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1.
Nat Commun ; 11(1): 5420, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110080

RESUMO

Biomarkers are needed for predicting the effectiveness of disease modifying antirheumatic drugs (DMARDs). Here, using functional lipid mediator profiling and deeply phenotyped patients with early rheumatoid arthritis (RA), we observe that peripheral blood  specialized pro-resolving mediator (SPM) concentrations are linked with both DMARD responsiveness and disease pathotype. Machine learning analysis demonstrates that baseline plasma concentrations of resolvin D4, 10S, 17S-dihydroxy-docosapentaenoic acid, 15R-Lipoxin (LX)A4 and n-3 docosapentaenoic-derived Maresin 1 are predictive of DMARD responsiveness at 6 months. Assessment of circulating SPM concentrations 6-months after treatment initiation establishes that differences between responders and non-responders are maintained, with a decrease in SPM concentrations in patients resistant to DMARD therapy. These findings elucidate the potential utility of  plasma SPM concentrations as biomarkers of DMARD responsiveness in RA.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Líquido Sinovial/efeitos dos fármacos , Antirreumáticos/sangue , Artrite Reumatoide/patologia , Estudos de Coortes , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Graxos Insaturados/sangue , Humanos , Lipoxinas/sangue , Resultado do Tratamento
2.
Life Sci ; 261: 118459, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961230

RESUMO

Rheumatoid arthritis is a chronic, inflammatory joint disease leading to inflammation of synovial membrane that lines the joints. This inflammation further progresses and results in destruction of joints and surrounding cartilages. The underlying factors can be oxidative stress, pro-inflammatory mediators, imbalance and attenuation between various enzymes and proteins (like nuclear factor erythroid 2 related factor 2/Nrf2 and ubiquitin). Protein degradation pathways comprises of lysosomal, proteasomal pathway, and autophagosome (that are carried out in mammalian cells) are regulated through ubiquitin. Ubiquitin proteasomal system is dominating pathway for carrying out non-lysosomal proteolysis of intracellularly proteins. Fundamental processes including cell cycle progression, process of division, apoptosis, modulation of immune responses and cell trafficking are regulated by process of ubiquitination. Ubiquitin proteasomal pathway (UPP) includes ubiquitin moieties which are covalently attached to proteins and guides them proteasome for degradation. Misfolded, oxidized and damaged proteins which are responsible for critical processes, are major targets of degradation process. Any alteration in this system leads to dysregulated cellular homeostasis; progressively leading to numerous diseases including rheumatoid arthritis. Factors including TAK1, TRAF6 undergo are required for the progression of disease and thus contributes towards pathology of inflammatory disorders such as rheumatoid arthritis. This review will include all linked aspects which contribute its major role in rheumatoid arthritis.


Assuntos
Artrite Reumatoide/metabolismo , Ubiquitinação , Animais , Artrite Reumatoide/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/metabolismo
3.
Hum Cell ; 33(4): 1081-1090, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32918701

RESUMO

Long non-coding RNAs (lncRNAs) function in rheumatoid arthritis (RA). The present work was designed to explore the roles of lncRNA PVT1 in RA and the related mechanism. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine mRNA level. The binding sites between PVT1 and miR-145-5p were verified by a dual-luciferase reporter assay. Furthermore, RA-FLSs were treated with TNF-α to establish the RA model. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) assays were performed to detect cell proliferation. Flow cytometry and TUNEL assays were performed to detect cell apoptosis. Enzyme-linked immunosorbent assay (ELISA) was used to determine levels of inflammatory cytokines. PVT1 was significantly increased and miR-145-5p was decreased in synovial tissues of RA patients. miR-145-5p is a target miRNA of PVT1, and the levels of PVT1 and miR-145-5p in synovial tissues of RA patients were negatively correlated. In RA-FLSs, tumour necrosis factor-α (TNF-α) led to increased PVT1 levels and decreased miR-145-5p levels. Knockdown of PVT1 inhibited TNF-α-induced RA-FLS over-proliferation and reversed TNF-α-induced RA-FLS apoptosis reduction. Moreover, knockdown of PVT1 inhibited TNF-α-induced production of interleukin (IL)-1ß and IL-6 and the activation of NF-κB through miR-145-5p. PVT1 can regulate apoptosis and inflammatory responses in RA-FLSs by targeting miR-145-5p.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Proliferação de Células/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/fisiologia , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Adulto , Idoso , Apoptose/genética , Artrite Reumatoide/tratamento farmacológico , Células Cultivadas , Citocinas/metabolismo , Feminino , Expressão Gênica , Humanos , Inflamação/genética , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Necrose Tumoral alfa
4.
Life Sci ; 258: 118164, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739467

RESUMO

High mobility group box-1 (HMGB1) protein is a diverse, single polypeptide moiety, present in mammalian eukaryotic cells. In response to stimuli, this nuclear protein is actively secreted in to the extracellular compartment or passively released by the necrotic cells, in order to mediate inflammatory responses, by forming complexes with IL-1α, IL-1ß, LPS and other moieties, and binding to RAGE, TLR and other receptor ligands, initiating downstream, signaling processes. This molecule acts as a proinflammatory cytokine and contributes to the progression of diseases like, acute lung injury, autoimmune liver damage, graft rejection immune response and arthritis. Small concentrations of HMGB1 are released during apoptosis, which facilitates oxidative regulation on Cys106, and propagates immune inactivating tolerogenic signals in the body. The review portrays the role of HMGB1 in rheumatoid arthritis, evidently supported by pre-clinical and clinical investigations, demonstrating extensive HMGB1 expression in synovial tissue and fluid as well as serum, excessive expression of transduction receptor signaling molecules, bone remodeling and uncontrolled expression of bone destroying osteoclastogenesis, resulting in destruction of articular cartilage, bone deformation and synovial proliferation, alleviating the pathogenesis in RA disease. Moreover, the review highlights the therapeutic regime targeting HMGB1, facilitating inhibition of its actions and release into the extracellular compartment, to ameliorate the destructive events that prevail in rheumatoid arthritis.


Assuntos
Artrite Reumatoide/patologia , Proteína HMGB1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/fisiopatologia , Remodelação Óssea/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Cartilagem Articular/fisiopatologia , Proteína HMGB1/análise , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Terapia de Alvo Molecular , Osteogênese/efeitos dos fármacos
5.
Medicine (Baltimore) ; 99(32): e21480, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769882

RESUMO

BACKGROUND: The introduction of biological disease-modifying anti-rheumatic drugs into clinical practice has dramatically improved the clinical outcomes of individuals with rheumatoid arthritis (RA). We are conducting the IFX-SIRIUS STUDY I that evaluates whether switching from originator infliximab (IFX) to its biosimilar, CT-P13, is not inferior in maintaining nonclinical relapse to continue treatment with originator IFX in patients with RA achieving clinical remission. It is the next great issue whether disease activity can be maintained in good condition after discontinuation of CT-P13 because no evidence is available regarding the clinical value of discontinuing biosimilars in patients with RA. Thus, we will evaluate whether a condition without clinical relapse will be maintained after discontinuation of CT-P13 in patients with RA, achieving clinical remission or low disease activity during the IFX-SIRIUS STUDY I. METHODS/DESIGN: This study is an interventional, multicenter, open-label, single-arm clinical trial with a 48-week follow-up. Patients with RA who are treated with CT-P13 and sustained nonclinical relapse during the IFX-SIRIUS STUDY I will be included. Patients will discontinue CT-P13 after the study period of the IFX-SIRIUS STUDY I. We will evaluate disease activity by clinical disease activity indices and musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who do not have clinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of multiple biomarkers, such as cytokines and chemokines. In addition, if a clinical relapse occurs in patients after the discontinuation of CT-P13, we will evaluate the effectiveness and safety of restarting CT-P13. DISCUSSION: The study results are expected to show the clinical benefit of the discontinuation of CT-P13 and effectiveness and safety of restarting CT-P13 after clinical relapse. The strength of this study is to prospectively evaluate the therapeutic effectiveness by not only clinical disease activity indices but also standardized MSUS findings in multiple centers. We will explore whether parameters at baseline can predict a nonclinical relapse after the discontinuation of CT-P13 by integrating multilateral assessments, that is, patient's characteristics, clinical disease activity indices, MSUS findings, and serum biomarkers. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on April 20, 2020 as jRCTs071200007.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/patologia , Medicamentos Biossimilares/administração & dosagem , Substituição de Medicamentos , Infliximab/administração & dosagem , Adulto , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/análise , Estudos de Equivalência como Asunto , Feminino , Humanos , Quimioterapia de Indução , Japão , Masculino , Recidiva , Resultado do Tratamento , Ultrassonografia
6.
Nat Med ; 26(8): 1295-1306, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601335

RESUMO

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKposTREM2high and MerTKposLYVE1pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTKpos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTKpos STM subpopulations could therefore be a potential treatment strategy for RA.


Assuntos
Artrite Reumatoide/metabolismo , Inflamação/metabolismo , Macrófagos/imunologia , Líquido Sinovial/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Biópsia , Linhagem da Célula/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Articulações/imunologia , Articulações/metabolismo , Articulações/patologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Macrófagos/metabolismo , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Líquido Sinovial/imunologia , Membrana Sinovial
7.
Adv Exp Med Biol ; 1262: 115-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32613582

RESUMO

Arthritis is one of the most common disease states worldwide but is still publicly misunderstood and lacks engaging public awareness materials. Within the UK, the most prevalent types of arthritis are osteoarthritis (OA) and rheumatoid arthritis (RA). The two are commonly mistaken as the same disease but, in fact, have very different pathogenesis, symptoms and treatments. This chapter describes a study which aimed to assess whether an augmented reality (AR) application could be used to raise awareness about the difference between OA and RA.An application was created for Android tablets that included labelled 3D models, animations and AR scenes triggered from a poster. In total 11 adult participants tested the application taking part in a pretest and posttest which aim to measure the usability of the application and the acquisition of knowledge on OA and RA. A T-test was performed to assess the effectiveness of the application from the pretest and posttest questionnaire outcomes. Overall results were encouraging reporting a very significant acquisition of knowledge and a highly satisfactory user experience.


Assuntos
Artrite Reumatoide , Realidade Aumentada , Educação em Saúde , Osteoartrite , Adulto , Artrite Reumatoide/patologia , Educação em Saúde/métodos , Educação em Saúde/normas , Humanos , Aplicativos Móveis/normas , Osteoartrite/patologia , Inquéritos e Questionários , Reino Unido
8.
PLoS One ; 15(7): e0235637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628710

RESUMO

BACKGROUND: The high risk of cardiovascular disease is well recognized in rheumatoid arthritis. Type 2 diabetes also attributes to this increase in risk. Rheumatoid arthritis is a chronic inflammatory condition, which aggravates insulin resistance, placing the patients at a higher risk of type 2 diabetes and subsequent cardiovascular outcomes. Methotrexate treatment, as a gold standard anti-inflammatory drug in the treatment of rheumatoid arthritis has shown beneficial effects on cardiovascular health. However, its impact on type 2 diabetes is still unknown. OBJECTIVE: To assess the strength of the association between exposure to methotrexate and the rate of development of type 2 diabetes in rheumatoid arthritis patients. METHODS: All rheumatoid arthritis studies reporting the use of methotrexate as an exposure and type 2 diabetes as an outcome were searched until March 2020 using MEDLINE, Cochrane and Scopus databases. Studies were included if the diagnosis of rheumatoid arthritis was made according to current guidelines or by a rheumatologist, and if there was information about methotrexate exposure and the type 2 diabetes outcome. The author and an independent assessor evaluated the articles for eligibility. Meta-analyses combined relative risk estimates from each study where raw counts were available. RESULTS: Sixteen studies reporting sufficient data for inclusion in the meta-analyses were identified. Methotrexate showed a promising effect on the risk of type 2 diabetes as this risk decreased in rheumatoid arthritis patients using methotrexate (Relative risk 0.48, 95% CI 0.16, 1.43). CONCLUSION: Rheumatoid arthritis patients on methotrexate treatment had a lower risk of developing type 2 diabetes compared to rheumatoid arthritis patients not exposed to methotrexate. This finding highlights the need for future, randomized control trials to confirm the beneficial effect of methotrexate on type 2 diabetes in the rheumatoid arthritis population.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Metotrexato/uso terapêutico , Fatores Etários , Antirreumáticos/efeitos adversos , Artrite Reumatoide/patologia , Diabetes Mellitus Tipo 2/etiologia , Humanos , Metotrexato/efeitos adversos , Risco , Índice de Gravidade de Doença
9.
Mol Immunol ; 125: 131-139, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673817

RESUMO

Circular RNAs (circRNAs) have been demonstrated to play crucial roles in the development and progression of various types of cancers by serving as microRNA sponges to regulate the expression of target genes. Although in-depth studies of circRNAs have been conducted, their functional and pathological significance in autoimmune diseases, including rheumatoid arthritis (RA), remains unclear. Our previous study verified that hsa_circ_0088036 (circ0088036) is significantly elevated in peripheral blood mononuclear cells from patients with RA. The present study aimed to explore the roles of circ0088036 in the pathogenesis of RA. The circ0088036/miR-140-3p/silent information regulator 1 (SIRT 1) axis was predicted by bioinformatics tools. Circ0088036 was found to be aberrantly upregulated in fibroblast-like synoviocytes (FLSs) in RA compared with FLSs in osteoarthritis (OA). Functionally, upregulated circ0088036 promoted the proliferation and migration of RA-FLSs. Mechanistically, circ0088036 acted as a miR-140-3p sponge to upregulate SIRT 1 expression, subsequently promoting RA progression. In conclusion, this study revealed that circ0088036 may play an essential role in promoting synovial pathogenesis via the circ0088036/miR-140-3p/SIRT 1 axis in RA, providing new insight into circRNAs during RA progression.


Assuntos
Artrite Reumatoide/genética , Regulação da Expressão Gênica/genética , MicroRNAs/genética , RNA Circular/genética , Sirtuína 1/biossíntese , Sinoviócitos/patologia , Adulto , Artrite Reumatoide/patologia , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima
10.
Expert Rev Clin Immunol ; 16(8): 751-770, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32722946

RESUMO

INTRODUCTION: Main clinical manifestations of SARS-CoV-2 infection are characterized by fever, dyspnea, and interstitial pneumonia, frequently evolving in acute respiratory distress syndrome (ARDS). AREAS COVERED: Features of coronavirus disease 2019 (COVID-19) presents some common points with interstitial lung disease (ILD) both idiopathic and related to rheumatoid arthritis (RA), typically characterized by a chronic progression over time and possibly complicated by acute exacerbation (AE). The study of common pathogenetic mechanisms, such as the involvement of toll-like receptor 4, could contribute to the knowledge and treatment of idiopathic and RA-ILD. Moreover, hyperinflammation, mainly characterized by increase of effector T-cells and inflammatory cytokines, and activation of coagulation cascade, observed in COVID-19 related ARDS have been already shown in patients with AE of idiopathic and RA-ILD. A literature search was performed in PubMed, Embase, Scopus, and Web of Science, together with a manual search in COVID-resource centers of the main journals. EXPERT OPINION: Despite the uncertainty about pathogenetic aspects about COVID-19- pneumonia, it could be a possible model for other forms of ILD and AE. The great amount of data from studies on COVID-19 could be helpful in proposing safe therapeutic approaches for RA-ILD, in understanding pathogenesis of usual interstitial pneumonia and to develop new therapeutic strategies for AE.


Assuntos
Artrite Reumatoide/patologia , Infecções por Coronavirus/patologia , Doenças Pulmonares Intersticiais/patologia , Pneumonia Viral/patologia , Artrite Reumatoide/terapia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/terapia , Progressão da Doença , Humanos , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/terapia , Pulmão/patologia , Doenças Pulmonares Intersticiais/terapia , Pandemias , Pneumonia Viral/terapia , Exacerbação dos Sintomas , Receptor 4 Toll-Like/metabolismo
11.
PLoS One ; 15(7): e0233814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726313

RESUMO

The clinical efficacy for treating of celastrol rheumatoid arthritis (RA) has been well-documented, but its mechanism of action remains unclear. Here we explored through what proteins and processes celastrol may act in activated fibroblast-like synoviocytes (FLS) from RA patients. Differential expression of genes and proteins after celastrol treatment of FLS was examined using RNA sequencing, label-free relatively quantitative proteomics and molecular docking. In this paper, expression of 26,565 genes and 3,372 proteins was analyzed. Celastrol was associated with significant changes in genes that respond to oxidative stress and oxygen levels, as well as genes that stabilize or synthesize components of the extracellular matrix. These results identify several potential mechanisms through which celastrol may inhibit inflammation in RA.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Proteômica/métodos , Transcriptoma/efeitos dos fármacos , Triterpenos/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Células Cultivadas , Cromatografia Líquida , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Espectrometria de Massas por Ionização por Electrospray , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Espectrometria de Massas em Tandem , Triterpenos/uso terapêutico
12.
PLoS One ; 15(7): e0236508, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726333

RESUMO

Extracellular vesicles (EVs) are cell membrane-derived phospholipid bilayer nanostructures that contain bioactive proteins, enzymes, lipids and polymers of nucleotides. They play a role in intercellular communication and are present in body fluids. EVs can be isolated by methods like ultracentrifugation (UC), polyethylene-glycol-precipitation (PEG) or size exclusion chromatography (SEC). The co-presence of immunoglobulins (Ig) in EV samples isolated from plasma (pEVs) is often reported and this may influence the assessment of the biological function and phenotype of EVs in bio- and immunoassay. Here, we studied the presence of an Ig-based therapeutic (etanercept) in pEV samples isolated from rheumatoid arthritis (RA) patients and improved the isolation method to obtain purer pEVs. From plasma of etanercept (Tumor-necrosis-factor (TNF)-α antibodies)-treated RA patients pEVs were isolated by either UC, PEG or SEC. SEC isolated pEVs showed the highest particle-to-protein ratio. Strong TNF-α inhibition determined in a TNF-α sensitive reporter assay was observed by pEVs isolated by UC and PEG, and to a lesser extent by SEC, suggesting the presence of functional etanercept. SEC isolation of etanercept or labelled immunoglobulin G (IgG) showed co-isolation of these antibodies in the pEV fraction in the presence of plasma or a high protein (albumin) concentration. To minimize the presence of etanercept or immunoglobulins, we extended SEC (eSEC) column length from 56mm to 222mm (total stacking volume unchanged). No effect on the amount of isolated pEVs was observed while protein and IgG content were markedly reduced (90%). Next, from six etanercept- treated RA patients, pEVs were isolated on a eSEC or standard SEC column, in parallel. TNF-α inhibition was again observed in pEVs isolated by conventional SEC but not by eSEC. To confirm the purer pEVs isolated by eSEC the basal IL-8 promoter activation in human monocytes was determined and in 4 out of 5 SEC isolated pEVs activation was observed while eSEC isolated pEVs did not. This study shows that extended SEC columns yielded pEVs without detectable biologicals and with low protein and IgG levels. This isolation method will improve the characterization of pEVs as potential biomarkers and mediators of disease.


Assuntos
Produtos Biológicos/sangue , Proteínas Sanguíneas/análise , Vesículas Extracelulares/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Cromatografia em Gel , Etanercepte/sangue , Etanercepte/uso terapêutico , Vesículas Extracelulares/química , Humanos , Imunoglobulina G/análise , Interleucina-8/genética , Regiões Promotoras Genéticas , Ativação Transcricional , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
13.
Cell Prolif ; 53(7): e12854, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32530555

RESUMO

Macrophages maintain a dynamic balance in physiology. Various known or unknown microenvironmental signals influence the polarization, activation and death of macrophages, which creates an imbalance that leads to disease. Rheumatoid arthritis (RA) is characterized by the massive infiltration of a variety of chronic inflammatory cells in synovia. Abundant activated macrophages found in RA synovia are an early hallmark of RA, and the number of these macrophages can be decreased after effective treatment. In RA, the proportion of M1 (pro-inflammatory macrophages) is higher than that of M2 (anti-inflammatory macrophages). The increased pro-inflammatory ability of macrophages is related to their excessive activation and proliferation as well as an enhanced anti-apoptosis ability. At present, there are no clinical therapies specific to macrophages in RA. Understanding the mechanisms and functional consequences of the heterogeneity of macrophages will aid in confirming their potential role in inflammation development. This review will outline RA-related macrophage properties (focus on polarization, metabolism and apoptosis) as well as the origin of macrophages. The molecular mechanisms that drive macrophage properties also be elucidated to identify novel therapeutic targets for RA and other autoimmune disease.


Assuntos
Apoptose/fisiologia , Artrite Reumatoide/patologia , Macrófagos/patologia , Animais , Proliferação de Células/fisiologia , Humanos , Inflamação/patologia
14.
Int J Nanomedicine ; 15: 3497-3509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547009

RESUMO

Purpose: The existing treatment modalities for rheumatoid arthritis are less effective and safe, therefore it is essential to develop new treatments that particularly target the inflamed joints with decreased off-target side-effects. The current study proposes a nanoparticle-based therapeutic approach to target the anti-oxidant defense system of arthritic Balb/c mice. Methods: Biogenic selenium nanoparticles (SeNPs) were synthesized by using Trachyspermum ammi seed extract and were evaluated for their toxicological, as well as their therapeutic potential in collagen-induced arthritic mice. Results: The tested doses of SeNPs had no significant toxic effects on liver, kidney, spleen, and serum biochemical parameters in comparison to healthy mice. The SeNPs treatment reduced the disease severity, as demonstrated by decreased paw edema along with reduced lymphocytic cellular infiltration in the histopathological findings. SeNPs also revealed dose-independent improvement in the redox state of inflamed synovium by significantly improving the activity of antioxidant enzymes in comparison to the arthritic controls. Conclusion: It is therefore concluded that nano-selenium in combination with TAE extract showed enhanced therapeutic efficacy as compared to their individual effects.


Assuntos
Antirreumáticos/uso terapêutico , Apiaceae/química , Artrite Reumatoide/tratamento farmacológico , Nanopartículas/química , Selênio/toxicidade , Selênio/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antirreumáticos/farmacologia , Artrite Reumatoide/patologia , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Bovinos , Edema/patologia , Feminino , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Oxirredução , Extratos Vegetais/química , Selênio/administração & dosagem , Selênio/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Baço/efeitos dos fármacos , Baço/patologia
15.
PLoS One ; 15(6): e0234813, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555638

RESUMO

BACKGROUND: Autoimmune conditions (AICs) and/or their treatment may alter risk of human papilloma virus (HPV) infection and females with AICs are therefore at an increased risk of cervical dysplasia. However, inclusion of these at-risk populations in cervical cancer screening and HPV-vaccination guidelines, are mostly lacking. This study aimed to determine the prevalence of cervical dysplasia in a wide range of AICs and compare that to HIV and immunocompetent controls to support the optimisation of cervical cancer preventive health measures. METHODS: Data linkage was used to match cervical screening episodes to emergency department records of females with AICs or HIV to immunocompetent controls over a 14-year period. The primary outcome was histologically confirmed high-grade cervical disease. Results, measured as rates by cytology and histology classification per 1,000 females screened, were analysed per disease group, and intergroup comparisons were performed. RESULTS: Females with inflammatory bowel disease (2,683), psoriatic and enteropathic arthropathies (1,848), multiple sclerosis (MS) (1,426), rheumatoid arthritis (1,246), systemic lupus erythematosus and/or mixed connective tissue disease (SLE/MCTD) (702), HIV (44), and 985,383 immunocompetent controls were included. SLE/MCTD and HIV groups had greater rates of high-grade histological and cytological abnormalities compared to controls. Increased rates of low-grade cytological abnormalities were detected in all females with AICs, with the exception of the MS group. CONCLUSIONS: Females with SLE/MCTD or HIV have increased rates of high-grade cervical abnormalities. The increased low-grade dysplasia rate seen in most females with AICs is consistent with increased HPV infection. These findings support expansion of cervical cancer preventative programs to include these at-risk females.


Assuntos
Doenças Autoimunes/patologia , Displasia do Colo do Útero/patologia , Adulto , Artrite Reumatoide/complicações , Artrite Reumatoide/patologia , Austrália/epidemiologia , Doenças Autoimunes/complicações , Bases de Dados Factuais , Feminino , Infecções por HIV/complicações , Infecções por HIV/patologia , Humanos , Imunocompetência , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Prevalência , Fatores de Risco , Displasia do Colo do Útero/complicações , Displasia do Colo do Útero/epidemiologia
16.
Curr Top Microbiol Immunol ; 426: 119-141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483659

RESUMO

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. RA mainly affects the joints, with inflammation of the synovial membrane, characterized by hyperplasia, neo-angiogenesis, and immune cell infiltration that drives local inflammation and, if untreated, can lead to joint destruction and disability. In parallel to the well-known clinical heterogeneity, the underlying synovitis can also be significantly heterogeneous. In particular, in about 40% of patients with RA, synovitis is characterized by a dense lymphocytic infiltrate that can acquire the features of fully functional tertiary lymphoid organs (TLO). These structures amplify autoimmunity and inflammation locally associated with worse prognosis and potential implications for treatment response. Here, we will review the current knowledge on TLO in RA, with a focus on their pathogenetic and clinical relevance.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Tecido Linfoide/patologia , Autoimunidade , Humanos , Tecido Linfoide/imunologia , Neovascularização Patológica , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/patologia
17.
Nature ; 582(7811): 259-264, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499639

RESUMO

The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity3-5; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Receptor Notch3/metabolismo , Transdução de Sinais , Membrana Sinovial/patologia , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Células Endoteliais/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Receptor Notch3/antagonistas & inibidores , Receptor Notch3/deficiência , Receptor Notch3/genética , Antígenos Thy-1/metabolismo
18.
PLoS One ; 15(6): e0233897, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484820

RESUMO

OBJECTIVES: miR-155 plays a critical role in the inflammatory process and in diseases such as rheumatoid arthritis (RA). miR155 gene expression is regulated by its gene promoter region CpG island methylation. Previous studies have shown inconsistent changes in circulating levels of mir-155 in RA patients. The aims of our study were to evaluate miR-155 levels in plasma, to investigate its gene methylation level, and to correlate these levels with RA disease activity. METHODS: One hundred and twenty-five patients with RA, and 30 age and sex-matched healthy controls (HC) were enrolled. Whole blood and plasma samples were collected and stored at -80°C until analysis. DAS28 score at the time of the blood draw was used to assess RA disease activity. The methylation status of miR-155 host gene was determined in whole blood by quantitative real-time methylation-specific PCR (qPCR). miR-155 expression levels were evaluated by quantitative reverse transcription PCR. RESULTS: We found significantly lower circulating miR155 levels in RA patients compared to HC. Interestingly, the miR-155 gene methylation level was significantly higher in RA patients than in HC. miR-155 levels did not correlate with ACPA or RF positivity or disease activity. CONCLUSIONS: We show here higher miR-155 methylation in whole blood and lower plasma miR155 expression in RA patients in comparison to HC. The evaluation of miR-155 host gene methylation status or miR155 plasma level might be a potentially useful marker in RA determination.


Assuntos
Artrite Reumatoide/sangue , Biomarcadores/sangue , Metilação de DNA/genética , MicroRNAs/sangue , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Ilhas de CpG/genética , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
19.
Life Sci ; 254: 117734, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380080

RESUMO

Autophagy is considered as an important intracellular mechanism that degrades cytoplasmic components to furnish additional energy. It has cytoprotective effects through the degradation of intracellular pathogens, damaged organelles, and protein aggregates. On the other hand, there are reports of an association between autophagy and autoimmune diseases. Indeed, it has been evident that autophagy is dysregulated in various autoimmune diseases including rheumatoid arthritis (RA). Autophagy is implicated in the maturation survival and proliferation of various immune and non-immune cells, which play pivotal roles in RA pathogenesis. Additionally, autophagy seems to be involved in citrullination and presentation of citrullinated peptides to T lymphocyte cells. Presentation of citrullinated peptides through MHC compartments to the T cells leads to immune response and chronic inflammation. Evidence suggests that autophagy could be implicated in apoptosis resistance of RA fibroblast-like synoviocyte (RA FLS), osteoclastogenesis, and finally severe bone and cartilage destruction. Since autophagy could be an important phenomenon in RA pathogenesis, we summarized the roles of autophagy in citrullination, osteoclastogenesis, RA FLS cells survival, apoptosis resistance of cells, lymphocyte homeostasis and its clinical outcomes in RA disease.


Assuntos
Artrite Reumatoide/patologia , Autofagia , Artrite Reumatoide/imunologia , Artrite Reumatoide/terapia , Humanos
20.
Ann Rheum Dis ; 79(7): 891-900, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381568

RESUMO

OBJECTIVES: To decipher the phenotype of endothelial cells (ECs) derived from circulating progenitors issued from patients with rheumatoid arthritis (RA). METHODS: RA and control ECs were compared according to their proliferative capacities, apoptotic profile, response to tumour necrosis factor (TNF)-α stimulation and angiogenic properties. Microarray experiments were performed to identify gene candidates relevant to pathological angiogenesis. Identified candidates were detected by RT-PCR and western blot analysis in ECs and by immunohistochemistry in the synovium. Their functional relevance was then evaluated in vitro after gene invalidation by small interfering RNA and adenoviral gene overexpression, and in vivo in the mouse model of methyl-bovine serum albumin-(mBSA)-induced arthritis. RESULTS: RA ECs displayed higher proliferation rate, greater sensitisation to TNF-α and enhanced in vitro and in vivo angiogenic capacities. Microarray analyses identified the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) as a relevant gene candidate. Decreased SIRT1 expression was detected in RA ECs and synovial vessels. Deficient endothelial SIRT1 expression promoted a proliferative, proapoptotic and activated state of ECs through the acetylation of p53 and p65, and lead the development of proangiogenic capacities through the upregulation of the matricellular protein cysteine-rich angiogenic protein-61. Conditional deletion of SIRT1 in ECs delayed the resolution of experimental methyl-bovine serum albumin-(mBSA)-induced arthritis. Conversely, SIRT1 activation reversed the pathological phenotype of RA ECs and alleviates signs of experimental mBSA-induced arthritis. CONCLUSIONS: These results support a role of SIRT1 in RA and may have therapeutic implications, since targeting angiogenesis, and especially SIRT1, might be used as a complementary therapeutic approach in RA.


Assuntos
Artrite Reumatoide/genética , Neovascularização Patológica/genética , Sirtuína 1/metabolismo , Membrana Sinovial/irrigação sanguínea , Adulto , Animais , Apoptose/genética , Artrite Experimental , Artrite Reumatoide/patologia , Proliferação de Células/genética , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/genética
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