TET1 is an important transcriptional activator of TNFα expression in macrophages.

Activation of macrophages and overexpression of TNFα is associated with the pathogenesis of chronic inflammatory diseases. However, the mechanisms leading to TNFα overexpression are still unknown. 5-methylocytosine (5-mC) is an epigenetic modification that is associated with silenced genes.

Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides.

Most DAMPs in inflammatory diseases are TLR2- and TLR4-ligands and according to the current concept, repeated stimuli would result in tolerance. Aims of the study were to verify this assumption, to investigate whether epigenetic effectors are involved and to explore the situation in rheumatoid arthritis (RA). A trained immunity (TI) and tolerance protocol was established using peripheral blood monocytes from healthy donors, β-glucan and lipopolysaccharide (LPS).

Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases.

A large number of cardiovascular events are not prevented by current therapeutic regimens. In search for additional, innovative strategies, immune cells have been recognized as key players contributing to atherosclerotic plaque progression and destabilization. Particularly the role of innate immune cells is of major interest, following the recent paradigm shift that innate immunity, long considered to be incapable of learning, does exhibit immunological memory mediated via epigenetic reprogramming.

SAVE-AMD: Safety of VEGF Inhibitors in Age-Related Macular Degeneration.

Objective: To determine whether intraocular treatment with vascular endothelial growth factor (VEGF) inhibitors change systemic endothelial function (EF) in patients with neovascular age-related macular degeneration (AMD).

Methods: In this prospective, randomized, 2-center, double-masked controlled interventional trial, patients with neovascular and dry AMD were enrolled. Eligible neovascular AMD patients received 2 intravitreal loading doses of either ranibizumab 0.

Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism.

The development of rheumatoid arthritis (RA) is linked to functional changes in synovial fibroblasts (SF) and local infiltration of T lymphocytes. Fibroblasts possess the capacity to suppress T cell responses, although the molecular mechanisms of this suppression remain incompletely understood. In this study, we aimed to define the mechanisms by which noninflammatory SF modulate Th cell responses and to determine the immunosuppressive efficacy of RASF.

Expression and Regulation of PIWIL-Proteins and PIWI-Interacting RNAs in Rheumatoid Arthritis.

Objective: The PIWIL (P-element induced wimpy testis like protein) subfamily of argonaute proteins is essential for Piwi-interacting RNA (piRNA) biogenesis and their function to silence transposons during germ-line development. Here we explored their presence and regulation in rheumatoid arthritis (RA).

Methods: The expression of PIWIL genes in RA and osteoarthritis (OA) synovial tissues and synovial fibroblasts (SF) was analysed by Real-time PCR, immunofluorescence and Western blot.

MicroRNAs interfere with DNA methylation in rheumatoid arthritis synovial fibroblasts.

Background: The DNA of rheumatoid arthritis synovial fibroblasts (RASF) is globally hypomethylated; this contributes to an aggressive behaviour. In an attempt to remethylate these cells, we supplemented with methyl donors. We investigated the possible interference of microRNAs (miRs).

Epigenome analysis reveals TBX5 as a novel transcription factor involved in the activation of rheumatoid arthritis synovial fibroblasts.

In this study, we analyzed the methylation status of human promoters in rheumatoid arthritis synovial fibroblasts (RASF). Differentially methylated genes between RASF and osteoarthritis synovial fibroblasts (OASF) were identified by methylated DNA immunoprecipitation and hybridization to human promoter tiling arrays. The methylation status was confirmed by pyrosequencing.

Clinical criteria replenish high-sensitive troponin and inflammatory markers in the stratification of patients with suspected acute coronary syndrome.

Objectives: In patients with suspected acute coronary syndrome (ACS), rapid triage is essential. The aim of this study was to establish a tool for risk prediction of 30-day cardiac events (CE) on admission. 30-day cardiac events (CE) were defined as early coronary revascularization, subsequent myocardial infarction, or cardiovascular death within 30 days.

The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis.

Objectives: S100A4 has been implicated in cancer and several inflammatory diseases, including RA. The aim of the present study was to determine whether S100A4 can stimulate proinflammatory cytokine production in mononuclear cells.

Methods: Peripheral blood mononuclear cells (PBMCs) isolated from patients with RA were stimulated with S100A4, S100A8, S100A9 and S100A12.

Inhibition of spermidine/spermine N1-acetyltransferase activity: a new therapeutic concept in rheumatoid arthritis.

Objective: Changes in polyamine-modulated factor 1 (PMF-1) promoter methylation might favor the expression of spermidine/spermine N1-acetyltransferase 1 (SSAT-1), causing excessive consumption of S-adenosyl methionine (SAM). This study was undertaken to evaluate the effect of SSAT-1 activity inhibition, either alone or in combination with SAM.

Methods: Synovial fibroblasts were isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA).

Genetics: a new interpretation of genetic studies in RA.

Understanding the genetics of rheumatoid arthritis (RA) is complex, multiple genes and environmental factors are involved. A new multicentre genetic study summarizes the fundamental gene polymorphisms, pathways and cell types that are related to RA and, based on this analysis, proposes new targets for RA drug treatments.

Exposure to mimivirus collagen promotes arthritis.

Collagens, the most abundant proteins in animals, also occur in some recently described nucleocytoplasmic large DNA viruses such as Mimiviridae, which replicate in amoebae. To clarify the impact of viral collagens on the immune response of animals exposed to Mimiviridae, we have investigated the localization of collagens in Acanthamoeba polyphaga mimivirus particles and the response of mice to immunization with mimivirus particles. Using protein biotinylation, we have first shown that viral collagen encoded by open reading frame L71 is present at the surface of mimivirus particles.

Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts.

Objective: Fibrin deposits are characteristic of the synovial tissues in rheumatoid arthritis (RA). Once citrullinated, fibrin becomes an autoantigen and is thought to contribute in this way to perpetuate the disease. Our study aimed to analyse the responses of RA synovial fibroblasts (RASF) to native and citrullinated fibrin.

Antibody phage display assisted identification of junction plakoglobin as a potential biomarker for atherosclerosis.

To date, no plaque-derived blood biomarker is available to allow diagnosis, prognosis or monitoring of atherosclerotic vascular diseases. In this study, specimens of thrombendarterectomy material from carotid and iliac arteries were incubated in protein-free medium to obtain plaque and control secretomes for subsequent subtractive phage display. The selection of nine plaque secretome-specific antibodies and the analysis of their immunopurified antigens by mass spectrometry led to the identification of 22 proteins.

Cartilage destruction in granulomatosis with polyangiitis (Wegener's granulomatosis) is mediated by human fibroblasts after transplantation into immunodeficient mice.

A key feature of granulomatosis with polyangiitis (GPA; or Wegener's granulomatosis) is the granulomatous inflammation of the upper respiratory tract, which leads to the subsequent destruction of adjacent tissues. The aim of our work was to study the histopathological and cellular components of tissue destruction of human GPA tissue transplanted into immunodeficient mice. Biopsy specimens from patients with active GPA (n = 10) or sinusitis (controls, n = 6) were s.

Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study.

Aims: Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects.

Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts.

Objective: Global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts (RASFs) contributes to their intrinsic activation. The aim of this study was to investigate whether increased polyamine metabolism is associated with a decreased level of S-adenosyl methionine (SAM), causing global DNA hypomethylation.

Methods: Synovial fibroblasts were isolated from synovial tissue obtained from 12 patients with RA and from 6 patients with osteoarthritis (OA).

Down-regulation of microRNA-34a* in rheumatoid arthritis synovial fibroblasts promotes apoptosis resistance.

Objective: To investigate the expression and effect of the microRNA-34 (miR-34) family on apoptosis in rheumatoid arthritis synovial fibroblasts (RASFs).

Methods: Expression of the miR-34 family in synovial fibroblasts with or without stimulation with Toll-like receptor (TLR) ligands, tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), hypoxia, or 5-azacytidine was analyzed by real-time polymerase chain reaction (PCR). Promoter methylation was studied by combined bisulfite restriction analysis.

Myeloid related proteins activate Toll-like receptor 4 in human acute coronary syndromes.

Introduction: We previously reported increased expression of TLR4 on monocytes in thrombi from patients with acute coronary syndromes (ACS). In mice, myeloid related protein (MRP) 8 and MRP14, cytoplasmic proteins of neutrophils and monocytes, activate Toll-like receptor (TLR) 4 during sepsis. In human ACS, we investigated now whether the pro-inflammatory action of MRPs occurs through TLR4 in monocytes derived from thrombi.

The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies.

Objectives: The S100A4 protein is known as a metastasis promoting factor; however, its involvement in non-malignant diseases such as RA and psoriasis has been recently described. The aim of this study was to investigate the expression and possible role of S100A4 in idiopathic inflammatory myopathies.

Methods: S100A4 protein expression was detected by immunohistochemistry in muscle tissue from control individuals (n = 11) and patients with PM and DM (n = 8/6).

Epigenetic deregulation in rheumatoid arthritis.

In this chapter, we discuss the current understanding of the possible epigenetics changes that occur in rheumatoid arthritis. In particular, we describe that deregulation ofDNA methylation and histone modifications can occur in the immune system and lead to rheumatoid arthritis. In addition, we discuss the role of rheumatoid arthritis synovial fibroblasts in autoimmunity.

Acetaminophen increases blood pressure in patients with coronary artery disease.

Background: Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease.

Trex-1 deficiency in rheumatoid arthritis synovial fibroblasts.

Objective: To explore whether the increased expression of long interspersed nuclear element 1 (LINE-1; L1) messenger RNA (mRNA) and protein in rheumatoid arthritis synovial fibroblasts (RASFs) is associated with decreased expression of Trex-1, an exonuclease involved in the metabolization of L1 DNA:RNA hybrids.

Methods: Chromatin immunoprecipitation was used to detect L1-related p40 protein (L1-ORF1p) binding sequences in RASFs. Luciferase activity was measured in the synovial fibroblasts following cotransfection of the episomal plasmid with pJM105 expressing L1-ORF1p and pGL3-TS3 carrying the target sequence for L1-ORF1p.

Cellular actors, Toll-like receptors, and local cytokine profile in acute coronary syndromes.

Aims: Inflammation plays a key role in acute coronary syndromes (ACS). Toll-like receptors (TLR) on leucocytes mediate inflammation and immune responses. We characterized leucocytes and TLR expression within coronary thrombi and compared cytokine levels from the site of coronary occlusion with aortic blood (AB) in ACS patients.