Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To improve the understanding of neuronal cell swelling in cerebral ischemia, cell volume regulation, viability, intracellular electrolytes, and lactate production of Neuro-2A neuroblastoma cells were studied using an in vitro model. The volume regulatory capacity of Neuro-2A cells was assessed after incubation in hypo- and hypertonic media. Anoxia was studied alone and together with inhibition of glycolysis by iodoacetate. Reducing the tonicity of the incubation medium to 250, 200, or 150 mosm/l caused immediate swelling followed by a regulatory volume decrease within 20 min, which, however, was not complete. The final cell volume after regulation depended on the tonicity of the medium and remained above control. There was no regulatory volume increase after cell shrinking in hypertonic media. Despite the severe anisotonic incubation, viability decreased only slightly without reaching statistical significance. In contrast to in vivo conditions, anoxia for 90 min with or without iodoacetate for additional inhibition of anaerobic energy metabolism neither caused neuronal cell swelling nor a decrease of viability. Reoxygenation after the anoxic period also did not induce volume and viability changes. Intracellular K+ of Neuro-2A cells was markedly decreased, while Na+ increased in a 1:1 ratio during complete energy failure by anoxia plus iodoacetate. A similar effect, occurring however somewhat delayed, was seen when the Neuro-2A suspension was exposed to iodoacetate alone. Anoxia without inhibition of glycolysis had no effect on intracellular ion concentrations, but lactate production was nearly six times higher than normal. In vitro, with a large extracellular volume and sufficient glucose supply, the energetic demands of Neuro-2A cells to maintain stable transmembraneous ion gradients during anoxia are obviously met by anaerobic glycolysis. The current results confirm that neuronal cells are able to adequately regulate cell volume in response to hyposmotic stress. On the other hand, maintenance of a normal cell size during complete energy deprivation suggests strongly that energy failure per se does not suffice to induce neuronal swelling. Cell swelling in cerebral ischemia in vivo thus appears a secondary phenomenon due to mediator mechanisms such as tissue acidosis or elevated extracellular glutamate levels.
 ...
PMID:Anoxia in vitro does not induce neuronal swelling or death. 883 70

1. The effects of hypoosmotic stress on cell volume and amino acid efflux were evaluated in the human neuroblastoma cell line CHP-100 with the Coulter Counter Multisizer and radiolabeled amino acid efflux, respectively. 2. CHP-100 cells swelled by approximately 35 +/- 5% (means +/- SE) when the osmolarity of the solution was decreased from 290 to 190 mOsm/kg H2O. The rapid swelling was followed by a biphasic regulatory volume decrease (RVD). 3. In cells loaded with 14C-taurine, hypoosmotic stress induced a 300 +/- 22% (n = 23, P < 0.05) increase in taurine efflux compared with controls. This efflux was inhibited by the chloride channel blockers 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), 4,4'-diisothio-cyanostilbene-2,2'-disulfonic acid (DIDS), niflumic acid and by the volume-activated anion channel blocker tamoxifen. In addition, the swelling-activated taurine efflux was dependent upon extracellular calcium. 4. Similarly, in cells loaded with 14C-glycine, hypoosmotic stress significantly increased glycine efflux, which was also sensitive to NPPB. In contrast, efflux of 3H-glutamate was not significantly altered after hypoosmotic stress. 5. With the use of patch clamp recording techniques, Cl- channels were activated in cell attached patches after exposure to hypoosmotic solutions. 6. In nystatin perforated patches, permeability of the hypoosmotically activated anion channel was observed to be SCN- > I- > Br- > Cl- >> Glutamate. 7. It is concluded that in CHP-100 cells, anion channels are activated during hypoosmotic stress and these channels represent a pathway for efflux of amino acids.
 ...
PMID:Swelling-activated amino acid efflux in the human neuroblastoma cell line CHP-100. 887 Nov 97

We evaluated expression of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor (GluR) genes by reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blotting in nine established cell lines: rat CG-4 (oligodendroglial lineage) and RINm5F insulinoma cells; human CHP134, SMS-KCNR, SKNSH, and Nb69 neuroblastoma cells; and human D384Med, D425Med, and D458Med medulloblastoma cells. CG-4 expressed mRNAs encoding GluR2-7, KA-1, and KA-2 non-NMDA GluR (Yoshioka et al.: J Neurochem 64:2442-2448, 1995) and NR1 (NMDAR1) and NR2D NMDA GluR. After differentiation to oligodendrocyte-like cells, CG-4 also expressed NR2B mRNA. Rat insulinoma cells expressed GluR5 and KA-2 non-NMDA and NR1 and NR2D NMDA GluR mRNAs. The four human neuroblastoma lines all expressed mRNAs encoding GluR2-4, 6, 7 and KA-1 non-NMDA and NR1 NMDA GluR, and the three human medulloblastoma cell lines all expressed mRNAs encoding GluR1, 6 and KA-1, but none of the NMDA GluRs. Whereas CG-4 is susceptible to kainate excitotoxicity, treatment of insulinoma, neuroblastoma, and medulloblastoma lines with L-glutamate, kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), or NMDA failed to cause cell damage or to augment 45Ca2+ influx. Thus, despite expressing a variety of non-NMDA and NMDA GluR genes, the human neuroblastoma and medulloblastoma and rat insulinoma lines failed to assemble Ca(2+)-permeable NMDA or non-NMDA GluR channels. This failure confers protection against excitotoxicity and may contribute to progression of tumors of these types.
 ...
PMID:Expression of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor genes in neuroblastoma, medulloblastoma, and other cells lines. 891 93

The use of the undecapeptide cyclosporine and the macrolide tacrolimus as immunosuppressants in transplantation medicine and for the therapy of immune diseases often provokes side effects, among the most important one is neurotoxicity. Changes in the cellular metabolism of glial cells (C6 rat glioma), neuronal cells (N1E-115 mouse neuroblastoma) and primary glia cells (isolated from rats) after addition of cyclosporine and tacrolimus were investigated using 1H-, 13C- and 31P-NMR spectroscopy in vitro. Cells were exposed to various concentrations of the drugs from 3 h to 42 days. The immunosuppressants (cyclosporine IC50 : 55 mumol/l; tacrolimus IC50 : 47 mumol/l) inhibited cell proliferation in a concentration- and time-dependent fashion. Multinuclear NMR studies of PCA extracts of drug-treated cells showed a significant deterioration in the energy status (a decreasing level of PCr : -46 +/- 11%; an increasing NDP/NTP ratio: +136 +/- 4% and an increasing level of Pi : +248 +/- 15%; mean +/- standard deviation). It also showed decreasing concentrations of major cell metabolites like NAA (-59 +/- 12%) in neuroblastoma cells and myo-inositol (-47 +/- 6%) in glia cells compared with untreated controls. Immunosuppressive treatment caused a large reduction of taurine (-36 +/- 12%) and glutamate (-68 +/- 10%) in all cell cultures, whereas intermediates of phospholipid biosynthesis (PE: +59 +/- 13%; PC: +127 +/- 27%;) and breakdown (GPE: +215 +/- 24%; GPC: +245 +/- 17%) increased. No significant differences were observed between the two immunosuppressants. The toxic effects of immunosuppressants on cell cultures are in line with MRI studies of brain oedema observed in patients under immunosuppressive treatment.
 ...
PMID:Evaluation of the effects of immunosuppressants on neuronal and glial cells in vitro by multinuclear magnetic resonance spectroscopy. 897 22

1. Crude synaptosomes (P2) and synaptosomal membranes were prepared from normal C57/B110 mouse brains and Wistar rats respectively. 2. [3H]Pro binding to mouse brain synaptic membranes was examined in the presence of competitive NMDA antagonist, MK-801, or HA-966. Conversely, the effects of l-proline on [3H]MK-801 binding were also probed. The effects of l-proline on glutamate-medicated [Ca+2]i levels were tested. 3. The authors could not detect any effect of proline on glutamate-mediated [CA+2]i levels using FURA-2 in synaptosomes or neuroblastoma cells. 4. NMDA competitive antagonists, AP-7, CPP, and CGS 19755 inhibit [3H]Pro binding to mouse brain synaptic membranes. 5. MK-801, a NMDA channel blocker, also inhibits [3H]Pro binding, but 200 mM proline is incapable of inhibiting [3H]MK-801 binding. 6. HA-966, a glycine site partial agonist inhibits [3H]Pro binding. Proline has modest effects on [3H]glycine binding.
 ...
PMID:Proline-glutamate interactions in the CNS. 907 63

Sabeluzole was described to have antiischemic, antiepileptic, and cognitive-enhancing properties, and is currently under development for Alzheimer's disease. Recently, it was reported that repeated treatments with sabeluzole protect cultured rat hippocampal neurons against NMDA- and glutamate-induced neurotoxicity. We evaluated the possibility that sabeluzole elicits neuroprotection by acting, either directly or indirectly, on tau proteins. We found that repeated treatments during development of primary cultures of cerebellar granule cells with nanomolar concentrations of sabeluzole resulted in mature cells that were resistant to the excitotoxicity induced by glutamate. Also, sabeluzole treatment specifically prevented the glutamate-induced increase of tau expression without modifying the basal pattern of expression of tau proteins, as shown by measurement of mRNA and protein levels. In human neuroblastoma cell line SH-SY5Y, differentiated by treatment with retinoic acid, doxorubicin increased tau immunoreactivity, and later induced cell death. Both effects were prevented by sabeluzole. Our data indicate that increased tau expression is a common response to different types of cells to neurotoxic agents, and that sabeluzole-induced neuroprotection is functionally associated with the prevention of the injury-mediated increase of tau expression.
 ...
PMID:Priming of cultured neurons with sabeluzole results in long-lasting inhibition of neurotoxin-induced tau expression and cell death. 913 69

Data are presented that provide convincing evidence for the expression of structurally normal and functional NMDA receptors by acetylcholine-producing human LA-N-2 neuroblastoma cells in culture. Reverse transcription and polymerase chain reaction (RT-PCR), followed by cloning and DNA sequencing, revealed the presence in these cells of mRNA representing the key subunit, NMDAR1, of the receptor. This mRNA was further demonstrated by Northern analysis to be the same size as that described for human neurons. The neutral red cytotoxicity assay was utilized to examine the influence on these neuroblastoma cells of a 48-h incubation with either L-glutamic acid or the specific NMDA agonist N-phthalamoyl-L-glutamic acid (NPG). Cell cytotoxicity was shown by this assay to be increased through incubation with glutamate at 1 and 10 mM by 27 and 37%, and through incubation with NPG at 0.1 and 1 mM by 28 and 46%. A possible mechanism of these toxic effects was further evaluated using the whole-cell configuration of the patch-clamp technique and the specific NMDA agonists (+/-)1-aminocyclobutane-cis-1,3-dicarboxylic acid (ACDA) and NPG. Using this procedure, a voltage-dependent tetrodotoxin-sensitive inward sodium current was found to be increased (x 1.5) by L-glutamic acid and by both NMDA agonists in the presence of glycine. Another voltage-gated inward current, probably carried by calcium ions, was increased three- to fourfold. Hence, these glutamate activities observed in human LA-N-2 neuroblastoma cells appear to occur through the activation of functional NMDA receptors in much the same way as reported for neurons, and both glutamate and NMDA agonists can be toxic to these neuroblastoma cells. Our findings, therefore, suggest this cell line will provide a model suitable for investigating the mechanisms of NMDA-related long-term potentiation (LTP) in neurons and of the NMDA-related neurotoxic effects of glutamate in disease states that involve a reduction in cholinergic function.
 ...
PMID:Presence of functional NMDA receptors in a human neuroblastoma cell line. 913 30

The induction of glutamine starvation has been suggested as a potential target for antitumoral treatment using inhibitors of amidotransferase, an enzyme which mediates the conversion of glutamate to glutamine. Using multicellular aggregates from tumor cell lines, the effect of treatment with a suggested glutamine antagonist, 6-diazo-5-axo-L-norleucine (DON), was investigated. As indicators of treatment response, three different parameters were measured: aggregate size, uptake of 14C-methionine and secretion of Chromogranin A. Of six cell types evaluated (carcinoid, glioma, neuroblastoma pancreas and bladder cancer), the largest inhibition of 14Cmethionine uptake, amounting to 60%, was found in the carcinoid cell line BON. In this cell line the maximum effect was reached already at 10 microM concentration. DON induced marked growth inhibition in the BON aggregates which lasted 3-4 weeks after which regrowth started. During this period the secretion of chromogranin and methionine uptake was also inhibited. These studies suggest that the neuroendocrine cell line BON is especially vulnerable to treatment by DON and show that strong inhibitory effects are found at concentrations lower than that achieved in patient blood in previous clinical trials.
 ...
PMID:Effect of 6-diazo-5-oxo-L-norleucine (DON) on human carcinoid tumor cell aggregates. 925 48

Transport of alpha-ketoisocaproate (KIC), a ketoacid originating from leucine and proposed to be involved in the buffering of glutamate in neurones, was studied in neuroblastoma NB-2a cells. The accumulated KIC was mostly transaminated to leucine, while free keto-acid was detectable either only after prolonged times or after inhibiting transaminase with aminooxyacetate. Accumulation of KIC was found to be inhibited by other branched-chain ketoacids, while lactate and beta-hydroxybutyrate were ineffective. The transport of KIC, resembling a facilitated diffusion, was decreased by phloretin, alpha-cyano-4-hydroxycinnamate, 4,4'-diisothiocyano-2,2'-stilbenedisulphonate, and p-chlorimercuribenzoate. The process of accumulation did not resemble a symport with protons; therefore an involvement of the known proton-coupled monocarboxylate transporters (MCT) was excluded. Distribution of KIC suggests a mechanism involving a cotransport with 2 [Na+].
 ...
PMID:Transport of alpha-ketoisocaproate in neuroblastoma NB-2a cells. 926 30

Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders associated with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic reduction of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the xc- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric analysis of freshly prepared human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.
 ...
PMID:Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. 928 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>