Marburg virus (MARV) infection often causes fulminant shock due to pathologic immune responses and alterations of the vascular system. Cytokines released from virus-infected monocytes/macrophages provoke endothelial activation and vascular hyperpermeability and contribute to the development of shock. Tyrosine phosphorylation of cell-junction proteins is important for the regulation of paraendothelial barrier function. We showed that mediators released from MARV-infected monocytes/macrophages, as well as recombinant tumor necrosis factor (TNF)- alpha /H2O2 and interferon (IFN)- gamma , caused tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1) but not of the vascular endothelial (VE) cadherin/catenin complex proteins. Tyrosine phosphorylation of PECAM-1 was associated with delayed opening of interendothelial junctions. Interestingly, we observed an early increase in water permeability in response to TNF- alpha /H2O2 that was not due to an opening of the interendothelial junctions. These data indicate 2 distinct mechanisms for the TNF- alpha /H2O2-mediated decrease in endothelial barrier function involving tyrosine phosphorylation of PECAM-1 but not requiring tyrosine phosphorylation of VE-cadherin or catenin proteins.
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http://dx.doi.org/10.1086/520606 | DOI Listing |
Alzheimers Dement
December 2024
McGill University, Montreal, QC, Canada.
Background: Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022).
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of Iowa, Iowa City, IA, USA.
Background: The dorsal raphe nucleus (DRN) is the primary source of serotonergic projections to supratentorial structures. We and others have shown that it is selectively vulnerable to tau pathology in both human and mouse models of early AD. Although well characterized in mice, the neurochemical anatomy of the human DRN, and in particular the role of Vesicular glutamate transporter-3 (VGLUT3)-expressing neocortical projection neurons in tau pathology, remains unclear.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by the presence of phosphorylated tau neurofibrillary tangles and extracellular deposits of amyloid beta plaques (Aβ) in the brain. Microglia cells have been proposed to be involved in amyloid plaque formation since activated microglia produce inflammatory cytokines that contribute to a hostile neuronal environment, exacerbating AD pathogenesis.
Method: We aim to evaluate if the pharmacological inhibition of the myeloid/microglial receptor tyrosine kinase AXL, with bemcentinib (BGB) could be used as a novel therapeutic approach for AD.
Alzheimers Dement
December 2024
The Medical University of South Carolina, Charleston, SC, USA.
Background: Alzheimer's disease (AD) pathology can start accumulating 20-30 years before cognitive symptoms occur, with increases in inflammation, amyloid-β (Aβ), and hyperphosphorylated Tau during this time. Previous studies have shown that the post-translational modification of a single N-acetylglucosamine moiety to serine or threonine residues to cytosolic or nuclear proteins, known as O-GlcNAcylation, can modify a plethora of cellular processes, including the processing of the amyloid precursor protein, competing with phosphorylation on tau, as well as having anti-inflammatory effects. This study is designed to evaluate how increasing O-GlcNAcylation is impacting AD pathology in the most comprehensive AD rat model to date, the TgF344-AD rat model.
View Article and Find Full Text PDFFront Chem Biol
August 2024
Center for Structure-based Drug Design and Development, Department of Pharmaceutical Sciences, Concordia University Wisconsin, Mequon, WI, United States.
Introduction: Dual specific phosphatases (DUSPs) are mitogen-activated protein kinase (MAPK) regulators, which also serve as drug targets for treating various vascular diseases. Previously, we have presented mechanistic characterizations of DUSP5 and its interaction with pERK, proposing a dual active site.
Methods: Herein, we characterize the interactions between the DUSP5 phosphatase domain and the pT-E-pY activation loop of ERK2, with specific active site assignments.
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