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)

Neuroblastoma cells in culture contain low levels of cyclic AMP, a second messenger which plays a major role in neuronal maturation. In this study, human neuroblastoma cells, SK-N-SH-SY5Y, were induced to differentiate by treatment with either nerve growth factor (50 ng/ml), retinoic acid (10 microM), dibutyryl cyclic AMP (1 mM), or 12-O-tetradecanoylphorbol-13-acetate (0.1 microM), and the ability of several neurotransmitters or hormones to stimulate adenylyl cyclase was tested. Although all four differentiation factors caused morphological changes towards a neuronal phenotype, only retinoic acid dramatically enhanced cyclic AMP accumulation, specifically upon stimulation with prostaglandin E1 (PGE1). PGE2 was also active, but less potent, than PGE1, whereas the other cyclic AMP-stimulating agents tested were largely unaffected. Further, the rapid desensitization of the PGE1-cyclic AMP response observed in control cells after 20 min of PGE1 exposure did not occur in retinoic acid-treated cells, and the EC50 values for PGE1 were reduced from approximately 240 to 14 nM after retinoic acid treatment. The increased sensitivity to PGE was associated with an increase of high-affinity PGE1 binding sites, whereas the Gs coupling proteins and adenylyl cyclase were not measurably affected. A similar enhancement of the PGE1-cyclic AMP response by retinoic acid was also observed in two additional human neuroblastoma cell lines tested, Kelly and IMR-32, suggesting that up-regulation of the prostaglandin response by retinoic acid is common among neuroblastoma cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differentiation of human neuroblastoma cells: marked potentiation of prostaglandin E-stimulated accumulation of cyclic AMP by retinoic acid. 290 24

The details of a radioimmunoassay capable of measuring as 5 pg of prostaglandin A, E, and F (PGA, PGE, and PGF) in human and rat plasma are described. Plasma samples are extracted (with 4000 cpm [(3)H] PGE(1) added for calculation of recovery) with an organic solvent system at an apparent pH of 5.8 and then chromatographed on silicic acid columns with increasing concentrations of methanol to separate PGA, PGE, and PGF. Each chromatographed sample is measured by radioimmunoassay, using the homologous antibody and tritiated marker. 40 normal individuals had mean plasma concentrations of PGA, PGE, and PGF of 1062+/-107 pg/ml, 385+/-30 pg/ml, and 141+/-15 pg/ml, respectively. Elevated PGE levels were measured in the plasma of patients with medullary carcinoma of the thyroid, carcinoid, and neuroblastoma. Treatment of rats with indomethacin decreased serum PGE levels by 67%. The radioimmunoassay appears to be of considerable experimental as well as clinical interest.
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PMID:Radioimmunoassay measurement of prostaglandins E, A, and F in human plasma. 468 79

Addition of linoleic acid (50 microM) to culture medium significantly increases levels of polyunsaturated fatty acids (PUFA) in membrane phospholipids of NIE-115 neuroblastoma. Basal levels of cyclic AMP are elevated significantly in supplemented cells. Exogenous prostaglandins (PG) PGE1 and PGD2 stimulate cAMP formation in NIE-115 neuroblastoma. Supplemented cells produce higher levels of PGE and PGD than do control cultures. Inclusion of cyclooxygenase inhibitors in culture medium does not block elevation of cyclic nucleotide in supplemented cells. Endogenous PG production and receptor activation cannot account for increased cAMP in EFA-supplemented neuroblastoma.
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PMID:Increasing membrane polyunsaturated fatty-acid content augments cyclic AMP formation and prostaglandin production in NIE-115 neuroblastoma. 609 86

Prostaglandins (PGs), which are generated by the enzymatic activity of cyclooxygenase (COX)-1 and -2, modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the neuronal induction of COX-2 has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). The regulation of COX expression in neuronal cells is only partly understood and has been mainly linked to synaptic activity. In pathophysiological situations, however, cytokines may be potent stimulators of neuronal COX expression. Here we show that interleukin (IL)-1beta induces COX-2 mRNA and protein synthesis and the release of PGE(2) in the human neuroblastoma cell line SK-N-SH. We further demonstrate that both a free radical scavenger and an inhibitor of p38 mitogen-activated protein kinase (MAPK) reduce IL-1beta-induced synthesis of COX-2. IL-1beta induces p38 MAPK phosphorylation and activation of the nuclear factor-kappaB independently from each other. Our data suggest that IL-1beta-induced COX-2 expression in SK-N-SH cells is regulated by different mechanisms, presumably involving mRNA transcription and mRNA stability. The ability of p38 MAPK to augment COX-2 expression in human neuroblastoma cells, as shown here, suggests that p38 MAPK may be involved in neuronal expression of COX-2 in AD.
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PMID:Interleukin-1beta induces cyclooxygenase-2 and prostaglandin E(2) synthesis in human neuroblastoma cells: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB. 1103 91

The prostaglandin-evoked cAMP production was studied in human neuroblastoma SK-N-BE(2)C cells during neuronal differentiation induced by all-trans retinoic acid. The incubation with 5 microM all-trans retinoic acid for 4-6 days promoted neurite outgrowth of cells. After differentiation, prostaglandin E(2) (PGE(2))-induced cAMP production was dramatically increased, whereas forskolin- and AlF-induced cAMP productions were not changed. The increase reached maximum after 4-days of incubation with all-trans retinoic acid. The differentiation caused an increase in the maximal response and a decrease in the half-maximal effective concentration of the PGE(2)-induced cAMP production. In addition, the binding of [(3)H]PGE(2) to membrane receptors was enhanced in differentiated cells. However, the order of potency of the various prostaglandins (PGE(1) = PGE(2) > PGD(2) = PGF(2alpha) = PGI(2)) in cAMP production did not change during the differentiation, suggesting that mainly E-prostanoid (EP) receptors were involved. Butaprost, an EP(2) receptor specific agonist, increased the cAMP level in a concentration dependent manner and had a similar potentiating effect on cAMP production as PGE(2) upon differentiation. Northern blot analysis using the human cDNA probes shows that the EP(2) mRNA level was about seven times higher in differentiated cells, while the dopamine beta-hydroxylase (DBH) mRNA completely disappeared. Our results, thus, suggest that elevated gene expression of the prostanoid EP(2) receptor results in an increase in the PGE(2)-evoked cAMP production in SK-N-BE(2)C cells during neuronal differentiation.
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PMID:Potentiation of PGE(2)-mediated cAMP production during neuronal differentiation of human neuroblastoma SK-N-BE(2)C cells. 1167 58

The objective of these studies was to characterize the effects of a broad range of prostanoid agonists upon the stimulation of cAMP production in National Cancer Bank (NCB-20; mouse neuroblastoma/hamster brain hybridoma) cells. The pharmacology of these functional responses in NCB-20 cells was compared with that of the classic endogenous IP receptor present on human platelets using [3H]-iloprost binding techniques. In both assay systems, agonists from the IP prostanoid class exhibited the highest affinities and functional potencies. Specific prostanoids exhibited the following rank order of potency (EC50 +/- SEM) in stimulating cAMP production in the NCB-20 cells: carbaprostacyclin (4.3 +/- 0.9 nM) = PGI2 (6.6 +/-1.5 nM) > iloprost (75+/-13 nM) > 11-deoxy PGE, (378+/-138 nM) > misoprostol (1,243+/-48) > PGE2 (3020+/-700 nM) > ZK-118182 (7265+/-455 nM). Iloprost wasthe most potent compound in the human platelet binding assay while prostanoidsfromthe DPand EP receptor classes showed modest affinity. These studies provide functional and binding information for a broad range of both natural and synthetic prostanoid receptor ligands at the endogenous IP receptor in two different cell types.
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PMID:Pharmacology of functional endogenous IP prostanoid receptors in NCB-20 cells: comparison with binding data from human platelets. 1199 17

The mechanisms of neuronal loss during the course of the prion diseases are not fully understood. In this study, neurones treated with certain non-steroidal anti-inflammatory drugs (NSAIDs) were protected against the otherwise toxic effects of a peptide derived from the prion protein, or extracts containing infectious prions (PrP ). These NSAIDs inhibit the cyclo-oxygenase (cox) enzymes that metabolise arachidonic acid to prostaglandins (PG). Conversely, drugs that inhibited the metabolism of arachidonic acid to leucotrienes enhanced neurotoxicity. Studies with selective inhibitors highlighted the importance of the cox-1 isoform in prion-induced neurotoxicity. The cox-1 inhibitors also inhibited neuronal PGE production and protected both neuroblastoma cells and primary cortical neurones against prions. They also reduced microglia-mediated killing of prion-treated neurones.
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PMID:Cyclo-oxygenase inhibitors protect against prion-induced neurotoxicity in vitro. 1239 95

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15-deoxy-PGJ(2)), a naturally occurring ligand, activates the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma has been found to induce cell differentiation in such cells as adipose cells and macrophages. Herein, we investigated whether 15-deoxy-PGJ(2) has neuronal cell differentiation and possible underlying molecular mechanisms. Dopaminergic differentiating PC-12 cells treated with 15-deoxy-PGJ(2) (0.2 to 1.6 microM) alone showed measurable neurite extension and expression of neurofilament, a marker of cell differentiation. However, a much greater extent of neurite extension and expression of neurofilament was observed in the presence of NGF (50 ng/ml). In parallel with its increasing effect on the neurite extension and expression of neurofilament, 15-deoxy-PGJ(2) enhanced NGF-induced p38 MAP kinase expression and its phosphorylation in addition to the activation of transcription factor AP-1 in a dose-dependent manner. Moreover, pretreatment of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), a specific inhibitor of p38 MAP kinase, inhibited the promoting effect of 15-deoxy-PGJ(2) (0.8 microM) on NGF-induced neurite extension. This inhibition correlated well with the ability of SB203580 to inhibit the enhancing effect of 15-deoxy-PGJ(2) on the expression of p38 MAP kinase and activation of AP-1. The promoting ability of 15-deoxy-PGJ(2) did not occur through PPAR-gamma because synthetic PPAR-gamma agonist and antagonist did not change the neurite-promoting effect of 15-deoxy-PGJ(2). In addition, contrast to other cells (embryonic midbrain and neuroblastoma SK-N-MC cells), PPAR-gamma was not expressed in PC-12 cells. Other structure-related prostaglandins (PGD(2) and PGE(2)) acting via a cell surface G-protein-coupled receptor (GPCR) did not increase basal or NGF-induced neurite extension. Moreover, GPCR (PGE(2) and PGD(2) receptors) antagonists did not alter the promoting effect of 15-deoxy-PGJ(2) on neurite extension and activation of p38 MAP kinase, suggesting that the promoting effect of 15-deoxy-PGJ(2) may not be mediated by GPCR either. These data demonstrate that activation of p38 MAP kinase in conjunction with AP-1 signal pathway may be important in the promoting activity of 15-deoxy-PGJ(2) on the differentiation of PC-12 cells.
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PMID:Activation of p38 mitogen-activated protein kinase and activator protein-1 during the promotion of neurite extension of PC-12 cells by 15-deoxy-delta12,14-prostaglandin J2. 1260 68

Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis.
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PMID:Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide. 1273 Sep 64

Increased accumulation of alpha-synuclein is associated with certain neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD). One mechanism of alpha-synuclein-induced toxicity involves increased oxidative stress. It was unknown whether neurons overexpressing alpha-synuclein would exhibit increased sensitivity to hydrogen peroxide (H(2)O(2)) or 3-morpholinosydnonimine (SIN-1; a nitrous oxide donor). To study this, we developed a murine neuroblastoma (NB) cell line that overexpresses wild-type human alpha-synuclein (NBP2-PN54) under the control of the cytomegalovirus (CMV) promoter using a retroviral vector. Human alpha-synuclein mRNA and protein were readily detectable in NBP2-PN54 cells. Results showed that differentiated NBP2-PN54 cells exhibited decreased viability in comparison to differentiated vector (NBP2-PN1) and parent (NBP2) control cells. These cells also exhibited increased sensitivity to PGE(2), H(2)O(2) and SIN-1. Because of involvement of proteasome inhibition in neurodegeneration, we also investigated whether treatment of differentiated NBP2-PN54 cells with PGE(2), H(2)O(2) or SIN-1 inhibits proteasome activity. Results showed that H(2)O(2) and SIN-1 inhibited proteasome activity, but PGE(2) did not. These results suggest that overexpression of alpha-synuclein not only participates directly in degeneration of neurons, but it also increases the vulnerability of neurons to other potential neurotoxins.
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PMID:Overexpression of alpha-synuclein decreased viability and enhanced sensitivity to prostaglandin E(2), hydrogen peroxide, and a nitric oxide donor in differentiated neuroblastoma cells. 1507 71


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