Inhibitors of histone deacetylase (HDAC) have anti-inflammatory and antifibrotic effects in several organs tissues, but their effect on the progression renal disease is unknown. Here, we studied valproic acid adriamycin-induced nephropathy mice. Administration before kidney injury prevented development proteinuria onset glomerulosclerosis. Even after postponing treatment until peak proteinuria, rapidly decreased quantity attenuated disease. Valproic abrogated decrease glomerular acetylation...

Histone deacetylase (HDAC) inhibitors have been extensively studied in experimental models of cancer, where their inhibition deacetylation has proven to regulate cell survival, proliferation, differentiation and apoptosis. This turn led the use a variety HDAC clinical trials. In recent years applicability other areas disease explored, including treatment fibrotic disorders. Impaired wound healing involves continuous deposition cross-linking extracellular matrix governed by myofibroblasts...

The leptin/leptin receptor system shows strong similarities to the long-chain cytokine interleukin-6 (IL-6) and granulocyte colony-stimulating factor cytokine/receptor systems. IL-6 family cytokines interact with their receptors through three different binding sites I-III. leptin structure was superposed on crystal structures of several cytokines, a series mutants generated focusing effect mutations (LR) signaling membrane proximal homology domain (CRH2) LR determined. Mutations in site I at...

Abstract The glucocorticoid receptor (GR) is a transcription factor regulating its target genes either positively, through direct binding to the promoter of genes, or negatively by interference with activity factors involved in proinflammatory gene expression. well-known adverse effects glucocorticoids are believed be mainly caused their GR-mediated gene-activating properties. Although dimerization GR thought essential for properties, no compound has yet been described which selectively...

The phase 2 MANTA and MANTA-RAy studies were developed in consultation with global regulatory authorities to investigate potential impacts of filgotinib, a Janus kinase 1 preferential inhibitor, on semen parameters men active inflammatory diseases. Here we describe the methods rationale for these studies. included (aged 21–65 years) bowel disease (IBD) rheumatic diseases, respectively. Participants had no history reproductive health issues, following parameter values (≥ 5th percentile World...

To update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis.

Activation of the NF-κB/Rel family transcription factors proceeds through a catalytic complex containing IκB kinase (IKK)-1 and IKK2. Targeted disruption each IKK genes suggests that these two kinases may mediate distinct functions in activation pathway. In our studies human T-cell lymphotropic virus type 1 (HTLV-1) Tax oncoprotein, we have uncovered new function IKK1 required for complete NF-κB transcriptional program. IKK1–/– murine embryonic fibroblasts (MEFs), normally induced early...

Glucocorticoids (GCs) are in widespread use to treat inflammatory bone diseases, such as rheumatoid arthritis (RA). Their anti-inflammatory efficacy, however, is accompanied by deleterious effects on bone, leading GC-induced osteoporosis (GIO). These include up-regulation of the receptor activator NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio promote bone-resorbing osteoclasts and inhibition bone-forming osteoblasts. We previously identified suppression osteoblast differentiation monomer...

The conversion of a quiescent vitamin A storing hepatic stellate cell (HSC) to matrix producing, contractile myofibroblast-like activated HSC is key event in the onset liver disease following injury any aetiology. Previous studies have shown that class I histone deacetylases (HDACs) are involved phenotypical changes occurring during activation and pancreas.In current study we investigate role II HDACs activation.We characterized expression freshly isolated mouse HSCs. We inhibited HDAC...

We investigated the cytosolic proteome of inflamed synovial tissue by hierarchical clustering analysis and validated feasibility this identifying proteins that were differentially expressed between rheumatoid arthritis (RA), spondyloarthropathy (SpA), osteoarthritis (OA). Synovial biopsy samples obtained from 18 patients undergoing needle arthroscopy for knee synovitis associated with RA (n = 6) SpA 6), joint effusion OA 6). Cytosolic extracted subjected to two-dimensional gel...

α-Galactosyl ceramide (α-GalCer, also known as KRN 7000) is the prototypical antigen for invariant natural killer T (NKT) cells. Stimulation of NKT cells by CD1d-mediated α-GalCer presentation leads to rapid release Th1 and Th2 cytokines. Since cytokines antagonize each other's effects, analogues that induce a biased Th1/Th2 response are highly awaited. With exception C-glycoside (α-C-GalCer), most able polarized cytokine responses characterized modifications phytosphingosine or fatty acyl...

Abstract In this study, the role of IL-15 and its regulation by transcription factor IFN regulatory factor-1 (IRF-1) in murine Vγ3 T cell development activity is assessed. Compared with wild-type (WT) mice, reduced numbers mature cells were found fetal thymus IL-15−/− while IRF-1−/− mice displayed normal frequencies. Vγ3+ dendritic epidermal (DETCs) absent but present mice. DETCs from morphologically a less phenotype showed different emergence kinetics during ontogeny. This corresponded...

The glycosphingolipid alpha-galactosylceramide (alpha-GalCer) has been shown to be a potent activator of invariant NKT (iNKT) cells, rapidly inducing large amounts both Th1 and Th2 cytokines upon injection in mice. C-glycoside analog alpha-GalCer (alpha-C-GalCer), by contrast, results an enhanced Th1-type response activation iNKT cells. We administered single dose these Ags DBA/1 mice during the early induction phase collagen-induced arthritis demonstrated therapeutic efficacy when rather...

<h3>Objectives:</h3> Improved DNA sequencer-aided fluorophore-assisted carbohydrate electrophoresis (DSA-FACE) technology was used to monitor the changes in galactosylation status of serum immunoglobulins during immune response and therapy autoimmune arthritis. <h3>Methods:</h3> Collagen-induced arthritis (CIA) induced susceptible DBA/1 mice undergalactosylation (UGS) determined using improved DSA-FACE technology. Prophylactic intravenous tolerisation with type II collagen as well...

To investigate the role of invariant natural killer T (iNKT) cells in TNF(DeltaARE/+) mice, an animal model spondylarthritis (SpA) with both gut and joint inflammation.The frequency activation iNKT were analyzed on mononuclear from lymph nodes livers using flow cytometry alpha-galactosylceramide/CD1d tetramers quantitative polymerase chain reaction for V(alpha)14-J(alpha)18 rearrangement. Bone marrow-derived dendritic (DCs) obtained by expansion primary granulocyte-macrophage...

Background: Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for improved alternatives classic steroids. We sought unravel how two glucocorticoid receptor-activating compounds, dexamethasone and Compound A, influence receptor levels this can be correlated their gene regulatory potential. Methods: A were applied short-term long-term treatment protocol. By quantitative PCR analysis fibroblast-like synoviocytes (FLS) potential of both...

Tumor antigen-encoding mRNA for dendritic cell (DC)-based vaccination has gained increasing popularity in recent years. Within this context, two main strategies have entered the clinical trial stage: use of ex vivo antigen loading DCs and direct application as a source vivo. transfected with mRNA-encoding Wilms' tumor 1 (WT1) protein shown promising results. Using stepwise approach, we re-engineered WT1 cDNA-carrying transcription vector to improve translational characteristics...

Abstract Murine NK cells express inhibitory receptors belonging to the Ly49 and CD94/NKG2 family. Ly49E CD94 are only cell receptor transcripts detectable in fetal cells. Still unproved is surface expression of on Here we generated two novel mAbs, a mAb recognizing with cross-reactivity Ly49C, against NKG2A/C/E. was immunoprecipitated as disulfide-linked homodimer 46-kDa subunits. Removal N-linked carbohydrates revealed 31-kDa protein backbone. NKG2A 38-kDa protein. Although frequency...

Ly49 and CD94/NKG2 inhibitory receptors are predominantly expressed on murine NK cells, but they also a subpopulation of peripheral CD8 memory TCR alphabeta lymphocytes. In this study we demonstrate that Ly49E mature Vgamma3(+) cells in the fetal thymus. Expression correlated with phenotype, such as expression CD44, 2B4, IL-2Rbeta (CD122), absence IL-2Ralpha (CD25) expression. No Ly49A, C, D, G2, or I was observed. This phenotype is similar to thymic cells. Skin-located Vgamma3 T progeny not...

Abstract The current model used to define T cell export from the thymus suggests that emigrating lymphocytes seed peripheral organs as functionally mature cells. This holds true for majority of cells exported with exception invariant NK (iNKT) iNKT undergo lineage expansion after positive selection and acquire receptor expression once fully mature; yet, are retained in by an yet unidentified mechanism. In this study we demonstrate chemokine CXCR3. We propose CXCR3 ligands thymic medullary...

Abstract Background/Aims Filgotinib (FIL) is a Janus kinase 1 preferential inhibitor for the treatment of moderate to severe rheumatoid arthritis (RA) approved at doses 100 mg (FIL100) and 200 (FIL200). This integrated safety analysis provides an update on selected treatment-emergent adverse events FIL up median (maximum) exposure 4.3 (8.3) years. Methods data were from 7 clinical trials: Phase 2 DARWIN studies (NCT01888874, NCT01894516), 3 FINCH (NCT02889796, NCT02873936, NCT02886728),...

Background While treat-to-target (T2T) is endorsed for the management of rheumatoid arthritis (RA), data on degree implementation in clinical practice are limited. This study investigated use T2T RA a real-world setting across Europe. Methods The Adelphi Disease-Specific Programme was point-in-time survey rheumatologists and their consulting patients with conducted between January October 2020 Belgium, France, Germany, Italy, Spain UK. Rheumatologists completed an attitudinal survey, record...