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)

Brain cholesterol, which is synthesized in the central nervous system and also partly taken up from lipoproteins via the blood-brain barrier, is a major component of neuronal membranes. Oxidation of cholesterol leads to the formation of oxysterols, which have been shown to act cytotoxic. The influence of 7alpha-hydroperoxycholesterol, was investigated using the human neuroblastoma cell line SH-SY5Y. 7alpha-Hydroperoxycholesterol caused neuronal cell death; this neurotoxic effect was dose-dependent, within 48 h 10 microM led to 50%, 50 microM to 92% loss of cell viability, which was detected by cell morphology and Trypan blue exclusion. DNA-fragmentation or caspase-3 activity were not detectable, LDH release occurred rapidly and reactive oxygen species (ROS) were generated. Therefore we infer that 7alpha-hydroperoxycholesterol, apart from its role in atherosclerosis, leads to necrosis of neuronal cells.
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PMID:7alpha-Hydroperoxycholesterol causes CNS neuronal cell death. 1076 87

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

Tissue transglutaminase is a unique member of the transglutaminase family as it not only catalyzes a transamidating reaction, but also binds and hydrolyzes GTP and ATP. Tissue transglutaminase has been reported to be pro-apoptotic, however, conclusive evidence is still lacking. To elucidate the role of tissue transglutaminase in the apoptotic process human neuroblastoma SH-SY5Y cells were stably transfected with vector only (SH/pcDNA), wild-type tissue transglutaminase (SH/tTG) and tissue transglutaminase that has no transamidating activity but retains its other functions (SH/C277S). In these studies three different apoptotic stimuli were used osmotic stress, staurosporine treatment and heat shock to delineate the role of tissue transglutaminase as a transamidating enzyme in the apoptotic process. In SH/tTG cells, osmotic stress and staurosporine treatments resulted in significantly greater caspase-3 activation and apoptotic nuclear changes then in SH/pcDNA or SH/C277S cells. This potentiation of apoptosis in SH/tTG cells was concomitant with a significant increase in the in situ transamidating activity of tissue transglutaminase. However, in the heat shock paradigm, which did not result in any increase in the transamidating activity in SH/tTG cells, there was a significant attenuation of caspase-3 activity, LDH release and apoptotic chromatin condensation in SH/tTG and SH/C277S cells compared with SH/pcDNA cells. These findings indicate for the first time that the effect of tissue transglutaminase on the apoptotic process is highly dependent on the type of the stimuli and how the transamidating activity of the enzyme is affected. Tissue transglutaminase facilitates apoptosis in response to stressors that result in an increase in the transamidating activity of the enzyme. However, when the stressors do not result in an increase in the transamidating activity of tissue transglutaminase, than tissue transglutaminase can ameliorate the apoptotic response through a mechanism that is independent of its transamidating function. Further, neither the phosphatidylinositol-3-kinase pathway nor the extracellular-regulated kinase pathway is downstream of the modulatory effects of wild-type tissue transglutaminase or C277S-tissue transglutaminase in the apoptotic cascade.
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PMID:Tissue transglutaminase differentially modulates apoptosis in a stimuli-dependent manner. 1206 37

It has been reported by several groups that thoracic neuroblastoma (NB) are associated with a better outcome than NB of other localisation. Concerning the reason for this phenomenon, however, the findings have diverged and therefore therapeutic recommendations are not uniform. We performed a retrospective analysis of the prognostic factors and surgical results of 113 thoracic NB and compared these to 556 NB of other sites, all treated according to the protocol of the German Cooperative Study NB90. Compared to non-thoracic NB, thoracic NB showed a female preponderance (P = 0.018), more often with localised disease stages 1 - 3 (P < 0.001), lower LDH serum levels (P = 0.027), and less often with MYCN amplification (P = 0.04), while there was no statistically significant difference in the patients' ages and histological grades. In a separate analysis of localised (stages 1 - 3), stage 4 and stage 4 S NB, there were no differences between thoracic and non-thoracic NB in LDH secretion. MYCN amplification was different only in localised NB (P = 0.037). In a multivariate analysis, tumour stage (P < 0.0001), MYCN-status (P < 0.001) and serum-LDH (P = 0.008), but not thoracic localisation, were independent prognostic factors. A complete resection was achieved in 73/104 (70 %) operated thoracic NB, while 25 (24 %) were partially resected and 6 (6 %) only biopsied. Patients with thoracic NB had a better outcome only in stage 4, but not in stages 1 - 3 and 4 S (EFS; P = 0.028). There was no difference for all stages in the event-free survival between completely and incompletely resected tumours. Surgical complications occurred in 34 (20 %) of all operations, some of them severe, although there were no surgical deaths. Our results suggest that although thoracic NB has a relatively favourable prognosis, it should be treated in the same way as NB with non-thoracic localisation, with stratification according to tumour stage and biological properties, such as MYCN status. Radical surgery is only indicated if mutilation and life-threatening complications can be avoided.
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PMID:Characteristics and outcome of thoracic neuroblastoma. 1210 94

This multicentric study aimed to bring neuroblastoma patients together under IPOG-NBL-92 protocol and evaluate the results within the period between 1992 and 2001 in Izmir. Sixty-seven neuroblastoma patients from 4 pediatric oncology centers in Izmir were included in the study. IPOG-NBL-92 protocol modified from German Pediatric Oncology (GPO)-NB-90 protocol was applied: Patients in stage 1 received only surgery, while surgery plus 4 chemotherapy courses (cisplatin, vincristine, ifosfamide) were given in stage 2 and surgery plus 6 chemotherapy courses (cisplatin, vincristine, ifosfamide, epirubicin, cyclophosphamide) were given in stages 3 and 4 patients. In patients who were kept in complete remission (CR), a maintenance therapy of one year was applied. Radiotherapy was given to the primary site following induction chemotherapy plus surgery in stages 3 and 4 patients with partial remission (PR). The stages of the patients were as follows: 5% in stage 1, 39% in stage 3, 49% in stage 4, and 7% in stage 4S. Primary tumor site was abdomen in 88% of cases. CR rates were as 100% in stage 1, 76% in stage 3, 35% in stage 4, and 75% in stage 4S. Relapse was observed in 32% of patients in a median of 19 months. The median follow-up time for survivors was 33 (17-102) months. Five-year OS rate was 31% and the EFS rate was 30% in all patients. Five-year overall and event-free survival rates were 63 and 30% in stage 3, but 6 and 5%, respectively, in stage 4 patients. Univariate analysis established that the age, stage, primary tumor site, and high LDH and NSE levels conferred a significant difference. The IPOG-NBL-92 protocol has proved to be satisfactory with tolerable toxicity and reasonable CR and survival rates. However, more effective treatments suitable to Turkey's social and economic conditions are urgently needed for children over 1 year of age with advanced neuroblastoma.
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PMID:Experience of the Izmir Pediatric Oncology Group on Neuroblastoma: IPOG-NBL-92 Protocol. 1263 17

Endoplasmic reticulum (ER) stress has increasingly come into focus as a factor contributing to neuronal injury. Although caspase-dependent mechanisms have been implicated in ER stress, the signaling pathways involved remain unclear. In this study, we examined the role of the extracellular signal-regulated kinase (ERK), a mitogen-activated protein (MAP) kinase pathway that is highly conserved in many systems for balancing cell survival and death. Prolonged treatment of the human neuroblastoma cell line SH-SY5Y with thapsigargin, an inducer of ER stress, increased cell death over 24-48 h, as measured by LDH release. Caspases were involved; increased levels of active caspase-3 and cleaved caspase substrate PARP were detected, and treatment with Z-VAD-FMK reduced thapsigargin-induced cytotoxicity. In contrast, inhibition of calpain was not protective, although calpain was activated following thapsigargin treatment. An early and transient phosphorylation of ERK1/2 occurred after thapsigargin-induced ER stress, and targeting this pathway with the MEK inhibitors U0126 or PD98059 significantly reduced cell death. Similar cytoprotection was obtained against brefeldin A, another ER stress agent. However, protection against ER stress via ERK inhibition was not accompanied by amelioration of caspase-3 activation, PARP cleavage, or DNA laddering. These data indicate that ERK may contribute to non-caspase-dependent pathways of injury after ER stress.
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PMID:Involvement of ERK MAP kinase in endoplasmic reticulum stress in SH-SY5Y human neuroblastoma cells. 1503 Apr 7

Signaling through neurotrophic receptors is necessary for differentiation and survival of the developing nervous system. The present study examined the effects of the organic mercury compound thimerosal on nerve growth factor signal transduction and cell death in a human neuroblastoma cell line (SH-SY5Y cells). Following exposure to 100 ng/ml NGF and increasing concentrations of thimerosal (1 nM-10 microM), we measured the activation of TrkA, MAPK, and PKC-delta. In controls, the activation of TrkA MAPK and PKC-delta peaked after 5 min of exposure to NGF and then decreased but was still detectable at 60 min. Concurrent exposure to increasing concentrations of thimerosal and NGF for 5 min resulted in a concentration-dependent decrease in TrkA and MAPK phosphorylation, which was evident at 50 nM for TrkA and 100 nM for MAPK. Cell viability was assessed by the LDH assay. Following 24-h exposure to increasing concentrations of thimerosal, the EC50 for cell death in the presence or absence of NGF was 596 nM and 38.7 nM, respectively. Following 48-h exposure to increasing concentrations of thimerosal, the EC50 for cell death in the presence and absence of NGF was 105 nM and 4.35 nM, respectively. This suggests that NGF provides protection against thimerosal cytotoxicity. To determine if apoptotic versus necrotic cell death was occurring, oligonucleosomal fragmented DNA was quantified by ELISA. Control levels of fragmented DNA were similar in both the presence and absence of NGF. With and without NGF, thimerosal caused elevated levels of fragmented DNA appearing at 0.01 microM (apoptosis) to decrease at concentrations >1 microM (necrosis). These data demonstrate that thimerosal could alter NGF-induced signaling in neurotrophin-treated cells at concentrations lower than those responsible for cell death.
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PMID:Effects of thimerosal on NGF signal transduction and cell death in neuroblastoma cells. 1584 6

Prion diseases are fatal neurodegenerative disorders characterized by the accumulation in the brain of an abnormally misfolded, protease-resistant, and beta-sheet rich pathogenic isoform (PrP(SC)) of the cellular prion protein (PrP(C)). In the present work, we were interested to study the mode of prion protein interaction with the membrane using the 106-126 peptide and small unilamellar lipid vesicles as model. As previously demonstrated, we showed by MTS assay that PrP 106-126 induces alterations in the human neuroblastoma SH-SY5Y cell line. We demonstrated for the first time by lipid-mixing assay and by the liposome vesicle leakage test that PrP 106-126, a non-tilted peptide, induces liposome fusion thus a potential cell membrane destabilization, as supported by membrane integrity assay (LDH). By circular dichroism (CD) analysis we showed that the fusogenic property of PrP 106-126 in the presence of liposome is associated with a predominantly beta-sheet structure. These data suggest that the fusogenic property associated with a predominant beta-sheet structure exhibited by the prion peptides contributes to the neurotoxicity of these peptides by destabilizing cellular membranes. The latter might be attached at the membrane surface in a parallel orientation as shown by molecular modeling.
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PMID:Interaction of the 106-126 prion peptide with lipid membranes and potential implication for neurotoxicity. 1588 62

Seventy-four neuroblastoma patients were analyzed according to the clinical data including age, stage, bone metastases, primary tumor localization, tumor diameter, LDH, and serum ferritin. Histological examination of tumor specimens comprised calculation of proliferative index (PI) on slides stained with anti Ki-67 antibody and assessment of microvascular density (MVD) on anti-CD34 stained sections. Wide range of PI (1.5-79; median 37.8%) and MVD (41-385; median 172/mm2) values was observed. Significant relationship between higher PI and tumor diameter more than 5 cm (40.3 vs 37.2%) was found. Lower PI was found more frequently in stroma-rich tumors. Significantly higher median MVD was found in infant tumors and in smaller tumors <5 cm. Tendency to inverse relationship between PI and MVD was observed. The high values of both PI and MVD were found in some aggressive tumors in patients >1-year old. We evaluated the new parameter: proliferative-vascular index (PVI) as PVI=PIxMVD which ranged from 213-18333. Among eleven patients >1 year old, with PVI >7000, seven (64%) had a poor outcome within the mean period of 22 months. Our results suggest that the simultaneous estimation of proliferative activity and vascularity of neuroblastomas could be studied as a prognostic indicator. Further investigations are needed to confirm this finding.
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PMID:A correlation of microvascular density and proliferative activity to clinical and histological characteristics in neuroblastoma. 1665 96

Alzheimer's disease (AD) is characterized by the deposition of amyloid-beta (Abeta) protein in the brain. Immunization studies have demonstrated that anti-Abeta antibodies reduce Abeta deposition and improve clinical symptoms seen in AD. However, conventional antibody-based therapies risk an inflammatory response that can result in meningoencephalitis and cerebral hemorrhage. Here we report on the development of human-based single chain variable domain antibody fragments (scFvs) directed against the Abeta 25-35 region as potential therapeutics for AD that do not risk an inflammatory response. The 25-35 region of Abeta represents a promising therapeutic target since it promotes aggregation and is highly toxic. Two scFvs with differing affinities for Abeta were studied, and both inhibited aggregation of Abeta42 as determined by thioflavin T binding assay and atomic force microscopy analysis and blocked Abeta-induced toxicity toward human neuroblastoma SH-SY5Y cells as determined by MTT and LDH release assays. These results provide additional evidence that scFvs against Abeta provide an attractive alternative to more conventional antibody-based therapeutics for controlling aggregation and toxicity of Abeta.
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PMID:Single chain Fv antibodies against the 25-35 Abeta fragment inhibit aggregation and toxicity of Abeta42. 1698 13


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