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)

The effects of intracellularly generated H2O2 on cell viability, morphology, and biochemical markers of injury have been investigated in a clonal cell line of neuronal origin (140-3, mouse neuroblastoma X rat glioma) as a cell culture model for the role of oxidative stress in the long-term loss of neurons in the brain. The H2O2 was generated from the redox cycling of menadione, or by the oxidation of serotonin catalyzed by monoamine oxidase, to simulate the effect of amine neurotransmitter turnover. Incubation with menadione at concentrations as low as 10 microM for several hours resulted in significant losses of cell viability and altered morphology. Similar effects were evident in the presence of serotonin only after incubation overnight with concentrations > 1 mM. The cytotoxicity of either agent was potentiated by preincubation with specific inhibitors of two enzymes important to cellular antioxidant defenses, 3-amino-1,2,4-triazole for catalase and 1,3-bis(chloromethyl)-1-nitrosourea for glutathione reductase. Activity of another antioxidant enzyme of particular importance to antioxidant defenses in brain, the selenoprotein glutathione peroxidase, was stimulated fourfold by growth of cultures in the presence of sodium selenite as a source of active-site Se for the enzyme. The only effect of the selenite on other functionally coupled antioxidant enzymes was a decrease in activity of superoxide dismutase at concentrations > 200 nM. The selenite substantially protected cells against oxidative stress induced by combinations of menadione, 3-amino-1,2,4-triazole, and 1,3-bis(chloromethyl)-1-nitrosourea, but was only marginally effective with serotonin as a source of oxidative stress. The monoamine oxidase inhibitor pargyline increased cell survival in the presence of serotonin, demonstrating the role of this enzyme in its cytotoxicity. DNA damage (single strand breaks), but not lipid peroxidation, correlated with the cytotoxic effects of menadione.
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PMID:Oxidative stress in a clonal cell line of neuronal origin: effects of antioxidant enzyme modulation. 849 17

Human manganese-containing superoxide dismutase (MnSOD) is a nuclear encoded mitochondrial protein that scavenges potentially toxic superoxide radicals by dismuting O2- to O2 plus H2O2. To understand the molecular mechanism governing the transcriptional regulation of the human MnSOD gene, I have isolated and sequenced a genomic clone containing the 5' flanking region of the human MnSOD gene. One major transcription start site was mapped by primer extension to a guanine residue 67 base pairs upstream from the translation start site. Eight putative Sp1 binding elements and one AP1 consensus sequence, but no TATA or CAAT box, were found in the promoter region. Furthermore, a series of chimerical/CAT reporter gene constructs were used to transfect human hepatocellular carcinoma(HepG2) human neuroblastoma and human skin fibroblast cell lines to characterize the promoter and regulatory region of the human MnSOD gene. The results show that human MnSOD gene expression is governed by one promoter and that the basic promoter is located between nucleotides -34 and +38. The results also indicate that both positive and negative elements are involved in the regulation of the cell-type specific expression of the human MnSOD gene. The functional studies indicate that the Sp1 binding sites or G+C rich regions play an important role in regulation of expression of the human MnSOD gene in vivo.
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PMID:Characterization of the 5' flanking region of the human MnSOD gene. 860 39

The nitric oxide (N0-releasing agents sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) inhibit dioxygenase activity of lipoxygenase in human platelets and human CHP100 neuroblastoma cells, leading the latter to necrosis. The effect of both NO-donors on the dioxygenase reaction was investigated by using soybean lipoxygenase type II (LOX-2) as a model for the mammalian enzyme. SNP and SNAP were competitive inhibitors of LOX-2, with inhibition constants of 525 microM and 710 microM, respectively. Both compounds inactivated LOX-2 by reducing the catalytic iron to the inactive Fe(II) form and counteracted the H2O2-mediated activation of the LOX-2 catalyzed dioxygenase reaction. Similarly, the co-oxidative and per-oxidative activities of LOX-2 were also inhibited by the NO-releasing agents. These findings suggest that the biological role played by NO can be mediated, at least in part, by the inactivation of lipoxygenase, a key-enzyme for the arachidonic acid metabolism in human cells.
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PMID:Nitric oxide-donor compounds inhibit lipoxygenase activity. 861 94

Oxidative stress appears to contribute to neuronal dysfunction in a number of neurodegenerative conditions, notably including Alzheimer's disease, in which cholinergic receptor-linked signal transduction activity is severely impaired. To test whether oxidative stress could contribute to deficits in cholinergic signaling, responses to carbachol were measured in human neuroblastoma SH-SY5Y cells exposed to H2O2. DNA binding activities of two transcription factors that are respondent to oxidative conditions, AP-1 and NF kappa B, were measured in nuclear extracts. H2O2 and carbachol individually induced dose- and time-dependent increases in AP-1 and NF kappa B. In contrast, when given together, H2O2 concentration dependently (30-300 microM) inhibited the increase after carbachol in AP-1. Carbachol's stimulation of NF kappa B was not inhibited except with a high concentration (300 microM) of H2O2, which was associated with impaired activation of protein kinase C. Lower concentrations of H2O2 (30-300 microM) inhibited carbachol-induced [3H]phosphoinositide hydrolysis, and this inhibition correlated (r = 0.95) with the inhibition of carbachol-induced AP-1. Activation [3H]phosphoinositide hydrolysis by the calcium ionophore ionomycin was unaffected by H2O2, indicating that phospholipase C and phosphoinositides were impervious to this treatment. In contrast, activation with NaF of G-proteins coupled to phospholipase C was concentration dependently inhibited by H2O2, indicating impaired G-protein function. These effects of H2O2 are similar to signaling impairments reported in Alzheimer's disease brain, which involve deficits in receptor- and G-protein-stimulated phosphoinositide hydrolysis, but not phospholipase C activity. Thus, these findings indicate that oxidative stress may contribute to impaired phosphoinositide signaling in neurological disorders in which oxidative stress occurs, and that oxidative stress can differentially influence transcription factors activated by cholinergic stimulation.
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PMID:Cholinergic stimulation of AP-1 and NF kappa B transcription factors is differentially sensitive to oxidative stress in SH-SY5Y neuroblastoma: relationship to phosphoinositide hydrolysis. 881 74

In response to hyponatremia, brain cells extrude electrolytes and organic osmolytes, thereby minimizing brain edema. We demonstrate that rat brain is depleted of the antioxidant glutathione in response to hyponatremia and that osmotically-induced loss of glutathione makes neuronal cells more susceptible to oxidative injury. Total glutathione content of brain tissue decreased from 6.80 +/- 0.14 mumol/g dry wt in normonatremic controls to 5.00 +/- 0.31 mumol/g dry wt after 72 hours of hyponatremia. Following slow correction of hyponatremia, brain glutathione content returned to control values (6.77 +/- 0.34 mumol/g dry wt). Brain content of taurine, a beta-amino acid with antioxidant properties, similarly decreased in hyponatremia (29.6 +/- 0.9 to 17.1 +/- 1.2 mumol/g dry wt), then increased with slow correction (24.8 +/- 1.3 mumol/g dry wt). Although taurine served as an osmolyte in rat heart, liver and brain, osmotically-induced changes in glutathione content were found only in brain. We also studied osmotically-induced changes in glutathione and taurine content in C6 glioma and SK-N-SH neuroblastoma cells. In both cell lines, adaptive decreases in glutathione and taurine content were found in response to lowering medium sodium concentration from 140 mM to 100 mM. The cell content of these solutes increased after returning to media containing 140 mM sodium. Following exposure of both cell lines to hypoosmolar media, there was no increase in media content of glutathione. This suggest that osmotic depletion of glutathione is not due to cellular efflux of intact glutathione. We questioned if osmotic depletion of glutathione and taurine renders brain cells more susceptible to oxidative stress. Incubation of SK-N-SH cells with 1.0 mM H2O2 for four hours induced greater cytolytic injury in cells adapted to hypoosmolar media than in isoosmolar controls. Hypoosmolar C6 glioma cells were not significantly more sensitive to cytolytic injury from H2O2 than were cells grown in isosmolar media. We conclude that hypoosmolality induces glutathione depletion in rat brain in vivo and in cultured brain cells in vitro. Osmotic depletion of this antioxidant renders SK-N-SH neuronal cells more susceptible to oxidative injury.
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PMID:Depletion of glutathione from brain cells in hyponatremia. 882 31

Enhanced oxidative stress has been suggested to be involved in the degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease. The high turnover rate of dopamine and/or unsequestered dopamine may cause an increase of formation of hydrogen peroxide via either oxidative deamination of dopamine by monoamine oxidase or autoxidation. Hydrogen peroxide would be converted to more toxic hydroxyl free radicals. L-beta-3,4-Dihydroxyphenylalanine hydrochloride (L-DOPA), the most useful drug in the symptomatic treatment of Parkinson's disease, has been considered to possess deteriorating degenerative side-effects. The catecholaminergic neuroblastoma SH-SY5Y cells were chosen to investigate the cytotoxic effect of dopamine and L-DOPA. Both dopamine and L-DOPA were found to be cytotoxic towards SH-SY5Y cells. Such toxic effects were accompanied by an increase of oxidative stress in the cell cultures and could be reversed effectively by catalase and to a lesser extent by superoxide dismutase. The non-enzymatic antioxidants L-ascorbic acid, glutathione, N-acetyl-L-cysteine, but not (+)-alpha-tocopherol, also completely protected SH-SY5Y cells against the cytotoxic effects induced by dopamine and L-DOPA. Antioxidative factors, namely free radical scavengers (including N-tert-butyl-alpha-phenylnitrone, salicylic acid, and D-mannitol) and a strong iron chelator, deferoxamine, however, did not protect the SH-SY5Y cells against dopamine and L-DOPA. The generation of reactive oxygen species and the resulting enhanced oxidative stress was clearly involved in the dopamine- and L-DOPA-induced cytotoxic effects. Hydrogen peroxide played the most important role related to cytotoxicity of dopamine and L-DOPA.
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PMID:Dopamine- and L-beta-3,4-dihydroxyphenylalanine hydrochloride (L-Dopa)-induced cytotoxicity towards catecholaminergic neuroblastoma SH-SY5Y cells. Effects of oxidative stress and antioxidative factors. 906 40

The processing of Alzheimer's amyloid precursor protein was studied by Western blotting during H2O2 induced apoptosis in cultures of human neuroblastoma cells. A new 5.5 kDa fragment putatively containing intact A beta was detected and found to be highly associated with apoptosis. The results suggest a possible vicious cycle involving H2O2, A beta and apoptosis which may contribute to the neuronal death mechanism in Alzheimer's Disease.
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PMID:Processing of Alzheimer's amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells. 920 49

We report the effects of meta-iodobenzylguanidine (MIBG), a neuroblastoma-seeking agent, on cell proliferation and several oxidative stress-related parameters in the human neuroblastoma cell line SK-N-BE(2c). MIBG inhibited the proliferation of this cell line in micromolar concentrations. Measurements of the malondialdehyde (MDA) concentrations (a measure of the extent of lipid peroxidation) of cells treated with MIBG showed that increasing concentrations of MIBG led to an increase in MDA levels of the cells. This effect was most pronounced after one day of cellular exposure to MIBG and disappeared after 3 days. Disappearance of the elevated MDA levels caused by MIBG is probably the result of increased activity of the H2O2 detoxifying enzymes, catalase and glutathion peroxidase (GPx). The catalase- and GPx-enzyme activity of cells exposed to MIBG steadily increased with time, reaching a maximum after 4 days. Oxidative stress caused by MIBG thus at first leads to cellular damage (lipid peroxidation) but over a longer period does not lead to decreased proliferation rate of the cells, most likely because of cellular adaptation to increased oxidative stress by up-regulation of the H2O2 detoxifying enzymes catalase and GPx.
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PMID:MIBG causes oxidative stress and up-regulation of anti-oxidant enzymes in the human neuroblastoma cell line SK-N-BE(2c). 924 93

As a new treatment protocol for neuroblastoma, the chimeric (human/mouse) antiganglioside GD2 antibody chl4.18 is being clinically tested. To improve the therapeutic effect of the antibody alone, we are currently investigating the cytotoxicity of glucose-oxidase coupled to the antibody chl4.18 on spheroids of the neuroblastoma cell line SK-N-LO. The cytotoxic effect of glucose-oxidase is achieved by the production of hydrogenperoxide (H2O2) and probably by the following reaction of H2O2 with iron to form hydrogen radicals (OH.). The cytotoxicity of glucose-oxidase was measured by two viability tests (MTT and WST 1). After a 4 hour treatment of the spheroids with the immunoconjugate, a reduction of viability to 50% (MTT-test) and 25% (WST 1-test), respectively, was obtained. The difference between the results of these two tests, might be explained by the different measurement protocols.
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PMID:Cytotoxic effect of immunoconjugate composed of glucose-oxidase coupled to an anti-ganglioside (GD2) antibody on spheroids. 932 30

Oxidative stress appears to contribute to neuronal dysfunction associated with Alzheimer's disease and other CNS neurodegenerative disorders. This investigation examined if oxidative stress might contribute to impairments in cholinergic receptor-linked signaling systems and if intracellular glutathione levels modulated responses to oxidative stress. To do this the activation of the AP-1 and NF-kappaB transcription factors and of the phosphoinositide second-messenger system was measured in human neuroblastoma SH-SY5Y cells after exposure to the oxidants H2O2 or diamide, with or without prior depletion of cellular glutathione. H2O2 concentration-dependently inhibited carbachol-stimulated AP-1 activation and this inhibition was potentiated in glutathione-depleted cells. Carbachol-stimulated NF-kappaB activation was unaffected by H2O2 unless glutathione was depleted, in which case there was a H2O2 concentration-dependent inhibition. Glutathione depletion also potentiated the inhibition by H2O2 of carbachol- or G-protein (NaF)-stimulated phosphoinositide hydrolysis, whereas phospholipase C activated by the calcium ionophore ionomycin was not inhibited. The thiol-oxidizing agent diamide also inhibited phosphoinositide hydrolysis stimulated by carbachol or NaF, and glutathione depletion potentiated the diamide concentration-dependent inhibition. Unlike H2O2, diamide also inhibited ionomycin-stimulated phosphoinositide hydrolysis. Activation of both AP-1 and NF-kappaB stimulated by carbachol was inhibited by diamide, and glutathione depletion potentiated the inhibitory effects of diamide. Thus, diamide inhibited a wider range of signaling processes than did H2O2, but glutathione depletion increased the susceptibility of phosphoinositide hydrolysis and of transcription factor activation to inhibition by both H2O2 and diamide. These results demonstrate that the vulnerability of signaling systems to oxidative stress is influenced by intracellular glutathione levels, indicating that cell-selective susceptibility to inhibition of signal transduction systems by oxidative stress can arise from cellular variations in antioxidant capacity.
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PMID:Glutathione depletion exacerbates impairment by oxidative stress of phosphoinositide hydrolysis, AP-1, and NF-kappaB activation by cholinergic stimulation. 947 71


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