scholarly journals Dissecting the Molecular Mechanism of Wang-Bi Capsule in the Treatment of Experimental Rheumatoid Arthritis Based on Synovial Tissue Proteomic Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Haiyang Shu ◽  
Yingjie Shi ◽  
Li Li ◽  
Ning Zhao ◽  
Cheng Lu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Tissue ◽  
Proteomic Analysis ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Serum Levels ◽  
Expression Levels ◽  
Matrix Metalloproteinase 3 ◽  
Cxcr4 Signaling ◽  
Wang Bi

Wang-Bi capsule (WB) is a traditional Chinese medicine formula and has been applied for rheumatoid arthritis (RA) treatment for many years. However, its underlying molecular mechanisms still remain unclear. In this study, collagen-induced arthritis (CIA) rats were used to observe the therapeutic effect of WB used at different time points, and the proteomic analysis of synovial tissue was applied to reveal its basic molecular mechanisms. The results demonstrated that WB not only effectively ameliorated the symptoms and synovitis, but also downregulated the serum levels of inflammatory cytokines/chemokines in CIA rats. Furthermore, the proteomic analysis of synovial tissue showed that WB could regulate several signaling pathways associated with inflammation or cell migration, such as “IL-1 signaling,” “IL-8 signaling,” and “CXCR4 signaling.” The expression levels of proteins including matrix metalloproteinase 3 (MMP3), MMP19, lipopolysaccharide-binding protein (LBP), serine/threonine kinase interleukin-1 receptor-associated kinase 4 (IRAK4), and actin-related protein 2/3 complex subunit 5 (ARPC5) in these pathways were downregulated significantly by WB when compared with the model group. In sum, this study indicated that WB had obvious inhibitory effects on synovitis of CIA rats, and the mechanisms of which may be involved in downregulating the expression levels of several key proteins including MMP3, MMP19, LBP, IRAK4, and ARPC5.

scholarly journals Effect of Moxibustion on the Serum Levels of MMP-1, MMP-3, and VEGF in Patients with Rheumatoid Arthritis

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Zeyun Yu ◽  
Yingni Wang ◽  
Yuan Li ◽  
Chenxi Liao ◽  
Jingyang Dai ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Group ◽  
Matrix Metalloproteinase ◽  
Clinical Symptoms ◽  
Interleukin 1 ◽  
Serum Levels ◽  
Control Group ◽  
Matrix Metalloproteinase 3 ◽  
Disease Markers ◽  
Matrix Metalloproteinase 1

Background. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, which will eventually lead to joints deformity and functional damage. The aim of this research is to evaluate the effect of moxibustion on the serum indicators related to bone and cartilage metabolism, matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase 3 (MMP-3), and vascular endothelial growth factor (VEGF) in patients with RA and to explore the mechanism of moxibustion in the treatment of RA. Methods. We recruited 70 RA patients who met the inclusion criteria, and they were randomly divided into two groups, a treatment group and a control group in equal ratio. The control group took methotrexate, folate, or leflunomide orally, while the treatment group received methotrexate, folate, or leflunomide orally and moxibustion at ST36 (Zusanli), BL23 (Shen shu), and Ashi points. We compared the clinical symptoms, RA serological disease markers and serum contents of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), MMP-1, MMP-3, and VEGF of RA patients before and after treatment. Results. (1) The clinical symptoms and RA serological disease markers of the two groups improved after treatment (P < 0.05), while the clinical symptoms of the treatment group were significantly improved in comparison with the control group (P < 0.05). (2) The levels of IL-1β, TNF-α, and VEGF decreased in both groups after treatment (P < 0.05), but the treatment group was significantly decreased compared with the control group (P < 0.05). (3) There were significant differences in MMP-1 and MMP-3 contents after treatment in the treatment group (P < 0.05, P < 0.05), while there were no significant differences in the control group (P > 0.05, P > 0.05). Above all, the contents of IL-1β, TNF-α, MMP-1, MMP-3, and VEGF in the treatment group decreased more significantly than those in the control group (P < 0.05). Conclusion. The improvement effect of moxibustion on the clinical symptoms of RA patients may be related to influence on the contents of IL-1β, TNF-α, MMP-1, MMP-3, and VEGF, and moxibustion may play a potential role in bone protection.

scholarly journals Vitamin D as a Principal Factor in Mediating Rheumatoid Arthritis-Derived Immune Response

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Muhammad M. Aslam ◽  
Peter John ◽  
Attya Bhatti ◽  
Sidrah Jahangir ◽  
M. I. Kamboh
Keyword(s):  
Rheumatoid Arthritis ◽  
Vitamin D ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Genetic Factors ◽  
Autoimmune Disorder ◽  
Serum Levels ◽  
Principal Factor ◽  
Phosphate Homeostasis ◽  
Low Serum

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

scholarly journals Clinical Significance of Serum Levels of ROM (Reactive Oxygen Metabolites) in Patients With Rheumatoid Arthritis Treated With Biologic Agents as a Predictor for the CDAI-, SDAI-, and Boolean-Remission

2021 ◽  
Author(s):  
Arata Nakajima ◽  
Keiichiro Terayama ◽  
Masato Sonobe ◽  
Yorikazu Akatsu ◽  
Junya Saito ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Health Assessment ◽  
Multivariate Logistic Regression Analysis ◽  
Reactive Oxygen ◽  
Serum Levels ◽  
Current Treatment ◽  
Biologic Agents ◽  
Reactive Oxygen Metabolites ◽  
Matrix Metalloproteinase 3 ◽  
Oxygen Metabolites

Abstract We previously showed that reactive oxygen metabolites (ROM) serum levels were associated with the DAS28 in patients with rheumatoid arthritis (RA). In this study, we aimed to investigate whether ROM would be predictive of the CDAI-, SDAI- or Boolean-remission. Fifty-one biologic agents (BA)-naïve RA patients were included in this observational study. Associations between ROM, C-reactive protein (CRP), MMP (matrix metalloproteinase)-3, DAS28-ESR, CDAI, SDAI, and health assessment questionnaire (HAQ) at 12 weeks and the DAS28-, CDAI-, SDAI-, and Boolean-remission at 52 weeks were investigated. The DAS28-, CDAI-, SDAI- and Boolean-remission rates at 52 weeks were 66.7, 52.9, 54.9 and 54.9%, respectively. A multivariate logistic regression analysis revealed that ROM and HAQ at 12 weeks were associated with the CDAI-, SDAI- and Boolean-remission at 52 weeks. Receiver operating characteristic (ROC) analyses demonstrated that the cut-off value for CDAI remission was 389.5 U.Carr, and that for SDAI and Boolean remission was 389.5 U.Carr. ROM at 12 weeks of initial treatment with BAs was a predictor for the CDAI-, SDAI-, and Boolean-remission at 52 weeks. Serum levels of ROM may be a useful biomarker in the current treatment strategy aiming at the early remission of RA.

scholarly journals Association of interleukin-18 expression with enhanced levels of both interleukin-1? and tumor necrosis factor ? in knee synovial tissue of patients with rheumatoid arthritis

2003 ◽  
Vol 48 (2) ◽  
pp. 339-347 ◽  
Author(s):  
Leo A. B. Joosten ◽  
Timothy R. D. Radstake ◽  
Erik Lubberts ◽  
Liduine A. M. van den Bersselaar ◽  
Piet L. C. M. van Riel ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor ◽  
Synovial Tissue ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Interleukin 18 ◽  
Necrosis Factor

scholarly journals The Autophagy Level Is Increased in the Synovial Tissues of Patients with Active Rheumatoid Arthritis and Is Correlated with Disease Severity

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Li Zhu ◽  
Huaizhou Wang ◽  
Yu Wu ◽  
Zhengwen He ◽  
Yanghua Qin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Tissue ◽  
Active Rheumatoid Arthritis ◽  
Synovial Fibroblasts ◽  
Serum Levels ◽  
Serum Markers ◽  
Effector Cells ◽  
Joint Replacement Surgery ◽  
Replacement Surgery ◽  
Synovial Tissues

Rheumatoid arthritis (RA) is a complex and not fully understood autoimmune disease associated with multijoint damage. The main effector cells, the synovial fibroblasts, are apoptosis resistant and hyperplastic which indicate that autophagy level is high in synovial tissue. Real-time PCR, immunocytochemistry, and western blotting were used in this paper to study the autophagy status of the synovial tissues obtained from RA and OA patients at the time of joint replacement surgery. We further evaluated the correlation between autophagy levels with RA activity-associated serum markers with SPSS. The results showed that the expression levels (both in mRNA and in protein level) of autophagy-related proteins (belcin1, Atg5, and LC3) in the synovial tissue of patients with active rheumatoid arthritis (n=20) were significantly higher than those in OA patients (n=16). We further showed that the LC3-II/β-actin relative gray value was strongly correlated with the serum levels of several RA activity-related markers: CRP, ESR, CCP, and RF. Our results indicate that evaluating the autophagy level of synovial biopsies might be a useful way to diagnose RA and to estimate the disease activity. Reducing the expression level of autophagy-related genes might become a new therapeutic target for active rheumatoid arthritis.

Biomarkers in Remission According to Different Criteria in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 42 (11) ◽  
pp. 2066-2070 ◽  
Author(s):  
Sibel Yilmaz-Oner ◽  
Gulsen Ozen ◽  
Meryem Can ◽  
Pamir Atagunduz ◽  
Haner Direskeneli ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Type I Collagen ◽  
Activity Index ◽  
Disease Activity Index ◽  
Type Ii Collagen ◽  
Serum Levels ◽  
Type I ◽  
Matrix Metalloproteinase 3 ◽  
Das28 Remission

Objective.Remission is the primary aim in the treatment of patients with rheumatoid arthritis (RA). In this study, we aimed to evaluate biomarker profiles of patients in remission by different criteria and compare these profiles with controls.Methods.Serum levels of calprotectin, interleukin 6 (IL-6), type II collagen helical peptide, C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases (ICTP), matrix metalloproteinase 3 (MMP-3), resistin, and leptin were measured by ELISA in 80 patients. The patients were in Disease Activity Score at 28 joints with erythrocyte sedimentation rate (DAS28-ESR) remission, and had these characteristics: female/male 54/26, mean age 51.4 ± 12.1 years, mean disease duration 11.4 ± 8.1 years, rheumatoid factor positivity 68.7% (n = 55), anticyclic citrullinated peptide positivity 60.7% (n = 48). These patients were also evaluated for the American College of Rheumatology/European League Against Rheumatism (Boolean) and Simple Disease Activity Index (SDAI) remissions. Additionally, 80 age-, sex-, and comorbidity-matched individuals without rheumatic diseases were included in the study as controls.Results.At recruitment of 80 patients in DAS28 remission, 33 patients (41.2%) were found in Boolean remission and 39 patients (48.7%) were in SDAI remission. Serum MMP-3, ICTP, resistin, and IL-6 levels of the 80 patients in DAS28 remission were statistically significantly higher than the controls. Patients in Boolean and SDAI remissions had significantly higher serum ICTP, resistin, and IL-6 levels in comparison with the controls.Conclusion.The 3 commonly used remission criteria of RA are almost similar with regard to patients’ biomarker levels. Biomarker profiles of patients may provide complementary information to clinical evaluation of remission and may help to determine the patients under the risk of progression.

scholarly journals IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating of immunogenic hinge epitopes.

2020 ◽  
Author(s):  
Toshiyuki Ota ◽  
Shun-ichiro Ota ◽  
Ayumi Uchino ◽  
Shuji Nagano
Keyword(s):  
Rheumatoid Arthritis ◽  
Multivariate Logistic Regression Analysis ◽  
High Specificity ◽  
Serum Levels ◽  
Diagnostic Utility ◽  
Cumulative Number ◽  
Matrix Metalloproteinase 3 ◽  
Cutoff Values ◽  
Independent Variable ◽  
Inhibition Studies

Abstract Background. Pepsin agglutinators, discovered over 50 years ago, have been recently referred to as anti-hinge antibodies (AHAs) because of their reaction with the IgG hinge epitope. AHAs have different reactivity for each hinge epitope generated by each protease that cleaves the hinge region at different sites. Moreover, AHAs have different reactivity against different hinge epitopes derived from each IgG subclass even when the same protease is used. Since the expression of matrix metalloproteinase-3 (MMP-3) is enhanced in rheumatoid arthritis (RA), AHA production could also be increased. The purpose of this study was to determine whether the levels of AHAs against IgG hinge epitopes produced by MMP-3 are elevated in RA.Methods. The serum levels of IgG or IgA AHAs against the IgG1/IgG4 F(ab’)2 fragments, generated by either MMP-3 or pepsin, was measured using ELISA in 111 patients with RA and 81 healthy controls (HC). Receiver operating characteristic (ROC) analysis was used for obtaining optimal cutoff values and cutoff values indicating high specificity (>95%) of the AHA. The targeted epitope of a specific AHA was investigated through inhibition ELISA. Results. Seven AHAs were statistically higher in RA patients than HC, except IgG AHA against IgG1 F(ab’)2, which was generated by MMP-3 proteolytic cleavage. The areas under the ROC curve were of 0.66--0.80, although the sensitivities at high specificity were low (5.4--24.3%). The cumulative number of positive AHAs in each individual was statistically higher in RA patients than HC, suggesting the extreme extent of AHA repertoires in RA. Inhibition studies revealed that IgG AHAs against IgG4 F(ab’)2 fragments generated by pepsin cross-reacted with IgG1 F(ab’)2 fragments generated by pepsin. Multivariate logistic regression analysis identified the IgG AHA against IgG4 F(ab’)2 fragments generated by pepsin as an independent variable for RA diagnosis, even in RA patients who were negative for both RF and ACPA (odds ratio 1.18, 95% CI: 1.06−1.32; P=0.003). Additional experiments using non-RA patients finally strengthened the diagnostic utility.Conclusion. In RA patients, we observed diversification and amplification of AHA repertoires and diagnostic utility of the specific AHA against IgG4 F(ab’)2 fragments generated by pepsin but not MMP-3.

scholarly journals IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating of immunogenic hinge epitopes.

2020 ◽  
Author(s):  
Toshiyuki Ota ◽  
Shun-ichiro Ota ◽  
Ayumi Uchino ◽  
Shuji Nagano
Keyword(s):  
Rheumatoid Arthritis ◽  
Operating Characteristic ◽  
Multivariate Logistic Regression Analysis ◽  
High Specificity ◽  
Serum Levels ◽  
Cumulative Number ◽  
Matrix Metalloproteinase 3 ◽  
Cutoff Values ◽  
Independent Variable ◽  
Inhibition Studies

Abstract Background Pepsin agglutinators, discovered over 50 years ago, have been recently referred to as anti-hinge antibodies (AHAs) because of their reaction with the IgG hinge epitope. AHAs have different reactivity for each hinge epitope generated by each protease that cleaves the hinge region at different sites. Moreover, AHAs have different reactivity against different hinge epitopes derived from each IgG subclass even when the same protease is used. Since the expression of matrix metalloproteinase-3 (MMP-3) is enhanced in rheumatoid arthritis (RA), AHA production could also be increased. The purpose of this study was to determine whether the levels of AHAs against IgG hinge epitopes produced by MMP-3 are elevated in RA. Methods The serum levels of IgG or IgA AHAs against the IgG1/IgG4 F(ab’) 2 fragments, generated by either MMP-3 or pepsin, was measured using ELISA in 111 patients with RA and 81 healthy controls (HC). Receiver operating characteristic (ROC) analysis was used for obtaining optimal cutoff values and cutoff values indicating high specificity (>95%) of the AHA. The targeted epitope of a specific AHA was investigated through inhibition ELISA. Results Seven AHAs were statistically higher in RA patients than HC, except IgG AHA against IgG1 F(ab’) 2 , which was generated by MMP-3 proteolytic cleavage. The areas under the ROC curve were of 0.66--0.80, although the sensitivities at high specificity were low (5.4--24.3%). The cumulative number of positive AHAs in each individual was statistically higher in RA patients than HC, suggesting the extreme extent of AHA repertoires in RA. Inhibition studies revealed that IgG AHAs against IgG4 F(ab’) 2 fragments generated by pepsin cross-reacted with IgG1 F(ab’) 2 fragments generated by pepsin. Although the development of IgA AHAs in RA seems to be remarkable and specific, multivariate logistic regression analysis identified the IgG AHA against IgG4 F(ab’) 2 fragments generated by pepsin as an independent variable for RA diagnosis, even in RA patients who were negative for both RF and ACPA (odds ratio 1.18, 95% CI: 1.06−1.32; P =0.003).Conclusion In RA patients, we observed diversification and amplification of AHA repertoires and diagnostic utility of the specific AHA against IgG4 F(ab’) 2 fragments generated by pepsin but not MMP-3.

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