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  • 1
    Keywords: PEPTIDE ; CELLS ; EXPRESSION ; CELL ; Germany ; KINASE ; DEATH ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; NF-KAPPA-B ; FAMILY ; INDUCTION ; INTERVENTION ; PROTEIN-KINASE ; SEQUENCE ; SEQUENCES ; TARGET ; MOUSE ; IDENTIFICATION ; gene expression ; CELL-DEATH ; NUMBER ; PRODUCT ; OVEREXPRESSION ; RAT-BRAIN ; P21(WAF1/CIP1) ; CYCLIN G1 ; differential display,focal cerebral ischaemia,gene expression,middle cerebral artery occlusion,mouse ; PHOSPHORYLATES HUMAN CDC25C ; SERINE-216
    Abstract: Cerebral ischaemia induces transcriptional changes in a number of pathophysiologically important genes. Here we have systematically studied gene expression changes after 90 min and 24 h of permanent focal ischaemia in the mouse by an advanced fragment display technique (restriction-mediated differential display). We identified 56 transcriptionally altered genes, many of which provide novel hints to ischaemic pathophysiology. Particularly interesting were two pro-apoptotic genes (Grim19 and Tdag51), whose role in cerebral ischaemia and neuronal cell death has not been recognized so far. Among the unknown sequences, we identified a gene that was rapidly and transiently up-regulated. The encoded protein displayed high homology to the MARK family of serine-threonine protein kinases and has recently been described as MARKL1/MARK4. Here we demonstrate that this protein is a functional protein kinase with the ability to specifically phosphorylate a cognate peptide substrate for the AMP-kinase family. Upon overexpression in heterologous cells, the functional wild-type protein, but not its kinase-dead mutant, led to decreased cell viability. We conclude that the up-regulation of this kinase during focal ischaemia may represent an interesting new target for pharmacological intervention
    Type of Publication: Journal article published
    PubMed ID: 15009667
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; SURVIVAL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; IN-VIVO ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; VITRO ; GENERATION ; VOLUME ; DEATH ; DISEASE ; DISEASES ; DRUG ; DIFFERENTIATION ; LIGAND ; MECHANISM ; RAT ; CELL-SURVIVAL ; CELL-DEATH ; LONG-TERM SURVIVAL ; TRANSIENT GLOBAL-ISCHEMIA ; STEM-CELLS ; CENTRAL-NERVOUS-SYSTEM ; COLONY-STIMULATING FACTOR ; STROKE ; signaling ; ADULT ; FOCAL CEREBRAL-ISCHEMIA ; NEURONS ; cell survival ; CEREBRAL-ISCHEMIA ; NEURAL STEM-CELLS ; cell death ; progenitor ; FUNCTIONAL RECOVERY ; MATURE ; RECOVERY ; NEURONAL DIFFERENTIATION ; HIPPOCAMPAL-NEURONS ; FACTOR G-CSF ; INFARCT ; NEWLY GENERATED NEURONS ; RAT DENTATE GYRUS
    Abstract: G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong antiapoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases
    Type of Publication: Journal article published
    PubMed ID: 16007267
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  • 3
    Keywords: 3-KINASE, AKT, APOPTOSIS, ARTERY, BARRIER, Bcl-2, BLOOD, BLOOD-BRAIN, BLOOD-BRAIN-BARRIER, BLOOD-FLO
    Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine responsible for the proliferation, differentiation, and maturation of cells of the myeloid lineage, which was cloned more than 20 years ago. Here we uncovered a novel function of GM-CSF in the central nervous system (CNS). We identified the GM-CSF alpha-receptor as an upregulated gene in a screen for ischemia-induced genes in the cortex. This receptor is broadly expressed on neurons throughout the brain together with its ligand and induced by ischemic insults. In primary cortical neurons and human neuroblastoma cells, GM-CSF counteracts programmed cell death and induces BCL-2 and BCL-XI expression in a dose- and time-dependent manner. Of the signaling pathways studied, GMCSF most prominently induced the PI3K-Akt pathway, and inhibition of Akt strongly decreased antiapoptotic activity. Intravenously given GM-CSF passes the blood-brain barrier, and decreases infarct damage in two different experimental stroke models (middle cerebral artery occlusion (MCAO), and combined common carotid/distal MCA occlusion) concomitant with induction of BCL-XI expression. Thus, GM-CSF acts as a neuroprotective protein in the CNS. This finding is remarkably reminiscent of the recently discovered functionality of two other hematopoietic factors, erythropoietin and granulocyte colony-stimulating factor in the CNS. The identification of a third hematopoietic factor acting as a neurotrophic factor in the CNS suggests a common principle in the functional evolution of these factors. Clinically, GM-CSF now broadens the repertoire of hematopoietic factors available as novel drug candidates for stroke and neurodegenerative diseases
    Type of Publication: Journal article published
    PubMed ID: 17457367
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; VITRO ; VIVO ; DISEASE ; GENE ; DRUG ; DIFFERENTIATION ; MICE ; MRI ; BIOLOGY ; TARGET ; MOUSE ; TRANSGENIC MICE ; FIBER ; INSTABILITY ; LENGTH ; NEURITE OUTGROWTH ; INJURY ; G-CSF ; DEFICIENT MICE ; FOCAL CEREBRAL-ISCHEMIA ; HIPPOCAMPAL ; FUNCTIONAL RECOVERY ; spinal cord injury ; HIPPOCAMPAL-NEURONS ; FACTOR G-CSF ; regeneration ; outcome ; SPINAL-CORD-INJURY ; CORTICOSPINAL TRACT ; hematopoietic growth factor ; MANGANESE-ENHANCED MRI ; MOTOR FUNCTION ; PROMOTES RECOVERY ; RESONANCE-IMAGING MEMRI
    Abstract: P〉Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth factor, protects neurons in vitro and in vivo, and has regenerative potential in various neurological disease models. Spinal cord injury (SCI) following trauma or secondary to skeletal instability is a terrible condition with no effective therapies available at present. In this study, we show that the G-CSF receptor is up-regulated upon experimental SCI and that G-CSF improves functional outcome in a partial dissection model of SCI. G-CSF significantly decreases apoptosis in an experimental partial spinal transsection model in the mouse and increases expression of the anti-apoptotic G-CSF target gene Bcl-X-L. In vitro, G-CSF enhances neurite outgrowth and branching capacity of hippocampal neurons. In vivo, G-CSF treatment results in improved functional connectivity of the injured spinal cord as measured by Mn2+-enhanced MRI. G-CSF also increased length of the dorsal corticospinal tract and density of serotonergic fibers cranial to the lesion center. Mice treated systemically with G-CSF as well as transgenic mice over-expressing G-CSF in the CNS exhibit a strong improvement in functional outcome as measured by the BBB score and gridwalk analysis. We show that G-CSF improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. We conclude that G-CSF constitutes a promising and feasible new therapy option for SCI
    Type of Publication: Journal article published
    PubMed ID: 20202082
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  • 5
    Abstract: It has been suggested that the behavior and function of Paneth cells in metaplasia are different from those found in normal intestinal mucosa. In this study, we investigated whether calnexin, a protein involved in secretory pathways, might be associated with differentiation and function of Paneth cells in normal small intestine, in complete intestinal metaplasia of the stomach, and in Paneth cell-rich adenomas. Differentiation and function of Paneth cells was monitored by Ki67, lysozyme, and morphologic features. Using a newly established monoclonal antibody, we found that calnexin is regularly synthesized by Paneth cells of normal small intestine. In these cells, the staining intensity of calnexin was inversely correlated with their content of secretory granules (lysozyme). In contrast, Paneth cells of intestinal metaplasia and Paneth cell-rich adenomas showed a reduced immunostaining of both calnexin and lysozyme. Moreover, these Paneth cells synthesized the proliferation marker Ki67, a phenomenon that was never observed in Paneth cells of normal small intestine. In vitro experiments using CaCo2 cells showed that the expression of calnexin is not directly affected by the induction of mitosis. In conclusion, calnexin probably reflects the status of Paneth cell differentiation and function. The results do not necessarily indicate that calnexin has a function in Paneth cell proliferation.
    Type of Publication: Journal article published
    PubMed ID: 12480915
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