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Canonical pathways in stroke

John H Griffin, Berislav V Zlokovic, Laurent O Mosnier
Protein C is a plasma serine protease zymogen whose active form, activated protein C (APC), exerts potent anticoagulant activity. In addition to its antithrombotic role as a plasma protease, pharmacologic APC is a pleiotropic protease that activates diverse homeostatic cell signaling pathways via multiple receptors on many cells. Engineering of APC by site-directed mutagenesis provided a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks > 90 % anticoagulant activity but retains normal cell signaling activities...
June 4, 2018: Blood
Natasha Shroff, Bradley P Ander, Xinhua Zhan, Boryana Stamova, DaZhi Liu, Heather Hull, Farah R Hamade, Cheryl Dykstra-Aiello, Kwan Ng, Frank R Sharp, Glen C Jickling
The histone deacetylase 9 (HDAC9) polymorphism rs2107595 is associated with an increased risk for large vessel atherosclerotic stroke (LVAS). In humans, there remains a need to better understand this HDAC9 polymorphism's contribution to large vessel stroke. In this pilot study, we evaluated whether the HDAC9 polymorphism rs2107595 is associated with differences in leukocyte gene expression in patients with LVAS. HDAC9 SNP rs2107595 was genotyped in 155 patients (43 LVAS and 112 vascular risk factor controls)...
April 13, 2018: Translational Stroke Research
Biao Tang, Chang-Qing Deng
Pyroptosis is a form of inflammatory programmed cell death activated by caspase-1 and caspase-4/5/11, and involves in the pathogenesis of infectious diseases and nervous system diseases. Pyroptosis is mediated by canonical inflammasome pathway and non-canonical inflammasome pathway. The canonical inflammasome pathway is activated in stroke and aggravates brain injury. Inhibition of inflammasome, caspase-1, IL-1β and IL-18 ameliorates brain injury. These studies indicate that canonical inflammasome pathway contributes to post-stroke brain injury, therefore, pyroptosis has become a potential therapeutic target for preventing excessive cell death during stroke...
February 25, 2018: Sheng Li Xue Bao: [Acta Physiologica Sinica]
Peng-Qian Wang, Qiong Liu, Wen-Juan Xu, Ya-Nan Yu, Ying-Ying Zhang, Bing Li, Jun Liu, Zhong Wang
Both baicalin (BA) and jasminoidin (JA) are active ingredients in Chinese herb medicine Scutellaria baicalensis and Fructus gardeniae, respectively. They have been shown to exert additive neuroprotective action in ischemic stroke models. In this study we used transcriptome analysis to explore the pure therapeutic mechanisms of BA, JA and their combination (BJ) contributing to phenotype variation and reversal of pathological processes. Mice with middle cerebral artery obstruction were treated with BA, JA, their combination (BJ), or concha margaritifera (CM)...
January 18, 2018: Acta Pharmacologica Sinica
Michael R Jones, Joshua Yue, Angela K Wilson
Improper signaling of the nuclear factor-κB (NF-κB) pathway plays a critical role in many inflammatory disease states including cancer, stroke, and viral infections. Although the signaling pathways are known, how these molecular mechanisms respond to changes in the intracellular microenvironment such as pH, ionic strength, and temperature, remains elusive. Molecular dynamics simulations were employed to differentiate the structural dynamics of the NF-κB Inducing Kinase (NIK), a protein kinase responsible for invoking the non-canonical NF-κB pathway, in its native and mutant form, and in the absence and presence of salt concentration in efforts to probe whether changes in the ionic environment stabilize or destabilize the NIK dimer...
January 8, 2018: Journal of Structural Biology
Audrey Boulamery, Sophie Desplat-Jégo
Observed in many central nervous system diseases, neuroinflammation (NI) proceeds from peripheral immune cell infiltration into the parenchyma, from cytokine secretion and from oxidative stress. Astrocytes and microglia also get activated and proliferate. NI manifestations and consequences depend on its context and on the acute or chronic aspect of the disease. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 pathway has been involved in chronic human inflammatory pathologies such as neurodegenerative, autoimmune, or malignant diseases...
2017: Frontiers in Immunology
Glen C Jickling, Bradley P Ander, Natasha Shroff, Miles Orantia, Boryana Stamova, Cheryl Dykstra-Aiello, Heather Hull, Xinhua Zhan, DaZhi Liu, Frank R Sharp
OBJECTIVE: To evaluate microRNA let7i in ischemic stroke and its regulation of leukocytes. METHODS: A total of 212 patients were studied: 106 with acute ischemic stroke and 106 controls matched for risk factors. RNA from circulating leukocytes was isolated from blood collected in PAXgene tubes. Let7i microRNA expression was assessed using TaqMan quantitative reverse transcription PCR. To assess let7i regulation of gene expression in stroke, messenger RNA (mRNA) from leukocytes was measured by whole-genome Human Transcriptome Array Affymetrix microarray...
November 22, 2016: Neurology
Olivier Martinaud, Nicolas Mirlink, Sandrine Bioux, Evangéline Bliaux, Cécile Champmartin, Dorothée Pouliquen, Yohann Cruypeninck, Didier Hannequin, Emmanuel Gérardin
Agnosia for mirrored stimuli is a rare clinical deficit. Only eight patients have been reported in the literature so far and little is known about the neural substrates of this agnosia. Using a previously developed experimental test designed to assess this agnosia, namely the Mirror and Orientation Agnosia Test (MOAT), as well as voxel-lesion symptom mapping (VLSM), we tested the hypothesis that focal brain-injured patients with right parietal damage would be impaired in the discrimination between the canonical view of a visual object and its mirrored and rotated images...
May 2016: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
Antonio Berretta, Emma K Gowing, Christine L Jasoni, Andrew N Clarkson
Although recovery following a stroke is limited, undamaged neurons under the right conditions can establish new connections and take on-board lost functions. Sonic hedgehog (Shh) signaling is integral for developmental axon growth, but its role after injury has not been fully examined. To investigate the effects of Shh on neuronal sprouting after injury, we used an in vitro model of glial scar, whereby cortical astrocytes were mechanically traumatized to mimic reactive astrogliosis observed after stroke. This mechanical trauma impaired neurite outgrowth from post-natal cortical neurons plated on top of reactive astrocytes...
February 23, 2016: Scientific Reports
Jie Yu, Zhuyun Jiang, Ling Ning, Zhilong Zhao, Na Yang, Lu Chen, Hui Ma, Li Li, Ya Fu, Huifeng Zhu, Hongyi Qi
Heat-shock protein 70 (HSP70) is known to function as a protective molecular chaperone that is massively induced in response to misfolded proteins following cerebral ischemia. The objective of this study was to characterize HSP70 induction by Z-ligustilide and explore its potential role in protection against cerebral ischemia-reperfusion injury. Our results demonstrated that the intranasal administration of Z-ligustilide reduced infarct volume and improved neurological function in a rat stroke model. Meanwhile, Z-ligustilide enhanced the cell viability of PC12 cells insulted by oxygen-glucose deprivation-reoxygenation (OGD-Reoxy) and decreased apoptotic and necrotic cell death...
2015: Biological & Pharmaceutical Bulletin
J M Calandria, A Asatryan, V Balaszczuk, E J Knott, B K Jun, P K Mukherjee, L Belayev, N G Bazan
Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived mediator, induces cell survival in uncompensated oxidative stress (OS), neurodegenerations or ischemic stroke. The molecular principles underlying this protection remain unresolved. We report here that, in retinal pigment epithelial cells, NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways...
August 2015: Cell Death and Differentiation
Li Wu, Yongjun Jiang, Juehua Zhu, Zhuoyu Wen, Xiaohui Xu, Xiaomeng Xu, Yi Xie, Lian Yang, Lili Xu, Wenya Lan, Gelin Xu, Xinfeng Liu
Vascular endothelial growth factor (VEGF) is a promising candidate for the treatment of ischemic stroke. However, accumulating evidence demonstrated that VEGF could exacerbate blood-brain barrier (BBB) disruption after ischemic stroke. This study was designed to investigate the underlying mechanisms. In the present study, a transient (90 min) middle cerebral artery occlusion (MCAO) model was performed to induce ischemic stroke in mice. VEGF was administered intracerebroventricularly 3h after reperfusion. A gene expression microarray was utilized to investigate the differentially expressed genes among the sham, MCAO, and VEGF groups...
October 2014: Brain Research Bulletin
Laurent O Mosnier, Berislav V Zlokovic, John H Griffin
Despite years of research and efforts to translate stroke research to clinical therapy, ischaemic stroke remains a major cause of death, disability, and diminished quality of life. Primary and secondary preventive measures combined with improved quality of care have made significant progress. However, no novel drug for ischaemic stroke therapy has been approved in the past decade. Numerous studies have shown beneficial effects of activated protein C (APC) in rodent stroke models. In addition to its natural anticoagulant functions, APC conveys multiple direct cytoprotective effects on many different cell types that involve multiple receptors including protease activated receptor (PAR) 1, PAR3, and the endothelial protein C receptor (EPCR)...
November 2014: Thrombosis and Haemostasis
Tao Huang, Dakuan Gao, Xiaofan Jiang, Shijie Hu, Lei Zhang, Zhou Fei
Resveratrol (Res) or trans-3,4',5-trihydroxystilbene, has been proven to exert neuroprotective effects in cerebral ischemia. The aim of the present study was to investigate whether Res has neuroprotective effects in primary cortical neurons subjected to transient oxygen-glucose deprivation (OGD) via inhibiting the expression of the gene encoding stromelysin-1, also known as matrix metalloproteinase-3 (MMP-3), and via inhibiting cell apoptosis. Primary cortical cells were exposed to OGD, followed by reoxygenation to induce transient ischemia...
August 2014: Molecular Medicine Reports
Xinyu Wang, James A Bynum, Solomon Stavchansky, Phillip D Bowman
Cellular damage from oxidative stress, in particular following ischemic injury, occurs during heart attack, stroke, or traumatic injury, and is potentially reducible with appropriate drug treatment. We previously reported that caffeic acid phenethyl ester (CAPE), a plant-derived polyphenolic compound, protected human umbilical vein endothelial cells (HUVEC) from menadione-induced oxidative stress and that this cytoprotective effect was correlated with the capacity to induce heme oxygenase-1 (HMOX1) and its protein product, a phase II cytoprotective enzyme...
July 5, 2014: European Journal of Pharmacology
Alexander R Edelmann, Sarah Schwartz-Baxter, Christopher F Dibble, Warren C Byrd, Jim Carlson, Ivandario Saldarriaga, Sompop Bencharit
UNLABELLED: Cerebral cavernous malformations (CCM) are vascular anomalies caused by mutations in genes encoding KRIT1, OSM and PDCD10 proteins causing hemorrhagic stroke. We examine proteomic change of loss of CCM gene expression. Using human umbilical vein endothelial cells, label-free differential protein expression analysis with multidimensional liquid chromatography/tandem mass spectrometry was applied to three CCM protein knockdown cell lines and two control cell lines: ProteomeXchange identifier PXD000362...
June 2014: Expert Review of Proteomics
Marco Francesco Morini, Elisabetta Dejana
PURPOSE OF REVIEW: The development of a functionally and anatomically correct vascular network is a complex phenomenon that requires the combined activity of different signaling pathways and transcription factors. Notch signaling activation, for instance, is crucial for arterial specification. Here, we discuss the current knowledge on how other signaling pathways cooperate with Notch to orchestrate arterial differentiation of embryonic and postnatal vasculature. RECENT FINDINGS: The role of Notch in vascular development and arterial differentiation is well known...
May 2014: Current Opinion in Hematology
Jaquette Liljencrantz, Andrew Marshall, Rochelle Ackerley, Håkan Olausson
Recently, several studies have suggested a role for unmyelinated (C-tactile, CT) low-threshold mechanoreceptive afferents in the allodynic condition. In this psychophysical study we explored the integrity of both Aβ and CT afferent processing following application of the heat capsaicin model of tactile allodynia on the left forearm in healthy subjects (n=40). We measured tactile direction discrimination (TDD) to target the integrity of Aβ processing (n=20). The TDD accuracy was significantly lower in the allodynic compared to a control zone...
March 20, 2014: Neuroscience Letters
Luis M Blanco-Colio
Cardiovascular diseases (CVD) are the first cause of mortality in Western countries. CVD include several pathologies such as coronary heart disease, stroke or cerebrovascular accident, congestive heart failure, peripheral arterial disease, and aortic aneurysm, among others. Interaction between members of the tumor necrosis factor (TNF) superfamily and their receptors elicits several biological actions that could participate in CVD. TNF-like weak inducer of apoptosis (TWEAK) and its functional receptor and fibroblast growth factor-inducible molecule 14 (Fn14) are two proteins belonging to the TNF superfamily that activate NF-κB by both canonical and non-canonical pathways and regulate several cell functions such as proliferation, migration, differentiation, cell death, inflammation, and angiogenesis...
2014: Frontiers in Immunology
Robert W Freilich, Maya E Woodbury, Tsuneya Ikezu
Neuroinflammation contributes to many neurologic disorders including Alzheimer's disease, multiple sclerosis, and stroke. Microglia is brain resident myeloid cells and have emerged as a key driver of the neuroinflammatory responses. MicroRNAs (miRNAs) provide a novel layer of gene regulation and play a critical role in regulating the inflammatory response of peripheral macrophages. However, little is known about the miRNA in inflammatory activation of microglia. To elucidate the role that miRNAs have on microglial phenotypes under classical (M1) or alternative (M2) activation under lipopolysaccharide ('M1'-skewing) and interleukin-4 ('M2a'-skewing) stimulation conditions, we performed microarray expression profiling and bioinformatics analysis of both mRNA and miRNA using primary cultured murine microglia...
2013: PloS One
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