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)

Microglial cells play a major role in the pathogenesis of many neurological diseases by exacerbating neuronal and non-neuronal cell death, but the mechanisms involved are unclear. To investigate the microglial-neuronal interactions, we used the murine BV-2 microglial cell line and the human neuronal-like SK-N-SH neuroblastoma cell line in a co-culture system that enabled proximity-dependent interaction and communication, a trans-well system that allowed proximity-independent communication through diffusible molecules only, and a conditioned media system through which no proximity-dependent interactions or cell-to-cell communication is possible. Activation of BV-2 cells with lipopolysaccharide and interferon-gamma (LPS/IFN-gamma) decreased viability of the BV-2 cells alone and in co-cultures with SK-N-SH cells, but not SK-N-SH cells grown alone. In contrast, activation of BV-2 cells in the trans-well and conditioned media system did not have any effect on the viability of SK-N-SH cells, suggesting that microglia must be in close proximity to the neural cells to elicit cytotoxicity. To determine the molecules involved in proximity-dependent cell death, inhibitors of microglial activation were investigated. Only the specific inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea, and hypothermia, which is known to suppress microglial iNOS expression, prevented cell death after LPS/IFN-gamma activation. These results suggest that activated microglia release nitric oxide that is, at least partially, responsible for proximity-dependent microglial-mediated neural toxicity.
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PMID:Microglia induce neural cell death via a proximity-dependent mechanism involving nitric oxide. 1656 33

Increased expression of inducible nitric oxide synthase has been shown in murine Venezuelan equine encephalitis (VEE) virus infection. In this experimental model, melatonin (MTL) treatment has shown to be beneficial. The aim of this study was to determine the effect of VEE virus on the nitric oxide (NO) production and lipid peroxidation in neuroblastoma cell cultures, and to investigate the role of MTL during cell-virus interaction. Neuroblastoma cells were co-cultured with VEE virus and treated with MTL at doses ranging from 0 to 1.8 mM, for 6, 12, 24 and 48 h. NO and lipid peroxidation were measured in culture supernatants and in the cellular content by nitrite concentration and thiobarbituric acid assay, respectively. Expression of inducible nitric oxide synthase (iNOS) was determined by indirect immunofluorescence. Increased production of NO and lipid peroxidation products were found in supernatants and cellular contents of VEE virus treated cultures. Both NO and lipid peroxidation were decreased by MTL treatment in a time dependent manner. Increased iNOS expression was observed in VEE virus infected cultures that was reduced by MTL treatment. These results could be related to the beneficial role of MTL in the VEE experimental disease and address the possible therapeutic potential of the hormone in human VEE virus infection.
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PMID:Melatonin decreases nitric oxide production, inducible nitric oxide synthase expression and lipid peroxidation induced by Venezuelan encephalitis equine virus in neuroblastoma cell cultures. 1680 53

The activation of cellular inflammatory response is tightly linked to induced production of reactive oxygen species (ROS) and nitric oxide (NO), which in turn have been identified as important regulators of cellular iron metabolism. In the present study, we have used the microglia cell line BV-2 and the neuroblastoma cell line N2a to study the regulatory effects of the microbial agent lipopolysaccharide (LPS) on the expression of the transferrin receptor (TfR) and ferritin in cell lines with different characteristics. The receptor mainly responsible for LPS recognition is the Toll-like receptor 4 (TLR4) that triggers a variety of intracellular signalling cascades leading to the induction of transcription of target genes involved in the innate immune response. Among the pathways to be activated is the MAPK cascade leading to the activation of nuclear factor-kappaB that induces transcription of a variety of genes, e.g., inducible nitric oxide synthase (iNOS). The TLR4-mediated LPS response also induces the production of ROS through a mechanism(s) suggested to involve the activation of NADPH oxidase(s). This study shows that exposure of BV-2 and N2a cells to LPS results in decreased TfR protein levels and increased H-ferritin mRNA levels. The LPS down-regulatory effect on TfR protein expression is abolished by the NADPH oxidase inhibitor diphenyliodonium (DPI) but is not affected by the free radical scavenger N-acetyl-L-cysteine (NAC) or the iNOS inhibitor aminoguanidine (AG). The increased H-ferritin mRNA levels in response to LPS are not affected by DPI, NAC, or AG.
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PMID:NADPH oxidase inhibitor diphenyliodonium abolishes lipopolysaccharide-induced down-regulation of transferrin receptor expression in N2a and BV-2 cells. 1688 Oct 50

Many herbal medicines and dietary supplements sold as aids to improve memory or treat neurodegenerative diseases or have other favorable effects on the CNS contain a catechol or similar 1,2-dihydroxy aromatic moiety in their structure. As an approach to isolate and examine the neuroprotective properties of catechols, a simple catechol 4-t-Butylcatechol (TBC) has been used as a model. In this study, we investigated the effects of TBC on lipopolysaccharide (LPS)-activated microglial-induced neurotoxicity by using the in vitro model of coculture murine microglial-like cell line HAPI with the neuronal-like human neuroblastoma cell line SH-SY5Y. We also examined the effects of TBC on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells. TBC at concentrations from 0.1-10 microM had no toxic effect on HAPI cells and SH-SY5Y cells, and it inhibited LPS (100 ng/ml)-induced increases of superoxide, intracellular ROS, gp91(Phox), iNOS and a decrease of HO-1 in HAPI cells. Under coculture condition, TBC significantly reduced LPS-activated microglia-induced dopaminergic SH-SY5Y cells death. Moreover, TBC (0.1-10 microM) inhibited 6-OHDA-induced increases of intracellular ROS, iNOS, nNOS, and a decrease of mitochondria membrane potential, and cell death in SH-SY5Y cells. However, the neurotoxic effects of TBC (100 microM) on SH-SY5Y cells were also observed including the decrease in mitochondria membrane potential and the increase in COX-2 expression and cell death. TBC-induced SH-SY5Y cell death was attenuated by pretreatment with NS-398, a selective COX-2 inhibitor. In conclusion, this study suggests that TBC might possess protective effects on inflammation- and oxidative stress-related neurodegenerative disorders. However, the high concentration of TBC might be toxic, at least in part, for increasing COX-2 expression.
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PMID:Neuronal effects of 4-t-Butylcatechol: a model for catechol-containing antioxidants. 1819 Sep 40

Microglia are innate immune cells in the central nervous system. Activation of microglia plays an important role in the processes of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated microglia can produce various proinflammatory cytokines and nitric oxide (NO), which may exert neurotoxic effects. Inhibition of microglia activation may alleviate neurodegeneration under these conditions. To search for the novel therapeutic agents against neuroinflammatory diseases, we have screened a series of flavonoid compounds using a cell-based assay. Our studies showed that fisetin markedly suppressed the production of tumor necrosis factor (TNF)-alpha, NO, and prostaglandin (PG) E2 in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells or primary microglia cultures. Fisetin also inhibited the gene expression of TNF-alpha, interleukin (IL)-1 beta, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) at both mRNA and protein levels. Fisetin significantly suppressed I kappa B degradation, nuclear translocation of NF-kappa B, and phosphorylation of p38 mitogen-activated protein kinase (MAPKs) in the LPS-stimulated BV-2 microglia cells. In addition, fisetin reduced cytotoxicity of LPS-stimulated microglia toward B35 neuroblastoma cells in a co-culture system. These results indicate that fisetin has a strong anti-inflammatory activity in brain microglia, and could be a potential therapeutic agent for the treatment of neuroinflammatory diseases.
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PMID:Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. 1827 3

Nuclear factor-kB (NF-kB) is a family of DNA-binding proteins that are important regulators involved in immune and inflammatory responses, as well as in cell survival and apoptosis. In the nervous system NF-kB is activated under physiological and pathological conditions including learning and memory mechanisms and neurodegenerative diseases. NF-kB is activated in neurons in response to excitotoxic, metabolic and oxidative stress and there is a body of evidence to suggest that glutamate induces NF-kB by the main ionotropic glutamate receptors. In the present study, 3 nitroproprionic acid (3NP), an irreversible inhibitor of succinate dehydrogenase (SD, complex II) has been employed to provide an experimental model of Huntington's disease (HD). Specifically, we described 3NP-induced activation of NF-kB and of iNOS and nNOS genes in striatal treated slices. To aim to better understand the relationship between these identified dysregulated genes and mitochondrial dysfunction, we investigated in SK-N-MC human neuroblastoma cells following 3NP treatment, whether NF-kB nuclear translocation and activation might be involved in the mechanisms by which 3NP leads to transcriptional activation of NOS genes. These results are relevant to more precisely define the role of NF-kB in neuronal cells and better understand its putative involvement in neurodegeneration.
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PMID:NF-kB/NOS cross-talk induced by mitochondrial complex II inhibition: implications for Huntington's disease. 1832 71

To investigate the possible involvement of the nitric oxide radical (NO) in ciguatera fish poisoning (CFP), the in vitro effects of the main Pacific ciguatoxin (P-CTX-1B) and bacterial lipopolysaccharide (LPS) were comparatively studied on neuroblastoma Neuro-2a and on macrophage RAW 264.7 cell lines. NO accumulation was quantified by measuring nitrite levels in cellular supernatant using Griess reagent while the up-regulation of inducible nitric oxide synthase (iNOS) at the mRNA level was quantified via Real-Time Reverse-Transcription Polymerase Chain Reaction (RT-PCR). P-CTX-1B caused a concentration- and time-dependent induction of iNOS in RAW 264.7 cells but not in Neuro-2a cells. NO production was evidenced by increased nitrite levels in the 10 microM range after 48 h of RAW 264.7 cells exposure to LPS and P-CTX-1B (0.05 microg/ml and 6 nM, respectively). The expression of iNOS mRNA peaked at 8h for LPS then gradually decreased to low level at 48 h. In contrast, a sustained level was recorded with P-CTX-1B in the 8-48 h time interval. The addition of N(omega)-nitro-L-arginine methyl ester (L-NAME), a stereoselective NOS inhibitor, strongly diminished NO formation but had no effect on iNOS mRNA synthesis. The implication of NO in CFP paves the way for new therapies for both western and traditional medicines.
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PMID:Modulation of inducible nitric oxide synthase gene expression in RAW 264.7 murine macrophages by Pacific ciguatoxin. 1837 63

Microglial activation plays a pivotal role in the pathogenesis of neurodegenerative diseases by producing various proinflammatory cytokines and nitric oxide (NO). In the present study, the anti-inflammatory and subsequent neuroprotective effects of catechol and its derivatives including 3-methylcatechol, 4-methylcatechol, and 4-tert-butylcatechol were investigated in microglia and neuroblastoma cells in culture. The four catechol compounds showed anti-inflammatory effects with different potency. The catechols significantly decreased lipopolysaccharide (LPS)-induced NO and tumor necrosis factor (TNF)-alpha production in BV-2 microglia cells. The catechols also inhibited the expression of inducible nitric oxide synthase (iNOS) and TNF-alpha at mRNA or protein levels in the LPS-stimulated BV-2 cells. In addition, the catechols inhibited LPS-induced nuclear translocation of p65 subunit of nuclear factor (NF)-kappaB, IkappaB degradation, and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in BV-2 cells. Moreover, the catechols attenuated the cytotoxicity of LPS-stimulated BV-2 microglia toward co-cultured rat B35 neuroblastoma cells. The catechols, however, did not protect B35 cells against H(2)O(2) toxicity, indicating that the compounds exerted the neuroprotective effect by inhibiting the inflammatory activation of microglia in the co-culture. The anti-inflammatory and neuroprotective properties of the catechols in cultured microglia and neuroblastoma cells suggest a therapeutic potential of these compounds for the treatment of neurodegenerative diseases that are associated with an excessive microglial activation.
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PMID:Anti-inflammatory effects of catechols in lipopolysaccharide-stimulated microglia cells: inhibition of microglial neurotoxicity. 1849 97

Considering the importance of inflammation and apoptosis in neurodegenerative conditions, the potential suppressive effects of the Rg3, a by-product obtained during the steaming of red ginseng, may indicate that Rg3 could provide a beneficial therapeutic approach to treating or preventing neurodegenerative disease. We investigated the effect of Rg3 on Abeta42-mediated microglial activation and inflammation-mediated neurotoxicity in murine BV-2 microglial and Neuro-2a neuroblastoma cells, respectively. Rg3 effectively reduced inflammatory cytokine expression in Abeta42-treated BV-2, and inhibited the binding of NF-kappaB p65 to its DNA consensus sequences, and significantly reduced the expression of TNF-alpha in activated microglia. Pretreatment with Rg3 increased the survival rate of Neuro-2a exposed to TNF-alpha. These observations suggest that Rg3 reduced neurotoxicity by inhibiting chronic inflammation through the suppression of activated microglia. In addition, the expression of pro-inflammatory cytokines in BV-2 stimulated by Abeta42 was decreased but not eliminated by Rg3 when binding to the macrophage scavenger receptor type A (MSRA) was blocked with fucoidan. This implies that the inflammatory response may not be exclusively triggered via MSRA. More interestingly, iNOS was almost completely inhibited in the presence of Rg3 when MSRA binding was blocked with fucoidan. Moreover, Rg3 increased the expression of MSRA in BV-2 transfected with siRNA targeting MSRA mRNA, and this increased MSRA expression may play a role in the phagocytosis of Abeta42 peptides. Our results indicate that inhibition of the inflammatory repertoire of microglia, neuroprotection, and increased MSRA expression induced by Rg3 may at least partly explain its therapeutic effects in chronic neurodegenerative diseases.
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PMID:Prevention of inflammation-mediated neurotoxicity by Rg3 and its role in microglial activation. 1859 81

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may contribute to neuronal cell death. Inhibition of glial activation may alleviate neurodegeneration under these conditions. In the present study, the antiinflammatory and neuroprotective effects of tricyclic antidepressants were investigated using cultured brain cells as a model. The results showed that clomipramine and imipramine significantly decreased the production of nitric oxide or tumor necrosis factor-alpha (TNF-alpha) in microglia and astrocyte cultures. Clomipramine and imipramine also attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and TNF-alpha at mRNA levels. In addition, clomipramine and imipramine inhibited IkappaB degradation, nuclear translocation of the p65 subunit of NF-kappaB, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated microglia cells. Moreover, clomipramine and imipramine were neuroprotective as the drugs reduced microglia-mediated neuroblastoma cell death in a microglia/neuron co-culture. Therefore, these results imply that clomipramine and imipramine have antiinflammatory and neuroprotective effects in the central nervous system by modulating glial activation.
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PMID:Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants. 1863 62


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