Development of pH-sensitive dextran-based methotrexate nanodrug for rheumatoid arthritis therapy through inhibition of JAK-STAT pathways.

Rheumatoid arthritis (RA) is a chronic and symmetrical autoimmune disease that primarily characterized with articular synovial hyperplasia, joint swelling, cartilage and bone destruction. The in-depth understanding of the role of immune signaling pathway inhibitors provides inspiration for the construction of new and more effective strategy for RA therapy. In this study, by loading methotrexate (MTX) into an acetalated dextran biopolymer, AcDEX, we developed a pH-sensitive, MTX-loaded and molecularly targeted nanodrug MTX@pH-AcDEX NPs) to decrease the toxicity of MTX and simultaneously enhance its therapeutic effect. The resultant MTX@pH-AcDEX NPs showed the spherical morphology and notable pH-responsiveness with high drug loading of 88.32%. As demonstrated in vitro and in vivo, the reduced cytotoxicity of both RAW264.7 cells and LPS-activated RAW264.7 cells treated with MTX@pH-AcDEX NPs was found compared to free MTX. Upon intravenous administration into adjuvant-induced arthritis (AIA) rat model, the nanodrug had potent pharmacokinetic and pharmacodynamic profiles, which can accumulate in RA lesions and release MTX inhibitors for regulating the JAK-STAT pathways. As a result, the MTX@pH-AcDEX NPs achieved the cartilage and bone protective and a better anti-inflammatory effect with negligible systemic toxicity, suggesting the strong potential of safe and effective nanodrug for RA therapy as well as other autoimmune diseases.

Human epididymis protein 4 as a new diagnostic biomarker for rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: This study aimed to evaluate the role of human epididymis protein 4 (HE4) in the diagnosis and determination of the severity of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. METHODS: HE4 levels in peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) samples were determined via electrochemiluminescence immunoassays in 102 RA patients (46 patients with ILD and 56 patients without ILD) and 51 healthy controls (HCs). RESULTS: Serum HE4 levels were significantly higher in RA-ILD patients (141.8±65.92 pmol/l) than those in the RA-no ILD patients (82.67±26.17 pmol/l) and healthy controls (35.72±7.6 pmol/l) (p<0.0001). Consistent with serum HE4 levels, BALF HE4 levels were significantly higher in RA-ILD patients (637.6±154.9 pmol/l) than those in the RA-no ILD patients (427.3±111.2 pmol/l) and healthy controls (206.9±30.46 pmol/l) (p<0.0001). In RA-ILD patients, HE4 levels were positively correlated with HRCT (high-resolution computed tomography) fibrosis scores, whereas a significant inverse relationship was found between HE4 levels and lung function parameters (such as, diffusion capacity of the lung for carbon monoxide (DLCO)). The logistic regression analysis showed that high levels of BALF HE4 (≥595 pmol/l) were associated with RA-ILD (odds ratio [OR] =8.09; 95% confidence interval [CI] =1.317-49.682; p=0.024). CONCLUSIONS: Serum and BALF HE4 levels were elevated in RA-ILD patients and strongly associated with the severity of ILD, thus supporting their potential clinical value as a new diagnostic aid for patients with RA-ILD.

Factors associated with mortality in rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis.

BACKGROUND: Interstitial lung disease (ILD) is a common and potentially life-threatening complication for rheumatoid arthritis (RA) patients. However, there is a lack of clear prognostic factors in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients. The purpose of this study was to complete a systematic review and meta-analysis of the factors associated with mortality in RA-ILD patients. METHODS: Medline, EMBASE and the Cochrane Library were searched up to September 1, 2020. The Newcastle-Ottawa Scale (NOS) was applied to assess the methodological quality of the eligible studies. Study characteristics and magnitude of effect sizes were extracted. Then, pooled hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) and pooled risk ratios (RRs) with 95% CIs were calculated to assess the factors associated with mortality in RA-ILD. RESULTS: Twenty-three of 3463 articles were eligible, and ten factors associated with mortality for RA-ILD were evaluated in the meta-analysis. Older age (HRs = 1.04, 95% CI 1.03-1.05), male sex (HRs = 1.44, 95% CI 1.21-1.73), having a smoking history (HRs = 1.42, 95% CI 1.03-1.96), lower diffusing capacity of the lung for carbon monoxide (DLCO)% predicted (HRs = 0.98, 95% CI 0.97-1.00), forced vital capacity (FVC)% predicted (HRs = 0.99, 95% CI 0.98-1.00), composite physiological index (CPI) (HRs = 1.04, 95% CI 1.02-1.06), usual interstitial pneumonia (UIP) pattern on HRCT (HRs = 1.88, 95% CI 1.14-3.10 and RRs = 1.90, 95% CI 1.50-2.39), emphysema presence (HRs = 2.31, 95% CI 1.58-3.39), and acute exacerbation of ILD (HRs = 2.70, 95% CI 1.67-4.36) were associated with increased mortality in RA-ILD, whereas rheumatoid factor (RF) positive status was not associated. CONCLUSIONS: Through this systematic review and meta-analysis, we found that older age, male sex, smoking history, higher CPI, lower DLCO% predicted, lower FVC% predicted, UIP pattern on HRCT, emphysema presence and acute exacerbation of ILD were associated with an increased risk of mortality in RA-ILD.

Propofol Inhibits Proliferation and Invasion of Stomach Cancer Cells by Regulating miR-205/YAP1 Axis.

BACKGROUND: Propofol is a common clinical intravenous anesthetic. In the last few years, studies have revealed that propofol not only has good anesthetic effect but also has certain anticancer effect. However, its role in stomach cancer (SC) and related mechanisms are still under investigation. OBJECTIVE: This study was designed to determine the effect of propofol on SC and its related mechanisms. METHODS: Purchased SC cells were treated with propofol at different concentrations (5, 10, and 20 µg/mL), miR-205 overexpression, and YAP1 inhibition. Then, the Cell Counting Kit-8 (CCK8), Transwell, and flow cytometry were carried out to determine the biological behavior changes of treated cells and the expression of miR-205 and YAP1 after treatment. RESULTS: Propofol (10 µg/mL and 20 µg/mL) inhibited the growth of SC cells and promoted their apoptosis, and overexpressing miR-205 or inhibiting YAP1 can exert the same effects. In addition, propofol (10µg/mL and 20µg/mL) up-regulated miR-205 in SC cells. The dual-luciferase reporter assay revealed that YAP1 could be targeted and regulated by miR-205, and the rescue assay revealed that inhibiting miR-205 or overexpressing YAP1 could weaken the effect of propofol on the biological behaviors of SC cells. CONCLUSION: Propofol can strongly suppress the proliferation and invasion of SC cells and induce their apoptosis via the miR-205/YAP1 axis.

Taurine chloramine inhibits osteoclastogenesis and splenic lymphocyte proliferation in mice with collagen-induced arthritis.

Taurine chloramine (TauCl) is produced by activated neutrophils in the inflammatory joint cavities of rheumatoid arthritis and is known to have anti-inflammatory and anti-arthritic effects. However, the mechanisms underlying the anti-arthritic effect of TauCl have not been elucidated. Here, we investigated that mechanism using a collagen-induced arthritis (CIA) mouse model. DBA/1J mice were immunized with bovine type II collagen to induce CIA and were given daily subcutaneous injections of TauCl from the day of first collagen immunization. Severity of arthritis was scored by paw swelling and the arthritis score system. At the 8th week, mice were sacrificed for histological examination using hematoxylin and eosin, safranin-O and tartrate-resistant acid phosphatase (TRAP) staining. Effects of TauCl on osteoclastogenesis from bone marrow-derived preosteoclasts and proliferation of the lymphocytes obtained from spleens of CIA mice were determined. TauCl significantly attenuated the severity of paw swelling and reduced arthritis score in CIA mice. TauCl treated CIA mice showed significant reductions of synovial inflammation, cartilage damage and bone erosion. The number of TRAP-positive cells in the joints of TauCl treated CIA mice was reduced. TauCl inhibited osteoclastogenesis from the RANKL treated bone marrow-derived preosteoclasts in a dose-dependent manner. TauCl also inhibited the proliferation of splenic lymphocytes obtained from CIA mice. In conclusion, TauCl attenuated the severity of CIA by inhibiting lymphocyte proliferation and osteoclastogenesis. Combined our results suggest that TauCl produced endogenously in inflamed joints may suppress the development of rheumatoid arthritis and that TauCl may be used for therapeutic treatment of rheumatoid arthritis.