Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Most mitochondria-based methods used to investigate toxins require the use of relatively large amounts of material and hence compromised sensitivity in assay. We adopted procedures from methods initially developed to diagnose mitochondrial encephalomyopathies and unified these into a single assay. Eukaryotic cell membranes are selectively permeabilized with digitonin to render a system in which mitochondrial respiration can be measured rapidly and with considerable sensitivity. Mitochondria remain intact, uninjured, and in their natural environment where mitochondrial respiration can be measured in situ under physiologically relevant conditions. This approach furthermore allows measurement of toxin effects on individual mitochondrial complexes. Numerous compounds at varying concentrations can be screened for mitochondrial toxicity, while the site of mitochondrial inhibition can be determined simultaneously. We used this assay to investigate, in murine neuroblastoma (N-2alpha) cells, the mitochondrial inhibitory properties of the parkinsonian-inducing proneurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and its neurotoxic monoamine oxidase-B (MAO-B)-generated metabolite, the 1-methyl-4-phenylpyridinium species (MPP(+)). Within the time frame of each measurement (15 min), MPTP (< or = 1 mM) did not interfere with in situ mitochondrial respiration. As expected, MPP(+) was found to be a potent Complex I inhibitor but surprisingly also found to inhibit Complex IV. Optimized conditions for performing this assay are provided.
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PMID:Measurement of mitochondrial respiration in permeabilized murine neuroblastoma (N-2alpha) cells, a simple and rapid in situ assay to investigate mitochondrial toxins. 1565 41

Delayed cardio- and neuroprotection are observed following a preconditioning procedure evoked by a brief and nontoxic oxidative stress due to deprivation of oxygen, glucose, serum, trophic factors, and/or antioxidative enzymes. Preconditioning protection can be observed in vivo and is under clinical trials for preservation of cell viability following organ transplants of liver. Previous studies indicated that ischemic preconditioning increases the expression of heat-shock proteins (HSPs) and nitric oxide synthase (NOS). Our pilot studies indicate that the treatment of neuronal NOS inhibitor (7-nitroindazole) and 6Br-cGMP blocks and mimics, respectively, preconditioning protection in human neuroblastoma SH-SY5Y cells. This minireview focuses on nitric oxide-mediated cellular adaptation and the related cGMP/PKG signaling pathway in a compensatory mechanism underlying preconditioning-induced hormesis. Both preconditioning and 6Br-cGMP increase the induction of human thioredoxin (Trx) mRNA and protein for cytoprotection, which is largely prevented by transfection of cells with Trx antisense but not sense oligonucleotides. Cytosolic Trx1 and mitochondrial Trx2 suppress free radical formation, lipid peroxidation, oxidative stress, and mitochondria-dependent apoptosis; knock out/down of either Trx1 or Trx2 is detrimental to cell survival. Other recent findings indicate that a transgenic increase of Trx in mice increases tolerance against oxidative nigral injury caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Trx1 can be translocated into nucleus and phosphoactivated CREB for a delayed induction of mitochondrial anti-apoptotic Bcl-2 and antioxidative MnSOD that is known to increase vitality and survival of cells in the brain and the heart. In conclusion, preconditioning adaptation or a brief oxidative stress induces a delayed nitric oxide-mediated compensatory mechanism for cell survival and vitality in the central nervous system and the cardiovascular system. Preconditioning-induced adaptive tolerance may be signaling through a cGMP-dependent induction of cytosolic redox protein Trx1 and subsequently mitochondrial proteins such as Bcl-2, MnSOD, and perhaps Trx2 or HSP70.
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PMID:Induction of thioredoxin and mitochondrial survival proteins mediates preconditioning-induced cardioprotection and neuroprotection. 1596 87

Through the inhibition of monoamine oxidase type B (MAO-B), (-)-deprenyl (selegiline) prevents the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) and also prevents the neurotoxicity in the dopaminergic neurons in animal models. Cumulative observations suggest that selegiline may also protect against MPP+-induced neurotoxicity, possibly through the induction of pro-survival genes. We have observed that thioredoxin (Trx) mediates the induction of mitochondrial manganese superoxide dismutase (MnSOD) and Bcl-2 during preconditioning-induced hormesis. We therefore investigated whether the redox protein Trx plays any role in the neuroprotective mechanism of selegiline against MPP+-induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming that selegiline protects against MPP+-induced cytotoxicity, we observed further that selegiline, at 1 microM or less, induced Trx for protection against oxidative injury caused by MPP+. The induction of Trx was blocked by protein kinase A (PKA) inhibitor and mediated by a PKA-sensitive phospho-activation of mitogen-activated protein (MAP) kinase Erk1/2 and the transcription factor c-Myc. Selegiline-induced Trx and associated neuroprotection were concomitantly blocked by the antisense against Trx mRNA, but not the sense or antisense mutant phosphothionate oligonucleotides, not only in human SH-SY5Y cells but also in mouse primary neuronal culture of midbrain dopaminergic neurons. Furthermore, the redox cycling of Trx may mediate the protective action of selegiline because the inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated the effect of selegiline. Trx (1 microM) consistently increased the expression of mitochondrial proteins MnSOD and Bcl-2, supporting cell survival (Andoh et al., 2002). In conclusion, without modifying MAO-B activity, selegiline augments the gene induction of Trx, leading to elevated expression of antioxidative MnSOD and antiapoptotic Bcl-2 proteins for protecting against MPP+-induced neurotoxicity.
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PMID:Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (-)-deprenyl. 1609 47

In this study, we investigated the molecular mechanism of toxicity of 1-methyl-4-phenylpyridinium (MPP+), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes parkinsonism in experimental animals and humans. Using wild-type and human neuronal nitric oxide synthase (nNOS) stably transfected neuroblastoma cells (SH-SY5Y), we showed that nNOS overexpression in SH-SY5Y cells greatly enhanced proteasome activity and mitigated MPP+-induced apoptosis. During MPP+-induced oxidative stress, intracellular BH4 levels decreased, resulting in nNOS "uncoupling" (i.e., switching from nitric oxide to superoxide generation). Increasing the intracellular BH4 levels by sepiapterin supplementation restored the nNOS activity, inhibited superoxide formation, increased proteasome activity, decreased protein ubiquitination, and attenuated apoptosis in MPP+-treated cells. Implications of BH4 depletion in dopaminergic cells and sepiapterin supplementation to augment the striatal nNOS activity in the pathogenesis mechanism and treatment of Parkinson disease are discussed.
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PMID:Sepiapterin attenuates 1-methyl-4-phenylpyridinium-induced apoptosis in neuroblastoma cells transfected with neuronal NOS: role of tetrahydrobiopterin, nitric oxide, and proteasome activation. 1619 33

We attempted to clarify the role of Ca2+ in cell death caused by beta-amyloid protein (Abeta) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in SK-N-SH neuroblastoma, respectively. Two insults both reduced cell viability in a concentration-dependent manner and induced equal cytotoxicity in the presence of 20 microM Abeta and 0.4 mM MPTP for 72 h, respectively (68+/-7 vs. 64+/-6% viability). Time-related study showed that Abeta evoked cell death occurred quickly at 24 h. Relatively, MPTP exhibited a delayed cell death significantly after 72 h of culture. Pretreating the cells with nimodipine and chelating of Ca2+ by EGTA plus 1,2-bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) successfully rescued Abeta-induced cell death but failed to prevent MPTP toxicity. ELISA determination of mono/oligonucleosomes accumulation showed the mode of cell death evoked by MPTP was presumably apoptosis while by Abeta was necrosis. SK-N-SH cells constitutively expressed the alpha(1C) subunit of L-type Ca2+ channel and exposure to Abeta or MPTP for 96 h did not further modify its expression. By contrast, alpha(1D) subunit was undetectable or low level expressed in basal condition, but was induced to express after Abeta and MPTP stimulation in a time-dependent manner. Functional assay revealed that KCl-evoked [Ca2+]i rise was significantly greater in Abeta-, but not in MPTP-treated cells when compared with control. Taken together, these results showed that Abeta and MPTP elicited different mode of cell death in SK-N-SH. Nevertheless, Ca2+ overload seems to solely display a crucial role in Abeta-induced cytotoxicity and over-expressed alpha(1D) may contribute to the disruption of cellular Ca2+ homeostasis.
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PMID:Divergent role of calcium on Abeta- and MPTP-induced cell death in SK-N-SH neuroblastoma. 1621 83

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes selective degeneration of dopaminergic neurons in which the c-Jun NH2-terminal kinase (JNK) signalling cascade has been implicated. We have employed a differentiated mouse neuroblastoma N2a cell model to investigate the involvement of JNK and extracellular-regulated kinase (ERK) in MPTP-mediated toxicity and their role in neurofilament heavy chain (NF-H) phosphorylation. Acute treatment with a cytotoxic MPTP concentration (5 mM) caused rapid and sustained JNK phosphorylation and ERK dephosphorylation, accompanied by cell death. In contrast, subcytotoxic concentrations of 10 microM MPTP resulted in lower, transient JNK activation in the presence of sustained ERK activity. This resulted in an aberrant increase in a phosphorylation-dependent NF-H epitope, perikaryal accumulation of NF-H, and loss of axon-like processes, prior to cell death. Inhibition of MEK kinase, using PD98059, showed that MEK 1/2 or the downstream kinase, ERK, is required for N2a cell differentiation, NF-H phosphorylation and survival. Indeed, MPTP-induced cell death was exacerbated by the presence of PD98059. However, in the presence of MPTP, reducing JNK activity by using an upstream specific mixed-lineage kinase inhibitor (CEP-11004) significantly attenuated aberrant NF-H phosphorylation and perikaryal NF-H accumulation and maintained axon-like processes, in addition to attenuating cell death. This study reports a switch in the predominant kinase involved in NF phosphorylation in a neuronal cell model and may have implications for the formation of inclusions. Our studies provide further evidence that modulation of the JNK pathway could have a role in alleviating neuronal cell death.
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PMID:Role of extracellular-regulated kinase and c-Jun NH2-terminal kinase in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurofilament phosphorylation. 1644 69

The evidence for loss of Ca2+ homeostasis due to neuronal degeneration is considerable and rapidly increasing. In this study, we try to evaluate the protective effect of tetrandrine (TET), an alkaloid isolated from the Chinese medicinal herb Radix Stephania tetrandrae S., on amyloid-beta protein (Abeta) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced cell death in SK-N-SH neuroblastoma cells. Both compounds reduced cell viability in a concentration-dependent manner after 72 h in culture. Cell proliferation in the presence of 20 microM Abeta or 0.4 mM MPTP was reduced to 58.3 +/- 4.9 or 54.9 +/- 5.5 %, respectively. TET (0.1, 0.5 and 1 microM) alone had no significant effect on cell survival; however, it prevented Abeta-induced cell death in a concentration-dependent manner. In contrast, TET failed to counteract MPTP-induced cytotoxicity. Also, an L-type calcium channel blocker, nimodipine, solely reversed Abeta-induced cell death. On the other hand, ELISA determination of mono-/oligo-nucleosomes accumulation showed that the mode of cell death evoked by Abeta was necrosis while that evoked by MPTP was presumably apoptosis. These results suggest that TET may mitigate the harmful effects of Abeta on cell survival, probably by interfering via the necrotic signal related to Ca2+ overloading through the L-type calcium channel.
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PMID:Tetrandrine selectively protects against amyloid-beta protein - but not against MPTP-induced cytotoxicity in SK-N-SH neuroblastoma cells. 1705 60

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and its metabolite 1-methyl-4-phenylpyridinium (MPP(+)) are drugs that are widely used in experimental Parkinson disease (PD) models. What is the significance of ORP150/HSP12A, a molecular chaperone in the endoplasmic reticulum (ER), in the nigrostriatal system? Dopaminergic neuroblastoma SH-SY5Y cells and dopaminergic neurons of the substantia nigra pars compacta (SNpc) were examined. Our observations led to the hypothesis that ORP150 protects against MPTP/MPP(+)-induced neurotoxicity, and indicate the importance of the ER environment in maintaining the nigrostriatal pathways.
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PMID:Does ORP150/HSP12A protect dopaminergic neurons against MPTP/MPP(+)-induced neurotoxicity? 1733 Sep 88

1-Methyl-4-phenyl-pyridine ion (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinsonian syndrome in humans and animals, a neurotoxic effect postulated to derive from oxidative stress. We report here the first investigation of MPP+-induced oxidative stress in the murine neuroblastoma cell line N2A. Significant cell death was observed following exposure to 0.25 mM MPP+. Markers of oxidative stress included decreased intracellular levels of GSH after 48 h of exposure (85% depletion) as well as an increase in GSSG. Expression of both superoxide dismutase 1 (sod1) and catalase (cat) mRNA was increased, as well the activity of catalase. These cellular effects were, at least partially, reversed by treatment with the natural polyphenol mangiferin. Administration of mangiferin protected N2A cells against MPP+-induced cytotoxicity, restored the GSH content (to 60% of control levels), and down-regulated both sod1 and cat mRNA expression. Together, these results suggest that the protective effect of mangiferin in N2A cells is mediated by the quenching of reactive oxygen intermediates. Therefore, mangiferin could be a useful compound in therapies for degenerative diseases, including Parkinson's disease, in which oxidative stress plays a crucial role.
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PMID:Mangiferin protects against 1-methyl-4-phenylpyridinium toxicity mediated by oxidative stress in N2A cells. 1743 43

Oxidative stress and mitochondrial dysfunction caused by loss of complex I activity are presumed to be primary events leading to neurodegeneration in Parkinson's disease. Mitochondrial glutaredoxin (Grx2), a glutathione-dependent thiol disulfide oxidoreductase helps maintain redox homeostasis in the mitochondria. We therefore, examined the constitutive expression of Grx2 in brain and its role in MPTP-mediated mitochondrial dysfunction in the extrapyramidal system. Grx2 is constitutively expressed in both neuron and glia in mouse and human brain including the neurons in human substantia nigra. Grx2 mRNA and protein were transiently upregulated in midbrain and striatum 1 h but not 4 h after a single dose of MPTP. Downregulation of Grx2 using antisense oligonucleotides, in vivo, in mouse brain resulted in partial loss of complex I activity indicating that Grx2 may help maintain complex I function in the mitochondria. Further, overexpression of Grx2 abolished MPP(+)-mediated toxicity in vitro in neuroblastoma cells. Our results demonstrate the probable role of Grx2 in maintenance of the redox milieu in mitochondria and its potential neuroprotective role in preserving mitochondrial integrity in neurodegenerative diseases, such as Parkinson's disease.
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PMID:Constitutive expression and functional characterization of mitochondrial glutaredoxin (Grx2) in mouse and human brain. 1796 15


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