A pH-Responsive DNA Tetrahedron/Methotrexate Drug Delivery System Used for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that leads to progressive and aggressive joint inflammation. The disease process is characterized by the activation of macrophages, which then release tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), accelerating tissue damage. Tackling tissue damage is a crucial target in the treatment of RA. In this study, a macrophage-targeted and pH-response DNA tetrahedron/methotrexate drug delivery system was constructed by loading methotrexate (MTX) onto a DNA duplex. MTX was used as a drug model, and a pH-response DNA tetrahedron (TET) was used as the drug carrier, which was modified with hyaluronic acid (HA) to target macrophages. The aim of this study was to evaluate the potential of TET as an effective drug carrier for the treatment of RA. On this basis, we successfully prepared TETs loaded with MTX, and in vitro assays showed that the MTX-TET treatment could successfully target macrophages and induce macrophages to polarize to M1 phenotype. At the same time, we also injected MTX-TET intravenously into collagen-induced arthritis (CIA) model mice, and the redness and swelling of the paws of mice were significantly alleviated, proving that the MTX-TET could successfully target inflamed joints and release MTX to treat joint swelling. In addition, the histochemical results showed that the MTX-TET could reduce synovitis and joint swelling in CIA mice, reduce the level of inflammatory factors in vivo, and improve the disease status while maintaining a good biosafety profile. This study showed that the MTX-TET treatment has beneficial therapeutic effects on RA, providing a new strategy for the clinical treatment of RA.

Downregulation of MicroRNA-145-5p in Activated Microglial Exosomes Promotes Astrocyte Proliferation by Removal of Smad3 Inhibition.

In spinal cord injury, microglial activation plays an important role during the inflammatory process. Specifically, the cellular and molecular interactions between microglia and astrocytes are of critical importance. Cells can communicate with each other through the substances carried by exosomes, and overproliferated astrocytes would create a physical and chemical barrier that prevents neurite regeneration, thereby interfering with functional recovery. On the other hand, Smad3 is an important factor in the proliferation, migration, and apoptosis of astrocytes. In this study, supernatant and purified exosomes were collected from LPS-treated microglia and co-cultured with astrocytes. The results showed that astrocytic proliferation was promoted with higher levels of Smad3. Furthermore, miRNA sequencing analysis was performed on microglial exosomes after inflammation. The results revealed a differential expression of miR-145-5p in the exosomes. The Dual-Luciferase assay showed that miR-145-5p could bind to Smad3 mRNA and regulate the levels of Smad3 protein at the post-transcriptional level. Subsequently, exosomes were transfected with miR-145-5p mimics, and astrocytes after mechanical injury were cultured with these exosomes for 24 h. The levels of Smad3 and phosphor-Smad3 proteins were analyzed by western blot and qRT-PCR. CCK8 and flow cytometry showed lower proliferation of astrocytes after co-culturing with the exosomes transfected with the miR-145-5p mimic. This study finds that miR-145-5p was found to be a negative regulator of astrocyte proliferation, and that its downregulation promotes smad3 activity and thus astrocyte proliferation.

[Exosomal microRNAs: an emerging player in systemic lupus erythematosus].

Exosomes are nanometer-sized membranous extracellular vesicles that can be secreted by almost all types of cells in the body. Exosomes are involved in cell-to-cell communication through autocrine and paracrine forms. Exosomal microRNAs (miRNAs) are stable in plasma, urine and other body fluids, and have various biological functions. They play an irreplaceable role in the occurrence, development, immune regulation of systemic lupus erythematosus (SLE). Recent studies have proposed that exosomal miRNAs have promising application prospects in the pathogenesis, early diagnosis, and treatment of SLE. Therefore, this review aims to introduce the current research progress on exosomal miRNAs in SLE and analyze their potential application value.

The Association between the Decreased Expression Levels of FOXJ1 and the Activation of the NF-kB Pathway in Interstitial Lung Disease of MR L/Lpr Mice.

BACKGROUND: Pulmonary manifestations of systemic lupus erythematosus (SLE) are appearing in 4-5% of patients involving lung in almost half of the cases during the disease course. OBJECTIVE: We compared the autoimmune pulmonary inflammation in the lung tissue of mice to determine the association between decreased expression levels of Forkhead Box J1 (FOXJ1) and the activation of the NF-κB pathway in autoimmune pulmonary inflammation of MRL/Lpr mice. METHODS: The female BALB/c mice (n=6) and MRL/Lpr mice (n=30) were divided into 5 groups including a control group (BALB/c), and five MRL/Lpr mice groups (8W, 12W, 16W, 24W, and 32W). The infiltration of the inflammatory cells was determined in lung tissue by performing histological analysis. The western blotting was used to examine the expression levels of the age-related FOXJ1, and p50 and p65 proteins in the lungs of MRL/Lpr mice. The expression levels of MMP2 and MMP9 were determined via immunohistochemistry and immunofluorescence. RESULTS: There were severe infiltrates of lung cells with high levels of tracheal damage, perivascular injury and interstitial inflammatory cell infiltration when the MRL/Lpr mice from 16w to 32w comparing to the 8w old healthy MRL/Lpr mice in the control group (p<0.05). Moreover, the reduced expression levels of FOXJ1 were associated with the activation of the NF-κB pathway in interstitial lung disease of MRL/Lpr mice via the modulation of p50 and p65. In addition, the expression levels of MMP2 and MMP9 pro-inflammation factors increased in the lungs of the MRL/Lpr mice from 16w to 32w. CONCLUSIONS: The expression level of FOXJ1 might be an indicator of the degree of lung disease in lupus-prone mice.

Fatigue and contributing factors in Chinese patients with ankylosing spondylitis.

OBJECTIVES: Fatigue is a common symptom in patients with ankylosing spondylitis (AS). However, fatigue of AS patients has not been well elucidated in China. This study aimed to evaluate the predictors of fatigue and the effects of fatigue on health-related quality of life among patients with AS. METHOD: A total of 150 AS patients were involved in the study. A series of questionnaires included the following: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI), the 10-cm Visual Analog Scale (VAS), the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the Pittsburgh Sleep Quality Index (PSQI), the Health Assessment Questionnaire-Disability Index (HAQ-DI), the Short Form 36 Health Survey (SF-36), and the Fatigue Severity Scale (FSS). Independent samples t test, Mann-Whitney U test, chi-square analysis, Pearson/Spearman correlation, and binary logistic regression were used to analyze the data. RESULTS: The results demonstrated that 48.7% individuals with AS suffered from fatigue. Binary logistic regression indicated that waist-to-hip ratio, BASDAI, and sleep disturbance were independent predictors of fatigue in AS patients. Meanwhile, severe fatigue led to lower quality of life. CONCLUSION: These findings suggested that medical personnel should pay more attention to AS patients with fatigue and take effective measures to relieve fatigue. Key Points • Incidence of fatigue in AS patients is 48.7% according to this cross-sectional study. • The occurrence of fatigue was associated with higher WHR, higher BASDAI, and sleep disturbance. • We also found that the occurrence of fatigue significantly reduced the quality of life in AS patients both physically and psychologically.

Associated factors with adherence to standard exercise therapy and health-related quality of life in Chinese patients with ankylosing spondylitis.

Objectives: The aim of this study is to assess the current situations of standard exercise treatment and predictors of non-standard exercise in Chinese patients with ankylosing spondylitis (AS). An analysis of the effect of standard exercise on health-related quality of life (HR-QoL) was also conducted.Methods: In the cross-sectional study, a total of 259 AS patients were constantly invited to participate in this study and complete the questionnaire under the researchers' supervision in a clinical setting including sociodemographic variables, clinical variables, psychological variables, and HR-QoL. Data were analyzed by Mann-Whitney U test, Chi-square test as well as multivariable analysis of Binary Stepwise Logistic Regression.Results: The data showed that just 20.5% of them could complete the standard exercise. Exercise adherence was associated with employment, educational level, marital status, place of residence, treatment of Tumor Necrosis Factor-α inhibitor, knowledge about exercise, disease duration, clinical variables, and anxiety. The HR-QoL in the group of standard exercise was better than that in the non-standard exercise group. Logistic Regression Analysis showed that lower educational level, less knowledge about benefits of exercise treatment and higher score of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were the independent risk factors of exercise treatment non-adherence.Conclusion: AS patients educated less than 9 years or with higher BASDAI score were more likely not to adhere to standard exercise treatment. Non-adherence to exercise treatment among AS patients is exceedingly common, particularly in patients without knowledge about benefits of exercise treatment. Standard exercise treatment can also improve HR-QoL of AS patients.

Gout and risk of diabetes mellitus: meta-analysis of observational studies.

To determine the prevalence of diabetes mellitus (DM) in people with gout, and investigate the relationship between gout and the occurrence of DM. Systematic review and meta-analysis of epidemiological studies. Data sources: MEDLINE, Web of Science, EMBASE and CINAHL databases, hand-searched reference lists, citation history and contact with authors. Eligibility criteria: cohort, case-control or cross-sectional studies which examined the occurrence of DM amongst adults with gout (with or without gout group) in primary care or general population samples. Prevalence and risk estimate meta-analyses were performed using a random-effects model. A total of 23 identified studies matched the inclusion criteria, reporting on a total of 575 284 gout patients. Meta-analyses revealed that the prevalence of DM in gout patients was 16% (95% CI, 14-18%, I2 = 99.8%) according to clinical interviews. In the subgroup analysis, the prevalence of DM was higher in the female population (18%, 95%CI 2.7-33.3%) than the male population (12.6%, 95%CI 8.2-17.1%). As age increased, the incidence of diabetes in gout population increased. DM is commonly found among patients with gout. Patients with gout should be actively screened for DM and its consequences.