CXCL4 triggers monocytes and macrophages to produce PDGF-BB, culminating in fibroblast activation: Implications for systemic sclerosis

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Serum microRNA screening and functional studies reveal miR-483-5p as a potential driver of fibrosis in systemic sclerosis

Abstract Objective MicroRNAs (miRNAs) are regulatory molecules, which have been addressed as potential biomarkers and therapeutic targets in rheumatic diseases. Here, we investigated the miRNA signature in the serum of systemic sclerosis (SSc) patients and we further assessed their expression in early stages of the disease. Methods The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Three miRNAs were examined in an additional cohort of 107 SSc patients and 24 healthy donors by single qPCR. MiR-483-5p expression was further analysed in the serum of patients with localized scleroderma (LoS) (n = 22), systemic lupus erythematosus (SLE) (n = 33) and primary Sjogren's syndrome (pSS) (n = 23). The function of miR-483-5p was examined by transfecting miR-483-5p into primary human dermal fibroblasts and pulmonary endothelial cells. Results 30 miRNAs were significantly increased in patients with SSc. Of these, miR-483-5p showed reproducibly higher levels in an independent SSc cohort and was also elevated in patients with preclinical-SSc symptoms (early SSc). Notably, miR-483-5p was not differentially expressed in patients with SLE or pSS, whereas it was up-regulated in LoS, indicating that this miRNA could be involved in the development of skin fibrosis. Consistently, miR-483-5p overexpression in fibroblasts and endothelial cells modulated the expression of fibrosis-related genes. Conclusions Our findings showed that miR-483-5p is up-regulated in the serum of SSc patients, from the early stages of the disease onwards, and indicated its potential function as a fine regulator of fibrosis in SSc

Beneficis de l’activitat física moderada aquàtica i terrestre, tant per a la dona gestant com per al fetus, durant l’embaràs

[cat] L’activitat física durant l’embaràs té molts beneficis, tant per a la dona gestant com per al fetus. En el procés de gestació el cos de la dona experimenta una sèrie de canvis anatòmics, fisiològics i emocionals. Davant aquestes modificacions es planteja el dubte de quin tipus d’activitat física és més adequada per a les embarassades i per als fetus. S’ha realitzat una revisió sistemàtica dels darrers 10 anys, identificant els millors articles de la literatura que aporten evidència científica respecte a aquest tema. L’objectiu d’aquest treball de fi de grau és identificar quins beneficis aporta la realització d’activitat física moderada durant l’embaràs, tant per a la dona gestant com per al fetus, i analitzar quin tipus d’exercici físic és més adequat durant la gestació, el que es desenvolupa en medi aquàtic o en medi terrestre. Es pot afirmar que l’activitat física moderada en medi aquàtic és més beneficiosa per a la dona embarassada i per al fetus. Entre els principals beneficis que aporta la realització d’activitat física durant l’embaràs trobem la prevenció d’augment de pes de l’embarassada, la prevenció de la diabetis mellitus gestacional, disminució de la lumbàlgia, prevenció de la depressió postpart, prevenció dels trastorns del son, ajuda a combatre la fatiga causada per l’embaràs, disminució de l’edema, prevenció de la preclàmpsia, augmenta la força dels músculs del sòl pelvià evitant així els trastorns que hi ha associats com la incontinència urinària, disminució del nombre d’episiotomies i de cesàries, entre d’altres

Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting

Background and objective Systemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Methods Chromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression. Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. Conclusion SSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc