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ID PMID Title PublicationDate abstract
30306514 Tackling Pain Associated with Rheumatoid Arthritis: Proton-Sensing Receptors. 2018 Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. Chronic pain that comes with RA turns independent, essentially becoming its own disease. It could partly explain that a significant number (50%) of RA patients fail to respond to current RA therapies that focus mainly on suppression of joint inflammation. The acute phase of pain seems to associate with joint inflammation in early RA. In established RA, the chronic phase of pain could be linked to inflammatory components of neuron-immune interactions and noninflammatory components. Accumulating evidence suggests that the initial inflammation and autoimmunity in RA (preclinical RA) begin outside of the joint and may originate at mucosal sites and alterations in the composition of microbiota located at mucosal sites could be essential for mucosal inflammation, triggering joint inflammation. Fibroblast-like synoviocytes in the inflamed joint respond to cytokines to release acidic components, lowering pH in synovial fluid. Extracellular proton binds to proton-sensing ion channels, and G-protein-coupled receptors in joint nociceptive fibers may contribute to sensory transduction and release of neurotransmitters, leading to pain and hyperalgesia. Activation of peripheral sensory neurons or nociceptors further modulates inflammation, resulting in neuroinflammation or neurogenic inflammation. Peripheral and central nerves work with non-neuronal cells (such as immune cells, glial cells) in concert to contribute to the chronic phase of RA-associated pain. This review will discuss actions of proton-sensing receptors on neurons or non-neuronal cells that modulate RA pathology and associated chronic pain, and it will be beneficial for the development of future therapeutic treatments.
29474183 Health-Related Quality of Life and Functional Ability of Patients with Rheumatoid Arthriti 2018 May OBJECTIVES: To assess the health-related quality of life and functional ability of patients with rheumatoid arthritis (RA) using the Thai EuroQol five-dimensional questionnaire (EQ-5D) and the Thai Health Assessment Questionnaire (HAQ), and to analyze correlations between the scores from both questionnaires. METHODS: This cross-sectional study was conducted among 221 patients with RA aged 18 years or older at a tertiary care hospital in Thailand. Data collection methods included individual patient interviews and data gathering from medical records. The correlations between the EQ-5D and HAQ scores were analyzed using Spearman's rank correlation coefficients. RESULTS: Most patients were female (78.3%), aged 41 to 60 years (57.0%), having had RA for 12 to 60 months (43.0%), and being in an active disease state (60.6%). From the EQ-5D, most patients reported no problems in each dimension, except for mobility and pain/discomfort. For the HAQ, most patients reported no difficulty for almost all activities, except for arising. The medians (interquartile ranges) for the EQ-5D utility, EuroQol visual analogue scale (EQ VAS), and HAQ scores were 0.65 (0.55-0.73), 70 (50-80), and 0.25 (0.00-0.81), respectively. The Spearman's rank correlation coefficients were 0.42 for the EQ-5D utility and EQ VAS scores (P = 0.01), -0.65 for the EQ-5D utility and HAQ scores (P < 0.001), and -0.39 for the EQ VAS and HAQ scores (P < 0.001). CONCLUSIONS: The health-related quality of life and functional ability of most patients in our study were partially affected by the disease. The EQ-5D and HAQ scores significantly correlated at a moderate to strong level.
30521345 Route to Rheumatoid Arthritis by Macrophage-Derived Microvesicle-Coated Nanoparticles. 2019 Jan 9 The targeted delivery of therapeutics to sites of rheumatoid arthritis (RA) has been a long-standing challenge. Inspired by the intrinsic inflammation-targeting capacity of macrophages, a macrophage-derived microvesicle (MMV)-coated nanoparticle (MNP) was developed for targeting RA. The MMV was efficiently produced through a novel method. Cytochalasin B (CB) was applied to relax the interaction between the cytoskeleton and membrane of macrophages, thus stimulating MMV secretion. The proteomic profile of the MMV was analyzed by iTRAQ (isobaric tags for relative and absolute quantitation). The MMV membrane proteins were similar to those of macrophages, indicating that the MMV could exhibit bioactivity similar to that of RA-targeting macrophages. A poly(lactic- co-glycolic acid) (PLGA) nanoparticle was subsequently coated with MMV, and the inflammation-mediated targeting capacity of the MNP was evaluated both in vitro and in vivo. The in vitro binding of MNP to inflamed HUVECs was significantly stronger than that of the red blood cell membrane-coated nanoparticle (RNP). Compared with bare NP and RNP, MNP showed a significantly enhanced targeting effect in vivo in a collagen-induced arthritis (CIA) mouse model. The targeting mechanism was subsequently revealed according to the proteomic analysis, indicating that Mac-1 and CD44 contributed to the outstanding targeting effect of the MNP. A model drug, tacrolimus, was encapsulated in MNP (T-RNP) and significantly suppressed the progression of RA in mice. The present study demonstrates MMV as a promising and rich material, with which to mimic macrophages, and demonstrates that MNP is an efficient biomimetic vehicle for RA targeting and treatment.
29482402 Etanercept for the treatment of rheumatoid arthritis. 2018 Mar 1 Etanercept was the first specific anticytokine therapy approved for the treatment of rheumatoid arthritis (RA). Its clinical efficacy and safety has been demonstrated by several clinical trials in early as well as established disease. Etanercept, along with other TNF inhibitors, have revolutionized management of RA and dramatically improved disease activity, function, quality of life and mortality for these patients. It is structurally distinct from other TNF inhibitors and thus has desirable profiles for immunogenicity, drug survival and infection rate. With the increasing number of etanercept biosimilars, there will likely be a resurgence of their prescription. This article reviews the pharmacology, efficacy and safety of the etanercept reference product, and its biosimilars, in the context of RA treatment.
29165795 Therapeutic potency of mTOR signaling pharmacological inhibitors in the treatment of proin 2018 Jun Mammalian target of rapamycin (mTOR) signaling pathway controls cell energy metabolism. There is an interplay between mTOR and proinflammatory signaling pathways, supporting the role of the pathway in the pathogenesis of inflammatory diseases. Inhibition of mTOR signaling using specific pharmacological inhibitors could offer therapeutic promise in several inflammatory-associated diseases. In this review, we summarize recent findings on the regulatory effects of mTOR signaling on inflammation and the therapeutic potency of mTOR pharmacological inhibitors in the treatment of inflammatory diseases including cancer, neurodegenerative diseases, atherosclerosis, sepsis, and rheumatoid arthritis for a better understanding and hence a better management of these diseases.
30173151 Heart Rate-corrected QT Interval Duration in Rheumatoid Arthritis and Its Reduction with T 2018 Dec OBJECTIVE: Individuals with rheumatoid arthritis (RA) are at a heightened risk of sudden cardiac death, an outcome increased in those with prolongation of the corrected electrocardiographic QT interval (QTc). We compared QTc between patients with RA and demographically matched controls and studied the change in QTc after treatment with the interleukin 6 inhibitor tocilizumab (TCZ). METHODS: Standard 12-lead electrocardiograms were obtained and QTc was measured in patients with RA at baseline and after 24 weeks of TCZ treatment, then compared with non-RA controls who were frequency-matched on age and sex. Indicators of the baseline QTc and predictors of change in QTc were studied using multivariable linear regression. RESULTS: A total of 94 RA and 42 non-RA controls were studied. The average baseline QTc was 10 ms longer in the RA group vs controls (422 vs 412 ms, respectively; p < 0.001) and decreased to an average of 406 ms with treatment (p < 0.001). Baseline QTc was significantly and independently higher among those with anticyclic citrullinated peptide antibodies seropositivity, higher swollen joint counts, and higher levels of C-reactive protein (CRP) and matrix metalloproteinase 3. Each log unit decrease in CRP with treatment was associated with an average reduction in QTc of 2.9 ms (p = 0.002) after adjusting for age and baseline QTc. Clinical response measures were not associated with the change in QTc. CONCLUSION: The marked normalization of QTc observed with TCZ treatment, and its close parallel with CRP reduction, support the premise that systemic inflammation contributes to cardiac repolarization abnormalities in RA that may be amenable to treatment.
29703029 Attrition rupture of ulnar nerve in a patient with rheumatoid elbow arthritis: A case repo 2018 Apr RATIONALE: Cubital tunnel syndrome has been recognized as a common pathology in rheumatoid arthritis (RA) of the elbow. We encountered a patient with RA of the elbow showing attrition rupture of the ulnar nerve. This pathology is extremely rare, and we discussed preventive measures for similar cases in the future based on our case. PATIENT CONCERNS: A 53-year-old woman, received drug treatment for RA since 30 years earlier, had numbness in the left ulnar nerve territory, dorsal interossei muscle atrophy, and resulting claw hand. DIAGNOSES: Plain x-ray examination showed bone destruction of the left elbow joint and marked osteophyte formation in the medial joint space. In nerve conduction velocity (NCV) tests, the Motor NCV was immeasurable in the ulnar nerve territory. Based on these findings, a diagnosis of left cubital tunnel syndrome was made, and anterior transposition of the ulnar nerve was planned. INTERVENTIONS: When the ulnar nerve dissection was advanced, about 80% portion of the ulnar nerve was ruptured. After the ends of the divided nerve were freshened, end-to-end anastomosis was possible by anterior transposition of the ulnar nerve. OUTCOMES: Two years after the operation, numbness and muscle atrophy also remained. There were no changes in the level of daily activities after the operation. However, motor NCV, showed improvement (22.8 m/s) after the operation. LESSONS: In patients with RA showing ulnar neuropathy symptoms, marked osteophyte formation in the medial joint space or valgus deformity may indicate attrition nerve rupture. In the future, when such patients with RA are examined, active nerve exposure and dissection should be considered in terms of ulnar nerve protection.
28831575 A simplified and validated ultrasound scoring system to evaluate synovitis of bilateral wr 2018 Jan The objective of this study was to develop and validate an optimal simplified combination of joints for ultrasonographic assessment of synovitis in wrists and hands in patients with rheumatoid arthritis (RA). Twenty-two joints, including bilateral wrists, all proximal interphalangeal (PIP), and metacarpophalangeal (MCP) joints, were evaluated by grey-scale (GS) and power Doppler (PD) ultrasound using semi-quantitative scoring systems in 705 RA patients. Candidate joint sets were then selected by multiple linear regression analysis and the optimal candidate set was eventually validated in 235 RA patients. Through multiple linear regression analysis, the standard coefficient (β) of MCP2, MCP3, and MCP5 joints in terms of GS was higher than other joints. The adjusted R (2) of the model composed of wrist, MCP2, MCP3, and MCP5 joints was greater than 0.9. Among the sum GS and PD scores of various selected joint combinations, total score-8, including bilateral wrist, MCP2, MCP3, and MCP5 joints, not only showed highest sensitivity and negative predictive value (93.86 and 92.90% for GS; 97.20 and 97.21% for PD, respectively) but also the best correlation with the total score-22 (r = 0.955 and 0.972 for GS and PD). The score-8 was further validated in 235 RA patients. The sensitivity for detecting synovitis by GS and PD was 94.35 and 94.12%, and the negative predictive values were 94.07 and 95.68%, respectively. Total score-8 system, including bilateral wrist, MCP2, MCP3, and MCP5 joints, is simple and efficient to pick up active synovitis of wrists and hands in patients with RA in daily practice.
28705494 Inflammation initiated by stressed organelles. 2018 Jul Key cellular functions including those related to energy metabolism, organization of the genetic information or production of membrane-bound and secreted proteins are compartmentalized within organelles. Various stresses such as differentiation programs, viral and bacterial infections, perturbations in protein production, mechanical constraints, changes in the environment and nutriment accessibility can impact cellular homeostasis and organelle integrity. Perturbations of these cellular compartments trigger repair and adaptation programs aimed at restoring homeostasis. These events are often associated with low-grade inflammation also termed parainflammation. While the nature and mechanisms of danger signals released by irremediably damaged cells are well understood, how transiently stressed cells trigger inflammation is still poorly understood. Emerging studies highlighted new mechanisms by which stress pathways promote inflammation. Cytosolic innate immune pathways are engaged by signals stemming from perturbed organelles such as the mitochondria, the endoplasmic reticulum (ER) or the nuclear envelope (NE). These observations indicate that these pathways function as guardians of cellular homeostasis and may contribute to disease in pathologies characterized by perturbations of cellular homoeostasis. Mitochondria-stress, ER-stress or NE-stress are emerging as proinflammatory signals that contribute to human conditions and diseases.
29742538 Chronotropic Incompetence and Reduced Heart Rate Recovery in Rheumatoid Arthritis. 2018 Oct BACKGROUND/OBJECTIVE: Recent studies have indicated that cardiac autonomic dysfunction is an early sign of cardiovascular impairment in rheumatoid arthritis (RA). Previous studies have mainly focused on resting assessments; however, analysis of heart rate (HR) responses to exercise might provide additional information on cardiac autonomic dysfunction in this disease. Thus, we aimed to assess the HR responses during and after a maximal graded exercise test in patients with RA and healthy controls (CONs). METHODS: This was a cross-sectional study in which 27 female RA patients and 14 female CONs frequency matched by physical activity, age, and body mass index were compared for HR responses during and after a maximal graded exercise test. RESULTS: Rheumatoid arthritis patients showed reduced chronotropic response (94.3% ± 16.3% vs. 106.1% ± 10.3%, p = 0.02) and lower HR recovery (HRR) at 30 seconds (8.6 ± 6.7 vs. 13.4 ± 5.2 beats/min [bpm], p = 0.02), 60 seconds (16.5 ± 7.8 vs. 24.0 ± 9.9 bpm, p = 0.01), 120 seconds (32.6 ± 9.9 vs. 40.7 ± 12.3 bpm, p = 0.03), and 180 seconds (46.5 ± 12.6 vs. 55.5 ± 13.4 bpm, p = 0.05) post-maximal exercise test when compared with CONs. Moreover, the prevalence of chronotropic incompetence (i.e., failure to reach 80% of the HR-predicted response) and abnormal HRR (i.e., HRR ≤12 bpm) were, respectively, 22.2% and 37.1% in RA patients. CONCLUSIONS: Patients with RA showed reduced chronotropic response to exercise and slower postexercise HRR. These abnormal autonomic responses to exercise indicate the presence of cardiac autonomic dysfunction and increased cardiovascular risk in this population.
29213124 The RA-MAP Consortium: a working model for academia-industry collaboration. 2018 Jan Collaboration can be challenging; nevertheless, the emerging successes of large, multi-partner, multi-national cooperatives and research networks in the biomedical sector have sustained the appetite of academics and industry partners for developing and fostering new research consortia. This model has percolated down to national funding agencies across the globe, leading to funding for projects that aim to realise the true potential of genomic medicine in the 21st century and to reap the rewards of 'big data'. In this Perspectives article, the experiences of the RA-MAP consortium, a group of more than 140 individuals affiliated with 21 academic and industry organizations that are focused on making genomic medicine in rheumatoid arthritis a reality are described. The challenges of multi-partner collaboration in the UK are highlighted and wide-ranging solutions are offered that might benefit large research consortia around the world.
30113458 Multidrug-resistance Acinetobacter baumannii pneumonia in a rheumatoid arthritis patient r 2018 Aug INTRODUCTION: Multidrug-resistant Acinetobacter baumannii (MDRAB) pneumonia with severe sepsis in a patient with rheumatoid arthritis (RA), who is predisposed after treatment with tumor necrosis factor inhibitor (TNFI), is a rare severe infection and can be successfully treated with prompt antibiotics. CASE PRESENTATION: A 75-year-old woman was diagnosed with RA >30 years previously. After inadequate treatment responses to conventional disease-modifying antirheumatic drugs (DMARDs), she developed progressive RA, including swollen joints in both hands, and had a high disease activity score of 4.96 when presenting at our rheumatology clinic. She had started taking the TNFI, golimumab (50 mg/month), 3 years before and developed a productive cough 4 weeks before this admission. One week after admission, she developed fever, dyspnea, hypoxemia, tachycardia, and increased serum C-reactive protein level. DIAGNOSIS: Chest plain film (CxR) and computed tomography of the chest showed hospital-acquired pneumonia; microbial examination of the sputum showed the presence of MDRAB. THERAPEUTICS: She was prescribed a full course of antibiotics with cefoperazone sulbactam. OUTCOMES: CxR showed complete remission of pneumonia. CONCLUSION: Biological DMARDs, such as TNFI, act as a double-edged sword: these drugs are used to treat autoimmune diseases, but they increase the risk of infection. The trend toward antibiotic resistance and persistent environmental survival of MDRAB is an emerging problem in countries with high rates of antibiotic abuse. TNFI may affect intestinal immunity by inducing dysbiosis, which affects T helper 17-mediated mucosal immunity and can contribute to A baumannii colonization and the development of MDRAB in frequently hospitalized patients.
30138371 Differential expression of vitamin D associated genes in the aorta of coronary artery dise 2018 BACKGROUND: Vitamin D has an important role in the immune system, and has been linked to rheumatoid arthritis (RA) and coronary artery disease (CAD). The exact mechanisms by which vitamin D is involved in these processes are still unclear. Therefore, we wanted to search for differences in expression of genes involved in the vitamin D receptor (VDR) activation pathway and genes that are known to alter upon vitamin D stimulation, in the aortic adventitia of CAD patients with and without RA. METHODS: Affymetrix microarray was used to determine gene expression profile in surgical specimens from the adventitia of the ascending aorta of CAD patients with RA (n = 8) and without RA (n = 8) from the Feiring Heart Biopsy Study. RESULTS: We identified three vitamin D associated genes that were differentially expressed between RA and non-RA patients: Growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) (FC = 1.47; p = 0.006), Nuclear Receptor Co-repressor 1 (NCOR1) (FC = 1,21; p = 0.005) and paraoxonases 2 (PON2) (FC = -1.37; p = 0.01). High expression of GADD45A in RA tissues was confirmed by real-time qRT-PCR. GADD45A expression correlated with plasma levels of 1,25(OH)2D3 (rs = 0.69; p = 0.003). CONCLUSIONS: Microarray analyses revealed higher expression of GADD45A and NCOR1; and lower expression of PON2 in the aortic adventitia of RA than non-RA patients. Further studies are needed to elucidate if and how GADD45A, NCOR1 and PON2 are involved in the development of accelerated atherosclerosis in RA. In theory, some of these factors might have proatherogenic effects whereas others might reflect an underlying vascular pathology promoting atherogenesis (such as vascular stress).
30039251 Incidence, risk factors, and fracture healing of atypical femoral fractures: a multicenter 2018 Nov The incidence of atypical femoral fractures (AFFs) was 2.95% among 6644 hip and femoral fractures. Independent risk factors included the use of bisphosphonates (BPs), osteopenia or osteoporosis, rheumatoid arthritis, increased femoral curvatures, and thicker femoral cortices. Patients with AFFs and BP treatment were more likely to have problematic healing than those with typical femoral fractures (TFFs) and no BP treatment. INTRODUCTION: To determine the incidence and risk factors of atypical femoral fractures (AFFs), we performed a multicenter case-control study. We also investigated the effects of bisphosphonates (BPs) on AFF healing. METHODS: We retrospectively reviewed the medical records and radiographs of 6644 hip and femoral fractures of patients from eight tertiary referral hospitals. All the radiographs were reviewed to distinguish AFFs from TFFs. Univariate and multivariate logistic regression analyses were performed to identify risk factors, and interaction analyses were used to investigate the effects of BPs on fracture healing. RESULTS: The incidence of AFFs among 6644 hip and femoral fractures was 2.95% (90 subtrochanter and 106 femoral shaft fractures). All patients were females with a mean age of 72 years, and 75.5% were exposed to BPs for an average duration of 5.2 years (range, 1-17 years). The use of BPs was significantly associated with AFFs (p < 0.001, odds ratio = 25.65; 95% confidence interval = 10.74-61.28). Other independent risk factors for AFFs included osteopenia or osteoporosis, rheumatoid arthritis, increased anterior and lateral femoral curvatures, and thicker lateral femoral cortex at the shaft level. Interaction analyses showed that patients with AFFs using BPs had a significantly higher risk of problematic fracture healing than those with TFFs and no BP treatment. CONCLUSIONS: The incidence of AFFs among 6644 hip and femoral fractures was 2.95%. Osteopenia or osteoporosis, use of BPs, rheumatoid arthritis, increased anterior and lateral femoral curvatures, and thicker lateral femoral cortex were independent risk factors for the development of AFFs. Patients with AFFs and BP treatment were more likely to have problematic fracture healing than those with TFFs and no BP treatment.
29925278 Sirukumab for the treatment of rheumatoid arthritis: update on sirukumab, 2018. 2018 Jul Interleukin-6 (IL-6) is well-known for its pro-inflammatory properties, has been proven to target a wide range of cells in the joint, and has been implicated in extra-articular and articular manifestations in rheumatoid arthritis (RA). Tocilizumab (TCZ) is now widely used in patients with active RA and a number of additional agents that target the IL-6 pathways are under development, including sirukumab (SRK). Areas covered: SRK is an IgG1κ human anti-IL-6 monoclonal antibody which binds to IL-6 and prevents IL-6-mediated downstream effects. Initial trial results in phase-III studies in patients with RA seemed promising, showing improved results in patients with moderate-to-severe RA. Data derive from the phase-II study and the various SIRROUND studies (phase III). Expert commentary: The available data show that SRK50 mg every 4 weeks or 100 mg every 2 weeks will be effective in treating the RA population, with clinical improvements as early as week 2 and sustained over time. The adverse-event profile seems to be similar to TCZ, except for an increased mortality post open-label studies due to infections and cardiovascular events, our knowledge of which will be deepened with post-marketing surveillance and registry data.
29380961 Experiences of a patient-initiated self-monitoring service in inflammatory arthritis: A qu 2018 Jun OBJECTIVES: The aim of the present study was to explore patients' experience of a patient-initiated self-monitoring service for people with rheumatoid or psoriatic arthritis who are on methotrexate. METHODS: The study took the form of qualitative semi-structured interviews, embedded within a randomized controlled trial. Twelve participants who were randomly assigned to the intervention arm were interviewed. Interviews digitally, transcribed verbatim and analysed using inductive thematic analysis. The study received full National Health Service ethics approval from Camden and Islington Community Local Research Ethics Committee (Ref. 09/H0722/91). RESULTS: Analysis revealed five key themes. Participants described usual care as burdensome and an inefficient use of time, particularly those in employment. Being able to self-monitor and initiate their own care increased patients' knowledge about their illness and its treatment, and enabled them to gain a sense of control and ownership over their arthritis. They appreciated the personalized nature of the new service, which allowed them to be seen at a time and by a method more appropriate to their needs. There were, however, some concerns about fidelity to the service protocol, confusion about the lack of consistency between symptoms and laboratory results, and anxiety about self-monitoring. CONCLUSIONS: Overall, participants were positive about the new service, in comparison with usual care, valuing its tailored approach and empowering effects. Further work is needed to ensure adherence to the service protocol and address anxieties around self-monitoring prior to any widespread implementation of the service.
29934747 Associations between D3R expression in synovial mast cells and disease activity and oxidan 2018 Oct Dopamine D3 receptor (D3R) on immune cells is involved in the pathogenesis of rheumatoid arthritis (RA). Mast cells (MCs) are currently identified as important effector cells in synovial inflammation of RA, but little is known about the role of D3R on synovial MCs in the pathogenesis of RA. Several inflammatory cells in the synovium induce reactive oxygen species (ROS) formation which are involved in the progression of RA. However, it is unclear whether D3R on synovial MCs is related to the levels of ROS in RA patients. In this study, a total of 73 patients with RA were divided into three groups according to disease activity DAS28 scores. The number of cases in group 1, group 2, and group 3 was 19, 26, and 28, respectively. We examined D3R-positive MC numbers in the synovial fluid and ROS levels in each group of RA patients, and we also analyzed the association of D3R-positive MC numbers with RA disease activity and ROS levels. MDA and protein carbonylation in the serum and synovial fluid were measured to reflect the level of lipid peroxidation and protein oxidation, respectively. Additionally, superoxide dismutase (SOD) and catalase (CAT) in the serum and synovial fluid were used to be markers of antioxidant levels. Our results showed that D3R-positive MCs in the synovial fluid showed a declining trend with the increased disease activity DAS28 score in RA patients. There was negative correlation between D3R-positive MC numbers in the synovial fluid and disease severity DAS28 score of RA patients. Moreover, D3R-positive MC numbers in the synovial fluid were negatively correlated with the level of MDA and protein carbonylation while were positively correlated with antioxidant levels such as SOD and CAT in RA patients. Our results suggested that D3R on MCs may be involved in ROS-mediated pathogenesis of RA.
30557838 A smart nanosensor for the detection of human immunodeficiency virus and associated cardio 2019 Feb 1 Human immunodeficiency virus (HIV), which isa worldwide public health issue, is commonly associated with cardiovascular disorders (CVDs) and rheumatoid arthritis (RA). A smart nanosensor was developed for the detection of HIV and its related diseases (CVDs and RA) using graphene-based field-effect transistors (FETs). In this study, amine-functionalized graphene (afG) was conjugated with antibodies [anti-p24 for HIV, anti-cardiac troponin 1 (anti-cTn1) for CVDs, and anti-cyclic citrullinated peptide (anti-CCP) for RA] to detect various biomarkers. The antibodies were covalently conjugated to afG via carbodiimide activation. The bioconjugate (graphene-antibody) was characterized by various biophysical techniques such as UV-Vis, Raman spectroscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM). The electrochemical performance of the sensor was evaluated with respect to changes in the resistance of the electrode surface due to the interaction of the antigen with its specific antibody. The developed sensor was highly sensitive and showed a linear response to p24, cTn1, and, CCP from 1 fg/mL to 1 μg/mL. The limit of detection (LOD) was 100 fg/mL for p24 and 10 fg/mL for cTn1 and CCP under standard optimized conditions. The graphene-based smart nanodevice demonstrated excellent performance; thus, it could be used for the on-site detection of HIV, CVD, and RA biomarkers in real samples.
30053832 A bivalent compound targeting CCR5 and the mu opioid receptor treats inflammatory arthriti 2018 Jul 27 BACKGROUND: Pain accompanies rheumatoid arthritis and other chronic inflammatory conditions and is difficult to manage. Although opioids provide potent analgesia, chronic opioid use can cause tolerance and addiction. Recent studies have demonstrated functional interactions between chemokine and opioid receptor signaling pathways. Reported heterodimerization of chemokine and opioid receptors led our group to develop bivalent compounds that bind both types of receptors, with the goal of targeting opioids to sites of inflammation. MCC22 is a novel bivalent compound containing a CCR5 antagonist and mu opioid receptor (MOR) agonist pharmacophores linked through a 22-atom spacer. We evaluated the efficacy of MCC22 in the K/B.g7 T-cell receptor transgenic mouse model of spontaneous inflammatory arthritis. METHODS: MCC22 or morphine was administered intraperitoneally at varying doses to arthritic K/B.g7 mice or nonarthritic control mice. Mechanical pain hypersensitivity was measured each day before and after drug administration, using the electronic von Frey test. The potency of MCC22 relative to that of morphine was calculated. Functional readouts of pain included grip strength and nesting behavior. A separate dosing regimen was used to determine whether the drugs induced pharmacologic tolerance. RESULTS: MCC22 provided ~ 3000-fold more potent analgesia than morphine in this model. Daily treatment with MCC22 also led to a cumulative analgesic effect, reducing the daily baseline pain level. MCC22 produced no observable analgesic effect in nonarthritic control mice. Importantly, repeated administration of MCC22 did not induce pharmacologic tolerance, whereas a similar regimen of morphine did. Both grip strength and nesting behaviors improved among arthritic mice treated with MCC22. Ankle thickness and arthritis scores were not affected by MCC22. The analgesic effect of MCC22 was abolished in K/B.g7 mice genetically lacking CCR5, demonstrating the receptor specificity of the antagonist pharmacophore. CONCLUSIONS: MCC22 is a novel bivalent ligand that targets CCR5 and MOR. Our findings demonstrate that MCC22 provides highly potent analgesia and improved functional outcomes in a model of inflammatory arthritis, without inducing typical opioid tolerance. These findings suggest that MCC22 or similar compounds could be used to treat the pain associated with inflammatory arthritis and related conditions, while minimizing the risks typically associated with chronic opioid use.
30286793 E2F2 directly regulates the STAT1 and PI3K/AKT/NF-κB pathways to exacerbate the inflammat 2018 Oct 4 BACKGROUND: Expression of E2F transcription factor 2 (E2F2), a transcription factor related to the cell cycle, is abnormally high in rheumatoid arthritis synovial fibroblasts (RASFs). Deregulated expression of E2F2 leads to abnormal production of proinflammatory cytokines, such as interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α in RASFs. However, the underlying mechanism by which E2F2 regulates expression of IL-1α, IL-1β, and TNF-α has not been fully elucidated. This study aimed to elucidate this mechanism and confirm the pathological roles of E2F2 in rheumatoid arthritis (RA). METHODS: E2f2 knockout (KO) and wild-type (WT) mice were injected with collagen to induce RA. Cytokine production was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Western blot and qRT-PCR were performed to evaluate the effect of E2F2 on signaling pathway activity. Chromatin immunoprecipitation (ChIP)-PCR and luciferase assays were used to detect the transcriptional activity of target genes of E2F2. Nuclear translocation of STAT1 and p65 were assayed by Western blot, co-immunoprecipitation (co-IP), and immunofluorescence experiments. RESULTS: The occurrence and severity of collagen-induced arthritis were decreased in E2f2-KO mice compared with WT mice. The expression of IL-1α, IL-1β, and TNF-α was also suppressed in mouse embryonic fibroblasts (MEFs) from E2f2-KO mice and RASFs with E2F2 knocked down. Mechanistically, we found that E2F2 can upregulate the expression of STAT1 and MyD88 through direct binding to their promoters, facilitate the formation of STAT1/MyD88 complexes, and consequently activate AKT. However, silencing STAT1/MyD88 or inactivating AKT significantly attenuated the induction of IL-1α, IL-1β, and TNF-α caused by the introduction of E2F2. CONCLUSIONS: This study confirms the pathological role of E2F2 in RA and found that the E2F2-STAT1/MyD88-Akt axis is closely related with the inflammatory phenotype in RASFs.