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ID PMID Title PublicationDate abstract
33634679 New bitongling (NBTL) ameliorates rheumatoid arthritis in rats through inhibiting JAK2/STA 2021 Feb 17 Rheumatoid arthritis (RA) is featured by a variety of physical symptoms and fibroblast-like synoviocytes (FLSs) abnormal proliferation. Increasing evidence has demonstrated that traditional Chinese medicine exerts an important role in RA treatment. New bitongling (NBTL) as one of the traditional Chinese medicine has been reported to be involved in the progression of RA, but the exact mechanism is unclear. In our study, we intended to investigate the effect of NBTL on RA to identify the mechanisms related to JAK2/STAT3 signaling pathway. Extracts of Tripterygium wilfordii (TW), a traditional Chinese herbal medicine, have been widely used for treating RA in China for several decades, so, TW was used as a positive control drug for TBNL. RA rats were constructed by immunization with collagen type II to evaluate the action of NBTL in vivo. Body weight and arthritic index were evaluated. Hematoxylin and Eosin staining was performed to analysis the morphological changes of ankle joints tissue. TUNEL and flow cytometry were performed to examine cell apoptosis, while CCK8 and Ethynyl-2'-deoxyuridine (EdU) were performed to examine cell proliferation. In addition, the markers of inflammation were detected by Western blot, ELISA, and RT-qPCR. Firstly, we find that rats treated with NBTL or TW not only reduced swelling degree and bone destruction, but also repressed IL-1 β and IL-6 levels. In addition, NBTL and TW could increase the weight of rats, and promote the level of IL-10 and IL-4 in vivo. Furthermore, NBTL inhibited inflammation of FLS, induced cell apoptosis and hindered cell proliferation, which was reversed by dipeptidyl peptidase (DPP), a JAK2/STAT3 pathway activator. Taken together, NBTL potentially retarded RA via JAK2/STAT3 pathway, highlighting novel mechanisms associated with RA.
32779111 Dextran sulfate-modified pH-sensitive layered double hydroxide nanocomposites for treatmen 2021 Jun To reduce the side effects of methotrexate and increase its anti-inflammatory effect, we developed a drug delivery system, dextran sulfate-modified methotrexate-loaded layered double hydroxide nanocomposites (LDH-MTX-DS), with both targeting and pH-sensitivity for the treatment of rheumatoid arthritis. The nanocomposites had a mean particle size of 303.1 ± 8.07 nm, zeta potential of - 12.4 ± 0.7 mV, encapsulation efficiency of 49.64%, and loading efficiency of 16.81%. In vitro release experiments demonstrated that the drug was released faster in PBS at pH 5.5 than at pH 7.4, which reflected the pH-sensitivity of this system. Cellular uptake assays displayed higher cellular uptake rate of the dextran sulfate-modified targeting carrier compared with that of a non-targeting carrier (P < 0.01), which indicated that the LDH-MTX-DS could actively target scavenger receptors on the surface of activated RAW 264.7 cells. In vivo pharmacodynamic experiments showed that, after the second (P < 0.001) and third (P < 0.05) administrations, the preparation group exhibited significantly improved therapeutic efficacy in adjuvant-induced arthritis (AIA) rats when compared with free MTX alone. These results indicated that this drug delivery system was promising in the treatment of rheumatoid arthritis. Graphical abstract.
34717606 Influence of perceived barriers and facilitators for physical activity on physical activit 2021 Oct 30 BACKGROUND: Barriers and facilitators to physical activity in inflammatory arthritis can be assessed through the Inflammatory arthritis FAcilitators and Barriers (IFAB) questionnaire. The objective was to measure the correlation between IFAB and self-reported physical activity levels. METHODS: This was an international, multicentric, cross-sectional study in 2019-20. Consecutive spondyloarthritis (axSpA), rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients completed the 10-item IFAB, which ranges from - 70 to 70 with lower scores indicating more barriers. Physical activity was measured by the IPAQ-S questionnaire, steps per day collected by smartphone, and psychological readiness to change by stages of behaviour change. Spearman correlations and multivariable linear regression were calculated. RESULTS: Of 245 patients included, 150 were analysed: 69 (46%) axSpA, 63 (42%) RA, 18 (12%) PsA. Mean age was 48.6 years (standard deviation, SD 17.1), mean disease duration 11.7 (10.1) years and 60% were women. Barriers to physical activity were moderate: mean IFAB, 6 (SD 19.2); 39 (26%) patients scored less than - 5, corresponding to significant barriers. The mean physical activity was 2837 (SD 2668, median 1784) MET-minutes per week. The IPAQ-S questionnaire was correlated with the IFAB (rho 0.28, p < 0.001), as well as the stage of behaviour change (rho 0.35, p < 0.001) though not with steps per day. Multivariable analyses were confirmatory. CONCLUSION: Perceived barriers and facilitators to physical activity were correlated with physical activity, indicating that targeting patients with high barriers and low facilitators to physical activity could be an effective option to improve physical activity levels. TRIAL REGISTRATION: ClinicalTrial NCT04426747 . Registered 11 June 2020 - Retrospectively registered.
33929089 Exposure-response modeling of peficitinib efficacy in patients with rheumatoid arthritis. 2021 May The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure-response models. The analysis incorporated results from three multicenter, placebo-controlled, double-blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28-CRP measurements were modeled by a non-linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure-response models of effect of peficitinib on duration-dependent increase in ACR20 response rate and decrease in DAS28-CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal E(max) saturable of drug exposure in RA patients. The significant covariates were DAS28-CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28-CRP model. The covariate effects were highly consistent between the two models. Our exposure-response models of peficitinib in RA patients satisfactorily described duration-dependent improvements in ACR20 response rates and DAS28-CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment. CLINICAL TRIAL REGISTRATION: NCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).
34139735 [A Case of Rheumatoid Arthritis Caused by Pembrolizumab Treatment for Non-Small Cell Lung 2021 Jun A man in his 40s underwent a transbronchial lung biopsy and received a diagnosis of adenocarcinoma of the right upper lobe of the lung(cT4N0M0, Stage â…¢)with no EGFR gene mutation, no ALK fusion gene, no ROS1 fusion gene, and a tumor proportion score(TPS)of 50-74%. During the postoperative follow-up period, enlarged right supraclavicular lymph nodes and right upper and lower paratracheal lymph nodes were detected, diagnosed as recurrence by positron emission tomography-computed tomography. Although a positive rheumatoid factor test, as the patient had no symptoms of rheumatoid arthritis(RA), treatment with pembrolizumab was initiated. Before the second treatment course, a pharmacist conversing with the patient observed that the patient was experiencing pain in his fingers. After discussing the possibility of treatment continuation and test items with the attending physician, the patient underwent tests and received a diagnosis of RA.
33686476 Prevalence of liver fibrosis by Fibroscan in patients on long-term methotrexate therapy fo 2021 Sep INTRODUCTION: Data on the long-term use of methotrexate (MTX) causing liver fibrosis in patients with rheumatoid arthritis (RA) is sparse. Liver biopsy is the gold standard to assess fibrosis but is an invasive procedure. Transient elastography (TE) by Fibroscan is a noninvasive validated tool to detect and quantify liver fibrosis. The present study aimed to assess the prevalence of liver fibrosis by Fibroscan in patients with RA on long-term MTX therapy and its correlation with cumulative dose of MTX. METHODS: This cross-sectional study included adult patients (≥ 18 years age) of RA who had been on MTX for ≥ 3 years. The patients' records were reviewed, and the cumulative dose of MTX was calculated. Liver fibrosis was assessed by TE method, and the cutoff value of 7.1 kPa (kilopascal) was considered abnormal (liver fibrosis). Spearman's rank test was used to assess the correlation between the cumulative dose of MTX and Fibroscan score. RESULTS: Seventy-five patients were enrolled of which 69 were females (92%). The mean age was 47.2 ± 11.3 years. The mean body mass index and waist circumference were 24.8 ± 3.9 kg/m(2) and 91.6 ± 9.9 cm, respectively. The median duration and cumulative dose of MTX were 336 weeks (interquartile range,144-912 weeks) and 6300 mg (interquartile range, 2400-22,000 mg), respectively. The mean liver stiffness was 5.22 ± 2.03 kPa. Twelve patients (16%) had Fibroscan score ≥ 7.1 kPa, of which 3 patients had severe liver stiffness (9.5 to 12.5 kPa) and one patient had liver stiffness in the range of cirrhosis (> 12.5 kPa). Fibroscan scores significantly correlated with cumulative dose of MTX (r= 0.30, p = 0.008). CONCLUSIONS: Long-term MTX therapy in RA was associated with increased liver stiffness on Fibroscan. Key Points • Fibroscan is a useful tool for monitoring MTX-induced liver fibrosis. • Liver fibrosis as evidenced by increased liver stiffness on Fibroscan is prevalent among patients on long-term MTX therapy for RA.
33488616 Activated Platelets Convert CD14(+)CD16(-) Into CD14(+)CD16(+) Monocytes With Enhanced FcΠ2020 Monocytes are important cellular effectors of innate immune defense. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. The expansion of intermediate CD14(+)CD16(+) monocytes has been reported in chronic inflammatory diseases including rheumatoid arthritis (RA). However, the mechanism underlying induction of CD16 and its role in monocytes remains poorly understood. Here, we demonstrate that activated platelets are important for induction of CD16 on classical CD14(+)CD16(-) monocytes by soluble factors such as cytokines. Cytokine neutralization and signaling inhibition assays reveal that sequential involvement of platelet-derived TGF-β and monocyte-derived IL-6 contribute to CD16 induction on CD14(+)CD16(-) monocytes. Activated platelet-induced CD16 on monocytes participates in antibody-dependent cellular phagocytosis (ADCP) and its level is positively correlated with phagocytic activity. CD14(+)CD16(-) monocytes treated with activated platelets preferentially differentiate into M2 macrophages, likely the M2c subset expressing CD163 and MerTK. Lastly, the amount of sCD62P, a marker of activated platelets, is significantly elevated in plasma of RA patients and positively correlates with clinical parameters of RA. Our findings suggest an important role of activated platelets in modulating phenotypical and functional features of human monocytes. This knowledge increases understanding of the immunological role of CD14(+)CD16(+) cells in chronic inflammatory diseases.
34783244 Programmable Polymeric Microneedles for Combined Chemotherapy and Antioxidative Treatment 2021 Nov 24 Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Antioxidative treatment combined with chemotherapy holds great promise for RA treatment, and the ability to efficiently deliver drugs and antioxidants to the RA synovial joint is highly desired. Herein, we developed a programmable polymeric microneedle (MN) platform for transdermal delivery of methotrexate (MTX) and reactive oxygen species (ROS) scavengers for RA treatment. The biodegradable MNs made of polyvinylpyrrolidone (PVP) were incorporated with polydopamine/manganese dioxide (termed PDA@MnO(2)) and MTX. After insertion into skin tissue, the MNs degraded, thus enabling release of loaded MTX and PDA@MnO(2). The PDA@MnO(2) could be utilized as an MRI contrast agent in the RA synovial microenvironment. It also acted as a robust antioxidant to remove ROS and decrease RA inflammation, which when combined with the MTX-mediated chemotherapy led to an ideal outcome for RA treatments in a murine model. This work not only represents a valuable MN-assisted RA therapeutic agent transdermal delivery approach but also opens a new avenue for chemotherapy and antioxidative synergistic treatment of RA.
32613884 Risk factors of postoperative delayed wound healing in patients with rheumatoid arthritis 2021 May OBJECTIVES: This retrospective study aimed to investigate the risk factors associated with delayed wound healing (DWH) after orthopedic surgery in rheumatoid arthritis (RA) patients treated with biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: We reviewed medical records of 276 orthopedic procedures for 187 RA patients treated with bDMARDs. As a preoperative nutritional status assessment, we evaluated body mass index, prognostic nutritional index (PNI), and controlling nutritional status (CONUT). We evaluated DAS28-CRP, DAS28-ESR, face scale, global health, and HAQ-DI to assess the disease activity. Univariate and multivariate logistic regression analyses were performed to evaluate the risk factors for DWH. RESULTS: In 276 procedures, DWH was identified in 24 patients (8.7%). Disease duration, foot and ankle surgery, and preoperative use of tocilizumab were significant in the univariate analyses. These variables were entered into a multivariate model, and it was revealed that preoperative use of tocilizumab and procedures in the foot and ankle were associated with an increased risk of DWH. CONCLUSION: The current retrospective study suggested that preoperative use of tocilizumab and procedures in the foot and ankle were risk factors for DWH.
33675063 Circulating anti-citrullinated protein antibodies containing secretory component are progn 2021 Jun Autoantibodies related to rheumatoid arthritis (RA), such as anti-citrullinated protein antibodies (ACPA), are often detectable in the preclinical period years before arthritis onset. However, events triggering arthritis development remain incompletely known. We aimed to determine whether ACPA isotype levels are prognostic for arthritis development in patients presenting with immunoglobulin (Ig)G ACPA and musculoskeletal pain. Study participants (n = 82) had musculoskeletal pain of any sort and duration and a positive IgG ACPA test. None of the patients had arthritis upon clinical examination at baseline, but during follow-up (mean = 6 years), 48% developed at least one arthritic joint. IgG, IgA, IgM and secretory component (SC)-containing ACPA was measured in longitudinally collected serum samples. Cox regression analysis was performed to test the prognostic value of baseline antibody levels and changes over time. All analysed ACPA isotype levels were associated with arthritis development in univariable Cox regression analysis. In multivariable analysis, baseline SC ACPA levels were independently prognostic for arthritis development in multivariable analysis [hazard ratio (HR) = 1·006, 95% confidence interval (CI) = 1·001-1·010, P = 0·012]. There were no significant changes in ACPA isotype levels over time, and no significant association between changes over time and arthritis development. In this prospective longitudinal study, baseline serum SC ACPA levels, but neither IgG, IgA nor IgM ACPA are prognostic for future arthritis development. Repeated measurement of ACPA isotypes do not bring additional prognostic value. The results reinforce a mucosal connection in RA development and encourage further exploration of the mechanisms underlying secretory ACPA formation as a trigger for arthritis development.
33798506 Glaucocalyxin A suppresses inflammatory responses and induces apoptosis in TNF-a-induced h 2021 May 25 The pathogenesis of rheumatoid arthritis (RA) is characterized by synoviocyte hyperplasia and proinflammatory cytokine secretion, as well as the destruction of cartilage and bone. Glaucocalyxin A (GLA) is an alkaloid derived from a Chinese medicinal plant that exhibits anti-inflammatory, anti-tumor and neuroprotective properties. We investigated the effects of GLA on RA-fibroblast-like synoviocytes (FLS cells), and collagen-induced arthritis (CIA), and further explored the underlying mechanisms. GLA inhibited TNF-a-induced RA-FLS proliferation, increased apoptotic ratios and upregulated levels of caspase-3, cleaved PARP, and Bax. GLA also inhibited the expression of IL-10, IL-1β, and IL-6 in vitro. Levels of p-STAT3 were downregulated in a dose-dependent manner. Over-expression of STAT3 partly neutralized the GLA-mediated elevation of caspase-3 and cleaved PARP levels as well as the downregulation of IL-10, IL-1B and IL-6 expression levels. This suggests that GLA inactivated the STAT3 pathway. Furthermore, the production of inflammatory cytokines in RA-FLS and a CIA rat model were inhibited effectively by GLA. Taken together, our data suggest that GLA is a potential long-term therapeutic agent for patients with RA.
33994144 Guards! Guards! How innate lymphoid cells ensure local law and order. 2021 Apr This special issue of the Biomedical Journal is dedicated to the latest official recruits in the field of immunology: innate lymphoid cells, the tissue-resident sentinels and first responders to damage or invasion. Subsequently, we consider extracellular vesicle release during bacterial infection, how immunomodulation can avoid compromising Mycobacterium tuberculosis clearance, and how innate immunity jeopardises the organism during rheumatoid arthritis. Moreover, we ponder over the predictive value of cardiac troponin in influenza, the virtues of cashew nuts and bilirubin, as well as holes in the heart. Finally, we learn that mandibular movement during swallowing increases with the vertical dimension of occlusion, and that early controlled relaxation incisions restore the blood supply to the extremities in harlequin ichthyosis neonates.
33663170 [Clinical analysis of 46 rheumatoid arthritis patients with peripheral neuropathy]. 2021 Mar 1 Objective: To study clinical features of rheumatoid arthritis (RA) patients with peripheral neuropathy (PN). Methods: The clinical data of 46 RA patients with PN in the First Affiliated Hospital of Zhengzhou University from August 2012 to August 2019 were retrospectively analyzed, including clinical manifestations, laboratory and imaging results, previous treatment, treatment and clinical outcome. The other 92 RA patients without PN at the same period were selected as controls. Results: In RA patients with PN, the male to female ratio was 1∶2.1 with an average age (59.1±11.8) years. The course of RA and PN was 102.0 (19.0-156.0) months and 4.2 (0.7-5.5) months respectively. Numbness (84.8%, 39/46) and muscle weakness (21.7%, 10/46) were the most common symptoms. According to results of electromyography, polyneuropathy (60.0%, 27/46) was the predominant manifestation, followed by mononeuritis multiplex (31.1%, 14/46). Compared to RA patients, rheumatoid factor (RF) (P<0.001) and the percentage of cutaneous vasculitis (P=0.042) were higher in RA patients with PN. Logistic regression analysis revealed significant correlation between RF>178.4 IU/ml (OR＝5.626, 95%CI 2.509-12.618, P<0.001) and development of PN. Paresthesia in 27 patients (58.7%, 27/46) were relieved after treatment of high dose glucocorticoid and immunoglobulins (IVIG). Twelve patients were followed up regularly and the mean duration of follow-up was 17.0(4.8-52.8)months. Paresthesia in 10 (10/12) patients were relieved compared to that at discharge, 1 (1/12) patient achieved complete remission. Conclusion: Numbness and muscle weakness are the common symptoms in RA patients with PN and polyneuropathy is the main type. RF>178.4 IU/ml is correlated with the development of PN in RA patients. Intensive treatment such as high dose glucocorticoid and IVIG are effective.
33427617 Postural control and disability in patients with early rheumatoid arthritis. 2021 Nov OBJECTIVES: Rheumatoid arthritis (RA) may affect the postural control through abnormal sensory inputs and impaired motor responses. Sensory Organization Test (SOT) objectively evaluates contribution of different sensorial afferences in postural control. The aim of the study is to assess mechanisms of postural instability and their relations with disability and disease characteristics in an early RA(ERA) cohort. METHODS: The equilibrium scores were assessed in 30 ERA patients and 30 age- and sex-matched controls. The somatosensory (SOM), visual (VIS) and vestibular (VEST) ratios were computed to assess the use of different sensory and the composite equilibrium score (CES) as a measure of global balance performance. RESULTS: ERA patients had lower CES (78.4±6.0% vs. 83.4±5.0%, p=0.002), SOM ratio (98.5±1.8% vs. 99.6±2.1%, p=0.035), VIS ratio (85.2±7.6% vs. 91.5±6.0%, p=0.001) and VEST ratio (70.8±10.0% vs. 80.3±7.8%, p<0.001) compared to controls. The presence of ankle arthritis correlated negatively to both SOM (r=-0.369, p=0.045) and VIS ratio (r=0.470, p=0.009), pain severity to CES (r=-0.389, p=0.045) and VIS ratio (r=-0.385, p=0.048) and HAQ-DI to CES (r=-0.591, p=0.001), SOM (r=-0.510, p=0.004) and VIS ratio (r=-0.390, p=0.033.). Patients-reported postural instability was associated with lower CES (75.4±5.4% vs. 80.7±5.5%, p=0.016) and VEST ratios (66.5±10.1% vs. 74.1±8.8%, p=0.036). SOT outcomes did not differ according to acute phase reactants, disease activity or autoantibody positivity. CONCLUSIONS: RA patients showed an early impairment of postural control related to the degree of disability and subjective postural instability. Our data suggest that the lack of balance could result from both impaired motor response and abnormal sensory organisation.
34358541 Folate receptor-targeting semiconducting polymer dots hybrid mesoporous silica nanoparticl 2021 Sep 25 With ideal optical properties, semiconducting polymer quantum dots (SPs) have become a research focus in recent years; a considerable number of studies have been devoted to the application of SPs in non-invasive and biosafety phototherapy with near-infrared (NIR) lasers. Nevertheless, the relatively poor stability of SPs in vitro and in vivo remains problematic. PCPDTBT was chosen to synthesize photothermal therapy (PTT) and photodynamic therapy (PDT) dual-model SPs, considering its low band gap and desirable absorption in the NIR window. For the first time, cetrimonium bromide was used as a stabilizer to guarantee the in vitro stability of SPs, and as a template to prepare SP hybrid mesoporous silica nanoparticles (SMs) to achieve long-term stability in vivo. The mesoporous structure of SMs was used as a reservoir for the hypoxia-activated prodrug Tirapazamine (TPZ). SMs were decorated with polyethylene glycol-folic acid (SMPFs) to specifically target activated macrophages in rheumatoid arthritis (RA). Upon an 808 nm NIR irradiation, the SMPFs generate intracellular hyperthermia and excessive singlet oxygen. Local hypoxia caused by molecular oxygen consumption simultaneously activates the cytotoxicity of TPZ, which effectively kills activated macrophages and inhibits the progression of arthritis. This triple PTT-PDT-chemo synergistic treatment suggests that SMPFs realize the in vivo application of SPs and may be a potential nano-vehicle for RA therapy with negligible side-toxicity.
34794509 Correlation and agreement between physical and ultrasound examination after a training ses 2021 Nov 18 OBJECTIVES: Assessing disease activity in rheumatoid arthritis (RA) patients requires comprehensive quantification of tender and swollen joints. We aimed to evaluate the correlation and agreement between rheumatologists after a training session dedicated to the standardization of synovitis assessment and compare its performance with a reference imaging modality such as musculoskeletal ultrasonography (MSUS). METHODS: In this cross-sectional study, a total of 28 and 10 joints in RA patients were evaluated by physical examination and ultrasound (US), respectively. After participating in a training session, individual joint assessment for tenderness and swelling was performed by three rheumatologists. MSUS examination was performed separately by an experimented radiologist in a standardized manner, evaluating findings according to the Outcome Measures in Rheumatology Clinical Trial (OMERACT) guidelines. RESULTS: A total of 80 RA patients were included, with a mean Disease Activity Score based on 28 joints (DAS28)-ESR of 4.02. The interobserver overall agreement and concordance rate in a total of 2240 joints assessed was 81.7% (k = 0.449, p < 0.0001) for tender joints and 66% (k = 0.227, p < 0.0001) for swollen joints. The overall concordance rate was fair (Fleiss' kappa = 0.21, p = 0.027) with an overall agreement of 67.18% yet, more joints were found to be swollen by the US assessment, compared to the physical examination (43% vs 39%). CONCLUSION: In our study population, joint tenderness showed better interobserver agreement, correlation, and concordance rate than joint swelling. When comparing the US assessment to the physical examination, a fair overall concordance rate supports the need for the implementation of training sessions dedicated to standardization in rheumatology clinics.
34599900 ITGA2 protein is associated with rheumatoid arthritis in Chinese and affects cellular func 2021 Dec BACKGROUND: We identified proteins significant for rheumatoid arthritis (RA) in peripheral blood mononuclear cells (PBMCs), and to clarify mechanisms mediated by underlying proteins that may involve in the pathogenesis of RA. METHODS: Proteome-wide protein expressions were profiled by employing label-free quantitative proteomics methodology (Easy-nLC1000 and Q-exactive). The t-test was applied to identify differentially expressed proteins (DEP, p ≤ 0.05) between RA case and control samples. Gene Ontology enrichment analyses and Protein-Protein Interaction analyses were performed to annotate functions of DEPs. The selected DEP was validated in independent samples using Simple Western assay. Plasma protein level of α2 component of integrin (ITGA2) was measured by using ELISA. The DEP, ITGA2, was assessed for its effects on T cell proliferation, cell cycle, apoptosis, and inflammatory cytokine expression. RESULTS: Sixty-four DEPs (p < 0.05) were identified in PBMCs. The selected ITGA2 (Fold Change, FC = 2.20, p = 1.49E-02) was validated to be up-regulated (FC = 12.33, p = 4.90E-2) with RA, and plasma ITGA2 protein level significantly elevated in RA patients vs. controls. Over-expression of ITGA2 could promote proliferation and inhibit apoptosis of Jurkat T cell, and induce IL-8, IFN-γ and TNF-α expression in Jurkat T cells. CONCLUSIONS: ITGA2 protein was significantly over-expressed in PBMCs in RA patients, and affects T cell growth and pro-inflammatory cytokine expression in T cells.
33904676 Association of rs3135500 and rs3135499 Polymorphisms in the MicroRNA-binding Site of Nucle 2021 Apr 17 The nucleotide-binding oligomerization domain 2 (NOD2) is the key regulator of inflammatory responses and has been involved in the pathogenesis of rheumatoid arthritis (RA). Laboratory and in silico evaluations have demonstrated that some polymorphisms in 3'UTR of NOD2 gene could influence the secondary structure of this region and similarly thermodynamic features of hybridization site and finally deregulate the expression of NOD2. In the current study, for the first time, we evaluated the possible association between single nucleotide polymorphisms (SNPs) rs3135500 and rs3135499 in the NOD2 gene with RA risk in the Iranian population. One hundred and fifteen patients with RA and 120 healthy subjects were recruited in this case-control study. Genotyping of rs3135500 and rs3135499 polymorphisms were accomplished using the real‑time polymerase chain reaction high resolution melting (HRM) method. We found a substantial association of AA and AG genotypes in rs3135500 with the risk of RA (AA vs GG; OR=5.547; 95%CI [2.564-11.999]; p<0.001 and AG vs GG; OR=2.179; 95%CI [1.145-4.147]; p=0.017). Moreover, in the patient group, there was a significant relationship between the increased concentration of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) with rs3135500 (A allele) (p<0.05). However, there were no important associations between rs3135499 with the risk of RA (p>0.05). However, we found a noteworthy association of the C allele in rs3135499 with an increased level of CRP in patients (p>0.05). Our findings propose a considerable association between NOD2 polymorphisms with increased risk of RA and disease activity.
33965503 Shield and sword nano-soldiers ameliorate rheumatoid arthritis by multi-stage manipulation 2021 Jul 10 Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel anti-inflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs). The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium. Synergistically, MMP-9, which is secreted by the recruited neutrophils and degrade the main component of articular cartilage, is reduced by the hydrophobic fragment d-α-tocopheryl succinate (TOS), functioning as a sword. In collagen-induced arthritis (CIA) mouse model, LT NPs show significant targeting effect, and exhibit prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. Our work proves that the multi-stage manipulation of neutrophils is feasible and effective, providing a new concept for RA treatment.
34003681 Compensation of Adiponectin-Induced Adenosine Monophosphate-Activated Protein Kinase and p 2021 May Rheumatoid arthritis (RA) is a chronic inflammatory disorder marked by synovitis, ultimately leading to cartilage and bone destruction. In RA, adiponectin levels are increased in serum and synovial fluid. Adiponectin belongs to the adipokines, a group of highly bioactive substances secreted by adipocytes and other cell types. It has been shown to induce the production of proinflammatory and prodestructive factors by human RA synovial fibroblasts (RASF), suggesting a role in the pathophysiology of the disease. Although adenosine monophosphate-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) are known to be involved in adiponectin signaling in RASF, no literature is available about whether the different adiponectin isoforms affect AMPK and p38 MAPK signaling in the same manner. In this study, we elucidated the signaling mechanisms in RASF, activated in response to selective stimulation with the 2 biologically most potent adiponectin isoforms, and possible approaches to inhibit adiponectin-mediated effects in RASF. All adiponectin isoforms induced p38 MAPK and AMPK phosphorylation to various degrees. Blocking AMPK activation increased p38 MAPK phosphorylation, while blocking p38 MAPK activation increased AMPK phosphorylation, both independent of the effect of adiponectin. Neither AMPKα1 nor AMPKα2 knockdown reduced interleukin (IL)-6/IL-8 release. Targeting transforming growth factor-activated kinase 1 (TAK1), a signaling molecule upstream of p38 MAPK, reduced the IL-6/IL-8 release. Taken together, our study showed that, in the case of adiponectin isoforms, inhibiting the p38 MAPK or the AMPK signaling pathway individually is not sufficient, probably due to compensatory interactions between these pathways. TAK1 might provide an alternative approach by ameliorating the proinflammatory effects of adiponectin in RA. Our results do not suggest that targeting individual adiponectin isoforms specifically in RA would provide a benefit over targeting adiponectin as a whole. However, whether targeting individual adiponectin isoforms would allow minimizing the loss of the beneficial effects of adiponectin within the metabolic and cardiovascular system still needs further investigation.