UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prevailing view is that the glutamine (Gln) transporter (GlnT/ATA1/SAT1/SNAT1) is a member of the system A transporter superfamily with the ability to fuel the glutamate/Gln cycle at nerve terminals in glutamatergic neurons. Semiquantitative reverse transcription-polymerase chain reaction revealed similarly high expression of mRNA for GlnT by rat brain neocortical astrocytes as well as neurons, with progressively lower expression by cerebellar astrocytes, hippocampal astrocytes, and whole-brain microglia in culture. [(3)H]Gln was accumulated in a temperature-dependent manner with a saturable profile in both cultured neocortical neurons and astrocytes, whereas biochemical and pharmacological analyses on [(3)H]Gln accumulation revealed the expression of both system A and system L transporters by cultured neocortical neurons and astrocytes. Exposure to lipopolysaccharide (LPS) for 24 hr resulted in a significant decrease in both GlnT mRNA expression and [(3)H]Gln accumulation, with a concomitant drastic increase in nitrite formation in cultured neocortical astrocytes. Moreover, LPS significantly inhibited the promoter activity of GlnT in the astrocytic cell line C6 glioma cells as well as primary rat neocortical astrocytes in culture. These results suggest that activation by LPS would lead to down-regulation of the expression of GlnT responsible for the incorporation of extracellular Gln into intracellular spaces across plasma membranes through the inhibition of its promoter activity in cultured rat neocortical astrocytes.
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PMID:Functional expression of A glutamine transporter responsive to down-regulation by lipopolysaccharide through reduced promoter activity in cultured rat neocortical astrocytes. 1658 2

The sensitivity of brain tumour cells to wild-type or recombinant parvoviruses H1-PV and MVMp makes these agents promising candidates for gene therapy of astrocytoma. This application raises the question of whether parvoviruses exert deleterious or bystander effects on normal glial cells surrounding tumours. We addressed this question in the mouse model by using cell cultures derived from BALB/c, C57BL/6 and VM/Dk strains. Astrocytes and a large proportion of microglia cultures were competent for MVMp uptake. Infection was, however, abortive as replication-associated viral proteins synthesis took place in less than 10% of astrocytes and no progeny virions were produced. This restriction was even more pronounced for microglia in which no viral protein expression could be detected, save for a minute fraction of VM/Dk-derived cells. Infection with MVMp had no significant effect on glial cell survival and did not interfere with their immune potential. Indeed, neither the lipopolysaccharide (LPS)/interferon (IFN-gamma)-induced cytotoxicity of VM/Dk-derived microglia towards the mouse glioma (MT539MG) cell line, nor the glial cells capacity for tumour necrosis factor alpha production upon LPS stimulation or LPS/IFN-gamma stimulation were affected by infection with MVMp. Moreover, stimulation with LPS and/or IFN-gamma resulted in a decreased expression of the viral replicative and cytotoxic protein NS1. Together, our data indicate that, in the natural host, a majority of normal glial cells are not competent for MVMp replication and that the abortive infection taking place in a minor fraction of these cells fails to impede their survival and immunocompetence, giving credit to the consideration of autonomous parvoviruses for glioma therapy.
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PMID:Oncolytic murine autonomous parvovirus, a candidate vector for glioma gene therapy, is innocuous to normal and immunocompetent mouse glial cells. 1669 1

In the present study we sought to examine cell-cell interactions by investigating the effects of factors released by stimulated microglia on inducible nitric oxide (NO) synthase (iNOS) induction in astrocytoma cells. After examining the temporal profiles of proinflammatory molecules induced by lipopolysaccharide (LPS) stimulation in BV2 microglial cells, iNOS and IL-1beta were observed to be the first immediate-response molecules. Removal of LPS after 3 hr stimulation abrogated NO release, whereas a full induction of IL-1beta was retained in BV2 cells. We observed consistently that conditioned medium (CM) from activated microglia resulted in the induction of iNOS in C6 cells, and IL-1beta was shown to be a key regulator of iNOS induction. An IL-1beta-neutralizing antibody diminished NO induction. Incubation with recombinant IL-1beta stimulated NO release to a lesser extent compared to microglial CM; co-treatment of LPS and IL-1beta had a potent, synergistic effect on NO release from C6 cells. Transient transfection with MEK kinase 1 (MEKK1) or nuclear factor-kappa B (NF-kappaB) expression plasmids induced iNOS, and IL-1beta further enhanced the MEKK1 response. Furthermore, IL-1beta-mediated NO release from C6 cells was significantly suppressed by inhibition of p38 mitogen activated protein kinase (MAPK) or NF-kappaB by specific chemical inhibitors. Both IL-1beta and MEKK1 stimulated p38 and JNK MAPKs, as well as the NF-kappaB pathway, to induce iNOS in C6 cells. Microglia may represent an anti-tumor response in the central nervous system, which is potentiated by the local secretion of immunomodulatory factors that in turn affects astrocytoma (glioma) cells. A better understanding of microglia-glioma or microglia-astrocyte interactions will help in the design of novel immune-based therapies for brain tumors or neuronal diseases.
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PMID:IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways. 1688 Oct 54

Nitric oxide (NO) plays a significant role in the pathophysiology of the central nervous system including inflammatory, ischemic and traumatic injuries. We demonstrated the possible involvement of protein kinase C (PKC) as well as protein kinase A (PKA) in the regulation of NO synthesis induced by lipopolysaccharide (LPS) treatment. In this study, the role of phorbol 12-myristate 13-acetate (PMA), cholera toxin (CTX), pertussis toxin (PTX), prostaglandin E(2) (PGE(2)) and norepinephrine (NE) in the regulation of NO synthesis was examined in C6 glioma cells. Stimulation with LPS (1 microg/ml) evoked increases in NO production in C6 glioma cells. LPS-induced NO production was enhanced by pretreatment with PMA, CTX and PGE(2). PTX pretreatment had no effect on NO production induced by LPS. In addition, NE inhibited NO production elicited by LPS treatment. These results suggest that NO production induced by LPS in C6 glioma cells is regulated by several kinds of pathways in which CTX-specific G protein, PKC, prostanoid EP(4) receptor and adrenergic receptor may play important roles.
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PMID:The effects of phorbol 12-myristate 13-acetate, cholera toxin, prostaglandin E2 and norepinephrine on inducible nitric oxide synthase activation induced by lipopolysaccharide in C6 cells. 1704 12

Effects of hydrogen peroxide on morphological characteristics, proliferation index, menadione-dependent lucigenin-enhanced chemiluminescence of C6 glioma cells were studied. It was established that H2O2 at 1 x 10(-8) - 5 x 10(-7) M concentrations acts as a regulator of morphological and functional properties of astrocytes by inducing their reactivation that is manifested as a cell body hypertrophy and an increase of proliferative activity and of menadione-dependent production of superoxide (O2- ). Cytodestructive action of hydrogen peroxide at a concentration higher than 1 microM on C6 glioma cells shows itself as a decrease of their proliferation index and the ability to generate O2- under menadione action. Using lipopolysaccharide B as a functional stimulator it has been shown that H2O2 modifies signaling pathways leading to the increase of mitotic activity of C6 glioma cells and decreases the yield of lucigenin-enhanced chemiluminescence of astrocytes under menadione action to the level of control values.
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PMID:[Regulation of morphologicaland functional properties of astroglial cells by hydrogen peroxide]. 1723 75

The alkylating agent temozolomide, commonly used in the treatment of malignant glioma, causes cellular cytotoxicity by forming O(6)-methylguanine adducts. In this report, we investigated whether temozolomide alters the activity of the transcription factor nuclear factor-kappaB (NF-kappaB). Temozolomide inhibits basal and tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB transcriptional activity without altering phosphorylation or degradation of inhibitor of kappaB-alpha. Inhibition of NF-kappaB is secondary to attenuation of p65 DNA binding, not nuclear translocation. Inhibition of DNA binding is shown both in vitro, with gel shift studies and DNA binding assays, and in vivo at kappaB sites. Consistent with inhibition of NF-kappaB activity, temozolomide reduces basal and TNFalpha-induced kappaB-dependent gene expression. Temozolomide also inhibits NF-kappaB activated by inducers other than TNFalpha, including lipopolysaccharide, doxorubicin, and phorbol 12-myristate 13-acetate. The inhibitory action of temozolomide on NF-kappaB is observed to be maximal following pretreatment of cells with temozolomide for 16 h and is also seen with the S(N)1-type methylating agent methylnitrosourea. The ability of temozolomide to form O(6)-methylguanine adducts is important for inhibition of NF-kappaB as is the presence of a functioning mismatch repair system. Activation of NF-kappaB with TNFalpha before administration of temozolomide reduces the cytotoxicity of temozolomide, whereas 16-h pretreatment with temozolomide resensitizes cells to killing. This work shows a mechanism whereby O(6)-methylguanine adducts formed by temozolomide lead to inhibition of NF-kappaB activity and illustrates a link between mismatch repair processing of alkylator-induced DNA damage and cell death.
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PMID:Inhibition of nuclear factor-kappaB activity by temozolomide involves O6-methylguanine induced inhibition of p65 DNA binding. 1763

The neurosteroid pregnenolone sulfate (PREGS), which is synthesized in glial cells, plays a significant role in learning and memory performance. The aim of this study was to investigate the regulation of expression of the steroid sulfotransferase SULT2B1a, which catalyzes the conversion of pregnenolone to PREGS, using the rat C6 glioma cell line. Rat C6 glioma cells expressed the SULT2B1a isoform, which sulfonates pregnenolone, but, neither the SULT2B1b isoform, which catalyzes cholesterol, nor the prototypical steroid sulfotransferase SULT2A1 were expressed in these cells. Increasing concentrations of l-glutamic acid in the presence of cyclothiazide, which prevents AMPA receptor desensitization, attenuated SULT2B1a mRNA expression; however, neither NMDA nor kainic acid had a significant effect. Exposure to the synthetic glutamate analogue alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the presence of cyclothiazide also inhibited SULT2B1a expression. Attenuation of SULT2B1a expression by L-glutamic acid was reversed by the selective AMPA/kainate receptor antagonist 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), and partially reversed by the specific neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI). Induction of inducible NOS by TNF-alpha in combination with lipopolysaccharide (LPS) dramatically attenuated SULT2B1a expression; this was partially reversed by the specific inducible NOS inhibitor N(6)-(1-iminoethyl)-L-lysine hydrochloride (L-NIL). Furthermore, exposure to exogenous NO donors inhibited SULT2B1a mRNA expression, and exposure to sodium nitroprusside, LPS/TNF-alpha and L-glutamic acid in combination with cyclothiazide increased the production of nitrite, a stable degradation product of NO. These findings suggest that expression of SULT2B1a, which catalyzes PREGS production, is inhibited by activation of excitatory amino acid receptors of the AMPA subtype, via facilitation of intracellular NO signaling.
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PMID:Regulation of SULT2B1a (pregnenolone sulfotransferase) expression in rat C6 glioma cells: relevance of AMPA receptor-mediated NO signaling. 1805 34

Melatonin (N-acetyl-5-methoxytryptamine), an indole hormone, is the chief secretory product of the pineal gland and is an efficient free radical scavenger and antioxidant, both in vitro and in vivo. The role of melatonin as an immunomodulator is, in some cases, contradictory. Although melatonin is reported to influence a variety of inflammatory and immune responses, evidence supporting its effects on important glioma cells-derived mediators is incomplete. We studied, in rat glioma cell line (C6), the role of melatonin (100 microm-1 mm) in the regulation of the expression of nitric oxide synthase (NOS) caused by incubation with lipopolysaccharide (LPS)/interferon (IFN)-gamma (1 microg/mL and 100 U/mL, respectively) and defined the mode of melatonin's action. Treatment with LPS/IFN-gamma for 24 hr elicited the induction of inducible (iNOS) activity as determined by nitrite and nitrate (NO(x)) accumulation in the culture medium. Preincubation with melatonin abrogated the mixed cytokines-mediated induction of iNOS. The effect of melatonin was concentration-dependent. Moreover, Western blot analysis showed that melatonin inhibited LPS/IFN-gamma-induced expression of COX-2 protein, but not that of constitutive cyclooxygenase. Inhibition of iNOS and COX-2 expression was associated with inhibition of activation of the transcription factor nuclear factor kappa B (NF-kappaB). The ability of melatonin to inhibit NF-kappaB activation was further confirmed by studies on the degradation of the inhibitor of NF-kappaB, IkappaB-alpha. Increased production of lipid peroxidation products using thiobarbituric acid assay were found in cellular contents from activated cultures. Lipid peroxidation was decreased by melatonin treatment in a concentration-dependent manner. Moreover, several genes having roles in heat-shock response were downregulated in melatonin-treated cells, such as 70 proteins, reflecting the reduced oxidative stress in these cells. The mechanisms underlying in vitro the neuroprotective properties of melatonin involve modulation of transcription factors and consequent altered gene expression, resulting in downregulation of inflammation.
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PMID:Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. 1807 52

The role of microglia, the brain resident macrophages, in glioma biology is still ill-defined. Despite their cytotoxic potential, these cells that significantly infiltrate the tumor mass seem to support tumor growth rather than tumor eradication. A proper activation of microglia anti-tumor activities within the tumor may provide a valuable additional arm of defense to immunotherapies against brain tumors. We herewith report a detailed characterization of (lipopolysaccharide and interferon-gamma)-induced anti-tumor activities of mouse primary microglia towards two TNF-alpha and TRAIL resistant glioma cell lines, in cell monolayer or spheroid cultures and in collagen-embedded tumor explants. Irrespective of the mouse strain, stimulated microglia secreted proteic factors that decreased proliferation and migration of these glioma cells and efficiently killed them. Death occurred specifically in glioma cells as demonstrated by the lack of toxicity of microglia supernatant towards primary cultures of astrocytes or neurons. Cell death was characterized by the early accumulation of acidic vesicles, phosphatidylserine exposure, appearance of double-membrane cytoplasmic vesicles, extensive zeiosis and a very late loss of DNA in cells that had lost membrane integrity. Inhibition of autophagosome formation efficiently protected glioma cells from death whereas caspase inhibition could only prevent DNA loss but not cytotoxicity. Death however, resulted from a blockade by microglia supernatant of the basal autophagic flux present in the glioma cells. These observations demonstrate that glioma cells resistant to apoptotic death ligands could be successfully and specifically killed through autophagy-dependent death induced by appropriately activated microglia.
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PMID:TNF-alpha- and TRAIL-resistant glioma cells undergo autophagy-dependent cell death induced by activated microglia. 1894 50

The glycosylated phenylpropanoid verbascoside (VB), isolated from cultured cells of the medicinal plant Syringa vulgaris (Oleaceae), has previously been characterized as an effective scavenger of biologically active free radicals and an inhibitor of lipid peroxidation. The aim of the present study was to evaluate in a rat glioma cell line (C6) the effect of VB biotechnologically produced by S. vulgaris plant cell cultures in the regulation of the inflammatory response. We used a model of central nervous system inflammation induced by bacterial endotoxin/cytokine (lipopolysaccharide (LPS)/interferon (IFN)-gamma, 1 microg/ml and 100 U/ml, respectively). Our results show that the treatment with LPS/IFN-gamma for 24 h elicited the induction of inducible nitric oxide synthase (iNOS) activity as determined by NO(x) accumulation in the culture medium. Preincubation with VB (10-100 microg/ml) abrogated the mixed cytokine-mediated induction of iNOS. The effect was concentration-dependent. Our studies also showed an inhibitory effect of VB on neuronal nitric oxide synthase expression. Moreover, Western blot analysis showed that this glycoside prevents specifically the activation of the proinflammatory enzyme cyclooxygenase (COX)-2 in glioma cells without simultaneous inhibition of COX-1 enzyme. Moreover, we found that VB reduced the expression of proinflammatory enzymes in LPS/IFN-gamma through the inhibition of the activation of nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. The mechanisms underlying in vitro the neuroprotective properties of VB involve modulation of transcription factors and consequent altered gene expression, resulting in downregulation of inflammation. These findings provide support that VB may provide a promising approach for the treatment of oxidative-stress-related neurodegenerative diseases.
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PMID:Protective effect of verbascoside in activated C6 glioma cells: possible molecular mechanisms. 1990 26

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