88 research outputs found

    RGMa inhibition promotes axonal growth and recovery after spinal cord injury

    Get PDF
    Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We report RGMa as a potent inhibitor of axon regeneration in the adult central nervous system (CNS). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the RhoA–Rho kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is induced around the injury site after spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration

    SICA-mediated cytoadhesion of Plasmodium knowlesi-infected red blood cells to human umbilical vein endothelial cells

    Get PDF
    Zoonotic malaria due to Plasmodium knowlesi infection in Southeast Asia is sometimes life-threatening. Post-mortem examination of human knowlesi malaria cases showed sequestration of P. knowlesi-infected red blood cells (iRBCs) in blood vessels, which has been proposed to be linked to disease severity. This sequestration is likely mediated by the cytoadhesion of parasite-iRBCs to vascular endothelial cells; however, the responsible parasite ligands remain undetermined. This study selected P. knowlesi lines with increased iRBC cytoadhesion activity by repeated panning against human umbilical vein endothelial cells (HUVECs). Transcriptome analysis revealed that the transcript level of one gene, encoding a Schizont Infected Cell Agglutination (SICA) protein, herein termed SICA-HUVEC, was more than 100-fold increased after the panning. Transcripts of other P. knowlesi proteins were also significantly increased, such as PIR proteins exported to the iRBC cytosol, suggesting their potential role in increasing cytoadhesion activity. Transgenic P. knowlesi parasites expressing Myc-fused SICA-HUVEC increased cytoadhesion activity following infection of monkey as well as human RBCs, confirming that SICA-HUVEC conveys activity to bind to HUVECs

    Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death

    Get PDF
    Recent studies have suggested that neuronal death in Alzheimer's disease or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-β (Aβ)–induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans. We found that human caspase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not with other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of Aβ, and Aβ-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus, caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease

    In Vivo Function and Evolution of the Eutherian-Specific Pluripotency Marker UTF1

    No full text
    Embryogenesis in placental mammals is sustained by exquisite interplay between the embryo proper and placenta. UTF1 is a developmentally regulated gene expressed in both cell lineages. Here, we analyzed the consequence of loss of the UTF1 gene during mouse development. We found that homozygous UTF1 mutant newborn mice were significantly smaller than wild-type or heterozygous mutant mice, suggesting that placental insufficiency caused by the loss of UTF1 expression in extra-embryonic ectodermal cells at least in part contributed to this phenotype. We also found that the effects of loss of UTF1 expression in embryonic stem cells on their pluripotency were very subtle. Genome structure and sequence comparisons revealed that the UTF1 gene exists only in placental mammals. Our analyses of a family of genes with homology to UTF1 revealed a possible mechanism by which placental mammals have evolved the UTF1 genes.This study was supported in part by the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), and mostly by the Support Program for the Strategic Research Foundation at Private Universities, 2008–2012. This study was performed as a part of the Core Research for Evolutional Science and Technology (CREST) Agency. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

    Single- versus two- layer intestinal anastomosis: a meta-analysis of randomized controlled trials

    Get PDF
    BACKGROUND: To compare single- with two- layer intestinal anastomosis after intestinal resection: a meta-analysis of randomized controlled trials. METHODS: Randomized controlled trials comparing single- with two-layer intestinal anastomosis were identified using a systematic search of Medline, Embase and the Cochrane Library Databases covering articles published from 1966 to 2004. Outcome of primary interest was postoperative leak. A risk ratio for trial outcomes and weighted pooled estimates for data were calculated. A fixed-effect model weighted using Mantel-Haenszel methods and a random-effect model using DerSimonian-Laird methods were employed. RESULTS: Six trials were analyzed, comprising 670 participants (single-layer group, n = 299; two-layer group, n = 371). Data on leaks were available from all included studies. Combined risk ratio using DerSimonian-Laird methods was 0.91 (95% CI = 0.49 to 1.69), and indicated no significant difference. Inter-study heterogeneity was significant (χ(2 )= 10.5, d.f. = 5, p = 0.06). CONCLUSION: No evidence was found that two-layer intestinal anastomosis leads to fewer post-operative leaks than single layer. Considering duration of the anastomosis procedure and medical expenses, single-layer intestinal anastomosis appears to represent the optimal choice for most surgical situations

    An In Vitro Model for Lewy Body-Like Hyaline Inclusion/Astrocytic Hyaline Inclusion: Induction by ER Stress with an ALS-Linked SOD1 Mutation

    Get PDF
    Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) containing mutant Cu/Zn superoxide dismutase 1 (SOD1) are morphological hallmarks of familial amyotrophic lateral sclerosis (FALS) associated with mutant SOD1. However, the mechanisms by which mutant SOD1 contributes to formation of LBHI/Ast-HI in FALS remain poorly defined. Here, we report induction of LBHI/Ast-HI-like hyaline inclusions (LHIs) in vitro by ER stress in neuroblastoma cells. These LHI closely resemble LBHI/Ast-HI in patients with SOD1-linked FALS. LHI and LBHI/Ast-HI share the following features: 1) eosinophilic staining with a pale core, 2) SOD1, ubiquitin and ER resident protein (KDEL) positivity and 3) the presence of approximately 15–25 nm granule-coated fibrils, which are morphological hallmark of mutant SOD1-linked FALS. Moreover, in spinal cord neurons of L84V SOD1 transgenic mice at presymptomatic stage, we observed aberrant aggregation of ER and numerous free ribosomes associated with abnormal inclusion-like structures, presumably early stage neuronal LBHI. We conclude that the LBHI/Ast-HI seen in human patients with mutant SOD1-linked FALS may arise from ER dysfunction

    Vascular and Neuronal Network Formation Regulated by Growth Factors and Guidance Cues

    No full text
    Blood vessels and nerves are distributed throughout the body and show a high degree of anatomical parallelism and functional crosstalk. These networks transport oxygen, nutrients, and information to maintain homeostasis. Thus, disruption of network formation can cause diseases. Nervous system development requires the navigation of the axons of neurons to their correct destination. Blood vessel formation occurs via vasculogenesis and angiogenesis. Vasculogenesis is the process of de novo blood vessel formation, and angiogenesis is the process whereby endothelial cells sprout from pre-existing vessels. Both developmental processes require guidance molecules to establish precise branching patterns of these systems in the vertebrate body. These network formations are regulated by growth factors, such as vascular endothelial growth factor; and guidance cues, such as ephrin, netrin, semaphorin, and slit. Neuronal and vascular structures extend lamellipodia and filopodia, which sense guidance cues that are mediated by the Rho family and actin cytosol rearrangement, to migrate to the goal during development. Furthermore, endothelial cells regulate neuronal development and vice versa. In this review, we describe the guidance molecules that regulate neuronal and vascular network formation

    Vascular and Neuronal Network Formation Regulated by Growth Factors and Guidance Cues

    No full text
    Blood vessels and nerves are distributed throughout the body and show a high degree of anatomical parallelism and functional crosstalk. These networks transport oxygen, nutrients, and information to maintain homeostasis. Thus, disruption of network formation can cause diseases. Nervous system development requires the navigation of the axons of neurons to their correct destination. Blood vessel formation occurs via vasculogenesis and angiogenesis. Vasculogenesis is the process of de novo blood vessel formation, and angiogenesis is the process whereby endothelial cells sprout from pre-existing vessels. Both developmental processes require guidance molecules to establish precise branching patterns of these systems in the vertebrate body. These network formations are regulated by growth factors, such as vascular endothelial growth factor; and guidance cues, such as ephrin, netrin, semaphorin, and slit. Neuronal and vascular structures extend lamellipodia and filopodia, which sense guidance cues that are mediated by the Rho family and actin cytosol rearrangement, to migrate to the goal during development. Furthermore, endothelial cells regulate neuronal development and vice versa. In this review, we describe the guidance molecules that regulate neuronal and vascular network formation
    • …
    corecore