<div><h4>Myosin light chain 6 (Myl6) interacts with kindlin-3 and is required to support integrin αβ activation in platelets in mice.</h4><i>Xu Z, Zhou Y, Yu H, Chen X, Ma YQ</i><br /><b>Background</b><br />Kindlin-3 in platelets plays an essential role in supporting integrin α<sub>IIb</sub>β<sub>3</sub> activation, platelet spreading, aggregation, and clot retraction by binding to the integrin β<sub>3</sub> cytoplasmic tail. However, the mechanism by which kindlin-3 mediates the crosstalk between integrin α<sub>IIb</sub>β<sub>3</sub> and myosin in platelets remains unknown.<br /><b>Objectives</b><br />To examine the role of myosin light chain 6 (Myl6) in supporting integrin α<sub>IIb</sub>β<sub>3</sub> activation in platelets.<br /><b>Methods</b><br />Myl6<sup>fl/fl</sup>PF4-Cre mice with a deficiency of Myl6 in the megakaryocyte lineage were generated, and integrin α<sub>IIb</sub>β<sub>3</sub> activation in Myl6-deficient platelets was analyzed.<br /><b>Results</b><br />We identified a novel kindlin-3 binding protein, Myl6, an essential light chain of myosin in platelets. Myl6<sup>fl/fl</sup>PF4-Cre mice exhibited significant macrothrombocytopenia resulting from defective proplatelet formation. In the absence of Myl6, integrin α<sub>IIb</sub>β<sub>3</sub> activation in platelets was significantly suppressed, and platelet aggregation was substantially impaired. Interestingly, the deficiency of Myl6 in platelets preferentially affected the binding of a multivalent ligand compared to a monovalent ligand to integrin α<sub>IIb</sub>β<sub>3</sub> upon activation, indicating that Myl6 may contribute to the avidity modulation of integrin α<sub>IIb</sub>β<sub>3</sub> by binding to kindlin-3. Furthermore, blood coagulation ability was impaired in Myl6<sup>fl/fl</sup>PF4-Cre mice, and consistently, these mice exhibited defects in both hemostatic and thrombotic functions.<br /><b>Conclusion</b><br />In summary, these results suggest that Myl6, as a novel kindlin-3 binding partner, is required to support integrin α<sub>IIb</sub>β<sub>3</sub> activation in platelets, which plays an important role in both hemostasis and thrombosis.<br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 Jul 2024; 22:2009-2017</small></div>

<div><h4>NCAM mimetic peptide P2 synergizes with bone marrow mesenchymal stem cells in promoting functional recovery after stroke.</h4><i>Lan XY, Liang XS, Cao MX, Qin HM, ... Boltze J, Li S</i><br /><AbstractText>The neural cell adhesion molecule (NCAM) promotes neural development and regeneration. Whether NCAM mimetic peptides could synergize with bone marrow mesenchymal stem cells (BMSCs) in stroke treatment deserves investigation. We found that the NCAM mimetic peptide P2 promoted BMSC proliferation, migration, and neurotrophic factor expression, protected neurons from oxygen-glucose deprivation through ERK and PI3K/AKT activation and anti-apoptotic mechanisms <i>in vitro</i>. Following middle cerebral artery occlusion (MCAO) in rats, P2 alone or in combination with BMSCs inhibited neuronal apoptosis and induced the phosphorylation of ERK and AKT. P2 combined with BMSCs enhanced neurotrophic factor expression and BMSC proliferation in the ischemic boundary zone. Moreover, combined P2 and BMSC therapy induced translocation of nuclear factor erythroid 2-related factor, upregulated heme oxygenase-1 expression, reduced infarct volume, and increased functional recovery as compared to monotreatments. Treatment with LY294002 (PI3K inhibitor) and PD98059 (ERK inhibitor) decreased the neuroprotective effects of combined P2 and BMSC therapy in MCAO rats. Collectively, P2 is neuroprotective while P2 and BMSCs work synergistically to improve functional outcomes after ischemic stroke, which may be attributed to mechanisms involving enhanced BMSC proliferation and neurotrophic factor release, anti-apoptosis, and PI3K/AKT and ERK pathways activation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 Jul 2024; 44:1128-1144</small></div>

<div><h4>Vitamin D deficiency promotes intracranial aneurysm rupture.</h4><i>Kimura T, Rahmani R, Miyamoto T, Kamio Y, ... Lawton MT, Hashimoto T</i><br /><AbstractText>Intracranial aneurysm rupture causes severe disability and high mortality. Epidemiological studies show a strong association between decreased vitamin D levels and an increase in aneurysm rupture. However, the causality and mechanism remain largely unknown. In this study, we tested whether vitamin D deficiency promotes aneurysm rupture and examined the underlying mechanism for the protective role of vitamin D against the development of aneurysm rupture utilizing a mouse model of intracranial aneurysm. Mice consuming a vitamin D-deficient diet had a higher rupture rate than mice with a regular diet. Vitamin D deficiency increased proinflammatory cytokines in the cerebral arteries. Concurrently, vitamin D receptor knockout mice had a higher rupture rate than the corresponding wild-type littermates. The vitamin D receptors on endothelial and vascular smooth muscle cells, but not on hematopoietic cells, mediated the effect of aneurysm rupture. Our results establish that vitamin D protects against the development of aneurysmal rupture through the vitamin D receptors on vascular endothelial and smooth muscle cells. Vitamin D supplementation may be a viable pharmacologic therapy for preventing aneurysm rupture.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 Jul 2024; 44:1174-1183</small></div>

<div><h4>The role of serum/glucocorticoid-regulated kinase 1 in brain function following cerebral ischemia.</h4><i>Wu CY, Zhang Y, Xu L, Huang Z, ... Zhang Q, Lee RH</i><br /><AbstractText>Cardiopulmonary arrest (CA) is a major cause of death/disability in the U.S. with poor prognosis and survival rates. Current therapeutic challenges are physiologically complex because they involve hypoperfusion (decreased cerebral blood flow), neuroinflammation, and mitochondrial dysfunction. We previously discovered novel serum/glucocorticoid-regulated kinase 1 (SGK1) is highly expressed in brain of neurons that are susceptible to ischemia (hippocampus and cortex). We inhibited SGK1 and utilized pharmacological (specific inhibitor, GSK650394) and neuron-specific genetic approaches (shRNA) in rodent models of CA to determine if SGK1 is responsible for hypoperfusion, neuroinflammation, mitochondrial dysfunctional, and neurological deficits after CA. Inhibition of SGK1 alleviated cortical hypoperfusion and neuroinflammation (via Iba1, GFAP, and cytokine array). Treatment with GSK650394 enhanced mitochondrial function (via Seahorse respirometry) in the hippocampus 3 and 7 days after CA. Neuronal injury (via MAP2, dMBP, and Golgi staining) in the hippocampus and cortex was observed 7 days after CA but ameliorated with SGK1-shRNA. Moreover, SGK1 mediated neuronal injury by regulating the Ndrg1-SOX10 axis. Finally, animals subjected to CA exhibited learning/memory, motor, and anxiety deficits after CA, whereas SGK1 inhibition via SGK1-shRNA improved neurocognitive function. The present study suggests the fundamental roles of SGK1 in brain circulation and neuronal survival/death in cerebral ischemia-related diseases.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 Jul 2024; 44:1145-1162</small></div>