Glucocorticoids promote joint microenvironment alteration of GABBR1 expression associated with mitigating rheumatoid arthritis.

GABBR1 receptors have been implicated in the progression of rheumatoid arthritis (RA), and p38 MAP kinase (MAPK) was shown to be downregulated by GABA and result in unchecked production of pro-inflammatory cytokine. GABBR1 is a member of GABA receptors, and it is known to be upregulated and plays a vital role in RA. Glucocorticoids are efficient therapeutics in rheumatoid arthritis (RA) and are known to regulate GABA actions; therefore, we intended to investigate the potential of glucocorticoids in RA concerning the potential pathway GABBR1/MAPK. Joint specimens were obtained from collagen-induced arthritis mouse model. A double-blind semi-quantitative analysis of vascularity, cell infiltration, as well as lining thickness by help of a 4-point scale setting was used to assess joint inflammation. Expression of GABBR1 and p38 was evaluated immunohistochemically. In vitro peripheral blood (PB), synovial fluid (SF), and mononuclear cells (MCs) were acquired from RA mice. Western blotting was used for detecting expression of GABBR1 and p38 proteins. The presence of high levels of GABBR1 and p38 was prevalent in RA joints relative to healthy joints and related to the inflammation level. Glucocorticoid treatment alters GABBR1 along with p38 protein expression in joints while reducing joint inflammation. Ex vivo and in vitro assays revealed glucocorticoids have a direct impact on p38, such as the decreased GABBR1 expression level after dexamethasone incubation with SFMC. GABBR1 together with p38 expression in RA joints depends on local inflammation and can be targeted by glucocorticoids.

The Association between Leisure-Time Physical Activity Intensity and Duration with the Risk of Mortality in Patients with Chronic Kidney Disease with or without Cardiovascular Diseases.

Introduction: For chronic kidney disease (CKD) patients with or without cardiovascular diseases, the associations between leisure-time physical activity intensity (LTPA) and daily exercise time with mortality risk remain unclear. Method: This study enrolled 3279 CKD patients from National Health and Nutrition Examination Survey (NHANES) 2007-2014 survey. Patients were grouped into different groups according to LTPA intensity (none, moderate, vigorous) and duration (0 min, 0-30 min, 30-60 min, > 60 min). We selected the confounders based on their connections with the outcomes of interest or a change in effect estimate of more than 10%. Multivariable-adjusted Cox proportional hazards models were used to examine the associations between LTPA and mortality. The three-knot cubic spline (10, 50, and 90%) was employed to investigate the relationship between the dose of LTPA duration and all-cause death. Patients were divided into different groups according to cardiovascular diseases (CVD). Results: A total of 564 all-cause death were recorded in this study. Multivariable Cox regression showed that moderate LTPA was associated with a reduced risk of mortality by 38% (hazard ratio (HR): 0.62, 95% confidence interval (CI): 0.44-0.88) in CKD patients, while vigorous LTPA did not have evident survival benefits (HR: 0.91, 95% CI: 0.46-2.64). Subgroups analysis demonstrated that those who engaged in moderate LTPA have a significantly lower risk of mortality (HR: 0.67, 95% CI: 0.47-0.95) in patients without CVD, while patients complicated with CVD did not benefit from the practice (HR: 0.61, 95% CI: 0.37-1.02). Physical exercise for more than 30 minutes was associated with a lower risk of mortality in general CKD patients (30-60 min: HR: 0.23, 95% CI: 0.09-0.58, > 60 min: HR: 0.23, 95% CI: 0.08-0.63) and those without CVD (30-60 min/d: HR: 0.32, 95% CI: 0.12-0.83, > 60 min/d: HR: 0.20, 95% CI: 0.06-0.71); however, this positive outcome was not seen in patients complicated with CVD (30-60 min/d: HR: 0.67, 95% CI: 0.11-4.04, > 60 min/d: HR: 1.14, 95% CI: 0.14-9.11). Conclusions: Moderate LTPA for more than 30 minutes is associated with a reduced risk of mortality in general CKD patients and those without CVD. However, LTPA did not reduce the risk of mortality in CKD patients complicated with CVD.