Treg细胞抑制基质金属蛋白酶-9对类风湿性关节炎伴急性脑缺血损伤的研究进展

近些年的研究相继发现类风湿性关节炎（rheumatoid arthritis,RA）患者较健康人群更易得急性脑缺血等心脑血管疾病,RA的发生也会进一步加重急性脑缺血的发展。其中,基质金属蛋白酶-9（matrix metaloproteinase-9,MMP-9）可降解细胞外基质,破坏血脑屏障,引发炎性细胞和致炎因子等浸润,对构建脑缺血后炎性反应的级联放大网络起到重要作用。Treg细胞,即调节性T细胞（ regulatory T cells ）,作为免疫抑制性细胞可多途径抑制MMP-9的活性,从而治疗急性脑缺血,缓解RA症状：（1）Treg细胞可通过负反馈阻断NF-κB通路,抑制MMP-9的活性;（2）Treg细胞可调控转化生长因子-β1（transforming growth factor-β1,TGF-β1)和肿瘤坏死因子(tumor necrosis factor-α,TNF-α)的表达抑制MMP-9的转录;（3）Treg细胞可通过转化急性脑缺血后被激活的小胶质细胞/巨噬细胞的极化类型,抑制小胶质细胞/巨噬细胞对MMP-9的促分泌作用,加强M2型小胶质细胞/巨噬细胞的免疫耐受;（4）Treg细胞可释放抑炎因子,拮抗致炎性的Th17细胞,平衡体内免疫,缓解RA和急性脑缺血所引发的炎症等。本文综述Treg细胞在RA合并急性脑缺血中通过抑制MMP-9的活性等起治疗作用,旨在为类风湿性关节炎合并急性脑缺血的有效治疗和研究提供参考。     

E26 Transformation-Specific-1 (ETS1) and WDFY Family Member 4 (WDFY4) Polymorphisms in Chinese Patients with Rheumatoid Arthritis

E26 transformation-specific-1 (ETS1) and WDFY family member 4 (WDFY4) are closely related with systemic lupus erythematosus. We hypothesized that ETS1 and WDFY4 polymorphisms may contribute to rheumatoid arthritis (RA) susceptibility. We studied ETS1 rs1128334 G/A and WDFY4 rs7097397 A/G gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. When the WDFY4 rs7097397 AA homozygote genotype was used as the reference group, the AG genotype was associated with a significantly increased risk for RA. In the dominant model, when the WDFY4 rs7097397 AA homozygote genotype was used as the reference group, the AG/GG genotypes were associated with a significant increased susceptibility to RA. In stratification analyses, a significantly increased risk for RA associated with the WDFY4 rs7097397 AG genotype was evident among female patients, younger patients, C-reactive protein (CRP) negative patients and both anti-cyclic citrullinated peptide antibody (ACPA) positive patients and negative patients compared with the WDFY4 rs7097397 AA genotype. These findings suggested that WDFY4 rs7097397 A/G may be associated with the risk of RA, especially among younger, female patients, CRP-negative patients and both ACPA positive and negative patients. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. To confirm these findings, validation by a larger study from a more diverse ethnic population is needed.     

Design and development of bioinspired calcium phosphate nanoparticles of MTX: pharmacodynamic and pharmacokinetic evaluation

The aim of this investigation is the management of rheumatoid arthritis (RA) by developing methotrexate-loaded calcium phosphate nanoparticles (MTX-CAP-NP) and to evaluate pharmacokinetic and pharmacodynamic behavior in adjuvant induced arthritis model. The nanoparticles were synthesized by wet precipitation method and optimized by Box-Behnken experimental design. MTX-CAP-NPs were characterized by TEM, FTIR, DSC and XRD studies. The particle size, zeta potential and entrapment efficiency of the optimized nanoparticles were found to be 204.90?±?64?nm, ?11.58?±?4.80?mV, and 88.33?±?3.74%, respectively. TEM, FTIR, DSC and XRD studies revealed that the developed nanoparticles were nearly spherical in shape and the crystalline structure of CAP-NP was not changed after MTX loading. The pharmacokinetic studies revealed that MTX-CAP-NP enhanced bioavailability of MTX by 2.6-fold when compared to marketed formulation (FOLITRAX-10). Under pharmacodynamic evaluation, arthritic assessment, radiography and histopathology studies revealed that CAP has ability to regenerate cartilage and bone therefore, together with MTX, MTX-CAP-NPs have shown significant reduction in disease progression. The overall work demonstrated that the developed nanodelivery system was well tolerated and more effective than the marketed formulation.     

Folate-conjugated albumin nanoparticles for rheumatoid arthritis-targeted delivery of etoricoxib

Objective: The present study discusses folic acid-etoricoxib-bovine serum albumin nanoparticles (F-ETX-NPs) using folic acid as an over expressed folate receptor ligand for activated macrophages in targeting of rheumatoid arthritis.

Materials and methods: For this purpose etoricoxib-loaded BSA nanoparticles (ETX-NPs) were prepared by desolvation method and activated folic acid conjugation with free amine group of BSA was confirmed by FTIR study and zeta potential measurements.

Results: The F-ETX-NPs showed spherical in shape with 215.8?±?3.2?nm average size?+?7.8?mV zeta potential, 72?±?1.3% etoricoxib entrapment efficiency and showed 93.1?±?2.2% cumulative etoricoxib release upto 72?h. The etoricoxib concentration from F-ETX-NPs was found to be 9.67?±?0.34?µg/g in inflamed joint after 24?h administration revealed remarkably targeting potential to the activated macrophages cells and keep at a high level during the experiment.

Discussion and conclusion: These results suggest that F-ETX-NPs are potentially vector for activated macrophages cells targeting of rheumatoid arthritis.     

Long-term sustained-released in situ gels of a water-insoluble drug amphotericin B for mycotic arthritis intra-articular administration: preparation,in vitro and in vivo evaluation

Amphotericin B (AMB) was often used in intra-articular injection administration for fungal arthritis, because it could often bring a satisfactory therapeutic efficacy and a minimum systemic toxic side effect. However, because of the multiple operations and the frequent injections, the compliance of the patients was bad. Therefore, to develop a long-term sustained-released preparation of AMB for mycotic arthritis intra-articular administration is of great significance. The purpose of present study was to develop a long-term sustained-released in situ gel of a water-insoluble drug AMB for mycotic arthritis intra-articular administration. Based on the evaluations of the in vitro properties of the formulations, the formulation containing 10% (w/w) ethanol, 15% (w/w) PG, 0.75% (w/w) HA, 5% (w/w) purified soybean oil, 0.03% (w/w) α-tocopherol, 15% (w/w) water and 55% (w/w) glyceryl monooleate was selected as a suitable intra-articular injectable in situ gel drug delivery system for water-insoluble drug AMB. Furthermore, the results of the in vivo study on rabbits showed that the selected formulation was a safe and effective long-term sustained-released intra-articular injectable AMB preparation. Therefore, the presented in situ AMB gel could reduce the frequency of the administration in the AMB treatment of fungal arthritis, and then would get a good patient compliance.     

Development of a shortened center for epidemiological studies depression scale for assessment of depression in rheumatoid arthritis.

Objective: The purpose was to develop a short-form version of the Center for Epidemiologic Studies Depression Scale (CES-D) for the identification of persons with major depressive disorder (MDD) within a population with rheumatoid arthritis (RA). Study Design: Data were analyzed from 337 persons with RA. Forty-six participants met the diagnostic criteria for MDD; 291 participants were classified in the non-MDD category (including 21 participants with dysthymia and 18 participants with minor depressive disorder). A short-form version of the CES-D was developed, and multiple cutoff scores were examined. Results: A cutoff score of ≥5 from a 9-item, short-form CES-D was found to be generally as efficient as the more commonly used full-scale cutoff score of ≥16 for classifying participants with MDD within an RA population. Although the shortened CES-D scale (cutoff score ≥5) was slightly more sensitive, it also exhibited slightly less specificity than the full-scale cutoff score of ≥16. Conclusion: The results suggest that a short-form CES-D can be used to screen for MDD within an RA sample with a degree of efficiency that is generally comparable to that of the full-scale instrument. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adjuvant properties of a biocompatible thermo-responsive polymer of N-isopropylacrylamide in autoimmunity and arthritis

To evaluate the thermo-responsive poly(N-isopropylacrylamide) (PNiPAAm) polymer as an adjuvant, we synthesized PNiPAAm through free radical polymerization and characterized it both in vitro and in vivo. The polymer when mixed with collagen type II (CII) induced antigen-specific autoimmunity and arthritis. Mice immunized with PNiPAAm–CII developed significant levels of CII-specific IgG response comprising major IgG subclasses. Antigen-specific cellular recall response was also enhanced in these mice, while negligible level of IFN-γ was detected in splenocyte cultures, in vitro. PNiPAAm–CII-immunized arthritic mouse paws showed massive infiltration of immune cells and extensive damage to cartilage and bone. As determined by immunostaining, most of the CII protein retained its native configuration after injecting it with PNiPAAm in naive mice. Physical adsorption of CII and the high-molecular-weight form of moderately hydrophobic PNiPAAm induced a significant anti-CII antibody response. Similar to CII, mice immunized with PNiPAAm and ovalbumin (PNiPAAm–Ova) induced significant anti-ovalbumin antibody response. Comparable levels of serum IFN-γ, IL-1β and IL-17 were observed in ovalbumin-immunized mice with complete Freund, incomplete Freund (CFA and IFA) or PNiPAAm adjuvants. However, serum IL-4 levels were significantly higher in PNiPAAm–Ova and CFA–Ova groups compared with the IFA–Ova group. Thus, we show for the first time, biocompatible and biodegradable thermo-responsive PNiPAAm can be used as an adjuvant in several immunological applications as well as in better understanding of the autoimmune responses against self-proteins.     

A Longitudinal Examination of Causal Attributions and Depression Symptomatology in Rheumatoid Arthritis.

Objective: Examine longitudinal relationships between causal attributions and depression symptoms in adults with rheumatoid arthritis (RA). Study Design: Cross-lagged panel correlations tested the temporal precedence of attributions relative to depression symptoms over 1 year. Participants: Forty-two participants completed self-report instruments on 2 occasions. Main Outcome Measures: The Inventory to Diagnose Depression and the Attributional Style Questionnaire. Results: Time 1 attributions predicted increased levels of depression symptoms at Time 2 after perceived pain and disability were controlled: Time 1 depression symptoms were unrelated to Time 2 attributions. Cross-lagged correlation comparisons revealed statistical dominance for attribution-depression relationships relative to depression-attribution relationships. Conclusions: Results support cognitive diathesis conceptualizations of depression and support cognitive-behavioral treatments for depression in RA. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Vulnerability and resilience in women with arthritis: Test of a two-factor model.

The purpose of this study was to test a 2-factor model of affective health in women with rheumatoid arthritis (RA; n = 82) or osteoarthritis (OA; n = 88). Positive and negative social interactions and affect were assessed for 11 consecutive weeks. For each participant, Vulnerability and Resilience factors were created from factor analyses of positive and negative personal characteristics, respectively. Multilevel analyses tested the hypothesis that weekly changes in social interactions or affect would only be predicted by the factor of the same valence. The Vulnerability (and not the Resilience) factor predicted changes in negative interactions. The Resilience (and not the Vulnerability) factor predicted changes in positive interactions. The Vulnerability (and not the Resilience) factor predicted changes in current and next-week negative affect. The Resilience and Vulnerability factors each predicted changes in current and next-week positive affect, although the effects for Vulnerability were smaller than for Resilience. Finally, the Vulnerability factor interacted with pain to predict more future negative affect. The main implication is that both Vulnerability and Resilience should be considered in theory, research, and interventions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)