UMLS:C0027819 - FACTA Search

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

We report the detection of endogenous intracellular glutathionyl (GS.) radicals in the intact neuroblastoma cell line NCB-20 under oxidative stress. Spin-trapping and electron paramagnetic resonance (EPR) spectroscopic methods were used for monitoring the radicals. The cells incubated with the spin trap 5,5-dimethyl-1-pyrroline 1-oxide (DMPO) were challenged with H2O2 generated by the enzymic reaction of glucose/glucose oxidase. These cells exhibit the EPR spectrum of the GS. radical adduct of DMPO (DMPO-.SG) without exogenous reduced glutathione (GSH). The identity of this radical adduct was confirmed by observing hyperfine coupling constants identical to previously reported values in in vitro studies, which utilized known enzymic reactions, such as horseradish peroxidase and Cu/Zn superoxide dismutase, with GSH and H2O2 as substrates. The formation of the GS. radicals required viable cells and continuous biosynthesis of GSH. No significant effect on the resonance amplitude by the addition of a membrane-impermeable paramagnetic broadening agent indicated that these radicals were located inside the intact cell. N-Acetyl-L-cysteine (NAC)-treated cells produced NAC-derived free radicals (NAC.) in place of GS. radicals. The time course studies showed that DMPO-.SG formation exhibited a large increase in its concentration after a lag period, whereas DMPO-NAC. formation from NAC-treated cells did not show this sudden increase. These results were discussed in terms of the limit of antioxidant enzyme defenses in cells and the potential role of the GS. radical burst in activation of the transcription nuclear factor NF-kappa B in response to oxidative stress.
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PMID:Endogenous intracellular glutathionyl radicals are generated in neuroblastoma cells under hydrogen peroxide oxidative stress. 775 47

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

The dopaminergic neurotoxin N-methyl,4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) causes a syndrome in primates and humans which mimics Parkinson's disease (PD) in clinical, pathological, and biochemical findings, including diminished activity of complex I in the mitochondrial electron transport chain. Reduced complex I activity is found in sporadic PD and can be transferred through mitochondrial DNA, suggesting a mitochondrial genetic etiology. We now show that MPTP treatment of mice and N-methylpyridinium (MPP+) exposure of human SH-SY5Y neuroblastoma cells increases oxygen free radical production and antioxidant enzyme activities. Cybrid cells created by transfer of PD mitochondria exhibit similar characteristics; however, PD cybrids' antioxidant enzyme activities are not further increased by MPP+ exposure, as are the activities in control cybrids. PD mitochondrial cybrids are subject to metabolic and oxidative stresses similar to MPTP parkinsonism and provide a model to determine mechanisms of oxidative damage and cell death in PD.
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PMID:Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease. 943 2

Dopamine (DA) is oxidized to the neurotoxic prooxidant species H2O2, OH., and DA quinones. We tested whether dimethyl fumarate (DMF), an electrophile shown to induce a pleiotropic antioxidant response in nonneuronal cells, could reduce the toxicity of DA metabolites in neural cells. Treatment of the N18-RE-105 neuroblastoma-retina hybridoma cell line with 30-150 microM dopamine led to cell death within 24 h, which increased steeply with dose, decreased with higher plating density, and was blocked by the H2O2-metabolizing enzyme catalase. Pretreatment with DMF (30 microM, 24 h) significantly attenuated DA and H2O2 toxicity (40-60%) but not that caused by the calcium ionophore ionomycin. DMF treatment also elevated total intracellular GSH and increased activities of the antioxidant enzymes quinone reductase (QR), glutathione S-transferase (GST), glutathione reductase, and the pentose phosphate enzyme glucose-6-phosphate dehydrogenase. To assess the protective efficacy of QR and GST, a stable cell line was constructed in which these enzymes were overexpressed. Cell death in the overexpressing line was not significantly different from that in a cell line expressing normal QR and GST activities, indicating that these two enzymes alone are insufficient for protection against DA toxicity. Although the relative importance of a single antioxidant enzyme such as QR or GST may be small, antioxidant inducers such as DMF may prove valuable as agents that elicit a broad-spectrum neuroprotective response.
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PMID:Activation of endogenous antioxidant defenses in neuronal cells prevents free radical-mediated damage. 964 52

The antioxidant responsive element (ARE) is a cis-acting regulatory element located in the 5'-flanking region of several genes encoding phase II detoxification enzymes, including NAD(P)H:quinone oxidoreductase (NQO1). We report here that activation of the NQO1 ARE by tert-butylhydroquinone (tBHQ) is dependent on Nrf2 and not oxidative stress in IMR-32 human neuroblastoma cells. Overexpression of wild-type Nrf2 activated ARE in a dose-dependent manner, and ARE activation by tBHQ or diethyl maleate (DEM) was inhibited by dominant/negative Nrf2 not by dominant/negative c-Jun. According to our observation, the palindromic sequence (5' to the core) and the GC box in the ARE core sequence are essential for maximal inducibility by tBHQ or DEM. Overexpression of Nrf2 selectively activated wild-type ARE up to 24 h. In addition, a dramatic nuclear translocation of Nrf2 by tBHQ supports a role for Nrf2 in ARE activation. Although oxidative stress is hypothesized to be a major driving force for ARE activation, pretreatment of antioxidant or antioxidant enzyme did not block tBHQ-mediated ARE activation. In contrast, ARE activation by DEM was inhibited by antioxidants or catalase. These results suggest that ARE activation signals from tBHQ and DEM converge at Nrf2 transcription factor through independent mechanisms.
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PMID:Nrf2-dependent activation of the antioxidant responsive element by tert-butylhydroquinone is independent of oxidative stress in IMR-32 human neuroblastoma cells. 1116 12

Calcineurin is a serine/threonine phosphatase involved in a wide range of cellular responses to calcium mobilizing signals. Previous evidence supports the notion of the existence of a redox regulation of this enzyme, which might be relevant for neurodegenerative processes, where an imbalance between generation and removal of reactive oxygen species could occur. In a recent work, we have observed that calcineurin activity is depressed in two models for familial amyotrophic lateral sclerosis (FALS) associated with mutations of the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1), namely in neuroblastoma cells expressing either SOD1 mutant G93A or mutant H46R and in brain areas from G93A transgenic mice. In this work we report that while wild-type SOD1 has a protective effect, calcineurin is oxidatively inactivated by mutant SOD1s in vitro; this inactivation is mediated by reactive oxygen species and can be reverted by addition of reducing agents. Furthermore, we show that calcineurin is sensitive to oxidation only when it is in an 'open', calcium-activated conformation, and that G93A-SOD1 must have its redox-active copper site available to substrates in order to exert its pro-oxidant properties on calcineurin. These findings demonstrate that both wild-type and mutant SOD1s can interfere directly with calcineurin activity and further support the possibility of a relevant role for calcineurin-regulated biochemical pathways in the pathogenesis of FALS.
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PMID:Oxidative inactivation of calcineurin by Cu,Zn superoxide dismutase G93A, a mutant typical of familial amyotrophic lateral sclerosis. 1170 56

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor function and eventual death as a result of degeneration of motor neurons in the spinal cord and brain. The discovery of mutations in SOD1, the gene encoding the antioxidant enzyme Cu/Zn-superoxide dismutase (CuZnSOD), in a subset of ALS patients has led to new insight into the pathophysiology of ALS. Utilizing a novel adenovirus gene delivery system, our laboratory has developed a human cell culture model using chemically differentiated neuroblastoma cells to investigate how mutations in SOD1 lead to neuronal death. Expression of mutant SOD1 (G37R) resulted in a time and dose-related death of differentiated neuroblastoma cells. This cell death was inhibited by overexpression of the antioxidant enzyme manganese superoxide dismutase (MnSOD). These observations support the hypothesis that mutant SOD1-associated neuronal death is associated with alterations in oxidative stress, and since MnSOD is a mitochondrial enzyme, suggest that mitochondria play a key role in disease pathogenesis. Our findings in this model of inhibition of mutant SOD1-associated death by MnSOD represent an unique approach to explore the underlying mechanisms of mutant SOD1 cytotoxicity and can be used to identify potential therapeutic agents for further testing.
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PMID:Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase. 1206 30

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin used in cellular models of Parkinson's Disease. Although intracellular iron plays a crucial role in MPP(+)-induced apoptosis, the molecular signalling mechanisms linking iron, reactive oxygen species (ROS) and apoptosis are still unknown. We investigated these aspects using cerebellar granule neurons (CGNs) and human SH-SY5Y neuroblastoma cells. MPP(+) enhanced caspase 3 activity after 24 h with significant increases as early as 12 h after treatment of cells. Pre-treatment of CGNs and neuroblastoma cells with the metalloporphyrin antioxidant enzyme mimic, Fe(III)tetrakis(4-benzoic acid)porphyrin (FeTBAP), completely prevented the MPP(+)-induced caspase 3 activity as did overexpression of glutathione peroxidase (GPx1) and pre-treatment with a lipophilic, cell-permeable iron chelator [N, N '-bis-(2-hydroxybenzyl)ethylenediamine-N, N '-diacetic acid, HBED]. MPP(+) treatment increased the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labelling)-positive cells which was completely blocked by pre-treatment with FeTBAP. MPP(+) treatment significantly decreased the aconitase and mitochondrial complex I activities; pre-treatment with FeTBAP, HBED and GPx1 overexpression reversed this effect. MPP(+) treatment increased the intracellular oxidative stress by 2-3-fold, as determined by oxidation of dichlorodihydrofluorescein and dihydroethidium (hydroethidine). These effects were reversed by pre-treatment of cells with FeTBAP and HBED and by GPx1 overexpression. MPP(+)-treatment enhanced the cell-surface transferrin receptor (TfR) expression, suggesting a role for TfR-induced iron uptake in MPP(+) toxicity. Treatment of cells with anti-TfR antibody (IgA class) inhibited MPP(+)-induced caspase activation. Inhibition of nitric oxide synthase activity did not affect caspase 3 activity, apoptotic cell death or ROS generation by MPP(+). Overall, these results suggest that MPP(+)-induced cell death in CGNs and neuroblastoma cells proceeds via apoptosis and involves mitochondrial release of ROS and TfR-dependent iron.
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PMID:1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. 1252 38

The neuropathology of Parkinson's disease (PD) involves a reduction of endogenous antioxidant enzyme systems, heightened oxidative stress and mitochondrial aberrations in the region of the substantia nigra. Similarly, neurotoxins commonly used to investigate PD pathology include 6-hydroxydopamine (6-OHDA), a powerful hydrogen peroxide (H(2)0(2)) pro-oxidant and 1-methyl-4-phenylpyridinium ion (MPP+), a mitochondrial complex I inhibitor that exerts detrimental effects on cellular energy production. Pyruvic acid is a neuronal metabolic energy fuel that can also rapidly undergo decarboxylation to diffuse H(2)0(2) into H(2)0. In this study, we investigated the effect of pyruvic acid against 6-OHDA, MPP+ and H(2)0(2) toxicity in murine brain neuroblastoma cells. The results obtained indicated that the toxicity of 6-OHDA was inversely related to the autoxidative formation of H(2)0(2). Pyruvic acid exhibited powerful non-enzymatic stoichiometric H(2)0(2) trapping properties, and protected against both 6-OHDA and H(2)0(2) toxicity. While both sodium pyruvate and pyruvate were highly protective against oxidative stress, pyruvate in its free acid form only was protective against MPP+, indicating a requirement for effective transport in order to fuel glycolysis. The protective properties of glucose were compared to pyruvic acid, and the data indicated that glucose did not exhibit antioxidant properties and was effective in blocking MPP+, but not 6-OHDA or H(2)0(2) toxicity. On the other hand, pyruvic acid was protective against all three toxins, and unlike glucose, completely blocked MPP+ toxicity in a combination insult model with up to 500 microM of H(2)0(2). Moreover, the data obtained indicate that pyruvic acid exerts powerful neuroprotective properties by providing simultaneous resistance to oxidative stress and mitochondrial insult. These protective effects are the result of a unique dual property of pyruvic acid with concurrent ability to serve as an effective neuronal energy substrate for glycolysis and to act as an exceptionally powerful antioxidant.
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PMID:Pyruvic acid cytoprotection against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and hydrogen peroxide toxicities in vitro. 1252 92

The antioxidant enzyme Cu,Zn superoxide dismutase has so far been considered costitutively expressed and exclusively localized into cytosol. In this paper we investigated Cu,Zn superoxide dismutase export in neuroblastoma SK-N-BE cells by flow cytometry analysis, confocal immunofluorescence analysis and enzyme-linked immunosorbed assay. Immunofluorescence analysis shows that the enzyme is exported by microvesicular granules; moreover the treatment of cells with brefeldin A and with 2-deoxy-D-glucose and sodium azide strongly decreases the amount of CuZn superoxide dismutase detected in the medium. Therefore the involvement of ATP-dependent mechanisms, likely including BFA-sensitive intracytoplasmic vesicles in Cu,Zn SOD export from SK-N-BE cells, has to be hypothesized. Microvesicular-mediated Cu,Zn SOD export in neurons could represent a relevant phenomenon able to influence cell excitability that is affected by reactive oxygen species.
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PMID:The Cu,Zn superoxide dismutase in neuroblastoma SK-N-BE cells is exported by a microvesicles dependent pathway. 1257 32

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