Gammelgaardwallace3261

Targeting neuroinflammation is a novel frontier in the prevention and treatment of epilepsy. A substantial body of evidence supports a key role for neuroinflammation in epileptogenesis, the pathological process that leads to the development and progression of spontaneous recurrent epileptic seizures. It is also well recognized that traumatic brain injury (TBI) induces a vigorous neuroinflammatory response and that a significant proportion of patients with TBI suffer from debilitating post-traumatic epilepsy. The complement system is a potent effector of innate immunity and a significant contributor to secondary tissue damage and to epileptogenesis following central nervous system injury. Several therapeutic agents targeting the complement system are already on the market to treat other central nervous system disorders or are well advanced in their development. The purpose of this review is to summarize findings on complement activation in experimental TBI and epilepsy models, highlighting the potential of drug repurposing in the development of therapeutics to ameliorate post-traumatic epileptogenesis.After intra-articular injection, synovium-derived mesenchymal stem cells (SMSCs) can adhere to damaged cartilage (a process called homing) and then repair the cartilage defect. Nonetheless, the main obstacle of the current method is the insufficient homing ratio of SMSCs, which fails to meet the requirements for cartilage repair and thereby greatly limits the therapeutic effect. In this study, the optimal homing time of SMSCs was determined by evaluating the SMSCs homing efficiency at 1, 3, 7, 14, and 28 d after injury using a rat cartilage defect model. The ability of platelet-derived microparticles (PMPs) to promote SMSCs homing was evaluated by cartilage/subchondral bone cell adhesion, transmembrane migration and intra-articular cell distribution assays. SMSCs had an optimal homing efficiency in the very early stage (1 d) after cartilage injury. We found that PMPs, which were abundant in the synovial fluid (SF) at this early stage, were responsible for this augmented SMSCs homing. An ex vivo cell adhesion assay revealed that the coincubation of SMSCs with PMPs at a 150 ratio markedly enhanced cell adhesion to cartilage and the subchondral bone surface. The transmembrane cell migration assay yielded similar results. Further in vivo homing assays revealed that PMPs possess excellent homing capacity, which they transferred, to some extent, to SMSCs by coating the cell surface. We measured the expression of homing-related genes in SMSCs exposed to PMPs and identified several upregulated genes. Moreover, platelet-specific adhesion molecules, particularly GPIIb/IIIa, CXCR4, ITGβ1, and ITGα2, were determined to play a critical role in the homing of SMSC/PMP complexes. This improvement in SMSCs homing increased the volume of regenerated tissue in the cartilage defect. In conclusion, PMPs significantly promoted the homing of SMSCs to cartilage, which facilitated cartilage regeneration. These data suggest a safe and promising strategy for improving the outcome of stem cell therapy.Background Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin-cleaved osteopontin on fibrosis in the heart and explore the role of syndecan-4 in regulating cleavage of osteopontin. Methods and Results Osteopontin was upregulated and cleaved by thrombin in the pressure-overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin-induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan-4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan-4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan-4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions Thrombin-cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan-4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan-4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.The canalicular system (CS) has been defined as 1) an inward, invaginated membrane connector that supports entry into and exit from the platelet; 2) a static structure stable during platelet isolation; and 3) the major source of plasma membrane (PM) for surface area expansion during activation. Recent analysis from STEM tomography and serial block face electron microscopy has challenged the relative importance of CS as the route for granule secretion. Here, We used 3D ultrastructural imaging to reexamine the CS in mouse platelets by generating high-resolution 3D reconstructions to test assumptions 2 and 3. Qualitative and quantitative analysis of whole platelet reconstructions, obtained from immediately fixed or washed platelets fixed post-washing, indicated that CS, even in the presence of activation inhibitors, reorganized during platelet isolation to generate a more interconnected network. Further, CS redistribution into the PM at different times, post-activation, appeared to account for only about half the PM expansion seen in thrombin-activated platelets, in vitro, suggesting that CS reorganization is not sufficient to serve as a dominant membrane reservoir for activated platelets. selleck chemicals llc In sum, our analysis highlights the need to revisit past assumptions about the platelet CS to better understand how this membrane system contributes to platelet function.Objective Matrix Gla protein (MGP) is a potent calcification inhibitor. Mgp-/- mice display increased proportion of brown adipose tissue. However, whether MGP is involved in fat metabolism remains unclear. This study aims to investigate the involvement. Methods Expression of adipocyte differentiation markers was examined by RT-qPCR. Adipocyte formation was assessed by Oil Red staining. Serum triglyceride, cholesterol, and desphosphorylated-uncarboxylated MGP (dp-ucMGP) were quantified by ELISA. Visceral fat was detected by bioelectrical impedance analysis. Results MGP is highly expressed in visceral fat. MGP expression is induced during preadipocyte differentiation. Knockout of MGP leads to retardation of 3T3-L1 differentiation. Intracellular triglyceride amount is impaired while glycerol release is increased in MGP-depleted cells. Serum dp-ucMGP level is significantly increased in individual with higher visceral fat index (VFI) and waist height ratio (WHtR), but not body mass index (BMI). Additionally, dp-ucMGP positively correlates to low-density lipoprotein cholesterol (LDL-C) level. Conclusions MGP is involved in fat metabolism and serum inactive MGP level is associated with visceral fat. Our study uncovers for the first time the link between MGP and fat metabolism, and sheds light on the potential of dp-ucMGP as a novel serum marker.OBJECTIVE To investigate the association of genetic markers in ESR1 and ESR2 with craniofacial measurements. DESIGN Cross-sectional study. SETTING School of Dentistry of Ribeirão Preto, University of São Paulo. PARTICIPANTS A total of 146 biologically unrelated, self-reported Caucasian Brazilians with no syndromic conditions were included. METHODS Sagittal and vertical measurements (ANB, S-N, Ptm'-A', Co-Gn, Go-Pg, N-Me, ANS-Me, S-Go and Co-Go) from lateral cephalograms were examined for craniofacial evaluation. DNA was extracted from saliva and genetic markers in ESR1 (rs2234693 and rs9340799) and in ESR2 (rs1256049 and rs4986938) were analysed by real-time polymerase chain reaction. Hardy-Weinberg equilibrium was evaluated using the Chi-square test within each marker. The associations between craniofacial dimensions and genotypes were analysed by linear regression and adjusted by sex and age. The established alpha was 5%. RESULTS Individuals carrying CC in ESR1 rs2234693 had a decrease of -3.146 mm in ANS-Me (P = 0.044). In addition, rs4986938 in ESR2 was associated with S-N measurement (P = 0.009/ ß = -3.465). This marker was also associated with Go-Pg measurement, in which the CC genotype had a decrease of -3.925 mm in the length of the mandibular body (P = 0.043). CONCLUSION The present study suggests that in ESR1 and ESR2 are markers for variations in the craniofacial dimensions. However, further research should confirm the results.BACKGROUND It is commonly assumed that increased dietary fat and/or caloric excess induces chronic inflammatory processes, since the association between obesity and chronic adipose tissue with systemic inflammation has been shown previously. As far as we know, the reported health benefits of a VLCHF or ketogenic diet have not adequately involved an evaluation of biomarkers of inflammation. AIM This study investigated the effects of a four-week very low-carbohydrate high-fat (VLCHF) diet in healthy young individuals on biomarkers of inflammation. METHODS Eighteen moderately trained males (age 23.8 ± 2.1 years) were assigned to two groups. One group switched to a non-standardised VLCHF diet for four weeks, while the second group remained consuming their normal habitual diet (HD). Biomarkers of inflammation (adiponectin, leptin, resistin and interleukin-6) and substrate metabolism (fasting glucose and triacylglyceride concentrations) were analysed from blood at baseline and after four weeks. RESULTS There was moderate evidence for substantial changes in leptin serum concentrations in the VLCHF group, with small to large decreases compared to the HD group after four weeks (effect size = 0.78, 95% CI 0.42, 0.93, p = 0.008; Bayes Factor10 = 5.70). No substantial between-group change differences over time were found across any other biomarkers. CONCLUSIONS A four-week period of consuming a VLCHF diet in healthy young men was not associated with any considerable changes in markers of inflammation but showed evidence for lowered serum leptin concentrations relative to the HD group.Background Attention Deficit Hyperactivity Disorder (ADHD) among children is associated with difficulties in everyday functioning. According to the Common-Sense Model of Illness Representations (CSM), individuals' beliefs about their illness condition guide their attempts to cope with it. The model suggests five dimensions of illness representations beliefs regarding the identity of the symptoms, its duration, causes, consequences, and one's ability to achieve control over it.Aims The study aimed to explore the validity of the CSM-dimensions of illness representations for children with ADHD, while also exploring the possible relationships between types of beliefs and coping strategies.Method A deductive qualitative content analysis was used for analyzing data constructed from semi-structured individual interviews with 14 children diagnosed with ADHD.Results The results have shown that there is a variation in children's beliefs regarding their ADHD. Those beliefs are, for the most part, captured by the five CSM-dimensions.