Epigenetic Regulation of Cyclooxygenase-2 by methylation of c8orf4 in Pulmonary Fibrosis.

Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis produce low levels of prostaglandin E2, due to a limited capacity to up-regulate cyclooxygenase-2. This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood.In the present study we examined whether the reduced level of cyclooxygenase-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5 Aza-2’-deoxycytidine restored cyclooxygenase-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of prostaglandin E2 production, collagen mRNA expression and sensitivity to apoptosis. Cyclooxygenase-2 methylation assessed by bisulphite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, c8orf4, which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knock-down of c8orf4 in control fibroblasts down-regulated cyclooxygenase-2 and prostaglandin E2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates cyclooxygenase-2 expression in lung fibroblasts through binding of the pr...
Source: Clinical Science - Category: Biomedical Science Authors: Tags: PublishAheadOfPrint Source Type: research

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ConclusionsThis study is first to demonstrate that X-chromosome-linked IRAK1 polymorphisms are associated with the risk of NMOSD and provide novel insights into the underlying mechanisms of this disease. Further studies are needed to elucidate the function of IRAK1 variants in the pathogenesis of NMOSD and the underlying molecular mechanisms.
Source: Multiple Sclerosis and Related Disorders - Category: Neurology Source Type: research
This study aimed to assess the serum levels of α‑Klotho in SSc patients compared to healthy controls, and to correlate them with the disease parameters. METHODS: Forty-two SSc patients were included in this study. History taking, clinical examination, and related investigations were performed. The modified Rodnan skin score (mRss) was used to assess skin tightness in SSc patients. Twenty-seven age- and sex-matched healthy participants served as controls. Serum α‑Klotho was assessed in the two groups. RESULTS: SSc patients comprised 39 females and 3 males; mean age was 42.2 ±&thi...
Source: Zeitschrift fur Rheumatologie - Category: Rheumatology Authors: Tags: Z Rheumatol Source Type: research
We describe the case of a female patient with limited SSc (lcSSc), a diagnosis based on the presence of sclerodactyly, Raynaud phenomenon, microvascular involvement, and positive anti-centromere antibodies. On follow-up, she developed chest pain, a second-degree A-V block, and restrictive cardiomyopathy (without cardiovascular risk factors). Although heart involvement is common in these two entities, the abnormal thickening of lateral and inferior wall, the infiltration pattern and the conduction system disorders presented herein are more characteristic in a heterozygous female with a cardiac variant of FD. The diagnosis o...
Source: Rheumatology International - Category: Rheumatology Source Type: research
Conclusion: This study is the largest to date analyzing the potential influence of neighborhood deprivation on ADs. Our results indicate that neighborhood deprivation may affect risk of ADs, independent of individual level sociodemographic characteristics. For health care policies, both individual and neighborhood level approaches seem to be of importance.
Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Article Source Type: research
Authors: Barsotti S, Orlandi M, Codullo V, Di Battista M, Lepri G, Della Rossa A, Guiducci S Abstract Systemic sclerosis (SSc) is a complex disorder characterised by the involvement of small arteries, microvessels and connective tissue, with deposition of fibrotic tissue and microvascular obliteration in the skin and internal organs. Due to the multifaceted nature of the disease, several articles are published in the medical literature every year, aimed at exploring different aspects of the pathogenesis, internal organ involvement and clinical aspects, and possible therapeutic approaches. In this article we have re...
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
CONCLUSIONS: The VFG study is a useful technique for the morphological and functional evaluation of swallowing in SSc patients. PMID: 31587696 [PubMed - in process]
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
Authors: Paolino S, Ferrari G, Pizzorni C, Patanè M, Smith V, Cutolo M, Sulli A Abstract OBJECTIVES: To retrospectively study nailfold videocapillaroscopy (NVC) changes in mixed connective tissue disease (MCTD) patients and to compare the capillary morphological abnormalities between patients affected by MCTD and systemic sclerosis (SSc) over time. METHODS: Ten MCTD patients on whom NVC had been performed, with a follow-up of three years, were selected. In addition, ten patients affected by SSc with similar age and disease duration of MCTD patients were enrolled to compare NVC abnormalities at baseline (...
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
CONCLUSIONS: In SSc patients, CEEE is not associated with the extent of microvascular derangement. No associations between CEEE and organ involvement were found. PMID: 31587694 [PubMed - in process]
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
Authors: Gasperini ML, Gigante A, Iacolare A, Pellicano C, Collalti G, Rosato E PMID: 31587693 [PubMed - in process]
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
CONCLUSIONS: Altogether, our results indicate that the increased production of IL-10 by 1,25(OH)2D3 -treated Tregs could provide a "suppressive" cytokine milieu able to modulate immune response but it is not sufficient to restore the immune suppressive functions of Tregs. PMID: 31587692 [PubMed - in process]
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
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