Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

1-Methyl-4-phenylpyridinium ion (MPP+), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome characterized by elevation of intracellular reactive oxygen species level and apoptotic death. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. Adiponectin can also suppress superoxide generation in endothelial cells. In the present study, we investigated the protective effects of adiponectin on MPP+-induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as the underlying mechanism. Our results suggest that the protective effects of adiponectin on MPP+-induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase, and regulation of Bcl-2 and Bax expression. These data indicated that adiponectin might provide a useful therapeutic strategy for the treatment of progressive neurodegenerative diseases such as Parkinson's disease.
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PMID:Adiponectin protects human neuroblastoma SH-SY5Y cells against MPP+-induced cytotoxicity. 1655 29

Superoxide dismutases (SODs) represent the first line of defense against oxidative stress, which is considered an essential factor in several neurodegenerative diseases and aging. We investigated the role of the copper,zinc superoxide dismutase (SOD1) in the maintenance of intracellular redox homeostasis by analyzing the early effects of SOD1 down-regulation in SH-SY5Y neuroblastoma cells. Through the use of small interference RNA, SOD1 was efficiently down-regulated at 48 h after transfection without any significant effect on cell viability. The steady-state concentration of superoxide was significantly increased after 12 h, when SOD1 was only slightly decreased, and progressively returned to values close to those observed in control cells. The superoxide increase was buffered by the enhanced levels of antioxidant glutathione (GSH); however, GSH increase was not sufficient to avoid damage to proteins in terms of carbonyls. GSH-depleting agents, such as BSO or diamide, further increased protein damage and committed SOD1 deficient cells to death, confirming the pivotal role played by this antioxidant. Although SOD1 declined mostly in the cytosolic compartment, mitochondria were significantly affected with impairment of the mitochondrial transmembrane potential and a decrease in ATP production. Together with these effects carbonylation of mitochondrial proteins was detected and in particular a consistent carbonylation and decrease of the antiapoptotic protein Bcl-2. These conditions induced a high susceptibility of SOD1-depleted cells to treatment with the mitochondrial reactive oxygen species producing agent rotenone. Overall, the results demonstrate that loss of SOD1 leads to severe damage of mitochondria, suggesting an important biological role for this enzyme in the preservation of mitochondrial homeostasis.
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PMID:Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuroblastoma cells: a rationale for the redundancy of SOD1. 1679 May 27

The fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS) is characterized by selective loss of motor neurons and mutations in the copper-zinc superoxide dismutase (SOD1) enzyme underlie one form of familial ALS. The pathogenic mechanism of these mutations is elusive but is thought to involve oxidative stress and protein aggregation. These two phenomena are known to induce heat shock proteins (Hsps) which protect stressed cells through their chaperoning and anti-apoptotic activity. In order to investigate the role of Hsp27 in mutant SOD1-dependent cell death, we used mutant and wild type SOD1 overexpressing N2a mouse neuroblastoma cells. Mutant SOD1-dependent cell death could be induced by heat shock, and by treating the cells with cyclosporine A or lactacystin. Transfection with an Hsp27 expression construct did not protect the N2a cells against mutant SOD1-dependent cell death. However, pre-conditioning N2a cells with a mild heat shock was accompanied by a significant upregulation of Hsp27 in the mutant SOD1 cells, and protected these cells against subsequent cell death induced by a more severe heat shock. Selective inhibition of the Hsp27 upregulation, through the use of Hsp27 siRNA, did not attenuate the protective effect of this treatment. These results show that activation of the heat shock response protects cells against mutant SOD1-dependent cell death, but that Hsp27 is not an essential component of the stress response leading to protection.
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PMID:Role of heat shock response and Hsp27 in mutant SOD1-dependent cell death. 1680 87

Mitochondrial damage induced by superoxide dismutase (SOD1) mutants has been proposed to have a causative role in the selective degeneration of motoneurons in amyotrophic lateral sclerosis (ALS). In order to investigate the basis of the tissue specificity of mutant SOD1 we compared the effect of the continuous expression of wild-type or mutant (G93A) human SOD1 on mitochondrial morphology in the NSC-34 motoneuronal-like, the N18TG2 neuroblastoma and the non-neuronal Madin-Darby Canine Kidney (MDCK) cell lines. Morphological alterations of mitochondria were observed in NSC-34 expressing the G93A mutant (NSC-G93A) but not the wild-type SOD1, whereas a ten-fold greater level of total expression of the mutant had no effect on mitochondria of non-motoneuronal cell lines. Fragmented network, swelling and cristae remodelling but not vacuolization of mitochondria or other intracellular organelles were observed only in NSC-G93A cells. The mitochondrial alterations were not explained by a preferential localization of the mutant within NSC-G93A mitochondria, as a higher amount of the mutant SOD1 was found in mitochondria of MDCK-G93A cells. Our results suggest that mitochondrial vulnerability of motoneurons to G93ASOD1 is recapitulated in NSC-34 cells, and that peculiar features in network dynamics may account for the selective alterations of motoneuronal mitochondria.
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PMID:Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial ALS-linked G93ASOD1. 1690 49

NAD(P)H quinone oxidoreductase 1 (NQO1) can metabolize dopamine-derived quinones (DAQ) and absence of NQO1 due to the NQO1*2 polymorphism has been suggested to be a risk factor for Parkinson's disease. In order to define whether NQO1 plays a protective role in dopamine toxicity, we have examined the potential role of NQO1 in the SK-N-MC human neuroblastoma cell line. SK-N-MC cells were stably transfected with NQO1 to generate stable clones with NQO1 enzymatic activity of 245 nmol/mgmin while vector control and parental cells had NQO1 activities of less than 12 nmol/mgmin. Incubation of dopamine for 24 h in both parental and vector control SK-N-MC cells resulted in 85% and 72% cell death as assessed by annexin-V/propidium iodide analysis. In agreement, 88% and 84% of parental and vector control cells, respectively underwent loss of mitochondrial membrane potential (MMP) assessed by tetramethylrhodamine ethyl ester. In contrast, NQO1-transfected cells were resistant to dopamine toxicity and both cell death and loss of MMP were markedly abrogated in NQO1-transfected SK-N-MC cells. When dopamine was added to medium, oxygen uptake could be detected indicating autoxidation with concomitant formation of oxygen radicals and quinones. However, dopamine-induced cell death was not affected by the inclusion of either superoxide dismutase or catalase suggesting that superoxide and hydrogen peroxide were not involved in toxicity. Quinones formed in medium may exert toxicity extracellularly or intracellularly but the protective role of NQO1 argues for an intracellular mechanism. In summary, transfection of SK-N-MC cells with NQO1 protects against dopamine-induced toxicity.
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PMID:Overexpression of NQO1 protects human SK-N-MC neuroblastoma cells against dopamine-induced cell death. 1697 7

Oxidative stress has been implicated in pesticide-induced neurotoxicity, based on its role in the cascade of biochemical changes that lead to dopaminergic neuronal cell death. We have, therefore, examined the role of oxidative stress caused by the pesticides endosulfan and zineb in human neuroblastoma cells (SH-SY5Y) in culture. Upon treatment with 50-200 microM concentrations of either of these pesticides, SH-SY5Y cells generated both superoxide anion and hydrogen peroxide in a dose-and time-dependent manner. Mixtures of the pesticides significantly enhanced the production of these reactive oxygen species compared to individual pesticide exposures. Pesticide treatment decreased superoxide dismutase, glutathione peroxidase, and catalase activities in SH-SY5Y cells. Additionally, these pesticides induced lipid peroxide (thiobarbituric acid reactive products) formation in these cells. While both pesticides individually (at 100 microM) increased caspase-3 activity, cells exposed to a mixture of the pesticides exhibited significantly low levels of this enzyme, probably due to excessive necrotic cell death. Furthermore, exposure to these pesticides increased nuclear NFkappaB activity. Taken together, these findings suggest that the cytotoxicity of endosulfan and zineb, both individually and in mixtures may, at least in part, be associated with the generation of reactive oxygen species with concomitant increased expression of NFkappaB.
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PMID:Reactive oxygen species in in vitro pesticide-induced neuronal cell (SH-SY5Y) cytotoxicity: role of NFkappaB and caspase-3. 1718 34

1-Methyl-4-phenylpyridinium ion (MPP(+)), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of intracellular reactive oxygen species (ROS) level and apoptotic death. Rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In the present study, we investigated the protective effects of rosiglitazone on MPP(+) induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as underlying mechanism. Our results suggested that the protective effects of rosiglitazone on MPP(+) induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase and regulating the expression of Bcl-2 and Bax. These data indicated that rosiglitazone might provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinson's disease.
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PMID:Rosiglitazone protects human neuroblastoma SH-SY5Y cells against MPP+ induced cytotoxicity via inhibition of mitochondrial dysfunction and ROS production. 1726 88

A dominant mutation in the gene for copper-zinc superoxide dismutase (SOD1) is the most frequent cause of the inherited form of amyotrophic lateral sclerosis. Mutant SOD1 provokes progressive degeneration of motor neurons by an unidentified acquired toxicity. Exploiting both affinity purification and mass spectrometry, we identified a novel interaction between heat-shock protein 105 (Hsp105) and mutant SOD1. We detected this interaction both in spinal cord extracts of mutant SOD1(G93A) transgenic mice and in cultured neuroblastoma cells. Expression of Hsp105, which is found in mouse motor neurons, was depressed in the spinal cords of SOD1(G93A) mice as disease progressed, while levels of expression of two other heat-shock proteins, Hsp70 and Hsp27, were elevated. Moreover, Hsp105 suppressed the formation of mutant SOD1-containing aggregates in cultured cells. These results suggest that techniques that raise levels of Hsp105 might be promising tools for alleviation of the mutant SOD1 toxicity.
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PMID:Heat-shock protein 105 interacts with and suppresses aggregation of mutant Cu/Zn superoxide dismutase: clues to a possible strategy for treating ALS. 1740 32

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder characterized by the selective loss of motor neurons from the spinal cord and brain. About 10% of ALS cases are familial (FALS), and in 20% of these cases the disease has been linked to mutations in the Cu,Zn-SOD1 gene. Although the molecular mechanisms causing these forms of ALS are still unclear, evidence has been provided that motor neurons injuries associated with mutant superoxide dismutase (SOD1)-related FALS result from a toxic gain-in-fuction of the mutated enzyme. To understand better the role of these mutations in the pathophysiology of FALS we have compared the pattern of proteins expressed in human neuroblastoma SH-SY5Y cell line with those of cell lines transfected with plasmids expressing the wild-type human SOD1 and the H46R and G93A mutants. 2-DE coupled to MALDI-TOF-MS were the proteomic tools used for identification of differentially expressed proteins. These included cytoskeletal proteins, proteins that regulate energetic metabolism and intracellular redox conditions, and the ubiquitin proteasome system. The proteomic approach allowed to expand the knowledge on the pattern of proteins, with altered expression, which we should focus on, for a better understanding of the possible mechanism involved in mutated-SOD1 toxicity. The cellular models considered in this work have also evidenced biochemical characteristics common to other SOD1-mutated cellular lines connected to the pathogenesis of ALS.
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PMID:2-DE and MALDI-TOF-MS for a comparative analysis of proteins expressed in different cellular models of amyotrophic lateral sclerosis. 1797 59

Neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD) have been associated with increased production of reactive oxygen species. In AD and PD patients, superoxide dismutase (SOD1) was also indicated as a major target of oxidative damage. In particular, in brain tissue of these patients, different SOD1 isoforms have been identified, although their functional role still remains to be elucidated. In the light of the possibility that different SOD1 entities could be expressed also in other neurodegenerative disorders, as a sort of unifying event with AD and PD, we have investigated amyotrophic lateral sclerosis (ALS) using human neuroblastoma SH-SY5Y cells with mutated SOD1 gene H46R as cellular model. 2-DE using a narrow-range IPG 4-7 strips in the first dimension and linear 15% SDS-PAGE in the second allowed to separate different SOD1 spots. MALDI-TOF MS and CapLC-MS/MS have been used for their complete identification. This is the first report in which the presence of SOD1 (iso) forms in a cellular model of ALS has been evidenced.
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PMID:Optimizing separation efficiency of 2-DE procedures for visualization of different superoxide dismutase forms in a cellular model of amyotrophic lateral sclerosis. 1798 32


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