactive GO orbital fibroblasts which were distinct from active GO orbital fibroblasts. In orbital fibroblasts from active GO hypermethylated genes link to inflammation while those genes hypomethylated are involved in adipogenesis and autoimmune-related genes. For the network analysis, overlapped between hypermethylated and hypomethylated genes were observed including NF-B, ERK1/2, Alp, RNA polymerase II, Akt and IFNα. In addition, NF-κB, Akt and IFNα were also identified in networks from the differentially expressed proteins. In general, poor correlation between protein expression, DNA methylation and mRNA expression in our study was observed.
2021-01-27 | PXD022257 | Pride
Project description:Streptomyces avidinii CG 885 genome sequencing
| PRJNA330489 | ENA