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

Glial cell line-derived neurotrophic factor (GDNF) was reported to be effective for treating subjects with neurodegenerative diseases such as Parkinson's disease. In search of finding a compound which promotes GDNF secretion, we found that concanamycin A (ConA), a vacuolar ATPase (V-type ATPase) inhibitor purified from Streptomyces diastatochromogens, enhanced GDNF secretion from glioma cells. The rat glioma cell line, C6, and the human glioma cell lines, U87MG and T98G, abundantly expressed GDNF mRNA, and secreted GDNF into culture media, and this event was potently enhanced by a Ca(2+) ionophore and by phorbol ester, as noted in other cells. ConA concentration dependently and potently increased GDNF release from C6, U87MG and T98G cells into culture media. In addition, ConA enhanced GDNF secretion from astrocyte primary cultures prepared from the human fetus with the same potency seen in glioma cell lines. Likewise, another V-type ATPase inhibitor, bafilomycinA1 facilitated GDNF release from C6, U87MG and T98G glioma cells, in a concentration-dependent manner. The potencies of these V-type ATPase inhibitors in enhancing GDNF secretion were consistent with those which inhibited V-type ATPase activity. These results suggest that blockade of V-type ATPase potently stimulates the secretion of GDNF from glial cells. The V-type ATPase inhibitors may be beneficial to use for the treatment of diseases in which increase in GDNF could be effective.
 ...
PMID:Increase in secretion of glial cell line-derived neurotrophic factor from glial cell lines by inhibitors of vacuolar ATPase. 1254 48

The extrusion of protons is considered a very general parameter of the activation of many kinds of membrane or intracellular molecules, such as receptors, ion channels, and enzymes. We found that pepstatin A caused a reproducible, concentration-related increase in the extracellular acidification rate in two microglial cell lines, Ra2 and 6-3. Washing abolished pepstatin A-induced acidification immediately. However, pepstatin A did not cause the extracellular acidification in other cell types, such as CHO, C6 glioma, and NIH3T3 cells. These observations strongly suggest that pepstatin A interacts with certain membrane proteins specific to both Ra2 and 6-3 cells from outside. N-methylmaleimide and N,N'-dicyclohexylcarbodiimide, inhibitors of H(+)-ATPase, were found to reduce pepstatin A-induced response strongly, while bafilomycin A1, a vacuolar H(+)-ATPase inhibitor, vanadate, a P-type H(+)-ATPase inhibitor, and NaN3, an F1 ATPase inhibitor, virtually did not. 5-(N-ethyl-N-isopropyl) amiloride, an inhibitor of Na(+)/H(+) exchanger isoform 1, greatly enhanced pepstatin-induced response, while amiloride did not. Zn(2+), a voltage-dependent proton channel blocker, did not affect pepstatin-induced response neither. Staurosporine, a nonspecific inhibitor of protein kinase C, inhibited pepstatin A-induced response, while chelerythrine, more selective inhibitor of protein kinase C, greatly enhanced it. H-7 and H-8 did not affected the response. These findings suggest that pepstatin A induces extracellular acidification in microglia cell lines, Ra2 and 6-3, through an N-methylmaleimide- and N,N'-dicyclohexylcarbodiimide-sensitive, but bafilomycin A1-insensitive, ATPase, which seems to be distinct from protein kinase C-dependent process.
 ...
PMID:Pepstatin A induces extracellular acidification distinct from aspartic protease inhibition in microglial cell lines. 1283 8

The beta2 subunit of Na,K-ATPase, initially described as adhesion molecule on glia (AMOG), has been shown to mediate neurone-astrocyte adhesion as well as neural cell migration in vitro. We have investigated the expression of AMOG/beta2 in human gliomas and its effect on glioma cell adhesion and migration. Compared to normal astrocytes of human brain, AMOG/beta2 expression levels of neoplastic astrocytes were down-regulated in biopsy specimens and inversely related to the grade of malignancy. One rat and four human glioma cell lines showed complete loss of AMOG. To investigate the function of AMOG/beta2, its expression was re-established by transfecting an expression plasmid into AMOG/beta2-negative C6 rat glioma cells. In vitro assays revealed increased adhesion and decreased migration on matrigel of AMOG/beta2-positive cells as compared to their AMOG/beta2-negative counterparts. We conclude that increasing loss of AMOG/beta2 during malignant progression parallels and may underlie the extensive invasion pattern of malignant gliomas.
 ...
PMID:AMOG/beta2 and glioma invasion: does loss of AMOG make tumour cells run amok? 1288 97

The membrane composition and the isoprenoid pathway metabolites important in maintaining cell membrane integrity was studied in neurological and psychiatric disorders. The results indicate alteration in cholesterol:phospholipid ratio of the RBC membrane which is increased in glioma, schizophrenia, and bipolar mood disorder (MDP); decreased in multiple sclerosis and Parkinson's disease; and not significantly altered in epilepsy. The concentration of total glycosaminoglycans (GAG), hexose, and fucose decreased in the RBC membrane and increased in the serum. The RBC membrane Na+-K+ ATPase activity was reduced and serum HMG CoA reductase activity was increased. There were increased serum levels of digoxin, cholesterol, and dolichol and decreased levels of ubiquinone. The serum magnesium and tyrosine levels were reduced and tryptophan increased. The results indicate a defect in membrane formation and a decreased membrane Na+-K+ ATPase activity in all the disorders studied. The results are discussed, and a hypothesis regarding the relationship between these disorders and defective membrane architecture and membrane Na+-K+ ATPase inhibition is presented.
 ...
PMID:Isoprenoid pathway-related membrane dysfunction in neuropsychiatric disorders. 1458 55

Psychiatric abnormalities have been described in primary neurological disorders like multiple sclerosis, primary generalized epilepsy, Parkinson's disease, subacute sclerosing panencephalitis (SSPE), central nervous system glioma, and syndrome X with vascular dementia. It was therefore considered pertinent to compare monoamine neurotransmitter pattern in schizophrenia with those in the disorders described above. The end result of neurotransmission is changes in membrane Na(+)-K+ ATPase activity. Membrane Na(+)-K+ ATPase inhibition can lead to magnesium depletion, which can lead to an upregulated isoprenoid pathway. The isoprenoid pathway produces three important metabolites--digoxin, an endogenous membrane Na(+) -K+ ATPase inhibitor; ubiquinone, a membrane antioxidant and component of mitochondrial electron transport chain; and dolichol, important in N-glycosylation of protein. The serum/plasma levels of digoxin, dolichol, ubiquinone, magnesium, HMG CoA reductase activity, and RBC Na(+)-K+ ATPase activity were estimated in all these disorders. The result showed that the concentration of serum tryptophan and serotonin was high and serum tyrosine, dopamine, adrenaline, and noradrenaline low in all the disorders studied. The plasma HMG CoA reductase activity, serum digoxin, and serum dolichol levels were high and serum ubiquinone levels, serum magnesium, and RBC Na(+)-K+ ATPase activity were low in all the disorders studied. The significance of these changes in the pathogenesis of syndrome X, multiple sclerosis, primary generalized epilepsy, schizophrenia, SSPE, and Parkinson's disease is discussed in the setting of the interrelationship between these disorders documented in literature.
 ...
PMID:Schizoid neurochemical pathology-induced membrane Na(+)-K+ ATPase inhibition in relation to neurological disorders. 1460 43

Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 microM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein light-chain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H(+)-ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.
 ...
PMID:Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. 1471 59

Astrocytosis is a sequential morphological change of astrocytic reaction to tissue damage, and is associated with regulation of antioxidant defense mechanisms to reduce oxidative damage. The repair enzymes to oxidative DNA damage, oxidized purine-nucleoside triphosphatase (hMTH1) and a mitochondrial type of 8-oxoguanine DNA glycosylase (hOGG1-2a) in brain tumors and neurons of Alzheimer's disease, were previously reported. In the present study, glial expression of these repair enzymes under such pathological conditions as cerebrovascular diseases and metastatic brain tumors, were investigated. Furthermore, an in-vitro experiment using a glioma cell-line under oxidative stress was performed to verify the immunohistochemical results of post-mortem materials. As a result, hOGG1-2a immunoreactivities in reactive astrocytes were more intense than those to hMTH1. Oligodendrocytes of acute or subacute stage of brain infarction were strongly immunoreactive to both repair enzymes. In-vitro study revealed that, hOGG1-2a is constitutively expressed in both untreated glioma cells and the glioma cells under oxidative stress. However, although no immunoreactivity to hMTH1 was found in the control cells, accumulation of hMTH1 was rapidly induced by oxidative stress. These results indicate that the two repair enzymes to oxidative DNA damage are differentially regulated in glial cells, and that there is a difference in the expression of the repair enzymes between reactive astrocytes and oligodendrocytes.
 ...
PMID:Defense mechanism to oxidative DNA damage in glial cells. 1513 89

In kidney, the Na,K-ATPase is associated with a single span protein, the gamma subunit (FXYD2). Two splice variants are differentially expressed along the nephron and have a differential influence on Na,K-ATPase when stably expressed in mammalian cells in culture. Here we used a combination of gene induction and gene silencing techniques to test the functional impact of gamma by means other than transfection. NRK-52E cells (of proximal tubule origin) do not express gamma as a protein under regular tissue culture conditions. However, when they were exposed to hyperosmotic medium, induction of only the gammaa splice variant was observed, which was accompanied by a reduction in the rate of cell division. Kinetic analysis of stable enzyme properties from control (alpha1beta1) and hypertonicity-treated cultures (alpha1beta1gammaa) revealed a significant reduction (up to 60%) of Na,K-ATPase activity measured under V(max) conditions with little or no change in the amounts of alpha1beta1. This effect as well as the reduction in cell growth rate was practically abolished when gamma expression was knocked down using specific small interfering RNA duplexes. Surprisingly, a similar induction of endogenous gammaa because of hypertonicity was seen in rat cell lines of other than renal origin: C6 (glioma), PC12 (pheochromocytoma), and L6 (myoblasts). Furthermore, exposure of NRK-52E cells to other stress inducers such as heat shock, exogenous oxidation, and chemical stress also resulted in a selective induction of gammaa. Taken together, the data imply that induction of gammaa may have adaptive value by being a part of a general cellular response to genotoxic stress.
 ...
PMID:Stress-induced expression of the gamma subunit (FXYD2) modulates Na,K-ATPase activity and cell growth. 1528 Mar 68

3-Hydroxyglutaric acid (3HGA) accumulates in the inherited neurometabolic disorder known as glutaryl-CoA dehydrogenase deficiency. The disease is clinically characterized by severe neurological symptoms, frontotemporal atrophy and striatum degeneration. Because of the pathophysiology of the brain damage in glutaryl-CoA dehydrogenase deficiency is not completed clear, we investigated the in vitro effect of 3HGA (0.01-5.0mM) on critical enzyme activities of energy metabolism, including the respiratory chain complexes I-V, creatine kinase isoforms and Na(+),K(+)-ATPase in cerebral cortex and striatum from 30-day-old rats. Complex II activity was also studied in rat C6-glioma cells exposed to 3HGA. The effect of 3HGA was further investigated on the rate of oxygen consumption in mitochondria from rat cerebrum. We observed that 1.0mM 3HGA significantly inhibited complex II in cerebral cortex and C6 cells but not the other activities of the respiratory chain complexes. Creatine kinase isoforms and Na(+),K(+)-ATPase were also not affected by the acid. Furthermore, no inhibition of complex II activity occurred when mitochondrial preparations from cerebral cortex or striatum homogenates were used. In addition, 3HGA significantly lowered the respiratory control ratio in the presence of glutamate/malate and succinate under stressful conditions or when mitochondria were permeabilized with digitonin. Since 3HGA stimulated oxygen consumption in state IV and compromised ATP formation, it can be presumed that this organic acid might act as an endogenous uncoupler of mitochondria respiration. Finally, we observed that 3HGA changed C6 cell morphology from a round flat to a spindle-differentiated shape, but did not alter cell viability neither induced apoptosis. The data provide evidence that 3HGA provokes a moderate impairment of brain energy metabolism and do not support the view that 3HGA-induced energy failure would solely explain the characteristic brain degeneration observed in glutaryl-CoA dehydrogenase deficiency patients.
 ...
PMID:3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. 1611 21

The role of actin cytoskeleton functional state in glioma C6 cell morphology and calcium signaling was investigated through modification of myosin II activity by blocking Rho-associated kinase with the specific inhibitor Y-27632. Treatment of glioma C6 cells with ROCK inhibitor resulted in actin cytoskeleton reorganization and also in the changed shape and distribution of mitochondria. Changes in the distribution of ER, the main calcium store in glioma C6 cells, were not visible. The inhibition of myosin II activity influences the first phase of calcium signaling evoked by agonist, and both phases of thapsigargin-evoked calcium response. We suggest that the observed increase in Ca2+ release from intracellular stores induced by IP3 formation as well as inhibition of SERCA ATPase is at least in part related to severely affected mitochondria. Enhancement of capacitative calcium entry evoked by thapsigargin is probably associated with the reorganization of the acto-myosin II system. ATP-induced calcium response presents no changes in the second phase. We observed that ATP stimulation of Y-27632 pretreated cells leads to immediate morphological rearrangement of glioma C6 cells. It is a consequence of actin cytoskeleton reorganization: formation of stress fibers and relocation of phosphorylated myosin II to actin filaments. It seems that the agonist-evoked strong calcium signal may be sufficient for myosin II activation and the stress fiber organization. This is the first work showing the dependence between the functional state of the acto-myosin II system and calcium signaling stressing the reversible character of this relationship.
 ...
PMID:Effect of Rho-associated kinase inhibition on actin cytoskeleton structure and calcium response in glioma C6 cells. 1711 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>