IRF8-Dependent Type I Conventional Dendritic Cells (cDC1s) Control Post-Ischemic Inflammation and Mildly Protect Against Post-Ischemic Acute Kidney Injury and Disease.

Post-ischemic acute kidney injury and disease (AKI/AKD) involve acute tubular necrosis and irreversible nephron loss. Mononuclear phagocytes including conventional dendritic cells (cDCs) are present during different phases of injury and repair, but the functional contribution of this subset remains controversial. Transcription factor interferon regulatory factor 8 (IRF8) is required for the development of type I conventional dendritic cells (cDC1s) lineage and helps to define distinct cDC1 subsets.

The hydrogen-peroxide producing NADPH oxidase 4 does not limit neointima development after vascular injury in mice.

Objective: The NADPH oxidase Nox4 is an important source of HO. Nox4-derived HO limits vascular inflammation and promotes smooth muscle differentiation. On this basis, the role of Nox4 for restenosis development was determined in the mouse carotid artery injury model.

A guide to genetically encoded tools for the study of H O.

Cell metabolism heavily relies on the redox reactions that inevitably generate reactive oxygen species (ROS). It is now well established that ROS fluctuations near basal levels coordinate numerous physiological processes in living organisms, thus exhibiting regulatory functions. Hydrogen peroxide, the most long-lived ROS, is a key contributor to ROS-dependent signal transduction in the cell.

The Mitochondria-to-Cytosol HO Gradient Is Caused by Peroxiredoxin-Dependent Cytosolic Scavenging.

Fluorescent protein-based reporters used to measure intracellular HO were developed to overcome the limitations of small permeable dyes. The two major families of genetically encoded redox reporters are the reduction-oxidation sensitive green fluorescent protein (roGFP)-based proteins fused to peroxiredoxins and HyPer and derivatives. We have used the most sensitive probes of each family, roGFP2-Tpx1.

Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients.

Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels.

NOX1/NADPH oxidase is involved in the LPS-induced exacerbation of collagen-induced arthritis.

We investigate as yet an unidentified role of NOX1, a non-phagocytic isoform of the superoxide-generating NADPH oxidase, in immune responses using Nox1-knockout mice (Nox1-KO). The transcripts of NOX1 was expressed in lymphoid tissues, including the spleen, thymus, bone marrow, and inguinal lymphoid nodes. When antibody production after ovalbumin (OVA) immunization was examined, no significant differences were observed in serum anti-OVA IgG levels between wild-type mice (WT) and Nox1-KO.

MIR503HG Loss Promotes Endothelial-to-Mesenchymal Transition in Vascular Disease.

[Figure: see text].

Hippocampal neurons respond to brain activity with functional hypoxia.

Physical activity and cognitive challenge are established non-invasive methods to induce comprehensive brain activation and thereby improve global brain function including mood and emotional well-being in healthy subjects and in patients. However, the mechanisms underlying this experimental and clinical observation and broadly exploited therapeutic tool are still widely obscure. Here we show in the behaving brain that physiological (endogenous) hypoxia is likely a respective lead mechanism, regulating hippocampal plasticity via adaptive gene expression.

Secreted modular calcium-binding protein 1 binds and activates thrombin to account for platelet hyperreactivity in diabetes.

Secreted modular calcium-binding protein 1 (SMOC1) is an osteonectin/SPARC-related matricellular protein, whose expression is regulated by microRNA-223 (miR-223). Given that platelets are rich in miR-223, this study investigated the expression of SMOC1 and its contribution to platelet function. Human and murine platelets expressed SMOC1, whereas platelets from SMOC1+/- mice did not present detectable mature SMOC1 protein.

Epigenetic gene expression links heart failure to memory impairment.

In current clinical practice, care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients.

Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice.

Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar.

Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases.

Background And Purpose: Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here.

CaMKII Met281/282 oxidation is not required for recovery of calcium transients during acidosis.

CaMKII is needed for the recovery of Ca transients during acidosis but also mediates postacidic arrhythmias. CaMKIIδ can sustain its activity following Met281/282 oxidation. Increasing cytosolic Na during acidosis as well as postacidic pH normalization should result in prooxidant conditions within the cell favoring oxidative CaMKIIδ activation.

DGK and DZHK position paper on genome editing: basic science applications and future perspective.

For a long time, gene editing had been a scientific concept, which was limited to a few applications. With recent developments, following the discovery of TALEN zinc-finger endonucleases and in particular the CRISPR/Cas system, gene editing has become a technique applicable in most laboratories. The current gain- and loss-of function models in basic science are revolutionary as they allow unbiased screens of unprecedented depth and complexity and rapid development of transgenic animals.

Immunomodulatory role of reactive oxygen species and nitrogen species during T cell-driven neutrophil-enriched acute and chronic cutaneous delayed-type hypersensitivity reactions.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production.

Mapping the Endothelial Cell -Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function.

Background: In vascular endothelial cells, cysteine metabolism by the cystathionine γ lyase (CSE), generates hydrogen sulfide-related sulfane sulfur compounds (HS), that exert their biological actions via cysteine -sulfhydration of target proteins. This study set out to map the "-sulfhydrome" (ie, the spectrum of proteins targeted by HS) in human endothelial cells.

Methods: Liquid chromatography with tandem mass spectrometry was used to identify -sulfhydrated cysteines in endothelial cell proteins and β3 integrin intraprotein disulfide bond rearrangement.

Proximity to injury, but neither number of nuclei nor ploidy define pathological adaptation and plasticity in cardiomyocytes.

The adult mammalian heart consists of mononuclear and binuclear cardiomyocytes (CMs) with various ploidies. However, it remains unclear whether a variation in ploidy or number of nuclei is associated with distinct functions and injury responses in CMs, including regeneration. Therefore, we investigated transcriptomes and cellular as well as nuclear features of mononucleated and binucleated CMs in adult mouse hearts with and without injury.

Vitamin D-A New Perspective in Treatment of Cerebral Vasospasm.

Background: Cerebral vasospasm (CVS) is a frequent complication after subarachnoid hemorrhage (SAH), with no sufficient therapy and a complex pathophysiology.

Objective: To explore the vitamin D system as a potential treatment for CVS.

Methods: 25-vitamin D3 levels tested between 2007 and 2015 and data of SAH patients admitted during the months with a peak vs nadir of VitD3 values were analyzed, retrospectively.