Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells.

Facioscapulohumeral dystrophy (FSHD) is a muscle disease caused by inappropriate expression of the double homeobox 4 (DUX4) gene in skeletal muscle, and its downstream activation of pro-apoptotic transcriptional programs. Inhibitors of expression have the potential to treat FSHD. Apabetalone is a clinical-stage bromodomain and extra-terminal (BET) inhibitor, selective for the second bromodomain on BET proteins.

Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment.

Epigenetic mechanisms are implicated in transcriptional programs driving chronic kidney disease (CKD). Apabetalone is an orally available inhibitor of bromodomain and extraterminal (BET) proteins, which are epigenetic readers that modulate gene expression. In the phase 3 BETonMACE trial, apabetalone reduced risk of major adverse cardiac events (MACE) by 50% in the CKD subpopulation, indicating favorable effects along the kidney-heart axis.

Step up to the platelet: Role of platelets in inflammation and infection.

Platelets are anucleated cells derived from megakaryocytes that are primarily responsible for hemostasis. However, in recent years, these cytoplasts have become increasingly recognized as immune cells, able to detect, interact with, and kill pathogens. As platelets are involved in both immunity and coagulation, they have a central role in immunothrombosis, a physiological process in which immune cells induce the formation of microthrombi to both prevent the spread of pathogens, and to help facilitate clearance.

Neutrophil Extracellular Traps Induced by Shiga Toxin and Lipopolysaccharide-Treated Platelets Exacerbate Endothelial Cell Damage.

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in the pediatric population. The etiology of HUS is linked to Gram-negative, Shiga toxin (Stx)-producing enterohemorrhagic bacterial infections. While the effect of Stx is focused on endothelial damage of renal glomerulus, cytokines induced by Stx or bacterial lipopolysaccharide (LPS) and polymorphonuclear cells (PMNs) are involved in the development of the disease.

Platelet-Mediated NET Release Amplifies Coagulopathy and Drives Lung Pathology During Severe Influenza Infection.

The influenza A virus (IAV) causes a respiratory tract infection with approximately 10% of the population infected by the virus each year. Severe IAV infection is characterized by excessive inflammation and tissue pathology in the lungs. Platelet and neutrophil recruitment to the lung are involved in the pathogenesis of IAV, but the specific mechanisms involved have not been clarified.

Modulation of the liver immune microenvironment by the adeno-associated virus serotype 8 gene therapy vector.

Adeno-associated viruses (AAVs) are emerging as one of the vehicles of choice for gene therapy. However, the potential immunogenicity of these vectors is a major limitation of their use, leading to the necessity of a better understanding of how viral vectors engage the innate immune system. In this study, we demonstrate the immune response mediated by an AAV vector in a mouse model.

Patrolling Alveolar Macrophages Conceal Bacteria from the Immune System to Maintain Homeostasis.

During respiration, humans breathe in more than 10,000 liters of non-sterile air daily, allowing some pathogens access to alveoli. Interestingly, alveoli outnumber alveolar macrophages (AMs), which favors alveoli devoid of AMs. If AMs, like most tissue macrophages, are sessile, then this numerical advantage would be exploited by pathogens unless neutrophils from the blood stream intervened.

Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets.

Every day, megakaryocytes produce billions of platelets that circulate for several days and eventually are cleared by the liver. The exact removal mechanism, however, remains unclear. Loss of sialic acid residues is thought to feature in the aging and clearance of platelets.

Acetylsalicylic acid inhibits intravascular coagulation during Staphylococcus aureus-induced sepsis in mice.

Antiplatelet therapies have been proposed for the treatment of sepsis, a syndrome resulting from a dysregulated immune response and inappropriate activation of coagulation. Acetylsalicylic acid (ASA) may serve as a potential therapeutic strategy to prevent infection-induced coagulopathy and associated tissue damage. Using intravital microscopy, we found that Staphylococcus aureus infection induced neutrophil recruitment, platelet aggregation, and neutrophil extracellular trap (NET) release in the liver.

Inhibition of immunothrombosis does not affect pathogen capture and does not promote bacterial dissemination in a mouse model of sepsis.

After infection, neutrophils release neutrophil extracellular traps (NETs), decondensed DNA fibers decorated with both nuclear proteins and proteins derived from intracellular granules. These structures have a fundamental role in the development of immunothrombosis; a physiological process mediated by immune cells and molecules from the coagulation system that facilitates the recognition, containment, and destruction of pathogens. Although NETs and immunothrombi are widely hypothesized to be key host defense responses responsible for limiting bacterial dissemination, their actual role in this process has not been formally assessed within the context of a bloodstream infection.

Platelets Promote Macrophage Polarization toward Pro-inflammatory Phenotype and Increase Survival of Septic Mice.

We investigated the contribution of human platelets to macrophage effector properties in the presence of lipopolysaccharide (LPS), as well as the beneficial effects and time frame for platelet transfusion in septic animals. Our results show that platelets sequester both pro-(TNF-α/IL-6) and anti-(IL-10) inflammatory cytokines released by monocytes. Low LPS concentrations (0.

Reagent-dictated site selectivity in intermolecular aliphatic C-H functionalizations using nitrogen-centered radicals.

The site selectivities of intermolecular, aliphatic C-H bond functionalizations are central to the value of these transformations. While the scope of these reactions continues to expand, the site selectivities remain largely dictated by the inherent reactivity of the substrate C-H bonds. Herein, we introduce reagent-dictated site selectivity to intermolecular aliphatic C-H functionalizations using nitrogen-centered amidyl radicals.

Nucleosomes and neutrophil extracellular traps in septic and burn patients.

NETosis is a host defense mechanism associated with inflammation and tissue damage. Experimental models show that platelets and von Willebrand factor (VWF) are key elements for intravascular NETosis. We determined NETosis in septic and burn patients at 1 and 4days post-admission (dpa).

NETosis before and after Hyperglycemic Control in Type 2 Diabetes Mellitus Patients.

Introduction And Objective: Diabetes is characterized by chronic inflammation, endothelial dysfunction, increased risk of infections and early cardiovascular disease. By releasing neutrophil extracellular traps (NETs), neutrophils kill bacteria and exert pro-inflammatory and pro-thrombotic activities. Increased NETosis has been found in cross-sectional studies including treated type 2 diabetes mellitus (T2DM) patients.

Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms.

The mechanisms underlying increased thrombotic risk in chronic myeloproliferative neoplasms (MPN) are incompletely understood. We assessed whether neutrophil extracellular traps (NETs), which promote thrombosis, contribute to the procoagulant state in essential thrombocythemia, polycythemia vera and myelofibrosis (MF) patients. Although MPN neutrophils showed increased basal reactive oxygen species (ROS), enhanced NETosis by unstimulated neutrophils was an infrequent finding, whereas PMA-triggered NETosis was impaired, particularly in MF, due to decreased PMA-triggered ROS production.

Platelets: New Bricks in the Building of Neutrophil Extracellular Traps.

In addition to being key elements in hemostasis and thrombosis, platelets have an important role in the inflammatory and innate immune response. This activity is associated with their capability to recognize pathogens through the expression of toll-like receptors, the secretion of various cytokines, chemokines, and growth factors stored within their granules, and the expression of cell adhesion molecules that allows interaction with other immune cells, mainly neutrophils and monocytes. As part of the first line of defense, neutrophils control invading pathogens by phagocytosis, the release of antimicrobial proteins during degranulation, or through the formation of web-like structures named neutrophil extracellular traps (NETs).

Telemedicine in pediatric wound care.

Background: Telemedical wound care is one of the possible applications of teledermatology. The treatment of pediatric wounds needs frequent and periodic assessments of their local status and adjustment of dressings choice.

Materials And Methods: We present our experience using telemedicine in the successful assessment and treatment of 19 pediatric patients at the OPBG, Rome .

Telemedicine Home Program in Patients with Cystic Fibrosis: Results after 10 Years.

Objectives: We studied the effect of Telehomecare (THC) in a group of cystic fibrosis (CF) patients.

Materials And Methods: Forced Expiratory Volume in the first second (FEV1) was monitored at home, with the aim of an early recognition of the relapses of pulmonary infections. FEV1 was monitored for 4.

Extracellular histones reduce survival and angiogenic responses of late outgrowth progenitor and mature endothelial cells.

Unlabelled: ESSENTIALS: Extracellular histones are highly augmented in sites of neovessel formation, such as regeneration tissues. We studied histone effect on survival and angiogenic activity of mature and progenitor endothelial cells. Extracellular histones trigger apoptosis and pyroptosis and reduce angiogenesis in vivo and in vitro.

Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets.

In addition to being key elements in hemostasis and thrombosis, platelets amplify neutrophil function. We aimed to gain further insight into the stimuli, mediators, molecular pathways, and regulation of neutrophil extracellular trap formation mediated by human platelets. Platelets stimulated by lipopolysaccharide, a wall component of gram-negative bacteria, Pam3-cysteine-serine-lysine 4, a mimetic of lipopeptide from gram-positive bacteria, Escherichia coli, Staphylococcus aureus, or physiologic platelet agonists promoting neutrophil extracellular trap formation and myeloperoxidase-associated DNA activity under static and flow conditions.

Neutrophil Extracellular Traps are Involved in the Innate Immune Response to Infection with Leptospira.

NETosis is a process by which neutrophils extrude their DNA together with bactericidal proteins that trap and/or kill pathogens. In the present study, we evaluated the ability of Leptospira spp. to induce NETosis using human ex vivo and murine in vivo models.

Galectin-8 elicits pro-inflammatory activities in the endothelium.

Galectins (Gals), a family of mammalian lectins, play diverse roles under physiological and pathological conditions. Here, we analyzed the tandem-repeat Gal-8 synthesis, secretion and effects on the endothelium physiology. Gal-8M and Gal-8L isoforms were secreted under basal conditions by human microvascular endothelial cells (HMEC-1).

Functional responses and molecular mechanisms involved in histone-mediated platelet activation.

Histones are highly alkaline proteins found in cell nuclei and they can be released by either dying or inflammatory cells. The recent observations that histones are major components of neutrophil extracellular traps and promote platelet aggregation and platelet-dependent thrombin generation have shown that these proteins are potent prothrombotic molecules. Because the mechanism(s) of platelet activation by histones are not completely understood, we explored the ability of individual recombinant human histones H1, H2A, H2B, H3 and H4 to induce platelet activation as well as the possible molecular mechanisms involved.