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ID PMID Title PublicationDate abstract
30498997 The inflammatory function of human IgA. 2019 Mar The prevailing concept regarding the immunological function of immunoglobulin A (IgA) is that it binds to and neutralizes pathogens to prevent infection at mucosal sites of the body. However, recently, it has become clear that in humans IgA is also able to actively contribute to the initiation of inflammation, both at mucosal and non-mucosal sites. This additional function of IgA is initiated by the formation of immune complexes, which trigger Fc alpha Receptor I (FcαRI) to synergize with various other receptors to amplify inflammatory responses. Recent findings have demonstrated that co-stimulation of FcαRI strongly affects pro-inflammatory cytokine production by various myeloid cells, including different dendritic cell subsets, macrophages, monocytes, and Kupffer cells. FcαRI-induced inflammation plays a crucial role in orchestrating human host defense against pathogens, as well as the generation of tissue-specific immunity. In addition, FcαRI-induced inflammation is suggested to be involved in the pathogenesis of various chronic inflammatory disorders, including inflammatory bowel disease, celiac disease, and rheumatoid arthritis. Combined, IgA-induced inflammation may be used to either promote inflammatory responses, e.g. in the context of cancer therapy, but may also provide new therapeutic targets to counteract chronic inflammation in the context of various chronic inflammatory disorders.
30355941 The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of 2018 BACKGROUND/AIMS: The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway plays a protective role in both acute neuronal damage and chronic neurodegeneration-related oxidative stress. Circular RNAs (circRNAs) are involved with various diseases in the central nervous system (CNS). This study aimed to identify the key circRNAs involved in Nrf2-neuroprotection against oxidative stress. METHODS: The differentially expressed circRNAs (DEcircRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice were identified by microarray analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was then used to validate the expression of selected DEcircRNAs in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice. Based on our previous microarray analysis of the differentially expressed mRNAs (DEmRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice, the DEcircRNA-miRNA-DEmRNA interaction network was constructed. Functional annotation of DEmRNAs that shared the same binding miRNAs with DEcircRNAs was performed using gene ontology (GO) and pathway analyses. RESULTS: A total of 65 and 150 significant DEcircRNAs were obtained in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, respectively, and seventeen shared DEcircRNAs were found in both these two tissues. The qRT-PCR results were generally consistent with the microarray results. The DEcircRNA-miRNA-DEmRNA interaction network and pathway analysis indicated that mmu_circRNA_34132, mmu_circRNA_017077 and mmu-circRNA-015216 might be involved with Nrf2-mediated neuroprotection against oxidative stress. Mmu_circRNA_015216 and mmu_circRNA_017077 might play roles in the Nrf2-related transcriptional misregulation and Nrf2-mediated processes of rheumatoid arthritis, respectively. In addition to these two processes, mmu_circRNA_34132 may be a potential regulator of Nrf2-mediated protection for diabetes mellitus and Nrf2-mediated defence against ROS in hearts. CONCLUSION: In conclusion, our study identified the key DEcircRNAs in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, which might provide new clues for further exploring the mechanism of Nrf2-mediated neuroprotection against oxidative stress and other Nrf2-mediated processes.
30266548 Acetabular Chondral Lesions Associated With Femoroacetabular Impingement Treated by Autolo 2018 Nov PURPOSE: The aim of this retrospective study was to investigate, at 8 years, the clinical follow-up and failure rate (revision rate/conversion to arthroplasty) of patients with hip chondral lesions associated with femoroacetabular impingement and to compare over time the treatment by microfracture (MFx) and autologous matrix-induced chondrogenesis (AMIC). METHODS: Patients aged between 18 and 55 years, with acetabular grade III and IV chondral lesions (Outerbridge), measuring 2 to 8 cm(2) operated on at least 8 years before enrollment. Exclusion criteria were rheumatoid arthritis, dysplasia, or axial deviation of the femoral head. There were no arthritic lesions, Tonnis < 2, or joint space of at least 2 mm. MFx was performed with an awl, and the Chondro-Gide membrane used for the AMIC procedure was placed without glue. Outcomes used modified Harris hip score (mHHS) at 6 months and yearly for 8 years and patient acceptable symptomatic state. RESULTS: Among 130 patients, 109 fulfilled inclusion criteria. Fifty were treated by MFx and 59 by AMIC. The mHHS significantly improved in both groups from 46 ± 6.0 to 78 ± 8.8 for mHHS at 6-12 months, even for lesions > 4 cm(2). From 2 to 8 years, mHHS in the AMIC group was better than in the MFx group (P < .005). This mHHS improvement in the AMIC group was maintained through the 8-year follow-up period, whereas it deteriorated after 1 year in the MFx group (P < .005). Eleven patients (22%) in the MFx group required total hip arthroplasty (THA); none in the AMIC group did. Patient acceptable symptomatic state analysis confirmed similar short-term improvement, but a significant (P < .007) degradation after 2-8 years in MFx patients. CONCLUSIONS: MFx and AMIC techniques led to marked clinical short-term improvement in patients with chondral defects resulting from femoroacetabular impingement in the first 2 years. However, AMIC gave significantly better results as measured by mHHS, which were maintained after 8 years, the results of MFx in the hip deteriorated over time with 22% of patients undergoing conversion to THA. No patient in the AMIC group was converted to THA; the results of AMIC appeared stable over time and independent of lesion size. LEVEL OF EVIDENCE: III, retrospective patient group study.
30243784 Advances in the treatment of systemic lupus erythematosus: From back to the future, to the 2019 Jul There have been many advances in the diagnosis and therapeutic management of systemic lupus erythematosus (SLE) over the past decades. Following more than eleven centuries of therapeutic uncertainty, the discovery of the therapeutic properties of glucocorticoids is without any doubt one of the most significant advance in the field of autoimmune diseases. The many progresses made by rapidly growing chemical industry of the 19th century chemistry have allowed the identification of valuable therapeutic compounds such as anti-malarials, cyclophosphamide, azathioprine, cyclosporine and later mycophenolate mofetil, which have all profoundly changed the face of the disease. A very visible consequence of this is the profound improvement in the prognosis of the disease, with 10-year survival rates of more than 90% in most dedicated centres. Following the development of biotherapies in rheumatoid arthritis, the late 20th century has slowly opened a new era for the treatment of SLE, that of targeted therapies. With the approval of belimumab in 2011 and 74 targeted therapies in clinical development, we may expect great changes in the therapeutic management of SLE. Those molecules target inflammatory cytokines or chemokines and their receptors, B cells or plasma cells, intracellular signalling pathways, B/T cells co-stimulation molecules, interferons, plasmacytoid dendritic cells, as well as various other targets of interest. Current challenges are now slowly shifting from whether some new drugs will be available to how to select the most adequate drug (or drug combination) at the patient-level.
30133709 Development and validation of stability indicating reversed-phase liquid chromatographic m 2018 Dec Methotrexate (MTX) and teriflunomide (TEF) are the two most effective disease-modifying antirheumatic drugs used as combination therapy for rheumatoid arthritis and no robust high-performance liquid chromatography (HPLC) method is available for their simultaneous estimation to date. Therefore, we have developed and validated an isocratic reversed-phase HPLC method for simultaneous analysis of MTX and TEF spiked in the form of active pharmaceutical ingredients, tablets and nanoformulations. The best separation was achieved on a BDS, C(18) , 4.6 × 250 mm, 5 μm analytical column (Thermo Hypersil) with methanol-ethylammonium formate-potassium dihydrogen phosphate buffer (55 mm, pH 3.5; 65:5:30, v/v) as mobile phase at a flow rate of 0.8 mL/min. All the samples were subjected to force degradation studies. Responses of MTX and TEF were found to be a linear function of concentration over the range 1-50 μg/mL (r(2)  = 0.9976 and 0.9982). The limits of detection and limit of quantification were 7.74 and 25.82 ng/mL and 10.74 and 35.80 ng/mL, respectively. Degradation products produced under the stress studies did not interfere with the detection of MTX and TEF and therefore the developed method can be regarded as stability indicating.
29922175 Vascular Morphogenesis in the Context of Inflammation: Self-Organization in a Fibrin-Based 2018 Introduction: New vessel formation requires a continuous and tightly regulated interplay between endothelial cells with cells of the perivascular microenvironment supported by mechanic-physical and chemical cues from the extracellular matrix. Aim: Here we investigated the potential of small fragments of synovial tissue to form de novo vascular structures in the context of inflammation within three dimensional (3D) fibrin-based matrices in vitro, and assessed the contribution of mesenchymal stromal cell (MSC)-immune cell cross-talk to neovascularization considering paracrine signals in a fibrin-based co-culture model. Material and Methods: Synovial tissue fragments from patients with rheumatoid arthritis (RA) and inflammatory osteoarthritis (OA) were cultivated within 3D fibrin matrices for up to 4 weeks. Cellular and structural re-arrangement of the initially acellular matrix were documented by phase contrast microscopy and characterized by confocal laser-scanning microscopy of topographically intact 3D cultures and by immunohistochemistry. MSC-peripheral blood mononuclear cell (PBMC) co-cultures in the 3D fibrin system specifically addressed the influence of perivascular cell interactions to neo-vessel formation in a pro-inflammatory microenvironment. Cytokine levels in the supernatants of cultured explant tissues and co-cultures were evaluated by the Bio-Plex cytokine assay and ELISA. Results: Vascular outgrowth from the embedded tissue into the fibrin matrix was preceded by leukocyte egress from the tissue fragments. Neo-vessels originating from both the embedded sample and from clusters locally formed by emigrated mononuclear cells were consistently associated with CD45(+) leukocytes. MSC and PBMC in co-culture formed vasculogenic clusters. Clusters and cells with endothelial phenotype emerging from them, were surrounded by a collagen IV scaffold. No vascular structures were observed in control 3D monocultures of PBMC or MSC. Paracrine signals released by cultured OA tissue fragments corresponded with elevated levels of granulocyte-colony stimulating factor, vascular endothelial growth factor and interleukin-6 secreted by MSC-PBMC co-cultures. Conclusion: Our results show that synovial tissue fragments with immune cell infiltrates have the potential to form new vessels in initially avascular 3D fibrin-based matrices. Cross-talk and cluster formation of MSC with immune cells within the 3D fibrin environment through self-organization and secretion of pro-angiogenic paracrine factors can support neo-vessel growth.
29669571 Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in 2018 Apr 18 Registry data worldwide indicate an overall female predominance for pulmonary arterial hypertension (PAH) of 2-4 over men. Genetic predisposition accounts for only 1-5% of PAH cases, while autoimmune diseases and infections are closely linked to PAH. Idiopathic PAH may include patients with undiagnosed autoimmune diseases based on the relatively high presence of autoantibodies in this group. The two largest PAH registries to date report a sex ratio for autoimmune connective tissue disease-associated PAH of 9:1 female to male, highlighting the need for future studies to analyze subgroup data according to sex. Autoimmune diseases that have been associated with PAH include female-dominant systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and thyroiditis as well as male-dominant autoimmune diseases like myocarditis which has been linked to HIV-associated PAH. The sex-specific association of PAH to certain infections and autoimmune diseases suggests that sex hormones and inflammation may play an important role in driving the pathogenesis of disease. However, there is a paucity of data on sex differences in inflammation in PAH, and more research is needed to better understand the pathogenesis underlying PAH in men and women. This review uses data on sex differences in PAH and PAH-associated autoimmune diseases from registries to provide insight into the pathogenesis of disease.
29610271 Mining the Human Tissue Proteome for Protein Citrullination. 2018 Jul Citrullination is a posttranslational modification of arginine catalyzed by five peptidylarginine deiminases (PADs) in humans. The loss of a positive charge may cause structural or functional alterations, and while the modification has been linked to several diseases, including rheumatoid arthritis (RA) and cancer, its physiological or pathophysiological roles remain largely unclear. In part, this is owing to limitations in available methodology to robustly enrich, detect, and localize the modification. As a result, only a few citrullination sites have been identified on human proteins with high confidence. In this study, we mined data from mass-spectrometry-based deep proteomic profiling of 30 human tissues to identify citrullination sites on endogenous proteins. Database searching of ∼70 million tandem mass spectra yielded ∼13,000 candidate spectra, which were further triaged by spectrum quality metrics and the detection of the specific neutral loss of isocyanic acid from citrullinated peptides to reduce false positives. Because citrullination is easily confused with deamidation, we synthetized ∼2,200 citrullinated and 1,300 deamidated peptides to build a library of reference spectra. This led to the validation of 375 citrullination sites on 209 human proteins. Further analysis showed that >80% of the identified modifications sites were new, and for 56% of the proteins, citrullination was detected for the first time. Sequence motif analysis revealed a strong preference for Asp and Gly, residues around the citrullination site. Interestingly, while the modification was detected in 26 human tissues with the highest levels found in the brain and lung, citrullination levels did not correlate well with protein expression of the PAD enzymes. Even though the current work represents the largest survey of protein citrullination to date, the modification was mostly detected on high abundant proteins, arguing that the development of specific enrichment methods would be required in order to study the full extent of cellular protein citrullination.
29519701 Translational overview of cytokine inhibition in acute myocardial infarction and chronic h 2018 Aug Many cytokines are currently under investigation as potential target to improve cardiac function and outcome in the setting of acute myocardial infarction (MI) or chronic heart failure (HF). Here we aim to provide a translational overview of cytokine inhibiting therapies tested in experimental models and clinical studies. In various experimental studies, inhibition of interleukin-1 (IL-1), -6 (IL-6), -8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), CC- and CXC chemokines, and tumor necrosis factor-α (TNF-α) had beneficial effects on cardiac function and outcome. On the other hand, neutral or even detrimental results have been reported for some (IL-1, IL-6, IL-8, and MCP-1). Ambivalence of cytokine function, differences in study designs, treatment regimens and chosen endpoints hamper the translation of experimental research into clinical practice. Human studies are currently limited to IL-1β inhibition, IL-1 receptor antagonists (IL-1RA), IL-6 receptor antagonists (IL-6RA) or TNF inhibition. Despite favorable effects on cardiovascular events observed in retrospective cohort studies of rheumatoid arthritis patients treated with TNF inhibition or IL-1RA, most prospective studies reported disappointing and inconsistent results. Smaller studies (n < 100) generally reported favorable results of anticytokine therapy on cardiac function, but only one of the larger studies (n > 100) evaluating IL-1β inhibition presented positive results on outcome. In conclusion, of the 10 anticytokine therapies tested in animals models beneficial effects have been reported in at least one setting. In larger clinical studies, findings were unsatisfactory in all but one. Many anticytokine therapies with promising animal experimental data continue to require further evaluation in humans.
29341591 The Development of Benzimidazole-Based Clickable Probes for the Efficient Labeling of Cell 2018 Mar 16 Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets. Herein, we report the development of next generation cell permeable and "clickable" probes (BB-Cl-Yne and BB-F-Yne) for covalent labeling of the PADs both in vitro and in cell-based systems. Using advanced chemoproteomic technologies, we also report the off targets of both BB-Cl-Yne and BB-F-Yne. The probes are highly specific for the PADs, with relatively few off targets, especially BB-F-Yne, suggesting the preferential use of the fluoroacetamidine warhead in next generation irreversible PAD inhibitors. Notably, these compounds can be used in a variety of modalities, including the identification of off targets of the parent compounds and as activity-based protein profiling probes in target engagement assays to demonstrate the efficacy of PAD inhibitors.
29269521 Clinicopathological characteristics of T-cell non-Hodgkin lymphoma arising in patients wit 2018 Mar Although it is known that B-cell lymphomas occur more frequently in immunocompromised patients, thus far such an association has not been clearly established for T-cell lymphomas. Of the 251 patients who were diagnosed with a T-cell non-Hodgkin lymphoma in our center between 1999 and 2014, at least 25 were identified in immunocompromised patients. Herein, we retrospectively analyzed the clinical and pathological characteristics of these 25 cases. In addition, we searched the literature and present an overview of 605 previously published cases. The actual number of patients with B-cell chronic lymphocytic leukemia and patients on immunosuppressive drugs for inflammatory bowel disease or rheumatoid arthritis in the total cohort of 251 patients diagnosed with T-cell non-Hodgkin lymphoma was much higher than the number of patients expected to have these diseases in this cohort, based on their prevalence in the general population. This, together with the large number of additional cases found in the literature, suggest that the risk of developing T-cell non-Hodgkin lymphoma is increased in immunocompromised patients. Compared to T-cell non-Hodgkin lymphoma in the general population, these lymphomas are more often located extranodally, present at a younger age and appear to have a poor outcome. The observations made in the study herein should raise awareness of the possible development of T-cell non-Hodgkin lymphoma in immunodeficient patients, and challenge the prolonged use of immunosuppressive drugs in patients who are in clinical remission of their autoimmune disease.
29034546 Bradykinin system is involved in endometriosis-related pain through endothelin-1 productio 2018 Mar BACKGROUND: Endometriosis is a gynaecological disease exhibiting severe pelvic pain, but the mechanism of pain production remains unknown. Bradykinin (BK) is known as an inflammatory mediator, and shows elevated levels in inflammatory diseases such as rheumatoid arthritis. In the present study, we evaluated whether BK is involved in endometriosis-related pain. METHODS: Endometriotic lesions were used for immunohistochemistry. Primary cultures of endometriotic stromal cells (ESC) were stimulated with IL-1β and/or BK. Quantitative RT-PCR was used to evaluate the mRNA expressions of BK receptors (BKR) and endothelin-1 in ESC. The concentration of endothelin-1 in cystic fluid of endometrioma or non-endometrioma was measured with ELISA. The conditioned medium of ESC stimulated with IL-1β and/or BK was injected intraplantarly in mice, and evaluated whether pain-related licking behaviour was elicited. RESULTS: The expressions of BK and BKR in endometriotic lesions were observed by immunohistochemistry. In vitro experiments showed that IL-1β induced BKR-B1 and B2 on ESC. Activation of these receptors by BK significantly induced endothelin-1 expression in ESC, which was negated completely by HOE-140, a BKR-B2 antagonist. The cystic fluid of endometrioma contained higher amount of endothelin-1 compared to non-endometrioma. Intraplantar injection of the conditioned medium of ESC treated with IL-1β and BK significantly induced licking behaviour, which was suppressed with BQ-123, an endothelin type-A receptor antagonist. CONCLUSIONS: The present study demonstrated the presence and the function of the BK axis in endometriosis, and established a potential new therapy target for endometriosis-related pain. SIGNIFICANCE: The present study demonstrated (1) the presence and the function of the BK system in endometriosis, (2) activation of BKR induced endothelin-1 in endometriotic lesion and (3) blocking endothelin-1 was effective to decrease pain.
28650278 Late-onset systemic lupus erythematosus: Is it "mild lupus"? 2018 Feb Objective The objective of this paper is to investigate the clinical characteristics and prognosis of patients with late-onset systemic lupus erythematosus (SLE) using a prospective observational cohort. Methods Late-onset SLE (≥50 years old) was compared with adult-onset SLE (≥18 and <50 years old) using 1997 ACR classification criteria for SLE, autoantibodies, disease activity measured by Adjusted Mean SLE Disease Activity Index (AMS), and damage measured by Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI). The standardized mortality ratio (SMR) was calculated. Results A total of 917 patients with SLE were enrolled. The mean number of cumulative ACR criteria in late-onset SLE ( n = 32, 3.5%) was lower than that in adult-onset SLE (4.6 ± 1.2 vs. 5.5 ± 1.4, p < 0.05). The percentage of patients with low complement was lower in late-onset SLE than adult-onset SLE ( p < 0.05). AMS was also lower in late-onset SLE (2.7 ± 2.1 vs. 4.3 ± 2.6, p < 0.01), but SDI was similar between the two groups (50% vs. 43.4%, p = 0.58). The SMR of late-onset SLE was 1.58 (95% CI 0.58-3.43), while the SMR of adult-onset SLE was 3.34 (2.34-4.63). Conclusion Compared with adult-onset SLE, late-onset SLE has a lower number of ACR criteria and lower disease activity. Organ damage is not different, but prognosis and mortality are more favorable.
29958151 Assessment of potentially inappropriate medications in elderly according to Beers 2015 and 2018 Sep OBJECTIVE: To assess and compare, according to Beers and STOPP criteria, the frequency and causes of potentially inappropriate medications (PIMs) in elderly, as well as the relationship between PIMs use and patient's treatment satisfaction, evaluated using the Treatment Satisfaction Questionnaire for Medications (TSQM). METHOD: 350 patients (mean age = 73.49 years), taking a total of 1893 medications, were enrolled from community pharmacies. RESULTS: 6.2% and 20.4% of the medications were inappropriate according to the STOPP and Beers lists respectively; 103 (29.4%) and 210 (60%) patients had at least one PIM according to STOPP and Beers criteria respectively. The most common cause of PIM was a full dose of proton pomp inhibitor for >8 weeks (STOPP) and using a drug that exacerbates/causes syndrome of inappropriate antidiuretic hormone secretion (Beers). The number of medications taken by the participant, advanced age, female gender, prescription of medications for anxiety/depression, ulcers/gastroesophageal reflux, rheumatoid arthritis and epilepsy significantly increased the PIMs number. When using STOPP criteria, all TSQM subscale scores were significantly lower among patients with PIM use compared to those without PIM. The same trend was observed for Beers critertia, with a significant difference reached for side effects and convenience subscales only. CONCLUSION: Selecting the appropriate tools to assess PIMs, prescribers and patient education regarding the risks associated with PIMs, and patient's perception and satisfaction regarding his treatment, are critical issues to be addressed among older adults.
29932968 Time trends in the prevalence of cancer and non-cancer diseases among older U.S. adults: M 2018 Sep Longer lifespan is accompanied by a larger number of chronic diseases among older adults. Because of a growing proportion of older adults in the U.S., this brings the problem of age-related morbidity to the forefront as a major contributor to rising medical expenditures. We evaluated 15-year time trends (from 1998 to 2013) in the prevalence of 48 acute and chronic non-cancer diseases and cancers in older U.S. adults aged 65+ and estimated the annual percentage changes of these prevalence trends using SEER-Medicare and HRS-Medicare data. We found that age-adjusted prevalence of cancers of kidney, pancreas, and melanoma, as well as diabetes, renal disease, limb fracture, depression, anemia, weight deficiency, dementia/Alzheimer's disease, drug/medications abuse and several other diseases/conditions increased over time. Conversely, prevalence of myocardial infarction, heart failure, cardiomyopathy, pneumonia/influenza, peptic ulcer, and gastrointestinal bleeding, among others, decreased over time. There are also diseases whose prevalence did not change substantially over time, e.g., a group of fast progressing cancers and rheumatoid arthritis. Analysis of trends of multiple diseases performed simultaneously within one study design with focus on the same time interval and the same population for all diseases allowed us to provide insight into the epidemiology of these conditions and identify the most alarming and/or unexpected trends and trade-offs. The obtained results can be used for health expenditures planning for growing sector of older adults in the U.S.
28128443 Potential Therapeutic Applications of Adenosine A(2A) Receptor Ligands and Opportunities f 2018 Jan Adenosine A(2A) receptors (A(2A) Rs) are highly expressed in the human striatum, and at lower densities in the cerebral cortex, the hippocampus, and cells of the immune system. Antagonists of these receptors are potentially useful for the treatment of motor fluctuations, epilepsy, postischemic brain damage, or cognitive impairment, and for the control of an immune checkpoint during immunotherapy of cancer. A(2A) R agonists may suppress transplant rejection and graft-versus-host disease; be used to treat inflammatory disorders such as asthma, inflammatory bowel disease, and rheumatoid arthritis; be locally applied to promote wound healing and be employed in a strategy for transient opening of the blood-brain barrier (BBB) so that therapeutic drugs and monoclonal antibodies can enter the brain. Increasing A(2A) R signaling in adipose tissue is also a potential strategy to combat obesity. Several radioligands for positron emission tomography (PET) imaging of A(2A) Rs have been developed in recent years. This review article presents a critical overview of the potential therapeutic applications of A(2A) R ligands, the use of A(2A) R imaging in drug development, and opportunities and limitations of PET imaging in future research.
30410049 Homotaurine, a safe blood-brain barrier permeable GABA(A)-R-specific agonist, ameliorates 2018 Nov 8 There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABA(A)-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABA(A)-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer's disease clinical trials. Homotaurine also acts as GABA(A)-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8(+)CD122(+)PD-1(+) and CD4(+)Foxp3(+) Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB-permeable GABA(A)-R agonists as a new class of treatment to enhance CD8(+) and CD4(+) Treg responses and limit Th17 and Th1-medaited inflammation in the CNS.
30365099 Bioinformatics analysis to identify key genes and pathways influencing synovial inflammati 2018 Dec Osteoarthritis (OA) is a chronic arthropathy that occurs in the middle‑aged and elderly population. The present study aimed to identify gene signature differences between synovial cells from OA synovial membrane with and without inflammation, and to explain the potential mechanisms involved. The differentially expressed genes (DEGs) between 12 synovial membrane with inflammation and 12 synovial membrane without inflammation from the dataset GSE46750 were identified using the Gene Expression Omnibus 2R. The DEGs were subjected to enrichment analysis, protein‑protein interaction (PPI) analysis and module analysis. The analysis results were compared with text‑mining results. A total of 174 DEGs were identified. Gene Ontology enrichment results demonstrated that functional molecules encoded by the DEGs primarily had extracellular location, molecular functions predominantly involving 'chemokine activity' and 'cytokine activity', and were associated with biological processes, including 'inflammatory response' and 'immune response'. The Kyoto Encyclopedia of Genes and Genomes results demonstrated that DEGS may function through pathways associated with 'rheumatoid arthritis', 'chemokine signaling pathway', 'complement and coagulation cascades', 'TNF signaling pathway', 'intestinal immune networks for IgA production', 'cytokine‑cytokine receptor interaction', 'allograft rejection', 'Toll‑like receptor signaling pathway' and 'antigen processing and presentation'. The top 10 hub genes [interleukin (IL)6, IL8, matrix metallopeptidase (MMP)9, colony stimulating factor 1 receptor, FOS proto‑oncogene, AP1 transcription factor subunit, insulin‑like growth factor 1, TYRO protein tyrosine kinase binding protein, MMP3, cluster of differentiation (CD)14 and CD163] and four gene modules were identified from the PPI network using Cytoscape. In addition, text‑mining was used to identify the commonly used drugs and their targets for the treatment of OA. It was initially verified whether the results of the present study were useful for the study of OA treatment targets and pathways. The present study provided insight for the molecular mechanisms of OA synovitis. The hub genes and associated pathways derived from analysis may be targets for OA treatment. IL8 and MMP9, which were validated by text‑mining, may be used as molecular targets for the OA treatment, while other hub genes require further validation.
30197125 1-Methoxycarbony-β-carboline from Picrasma quassioides exerts anti-angiogenic properties 2018 Aug Angiogenesis is a crucial process in the development of inflammatory diseases, including cancer, psoriasis and rheumatoid arthritis. Recently, several alkaloids from Picrasma quassioides had been screened for angiogenic activity in the zebrafish model, and the results indicated that 1-methoxycarbony-β-carboline (MCC) could effectively inhibit blood vessel formation. In this study, we further confirmed that MCC can inhibit, in a concentration-dependent manner, the viability, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, as well as the regenerative vascular outgrowth of zebrafish caudal fin in vivo. In the zebrafish xenograft assay, MCC inhibited the growth of tumor masses and the metastatic transplanted DU145 tumor cells. The proteome profile array of the MCC-treated HUVECs showed that MCC could down-regulate several angiogenesis-related self-secreted proteins, including ANG, EGF, bFGF, GRO, IGF-1, PLG and MMP-1. In addition, the expression of two key membrane receptor proteins in angiogenesis, TIE-2 and uPAR, were also down-regulated after MCC treatment. Taken together, these results shed light on the potential therapeutic application of MCC as a potent natural angiogenesis inhibitor via multiple molecular targets.
30158831 Innate and Adaptive Cell Populations Driving Inflammation in Dry Eye Disease. 2018 Dry eye disease (DED) is the most common ocular disease and affects millions of individuals worldwide. DED encompasses a heterogeneous group of diseases that can be generally divided into two forms including aqueous-deficient and evaporative DED. Evidence suggests that these conditions arise from either failure of lacrimal gland secretion or low tear film quality. In its secondary form, DED is often associated with autoimmune diseases such as Sjögren's syndrome and rheumatoid arthritis. Current treatment strategies for DED are limited to anti-inflammatory medications that target the immune system as the source of deleterious inflammation and tissue injury. However, there is a lack of understanding of the underlying pathogenesis of DED, and subsequently, there are very few effective treatment strategies. The gap in our knowledge of the etiology of primary DED is in part because the majority of research in DED focused on secondary autoimmune causes. This review focuses on what is currently understood about the contribution of innate and adaptive immune cell populations in the pathogenesis of DED and highlights the need to continue investigating the central role of immunity driving DED.