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)

Oxidative stress has been known to be involved in the mechanism of toxic effects of various agents on many cellular systems. In this study we investigated the role of reactive oxygen species (ROS) in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced neuronal cell toxicity using SK-N-SH human neuroblastoma cells. TCDD inhibited proliferation of the cells in a dose-dependent manner, which was revealed by MTT staining, counting of cells stained with trypan blue and [3H]thymidine uptake assay. TCDD also suppressed the basal generation of ROS in a time- and concentration-dependent manner assessed by 2',7'-dichlorofluorescein fluorescence. In addition, TCDD induced a dose-dependent inhibition of lipid peroxidation, a biomarker of oxidative stress, whereas it significantly increased the level of glutathione (GSH), an intracellular free radical scavenger in the cells. Moreover, TCDD altered the activities of major antioxidant enzymes; increase in superoxide dismutase (SOD) and catalase, but decrease in glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Red). Pretreatment with L-buthionine-S,R-sulfoximine (BSO, 50 microM), an inhibitor of GSH synthesis, significantly prevented the TCDD-induced reduction in lipid peroxidation and cell proliferation. Interestingly, exogenous application of an oxidant, H2O2 (50 microM) markedly restored the inhibited cell proliferation induced by TCDD. Taken together, these results suggest that alteration of cellular redox balance may mediate the TCDD-induced inhibition of proliferation in human neuronal cells.
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PMID:2,3,7,8-tetrachlorobenzo-p-dioxin inhibits proliferation of SK-N-SH human neuronal cells through decreased production of reactive oxygen species. 1260 19

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin that causes Parkinson's disease in experimental animals and humans. Despite the fact that intracellular iron was shown to be crucial for MPP(+)-induced apoptotic cell death, the molecular mechanisms for the iron requirement remain unclear. We investigated the role of transferrin receptor (TfR) and iron in modulating the expression of alpha-synuclein (alpha-syn) in MPP(+)-induced oxidative stress and apoptosis. Results show that MPP(+) inhibits mitochondrial complex-1 and aconitase activities leading to enhanced H(2)O(2) generation, TfR expression and alpha-syn expression/aggregation. Pretreatment with cell-permeable iron chelators, TfR antibody (that inhibits TfR-mediated iron uptake), or transfection with glutathione peroxidase (GPx1) enzyme inhibits intracellular oxidant generation, alpha-syn expression/aggregation, and apoptotic signaling as measured by caspase-3 activation. Cells overexpressing alpha-syn exacerbated MPP(+) toxicity, whereas antisense alpha-syn treatment totally abrogated MPP(+)-induced apoptosis in neuroblastoma cells without affecting oxidant generation. The increased cytotoxic effects of alpha-syn in MPP(+)-treated cells were attributed to inhibition of mitogen-activated protein kinase and proteasomal function. We conclude that MPP(+)-induced iron signaling is responsible for intracellular oxidant generation, alpha-syn expression, proteasomal dysfunction, and apoptosis. Relevance to Parkinson's disease is discussed.
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PMID:Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. 1474 48

Glutathione (GSH) constitutes the single most important antioxidant in neurons, whereas iron causes oxidative stress that leads to cell damage and death. Although GSH and iron produce opposite effects on redox cell status, no mechanistic relationships between iron and GSH metabolism are known. In this work, we evaluated in SH-SY5Y neuroblastoma cells the effects of iron accumulation on intracellular GSH metabolism. After 2 d exposure to increasing concentrations of iron, cells underwent concentration-dependent iron accumulation and a biphasic change in intracellular GSH levels. Increasing iron from 1 to 5 microM resulted in a marked increase in intracellular oxidative stress and increased GSH levels. Increased GSH levels were due to increased synthesis. Further increases in iron concentration led to significant reduction in both reduced (GSH) and total (GSH + (2 x GSSG)) glutathione. Cell exposure to high iron concentrations (20-80 microM) was associated with a marked decrease in the GSH/GSSG molar ratio and the GSH half-cell reduction potential. Moreover, increasing iron from 40 to 80 microM resulted in loss of cell viability. Iron loading did not change GSH reductase activity but induced significant increases in GSH peroxidase and GSH transferase activities. The changes in GSH homeostasis reported here recapitulate several of those observed in Parkinson's disease substantia nigra. These results support a model by which progressive iron accumulation leads to a progressive decrease in GSH content and cell reduction potential, which finally results in impaired cell integrity.
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PMID:Progressive iron accumulation induces a biphasic change in the glutathione content of neuroblastoma cells. 1533 11

Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one) mimics the activity of glutathione peroxidase [Biochem. Pharmacol. 33 (1984) 3235], acts as a substrate for thioredoxin reductase [Proc. Natl. Acad. Sci. U.S.A. 99 (2002) 8579]. The present study focused on the cellular mechanism of its action against oxidative stress by using HT22 cells, a mouse neuroblastoma of hippocampal origin. Ebselen protected HT22 cells against death induced by glutamate and hydrogen peroxide but not against that by tumor necrosis factor alpha. Oxidative glutamate toxicity is initiated by depletion of total glutathione, and ebselen inhibited the decrease in glutathione and increased its basal level. Although glutamate increased intracellular levels of reactive oxygen species (ROS), ebselen suppressed their increase. Ebselen reduced the basal levels of ROS when it was applied in control cells. Ebselen also removed ROS from cells that had accumulated a level of them. The compound had a significant trolox equivalent activity concentration value in a cell-free system, suggesting that it has a direct ROS-scavenging capacity. Finally, ebselen-induced heme oxygenase-1 (HO-1) protein. These results indicate that ebselen protects neuronal cells against the oxidative stress at multiple steps, including an increase in glutathione, a ROS-scavenging activity and the induction of HO-1 protein.
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PMID:Protective effects on neuronal cells of mouse afforded by ebselen against oxidative stress at multiple steps. 1550 Sep 56

In this study we evaluated the effect of a novel, marine-derived, acidic oligosaccharide on scopolamine-induced amnesia in rats using the Morris water maze test. The results show that 30-day administration of this oligosaccharide, referred to as acidic oligosaccharide sugar chain (AOSC), to rats attenuates memory impairment by scopolamine, as evaluated by shortened escape latency, swimming distance, and increased swimming time of rats with memory impairment induced by scopolamine in the quadrant where the platform is placed. The data additionally suggest that an appropriate dose of scopolamine, a traditional muscarinic receptor antagonist, elevates oxidative damage in brain, characterized by inactivation of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and consequently, inhibition of ATPase in the hippocampus and cerebral cortex. AOSC ameliorates oxidative injuries caused by scopolamine by increasing the activities of SOD, GSH-Px, and ATPase. Further investigation by flow cytometry revealed that AOSC significantly reduces the overloading of intracellular free calcium ion ([Ca2+]i), thus suppressing apoptosis induced by H2O2 in human neuroblastoma SH-SY5Y cells. These findings suggest that AOSC can induce cognitive improvement via its antioxidant activity.
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PMID:Effect of acidic oligosaccharide sugar chain on scopolamine-induced memory impairment in rats and its related mechanisms. 1566 67

Bambusae concretio Salicea (BCS; plant family name: Phyllostachys bambusoides Siebold et Zuccarinii) is a medicinal plant used in Korea for the treatment of various symptoms accompanying hypertension and cerebrovascular disorders. Previously, it was shown that BCS is an effective protectant against oxidative glutamate toxicity in the murine neuroblastoma cells and human neuroblastoma cells. Treatment with BCS increased the secretion of the non-amyloidogenic amyloid precursor protein fragment, and decreased the secretion of amyloid-beta (Abeta) peptides from neuronal cells [Jeong, J.C., Seo, Y.J., Kim, H.M., Lee, Y.C., Kim, C.H., 2003. Inhibitory effects of Bombusae concretio Salicea on neuronal secretion of Alzheimer's beta-amyloid peptides, a neuro-degenerative peptide. Neurochemical Research 28, 1785-1792.]. To further examine the pharmacological activity of BCS, we studied the protective effect of the water extracts on Abeta25-35 peptide-induced neuronal death by microscopic observation and lactate dehydrogenase (LDH) assay, and action on antioxidative enzymes using cultured astrocyte cells. Ten microM Abeta25-35-induced cell death was protected by the application of water extract of BCS in a dose-dependent manner, and concentrations of 1-10 microg/ml had a significant effect compared to exposure to Abeta25-35 only. When antioxidative enzyme activities such as catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) were assayed after Abeta25-35 treatment, the enzymes were decreased in a similar fashion. However, those activities were enhanced by BCS treatment and this may have resulted from the potentiation of antioxidative ability by BCS. The ability of BCS to reduce cellular cytotoxicity induced by 10 microM Abeta25-35 suggests that BCS may be a protective agent for free radical generating compounds such as Abeta25-35, and that Abeta25-35 is not only a potent lipid peroxide inducer, but also causes changes in antioxidative enzymes. From the results, it was concluded that BCS has a protective effect on Abeta-induced neuronal death in cultured astrocyte cells through the inhibition of lipid peroxidation and protection of antioxidative enzymes.
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PMID:Effects of Bambusae concretio Salicea (Chunchukhwang) on amyloid beta-induced cell toxicity and antioxidative enzymes in cultured rat neuronal astrocytes. 1581 57

Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. Recently, it has been shown that fraxetin (coumarin) and myricetin (flavonoid) have significant neuroprotective effects against apoptosis induced by rotenone, increase the total glutathione levels in vitro, and inhibit lipid peroxidation. Thus, these considerations prompted us to investigate the way in which fraxetin and myricetin affect the endogenous antioxidant defense system, such as Mn and CuZn superoxide dismutase (MnSOD, CuZnSOD), catalase, glutathione reductase (GR), and glutathione peroxidase (GPx) on rotenone neurotoxicity in neuroblastoma cells. N-acetylcysteine (NAC), a potent antioxidant, was employed as a comparative agent. Also, the expression and protein levels of HSP70 by Northern and Western blot analysis were assayed in SH-SY5Y cells. After incubation for 16 h, rotenone significantly increased the expression and activity of MnSOD, GPx, and catalase. When cells were preincubated with fraxetin, there was a decrease in the protein levels and activity of both MnSOD and catalase, in comparison with the rotenone treatment. The myricetin effect was less pronounced. Activity and expression of GPx were increased by rotenone and pre-treatment with fraxetin did not modify significantly these levels. The significant enhancement in HSP70 expression at mRNA and protein levels induced by fraxetin was observed by pre-treatment of cells 0.5 h before rotenone insult. These data suggest that major features of rotenone-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that fraxetin partially protects against rotenone toxicity affecting the main protection system of the cells against oxidative injury.
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PMID:Effect of fraxetin on antioxidant defense and stress proteins in human neuroblastoma cell model of rotenone neurotoxicity. Comparative study with myricetin and N-acetylcysteine. 1590 44

Prostaglandin E2 (PGE2), one product of inflammatory reactions, and PGA1, which is formed during PGE2 extraction, induce degeneration in adenosine 3',5'-cyclic monophosphate (cAMP)-induced differentiated neuroblastoma (NB) cells in culture. The mechanisms of action of PGE2 on neurodegeneration are not well understood. To investigate this, we have utilized PGA(1), which mimics the effect of PGE2 and is very stable in solution. We have assayed selected markers of oxidative stress such as heme oxygenase-1 (HO-1), catalase, glutathione peroxidase (GPx1), mitochondrial superoxide dismutase (Mn-SOD-2) and cytosolic superoxide dismutase (Cu/Zn-SOD-1). The results showed that the treatment of differentiated NB cells with PGA1 for a period of 48 hr increased the expression of HO-1 and catalase, decreased the expression of GPx1 and Mn-SOD-2, and did not change the expression of Cu/Zn-SOD-1 as measured by gene array and confirmed by real-time PCR. The protein levels of HO-1 and GPx1 increased; however, the protein level of Mn-SOD-2 decreased and the levels of catalase and Cu/Zn-SOD-1 did not change as determined by Western blot. The increases in the levels of HO-1 and GPx1 reflected an adaptive response to increased oxidative stress, whereas decrease in the level of Mn-SOD-2 may make cells more sensitive to oxidative damage. These data suggest that one of the mechanisms of action of PGA1 on neurodegeneration may involve increased oxidative stress. This was supported further by the fact that a mixture of antioxidants (alpha-tocopherol, vitamin C, selenomethionine, and reduced glutathione), but not the individual antioxidants, reduced the level of PGA1-induced degeneration in differentiated NB cells. The addition of a single antioxidant at two or four times the concentration used in the mixture was toxic.
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PMID:Prostaglandin-induced neurodegeneration is associated with increased levels of oxidative markers and reduced by a mixture of antioxidants. 1592 Jul 43

The NMDA class of glutamate receptors plays a critical role in CNS, such as synaptic plasticity, axonal sprouting, growth, and migration. NMDA receptor stimulation has been shown to regulate polysialylated neural cell adhesion molecule (PSA-NCAM) expression in glial cell cultures and in hippocampal slice cultures. There is also growing evidence that molecular chaperons and ROS are related to the synaptic plasticity phenomena. We have examined the neuroprotective effect of subtoxic dose of NMDA in retinoic acid differentiated SH-SY5Y neuroblastoma cells. SH-SY5Y cell line differentiated with retinoic acid (10 muM) was exposed to NMDA (100 microM) or to antagonist MK-801 (200 nM) + NMDA and cells harvested after 24 h of treatment for PSA-NCAM, NCAM, and HSP70 expression study and for biochemical analysis. A significant increase was observed in PSA-NCAM, NCAM-180, NCAM-140, and HSP70 expression as seen by Western blotting and immunocytofluorescent studies in NMDA-treated cultures. Biochemical analysis revealed a significant increase in the activities of glutathione peroxidase (GPx) and copper zinc-superoxide dismutase (CuZnSOD) upon exposure to NMDA. No significant change was observed in the level of lipid peroxidation. All the changes observed reverted back to the control values upon pretreatment of cultures with MK-801, a non-competitive NMDA receptor antagonist, prior to NMDA exposure indicating the involvement of NMDA receptor in these changes. These results illustrate the neuroprotective role of subtoxic dose of NMDA in SH-SY5Y neuroblastoma cells.
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PMID:Neuroprotection mediated by subtoxic dose of NMDA in SH-SY5Y neuroblastoma cultures: activity-dependent regulation of PSA-NCAM expression. 1595 Jul 81

Reactive oxygen species are considered to contribute to the pathogenesis of Parkinson's disease (PD). In order to study viral vector-mediated overexpression of the antioxidant enzyme glutathione peroxidase (GPX) as a potential neuroprotective approach in both an in vitro and in vivo model of PD, we have developed a lentiviral vector carrying the human GPX1 gene. Neuroblastoma cells infected with this vector showed a 2-fold increase in GPX activity compared to cells infected with a control vector. In addition, overexpression of GPX protected 83.0 +/- 14.2% of these cells against 6-hydroxydopamine (6-OHDA)-induced toxicity, while only 22.9 +/- 4.6% of the cells infected with a control vector survived. Furthermore, lentivirus-mediated expression of GPX1 in nigral dopaminergic neurons in vivo prior to intrastriatal injection of 6-OHDA led to a small, but significant protection of these cells against drug-induced toxicity. These results indicate that antioxidative gene therapy strategies may be relevant for PD.
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PMID:Lentivirus-mediated expression of glutathione peroxidase: neuroprotection in murine models of Parkinson's disease. 1602 52


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