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1.
Zhonghua Yi Xue Za Zhi ; 99(35): 2745-2749, 2019 Sep 17.
Artigo em Chinês | MEDLINE | ID: mdl-31550796

RESUMO

Objective: To investigatea cellular/molecular mechanism of the CD40/TRAF1 signalling pathway involved in Rheumatoid arthritis (RA). Methods: 16 patients with active RA and 9 patients with Fractures who underwent total knee or hip replacement in The First Affiliated Hospital of Soochow University were included in the study. Synovial tissues (ST) and serum were obtained from each patient. The CD40, TRAF1, NF-κB p65 were detected by ELISA and Immunohistochemistry in serum and tissue respectively. Real time-PCR (RT-PCR) was applied to measure NF-κB-related gene expression. Results: CD40 and TRAF1 positive area (%) in RA patients were 28.7±5.4, 34.3±4.8 respectively, which were significantly higher (P<0.05) than Fracture controls (21.2±9.5, 21.6±8.7 respectively). The expression of total NF-κB p65, and phospho-NF-κB p65 proteins, as well as NF-κB-related gene expression, including cytokines (TNFα, IL-6), chemokines (MCP-1),and adhesion molecules (ICAM-1) were significantly higher in the ST of RA patients compared to Fracture controls. Conclusion: It is thus possible that the CD40/TRAF1 pathway acted as a positive regulator through NF-κB activation and NF-κB-dependent proinflammatory genes in RA.


Assuntos
Artrite Reumatoide/genética , Antígenos CD40/metabolismo , Transdução de Sinais , Fator 1 Associado a Receptor de TNF/metabolismo , Fator de Transcrição RelA/metabolismo , Antígenos CD40/genética , Células Cultivadas , Expressão Gênica , Humanos , Membrana Sinovial , Fator 1 Associado a Receptor de TNF/genética , Fator de Transcrição RelA/genética
2.
Gene ; 720: 144081, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31473322

RESUMO

Despite the existing research, the etiology of rheumatoid arthritis (RA), an autoimmune disease remains poorly understood with early and accurate diagnosis difficult to achieve. MicroRNAs (miRNAs) play an important role in biological processes as modulators of transcription and translation. Previous studies have demonstrated a downregulation of several genes in early RA stages and in addition, miRNAs may serve as early biomarkers of subclinical changes in early RA. When comparing the four groups (ANOVA P < 0.01, fold change > 4), we found 253 differentially expressed miRNAs. Of these, 97 miRNAs were identified as overexpressed in early rheumatoid arthritis. The validation of miRNA microarray expression was performed in a set by RT-qPCR and showed strong agreement with microarray expression data. The putative targets of overexpressed microRNAs in early RA were significantly enriched in apoptosis, tolerance loss and Wnt pathways. Moreover, ROC analysis showed values of AUC 0.76 and P < 0.05 for miR 361-5p, identifying this miRNA as a potential biomarker of disease. We identified specific microRNAs associated with early rheumatoid arthritis and proposed them as early biomarkers of disease. Our results provide novel insight into immune disease physiopathology and describe unreported microRNAs in RA with potential for clinical use.


Assuntos
Artrite Reumatoide/genética , Biomarcadores/análise , Genoma Humano , MicroRNAs/genética , Adulto , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Curva ROC
3.
J Assoc Physicians India ; 67(4): 22-25, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31309790

RESUMO

Introduction: With 1 billion tobacco users worldwide, nicotine dependence has a major impact on global health. Advances in medication development for nicotine dependence require an improved understanding of the neurobiology of this complex, relapsing brain disorder. Aims: To study association of µ Opioid Receptor polymorphism in patients of rheumatoid arthritis and its correlation with severity of disease and prevalent alleles of the OPRM1 genes. Material and Methods: This is a case control study wherein all available patients and volunteers were recruited. 142 controls subjects with no known history of disease and 85 study group cases were included. Results: Comparison of genotype frequencies showed a statistically significant difference between the studied groups (p<0.004). A statistically significant difference was found when the allelic frequencies between the two groups were compared (p<0.0001), with the 17T allele having a-1.7518 fold higher risk of having RA (risk ratio (RR)=1.7518, 95%CI of RR=1.2988-2.3627, OR =3.2914; 95%CI =1.9608-5.5251). Significant difference was also found when the allelic frequencies between the two groups were compared (p<0.0001), with the 118G allele having a 1.5-fold higher risk of developing RA (RR)=1.5801, 95%CI =1.3091-1.9071, OR=3.1357; 95%CI 2.1083-4.6638). Conclusion: The study definitely needs to be extended to larger cohort of patients and control samples and to a larger set of candidate µ opioid receptors. Extending the studies to a larger cohort will also allow genetic analyses of clinically defined endophenotypes observed in the patients of this chronic metabolic disease with attributes of autoimmune disorder and multiple symptoms in patients.


Assuntos
Artrite Reumatoide/genética , Receptores Opioides/genética , Estudos de Casos e Controles , Humanos , Polimorfismo Genético , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Índice de Gravidade de Doença
4.
Medicina (B Aires) ; 79(3): 161-166, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31284249

RESUMO

Rheumatoid arthritis is a clinical autoimmune syndrome that causes joint damage. The positive or negative anti-cyclic citrullinated protein (CCP) antibodies serodiagnosis differentiates two subsets of the disease, each with different genetic background. Previous studies have identified associations between KIR genes and rheumatoid arthritis but not with anti-CCP serodiagnosis. Therefore, we investigated the proportion of patients seropositive and seronegative to anti-CCP and its possible association with KIR (killer cell immunoglobulin-like receptor) genes. We included 100 patients with rheumatoid arthritis from western Mexico, who were determined for anti-CCP serodiagnosis by ELISA, and 16 KIR genes were genotyped by PCR-SSP. The proportion of seropositive anti-CCP patients was 83%, and they presented a higher frequency of KIR2DL2 genes than the seronegative group (73.6% vs. 46.2%, p = 0.044) which, in turn, presented a higher KIR2DL2-/KIR2DL3+ genotype frequency than the first ones (46.2% vs. 17.2%, p = 0.043). These results suggest different KIR genetic backgrounds for each subset of the disease according to anti-CCP serodiagnosis.


Assuntos
Artrite Reumatoide/diagnóstico , Autoanticorpos/sangue , Receptores KIR2DL2/genética , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Autoanticorpos/genética , Feminino , Genótipo , Humanos , Masculino , México , Pessoa de Meia-Idade , Fator Reumatoide/sangue
5.
Gene ; 712: 143911, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31176730

RESUMO

MicroRNA-23b (miR-23b) is associated with inflammation and autoimmune diseases. This study evaluated miR-23b expression and assessed its potential as a biomarker of disease activity for rheumatoid arthritis (RA). Differential expression of microRNAs was determined by miRNA microarray analysis in fibroblast-like synoviocytes (FLSs) from four trauma patients as healthy controls (HCs) and eight RA patients. The microarray results showed elevated expression of miR-23b in FLSs from RA patients and this finding was corroborated by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization using synovial tissues (STs). Furthermore, we found miR-23b levels in plasma of RA patients were significantly higher than in HCs, and plasma miR-23b levels positively correlated with the erythrocyte sedimentation rate (ESR), hypersensitive C-reactive protein (hs-CRP), C-reactive protein (CRP), DAS28, and platelet (PLT) count (P < 0.05). MiR-23b levels in plasma inversely correlated with the levels of hemoglobin (Hb), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (P < 0.05), but not with rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibodies (ACPA) (P > 0.05). Moreover, patients with anorexia showed higher levels of miR-23b in plasma than those without anorexia. Similar results were observed with fatigue. Appropriate treatment for RA not only ameliorated the disease condition but also reversed the elevated plasma miR-23b level remarkably. These results suggest that circulating miR-23b may be a promising biomarker for RA disease activity.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/genética , MicroRNAs/sangue , Adulto , Idoso , Anticorpos Anti-Proteína Citrulinada/metabolismo , Bilirrubina/química , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/análise , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Feminino , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hemoglobinas/química , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Contagem de Plaquetas , Fator Reumatoide/metabolismo , Membrana Sinovial/citologia , Membrana Sinovial/metabolismo
6.
Nat Immunol ; 20(7): 928-942, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061532

RESUMO

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Perfilação da Expressão Gênica , Membrana Sinovial/metabolismo , Transcriptoma , Artrite Reumatoide/patologia , Autoimunidade/genética , Biomarcadores , Biologia Computacional/métodos , Estudos Transversais , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Membrana Sinovial/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fluxo de Trabalho
7.
Artif Cells Nanomed Biotechnol ; 47(1): 1766-1771, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31066587

RESUMO

BACKGROUND: Understanding the mechanism of chondrocytes degeneration could provide a new potential therapeutic idea for rheumatoid arthritis (RA) treatment. MicroRNA-27b-3p (miR-27b-3p) has been shown to regulate a variety of cell behaviors in various cell types. However, the role of miR-27b-3p in RA remains unknown. MATERIALS AND METHODS: Expression of miR-27b-3p and HIPK2 in cartilage tissues and chondrocytes was characterized using qRT-PCR and Western blot. MiR-27b-3p was overexpressed or suppressed in chondrocytes to observe the potential role of miR-27b-3p. RESULTS: We found declined miR-27b-3p and elevated HIPK2 in RA tissues and cells using qRT-PCR. Dual-luciferase reporter assay validated HIPK2 is a direct target of miR-27b-3p, confirmed by Western blot results. Pearson correlation presented that there was a significantly negative correlation between miR-27b-3p and HIPK2 mRNA. Overexpression of miR-27b-3p significantly reduced the expression of pro-apoptotic protein c-caspase3 and increased the expression of anti-apoptotic Bcl-2; however, downregulation of miR-27b-3p has a significant effect of inducing apoptosis. Furthermore, overexpression of miR-27b-3p combined with recombinant HIPK2 protein showed the inhibitory effect of miR-27b-3p was abolished by HIPK2. CONCLUSION: We found declined miR-27b-3p and elevated HIPK2 in RA tissues and cells. Further in vitro studies demonstrated that miR-27b might inhibit chondrocyte apoptosis and thus attenuate RA development by directly inhibiting HIPK2 expression.


Assuntos
Apoptose/genética , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Proteínas de Transporte/genética , Condrócitos/patologia , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Sequência de Bases , Proliferação de Células/genética , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL
8.
Isr Med Assoc J ; 5(21): 333-338, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31140226

RESUMO

BACKGROUND: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes. OBJECTIVES: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA. METHODS: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394). RESULTS: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses. CONCLUSIONS: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.


Assuntos
Artrite Reumatoide , Metotrexato , Receptor A2A de Adenosina/genética , Receptor A3 de Adenosina/genética , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Testes Farmacogenômicos , Variantes Farmacogenômicos , Farmacovigilância , Polimorfismo de Nucleotídeo Único , Eslovênia
9.
Clin Exp Rheumatol ; 37(3): 347-357, 2019 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31111823

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by both genetic and environmental factors. Over the last few years, particular attention has been given to novel genes and to the close interaction between genetic factors and epigenetic mechanisms. Research has also focused on the influence of environmental factors on disease development, and on new mechanisms of the innate and adaptive immune system that can influence the different stages of RA. However, there are still several aspects of the disease that need further investigation. Shedding some light on the different aspects of RA pathogenesis will help to improve the current diagnostic tools and to identify new targets for the development of disease-modifying therapies. Thus, in this review we summarise the new insights in RA pathogenesis, resulting from literature research data published in the last year.


Assuntos
Artrite Reumatoide , Meio Ambiente , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Humanos , Fatores de Risco
10.
Gene ; 706: 124-130, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31077735

RESUMO

In this study, we constructed a tumor necrosis factor α (TNF-α)-induced synovial cell inflammatory model using human synoviocytes (HS) cell line to explore the function of miR-98 in rheumatoid arthritis (RA). miR-98 mimics or miR-98 inhibitor were transfected into HS cells to up-regulate or down-regulate the expression of miR-98. The proliferation and apoptosis of HS cells were determined using CCK8 assay and flow cytometry, respectively. TargetScan website was utilized to predict the targets of miR-98. Luciferase assay was carried out to verify that IL-10 is a target of miR-98. Western blot was performed to analyze the expression of IL-10, apoptosis-related and NF-κB signaling pathway-related proteins. Our results demonstrated that the expression of miR-98 was up-regulated in HS cells stimulated by TNF-α. Down-regulation of miR-98 by inhibitor in TNF-α-stimulated HS cells dramatically inhibited cell proliferation and promoted cell apoptosis compared with the miR-98 inhibitor NC group. The protein expression of Bcl-2 was declined while the levels of Bax and Bim were increased by miR-98 inhibitor in TNF-α-stimulated HS cells. IL-10 was predicted and verified as a target of miR-98. qRT-PCR and western blot results revealed that the level of IL-10 was negatively regulated by miR-98. Finally, we identified that down-regulation of miR-98 reduced the expression level of p-p65 and p-IκBα in TNF-α-stimulated HS cells. In summary, our present study demonstrated that down-regulation of miR-98 inhibited the proliferation and promoted the apoptosis of TNF-α-stimulated HS partly by targeting IL-10 and regulating NF-κB signaling pathway, insinuating miR-98 as a candidate biomarker in RA.


Assuntos
Apoptose/genética , MicroRNAs/genética , MicroRNAs/fisiologia , Artrite Reumatoide/genética , Linhagem Celular , Proliferação de Células/fisiologia , Fibroblastos/metabolismo , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , MicroRNAs/metabolismo , Modelos Biológicos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo , Sinoviócitos/fisiologia , Fator de Transcrição RelA/metabolismo , Ativação Transcricional , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/fisiologia , Regulação para Cima
11.
Clin Exp Rheumatol ; 37(5): 783-790, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30963994

RESUMO

OBJECTIVES: Biologics, including tumour necrosis factor inhibitors such as adalimumab (ADA), have significantly improved outcomes in rheumatoid arthritis (RA). Because the clinical course of RA and response to therapy may be influenced by the genetic background of the patient, the objective of this retrospective parallel-assigned case-control analysis was to evaluate the associations between candidate genetic markers for RA with clinical and radiographic responses to ADA + methotrexate (MTX) or MTX monotherapy in the Optimal Protocol for Treatment Initiation with MTX and ADA (OPTIMA) study. METHODS: Three candidate genetic markers were tested: HLA-DRB1 shared epitope (SE), interleukin 4 receptor (IL4R) single nucleotide polymorphism (SNP) rs1805010, and Fc gamma receptor IIb (FcgRIIb) SNP rs1050501. Genetic associations with week 26 clinical and radiographic responses during treatment with ADA + MTX or MTX monotherapy were assessed using summary statistics, chi-square or Fisher's exact test, correlation, regression models, and corrected for multiple-comparisons. RESULTS: Low disease activity (p=0.008) and improvement in American College of Rheumatology 20%, 50% and 70% response criteria (p=0.02, 0.01, and 0.02, respectively) were associated with HLA-DRB1 SE copy numbers in the ADA + MTX treatment arm, and the FcgRIIb SNP was a predictor of remission. The IL4R SNP correlated with radiographic progression in patients receiving MTX monotherapy, supporting previous findings. CONCLUSIONS: This pharmacogenetic analysis identified genetic components that contribute to clinical responses to anti-rheumatic therapy.


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos , Artrite Reumatoide , Metotrexato/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Quimioterapia Combinada , Marcadores Genéticos , Humanos , Recuperação de Função Fisiológica , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
12.
Nat Commun ; 10(1): 1776, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992449

RESUMO

Polygenic risk scores (PRS) have shown promise in predicting human complex traits and diseases. Here, we present PRS-CS, a polygenic prediction method that infers posterior effect sizes of single nucleotide polymorphisms (SNPs) using genome-wide association summary statistics and an external linkage disequilibrium (LD) reference panel. PRS-CS utilizes a high-dimensional Bayesian regression framework, and is distinct from previous work by placing a continuous shrinkage (CS) prior on SNP effect sizes, which is robust to varying genetic architectures, provides substantial computational advantages, and enables multivariate modeling of local LD patterns. Simulation studies using data from the UK Biobank show that PRS-CS outperforms existing methods across a wide range of genetic architectures, especially when the training sample size is large. We apply PRS-CS to predict six common complex diseases and six quantitative traits in the Partners HealthCare Biobank, and further demonstrate the improvement of PRS-CS in prediction accuracy over alternative methods.


Assuntos
Predisposição Genética para Doença , Modelos Genéticos , Herança Multifatorial/genética , Característica Quantitativa Herdável , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Teorema de Bayes , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Simulação por Computador , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Bases de Dados Genéticas/estatística & dados numéricos , Depressão/diagnóstico , Depressão/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
13.
Cell Mol Biol Lett ; 24: 8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019537

RESUMO

Background: This study aimed to investigate the effects of miR-613 on the proliferation, invasion and apoptosis of rheumatoid arthritis synovial fibroblasts (RASFs). Methods: Synovial tissue samples were collected from 20 rheumatoid arthritis (RA) patients and 10 patients with joint trauma undergoing joint replacement surgery. The RASFs were isolated and cultured. MiR-613 and DKK1 expression in both synovial tissues and cells was detected using quantitative real-time PCR (qRT-PCR). Dual luciferase reporter gene assay was employed to evaluate the effect of miR-613 on the luciferase activity of DKK1. Then RASFs were transfected with miR-613 mimics, si-DKK1 and pcDNA-DKK1. Changes in cellular proliferation, invasion and apoptosis were detected through BrdU assay, Transwell invasion assay and flow cytometry analysis, respectively. Results: MiR-613 was significantly down-regulated in RA tissues and RASFs compared to normal tissues and cells, whereas DKK1 was up-regulated in RA tissues and RASFs. Dual luciferase reporter gene assay showed that miR-613 could specifically bind to the 3'UTR of DKK1 and significantly inhibit the luciferase activity. Moreover, miR-613 significantly reduced the expression of DKK1. Overexpression of miR-613 or knockdown of DKK1 suppressed proliferation and invasion of RASFs, and induced RASF apoptosis. The reverse results were observed when DKK1 was up-regulated in miR-613-overexpressing RASFs. Conclusions: MiR-613 can inhibit proliferation and invasion and induce apoptosis of RASFs by directly targeting DKK1 expression.


Assuntos
Apoptose , Artrite Reumatoide/patologia , Movimento Celular , Regulação para Baixo/genética , Fibroblastos/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , MicroRNAs/metabolismo , Membrana Sinovial/patologia , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Apoptose/genética , Artrite Reumatoide/genética , Sequência de Bases , Ciclo Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Regulação para Cima/genética
14.
Artif Cells Nanomed Biotechnol ; 47(1): 951-956, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30942097

RESUMO

OBJECTIVE: This meta-analysis was aimed to verify the influences of interleukin 23 receptor (IL-23R) rs11209026 and rs2201841 polymorphisms on the susceptibility of rheumatoid arthritis (RA). METHODS: We searched potentially relevant studies on the relationships of IL-23R gene rs11209026 and rs2201841 polymorphisms with RA susceptibility from PubMed (Medline), CNKI and EMBASE web databases. Crude odds ratios (ORs) along with 95% confidence intervals (95% CIs) were calculated to assess the strength of association through the fixed- or random-effects model. RESULTS: Eight published articles containing 5544 RA patients and 5532 health individuals were included in our meta-analysis. In total analysis, we found IL-23R gene rs11209026 polymorphism was not related to RA susceptibility in all genetic models, but there was a significant association between rs2201841 polymorphism and RA susceptibility under G vs. A model. In stratified analysis by ethnicity, an increased RA susceptibility was detected for rs2201841 polymorphism in Caucasian group. CONCLUSION: The results of meta-analysis indicated that IL-23R gene rs2201841 polymorphism might be a susceptible factor for RA under G vs. A model, especially in Caucasian population.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético , Receptores de Interleucina/genética , Alelos , Humanos
15.
Biomed Res Int ; 2019: 8326246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31011579

RESUMO

Vitamin D is an anti-inflammatory molecule and has a role in prevention of arthritis development. Biologically active form 1, 25(OH)2D3 of vitamin D can only exert its action after binding its definite vitamin D receptor encoded by VDR gene. VDR gene polymorphism leads to dysfunctioning of 1, 25(OH)2D3 ultimately disease onset. The purpose of current study was to evaluate the effect of vitamin D level and VDR gene polymorphism on rheumatoid arthritis and osteoarthritis. Blood samples were collected from case and control after taking written consent. Serum was separated and vitamin D level as determined from each sample by ELISA. DNA was extracted from each blood sample and amplified by using gene specific primers. Genotyping was performed by Sangers sequencing and PCR-RFLP technique. It was found that vitamin D level was not significantly different among patients and controls. The rs10735810, rs1544410, rs7975232, and rs731236 were associated with the onset of arthritis at both allelic and genotypic level (p < 0.01). Nucleotide change on rs10735810 site leads to change of tryptophan with arginine. The frequencies of haplotype CGAT, CGGA, CGGT, CTAA, CTAT, TGAA, TGAT, TGGA, and TTGA were higher in patients and act as risk factors of RA onset, whereas haplotypes CGAT, CGAT, CGGT, CTGA, TGAT, TGGA, TTAA, and TTGA were associated with OA onset. In conclusion, serum vitamin D level may be normal among arthritis patients but polymorphism on VDR gene restricts vitamin D to perform its anti-inflammatory function by altering the 1, 25(OH)2 D3 binding sites.


Assuntos
Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Vitamina D/genética , Adulto , Alelos , Artrite Reumatoide/sangue , Calcitriol/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Vitamina D/sangue
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(5): 505-507, 2019 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-31030445

RESUMO

OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) of microRNA-146a (miR-146a) with clinical features of rheumatoid arthritis (RA). METHODS: In 126 patients with RA and 102 matched healthy controls, SNPs of miR-146a rs2910164 locus were determined with a high-resolution melting method. The association of such polymorphisms with disease activity score in 28 joints (DAS28) and clinical features of RA was assessed. RESULTS: The distribution of SNPs of miR-146a rs2910164 among RA patients did not differ from that of the control group. No significant association was found between miR-146a rs2910164 polymorphism with DAS28. However, RA patients with a GG genotype had a greater chance to develop extra-articular manifestations (P<0.01). CONCLUSION: Polymorphisms of miR-146a rs2910164 locus is not an independent risk factor for RA, though its GG genotype may be associated with extra-articular manifestations of RA.


Assuntos
Artrite Reumatoide , MicroRNAs/genética , Artrite Reumatoide/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
17.
Best Pract Res Clin Haematol ; 32(1): 74-88, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927978

RESUMO

Autoimmune diseases (ADs) are associated with an increased risk not only of lymphoproliferative disorders but also of myeloid malignancies. The excess risk of myelodysplastic syndromes and/or acute myeloid leukemia is observed across several AD types, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, among others. The risk of developing myeloid neoplasms (MNs) is dependent on several variables, including the specific AD type, chronicity and severity of the AD, type and duration of exposure of disease modifying anti-rheumatic drugs or cytotoxics/immunosuppressives, and genetic predisposition risk. Putative triggering factors linking AD to elevated MN risk include AD-directed medications, shared genetic susceptibilities between the two disease entities, and chronic immune stimulation or bone marrow infiltration by the AD. Molecular mechanisms underpinning leukemogenesis remain largely speculative and warrant further investigation. Leukemias arising in patients with AD are not always 'therapy-related' in that MNs may develop in certain AD subtypes even among patients with no prior therapy exposure. Only a few studies have attempted to determine factors associated with MN development in AD but failed to demonstrate consistent characteristic clinical or paraclinical features. These reports have failed to demonstrate a clear correlation between individual agent exposure and subsequent leukemia development due to the low rates of therapy exposure compounded by the rarity of MN occurrence. Notwithstanding, the leukemogenic potential is best documented with agents such as azathioprine, cyclophosphamide, and mitoxantrone; this risk of MN development does not appear to be shared by biologic approaches such as anti-tumor necrosis factors-alpha inhibitors. In this article, we discuss plausible biologic mechanisms underlying MN pathogenesis in AD and review the data available on the development of MNs in patients with AD.


Assuntos
Artrite Reumatoide , Ciclofosfamida/efeitos adversos , Predisposição Genética para Doença , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda , Lúpus Eritematoso Sistêmico , Mitoxantrona/efeitos adversos , Síndromes Mielodisplásicas , Segunda Neoplasia Primária , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Mitoxantrona/uso terapêutico , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia
18.
Cell Biochem Funct ; 37(4): 208-215, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30941802

RESUMO

Abnormal hyperplasia of fibroblast-like synoviocytes (FLS) leads to the progression of rheumatoid arthritis (RA). This study aimed to investigate the role of miR-124a in the pathogenesis of RA. The viability and cell cycle of FLS in rheumatoid arthritis (RAFLS) were evaluated by Cell Counting Kit 8 and flow cytometry assay. The expression of PIK3CA, Akt, and NF-κB in RAFLS was examined by real-time PCR and Western blot analysis. The production of tumour necrosis factor (TNF)-α and interleukin (IL)-6 was detected by ELISA. The joint swelling and inflammation in collagen-induced arthritis (CIA) mice were examined by histological and immunohistochemical analysis. We found that miR-124a suppressed the viability and proliferation of RAFLS and increased the percentage of cells in the G1 phase. miR-124a suppressed PIK3CA 3'UTR luciferase reporter activity and decreased the expression of PIK3CA at mRNA and protein levels. Furthermore, miR-124a inhibited the expression of the key components of the PIK3/Akt/NF-κB signal pathway and inhibited the expression of pro-inflammatory factors TNF-α and IL-6. Local overexpression of miR-124a in the joints of CIA mice inhibited inflammation and promoted apoptosis in FLS by decreasing PIK3CA expression. In conclusion, miR-124a inhibits the proliferation and inflammation in RAFLS via targeting PIK3/NF-κB pathway. miR-124a is a promising therapeutic target for RA.


Assuntos
Artrite Reumatoide/patologia , Fibroblastos , Inflamação/genética , MicroRNAs/genética , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética , Sinoviócitos/metabolismo , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proliferação de Células/genética , Colágeno , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Sinoviócitos/patologia
19.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945669

RESUMO

Antitumour necrosis factor-alpha (TNF-α) therapy is used as a clinical intervention for rheumatoid arthritis (RA) but differences exist in response to the treatment which makes the candidature of the screening of TNF-α alteration(s) at genetic and expression levels an important agenda prior to treatment. This study aims to determine the associative role of TNF-α -308G/A polymorphism and differential expression of TNF-α in the pathogenesis of RA. A case-control study where a total of 126 RA patients were enrolled based on ACR-EULAR (2010) criteria, along with 160 community matched age and sex controls over a period of three years. The differential expression level of TNF-α mRNA and protein level was studied and TNF-α -308G/A polymorphism was screened by T-ARMS PCR assay. All statistical analysis was performed using SPSS software. mRNA expression level of TNF-α was upregulated in RA cases (avg. 15.85 ± 9.52 fold) compared to control. TNF-α protein level was found to be higher in RA cases (28.62±7.17 pg/mL) compared to control (23.14±6.91 pg/mL). TNF-α -308 variant GA genotype was higher in RA (46.03%) than in control (25%). The presence of TNF-α -308 variant A allele was associated with increased risk of RA susceptibility (odds ratio (OR) = 2.559 at 95% confidence interval (CI), P< 0.001) but not severity (OR = 1.617 at 95% CI, P = 0.571). The presence of -308 variant genotype was associated with a higher TNF-α mRNA and protein expression. The presence of TNF-α -308A allele is associated with increased risk of RA susceptibility and differential TNF-α expression, and has prognostic significance. Association of higher TNF-α pro-inflammatory cytokine levels with northeast Indian patients makes them suitable subjects for anti-TNF-α therapy.


Assuntos
Artrite Reumatoide/patologia , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto Jovem
20.
Artif Cells Nanomed Biotechnol ; 47(1): 1628-1634, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31010320

RESUMO

Chronic inflammation in fibroblast-like synoviocytes (FLSs) induced by pro-inflammatory cytokines such as TNF-α plays a key role in the pathogenesis of rheumatoid arthritis (RA). The neurokinin-1 receptor (NK-1R) is one of the G protein-coupled receptors (GPCRs) mediating the intracellular signalling of substance P (SP). However, the possible implications of NK-1R in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and the pathogenesis of RA have not yet been reported. In the current study, we report that NK-1R is expressed in FLSs. Importantly, NK-1R expression was found to be significantly increased in RA-FLSs compared to normal FLSs. Interestingly, we found that treatment with tumour necrosis factor (TNF)-α increased the expression of NK-1R at both the gene and protein levels. Treatment with the NK-1R antagonist aprepitant reduced TNF-α-induced expression of NADPH oxidase 4 (NOX-4) and generation of reactive oxygen species (ROS) in FLSs. Our results also display that blockage of NF-1R using aprepitant inhibited TNF-α-induced expression and secretion of proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-6, and IL-8. Consistently, aprepitant prevented TNF-α-induced expression of matrix metalloproteinases (MMPs), including matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13). Mechanistically, our data demonstrate that treatment with aprepitant inhibited TNF-α-induced phosphorylation and degradation of inhibitor of NF-κB (IκBα). Notably, aprepitant attenuated TNF-α-induced nuclear translocation of nuclear factor κB (NF-κB) p65 and reduced luciferase activity of NF-κB in FLSs. The findings implicated a novel function of NK-1R in RA-FLSs. Blockage of NK-1R using its specific antagonist aprepitant might provide a new therapeutic strategy for RA.


Assuntos
Aprepitanto/farmacologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Fibroblastos/patologia , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Receptores da Neurocinina-1/metabolismo , Sinoviócitos/efeitos dos fármacos , Aprepitanto/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Antagonistas do Receptor de Neuroquinina-1/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Receptores da Neurocinina-1/genética , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Fator de Necrose Tumoral alfa/metabolismo
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