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 complete amino acid sequence of human retina and muscle aldose reductase was determined by nucleotide analysis of cDNA clones isolated using synthetic oligonucleotide probes based on partial amino acid sequences of purified human psoas muscle aldose reductase. The cDNA sequence differs substantially in the noncoding and coding regions of recently published sequences of this enzyme. The mRNA for aldose reductase was abundantly expressed in HeLa cells, but only scarcely in a neuroblastoma cell line. Recombinant baculovirus containing one of the muscle cDNA clones was constructed and used to infect Spodoptera frugiperda (SF9) cells. A prominent protein with an apparent molecular size of 36 kDa was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the culture medium as well as in the homogenate of SF9 cells after 2 days of infection. Culture medium or the supernatant fraction of cell homogenates containing this protein had high aldose reductase activity which showed characteristics of the reported human enzyme. These findings indicate that the amino acid sequence reported in this paper represents human retina and muscle aldose reductase and that functional human aldose reductase can be expressed in large amounts in a baculovirus expression system. The result should facilitate refined structural analysis and the development of new specific aldose reductase inhibitors for the treatment of diabetic complications.
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PMID:Cloning and expression of human aldose reductase. 211 46

Aldose reductase activity is increased in neuroblastoma cells grown in media containing 30 mM fructose and/or 30 mM glucose. Neuroblastoma cells cultured in media supplemented with increased concentrations of glucose and fructose amass greater amounts of sorbitol than do cells exposed to media containing only high glucose concentrations. The increase in sorbitol content is dependent on the fructose and glucose concentration in the media. The increase in sorbitol content caused by exposing neuroblastoma cells to media containing 30 mM glucose/30 mM fructose is due to a protein synthesis sensitive mechanism and not to an alteration in the redox state. The addition of sorbinil to media containing 30 mM glucose blocks the increase in sorbitol content. In contrast, sorbinil treatment of media containing 30 mM glucose/30 mM fructose does not totally block the increase in sorbitol levels. myo-Inositol accumulation and incorporation into inositol phospholipids and intracellular myo-inositol content are decreased in cells chronically exposed to media containing 30 mM glucose or 30 mM glucose/30 mM fructose compared to cells cultured in unsupplemented media or media containing 30 mM fructose. However, maximal depletion of myo-inositol accumulation and intracellular content occurs earlier in cells exposed to media containing 30 mM glucose/30 mM fructose than in cells exposed to media supplemented with 30 mM glucose. Sorbinil treatment of media containing 30 mM glucose/30 mM fructose maintains cellular myo-inositol accumulation and incorporation into phospholipids at near normal levels. myo-Inositol content in neuroblastoma cells chronically exposed to media containing 30 mM glucose or 30 mM glucose/30 mM fructose recovers within 72 h when the cells are transferred to unsupplemented media or media containing 30 mM fructose. In contrast, the sorbitol content of cells previously exposed to media containing 30 mM glucose or 30 mM glucose/30 mM fructose then transferred into media containing 30 mM fructose remains elevated compared to the sorbitol content of cells transferred into unsupplemented media. These data suggest that fructose may be activating or increasing sorbinil-resistant aldose reductase activity as well as partially blocking sorbitol dehydrogenase activity. The presence of increased concentrations of fructose in combination with increased glucose levels may enhance alterations in cell metabolism and properties due to increased sorbitol levels.
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PMID:Effect of fructose supplementation on sorbitol accumulation and myo-inositol metabolism in cultured neuroblastoma cells exposed to increased glucose concentrations. 211 46

Neuroblastoma cells were used to analyze the effect of elevated glucose levels on myo-inositol metabolism and Na+/K+-pump activity. The activity of the Na+/K+ pump in neuroblastoma cells is almost totally sensitive to ouabain inhibition. Culturing neuroblastoma cells in 30 mM glucose caused a significant decrease in Na+/K+-pump activity, myo-inositol metabolism, and myo-inositol content, compared to cells grown in the presence of 30 mM fructose. Glucose supplementation also caused a large intracellular accumulation of sorbitol. The aldose reductase inhibitor sorbinil prevented the abnormalities in myo-inositol metabolism and partially restored Na+/K+-pump activity in neuroblastoma cells cultured in the presence of elevated glucose levels. These results suggest that the accumulation of sorbitol by neuroblastoma cells exposed to elevated concentrations of extracellular glucose causes a decrease in myo-inositol metabolism and these abnormalities are associated with a reduction in Na+/K+-pump activity.
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PMID:Effect of increased glucose levels on Na+/K+-pump activity in cultured neuroblastoma cells. 283 22

In these studies we examined the effect of polyol accumulation on neural cell myo-inositol metabolism and properties. Neuroblastoma cells were cultured for two weeks in media containing 30 mM glucose, fructose, galactose or mannose with or without 0.4 mM sorbinil or 250 microM myo-inositol. Chronic exposure of neuroblastoma cells to media containing 30 mM glucose, galactose, or mannose caused a decrease in myo- inositol content and myo-[2-3H]inositol accumulation and incorporation into phosphoinositides compared to cells cultured in unsupplemented medium or medium containing 30 mM fructose as an osmotic control. These monosaccharides each caused an increase in intracellular polyol levels with galactitol > sorbitol = mannitol accumulation. Chronic exposure of neuroblastoma cells to media containing 30 mM glucose, galactose, or mannose caused a significant decrease in Na+/K+ ATPase transport activity, resting membrane potential, and bradykinin-stimulated 32P incorporation into phosphatidylinositol compared to cells cultured in medium containing 30 mM fructose. In contrast, basal incorporation of 32P into phosphatidylinositol or basal and bradykinin-stimulated 32P incorporation into phosphatidylinositol 4,5-bisphosphate were not effected. Each of these cellular functions as well as myo-inositol metabolism and content and polyol levels remained near control values when 0.4 mM sorbinil, an aldose reductase inhibitor, was added to the glucose, galactose, or mannose supplemented media. myo-Inositol metabolism and content and bradykinin-stimulated phosphatidylinositol synthesis were also maintained when media containing 30 mM glucose, galactose, or mannose was supplemented with 250 microM myo-inositol. The results suggest that polyol accumulation induces defects in neural cell myo-inositol metabolism and certain cell functions which could, if they occurred in vivo, contribute to the pathological defects observed in diabetic neuropathy.
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PMID:Reduced Na+/K+ ATPase transport activity, resting membrane potential, and bradykinin-stimulated phosphatidylinositol synthesis by polyol accumulation in cultured neuroblastoma cells. 817 72

Neuroblastoma is the most common extracranial solid tumour of childhood and comprises up to 50% of malignancies among infants. There is a great need of designing novel therapeutic strategies and proteome analysis is one approach for defining markers useful for tumour diagnosis, as well as molecular targets for novel experimental therapies. We started by comparing healthy adrenal glands (which are the election organs developing primary neuroblastoma, NB, tumours) and adrenal glands carrying primary NB tumours, taken from nude mice. Standard maps of healthy and tumour samples were generated by analysis with the PDQuest software. The comparison between such maps showed up- and down-regulation of 84 polypeptide chains, out of a total of 700 spots detected by a fluorescent stain, Sypro Ruby. Spots that were differentially expressed between the two groups, were analysed by MALDI-TOF mass spectrometry and 14 of these spots were identified so far. Among these proteins, of particular interest are the down-regulated proteins adrenodoxin (21-folds), carbonic anhydrase III (eight-folds) and aldose reductase related protein I (eight-folds), as well as the up-regulated protein peptidyl-propyl cis-trans isomerase A (five-folds). Moreover new proteins, which were absent in control samples, were expressed in tumour samples, such as nucleophosmin (NPM) and stathmin (oncoprotein 18).
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PMID:Proteomic analysis of an orthotopic neuroblastoma xenograft animal model. 1526 22

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

D-Galactose (D-gal) can induce oxidative stress in non-cancer cells and result in cell damage by disturbing glucose metabolism. However, the effect of D-gal on cancer cells is yet to be explored. In this study, we investigated the toxicity of D-gal to malignant cells specifically neuroblastoma cells. As the results, high concentrations of D-gal had significant toxicity to cancer cells, whereas the same concentrations of glucose had no; the viability loss via D-gal treatment was prominent to malignant cells (Neuro2a, SH-SY5Y, PC-3, and HepG2) comparing to non-malignant cells (NIH3T3 and LO(2)). Differing from the apoptosis induced by H(2) O(2), D-gal damaged cells showed the characters of necrotic cell death, such as trypan blue-tangible and early phase LDH leakage. Further experiments displayed that the toxic effect of D-gal can be alleviated by necroptosis inhibitor Necrostatin (Nec-1) and autophagy inhibitor 3-methyladenine (3-MA) but not by caspase inhibitor z-VAD-fmk. D-Gal treatment can transcriptionally up-regulate the genes relevant to necroptosis (Bmf, Bnip3) and autophagy (Atg5, TIGAR) but not the genes related to apoptosis (Caspase3, Bax, and p53). D-Gal did not activate Caspase-3, but prompted puncta-like GFP-LC3 distribution, an indicator for activated autophagy. The involvement of aldose reductase (AR)-mediated polyol pathway was proved because the inhibitor of AR can attenuate the toxicity of D-gal and D-gal treatment elevates the expression of AR. This study demonstrates for the first time that D-gal can induce non-apoptotic but necroptotic cell death in neuroblastoma cells and provides a new clue for developing the strategy against apoptosis-resistant cancers.
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PMID:D-galactose induces necroptotic cell death in neuroblastoma cell lines. 2182 10