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1.
BMC Musculoskelet Disord ; 25(1): 634, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39118036

RESUMO

BACKGROUND: Although rheumatoid arthritis (RA) is a chronic systemic tissue disease often accompanied by osteoporosis (OP), the molecular mechanisms underlying this association remain unclear. This study aimed to elucidate the pathogenesis of RA and OP by identifying differentially expressed mRNAs (DEmRNAs) and long non-coding RNAs (lncRNAs) using a bioinformatics approach. METHODS: Expression profiles of individuals diagnosed with OP and RA were retrieved from the Gene Expression Omnibus database. Differential expression analysis was conducted. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) pathway enrichment analyses were performed to gain insights into the functional categories and molecular/biochemical pathways associated with DEmRNAs. We identified the intersection of common DEmRNAs and lncRNAs and constructed a protein-protein interaction (PPI) network. Correlation analysis between the common DEmRNAs and lncRNAs facilitated the construction of a coding-non-coding network. Lastly, serum peripheral blood mononuclear cells (PBMCs) from patients with RA and OP, as well as healthy controls, were obtained for TRAP staining and qRT-PCR to validate the findings obtained from the online dataset assessments. RESULTS: A total of 28 DEmRNAs and 2 DElncRNAs were identified in individuals with both RA and OP. Chromosomal distribution analysis of the consensus DEmRNAs revealed that chromosome 1 had the highest number of differential expression genes. GO and KEGG analyses indicated that these DEmRNAs were primarily associated with " platelets (PLTs) degranulation", "platelet alpha granules", "platelet activation", "tight junctions" and "leukocyte transendothelial migration", with many genes functionally related to PLTs. In the PPI network, MT-ATP6 and PTGS1 emerged as potential hub genes, with MT-ATP6 originating from mitochondrial DNA. Co-expression analysis identified two key lncRNA-mRNA pairs: RP11 - 815J21.2 with MT - ATP6 and RP11 - 815J21.2 with PTGS1. Experimental validation confirmed significant differential expression of RP11-815J21.2, MT-ATP6 and PTGS1 between the healthy controls and the RA + OP groups. Notably, knockdown of RP11-815J21.2 attenuated TNF + IL-6-induced osteoclastogenesis. CONCLUSIONS: This study successfully identified shared dysregulated genes and potential therapeutic targets in individuals with RA and OP, highlighting their molecular similarities. These findings provide new insights into the pathogenesis of RA and OP and suggest potential avenues for further research and targeted therapies.


Assuntos
Artrite Reumatoide , Biologia Computacional , Perfilação da Expressão Gênica , Osteoporose , RNA Longo não Codificante , Humanos , Artrite Reumatoide/genética , RNA Longo não Codificante/genética , Osteoporose/genética , Mapas de Interação de Proteínas , RNA Mensageiro/genética , Redes Reguladoras de Genes , Feminino , Masculino , Ontologia Genética , Transcriptoma
2.
Cells ; 13(15)2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39120313

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Although much remains unknown about the pathogenesis of RA, there is evidence that impaired immune tolerance and the development of RA are related. And it is precisely the restoration of immune tolerance at the site of the inflammation that is the ultimate goal of the treatment of RA. Over the past few decades, significant progress has been made in the treatment of RA, with higher rates of disease remission and improved long-term outcomes. Unfortunately, despite these successes, the proportion of patients with persistent, difficult-to-treat disease remains high, and the task of improving our understanding of the basic mechanisms of disease development and developing new ways to treat RA remains relevant. This review focuses on describing new treatments for RA, including cell therapies and gene editing technologies that have shown potential in preclinical and early clinical trials. In addition, we discuss the opportunities and limitations associated with the use of these new approaches in the treatment of RA.


Assuntos
Artrite Reumatoide , Terapia Baseada em Transplante de Células e Tecidos , Edição de Genes , Humanos , Artrite Reumatoide/terapia , Artrite Reumatoide/genética , Edição de Genes/métodos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Animais
3.
Sci Rep ; 14(1): 17796, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090125

RESUMO

Rheumatoid arthritis (RA) is a common autoimmune disease, and some observational studies have indicated an association between Gastroesophageal Reflux Disease (GERD) and RA. However, the causal relationship between the two remains uncertain. We used Mendelian randomization (MR) to assess the causal relationship between GERD and RA. Two-sample Mendelian randomization analysis was performed using pooled data from large-scale genome-wide association studies. In addition, we performed multivariate MR analyses to exclude confounding factors between GERD and RA, including smoking quantity, drinking frequency, BMI, depression, and education attainment. The MR results for GERD on RA suggested a causal effect of the genetic susceptibility of GERD on RA (discovery dataset, IVW, odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.22-1.63, p = 2.81 × 10-6; validation dataset, IVW, OR = 1.38, 95% CI 1.23-1.55, P = 1.76 × 10-8). Multivariate MR analysis also supports this result. But the results of the reverse MR analysis did not reveal compelling evidence that RA can increase the risk of developing GERD. Our bidirectional Two-Sample Mendelian randomization analysis and multivariate MR analysis provide support for the causal effect of GERD on RA. This discovery could offer new insights for the prevention and treatment of RA.


Assuntos
Artrite Reumatoide , Refluxo Gastroesofágico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Artrite Reumatoide/genética , Humanos , Refluxo Gastroesofágico/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Razão de Chances
4.
Front Immunol ; 15: 1431452, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39139563

RESUMO

Background: Interactions between the immune and metabolic systems may play a crucial role in the pathogenesis of metabolic syndrome-associated rheumatoid arthritis (MetS-RA). The purpose of this study was to discover candidate biomarkers for the diagnosis of RA patients who also had MetS. Methods: Three RA datasets and one MetS dataset were obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms including Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest (RF) were employed to identify hub genes in MetS-RA. Enrichment analysis was used to explore underlying common pathways between MetS and RA. Receiver operating characteristic curves were applied to assess the diagnostic performance of nomogram constructed based on hub genes. Protein-protein interaction, Connectivity Map (CMap) analyses, and molecular docking were utilized to predict the potential small molecule compounds for MetS-RA treatment. qRT-PCR was used to verify the expression of hub genes in fibroblast-like synoviocytes (FLS) of MetS-RA. The effects of small molecule compounds on the function of RA-FLS were evaluated by wound-healing assays and angiogenesis experiments. The CIBERSORT algorithm was used to explore immune cell infiltration in MetS and RA. Results: MetS-RA key genes were mainly enriched in immune cell-related signaling pathways and immune-related processes. Two hub genes (TYK2 and TRAF2) were selected as candidate biomarkers for developing nomogram with ideal diagnostic performance through machine learning and proved to have a high diagnostic value (area under the curve, TYK2, 0.92; TRAF2, 0.90). qRT-PCR results showed that the expression of TYK2 and TRAF2 in MetS-RA-FLS was significantly higher than that in non-MetS-RA-FLS (nMetS-RA-FLS). The combination of CMap analysis and molecular docking predicted camptothecin (CPT) as a potential drug for MetS-RA treatment. In vitro validation, CPT was observed to suppress the cell migration capacity and angiogenesis capacity of MetS-RA-FLS. Immune cell infiltration results revealed immune dysregulation in MetS and RA. Conclusion: Two hub genes were identified in MetS-RA, a nomogram for the diagnosis of RA and MetS was established based on them, and a potential therapeutic small molecule compound for MetS-RA was predicted, which offered a novel research perspective for future serum-based diagnosis and therapeutic intervention of MetS-RA.


Assuntos
Artrite Reumatoide , Biologia Computacional , Aprendizado de Máquina , Síndrome Metabólica , Simulação de Acoplamento Molecular , Humanos , Síndrome Metabólica/genética , Síndrome Metabólica/diagnóstico , Artrite Reumatoide/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Mapas de Interação de Proteínas , Redes Reguladoras de Genes , Biomarcadores , Transcriptoma
5.
Gene ; 928: 148804, 2024 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-39089529

RESUMO

Rheumatoid arthritis (RA) is a multifactorial autoimmune inflammatory disease that mainly affects the joints, on reducing functional capacity and impacting quality of life. Cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) are crucial in the pathogenesis and treatment of this disease. Some patients using TNF inhibitors (TNFi) do not respond or lose their response to these medications. Clinical, sociodemographic, and genetic data were used to evaluate the associations of single nucleotide polymorphisms (SNP) in TNF, TNFRSF1A, and TNFRSF1B genes with the diagnosis of RA, standardized score results, laboratory tests, and response to TNFi. In one subsample, TNF and IL-6 serum levels cytokines were performed. A total of 654 subjects (360 healthy controls and 294 diagnosed with RA) were included in the analysis. Higher levels of TNF have been found in individuals diagnosed with RA. IL-6 levels were higher in individuals who did not respond to TNFi treatment, while responders had levels comparable to those without the disease. No associations were found between the SNPs studied and the diagnosis of RA; however, rs767455-C seems to play a role in the response to golimumab treatment, being related to better therapeutic response and lower mean serum leukocyte levels. In addition, rs1061622-G was associated with poorer functional capacity and rs1800629-A was associated with higher leukocyte values and serum transaminase levels. The rs1061622-G and rs767455-C may play a role in the response to TNFi treatment, especially for patients using golimumab, although they do not seem to be associated with the diagnosis of RA. Polymosphisms in the TNF pathway may impact baseline levels of immune cells and markers of renal and hepatic function in RA patients. Our results highlight the importance of evaluating the impact of these polymorphisms on TNFi response and safety, particularly in larger-scale studies.


Assuntos
Artrite Reumatoide , Interleucina-6 , Polimorfismo de Nucleotídeo Único , Receptores Tipo II do Fator de Necrose Tumoral , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/genética , Interleucina-6/genética , Interleucina-6/sangue , Receptores Tipo II do Fator de Necrose Tumoral/genética , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Idoso , Estudos de Casos e Controles , Antirreumáticos/uso terapêutico
6.
Cell Death Dis ; 15(8): 584, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39122678

RESUMO

TNF is a potent cytokine known for its involvement in physiology and pathology. In Rheumatoid Arthritis (RA), persistent TNF signals cause aberrant activation of synovial fibroblasts (SFs), the resident cells crucially involved in the inflammatory and destructive responses of the affected synovial membrane. However, the molecular switches that control the pathogenic activation of SFs remain poorly defined. Cyld is a major component of deubiquitination (DUB) machinery regulating the signaling responses towards survival/inflammation and programmed necrosis that induced by cytokines, growth factors and microbial products. Herein, we follow functional genetic approaches to understand how Cyld affects arthritogenic TNF signaling in SFs. We demonstrate that in spontaneous and induced RA models, SF-Cyld DUB deficiency deteriorates arthritic phenotypes due to increased levels of chemokines, adhesion receptors and bone-degrading enzymes generated by mutant SFs. Mechanistically, Cyld serves to restrict the TNF-induced hyperactivation of SFs by limiting Tak1-mediated signaling, and, therefore, leading to supervised NF-κB and JNK activity. However, Cyld is not critically involved in the regulation of TNF-induced death of SFs. Our results identify SF-Cyld as a regulator of TNF-mediated arthritis and inform the signaling landscape underpinning the SF responses.


Assuntos
Artrite Reumatoide , Enzima Desubiquitinante CYLD , Fibroblastos , Quinase I-kappa B , MAP Quinase Quinase Quinases , Transdução de Sinais , Membrana Sinovial , Fibroblastos/metabolismo , Fibroblastos/patologia , Enzima Desubiquitinante CYLD/metabolismo , Enzima Desubiquitinante CYLD/genética , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/genética , Animais , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Camundongos , Quinase I-kappa B/metabolismo , Quinase I-kappa B/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Humanos , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
Aging Clin Exp Res ; 36(1): 170, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39133382

RESUMO

BACKGROUND: Previous observational studies indicated a complex association between frailty and arthritis. AIMS: To investigate the genetic causal relationship between the frailty index and the risk of common arthritis. METHODS: We performed a large-scale Mendelian randomization (MR) analysis to assess frailty index associations with the risk of common arthritis in the UK Biobank (UKB), and the FinnGen Biobank. Summary genome-wide association statistics for frailty, as defined by the frailty index, and common arthritis including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PSA), and ankylosing spondylitis (AS). The inverse-variance weight (IVW) method served as the primary MR analysis. Heterogeneity testing and sensitivity analysis were also conducted. RESULTS: Our results denoted a genetic association between the frailty index with an increased risk of OA, the odds ratio (OR)IVW in the UKB was 1.03 (95% confidence interval [CI]: 1.01-1.05; P = 0.007), and ORIVW was 1.55 (95% CI: 1.16-2.07; P = 0.003) in the FinnGen. For RA, the ORIVW from UKB and FinnGen were 1.03 (1.01-1.05, P = 0.006) and 4.57 (1.35-96.49; P = 0.025) respectively. For PSA, the frailty index was associated with PSA (ORIVW = 4.22 (1.21-14.67), P = 0.023) in FinnGen, not in UKB (P > 0.05). However, no association was found between frailty index and AS (P > 0.05). These results remained consistent across sensitivity assessments. CONCLUSION: This study demonstrated a potential causal relationship that genetic predisposition to frailty index was associated with the risk of arthritis, especially RA, OA, and PSA, not but AS. Our findings enrich the existing body of knowledge on the subject matter.


Assuntos
Fragilidade , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Fragilidade/genética , Artrite/genética , Artrite/epidemiologia , Osteoartrite/genética , Osteoartrite/epidemiologia , Artrite Reumatoide/genética , Artrite Reumatoide/epidemiologia , Idoso , Masculino , Feminino , Artrite Psoriásica/genética , Artrite Psoriásica/epidemiologia , Predisposição Genética para Doença , Pessoa de Meia-Idade
8.
Medicine (Baltimore) ; 103(33): e39319, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39151504

RESUMO

Past observational studies have documented an association between rheumatoid arthritis (RA) and chronic respiratory diseases. Undertaking the approach of Mendelian randomization (MR) analysis, this research aims to delve deeper into the probability of a causal connection between RA and chronic respiratory diseases. Collated genome-wide association study data covering RA with 4199 cases against 208,254 controls, asthma comprising 8216 cases versus 201,592 controls, and chronic obstructive pulmonary disease (COPD) detailing 3315 cases in contrast to 201,592 controls were derived from the repository of the Japanese Biobank. A selection of 10 RA-related, 8 asthma-related, and 4 COPD-related single nucleotide polymorphisms notable for their statistical significance (P < 5 × 10-8) were identified as instrumental variables. The primary analytical technique was the inverse variance-weighted (IVW) method, alongside the MR-Egger protocol, weighted median, and weighted mode to reinforce the validity and solidity of the principal results. For scrutinizing possible implications of horizontal pleiotropy, we harnessed the MR-Egger intercept examination and the Mendelian Randomization Pleiotropy REsidual Sum and Outlier test. Employing the inverse variance-weighted technique, we established a positive correlation between genetic predispositions for RA and actual occurrences of asthma (odds ratios [OR] = 1.14; 95% confidence intervals [CI]: 1.04-1.24; P = .003). This correlation remained strong when testing the results utilizing various methods, including the MR-Egger method (OR = 1.32; 95% CI: 1.09-1.60; P = .023), the weighted median (OR = 1.16; 95% CI: 1.06-1.26; P < .001), and the weighted mode (OR = 1.21; 95% CI: 1.11-1.32; P = .002). Furthermore, our findings from the inverse variance-weighted method also demonstrated a positive association between genetically predicted RA and COPD (OR = 1.12; 95% CI: 1.02-1.29; P = .021). However, no such link was discerned in supplementary analyses. In a shifted perspective-the reverse MR analysis-no correlation was identified between genetically predicted instances of asthma (IVW, P = .717) or COPD (IVW, P = .177) and RA. The findings confirm a causal correlation between genetically predicted RA and an elevated risk of either asthma or COPD. In contrast, our results offer no support to the presumed causal relationship between genetic susceptibility to either asthma or COPD and the subsequent development of RA.


Assuntos
Artrite Reumatoide , Asma , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/epidemiologia , Asma/genética , Asma/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Japão/epidemiologia , Predisposição Genética para Doença , Feminino , Masculino , Pessoa de Meia-Idade , População do Leste Asiático
9.
Pathol Res Pract ; 261: 155508, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39116571

RESUMO

Rheumatoid arthritis (RA) is a common autoimmune condition and chronic inflammatory disease, mostly affecting synovial joints. The complex pathogenesis of RA is supportive of high morbidity, disability, and mortality rates. Pathological changes a common characteristic in RA synovial tissue is attributed to the inadequacy of apoptotic pathways. In that regard, apoptotic pathways have been the center of attention in RA therapeutic approaches. As the regulators in the complex network of apoptosis, microRNAs (miRNAs) are found to be vital modulators in both intrinsic and extrinsic pathways through altering their regulatory genes. Indeed, miRNA, a member of the family of non-coding RNAs, are found to be an important player in not even apoptosis, but proliferation, gene expression, signaling pathways, and angiogenesis. Aberrant expression of miRNAs is implicated in attenuation and/or intensification of various apoptosis routes, resulting in culmination of human diseases including RA. Considering the need for more studies focused on the underlying mechanisms of RA in order to elevate the unsatisfactory clinical treatments, this study is aimed to delineate the importance of apoptosis in the pathophysiology of this disease. As well, this review is focused on the critical role of miRNAs in inducing or inhibiting apoptosis of RA-synovial fibroblasts and fibroblast-like synoviocytes and how this mechanism can be exerted for therapeutic purposes for RA.


Assuntos
Apoptose , Artrite Reumatoide , MicroRNAs , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Apoptose/genética , Membrana Sinovial/patologia , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Transdução de Sinais , Fibroblastos/metabolismo , Fibroblastos/patologia , Animais
10.
Sci Rep ; 14(1): 18939, 2024 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-39147768

RESUMO

Rheumatoid arthritis (RA) and arthrofibrosis (AF) are both chronic synovial hyperplasia diseases that result in joint stiffness and contractures. They shared similar symptoms and many common features in pathogenesis. Our study aims to perform a comprehensive analysis between RA and AF and identify novel drugs for clinical use. Based on the text mining approaches, we performed a correlation analysis of 12 common joint diseases including arthrofibrosis, gouty arthritis, infectious arthritis, juvenile idiopathic arthritis, osteoarthritis, post infectious arthropathies, post traumatic osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, septic arthritis, and transient arthritis. 5 bulk sequencing datasets and 4 single-cell sequencing datasets of RA and AF were integrated and analyzed. A novel drug repositioning method was found for drug screening, and text mining approaches were used to verify the identified drugs. RA and AF performed the highest gene similarity (0.77) and functional ontology similarity (0.84) among all 12 joint diseases. We figured out that they share the same key pathogenic cell including CD34 + sublining fibroblasts (CD34-SLF) and DKK3 + sublining fibroblasts (DKK3-SLF). Potential therapeutic target database (PTTD) was established with the differential expressed genes (DEGs) of these key pathogenic cells. Based on the PTTD, 15 potential drugs for AF and 16 potential drugs for RA were identified. This work provides a new perspective on AF and RA study which enhances our understanding of their pathogenesis. It also shed light on their underlying mechanism and open new avenues for drug repositioning studies.


Assuntos
Artrite Reumatoide , Fibrose , Membrana Sinovial , Humanos , Artrite Reumatoide/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Membrana Sinovial/patologia , Membrana Sinovial/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Reposicionamento de Medicamentos , Microambiente Celular/efeitos dos fármacos , Mineração de Dados
11.
Int J Rheum Dis ; 27(8): e15282, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39091178

RESUMO

OBJECTIVE: To investigate the impact of IGJ on the proliferation, inflammation, and motility of rheumatoid arthritis (RA) fibroblast-like synoviocytes and elucidate the underlying mechanism. METHODS: The expression of IGJ RA fibroblast-like synoviocytes was assessed using immunoblot and qPCR. Cell growth was evaluated using CCK-8 and FCM assays. The effects on inflammatory response were determined by ELISA and immunoblot assays. Cell motility was assessed using transwell and immunoblot assays. The mechanism was further confirmed using immunoblot assays. RESULTS: IGJ expression was found to be elevated in fibroid synovial cells of RA. IGJ ablation inhibited the growth of MH7A cells and suppressed the inflammatory response. Knockdown of IGJ also blocked cell motility. Mechanically, the knockdown of IGJ suppressed the NF-κB axis in MH7A cells. CONCLUSION: IGJ suppresses RA in fibroblast-like synoviocytes via NF-κB pathway.


Assuntos
Artrite Reumatoide , Movimento Celular , Proliferação de Células , Fibroblastos , NF-kappa B , Transdução de Sinais , Sinoviócitos , Humanos , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Sinoviócitos/efeitos dos fármacos , Artrite Reumatoide/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , NF-kappa B/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Células Cultivadas , Linhagem Celular , Hialuronoglucosaminidase
12.
Clin Neurol Neurosurg ; 244: 108465, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39059285

RESUMO

BACKGROUND: Active rheumatoid arthritis (RA) may damage vascular endothelial cells, thereby increasing the likelihood of adverse cardiovascular events. However, it is not yet clearly established whether RA also increases the risk of adverse cerebrovascular events, particularly stroke. OBJECTIVE: This study was designed to evaluate the likelihood of a causal association between RA and stroke. METHOD: A two-sample Mendelian randomization (MR) analysis was performed using the inverse variance-weighted (IVW) average, weighted median, and MR-Egger regression methods. The analysis utilized publicly available summary statistics datasets from Genome-wide association studies (GWAS) meta-analyses for RA in individuals of European descent (total n = 484,598; case = 5427, control = 479,171) as the exposure cohort, and from GWAS meta-analyses for "vascular/heart problems diagnosed by doctor: stroke" in individuals included in the UK Biobank (total n = 461,880; case = 7055, control = 454,825, MRC-IEU consortium) as the outcome cohort. RESULTS: Eight single-nucleotide polymorphisms with genome-wide significance were selected from the GWASs on RA as the instrumental variables. The results of the MR-Egger and weighted median analyses showed no causal association between RA and stroke (OR = 1.081, 95 % CI [0.943-1.240], P = 0.304) vs. OR = 1.079, 95 % CI [0.988-1.179], P = 0.091), respectively. However, the inverse variance-weighted (IVW) analysis results revealed a causal association between RA and stroke (OR = 1.115, 95 % CI [1.040-1.194], P = 0.002). Cochran's Q test and MR-Egger regression revealed no evidence of heterogeneity and horizontal pleiotropy. CONCLUSION: The MR analysis results indicated that rheumatoid arthritis (RA) may be causally associated with an increased risk of stroke.


Assuntos
Artrite Reumatoide , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/complicações , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Predisposição Genética para Doença/genética
13.
Egypt J Immunol ; 31(3): 71-80, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38995670

RESUMO

Rheumatoid Arthritis (RA) is a chronic, progressive autoimmune disease, involves an intimate relationship between immune cells and cytokines and results in decreased lifespans and higher mortality rates. The goal of the current study was to investigate the impact of MicroRNA (miRNA)146a and interleukin-17 (IL-17) as prognosis markers in RA patients. This case-control study included 120 RA patients who visited the Rheumatology unit at Al-Saddar Medical City in the governorate of Najaf, and 30 normal controls. Venous blood samples were collected from both patients and controls. Blood samples were used for measuring IL-17 levels using an enzyme linked immunosorbent assay (ELISA) testing, and miRNA146a by the reverse transcription polymerase chain reaction (RT-PCR). The results showed higher frequency of RA in women than in men with elevate incidence in patients aged 40-59 years and 1-2 years RA disease duration of. The level of IL-17 was significantly higher in serum of RA patients compared with the control group (p < 0.0001). IL-17 level was significantly increased among the patients in RA stage 4 (p < 0.0001). IL-17 level was significantly increased in patients without treatment compared with treated patients. The expression of miRNA-146a was significantly higher in the patients' group than control group. In conclusion, IL-17 may play critical role in chronic inflammation and can be used as diagnostic biomarker for RA. miRNA-146a is overexpressed in RA patient relative to healthy individuals and it acts as a negative regulator for IL-17.


Assuntos
Artrite Reumatoide , Interleucina-17 , MicroRNAs , Humanos , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Artrite Reumatoide/diagnóstico , Interleucina-17/sangue , Interleucina-17/genética , MicroRNAs/sangue , MicroRNAs/genética , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos de Casos e Controles , Biomarcadores/sangue , Progressão da Doença
14.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(3): 777-782, 2024 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-38948285

RESUMO

As a member of the tumor necrosis factor receptor family, osteoprotegerin (OPG) is highly expressed in adults in the lung, heart, kidney, liver, spleen, thymus, prostate, ovary, small intestines, thyroid gland, lymph nodes, trachea, adrenal gland, the testis, and bone marrow. Together with the receptor activator of nuclear factor-κB (RANK) and the receptor activator of nuclear factor-κB ligand (RANKL), it forms the RANK/RANKL/OPG pathway, which plays an important role in the molecular mechanism of the development of various diseases. MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs performing regulatory functions in eukaryotes, with a size of about 20-25 nucleotides. miRNA genes are transcribed into primary transcripts by RNA polymerase, bind to RNA-induced silencing complexes, identify target mRNAs through complementary base pairing, with a single miRNA being capable of targeting hundreds of mRNAs, and influence the expression of many genes through pathways involved in functional interactions. In recent years, a large number of studies have been done to explore the mechanism of action of miRNA in diseases through miRNA isolation, miRNA quantification, miRNA spectrum analysis, miRNA target detection, in vitro and in vivo regulation of miRNA levels, and other technologies. It was found that miRNA can play a key role in the pathogenesis of osteoporosis, rheumatoid arthritis, and other diseases by targeting OPG. The purpose of this review is to explore the interaction between miRNA and OPG in various diseases, and to propose new ideas for studying the mechanism of action of OPG in diseases.


Assuntos
MicroRNAs , Osteoprotegerina , Receptor Ativador de Fator Nuclear kappa-B , Osteoprotegerina/metabolismo , Osteoprotegerina/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Ligante RANK/metabolismo , Ligante RANK/genética , Neoplasias/genética , Neoplasias/metabolismo , Animais , Transdução de Sinais , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo
15.
J Rheumatol ; 51(Suppl 1): 3-9, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38950968

RESUMO

Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated with highly unfavorable outcomes such as early mortality. The risk of developing RA is based on a perfect storm of gene-environment interactions underpinning this risk. The gene-environment interactions include a high frequency of shared epitope encoding HLA alleles, particularly HLA-DRB1*1402, in the background population, and prevalent predisposing environmental factors such as smoking and periodontal disease. Together, these provide a compelling rationale for an RA prevention agenda in FN communities. Our research team has worked in partnership with several FN communities to prospectively follow the first-degree relatives of FN patients with RA, with the aim of better understanding the preclinical stages of RA in this population. We have focused on specific features of the anticitrullinated protein antibodies (ACPA) and other proteomic biomarkers as predictors of future development of RA. These studies have now led us to consider interventions having a favorable risk-benefit ratio if applied at a stage prior to a hypothetical "point of no return," when the autoimmunity potentially becomes irreversible. Based on a supportive mouse model and available human studies of curcumin, omega-3, and vitamin D supplements, we are undertaking studies where we screen communities using dried blood spot technology adapted for the detection of ACPA, and then enrolling ACPA-positive individuals in studies that use a combination of these supplements. These studies are guided by shared decision-making principles.


Assuntos
Artrite Reumatoide , Humanos , Anticorpos Antiproteína Citrulinada/sangue , Artrite Reumatoide/prevenção & controle , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Interação Gene-Ambiente , Cadeias HLA-DRB1 , Indígenas Norte-Americanos
16.
Sci Rep ; 14(1): 15119, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956106

RESUMO

Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid arthritis (RA). The study was conducted on a cohort of 95 RA Iraqi patients. Based on their treatment response, the cohort was divided into two groups: the responder (47 patients) and the nonresponder (48 patients), identified after at least three months of methotrexate (MTX) treatment. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was employed to analyze the MTHFR variations, specifically at rs1801133 and rs1801131. Overall, rs1801131 followed both codominant and dominate models, in which in the codominant model, GG [OR (95% CI) 0.11 (0.022-0.553)] and TG [OR (95% CI) 0.106 (0.021-0.528)] predict responders compared to the TT genotype; meanwhile, for the dominate model, the presence of both GG and TG genotypes [OR (95% CI) 0.108 (0.023-0.507)] together predict responders compared to the TT genotype. The Ars1801133Grs1801131 haplotype was significantly associated with responders [OR (95% CI): 0.388 (0.208-0.723)], while the Grs1801133Trs1801131 haplotype was associated marginally with nonresponders [OR (95% CI) 1.980 (0.965-4.064)]. In the final multivariate analysis, GG/TGrs1801131 genotypes were independently related to responders after adjustment for patients, disease, and treatment characteristics, while TTrs1801131 genotypes were associated with nonresponders. The Iraqi RA patients showed genetic polymorphism in MTHFR gene rs1801131 with T carrier allele associated with nonresponders to MTX therapy. The rs1801131 followed both codominant and dominant models. The G-carried allele for rs1801131 showed an independent association with responder to MTX therapy after adjustment for patients, disease, and treatment characteristics.


Assuntos
Artrite Reumatoide , Metotrexato , Metilenotetra-Hidrofolato Redutase (NADPH2) , Polimorfismo de Nucleotídeo Único , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Metotrexato/uso terapêutico , Masculino , Feminino , Iraque , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Antirreumáticos/uso terapêutico , Genótipo
17.
Zhongguo Zhong Yao Za Zhi ; 49(11): 3081-3094, 2024 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-39041168

RESUMO

The effect and mechanism of Huangqin Qingre Chubi Capsules(HQC) on rheumatoid arthritis(RA) were studied.Seventy male SPF rats were randomly divided into normal group, model group, low-(0. 18 g·kg~(-1)), middle-(0. 36 g·kg~(-1)), and high-(0. 72 g·kg~(-1)) dose groups of HQC, methotrexate group(MTX, 0. 75 mg·kg~(-1)), and negative control group(NC group, model +saline). Adjuvant arthritis fibroblast-like synoviocytes(AA-FLS) were divided into normal group, model group, low-, middle-, and high-dose groups of HQC, and negative control group. RT-qPCR and Western blot were used to detect the m RNA and protein expressions of METTL3, SFRP4, ß-catenin, CCND1, c-Myc, MMP3, and fibronectin. The protein expression of MMP3 and ß-catenin was detected by immunofluorescence. The gene expression level of METTL3 on AA-FLS was knocked down to further examine the expression of each gene. ELISA measured the levels of IL-1ß, IL-6, and IL-8. The results showed that compared with the normal group, rats in the model group found redness and swelling in their limbs and significantly increased joint swelling. Compared with the model group, the joint swelling degree of each treatment group significantly decreased(P<0. 05). The paw retraction threshold and body weight mass index both significantly increased(P<0. 05). METTL3 was highly expressed on AA and negatively correlated with the expression of SFRP4. After treatment, the m RNA and protein expression of METTL3, ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 were significantly decreased on AA-FLS(P< 0. 05). Compared with the model group, knocking down METTL3 resulted in reduced m RNA and protein expression of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3(P< 0. 05). At the same time, the m RNA and protein expressions of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 in the HQC+METTL3 knockdown group were significantly lower than those in the METTL3 knockdown group(P<0. 05). HQC could reduce the levels of IL-1ß, IL-6, and IL-8 to varying degrees(P<0. 05). The results indicate that HQC has a significant improvement effect on arthritis in AA rats. The expression of METTL3 is significantly increased in synovial tissue and AA-FLS of AA rats, which may be a potential target for the diagnosis and treatment of RA. HQC improves RA through the METTL3-SFRP4/Wnt/ß-catenin signaling pathway and has significant antiinflammatory and anti-rheumatic effects.


Assuntos
Artrite Reumatoide , Cápsulas , Medicamentos de Ervas Chinesas , Via de Sinalização Wnt , beta Catenina , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/genética , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Ratos , Masculino , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , beta Catenina/genética , Metiltransferases/genética , Metiltransferases/metabolismo , Humanos , Ratos Sprague-Dawley , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Proteínas Proto-Oncogênicas
18.
Clinics (Sao Paulo) ; 79: 100441, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38976936

RESUMO

OBJECTIVE: This study aimed to identify differentially expressed microRNAs (miRNAs) in exosomes derived from the blood plasma of Rheumatoid Arthritis (RA) patients and explore their clinical significance and biological roles. METHODS: Illumina high-throughput sequencing was employed to measure miRNA expression levels in plasma exosomes, followed by validation using qRT-PCR. The correlation between exosomal miRNAs and disease activity was systematically analyzed. Additionally, the pathogenic effects of RA exosomes were investigated through bioinformatics analysis and in vitro experiments. RESULTS: Significantly reduced levels of exosomal miR-144-3p and miR-30b-5p were observed in RA patients, which were negatively correlated with DAS28 scores and anti-CCP antibody levels. ROC curve analysis showed that miR-144-3p and miR-30b-5p in plasma exosomes could effectively distinguish RA patients from healthy controls, with AUC values of 0.725 and 0.773, respectively. Combining bioinformatics analysis and in vitro experiments, it was demonstrated that plasma exosomes contribute to ongoing autoantibody production in RA by promoting B-cell differentiation and antibody production. CONCLUSION: The present study indicates that plasma exosomes from RA patients may be potentially pathogenic. Exosomal miR-144-3p and miR-30b-5p exhibit significant decreases in RA patients and are associated with disease activity, suggesting their potential as valuable biomarkers for RA.


Assuntos
Artrite Reumatoide , Linfócitos B , Exossomos , MicroRNAs , Humanos , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , MicroRNAs/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Linfócitos B/imunologia , Estudos de Casos e Controles , Adulto , Biomarcadores/sangue , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real
19.
J Prev Alzheimers Dis ; 11(4): 917-927, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39044503

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by intricate genetic and environmental etiology. The objective of this study was to identify robust non-genetic risk factors for AD through an updated umbrella review. METHODS: We conducted a comprehensive search of meta-analyses and systematic reviews on non-genetic risk factors associated with AD in PubMed, Cochrane, Embase, and Ovid Medline up to June 30, 2023. After collecting data, we estimated the summary effect size and their 95% confidence intervals. The degree of heterogeneity between studies was assessed using I2 statistics and a 95% prediction interval was determined. Additionally, we evaluated potential excess significant bias and small study effects within the selected candidate studies. RESULTS: The umbrella review encompassed a total of 53 eligible papers, which included 84 meta-analyses covering various factors such as lifestyle, diet, environmental exposures, comorbidity or infections, drugs, and biomarkers. Based on the evidence classification criteria employed in this study, two factors as convincing evidence (Class I), including rheumatoid arthritis (RA), potentially reduced the risk of AD, but diabetes significantly increased the risk of AD. Furthermore, three factors as highly suggestive evidence (Class II), namely depression, high homocysteine, and low folic acid level, potentially increased the risk of AD. CONCLUSION: Our findings highlight several risk factors associated with AD that warrant consideration as potential targets for intervention. However, it is crucial to prioritize the identified modifiable risk factors, namely rheumatoid arthritis, diabetes, depression, elevated homocysteine levels, and low folic acid levels to effectively address this complex neurodegenerative disorder.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , Doença de Alzheimer/epidemiologia , Humanos , Fatores de Risco , Artrite Reumatoide/genética , Biomarcadores/sangue , Estilo de Vida
20.
Medicine (Baltimore) ; 103(30): e39132, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058807

RESUMO

To investigate the causal relationship between rheumatoid arthritis (RA) and ankylosing spondylitis using Mendelian randomization (MR). Genetic loci independently associated with RA and ankylosing spondylitis in people of European origin were selected as instrumental variables using pooled data from large-scale genome-wide association studies. Three MR analyses, MR-Egger, weighted median, and inverse variance weighting, were used to investigate the causal relationship between RA and ankylosing spondylitis. Heterogeneity and multiplicity tests were used, and a sensitivity test using the "leave-one-out" method was used to explore the robustness of the results. The inverse variance weighting results showed an OR (95 % CI) of 1.25 (1.11-1.41), P < .001, indicating a causal relationship between RA and ankylosing spondylitis. And no heterogeneity and pleiotropy were found by the test and sensitivity analysis also showed robust results. The present study was conducted to analyze and explore the genetic data using two-sample MR analysis and the results showed that there is a causal relationship between RA and the occurrence of ankylosing spondylitis.


Assuntos
Artrite Reumatoide , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Espondilite Anquilosante , Espondilite Anquilosante/genética , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/complicações , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único
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