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)

Hereditary argininemia manifests as neurological disturbance and mental retardation, features not observed in other amino acidemias. The cytotoxic effect of a high concentration of L-arginine (L-Arg) was investigated using NB9 human neuroblastoma cells (NB9), which express neuronal nitric oxide synthase (nNOS). When the concentration of L-Arg in the medium increased from 50 microM to 2 mM after incubation for 48 hr, the intracellular concentration of L-Arg increased from 68.0 +/- 1 pmol/10(6) cells to 1310.0 +/- 5 pmol/10(6) cells and that of L-citrulline (L-Cit) from undetectable levels to 47.1 +/- 0.2 pmol/10(6) cells (mean +/- SD of three independent analyses). This increase in intracellular L-Arg levels caused a decrease in NOS activity by approximately 71%. Flow cytometric analysis showed that reactive oxygen species (ROS) are produced in NB9 exposed to 2 mM L-Arg. The production of ROS was abolished by a NOS inhibitor, NG-nitro-L arginine-methylester. Production of ROS was also observed when NB9 were treated with L-Cit for 48 hr. To investigate the effect of L-Cit on the activity of NOS, a kinetic study on nNOS was conducted using cellular extracts from NB9. The apparent Km value of nNOS for L-Arg was 8.4 microM, with a Vmax value of 8.2 pmol/min/mg protein. L-Cit competitively inhibited NOS activity, as indicated by an apparent Ki value of 65 nM. These results suggest that L-Cit formed by nNOS in L-Arg-loaded neuronal cells inhibits NOS activity and nNOS in these L-Arg-loaded cells functions as a NADPH oxidase to produce ROS, which may cause neurotoxicity in argininemia.
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PMID:High concentration of L-arginine suppresses nitric oxide synthase activity and produces reactive oxygen species in NB9 human neuroblastoma cells. 974 7

Direct in vivo evidence for the susceptibility of human neuronal cells to dengue virus has not been reported. In this study, we demonstrated that type 2 dengue (DEN-2) virus infection induced extensive apoptosis in the human neuroblastoma cell line SK-N-SH. Phospholipase A(2) (PLA(2)) was activated by DEN-2 infection, which led to the generation of arachidonic acid (AA). Inhibition of PLA(2) activity by the PLA(2) inhibitors, AACOCF(3) and ONO-RS-082, diminished DEN-2 virus-induced apoptosis. In contrast, the cyclooxygenase inhibitors aspirin and indomethacin, thought to increase AA accumulation by blocking AA catabolism, enhanced apoptosis. Exogenous AA induced apoptosis in a dose-dependent manner. Superoxide anion, which is thought to be generated through the AA-activated NADPH oxidase, was increased after infection. Pretreatment with superoxide dismutase (SOD) protected cells against DEN-2 virus-induced apoptosis. Furthermore, generation of superoxide anion was blocked by AACOCF(3). In addition, the transcription factors, NF-kappaB and c-Jun, were found to be activated after DEN-2 virus infection. However, pretreatment of cells with oligodeoxynucleotides containing NF-kappaB, but not c-Jun, binding sites (transcription factor decoy) strongly prevented dengue virus-induced apoptosis. The finding that AACOCF(3) and SOD significantly block activation of NF-kappaB suggests that this activation is derived from the AA-superoxide anion pathway. Our results indicate that DEN-2 virus infection of human neuroblastoma cells triggers an apoptotic pathway through PLA(2) activation to superoxide anion generation and subsequently to NF-kappaB activation. This apoptotic effect can be either directly derived from the action of AA and superoxide anion on mitochondria or indirectly derived from the products of apoptosis-related genes activated by NF-kappaB.
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PMID:Potential dengue virus-triggered apoptotic pathway in human neuroblastoma cells: arachidonic acid, superoxide anion, and NF-kappaB are sequentially involved. 1095 69

The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving signaling pathways mediated by free radicals or reactive oxygen species (ROS). The aim of this study was to identify mechanisms generating ROS and apoptosis of neuroblastoma cells in response to fenretinide. Fenretinide-induced ROS or apoptosis of SH-SY5Y or HTLA 230 neuroblastoma cells were not blocked by Nitro l-argenine methyl ester (l-NAME), an inhibitor of nitric oxide synthase. Flavoprotein-dependent superoxide-producing enzymes such as NADPH oxidase were also not involved in fenretinide-induced apoptosis or ROS generation. Similarly, ketoconazole, a cytochrome P450 inhibitor, and inhibitors of cyclooxygenase (COX) were also ineffective. In contrast, inhibition of phospholipase A(2) or lipoxygenases (LOX) blocked the induction of ROS and apoptosis in response to fenretinide. Using specific inhibitors of LOX, blocking 12-LOX but not 5- or 15-LOX inhibited both fenretinide-induced ROS and apoptosis. The effects of eicosatriynoic acid, a specific 12-LOX inhibitor, were reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid and 12 (S)-hydroxyeicosatetraenoic acid. The targeting of 12-LOX in neuroblastoma cells may thus be a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity.
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PMID:Mechanisms of free-radical induction in relation to fenretinide-induced apoptosis of neuroblastoma. 1285 36

In this study we have investigated the effects of the small GTP-binding-protein Ras on the redox signalling of the human neuroblastoma cell line, SK-N-BE stably transfected with HaRas(Val12). The levels of reactive oxygen species (ROS) and superoxide anions were significantly higher in HaRas(Val12) expressing (SK-HaRas) cells than in control cells. The treatment of cells with 4-(2-aminoethyl) benzenesulfonylfluoride, a specific inhibitor of the membrane superoxide generating system NADPH oxidase, suppressed the rise in ROS and significantly reduced superoxide levels produced by SK-HaRas cells. Moreover, HaRas(Val12) induced the translocation of the cytosolic components of the NADPH oxidase complex p67(phox) and Rac to the plasma membrane. These effects depended on the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK1/2) pathway, as the specific MEK inhibitor, PD98059, prevented HaRas-mediated increase in ROS and superoxide anions. In contrast, the specific phosphoinositide 3-kinase (PI3K) inhibitors LY294002 and wortmannin were unable to reverse the effects of HaRas(Val12). Moreover, cholinergic stimulation of neuroblastoma cells by carbachol, which activated endogenous Ras/ERK1/2, induced a significant increase in ROS levels and elicited membrane translocation of p67(phox) and Rac. ROS generation induced by carbachol required the activation of ERK1/2 and PI3K. Hence, these data indicate that HaRas-induced ERK1/2 signalling selectively activates NADPH oxidase system in neuroblastoma cells.
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PMID:HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway. 1548 92

Phosphoinositide-3 kinase (PI-3 kinase) and its downstream signaling molecules PDK-1 and Akt were analyzed in SK-N-SH and SK-N-BE(2) human neuroblastoma cell lines. When cells were stimulated with insulin, PI-3 kinase was activated in both cell lines, whereas the translocation of PDK-1 to the membrane fraction and phosphorylated Akt were observed only in SK-N-SH cells. Analyses of the insulin-mediated reactive oxygen species (ROS) generation and Phosphatase and Tensin homolog (PTEN) oxidation indicate that PTEN oxidation occurred in SK-N-SH cells, which can produce ROS, but not in SK-N-BE(2) cells, which cannot increase ROS in response to insulin stimulation. When SK-N-SH cells were pretreated with the NADPH oxidase inhibitor diphenyleneiodonium chloride before insulin stimulation, insulin-mediated translocation of PDK-1 to the membrane fraction and phosphorylation of Akt were remarkably reduced, whereas PI-3 kinase activity was not changed significantly. These results indicate that not only PI-3 kinase activation but also inhibition of PTEN by ROS is needed to increase cellular level of phosphatidylinositol 3,4,5-trisphosphate for recruiting downstream signaling molecules such as PDK-1 and Akt in insulin-mediated signaling. Moreover, the ROS generated by insulin stimulation mainly contributes to the inactivation of PTEN and not to the activation of PI-3 kinase in the PI-3 kinase/Akt pathway.
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PMID:The major target of the endogenously generated reactive oxygen species in response to insulin stimulation is phosphatase and tensin homolog and not phosphoinositide-3 kinase (PI-3 kinase) in the PI-3 kinase/Akt pathway. 1553 4

We recently demonstrated that superoxide (O2*-) is a key signaling intermediate in central angiotensin II (Ang II)-elicited blood pressure and drinking responses, and that hypertension caused by systemic Ang II infusion involves oxidative stress in cardiovascular nuclei of the brain. Intracellular Ca2+ is known to play an important role in Ang II signaling in neurons, and it is also linked to reactive oxygen species mechanisms in neurons and other cell types. However, the potential cross-talk between Ang II, O2*-, and Ca2+ in neural cells remains unknown. Using mouse neuroblastoma Neuro-2A cells, we tested the hypothesis that O2*- radicals are involved in the Ang II-induced increase in intracellular Ca2+ concentration ([Ca2+]i) in neurons. Ang II caused a rapid time-dependent increase in [Ca2+]i that was abolished in cells bathed in Ca2+-free medium or by pretreatment with the nonspecific voltage-gated Ca2+ channel blocker CdCl2, suggesting that voltage-sensitive Ca2+ channels are the primary source of Ang II-induced increases in [Ca2+]i in this cell type. Overexpression of cytoplasm-targeted O2*- dismutase via an adenoviral vector (AdCuZnSOD) efficiently scavenged Ang II-induced increases in intracellular O2*- and markedly attenuated the increase in [Ca2+]i caused by this peptide. Furthermore, adenoviral-mediated expression of a dominant-negative isoform of Rac1 (AdN17Rac1), a critical component for NADPH oxidase activation and O2*- production, significantly inhibited the increase in [Ca2+]i after Ang II stimulation. These data provide the first evidence that O2*- is involved in the Ang II-stimulated influx of extracellular Ca2+ in neural cells and suggest a potential intracellular signaling mechanism involved in Ang II-mediated oxidant regulation of central neural control of blood pressure.
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PMID:Superoxide mediates angiotensin II-induced influx of extracellular calcium in neural cells. 1569 59

Reactive oxygen species (ROS) and deposition of cleaved products of amyloid precursor protein (APP) are thought to contribute to neuronal loss observed in Alzheimer's disease (AD). The relationship between these factors was studied in a neuroblastoma and microglia co-culture system. Overexpression of wild-type APP (APP-wt) or APP with three mutations typical of familial AD (APP-3m) in SH-SY5Y neuroblastoma cells did not directly alter their morphology, growth rate, cell cycle or H(2)O(2) sensitivity. In a co-culture of APP-wt neuroblastoma cells with microglia, microglial cells generated ROS and neuronal cells died. The cell death was more pronounced in APP-3m-expressing neurons. Neuroblastoma cell death was attenuated by ROS-scavengers and was dose-dependently inhibited by the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI). Macrophage cell lines behaved similarly to microglia in the co-culture model. However, a macrophage cell line deficient in the NADPH oxidase subunit, gp91phox, failed to kill neurons. These results suggest that APP-dependent microglia activation and subsequent ROS generation by the phagocyte NADPH oxidase play a crucial role in neuronal killing in a cellular model of AD.
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PMID:A key role for the microglial NADPH oxidase in APP-dependent killing of neurons. 1626 66

Reactive oxygen species (ROS) are known to play an important role in glutamate-induced neuronal cell death. In the present study, we examined whether NADPH oxidase serves as a source of ROS production and plays a role in glutamate-induced cell death in SH-SY5Y human neuroblastoma cells. Stimulation of the cells with glutamate (100 mM) induced apoptotic cell death and increase in the level of ROS, and these effects of glutamate were significantly suppressed by the inhibitors of the NADPH oxidase, diphenylene iodonium, apocynin, and neopterine. In addition, RT-PCR revealed that SH-SY5Y cells expressed mRNA of gp91phox, p22phox and cytosolic p47phox, p67phox and p40phox, the components of the plasma membrane NADPH oxidase. Treatment with glutamate also resulted in activation and translocation of Rac1 to the plasma membrane. Moreover, the expression of Rac1N17, a dominant negative mutant of Rac1, significantly blocked the glutamate-induced ROS generation and cell death. Collectively, these results suggest that the plasma membrane-bound NADPH oxidase complex may play an essential role in the glutamate-induced apoptotic cell death through increased production of ROS.
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PMID:Rac1-NADPH oxidase-regulated generation of reactive oxygen species mediates glutamate-induced apoptosis in SH-SY5Y human neuroblastoma cells. 1629 59

3-nitro-L-tyrosine is formed by nitric oxide following different pathways such as NADPH oxidase, xanthine oxidase or glutamate NMDA receptor activation and is involved in the pathology of different neurological disorders. Unlike estradiol, a neuroprotective role of androgens against oxidative cell injury has not been fully investigated. This work targets the possible effects of testosterone on neuroblastoma cells exposed to 3-nitro-L-tyrosine. C1300 mouse undifferentiated neuroblastoma cells exposed to 3-nitro-L-tyrosine were cultured in the presence of testosterone. Morphological examination, proliferation and nuclear viability assays were performed. The expression of tyrosinated alpha-tubulin and incorporation of 3-nitro-L-tyrosine into protein were also estimated. Cells exposed to 3-nitro-L-tyrosine showed globular shape, reduced cytoplasmic processes and growth inhibition in comparison with controls. When testosterone was added to the medium, these changes were not evident. In addition, testosterone induced an upregulation of tyrosinated alpha-tubulin, a marker of neuronal plasticity, and a decrease in 3-nitro-L-tyrosine incorporation into tubulin. Our results suggest that testosterone exposure can diminish 3-nitro-L-tyrosine toxic effects on the morphology and growth rate of neuroblastoma cells. The upregulation of tyrosinated alpha-tubulin in testosterone-exposed cells would be consistent with concurrent plasticity events. Failure in alpha-tubulin nitration detected in cells exposed to both 3-nitro-L-tyrosine and testosterone, may support the idea that testosterone interferes with 3-nitro-L-tyrosine protein incorporation. Moreover, testosterone-induced neuroprotection likely entails a linkage with the androgen receptor as is suggested by the flutamide-induced inhibition of the hormone activity. Finally, the neuroprotective effects of testosterone in neuroblastoma cells could deal with the cellular antioxidant defence system, as shown by testosterone-induced increase in catalase activity.
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PMID:Testosterone induces neuroprotection from oxidative stress. Effects on catalase activity and 3-nitro-L-tyrosine incorporation into alpha-tubulin in a mouse neuroblastoma cell line. 1664 86

The activation of cellular inflammatory response is tightly linked to induced production of reactive oxygen species (ROS) and nitric oxide (NO), which in turn have been identified as important regulators of cellular iron metabolism. In the present study, we have used the microglia cell line BV-2 and the neuroblastoma cell line N2a to study the regulatory effects of the microbial agent lipopolysaccharide (LPS) on the expression of the transferrin receptor (TfR) and ferritin in cell lines with different characteristics. The receptor mainly responsible for LPS recognition is the Toll-like receptor 4 (TLR4) that triggers a variety of intracellular signalling cascades leading to the induction of transcription of target genes involved in the innate immune response. Among the pathways to be activated is the MAPK cascade leading to the activation of nuclear factor-kappaB that induces transcription of a variety of genes, e.g., inducible nitric oxide synthase (iNOS). The TLR4-mediated LPS response also induces the production of ROS through a mechanism(s) suggested to involve the activation of NADPH oxidase(s). This study shows that exposure of BV-2 and N2a cells to LPS results in decreased TfR protein levels and increased H-ferritin mRNA levels. The LPS down-regulatory effect on TfR protein expression is abolished by the NADPH oxidase inhibitor diphenyliodonium (DPI) but is not affected by the free radical scavenger N-acetyl-L-cysteine (NAC) or the iNOS inhibitor aminoguanidine (AG). The increased H-ferritin mRNA levels in response to LPS are not affected by DPI, NAC, or AG.
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PMID:NADPH oxidase inhibitor diphenyliodonium abolishes lipopolysaccharide-induced down-regulation of transferrin receptor expression in N2a and BV-2 cells. 1688 Oct 50


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