Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the past 7 years, West Nile zoonosis has been an emerging concern for public health in Europe, Middle East and more recently in North America. West Nile virus causes epidemic outbreaks in humans and infected patients may exhibit severe neurological symptoms. Because susceptibility and sensitivity to West Nile virus infections may depend on host genetic factors, a mouse model has been established to investigate the genetic determinism of host susceptibility to West Nile virus. A nonsense mutation in gene encoding the 1b isoform of the 2'-5'oligoadenylate synthetase (OAS1b) was constantly associated with the susceptibility of mouse strains to experimental West Nile virus infection. Oligoadenylate synthetase are interferon-inducible proteins playing a role in the endogeneous antiviral pathway. It was of interest to establish whether interferon-alpha and OAS 1B were sufficient to mediate resistance to West Nile virus infection. In the present study, we showed that interferon-alpha had the ability to modulate West Nile virus infection in mouse. In vitro, interferon-alpha protected mouse neuroblastoma cells against West Nile virus infection if cells have been pretreated with the cytokine for several hours. As a consequence of the presence of a stop codon, the Oas1b gene of the susceptible mice encodes a truncated and presumably inactive form, while resistant mice have a normal copy of the gene. Stable mouse neuroblastoma cell clones overexpressing mutant or wild-type OAS 1B were established. Replication of West Nile virus was less efficient in cells that produce the normal copy of OAS 1B as compared to those expressing the truncated form. Our data illustrate the notion that interferon-alpha and Oas genes may be critical for West Nile virus pathogenesis.
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PMID:Infection of mouse neurones by West Nile virus is modulated by the interferon-inducible 2'-5' oligoadenylate synthetase 1b protein. 1275 88

This study attempts to isolate and characterize West Nile virus-binding molecules on the plasma membrane of Vero and murine neuroblastoma cells that is responsible for virus entry. Pretreatment of Vero cells with proteases, glycosidases (endoglycosidase H, alpha-mannosidase), and sodium periodate strongly inhibited West Nile virus infection, whereas treatments with phospholipases and heparinases had no effect. The virus overlay protein blot detected a 105-kDa molecule on the plasma membrane extract of Vero and murine neuroblastoma cells that bind to WN virus. Treatment of the 105-kDa molecules with beta-mercaptoethanol resulted in the virus binding to a series of lower molecular weight bands ranging from 30 to 40 kDa. The disruption of disulfide-linked subunits did not affect virus binding. N-linked sugars with mannose residues on the 105-kDa membrane proteins were found to be important in virus binding. Specific antibodies against the 105-kDa glycoprotein were highly effective in blocking virus entry. These results strongly supported the possibility that the 105-kDa protease-sensitive glycoprotein with complex N-linked sugars could be the putative receptor for WN virus.
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PMID:Characterization of a 105-kDa plasma membrane associated glycoprotein that is involved in West Nile virus binding and infection. 1291 50

Lyssaviruses, which are members of the Rhabdoviridae family, induce apoptosis, which plays an important role in the neuropathogenesis of rabies. However, the mechanisms by which these viruses mediate neuronal apoptosis have not been elucidated. Here we demonstrate that the early induction of apoptosis in a model of lyssavirus-infected neuroblastoma cells involves a TRAIL-dependent pathway requiring the activation of caspase-8 but not of caspase-9 or caspase-10. The activation of caspase-8 results in the activation of caspase-3 and caspase-6, as shown by an increase in the cleavage of the specific caspase substrate in lyssavirus-infected cells. However, neither caspase-1 nor caspase-2 activity was detected during the early phase of infection. Lyssavirus-mediated cell death involves an interaction between TRAIL receptors and TRAIL, as demonstrated by experiments using neutralizing antibodies and soluble decoy TRAIL-R1/R2 receptors. We also demonstrated that the decapsidation and replication of lyssavirus are essential for inducing apoptosis, as supported by UV inactivation, cycloheximide treatment, and the use of bafilomycin A1 to inhibit endosomal acidification. Transfection of cells with the matrix protein induced apoptosis using pathways similar to those described in the context of viral infection. Furthermore, our data suggest that the matrix protein of lyssaviruses plays a major role in the early induction of TRAIL-mediated apoptosis by the release of a soluble, active form of TRAIL. In our model, Fas ligand (CD95L) appears to play a limited role in lyssavirus-mediated neuroblastoma cell death. Similarly, tumor necrosis factor alpha does not appear to play an important role.
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PMID:Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation. 1516 47

Dengue virus requires the presence of an unidentified cellular receptor on the surface of the host cell. By using a recently published affinity chromatography approach, an 84-kDa molecule, identified as heat shock protein 90 (HSP90) by matrix-assisted laser desorption ionization-time of flight mass spectrometry, was isolated from neuroblastoma and U937 cells. Based on the ability of HSP90 (84 kDa) to interact with HSP70 (74 kDa) on the surface of monocytes during lipopolysaccharide (LPS) signaling and evidence that LPS inhibits dengue virus infection, the presence of HSP70 was demonstrated in affinity chromatography eluates and by pull-down experiments. Infection inhibition assays support the conclusion that HSP90 and HSP70 participate in dengue virus entry as a receptor complex in human cell lines as well as in monocytes/macrophages. Additionally, our results indicate that both HSPs are associated with membrane microdomains (lipid rafts) in response to dengue virus infection. Moreover, methyl-beta-cyclodextrin, a raft-disrupting drug, inhibits dengue virus infection, supporting the idea that cholesterol-rich membrane fractions are important in dengue virus entry.
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PMID:Heat shock protein 90 and heat shock protein 70 are components of dengue virus receptor complex in human cells. 1579 42

The mechanisms that mediate innate immune recognition of CNS infections are unknown. This study provides a comparison of Toll-like receptor (TLR) gene expression in resting and virus infected CNS cells. N2a neuroblastoma cells expressed TLR 3 but demonstrated no change in TLR gene expression in response to either LPS or virus infection. N9 microglia and differentiated primary astrocytes expressed most TLR genes. TLR 2 expression was highest in N9 microglia and TLR 7 in astrocytes. In both glial cell types, LPS stimulation upregulated pro-inflammatory cytokines, TLR 2 and TLR 3 gene expression but down-regulated other TLR genes. RNA virus infection substantially increased levels of type-I interferon (IFN) and TLR 3 transcripts and to a lesser extent TLR 9 transcripts. Microglia and astrocytes thus have the ability to discriminate between pathogens and elicit an appropriate response.
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PMID:In response to pathogens, glial cells dynamically and differentially regulate Toll-like receptor gene expression. 1614 56

Increased expression of inducible nitric oxide synthase has been shown in murine Venezuelan equine encephalitis (VEE) virus infection. In this experimental model, melatonin (MTL) treatment has shown to be beneficial. The aim of this study was to determine the effect of VEE virus on the nitric oxide (NO) production and lipid peroxidation in neuroblastoma cell cultures, and to investigate the role of MTL during cell-virus interaction. Neuroblastoma cells were co-cultured with VEE virus and treated with MTL at doses ranging from 0 to 1.8 mM, for 6, 12, 24 and 48 h. NO and lipid peroxidation were measured in culture supernatants and in the cellular content by nitrite concentration and thiobarbituric acid assay, respectively. Expression of inducible nitric oxide synthase (iNOS) was determined by indirect immunofluorescence. Increased production of NO and lipid peroxidation products were found in supernatants and cellular contents of VEE virus treated cultures. Both NO and lipid peroxidation were decreased by MTL treatment in a time dependent manner. Increased iNOS expression was observed in VEE virus infected cultures that was reduced by MTL treatment. These results could be related to the beneficial role of MTL in the VEE experimental disease and address the possible therapeutic potential of the hormone in human VEE virus infection.
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PMID:Melatonin decreases nitric oxide production, inducible nitric oxide synthase expression and lipid peroxidation induced by Venezuelan encephalitis equine virus in neuroblastoma cell cultures. 1680 53

The activity of Topoisomerase II alpha and beta isoforms is tightly regulated during different phases of cell cycle. In the present study, the action of anti-inflammatory agents, nordihydroguaretic acid (NDGA) is analyzed in HIV-1 infected CXCR4(+), CCR5(+) and CD4(-) SK-N-SH neuroblastoma, CXCR4(+), CCR5(+) and CD4(-) 1321N1 astrocytoma and CXCR4(+), CCR5(+/-) and CD4(-) GO-G-CCM glioblastoma cell lines. In SK-N-SH and 1321N1 the expression of Topoisomerase II alpha is concomitant with that of LOX-5 and is highly sensitive to NDGA, while the Topoisomerase II beta is expressed along with TNFalpha and exhibits low sensitivity to NDGA, suggesting distinct pathways of regulation for the two isoforms. HIV-1 infection in these cells enhanced the expression of Topo II alpha and beta. Further, the regulation of Topo II beta and TNFalpha in infected and uninfected SK cells is distinctly different. HIV-1 gp120 derived peptides could block HIV-1 mediated inflammation and Topoisomerase II alpha and beta expression, suggesting the viral mediated response. A combination of NDGA, gp-120 derived peptides and AZT has completely blocked the viral replication, suggesting the enhancement of potency of AZT under the suppression of inflammatory response. In contrast, the expression of Topo II alpha and beta was stimulated by NDGA in GO-G-CCM cells showing distinct regulatory pathway in these cells that was resistant to HIV-1 infection. This suggests the requirement of inflammatory response for productive viral infection. In summary, an induction of co-receptor mediated inflammatory response can distinctly enhance regulated expression of the cellular Topo II alpha and beta and promote productive infection in neurons and astrocytes.
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PMID:Regulation of topoisomerase II alpha and beta in HIV-1 infected and uninfected neuroblastoma and astrocytoma cells: involvement of distinct nordihydroguaretic acid sensitive inflammatory pathways. 1739 42

While a number of studies have documented the neurotropism of Japanese encephalitis virus (JEV), little is known regarding the molecular mechanism of neuronal death following viral infection. The tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) has been suggested to be the crucial signal adaptor that mediates all intracellular responses from TNFR-1. Using mouse (Neuro2a) and human (SK-N-SH) neuroblastoma cell lines, we have shown that the altered expression of TNFR-1 and TRADD following JEV infection regulates the downstream apoptotic cascades. Activation of TRADD led to mitochondria-mediated neuronal apoptosis. As TRADD-knockout animals or deficient cell lines are unavailable, it has been difficult to definitively address the physiological role of TRADD in diseases pathology following JEV infection. We circumvented this problem by silencing TRADD expression with small-interfering RNA (siRNA) and have found that TRADD is required for TNFR-1-initiated neuronal apoptosis following in vitro infection with JEV. Interestingly, siRNA against TRADD also decreased the viral load in Neuro2a cells. Furthermore, siRNA against TRADD increased the survival of JEV-infected mice by altering the expression of pro apoptotic versus antiapoptotic molecules. These studies show that the engagement of TNFR-1 and TRADD following JEV infection plays a crucial role in neuronal apoptosis.
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PMID:Tumor necrosis factor receptor-1-induced neuronal death by TRADD contributes to the pathogenesis of Japanese encephalitis. 1766 51

Measles virus remains a substantial cause of morbidity and mortality, producing acute infection with a potential for development of viral persistence. To study the events underlying acute and persistent measles virus infection, we performed a global transcriptional analysis on murine neuroblastoma cells that were acutely or persistently infected with measles virus. In general, we found that acute infection induced significantly more gene expression changes than did persistent infection. A functional enrichment analysis to identify which host pathways were perturbed during each of these infections identified several pathways related to cholesterol biosynthesis, including cholesterol metabolic processes, hydroxymethylglutaryl-coenzyme A (CoA) reductase activity, and acetyl-CoA C-acetyltransferase activity. We also found that measles virus colocalized to lipid rafts in both acute and persistent infection models and that the majority of genes associated with cholesterol synthesis were downregulated in persistent infection relative to acute infection, suggesting a possible link with the defective viral budding in persistent infection. Further, we found that pharmacological inhibition of cholesterol synthesis resulted in the inhibition of viral budding during acute infection. In summary, persistent measles viral infection was associated with decreased cholesterol synthesis, a lower abundance of cholesterol and lipid rafts in the cell membrane, and inhibition of giant-cell formation and release of viral progeny.
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PMID:Impaired cholesterol biosynthesis in a neuronal cell line persistently infected with measles virus. 1929 98

Inhibitory M(2) muscarinic receptors on airway parasympathetic nerves normally limit acetylcholine release. Viral infections decrease M(2) receptor function, increasing vagally mediated bronchoconstriction. Since retinoic acid deficiency causes M(2) receptor dysfunction, we tested whether retinoic acid would prevent virus-induced airway hyperreactivity and prevent M(2) receptor dysfunction. Guinea pigs infected with parainfluenza virus were hyperreactive to electrical stimulation of the vagus nerves, but not to intravenous acetylcholine, indicating that hyperreactivity was due to increased release of acetylcholine from parasympathetic nerves. The muscarinic agonist pilocarpine, which inhibits vagally mediated bronchoconstriction in control animals, no longer inhibited vagally induced bronchoconstriction, demonstrating M(2) receptor dysfunction. Treatment with all-trans retinoic acid (1 mg/kg) prevented virus-induced hyperreactivity and M(2) receptor dysfunction. However, retinoic acid also significantly reduced viral titers in the lungs and attenuated virus-induced lung inflammation. In vitro, retinoic acid decreased M(2) receptor mRNA expression in both human neuroblastoma cells and primary cultures of airway parasympathetic neurons. Thus, the protective effects of retinoic acid on airway function during viral infection appear to be due to anti-inflammatory and antiviral mechanisms, rather than to direct effects on M(2) receptor gene expression.
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PMID:Retinoic acid prevents virus-induced airway hyperreactivity and M2 receptor dysfunction via anti-inflammatory and antiviral effects. 1946 17


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