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)

We have previously defined a homozygously deleted region at chromosome 1p36.2-p36.3 in human neuroblastoma cell lines, NB-1 and NB-C201, and identified six genes including DFF45/ICAD within this region. In this study, we found that NB-C201 cells are much more resistant to various genotoxic stresses such as cisplatin (CDDP) than CHP134 and SH-SY5Y cells that do not have the homozygous deletion. To examine a role(s) of DFF45 in the regulation of apoptosis in response to CDDP, we have established stably DFF45-expressing NB-C201 cell clones (DFF45-1 and DFF45-3) and a control cell clone (NB-C201-C) using a retrovirus-mediated gene transfer. In contrast to NB-C201-C cells, DFF45-3 cells displayed apoptotic nuclear fragmentation in response to CDDP. Although CDDP-induced proteolytic cleavage of procaspase-3 and DFF45 in DFF45-3 cells, we could not detect a typical apoptotic DNA fragmentation. Additionally, deletion analysis revealed that C-terminal region of DFF45 is required for inducing nuclear fragmentation. Unexpectedly, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that DFF45 has undetectable effect on CDDP sensitivity of NB-C201 cells. Taken together, our present results suggest that DFF45/DFF40 system may be sufficient for CDDP-induced nuclear fragmentation but not DNA cleavage.
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PMID:DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells. 1735 5

In order to examine the neuroprotective effects of the alpha7 nicotinic receptor (nAChR) in relationship to the pathogenesis of Alzheimer's disease (AD), neuroblastoma (SH-SY5Y) cells were transfected with small interference RNAs (siRNAs) that targets specifically towards alpha7 nAChR or exposed to 20microM 3-[2,4-dimethoxybenzylidene] anabaseine (DMXB), a selective agonist of this same receptor. The levels of alpha7 nAChR mRNA and protein were measured by RT-PCR and Western blotting, respectively. The levels of the alpha-form of secreted amyloid precursor protein (alphaAPPs), total APP and the extracellular signal-regulated kinase 1/2 (ERK1/2) were also determined by Western blotting. SH-SY5Y cells transfected with siRNA or exposed to DMXB were then treated with 1microM Abeta(25-35), following which the levels of lipid peroxidation and rate of reduction of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] were characterized by utilizing spectrophotometric procedures. Compared to controls, SH-SY5Y cells transfected with siRNA expressed the decreases in the levels of alpha7 nAChR mRNA and protein by 81% and 69% lower levels, respectively; exhibited reduced levels of the alphaAPPs and ERK1/2 proteins; and demonstrated enhanced lipid peroxidation and a decreased rate of MTT reduction. In cells exposed to DMXB, the level of alpha7 nAChR protein was elevated by 23%, with no alteration in the content of the corresponding mRNA; the levels of the alphaAPPs and ERK1/2 proteins were increased. Inhibition of the expression of the alpha7 nAChR gene enhanced the toxicity exerted by Abeta, whereas stimulation of this receptor attenuated this toxicity exerted. These findings indicate that alpha7 nAChR may play a significant neuroprotective role by enhancing cleavage of APP by alpha-secretase, regulating signal transduction, improving antioxidant defenses and inhibiting the toxicity of Abeta, which is connected with the pathogenesis of AD.
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PMID:The consequences of reducing expression of the alpha7 nicotinic receptor by RNA interference and of stimulating its activity with an alpha7 agonist in SH-SY5Y cells indicate that this receptor plays a neuroprotective role in connection with the pathogenesis of Alzheimer's disease. 1749 9

We previously identified a cluster of prostanoid receptor genes, prostaglandin D2 receptor (PTGDR) and prostaglandin E receptor 2 (PTGER2), as possible targets for DNA methylation in advanced types of neuroblastoma (NB) using bacterial artificial chromosome array-based methylated CpG island amplification method. Among them, in this study, we found that PTGER2 was frequently silenced in NB cell lines, especially in those with MYCN amplification, through epigenetic mechanisms. In NB cell lines, DNA methylation pattern within a part of CpG island was inversely correlated with PTGER2 expression, and histone H3 and H4 deacetylation and histone H3 lysine 9 methylation within the putative promoter region were more directly correlated with silencing of this gene. Methylation of PTGER2 was observed more frequently in advanced-type of primary NBs compared with early-stage tumors. Growth of NB cells lacking endogenous PTGER2 expression was inhibited by restoration of the gene product by transient and stable transfection. A PTGER2-selective agonist, butaprost, increased intracellular cyclic adenosine monophosphate (cAMP) level, inhibited cell growth and induced apoptosis of NB cells stably expressing exogenous PTGER2. 8-Bromo-cAMP also inhibited growth of NB cells lacking PTGER2 expression, but not cells expressing this gene. Taken together, it is suggested that NB cells may lose responsiveness to PTGER2-mediated growth inhibition/apoptosis through epigenetic silencing of PTGER2 and/or disruption of downstream cAMP-dependent pathway during the neuroblastomagenesis.
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PMID:Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas. 1753 65

Increasing evidence suggests that Alzheimer's disease is associated with mitochondrial dysfunction and oxidative damage. To develop a cellular model of Alzheimer's disease, we investigated the effects of thioredoxin (Trx) expression in the response to mitochondrial dysfunction-enhanced oxidative stress in the SH-SY5Y human neuroblastoma cells. Treatment of SH-SY5Y cells with 15 mM of NaN3, an inhibitor of cytochrome c oxidase (complex IV), led to alteration of mitochondrial membrane potential but no significant changes in cell viability. Therefore, cells were first treated with 15 mM NaN3 to induce mitochondrial dysfunction, then, exposed to different concentrations of H2O2. Cell susceptibility was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and morphological observation. Expressions of Trx mRNA and protein were determined by RT-PCR; and Western-blot analysis, respectively. It was found that the SH-SY5Y cells with mitochondrial impairment had lower levels of Trx mRNA and protein, and were significantly more vulnerable than the normal cells after exposure to H2O2 while no significant changes of Trx mRNA and protein in SH-SY5Y cells exposed to H2O2 but without mitochondrial complex IV inhibition. These results, together with our previous study in primary cultured neurons, demonstrated that the increased susceptibility to oxidative stress is induced at least in part by the down-regulation of Trx in SH-SY5Y human neuroblastoma cells with mitochondrial impairment and also suggest the mitochondrial dysfunction-enhanced oxidative stress could be used as a cellular model to study the mechanisms of Alzheimer's disease and agents for prevention and treatment.
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PMID:Mitochondrial dysfunction enhances susceptibility to oxidative stress by down-regulation of thioredoxin in human neuroblastoma cells. 1761 13

Six chalcones from Angelica keiskei KOIDZUMI (Ashitaba in Japanese) and two chalcones from Humulus lupulus L. (hop) were examined for their cytotoxicity in two human neuroblastoma cell lines (IMR-32 and NB-39) and normal cells (primary culture of rat cerebellar granule cells) by [3-(4,5)-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. All chalcones exhibited cytotoxicity against neuroblastoma cells, and two of them (isobavachalcone and xanthoangelol H) had no effect on normal cells even at high concentration (10(-4) M) exposure. Typical morphologic features of apoptosis, including cell shrinkage, chromatin condensation, nuclear fragmentation and formation of apoptotic bodies, were observed in isobavachalcone-treated cells by Hoechst 33342 staining. Western blot analysis showed that isobavachalcone significantly reduced pro-caspase-3 and pro-caspase-9, and subsequently increased the level of cleaved caspase-3 and cleaved caspase-9 in both neuroblastoma cell lines. Moreover, Bax was markedly induced by isobavachalcone application. These results suggest that isobavachalcone induces apoptotic cell death in neuroblastoma via the mitochondrial pathway and has no cytotoxicity against normal cells. Therefore, isobavachalcone may be applicable as an efficacious and safe drug for the treatment of neuroblastoma.
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PMID:Isobavachalcone, a chalcone constituent of Angelica keiskei, induces apoptosis in neuroblastoma. 1791 55

Alzheimer's disease (AD) is a common neurodegenerative disorder, but the initiating molecular processes contributing to neuronal death are not well understood. AD is associated with elevated soluble and aggregated forms of amyloid beta (Abeta) and with oxidative stress. Furthermore, there is increasing evidence for a detrimental role of iron in the pathogenic process. In this context, iron chelation by compounds such as 3-hydroxypyridin-4-one, deferiprone (Ferriprox) may have potential neuroprotective effects. We have evaluated the possible neuroprotective actions of deferiprone against a range of AD-relevant insults including ferric iron, H(2)O(2) and Abeta in primary mouse cortical neurones. We have investigated the possible neuroprotective actions of deferiprone (1, 3, 10, 30 or 100 microM) in primary neuronal cultures following exposure to ferric iron [ferric nitrilotriacetate (FeNTA); 3 and 10 microM], H(2)O(2) (100 microM) or Abeta1-40 (3, 10 and 20 microM). Cultures were treated with deferiprone or vehicle either immediately or up to 6 h after the insult in a 24-well plate format. In order to elucidate a possible neuroprotective action of deferiprone against Parkinson's disease relevant insults another group of experiments were performed in the human neuroblastoma catecholaminergic SHSY-5Y cell line. SHSY-5Y cells were treated with MPP(+) iodide, the active metabolite of the dopaminergic neurotoxin MPTP and the neuroprotective actions of deferiprone evaluated. Cytotoxicity was assessed at 24 h by lactate dehydrogenase release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide turnover (FeNTA and hydrogen peroxide) and morphometric analysis of cell viability by Hoechst 33324/propidium iodide (FeNTA, Abeta and MPP(+)) or 6-carboxyfluorescein diacetate and annexin V-Cy3 (Abeta). The present study demonstrates that deferiprone protects against FeNTA, hydrogen peroxide, MPP(+) and Abeta1-40-induced neuronal cell death in vitro, which is consistent with previous in vitro and in vivo studies that have demonstrated similar protection with other iron chelators.
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PMID:Neuroprotective actions of deferiprone in cultured cortical neurones and SHSY-5Y cells. 1833 85

Progressive spinal muscular atrophy (SMA), the most prevalent hereditary lower motor neuron disease, is caused by mutations in the telomeric copy of the survival of motor neuron (SMN1) gene. Unlike other cells, lower motor neurons cannot tolerate low levels of smn protein. However, it is unclear as to the nature of the cell death involved. There is evidence that lower motor neurons undergo apoptosis in SMA, leading to muscle weakness and wasting. This study investigated whether SMN1 regulation in a motor neuron model affected indices of apoptotic cell death. Decreased smn expression in neuroblastoma hybrid (NSC-34) cell lines by small interfering RNA (siRNA) was demonstrated at the mRNA and protein level. Smn-depleted cells showed elevated caspase-3 activity, decreased cell viability and increased percentage of TUNEL positive cells. Conversely, NSC-34 cell smn overexpression by adenoviral gene transfer decreased staurosporine-induced caspase-3 elevation and mitigated induced cell toxicity as assessed by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. However, increased smn expression by itself did not increase cell viability. These data suggest not only that decreased smn levels increase apoptosis in an in vitro model of SMA, but also that increased smn can protect against neural injury.
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PMID:Survival motor neuron protein regulates apoptosis in an in vitro model of spinal muscular atrophy. 1836 39

Polybrominated diphenyl ethers (PBDEs) are used extensively as flame-retardants and are ubiquitous in the environment and in wildlife and human tissue. Recent studies have shown that PBDEs induce neurotoxic effects in vivo and apoptosis in vitro. However, the signaling mechanisms responsible for these events are still unclear. In this study, we investigated the action of a commercial mixture of PBDEs (pentabrominated diphenyl ether, DE-71) on a human neuroblastoma cell line, SK-N-SH. A cell viability test showed a dose-dependent increase in lactate dehydrogenase leakage and 3-(4,5-dimethylthia-zol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction. Cell apoptosis was observed through morphological examination, and DNA degradation in the cell cycle and cell apoptosis were demonstrated using flow cytometry and DNA laddering. The formation of reactive oxygen species was not observed, but DE-71 was found to significantly induce caspase-3, -8, and -9 activity, which suggests that apoptosis is not induced by oxidative stress but via a caspase-dependent pathway. We further investigated the intracellular calcium ([Ca(2+)](i)) levels using flow cytometry and observed an increase in the intracellular Ca(2+) concentration with a time-dependent trend. We also found that the N-methyl d-aspartate (NMDA) receptor antagonist MK801 (3 microM) significantly reduced DE-71-induced cell apoptosis. The results of a Western blotting test demonstrated that DE-71 treatment increases the level of Bax translocation to the mitochondria in a dose-dependent fashion and stimulates the release of cytochrome c (Cyt c) from the mitochondria into the cytoplasm. Overall, our results indicate that DE-71 induces the apoptosis of [Ca(2+)](i) in SK-N-SH cells via Bax insertion, Cyt c release in the mitochondria, and the caspase activation pathway.
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PMID:DE-71-induced apoptosis involving intracellular calcium and the Bax-mitochondria-caspase protease pathway in human neuroblastoma cells in vitro. 1845 45

Parkinson's disease (PD) is one of the most important neurodegenerative worldwide disorders. The potential cytoprotective effects of aqueous extract of Valeriana officinalis on rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells were demonstrated. The cytotoxicity, cell viability and analysis of cellular morphology were performed by MTT-tetrazole (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and phase contrast microscopy, respectively. Significant changes in the cellular morphology, and condensation of the cell body could be observed when cells were treated with 300 nM rotenone for 48 h. Three different concentrations of Valeriana officinalis extract were used (0.049, 0.098 and 0.195 mg/mL). These extracts brought about an increase of 7.0 +/- 1.3%, 14.5 +/- 1.3% and 14.5 +/- 3.2% in cell viability. Our results indicated that neuroprotector action of the Valeriana officinalis extract provides support for later studies as they help understanding this drug for the development of cytoprotective various therapies in PD.
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PMID:Cytoprotective effect of Valeriana officinalis extract on an in vitro experimental model of Parkinson disease. 1851 51

Recent evidence indicates that methyl jasmonate, a plant stress hormone, exhibits anticancer activity on human cancer cells. Whether methyl jasmonate could inhibit the growth of human neuroblastoma cells still, however, remains largely unknown. In this study, administration of methyl jasmonate to cultured neuroblastoma cell lines, SK-N-SH and BE(2)-C, resulted in a decrease of cell viability in a dose-dependent and time-dependent manner as demonstrated by MTT colorimetry and colony formation assay. The results from RT-PCR indicated that the expression of proliferating cell nuclear antigen, but not of cyclin D1, was downregulated by methyl jasmonate. Accordingly, the cell cycle of methyl jasmonate-treated neuroblastoma cells was arrested at the G0/G1 phase. Moreover, incubation of SK-N-SH and BE(2)-C cells with methyl jasmonate resulted in characteristic changes of apoptosis, as demonstrated by acridine orange-ethidium bromide (AO/EB) staining, Hoechst 33258 staining and flow cytometry. Moreover, methyl jasmonate decreased the expression of the X-linked inhibitor of apoptosis protein and survivin, critical members of the inhibitors of apoptosis protein family, in neuroblastoma cells. These findings indicate that methyl jasmonate suppresses the growth of cultured human neuroblastoma cells associated with downregulation of proliferating cell nuclear antigen, and induces apoptosis accompanied by downregulation of the X-linked inhibitor of apoptosis protein and survivin, which lays the groundwork for further investigation into the mechanisms of methyl jasmonate-mediated anticancer activities.
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PMID:Methyl jasmonate downregulates expression of proliferating cell nuclear antigen and induces apoptosis in human neuroblastoma cell lines. 1852 16


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