miR-19a-3p containing exosomes improve function of ischemic myocardium upon shock wave therapy

AIMS: As many current approaches for heart regeneration exert unfavorable side-effects, the induction of endogenous repair mechanisms in ischemic heart disease is of particular interest. Recently, exosomes carrying angiogenic miRNAs have been described to improve heart function. However, it remains challenging to stimulate specific release of reparative exosomes in ischemic myocardium. In the present study, we sought to test the hypothesis that the physical stimulus of shock wave therapy (SWT) causes the release of exosomes. We aimed to substantiate the pro-angiogenic impact of the released factors, to identify the nature of their cargo, and to test their efficacy in vivo supporting regeneration and recovery after myocardial ischemia. METHODS AND RESULTS: Mechanical stimulation of ischemic muscle via SWT caused extracellular vesicle (EV) release from endothelial cells both in vitro and in vivo. Characterization of EVs via electron microscopy, nanoparticle tracking analysis and flow cytometry revealed specific exosome morphology and size with presence of exosome markers CD 9, CD81 and CD63. Exosomes exhibited angiogenic properties activating protein kinase b (Akt) and extracellular-signal regulated kinase (ERK) resulting in enhanced endothelial tube formation and proliferation. A miRNA array and transcriptome analysis via next-generation sequencing were performed to specify exosome content. miR-19a-3p was identified as responsible cargo, antimir-19a-3p antagonized angiogenic exosome effects. Exosomes and target miRNA were injected intramyocardially in mice after left anterior descending artery (LAD) ligation. Exosomes resulted in improved vascularization, decreased myocardial fibrosis and increased left ventricular ejection fraction as shown by transthoracic echocardiography. CONCLUSIONS: The mechanical stimulus of SWT causes release of angiogenic exosomes. miR-19a-3p is the vesicular cargo responsible for the observed effects. Released exosomes induce angiogenesis, decrease myocardial fibrosis and improve left ventricular function after myocardial ischemia. Exosome release via SWT could develop an innovative approach for the regeneration of ischemic myocardium

The role of innate immunity and bioactive lipid mediators in COVID-19 and influenza

In this review, we discuss spatiotemporal kinetics and inflammatory signatures of innate immune cells specifically found in response to SARS-CoV-2 compared to influenza virus infection. Importantly, we cover the current understanding on the mechanisms by which SARS-CoV-2 may fail to engage a coordinated type I response and instead may lead to exaggerated inflammation and death. This knowledge is central for the understanding of available data on specialized pro-resolving lipid mediators in severe SARS-CoV-2 infection pointing toward inhibited E-series resolvin synthesis in severe cases. By investigating a publicly available RNA-seq database of bronchoalveolar lavage cells from patients affected by COVID-19, we moreover offer insights into the regulation of key enzymes involved in lipid mediator synthesis, critically complementing the current knowledge about the mediator lipidome in severely affected patients. This review finally discusses different potential approaches to sustain the synthesis of 3-PUFA-derived pro-resolving lipid mediators, including resolvins and lipoxins, which may critically aid in the prevention of acute lung injury and death from COVID-19.Proteomic

Deguelin Attenuates Reperfusion Injury and Improves Outcome after Orthotopic Lung Transplantation in the Rat

The main goal of adequate organ preservation is to avoid further cellular metabolism during the phase of ischemia. However, modern preservation solutions do rarely achieve this target. In donor organs hypoxia and ischemia induce a broad spectrum of pathologic molecular mechanisms favoring primary graft dysfunction (PGD) after transplantation. Increased hypoxia-induced transcriptional activity leads to increased vascular permeability which in turn is the soil of a reperfusion edema and the enhancement of a pro-inflammatory response in the graft after reperfusion. We hypothesize that inhibition of the respiration chain in mitochondria and thus inhibition of the hypoxia induced mechanisms might reduce reperfusion edema and consecutively improve survival in vivo. In this study we demonstrate that the rotenoid Deguelin reduces the expression of hypoxia induced target genes, and especially VEGF-A, dose-dependently in hypoxic human lung derived cells. Furthermore, Deguelin significantly suppresses the mRNA expression of the HIF target genes VEGF-A, the pro-inflammatory CXCR4 and ICAM-1 in ischemic lungs vs. control lungs. After lung transplantation, the VEGF-A induced reperfusion-edema is significantly lower in Deguelin-treated animals than in controls. Deguelin-treated rats exhibit a significantly increased survival-rate after transplantation. Additionally, a downregulation of the pro-inflammatory molecules ICAM-1 and CXCR4 and an increase in the recruitment of immunomodulatory monocytes (CD163+ and CD68+) to the transplanted organ involving the IL4 pathway was observed. Therefore, we conclude that ischemic periods preceding reperfusion are mainly responsible for the increased vascular permeability via upregulation of VEGF. Together with this, the resulting endothelial dysfunction also enhances inflammation and consequently lung dysfunction. Deguelin significantly decreases a VEGF-A induced reperfusion edema, induces the recruitment of immunomodulatory monocytes and thus improves organ function and survival after lung transplantation by interfering with hypoxia induced signaling

ESC Joint Working Groups on Cardiovascular Surgery and the Cellular Biology of the Heart Position Paper: Perioperative myocardial injury and infarction in patients undergoing coronary artery bypass graft surgery

International audienc

Comparing early adolescents’ positive bystander responses to cyberbullying and traditional bullying: the impact of severity and gender

Young people are frequently exposed to bullying events in the offline and online domain. Witnesses to these incidents act as bystanders and play a pivotal role in reducing or encouraging bullying behaviour. The present study examined 868 (47.2% female) 11-13-year-old early adolescent pupils’ bystander responses across a series of hypothetical vignettes based on traditional and cyberbullying events. The vignettes experimentally controlled for severity across mild, moderate, and severe scenarios. The findings showed positive bystander responses (PBRs) were higher in cyberbullying than traditional bullying incidents. Bullying severity impacted on PBRs, in that PBRs increased across mild, moderate, and severe incidents, consistent across traditional and cyberbullying. Females exhibited more PBRs across both types of bullying. Findings are discussed in relation to practical applications within the school. Strategies to encourage PBRs to all forms of bullying should be at the forefront of bullying intervention methods

The Interrelated Effects of Traditional and Cybervictimization on the Development of Internalizing Symptoms and Aggressive Behaviors in Elementary School

Although the effect of physical and relational (i.e., traditional) victimization on psychopathology is established, the interdependent contribution of cybervictimization is unclear. We test a longitudinal path model theorizing that (a) children’s physical and relational victimization in Grade 4 or 5 is associated with more cybervictimization experiences when they are in Grade 5 or 6 (when independent access to cybertechnology typically begins to increase), and (b) cybervictimization and traditional victimization experiences are associated with internalizing symptoms and aggressive behaviors at the end of Grade 5 or 6 (controlling for prior levels). Five waves of data were collected from children, parents, and teachers in 27 rural Canadian schools involved in an evaluation of a bullying-prevention program. Analyses for this study were based on the subsample of participants in Grades 5 and 6 (n = 714, Mage = 11.0) who completed cybervictimization questionnaires in the final two waves (i.e., fall and spring of 1 academic year). Participants also completed all other measures at each assessment point. All forms of victimization were correlated with internalizing symptoms and aggressive behaviors, within time. Across time, relational victimization was independently associated with more cybervictimization and physical victimization. Relational victimization was also independently associated with more aggressive behaviors for boys only, but not with internalizing symptoms for girls or boys. Physical and cybervictimization was not related to aggressive behaviors or internalizing symptoms over time. Prevention efforts that target relational victimization may reduce cybervictimization and physical victimization and aggressive behaviors in elementary school