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)

A simple, highly efficient, and regioselective synthesis of functionalized quinolines through Vilsmeier cyclization of a variety of alpha-oxoketene-N,S-anilinoacetals has been reported. The cyclization is found to be facile with N,S-acetals bearing strongly activating groups on aniline, whereas yields of quinolines are moderate in other cases. The reaction could also be extended for the synthesis of substituted tricyclic benzo[h]quinoline, pyrido[2,3-h]quinoline, 4,7-diphenylphenanthroline, and tetracyclic quino[8,7-h]quinoline by performing a Vilsmeier reaction on N,S-acetals derived from 1-naphthylamine, m-phenylenediamine, o-phenylenediamine, and 1,5-diaminonaphthalene, respectively. A few of the newly synthesized quinolines are subjected to further transformation to afford 2-unsubstituted (Raney-Ni/Ethanol), quinoline-5,8-quinone (NBS/H(2)SO(4)), or 2-alkyl/aryl aminoquinolines through sequential m-CPBA oxidation to the corresponding (2-methylsulfonyl)quinoline followed by replacement with appropriate amines. Similarly, cycloannulation of a few 2-methylthio-3-benzoylquinolines with hydrazine hydrate under microwave irradiation afforded the corresponding substituted and fused pyrazolo[3,4-b]quinolines in excellent yields, whereas TBTH/AIBN-mediated cyclization of the corresponding 3-(2-bromobenzoyl)-2-methylthioquinolines yielded the corresponding benzothiopyrano-fused quinolines through radical translocation.
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PMID:Reaction of alpha-oxoketene-N,S-arylaminoacetals with Vilsmeier reagents: an efficient route to highly functionalized quinolines and their benzo/hetero-fused analogues. 1273 79

Despite its negative redox potential, nitroxyl (HNO) can trigger reactions of oxidation. Mechanistically, these reactions were suggested to occur with the intermediate formation of either hydroxyl radical (.OH) or peroxynitrite (ONOO-). In this work, we present further experimental evidence that HNO can generate.OH. Sodium trioxodinitrate (Na2N2O3), a commonly used donor of HNO, oxidized phenol and Me2SO to benzene diols and.CH3, respectively. The oxidation of Me2SO was O2-independent, suggesting that this process reflected neither the intermediate formation of ONOO- nor a redox cycling of transition metal ions that could initiate Fenton-like reactions. In solutions of phenol, Na2N2O3 yielded benzene-1,2-diol and benzene-1,4-diol at a ratio of 2:1, which is consistent with the generation of free.OH. Ethanol and Me2SO, which are efficient scavengers of.OH, impeded the hydroxylation of phenol. A mechanism for the hydrolysis of Na2N2O3 is proposed that includes dimerization of HNO to cis-hyponitrous acid (HO-N=N-OH) with a concomitant azo-type homolytic fission of the latter to N2 and.OH. The HNO-dependent production of.OH was with 1 order of magnitude higher at pH 6.0 than at pH 7.4. Hence, we hypothesized that HNO can exert selective toxicity to cells subjected to acidosis. In support of this thesis, Na2N2O3 was markedly more toxic to human fibroblasts and SK-N-SH neuroblastoma cells at pH 6.2 than at pH 7.4. Scavengers of.OH impeded the cytotoxicity of Na2N2O3. These results suggest that the formation of HNO may be viewed as a toxicological event in tissues subjected to acidosis.
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PMID:Formation of nitroxyl and hydroxyl radical in solutions of sodium trioxodinitrate: effects of pH and cytotoxicity. 1292 Jan 23

Developmental changes in cell numbers represent the dynamic balance between cell proliferation and death. One obstacle to assessing this balance is an inability to quantify the total amount of cell death, i.e., with a positive indicator such as terminal dUTP nick end labeling (TUNEL) or caspase activity. A novel mathematical model is described wherein data on daily cell growth (the change in cell number) and cell cycle kinetics can be used to determine the total amount of cell death. Two sets of data from previously published studies were tested in this model; primary cultured cortical neurons and B104 neuroblastoma cells. These two preparations have contrasting features: neuronal cultures are heterogeneous and have relatively few cells that are actively cycling (i.e., the growth fraction for these cells is low), whereas B104 cells are relatively homogeneous cultures in which the growth fraction is high. In primary cortical cultures, there was a balance in cell production and death. Treatment with a potent anti-mitogen, ethanol (400 mg/dl), affected this balance principally by reducing cell production, although the rate of cell death was also increased. In untreated B104 cells, there was eight-fold more cell production than cell death. Growth factors such as platelet-derived growth factor BB doubled cell production. Ethanol reduced cell production by >60%, and it eliminated growth factor-mediated cell production. All of these changes occurred in the absence of an effect on the amount of cell death. Thus, the model is ideal for predicting the effects of an epigenetic factor (e.g., a growth factor, toxin, or pharmacological agent) on cell development and can be useful in determining the consequences of a genetic manipulation as well.
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PMID:Balance of cell proliferation and death among dynamic populations: a mathematical model. 1455 83

Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu(2+) promoted enzyme activity and methylation, while Cu(+), Pb(2+), Hg(2+) and Al(3+) were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC(50) of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.
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PMID:Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. 1511 82

Neurobiological actions of ethanol have been linked to perturbations in cyclic AMP (cAMP)-dependent signaling processes. Chronic ethanol exposure leads to desensitization of cAMP production in response to physiological ligands (heterologous desensitization). Ethanol-induced alterations in neuronal expression of G proteins G(s) and G(i) have been invoked as a cause of heterologous desensitization. However, effects of ethanol on G protein expression vary considerably among different experimental protocols, various brain regions and diverse neuronal cell types. Dynamic palmitoylation of G protein alpha subunits is critical for membrane localization and protein-protein interactions, and represents a regulatory feature of G protein function. We studied the effect of ethanol on G alpha(s) palmitoylation. In NG108-15 rat neuroblastoma x glioma hybrid cells, acute exposure to pharmacologically relevant concentrations of ethanol (25-100 mm) inhibited basal and prostaglandin E1-stimulated incorporation of palmitate into G alpha(s). Exposure of NG108-15 cells to ethanol for 72 h induced a shift in G alpha(s) to its non-palmitoylated state, coincident with an inhibition of prostaglandin E1-induced cAMP production. Both parameters were restored following 24 h of ethanol withdrawal. Chronic ethanol exposure also induced the depalmitoylation of G alpha(s) in human embryonic kidney (HEK)293 cells that overexpress wild-type G alpha(s) and caused heterologous desensitization of adenylyl cyclase. By contrast, HEK293 cells that express a non-palmitoylated mutant of G alpha(s) were insensitive to heterologous desensitization after chronic ethanol exposure. In summary, the findings identify a novel effect of ethanol on post-translational lipid modification of G alpha(s), and represent a mechanism by which ethanol might affect adenylyl cyclase activity.
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PMID:Ethanol inhibits palmitoylation of G protein G alpha(s). 1514 Jan 91

The promoting effect of ethanol against the cytotoxicity of hydrogen peroxide (H2O2) in differentiated PC12 cells was assessed by measuring the effect on the mitochondrial membrane permeability. Treatment of PC12 cells with H2O2 resulted in the nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species (ROS) and depletion of GSH. In PC12 cells and dopaminergic neuroblastoma SH-SY5Y cells, the promoting effect of ethanol on the H2O2-induced cell death was increased with exposure time. Ethanol promoted the nuclear damage, change in the mitochondrial membrane permeability, ROS formation and decrease in GSH contents due to H2O2 in PC12 cells. Catalase, carboxy-PTIO, Mn-TBAP, N-acetylcysteine, cyclosporin A and trifluoperazine inhibited the H2O2 and ethanol-induced mitochondrial dysfunction and cell injury. The results show that the ethanol treatment promotes the cytotoxicity of H2O2 against PC12 cells. Ethanol may enhance the H2O2-induced viability loss in PC12 cells by promoting the mitochondrial membrane permeability change, release of cytochrome c and subsequent activation of caspase-3, which is associated with the increased formation of ROS and depletion of GSH. The findings suggest that ethanol as a promoting agent for the formation of mitochondrial permeability transition may enhance the neuronal cell injury caused by oxidants.
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PMID:Synergistic effects of hydrogen peroxide and ethanol on cell viability loss in PC12 cells by increase in mitochondrial permeability transition. 1592 45

Scutellariae radix is a Chinese herbal medicine that has been used to treat disease conditions accompanying inflammation and oxidative stress. In the present study, we examined the effect of Scutellariae radix extracts during acute ethanol exposure in N(2)a neuroblastoma. The Scutellariae radix extracts effectively inhibited ethanol-induced apoptosis and caspase-3/-7 activation. Ethanol induced the expression of caspase-11 that has been known as a dual regulator of pathological apoptosis and inflammatory response. The ethanol-induced caspase-11 expression was suppressed by pretreatment of the Scutellariae radix extracts. Furthermore, the activation of caspase-3/-7 and apoptosis were significantly inhibited in caspase-11-/- mouse embryonic fibroblasts following ethanol treatment. These results suggest that caspase-11 has a regulatory role in ethanol-induced apoptosis, and the suppression of caspase-11 may be a mechanism by which Scutellariae radix exerts its cytoprotective effect.
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PMID:Scutellariae radix extracts suppress ethanol-induced caspase-11 expression and cell death in N(2)a cells. 1629 Feb 52

Ethanol has deleterious effects on neuronal cells both in vivo and in vitro, but the mechanisms are unknown. Here, treatment with increasing doses of ethanol (from 20 up to 600mM) decreased the viability of a mouse hippocampal neuroblastoma cell line, HT22. The glutathione concentration decreased and intracellular reactive oxygen species (ROS) increased in a dose-and time-dependent manner, suggesting that the neurotoxicity was due to oxidative stress. Expression of heme oxygenase (HO)-1, a redox regulator and heat shock protein, increased with time after ethanol treatment, but HO-2 was expressed constitutively. The addition of 5microM zinc protoporphyrin IX (ZnPP IX), a competitive HO inhibitor, with the ethanol further reduced cell viability and increased intracellular ROS, but these effects were reversed by co-treatment with 50nM bilirubin, a well-known antioxidant and a product of HO catalysis. These results suggest that HO has a protective role in hippocampal neurons as an intrinsic factor against ethanol-induced oxidative stress and the protection depends on the degree of oxidative stress.
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PMID:Heme oxygenase protects hippocampal neurons from ethanol-induced neurotoxicity. 1685 15

Ethanol (EtOH) alters neural activity through interaction with various neurotransmitters and neuromodulators. The endogenous opioid system seems to play a key role in the activities of EtOH, since the opioid antagonist naltrexone (ReVia) attenuates craving. We have investigated the transcriptional regulation of opioid system genes in response to EtOH exposure for up to 96 h in human neuroblastoma SH-SY5Y cells using quantitative real-time polymerase chain reaction. We observed a significant decrease in the expression of opioid peptide precursors (proopiomelanocortin, proenkephalin, and prodynorphin) and of the kappa opioid receptor after 48 and 72 h of EtOH exposure (10 and 40 mM). These alterations were not present when the EtOH metabolism was blocked by 4-methylpyrazole. To evaluate whether the effects evoked by EtOH were possibly due to the first product of EtOH metabolism, cells were exposed to 0.4 mM acetaldehyde. We observed the same pattern of changes for prodynorphin, proenkephalin, and the kappa opioid receptor as after 72 h exposure to EtOH. These results contribute to our understanding of EtOH action at a cellular level and provide evidence of the role of acetaldehyde in mediating some of the EtOH-induced effects.
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PMID:The role of acetaldehyde in mediating effects of alcohol on expression of endogenous opioid system genes in a neuroblastoma cell line. 1793 66

One of the most devastating effects of ethanol exposure during development is the loss of neurons in selected brain areas. The underlying cellular/molecular mechanisms remain unclear. The endoplasmic reticulum (ER) is involved in posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress, which is characterized by translational attenuation, synthesis of ER chaperone proteins such as GRP78, and activation of transcription factors such as ATF4, ATF6, and CHOP. Sustained ER stress ultimately leads to cell death. ER stress response can be induced experimentally by treatment with tunicamycin and thapsigargin. Using SH-SY5Y neuroblastoma cells and primary cerebellar granule neurons as in vitro models, we demonstrated that exposure to ethanol alone had little effect on the expression of markers for ER stress; however, ethanol drastically enhanced the expression of GRP78, CHOP, ATF4, ATF6, and phosphorylated PERK and eIF2 alpha when induced by tunicamycin and thapsigargin. Consistently, ethanol promoted tunicamycin- and thapsigargin-induced cell death. Ethanol rapidly caused oxidative stress in cultured neuronal cells; antioxidants blocked ethanol's potentiation of ER stress and cell death, suggesting that the ethanol-promoted ER stress response is mediated by oxidative stress. CHOP is a proapoptotic transcription factor. We further demonstrated that CHOP played an important role in ethanol-promoted cell death. Thus, the effect of ethanol may be mediated by the interaction between oxidative stress and ER stress.
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PMID:Ethanol promotes endoplasmic reticulum stress-induced neuronal death: involvement of oxidative stress. 1794 Oct 56


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