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)

Parkinson's disease (PD) is the most common motor disorder affecting the elderly. PD is characterized by the formation of Lewy bodies and death of dopaminergic neurons. The mechanisms underlying PD are unknown, but the discoveries that mutations in alpha-synuclein can cause familial PD and that alpha-synuclein accumulates in Lewy bodies suggest that alpha-synuclein participates in the pathophysiology of PD. Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T, or A30P alpha-synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain alpha-synuclein and ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the amount of alpha-synuclein expressed and the type of alpha-synuclein expressed, with the amount of alpha-synuclein aggregation following a rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation, alpha-synuclein also appears to induce toxicity. BE-M17 neuroblastoma cells overexpressing alpha-synuclein show up to a fourfold increase in vulnerability to toxicity induced by iron. The vulnerability follows the same rank order as for aggregation. These data raise the possibility that alpha-synuclein acts in concert with iron and dopamine to induce formation of Lewy body pathology in PD and cell death in PD.
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PMID:The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. 1093 54

The main metabolic pathway affected in Parkinson's disease is that of dopamine oxidation and melanin formation in substantia nigra which involves both oxidative and reductive enzymes. The cyclic nature of the biosynthetic pathway from dopamine to melanin implies that a derangement at any of the steps may result in the disappearance of melanin. Possible pathogenetic events such as oxidative stress have therefore no clearcut interpretation since they may be both cause or consequence of the disease. This paper documents the existence of a peroxidase converting dopamine to dopaminochrome in the presence of hydrogen peroxide in the substantia nigra of autopsied human brain. The activatory effect of dopaminochrome on a purified peroxidase is shown, together with the inhibitory effect of dopaminochrome-derived melanin and the activatory effect of melanin/Fe. The toxic effect of dopaminochrome on murine neuroblastoma cells cultured in vitro is demonstrated together with the inhibition of dopaminochrome melanization induced by acetylcholine in vitro.
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PMID:Enzymatic dopamine peroxidation in substantia nigra of human brain. 1095 69

Neuron death in Alzheimer's disease is believed to be triggered by an increased production of amyloidogenic beta-amyloid peptides, involving both increased oxidative stress and activation of a conserved death program. Bcl-xL, an anti-apoptotic protein of the Bcl-2 family, is expressed at high levels in the adult nervous system. Exposure of neuronal cultures to subtoxic concentrations of beta-amyloid peptide 1-40 (1-10microM) or the fragment 25-35 (1-10microM) up-regulated both bcl-xL mRNA and Bcl-xL protein levels, determined by reverse transcriptase-polymerase chain reaction and western blot analysis. Bcl-xL protein was also up-regulated during oxidative stress induced by exposure to hydrogen peroxide (3-100microM) or ferric ions (1-10microM). In contrast, apoptotic stimuli (exposure to staurosporine or serum withdrawal) actually decreased neuronal Bcl-xL expression. To investigate the role of Bcl-xL in cell death relevant to Alzheimer's disease, we stably overexpressed Bcl-xL in human SH-SY5Y neuroblastoma cells. Cells overexpressing Bcl-xL were significantly protected from beta-amyloid neurotoxicity and staurosporine-induced apoptosis compared to vector-transfected controls. In contrast, Bcl-xL overexpression only conferred a mild protection against oxidative injury induced by hydrogen peroxide. We conclude that up-regulation of Bcl-xL expression in response to subtoxic concentrations of beta-amyloid is a stress response that increases the resistance of neurons to beta-amyloid neurotoxicity primarily by inhibiting apoptotic processes.
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PMID:Up-regulation of Bcl-xL in response to subtoxic beta-amyloid: role in neuronal resistance against apoptotic and oxidative injury. 1122 77

Oxidative stress plays an important role in the pathological process of neurodegenerative diseases. The effects of four major flavonoids present in Scutellaria baicalensis Georgi on hydrogen peroxide-induced neuronal cell damage are studied in this paper. When human neuroblastoma SH-SY5Y cells were incubated in Hanks' solution with the addition of 400 microM hydrogen peroxide for 2 h, the viability of cells was decreased remarkably, while the cell lipid peroxidation and the percentage of lactose dehydrogenase released into the culture medium was significantly increased. Addition of 10 microM of baicalein and baicalin significantly attenuated the cellular injury induced by hydrogen peroxide, while the effect of wogonin was marginal and wogonoside showed no effect at the tested concentration. In a separate experiment, 10 microM of baicalein and baicalin also antagonized the intracellular free-calcium concentration ([Ca2+]i) increase caused by 1 mM hydrogen peroxide. The effects of baicalein in both experiments were similar to those of quercetin, a well-studied antioxidant flavonoid. These results demonstrated the protective effects of flavonoids originating from Scutellaria baicalensis Georgi on the oxidative injury of neuronal cells.
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PMID:Protective effects of flavonoids in the roots of Scutellaria baicalensis Georgi against hydrogen peroxide-induced oxidative stress in HS-SY5Y cells. 1124 19

Recently, it has been shown that release of cytochrome c from the mitochondria to the cytosol is required for activation of the caspase-3-dependent cascade in apoptosis, and also for alpha-synuclein aggregation. In the present study, we examined the effects of talipexole and pramipexole on the release of cytochrome c and alpha-synuclein, their aggregations, and activation of caspases. Treatment of human neuroblastoma SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP(+), 1 mM) induced the first event, which was the release of cytochrome c from the organellar fraction to the cytosolic fraction, then came the DNA fragmentation, and caused the last event, which was the accumulation of alpha-synuclein protein in the cytosolic fraction. Talipexole and pramipexole at low concentration (0.1-1 mM) significantly inhibited the accumulation of cytochrome c or alpha-synuclein in the cytosolic fraction. These drugs at high concentration (3-10 mM) inhibited in vitro aggregation of cytochrome c by hydrogen peroxide or that of alpha-synuclein by cytochrome c and hydrogen peroxide. In addition, in vitro activation of caspase-3 induced by cytochrome c and/or dATP was also inhibited by drugs at high concentration (5-10 mM). These results suggest that talipexole and pramipexole may have protective effects against the neurodegeneration, which is induced by intracellular accumulation of cytochrome c and alpha-synuclein.
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PMID:Release and aggregation of cytochrome c and alpha-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole. 1130 Oct 60

Mitochondria are recognized as modulators of neuronal viability during ischemia, hypoxia and toxic chemical exposure, wherein mitochondria dysfunction leading to ATP depletion may be a common pathway of cell death. Estrogens have been reported to be neuroprotective and proposed to play a role in the modulation of cerebral energy/glucose metabolism. To address the involvement of 17beta-estradiol preservation of mitochondrial function, we examined various markers of mitochondrial activity in human SK-N-SH neuroblastoma cells exposed to 3-nitroproprionic acid (3-NPA), a succinate dehydrogenase inhibitor which uncouples oxidative phosphorylation. 3-NPA (10 mM) significantly increased ATP levels at 2 h then caused a 40% and a 50% decrease in ATP levels from baseline when treated for 12 h and 24 h, respectively. 3-NPA also induced significant increases in levels of cellular hydrogen peroxide and peroxynitrite at 2 h and a 60% decrease in mitochondrial membrane potential (MMP) at 12 h exposure. 17beta-Estradiol (17beta-E(2)) pretreatment restored the ATP level back to 80% at 12 h of that in control cells treated with 3-NPA but without E(2), blunted the effect of 3-NPA on MMP and reactive oxygen species levels. The present study indicates that 17beta-E(2) can preserve mitochondrial function in the face of inhibition of oxidative phosphorylation.
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PMID:Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cells. 1133 9

Glutathione-S-transferases (GSTs) are a superfamily of enzymes that function to catalyze the nucleophilic attack of glutathione on electrophilic groups of a second substrate. GSTs are present in many organs and have been implicated in the detoxification of endogenous alpha, beta unsaturated aldehydes, including 4-hydroxynonenal (HNE). Exogenous GST protects hippocampal neurons against HNE in culture. To test the hypothesis that overexpression of GST in cells would increase resistance to exogenous or endogenous HNE induced by oxidative stress, stable transfectants of SY5Y neuroblastoma cells with GST were established. Stable GST transfectants demonstrated enzyme activities 13.7 times (Clone 1) and 30 times (Clone 2) higher than cells transfected with vector alone. GST transfectants (both Clones 1 and 2) demonstrated significantly (p <.05) increased resistance to ferrous sulfate/hydrogen peroxide (20.9% for Clone 1; 46.5% for Clone 2), amyloid beta-peptide (12.2% for Clone 1; 27.5.% for Clone 2), and peroxynitrite (24.3% for Clone 1; 43.9% for Clone 2), but not to exogenous application of HNE in culture medium. GST transfectants treated with 1,1,4-tris (acetyloxy)nonane, a nontoxic derivative of HNE that is degraded to HNE intracellularly, demonstrated a statistically significant (p <.05) increase in viability in a dose-dependent manner compared with SY5Y cells transfected with vector alone. These results suggest that overexpression of GST increases resistance to endogenous HNE induced by oxidative stress or released in the degradation of 1,1,4-tris (acetyloxy)nonane, but not to exogenous application of HNE.
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PMID:Expression of glutathione-S-transferase isozyme in the SY5Y neuroblastoma cell line increases resistance to oxidative stress. 1142 92

The reaction of proteins with reducing sugars leads to the formation of 'advanced glycation endproducts' (AGEs). They accumulate in Alzheimer's disease brain in the vicinity of beta-amyloid plaques. AGEs are cytotoxic by a mechanism involving reactive oxygen species, which implies that they could compromise glutathione redox status. In this study, we show that AGEs (BSA-AGE and beta-amyloid-AGE) persistently increase the ratio of oxidized to reduced glutathione in a dose- and time-dependent manner in SH-SY5Y neuroblastoma cells. The level of oxidized glutathione accounted to 10-14% and persisted for up to 24 h in the presence of added AGEs. In contrast, the unmodified beta-amyloid peptides A beta (1-40) and A beta (25-35) had no significant effect on glutathione redox status. The AGE-induced increase in oxidized glutathione could be prevented by the radical scavengers N-acetylcysteine, alpha-lipoic acid and 17beta-estradiol or by application of catalase, indicating that superoxide and hydrogen peroxide production precedes the AGE-mediated depletion of reduced glutathione.
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PMID:Advanced glycation endproducts change glutathione redox status in SH-SY5Y human neuroblastoma cells by a hydrogen peroxide dependent mechanism. 1157 38

The mitogen-activated protein kinase (MAP kinase) pathway participates in a number of reactions of the cell when responding to various external stimuli. These stimuli include growth factor binding to its receptor as well as stressful situations such as hypoxia and oxidative stress. It has been postulated that one of the mechanisms by which beta-amyloid exerts its toxic effects is to produce oxidative stress. This study therefore investigated whether the MAP-kinase pathway was activated in cells following exposure to beta-amyloid. Neuroblastoma (N2alpha) cells were used in all experiments. The cells were exposed to 50, 100, and 500 microM glutamate, and 10, 30, and 50 microM beta-amyloid, for 24 h. The methylthiazolyl tetrazolium salt (MTT) assay was performed to determine the degree of toxicity. The generation of hydrogen peroxide was detected by fluorescence microscopy using the dye dihydrochlorofluorescein diacetate (DCDHF). Extracellular-signal-regulated kinase (ERK) and p38 MAP-kinase phosphorylation, as representatives of the MAP-kinase pathway, was determined. Treating N2alpha cells with beta-amyloid resulted in a greater than 50% reduction in cell viability. These cells also showed a significantly higher presence of hydrogen peroxide. Western Blot analysis revealed that the phosphorylation of p38 MAP kinase was dose-dependently increased in cells exposed to glutamate and beta-amyloid. On the other hand, the phosphorylation of ERK was significantly reduced in these cells. These data therefore suggest that the toxic effects of beta-amyloid involve the generation of hydrogen peroxide, leading to the activation of p38 and the down-regulation of ERK.
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PMID:The role of the MAP-kinase superfamily in beta-amyloid toxicity. 1176 30

The interaction of neurotrophins and their tyrosine kinase receptors (trks) is essential for differentiation and survival of brain cells. In Alzheimer's disease (AD), the number of neurotrophins and receptors is markedly decreased. The cause of this reduction is unclear, but the role of beta-amyloid (Abeta) seems central in understanding the mechanisms controlling neurotrophin and trk expression. In the study reported here, we exposed SHSY5Y neuroblastoma cells to Abeta or hydrogen peroxide (H(2)O(2)) and measured the expression of trk-A and p75 at the protein and molecular levels. Both Abeta and H(2)O(2) induced oxidative stress (measured by a decrease in cellular glutathione), which decreased trk-A levels and increased p75 levels, decreased messenger RNA (mRNA) levels of both receptors, and increased nerve growth factor (NGF) secretion. Pretreatment of cells with the antioxidant melatonin returned levels of protein expression, mRNA, and NGF secretion to normal. These results are significant, as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.
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PMID:Oxidative stress modulates tyrosine kinase receptor A and p75 receptor (low-affinity nerve growth factor receptor) expression in SHSY5Y neuroblastoma cells. 1202 22


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