Alterations in the polysialylated neural cell adhesion molecule and retinal ganglion cell density in mice with diabetic retinopathy

AIM: To investigate the impact of polysialylated neural cell adhesion molecule (PSA-NCAM) on the survival of retinal ganglion cells (RGCs) in the experimentally induced diabetes in mice. METHODS: Diabetes was induced in 2.5 months old Swiss Webster mice by intraperitoneal injection of streptozotocin (STZ, 90 mg/kg) once daily for two consecutive days. Examination of the proteins of interest in the retinas from diabetic mice at 2mo after diabetes induction was performed using immunohistochemistry and Western blot analysis. RGCs were counted in the wholemounted retinas, and Brn3a marker was used. RESULTS: Examination of retinas from diabetic mice at 2mo after diabetes induction revealed a considerable reduction in RGC density. Our experiments also demonstrated a redistribution of PSA-NCAM in the retina of diabetic animals. PSA-NCAM immunoreactivity was diminished in the inner part of the retina where RGCs were located. In contrast, an enhanced PSA-NCAM immunoreactivity was detected in the outer layers of the retina. PSA-NCAM signal was co-localized with glial fibrillary acidic protein immunoreactivity in the Müller cell branches. Previous studies have shown that matrix metalloproteinase-9 (MMP-9) is responsible for the reduction in PSA-NCAM levels in neuronal cells. The reduced levels of PSA-NCAM in inner layers (nerve fiber layer, ganglion cell layer) were accompanied by the increased expression of MMP-9. In contrast, in the outer retinal layers, the expression of MMP-9 was much less pronounced. CONCLUSION: MMP-9 induces PSA-NCAM shedding in the inner part of the retina and the decreased level of PSA-NCAM in the inner part of the retina might be, at least in part, responsible for the loss of RGCs in diabetic mice

Elocalcitol, a fluorinated vitamin D derivative, prevents high-fat diet-induced obesity via SCAP downregulation and miR-146a-associated mechanisms

BackgroundObesity is an emerging health problem worldwide as it is associated with increased risk of cardiovascular, metabolic, mental disorders, and cancer. Therapeutic weight management remains one of the options for the treatment of excess weight and associated comorbidities. In this study, the therapeutic potential of elocalcitol, a fluorinated derivative of vitamin D, was studied on the model of high-fat diet (HFD)-induced obesity in mice.ResultsIt was demonstrated that co-administration of elocalcitol in the doses 15 ug/kg (i.p.) twice a week for 16 weeks prevented body weight gain by approximately 15%. The significant retardation in the body weight gain was observed already on the second week of elocalcitol treatment. Administration of elocalcitol also reduced visceral and epididymal fat accumulation by 55% and 35%, respectively, metabolic syndrome development, and lipid droplets accumulation in the liver of mice exposed to HFD. In contrast, the administration of cholecalciferol (vitamin D)—a precursor to calcitriol, the biologically active form of vitamin D, did not affect significantly the signs of obesity and metabolic syndrome, suggesting that the anti-obese effects of elocalcitol are not related to the canonical vitamin D receptor (VDR). Further studies have demonstrated that the preventive effect of elocalcitol is associated with the decreased levels of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and upregulation insulin-inducing gene-1 (Insig1) mRNA expression suggesting that the anti-obese effect of elocalcitol is mediated via inhibition of SREBP-mediated lipogenesis. We also demonstrated that elocalcitol prevents an increase in the expression of proinflammatory cytokines such as interleukin-1 beta (Il1b), tumor necrosis factor-alpha (Tnf), and interleukin-18 (Il18), and this effect was associated with upregulation of microRNA-146a (miR-146a). Deletion of the miR-146a gene reduced the anti-obese effects of elocalcitol and prevented its actions on the SCAP levels. The data indicate that elocalcitol’s reduction of SCAP is at least partly mediated by miR-146a modulation.ConclusionThe study demonstrates that elocalcitol prevents HFD-induced obesity and metabolic syndrome in mice, likely by inhibiting SREBP-mediated lipogenesis and upregulating miR-146a. These findings provide valuable insights into the anti-obesity mechanisms of fluorinated D-vitamin analogs and suggest potential therapeutic strategies for obesity prevention

CSF1R Regulates Schizophrenia-Related Stress Response and Vascular Association of Microglia/Macrophages

BACKGROUND: Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility. METHODS: We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating factor 1 receptor (CSF1R). Furthermore, we studied a mouse model of chronic unpredictable stress (CUS) combined with a CSF1R inhibitor (CSF1Ri) (n = 9 ~ 10/group) on anxiety behaviours and microglial biology. RESULTS: FES patients showed higher scores of perceived stress scale (PSS, p \u3c 0.05), lower blood CSF1R mRNA (FDR = 0.003) and protein (p \u3c 0.05) levels, and smaller volumes of the superior frontal gyrus and parahippocampal gyrus (both FDR \u3c 0.05) than HCs. In blood RNA-seq, CSF1R-associated differentially expressed blood genes were related to brain development. Importantly, CSF1R facilitated a negative association of the superior frontal gyrus with PSS (p \u3c 0.01) in HCs but not FES patients. In mouse CUS+CSF1Ri model, similarly as CUS, CSF1Ri enhanced anxiety (both p \u3c 0.001). Genes for brain angiogenesis and intensity of CD31 CONCLUSION: Microglial/macrophagic CSF1R regulated schizophrenia-associated stress and brain angiogenesis

Analysis of potential interactions between warfarin and prescriptions in Estonian outpatients aged 50 years or more

In Estonia, warfarin is widely prescribed by general practitioners to prevent and treat thromboembolic diseases. To date, there has been no systematic analysis of the potential risk of warfarin interactions with other drugs in the outpatient population. Objective: The aim of the study was to analyze the incidence of potential interactions in prescription schemes in Estonia in a cohort of outpatients receiving warfarin treatment. Methods: The retrospective study population included 203,646 outpatients aged 50 years or older of whom 7,175 received warfarin therapy. Patients who had used at least one prescription drug for a minimum period of 7 days concomitantly with warfarin were analyzed. Potential drug interactions were analyzed using Epocrates online, Stockley�s Drug Interactions and domestic drug interaction databases. Results: The average number of drugs used concomitantly with warfarin was 4.8 (SD=1.9) (males: 4.7 SD=2.0, females: 4.9 SD=2.0). No potential interactions in treatment regimens were found in 38% of patients, one potential interaction was observed in 29% and two or more potential interactions were observed in 33% of patients. The mean number of all potential interactions was 1.2 per patient and about the same in men and women. Potential interactions were associated with the number of drugs. Warfarin-related interactions were detected in 57% of patients, and the number of interactions related to warfarin per patient varied from 1 to 5. Most frequent were use of warfarin with NSAIDs (14%), followed by simvastatin (9%) and amiodarone (7%). Conclusion: This study shows that 57% of outpatients in Estonia receiving warfarin have drugs potentially interacting with warfarin in their treatment schemes. Most interactions (14%) with warfarin are associated with the prescription of NSAIDs.En Estonia, la warfarina es prescrita por médicos generales para tratar enfermedades tromboembólicas. Hasta la fecha, no se ha realizado un análisis sistemático del riesgo de interacciones potenciales de la warfarina con otros medicamentos en la población ambulatoria. Objetivo: El objetivo de este estudio fue analizar la incidencia de interacciones potenciales en los esquemas prescritos en Estonia en una cohorte de pacientes ambulatorios recibiendo warfarina. Métodos: El estudio retrospectivo incluyó 203.646 pacientes ambulatorios de 50 o más años de los que 7.175 recibían tratamiento con warfarina. Se analizó a los pacientes que usaron como mínimo un medicamento de prescripción por un periodo mínimo de 7 días concomitante con warfarina. Las interacciones potenciales fueron analizadas usando Epocrates online, Stockley�s Drug Interactions, y bases de datos locales de interacciones. Resultados: El numero medio de medicamentos usados concomitantemente con warfarina fue de 4,8 (DE=1,9) (hombres 4,7 DE=2,0; mujeres 4,9 DE=2,0). No se encontraron interacciones potenciales en el 38% de los pacientes, se observó una interacción potencial en el 29%, y se encontraron dos o más interacciones potenciales en el 33% de pacientes. El número medio de interacciones potenciales fue de 1,2 por paciente, prácticamente igual en hombres y en mujeres. Las interacciones potenciales estaban asociadas con el número de medicamentos. Se detectaron interacciones relacionadas con la warfarina en el 57% de los pacientes, y el número de interacciones relacionadas con warfarina varió de 1 a 5. Las más frecuentes fueron el uso de warfarina con AINE (14%), seguidas de sinvastatina (9%) y amiodarona (7%). Conclusión: Este estudio muestra que el 57% de los pacientes ambulatorios que reciben warfarina en estonia tienen medicamentos potencialmente interaccionando con la warfarina en sus esquemas terapéuticos. La mayoría de las interacciones (14%) con warfarina estaban asociadas a los AINE

Analysis of the efficiency of balancing pistons of feed pumps

BACKGROUND: Thermo power industry demands the high level of reliability of pump equipment. Regarding that, improvement of reliability of feed pump structure and balancing device in particular is a relevant issue.&#x0D; AIMS: To perform numerical simulation of a balancing device in order to determine its optimal design and parameters. The study object is the balancing device of the PEN 290-115 feed pump&#x0D; METHODS: Two types of the balancing piston, two-stage and single-stage, were studied. The series of computational fluid dynamics simulations of the three-dimensional flow of a viscous liquid were performed using the ANSYS CFX software in order to study the efficiency of given designs.&#x0D; RESULTS: The calculated characteristics of the two designs of the unloading device were obtained. The influence of roughness and radial clearance on the efficiency of a cylindrical piston was studied. The simulation results showed that the radial clearance decrease leads to balancing device losses decrease. The roughness value increase may also lead to the leaks decrease, but its excessive increase leads to friction losses increase, so it is necessary to control both parameters when searching for the optimal roughness value.&#x0D; CONCLUSIONS: The optimal design of the balancing piston, which combines simplicity of manufacturing, reliability and energy efficiency, is proposed.</jats:p