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ID PMID Title PublicationDate abstract
28320433 Association of the lupus low disease activity state (LLDAS) with health-related quality of 2017 Mar 20 BACKGROUND: Systemic lupus erythematosus (SLE) is associated with significant impairment of health-related quality of life (HR-QoL). Recently, meeting a definition of a lupus low disease activity state (LLDAS), analogous to low disease activity in rheumatoid arthritis, was preliminarily validated as associated with protection from damage accrual. The LLDAS definition has not been previously evaluated for association with patient-reported outcomes. The objective of this study was to determine whether LLDAS is associated with better HR-QoL, and examine predictors of HR-QoL, in a large multiethnic, multinational cohort of patients with SLE. METHODS: HR-QoL was measured using the Medical Outcomes Study 36-item short form health survey (SF-36v2) in a prospective study of 1422 patients. Disease status was measured using the SLE disease activity index (SLEDAI-2 K), physician global assessment (PGA) and LLDAS. RESULTS: Significant differences in SF-36 domain scores were found between patients stratified by ethnic group, education level and damage score, and with the presence of active musculoskeletal or cutaneous manifestations. In multiple linear regression analysis, Asian ethnicity (p < 0.001), a higher level of education (p < 0.001), younger age (p < 0.001) and shorter disease duration (p < 0.01) remained significantly associated with better physical component scores (PCS). Musculoskeletal disease activity (p < 0.001) was negatively associated with PCS, and cutaneous activity (p = 0.04) was negatively associated with mental component scores (MCS). Patients in LLDAS had better PCS (p < 0.001) and MCS (p < 0.001) scores and significantly better scores in multiple individual SF-36 domain scores. Disease damage was associated with worse PCS (p < 0.001), but not MCS scores. CONCLUSIONS: Ethnicity, education, disease damage and specific organ involvement impacts HR-QoL in SLE. Attainment of LLDAS is associated with better HR-QoL.
29430085 Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the E 2017 There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis-mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-α, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue.
29362722 The Identification of Key Genes and Pathways in Glioma by Bioinformatics Analysis. 2017 Glioma is the most common malignant tumor in the central nervous system. This study aims to explore the potential mechanism and identify gene signatures of glioma. The glioma gene expression profile GSE4290 was analyzed for differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were applied for the enriched pathways. A protein-protein interaction (PPI) network was constructed to find the hub genes. Survival analysis was conducted to screen and validate critical genes. In this study, 775 downregulated DEGs were identified. GO analysis demonstrated that the DEGs were enriched in cellular protein modification, regulation of cell communication, and regulation of signaling. KEGG analysis indicated that the DEGs were enriched in the MAPK signaling pathway, endocytosis, oxytocin signaling, and calcium signaling. PPI network and module analysis found 12 hub genes, which were enriched in synaptic vesicle cycling rheumatoid arthritis and collecting duct acid secretion. The four key genes CDK17, GNA13, PHF21A, and MTHFD2 were identified in both generation (GSE4412) and validation (GSE4271) dataset, respectively. Regression analysis showed that CDK13, PHF21A, and MTHFD2 were independent predictors. The results suggested that CDK17, GNA13, PHF21A, and MTHFD2 might play important roles and potentially be valuable in the prognosis and treatment of glioma.
29299471 Outcomes of a newer-generation cementless total knee arthroplasty design in patients less 2017 Dec BACKGROUND: Younger patients undergoing cemented total knee arthroplasty (TKA) may be at risk for lower implant survivorship and higher revision rates due to the historical increased prevalence of aseptic loosening and instability in this cohort. The recent advances of cementless TKAs may mitigate some of these complications. However, there is a paucity of studies reporting on patients who are under 50 years who have undergone a cementless TKA. Therefore, this study evaluated: (I) implant survivorship; (II) functional outcomes and complications; and (III) radiographic outcomes in patients who were less than 50 years of age and underwent cementless TKA. METHODS: A total of 29 patients (31 knees) younger than 50 years who underwent primary TKA at a single institution (Mount Sinai Beth Israel, New York, New York, USA) from June 2008 to May 2014 were included. Their mean follow-up was 4 years (range, 2 to 6 years). The cohort included 20 women and 9 men who had a mean age of 45 years (range, 34 to 49 years), and a mean body mass index (BMI) of 33 kg/m(2) (range, 22 to 54 kg/m(2)). The preoperative knee diagnoses were osteoarthritis (n=24), osteonecrosis (n=5), and rheumatoid arthritis (n=2). A Kaplan-Meier analysis was used to calculate the all cause implant survivorship. Functional outcomes and all complications were recorded for each patient. Additionally, radiographic evaluation using the new Knee Society Radiographic Evaluation and Scoring System was performed. RESULTS: The overall implant survivorship was 100%; there were no failures or revision surgeries performed as of the latest follow-up visit. At the latest follow-up, the mean Knee Society pain score was 92 points (range, 80 to 95 points) and the mean Knee Society function score was 84 points (range, 70 to 90 points). Additionally, the mean knee extension was 1 degree (range, 0 to 5 degrees) and the mean knee flexion was 125 degrees (range, 95 to 140 degrees). Furthermore, at the latest follow-up, on radiographic evaluation, there was no evidence of component loosening, subsidence, radiolucency, gap formation, or reactive changes, and there were no postoperative complications. CONCLUSIONS: Cementless fixation of TKAs had excellent survivorship and functional and radiographic outcomes at midterm follow-up in patients younger than 50 years. Although longer follow-up is needed, these cementless TKA implants appear to provide promising results in younger patient populations.
29248714 FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk b 2018 Mar 28 Cancer associated fibroblast (CAF) is a well-known microenvironment contributor for the development of hepatocellular carcinoma (HCC), while forkhead box (FOX) proteins are also critical to exacerbate HCC malignancy. However, whether FOX proteins are involved in the crosstalk between CAFs and HCC cells remains unclear. In the present study, we reveal that CAFs induce forkhead box Q1 (FOXQ1) expression, and N-myc downstream-regulated gene 1 (NDRG1) is therefore trans-activated to enhance HCC initiation. Intriguingly, pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling is induced by FOXQ1/NDRG1 axis, thus recruiting hepatic stellate cells (HSCs), the main cellular source of CAFs, to the tumor microenvironment. Thereby, tumor initiating properties are enhanced at least partly through a positive feedback loop between CAFs and HCC cells. Importantly, leflunomide, a pSTAT6 inhibitor that has been approved for the treatment of rheumatoid arthritis, significantly blocks the loop and HCC progression. High expression of CAF marker, ACTA2, and induced FOXQ1/NDRG1 axis in HCC tissues predict unfavorable prognosis. Collectively, our findings uncover a positive feedback loop between CAFs and FOXQ1/NDRG1 axis in neoplastic cells to drive HCC initiation, thus providing new potential therapeutic targets for HCC.
29242565 Anti-IL-20 monoclonal antibody inhibited tumor growth in hepatocellular carcinoma. 2017 Dec 14 Interleukin (IL)-20 is a proinflammatory cytokine involved in rheumatoid arthritis, atherosclerosis, and osteoporosis. However, the role of IL-20 in hepatocellular carcinoma (HCC) is unclear. We explored the function of IL-20 in HCC. Tumor tissue samples were analyzed the expression of IL-20 and cyclin D1 by using immunohistochemistry staining and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. To examine the role of anti-IL-20 monoclonal antibody (7E) in tumor growth, BALB/c mice was injected with ML-1 cells and treated with 7E. HCC tumor tissue expressed higher levels of IL-20 than did non-tumor tissue. High IL-20 expression in HCC was correlated with poor overall survival (relative risk:>3). IL-20 and cyclin D1 expression were also highly correlated in HCC patient specimens and 3 human HCC cell lines. IL-20 also increased cell proliferation and migration, and it regulated matrix metalloproteinase (MMP)-13, tumor necrosis factor (TNF)-α, cyclin D1, and p21(WAF1) expression in ML-1 cells. 7E attenuated tumor growth in mice inoculated with ML-1 cells. The expression of cyclin D1, TNF-α, MMP-9, and vascular endothelial growth factor was significantly inhibited after 7E treatment. The findings of this study suggest that IL-20 plays a role in the tumor progression of HCC.
29214470 Clinical and anti-aging effect of mud-bathing therapy for patients with fibromyalgia. 2018 Jul Spa bathing is known as a medical treatment for certain diseases causing chronic pains. Spa water contains mineral components which lower the specific heat of the water, resulting in a higher efficiency to warm body-core temperature. This phenomenon yields pain-relieving effect for rheumatoid arthritis, low back pain, sciatic neuralgia, fibromyalgia, etc. Here we introduce medical and biological effects of mud-spa-bathing therapy for fibromyalgia other than pain relief, the changes of blood examination data, and the telomere length of circulating leukocytes. The enrolled 7 patients with fibromyalgia syndrome were hospitalized and were subject to daily mud bathing at 40 °C for 10 min for about a month. Then, their subjective pain was reduced to about a quarter in average. They also showed lowered serum triglyceride and C-reactive protein level, maintaining the levels of aspartate transaminase and creatine phosphokinase, and increases of the red blood cell count, the serum albumin level, and the serum LDL-cholesterol level in comparison with cases without mud-bathing therapy, suggesting that mud bathing prevents inflammation and muscle atrophy and improves nutritional condition in fibromyalgia. In addition, the analysis of telomere length of peripheral leukocytes revealed a trend of negative correlation between telomere shortening and laboratory data change of hemoglobin and serum albumin. These telomeric changes can be explained hypothetically by an effect of mud bathing extending life-span of circulating leukocytes.
28803127 Direct antioxidant properties of methotrexate: Inhibition of malondialdehyde-acetaldehyde- 2017 Oct Methotrexate (MTX) is an immunosuppressant commonly used for the treatment of autoimmune diseases. Recent observations have shown that patients treated with MTX also exhibit a reduced risk for the development of cardiovascular disease (CVD). Although MTX reduces systemic inflammation and tissue damage, the mechanisms by which MTX exerts these beneficial effects are not entirely known. We have previously demonstrated that protein adducts formed by the interaction of malondialdehyde (MDA) and acetaldehyde (AA), known as MAA-protein adducts, are present in diseased tissues of individuals with rheumatoid arthritis (RA) or CVD. In previously reported studies, MAA-adducts were shown to be highly immunogenic, supporting the concept that MAA-adducts not only serve as markers of oxidative stress but may have a direct role in the pathogenesis of inflammatory diseases. Because MAA-adducts are commonly detected in diseased tissues and are proposed to mitigate disease progression in both RA and CVD, we tested the hypothesis that MTX inhibits the generation of MAA-protein adducts by scavenging reactive oxygen species. Using a cell free system, we found that MTX reduces MAA-adduct formation by approximately 6-fold, and scavenges free radicals produced during MAA-adduct formation. Further investigation revealed that MTX directly scavenges superoxide, but not hydrogen peroxide. Additionally, using the Nrf2/ARE luciferase reporter cell line, which responds to intracellular redox changes, we observed that MTX inhibits the activation of Nrf2 in cells treated with MDA and AA. These studies define previously unrecognized mechanisms by which MTX can reduce inflammation and subsequent tissue damage, namely, scavenging free radicals, reducing oxidative stress, and inhibiting MAA-adduct formation.
28629539 UPLC/ESI-QTOF-MS-based metabolomics survey on the toxicity of triptolide and detoxication 2017 Jun Triptolide (TP) from Tripterygium wilfordii has been demonstrated to possess anti-inflammatory, immunosuppressive, and anticancer activities. TP is specially used for the treatment of awkward rheumatoid arthritis, but its clinical application is confined by intense side effects. It is reported that licorice can obviously reduce the toxicity of TP, but the detailed mechanisms involved have not been comprehensively investigated. The current study aimed to explore metabolomics characteristics of the toxic reaction induced by TP and the intervention effect of licorice water extraction (LWE) against such toxicity. Obtained urine samples from control, TP and TP + LWE treated rats were analyzed by UPLC/ESI-QTOF-MS. The metabolic profiles of the control and the TP group were well differentiated by the principal component analysis and orthogonal partial least squares-discriminant analysis. The toxicity of TP was demonstrated to be evolving along with the exposure time of TP. Eight potential biomarkers related to TP toxicity were successfully identified in urine samples. Furthermore, LWE treatment could attenuate the change in six of the eight identified biomarkers. Functional pathway analysis revealed that the alterations in these metabolites were associated with tryptophan, pantothenic acid, and porphyrin metabolism. Therefore, it was concluded that LWE demonstrated interventional effects on TP toxicity through regulation of tryptophan, pantothenic acid, and porphyrin metabolism pathways, which provided novel insights into the possible mechanisms of TP toxicity as well as the potential therapeutic effects of LWE against such toxicity.
28577224 Long-term use of proton pump inhibitors among community-dwelling persons with and without 2017 Sep PURPOSE: The aim of this study is to determine the prevalence of use and long-term use (≥180 days) of proton pump inhibitors (PPIs) and associated factors among community-dwellers with and without Alzheimer's disease (AD). METHODS: MEDALZ cohort encompassed all persons who received a verified diagnosis of AD in Finland during the years 2005-2011 and their age-, sex-, and region of residence-matched comparison persons, including 69,353 persons with and 69,353 persons without AD. Data was derived from several Finnish administrative registers. A mathematical modelling method, PRE2DUP, was used for converting dispensing data to drug use periods (when regular PPI use started and ended). Morbid conditions and concomitant drugs associated with use and long-term use of PPIs were assessed with logistic regression models. RESULTS: Use of PPIs was more common among comparison persons than persons with AD (39.0 and 35.8%, respectively, p < 0.001), whereas long-term use of PPIs was more frequent among persons with than without AD (20.3 and 17.9%, respectively, p < 0.001). Factors related to long-term use of PPIs were female sex, history of gastrointestinal bleedings, AD, rheumatoid arthritis, cardiovascular disease, asthma/COPD and use of bisphosphonates, SSRIs and antithrombotic agents. Median follow-up time was 2.6 years among persons with AD and 3.5 years among persons without AD. Median duration of the first long-term PPI use was similar in both groups (1.4 years). CONCLUSION: Long-term use of PPIs was common among persons with and without AD. Due to possible adverse events associated with the long-term use of PPIs, need for PPIs should be assessed regularly.
28482858 Tight controlled dose reduction of biologics in psoriasis patients with low disease activi 2017 May 8 BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory skin disorder for which several targeted biologic therapies became available in the last 10 years. Data from patients with rheumatoid arthritis revealed that dose tapering combined with tight control of disease activity is successful. For psoriasis patients the lowest effective dose of biologics needs to be determined. The objective was to assess whether dose tapering of biologics guided by Psoriasis Area and Severity Index (PASI) and Dermatology Quality of Life Index (DLQI) scores in psoriasis patients with controlled disease activity is non-inferior (NI) to usual care. METHODS/DESIGN: This is a multicenter, pragmatic, randomized, non-inferiority trial with cost- effectiveness analysis. One hundred and twenty patients with stable low disease activity (PASI ≤ 5 and DLQI ≤ 5) for at least 6 months with a stable use of adalimumab, etanercept or ustekinumab will be randomized 1:1 to the dose reduction group or usual care. In the dose reduction group, the treatment intervals will be prolonged stepwise, resulting in a 33% and 50% dose reduction, respectively. Disease activity is monitored every three months with PASI and DLQI. In case of flare the treatment is adjusted to the previous effective dose. The primary outcome (PASI) at 12 months will be analyzed with ANCOVA in which the baseline PASI will be included as covariate to gain efficiency. The secondary outcomes include number of and time to disease flares, health-related quality of life, serious adverse events, and costs. DISCUSSION: With this study we want to assess whether disease activity guided dose reduction of biologics can be achieved for psoriasis patients with low stable disease activity, without losing disease control. By using the lowest effective dose of biologics, we expect to minimize side effects and save costs. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov ( NCT 02602925 ). Trial registration date October 9 2015.
28412711 Biologic Disease-modifying Antirheumatic Drug (bDMARD)-induced Neutropenia: A Registry fro 2017 Jun OBJECTIVE: To examine the rate, risks factors, and consequences of neutropenia induced by intravenous (IV) biologic disease-modifying antirheumatic drugs (bDMARD). METHODS: We conducted a retrospective cohort study in 499 patients with rheumatic diseases treated by IV abatacept (ABA), infliximab (IFX), or tocilizumab (TCZ). RESULTS: Rheumatoid arthritis (RA) was the most frequent diagnosis (72%). Fifty-two patients (10.4%) experienced at least 1 episode of neutropenia. No episodes of grade 4 neutropenia were documented. TCZ was more frequently related to neutropenia than ABA or IFX (18.6% vs 3.8% and 2.8%, respectively, p < 0.001). The following factors were identified as predictors of experiencing neutropenia with IV bDMARD: history of neutropenia with methotrexate (MTX; synthetic DMARD; OR 1.56, 95% CI 1.17-7.14), concomitant treatment by MTX (OR 1.21, 95% CI 1.01-2.64), and TCZ treatment (OR 2.72, 95% CI 1.53-9.05). Patients experiencing a TCZ-induced neutropenia did not show a higher risk of severe infections; however, this group had a shorter drug survival (9 mos vs 20 mos, p < 0.02) compared with TCZ patients without neutropenia. CONCLUSION: Among 3 different classes of IV bDMARD, TCZ is associated with the higher risk of neutropenia. No increased frequency of infection episodes was documented in this group.
28300829 Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulati 2017 Mar 16 Cystatin SN (CST1) is a specific inhibitor belonging to the cystatin superfamily that controls the proteolytic activities of cysteine proteases such as cathepsins. Our previous study showed that high CST1 expression enhances tumor metastasis and invasiveness in colorectal cancer. Recently, auranofin (AF), a gold(I)-containing thioredoxin reductase 1 (TrxR1) inhibitor, has been used clinically to treat rheumatoid arthritis. AF is a proteasome-associated deubiquitinase inhibitor and can act as an anti-tumor agent. In this study, we investigated whether CST1 expression induces autophagy and tumor cell survival. We also investigated the therapeutic effects of AF as an anti-tumor agent in colorectal cancer (CRC) cells. We found that CRC cells expressing high levels of CST1 undergo increased autophagy and exhibit chemotherapeutic resistance to AF-induced cell death, while those expressing low levels of CST1 are sensitive to AF. We also observed that knockdown of CST1 in high-CST1 CRC cells using CST1-specific small interfering RNAs attenuated autophagic activation and restored AF-induced cell mortality. Conversely, the overexpression of CST1 increased autophagy and viability in cells expressing low levels of CST1. Interestingly, high expression of CST1 attenuates AF-induced cell death by inhibiting intracellular reactive oxygen species (ROS) generation, as demonstrated by the fact that the blockage of ROS production reversed AF-induced cell death in CRC cells. In addition, upregulation of CST1 expression increased cellular glutathione reductase (GR) activity, reducing the cellular redox state and inducing autophagy in AF-treated CRC cells. These results suggest that high CST1 expression may be involved in autophagic induction and protects from AF-induced cell death by inhibition of ROS generation through the regulation of GR activity.
28292965 Repurposed JAK1/JAK2 Inhibitor Reverses Established Autoimmune Insulitis in NOD Mice. 2017 Jun Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics used to treat other diseases to treat type 1 diabetes, especially when there is evidence for overlapping mechanisms. Janus kinase (JAK) 1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and signal transducer and activator of transcription (STAT) 1 pathway in human type 1 diabetes and in mouse models, especially in β-cells. We tested the hypothesis that using these drugs to block the JAK-STAT pathway would prevent autoimmune diabetes. The JAK1/JAK2 inhibitor AZD1480 blocked the effect of cytokines on mouse and human β-cells by inhibiting MHC class I upregulation. This prevented the direct interaction between CD8(+) T cells and β-cells, and reduced immune cell infiltration into islets. NOD mice treated with AZD1480 were protected from autoimmune diabetes, and diabetes was reversed in newly diagnosed NOD mice. This provides mechanistic groundwork for repurposing clinically approved JAK1/JAK2 inhibitors for type 1 diabetes.
28131664 Survival and outcomes after lung transplantation for non-scleroderma connective tissue-rel 2017 Jul BACKGROUND: Patients with non-scleroderma connective tissue-related lung disease (NS-CTLD), including rheumatoid arthritis, idiopathic inflammatory myopathies, Sjögren syndrome, mixed connective tissue disease, and systemic lupus erythematosus, may be at risk for worse outcomes after lung transplantation because of immune dysregulation or extrapulmonary manifestations of their underlying disease. We compared survival, acute and chronic rejection, and extrapulmonary organ dysfunction after transplantation in patients with NS-CTLD and idiopathic pulmonary fibrosis (IPF). METHODS: This was a retrospective cohort study of patients with NS-CTLD and IPF who were listed in the Scientific Registry of Transplant Recipients and underwent lung transplantation from May 5, 2005, to March 1, 2016. RESULTS: Patients with NS-CTLD (n = 275) were younger, a higher percentage female and non-white than patients with IPF (n = 6,346). NS-CTLD patients did not have worse adjusted survival (hazard ratio, 1.14, 95% confidence interval [CI], 0.92-1.42; p = 0.24). They were not more likely to have an episode of acute cellular rejection (odds ratio, 0.96; 95% CI, 0.72-1.28; p = 0.77) or to develop bronchiolitis obliterans syndrome (odds ratio, 0.82; 95% CI, 0.60-1.12; p = 0.21). Patients with NS-CTLD were not more likely to require plasmapheresis or dialysis or to develop a lymphoproliferative malignancy or liver disease after transplantation. CONCLUSIONS: We found no significant differences in survival, acute or chronic rejection, or extrapulmonary organ dysfunction in patients who underwent lung transplantation for NS-CTLD compared with IPF. In appropriately selected candidates, NS-CTLD should not be considered a contraindication to lung transplantation.
28064083 Identification of novel PAD4 inhibitors based on a pharmacophore model derived from transi 2017 Mar 1.4 Protein arginine deiminases 4 (PAD4) is an attractive target for the development of novel and selective inhibitors of Rheumatoid Arthritis (RA). F-amidine is known as mechanism-based inhibitor targeting PAD4 and used as inactivators by covalently modifying the active site Cys645. To identify novel structural inhibitors of PAD4, we investigated the flexibility of protein on basis of the transition state geometry of PAD4 inhibited by F-amidine from our previous QM/MM calculation. And a pharmacophore model was generated containing four features (ADHH) using five representative structures from molecular dynamic (MD) simulation on basis of the transition state geometry of PAD4 inhibited by F-amidine. We performed virtual screening using the pharmacophore model and molecular docking methods, resulting in the discovery of two molecules with K(D) (dissociation equilibrium constant) values of 112μM and 218μΜ against PAD4 through Surface Plasmon Resonance (SPR) experiments. These two molecules could potentially serve as PAD4 inhibitors.
28045034 Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented 2017 Jan 3 Cellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn's disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence.
28038706 Hepatosplenic T-cell lymphoma arising in patients with immunodysregulatory disorders: a st 2017 Feb Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive extranodal T-cell lymphoma that can arise in patients with underlying immune disorders. Others have suggested that tumor necrosis factor (TNF)-α inhibitor therapy for immune disorders increases the risk of HSTCL. To assess for a potential relationship between HSTCL and the use of TNF-α inhibitors, we searched for patients with HSTCL and underlying immune disorders at our institution. We identified 7 patients with a median age of 38 years. Five patients had Crohn disease, 1 ulcerative colitis, and 1 rheumatoid arthritis. In 6 patients, medication history for the immune disorder was available: 6 patients received 6-mercaptopurine or azathioprine, and 2 patients received steroids; no patients received TNF-α inhibitors. In all 7 patients, the histologic, immunophenotypic, and cytogenetic findings were similar to cases of HSTCL that arise in immunocompetent patients. We reviewed the literature and identified 60 patients with immune disorders who subsequently developed HSTCL. These patients were treated with immunosuppressive drugs in 89%, TNF-α inhibitors in 56%, and both therapies in 54%, and 1 (2%) patient was treated with TNF-α inhibitors only. Our cohort and literature review indicates that TNF-α inhibitor therapy is not essential for the development of HSTCL in patients with immunodysregulatory disorders, and implies that immunosuppressive drugs or other factors (eg, genetic predisposition, chronic antigenic stimulation) may be more critical in the pathogenesis in this context. Although these data are observational, they have implications for the use of TNF-α inhibitors in patients with inflammatory bowel disease and other immunodysregulatory disorders.
28012205 Activated α(2) -Macroglobulin Induces Mesenchymal Cellular Migration Of Raw264.7 Cells Th 2017 Jul Distinct modes of cell migration contribute to diverse types of cell movements. The mesenchymal mode is characterized by a multistep cycle of membrane protrusion, the formation of focal adhesion, and the stabilization at the leading edge associated with the degradation of extracellular matrix (ECM) components and with regulated extracellular proteolysis. Both α(2) -Macroglobulin (α(2) M) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1), play important roles in inflammatory processes, by controlling the extracellular activity of several proteases. The binding of the active form of α(2) M (α(2) M*) to LRP1 can also activate different signaling pathways in macrophages, thus inducing extracellular matrix metalloproteinase-9 (MMP-9) activation and cellular proliferation. In the present study, we investigated whether the α(2) M*/LRP1 interaction induces cellular migration of the macrophage-derived cell line, Raw264.7. By using the wound-scratch migration assay and confocal microscopy, we demonstrate that α(2) M* induces LRP1-mediated mesenchymal cellular migration. This migration exhibits the production of enlarged cellular protrusions, MT1-MMP distribution to these leading edge protrusions, actin polymerization, focal adhesion formation, and increased intracellular LRP1/β1-integrin colocalization. Moreover, the presence of calphostin-C blocked the α(2) M*-stimulated cellular protrusions, suggesting that the PKC activation is involved in the cellular motility of Raw264.7 cells. These findings could constitute a therapeutic target for inflammatory processes with deleterious consequences for human health, such as rheumatoid arthritis, atherosclerosis and cancer. J. Cell. Biochem. 118: 1810-1818, 2017. © 2016 Wiley Periodicals, Inc.
28911876 Immunoglobulin isotype switching of antibodies to vimentin is associated with development 2017 Dec BACKGROUND: Immune responses to tissue-restricted self-antigens are thought to play a role in chronic rejection after solid organ transplantation. De novo development of antibodies (Abs) to vimentin have been reported to be associated with interstitial fibrosis/tubular atrophy after kidney transplant, and it has been suggested that immunoglobulin isotype switching of Abs to vimentin may occur during this process. We aimed to determine the correlation between immunoglobulin isotype switching of Abs to vimentin and development of transplant glomerulopathy (TG) after kidney transplant, and to determine whether citrullinated modification of vimentin is required for de novo anti-vimentin development. METHODS: Sera were collected from 24 patients with TG (diagnosed on biopsy), 24 matched stable kidney transplant recipients (KTxRs) and 22 normal healthy subjects who did not undergo transplant. Serum vimentin Abs concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Immunoglobulin isotypes of anti-vimentin were determined using isotype-specific Abs conjugated with horseradish peroxidase. Samples were considered positive to vimentin Abs if the values were above mean+2× standard deviations of the levels in the healthy control subjects. Specificities of anti-vimentin for mutated citrullinated vimentin and anti-mutated citrullinated vimentin were measured by ELISA. RESULTS: In this retrospective analysis of 24 KTxRs with TG, 16/24 (67%) patients with biopsy-proven TG developed Abs to vimentin (645±427ng/ml). In contrast, only 4/24 (17%) stable KTxRs had detectable Abs to vimentin (275±293ng/ml; p=0.001). Of the patients with TG, 15/24 (63%) developed Abs to vimentin of IgG isotype (572±276ng/ml), whereas only 6/24 (25%) stable KTxRs (310±288ng/ml) had anti-vimentin of IgG isotype (p=0.002). However, no significant difference was noted in the concentration of IgM isotype anti-vimentin between KTxRs with TG (9/24 [38%], 407±401ng/ml) and stable KTxRs (5/24 [21%], 348±439ng/ml; p=0.631). The serum concentration of Abs specific for the mutated form of citrullinated vimentin was not significantly different between KTxRs with TG and stable KTxRs. CONCLUSIONS: Patients with biopsy-proven TG demonstrated significantly increased levels of anti-vimentin Abs of the IgG isotype compared with stable KTxRs. Anti-vimentin in stable KTxRs was primarily of IgM isotype. Therefore, the observed isotype switching of anti-vimentin from IgM to IgG isotype strongly suggests ongoing immune responses to vimentin in KTxRs diagnosed with TG. Furthermore, as opposed to patients with rheumatoid arthritis (who develop immune responses primarily to citrullinated vimentin), KTxRs diagnosed with TG developed immune responses to non-citrullinated vimentin, suggesting that modification of vimentin protein via citrullination is not required for the de novo anti-vimentin response seen in patients with TG.