Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most mitochondria-based methods used to investigate toxins require the use of relatively large amounts of material and hence compromised sensitivity in assay. We adopted procedures from methods initially developed to diagnose mitochondrial encephalomyopathies and unified these into a single assay. Eukaryotic cell membranes are selectively permeabilized with digitonin to render a system in which mitochondrial respiration can be measured rapidly and with considerable sensitivity. Mitochondria remain intact, uninjured, and in their natural environment where mitochondrial respiration can be measured in situ under physiologically relevant conditions. This approach furthermore allows measurement of toxin effects on individual mitochondrial complexes. Numerous compounds at varying concentrations can be screened for mitochondrial toxicity, while the site of mitochondrial inhibition can be determined simultaneously. We used this assay to investigate, in murine neuroblastoma (N-2alpha) cells, the mitochondrial inhibitory properties of the parkinsonian-inducing proneurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and its neurotoxic monoamine oxidase-B (MAO-B)-generated metabolite, the 1-methyl-4-phenylpyridinium species (MPP(+)). Within the time frame of each measurement (15 min), MPTP (< or = 1 mM) did not interfere with in situ mitochondrial respiration. As expected, MPP(+) was found to be a potent Complex I inhibitor but surprisingly also found to inhibit Complex IV. Optimized conditions for performing this assay are provided.
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PMID:Measurement of mitochondrial respiration in permeabilized murine neuroblastoma (N-2alpha) cells, a simple and rapid in situ assay to investigate mitochondrial toxins. 1565 41

1-methyl-4-phenylpyridinium ion (MPP(+)), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of intracellular reactive oxygen species (ROS) level and apoptotic death. Salvianic acid A (SA), isolated from the Chinese herbal medicine Salvia miltiorrhiza, is capable of protecting diverse kinds of cells from damage caused by a variety of toxic stimuli. In the present study, we investigated the protective effects of SA on MPP(+)-induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as the underlying mechanism. Treatment of SH-SY5Y cells with MPP(+) caused the loss of cell viability, and condensation and fragmentation of nuclei, which was associated with the elevation of ROS level, the increase in Bax/Bcl-2 ratio, and the activation of caspase-3. MPP(+) induced mitochondria dysfunction characterized by mitochondrial membrane potential loss and cytochrome c release. These phenotypes induced by MPP(+) were reversed by SA. Our results suggested that the protective effects of SA on MPP(+)-induced cytotoxicity may be ascribed to its antioxidative properties and anti-apoptotic activity via regulating the expression of Bcl-2 and Bax. These data indicated that SA might provide a useful therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinson's disease.
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PMID:Salvianic acid A protects human neuroblastoma SH-SY5Y cells against MPP+-induced cytotoxicity. 1568 Oct 30

We have investigated here the mechanism of dephosphorylation and activation of death-associated protein kinase (DAPK) and the role of lysosome in neuroblastoma cells (SH-SY5Y) treated with mitochondrial toxins, such as MPP(+) and rotenone. Mitochondrial respiratory chain inhibitors and uncouplers decreased mitochondrial membrane potential leading to DAPK dephosphorylation and activation. The class III phosphoinositide 3-kinase inhibitors attenuated DAPK dephosphorylation induced by mitochondrial toxins. Complex I inhibition by mitochondrial toxins (e.g. MPP(+)) resulted in mitochondrial swelling and lysosome reduction. Inhibition of class III phosphoinositide 3-kinase attenuated MPP(+)-induced lysosome reduction and cell death. The role of DAPK as a sensor of mitochondrial membrane potential in mitochondrial diseases was addressed.
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PMID:Death-associated protein kinase as a sensor of mitochondrial membrane potential: role of lysosome in mitochondrial toxin-induced cell death. 1608 44

We established previously that alpha-synuclein displayed a protective anti-apoptotic phenotype in neurons, mainly by down-regulating p53-dependent caspase-3 activation (Alves da Costa, C., Ancolio, K., and Checler, F. (2000) J. Biol. Chem. 275, 24065-24069; Alves da Costa, C., Paitel, E., Vincent, B., and Checler, F. (2002) J. Biol. Chem. 277, 50980-50984). This function was abolished by Parkinson disease-linked pathogenic mutations and by the dopaminergic toxin, 6-hydroxydopamine (6OH-DOPA) (Alves da Costa, C., Paitel, E., Vincent, B., and Checler, F. (2002) J. Biol. Chem. 277, 50980-50984). However, the mechanisms by which 6OH-DOPA interfered with alpha-synuclein function remained unclear. Here we showed that 6OH-DOPA prevents alpha-synuclein-mediated anti-apoptotic function by altering its degradation. Thus, 6OH-DOPA treatment of TSM1 neurons and SH-SY5Y neuroblastoma cells enhances endogenous alpha-synuclein-like immunoreactivity and inhibits the catabolism of endogenous and recombinant alpha-synucleins by purified 20 S proteasome. Furthermore, we demonstrated that 6OH-DOPA directly inhibits endogenous proteasomal activity in TSM1 and SH-SY5Y cells and also blocks purified proteasome activity in vitro. This inhibitory effect can be prevented by the anti-oxidant phenyl-N-butylnitrone. We also established that 6OH-DOPA triggers the aggregation of recombinant alpha-synuclein in vitro. Therefore, we conclude that 6OH-DOPA abolishes alpha-synuclein anti-apoptotic phenotype by inhibiting its proteasomal degradation, thereby increasing its intracellular concentration and potential propensity to aggregation, the latter phenomenon being directly exacerbated by 6OH-DOPA itself. Interestingly, 1-methyl-4-phenylpyridinium (MPP(+)), another toxin inducer of Parkinson disease-like pathology, does not affect alpha-synuclein protective function and fails to trigger aggregation of recombinant alpha-synuclein. Furthermore, MPP(+) does not alter cellular proteasomal activity, and only high concentrations of the toxin affect purified 20 S proteasome by a mechanism that remains insensitive to phenyl-N-butylnitrone. The drastically distinct effects of 6OH-DOPA and MPP(+) on alpha-synuclein function are discussed with respect to Parkinson disease pathology and animal models mimicking this pathology.
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PMID:6-Hydroxydopamine but not 1-methyl-4-phenylpyridinium abolishes alpha-synuclein anti-apoptotic phenotype by inhibiting its proteasomal degradation and by promoting its aggregation. 1646 50

beta-Carbolines structurally related to the selective dopaminergic neurotoxin 1-methyl-4- phenylpyridinium (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. The chloral-derived mammalian alkaloid derivative 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is formed endogenously by a Pictet-Spengler condensation from the biogenic amine tryptamine (Ta) and the hypnotic aldehyde chloral (Clo). Here we examine the dopaminergic toxicity of TaClo and related compounds by testing their differential cytotoxicities in dopaminergic SH-SY5Y and non-dopaminergic murine Neuro2A neuroblastoma cell lines as well as in heterologous expression systems of the dopamine transporter (DAT) using both HEK-293 and Neuro2A cells. All TaClo derivatives showed significant cytotoxicity in all cell lines after 72 hours with the following rank order of toxic potency: 1-Tribromomethyl-1,2,3,4-tetrahydro-beta-carboline (TaBro) > TaClo > MPP(+) > 1,2,3,4-tetrahydro-beta-carboline (THbetaC) > 2[N]-methyl-TaClo > 2[N]-methyl-THbetaC. In contrast to MPP(+), there was no selectivity towards dopaminergic cells or cells ectopically expressing the DAT in vitro. Our results suggest that TaClo and related analogs are strong cytotoxins without selectivity towards dopaminergic cells.
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PMID:Cytotoxicity of chloral-derived beta-carbolines is not specific towards neuronal nor dopaminergic cells. 1686 95

Sensitive to apoptosis gene (SAG), a novel zinc RING finger protein, exhibits anti-apoptotic and antioxidant activity against a variety of redox reagents. In the present study, we have determined that SAG suppresses 1-methyl-4-phenylpyridinium ion (MPP(+))-induced neurotoxicity via the downregulation of ROS generation and c-Jun N-terminal kinase 1 (JNK1) activity. Both transient and constitutively overexpressed SAG were found to inhibit the MPP(+)-induced neurotoxicity of SH-SY5Y neuroblastoma cells. In the SAG-expressing cells, MPP(+) induced ROS generation was suppressed to a significant degree as compared to the cells treated only with MPP(+). MPP(+)-induced JNK1 activation was also determined to be suppressed markedly by SAG. Furthermore, SAG inhibits MEKK1 dependent c-Jun transcription activity in SH-SY5Y cells. Thus, we concluded that SAG is a cellular protective molecule, which appears to function as an antioxidant, suppressing MPP(+)-induced neurotoxicity.
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PMID:SAG protects human neuroblastoma SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity via the downregulation of ROS generation and JNK signaling. 1724 May 29

1-Methyl-4-phenylpyridinium ion (MPP(+)), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of intracellular reactive oxygen species (ROS) level and apoptotic death. Rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In the present study, we investigated the protective effects of rosiglitazone on MPP(+) induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as underlying mechanism. Our results suggested that the protective effects of rosiglitazone on MPP(+) induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase and regulating the expression of Bcl-2 and Bax. These data indicated that rosiglitazone might provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinson's disease.
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PMID:Rosiglitazone protects human neuroblastoma SH-SY5Y cells against MPP+ induced cytotoxicity via inhibition of mitochondrial dysfunction and ROS production. 1726 88

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and its metabolite 1-methyl-4-phenylpyridinium (MPP(+)) are drugs that are widely used in experimental Parkinson disease (PD) models. What is the significance of ORP150/HSP12A, a molecular chaperone in the endoplasmic reticulum (ER), in the nigrostriatal system? Dopaminergic neuroblastoma SH-SY5Y cells and dopaminergic neurons of the substantia nigra pars compacta (SNpc) were examined. Our observations led to the hypothesis that ORP150 protects against MPTP/MPP(+)-induced neurotoxicity, and indicate the importance of the ER environment in maintaining the nigrostriatal pathways.
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PMID:Does ORP150/HSP12A protect dopaminergic neurons against MPTP/MPP(+)-induced neurotoxicity? 1733 Sep 88

Autophagy is a degradative mechanism involved in the recycling and turnover of cytoplasmic constituents from eukaryotic cells. This phenomenon of autophagy has been observed in neurons from patients with Parkinson's disease (PD), suggesting a functional role for autophagy in neuronal cell death. On the other hand, it has been demonstrated that exposure to pesticides can be a risk factor in the incidence of PD. In this sense, paraquat (PQ) (1,1'-dimethyl-4,4'-bipyridinium dichloride), a widely used herbicide that is structurally similar to the known dopaminergic neurotoxicant MPP(+) (1-methyl-4-phenyl-pyridine), has been suggested as a potential etiologic factor for the development of PD. The current study shows, for the first time, that low concentrations of PQ induce several characteristics of autophagy in human neuroblastoma SH-SY5Y cells. In this way, PQ induced the accumulation of autophagic vacuoles (AVs) in the cytoplasm and the recruitment of a LC3-GFP fusion protein to AVs. Furthermore, the cells treated with PQ showed an increase of the long-lived protein degradation which is blocked in the presence of the autophagy inhibitor 3-methyladenine and regulated by the mammalian target of rapamycin (mTOR) signaling. Finally, the cells succumbed to cell death with hallmarks of apoptosis such as phosphatidylserine exposure, caspase activation, and chromatin condensation. While caspase inhibition retarded cell death, autophagy inhibition accelerated the apoptotic cell death induced by PQ. Altogether, these findings show the relationship between autophagy and apoptotic cell death in human neuroblastoma cells treated with PQ.
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PMID:Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells. 1743 67

Neurodegenerative diseases such as Parkinson's disease are illnesses associated with high morbidity and mortality with few, or no effective, options available for their treatment. In addition, the direct cause of selective dopaminergic cell loss in Parkinson's disease has not been clearly understood. Taken together, several studies have demonstrated that melatonin has a neuroprotective effect both in vivo and in vitro. Accordingly, the effects of melatonin on 1-methyl, 4-phenyl, pyridinium ion (MPP(+))-treated cultured human neuroblastoma SK-N-SH cell lines were investigated in the present study. The results showed that MPP(+) significantly decreased cell viability. By contrast, an induction of phosphorylation of c-Jun, activation of caspase-3 enzyme activity, cleavage of DNA fragmentation factors 45 and DNA fragmentation were observed in MPP(+)-treated cells. These changes were diminished by melatonin. These results demonstrate the cellular mechanisms of neuronal cell degeneration induced via c-Jun-N-terminal kinases and caspase-dependent signaling, and the potential role of melatonin on protection of neuronal cell death induced by this neurotoxin.
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PMID:Melatonin inhibits MPP+-induced caspase-mediated death pathway and DNA fragmentation factor-45 cleavage in SK-N-SH cultured cells. 1764 89


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