Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acrolein, an unsaturated aldehydic product of lipid peroxidation, has been implicated in the pathogenesis of various neurodegenerative disorders including Parkinson's disease. However, protection against acrolein toxicity in neuronal cells via chemical upregulation of cellular aldehyde-detoxification factors has not been investigated. In this study, we have investigated the induction of glutathione (GSH), GSH S-transferase (GST), and aldose reductase (AR) by the unique nutraceutical compound 3H-1,2-dithiole-3-thione (D3T); and the protective effects of the D3T-mediated cellular defenses on acrolein-mediated toxicity in human neuroblastoma SH-SY5Y cells. Incubation of SH-SY5Y cells with D3T (10-100 microM) resulted in a marked concentration- and time-dependent induction of GSH, but not GST or AR. D3T treatment also led to increased mRNA expression of gamma-glutamylcysteine ligase (GCL), the key enzyme in GSH biosynthesis. Incubation of SH-SY5Y cells with 40 microM acrolein for 0.5 or 1 h resulted in a significant depletion of cellular GSH, which preceded the decrease of cell viability, suggesting critical involvement of GSH in acrolein-induced cytotoxicity. Pretreatment of SH-SY5Y cells with 100 microM D3T afforded a dramatic protection against acrolein-induced cytotoxicity, as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) reduction, lactate dehydrogenase release, as well as morphological changes. To further demonstrate the involvement of GSH in protection against acrolein-induced cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. Depletion of cellular GSH by 25 microM BSO dramatically potentiated acrolein-induced cytotoxicity. Cotreatment of SH-SY5Y cells with BSO and D3T was found to prevent the D3T-mediated GSH induction and completely reverse the cytoprotective effects of D3T on acrolein-induced toxicity. Taken together, this study demonstrates that upregulation of GSH is a predominant mechanism underlying D3T-mediated protection against acrolein-induced neurocytotoxicity.
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PMID:Upregulation of cellular glutathione by 3H-1,2-dithiole-3-thione as a possible treatment strategy for protecting against acrolein-induced neurocytotoxicity. 1907 13

The ability of galantamine (Reminyl) to inhibit the aggregation and toxicity of the beta-amyloid peptide (Abeta) was investigated. Galantamine showed concentration-dependent inhibition of aggregation of both Abeta 1-40 and Abeta 1-42, as determined by an ELISA method. Electron microscope studies of Abeta 1-40 incubated in the presence of galantamine revealed fibrils that were disordered and clumped in appearance. MTT and lactate dehydrogenase assays, employing SH-SY5Y human neuroblastoma cells, showed that galantamine reduced the cytotoxicity induced by Abeta 1-40. Galantamine also dramatically reduced Abeta 1-40-induced cellular apoptosis in these cells. There is some evidence that galantamine may not be acting purely as a symptomatic treatment. Disease-modifying effects of the drug could be due to an additional effect on Abeta aggregation and/or toxicity.
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PMID:Galantamine inhibits beta-amyloid aggregation and cytotoxicity. 1924 60

Neuroblastomas originating from different sites might have different clinical and biological characteristics. In the present study, the clinical (age, sex and stage) and biological (N-myc amplification, Shimada pathology and levels of lactate dehydrogenase, ferritin and neuron-specific enolase) characteristics of patients with newly diagnosed neuroblastoma were compared according to the site of tumor origin (extra-abdominal versus abdominal). The event-free survival rate (EFS) was also compared between the two groups. Among 143 neuroblastomas, 115 tumors originated from the abdomen, 26 from extra-abdominal sites and 2 from unknown primary sites. Frequencies of stage 4 tumor and N-myc amplified tumor were lower in the extra-abdominal group than in the abdominal group (34.6% vs. 60.0%, P=0.019 and 4.2% vs. 45.0%, P<0.001, respectively). Levels of lactate dehydrogenase, ferritin and neuron-specific enolase were significantly lower in the extra-abdominal group than in the abdominal group. The probability of 5-yr EFS (+/-95% confidence interval) was higher in the extra-abdominal group than in the abdominal group (94.4+/-10.6% vs. 69.4+/-9.4%, P=0.026). Taken together, neuroblastomas originating from extra-abdominal sites might be associated with more favorable clinical and biological characteristics and a better outcome than neuroblastomas originating from abdomen.
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PMID:Neuroblastoma originating from extra-abdominal sites: association with favorable clinical and biological features. 1954 10

The Italian Neuroblastoma Registry was investigated to describe 781 children with neuroblastoma experiencing tumour recurrence (424 progressions and 357 relapses). Ten-year overall survival (OS) was 6.8% (95% confidence interval (CI) 4.3-10.0) after progression and 14.4% (95% CI 10.5-18.9) after relapse. For both circumstances, OS was better for age at diagnosis <18 months, less advanced International Neuroblastoma Staging System (INSS) stage, normal lactate dehydrogenase (LDH) serum level, normal MYCN gene status (P<0.001) and a non-abdominal primary site (P=0.034 for progression, and P=0.004 for relapses). A local type of recurrence had a significantly better outcome only in case of relapse (P<0.001). Probability of survival increased by era of diagnosis. Survival of children with recurrent neuroblastoma is very poor. A small cohort of patients, mainly represented by children with stages 1 and 2 who underwent local recurrence or developed late relapse may still benefit from further conventional treatment. For the remaining larger proportion of patients, experimental therapies should be proposed.
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PMID:Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry. 1961 26

Alzheimer's disease is the major cause of senile dementia with the hallmark of beta-amyloid deposition in neurons. Although the main cause(s) of this deposition is not fully understood, however, the wealth of the present literature data supports the pivotal role of reactive oxygen and nitrogen species in both the initiation and progression of beta-amyloid aggregation and deposition. In the present study, we were interested to evaluate the free-radical protecting effect of AA3E2, a triazine derivative with a beta-amyloid-breaking activity, among SK-N-MC neuroblastoma cells exposed to hydrogen peroxide (H(2)O(2)) as an exogenous source of free radicals. Exposure of the cells to different doses of AA3E2 (1-16 microM) for 3h followed by subsequent exposure to a single dose of H(2)O(2) (mainly 150 microM) attenuated the extent of superoxide dismutase (SOD) and catalase (CAT) inhibition by H(2)O(2), in a dose dependent manner. Furthermore, significant reduction was observed in the extent of cellular lactate dehydrogenase release, intracellular ROS and the extent of apoptosis among the cells pre-treated with AA3E2. Based on these data, an antioxidant mode of action is proposed for AA3E2 besides its previously beta-amyloid-breaking activity.
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PMID:Inhibition of H2O2-induced neuroblastoma cell cytotoxicity by a triazine derivative, AA3E2. 1961 24

Oestrogens are powerful endogenous and exogenous neuroprotective hormones in animal models of brain injury, including focal cerebral ischaemia. This protective effect has been demonstrated under a variety of different treatments and injury paradigms, such as in vivo and in vitro stroke conditions. Neuroprotection in the central nervous system by progesterone is less defined. In the present study, cultured cortical and midbrain mouse neurones and human neuroblastoma cells (SH-SY5Y) were exposed to combined glucose-serum deprivation (CGSD), which is regarded as a reliable model mimicking the effects of ischaemia in vitro. Cell viability was assayed using lactate dehydrogenase release and metabolic activity. Conditions for CGSD treatment were chosen to yield half-maximal cell death rates. The validity of CGSD in vitro was compared with permanent middle cerebral artery occlusion (MCAO) in vivo. CGSD for 4 h induced half-maximal neuronal cell death. MCAO in vivo for the same period resulted in significant neuronal loss, also suggesting the validity of CGSD as a suitable stroke-like in vitro model. Combined steroid treatment (17beta-oestradiol and progesterone) but not the application of single steroids abolished CGSD-induced cell death of cortical neurones in vitro. By contrast, no cell protection was found in midbrain neurones or neuroblastoma cells. The co-application of oestrogen (ICI 182,780) or progesterone (RU-486) receptor antagonists did not obviously counteract the protective steroid effects. This suggests the operation of nonclassical steroid mechanisms and their implication in mediation of hormonal effects. The surplus of combined protective hormonal effects might be a result of the observed influence of progesterone application on neuronal oestradiol synthesis. The data obtained in the present study clearly highlight the potential of a combined steroid treatment under toxic degenerative brain pathologies.
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PMID:Combined 17beta-oestradiol and progesterone treatment prevents neuronal cell injury in cortical but not midbrain neurones or neuroblastoma cells. 1968 48

Regular consumption of green tea benefits people in prevention from cardiovascular disorders, obesity as well as neurodegenerative diseases. (-)-Epigallocatechin-3-gallate (EGCG) is regarded as the most biologically active catechin in green tea. However, the stability and bioavailability of EGCG are restricted. The purpose of the present study was to investigate whether a pro-drug, a fully acetylated EGCG (pEGCG), could be more effective in neuroprotection in Parkinsonism mimic cellular model. Retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cells were pre-treated with different concentrations of EGCG and pEGCG for 30 min and followed by incubation of 25 microM 6-hydroxydopamine (6-OHDA) for 24h. We found that a broad dosage range of pEGCG (from 0.1 to 10 microM) could significantly reduce lactate dehydrogenase release. Likewise, 10 microM of pEGCG was effective in reducing caspase-3 activity, while EGCG at all concentrations tested in the model failed to attenuate caspase-3 activity induced by 6-OHDA. Furthermore, Western-blot analysis showed that Akt could be one of the specific signaling pathways stimulated by pEGCG in neuroprotection. It was demonstrated that 25 microM of 6-OHDA significantly suppressed the phosphorylation level of Akt. Only pEGCG at 10 microM markedly increased its phosphorylation level compared to 6-OHDA alone. Taken together, as pEGCG has higher stability and bioavailability for further investigation, it could be a potential neuroprotective agent and our current findings may offer certain clues for optimizing its application in future.
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PMID:A pro-drug of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) prevents differentiated SH-SY5Y cells from toxicity induced by 6-hydroxydopamine. 2002 75

Bupivacaine is one of the amide type local anesthetics and is widely used for epidural anesthesia and blockade of nerves. Bupivacaine administration locally could result in neuron injury showing transient neurologic symptoms. Dexamethasone is a synthetic glucocorticoid and may exert cytoprotective properties against damage induced by some stimuli. In the present study, we evaluated the effects of dexamethasone on bupivacaine-induced toxicity in mouse neuroblastoma N2a cells. N2a cells were exposed to bupivacaine in the presence or absence of dexamethasone. After treatment, the cell viability, nuclear condensation, and lactate dehydrogenase levels were evaluated. Mitochondrial potential and Akt (threonine-serine protein kinase B) activation were also examined. In a separate experiment, we examined the effect of Akt inhibition by triciribine on cell viability following dexamethasone treatment. We also investigated whether dexamethasone could prevent lidocaine-induced neurotoxicity. Treatment of N2a cells with bupivacaine resulted in significant cell injury as evidenced by morphological changes, LDH leakage, and nuclear condensation. Pretreatment of the cells with dexamethasone significantly attenuated bupivacaine- and lidocaine-induced cell injury. Dexamethasone treatment prevented the decline of mitochondrial potential caused by bupivacaine and increased the levels of Akt phosphorylation. Importantly, pharmacological inhibition of Akt abolished the protective effect of dexamethasone against bupivacaine-induced cell injury. Our data suggest that pretreatment of neuroblastoma cells with dexamethasone exerts a protective effect on bupivacaine-induced neuronal cell injury. The mechanisms involve activating the Akt signaling pathway.
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PMID:Dexamethasone attenuated bupivacaine-induced neuron injury in vitro through a threonine-serine protein kinase B-dependent mechanism. 2003 43

Neuroblastoma cells, cultivated on plastic dishes, in presence of 15 mM glucose resist very well to hypoxia. Cells incubated on plastic dishes, if left unshaken, showed a Pasteur effect at an oxygen concentration below 10%. Oxygen diffusion was the limiting factor in these plastic dishes since improved oxygen diffusion, as a result of shaking, decreased the lactate production considerably at all oxygen concentrations used. When cells were cultivated on Petriperm((R)) dishes, coated with polylysine, oxygen diffusion was no longer a rate-limiting factor: less lactate was produced at 21% O(2) and hypoxia, down to 2.5% O(2) did not show any increase in the rate of lactate production, while Antimycin A drastically increased the glycolytic rate. A situation of limited oxygen availability resulted in two different kinds of adaptation of the neuroblastoma cells: first an instantaneous metabolic regulation leading to an increased glycolytic rate-the Pasteur effect-followed later by an increase in the activities of the glycolytic enzymes-hexokinase (EC 2.7.1.1), phosphoglucose isomerase (EC 5.3.1.9), 6-phosphofructokinase (EC 2.7.1.11), pyruvate kinase (EC 2.7.1.40) and lactate dehydrogenase (EC 1.1.1.27) and a simultaneous decrease of the mitochondrial cytochrome c oxidase (EC 1.9.3.1) activity. However, when the glucose concentration in the medium was decreased to 5 mM the cells were affected by hypoxia already at 5% O(2): cells released lactate dehydrogenase extracellularly and their protein content was decreased. This toxic effect of hypoxia was related to the exhaustion of the glucose supply.
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PMID:Effect of oxygen and glucose availability on the glycolytic rate in neuroblastoma cells under different conditions of culture. 2048 70

Melatonin is a potent free radical scavenger, antioxidant and neuroprotective drug. On the other hand, galantamine is a cholinergic drug with antioxidant and neuroprotective properties linked to inhibition of acetylcholinesterase and allosteric modulation of nicotinic receptors. This investigation evaluated a possible synergistic neuroprotective effect of subeffective concentrations of combined galantamine and melatonin. Human neuroblastoma SH-SY5Y cells were subjected to a mitochondrial oxidative stress, by blockade of mitochondrial complexes I and V with rotenone and oligomycin-A (R/O); cells were treated for 24 hr with R/O. This caused 40% of the cell to die as measured by lactate dehydrogenase (LDH) release. Cell incubation with increasing concentrations of galantamine (10-300 nm) or melatonin (0.3-10 nm) for 24 hr, followed by a 24-hr period with R/O, caused a concentration-dependent protection; maximum protection was achieved with 300 nm galantamine (56% protection) and 10 nm melatonin (50% protection). Combination of subeffective concentrations of melatonin (0.3 nm) and galantamine (30 nm) caused a synergistic and significant protection that was similar to the maximum protection afforded by effective concentrations of melatonin or galantamine alone. This protective effect was completely reversed when nicotinic and melatonin receptors were blocked respectively by mecamylamine and luzindole. The neuroprotective effect was prevented by chelerythrine, LY294002, and Sn (IV) protoporphyrin IX dichloride (SnPP), indicating the participation of the PKC/PI3K/Akt activation and induction of the antioxidant enzyme heme oxygenase-1. The synthesis of novel multitarget compounds having in a single molecule the combined neuroprotective properties of galantamine and melatonin could be a new strategy for potential therapeutic agents in neurodegenerative diseases.
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PMID:Synergistic neuroprotective effect of combined low concentrations of galantamine and melatonin against oxidative stress in SH-SY5Y neuroblastoma cells. 2053 82


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