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)

The active form of Vitamin D(3) has been reported to prevent neuronal damage caused by a variety of insults, however, it may also induce undesirable hypercalcemic effects. In the present study, we evaluated effects of (24R)-1,24-dihydroxycholecalciferol (PRI-2191) on hydrogen peroxide- and excitatory amino acid-induced neuronal damage in human neuroblastoma (SH-SY5Y) cell line. Exposure of SH-SY5Y cells to N-methyl-d-aspartate (NMDA; 5mM), kainate (0.2mM) and hydrogen peroxide (0.1-1mM) significantly enhanced lactate dehydrogenase release. Furthermore, the neurotoxic effects of hydrogen peroxide was dependent on c-Jun N-terminal kinase (JNK)- and p38- mitogen-activated protein kinase (MAPK) activity. Both secosteroids at nanomolar concentrations inhibited neuronal damage, but their efficacy varied depending on the toxic agent. PRI-2191 was equipotent as 1alpha,25-dihydroxyVitamin D(3) in protecting SH-SY5Ycells against NMDA toxicity, and had stronger effect against hydrogen peroxide-induced damage, but was less efficient against kainate-induced injury. The obtained results suggest potential usefulness of PRI 2191 in the treatment of neurodegenerative diseases.
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PMID:Neuroprotective effects of (24R)-1,24-dihydroxycholecalciferol in human neuroblastoma SH-SY5Y cell line. 1522 2

Amyloidbetapeptide (A beta) is implicated in neuronal cell death in Alzheimer's disease, but the molecular mechanisms are still unclear. We analyzed its mechanism and found several potential rescue factors against A beta-mediated apoptosis. A beta(1-40) stimulated phosphorylation of tau and JNK and induced cell death in SH-SY5Y cells. The cell death was inhibited by insulin-like growth factor-1, suggesting that the JNK pathway may be involved in A beta(1-40)-induced cytotoxicity. Using the human fetus brain cDNA library-targeted differential display technique, a new gene BF5-1 (32aa) was found as a rescue factor against A beta(1-40). BF5-1 has partially the same amino acid sequences as those of the C-terminus of cytochrome c oxidase subunit VIIb (COX-VIIb). COX-VIIb mRNA is increased in AD brains and its overexpression in cells enhanced A beta(1-40)-toxicity. These data suggest that BF5-1 may act as a dominant negative mutant of COX-VIIb. A beta(1-42) also induced cell death in rat neuroblastoma B104 cells, which was abolished by addition of IL-11. By cDNA subtraction analysis in the cell death, the enhanced expression of L-phosphoserine phosphatase was found, but this was also abolished by IL-11. The glutamate neurotoxicity was stimulated in the presence of D-serine, suggesting that NMDA receptors may be involved in A beta(1-42)-induced cytotoxicity. A beta(1-42) also induced increase of a new gene p18A beta rP (p18-amyloid-beta-responsive protein; 166 aa) mRNA expression; overexpression of this gene in PC12 cells induced cell death. By the application of a death trap method, a new gene, p60TRP (p60-Transcription-Regulating-Protein; rat:539 aa, human:547aa), was found as a potential rescue factor against the cell death by p18A beta rP. Thus, our cell death systems and/or new rescue proteins may provide suitable tools for the establishment of drug screening systems leading to the identification of new low-molecular candidates applicable for the treatment of AD.
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PMID:[Possible mechanisms of A beta(1-40)- or A beta(1-42)-induced cell death and their rescue factors]. 1533 86

Anandamide (arachidonoylethanolamide or AEA) is an endocannabinoid that acts at vanilloid (VR1) as well as at cannabinoid (CB1/CB2) and NMDA receptors. Here, we show that AEA, in a dose-dependent manner, causes cell death in cultured rat cortical neurons and cerebellar granule cells. Inhibition of CB1, CB2, VR1 or NMDA receptors by selective antagonists did not reduce AEA neurotoxicity. Anandamide-induced neuronal cell loss was associated with increased intracellular Ca(2+), nuclear condensation and fragmentation, decreases in mitochondrial membrane potential, translocation of cytochrome c, and upregulation of caspase-3-like activity. However, caspase-3, caspase-8 or caspase-9 inhibitors, or blockade of protein synthesis by cycloheximide did not alter anandamide-related cell death. Moreover, AEA caused cell death in caspase-3-deficient MCF-7 cell line and showed similar cytotoxic effects in caspase-9 dominant-negative, caspase-8 dominant-negative or mock-transfected SH-SY5Y neuroblastoma cells. Anandamide upregulated calpain activity in cortical neurons, as revealed by alpha-spectrin cleavage, which was attenuated by the calpain inhibitor calpastatin. Calpain inhibition significantly limited anandamide-induced neuronal loss and associated cytochrome c release. These data indicate that AEA neurotoxicity appears not to be mediated by CB1, CB2, VR1 or NMDA receptors and suggest that calpain activation, rather than intrinsic or extrinsic caspase pathways, may play a critical role in anandamide-induced cell death.
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PMID:Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways. 1537 83

Our purpose was to investigate in human neurons the neuroprotective pathways induced by Fractalkine (FKN) against glutamate receptor-induced excitotoxicity. CX(3)CR1 and FKN are expressed constitutively in the tested human embryonic primary neurons and SK-N-SH, a human neuroblastoma cell line. Microfluorometry assay demonstrated that CX(3)CR1 was functional in 44% of primary neurons and in 70% of SK-N-SH. Fractalkine induced ERK1/2 phosphorylation within 1 min and Akt phosphorylation after 10 min, and both phosphorylation decreased after 20 min. No p38 and SAPK/JNK activation was observed after FKN treatment. Application of FKN triggered a 53% reduction of the NMDA-induced neuronal calcium influx, which was insensitive to pertussis toxin and LY294002 an inhibitor of Akt pathway, but abolished by PD98059, an ERK1/2 pathway inhibitor. Moreover, FKN significantly reduced neuronal NMDA-induced apoptosis, which was pertussis toxin insensitive and abolished in presence of PD98059 and LY294002. In conclusion, FKN protected human neurons from NMDA-mediated excitotoxicity in at least two ways with different kinetics: (i) an early ERK1/2 activation which reduced NMDA-mediated calcium flux; and (ii), a late Akt activation associated with the previously induced ERK1/2 activation.
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PMID:Fractalkine reduces N-methyl-d-aspartate-induced calcium flux and apoptosis in human neurons through extracellular signal-regulated kinase activation. 1561 Jan 55

The NMDA class of glutamate receptors plays a critical role in CNS, such as synaptic plasticity, axonal sprouting, growth, and migration. NMDA receptor stimulation has been shown to regulate polysialylated neural cell adhesion molecule (PSA-NCAM) expression in glial cell cultures and in hippocampal slice cultures. There is also growing evidence that molecular chaperons and ROS are related to the synaptic plasticity phenomena. We have examined the neuroprotective effect of subtoxic dose of NMDA in retinoic acid differentiated SH-SY5Y neuroblastoma cells. SH-SY5Y cell line differentiated with retinoic acid (10 muM) was exposed to NMDA (100 microM) or to antagonist MK-801 (200 nM) + NMDA and cells harvested after 24 h of treatment for PSA-NCAM, NCAM, and HSP70 expression study and for biochemical analysis. A significant increase was observed in PSA-NCAM, NCAM-180, NCAM-140, and HSP70 expression as seen by Western blotting and immunocytofluorescent studies in NMDA-treated cultures. Biochemical analysis revealed a significant increase in the activities of glutathione peroxidase (GPx) and copper zinc-superoxide dismutase (CuZnSOD) upon exposure to NMDA. No significant change was observed in the level of lipid peroxidation. All the changes observed reverted back to the control values upon pretreatment of cultures with MK-801, a non-competitive NMDA receptor antagonist, prior to NMDA exposure indicating the involvement of NMDA receptor in these changes. These results illustrate the neuroprotective role of subtoxic dose of NMDA in SH-SY5Y neuroblastoma cells.
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PMID:Neuroprotection mediated by subtoxic dose of NMDA in SH-SY5Y neuroblastoma cultures: activity-dependent regulation of PSA-NCAM expression. 1595 Jul 81

Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression of cyclin D1, up-regulates the cell cycle regulators and tumor suppressor proteins p21 and p53, and increases the number of lung adenocarcinoma cells in the G(2) and S phases of the cell cycle. Silencing of the tumor suppressor protein p21 abolishes antiproliferative action of dizocilpine. Consistent with inhibition of the extracellular signal-regulated kinase 1/2-signaling cascade, dizocilpine reverses the stimulation of proliferation induced by epidermal, insulin, and basic fibroblast growth factors in lung adenocarcinoma cells. Furthermore, dizocilpine prolongs the survival of mice with metastatic lung adenocarcinoma and slows the growth of neuroblastoma and rhabdomyosarcoma in mice. These findings reveal the mechanism of antiproliferative action of dizocilpine and indicate that it may be useful in the therapy of human cancers.
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PMID:NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth. 1623 Jun 11

Expression of the N-methyl-D-aspartate receptor (NMDAr) and its involvement in cellular proliferation is well-known in tumors of neuronal tissue, such as glioma and neuroblastoma. We have investigated NMDAr expression in the normal, hyperplastic and neoplastic human prostate by immunohistochemistry. Low stromal NMDAr immunostaining was observed in 2 of 12 (17%) normal prostate specimens, but epithelial NMDAr staining was not seen. Of 18 benign prostatic hyperplasia (BPH) specimens, none had stromal NMDAr staining, but 2 had low and 1 had high epithelial NMDAr immunoreactivity. Moderate to high NMDAr immunostaining was observed in the stroma of 60 of 145 (41%) prostate cancer (PCa) specimens. Epithelial NMDAr staining was low in 26 (18%) and moderate to high in 36 (25%) of 145 PCa specimens. We have also examined the effects of the NMDAr antagonist memantine on the growth of ten human cancer cell lines: four prostate, two breast and four colon. The NMDAr antagonist memantine inhibited in-vitro growth of all ten cell lines, with half-maximal growth-inhibition at 5 to 20 microg/ml (23 to 92 microM) memantine. An NMDA agonist, L-cysteinesulfinic acid, stimulated cellular proliferation of all ten cell lines, with maximal growth-stimulation (30% to 75%, depending on the cell line) observed between doses of 33 to 66 microM. Our data provide evidence for the expression and activity of NMDAr in prostate cancer.
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PMID:N-methyl-D-aspartate receptor in human prostate cancer. 1636

CXCR4, a chemokine receptor constitutively expressed in the brain, binds both ligands, the chemokine SDF-1alpha and the HIV envelope glycoprotein gp120(IIIB). There seem to be intracellular differences between the neuronal apoptosis induced by SDF-1alpha and that induced by gp120(IIIB), but the apoptotic pathways involved have not been compared in human neuronal cells. In this study, we characterized the apoptotic intracellular pathways activated by neurotoxic concentrations of SDF-1alpha and gp120(IIIB) in human neuroblastoma cells SK-N-SH. SDF-1alpha (10 nM) and gp120(IIIB) (2 nM) induced similar levels of apoptosis after 24 h of incubation (49 +/- 4% and 48 +/- 3%, respectively, of the neurons were apoptotic). SDF1alpha-induced apoptosis was completely abolished by the inhibition of Src phosphorylation by PP2. Exposure to SDF-1alpha (10 nM) triggered an increase in Src phosphorylation, with a maximum after 20 min of incubation (1.80 +/- 0.24 times higher than control, P = 0.01). NMDA calcium flux was enhanced only if cells were incubated with SDF-1alpha for 20 min before applying NMDA. By contrast, gp120(IIIB)-induced apoptosis was not affected by the inhibition of Src phosphorylation. Moreover, gp120(IIIB) enhanced NMDA calcium flux immediately, without modifying Src phosphorylation status. Finally, levels of phospho-JNK increased following exposure to gp120(IIIB) (by a factor of 1.46 +/- 0.4 at 120 min, P = 0.03), but not after exposure to SDF-1alpha. Thus, SDF-1alpha and gp120(IIIB) induced a similar level of neuronal apoptosis, but by activating different intracellular pathways. SDF-1alpha enhanced NMDA activity indirectly via Src phosphorylation, whereas gp120(IIIB) probably activated the NMDA receptor directly and phosphorylated JNK.
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PMID:Effects of SDF-1alpha and gp120IIIB on apoptotic pathways in SK-N-SH neuroblastoma cells. 1648 Nov 5

Lig-8, a lignophenol derivative from bamboo lignin, potently suppresses oxidative stress-induced apoptosis. Here, we first examined in vitro whether lig-8 protects against neuronal damage induced by oxygen-glucose deprivation (OGD) followed by reoxygenation, tunicamycin [endoplasmic reticulum (ER)-stress inducer], or PSI (proteasome inhibitor). In pheochromocytoma (PC12) cell cultures, lig-8 (1 to 30 microM) concentration-dependently inhibited OGD- and tunicamycin (2 microg/ml)-induced cell deaths (significant at >/=3 microM and >/=1 microM, respectively). In human neuroblastoma (SH-SY5Y) cell culture, the PSI-induced apoptotic cell death and fusion protein accumulation (revealing reduced proteasome activity) was inhibited by lig-8 (30 microM). On the other hand, lig-8 at 30 microM alone did not affect any proteasome activity under resting conditions. In vivo, lig-8 (0.1 nmol/eye) reduced intravitreal N-methyl-D-aspartate (NMDA, 20 nmol)-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness). Hence, lig-8 protects, partly by inhibiting excessive ER-stress, against neuronal damage in vitro and in vivo.
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PMID:Lig-8, a bioactive lignophenol derivative from bamboo lignin, protects against neuronal damage in vitro and in vivo. 1703 Oct 70

NMDA receptors exhibit a dichotomy of signaling with excessive stimulation leading to neuronal damage that occurs during neurodegenerative disorders, whereas the normal burst of activity results in plastic responses with the expression of molecular substrates of long-term plasticity, growth and survival. Control of polysialylated neural cell adhesion molecule (PSA-NCAM) expression by NMDA receptor activation has been described in several systems, suggesting a functional link between these two proteins. The coordinated induction of several different transcription factors initiated by NMDA receptor stimulation may be a key mechanism in the orchestration of specific target gene expression that underlies various aspects of CNS function, including plastic responses. We report here the transcriptional regulation of PSA-NCAM expression by subtoxic dose of NMDA in retinoic acid-differentiated SH-SY5Y cell cultures. SH-SY5Y cell cultures differentiated with retinoic acid (10 microM) were exposed to NMDA (100 microM) or to antagonist MK-801 (200 nM) prior to treatment with NMDA and cells were harvested after 24 h of treatment to study the expression of PSA-NCAM, nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) by Western blotting and dual immunocytofluorescence and expression of polysialyltransferase (PST) mRNA by fluorescent in situ hybridization (FISH). We observed the induction of transcription factors NF-kappaB and AP-1 along with PSA-NCAM expression in response to NMDA receptor activation. Also, PSA-NCAM regulation in response to NMDA receptor activity was shown to be transcriptionally controlled, as seen by temporal and spatial changes observed in the expression of PST mRNA in NMDA-treated SH-SY5Y cell cultures. This raises the interesting possibility that NF-kappaB and AP-1 expression is involved in propagating the signals of NMDA receptor activity that leads to downstream strengthening of long-term plasticity changes in differentiated SH-SY5Y neuroblastoma cell cultures. Thus understanding the regulation of PSA-NCAM expression by NMDA receptor-mediated activity may represent a fundamental prerequisite for the development of therapies in order to maintain neuronal plasticity throughout life and functional recovery after brain damage.
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PMID:Transcriptional regulation of polysialylated neural cell adhesion molecule expression by NMDA receptor activation in retinoic acid-differentiated SH-SY5Y neuroblastoma cultures. 1749 25


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