Studies suggest the potential role of a sarcoplasmic reticulum (SR) Ca leak in cardiac contractile dysfunction in sepsis. However, direct supporting evidence is lacking, and the mechanisms underlying this SR leak are poorly understood. Here, we investigated the changes in cardiac Ca handling and contraction in LPS-treated rat cardiomyocytes and a mouse model of polymicrobial sepsis produced by cecal ligation and puncture (CLP). LPS decreased the systolic Ca transient and myocyte contraction as well as SR Ca content. Meanwhile, LPS increased Ca spark-mediated SR Ca leak. Preventing the SR leak with ryanodine receptor (RyR) blocker tetracaine restored SR load and increased myocyte contraction. Similar alterations in Ca handling were observed in cardiomyocytes from CLP mice. Treatment with JTV-519, an anti-SR leak drug, restored Ca handling and improved cardiac function. In the LPS-treated cardiomyocytes, mitochondrial reactive oxygen species and oxidative stress in RyR2 were increased, whereas the levels of the RyR2-associated FK506-binding protein 1B (FKBP12.6) were decreased. The Toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 reduced the oxidative stress in LPS-treated cells, decreased the SR leak, and normalized Ca handling and myocyte contraction. Consistently, TLR4 deletion significantly improved cardiac function and corrected abnormal Ca handling in the CLP mice. This study provides evidence for the critical role of the SR Ca leak in the development of septic cardiomyopathy and highlights the therapeutic potential of JTV-519 by preventing SR leak. Furthermore, it reveals that TLR4 activation-induced mitochondrial reactive oxygen species production and the resulting oxidative stress in RyR2 contribute to the SR Ca leak.
In the cardiovascular system, Ca controls cardiac excitation-contraction coupling and vascular contraction and dilation. Disturbances in intracellular Ca homeostasis induce malfunctions of the cardiovascular system, including cardiac pump dysfunction, arrhythmia, remodeling, and apoptosis, as well as hypertension and impairment of vascular reactivity. Therefore, developing drugs and strategies manipulating Ca handling are highly valued in the treatment of cardiovascular disease. Resveratrol (Res) and polydatin (PD), a Res glucoside, have been well established to have beneficial effects on improving cardiovascular function. Studies from our laboratory and others have demonstrated that they exhibit inotropic effects on normal heart and therapeutic effects on hypertension, cardiac ischemia/reperfusion injury, hypertrophy, and heart failure by manipulating Ca mobilization. The actions of Res and PD on Ca signals delicately manipulated by multiple Ca -handling proteins are pleiotropic and somewhat controversial, depending on cellular species and intracellular oxidative status. Here, we focus on the effects of Res and PD on controlling Ca homeostasis in the heart and vasculature under normal and diseased conditions and highlight the key direct and indirect molecules mediating these effects.
We identified abnormally methylated, differentially expressed genes (DEGs) and pathogenic mechanisms in different immune cells of RA and SLE by comprehensive bioinformatics analysis. Six microarray data sets of each immune cell (CD19+ B cells, CD4+ T cells and CD14+ monocytes) were integrated to screen DEGs and differentially methylated genes by using R package “limma.” Gene ontology annotations and KEGG analysis of aberrant methylome of DEGs were done using DAVID online database. Protein-protein interaction (PPI) network was generated to detect the hub genes and their methylation levels were compared using DiseaseMeth 2.0 database. Aberrantly methylated DEGs in CD19+ B cells (173 and 180), CD4+ T cells (184 and 417) and CD14+ monocytes (193 and 392) of RA and SLE patients were identified. We detected 30 hub genes in different immune cells of RA and SLE and confirmed their expression using FACS sorted immune cells by qPCR. Among them, 12 genes (BPTF, PHC2, JUN, KRAS, PTEN, FGFR2, ALB, SERB-1, SKP2, TUBA1A, IMP3, and SMAD4) of RA and 12 genes (OAS1, RSAD2, OASL, IFIT3, OAS2, IFIH1, CENPE, TOP2A, PBK, KIF11, IFIT1, and ISG15) of SLE are proposed as potential biomarker genes based on receiver operating curve analysis. Our study suggests that MAPK signaling pathway could potentially differentiate the mechanisms affecting T- and B- cells in RA, whereas PI3K pathway may be used for exploring common disease pathways between RA and SLE. Compared to individual data analyses, more dependable and precise filtering of results can be achieved by integrating several relevant data sets.
Background:Urinary tract infection (UTI) during acute ischemic stroke is associated with a longer hospital length of stay and unfavorable functional outcomes.Objective:We investigated the benefits of portable bladder ultrasound (PBU) scanning during acute ischemic stroke.Methods:We retrospectively reviewed patients with acute ischemic stroke from January 2011 to February 2017. Patients were divided into group 1 (PBU not available) and group 2 (PBU available), before or after the split date, April 9, 2014. Portable bladder ultrasound scanning was conducted by nurses to measure postvoid residual urine volume in patients with impaired consciousness and/or dependent ambulation.Results:In total, 1928 patients were enrolled, of whom 109 (5.7%) had UTI and 901 (46.7%) experienced unfavorable outcomes (modified Rankin scale score ≥ 3). Multivariate analysis revealed that factors that influenced UTI were age of 75 years or older, female gender, initial total National Institutes of Health Stroke Scale (NIHSS) score of 5 or higher, initial NIHSS conscious score of 1 or higher, initial NIHSS leg score of 2 or higher, and urinary catheterization. Factors influencing unfavorable outcomes were similar to those influencing UTI but further comprised UTI. C-statistic for UTI detection was 0.864 for model fitting, including significant factors in logistic regression. Compared with group 1, group 2 had a higher incidence of urinary catheterization (13.1% vs 8.2%), a lower incidence of UTI (4.0% vs 6.9%), and a shorter length of stay (11.9 vs 13.6 days).Conclusions:Portable bladder ultrasound scanning reduced the incidence of UTI and shortened length of stay. We suggest routine PBU procedures for patients with acute ischemic stroke who fulfill the AGN3 criteria for a high risk of UTI.
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