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
Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, necessitating innovative therapeutic approaches. This study demonstrates that the compound CC-885 exerts potent anti-tumor effects in HCC both in vitro and in vivo. CC-885 significantly inhibited proliferation, migration, and invasion of HCC cells. In vivo, CC-885 markedly reduced tumor growth and angiogenesis in chick embryo and mouse xenograft models. Mechanistically, CC-885 selectively reduced GOLM1 protein levels via ubiquitin-mediated proteasomal degradation, without affecting its mRNA levels. GOLM1 knockdown mimicked the anti-proliferative effects of CC-885, while overexpression of GOLM1 conferred resistance to CC-885-induced apoptosis and growth inhibition. CC-885 facilitated the interaction between GOLM1 and the E3 ubiquitin ligase CRBN, promoting GOLM1 ubiquitination and degradation. Transcriptomic analyses revealed that CC-885 and GOLM1 knockdown modulated key pathways involved in apoptosis, NF-κB signaling, and cell proliferation. These findings highlight CC-885 as a promising therapeutic agent for HCC, primarily by facilitating the CRBN-dependent degradation of GOLM1, underscoring its potential for clinical application.
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.
Project description:Dnmt1 epigenetically propagates symmetrical CG methylation in many eukaryotes. Their genomes are typically depleted of CG dinucleotides because of imperfect repair of deaminated methylcytosines. Here, we extensively survey diverse species lacking Dnmt1 and show that, surprisingly, symmetrical CG methylation is nonetheless frequently present and catalyzed by a different DNA methyltransferase family, Dnmt5. Numerous Dnmt5-containing organisms that diverged more than a billion years ago exhibit clustered methylation, specifically in nucleosome linkers. Clustered methylation occurs at unprecedented densities and directly disfavors nucleosomes, contributing to nucleosome positioning between clusters. Dense methylation is enabled by a regime of genomic sequence evolution that enriches CG dinucleotides and drives the highest CG frequencies known. Species with linker methylation have small, transcriptionally active nuclei that approach the physical limits of chromatin compaction. These features constitute a previously unappreciated genome architecture, in which dense methylation influences nucleosome positions, likely facilitating nuclear processes under extreme spatial constraints. DNA methylation, RNA and nucleosome sequencing data for diverse eukaryotes