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)

L-Deprenyl, an irreversible MAO-B (monoamine oxidase B, EC 1.4.3.4) inhibitor, is used for the treatment of Parkinson's disease and to delay the progression of Alzheimer's disease. L-Deprenyl also exhibits protective effects against neuronal apoptosis which are independent of its ability to inhibit MAO-B. The purpose of this study was to compare the antiapoptotic efficacy of L-deprenyl against different types of apoptotic inducers in three neuronal cell culture models. The level of apoptosis was quantified by measuring the activation of caspase-3 enzyme, which is the main apoptotic executioner in neuronal cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27) assays were used to demonstrate the cytotoxic response of apoptotic treatments. Our results showed that okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induced a prominent increase in caspase-3 activity both in cultured hippocampal and cerebellar granule neurons as well as in Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl offered a significant protection against the apoptotic response induced by okadaic acid in all three neuronal models. The best protection appeared at the concentration level of 10(-9) M. L-Deprenyl also provided a protection against apoptosis after AraC (cytosine beta-D-arabinoside) treatment in hippocampal neurons and Neuro-2a cells and after etoposide treatment in Neuro-2a cells. However, L-deprenyl did not offer any protection against apoptosis caused by serum withdrawal or potassium deprivation. Okadaic acid treatment in vivo is known to induce an Alzheimer's type of hyperphosphorylation of tau protein, formation of beta-amyloid plaques, and a severe memory impairment. Our results show that the okadaic acid model provides a promising tool to study the molecular basis of Alzheimer's disease and to screen the neuroprotective capacity of L-deprenyl derivatives.
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PMID:Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells. 1079 57

The expression of HIV-1 negative factor (nef) has been positively correlated with HIV disease progression [Z. Hanna, D.G. Kay, N. Rebai, A. Guimond, S. Jothy, P. Jocicoeur, Nef harbors a makor determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice. Cell 95 (1998) 163-175]. Nef expression has been detected in HIV infected human brains with neuronal damage [A. Ranki, M. Nyberg, V. Ovod, M. Haltia, I. Elovaara, R. Raininko, H. Haapsalo, K. Krohn, Abundant expression of HIV Nef and Rev proteins in brain astrocytes in associated with dementia, AIDS 9(9) (1995) 1001-1008; Y. Saito, L.R. Sharer, M.G. Epstein, J. Michaels, M. Mintz, M. Londer, K. Golding, B.M. Blumberg, Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmorten paediatric central tissues, Neurology 14 (1994) 474-480]. It is postulated that nef may contribute to the neuronal damage observed in the brain of those with late HIV disease. To test this, the potential toxicity of recombinant nef (from HIV-1 IIIB) was compared to the neurotoxin human tumour necrosis alpha (TNFalpha) on human brain cells in culture. SK-N-SH neuroblastoma, primary human neurons and glial cells were exposed to recombinant nef or TNFalpha protein for 3 days or twice over 6 days. Cell viability was assessed by Trypan Blue, lactate dehydrogenase (LDH) release and MTT assays. Nuclear fragmentation was detected using the Hoechst Blue nuclear dye assay. Both nef and TNFalpha (100 ng/ml) caused a significant 30% reduction of SK-N-SH cell numbers after 3 days exposure (P=0. 001). At this time, exposure to nef caused evident fragmented nuclei in these cultures. Human neuronal cultures had a 32 and 33% decrease in cell number after 6 days exposure to either nef or TNFalpha, respectively (P<0.001). Furthermore, as previously shown [J. He, C.M. DeCastro, G.R. Vandenbark, J. Busciglio, D. Gabuzda, Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protoonocogene, Proc. Natl. Acad. Sci. 94 (1997) 3954-3959], a 3-day exposure to nef significantly reduced human glial cell number by 25% (P=0.001). Recombinant nef and TNFalpha compromise human neurons in culture. Thus, like other virotoxins, it is shown for the first time that nef may also contribute to neuronal damage that has been reported in dementia in late HIV disease.
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PMID:Recombinant nef HIV-IIIB protein is toxic to human neurons in culture. 1080 40

The effects of an oxidative insult on cell survival and tau metabolism were investigated in human neuroblastoma SH-SY5Y cells. In this treatment paradigm cells were exposed to the membrane permeant oxidant tert-butylhydroperoxide (tBHP) for 40 min, returned to fresh media and cell survival/death was monitored during the post-treatment period. Cell viability decreased significantly by 6 hr after tBHP exposure, and by 24 hr lactate dehydrogenase (LDH) release was 40.1 +/- 8.8% in tBHP treated cells compared to 8.1 +/- 4.7% in control cells. This oxidative stress paradigm also resulted in significant activation of caspase-3 by 2 hr post-treatment and nuclear apoptotic morphology. Furthermore, tBHP treatment also resulted in delayed tau proteolysis that was first evident 2 hr post-treatment. Treatment of the cells with the general caspase inhibitor Boc-Asp(OMe)-Fluoromethylketone (BAF) completely inhibited caspase-3 activation in response to tBHP, and delayed, but did not prevent cell death. BAF treatment also decreased tau proteolysis. In vitro, recombinant tau was readily proteolyzed by active recombinant caspase-3 into a stable breakdown product. Further tau in the cell lysates was cleaved by active recombinant caspase-3 at a rate, and to an extent similar to that observed for the well-established caspase-3 substrate poly(ADP-ribose)polymerase (PARP). These results suggest that oxidative stress-induced cell death occurs through both caspase-dependent and-independent pathways, and that tau is likely an in situ substrate of caspase-3.
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PMID:Transient oxidative stress in SH-SY5Y human neuroblastoma cells results in caspase dependent and independent cell death and tau proteolysis. 1095 21

Both lithium and valproate have been used in the treatment of manic-depressive illness with very limited understanding of their therapeutic mechanism of action. Recent literature suggests that blocking of potassium channels may be a common therapeutic mechanism of many antidepressant agents. To determine whether the commonly used antimanic agents could prevent potassium efflux-induced cell damage and apoptosis and the underlying mechanisms, we treated SH-SY5Y human neuroblastoma cells with the potassium ionophore, valinomycin (2-100 microM) and observed cell shrinkage, mitochondria damage, a significant increase in of lactate dehydrogenase (LDH) activity and caspase-3 protein expression. Cells treated with lithium (0.5-3 mM) or valproate (0.07-1.4 mM) alone produced no apoptotic morphological and biochemical changes while both mood stabilizers pretreatment reduced or prevented the apoptotic morphological changes. However, valinomycin-induced caspase-3 elevation was only prevented by lithium pretreatment while both lithium and valproate attenuated valinomycin-induced LDH release. Our results suggest that lithium and valproate share a common neuroprotective action against potassium efflux-induced cell apoptosis with different mechanisms.
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PMID:A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblastoma cells: caspase-3 dependency. 1107 36

Protective effects of CV-3611, a free radical scavenger, on retinal ischemic injury in the rat and on glutamate-induced cytotoxicity in a cell line were evaluated. Transient retinal ischemia was induced by raising intraocular pressure of rats to 110 mm Hg for 45 min, and the electroretinogram (ERG) was measured to evaluate retinal function. No ERG could be recorded immediately after reperfusion, and thereafter the ERG gradually recovered. Recovery of the a-wave latency and the amplitudes of the a and b waves in the CV-3611-treated (10 mg/kg, p.o.) group were significantly better than those in the control group up to 24 h after reperfusion. In both the control and CV-3611 group, the b wave showed better recovery than the a wave up to 6 h after reperfusion, while the relationship was reversed after 24-hour reperfusion. Glutamate (10 mM)-induced cytotoxicity in the N18-RE-105 cell, a neural retina-neuroblastoma hybridoma, was quantified by measuring lactate dehydrogenase. Three and 10 microM of CV-3611 significantly attenuated the glutamate-induced cytotoxicity in N18-RE-105 cells. Thus, the radical scavenger (CV-3611) promoted the recovery of retinal function after ischemia-reperfusion injury and ameliorated glutamate-induced cytotoxicity. These results suggest that oxygen free radicals play an important role in the early phase of retinal ischemic injury. Moreover, differential recovery processes of the a and b waves after ischemia suggest that the selective vulnerability of the retina to ischemia could change functionally during the period of reperfusion.
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PMID:Involvement of oxygen free radicals in experimental retinal ischemia and the selective vulnerability of retinal damage. 1146 71

Lithium and nickel present low toxicity, but are able to cause alterations in different tissues. The toxic effects of lithium and nickel at different cellular levels were assessed using two inorganic chemical species: lithium chloride and nickel(II) chloride. Mouse neuroblastoma cell cultures (Neuro-2a) were exposed to both compounds for 24 h. The cytotoxic effects evaluated were cell proliferation by quantification of total protein content, cytoplasmic membrane integrity to cytosolic lactate dehydrogenase leakage, and lysosomal hexosaminidase release. Metabolic markers were lactate dehydrogenase activity and mitochondrial succinate dehydrogenase activity. Lysosomal markers were relative neutral red uptake by lysosomes, and lysosomal hexosaminidase sphingolipid degradation activity. Acetylcholinesterase activity on intact cells was also quantified. Nickel was found to be 36 times more toxic than lithium to neuroblastoma cell proliferation (EC(50)= 0.29 and 10.5 mM, respectively), but the relative extent of other alterations differed. Lithium stimulated nearly all the indicators studied, particularly lactate dehydrogenase, mitochondrial succinate dehydrogenase and acetylcholinesterase activities, as well as hexosaminidase release. In contrast, nickel mainly stimulated hexosaminidase release and inhibited lactate dehydrogenase activity. The stabilization of the cytoplasmic membrane to lactate dehydrogenase leakage simultaneously with the secretion of lysosomal hexosaminidase for both compounds also shows that functional metabolic alterations produced by lithium and nickel are more important than cytoplasmic damage.
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PMID:In vitro effects of lithium and nickel at different levels on Neuro-2a mouse neuroblastoma cells. 1156 64

Between 1985 and 1999, 128 children with neuroblastoma were treated at the Royal Alexandra Hospital for Children. The objective of this retrospective study was to report on a single institution's experience with neuroblastoma and to evaluate clinical and biological prognostic factors using univariate and multivariate assessment. Fifty-two percent presented with localized disease, 41% had stage IV disease, and 7% had stage IVs disease. The 5-year overall survival rate was 65%. Significant prognostic factors in univariate analysis included stage, site, histology, N-myc amplification, neuron-specific enolase (NSE), lactate dehydrogenase (LDH), and urinary dopamine. In multivariate assessment, the adjusted hazard ratio was 3.5 (95 %CI 1.4-8.5) for N-myc amplification, 8.7 (95% CI 3.0-25) for NSE > 300 ng/mL, and 3.6 (95% CI 1.3-10) for-LDH > 3000 U/L. This study confirmed that survival was heavily influenced by closely interrelated clinical and biological factors. Prospective studies including more recently identified molecular prognostic factors are warranted to predict the biological heterogeneity of neuroblastoma.
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PMID:Neuroblastoma: a single institution's experience with 128 children and an evaluation of clinical and biological prognostic factors. 1188 90

Freshly solubilized A beta peptides synergistically increase the magnitude of the constriction induced by endothelin-1 (ET-1), via the activation of a pro-inflammatory pathway. We report that mevinolin and mevastatin, two inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase are able to completely abolish the vasoactive properties of A beta in rat aortae. Mevinolin also appears to oppose the increased vascular reactivity to ET-1 induced by interleukin 1-beta and phospholipase A(2) suggesting that statins display some anti-inflammatory properties. We show that freshly solubilized A beta stimulates prostaglandin E(2) and F(2 alpha) production (by 6 and 3.6 times, respectively) in isolated rat aortae and that mevinolin completely antagonizes this effect confirming the anti-inflammatory action of mevinolin ex vivo in rat aortae. In addition, we observed that A beta vasoactivity is not mediated nor modulated by mevalonic acid suggesting that the anti-inflammatory action of the statins are not related to an inhibition of HMG-CoA reductase activity. Differentiated human neuroblastoma cells (IMR32) were used to assess the neurotoxic effect of pre-aggregated A beta by quantifying the release of lactate dehydrogenase (LDH) in the cell culture medium. A beta appears to enhance LDH release by 30% in IMR32 cells, an effect that can be completely opposed by mevastatin. Taken together these data show that statins can antagonize the effect of A beta in different assays and provide new clues to understand the prophylactic action of the statins against Alzheimer's disease.
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PMID:Statins inhibit A beta-neurotoxicity in vitro and A beta-induced vasoconstriction and inflammation in rat aortae. 1188 11

Excitotoxic effects leading to neuronal cell degeneration are often accompanied by a prolonged increase in the intracellular level of Ca(2+) ions and L-glutamate-induced toxicity is assumed to be mediated via a Ca(2+)-dependent mechanism. Due to their buffering properties, EF-hand Ca(2+)-binding proteins (CaBPs) can affect intracellular Ca(2+) homeostasis and a neuroprotective role has been attributed to some of the family members including calretinin, calbindin D-28k and parvalbumin. We have stably transfected N18-RE 105 neuroblastoma-retina hybrid cells with the cDNAs for the three CaBPs and investigated the effect of these proteins on the L-glutamate-induced, Ca(2+)-dependent cytotoxicity. Several clones for each CaBP were selected according to immunocytochemical staining and characterization of the overexpressed proteins by Western blot analysis. In calretinin- and parvalbumin-expressing clones, expression levels were quantitatively determined by ELISA techniques. Cytotoxicity of transfected clones was quantified by measurement of the activity of lactate dehydrogenase (LDH) that was released into the medium after L-glutamate (10 mM) exposure as a result of necrotic cell death. In untransfected and parvalbumin-transfected cells, LDH released into the medium progressively increased (starting from the 20th hour) reaching maximum levels after 28-30 h of glutamate application. In contrast, LDH release in both, calretinin and calbindin D-28k-transfected clones, was not significantly different from unstimulated transfected or untransfected cells over the same period of time. The results indicate that the 'fast' Ca(2+)-buffers calretinin and calbindin D-28k, but not the 'slow' buffer parvalbumin can protect N18-RE 105 cells from this type of Ca(2+)-dependent L-glutamate-induced delayed cytotoxicity.
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PMID:Calretinin and calbindin D-28k, but not parvalbumin protect against glutamate-induced delayed excitotoxicity in transfected N18-RE 105 neuroblastoma-retina hybrid cells. 1212 80

A missense mutation (N1411) in Presenilin-2 (PS-2) gene is associated with early-onset familial Alzheimer's disease. In this study, SK-N-SH human neuroblastoma cells were transfected with wild-type and mutant PS-2 gene to examine presenilin-2 effects on apoptosis. Serum deprivation resulted in enhanced apoptosis in mutant PS-2 comparing with wild-type PS-2. Similarly, mutant PS-2 induced lactate dehydrogenase release to greater extent than wild-type PS-2. Time course experiment demonstrated that the increase in caspase-3-like activity was more pronounced and accelerated in mutant PS-2, compared to wild-type PS-2. While a significant decrease in bcl-2, an anti-apoptotic molecule, occurred in the cells overexpressing mutant PS-2, no significant change was observed in bax, a pro-apoptotic molecule, as compared with the cells overexpressing wild-type PS-2. Our study demonstrated that mutant PS-2 induces apoptosis accompanied by increased caspase-3-like activity and decreased bcl-2 expression in neuronal cells after serum-deprivation.
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PMID:N141I mutant presenilin-2 gene enhances neuronal cell death and decreases bcl-2 expression. 1217 18


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