Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anatomy, clinical features, etiology, and morphology are the major organizing principles in existing disease ontologies. Assuming that biological pathways (including protein physical interactions, metabolic reactions, regulatory networks) will be in the near future key components in classifications of diseases, we have analyzed how information about pathways can be integrated into disease ontologies. We designed a disease ontology in OWL. SNOMED CT was used to provide the initial disease descriptions. In a second step, we integrated information from the KEGG PATHWAY and the GO annotation data-bases into the disease ontology. In the last step, we analyzed the classification of diseases. For example glioma of brain shares 30 pathways with other cancers, and 19 pathways with Alzheimer's disease. As our knowledge about biological pathways is constantly evolving, this approach can be used for integrating automatically this knowledge in existing ontologies. Thanks to the automatic classification associated with formal ontologies, this approach helps identify physio-pathological classes and taxonomic relations in diseases ontologies. It can therefore be used to create new partitions, focusing on pathways, in biomedical ontologies.
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PMID:Integrating biological pathways in disease ontologies. 1791 25

Epidemiological studies suggest that intake of omega-3 polyunsaturated fatty acids improves neurological disorders such as Alzheimer's disease which exhibit inflammatory pathology. We therefore investigated the anti-inflammatory effects of eicosapentaenoic acid (EPA) on interleukin (IL)-1beta-stimulated C6 glioma cells. In the present study, EPA inhibited pro-inflammatory cytokine IL-6 production, a characteristic of certain neurodegenerative disorders, in IL-1beta-stimulated C6 glioma cells in dose-dependent fashion. EPA down-regulated the expression of IL-6 at mRNA level, indicating that the effect of EPA occurs at the transcriptional level. In addition, peroxisome proliferator-activated receptor (PPAR) gamma antagonists abolished the inhibitory effect of EPA on IL-1beta-induced IL-6 production, whereas PPARalpha antagonist did not block the inhibitory effect of EPA. EPA might thus contribute to the regulation of pro-inflammatory cytokine production in astrocytes through interaction with PPARgamma. Among the PPARgamma ligands tested in this study, ciglitazone, a synthetic agonist of PPARgamma, effectively inhibited IL-6 production, but while neither rosiglitazone nor 15-deoxy-Delta(12,14)-prostaglandin J2 did. These findings indicate that the coordination of PPAR gamma ligands is important in inhibiting the production of IL-6 in C6 glioma cells.
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PMID:Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma. 1876 11

Of recent, clinical interest have been two related human G-protein coupled receptors: formylpeptide receptor (FPR), linked to antibacterial inflammation and malignant glioma cell metastasis; and FPR like-1 (FPRL1), linked to chronic inflammation in systemic amyloidosis, Alzheimer's disease, and prion diseases. In association with the National Institutes of Health (NIH) Molecular Library Screening Network, we implemented a flow-cytometry-based high-throughput screening (HTS) approach for identifying selective small molecule FPR and FPRL1 ligands. The screening assay measured the ability of test compounds to competitively displace a high-affinity, fluorescein- labeled peptide ligand from FPR, FPRL1, or both. U937 cells expressing FPR and rat basophil leukemia (RBL) cells expressing FPRL1 were tested together in a "duplex" format. The U937 cells were color coded with red-fluorescent dye allowing their distinction during analysis. Compounds, cells, and fluorescent ligand were sequentially combined (no wash) in 15 microl assay volumes in 384-well plates. Throughput averaged approximately 11 min per plate to analyze approximately 4,000 cells ( approximately 2,000/receptor) in a 2 microl aspirate from each well. In primary single concentration HTS of 24,304 NIH Small Molecule Repository compounds, 253 resulted in inhibition >30% (181 for FPR, 72 for FPRL1) of which 40 had selective binding inhibition constants (K(i)) < or = 4 microM (34 for FPR and 6 for FPRL1). An additional 1,446 candidate compounds were selected by structure-activity-relationship analysis of the hits and screened to identify novel ligands for FPR (3570-0208, K(i) = 95 +/- 10 nM) and FPRL1 (BB-V-115, K(i) = 270 +/- 51 nM). Each was a selective antagonist in calcium response assays and the most potent small molecule antagonist reported for its respective receptor to date. The duplex assay format reduced assay time, minimized reagent requirements, and provided selectivity information at every screening stage, thus proving to be an efficient means to screen for selective receptor ligand probes.
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PMID:Duplex high-throughput flow cytometry screen identifies two novel formylpeptide receptor family probes. 1878 69

S100B is an astrocyte-derived cytokine implicated in the IL-1beta-triggered cytokine cycle in Alzheimer's disease. However, the secretion of S100B following stimulation by IL-1beta has not been directly demonstrated. We investigated S100B secretion in cortical primary astrocyte cultures, C6 glioma cells and acute hippocampal slices exposed to IL-1beta. S100B secretion was induced by IL-1beta in all preparations, involving MAPK pathway and, apparently, NF-small ka, CyrillicB signaling. Astrocytes and C6 cells exhibited different sensitivities to IL-1beta. These results suggest that IL-1beta-induced S100B secretion is a component of the neuroinflammatory response, which would support the involvement of S100B in the genesis of neurodegenerative diseases.
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PMID:S100B secretion is stimulated by IL-1beta in glial cultures and hippocampal slices of rats: Likely involvement of MAPK pathway. 1904 33

The effect of amyloid beta-peptide (betaAP), which can have both neurotrophic or neurotoxic effects on neurons and has been implicated in the pathogenesis of Alzheimer's disease (AD), was studied on astrocytes using primary cultures and astrocyte cell lines (rat C6 glioma, human 1321NI astrocytoma cells). The cultures were exposed to 0.0005-50 mug/ml) betaAP fragments 1-40, 25-35, 31-35, or 40-41 (control) for 24 hr. Some of the fragments were maintained at 37 degrees C for 48 hr to induce aggregation and some of the cell cultures were pretreated with the differentiating agent dBcAMP before the experiments. The astrocyte responses were evaluated for lysosome activity (neutral red assay) and levels of structural proteins, glial fibrillary acidic protein, vimentin, and S-100, which are altered in the dystrophic plaques with associated astrogliosis in AD. The cells frequently responded with biphasic responses, with initial (low-dose) activation-type responses (i.e., increases of indicator compared to controls), before reductions with altered morphology (increased branching of cells) at higher concentrations. However, cell death (with EC(50) values) was not observed, even at the maximum concentrations of betaAP fragments. The findings suggest that the astrocytes have a relatively high resistance against the betaAP toxicity.
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PMID:Responses of Cultured Astrocytes, C6 Glioma and 1321NI Astrocytoma Cells to Amyloid beta-Peptide Fragments. 1933 Jan 8

The epidermal growth factor receptor (EGFR) family (also known as the ErbB protein family) is comprised of four structurally-related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease. In contrast, excessive ErbB signaling is associated with the development of a wide variety of solid tumors. ErbB-1 and -2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of solid tumors. Several molecular strategies have been developed recently to modulate either EGFR or the downstream signal beyond the cell surface receptor. In the present study, we used human EGFR-overexpressing glioma xenograft cells 4910 and 5310 and targeted MMP-2 expression using an adenoviral RNAi construct. We observed that the RNAi-mediated downregulation of MMP-2 causes the upregulation of ErbB-2 in certain EGFR-overexpressing glioma xenograft cells both in vitro and in vivo. Targeted MMP-2 downregulation was observed in a dose-dependent manner with no apparent off-target effects in these xenograft cells. We also noted that the overexpression of ErbB-2 induced by MMP-2 downregulation is consistent with p50-mediated cell death in 5310 cells but not in 4910 cells. In addition, APAF-1 expression levels increased in correlation with increased ErbB-2 expression after MMP-2 downregulation in vitro and in vivo. Our results suggest that MMP-2 may play a role in a hitherto unknown signaling pathway mediated via ErbB-2 in certain cancer cell types.
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PMID:MMP-2 downregulation mediates differential regulation of cell death via ErbB-2 in glioma xenografts. 1957 38

A disintegrin and metalloproteinase 19 (ADAM19, or adamalysin 19) is a cell surface glycoprotein with a signal sequence, a prodomain, a metalloproteinase domain, a disintegrin domain, a cysteine-rich domain, a epidermal growth factor-like domain, a transmembrane domain, and a cytoplasmic domain. It is an endopeptidase that cleaves extracellular matrix proteins and sheds growth factors and cytokines such as neuregulins, heparin-binding epidermal growth factor, tumor necrosis factor (TNF)-alpha, and TNF-related activation-induced cytokine. The ADAM19 gene was cloned from human, monkey, and mouse. It is expressed in multiple organs and tissues including heart, lung, bones, brain, spleen, liver, skeletal muscle, kidney, and testes. ADAM19 plays essential roles in embryo implantation, cardiovascular morphogenesis, neurogenesis, and other developmental processes. It has constitutive alpha-secretase activity associated with processing Alzheimer's disease amyloid precursor protein (APP) to non-amyloidogenic fragments; thus, it is neuroprotective. Those observations indicate that inhibition of ADAM19 activity is undesirable during embryo development and morphogenesis, and during the development of Alzheimer's disease. On the contrary, in adults, ADAM19 is upregulated in human brain tumors such as astrocytoma and glioblastoma and is correlated with the invasiveness of glioma. It is also over-expressed by many human cancerous cell lines including cancers of the colon, ovary, lung, and brain. Abnormally high expression of ADAM19 is also linked to inflammation and fibrosis of the lung and kidney. Targeted inhibition of ADAM19 may be crucial for the treatment of certain types of tumors and inflammatory diseases.
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PMID:ADAM19/adamalysin 19 structure, function, and role as a putative target in tumors and inflammatory diseases. 1960 35

Elevated tissue levels of zinc (Zn) have been associated with neurodegenerative diseases such as global ischemia, seizure, and Alzheimer's. The mechanism of action of Zn in causing neuronal injury is not clear. One of the possible mechanisms is the ability of Zn to alter cellular energy metabolism. Using the C6 glioma cell as a model, the present study aimed to determined the effects of increasing concentrations of Zn on cellular energy states, as defined by the levels of adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), and adenosine 5'-monophosphate (AMP), the total adenosine nucleotides (TAN) (TAN = ATP + ADP + AMP), and the energy charge potential (ECP = [ATP + 0.5 ADP]/TAN). Uptake of Zn was visualized by the appearance of N-(6-methoxy-8-quinolyl)-p-toluene sulfonamide (TSQ)-stained fluorescent granules after a 3-h exposure to Zn in the medium. At [Zn] = 1 mM, cells appeared apoptotic. Levels of ATP and TAN decreased as the level of Zn increased. The change mirrors the increase in cell death as determined by the trypan blue exclusion test. However, when the ratio of ATP:ADP:AMP within the TAN was calculated, the percentage of ATP in the TAN increased significantly, while that of AMP decreased. The change in the relative AMP level mirrored the change in cell viability as measured by the MTT assay, which indicated a decreased in mitochondrial activity. Cellular ECP increased significantly from 0.85 +/- 0.007 to 0.92 +/- 0.04. The elevated ECP and relative ATP level, together with a significant decrease in the relative AMP level, are all indicators of inhibition of cellular metabolism. These results support the notion that acute exposure of C6 glioma cells to a high concentration of Zn might initially result in a decrease in relative AMP and an inhibition of mitochondrial activity. However, the ultimate toxic action of Zn on the C6 glioma cells appears to be due to a gradual inhibition of energy utilization, leading to cell shrinkage and apoptosis.
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PMID:Modulation of energy metabolism in c6 glioma cells as possible mechanism contributing to zinc neurotoxicity. 2002 Nov 52

Vascularization of the vertebrate brain takes place during embryonic development from a preformed perineural vascular plexus. As a consequence of the intimate contact with neuroectodermal cells the vessels, which are entering the brain exclusively via sprouting angiogenesis, acquire and maintain unique barrier properties known as the blood-brain barrier (BBB). The endothelial BBB depends upon the close association of endothelial cells with pericytes, astrocytes, neurons and microglia, which are summarized in the term neuro-vascular unit. Although it is known since decades that the CNS tissue provides the cues for BBB induction and differentiation in endothelial cells, the molecular mechanism remained obscure.Only recently, the canonical Wnt/beta-catenin pathway and the Wnt7a/7b growth factors have been implicated in brain angiogenesis on the one hand and in BBB induction on the other. This breakthrough in understanding the differentiation of the brain vasculature prompted us to review these findings embedded in the emerging concepts of Wnt signaling in the vasculature. In particular, interactions with other pathways that are crucial for vascular development such as VEGF, Notch, angiopoietins and Sonic hedgehog are discussed. Finally, we considered the potential role of the Wnt pathway in vascular brain pathologies in which BBB function is hampered, as for example in glioma, stroke and Alzheimer's disease.
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PMID:Differentiation of the brain vasculature: the answer came blowing by the Wnt. 2015 Sep 91

Presenilin-1 (PSEN1) is a primary component of the gamma-secretase complex, and total levels of its holoprotein and endoproteolytic fragments are tightly regulated. We examined the effects of several types of endoplasmic reticulum (ER) stress on quantitative changes in the levels of PSEN1 mRNA, holoprotein, and fragments. The ER stress-inducing chemical compounds tunicamycin, brefeldin-A, thapsigargin, and staurosporine were added to the culture media of various human cell lines. Tunicamycin treatment caused a doubling of PSEN1 holoprotein production in HEK293 cells and an increase in holoprotein production to approximately 180% in GOTO human neuroblastoma and KNS-42 human glioma cell lines, without changing the amounts of PSEN1 N- or C-terminal fragments. The elevated holoprotein level in HEK293 cells was accompanied by an increase in PSEN1 mRNA expression. HEK293 cells that stably overexpressed PSEN1 holoprotein showed increased resistance to ER stress induced by tunicamycin, but they did not show resistance to ER stress caused by thapsigargin, a specific inhibitor of sarco ER calcium-ATPase (SERCA). In wild-type HEK293 cells under ER stress induced by tunicamycin, an increased amount of SERCA interacted with PSEN1 holoprotein. PSEN1 production varied among cell types and circumstances. The results suggested that the holoprotein forms a complex with the SERCA channel and participates in the regulation of intracellular calcium homeostasis. These findings provide support for the calcium hypothesis of Alzheimer's disease.
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PMID:Presenilin-1 holoprotein is an interacting partner of sarco endoplasmic reticulum calcium-ATPase and confers resistance to endoplasmic reticulum stress. 2016 84


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