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ID PMID Title PublicationDate abstract
29652046 [Hydrogalvanic baths as a method of medical rehabilitation: a literature review and the pr 2018 Apr 9 The hydrogalvanic baths provide a tool for the combined application of warm fresh water and low frequency electric current. These procedures are suitable for both systemic and local treatments. The mechanism behind their therapeutic action is based on synergistic effect of two therapeutic agents. This article presents the literature and historical review of the method as well as the current concept of hydrohalvanic therapy. The history of its development is associated with the improvement of the technical equipment and accumulation of clinical experience. Numerous studies carried out up to the present time have demonstrated that hydrohalvanic therapy can be effectively applied for the treatment of diabetic angiopathy, rheumatoid and gouty arthritis, fibromyalgia, ankylosing spondylitis. At the same time, the high potential of this method remains underestimated. At present, one of the most promising approaches to its clinical applications is the treatment of lumbosacral radiculopathy caused by degenerative vertebral disk lesions. The hydrogalvanic baths have analgesic, anti-inflammatory, and decongestant effects, improve microcirculation, and reduce sensory impairment. It is necessary to continue clinical investigations to obtain further evidence of the effectiveness of the method under consideration for the treatment of lumbosacral radiculopathy and to evaluate its short- and long-term effects. Their results will hopefully provide an opportunity to include the hydrogalvanic baths in the programs of medical rehabilitation of the patients presenting with lumbosacral radiculopathy.
29781582 Sphingosine 1-Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function a 2018 Nov OBJECTIVE: Immune complex (IC) deposition activates polymorphonuclear neutrophils (PMNs), increases vascular permeability, and leads to organ damage in systemic lupus erythematosus and rheumatoid arthritis. The bioactive lipid sphingosine 1-phosphate (S1P), acting via S1P receptor 1 (S1P(1) ), is a key regulator of endothelial cell (EC) barrier function. This study was undertaken to investigate whether augmenting EC integrity via S1P(1) signaling attenuates inflammatory injury mediated by ICs. METHODS: In vitro barrier function was assessed in human umbilical vein endothelial cells (HUVECs) by electrical cell-substrate impedance sensing. Phosphorylation of myosin light chain 2 (p-MLC-2) and VE-cadherin staining in HUVECs were assessed by immunofluorescence. A reverse Arthus reaction (RAR) was induced in the skin and lungs of mice with S1P(1) deleted from ECs (S1P(1) EC-knockout [ECKO] mice) and mice treated with S1P(1) agonists and antagonists. RESULTS: S1P(1) agonists prevented loss of barrier function in HUVECs treated with IC-activated PMNs. S1P(1) ECKO and wild-type (WT) mice treated with S1P(1) antagonists had amplified RAR, whereas specific S1P(1) agonists attenuated skin and lung RAR in WT mice. ApoM-Fc, a novel S1P chaperone, mitigated EC cell barrier dysfunction induced by activated PMNs in vitro and attenuated lung RAR. Expression levels of p-MLC-2 and disruption of VE-cadherin, each representing manifestations of cell contraction and destabilization of adherens junctions, respectively, that were induced by activated PMNs, were markedly reduced by treatment with S1P(1) agonists and ApoM-Fc. CONCLUSION: Our findings indicate that S1P(1) signaling in ECs modulates vascular responses to IC deposition. S1P(1) agonists and ApoM-Fc enhance the EC barrier, limit leukocyte escape from capillaries, and provide protection against inflammatory injury. The S1P/S1P(1) axis is a newly identified target to attenuate tissue responses to IC deposition and mitigate end-organ damage.
30446980 Why Biologics and Biosimilars Remain So Expensive: Despite Two Wins for Biosimilars, the S 2018 Nov Biologics and biosimilars are medicines made from living cells that treat common and serious diseases such as cancer, diabetes, rheumatoid arthritis, and other inflammatory diseases. They are highly targeted, efficacious, and represent an increasingly important part of physicians' armamentaria in the combat against these medical conditions. Yet they are extremely expensive, costing on average $10,000-$30,000 per year and exceed $500,000 for the most expensive biologics. The advent of biosimilar drugs, or high similar copies of biologics, was supposed to help reduce costs, but thus far the cost of treatment with biologics or biosimilars has not fallen sharply in the USA. We argue that a primary hurdle is the extent of patent protection for the reference biologics that impedes greater numbers of biosimilars entering into the market. To date, of the 12 biosimilars approved for marketing by the US Food and Drug Administration (FDA), only five are commercially available. All but one of the remaining biosimilars are withheld from commercialization due to patent disputes. We argue that the market for biologics and biosimilars will become price competitive only if more biosimilars are available to patients. To this end, the process to eliminate marginally inventive patents held by the reference drug makers must be streamlined and improved. In this perspective article, we suggest actions to improve the pre-FDA approval patent resolution process known as the patent dance, the streamlined patent invalidation process known as Inter Partes Reviews, and the process of granting patents.
30097125 Total sesquiterpene lactones isolated from Inula helenium L. attenuates 2,4-dinitrochlorob 2018 Jul 15 BACKGROUND: Inula helenium L. is an herb whose anti-inflammatory properties are attributed to its active components, the sesquiterpene lactones (SLs). Our previous study demonstrated that the total sesquiterpene lactones isolated from Inula helenium L. (TSL-IHL), consisting mainly of alantolactone (AL) and isoalantolactone (IAL), may have potential in the prevention and treatment of rheumatoid arthritis (RA). However, the effect of TSL-IHL on atopic dermatitis (AD) has not been studied yet. AIM OF THE STUDY: The present study evaluates the potential of TSL-IHL as a treatment for AD. METHODS/STUDY DESIGNS: The effects of TSL-IHL on the expression of inflammatory genes and the activation of NF-κB signaling pathway in HaCat cells were examined by quantitative real-time PCR and western blotting, respectively, and compared with those of AL and IAL. The protective effect of TSL-IHL against AD was tested in a mouse model induced by 2,4-dinitrochlorobenzene (DNCB), in which AD-like skin lesions were induced in ICR mice by sensitizing once with 100 µl of 7% DNCB painted on their shaved back skin and then challenging with 20 µl of 0.2% DNCB five times on their right ears at 3 day intervals starting on day 5 post-sensitization. RESULTS: TSL-IHL, as well as AL and IAL, could all inhibit TNF-α-induced activation of NF-κB and the expression of TNF-α, IL-1, and IL-4 in HaCat cells in a dose-dependent manner in the range of 0.6-2.4 µg/ml. The topical application of TSL-IHL (1% W/W in emollient cream) attenuated DNCB-induced dermatitis severity and right ear swelling. The serum levels of IgE, TNF-α and IFN-γ in TSL-IHL-treated mice were reduced by 81.39%, 89.69%, and 87.85%, respectively, while the mRNA levels of IL-4, IL-5 and IL-13, in the back-skin lesions of TSL-IHL-treated mice were reduced by 39.21%, 40.62% and 48.12%, respectively, compared with the untreated controls. Histopathological examination showed that TSL-IHL treatment reduced epidermis/dermis thickening and dermal inflammatory infiltration in both ear and back skins. CONCLUSIONS: We suggest that TSL-IHL inhibited the development of AD-like skin symptoms by regulating cytokine expression and may be an effective alternative therapy for AD.
29957733 Expanding the Spectrum of EBV-positive Marginal Zone Lymphomas: A Lesion Associated With D 2018 Oct Traditionally low-grade B-cell lymphomas have been excluded from the category of monomorphic posttransplant lymphoproliferative disorders. However, recent reports identified Epstein-Barr virus-positive (EBV) extranodal marginal zone lymphomas (MZL), almost exclusively seen in the posttransplant setting. Some reported cases responded to reduced immunosuppression, suggesting that they should be considered as a form of posttransplant lymphoproliferative disorders. We identified 10 cases of EBV MZL, 9 in extranodal sites and 1 presenting in lymph node. Two cases arose following solid organ transplantation, but other settings included iatrogenic immunosuppression for rheumatoid arthritis (2); prior chemotherapy (2); congenital immune deficiency (1); and increased age (3), as the only potential cause of immune dysfunction. There were 4 males and 6 females; age range 18 to 86. The atypical plasmacytoid and/or monocytoid B cells were positive for EBV in all cases, with either latency I or II in all cases tested. Monotypic light chain expression was shown in all with 6 cases positive for IgG, and 2 for IgM, undetermined in 2. Clonal immunoglobulin gene rearrangement was positive in all cases with successful amplification. MYD88 L265P was wild type in the 6 cases tested. We show that EBV MZLs can arise in a variety of clinical settings, and are most often extranodal. Treatment varied, but most patients had clinically indolent disease with response to reduction of immune suppression, or immunochemotherapy.
29950160 Synergistic effect of cumulative corticosteroid dose and immunosuppressants on avascular n 2018 Sep Objectives Avascular necrosis (AVN) is one of the most common causes of organ damage in patients with systemic lupus erythematosus (SLE) and often causes serious physical disability. The aims of this study were to investigate clinical risk factors associated with symptomatic AVN and to analyze their synergistic effects in a large SLE cohort in Korea. Methods Patients with SLE were enrolled and followed from 1998 to 2014 in the Hanyang BAE Lupus cohort, and damage was measured annually according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). AVN was confirmed by imaging study if patients had symptoms. To determine risk factors for AVN, clinical, laboratory and therapeutic variables were analyzed by logistic regression. Relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S) were calculated to measure interactions between significant variables. Results Among 1219 SLE patients, symptomatic AVN was the most common type of musculoskeletal damage (10.8%, n = 132). SLE patients with AVN showed an earlier onset age, demonstrated AVN more commonly in conjunction with certain other clinical manifestations such as renal and neuropsychiatric disorders, and received significantly higher total cumulative corticosteroid dose and immunosuppressive agents than did patients without AVN. However, in multivariable analysis, only two variables including use of a cumulative corticosteroid dose greater than 20 g (odds ratio (OR) 3.62, p = 0.015) and use of immunosuppressants including cyclophosphamide or mycophenolate mofetil (OR 4.51, p < 0.001) remained as significant risk factors for AVN. Patients with cumulative corticosteroid dose > 20 g and immunosuppressant use had a 15.44-fold increased risk for AVN, compared with patients without these risk factors ( p < 0.001). RERI, AP and S, which define the strength of interactions between two risk factors, were 9.01 (95% confidence interval (CI) 1.30-16.73), 0.58 (95% CI 0.36-0.81) and 2.66 (95% CI 1.42-4.99), respectively, supporting the presence of synergistic interactions in the development of symptomatic AVN in our Korean lupus cohort. Conclusions An individual risk assessment for AVN development should be made prior to and during treatment for SLE, especially in patients with high-dose corticosteroid and immunosuppressant use regardless of clinical manifestations and disease activity.
29915899 Stable expression of infliximab in CRISPR/Cas9-mediated BAK1-deficient CHO cells. 2018 Aug OBJECTIVES: To establish stable infliximab-expressing Chinese hamster ovary (CHO) cells with high tolerance to serum-free culture. RESULTS: Bcl-2 antagonist/killer 1 (BAK1), which is a key mediator of the apoptosis pathway, was disrupted, and infliximab, which is a broadly used monoclonal antibody for the treatment of rheumatoid arthritis and other autoimmune diseases, was incorporated into the BAK1 locus of the CHO chromosome using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas genome-editing technique. The activating effects of serum starvation on BAK1 and cytochrome C (CytC) were suppressed in the genome-edited cells, and the ability of the cells to resist the serum starvation-induced loss of mitochondrial membrane potential and apoptosis was increased, as indicated by the results of polymerase chain reaction (PCR), flow cytometry, enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography (HPLC) analysis. In addition, during subsequent passages, infliximab could be stably produced in the genome-edited CHO cells, and the recombinant antibody could effectively antagonize the cytotoxic effect of tumor necrosis factor α (TNFα). CONCLUSIONS: A CHO cell line capable of stably expressing infliximab and adapting to serum-free culture was constructed. This work lays the foundation for the development of infliximab biosimilars.
29891807 Protective Effects of Peucedanum japonicum Extract against Osteoarthritis in an Animal Mod 2018 Jun 11 Peucedanum japonicum Thunberg is an herbal medicine used to treat neuralgia, rheumatoid arthritis, and inflammatory-related diseases. However, its effects on osteoarthritis (OA) and its regulatory mechanisms have not been investigated by network analysis. Here, we investigated the pharmacological effects of Peucedanum japonicum extract (PJE) on OA, by combining in vivo effective verification and network pharmacology prediction. Rats in which OA was induced by monosodium iodoacetate (MIA) were treated with PJE (200 mg/kg), and histopathological parameters, weight bearing distribution and inflammatory factors in serum and joint tissue were measured after 28 days of treatment. Additionally, in silico network analysis was used to predict holistic OA regulatory mechanisms of PJE. The results showed that PJE exerted potential protective effects by recovering hind paw weight bearing distribution, alleviating histopathological features of cartilage and inhibiting inflammatory mediator levels in the OA rat model. Furthermore, network analysis identified caspase-3 (CASP3), caspase-7 (CASP7), and cytochrome P450 2D6 (CYP2D6) as potential target genes; in addition, the TNF (Tumor necrosis factor) signaling pathway was linked to OA therapeutic action. Our combined animal OA model and network analysis confirmed the therapeutic effects of PJE against OA and identified intracellular signaling pathways, active compounds and target genes linked to its therapeutic action.
29800570 Necrostatin-7 suppresses RANK-NFATc1 signaling and attenuates macrophage to osteoclast dif 2018 Sep 5 Osteoclasts play a crucial role in osteolytic bone diseases, such as osteoporosis, rheumatoid arthritis, periodontitis, Paget's disease of bone and bone metastatic tumors. Therefore, controlling osteoclast differentiation and function has been considered a promising therapeutic strategy. Here, we show that necrostatin (Nec)-7, an inhibitor of programmed necrosis, strongly suppressed receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption, without compromising macrophage colony-stimulating factor (M-CSF)-supported survival and growth of osteoclast precursor cells. Accordingly, Nec-7 significantly decreased the levels of RANKL-induced osteoclastogenic marker genes, such as cathepsin K. Mechanistically, Nec-7 neither affected MAPK nor NF-κB activation; however, it strongly inhibited the RANKL receptor (RANK) to nuclear factor of activated T cells c1 (NFATc1) signaling. Lentiviral expression of RANK in bone marrow-derived macrophages significantly restored osteoclastogenesis and NFATc1 amplification in Nec-7-treated cells. In this study, we revealed that Nec-7-sensitive pathways are crucially involved in osteoclast formation and function. Investigation of the molecular mechanism(s) through which Nec-7 inhibits RANK-NFATc1 signaling axis may lead to the development of new therapeutic strategies for bone disease.
29748389 Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the 2018 Jun 29 Chronic inflammation is associated with multiple human disorders, such as rheumatoid arthritis, metabolic diseases, and neurodegenerative diseases. Therefore, alleviation of inflammation induced by environmental stimuli is important for disease prevention or treatment. Cereblon (CRBN) functions as a substrate receptor of the cullin-4 RING E3 ligase to mediate protein ubiquitination and degradation. Although it has been reported that CRBN reduces the inflammatory response through its nonenzymatic function, its role as a substrate receptor of the E3 ligase is not explored in mediating this process. Here we used a quantitative proteomics approach to find that the major component of the activator protein 1 (AP-1) complex, c-Jun, is significantly down-regulated upon CRBN expression. Biochemical approaches further discover that CRBN interacts and partially colocalizes with c-Jun and promotes the formation of Lys(48)-linked polyubiquitin chains on c-Jun, enhancing c-Jun degradation. We further reveal that CRBN attenuates the transcriptional activity of the AP-1 complex and reduces the mRNA expression and protein level of several pro-inflammatory cytokines. Moreover, flow cytometry analyses show that CRBN attenuates lipopolysaccharide-induced apoptosis in differentiated THP-1 cells. Through genetic manipulation and pharmacological inhibition, we uncover a new molecular mechanism by which CRBN regulates the inflammatory response and apoptosis induced by lipopolysaccharide. Our work and previous studies demonstrate that CRBN suppresses the inflammatory response by promoting or inhibiting the ubiquitination of two key molecules at different levels of the inflammatory cascade through its enzymatic function as a substrate receptor and its nonenzymatic function as a protein binding partner.
28916304 Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treat 2018 Feb BACKGROUND: Abdominal aortic aneurysms (AAAs) are a major source of morbidity and mortality despite continuing advances in surgical technique and care. Although the inciting factors for AAA development continue to be elusive, accumulating evidence suggests a significant periaortic inflammatory response leading to degradation and dilation of the aortic wall. Previous human trials have demonstrated safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of inflammation-related pathologies such as rheumatoid arthritis, graft versus host disease, and transplant rejection. Therefore, herein, we describe the Aortic Aneurysm Repression with Mesenchymal Stem Cells (ARREST) trial, a phase I investigation into the safety of MSC infusion for patients with small AAA and the cells' effects on modulation of AAA-related inflammation. METHODS: ARREST is a phase I, single-center, double-blind, randomized controlled trial (RCT) investigating infusion both dilute and concentrated MSCs compared to placebo in 36 small AAA (35-45 mm) patients. Subjects will be followed by study personnel for 12 months to ascertain incidence of adverse events, immune cell phenotype expression, peripheral cytokine profile, and periaortic inflammation. Maximum transverse aortic diameter will be assessed regularly for 5 years by a combination of computed tomography and duplex sonography. RESULTS: Four patients have thus far been enrolled, randomized, and treated per protocol. We anticipate the conclusion of the treatment phase within the next 24 months with ongoing long-term follow-up. CONCLUSIONS: ARREST will be pivotal in assessing the safety of MSC infusion and provide preliminary data on the ability of MSCs to favorably modulate the pathogenic AAA host immune response. The data gleaned from this phase I trial will provide the groundwork for a larger, phase III RCT which may provide the first pharmaceutical intervention for AAA.
28803906 Viscosupplementation for Hip Osteoarthritis: A Systematic Review and Meta-Analysis of the 2018 Mar OBJECTIVE: To assess the efficacy of viscosupplementation (hyaluronic acid [HA]) on the pain and disability caused by hip osteoarthritis, and to determine the occurrence of adverse events. DATA SOURCES: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov database, and specific journals up to March 2017. STUDY SELECTION: Randomized controlled trials (RCTs) comparing HA with any other intra-articular injection. DATA EXTRACTION: Performed according to Cochrane/Grades of Recommendation, Assessment, Development, and Evaluation criteria. Two authors extracted data and assessed the risk of bias and quality of evidence. A random-effects meta-analysis was conducted. DATA SYNTHESIS: Eight RCTs were retrieved (n=807): 4 comparing HA to placebo; 3 to platelet-rich plasma (PRP); 3 to methylprednisolone; and 1 to mepivacaine. Some RCTs had 3 arms. There is very low evidence that HA is not superior to placebo for pain at 3 months (standardized mean difference [SMD]=-.06; 95% CI, -.38 to .25; P=.69), and high evidence that it is not superior in adverse events (risk ratio [RR]=1.21; 95% CI, .79-1.86; P=.38). There is low evidence that HA is not superior to PRP for pain at 1 month. There is very low evidence that HA is not superior to PRP for pain at 6 and 12 months (mean difference in visual analog scale [in cm]: -.05 [95% CI, -.81 to .71], 1.0 [95% CI, -1.5 to 3.50], and .81 [95% CI, -1.11 to 2.73], respectively). There is high evidence that HA is no different from methylprednisolone for pain at 1 month (SMD=.02; 95% CI, -.18 to .22; P=.85). There is low evidence that HA is no different from methylprednisolone for Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International Responders Index at 1 month (RR=.44; 95% CI, .10-1.95; P=.28). There is high evidence that HA is no different from methylprednisolone for adverse events (RR=1.21; 95% CI, .79-1.87; P=.38). CONCLUSIONS: We do not recommend viscosupplementation for hip osteoarthritis. Compared with placebo, data show scarce evidence of its efficacy up to 3 months, and suggest no difference at 6 months. However, future RCTs could present HA as an alternative to methylprednisolone for short-term symptom relief.
29961573 Serum lipoprotein(a) is not modified by interleukin-6 receptor antagonism or associated wi 2019 Jan 1 BACKGROUND: The IL-6 receptor antagonist tocilizumab has been shown to attenuate the proatherogenic lipoprotein a [Lp(a)] in rheumatoid arthritis. We evaluated if a single dose of tocilizumab reduced Lp(a) in patients with non-ST-elevation myocardial infarction (NSTEMI). METHODS: Lp(a) was assessed by immunoassay (n = 117 patients) at 7 consecutive time-points between day 1 and 3 and at 3 and 6 months follow-up. RESULTS: Tocilizumab did not affect Lp(a) at any time-point during the study and was not associated with cardiovascular risk factors. CONCLUSIONS: Short-time inhibition of IL-6 with tocilizumab in patients with NSTEMI did not influence Lp(a) levels.
29622655 Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects 2018 Jul The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in coculture with bone marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. Transcriptome analysis and unbiased phosphoproteomics revealed that bone marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.
30426543 Cepharanthine suppresses osteoclast formation by modulating the nuclear factor-κB and nuc 2018 Nov 13 The increased activation of osteoclasts is the major manifestation of several lytic bone diseases, including osteoporosis, rheumatoid arthritis, aseptic loosening of orthopedic implants, Paget disease and malignant bone diseases. One important bone-protective therapy in these diseases focuses on the inhibition of osteoclast differentiation and resorptive function. Given that the deleterious side-effects of currently available drugs, it is beneficial to search for effective and safe medications from natural compounds. Cepharanthine (CEP) is a compound extracted from Stephania japonica and has been found to have antioxidant and anti-inflammatory effects. In this study, we found that CEP inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation and bone-resorbing activities using osteoclastogenesis and bone resorption assay. By polymerase chain reaction, we also found that CEP inhibited the expression of osteoclast-differentiation marker genes including Ctsk, Calcr, Atp6v0d2, Mmp9 and Nfatc1. Mechanistic analyses including Western blot and luciferase reporter assay revealed that CEP inhibited RANKL-induced activation of NF-κB and nuclear factor of activated T-cell, which are essential for the formation of osteoclast. Collectively, these data suggested that CEP can potentially be used as an alternative therapy for preventing or treating osteolytic diseases.
30383519 Tocilizumab, a Humanized Monoclonal Antibody Against the Interleukin-6 Receptor, Inhibits 2018 Nov Rheumatoid arthritis (RA) with diabetes increases the risk of cardiovascular diseases. Interleukin-6 (IL-6) promotes the disease activity of RA and insulin resistance. This study aimed to evaluate the potential effects and molecular mechanisms of IL-6 blocker, tocilizumab, in atherosclerosis with diabetes. Human aortic smooth muscle cells (HASMCs) cultured under hyperglycemic conditions were evaluated for migration, expression of adhesion molecules, and matrix metalloproteinases before and after treatment with tocilizumab. High glucose (HG) significantly increased expression of IL-6, intercellular adhesion molecule (ICAM-1), matrix metalloproteinase-2 & 9, and migration of vascular smooth muscle cells. Tocilizumab suppressed HG-induced expression of ICAM-1, MMP-2, and MMP-9. Pretreatment with tocilizumab also inhibited migration, MAPK signaling, and nuclear translocation of p65-NF-κB in HG-stimulated HASMCs. Our data suggested that tocilizumab may exert an antiatherosclerotic activity in diabetes.
30209191 Cutting Edge: The Heat Shock Protein gp96 Activates Inflammasome-Signaling Platforms in AP 2018 Oct 15 Several heat shock proteins (HSPs) prime immune responses, which are, in part, a result of activation of APCs. APCs respond to these immunogenic HSPs by upregulating costimulatory molecules and secreting cytokines, including IL-1β. These HSP-mediated responses are central mediators in pathological conditions ranging from cancer, sterile inflammation associated with trauma, and rheumatoid arthritis. We tested in this study the requirement of inflammasomes in the release of IL-1β by one immunogenic HSP, gp96. Our results show that murine APCs activate NLRP3 inflammasomes in response to gp96 by K(+) efflux. This is shown to initiate inflammatory conditions in vivo in the absence of additional known inflammasome activators or infection. These results document a novel mechanism by which proteins of endogenous origin, the HSPs, can modulate an inflammatory response following their release from aberrant cells.
30115527 Interferon alpha: The key trigger of type 1 diabetes. 2018 Nov IFNα is a cytokine essential to a vast array of immunologic processes. Its induction early in the innate immune response provides a priming mechanism that orchestrates numerous subsequent pathways in innate and adaptive immunity. Despite its beneficial effects in viral infections IFNα has been reported to be associated with several autoimmune diseases including autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, primary biliary cholangitis, and recently emerged as a major cytokine that triggers Type 1 Diabetes. In this review, we dissect the role of IFNα in T1D, focusing on the potential pathophysiological mechanisms involved. Evidence from human and mouse studies indicates that IFNα plays a key role in enhancing islet expression of HLA-I in patients with T1D, thereby increasing autoantigen presentation and beta cell activation of autoreactive cytotoxic CD8 T-lymphocytes. The binding of IFNα to its receptor induces the secretion of chemokines, attracting monocytes, T lymphocytes, and NK cells to the infected tissue triggering autoimmunity in susceptible individuals. Furthermore, IFNα impairs insulin production through the induction of endoplasmic reticulum stress as well as by impairing mitochondrial function. Due to its central role in the early phases of beta cell death, targeting IFNα and its pathways in genetically predisposed individuals may represent a potential novel therapeutic strategy in the very early stages of T1D.
30033738 Joint Fluid Proteome after Anterior Cruciate Ligament Rupture Reflects an Acute Posttrauma 2020 Jul OBJECTIVE: The purpose of this study was to evaluate changes in the synovial fluid proteome following acute anterior cruciate ligament (ACL) injury. DESIGN: This study represents a secondary analysis of synovial fluid samples collected from the placebo group of a previous randomized trial. Arthrocentesis was performed twice on 6 patients with an isolated acute ACL tear at a mean of 6 and 14 days postinjury. Synovial fluid was analyzed by a highly multiplexed assay of 1129 proteins (SOMAscan version 3, SomaLogic, Inc., Boulder, CO). Pathway analysis using DAVID was performed; genes included met 3 criteria: significant change between the 2 study time points using a paired t test, significant change between the 2 study time points using a Mann-Whitney nonparametric test, and significant Benjamini post hoc analysis. RESULTS: Fifteen analytes demonstrated significant increases between time points. Five of the 15 have been previously associated with the onset and/or severity of rheumatoid arthritis, including apoliopoprotein E and isoform E3, vascular cell adhesion protein 1, interleukin-34, and cell surface glycoprotein CD200 receptor 1. Chondrodegenerative enzymes and products of cartilage degeneration all increased over time following injury: MMP-1 (P = 0.08, standardized response mean [SRM] = 1.00), MMP-3 (P = 0.05, SRM = 0.90), ADAM12 (P = 0.03, SRM = 1.31), aggrecan (P = 0.08, SRM = 1.13), and CTX-II (P = 0.07, SRM = 0.56). Notable pathways that were differentially expressed following injury were the cytokine-cytokine receptor interaction and osteoclast differentiation pathways. CONCLUSIONS: The proteomic results and pathway analysis demonstrated a pattern of cartilage degeneration, not only consistent with previous findings but also changes consistent with an inflammatory arthritogenic process post-ACL injury.
29957268 Differential clinical features of patients with clinically amyopathic dermatomyositis who 2018 Jul BACKGROUND: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies have been identified as myositis-specific autoantibodies that are often associated with clinically amyopathic dermatomyositis (CADM) and a poor prognosis due to rapidly progressive interstitial lung disease (RP-ILD) in East Asian patients. Besides anti-MDA5 autoantibodies, patients with CADM may have myositis-associated autoantibodies (MAAs), which characterize other connective tissue diseases such as rheumatoid arthritis and Sjögren's syndrome. However, the clinical significance of the coexistence of anti-MDA5 autoantibodies and MAAs in patients with CADM remains unclear. METHODS: We retrospectively analyzed 24 patients with CADM who had anti-MDA5 autoantibodies. Their clinical phenotypes including laboratory test results, high-resolution lung computed tomography data, response to therapy, and prognosis were compared between those who were positive and negative for MAAs, such as antinuclear antibody (ANA), anti-cyclic citrullinated peptide (CCP), anti-SSA, and anti-SSB antibodies. RESULTS: Among 24 patients, 9 (37.5%) additionally had at least one of the MAAs examined in this study: 1 patient was positive for ANA, 5 for anti-CCP, 5 for either anti-SSA or anti-SSB, 1 for anti-cardiolipin, and 1 for anti-Scl-70. Although all anti-MDA5-positive patients with CADM had ILD, the MAA-positive patients showed a lower risk of developing RP-ILD (p = 0.03), a more favorable response to combination therapy of corticosteroids and immunosuppressive agents, and a lower mortality rate than patients with no MAAs (p = 0.03). CONCLUSIONS: Our data suggest that anti-MDA5-positive patients with CADM who also have MAAs have a better prognosis than those without MAAs; thus, anti-MDA5 autoantibodies by themselves may not be strong predictors of worse clinical outcomes in patients with CADM. Coexistent MAAs could be biomarkers for a favorable prognosis in anti-MDA5-positive patients with CADM.