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)

The E693G (Arctic) mutation of the amyloid precursor protein was recently found to lead to early-onset Alzheimer's disease in a Swedish family. In the present study, we report that the Arctic mutation decreases cell viability in human neuroblastoma cells. The cell viability, as measured by the MTT assay and propidium iodide staining, was further compromised following exposure to calcium ionophore A23187, microtubule-binding colchicine or oxidative stress inducer hydrogen peroxide. The manner of cell death was found to be apoptotic. During apoptosis, cells with the Arctic mutation also decreased their secretion of beta-secretase cleaved amyloid precursor protein. The enhanced sensitivity to toxic stress in cells with the Arctic mutation most likely contributes to the pathogenic pathway leading to Alzheimer's disease.
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PMID:The Arctic Alzheimer mutation enhances sensitivity to toxic stress in human neuroblastoma cells. 1205 36

Complement (C) activation is believed to play an adverse role in several chronic degenerative disease processes, including atherosclerosis, myocardial infarction and Alzheimer's disease. We developed several in vitro quantitative assays to evaluate processes which activate C in human serum, and to assess candidates which might block that activation. Binding of C-reactive protein (CRP) to immobilized cell surfaces was used as a tissue-based method of activation, while immunoglobulin G in solution was used as a surrogate antibody method. Activation was assessed by deposition of C fragments on fixed cell surfaces, or by capture of C5b-9 from solution. We observed that several cell lines, including SH-SY5Y, U-937, THP-1 and ECV304, bound CRP and activated C following attachment of cells to a plastic surface by means of air drying. Treatment of human neuroblastoma SH-SY5Y cells with the reactive oxygen intermediates generated by xanthine (Xa) - xanthine oxidase (XaOx) prior to air drying or by hydrogen peroxide solutions after air drying, enhanced C activation, possibly through oxidation of the cell lipid membrane. Several C inhibitors were tested for their effectiveness in blocking these systems. Pentosan polysulphate (PPS), an orally active agent, blocked C activation in the same concentration range of 1-1000 microg/ml as heparin, dextran sulphate, compstatin and fucoidan. PPS may have practical application as a C inhibitor.
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PMID:Effects of C-reactive protein and pentosan polysulphate on human complement activation. 1210 Jul 26

Growth arrest DNA damage-inducible 153 (GADD153) expression was increased in 1-methyl-4-phenyl-pyridinium (MPP(+))-treated human SH-SY5Y neuroblastoma cells as determined by gene microarray analysis. GADD153 expression increased after 24 hr of MPP(+) (1 mM) exposure and preceded activation of caspase 3. Comparison of GADD153 expression among cultures treated with other toxins whose primary mode of action is either via mitochondrial impairment (rotenone) or via oxidative stress (6-hydroxydopamine or hydrogen peroxide) showed that GADD153 was uniquely up-regulated by MPP(+). Together these data suggest that a cellular mechanism distinct from mitochondrial impairment or oxidative stress contributes significantly to the up-regulation of GADD153 by MPP(+) and that GADD153 may function as an inducer of apoptosis following MPP(+) exposure. Published 2002 Wiley-Liss, Inc.
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PMID:Specific up-regulation of GADD153/CHOP in 1-methyl-4-phenyl-pyridinium-treated SH-SY5Y cells. 1211 36

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are signal-transducing molecules that regulate the activities of a variety of proteins. In the present investigation, we have compared the effects of superoxide (O2-), nitric oxide (NO), and hydrogen peroxide (H2O2) on the activities of three highly homologous serine/threonine phosphatases, protein phosphatase type 1 (PP1), protein phosphatase type 2A (PP2A), and calcineurin (protein phosphatase type 2B). Although superoxide, generated from xanthine/xanthine oxidase or paraquat, and NO, generated from (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide or sodium nitroprusside, potently inhibited the phosphatase activity of calcineurin in neuroblastoma cell lysates, they had relatively little effect on the activities of PP1 or PP2A. In contrast, H2O2 inhibited the activities of all three phosphatases in lysates but was not a potent inhibitor for any of the enzymes. Calcineurin inactivated by O2-, NO, and H2O2 could be partially reactivated by the reducing agent ascorbate or by the thiol-specific reagent dithiothreitol (DTT). Maximal reactivation was achieved by the addition of both reagents, which suggests that ROS and RNS inhibit calcineurin by oxidizing both a catalytic metal(s) and a critical thiol(s). Reactivation of H2O2-treated PP1 also required the combination of both ascorbate and DTT, whereas PP2A required only DTT for reactivation. These results suggest that, despite their highly homologous structures, calcineurin is the only major Ser/Thr phosphatase that is a sensitive target for inhibition by superoxide and nitric oxide and that none of the phosphatases are sensitive to inhibition by hydrogen peroxide.
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PMID:Differential susceptibilities of serine/threonine phosphatases to oxidative and nitrosative stress. 1214 65

The medicinal plant Hypericum perforatum Linn, commonly known as St. John's wort, has been used as an antidepressant. To investigate whether St. John's wort possesses a protective effect against hydrogen peroxide (H(2)O(2))-induced cytotoxicity in neuronal cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 4,6-diamidino-2-phenylindole staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, flow cytometry analysis, DNA fragmentation assay, and caspase-3 enzyme assay were performed on SK-N-MC human neuroblastoma cells. Cells treated with H(2)O(2) exhibited several apoptotic features, while those pre-treated with St. John's wort prior to H(2)O(2) exposure showed a decreased occurrence of apoptotic features. In addition, pre-treatment with St. John's wort inhibited H(2)O(2)-induced increase in caspase-3 enzyme activity. These results suggest that St. John's wort may exert a protective effect against H(2)O(2)-induced apoptosis in human neuroblastoma cells.
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PMID:Protective effect of Hypericum perforatum Linn (St. John's wort) against hydrogen peroxide-induced apoptosis on human neuroblastoma cells. 1216 6

Oxidative injury and the resulting death of neurons is a major pathological factor involved in numerous neurodegenerative diseases. However, the development of drugs that target this mechanism remains limited. The goal of this study was to test a compound library of approved Food and Drug Administration drugs against a hydrogen peroxide-induced oxidant injury model in neuroblastoma cells. We identified 26 neuroprotective compounds, of which megestrol, meclizine, verapamil, methazolamide, sulindac, and retinol were examined in greater detail. Using large-scale oligonucleotide microarray analysis, we identified genes modulated by these drugs that might underlie the cytoprotection. Five key genes were either uniformly upregulated or downregulated by all six drug treatments, namely, tissue inhibitor of matrix metalloproteinase (TIMP1), ret-proto-oncogene, clusterin, galanin, and growth associated protein (GAP43). Exogenous addition of the neuropeptide galanin alone conferred survival to oxidant-stressed cells, comparable to that seen with the drugs. Our approach, which we term "interventional profiling," represents a general and powerful strategy for identifying new bioactive agents for any biological process, as well as identifying key downstream genes and pathways that are involved.
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PMID:Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays. 1238 92

The neuropathology of Parkinson's disease (PD) involves a reduction of endogenous antioxidant enzyme systems, heightened oxidative stress and mitochondrial aberrations in the region of the substantia nigra. Similarly, neurotoxins commonly used to investigate PD pathology include 6-hydroxydopamine (6-OHDA), a powerful hydrogen peroxide (H(2)0(2)) pro-oxidant and 1-methyl-4-phenylpyridinium ion (MPP+), a mitochondrial complex I inhibitor that exerts detrimental effects on cellular energy production. Pyruvic acid is a neuronal metabolic energy fuel that can also rapidly undergo decarboxylation to diffuse H(2)0(2) into H(2)0. In this study, we investigated the effect of pyruvic acid against 6-OHDA, MPP+ and H(2)0(2) toxicity in murine brain neuroblastoma cells. The results obtained indicated that the toxicity of 6-OHDA was inversely related to the autoxidative formation of H(2)0(2). Pyruvic acid exhibited powerful non-enzymatic stoichiometric H(2)0(2) trapping properties, and protected against both 6-OHDA and H(2)0(2) toxicity. While both sodium pyruvate and pyruvate were highly protective against oxidative stress, pyruvate in its free acid form only was protective against MPP+, indicating a requirement for effective transport in order to fuel glycolysis. The protective properties of glucose were compared to pyruvic acid, and the data indicated that glucose did not exhibit antioxidant properties and was effective in blocking MPP+, but not 6-OHDA or H(2)0(2) toxicity. On the other hand, pyruvic acid was protective against all three toxins, and unlike glucose, completely blocked MPP+ toxicity in a combination insult model with up to 500 microM of H(2)0(2). Moreover, the data obtained indicate that pyruvic acid exerts powerful neuroprotective properties by providing simultaneous resistance to oxidative stress and mitochondrial insult. These protective effects are the result of a unique dual property of pyruvic acid with concurrent ability to serve as an effective neuronal energy substrate for glycolysis and to act as an exceptionally powerful antioxidant.
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PMID:Pyruvic acid cytoprotection against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and hydrogen peroxide toxicities in vitro. 1252 92

The role of the N-terminal half of the prion protein (PrPC) in normal cellular function and pathology remains enigmatic. To investigate the biological role of the N-terminus of PrP, we examined the cellular properties of a construct of murine PrP, PrP-DA, in which the N-terminus is tethered to the membrane by an uncleaved signal peptide and which retains the glycosyl-phosphatidylinositol anchor. Human neuroblastoma SH-SY5Y cells expressing PrP-DA were more susceptible to hydrogen peroxide and copper induced toxicity than wtPrP expressing cells. The PrP-DA expressing cells had an increased level of intracellular free radicals and reduced levels of superoxide dismutase and glutathione peroxidase as compared to the wtPrP expressing cells. The membrane topology, cell surface location, lipid raft localisation, intracellular trafficking and copper-mediated endocytosis of PrP-DA were not significantly different from wtPrP. However, cells expressing PrP-DA accumulated an N-terminal fragment that was resistant to proteinase K. The data presented here are consistent with the N-terminal region of PrPC having a role in the cellular response to oxidative stress, and that tethering this region of the protein to the membrane compromises this function through the accumulation of a protease-resistant N-terminal fragment, similar to that seen in some forms of human prion disease.
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PMID:Tethering the N-terminus of the prion protein compromises the cellular response to oxidative stress. 1255 68

Elevated production of hydrogen peroxide (H2O2) in the central nervous system has been implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, ischemic reperfusion, stroke, and Alzheimer's disease. Pyruvic acid has a critical role in energy metabolism and a capability to nonenzymatically decarboxylate H2O2 into H2O. This study examined the effects of glycolytic regulation of pyruvic acid on H2O2 toxicity in murine neuroblastoma cells. Glycolytic energy substrates including D-(+)-glucose, D-(-) fructose and the adenosine transport blocker dipyridamole, were not effective in providing protection against H2O2 toxicity, negating energy as a factor. On the other hand, pyruvic acid completely prevented H2O2 toxicity, restoring the loss of ATP and cell viability. H2O2 toxicity was also attenuated by D-fructose 1,6 diphosphate (FBP), phospho (enol) pyruvate (PEP), niacinamide, beta-nicotinamide adenine dinucleotide (beta-NAD+), and reduced form (beta-NADH). Both FBP and PEP exerted positive kinetic effects on pyruvate kinase (PK) activity. Interestingly, only pyruvic acid and beta-NADH exhibited powerful stoichiometric H2O2 antioxidant properties. Further, beta-NADH may exert positive effects on PK activity. Subsequent pyruvic acid accumulation can lead to the recycling of beta-NAD+ through lactate dehydrogenase and beta-NADH through glyceraldehyde-3-phosphate dehydrogenase. It was concluded from these studies that intracellular pyruvic acid and beta-NADH appear to act in concert through glycolysis, to enhance H2O2 intracellular antioxidant capacity in neuroblastoma cells. Future research will be required to examine whether similar effects are observed in primary neuronal culture or intact tissue.
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PMID:Cytoprotection of pyruvic acid and reduced beta-nicotinamide adenine dinucleotide against hydrogen peroxide toxicity in neuroblastoma cells. 1271 24

This study was designed to isolate new genes related to apoptosis in rat pheochromocytoma (PC12) cells treated with hydrogen peroxide (H2O2), and to characterize the roles of the genes using both in vitro and in vivo models of oxidative injury. cDNA libraries were prepared from H2O2-treated and -untreated PC12 cells, and a ribosomal protein S9 (RPS9) clone was isolated by a differential screening method. Increase of RPS9 expression in both H2O2-treated PC12 and neuroblastoma (Neuro-2A) cells was shown by Northern blot analysis. Viability of the antisense-transfected Neuro-2A (RPS9-AS) cells following H2O2 treatment was significantly reduced in a dose-dependent manner. In an in vivo model of transient forebrain ischemia, an increase in RPS9 expression was prominent by 1 day postischemia in the granule cell layer neurons of the dentate gyrus. Both activation of caspase-3 and significant recovery of viability following pretreatment with cycloheximide were shown in RPS9-AS cells treated with H2O2. These data suggest that RPS9 plays a protective role in oxidative injury of neuronal cells.
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PMID:Alterations in mRNA expression of ribosomal protein S9 in hydrogen peroxide-treated neurotumor cells and in rat hippocampus after transient ischemia. 1271 47


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