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Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke
Sci Signal. 2023 Jun 6;16(788):eadd6364. doi: 10.1126/scisignal.add6364. Epub 2023 Jun 6.ABSTRACTBrain swelling causes morbidity and mortality in various brain injuries and diseases but lacks effective treatments. Brain swelling is linked to the influx of water into perivascular astrocytes through channels called aquaporins. Water accumulation in astrocytes increases their volume, which contributes to brain swelling. Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which compl...
Source: Science Signaling - June 6, 2023 Category: Biomedical Science Authors: Jesse A Stokum Bosung Shim Serban Negoita Natalya Tsymbalyuk Orest Tsymbalyuk Svetlana Ivanova Kaspar Keledjian Joseph Bryan Mordecai P Blaustein Ruchira M Jha Kristopher T Kahle Volodymyr Gerzanich J Marc Simard Source Type: research

Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke.
Abstract The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)-selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration o...
Source: Science Signaling - April 6, 2020 Category: Biomedical Science Authors: Ma F, Sun P, Zhang X, Hamblin MH, Yin KJ Tags: Sci Signal Source Type: research

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein.
Abstract Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transi...
Source: Science Signaling - December 11, 2018 Category: Biomedical Science Authors: Kim T, Mehta SL, Morris-Blanco KC, Chokkalla AK, Chelluboina B, Lopez M, Sullivan R, Kim HT, Cook TD, Kim JY, Kim H, Kim C, Vemuganti R Tags: Sci Signal Source Type: research

Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins.
Abstract Toll-like receptors (TLRs) recognize various pathogen- and host tissue-derived molecules and initiate inflammatory immune responses. Exaggerated or prolonged TLR activation, however, can lead to etiologically diverse diseases, such as bacterial sepsis, metabolic and autoimmune diseases, or stroke. Despite the apparent medical need, no small-molecule drugs against TLR pathways are clinically available. This may be because of the complex signaling mechanisms of TLRs, which are governed by a series of protein-protein interactions initiated by Toll/interleukin-1 receptor homology domains (TIR) found in TLRs a...
Source: Science Signaling - August 14, 2018 Category: Biomedical Science Authors: Ippagunta SK, Pollock JA, Sharma N, Lin W, Chen T, Tawaratsumida K, High AA, Min J, Chen Y, Guy RK, Redecke V, Katzenellenbogen JA, Häcker H Tags: Sci Signal Source Type: research

An engineered S1P chaperone attenuates hypertension and ischemic injury.
We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc co...
Source: Science Signaling - August 15, 2017 Category: Biomedical Science Authors: Swendeman SL, Xiong Y, Cantalupo A, Yuan H, Burg N, Hisano Y, Cartier A, Liu CH, Engelbrecht E, Blaho V, Zhang Y, Yanagida K, Galvani S, Obinata H, Salmon JE, Sanchez T, Di Lorenzo A, Hla T Tags: Sci Signal Source Type: research

PDZRN3 destabilizes endothelial cell-cell junctions through a PKC ζ-containing polarity complex to increase vascular permeability.
PDZRN3 destabilizes endothelial cell-cell junctions through a PKCζ-containing polarity complex to increase vascular permeability. Sci Signal. 2017 Jan 31;10(464): Authors: Sewduth RN, Kovacic H, Jaspard-Vinassa B, Jecko V, Wavasseur T, Fritsch N, Pernot M, Jeaningros S, Roux E, Dufourcq P, Couffinhal T, Duplàa C Abstract Endothelial cells serve as a barrier between blood and tissues. Maintenance of the endothelial cell barrier depends on the integrity of intercellular junctions, which is regulated by a polarity complex that includes the ζ isoform of atypical protein kinase C (PKCζ) and partitionin...
Source: Science Signaling - January 30, 2017 Category: Biomedical Science Authors: Sewduth RN, Kovacic H, Jaspard-Vinassa B, Jecko V, Wavasseur T, Fritsch N, Pernot M, Jeaningros S, Roux E, Dufourcq P, Couffinhal T, Duplàa C Tags: Sci Signal Source Type: research