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)

Interleukin (IL)-1alpha and IL-6 are powerful inflammatory cytokines produced in brain primarily by microglia and astrocytes. Here we demonstrate, using an in vitro assay system, that they can have a direct neuroprotective action against oxidative attack. Exposure of retinoic acid-differentiated human SH-SY5Y neuroblastoma cells to 270 microM hydrogen peroxide caused activation of caspase 3 and significant neuronal death. Treatment with IL-1alpha or IL-6 caused a dose-dependent increase in survival as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. An antibody against single-strand DNA demonstrated many apoptotic neuroblastoma cells following exposure to hydrogen peroxide, with a decrease following cytokine treatment. These data indicate that IL-1alpha and IL-6 can, under appropriate circumstances, protect neurons from oxidative damage in addition to their well-known action of stimulating inflammation.
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PMID:Interleukin 1alpha and interleukin 6 protect human neuronal SH-SY5Y cells from oxidative damage. 1513 88

In this study we evaluated UCN-01, a small molecule that inhibits protein kinases by interacting with the ATP-binding site, as a potential anti-cancer agent for neuroblastoma. UCN-01 was effective at inducing apoptosis in six neuroblastoma cell lines with diverse cellular and genetic phenotypes. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assays, detection of active caspase-3 and cleaved poly ADP-ribose polymerase (PARP) confirmed that UCN-01 induced apoptosis. Cell cycle analysis determined that the UCN-01 treated cells accumulated in S phase by 16 h. Unlike vinblastine and docetaxel that increased survivin expression, UCN-01 treatment did not increase X-linked inhibitor of apoptosis protein (XIAP) and survivin levels. Analysis of specific phosphoepitopes on chk1/2, Akt, and GSK3beta following UCN-01 treatment determined that there was no significant change in phospho-chk1/2. However, there was decreased immunoreactivity at Ser473 and Thr308 of Akt and Ser9 of GSK3beta by 4 h indicating that the Akt survival pathway and downstream signalling was compromised. Thus, UCN-01 was effective at inducing apoptosis in neuroblastoma cell lines.
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PMID:UCN-01 alters phosphorylation of Akt and GSK3beta and induces apoptosis in six independent human neuroblastoma cell lines. 1525 49

In amyloid diseases, it is not evident which protein aggregates induce cell death via specific molecular mechanisms and which cause damage because of their mass accumulation and mechanical properties. We showed that equine lysozyme assembles into soluble amyloid oligomers and protofilaments at pH 2.0 and 4.5, 57 degrees C. They bind thioflavin-T and Congo red similar to common amyloid structures, and their morphology was monitored by atomic force microscopy. Molecular volume evaluation from microscopic measurements allowed us to identify distinct types of oligomers, ranging from tetramer to octamer and 20-mer. Monomeric lysozyme and protofilaments are not cytotoxic, whereas the oligomers induce cell death in primary neuronal cells, primary fibroblasts, and the neuroblastoma IMR-32 cell line. Cytotoxicity was accessed by ethidium bromide staining, MTT reduction, and TUNEL assays. Primary cultures were more susceptible to the toxic effect induced by soluble amyloid oligomers than the neuroblastoma cell line. The cytotoxicity correlates with the size of oligomers; the sample incubated at pH 4.5 and containing larger oligomers, including 20-mer, appears to be more cytotoxic than the lysozyme sample kept at pH 2.0, in which only tetramers and octamers were found. Soluble amyloid oligomers may assemble into rings; however, there was no correlation between the quantity of rings in the sample and its toxicity. The cytotoxicity of transient oligomeric species of the ubiquitous protein lysozyme indicates that this is an intrinsic feature of protein amyloid aggregation, and therefore soluble amyloid oligomers can be used as a primary therapeutic target and marker of amyloid disease.
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PMID:Does the cytotoxic effect of transient amyloid oligomers from common equine lysozyme in vitro imply innate amyloid toxicity? 1557 61

The neurotoxic effects and influence of beta-amyloid peptide (Abeta)(1-42) on membrane lipids and nicotinic acetylcholine receptors (nAChRs) in human SH-SY5Y neuroblastoma cells were investigated in parallel. Exposure of the cultured cells to varying concentrations of Abeta(1-42) evoked a significantly decrease in cellular reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyl tetrazolium bromide), together with enhanced lipid peroxidation and protein oxidation. Significant reductions in the total contents of phospholipid and ubiquinone-10, as well as in the levels of the alpha3 and alpha7 subunit proteins of nAChRs were detected in cells exposed to Abeta(1-42). In contrast, such treatment had no effect on the total cellular content of cholesterol. Among these alterations, increased lipid peroxidation and decreased levels of cellular phospholipids were most sensitive to Abeta(1-42), occurring at lower concentrations. In addition, when SH-SY5Y cells were pretreated with the antioxidant Vitamin E, prior to the addition of Abeta(1-42), these alterations in neurotoxicity, oxidative stress, composition of membrane lipids and expression of nAChRs were partially prevented. These findings suggest that stimulation of lipid peroxidation by Abeta may be involved in eliciting the alterations in membrane lipid composition and the reduced expression of nAChRs associated with the pathogenesis of AD.
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PMID:Oxidative stress induced by beta-amyloid peptide(1-42) is involved in the altered composition of cellular membrane lipids and the decreased expression of nicotinic receptors in human SH-SY5Y neuroblastoma cells. 1586 39

Environmental exposure to mercurials continues to be a public health issue due to their deleterious effects on immune, renal and neurological function. Recently the safety of thimerosal, an ethyl mercury-containing preservative used in vaccines, has been questioned due to exposure of infants during immunization. Mercurials have been reported to cause apoptosis in cultured neurons; however, the signaling pathways resulting in cell death have not been well characterized. Therefore, the objective of this study was to identify the mode of cell death in an in vitro model of thimerosal-induced neurotoxicity, and more specifically, to elucidate signaling pathways which might serve as pharmacological targets. Within 2 h of thimerosal exposure (5 microM) to the human neuroblastoma cell line, SK-N-SH, morphological changes, including membrane alterations and cell shrinkage, were observed. Cell viability, assessed by measurement of lactate dehydrogenase (LDH) activity in the medium, as well as the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, showed a time- and concentration-dependent decrease in cell survival upon thimerosal exposure. In cells treated for 24 h with thimerosal, fluorescence microscopy indicated cells undergoing both apoptosis and oncosis/necrosis. To identify the apoptotic pathway associated with thimerosal-mediated cell death, we first evaluated the mitochondrial cascade, as both inorganic and organic mercurials have been reported to accumulate in the organelle. Cytochrome c was shown to leak from the mitochondria, followed by caspase 9 cleavage within 8 h of treatment. In addition, poly(ADP-ribose) polymerase (PARP) was cleaved to form a 85 kDa fragment following maximal caspase 3 activation at 24 h. Taken together these findings suggest deleterious effects on the cytoarchitecture by thimerosal and initiation of mitochondrial-mediated apoptosis.
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PMID:Mitochondrial mediated thimerosal-induced apoptosis in a human neuroblastoma cell line (SK-N-SH). 1586 95

The effect of the CTP synthetase inhibitor cyclopentenyl cytosine (CPEC) on the metabolism and cytotoxicity of 2',2'-difluorodeoxycytidine (dFdC, gemcitabine) and the expression and activity of deoxycytidine kinase (dCK) was studied in human neuroblastoma cell lines. The cytotoxicity of dFdC and CPEC was studied in a panel of MYCN-amplified and MYCN-single-copy neuroblastoma cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-assays. dFdC-metabolism was studied in SK-N-BE(2)c cells using [3H]-radiolabeled dFdC. dCK activity and expression were measured using enzyme assays, immunoblot and quantitative PCR, respectively. Both MYCN-amplified and MYCN-single-copy neuroblastoma cell lines were highly sensitive to dFdC, with concentration of the drug resulting in 50% effect when compared to untreated controls (ED50) values in the nanomolar range after a 3-h exposure to dFdC. There was no correlation of the observed ED50 with the dCK activity. Treatment with dFdC induced cell death in MYCN-amplified cells whereas MYCN-single-copy-cell lines underwent neuronal differentiation. Pre-incubation with CPEC significantly increased dFdC-cytotoxicity from 1.3 to 5.3-fold in 13 out of 15 cell lines. [3H]dFdC-anabolism increased 6-44 fold in SK-N-BE(2)c cells after incubation with CPEC and was paralleled by a significant increase in expression and activity of dCK. In conclusion, the combination of dFdC and CPEC is highly toxic to neuroblastoma in vitro.
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PMID:Cyclopentenyl cytosine-induced activation of deoxycytidine kinase increases gemcitabine anabolism and cytotoxicity in neuroblastoma. 1613 34

Beta-amyloid (betaA)-induced oxidative toxicity on neuronal cells is a principal route in Alzheimer's disease (AD), and its toxicity occurs after fibril formation. Inhibitory or promoting effects of naturally occurring compounds on betaA fibril formation were evaluated. Among 214 tested compounds, curcuminoids, flavone type flavonoids, and naphthoquinones were shown to be potent inhibitors of betaA fibrilization. The addition of the curcuminoids, curcumin, demethoxycurcumin, and bisdemethoxycurcumin strongly inhibited betaA fibril formation. Flavonoids such as quercetin, rhamnetin, and fisetin strongly inhibited betaA fibril formation. Limonoids, cinnamic acids, and catechins enhanced fibril formation in vitro. Anthothecol possessed the most enhancing activity on fibril formation of the compounds tested. On the other hand, it was found that curcuminoids showed cytotoxicity with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and did not protect HT22 murine neuroblastoma cells from betaA(25-35) insult. Two flavone type flavonoids, morin and quercetin, exhibited no cytotoxicity and strongly protected HT22 murine neuroblastoma cells from betaA(25-35) oxidative attack. Conclusively, morin or quercetin could be a key molecule for the development of therapeutics for AD.
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PMID:Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid. 1624 50

Parkinson's disease is associated with degeneration of dopaminergic cell bodies in the substantia nigra. It has been suggested that salsolinol, an endogenous metabolite of dopamine, may be involved in this process. An inverse relationship between Parkinson's disease and smoking (nicotine intake) has been observed in epidemiological studies. Moreover, neuroprotective effects of nicotine in various experimental models have been observed. In this study we sought to determine whether salsolinol-induced cytotoxicity in SH-SY5Y human neuroblastoma cells, a cloned cell line which expresses dopaminergic activity, could also be prevented by nicotine pretreatment, and if so, which nicotinic receptors may mediate the actions of nicotine. Exposure of SH-SY5Y cells to 0.8 mM salsolinol for 24 hours resulted in approximately 80% cell death as determined by 3,[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Pretreatment of cells with 0.1 mM nicotine resulted in inhibition of salsolinol-induced cytotoxicity. The effects of nicotine were blocked by mecamylamine, a non-selective nicotinic antagonist as well as conotoxins with selective antagonism against alpha3-containing nicotinic receptor subunits. The effects of nicotine were not affected by dihydro-beta-erythroidine or methyllycaconitine, selective antagonists against alpha4-beta2 or alpha7 nicotinic receptors, respectively. It is suggested that selective nicotinic agonists may be of therapeutic potential in at least a subpopulation of Parkinsonian patients.
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PMID:Neuroprotective effects of nicotine against salsolinol-induced cytotoxicity: implications for Parkinson's disease. 1637 23

At the concentrations normally found in the brain extracellular space the glial-derived protein, S100B, protects neurons against neurotoxic agents by interacting with the receptor for advanced glycation end products (RAGE). It is known that at relatively high concentrations S100B is neurotoxic causing neuronal death via excessive stimulation of RAGE. S100B is detected within senile plaques in Alzheimer's disease, where its role is unknown. The present study was undertaken to evaluate a putative neuroprotective role of S100B against Abeta amyloid-induced neurotoxicity. We treated LAN-5 neuroblastoma cultures with toxic amounts of Abeta25-35 amyloid peptide. Our results show that at nanomolar concentrations S100B protects cells against Abeta-mediated cytotoxicity, as assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein isothiocyanate nick end-labeling (TUNEL) experiments, by countering the Abeta-mediated decrease in the expression of the anti-apoptotic factor Bcl-2. This effect depends on S100B binding to RAGE because S100B is unable to contrast Abeta-mediated neurotoxicity in neurons overexpressing a signaling-deficient RAGE mutant lacking the cytosolic and transducing domain. Our data suggest that at nanomolar doses S100B counteracts Abeta peptide neurotoxicity in a RAGE-mediated manner. However, at micromolar doses S100B is toxic to LAN-5 cells and its toxicity adds to that of the Abeta peptide, suggesting that additional molecular mechanisms may be involved in the neurotoxic process.
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PMID:S100B protects LAN-5 neuroblastoma cells against Abeta amyloid-induced neurotoxicity via RAGE engagement at low doses but increases Abeta amyloid neurotoxicity at high doses. 1647 16

Previous studies showed that prenatal cocaine in an animal model decreased brain-derived neurotrophic factor (BDNF) activity in offspring's brain. Since BDNF is one of target genes of cAMP response element-binding protein (CREB), this study examined effects of cocaine on CREB activities in a human neuroblastoma (SK-N-AS) cell line. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazodium bromide) assay indicated that cocaine exposure at 5 microM for 24 h had no significant influences on cell viability. However, a 24-h exposure to cocaine at the same concentration significantly decreased the level of phosphorylated CREB, although no significant changes in total CREB proteins were observed. Consistent with reduced CREB phosphorylation, the electrophoretic mobility shift assay showed that exposure to 5 microM of cocaine for 24 h also inhibited CREB binding activity and significantly decreased BDNF mRNA expression. In addition, exposure to 5 microM cocaine for 24 h attenuated the glutamic acid-evoked increase in the intracellular Ca2+ concentration. Taken together, these findings suggest that cocaine exposure at the sublethal concentration downregulates CREB functions in the cultured SK-N-AS cell line, and that diminished intracellular Ca2+ responses may be associated in part with cocaine-induced downregulation of CREB activity.
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PMID:Cocaine exposure at a sublethal concentration downregulates CREB functions in cultured neuroblastoma cells. 1648 97


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