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ID PMID Title PublicationDate abstract
33007998 Differential Effect of Extracellular Acidic Environment on IL-1β Released from Human and 2020 Sep 30 Areas of locally decreased pH are characteristic for many chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis, acute pathologies such as ischemia reperfusion, and tumor microenvironment. The data on the effects of extracellular acidic pH on inflammation are conflicting with respect to interleukin 1 beta (IL-1β) as one of the most potent proinflammatory cytokines. In this study, we used various mouse- and human-derived cells in order to identify potential species-specific differences in IL-1β secretion pattern in response to extracellular acidification. We found that a short incubation in mild acidic medium caused significant IL-1β release from human macrophages, however, the same effect was not observed in mouse macrophages. Rather, a marked IL-1β suppression was observed when mouse cells were stimulated with a combination of various inflammasome instigators and low pH. Upon activation of cells under acidic conditions, the cytosolic pH was reduced while metabolic activity and the expression of the main inflammasome proteins were not affected by low pH. We show that IL-1β secretion in mouse macrophages is reversible upon restoration of physiological pH. pH sensitivity of NLRP3, NLRC4 and AIM2 inflammasomes appeared to be conferred by the processes upstream of the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and most likely contributed by the cell background rather than species-specific amino acid sequences of the sensor proteins.
32980229 Modulating the wayward T cell: New horizons with immune checkpoint inhibitor treatments in 2020 Dec The T-cell response is regulated by the balance between costimulatory and coinhibitory signals. Immune checkpoints are essential for efficient T-cell activation, but also for maintaining self-tolerance and protecting tissues from damage caused by the immune system, and for providing protective immunity. Modulating immune checkpoints can serve diametric goals, such that blocking a coinhibitory molecule can unleash anti-cancer immunity whereas stimulating the same molecule can reduce an over-reaction in autoimmune disease. The purpose of this review is to examine the regulation of T-cell costimulation and coinhibition, which is central to the processes underpinning autoimmunity, transplant rejection and immune evasion in cancer. We will focus on the immunomodulation agents that regulate these unwanted over- and under-reactions. The use of such agents has led to control of symptoms and slowing of progression in patients with rheumatoid arthritis, reduced rejection rates in transplant patients, and prolonged survival in patients with cancer. The management of immune checkpoint inhibitor treatment in certain challenging patient populations, including patients with pre-existing autoimmune conditions or transplant patients who develop cancer, as well as the management of immune-related adverse events in patients receiving antitumor therapy, is examined. Finally, the future of immune checkpoint inhibitors, including examples of emerging targets that are currently in development, as well as recent insights gained using new molecular techniques, is discussed. T-cell costimulation and coinhibition play vital roles in these diverse therapeutic areas. Targeting immune checkpoints continues to be a powerful avenue for the development of agents suitable for treating autoimmune diseases and cancers and for improving transplant outcomes. Enhanced collaboration between therapy area specialists to share learnings across disciplines will improve our understanding of the opposing effects of treatments for autoimmune disease/transplant rejection versus cancer on immune checkpoints, which has the potential to lead to improved patient outcomes.
32959462 Relationship between natural and infection-induced antibodies in systemic autoimmune disea 2021 Jan Infection or vaccine-induced T cell-dependent immune response and the subsequent high-affinity neutralizing antibody production have been extensively studied, while the connection between natural autoantibodies (nAAbs) and disease-specific antibodies has not been thoroughly investigated. Our goal was to find the relationship between immunoglobulin (Ig)M and IgG isotype nAAbs and infection or vaccine-induced and disease-related autoantibody levels in systemic autoimmune diseases (SAD). A previously described indirect enzyme-linked immunosorbent assay (ELISA) test was used for detection of IgM/IgG nAAbs against citrate synthase (anti-CS) and F4 fragment (anti-F4) of DNA topoisomerase I in 374 SAD samples, with a special focus on systemic lupus erythematosus (SLE) (n = 92), rheumatoid arthritis (n = 73) and systemic sclerosis (n = 157) disease groups. Anti-measles IgG and anti-dsDNA IgG/IgM autoantibodies were measured using commercial and in-house indirect ELISA tests. In all SAD groups the anti-measles IgG-seropositive cases showed significantly higher anti-CS IgG titers (P = 0·011). In anti-dsDNA IgG-positive SLE patients, we detected significantly higher levels of anti-CS and anti-F4 IgG nAAbs (P = 0·001 and < 0·001, respectively). Additionally, we found increased levels of IgM isotypes of anti-CS and anti-F4 nAAbs in anti-dsDNA IgM-positive SLE patients (P = 0·002 and 0·016, respectively). The association between IgG isotypes of pathogen- or autoimmune disease-related antibodies and the IgG nAAbs may underscore the immune response-inducible nature of the diseases investigated. The relationship between protective anti-dsDNA IgM and the IgM isotype of anti-F4 and anti-CS may provide immunoserological evidence for the beneficial roles of nAAbs in SLE patients.
32929180 An objective method of diagnosing hydroxychloroquine maculopathy. 2021 Jul BACKGROUND: Hydroxychloroquine (HCQ) maculopathy is irreversible; primary prevention is done by regular monitoring. Guidelines of the Royal College of Ophthalmologists identify definite toxicity as having abnormal results of two screening tests, we present a quantitative method for interpreting these guidelines. METHODS: We obtained ocular coherence tomography (OCT) scans of 100 patients who have been on HCQ for 5 years or more (patients) and 70 age-matched controls. Both groups had 10'2 visual field (VF) test. We used linear regression to determine the cut-off points for each of the eight Early Treatment of Diabetic Retinopathy Study (ETDRS) macular sectors for the VF and OCT. We calculated the probability of developing maculopathy using logistic regression. RESULTS: Mean patient age: 59.9 years, 85% females, no statistically significant age difference between the patients and the control groups. DIAGNOSIS: 64% rheumatoid arthritis, 14% Sjogren's syndrome, 16% systemic lupus and 6% various other rheumatology conditions. Mean duration of use was 6.3 years. Logistic regression results show strong negative correlation between the outer nuclear layer (ONL) volume and probability of toxicity. Goodness of fit was tested using Hosmer and Lemeshow test that indicates a high significance with a high P-value of 1. CONCLUSIONS: Combining the ONL volume reduction and VF retinal sensitivity reduction per each of the eight ETDRS macular sectors provides an accurate and objective way of diagnosing HCQ maculopathy, this helps busy eye units establishing an optometrist-led or virtual service because it is independent of the assessor's level of experience.
32881084 Molecular dynamics analysis of the binding of human interleukin-6 with interleukin-6 α-re 2021 Feb Human interleukin-6 (hIL-6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL-6 binding to the IL-6 receptor (IL-6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti-IL-6 and IL-6R antibodies are clinically approved inhibitors of IL-6 signaling pathway for treating rheumatoid arthritis and Castleman's disease, respectively. There is a potential to develop novel small molecule IL-6 antagonists derived from understanding the structural basis for IL-6/IL-6Rα interactions. Here, we combine homology modeling with extensive molecular dynamics (MD) simulations to examine the association of hIL-6 with IL-6Rα. A comparison with MD of apo hIL-6 reveals that the binding of hIL-6 to IL-6Rα induces structural and dynamic rearrangements in the AB loop region of hIL-6, disrupting intraprotein contacts and increasing the flexibility of residues 48 to 58 of the AB loop. In contrast, due to the involvement of residues 59 to 78 in forming contacts with the receptor, these residues of the AB loop are observed to rigidify in the presence of the receptor. The binary complex is primarily stabilized by two pairs of salt bridges, Arg181 (hIL-6)- Glu182 (IL-6Rα) and Arg184 (hIL-6)- Glu183 (IL-6Rα) as well as hydrophobic and aromatic stacking interactions mediated essentially by Phe residues in both proteins. An interplay of electrostatic, hydrophobic, hydrogen bonding, and aromatic stacking interactions facilitates the formation of the hIL-6/IL-6Rα complex.
32878183 Complement C4 Gene Copy Number Variation Genotyping by High Resolution Melting PCR. 2020 Aug 31 BACKGROUND: Complement C4 gene copy number variation plays an important role as a determinant of genetic susceptibility to common diseases, such as systemic lupus erythematosus, schizophrenia, rheumatoid arthritis, and infectious diseases. This study aimed to develop an assay for the quantification of copy number variations in the C4 locus. METHODS: the assay was based on a gene ratio analysis copy enumeration (GRACE) PCR combined with high resolution melting (HRM) PCR. The test was optimized using samples of a known genotype and validated with 72 DNA samples from healthy blood donors. RESULTS: to validate the assay, standard curves were generated by plotting the C4/RP1 ratio values against copy number variation (CNV) for each gene, using genomic DNA with known C4 CNV. The range of copy numbers in control individuals was comparable to distributions observed in previous studies of European descent. CONCLUSIONS: the method herein described significantly simplifies C4 CNV diagnosis to validate the assay.
32716310 A Companion App to Support Rheumatology Patients Treated with Certolizumab Pegol: Results 2020 Jul 27 BACKGROUND: Certolizumab pegol (CZP) is an anti-tumor necrosis factor drug approved for the treatment of multiple moderate to severe chronic inflammatory diseases. In the European Union, CZP is approved for administration by subcutaneous self-injection using a prefilled syringe, prefilled pen, or reusable electromechanical auto-injector (electronic device). CimplyMe is a companion app for use alongside CZP self-injection devices, designed to support CZP-treated patients self-managing their treatment and disease. OBJECTIVE: This study aimed to validate the usability of the companion app by demonstrating that tasks required for use can be performed successfully by intended end users. METHODS: We recruited 15 patients with moderate to severe rheumatoid arthritis, currently prescribed biologic treatment, and using apps on a smart phone. Patients were assessed on their ability to use the companion app in a setting designed to simulate a location where patients regularly administer biologic treatment. To assess the usability of the key features of the app, 8 critical and 3 noncritical tasks were designed. Patients' success on each task was recorded through observations or knowledge-based questions. Successes with difficulty and use errors were also recorded. If a patient made a use error at the first attempt, a second attempt was allowed. Second-attempt use errors were recorded as a task failure. RESULTS: A total of 207 first attempts at the 14 components of the 8 critical tasks were evaluated (3 patients failed to complete one component); 178 (86.0%) critical tasks were successfully completed at the first attempt. The remaining first attempts comprised 16 (7.7%) successes with difficulty and 13 (6.3%) use errors, which had to be repeated. One critical task was not re-attempted by one patient due to time constraints; however, there were no use errors in the 12 completed second attempts. A total of 107 first attempts at the 3 noncritical tasks were made, all of which (107/107, 100.0%) were completed without use errors. CONCLUSIONS: In simulated testing, patients were able to successfully use the companion app without formal training. This study suggests the companion app is easy to use and could help patients prescribed CZP better manage their treatment and disease.
32705883 Plasma Level of von Willebrand Factor Propeptide at Diagnosis: A Marker of Subsequent Rena 2020 Jan INTRODUCTION: Patients with systemic autoimmune rheumatic diseases (SARDs) such as rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjögren syndrome, and systemic sclerosis, which are chronic inflammatory diseases, are prone to develop renal dysfunction, which is related to vascular endothelial cell damage. MATERIAL AND METHODS: We evaluated plasma levels of von Willebrand factor (VWF), VWF propeptide (VWF-pp), disintegrin-like and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and VWF multimer pattern in patients with SARDs at diagnosis and investigated whether they may serve as markers to identify patients destined to develop renal dysfunction within 1 year. Renal dysfunction was defined as subsequent reduced estimated glomerular filtration rate (eGFR) by >25% or the new appearance of abnormal urine findings such as proteinuria (protein > 30 mg/dL) or hematuria (red blood cells >20/HPF in urine sediments). Overall, 63 patients with SARDs were studied. RESULTS AND CONCLUSIONS: We observed a significant increase of VWF-pp and a significant decrease of ADAMTS13 in patients with SARDs compared with normal healthy controls. The highest level of VWF-pp was observed in patients with SLE among the groups. The levels of VWF and multimer pattern of VWF were not different compared with normal healthy controls. Von Willebrand factor propeptide predicted a subsequent decrease in eGFR at a cutoff point of 210% (sensitivity, 78.6%; specificity, 73.5%) and new urinary abnormal findings at a cutoff point of 232% (sensitivity, 77.8%; specificity, 77.8%) Using these cutoff points, multivariable analysis revealed that VWF-pp was a significant risk factor for renal dysfunction at an odds ratio of 8.78 and 22.8, respectively, and may lead to a new therapeutic approach to prevent vasculitis and renal dysfunction.
32486934 Rituximab use as induction therapy for lupus nephritis: a systematic review. 2020 Jul OBJECTIVE: Rituximab (RTX) has important usage in rheumatoid arthritis and vasculitis. There remains a need for more, better, and safer treatments for patients with lupus nephritis (LN). RTX has been trialed in such patients without definitive conclusions about its effectiveness. As a role for RTX has not been clearly established for LN, we carried out a systematic review and analysis. METHODS: We identified 31 studies of RTX for class I-VI LN, and assessed complete renal response (CRR) and partial renal response (PRR) using criteria including serum creatinine, proteinuria, and urinary sediment. Due to differences in the pediatric presentation of the disease, studies focusing on pediatric patients were excluded. RESULTS: One randomized controlled trial (RCT) showed superiority of RTX+cyclophosphamide (CYC) versus CYC alone (64% vs. 21% CRR and 19% vs. 36% PRR). Six prospective and retrospective studies utilizing RTX monotherapy found 66% CRR or PRR in all patients. Eleven studies that investigated RTX in combination with CYC or mycophenolate mofetil (MMF) also found 66% CRR or PRR in all patients. In total, the CRR for Caucasian, East Asian, and Hispanic patients were 77%, 38%, and 28%, respectively. CONCLUSIONS: RTX appeared to benefit certain LN patients, but most studies were not randomized or properly controlled, were heterogeneous in design, subjects, and LN types, and were not comparable, and must therefore be interpreted cautiously. RTX alone may not deplete B cells sufficiently for the perturbations of LN. In addition, RTX may induce responses differently among patients of different ethnic and racial backgrounds. Furthermore, there were wide variations in the baseline characteristics of the patients, namely LN class, time course of disease, age, and prior immunosuppressive use. We suggest a prospective RCT in patients aged 18-65 years with class IV LN. Ideally, the patients would not have received prior immunosuppression and would better represent different ethnicities. The treatment groups would be RTX, RTX+belimumab, CYC, and MMF groups, with pulse-dose steroids during induction followed by maintenance steroids and MMF. The CRR and PRR would be assessed at 12 and 24 months. This or a similar study might clarify RTX's role in the treatment of LN.
32411139 Targeting Signal 3 Extracellularly and Intracellularly in Graft-Versus-Host Disease. 2020 Allogeneic hematopoietic stem cell transplantation (allo-HCT) holds curative potential for many hematological disorders. However, the pathophysiology of the desired graft-versus-tumor effect is linked to life-threatening complications of acute graft-versus-host disease (GVHD). Allogeneic donor T lymphocytes are essential for causing GVHD, and their activation relies on the coordination of TCR engagement and co-stimulation, also known as Signal 1 and Signal 2. In addition to these signals, a network of secreted cytokines by immune cells provides a third signal, Signal 3, that is critical for the initiation and maintenance of GVHD. Strategies to target Signal 3 in human diseases have shown therapeutic benefit for inflammatory disorders such as Rheumatoid Arthritis and Inflammatory Bowel Disease. However, despite our growing understanding of their role in GVHD, the success of targeting individual cytokines has been modest with some notable exceptions. This review aims to describe current approaches toward targeting Signal 3 in clinical GVHD, and to highlight emerging studies in immune cell biology that may be harnessed for better clinical translation.
32406009 The effect of TJ-28 (Eppikajutsuto) on the prevention of hand-foot syndrome using Capecita 2020 Apr BACKGROUND: Eppikajututo (TJ-28, a Kampo medicine) is effective against rheumatoid arthritis and eczema. We conducted a randomized comparative trial to assess the efficacy of TJ-28 for preventing hand-foot syndrome (HFS) as a complication of adjuvant chemotherapy using capecitabine. METHODS: The present study was a multi-institutional randomized-controlled trial (UMIN000005899). Colorectal cancer patients scheduled to receive capecitabine chemotherapy as adjuvant therapy were randomly assigned to receive TJ-28 (7500 mg/day) or oral pyridoxine (60 mg/day). Patients were monitored for the development of grade ≥ 2 HFS according to the National Cancer Institute Common Toxicity Criteria until chemotherapy completion. RESULTS: Twenty-two patients were enrolled in this study. The relative dose intensity of capecitabine was 76.2% in the TJ-28 group and 68.2% in the pyridoxine group. Grade ≥ 2 HFS developed in 6 (50.0%) of 12 TJ-28 patients and in 4 (40.0%) of 10 pyridoxine patients. Chemotherapy treatment failure was observed in seven patients, mainly due to HFS, liver dysfunction, diarrhea, and neutropenia. Chemotherapy treatment failure due to HFS occurred in none of the TJ-28 group and 2 patients (20.0%) in the pyridoxine group (p = 0.114). CONCLUSION: Capecitabine-associated HFS was not markedly prevented by TJ-28 compared with pyridoxine. However, TJ-28 might support the continuation of chemotherapy with capecitabine. Further studies are warranted to clarify the benefits of TJ-28.
32215928 The JAK2 inhibitor AG490 regulates the Treg/Th17 balance and alleviates DSS-induced intest 2020 Aug The pathogenesis of inflammatory bowel disease (IBD) remains unclear, and it is currently believed that an imbalance in regulatory T (Treg) cells/T helper 17 cells (Th17 cells) is related to the occurrence and development of IBD. Recently, the JAK2 inhibitor AG490 has been used in animal models such as rheumatoid arthritis and bronchial asthma models and shown to exert immunoregulatory functions that improve disorder in the Treg/Th17 cell balance. This study aimed to evaluate the effect of AG490 on the intestinal inflammatory process in an IBD rat model. A dextran sulfate sodium (DSS)-induced IBD rat model was established, and disease activity index (DAI) scores were calculated. The histopathological damage score was determined by haematoxylin-eosin (H&E) staining. Treg/Th17 cells in the spleen were detected by flow cytometry. The levels of interleukin (IL)-10, IL-6 and IL-17A were detected by enzyme-linked immunosorbent assay (ELISA). AG490 attenuated DSS-induced IBD injury by regulating the Treg/Th17 balance and related cytokine secretion to reduce the DAI and colonic tissue damage. Thus, AG490 may be a new method for effective treatment of IBD.
32120162 Density functional theory study of gold(III)-dithiocarbamate complexes with characteristic 2020 May The application of gold as drug candidate dated back to 2500 BC and its relevance in medicine became more appealing following 1985 FDA approval of ingested Auranofin for the treatment of rheumatoid arthritis. In this study, we have provided a density functional theory (DFT) study of some gold(III)-dithiocarbamate complexes with characteristic anticancer potentials. DFT calculation of the reactivity and selectivity properties of these complexes with an enzyme template of thioredoxin reductase (TrxR) was carried out. The investigation proceeds with theoretical characterization of the selected compounds through spectroscopic analyses. IR and UV-vis analyses were carried out and the calculated values are comparable to experimental results. NMR assignment was determined for the gold compounds and the estimated theoretical chemical shift values agree with available experimental data from literature. The obtained DFT-based chemical parameters proved to be significant in evaluating the selectivity, reactivity and stability of the gold(III) complexes as potential anticancer moieties, specifically against TrxR. Calculated binding free energy gave similar order with the available in vitro inhibition profile of these gold(III)-dithiocarbamate complexes against TrxR. The outcome of this DFT study could serve as a useful guide towards future design of new and potent anticancer drug candidate. The investigated chemical reactivity properties could be considered and applied to a wide range of bioactive compounds and enzyme-inhibitor systems.
31984663 Contact activation-induced complex formation between complement factor H and coagulation f 2020 Apr BACKGROUND: The complement and coagulation systems share an evolutionary origin with many components showing structural homology. Certain components, including complement factor H (FH) and coagulation factor XII (FXII), have separately been shown to have auxiliary activities across the two systems. OBJECTIVES: The interaction between FXII and FH was investigated. METHODS: Using enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) complex formation between different FXII forms and FH was investigated. The presence of α-FXIIa:FH complexes upon contact activation in plasma was evaluated by ELISA and immunoprecipitation. RESULTS: We identified and characterized a direct interaction between the components and demonstrated that among different forms of FXII, only the activated α-FXIIa formed complexes with FH, with an apparent binding strength K(d) of 34 ± 9 nmol/L. The complex formation involved the kringle domain of the heavy chain of FXII. C1-inhibitor induced inhibition of α-FXIIa did not alter the binding of α-FXIIa toward FH. We further demonstrated the presence of α-FXIIa:FH complexes in normal human plasma upon contact activation, indicating formation of α-FXIIa:FH complexes as a consequence of α-FXIIa generation. Complex formation between α-FXIIa and FH was also assessed in hereditary angioedema (HAE) patients with C1-inhibitor deficiency as well as rheumatoid arthritis (RA) patients with high levels of anti-cyclic citrullinated peptide (anti-CCP) upon contact activation. We observed elevated levels of α-FXIIa:FH complexes in HAE patients, and equal levels of complexes in RA patients and healthy individuals upon contact activation. CONCLUSION: A direct interaction between α-FXIIa and FH is demonstrated. Our findings represent a new crosstalk between these systems, potentially important in the onset and pathology of inflammatory vascular diseases.
31958792 Interleukin-6: A Masterplayer in the Cytokine Network. 2020 Interleukin-6 (IL-6) is a member of the pro-inflammatory cytokine family, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in humans. IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R) or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130. Therefore, three modes for IL-6 signaling may occur in which IL-6 is binding to mIL-6R (classic), to sIL-6R (trans-signaling), or is joined through IL-6R to gp130 on nearby located cells (trans-presentation). These pathways, and the fact that gp130 is ubiquitously expressed, lead to the pleiotropic functions of IL-6. The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways as well as through the presence of sIL-6R and gp130 forms in the blood. Vice versa, an overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders as well as cancer development suggesting that IL-6 plays a significant role in the human cytokine network. Several therapeutic agents have been evaluated for inhibiting the cytokine itself, the signaling via the IL-6 receptor, or target kinases (e.g., JAK/STAT) associated with the signaling pathways. Amongst others, tocilizumab (anti-IL-6R humanized antibody) has been approved for the treatment of rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD), whereas siltuximab (an IL-6 antagonist) received approval for iMCD only. Although not all IL-6-associated diseases respond to IL-6 blockade, a better understanding of the underlying mechanisms of the IL-6 pathways may, therefore, help to find the best treatment for IL-6-associated diseases in the near future.
31866074 [Radiotherapy and immune suppression: A short review]. 2020 Jan The management of patients undergoing immunosuppressive agents is really challenging. Based on precaution principle, it seems mandatory to stop immunosuppressive (or immunomodulating) agents during radiation. Yet, it is impossible in grafted patients. It is possible in patients with autoimmune disease, but in this case, the autoimmune disease might modify patient's radio-sensitivity. We provide a short review about the safety of radiotherapy in grafted/auto-immune patients. The literature is limited with data coming from outdated case-report or case-control studies. It seems that radiotherapy is feasible in grafted patients, but special dose-constraints limitations must probably be considered for the transplant and the other organs at risk. There is very little data about the safety of radiotherapy, when associated with immunomodulating agents. The most studied drug is the methotrexate but only its prescription as a chemotherapy (high doses for a short period of time) was reported. When used as an immunomodulator, it should probably be stopped 4 months before and after radiation. Apart from rheumatoid arthritis, it seems that collagen vascular diseases and especially systemic scleroderma and systemic lupus erythematous feature increased radio-sensitivity with increased severe late toxicities. Transplanted patients and collagen vascular disease patients should be informed that there is very little data about safety of radiation in their case.
31783002 Choline attenuates inflammatory hyperalgesia activating nitric oxide/cGMP/ATP-sensitive po 2020 Jan 15 New findings on neural regulation of immunity are allowing the design of novel pharmacological strategies to control inflammation and nociception. Herein, we report that choline, a 7-nicotinic acetylcholine receptor (α7nAChRs) agonist, prevents carrageenan-induced hyperalgesia without affecting inflammatory parameters (neutrophil migration or cytokine/chemokines production) or inducing sedation or even motor impairment. Choline also attenuates prostaglandin-E(2) (PGE(2))-induced hyperalgesia via α7nAChR activation and this antinociceptive effect was abrogated by administration of LNMMA (a nitric oxide synthase inhibitor), ODQ (an inhibitor of soluble guanylate cyclase; cGMP), andglibenclamide(an inhibitor of ATP-sensitive potassium channels). Furthermore, choline attenuates long-lasting Complete Freund's Adjuvant and incision-induced hyperalgesia suggesting its therapeutic potential to treat pain in rheumatoid arthritis or post-operative recovery, respectively. Our results suggest that choline modulates inflammatory hyperalgesia by activating the nitric oxide/cGMP/ATP-sensitive potassium channels without interfering in inflammatory events, and could be used in persistent pain conditions.
31617124 Therapeutic potential of aryl hydrocarbon receptor in autoimmunity. 2020 Feb Aryl hydrocarbon receptor (AhR), a type of transcriptional factor, is widely expressed in immune cells. The activation of AhR signaling pathway depends on its ligands, which exist in environment and can also be produced by metabolism. Normal expressions of AhR and AhR-mediated signaling may be essential for immune responses, and effects of AhR signaling on the development and function of innate and adaptive immune cells have also been revealed in previous studies. Recent studies also indicate that aberrant AhR signaling may be related to autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), autoimmune uveitis (AU), autoimmune diabetes, Behcet's disease (BD) and myasthenia gravis (MG). Moreover, administration of AhR ligands or drugs has been proven effective for improving pathological outcomes in some autoimmune diseases or models. In this review, we summarize the effects of AhR on several innate and adaptive immune cells associated with autoimmunity, and the mechanism on how AhR participates in autoimmune diseases. In addition, we also discuss therapeutic potential and application prospect of AhR in autoimmune diseases, so as to provide valuable information for exploring novel and effective approaches to autoimmune disease treatments.
31267470 Resolvins: Emerging Players in Autoimmune and Inflammatory Diseases. 2020 Feb Resolvins, belonging to the group of specialized proresolving mediators (SPMs), are metabolic products of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and are synthesized during the initial phases of acute inflammatory responses to promote the resolution of inflammation. Resolvins are produced for termination of neutrophil infiltration, stimulation of the clearance of apoptotic cells by macrophages, and promotion of tissue remodeling and homeostasis. Metabolic dysregulation due to either uncontrolled activity of pro-inflammatory responses or to inefficient resolution of inflammation results in chronic inflammation and may also lead to atherosclerosis or other chronic autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, vasculitis, inflammatory bowel diseases, and type 1 diabetes mellitus. The pathogenesis of such diseases involves a complex interplay between the immune system and, environmental factors (non-infectious or infectious), and critically depends on individual susceptibility to such factors. In the present review, resolvins and their roles in the resolution of inflammation, as well as the role of these mediators as potential therapeutic agents to counteract specific chronic autoimmune and inflammatory diseases are discussed.
32342805 Identification of Candidate Genetic Markers and a Novel 4-genes Diagnostic Model in Osteoa 2020 BACKGROUND: Osteoarthritis (OA) is a joint disease that leads to a high disability rate and a low quality of life. With the development of modern molecular biology techniques, some key genes and diagnostic markers have been reported. However, the etiology and pathogenesis of OA are still unknown. OBJECTIVE: To develop a gene signature in OA. METHOD: In this study, five microarray data sets were integrated to conduct a comprehensive network and pathway analysis of the biological functions of OA related genes, which can provide valuable information and further explore the etiology and pathogenesis of OA. RESULTS AND DISCUSSION: Differential expression analysis identified 180 genes with significantly expressed expression in OA. Functional enrichment analysis showed that the up-regulated genes were associated with rheumatoid arthritis (p < 0.01). Down-regulated genes regulate the biological processes of negative regulation of kinase activity and some signaling pathways such as MAPK signaling pathway (p < 0.001) and IL-17 signaling pathway (p < 0.001). In addition, the OA specific protein-protein interaction (PPI) network was constructed based on the differentially expressed genes. The analysis of network topological attributes showed that differentially upregulated VEGFA, MYC, ATF3 and JUN genes were hub genes of the network, which may influence the occurrence and development of OA through regulating cell cycle or apoptosis, and were potential biomarkers of OA. Finally, the support vector machine (SVM) method was used to establish the diagnosis model of OA, which not only had excellent predictive power in internal and external data sets (AUC > 0.9), but also had high predictive performance in different chip platforms (AUC > 0.9) and also had effective ability in blood samples (AUC > 0.8). CONCLUSION: The 4-genes diagnostic model may be of great help to the early diagnosis and prediction of OA.