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)

Malonate, an inhibitor of mitochondrial complex II, is a widely used toxin to study neurodegeneration in Huntington's disease and ischemic stroke. We have shown previously that malonate increased reactive oxygen species (ROS) production in human SH-SY5Y neuroblastoma cells, leading to oxidative stress, cytochrome c release, and apoptotic cell death. Expression of a green fluorescent protein-Bax fusion protein in SH-SY5Y neuroblastoma cells demonstrated a Bax redistribution from the cytosol to mitochondria after 12 to 24 h of malonate treatment that coincided with mitochondrial potential collapse and chromatin condensation. Inhibition of Bax translocation using furosemide, as well as Bax gene deletion, afforded significant protection against malonate-induced apoptosis. Further experiments revealed that malonate induced a prominent increase in the level of activated p38 mitogen-activated protein (MAP) kinase and that treatment with the p38 MAP kinase inhibitor SKF86002 potently blocked malonate-induced Bax translocation and apoptosis. Treatment with vitamin E diminished ROS production, reduced the activation status of p38 MAP kinase, inhibited Bax translocation, and protected against malonate-induced apoptosis. Our data suggest that malonate-induced ROS production and subsequent p38 MAP kinase activation mediates the activation of the pro-apoptotic Bax protein to induce mitochondrial membrane permeabilization and neuronal apoptosis.
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PMID:Reactive oxygen species and p38 mitogen-activated protein kinase activate Bax to induce mitochondrial cytochrome c release and apoptosis in response to malonate. 1717 66

Disodium 2,4-sulphophenyl-N-tert-butylnitrone (NXY-059) is a novel free radical-trapping compound that is neuroprotective in both rodent and primate models of acute ischaemic stroke. Neuroprotection in vitro by NXY-059 has not been reported previously, and we have now investigated whether such an effect can be detected using a simple cell culture model of neurotoxicity. Neuron-like cells of the neuroblastoma-derived clonal cell line N1E-115 were exposed to the free radical-generating agent sodium nitroprusside (SNP), which produced a concentration-dependent reduction in mitochondrial complex II activity 24 h later (EC(50) approximately 100 micromolar). Cell death induced by SNP (100 micromolar), assessed either by an increased proportion of apoptotic nuclear morphology or by mitochondrial complex II activity, was inhibited by a cocktail of known antioxidants (ascorbate, reduced glutathione, and dithiothreitol, all at 100 micromolar) but not by NXY-059 at a concentration known to be neuroprotective in vivo (300 micromolar). Disodium 2,4-sulphophenyl-N-tert-butylnitrone was also without effect on H(2)O(2)-mediated cytotoxicity. These results support recent data suggesting that in vivo NXY-059 probably acts at the neurovascular unit rather than at an intracellular site as a neuroprotective agent.
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PMID:The nitrone disodium 2,4-sulphophenyl-N-tert-butylnitrone is without cytoprotective effect on sodium nitroprusside-induced cell death in N1E-115 neuroblastoma cells in vitro. 1755 59

Nuclear factor-kB (NF-kB) is a family of DNA-binding proteins that are important regulators involved in immune and inflammatory responses, as well as in cell survival and apoptosis. In the nervous system NF-kB is activated under physiological and pathological conditions including learning and memory mechanisms and neurodegenerative diseases. NF-kB is activated in neurons in response to excitotoxic, metabolic and oxidative stress and there is a body of evidence to suggest that glutamate induces NF-kB by the main ionotropic glutamate receptors. In the present study, 3 nitroproprionic acid (3NP), an irreversible inhibitor of succinate dehydrogenase (SD, complex II) has been employed to provide an experimental model of Huntington's disease (HD). Specifically, we described 3NP-induced activation of NF-kB and of iNOS and nNOS genes in striatal treated slices. To aim to better understand the relationship between these identified dysregulated genes and mitochondrial dysfunction, we investigated in SK-N-MC human neuroblastoma cells following 3NP treatment, whether NF-kB nuclear translocation and activation might be involved in the mechanisms by which 3NP leads to transcriptional activation of NOS genes. These results are relevant to more precisely define the role of NF-kB in neuronal cells and better understand its putative involvement in neurodegeneration.
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PMID:NF-kB/NOS cross-talk induced by mitochondrial complex II inhibition: implications for Huntington's disease. 1832 71

Fenretinide induces apoptosis in neuroblastoma by induction of reactive oxygen species (ROS). In this study, we investigated the role of mitochondria in fenretinide-induced cytotoxicity and ROS production in six neuroblastoma cell lines. ROS induction by fenretinide was of mitochondrial origin, demonstrated by detection of superoxide with MitoSOX, the scavenging effect of the mitochondrial antioxidant MitoQ and reduced ROS production in cells without a functional mitochondrial respiratory chain (Rho zero cells). In digitonin-permeabilized cells, a fenretinide concentration-dependent decrease in ATP synthesis and substrate oxidation was observed, reflecting inhibition of the mitochondrial respiratory chain. However, inhibition of the mitochondrial respiratory chain was not required for ROS production. Co-incubation of fenretinide with inhibitors of different complexes of the respiratory chain suggested that fenretinide-induced ROS production occurred via complex II. The cytotoxicity of fenretinide was exerted through the generation of mitochondrial ROS and, at higher concentrations, also through inhibition of the mitochondrial respiratory chain.
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PMID:Fenretinide induces mitochondrial ROS and inhibits the mitochondrial respiratory chain in neuroblastoma. 1994 Oct 60

Familial paraganglioma/pheochromocytoma (PGL/PCC) is genetically heterogenous with mutations in three of the four subunits of the heterotetrameric mitochondrial complex II enzyme succinate dehydrogenase (SDH) being causally responsible for the majority of cases. In addition to PGL/PCC an array of non-paraganglial tumors have been described in affected individuals. We present a 30-year follow-up on the family of a deceased patient who synchronously developed malignant neuroblastoma (NBL), PCC, and renal cell carcinoma (RCC). Other family members with late onset disease have come to our attention, and molecular study revealed a mutation in the SDHB gene. Despite the embryologic relationship, NBL has been seen in only two previous patients with familial PGL/PCC, both with deletions of the SDHB gene. Review of the literature suggests the lack of a reported association between NBL and familial PGL/PCC may be an ascertainment bias. We further suggest that study of the SDH genes in NBL survivors who develop secondary solid tumors, particularly RCC, may correct this bias, and provide for more effective and comprehensive tumor screening in this patient population.
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PMID:Paraganglioma, neuroblastoma, and a SDHB mutation: Resolution of a 30-year-old mystery. 2050 30

Dimebon, a drug currently being evaluated in multiple Phase III Alzheimer's disease trials, has previously been shown to have effects on isolated mitochondria at muM concentrations. Here the effects of nM concentrations of Dimebon on mitochondrial function were investigated both in primary mouse cortical neurons and human neuroblastoma cells (SH-SY5Y). Under non-stress conditions nM concentrations of Dimebon increased succinate dehydrogenase activity (MTT-assay), mitochondrial membrane potential (DeltaPsim), and cellular ATP levels. Dimebon treatment had no effect on mitochondria DNA content, implying that mitochondrial biogenesis was not induced. Under stress conditions, mitochondria in Dimebon-treated neurons showed increased resistance to elevated intracellular calcium concentrations, thus, maintaining their DeltaPsim throughout the experiment, in contrast to control neurons, which rapidly lost their DeltaPsim. Moreover, we show that serum-starved differentiated SH-SY5Y cells treated with Dimebon had an increased survival rate as compared to untreated cells. In conclusion, these data demonstrate that Dimebon enhances mitochondrial function both in the absence and presence of stress and Dimebon-treated cells are partially protected to maintain cell viability.
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PMID:Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. 2055 34

To compare the effects of cobalt at different cellular levels, cultured mouse neuroblastoma cells (Neuro-2a) were exposed for 24 hr to cobalt(II) chloride. The following toxicity indicators were assessed: cell proliferation by quantification of total protein content; cytoplasmic membrane integrity to cytosolic lactate dehydrogenase leakage; lysosomal hexosaminidase release; lactate dehydrogenase activity (LDH); mitochondrial succinate dehydrogenase activity (SDH); relative neutral red uptake by lysosomes (RNRU); lysosomal hexosaminidase activity (HEX), and acetylcholinesterase activity (AChE). The effect of cobalt on the various indicators differed. Cobalt was not very toxic to neuroblastoma cell proliferation (EC(50) = 200 mum). Cytoplasmic membrane permeability was not specifically increased, and LDH leakage occurred only at high concentrations, prior to the stimulation of HEX activity, an enzyme involved in sphingolipid degradation. In contrast, cobalt was lysosomotropic, with HEX release. The effects on lysosomal function were also studied with the RNRU, showing stimulation at low concentrations and inhibition at high concentrations. Neural AChE was decreased after an initial stimulation at low concentrations. LDH and SDH intracellular activities were both stimulated from low concentrations, mitochondrial SDH activity being the most sensitive marker studied. Metabolic stimulatory effects induced by cobalt were, therefore, more marked than changes in cytoplasmic and lysosomal membrane permeability.
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PMID:Effects of cobalt on mouse neuroblastoma cells cultured in vitro. 2065 Jan 2

In order to compare the effects of cocaine at morphological, basal cytotoxicity, biochemical and molecular levels, cultured mouse neuroblastoma cells (Neuro-2a) were exposed to a range of concentrations of cocaine hydrochloride. Neuroblastoma cell proliferation, evaluated by quantification of total protein content, was very sensitive to cocaine, being increasingly inhibited from 12 to 72 hr of exposure (EC(50) = 3.1 mm at 24 hr). Cytoplasmic membrane permeability to lactate dehydrogenase was not particularly increased and lysosomal function was stimulated from 0.05 to 1.5 mm, and inhibited from 2.5 mm. A shift to anaerobiosis was detected as intracellular lactate dehydrogenase (LDH) activity was increased and mitochondrial succinate dehydrogenase (SDH) activity decreased. Hexosaminidase (HEX), a lysosomal enzyme involved in sphingolipid degradation, was stimulated only at 1 mm and neural acetylcholinesterase (AChE) activity was stimulated from 2.5 mm. Morphological examination of exposed cultures revealed that most cells became bipolar and multipolar neurons by extension of neurites, but also suffered cytoplasmic vacuolization, hydropic degeneration and nuclear pyknosis. Although cells developing apoptosis were observed, no DNA oligonucleosomal fragmentation was detected by agarose gel electrophoresis of DNA from cells exposed to cocaine. In conclusion, in addition to predominance of anaerobiosis, little disruption of membranes and severe morphologic injury, biochemical and morphological differentiation-like effects were the most prominent alterations produced by cocaine on mouse neuroblastoma cells.
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PMID:Morphological, biochemical and molecular effects of cocaine on mouse neuroblastoma cells culture in vitro. 2065 45

To compare the effects of thallium at different cellular levels, cultured mouse neuroblastoma cells (Neuro-2A) were exposed for 24 hr to thallium(I) acetate. The following toxic indicators were assessed in the in vitro test system: cell proliferation by quantification of total protein content of the culture; cytoplasmic membrane integrity to cytosolic lactate dehydrogenase (LDH) leakage; lysosomal hexosaminidase release; lactate dehydrogenase activity; mitochondrial succinate dehydrogenase activity; relative neutral red uptake by lysosomes; lysosomal hexosaminidase sphingolipid degradation activity; acetylcholinesterase activity. The effects of thallium on the various indicators differed. Neural acetylcholinesterase activity was extremely sensitive to T1 inhibition. In contrast, hexosaminidase, an enzyme involved in glycosphingolipid degradation, was stimulated prior to cytoplasmic membrane disruption detected as LDH leakage. Relative neutral red uptake was slightly more sensitive than cell growth inhibition and the reduction in hexosaminidase release suggests an interaction with lysosomes. The low degree of sensitivity of cell proliferation, as judged by the protein content of the cultures, may reflect inhibition of protein degradation. LDH glycolytic activity was severely inhibited, but succinate dehydrogenase activity in the citric acid cycle was increased, probably owing to the mitochondrial accumulation of thallium.
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PMID:In vitro effects of thallium on mouse neuroblastoma cells. 2069 72

An in vitro model system has been developed to establish dose-response relationships of mercuric chloride (HgCl(2)) and methylmercuric chloride (HgCH(3)Cl). Mouse neuroblastoma cell cultures (Neuro-2a) were exposed for 24 hr and cytotoxic effects evaluated with eight different endpoints. Toxic indicators assessed in the in vitro test system were as follows: cell proliferation by quantification of total protein content; cytoplasmic membrane integrity by cytosolic lactate dehydrogenase leakage; lysosomal membrane stability by hexosaminidase release; lactate dehydrogenase activity; mitochondrial succinate dehydrogenase activity; relative neutral red uptake by lysosomes; lysosomal hexosaminidase sphingolipid degradation activity; acetylcholinesterase activity. The toxicity of the two chemical species of mercury on neuroblastoma cells differed. HgCl(2) inhibited LDH activity specifically and very potently. Gross disruption of cytoplasmic membrane was accompanied by stimulation of hexosaminidase. HgCH(3)Cl was 50 times more toxic than HgCl(2) to cell proliferation and also caused important alterations in both membrane stability and metabolic activities over a narrow range of doses. The data suggest that HgCl(2) acts mainly on cell membranes and LDH, whereas, although HgCH(3)Cl is more cytotoxic, it does not affect any of the above-mentioned endpoints as specifically.
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PMID:In vitro effects of mercuric chloride and methylmercury chloride on neuroblastoma cells. 2073 14


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