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)

Alzheimer's disease (AD) is a senile dementia characterized by a progressive loss of memory, together with cognitive and behavioral impairments. In the past it was indicated that the disease was associated with a loss of acetylcholine (ACh) in the cerebral cortex (Bowen et al., 1976; Davies and Maloney, 1976); afterward, it was indicated that the severity of dementia was correlated with the extent of cholinergic loss (Perry et al., 1981). Because one of the biochemical features of AD is modification by phosphorylation of the microtubule-associated protein tau (for review, see Avila et al., 2004), in this work we indicate the effect of ACh on tau phosphorylation at specific sites recognized by 12E8 and PThr50 antibodies in human neuroblastoma SH-SY5Y cells. Two sites in which modification might regulate the binding of tau to microtubules (Novak et al., 1991; Feijoo et al., 2004).
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PMID:Effect of acetylcholine on tau phosphorylation in human neuroblastoma cells. 1719 72

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of several multifunction drugs. These include ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], which combines the pharmacophore-neuroprotective effects of rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine or iron chelating moiety such as M30. In the case of M30 the pharmacophore of brain permeable iron chelator VK-28 plus the MAO inhibitor-neuroprotective propargylamine moiety of rasagiline are combined in a single molecule as a potential treatment for Alzheimer's disease, Lewy body disease, and Parkinson's disease with dementia. Here, we discuss the activities of ladostigil in terms of its cholinesterase cognitive enhancing potential, antiParkinson, antidepressant, neuroprotection and APP (amyloid precursor protein) processing potential. One major attribute of ladostigil is its neuroprotective activity in neuronal cell cultures and in vivo. Employing an apoptotic model of neuroblastoma SK-N-SH cells, the molecular mechanism of its neuroprotective activity has been determined. The current studies show that ladostigil significantly decreased apoptosis via inhibition of the cleavage and prevention of caspase-3 activation through a mechanism related to regulation of the Bcl-2 family proteins, resulting in reduced levels of Bad and Bax and induced levels of Bcl-2. In addition, ladostigil elevated the levels of pPKC(pan). We have also followed the regulation of APP processing and found that ladostigil markedly decreased apoptotic-induced levels of holo-APP, as well as stimulated the release of the non-amyloidogenic soluble APP (sAPPalpha) into the conditioned medium via a established protein kinsae C-MAPkinase dependent pathway. Similar to ladostigil, its S-isomer, TV3279, which is a ChE inhibitor lacking MAO inhibitory activity, exerted similar neuroprotective properties and APP processing, suggesting that the mode of action is independent of MAO inhibition. These effects were shown to reside in the propargylamine moiety. These findings indicate that the dual actions of the anti-apoptotic-neuroprotective activity and the ability to modulate APP processing, could make ladostigil a potentially valuable drug for the treatment of Alzheimer's disease.
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PMID:Implications of co-morbidity for etiology and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil. 1719 68

Alpha-synuclein has been implicated in the pathology of certain neurodegenerative diseases, including Parkinson disease (PD) and dementia with Lewy bodies (LBs). Overexpression of human alpha-synuclein in neuronal cells reduces cell viability, but the precise cellular and molecular mechanisms remain poorly understood. Gap junctional intercellular communication (GJIC) is thought to be essential for maintaining cellular homeostasis and growth control. In the present study, the effect of alpha-synuclein overexpression on GJIC in human dopaminergic neuroblastoma SH-SY5Y cells was investigated. Cells overexpressing wild-type alpha-synuclein were more vulnerable to hydrogen peroxide and 6-hydroxydopamine. GJIC was decreased in cells overexpressing alpha-synuclein. In addition, alpha-synuclein binds directly to connexin-32 (Cx32). As such, the post-translational modification of Cx32 was enhanced in cells overexpressing alpha-synuclein. These findings suggest that alpha-synuclein can modulate GJIC in a dopaminergic neuronal cell line through specific binding to Cx32.
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PMID:Alpha-synuclein overexpression reduces gap junctional intercellular communication in dopaminergic neuroblastoma cells. 1733 20

Alzheimer's disease (AD) is a senile dementia characterized by amyloid plaques, neurofibrillary tangles, and synaptic and cell loss. The "amyloid cascade" hypothesis suggests that amyloid-beta (Abeta), the peptide deposited as amyloid plaques, is the primary insult in AD. However, debate continues over the mechanism of Abeta toxicity and whether fibrillar or oligomeric Abeta is the active species of the peptide that ultimately causes the synaptic loss and dementia associated with AD. Brain-derived neurotrophic factor (BDNF) is required for survival and function of cells compromised in AD. Decreased BDNF causes defects in long-term potentiation and memory and correlates with cognitive decline. We previously demonstrated that BDNF reduction occurs early in the course of AD, suggesting that decreased BDNF may promote neuronal dysfunction in AD. We also demonstrated that three of seven human BDNF transcripts are specifically downregulated in AD. What pathological feature(s) of AD leads to the decreased BDNF is unknown. In this study, we administered both fibrillar and oligomeric conformations of Abeta(1-42) to differentiated SH-SY5Y, a human neuroblastoma cell line, and measured both phosphorylated cAMP response element-binding protein (CREB), a regulator of BDNF transcription, and BDNF total mRNA. We found that oligomeric but not fibrillar preparations of Abeta(1-42) significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric Abeta(1-42) decreases BDNF transcripts IV and V in these cells, demonstrating that Abeta(1-42) downregulates the major BDNF transcript decreased in vivo in the AD brain. Thus, oligomeric Abeta(1-42) could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.
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PMID:Oligomeric amyloid decreases basal levels of brain-derived neurotrophic factor (BDNF) mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells. 1734

Dementia of the Alzheimer type (DAT) is associated with the accumulation of beta-amyloid (A beta) peptides derived from beta-amyloid precursor protein (APP). Goldstein and coworkers have suggested that APP acts as a cargo receptor connecting post-Golgi vesicles and motor proteins. Sisodia and colleagues have suggested that APP is a passive passenger within the vesicles. Both views predict that one should be able to visualize colocalizations of APP with microtubules, the object of the present investigation. To avoid possible artifacts created by APP overexpression, we studied endogenous expression in a human neuroblastoma cell line (SK-N-SH). Using high resolution fluorescence microscopy and antibodies specific for the amino termini of APP and A beta sequences, we found that endogenous APP and A beta peptide immunoreactivities colocalized with microtubules in interphase cells. Disruption of microtubules, followed by fixation at various time points during repolymerization, allowed us to observe the sequence and timing of these colocalizations in interphase cells. In addition, to our surprise, we found that A beta immunoreactivities colocalize with the mitotic spindle, a bundle of specialized microtubules. Because of the condensed cytoplasm found in neurons, we suggest that SK-N-SH cells might be a more convenient experimental system for exploring the mechanisms that underlie these protein localizations and the pathology that might result from altered APP protein structure and function.
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PMID:Localizations of endogenous APP/APP-proteolytic products are consistent with microtubular transport. 1741 70

Two missense mutations (P123H and V70M) of beta-synuclein (beta-syn), the homologue of alpha-syn, have been recently identified in dementia with Lewy bodies. However, the mechanism through which these mutations influence the pathogenesis of dementia with Lewy bodies is unclear. To investigate the role of the beta-syn mutations in neurodegeneration, each mutant was stably transfected into B103 neuroblastoma cells. Cells overexpressing mutated beta-syn had eosinophilic cytoplasmic inclusion bodies immunopositive for mutant beta-syn, and electron microscopy revealed that these cells were abundant in various cytoplasmic membranous inclusions resembling the histopathology of lysosomal storage disease. Consistent with these findings, the inclusion bodies were immunopositive for lysosomal markers, including cathepsin B, LAMP-2, GM2 ganglioside, and ATP13A2, which has recently been linked to PARK9. Notably, formation of these lysosomal inclusions was greatly stimulated by co-expression of alpha-syn, was dependent on the phosphorylation of alpha-syn at Ser-129, and was more efficient with the A53T familial mutant of alpha-syn compared with wild type. Furthermore, the inclusion formation in cells overexpressing mutant beta-syn and transfected with alpha-syn was significantly suppressed by treatment with autophagy-lysosomal inhibitors, which were associated with impaired clearance of syn proteins and enhanced apoptosis, indicating that formation of lysosomal inclusions might be protective. Collectively, the results demonstrated unambiguously that overexpression of beta-syn mutants (P123H and V70M) in neuroblastoma cells results in an enhanced lysosomal pathology. We suggest that these missense mutations of beta-syn might play a causative role in stimulating neurodegeneration.
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PMID:Enhanced lysosomal pathology caused by beta-synuclein mutants linked to dementia with Lewy bodies. 1765 97

(1) HIV-1 and viral proteins-evoked chronic brain inflammation, which is characterized by microglial activation, is the pivotal neuropathogenesis of HIV-1-associated dementia (HAD). Platelet-activating factor (PAF), mainly released from activated microglia and acts as a high potent inflammatory mediator and a neurotoxin, is indicated to be a principle initiator of neuroinflammation, neuronal dysfunction, and apoptosis related to HAD. Thus, bis-interacting ligands of acetylcholinesterase (AChE) inhibition and PAF receptor antagonism would be of great interest in the therapeutic potential of HAD not only for improvement of cognitive performance, but also for disease-modifying. (2). We have previously reported that a novel tetrahydrofuran-derived bis-interacting ligand PMS777 had satisfying potencies for PAF receptor blockade and AChE inhibition, and markedly improved cholinergic dysfunction-induced cognitive impairment in mice. Continuing with our research, we further investigated the neuroprotective activities of PMS777 on PAF-triggered neuronal injury in human neuroblastoma SH-SY5Y cells. (3) The bis-interacting ligand PMS777 (10 muM) obviously alleviated PAF-induced cell apoptosis in SH-SY5Y cells. Pretreatment with PMS777 also markedly inhibited intracellular Ca(2+) overload, down-regulation of anti-apoptotic bcl-2 mRNA, stimulation of pro-apoptotic bax mRNA expression and activation of caspase-3 pathway. Also, PMS777 could fine-tune pro-inflammatory cyclooxygenase-2 (cox-2) mRNA expression in PAF-treated cells. (4) These results suggest that PMS777 possesses a neuroprotective profile via anti-apoptotic/inflammatory signaling and warrant further investigations in connection with the potential value of this compound in HAD treatment.
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PMID:PMS777, a bis-interacting ligand for PAF receptor antagonism and AChE inhibition, attenuates PAF-induced neurocytotoxicity in SH-SY5Y cells. 1771 22

Microglia are innate immune cells in the central nervous system. Activation of microglia plays an important role in the processes of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated microglia can produce various proinflammatory cytokines and nitric oxide (NO), which may exert neurotoxic effects. Inhibition of microglia activation may alleviate neurodegeneration under these conditions. To search for the novel therapeutic agents against neuroinflammatory diseases, we have screened a series of flavonoid compounds using a cell-based assay. Our studies showed that fisetin markedly suppressed the production of tumor necrosis factor (TNF)-alpha, NO, and prostaglandin (PG) E2 in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells or primary microglia cultures. Fisetin also inhibited the gene expression of TNF-alpha, interleukin (IL)-1 beta, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) at both mRNA and protein levels. Fisetin significantly suppressed I kappa B degradation, nuclear translocation of NF-kappa B, and phosphorylation of p38 mitogen-activated protein kinase (MAPKs) in the LPS-stimulated BV-2 microglia cells. In addition, fisetin reduced cytotoxicity of LPS-stimulated microglia toward B35 neuroblastoma cells in a co-culture system. These results indicate that fisetin has a strong anti-inflammatory activity in brain microglia, and could be a potential therapeutic agent for the treatment of neuroinflammatory diseases.
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PMID:Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. 1827 3

Alpha-synuclein (alphaSN) plays a major role in numerous neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Intracellular inclusions containing aggregated alphaSN have been reported in Alzheimer's and Parkinson's affected brains. Moreover, a proteolytic fragment of alphaSN, the so-called non-amyloid component of Alzheimer's disease amyloid (NAC) was found to be an integral part of Alzheimer's dementia related plaques. Despite the extensive research on this topic, the exact toxic mechanism of alphaSN remains elusive. We have taken the advantage of an alphaSN overexpressing SH-SY5Y cell line and investigated the effects of classical apoptotic factors (e.g. H(2)O(2), amphotericin B and ruthenium red) and aggregated disease-related peptides on cell viability compared to wild type neuroblastoma cells. It was found that alphaSN overexpressing cells are more sensitive to aggregated peptides treatment than normal expressing counterparts. In contrast, cells containing elevated amount of alphaSN were less vulnerable to classical apoptotic stressors than wild type cells. In addition, alphaSN overexpression is accompanied by altered phenotype, attenuated proliferation kinetics, increased neurite arborisation and decreased cell motility. Based on these results, the alphaSN overexpressing cell lines may represent a good and effective in vitro model for Alzheimer's and Parkinson's disease.
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PMID:Differences between normal and alpha-synuclein overexpressing SH-SY5Y neuroblastoma cells after Abeta(1-42) and NAC treatment. 1835 41

We examined the expression of SIRT1 in several experimental paradigms of human pathologies. We used a neuroblastoma cell line (B65), neuronal primary cultures (hippocampus and cerebellar granule cells) and in vivo approaches in rat and senescence murine models (SAM). Cell cultures and rats were treated with several well-know neurotoxins, i.e. rotenone, MPP(+), kainate and 3-nitropropionic acid. Subsequently, SIRT1 expression was compared in these different paradigms of neurotoxicity. The pattern of expression of SIRT1 in proliferating cell cultures (B65) was different to that in quiescent cell cultures. In the murine model of senescence (senescence-accelerated mice prone, SAMP8), SIRT1 expression progressively decreased, while in the control strain (senescence-accelerated mice resistant, SAMR1) it increased. Finally, we studied human samples of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Huntington's diseases (HD). SIRT1 expression decreased dramatically in HD, but there were no significant changes in Parkinson-related illnesses. In conclusion, SIRT1 expression may be a good sensor of toxic neuronal processes.
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PMID:Modulation of SIRT1 expression in different neurodegenerative models and human pathologies. 1853 40


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