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)

The inhibitory effects of the constituents of Gastrodia elata Bl. (GE) on glutamate-induced apoptosis in human neuronal cells were investigated using IMR32 human neuroblastoma cells. Glutamate (GLU) induced DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. GLU also induced a slow and sustained increase in intracellular Ca2+ concentration. Treatment with EGTA, an extracellular Ca2+ chelator, in a nominal Ca2+-free buffer solution abolished the GLU-induced intracellular Ca2+ increase, indicating that GLU stimulated Ca2+ influx pathway in the IMR32 cells. BAPTA, an intracellular Ca2+ chelator, significantly inhibited the GLU-induced apoptosis assessed by the flow cytometry measuring hypodiploid DNA content indicative of apoptosis, implying that intracellular Ca2+ rise may mediate the apoptotic action of GLU. Vanillin (VAN) and p-hydroxybenzaldehyde (p-HB), known constituents of GE, significantly inhibited both intracellular Ca2+ rise and apoptosis induced by GLU. These results suggest that the apoptosis-inhibitory actions of the constituents of GE may account, at least in part, for the basis of their antiepileptic activities. These results further suggest that intracellular Ca2+ signaling pathway may be a molecular target of the constituents of GE.
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PMID:Inhibitory effects of constituents of Gastrodia elata Bl. on glutamate-induced apoptosis in IMR-32 human neuroblastoma cells. 1048 82

The effects of protein kinase C (PKC) and protein kinase A (PKA) on the high affinity glutamate uptake in rat cerebral cortex synaptosomes, cell lines of human neuroblastoma SK-N-SH and human anaplastic astrocytoma BT-325 were studied by measurement of radioactivity of 3[H]-L-glutamate. The results were as follows: (1) PKC agonist phorbol-12-myristate, 13-acetate (PMA) stimulated the glutamate uptake in the rat cerebral cortex synaptosomes and cell line of BT-325, but not in the cell line of SK-N-SH. This effect of PMA was abolished in the presence of PKC antagonist sphingosine. (2) Glutamate uptake in all these three samples of neural tissues and cells was not affected by PKA agonist adenosine 3',5'-cyclicmonophosphate, N6,O2'-dibutyryl. The above results indicate that it is PKC that stimulates high affinity glutamate uptake in glial cells, although the possibility that neurons are also affected to some extent can not be ruled out.
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PMID:[The stimulation of glutamate uptake by the phorbol ester in rat cerebral cortex synaptosomes and cell line of human anaplastic astrocytoma BT-325]. 1132 78

Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-d-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca(2+) dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.
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PMID:Glutamate antagonists limit tumor growth. 1137 28

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

Glutamate and the NO donor, nitroprusside, synergistically induced the death of B50 cells from a rat CNS-derived neuroblastoma cell line. With low [nitroprusside] (10 microM) both nitroprusside and glutamate were required. Under these conditions, nuclei became pyknotic and caspases were activated. The activities of caspase-3 and caspase-6 (effector caspases) were higher than those of caspase-8 and caspase-9 (initiator caspases). The activation of all four caspases was inhibited by cyclosporin A, with the order of susceptibility caspase-8=caspase-9=caspase-6>caspase-3. To identify the possible locus of cyclosporin A action, we used an antisense oligodeoxynucleotide to suppress the level of cyclophilin-A to<5% of its control value. Cyclophilin-A suppression largely reproduced the inhibitory effects of cyclosporin A. These results provide the first indication that cyclophilin-A participates in the activation of the caspase cascade in neuronal cells, in particular in the form of cascade elicited by excitotoxic stimuli. It is concluded that neuroprotection by cyclosporin A against excitotoxin-induced apoptosis is, at least partly, due to inhibition of cyclophilin-A.
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PMID:Cyclophilin-A is involved in excitotoxin-induced caspase activation in rat neuronal B50 cells. 1190 43

The management of malignancies in humans constitutes a major challenge for contemporary medicine. Despite progress in chemotherapy, bone marrow transplantation, surgical measures, and radiation technologies, and in immunological and immunomodulatory approaches, humans continue to succumb to cancer due to tumor recurrence and metastatic disease. The excitatory neurotransmitter glutamate, which regulates proliferation and migration of neuronal progenitors and immature neurons during the development of the mammalian nervous system, is present in peripheral cancers. Since both neuronal progenitors and tumor cells possess propensity to proliferate and to migrate, and since glutamate and glutamate receptors are known to modify these phenomena in the nervous system, we proceeded to investigate the possible influence of glutamate antagonists on the proliferation and migration of tumor cells. We found and recently reported that glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) antagonists inhibit the proliferation of human colon adenocarcinoma, astrocytoma, breast and lung carcinoma, and neuroblastoma cells in vitro. The antiproliferative effect of glutamate antagonists is Ca(2+)-dependent and results from decreased cell division and increased cell death. Glutamate antagonists produce morphological alterations in tumor cells, which consist of reduced membrane ruffling and pseudopodial protrusions, and decrease their motility and invasive growth. Furthermore, glutamate antagonists enhance in vitro cytostatic and cytotoxic effects of common chemotherapeutic agents used in cancer therapy. These findings demonstrate the anticancer potential of glutamate antagonists and suggest that they may be used as an adjunctive measure in the treatment of cancer.
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PMID:Glutamate antagonists limit tumor growth. 1223 99

The present study demonstrates that human SK-N-SH neuroblastoma cells, differentiated by retinoic acid (RA), express functional NMDA receptors and become vulnerable to glutamate toxicity. During exposure to RA, SK-N-SH cells switched from non-neuronal to neuronal phenotype by showing antigenic changes typical of postmitotic neurons together with markers specific for cholinergic cells. Neuronally differentiated cells displayed positive immunoreactivity to the vesicular acetylcholine transporter and active acetylcholine release in response to depolarizing stimuli. The differentiation correlated with the expression of NMDA receptors. RT-PCR and immunoblotting analysis identified NMDA receptor subunits NR1 and NR2B, in RA-differentiated cultures. The NR1 protein immunolocalized to the neuronal cell population and assembled with the NR2B subunit to form functional N-methyl-D-aspartate (NMDA) receptors. Glutamate or NMDA application, concentration-dependently increased the intracellular Ca2+ levels and acetylcholine release in differentiated cultures, but not in undifferentiated SK-N-SH cells. Moreover, differentiated cultures became vulnerable to NMDA receptor-mediated excitotoxicity. The glutamate effects were enhanced by glycine application and were prevented by the NMDA receptor blocker MK 801, as well as by the NR2B selective antagonist ifenprodil. These data suggest that SK-N-SH cells differentiated by brief treatment with RA may represent an unlimited source of neuron-like cells suitable for studying molecular events associated with activation of human NR1/NR2B receptors.
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PMID:Expression of functional NR1/NR2B-type NMDA receptors in neuronally differentiated SK-N-SH human cell line. 1249 29

Cyclic ADP-ribose (cADP-ribose) is a putative second messenger or modulator. However, the role of cADP-ribose in the downstream signals of the metabotropic glutamate receptors (mGluRs) is unclear. Here, we show that glutamate stimulates ADP-ribosyl cyclase activity in rat or mouse crude membranes of retina via group III mGluRs or in superior cervical ganglion via group I mGluRs. The retina of mGluR6-deficient mice showed no increase in the ADP-ribosyl cyclase level in response to glutamate. GTP enhanced the initial rate of basal and glutamate-stimulated cyclase activity. GTP-gamma-S also stimulated basal activity. To determine whether the coupling mode of mGluRs to ADP-ribosyl cyclase is a feature common to individual cloned mGluRs, we expressed each mGluR subtype in NG108-15 neuroblastoma x glioma hybrid cells. The glutamate-induced stimulation of the cyclase occurs preferentially in NG108-15 cells over-expressing mGluRs1, 3, 5, and 6. Cells expressing mGluR2 or mGluRs4 and 7 exhibit inhibition or no coupling, respectively. Glutamate-induced activation or inhibition of the cyclase activity was eliminated after pre-treatment with cholera or pertussis toxin, respectively. Thus, the subtype-specific coupling of mGluRs to ADP-ribosyl cyclase via G proteins suggests that some glutamate-evoked neuronal functions are mediated by cADP-ribose.
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PMID:Subtype-specific coupling with ADP-ribosyl cyclase of metabotropic glutamate receptors in retina, cervical superior ganglion and NG108-15 cells. 1275 74

Glutamate excitotoxicity is strongly implicated as a major contributing factor in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Excitotoxicity results from elevated intracellular calcium ion (Ca(2+)) levels, which in turn recruit cell death signaling pathways. Recent evidence suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit (GluR) stoichiometry is a dominant factor leading to excess Ca(2+) loading in neurodegeneration. In particular, the Ca(2+) permeable glutamate receptor subunit 3 (GluR3) has been implicated in several neurologic conditions such as bipolar disorder and epilepsy. Recent proteomic analysis within our group on the copper zinc superoxide dismutase (SOD1)(G93A) transgenic mouse model of familial ALS (FALS) reveals a potentially deleterious upregulation of GluR3 in spinal cord compared to that in wild-type littermates. Based on this finding we designed a 12mer antisense peptide nucleic acid (PNA) directed against GluR3. This sequence significantly reduced levels of GluR3 protein and protected neuroblastoma x spinal cord (NSC-34) cells against death induced by the AMPA receptor-specific agonist (S)-5-fluorowillardiine. We subsequently treated SOD1(G93A) mice thrice weekly with intraperitoneal injections of the antisense PNA (2.5 mg/kg) commencing at postnatal day 50. Mice treated with the antisense sequence had significantly extended survival compared to mice injected with a nonsense sequence. Western blot analysis, however, did not reveal a significant reduction in GluR3 protein levels in whole extracts of the lumbar spinal cord. These results suggest that interference with the GluR3 component of the AMPA receptor assembly may be a novel strategy for controlling excitotoxic destruction of motor neurons and may lead to new therapeutic opportunities for the treatment of human ALS.
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PMID:Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS. 1526 27

Both amino acid transport and glutathione play a key role in regulating cancer cell growth. Glutamine can serve as an important ATP source for cancer cells, and it can supply glutamate, a precursor for the synthesis of glutathione, by the hydrolysis of glutamine. We examined the effects of glutamine concentrations [2 mM (control), 400 microM, 200 microM, and 0 microM] on cell growth, amino acid transport, and glutathione levels in a human neuroblastoma cell line, SK-N-SH, by using cell culture technique. Cell growth rates were dependent on glutamine concentrations in culture media. Glutamate transport significantly increased in glutamine-deprived groups, and this increase was remarkable in lower glutamine groups (200 microM and 0 microM glutamine). Glutamine deprivation resulted in a significant decrease in glutathione levels by 20% compared with control, but glutathione in 0 microM glutamine was maintained with the same levels found in 400 microM and 200 microM glutamine. DNA and protein synthesis correlated directly with glutamine concentrations in culture media. Our results suggest that glutamine mediates neuroblastoma cell proliferation by regulating amino acid transport and glutathione synthesis, both when sufficient nutrients are present and when key nutrients such as glutamine are in limited supply.
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PMID:Glutamine regulates amino acid transport and glutathione levels in a human neuroblastoma cell line. 1537 87


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