Summersdonnelly0077

Osteoarthritis (OA) is a common disease characterized by cartilage degeneration. In recent years much attention has been paid to Traditional Chinese Medicine (TCM) since its treatments have shown efficacy for ameliorating cartilage degradation with mild side effects. Osteoking is a TCM prescription that has long been used in OA treatment. However, the exact mechanism of Osteoking are not fully elucidated. In the current study, destabilization of the medial meniscus (DMM)-induced OA mice was introduced as a wild type animal model. After 8 weeks of administration of Osteoking, histomorphometry, OARSI scoring, gait analysis, micro-CT, and immunohistochemical staining for Col2, MMP-13, TGFβRII and pSmad-2 were conducted to evaluate the chondroprotective effects of Osteoking in vivo. Further in vitro experiments were then performed to detect the effect of Osteoking on chondrocytes. TGFβRIICol2ER transgenic mice were constructed and introduced in the current study to validate whether Osteoking exerts its anti-OA effects via the TGF-β signaling pathway. Results demonstrated that in wild type DMM mice, Osteoking ameliorated OA-phenotype including cartilage degradation, subchondral bone sclerosis, and gait abnormality. Col2, TGFβRII, and pSmad-2 expressions were also found to be up-regulated after Osteoking treatment, while MMP-13 was down-regulated. In vitro, the mRNA expression of MMP-13 and ADAMTS5 decreased and the mRNA expression of Aggrecan, COL2, and TGFβRII were up-regulated after the treatment of Osteoking in IL-1β treated chondrocytes. The additional treatment of SB505124 counteracted the positive impact of Osteoking on primary chondrocytes. In TGFβRIICol2ER mice, spontaneous OA-liked phenotype was observed and treatment of Osteoking failed to reverse the OA spontaneous progression. In conclusion, Osteoking ameliorates OA progression by decelerating cartilage degradation and alleviating subchondral bone sclerosis partly via the TGF-β signaling pathway.As a well-known multimodal-acting antidepressant, vortioxetine is thought to aim at several serotonin (5-HT) receptors and the 5-HT transporter. However, recently more and more proteins besides 5-HT are being reported to participate in the antidepressant mechanism of vortioxetine. As a widely known nuclear hormone receptor, peroxisome proliferator activated receptor α (PPARα) possesses transcriptional activity and is very important in the brain. Several reports have suggested that hippocampal PPARα is implicated in antidepressant responses. Here we speculate that hippocampal PPARα may participate in the antidepressant mechanism of vortioxetine. In this study, chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), behavioral tests, the western blotting and adenovirus associated virus (AAV)-mediated gene knockdown methods were used together. It was found that vortioxetine administration significantly reversed the inhibitory actions of both CUMS and CSDS on the hippocampal PPARα expression. Pharmacological blockade of PPARα notably prevented the antidepressant actions of vortioxetine in the CUMS and CSDS models. Moreover, genetic knockdown of PPARα in the hippocampus also significantly blocked the protecting effects of vortioxetine against both CUMS and CSDS. Therefore, the antidepressant effects of vortioxetine in mice require hippocampal PPARα.Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically "predictive" the expected response is based on stratification according to clinical, imaging, and laboratory data, with a "heuristic" approach based on "trial and error". Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially "broad-spectrum" mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g.,he field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules toward a patient-centered approach.Extracellular ATP and its ultimate degradation product adenosine are potent extracellular signaling molecules that elicit a variety of pathophysiological pathways in retina through the activation of P2 and P1 purinoceptors, respectively. Excessive build-up of extracellular ATP accelerates pathologic responses in retinal diseases, whereas accumulation of adenosine protects retinal cells against degeneration or inflammation. This mini-review focuses on the roles of ATP and adenosine in three types of blinding diseases including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Several agonists and antagonists of ATP receptors and adenosine receptors (ARs) have been developed for the potential treatment of glaucoma, DR and AMD antagonists of P2X7 receptor (P2X7R) (BBG, MRS2540) prevent ATP-induced neuronal apoptosis in glaucoma, DR, and AMD; A1 receptor (A1R) agonists (INO-8875) lower intraocular pressure in glaucoma; A2A receptor (A2AR) agonists (CGS21680) or antagonists (SCH58261, ZM241385) reduce neuroinflammation in glaucoma, DR, and AMD; A3 receptor (A3R) agonists (2-Cl-lB-MECA, MRS3558) protect retinal ganglion cells (RGCs) from apoptosis in glaucoma.Background Low-dose prescription of rivaroxaban was common among patients with atrial fibrillation (AF) in Asia. However, the benefits and harms of rivaroxaban at a low dosage in Asian patients with AF remains unclear. Accordingly, we aimed to collect and summarize all available evidence to fill this important knowledge gap. Methods In this systematic review and meta-analysis, we systematically searched databases of MEDLINE, EMBASE, and Cochrane Library for relevant studies from inception until February 23, 2021. Eligible retrospective nationwide or health insurance database studies or prospective registration studies that reported efficacy (stroke/systemic embolism), safety (major bleeding, intracranial hemorrhage, gastrointestinal bleeding), or other outcomes (myocardial infarction, death) of low-dose rivaroxaban in comparison with warfarin in AF patients were enrolled. Data extraction and study quality assessment were conducted by two authors independently. Low dosing of rivaroxaban (15/10 mg) was defined n compared with warfarin. Furthermore, consistent results were observed among different dose regimens (10/15/20 mg) in all the clinical outcomes (P interaction > 0.05 for each outcome). Meta-regression analysis failed to detect any potential confounding to impact the primacy outcomes. Conclusion Insights from the present meta-analysis, we found that low-dose rivaroxaban, even at a dosage of 10 mg daily, was associated with a reduced risk of stroke/SE and bleeding than warfarin in Asian AF patients. However, owing to considerable heterogeneity among included studies, further prospective studies are required to confirm these findings.Cardiorenal syndrome type 2 is characterized by kidney failure as a consequence of heart failure that affects >50% of heart failure patients. Murine transverse aortic constriction (TAC) is a heart failure model, where pressure overload is induced on the heart without any systemic hypertension or its consequences. Whether renal function is altered in this model is debated, and if so, at which time post-TAC renal dysfunction starts to contribute to worsening of cardiac function. We therefore studied the effects of progressive heart failure development on kidney function in the absence of chronically elevated systemic blood pressure and renal perfusion pressure. C57BL/6J mice (N = 129) were exposed to TAC using a minimally invasive technique and followed from 3 to 70 days post-TAC. Cardiac function was determined with 3D ultrasound and showed a gradual decrease in stroke volume over time. Renal renin expression and plasma renin concentration increased with progressive heart failure, suggesting hypoperfusion of the kidney. In addition, plasma urea concentration, a surrogate marker for renal dysfunction, was increased post-TAC. However, no structural abnormalities in the kidney, nor albuminuria were present at any time-point post-TAC. Progressive heart failure is associated with increased renin expression, but only mildly affected renal function without inducing structural injury. In combination, these data suggest that heart failure alone does not contribute to kidney dysfunction in mice.Background Various working memory (WM) trainings have been tested, but differences in experimental designs, the lack of theoretical background, and the need of identifying task-related processes such as filtering efficiency limit conclusions about their comparative efficacy. Objectives In this study, we compared the efficacy of a model-based WM training with (MB+) and without (MB) distractor inhibition on improving WM capacity to a dual n-back and active control condition. Methods This randomized clinical trial included 123 healthy elderly adults (78 women, 45 men; aged 64.1 ± 8.3 years). All groups underwent 12 40-min training sessions over 3 weeks and four cognitive testing sessions. The first two sessions served as double baseline to account for practice effects. Primary outcome was WM capacity post-training measured by complex span tasks. Near and far transfer was assessed by simple span, n-back, visuospatial and verbal learning, processing speed, and reasoning tasks. Results Due to preliminary terminatio in MB, and improved n-back performance (t (25) = 3.83, p less then 0.001) in the dual n-back training. Interpretation A model-based WM training including filtering efficacy may be a promising approach to increase WM capacity and needs further investigation in randomized controlled studies.Background Over the life span, the diffusion metrics in brain MRI show different, partly nonlinear changes. These age-dependent changes also seem to exhibit regional differences with respect to the brain anatomy. The age correction of a study cohort's diffusion metrics might thus require consideration of age-related factors. Methods Diffusion tensor imaging data sets were acquired from 219 healthy participants at ages between 19 and 81 years. Sorafenib Fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivity (AD and RD, respectively) maps were analyzed by a tract of interest-based fiber tracking approach. To describe diffusion metrics as a function of the participant age, linear splines were used to perform curve fitting in 21 specific tract systems covering different functional areas and diffusion directions. Results In the majority of tracts, an interpolation with a change of alteration rate during adult life described the diffusion properties more accurately than a linear model. Consequently, the diffusion properties remained relatively stable until a decrease (of FA) or increase (of MD, AD, and RD) started at a region-specific time point, whereas a uniform change of diffusion properties was observed only in a few tracts.