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)

Concentrations of heavy metals, including mercury, have been shown to be altered in the brain and body fluids of Alzheimer's disease (AD) patients. To explore potential pathophysiological mechanisms we used an in vitro model system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic mercury (HgCl2) on oxidative stress, cell cytotoxicity, beta-amyloid production, and tau phosphorylation. We demonstrated that exposure of cells to 50 microg/L (180 nM) HgCl2 for 30 min induces a 30% reduction in cellular glutathione (GSH) levels (n = 13, p<0.001). Preincubation of cells for 30 min with 1 microM melatonin or premixing melatonin and HgCl2 appeared to protect cells from the mercury-induced GSH loss. Similarly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays revealed that 50 microg/L HgCl2 for 24 h produced a 50% inhibition of MTT reduction (n = 9, p<0.001). Again, melatonin preincubation protected cells from the deleterious effects of mercury, resulting in MTT reduction equaling control levels. The release of beta-amyloid peptide (Abeta) 1-40 and 1-42 into cell culture supernatants after exposure to HgCl2 was shown to be different: Abeta 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas Abeta 1-42 showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared with untreated controls (n = 9, p<0.001). Preincubation of cells with melatonin resulted in an attenuation of Abeta 1-40 and Abeta 1-42 release. Tau phosphorylation was significantly increased in the presence of mercury (n = 9, p<0.001), whereas melatonin preincubation reduced the phosphorylation to control values. These results indicate that mercury may play a role in pathophysiological mechanisms of AD.
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PMID:Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. 1061 24

Mutations in the presenilin-1 (PS1) and presenilin-2 (PS2) genes account for the majority of early-onset familial Alzheimer's disease cases. Recent studies suggest that presenilin gene mutations predispose cells to apoptosis by mechanisms involving altered calcium homeostasis and oxidative damage. In the present study, we determined whether PS1 mutations also sensitize cells to hyperosmotic stress-induced apoptosis. For this, we established SH-SY5Y neuroblastoma cell lines stably transfected with wild-type PS1 or either the PS1 exon 9 deletion (deltaE9) or PS1 L250S mutants. Cultured cells were exposed to an overnight (17 h) serum deprivation, followed by a 30 min treatment with either 20 mM glucose, 10 nM insulin-like growth factor-1 or 20 mM glucose + 10 nM insulin-like growth factor-1. Cells were then cultured for a further 3, 6 or 24 h and stained for apoptotic condensed nuclei using propidium iodide. Confirmation that cells were undergoing an active apoptotic process was achieved by labelling of DNA strand breaks using the terminal dUTP nick end labelling (TUNEL) technique. We also determined cell viability using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Propidium iodide staining revealed that all cell lines and controls showed an increased number of apoptotic cells appearing with condensed nuclei at 24 h compared with 6 h and 3 h. High glucose-induced hyperosmotic stress resulted in significantly more apoptotic cells in the PS1 deltaE9 and PS1 L250S mutation cell lines at 24 h, compared with the wild-type PS1 lines (P < 0.001, ANOVA for both comparisons). Mean values (+/-S.D.) for the percentage number of apoptotic cells at 24 h following high glucose treatment were 16.1 +/- 3.5%, 26.7 +/- 5.5% and 31.0 +/- 5.7% for the wild-type PS1, PS1 deltaE9 and PS1 L250S lines, respectively. The pro-apoptotic effects of high glucose treatment were reversed by 10 nM insulin-like growth factor-1, although to a lesser extent in the mutation cell lines (5.8 +/- 2.4%, 15.2 +/- 7.3% and 13.2 +/- 2.0% for the wild-type PS1, PS1 deltaE9 (P < 0.01 for comparison with wild-type PS1) and PS1 L250S (P < 0.01 for comparison with wild-type PS1) transfected lines, respectively. TUNEL labelling of cells at 24 h following treatment gave essentially the same results pattern as obtained using propidium iodide. The percentage number of apoptotic cells with DNA strand breaks (means +/- S.D.) following high glucose treatment was 15.4 +/- 2.6% for the wild-type PS1, 26.8 +/- 3.2% for the PS1 deltaE9 (P < 0.001 for comparison with wild-type PS1) and 29.7 +/- 6.1% for the PS1 L250S transfected lines (P < 0.001 for comparison with wild-type PS1). The PS1 deltaE9 and PS1 L250S transfected lines also showed a higher number of apoptotic cells with DNA strand breaks at 24 h following high glucose plus insulin-like growth factor-1 treatment (11.4 +/- 2.0% and 14.3 +/- 2.8%, respectively), compared with values for the wild-type PS1 lines (8.5 +/- 2.4%). These differences were significant (P < 0.01) for the comparison of wild-type PS1 and PS1 L250S, but not PS1 deltaE9 lines. The mutation-related increases in number of apoptotic cells at 24 h following high glucose treatment were not accompanied by significant differences in cell viability at this time-point. Our results indicate that PS1 mutations predispose to hyperosmotic stress-induced apoptosis and that the anti-apoptotic effects of insulin-like growth factor-1 are compromised by these mutations. Perturbations of insulin-like growth factor-1 signalling may be involved in PS1 mutation-related apoptotic neuronal cell death in Alzheimer's disease.
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PMID:Alzheimer's disease presenilin-1 exon 9 deletion and L250S mutations sensitize SH-SY5Y neuroblastoma cells to hyperosmotic stress-induced apoptosis. 1065 39

Our laboratory has synthesized two new phenolic thioether amines, N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) and N[2-[(4-propionyloxyphenyl)thio]ethyl] propionamide (N,O-diPr-4-S-CAP). These compounds, along with the previously described phenolic thioether amine N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) and its acetyl form (N,O-diAc-4-S-CAP), are tyrosine-amine derivative analogues. The cytotoxicity of these compounds is thought to be tyrosinase dependent, which may make them suitable for targeted anti-melanoma therapy since only melanocytes and their malignant counterparts contain this active enzyme. To further investigate this hypothesis, we performed MTT [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide] assays to determine the cytotoxicity of these compounds in 10 different cell lines. Specifically, we examined to what extent cytotoxicity is related to tyrosinase and tyrosine hydroxylase activity using melanoma and neuroblastoma cells, which have a common metabolic pathway using tyrosinase and tyrosine hydroxylase, respectively. The most sensitive cell line was the highly pigmented SK-MEL-23 melanoma cell line, which shows a very high tyrosinase activity with the highest melanin pigmentation. KAN and SK-NSH (two neuroblastoma cell lines), which have no tyrosinase activity but high tyrosine hydroxylase, were also sensitive. However, C32 (a non-pigmented melanoma with a lower tyrosinase activity) was also sensitive, and MeWo (a moderately pigmented melanoma with a high tyrosinase activity) was less sensitive. This in vitro study may indicate that there is a non-tyrosinase-mediated mechanism of cytotoxicity for phenolic thioether amines in addition to the tyrosinase-mediated one described previously.
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PMID:Comparison of in vitro cytotoxicity of N-acetyl and N-propionyl derivatives of phenolic thioether amines in melanoma and neuroblastoma cells and the relationship to tyrosinase and tyrosine hydroxylase enzyme activity. 1071 35

Photoaffinity analogues of alpha-tocopherol have been prepared by substituting photosensitive functional groups at either the terminus of an alkyl chain of varying length mimicking the phytyl tail or on C-3 of the chroman portion of tocopherol. The alkyl chain-modified compounds 2a-d contain a hexyl to nonyl alkyl chain extending from C-2 of the chroman, terminating in a tetrafluoroazidobenzyloxy group. These compounds were prepared starting from the commercially available Trolox acid 4, followed by esterification, protection, and reduction to the silyl-protected Trolox aldehyde 7, which was coupled using Wittig chemistry to different omega-hydroxyphosphonium bromides. Reduction of the alkene product, coupling with p-azidotetrafluorobenzyl bromide, and deprotection of the phenolic silyl group gave compounds 2a-d in excellent yields. Chroman-functionalized photoaffinity labels were synthesized starting from the protected tocopherol chromene 16b which was a key intermediate for preparation of a 3-hydroxy derivative, either by reduction of epoxides produced directly with Jacobsen's catalysts or by treatment with NBS in wet DME to give two stereoisomeric bromohydrins which were cyclized and reduced to give the phenol-protected C-3 alcohols 19a,b. These alcohols were then converted to diazoacetate esters, and the protecting group was removed to give 3-diazoacetoxy alpha-tocopherols 3a,b.
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PMID:Synthesis of phytyl- and chroman-derivatized photoaffinity labels based on alpha-tocopherol. 1078 72

L-Deprenyl, an irreversible MAO-B (monoamine oxidase B, EC 1.4.3.4) inhibitor, is used for the treatment of Parkinson's disease and to delay the progression of Alzheimer's disease. L-Deprenyl also exhibits protective effects against neuronal apoptosis which are independent of its ability to inhibit MAO-B. The purpose of this study was to compare the antiapoptotic efficacy of L-deprenyl against different types of apoptotic inducers in three neuronal cell culture models. The level of apoptosis was quantified by measuring the activation of caspase-3 enzyme, which is the main apoptotic executioner in neuronal cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27) assays were used to demonstrate the cytotoxic response of apoptotic treatments. Our results showed that okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induced a prominent increase in caspase-3 activity both in cultured hippocampal and cerebellar granule neurons as well as in Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl offered a significant protection against the apoptotic response induced by okadaic acid in all three neuronal models. The best protection appeared at the concentration level of 10(-9) M. L-Deprenyl also provided a protection against apoptosis after AraC (cytosine beta-D-arabinoside) treatment in hippocampal neurons and Neuro-2a cells and after etoposide treatment in Neuro-2a cells. However, L-deprenyl did not offer any protection against apoptosis caused by serum withdrawal or potassium deprivation. Okadaic acid treatment in vivo is known to induce an Alzheimer's type of hyperphosphorylation of tau protein, formation of beta-amyloid plaques, and a severe memory impairment. Our results show that the okadaic acid model provides a promising tool to study the molecular basis of Alzheimer's disease and to screen the neuroprotective capacity of L-deprenyl derivatives.
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PMID:Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells. 1079 57

There is increasing evidence that sphingolipids are involved in cell survival, differentiation or commitment to death. The effect of different sphingolipids and inhibitors of mitogen-activated protein kinase (MAPK) cascade on SH-SY5Y neuroblastoma cell death has been studied. Permeant ceramide analogues C2-Cer, C8-Cer, and C8-Cer-1-phosphate, but not dihydro C2-Cer induce apoptosis, as shown by Hoechst staining. Inhibition of ceramidase and sphingosine kinase, as well as incubation with sphingosine, decreases cell viability, measured as 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide reduction, whereas addition of sphingosine-1-phosphate increases proliferation. Both PD98059 (MAPKK inhibitor) and SB202190 (p38 MAPK inhibitor) decreased viability, but only SB202190 abolished the effect of ceramide. These results suggest that in SH-SY5Y neuroblastoma cells, death is signalled by increases in ceramide, ceramide-phosphate or sphingosine content through p38 MAPK pathway while survival requires MAPK and high sphingosine-1-phosphate/ceramide ratio.
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PMID:Sphingomyelinase metabolites control survival and apoptotic death in SH-SY5Y neuroblastoma cells. 1080 17

Stannylacetylenes 7a-e react with Cp(2)Zr(H)Cl in THF at room temperature to give the alpha-zirconated vinylstannane intermediates 8a-e, which subsequently react with butyltellurenyl bromide (2.0 equiv) to give exclusively ketene stannyl(telluro) acetals 6a-e of E configuration. Similar reactions were performed using phenylselenenyl bromide (2.0 equiv) as the electrophile, but a mixture of products was formed including the expected ketene stannyl(seleno) acetals 12. Otherwise, the use of 1.4 equiv of Cp(2)Zr(H)Cl and 1.0 equiv of PhSeBr results in the exclusive formation of 12, in good yields. Treatment of ketene stannyl(telluro) acetals with iodine or NBS followed by reductive dehalogenation results in the formation of 1-iodo-1-telluroalkenes 4a-e and 1-bromo-1-telluroalkenes 5a-e, respectively, with total retention of the configuration.
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PMID:Hydrozirconation of stannylacetylenes. Synthesis and reactions of ketene Stannyl(Telluro) acetals 1081 95

Exposure to 1,3-dinitrobenzene (DNB) is associated with neuropathologic changes in specific brainstem nuclei, mediated by oxidative stress and mitochondrial dysfunction. The expression of Bcl-2-family proteins as a function of sensitivity to 1, 3-dinitrobenzene (DNB)-induced mitochondrial permeability transition (MPT) was examined in C6 glioma and SY5Y neuroblastoma cells. Neuroblastoma cells were 10-fold more sensitive than glioma cells to DNB-induced decreases in mitochondrial reducing potential, measured by reduction of the tetrazolium compound, 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT). The IC(50) values for DNB-related inhibition of MTT reduction were 107+/-25 microM in SY5Y cells and 1047+/-101 microM in C6 cells. Levels of reactive oxygen species (ROS) were increased in both SY5Y and C6 cells following DNB exposure by 4.6- and 6.0-fold above control, respectively. DNB caused abrupt depolarization of mitochondria in both neuroblastoma and glioma cells that was inhibited by trifluoperazine. The first order rate constants for mitochondrial depolarization were: C6, k=0.31+/-0.02 min(-1); SY5Y, k=0.14+/-0.01 min(-1). Onset of MPT occurred at 10-fold lower concentration of DNB in SY5Y cells than in C6 cells. The antioxidants, deferoxamine and alpha-tocopherol, effectively prevented DNB-induced MPT in C6 and SY5Y cells, suggesting involvement of ROS in the initiation of MPT. Exposure to DNB resulted in decreased cellular ATP content in SY5Y cells and efflux of mitochondrial calcium in both SY5Y and C6 cells, concurrent with onset of MPT. The expression of Bcl-2, Bcl-X(L), and Bax was evaluated in both cell types by Western blot analysis. C6 glioma cells strongly expressed Bcl-X(L) and only weakly expressed Bcl-2 and Bax, whereas SY5Y neuroblastoma cells expressed lower levels of Bcl-X(L) and higher levels of both Bcl-2 and Bax. Collectively, these results suggest that higher constitutive expression of Bcl-X(L), rather than Bcl-2, correlates with resistance to DNB-induced MPT in SY5Y and C6 cells and that differential regulation of the permeability transition pore may underlie the cell-specific neurotoxicity of DNB.
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PMID:Differential cellular regulation of the mitochondrial permeability transition in an in vitro model of 1,3-dinitrobenzene-induced encephalopathy. 1096 Jun 1

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme of the mevalonate pathway, the diverse array of end products of which are vital for a variety of cellular functions, including cholesterol synthesis and cell cycle progression. We showed previously that this enzyme holds a critical role in regulating tumor cell fate, including cell death, as its expression is down-regulated in response to retinoic acid, a potent anticancer therapeutic. Indeed, direct inhibition of HMG-CoA reductase with lovastatin, a competitive inhibitor of this enzyme, induced a pronounced apoptotic response in neuroblastoma and acute myeloid leukemic cells. We have now extended this work and evaluated a wide variety and large number of tumor-derived cell lines for their sensitivity to lovastatin-induced apoptosis. These cell lines were exposed to a wide range (0-100 microM) of lovastatin for 2 days and assayed for cell viability using the 3,4,5-dimethyl thiazlyl-2,2,5-diphenyltetrazolium bromide assay and the induction of apoptosis by flow cytometric and ultrastructural analyses. Lovastatin induced a pronounced apoptotic response in cells derived from juvenile monomyelocytic leukemia, pediatric solid malignancies (rhabdomyosarcoma and medulloblastoma), and squamous cell carcinoma of the cervix and of the head and neck. Interestingly, the subset of malignancies that are particularly sensitive to lovastatin-induced apoptosis correspond to those tumor subtypes that are sensitive to the biological and antiproliferative effects of retinoids in vitro. The nature of the biologically active form of lovastatin has been challenged recently as the growth-inhibitory effects of this drug were attributed to its prodrug lactone form that does not inhibit HMG-CoA reductase function. In this report, we demonstrate that the apoptotic properties of lovastatin are triggered by the open ring acid form that is a potent inhibitor of HMG-CoA reductase activity. Thus, we have identified a subset of tumors that are sensitive to lovastatin-induced apoptosis and show HMG-CoA reductase as a potential therapeutic target of these cancers.
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PMID:Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. 1120 4

17Beta-estradiol (betaE2) has been shown to attenuate the toxicity of beta-amyloid peptides (A beta) in neuronal cultures with the effective concentration of betaE2 ranging from low nM to high microM. This study compares the effective neuroprotective concentration of betaE2 against both A beta-mediated toxicity in a human neuroblastoma cell line, SK-N-SH using cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an endpoint to the effective betaE2 concentration obtained using a calcein acetoxymethyl ester (calcein AM) viability assay. The minimum betaE2 concentration required for protection varied 1000-fold between the two viability assays with 1 nM betaE2 conferring significant protection in the calcein AM assay but 1 microM betaE2 required for significant protection in the MTT assay Interestingly, the maximal inhibition of MTT reduction occured at sub-toxic A beta concentrations and did not correlate with other markers of cellular viability including calcein fluorescence, dye exclusion (propidium iodide or trypan blue), cellular ATP levels, or reduction of another tetrazolium dye, 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl) tetrazolium (MTS). By contrast, there was no difference between the MTT and calcein AM assays with respect to H2O2 toxicity or the neuroprotective effectiveness of 10 nM betaE2 against H2O2 toxicity. These results indicate that low concentrations of betaE2 can attenuate A beta and H2O2 toxicity in a human neuroblastoma cell line. Further, these results suggest that the MTT assay is not an appropriate assay for the determination of betaE2-mediated attenuation of A beta toxicity.
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PMID:Estradiol attenuation of beta-amyloid-induced toxicity: a comparison o. 1142 58


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