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)

Severe brain damage in patients with pneumococcal meningitis is in part caused by the cytosolic pneumococcal protein pneumolysin. The devastating effect of this neurotoxin might be alleviated by interfering with the cell death pathways that it sets in motion. An important player in these pathways is Bcl-X(L), an antiapoptotic protein of the Bcl-2 family, which is neuroprotective in various in vitro and in vivo models of cell death. We investigated whether its membrane-permeable form, the TAT-Bcl-X(L) fusion protein, is capable of protecting human SH-SY5Y neuroblastoma cells against pneumolysin-induced cell death. Under mild pneumolysin-induced neuronal injury, TAT-Bcl-X(L) increased cell viability significantly by approximately 40% (82.7 +/- 16.1% versus 70.0+/-8.2%; p = 0.04). When the cells were exposed to a more rigorous pneumolysin treatment, TAT-Bcl-X(L) had no protective effects. This suggests the involvement of additional neuronal death pathways in pneumolysin-induced cell death, which are not controlled by Bcl-X(L). Therefore, Bcl-X(L), a promising therapeutic candidate for ischemia and neurodegenerative diseases, is only of partial efficacy in preventing the direct neurotoxicity of pneumolysin.
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PMID:Limited protection of TAT-Bcl-X(L) against pneumolysin-induced neuronal cell death. 1596 Dec 28

Neuregulins are a family of growth factors with potent neuroprotective properties. We recently demonstrated that neuregulin-1 blocked delayed neuronal death following focal ischemic stroke in the rat. Focal ischemia results in the release of pro-inflammatory cytokines that produce profound changes in gene expression and contribute to cell death associated with stroke. Inflammatory and stress mediators are involved in the pathogenesis of focal ischemic brain damage. We examined whether neuregulin-1 can influence inflammatory and stress gene expression in the rat brain following transient middle cerebral artery occlusion (MCAO). In this study, we compared gene expression profiles in animals treated with neuregulin-1beta (NRG-1) or vehicle followed by MCAO. We used the Affymetrix GeneChip system to analyze gene expression in focal ischemia of the rat brain. Several inflammatory and stress genes were significantly induced following MCAO compared to sham controls including heat shock protein-70 (HSP70), interleukin-1beta, and macrophage chemotattractant protein-1 (JE/MCP-1). Treatment with NRG-1 attenuated the expression of many of these genes by 50% or more. In vitro studies demonstrated that NRG-1 suppressed inflammatory gene expression in activated macrophages. NRG-1 also prevented neuronal death induced by oxygen-glucose deprivation in a rat neuroblastoma cell line, suggesting that NRG-1 may have both direct and indirect neuroprotective capacity. These results demonstrate that NRG-1 can regulate inflammatory and stress gene expression and may give new insight to the molecular mechanisms involved in the neuroprotective role of neuregulins in stroke.
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PMID:Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression. 1602 88

Visceral organs display differential sensitivity to ischemia and reperfusion injury, but the cellular mechanisms underlying these differential responses are not completely understood. A significant response to ischemia identified in brain is stress to the endoplasmic reticulum (ER), as indicated by PKR-like endoplasmic reticulum eIF2alpha kinase (PERK)-mediated phosphorylation of eIF2alpha. To determine the generality of this response, we evaluated the PERK pathway in brain, GI tract, heart, liver, lung, kidney, pancreas and skeletal muscle following a clinically relevant, 10 min cardiac arrest-induced whole body ischemia and either 10 or 90 min reperfusion. The potential role of nitric oxide (NO) on PERK activation was investigated by conducting ischemia and reperfusion in the presence and absence of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME). Organ stress could be ranked with respect to the degree of eIF2alpha phosphorylation at 10 min reperfusion. Brain, kidney and GI tract were reactive organs, showing 15 to 20-fold increases in eIF2alpha(P) compared to controls. Moderately reactive organs included liver and heart, showing <10-fold increases in eIF2alpha(P). Pancreas, lung and skeletal muscle were nonreactive. Although treatment of cultured neuroblastoma 104 cells with the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP) activated PERK, administration of L-NAME had no effect on PERK activation or eIF2alpha phosphorylation in organs following ischemia and reperfusion. Thus, PERK is activated differentially in reperfused organs independent of NO. These results suggest that ER stress may play a role in differential responses of viscera to ischemia and reperfusion. ER stress in viscera may contribute to the pathophysiology of resuscitation from cardiac arrest and during organ transplantation procedures.
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PMID:PERK is activated differentially in peripheral organs following cardiac arrest and resuscitation. 1602 20

Granulocyte colony-stimulating factor (G-CSF) protects neurons against experimental focal cerebral ischemia. However, its neuroprotective effect on human brain is unknown. We sought to determine whether G-CSF can protect the human cerebral neurons in vitro. Human cerebral-neuroblastoma hybrid cell line (A1) was exposed to oxygen and glucose deprivation with or without G-CSF. G-CSF promoted cell survival and decreased cytotoxicity effectively at 25 ng/ml. G-CSF reduced early apoptotic (annexin V+/PI-), and late apoptotic or necrotic (annexin V+/PI+) cells, and decreased active caspase-3 immunoreactivity. G-CSF could protect human cerebral neurons following in vitro ischemia.
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PMID:G-CSF protects human cerebral hybrid neurons against in vitro ischemia. 1629 88

Cilostazol was developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). The anti-platelet and vasodilator properties of cilostazol have been extensively characterized and considered to contribute to the variety of clinical effects such as intermittent claudication and recurrent stroke. In this review, the novel action mechanism (s) of cilostazol are overviewed with the focus on the action of cilostazol in in vitro and in vivo studies as a maxi-K channel opener targeting anti-apoptotic signaling pathways. Under treatment with cilostazol (10 mg/kg intravenously or 30 mg/kg orally), a significant reduction in cerebral infarct area was evident in rats subjected to ischemia/reperfusion. Increase in cyclic AMP and decrease in TNF-alpha levels were identified in the ipsilateral cortex under treatment with cilostazol accompanied by decreased Bax formation and cytochrome c release with increased Bcl-2 production in the penumbral area as well as in the in vitro human umbilical endothelial cells. Cilostazol suppressed TNF-alpha-induced decrease in viability of SK-N-SH (human neuroblastoma) cells and HCN-1A (human cortical neuron) cells in association with decrease in PTEN phosphorylation and increase in Akt/CREB phosphorylation with suppression of DNA fragmentation, all of which were antagonized by iberiotoxin, a maxi-K(+) channel blocker. Further, cilostazol prevented TNF-alpha-induced PTEN phosphorylation and apoptotic cell death via increased CK2 phosphorylation in the SK-N-SH cells. Cilostazol increased K(+) current in SK-N-SH cells by opening the maxi-K channels. Thus, it was suggested that the action of cilostazol to promote cell survival was ascribed to the maxi-K channel opening-coupled upregulation of CK2 phosphorylation and downregulation of PTEN phosphorylation with resultant increased phosphorylation of Akt and CREB. These in vitro data were confirmed in the in vivo results of rats subjected to focal transient ischemic damage.
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PMID:Cilostazol: therapeutic potential against focal cerebral ischemic damage. 1647 48

Several studies have suggested that protein kinase C (PKC) plays a key role in the mechanism of cerebral ischemic/hypoxic preconditioning (I/HPC). However, detailed information regarding PKC isoforms in response to brain ischemia/hypoxia and their potential role in neuroprotection is unclear. Previous studies in our laboratory have demonstrated that the levels in membrane translocation of conventional PKC (cPKC) betaII, gamma, and novel PKCepsilon (nPKC), but not cPKCalpha, betaI, nPKCdelta, eta, mu, theta, and atypical PKC (aPKC) zeta and iota/lambda, were increased significantly in the hippocampus and cortex of intact mice with hypoxic preconditioning. To further detect cPKC and nPKC isoforms activation following prolonged hypoxia in vitro, we tested the membrane translocation (an indicator of PKC activation) of cPKCalpha, betaI, betaII, and gamma, and nPKCdelta, epsilon, eta, mu, and theta in a human neuroblastoma SH-SY5Y cell line following sustained hypoxic exposure (1% O(2)/5% CO(2)/94% N(2)). Using Western blot and immunocytochemistry methods, we found that the levels of cPKCalpha, betaI, betaII, and nPKCepsilon, but not nPKCdelta, eta, mu, and theta, membrane translocation were increased significantly (P < 0.05, n = 8) in a time-dependent manner (from 0.5 to 24 h) following sustained hypoxic exposure. Similarly, the immunostaining experiment also showed a noticeable translocation of cPKCalpha, betaI, betaII, and nPKCepsilon from the cytosol to the perinuclear or membrane-related areas after 6 h posthypoxic exposure. In addition, no cPKCgamma was detected in this cell line under either a normoxic or hypoxic condition. These results suggested that prolonged hypoxia may induce the activation of cPKCalpha, betaI, betaII, and nPKCepsilon by triggering their membrane translocation in SH-SY5Y cells.
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PMID:Increased isoform-specific membrane translocation of conventional and novel protein kinase C in human neuroblastoma SH-SY5Y cells following prolonged hypoxia. 1668 11

In recent years endothelin-converting enzyme (ECE-1) has been suggested to play an important role in amyloid-beta peptide metabolism as one of the amyloid-degrading enzymes. In this connection, the analysis of the levels of expression and distribution of ECE-1 in the brain under normal and pathologic conditions could be important in neurodegeneration and pathogenesis of Alzheimer disease. In our previous studies, we have demonstrated that expression of ECE-1 was significantly reduced in the cortex of adult rats after 15 mins of global ischemia. It was also significantly reduced in the striatum of rats subjected to prenatal hypoxia. In the present study, we analyzed effects of hypoxia and oxidative stress on ECE-1 in human neuroblastoma NB7 cells and effects of the cholinergic agonist carbachol and the phorbol ester, phorbol 12-myristate 13-acetate (PMA). We have found that chronic (24 hrs) hypoxia and oxidative stress resulted in 30% and 20% decrease in expression of ECE-1 at the protein level, respectively, although at the level of ECE-1 mRNA there were no statistically significant changes. Serum withdrawal from the incubation medium as well as addition of carbachol or PMA for 24 hrs also led to a significant reduction of the levels of ECE-1 protein in NB7 cells. Further study of the downstream signaling cascades involved in downregulation of ECE expression in NB7 cells and primary neuronal cells might provide us with new insights into possible therapeutic strategies for prevention or treatment of Alzheimer disease in elderly patients and those who suffer from stroke or cerebrovascular disorders.
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PMID:Regulation of endothelin-converting enzyme-1 expression in human neuroblastoma cells. 1674 Oct 47

Bax ihibitor-1 (BI-1) has been characterized as an inhibitor of Bax-induced cell death in plants and various mammalian cell systems. To explore the function of BI-1 in neurons, we overexpressed BI-1 tagged to HA or GFP in rat nigral CSM14.1 and human SH-SY5Y neuroblastoma cells. Stable BI-1 expression proved marked protection from cell death induced by thapsigargine, a stress agent blocking the Ca2+-ATPase of the endoplasmic reticulum (ER) but failed to inhibit cell death induced by staurosporine, a kinase inhibitor initiating mitochondria-dependent apoptosis. Moreover, BI-1 was neuroprotective in a paradigm mimicking ischemia, namely oxygen-glucose as well as serum deprivation. Examination of the subcellular distribution revealed that BI-1 predominantly locates to the ER and nuclear envelope but not mitochondria. Taken together, BI-1 overexpression in the ER is protective in neurons, making BI-1 an interesting target for future studies aiming at the inhibition of neuronal cell death during neurodegenerative diseases and stroke.
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PMID:Bax inhibitor-1 protects neurons from oxygen-glucose deprivation. 1675 4

It has been reported that a prior exposure of isoflurane, a commonly used volatile anesthetic in clinical practice, reduces brain cell death after ischemia. This isoflurane preconditioning-induced neuroprotection has been shown in rat in vivo and in vitro brain ischemia models. To investigate the mechanisms of this protection, we used the human neuroblastoma SH-SY5Y cells and simulated ischemia in vitro by oxygen-glucose deprivation. We found that isoflurane exposure for 30 min at 24 h before a 5-h oxygen-glucose deprivation dose-dependently reduced cell death. Isoflurane exposure induced phosphorylation/activation of extracellular signal-regulated kinase (ERK). Inhibition of the phospho-ERK expression abolished the isoflurane preconditioning-induced protection. Isoflurane exposure also increased the expression of early growth response gene 1 (Egr-1) and Bcl-2, proteins downstream of ERK. Egr-1 is a transcription factor and plays a role in cell survival. Bcl-2 is an anti-apoptotic protein. The increased expression of Egr-1 and Bcl-2 by isoflurane was inhibited by ERK inhibition. Thus, our results suggest a role of ERK/Egr-1/Bcl-2 pathway in the isoflurane preconditioning-induced protection in the human neuroblastoma SH-SY5Y cells.
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PMID:Isoflurane preconditioning protects human neuroblastoma SH-SY5Y cells against in vitro simulated ischemia-reperfusion through the activation of extracellular signal-regulated kinases pathway. 1680 62

Sympathetic neurons synthesize and release tissue plasminogen activator (t-PA). We investigated whether t-PA modulates sympathetic activity. t-PA inhibition markedly reduced contraction of the guinea pig vas deferens to electrical field stimulation (EFS) and norepinephrine (NE) exocytosis from cardiac synaptosomes. Recombinant t-PA (rt-PA) induced exocytotic and carrier-mediated NE release from cardiac synaptosomes and cultured neuroblastoma cells; this was a plasmin-independent effect but was potentiated by a fibrinogen cleavage product. Notably, hearts from t-PA-null mice released much less NE upon EFS than their wild-type (WT) controls (i.e., a 76.5% decrease; P<0.01), whereas hearts from plasminogen activator inhibitor-1 (PAI-1)-null mice released much more NE (i.e., a 275% increase; P<0.05). Furthermore, vasa deferentia from t-PA-null mice were hyporesponsive to EFS (P<0.0001) but were normalized by the addition of rt-PA. In contrast, vasa from PAI-1-null mice were much more responsive (P<0.05). Coronary NE overflow from hearts subjected to ischemia/reperfusion was much smaller in t-PA-null than in WT control mice (P<0.01). Furthermore, reperfusion arrhythmias were significantly reduced (P<0.05) in t-PA-null hearts. Thus, t-PA enhances NE release from sympathetic nerves and contributes to cardiac arrhythmias in ischemia/reperfusion. Because the risk of arrhythmias and sudden cardiac death is increased in hyperadrenergic conditions, targeting the NE-releasing effect of t-PA may have valuable therapeutic potential.
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PMID:The plasminogen activator system modulates sympathetic nerve function. 1694 Jan 68


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