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• Research Paper Volume 13, Issue 20 pp 23689-23701

  Analysis of gut microbiota and metabolites in patients with rheumatoid arthritis and identification of potential biomarkers

  Relevance score: 5.7992163

  Yumei Chen, Chiyu Ma, Lixiong Liu, Jingquan He, Chengxin Zhu, Fengping Zheng, Weier Dai, Xiaoping Hong, Dongzhou Liu, Donge Tang, Yong Dai

  Keywords: rheumatoid arthritis, gut microbiota, metabolites, biomarkers

  Published in Aging on October 20, 2021

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  Rheumatoid arthritis (RA) is an autoimmune disease described by joint destruction, synovitis and pannus formation. The gut microbiota acts as an environmental factor that plays an important role in RA, but little research regarding the etiopathogenic mechanisms of the microbiome in RA has been carried out. We used an integrated approach of 16S rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass spectrometry-based metabolomics to analyze the structure and diversity of the intestinal flora and metabolites of the gut microbiota in RA patients compared with healthy subjects. In this study, α-diversity analysis of the gut microbiota showed that there was no significant difference between the healthy control (HC) and RA groups. However, β-diversity analysis showed that there was a significant difference between the two groups. Further analysis of alteration of the gut microbiota revealed that at the phylum level, the relative abundance of p_Bacteroidetes was significantly decreased in the RA group, while that of Verrucomicrobia and Proteobacteria was significantly increased in the RA group. At the genus level, Bacteroides, Faecalibacterium and some probiotics were decreased in the RA group, while 97 genera, including Lactobacillus, Streptococcus and Akkermansia, were increased in the RA group. Seventy-four differentially abundant metabolites were identified between the HC and RA groups, and we identified two potential biomarkers (9,12-octadecadiynoic acid and 10Z-nonadecenoic acid) in RA.

• Research Paper Volume 13, Issue 18 pp 22544-22555

  Glaucocalyxin B inhibits cartilage inflammatory injury in rheumatoid arthritis by regulating M1 polarization of synovial macrophages through NF-κB pathway

  Relevance score: 5.8662906

  Chenyang Han, Yi Yang, Yongjia Sheng, Jin Wang, Xiaohong Zhou, Wenyan Li, Li Guo, Caiqun Zhang, Qiao Ye

  Keywords: Glaucocalyxin B, rheumatoid arthritis, cartilage injury, NF-κB, macrophages

  Published in Aging on September 27, 2021

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  Background: Glaucocalyxin B (Gla B) is a type of sesquiterpenoids. At present, there are rare studies on the pharmacological effects and targets of sesquiterpenoids, while multiple sesquiterpenoids have good anti-inflammatory properties. Therefore, in this study, we aimed to investigate the mechanism of Gla B on macrophages and rheumatoid arthritis.

  Methods: LPS/IFN-γ was used to induce M1 polarization of synovial macrophage (SMG) in vitro, followed by Gla B pretreatment (5 μM and 15 μM). Afterwards, flow cytometry was performed to detect the proportion of M1 cells (F4/80+CD86+), enzyme-linked immunosorbent assay (ELISA) was used to determine the expression levels of M1 cell markers (TNF-α, IL-1β, IL-6, iNOS and IL-12) as well as M2 cell markers (IL-10 and TGF- β1), immunofluorescence (IF) staining was utilized to measure the expression of CD86, the level of ROS was assessed by probe and Western blot was conducted to detect the expression of P65 and p-P65. M1 polarization was detected in SMG cells with P65 silencing after 15 μM Gla B intervention. The culture medium from M1 cell was used to culture cartilage cells in vitro, followed by detection of cartilage cell injury. In animal models, collagen antibodies and LPS were combined to induce RA mouse model. Afterwards, H and E staining was performed to detect pathological changes in mouse joint synovium, safranin O-fast green staining was used to determine cartilage injury, and immunohistochemistry was utilized to detect CD86 and P65 expression. Small molecule-protein docking and co-immunoprecipitation (Co-IP) were used to verify the targeted binding relationship between Gal B and P65.

  Results: LPS and IFN-γ could induce M1 polarization in SMG. Gal B could inhibit M1 polarization, decrease the levels of TNF-α, IL-1β, IL-6, iNOS and IL-12, inhibit the expression of P65 and p-P65 while did not affect the expression of IL-10 or TGF-β1. Gal B had no significant effect in SMG cells with P65 silencing. The small molecule-protein docking and Co-IP both showed that Gal B had a targeted binding relationship with P65, and Gal B could inhibit joint injury and inflammation in mice.

  Conclusion: Gal B could target the P65 protein. Moreover, Gal B could inhibit the inflammatory injury of articular cartilage in RA by regulating M1 polarization of SMG through inhibiting the NF-κB signaling.

• Research Paper Volume 13, Issue 16 pp 20511-20533

  A comprehensive transcriptomic analysis of alternate interferon signaling pathways in peripheral blood mononuclear cells in rheumatoid arthritis

  Relevance score: 4.2201395

  Liang Han, Shenghao Tu, Pan Shen, Jiahui Yan, Yao Huang, Xin Ba, Tingting Li, Weiji Lin, Huihui Li, Kun Yu, Jing Guo, Ying Huang, Kai Qin, Yu Wang, Zhe Chen

  Keywords: rheumatoid arthritis (RA), type I interferon, interferon-γ (IFN-γ), single-cell sequencing (SCS), peripheral blood mononuclear cells (PBMCs)

  Published in Aging on August 25, 2021

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  Interferon (IFN) signaling pathways play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Prior studies have mainly studied mixed alterations in the IFN signaling pathway in RA, but these studies have not been sufficient to elucidate how imbalanced IFN signaling subtly influences immune cells. Single-cell RNA (scRNA) sequencing makes it possible to better understand the alternations in the interferon signaling pathways in RA. In the present study, we found that IFN signaling pathways were activated in natural killer (NK) cells, monocytes, T cells, B cells, and most immune cell subclasses in RA. We then explored and analyzed the connections between abnormal IFN signaling pathways and cellular functional changes in RA. Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis and gene regulatory network (GRN) construction were also performed to identify key transcription factors in RA. Finally, we also investigated altered IFN signaling pathways in multiple RA peripheral blood samples, which indicated that abnormal IFN signaling pathways were universally observed in RA. Our study contributes to a better understanding of the delicate and precise regulation of IFN signaling in the immune system in RA. Furthermore, common alternations in IFN signaling pathway-related transcription factors could help to identify novel therapeutic targets for RA treatment.

• Research Paper Volume 13, Issue 15 pp 19397-19414

  Association between CTLA-4 gene polymorphism and risk of rheumatoid arthritis: a meta-analysis

  Relevance score: 5.508089

  Chuankun Zhou, Shutao Gao, Xi Yuan, Zixing Shu, Song Li, Xuying Sun, Jun Xiao, Hui Liu

  Keywords: CTLA-4, polymorphism, rheumatoid arthritis, meta-analysis

  Published in Aging on August 2, 2021

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  Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene polymorphisms may be involved in the risk of Rheumatoid arthritis (RA). However, evidence for the association remains controversial. Therefore, we performed a meta-analysis to confirm the relationship between CTLA-4 gene polymorphisms and RA. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association. Stratified analysis was conducted by ethnicity. In total, 66 case-control studies including 21681 cases and 23457 controls were obtained. For rs3087243 polymorphism, significant association was detected in Asians (A vs. G: OR=0.77, 95%CI=0.65-0.90, P=0.001; AA vs. GG: OR=0.67, 95%CI=0.48-0.94, P=0.02) and Caucasians (A vs. G: OR=0.89, 95%CI=0.86-0.93, P<0.00001; AA vs. GG: OR=0.81, 95%CI=0.75-0.88, P<0.00001). For rs231775 polymorphism, significant association was observed in the overall (G vs. A: OR =1.16, 95%CI=1.08-1.25, P<0.0001; GG vs. AA: OR=1.29, 95%CI=1.12-1.50, P=0.0006), and in Asians (G vs. A: OR=1.27, 95%CI=1.10-1.47, P=0.001; GG vs. AA: OR=1.58, 95%CI=1.24-2.01, P=0.0002), but not in Caucasians. However, there was no association between rs5742909 polymorphism and RA. This meta-analysis confirmed that rs3087243 and rs231775 polymorphism were associated with the risk of RA in both overall population and ethnic-specific analysis, but there was no association between rs5742909 polymorphism and RA risk.

• Research Paper Volume 13, Issue 13 pp 17227-17236

  miR-let-7c-5p and miR-149-5p inhibit proinflammatory cytokine production in osteoarthritis and rheumatoid arthritis synovial fibroblasts

  Relevance score: 4.5869985

  Yat-Yin Law, Wei-Fang Lee, Chin-Jung Hsu, Yen-You Lin, Chun-Hao Tsai, Chien-Chung Huang, Min-Huan Wu, Chih-Hsin Tang, Ju-Fang Liu

  Keywords: miR-let-7c-5p, miR-149-5p, osteoarthritis, rheumatoid arthritis, inflammation

  Published in Aging on July 1, 2021

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  Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common types of arthritis. Both are characterized by the infiltration of a number of proinflammatory cytokines into the joint microenvironment. miRNAs play critical roles in the disease processes of arthritic disorders. However, little is known about the effects of miRNAs on critical inflammatory cytokine production with OA and RA progression. Here, we found higher levels of proinflammatory cytokines including interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in human OA and RA synovial fibroblasts (SFs) compared with normal SFs. Searches of open-source microRNA (miRNA) software determined that miR-let-7c-5p and miR-149-5p interfere with IL-1β, IL-6 and TNF-α transcription; levels of all three proinflammatory cytokines were lower in human OA and RA patients compared with normal controls. Anti-inflammatory agents dexamethasone, celecoxib and indomethacin reduced proinflammatory cytokine production by promoting the expression of miR-let-7c-5p and miR-149-5p. Similarly, ibuprofen and methotrexate also enhanced miR-let-7c-5p and miR-149-5p expression in human SFs. The evidence suggests that increasing miR-let-7c-5p and miR-149-5p expression is a novel strategy for OA and RA.

• Research Paper Volume 13, Issue 11 pp 15580-15594

  Do eye diseases increase the risk of arthritis in the elderly population?

  Relevance score: 6.3942037

  Wenyi Jin, Qian Yao, Zilin Liu, Wenli Cao, Yubiao Zhang, Zhifei Che, Hao Peng

  Keywords: eye diseases, cataracts, glaucoma, arthritis

  Published in Aging on June 10, 2021

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  There are very few longitudinal studies which have previously conducted an investigation into whether eye diseases are a risk for arthritis, and how this occurs. The study employed a variety of machine-learning algorithms, including random forest for investigating the risks, and to elucidate these underlying mechanisms by focusing on five aspects containing 389 characterized variables (mental health and wellbeing; physical health; disability, functional impairment and helpers; health behavior; and health measures). The study population included 8,423 individuals. Cataracts, glaucoma, and other eye diseases increase the likelihood of arthritis after two years by 131.8% (odds ratio (OR)=2.318, 95% confidence interval: 1.748 to 3.038), 123.1% (OR=2.231, 1.306 to 3.626), and 91.1% (OR=1.911, 1.501 to 2.415). Random forest corroborated that cataract contributes the most to arthritis risks after two years, followed by other eye diseases and glaucoma (mean Gini-index: 5.20, 2.11, 1.31). It is of note that the potential mechanisms of cataract-induced arthritis risk were elucidated extensively. The control domains of life quality, negative aging self-perceptions, mobility (steadiness, physical limitations, and muscle strength) and memory impairments, and sleep quality mediated the relationship between cataracts and arthritis significantly. Furthermore, different eye diseases affected osteoarthritis, rheumatoid arthritis, and other arthritis to varying degrees. Eye diseases increased the risk of arthritis, whereby cataracts were the most significant. Interventions which target these discovered mechanisms may be the preferred levers for reducing cataract-related arthritis risk.

• Research Paper Volume 13, Issue 11 pp 15061-15077

  Development and validation of a nomogram for predicting stroke risk in rheumatoid arthritis patients

  Relevance score: 4.7871304

  Fangran Xin, Lingyu Fu, Bowen Yang, Haina Liu, Tingting Wei, Cunlu Zou, Bingqing Bai

  Keywords: rheumatoid arthritis, stroke, lipids, inflammatory markers, development and validation nomogram

  Published in Aging on June 3, 2021

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  We developed and validated a nomogram to predict the risk of stroke in patients with rheumatoid arthritis (RA) in northern China. Out of six machine learning algorithms studied to improve diagnostic and prognostic accuracy of the prediction model, the logistic regression algorithm showed high performance in terms of calibration and decision curve analysis. The nomogram included stratifications of sex, age, systolic blood pressure, C-reactive protein, erythrocyte sedimentation rate, total cholesterol, and low-density lipoprotein cholesterol along with the history of traditional risk factors such as hypertensive, diabetes, atrial fibrillation, and coronary heart disease. The nomogram exhibited a high Hosmer–Lemeshow goodness-for-fit and good calibration (P > 0.05). The analysis, including the area under the receiver operating characteristic curve, the net reclassification index, the integrated discrimination improvement, and clinical use, showed that our prediction model was more accurate than the Framingham risk model in predicting stroke risk in RA patients. In conclusion, the nomogram can be used for individualized preoperative prediction of stroke risk in RA patients.

• Research Paper Volume 13, Issue 10 pp 14109-14130

  Rheumatoid arthritis and osteoporosis: a bi-directional Mendelian randomization study

  Relevance score: 5.244157

  Ying-Qi Liu, Yong Liu, Zhuo-Yuan Chen, Hui Li, Tao Xiao

  Keywords: osteoporosis, rheumatoid arthritis, genome-wide association study, Mendelian randomization

  Published in Aging on May 18, 2021

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  Many observation studies have demonstrated a close relationship between rheumatoid arthritis (RA) and osteoporosis (OP). However, the causal genetic correlation between RA and OP remains unclear. In this study, we performed bi-directional Mendelian randomization (MR) analyses to explore causal inference between these two traits. The instrumental variables for RA were selected from a large-scale genome-wide association study (GWAS) (1,523 cases and 461,487 controls). Bone mineral density (BMD) at five different sites (heel (n=265,627), forearm (FA) (n=8,143), femoral neck (FN) (n=32,735), lumbar spine (LS) (n=28,498), and total body (n=28,498)) were used as phenotypes for OP. The inverse variance weighted (IVW) method did not detect any causal effect of BMDs on RA except heel BMD (beta = -7.57 × 10-4, p = 0.02). However, other methods (MR-Egger, weighted median, weighted mode, MR-PRESSO, and MR-RAPS) showed no causal association between heel BMD and RA. Likewise, we did not find a causal effect of RA on BMD at any sites. In conclusion, we found no evidence that RA is causally associated with OP/BMD, or vice versa. We suggested that the associations found in previous observational studies between RA and OP/BMD are possibly related to secondary effects such as antirheumatic treatment and reduced physical activity.

• Research Paper Volume 13, Issue 8 pp 11696-11704

  HLA-DPB1 rs9277535 polymorphism is associated with rheumatoid arthritis risk in a Chinese Han population

  Relevance score: 8.583199

  Zhicheng Yang, Weixi Liu, Ting Yan, Ruiping Liu

  Keywords: HLA-DPB1, polymorphism, rheumatoid arthritis

  Published in Aging on April 19, 2021

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  We used a custom-by-design 48-Plex single nucleotide polymorphism scan™ kit to investigate the relationship between susceptibility to rheumatoid arthritis (RA) and HLA-DPB1 rs9277535 polymorphism in 805 RA patients and 1095 healthy controls from the Chinese Han population. Blood plasma levels of HLA-DPB1 were also examined using enzyme-linked immunosorbent assays in 170 RA patients and 170 matched control individuals. Quantitative reverse transcription PCR (qRT-PCR) was used to evaluate relative HLA-DPB1 mRNA levels in these blood samples as well. The results indicated that some HLA-DPB1 rs9277535 polymorphisms decreased RA susceptibility. Stratified analysis indicated that risk of RA decreased specifically in women and those who were at least 55 years old. In addition, the AG and GG+AG genotypes were associated with CRP status, ACPA status, and ESR in RA patients when the AA genotype was used as the reference group. Furthermore, average HLA-DPB1 plasma levels were increased in RA patients, and HLA-DPB1 plasma levels and mRNA expression were lower in those with the GG genotype than in those with the AA genotype. These results indicate that HLA-DPB1 rs9277535 polymorphism is associated with a decreased risk of RA in the Chinese population.

• Research Paper Volume 12, Issue 23 pp 23427-23435

  Evolution of COVID-19 in patients with autoimmune rheumatic diseases

  Relevance score: 3.8568048

  Rongrong Pang, Jun Zhao, Zhenhua Gan, Zhiliang Hu, Xiang Xue, Yanjun Wu, Qinghua Qiao, Aifang Zhong, Xinyi Xia, Hui Liao, Zhihua Wang, Libo Zhang

  Keywords: coronavirus disease 2019, COVID-19, SARS-CoV-2 virus, autoimmune rheumatic diseases, systematic lupus erythematosus, rheumatoid arthritis

  Published in Aging on December 3, 2020

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  The characteristics of COVID-19 patients with autoimmune rheumatic diseases (AIRD) have rarely been reported. Patients with AIRD have suppressed immune defense function, which may increase their susceptibility to COVID-19. However, the immunosuppressive agents AIRD patients routinely used may be beneficial for protecting the cytokine storm caused by SARS-CoV-2. In this retrospective study, we included all confirmed cases in Huoshenshan Hospital from February 4 to April 9. Data were extracted from electronic medical records and were analyzed for clinical and laboratory features using SPSS (version 25.0). Of 3059 patients, 21 had the comorbidities with systematic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA), including 5 with SLE, 15 with RA, and 1 with Rhupus. The proportion was 57.1% for severe cases, 61.9% for either severe or critical cases, and 4.8% for critical cases. The main manifestations, ARDS and ICU admission rate, as well as the mortality and length of hospital stay of COVID-19 in AIRD patients were similar to COVID-19 patients in the general population. Our preliminary experience shows that patients with AIRD tend to have a higher risk of SARS-CoV-2 infection, and may be at risk for a severe but less likely critical disease course. Further investigation is needed to understand the immunological features of these diseases.

• Research Paper Volume 12, Issue 14 pp 14376-14390

  MicroRNA-15a/16/SOX5 axis promotes migration, invasion and inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes

  Relevance score: 5.8593297

  Hua Wei, Qin Wu, Yumeng Shi, Aishu Luo, Shiyu Lin, Xiaoke Feng, Jintao Jiang, Miaojia Zhang, Fang Wang, Wenfeng Tan

  Keywords: rheumatoid arthritis, miR-15a/16, SOX5, fibroblast-like synoviocytes

  Published in Aging on July 17, 2020

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  Fibroblast-like synoviocytes (FLSs) are key effector cells in the pathogenesis of rheumatoid arthritis (RA) and display a unique aggressive tumor-like phenotype with remarkable hyperplasia, increased cell migration and invasion. How FLSs undergo these changes in RA remains unknown. We previously reported a novel function of transcription factor SOX5 in RA-FLSs that promote cell migration and invasion. In this study, we found that miR-15a/16 directly targets the SOX5 3’UTR and suppresses SOX5 expression. Moreover, miR-15a/16 is significantly down-regulated in RA-FLSs, which negatively correlates with SOX5 expression. Transfection with miR-15a/16 mimics in RA-FLSs inhibits cell migration, invasion, IL-1β and TNFα expression. Overexpression SOX5 in RA-FLSs decreases miR-15a/16 expression and rescues miR-15a/16-mediated inhibitory effect. Furthermore, RA patients with the lower baseline serum miR-15a/16 level present poor response of 3 months disease-modifying antirheumatic drugs (DMARDs) therapy. Collectively, this study reveals that miR-15a/16/SOX5 axis functions as a key driver of RA-FLSs invasion, migration and inflammatory response in a mutual negative feedback loop and correlates with DMARDs treatment response in RA.

  

  MicroRNA-15a/16 targets the 3’UTR of SOX5. (A) Schematic representation of the putative target site for miR-15a/16 in the 3’UTR of SOX5. The binding sites of miR-15a/16 in SOX5 3’UTR were conserved among species. (B) 293T cells were co-transfected with luciferase reporter containing wild-type (WT), mutant (MUT) 3’UTR of SOX5 and miRNA mimics. Mutations within the seed sequence were marked as bold italic. After transfection for 48h, the luciferase intensity was measured and renilla intensity was used as for normalization. Bars show the mean ± SD of 3 independent experiments.

  
  
  

  

  Reciprocal repression between SOX5 and miR-15a/16. (A, B) RA-FLSs cell line of MH7A was transfected with miR-15a/16 mimics for 48h. SOX5 expression level was determined by RT-qPCR (A) and western-blot (B). (C) Graphs show the quantitation data derived from left western-blot figure. (D, E) MH7A was transfected with Ad-SOX5 for 48h. The expressions of miR-15a (D) and miR-16 (E) were detected by RT-qPCR. Bars show the mean ± SD of 3 independent experiments.

  
  
  

  

  Expression of miR-15a/16/SOX5 axis in primary FLSs from RA and OA patients. (A, B) Expression of miR-15a/16 (A) and SOX5 (B) in primary FLSs from RA (n = 10) and OA (n = 10) patients was detected simultaneously by RT-qPCR. (C) Correlation between the expression of miR-15a/16 and SOX5 mRNA. Bars show the mean ± SD.

  
  
  

  

  Regulation of miR-15a/16/SOX5 axis on RA-FLSs migration and invasion. (A) Following transfected with miR-15a, miR-16 mimics and miR-control for 48h, FLSs subjected to transwell (A, above) and transwell chamber invasion assay (A, below) after 24h. (B) Following transfected with miR-15a, miR-16 mimics and miR-control for 48h, FLSs were fixed and stained with FITC-phalloidin. Representative confocal microscopy images of three independent experiments are shown to illustrate stress fibers and appearance of lamellipodia. (C, D) Graphs show the quantitation data derived from the left figure A. Data are each representative of 3 independent experiments. (E, F) SOX5 overexpression alleviates the miR-15a/16 mimics-mediated inhibitory roles on migration (E) and invasion (F) in FLSs. Graphs show the quantitation data derived from 3 independent migration and invasion assay.

  
  
  

  

  Regulation of miR-15a/16/SOX5 axis on cytokine production in RA-FLSs. (A, B) Following transfected with miR-15a, miR-16 mimics and miR-control for 48h, expression of IL-1β,TNF-α, IL-6, IL-17 (A), MMP-1, MMP-3 and MMP-9 (B) was detected by RT-qPCR. (C, D) SOX5 overexpression alleviates the miR-15a/16 mimics-mediated inhibitory roles on IL-1β (C) and TNF-α (D) expression in FLSs. Bars show the mean ± SD of 3 independent experiments.

  
  
  

  

  Association miR-15a/16 with DMARDs treatment response in RA patients. (A, B) Expression of miR-15a (A) and miR-16 (B) in serum from RA patients (n = 32) at baseline and after 3 months DMARDs therapy. (C, D) RA patients were divided RA into responders and non-responders based on whether their DAS28 score was changed ≥ 1.2 after 3 months DMARDs therapy. Graphs show the serum levels of miR-15a (C) and miR-16 (D) in serum from responders (n = 18) and non-responders (n=14). (E, F) Changes of the serum levels miR-15a (E) and miR-16 (F) in responders (left) and non-responders (right) from baseline to after 3 months DMARDs therapy. Values are the mean ± SD.

  
  
  

• Research Paper Volume 12, Issue 12 pp 12305-12323

  Inhibition of BMP3 increases the inflammatory response of fibroblast-like synoviocytes in rheumatoid arthritis

  Relevance score: 6.743044

  Biao Song, Xiaofeng Li, Qingqing Xu, Suqin Yin, Sha Wu, Xiaoming Meng, Cheng Huang, Jun Li

  Keywords: adjuvant-induced arthritis, BMP3, inflammatory cytokines, chemokines

  Published in Aging on June 22, 2020

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  Rheumatoid arthritis (RA) is a persistent autoimmune disease. Fibroblast-like synoviocytes (FLS) are a key component of invasive pannus and a pathogenetic mechanism in RA. Expression of bone morphogenetic protein 3 (BMP3) mRNA is reportedly decreased in the arthritic synovium. We previously showed that BMP3 expression is significantly downregulated in the synovial tissues of RA patients and models of adjuvant-induced arthritis (AIA). In the present study, we explored the association between BMP3 and FLS migration and secretion of proinflammatory factors in RA. We found that inhibition of BMP3 expression using BMP3 siRNA increased the proinflammatory chemokines and migration of FLS stimulated with TNF-α. Inhibition of BMP3 expression also increased expression of IL-6, IL-1β, IL-17A, CCL-2, CCL-3, VCAM-1, MMP-3, and MMP-9, but not TIMP-1, in AIA and RA FLS. Correspondingly, induction of BMP3 overexpression through intra-articular injection of ad-BMP3 diminished arthritis severity in AIA rats. We also found that BMP3 may inhibit activation of TGF-β1/Smad signaling. These data indicate that BMP3 may suppress the proliferation and migration of FLS via the TGF-β1/Smad signaling pathway.

  

  BMP3 expression was significantly downregulated in RA. (A) Representative H&E staining of OA and RA synovial tissues (original magnification, ×20). (B) BMP3 expression in OA and RA synovial tissues was analyzed using IHC staining (original magnification, ×20). (C) BMP3 expression in OA and RA synovial tissues was analyzed using immunofluorescence staining (original magnification, ×20). (D) BMP3 expression in RA FLS treated with TNF-α was analyzed using immunofluorescence staining (original magnification, ×10). (E) The protein levels of BMP3 in OA and RA synovial tissues were analyzed using western blot. (F) The protein levels of BMP3 in RA FLS treated with various inflammation factors were analyzed using western blot. All values are expressed as the mean ± SD. ^*P < 0.05, ^**P < 0.01 vs control group.

  
  
  

  

  BMP3 expression was significantly downregulated in AIA. (A) Representative H&E staining of normal and AIA rat synovial tissues (original magnification, ×20). (B) BMP3 expression in normal and AIA rat synovial tissues was analyzed using IHC staining (original magnification, ×20). (C) BMP3 expression in normal and AIA rat synovial tissues was analyzed using immunofluorescence staining (original magnification, ×20). (D) BMP3 expression in FLS from AIA rats treated with TNF-α was analyzed using immunofluorescence staining (original magnification, ×10). (E) BMP3 protein levels in normal and AIA synovial tissues were analyzed using western blot. (F) BMP3 protein levels in AIA FLS treated with various inflammation factors were analyzed using western blot. All values are expressed as the mean ± SD. ^*P < 0.05, ^**P < 0.01 vs control group.

  
  
  

  

  BMP3 siRNA silencing increases the proinflammatory cytokines and chemokines in RA and AIA FLS. (A) The protein levels of BMP3, IL-6, IL-1β, and IL-17A in TNF-α–treated RA FLS transfected with BMP3 siRNA were analyzed using western blot. (B) The protein levels of BMP3, IL-6, IL-1β, and IL-17A in TNF-α–treated AIA FLS transfected with BMP3 siRNA were analyzed using western blot. (C) The mRNA levels of BMP3, IL-6, IL-1β, and IL-17A in TNF-α–treated RA FLS transfected with BMP3 siRNA were analyzed using qPCR. (D) The mRNA levels of BMP3, IL-6, IL-1β, and IL-17A in TNF-α–treated AIA FLS transfected with BMP3 siRNA were analyzed using qPCR. (E) The mRNA levels of CCL2, CCL3, and VCAM-1 in TNF-α–treated RA FLS transfected with BMP3 siRNA were analyzed using qPCR. (F) The mRNA levels of CCL2, CCL3, and VCAM-1 in TNF-α–treated AIA FLS transfected with BMP3 siRNA were analyzed using qPCR. All values are expressed as the mean ± SD. ^*P < 0.05, ^**P < 0.01 vs AIA group. ^#P < 0.05, ^##P < 0.01 vs NC-RNAi group.

  
  
  

  

  BMP3 siRNA silencing promotes the migration of RA and AIA FLS. (A) The protein levels of MMP-3, MMP-9, and TIMP-1 in TNF-α–treated RA FLS transfected with BMP3 siRNA were analyzed using western blot. (B) The protein levels of MMP-3, MMP-9, and TIMP-1 in TNF-α–treated AIA FLS transfected with BMP3 siRNA were analyzed using western blot. (C) The mRNA levels of MMP-3, MMP-9, and TIMP-1 in TNF-α–treated RA FLS transfected with BMP3 siRNA were analyzed using qPCR. (D) The mRNA levels of MMP-3, MMP-9, and TIMP-1 in TNF-α–treated AIA FLS transfected with BMP3 siRNA were analyzed using qPCR. (E) TNF-α–treated AIA FLS were transfected with BMP3 siRNA, and their migration into the wound-healing site after 24 hours was photographed (original magnification, ×10). (F) TNF-α–treated AIA FLS were transfected with BMP3 siRNA, and their migration into the wound-healing site after 24 hours was photographed (original magnification, ×10). All values are expressed as the mean ± SD. ^*P < 0.05, ^**P < 0.01 vs RA group. ^#P < 0.05, ^##P < 0.01 vs NC-RNAi group.

  
  
  

  

  Overexpression of BMP3 decreases proinflammatory cytokines and chemokines in RA and AIA FLS. (A) The protein levels of BMP3, IL-6, IL-1β, and IL-17A in TNF-α–treated RA FLS transfected with BMP3-pcDNA3.1 were analyzed using western blot. (B) The protein levels of BMP3, IL-6, IL-1β, and IL-17A in TNF-α–treated AIA FLS transfected with BMP3-PEX were analyzed using western blot. (C) The mRNA levels of BMP3, IL-6, IL-1β, and IL-17A in TNF-α–treated RA FLS transfected with BMP3-pcDNA3.1 were analyzed using qPCR. (D) The mRNA levels of BMP3, IL-6, IL-1β, and IL-17A in TNF-α–treated AIA FLS transfected with BMP3-PEX were analyzed using qPCR. (E) The mRNA levels of CCL2, CCL3, and VCAM-1 in TNF-α–treated RA FLS transfected with BMP3-pcDNA3.1 were analyzed using qPCR. (F) The mRNA levels of CCL2, CCL3, and VCAM-1 in TNF-α–treated AIA FLS transfected with BMP3-PEX were analyzed using qPCR. All values are expressed as the mean ± SD. ^*P < 0.05, ^**P < 0.01 vs AIA group. ^#P < 0.05, ^##P < 0.01 vs NC-PEX group.

  
  
  

  

  Overexpression of BMP3 inhibits the migration of RA and AIA FLS. (A) The protein levels of MMP-3, MMP-9, and TIMP-1 in TNF-α–treated RA FLS transfected with BMP3-pcDNA3.1 were analyzed using western blot. (B) The protein levels of MMP-3, MMP-9, and TIMP-1 in TNF-α–treated AIA FLS transfected with BMP3-PEX were analyzed using western blot. (C) The mRNA levels of MMP-3, MMP-9, and TIMP-1 in TNF-α–treated RA FLS transfected with BMP3-pcDNA3.1 were analyzed using qPCR. (D) The mRNA levels of MMP-3, MMP-9, and TIMP-1 in TNF-α–treated AIA FLS transfected with BMP3-PEX were analyzed using qPCR. (E) TNF-α–treated RA FLS were transfected with BMP3-pcDNA3.1, and their migration into the wound-healing site after 24 hours was photographed (original magnification, ×10). (F) TNF-α–treated AIA FLS were transfected with BMP3-PEX, and their migration into the wound-healing site after 24 hours was photographed (original magnification, ×10). All values are expressed as the mean ± SD. ^*P < 0.05, ^**P < 0.01 vs RA group. ^#P < 0.05, ^##P < 0.01 vs NC-pcDNA3.1 group.

  
  
  

  

  BMP3 regulates the proinflammatory response and migration of FLS and may be associated with the TGF-β1/Smad signaling pathway. (A) The protein levels of p-Smad2 in RA FLS transfected with BMP3 siRNA were analyzed using western blot. (B) The protein levels of p-Smad2 in RA FLS transfected with BMP3-PEX were analyzed using western blot. (C) The protein levels of p-Smad2 in AIA FLS transfected with BMP3-RNAi were analyzed using western blot. (D) The protein levels of p-Smad2 in AIA FLS transfected with BMP3-pcDNA3.1 were analyzed using western blot. All values are expressed as the mean ± SD. ^*P < 0.05, ^**P < 0.01 vs normal group. ^#P < 0.05, ^##P < 0.01 vs model group.

  
  
  

  

  Overexpression of BMP3 by adenovirus in vivo alleviated arthritis severity in AIA rats. (A) In vivo imaging of normal and AIA rats. (B) Overexpression of BMP3 in AIA rat synovial tissues injected with ad-BMP3 was analyzed using immunofluorescence staining (original magnification, ×20). (C) BMP3 expression in AIA rat synovial tissues injected with ad-BMP3 was analyzed using IHC staining (original magnification, ×20).

  
  
  

  

  Overexpression of BMP3 by adenovirus in vivo alleviated arthritis severity in AIA rats. (A) The swelling of ankle joints was quantified using a plethysmometer. (B) Arthritis scores were reduced in AIA rats injected with ad-BMP3. (C) Representative H&E staining of normal and AIA rat synovial tissues (original magnification, ×20). (D) BMP3 protein levels in normal and AIA synovial tissues were analyzed using western blot. (E) Levels of IL-6, IL-1β, and TNF-α expression in the serum of AIA rats injected with ad-BMP3. All values are expressed as the mean ± SD. ^*P < 0.05, ^**P < 0.01 vs normal group. ^#P < 0.05, ^##P < 0.01 vs ad-NC group.

  
  
  

• Research Paper Volume 12, Issue 4 pp 3190-3204

  Development and validation of a nomogram to predict coronary heart disease in patients with rheumatoid arthritis in northern China

  Relevance score: 4.620837

  Tingting Wei, Bowen Yang, Haina Liu, Fangran Xin, Lingyu Fu

  Keywords: rheumatoid arthritis, coronary heart disease, Framingham risk score, development and validation nomogram

  Published in Aging on February 29, 2020

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  We developed and validated a nomogram to predict coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) in northern China. We analyzed a cohort of RA patients admitted to the Department of Rheumatology and Immunology of the First Affiliated Hospital of China Medical University from 2011 to 2017. To select a high-performance model for clinical data prediction, we evaluated the F1-scores of six machine learning models. Based on the results, we selected multivariable logistic regression analysis for the development of a prediction model. We then generated an individualized prediction nomogram that included age, sex, hypertension, anti-cyclic citrullinated peptide antibody positivity, the erythrocyte sedimentation rate, and serum LDL-cholesterol, triglyceride and HDL-cholesterol levels. The prediction model exhibited better discrimination than the Framingham Risk Score in predicting CHD in RA patients. The area under the curve of the prediction model was 0.77, with a sensitivity of 63.9% and a specificity of 77.2%. The nomogram exhibited good calibration and clinical usefulness. In conclusion, our prediction model was more accurate than the Framingham Risk Score in predicting CHD in RA patients. Our nomogram combining various risk factors can be used for the individualized preoperative prediction of CHD in patients with RA.

  

  Model evaluation (F1-score) results based on the number of features across 6 models in training group and validation group. Abbreviation: GBDT: gradient boosting decision tree; KNN: k-nearest-neighbors; LR: logistic regression; RF: random forest; XGB: xgradient-boosting; SVM: support vector machine.

  
  
  

  

  RA patients developed to CHD’s nomogram. The CHD nomogram was developed in the training cohort, with serum lipids, inflammatory markers, and serological status in RA patients. Abbreviation: LDL, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; HDL, high-density lipoprotein cholesterol; RF+, positive rheumatoid factor; CRP, C-reactive protein; Anti-CCP-positive, positive anti-cyclic citrullinated peptide antibody; ESR, erythrocyte sedimentation rate.

  
  
  

  

  Calibration curves of the CHD and the model with the addition of sex and age prediction in each cohort. Abbreviation: (A) Calibration curve of the CHD in the simple model of the development cohort. (B) Calibration curve of the complex model with addition of adjusted sex and age in the development cohort. (C) Calibration curve of the CHD in the simple model of the validation cohort. (D) Calibration curve of the complex model with addition of adjusted sex and age in the validation cohort.

  
  
  

  

  Diagnostic value for FRS and the clinical prediction model to predict CHD. Abbreviation: FRS, diagnostic value for FRS to predict CHD; Pre1, diagnostic value for simple clinical prediction model to predict CHD; Pre2, diagnostic value for complex clinical prediction model to predict CHD.

  
  
  

  

  Decision curve analysis for serum lipids, inflammatory markers, and serological status in RA and CHD patients of the simple and complex model in the training cohorts. The y-axis represents the net benefit, the x-axis represents the high-risk threshold of CHD in RA patients. The red line represents the nomogram of predictors in simple model. The blue line represents the complex model with addition of sex and age. The gray line represents the assumption that all patients have CHD.

  
  
  

• Editorial Volume 11, Issue 22 pp 9969-9970

  Reduced lymphatic function contributes to age-related disease

  Relevance score: 6.122836

  Gaurav Baranwal, Joseph M. Rutkowski

  Keywords: lymphangiogenesis, aging, arthritis, Alzheimer’s disease

  Published in Aging on November 27, 2019

• Research Paper Volume 11, Issue 10 pp 3348-3361

  circFADS2 protects LPS-treated chondrocytes from apoptosis acting as an interceptor of miR-498/mTOR cross-talking

  Relevance score: 6.440936

  Guoqing Li, Wei Tan, Yuxuan Fang, Xia Wu, Wei Zhou, Chunwang Zhang, Yu Zhang, Yanqing Liu, Guangzheng Jiu, Dan Liu

  Keywords: rheumatoid arthritis, circFADS2, miR-498, mTOR, apoptosis

  Published in Aging on May 29, 2019

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  We aimed to investigate the regulation of circular RNAs in lipopolysaccharide (LPS)-treated chondrocytes isolated from SD rat. In this study, we analyzed how circFADS2 was regulated in LPS-treated chondrocytes and isolates from Rheumatoid arthritis (RA) patients and found that circFADS2 and mTOR were highly expressed whereas miR-498 expression was significantly reduced. We then silenced circFADS2 in LPS-treated chondrocytes; this resulted in a declined expression of type II collagen, but an increase in the expression of MMP-13, COX-2, and IL-6. Overall, silencing circFADS2 caused a significant reduction in the proliferative rate of LPS-treated chondrocytes, increased apoptotic levels, miR-498 upregulation, and mTOR downregulation. Dual-luciferase reporter assay indicated that circFADS2 directly targeted miR-498. In contrast, miR-498 down-regulation affected circFADS2 silencing, promoting extracellular matrix (ECM) degradation and apoptosis. The 3’ UTR of the mTOR gene is targeted by miR-498, and consequently, in cells transfected with miR-498, there was a significant reduction of mTOR expression at the protein and mRNA levels. Silencing mTOR had a similar effect to circFADS2 silencing on type II collagen, MMP-13, COX-2, and IL-6 expression, as well as cell proliferation and apoptosis. In conclusion, circFADS2 may affect LPS-induced chondrocytes properties by regulating the ECM catabolism, inflammation, and apoptosis in chondrocytes.

  

  Expression of various circRNAs in the cartilage tissue of RA patients. (A) Hierarchical clustering assessment of circRNAs that displayed variation in expression patterns between control and RA groups; every group comprised three individuals (over two-fold difference in expression; P < 0.05). Expression values are shown in various colors suggestive of high and low median expression levels. (B) Scatter plot was used to evaluate alterations in circRNA expression between control (group A) and RA (group B) specimens. Values corresponding to X and Y axes in the scatter plot were normalized signal values of specimens (log₂ scaled). Green lines indicate fold alterations. CircRNAs over the top green line and below the bottom green line indicate over two-fold changes. (C) Volcano plots were built to show fold change values and P values. The vertical lines show two-fold upregulation and downregulation between control and RA specimens (A versus B), and the horizontal line shows P value. The red point in the plot shows various expression patterns of circRNAs with statistical significance.

  
  
  

  

  circFADS2 is upregulated in RA patients and LPS-treated chondrocytes. (A) qPCR analysis showing upregulated circFADS2 expression levels in RA patients. (B) qPCR analysis showed expression of IL-1β, TNF-α, and IL-17 in LPS-treated chondrocytes. (C) CircFADS2 levels were significantly augmented in LPS-treated chondrocytes when compared to the control group (non-treated cells). *P < 0.05, **P < 0.01 vs. the indicated group.

  
  
  

  

  circFADS2 regulates ECM degradation and inflammation of LPS-treated chondrocytes. Chondrocytes were transfected with si-circFADS2 or si-NC, followed by LPS-treatment. (A) qPCR analysis was carried out to detect the levels of circFADS2 in each group. (B) Quantification of circFADS2 and GAPDH mRNA by northern blot analysis. (C) mRNA expression of the indicated proteins measured by qPCR; the results are normalized to the expression of GAPDH. (D) Western blotting revealing the expression of the indicated proteins; results are normalized to the expression of GAPDH. The protein levels of type II collagen, MMP13, COX-2, and IL-6 are shown in the WB-graph. (E) The IL-6 level in cells was examined by ELISA. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control group, ^## P < 0.01, ^### P < 0.001 vs. LPS group.

  
  
  

  

  circFADS2 silencing reduced cell viability and induced apoptosis in LPS-treated chondrocytes. (A) CCK8 assay showing that transfection with a circFADS2 silencer (si-circFADS2) inhibited cell proliferation of LPS-treated chondrocytes. (B) Soft agar colony formation assay for the LPS-treated chondrocytes transfected with si-circFADS2 or si-NC, and that of non-transfected cells. The right panel shows the number of colonies formed in each group. (C) Flow cytometry analysis showing the levels of apoptosis in the different groups of chondrocytes. (D) WB and (E) qPCR analysis showing that circFADS2 inhibition downregulates Bcl-2 and up-regulates Bax in LPS-treated chondrocytes. *P < 0.05, **P < 0.01 vs. LPS group.

  
  
  

  

  circFADS2 targets miR-498. (A) Bioinformatic analysis indicating that miR-498 has a circFADS2 binding site. (B) DLRA was performed following co-transfection of chondrocytes with a luciferase reporter containing either a WT (wild-type) or MU (mutant) circFADS2 and a miR-498 mimic. (C) qPCR analysis showing the decreased miR-498 expression levels in RA patients. (D) Chondrocytes were transfected with si-circFADS2 or si-NC and then treated with LPS. qPCR analysis was used to measure the miR-498 levels in each group. (E) Quantification of miR-498 and GAPDH mRNA by northern blot analysis. *P < 0.05, **P < 0.01 vs. control cells; ^# P < 0.05 vs. LPS group.

  
  
  

  

  miR-498 inhibitor reversed the effects of circFADS2 on LPS-treated chondrocytes. LPS-treated chondrocytes were co-transfected with si-circFADS2 and miR-498 inhibitor/miR-NC inhibitor. (A) qPCR analysis was performed to confirm the miR-498 levels in each group. (B, C) The mRNA and protein expression of the indicated proteins was determined by qPCR and WB. (D) The IL-6 level in cells was examined by ELISA. Results were normalized to GAPDH expression. *P < 0.05, **P < 0.01 vs. LPS group; ^# P < 0.05, ^## P < 0.01, ^### P < 0.001 vs. LPS+circFADSi+miR-NCi group.

  
  
  

  

  miR-498 silencing reversed cell viability and apoptosis regulated by circFADS2. LPS-treated chondrocytes were co-transfected with si-circFADS2 and miR-498 inhibitor/miR-NC inhibitor. (A) CCK8 assay showing that transfection with a miR-498 inhibitor reduced cell proliferation of LPS-treated chondrocytes. (B) Soft agar colony formation assay for the LPS-treated chondrocytes co-transfected with si-circFADS2 and miR-498 inhibitor/miR-NC inhibitor, and that of non-transfected LPS-induced cells. The right panel shows the number of colonies formed in each group. (C) Flow cytometry analysis showing the apoptosis levels in the different chondrocyte groups. (D) WB and (E) qPCR analysis showing that miR-498 inhibition upregulated Bcl-2 and decreased the levels of Bax, in LPS-treated chondrocytes. *P < 0.05, vs. LPS group; ^# P < 0.05, ^## P < 0.01 vs. LPS+circFADSi+miR-NCi group.

  
  
  

  

  miR-498 targets the mTOR. (A) Bioinformatic analysis showing that miR-498 has a binding site in the 3′-UTR of mTOR. (B) DLRA was performed following co-transfection of chondrocytes with a luciferase reporter containing either a WT (wild-type) or MU (mutant) mTOR and a miR-498 mimic. (C) qPCR analysis showing the significantly increased mTOR expression levels in RA patients. (D, E) Chondrocytes were transfected with si-circFADS2 or miR-498 mimic and then treated with LPS. qPCR and WB analysis were carried out to detect mTOR levels in each group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control cells; ^#P < 0.05, ^###P < 0.001 vs. LPS group.

  
  
  

  

  mTOR inhibition regulates ECM degradation, inflammation, and apoptosis of LPS-treated chondrocytes. LPS-treated chondrocytes were transfected with si-mTOR. (A) qPCR analysis was performed to confirm the mTOR mRNA levels in each group. (B) The protein levels of type II collagen, MMP13, COX-2, IL-6, and mTOR were determined by WB. (C) The IL-6 level in cells was examined by ELISA. (D) The mRNA levels of type II collagen, MMP13, COX-2, IL-6, and mTOR were determined by WB; results are normalized to the expression of GAPDH. (E) CCK8 assay showing that mTOR silencing inhibited cell proliferation of LPS-treated chondrocytes. (F) Flow cytometry analysis showing apoptosis levels in LPS-treated chondrocytes with mTOR silenced. *P < 0.05, **P < 0.01, ***P < 0.001 vs. LPS group.

  
  
  

• Editorial Volume 10, Issue 3 pp 290-292

  Taking a HIF pill for old age diseases?

  Relevance score: 4.4447365

  Stefan Kaluz, Chalet Tan, Erwin G. Van Meir

  Keywords: hypoxia, hypoxia-inducible factor, atherosclerosis and cardiovascular disease, osteoporosis, arthritis, retinal pathologies, cancer

  Published in Aging on March 1, 2018

  

  (A) Involvement of hypoxia and HIFs in aging-associated diseases; (B) Involvement of HIFs in hallmarks of solid tumors.

  
  
  

• Research Paper Volume 3, Issue 4 pp 368-373

  Association of PTPN22 1858T/T genotype with type 1 diabetes, Graves' disease but not with rheumatoid arthritis in Russian population

  Relevance score: 4.610395

  Daria Zhebrun, Yulia Kudryashova, Alina Babenko, Alexei Maslyansky, Natalya Kunitskaya, Daria Popcova, Alexandra Klushina, Elena Grineva, Anna Kostareva, Evgeny Shlyakhto

  Keywords: type 1 diabetes, Graves' disease, rheumatoid arthritis, protein tyrosine phosphatase nonreceptor 22, single-nucleotide polymorphism

  Published in Aging on April 6, 2011

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  The protein tyrosine phosphatase nonreceptor 22 gene (PTPN22) is an important negative regulator of signal transduction through the T-cell receptors (TCR). Recently a single-nucleotide polymorphism (SNP) 1858 C/T within this gene was shown to be a risk factor for several autoimmune diseases, such as rheumatoid arthritis (RA), Graves' Disease (GD), systemic lupus erythematosus (SLE), Wegener's granulomatosis (WG) and type 1 diabetes mellitus (T1D). The aim of this study was to analyze a possible association between 1858 C/T SNP and a number of autoimmune diseases, including RA, GD and T1D in Russian population. Patients with T1D, GD, RA and healthy controls were genotyped for the 1858 C/T SNP in PTPN22 gene. We found a significant association between PTPN22 1858 C/T SNP and T1D and GD. 1858T/T genotype was observed more frequently in T1D and GD patients compared to control subjects. No such association was observed for RA. In concordance with a previous data establishing PTPN22 1858 C/T SNP association with several autoimmune diseases, our findings provide further evidence that the PTPN22 gene may play an important role in the susceptibility to some autoimmune diseases.

• Research Paper pp undefined-undefined

  Role of m6A modification and novel circ_0066715/ miR-486-5p/ ETS1 axis in rheumatoid arthritis macrophage polarization progression

  Relevance score: 4.5869985

  Lei Wan, Jian Liu, Chuanbing Huang, Ziheng Zhu, Fangze Li, Guanghan Sun, Kun Wang, Shu Li, Ximeng Ma, Xi Chen, Wang Yuan

  Keywords: N6-methyladenosine methylation modification, circular RNA, microRNA, rheumatoid arthritis, macrophage polarization

  Published in Aging on Invalid Date

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  Rheumatoid arthritis (RA) is a systemic disease dominated by inflammatory synovitis. RA synovial macrophages tend undergo M1-type macrophage polarization. Then, polarized M1-type macrophages secrete abundant pro-inflammatory cytokines, causing joint and cartilage destruction. N6-methyladenosine (m6A) methylation modification, circular RNA (circRNA), microRNA (miRNA), messenger RNA (mRNA), etc. are involved in the inflammatory response of RA. We found that there is an imbalance of inflammatory polarization in RA, which is manifested by a sharp increase in inflammatory markers and a high inflammatory response. Here, we show that RA was closely associated with low expression of circ_0066715. The overexpression of circ_0066715 significantly increased the ETS1 levels in RA-FLS cells, decreased cytokine secretion by M1-type macrophages, elevated M2-type cytokines, and inhibited FLS proliferation. Interestingly, the overexpression of miR-486-5p significantly suppressed the attenuation of the cell function and the effect on M1 macrophage polarization caused by circ_0066715 positive expression. WTAP may be involved in the methylation process of ETS1 in RA. ETS1 m6A methylation levels were altered upon WTAP intervention. The overexpression or interference of circ_0066715 decreased or increased WTAP expression. Our findings provide a novel circRNA/miRNA/mRNA regulatory axis and m6A regulatory mechanism involved in the process of RA macrophage polarization, thereby providing a powerful diagnostic and therapeutic strategy for RA treatment.

• Research Paper pp undefined-undefined

  Identification of CD8+ T cell related biomarkers and immune infiltration characteristic of rheumatoid arthritis

  Relevance score: 4.233062

  Qizun Wang, Qianqian Li, Ronghuan Wang, Yanning Li, Jie Wang, Zhu Guo, Feng Li, Bohua Chen, Hongfei Xiang, Tianrui Wang, Xiaolin Wu

  Keywords: rheumatoid arthritis, immune infiltration, CD8⁺ T cells, machine learning, personalized therapy

  Published in Aging on Invalid Date

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  Rheumatoid arthritis (RA) is an autoimmune rheumatic disease, which do not respond well to current treatment partially. Therefore, further in-depth elucidation of the molecular mechanism and pathogenesis of RA is urgently needed for the diagnosis, personalized therapy and drug development. Herein, we collected 111 RA samples from Gene Expression Omnibus (GEO) database, and conducted differentially expressed genes and GESA analysis. Abnormal activation and imbalance of immune cells in RA were observed. WGCNA was utilized to explore the gene modules and CD8⁺ T cell-related genes (CRGs) were chosen for KEGG and GO analysis. Besides, to explore biomarkers of RA in depth, machine learning algorithms and bioinformatics analysis were used, and we identified GDF15, IGLC1, and IGHM as diagnostic markers of RA, which was confirmed by clinical samples. Next, ssGSEA algorithms were adopted to investigate the differences in immune infiltration of 23 immune cell subsets between RA and healthy control group. Finally, optimal classification analysis based on consensus clustering combined with ssGSEA algorithms were conducted. GDF15 was revealed that to be positively correlated with mast cells and type 2 T helper cells, but negatively correlated with most other immune cells. On the other hand, IGHM and IGLC1 were negatively correlated with CD56dim natural killer cells, while positively associated with other immune cells. Finally, RA samples in subtype A exhibited a higher immune infiltration status. This study could provide guidance for individualized treatment of RA patients and provide new targets for drug design.

• Research Paper pp undefined-undefined

  Mechanism of lysine oxidase-like 1 promoting synovial inflammation mediating rheumatoid arthritis development

  Relevance score: 4.5869985

  Jiawei Hu, Xuqiang Liu, Qiang Xu, Meisong Zhu, Song Wang, Kun Quan, Min Dai, Fengbo Mo, Haibo Zhan

  Keywords: lysine oxidase-like 1, rheumatoid arthritis, PI3K/AKT, basement membranes, synovitis

  Published in Aging on Invalid Date

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  Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes great distress to patients and society. Early diagnosis is the key to the successful treatment of RA. The basement membrane, one of the oldest tissue structures, is localized under the epithelium. Its complex composition and rich biological functions have made it a focus of research in recent years, while basement membrane-associated genetic variants are involved in most human disease processes. The aim of this study is to find new diagnostic biomarkers for RA and explore their role and possible mechanism in rheumatoid arthritis. The GSE12021, GSE55235 and GSE55457 datasets were downloaded from the GEO datase. Their fraction associated with basement membrane genes was analyzed and differentially expressed genes between the disease and normal groups were explored. We identified two basement membrane-associated genes, lysine oxidase-like 1(LOXL1) and discoid peptide receptor 2 (DDR2). Focusing on the more interesting LOXL1, we found that LOXL1 expression was significantly elevated in the synovium of patients with rheumatoid arthritis, and LOXL1 mRNA and protein levels were elevated in tumor necrosis factor α-stimulated human synovial sarcoma cells (SW982). And LOXL1 knockdown inhibited tumor necrosis factor α-induced inhibition in SW982 cells expression of inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX2), and interleukin-6 (IL-6). Interestingly, knockdown of LOXL1 inhibited the phosphorylation of PI3K and AKT. In summary, LOXL1 may become a novel diagnostic gene for RA, and knockdown of LoxL1 may inhibit synovial inflammation by affecting PI3K/AKT pathway.