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1.
Arthritis Res Ther ; 22(1): 231, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023644

RESUMO

BACKGROUND: miR-431-5p is dysregulated in various cancers and plays an important function in the development of cancer. However, its role in fibroblast-like synoviocytes (FLSs) in patients with rheumatoid arthritis (RA) remains to be understood. METHODS: Quantitative real-time polymerase chain reaction was used to detect the relative expression of miR-431-5p in synovial tissues and FLSs. Cell proliferation assays helped examine RA FLS proliferation. Flow cytometry was performed to determine apoptosis and cell cycle progression in RA FLSs. We used dual-luciferase assays to determine the correlation between miR-431-5p and its putative target, X-linked inhibitor of apoptosis (XIAP). Quantitative real-time PCR and western blotting were used to measure XIAP levels in synovial tissues and transfected RA FLSs. RESULTS: miR-431-5p was downregulated in synovial tissues and FLSs of patients with RA. Upregulation of miR-431-5p prohibited cell proliferation and the G0/G1-to-S phase transition but promoted apoptosis in RA FLSs, while miR-431-5p inhibition showed the opposite results. miR-431-5p directly targeted XIAP in RA FLSs and reversely correlated with XIAP levels in synovial tissues. Notably, XIAP silencing partially restored the effects of miR-431-5p inhibition in RA FLSs. CONCLUSION: miR-431-5p regulates cell proliferation, apoptosis, and cell cycle of RA FLSs by targeting XIAP, suggesting its potential in the treatment of RA.


Assuntos
Artrite Reumatoide , MicroRNAs , Sinoviócitos , Apoptose/genética , Artrite Reumatoide/genética , Proliferação de Células/genética , Células Cultivadas , Fibroblastos , Humanos , MicroRNAs/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
2.
Front Immunol ; 11: 1975, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983133

RESUMO

LncRNA NEAT1 functions as an oncogene in multiple human cancers. However, its expression and role in fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) remain unclear. Thus, we investigated the expression of NEAT1 in synovial tissues and FLSs in RA, to determine its role in the development of RA. Quantitative real-time polymerase chain reaction was used to measure the expression of NEAT1. FLS proliferation was evaluated using cell proliferation assays. Flow cytometry was used to analyze cell cycle progression and apoptosis in FLSs. Binding between NEAT1 and miR-410-3p was demonstrated by dual-luciferase assays. We found that NEAT1 was upregulated in synovial tissues and FLSs in RA. Upregulation of NEAT1 promoted cell proliferation, induced S-to G2/M phase transition, and suppressed apoptosis in RA FLSs. NEAT1 directly bound to and negatively modulated miR-410-3p expression, while positively regulating YinYang 1(YY1; a miR-410-3p target). Inhibiting miR-410-3p and upregulating YY1 partially restored the inhibitory role in cell viability induced by the depletion of NEAT1 in RA FLSs. Besides pro-proliferative and anti-apoptotic roles, upregulation of NEAT1 promoted migration, invasion, and inflammatory cytokines secretion in RA FLSs. Taken together, our results suggest that the NEAT1 may serve as a novel diagnostic and therapeutic target for patients with RA.


Assuntos
Artrite Reumatoide/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , Sinoviócitos/metabolismo , Fator de Transcrição YY1/genética , Apoptose/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Ciclo Celular/genética , Proliferação de Células/genética , Sobrevivência Celular , Células Cultivadas , Progressão da Doença , Suscetibilidade a Doenças , Fibroblastos/metabolismo , Humanos , MicroRNAs/metabolismo , Fator de Transcrição YY1/metabolismo
3.
Biomed Pharmacother ; 131: 110628, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32890968

RESUMO

BACKGROUND: Synovial fibroblasts (SFs) act as key effector cells mediating synovial inflammation and joint destruction in rheumatoid arthritis (RA). Fibroblast growth factor 2 (FGF2) and its receptors (FGFRs) play important roles in RASF-mediated osteoclastogenesis. Pentraxin 3 (PTX3) is a soluble pattern recognition receptor with nonredundant roles in inflammation and innate immunity. PTX3 is produced by various cell types, including SFs and is highly expressed in RA. However, the role of PTX3 in FGF2-induced osteoclastogenesis in RA and the underlying mechanism have been poorly elucidated. METHODS: We first determined the expression of FGF2 and RANKL in synovial tissue and synovial fluid of RA patients. We then examined the effect of PTX3 on RASF osteoclastogenesis induced by endogenous and exogenous FGF2 in isolated RASF cells treated with FGF2 and/or recombinant PTX3 (rPTX3). Thirdly, we analyzed the effect of PTX3 on FGF2 binding to FGFR-1 and HSPG receptors on RASFs. Lastly, we evaluated joint morphology after injection of rPTX3 into collagen-induced arthritis (CIA) mice. RESULTS: FGF2 was confirmed to be highly expressed in both synovial tissue and synovial fluid of RA patients. FGF2 promoted cell proliferation and increased the expressions of RANKL and ICAM-1 and RANKL/OPG to induce osteoclastogenesis in RASF, while anti-FGF2 neutralized this effect. PTX3 significantly inhibited FGF2-induced RASF cell growth and osteoclastogenesis by preventing the interaction of 125I-FGF2 and FGFRs on the same cells. In addition, administration of rPTX3 significantly ameliorated cartilage and bone destruction in mice with CIA. CONCLUSIONS: PTX3 exhibited an inhibitory effect on the autocrine and paracrine stimulation of FGF2 on SFs, and ameliorated bone destruction in CIA mice. PTX3 may be implicated in bone destruction in RA, which may provide theoretical evidence and potential therapeutic targets for RA treatment.


Assuntos
Artrite Reumatoide/metabolismo , Proteína C-Reativa/administração & dosagem , Fator 2 de Crescimento de Fibroblastos/biossíntese , Osteoclastos/metabolismo , Componente Amiloide P Sérico/administração & dosagem , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/patologia , Células Cultivadas , Colágeno/toxicidade , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Humanos , Camundongos , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Distribuição Aleatória , Líquido Sinovial/citologia , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/metabolismo
4.
Biomed Pharmacother ; 130: 110519, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32682111

RESUMO

Accumulating evidence suggests that miR-483-3p is implicated in maintaining biological properties in human cancers. However, its biological roles in rheumatoid arthritis (RA) remain unknown. miR-483-3p levels in synovial tissue samples and fibroblast-like synoviocytes (FLSs) were determined using quantitative real-time PCR. The CCK-8 assay and EdU staining were performed to assess cell proliferation in RA FLSs after transfection with miR-483-3p mimics or inhibitor. Flow cytometry with Annexin V-FITC staining or PI staining was performed to assess apoptosis or cell cycle progression in RA FLSs, respectively. miR-483-3p was upregulated in RA, which markedly promoted cell proliferation, induced the G0/G1-to-S phase transition, and suppressed apoptosis in RA FLSs, whereas miR-483-3p silencing yielded opposite results. Moreover, insulin growth factor 1 (IGF-1) was detected as a direct miR-483-3p target. IGF-1 silencing partially restored cell proliferation, the G0/G1-to-S phase transition, and apoptosis suppression in RA FLSs via miR-483-3p inhibition. Our results showed that miR-483-3p promotes RA FLSs proliferation by targeting IGF-1, suggesting a potential strategy for diagnostic and treatment strategy for RA.


Assuntos
Artrite Reumatoide/genética , Fibroblastos/patologia , Fator de Crescimento Insulin-Like I/genética , MicroRNAs/genética , Líquido Sinovial/citologia , Apoptose/genética , Artrite Reumatoide/patologia , Proliferação de Células , Células Cultivadas , Marcação de Genes , Humanos , MicroRNAs/metabolismo , Fase de Repouso do Ciclo Celular/genética , Fase S/genética , Regulação para Cima
5.
Int Immunopharmacol ; 79: 106056, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31865244

RESUMO

OBJECTIVE: Our aim was to study the efficacy and mechanism by which NTX alleviate arthritis in CIA rat models in vivo. METHODS: Female Wistar rats were randomly divided into 6 groups, their weights were observed and the severity of arthritis and pathological changes were evaluated by HE staining. T lymphocyte subsets were detected by flow cytometry. The expression of cytokines was detected in peripheral serum by ELISA. Real time PCR, immunohistochemical staining and western blot analysis were utilized to detect the mRNA and protein expression of opioid receptors, TLR4, RANKL and /NF-κB in synovial tissue and the spleen. RESULTS: The weight of the rats in the 10 mg/kg NTX group decreased the least, and had the least severe arthritis. CD4+ T cells, Th1 cells and Treg cells increased, and CD8+T cells, Th1 cells and Th17 cells decreased in the splenic lymphocytes. The expression of proinflammatory cytokines decreased, and the expression of anti-inflammatory cytokines increased. MOR and DOR were strongly expressed in the spleen, whereas KOR and DOR were strongly expressed in synovial tissue. The expression of TLR4, NF-κB and RANKL was reduced in the spleen and synovium in the NTX group. CONCLUSIONS: NTX relieved the severity of arthritis in the CIA rat models at a concentration of 10 mg/kg by regulating T lymphocyte subsets and the expression of cytokines. NTX affected opioid receptors to inhibit the TLR4/NF-κB signaling pathway, regulating the systemic immune response and decreasing osteoclast differentiation, thereby alleviating inflammation and the erosion of articular cartilage along with bone tissue.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Naltrexona/uso terapêutico , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Animais , Citocinas/metabolismo , Humanos , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
6.
Biomed Pharmacother ; 119: 109426, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31505424

RESUMO

In our previous study, miR-410-3p had been confirmed to regulate inflammatory cytokine release in rheumatoid arthritis fibroblast-like synoviocytes (RA FLSs). However, other biological functions of miR-410-3p in RA FLSs still remain unexplored. In the present study, we focused on the effect of miR-410-3p on proliferation, apoptosis, and cell cycle of RA FLSs, and explored the potential underlying mechanism. miR-410-3p mRNA levels in the synovium and FLSs of patients with RA and of healthy controls were quantitated by RT-qPCR. The levels of miR-410-3p were reduced in both synovium and FLSs from patients with RA. Next, we focused on the roles of miR-410-3p in cell viability, apoptosis, and cell cycle, by transfecting miR-410-3p mimics and inhibitor into RA FLSs, and conducting CCK-8 assay, EdU staining and flow cytometry. Results showed that miR-410-3p up-regulation suppressed proliferation, promoted apoptosis and G1-S phase transition while miR-410-3p down-regulation had opposite effects. YY1 was verified as a direct target gene of miR-410-3p through the luciferase reporter system; YY1 up-regulation was able to rescue the effects of miR-410-3p in RA FLSs. Taken together, our current findings might provide a potential therapeutic target for RA.


Assuntos
Apoptose/genética , Artrite Reumatoide/genética , Fibroblastos/patologia , MicroRNAs/metabolismo , Sinoviócitos/patologia , Fator de Transcrição YY1/metabolismo , Artrite Reumatoide/patologia , Sequência de Bases , Ciclo Celular/genética , Linhagem Celular , Proliferação de Células/genética , Fibroblastos/metabolismo , Humanos , MicroRNAs/genética , Sinoviócitos/metabolismo
7.
Inflammation ; 42(1): 331-341, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30242542

RESUMO

miR-410-3p acts as an oncogene or a tumor suppressor in some malignancies. However, its role in rheumatoid arthritis (RA) is unknown. The study was conducted to investigate the effect of miR-410-3p on the pathogenesis of RA. Real-time RT-PCR was used to determine the mRNA levels of miR-410-3p in synovial tissues and fibroblast-like synoviocytes (FLSs). An ELISA was performed to examine the production levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and matrix metalloproteinase (MMP)-9. Western blotting was conducted to determine the protein levels of IκB-α, p-IκBα, p65, and p-p65. Nuclear factor (NF)-κB activation and nuclear translocation assays were performed to confirm the activation of NF-κB. We found that the expression level of miR-410-3p was downregulated in synovial tissues and FLSs from RA. Overexpression of miR-410-3p significantly reduced the secretion of TNF-α, IL-1ß, IL-6, and MMP-9 in human RA fibroblast-like synoviocytes (HFLS-RA); whereas miR-410-3p inhibition increased the expression levels of these cytokines. Furthermore, miR-410-3p suppresses the activation of NF-κB signaling pathway. Moreover, NF-κB inhibitor restored the elevation of TNF-α, IL-1ß, IL-6, and MMP-9 induced by miR-410-3p inhibition. Our results demonstrate that miR-410-3p acts an inflammatory suppressor in the pathogenesis of RA by regulating the NF-κB signaling pathway. These data suggest a novel function of miR-410-3p and provide insight into the complex mechanisms involved in RA.


Assuntos
Artrite Reumatoide/metabolismo , Citocinas/metabolismo , MicroRNAs/fisiologia , NF-kappa B/metabolismo , Sinoviócitos/metabolismo , Células Cultivadas , Fibroblastos , Humanos , MicroRNAs/análise , Transdução de Sinais
8.
Neuropsychiatr Dis Treat ; 13: 2141-2150, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28860771

RESUMO

PURPOSE: Rheumatoid arthritis (RA) is significantly associated with depression and anxiety. Social support and self-efficacy are the coping resources of psychological distress. However, little research is available on the interaction of social support and self-efficacy in RA patients. This study aimed to identify the prevalence of depressive and anxiety symptoms and to examine whether or not self-efficacy moderates the associations of social support with depressive and anxiety symptoms in Chinese RA patients. METHODS: A multicenter, cross-sectional study was conducted in northeast of China from December 2014 to January 2016. A total of 297 RA patients completed the Center for Epidemiologic Studies Depression Scale, Zung Self-Rating Anxiety Scale, Multidimensional Scale of Perceived Social Support and General Self-Efficacy Scale. The associations of social support, self-efficacy and social support × self-efficacy interaction with depressive and anxiety symptoms were examined by hierarchical regression analysis. If the interaction was statistically significant, simple slope analysis was conducted. RESULTS: The prevalence of depressive symptoms was 58.2%, while 47.5% RA patients had anxiety symptoms. Social support and social support × self-efficacy interaction were significantly associated with depressive symptoms. Social support, self-efficacy and their interaction were significantly associated with anxiety symptoms. The association between social support and depressive symptoms was gradually reduced in the low (1 standard deviation [SD] below the mean, B=-0.614, ß=-0.876, P<0.001), mean (B=-0.395, ß=-0.563, P<0.001) and high (1 SD above the mean, B=-0.176, ß=-0.251, P=0.002) groups of self-efficacy. For anxiety symptoms, the association was also gradually reduced in the low (B=-0.527, ß=-0.774, P<0.001), mean (B=-0.288, ß=-423, P<0.001) and high (B=-0.049, ß=-0.071, P=0.447) groups of self-efficacy. CONCLUSION: There was a high prevalence of depressive and anxiety symptoms in Chinese RA patients. Self-efficacy could attenuate the associations of social support with depressive and anxiety symptoms. Adequate social support and self-efficacy intervention should be provided to alleviate psychological distress.

9.
Health Qual Life Outcomes ; 15(1): 149, 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28738816

RESUMO

BACKGROUND: Positive psychological constructs that can moderate or mediate the negative impact of disease activity on health-related quality of life (HRQOL) in patients with rheumatoid arthritis (RA) have not been explored widely. This study aimed to assess the associations of disease activity, resilience with HRQOL and the moderating and mediating roles of resilience among Chinese RA patients. METHODS: A multi-center, cross-sectional study was conducted in RA inpatients in northeast of China. A total 298 subjects completed the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and Ego-Resiliency Scale (ERS) to measure HRQOL and resilience. For the SF-36, physical function, physical role limitation, bodily pain and general health perception are gathered into physical component summary (PCS), while vitality, social functioning, emotional role limitation and mental health are gathered into mental component summary (MCS). Disease activity was evaluated by the Disease Activity Score 28-C-reactive protein (DAS28-CRP). Hierarchical regression analysis was applied to examine the associations of disease activity, resilience and the disease activity*resilience interaction with PCS and MCS, respectively. Asymptotic and resampling strategies were utilized to examine the mediating role of resilience. RESULTS: The mean scores of PCS and MCS were 40.67 and 59.14, respectively. Disease activity was negatively associated with both PCS and MCS, and resilience was only positively associated with MCS. The disease activity*resilience interaction term were significantly associated with MCS (ß = 0.144, P = 0.003). The associations between disease activity and MCS were gradually reduced in low (1 SD below the mean, ß = -0.369, P < 0.001), mean (ß = -0.218, P < 0.001) and high (1 SD above the mean, ß = -0.068, P = 0.369) groups of resilience. Resilience acted as a partial mediator in the disease activity-MCS association (effect size was -0.085, BCa 95% CI: -0.159, -0.028). CONCLUSIONS: Disease activity was negatively associated with both physical and mental HRQOL, and resilience was only positively associated with mental HRQOL. Resilience could attenuate and mediate the association between disease activity and mental HRQOL. In addition to controlling disease activity, targeted intervention strategies designed for resilience should be strengthened to improve the HRQOL of this population.


Assuntos
Artrite Reumatoide/psicologia , Qualidade de Vida/psicologia , Resiliência Psicológica , Adulto , Idoso , Artrite Reumatoide/fisiopatologia , China , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Índice de Gravidade de Doença , Inquéritos e Questionários
10.
PLoS One ; 12(3): e0173293, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28291837

RESUMO

OBJECTIVE: This study aimed to assess the association between perceived social support (PSS) and fatigue and the roles of hope, optimism, general self-efficacy and resilience as mediators or moderators on PSS-fatigue association among Rheumatoid Arthritis (RA) patients in China. METHODS: A multi-center, cross-sectional study was conducted withinpatients diagnosed with RA in northeast China, in which 305 eligible inpatients were enrolled. The Multidimensional Fatigue Inventory, Multidimensional Scale of Perceived Social Support, Herth Hope Index, Life Orientation Test Revised, General Self-Efficacy Scale and Ego-Resiliency Scale were completed. The associations of PSS, hope, optimism, general self-efficacy and resilience with fatigue and the moderating roles of these positive psychological constructs were tested by hierarchical linear regression. Asymptotic and resampling strategies were utilized to assess the mediating roles of hope, optimism, general self-efficacy and resilience. RESULTS: The mean score of the MFI was 57.88 (SD = 9.50). PSS, hope, optimism and resilience were negatively associated with RA-related fatigue, whereas DAS28-CRP was positively associated. Only resilience positively moderated the PSS-fatigue association (B = 0.03, ß = 0.13, P<0.01). Hope, optimism and resilience may act as partial mediators in the association between PSS and fatigue symptoms (hope: a*b = -0.16, BCa 95%CI: -0.27, -0.03; optimism: a*b = -0.20, BCa 95%CI: -0.30, -0.10; resilience: a*b = -0.12, BCa 95%CI: -0.21-0.04). CONCLUSIONS: Fatigue is a severe symptom among RA patients. Resilience may positively moderate the PSS-fatigue association. Hope, optimism and resilience may act as partial mediators in the association. PSS, hope, optimism and resilience may contribute as effective recourses to alleviate fatigue, upon which PSS probably has the greatest effect.


Assuntos
Artrite Reumatoide/psicologia , Fadiga/psicologia , Adulto , Idoso , Artrite Reumatoide/fisiopatologia , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Resiliência Psicológica , Autoeficácia
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