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)

Binding of idazoxan (IDA) to imidazoline receptors of the I2 subtype in astrocytes influences astroglial gene expression as evidenced by increased expression of glial fibrillary acidic protein and mRNA. To determine whether IDA affected glial inflammatory gene expression, we tested the effects of IDA on astroglial nitric oxide synthase type-2 (NOS-2) expression. NOS-2 was induced in primary rat astrocytes and C6 glioma cells by incubation with 1 microgram/ml lipopolysaccharide (LPS) plus three cytokines (tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma) or three cytokines alone. Cells were incubated with 1-100 microM IDA, and at 24 h NOS-2 expression assessed. In astrocytes and C6 cells, preincubation with IDA dose-dependently inhibited nitrite accumulation (IC50 approximately 25 microM), accompanied by a reduction in NOS-2 protein levels and L-citrulline synthesis activity in cell lysates. IDA also inhibited nitrite production in LPS stimulated RAW 264.7 macrophages. In astrocytes, but not C6 cells, longer preincubation times with IDA yielded significantly greater suppression, and maximal suppression (>90%) was achieved after a 8 h preincubation in 100 microM IDA. The degree of inhibition was diminished whether IDA was added after LPS plus cytokine mixture. In contrast to NE, continuous incubation with IDA was required to achieve suppression. IDA reduced induction of NOS-2 protein levels, steady state NOS-2 mRNA levels, and activity of a NOS-2 promoter construct stably transfected in C6 cells. These results show that IDA inhibits NOS-2 activity and protein expression in glial cells and macrophages, and suggest that this occurs by decreasing transcription from the NOS-2 promoter.
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PMID:Inhibition of astroglial nitric oxide synthase type 2 expression by idazoxan. 992 22

Progress in the definition of the roles of various costimulators and cytokines in determining the type and height of immune responses has made it important to explore genetically altered tumor cells expressing such molecules for therapeutic immunizations. We have studied the effect of therapeutic subcutaneous (s.c.) immunizations on the growth of preexisting intracerebral brain tumor isografts in the rat. Transfectant glioma cell clones expressing either rat interferon-gamma (IFN-gamma), rat interleukin-7 (IL-7), or rat B7-1 were selected. After irradiation (80 Gy) the clones were used for immunization (administered in up to four s.c. doses in a hind leg over 14-day intervals starting 1 day after the intracranial isografting of the parental tumor). Significant growth inhibition of the intracerebral parental tumors was induced by transfectants expressing IFN-gamma and IL-7, respectively. The strongest effect was observed with IFN-gamma-expressing cells, resulting in cures in 37% of the males and in 100% of the females. Immunization with IL-7 had a similar, strong initial effect, with significantly prolonged survival in the majority of the rats but a lower final cure rate (survival for >150 days). The B7-1-expressing tumor clones induced cures in seven of eight female rats; however, no cures were seen in the male rats. It was also shown that the B7-1-expressing cells were themselves strongly immunogenic in female rats, requiring high cell numbers to result in a progressively growing tumor upon s.c. isografting; this was not the case in male rats. As a whole, the results imply that despite the unfavorable location of intracerebral tumors, therapeutic s.c. immunizations with certain types of genetically altered tumor cells can induce complete regressions with permanent survival and without gross neurological or other apparent signs of brain damage. The present results demonstrate complete regressions when immunizations are initiated shortly after intracranial isografting, when the intracerebral tumor is small.
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PMID:Regression of intracerebral rat glioma isografts by therapeutic subcutaneous immunization with interferon-gamma, interleukin-7, or B7-1-transfected tumor cells. 1007 62

We investigated the feasibility of local treatment or tumor vaccination with a herpes simplex virus (HSV) type 1-defective vector. The vector was engineered to express murine interferon-gamma (IFN-gamma) for experimental gene therapy against mouse glioma Rous sarcoma virus (RSV). The murine IFN-gamma gene was driven by the cytomegalovirus promoter. The helper virus (tsk) was thermosensitive; consequently, this vector could only proliferate at 31 degrees C. A high level of murine IFN-gamma expression was confirmed in vitro and in vivo by immunohistochemistry using anti-mouse IFN-gamma monoclonal antibody. This engineered vector (dvHSV/MulFN-gamma) inhibited the proliferation of mouse glioma RSV cells in vitro, and an intratumoral (i.t.) local injection of the vector caused i.t. necrosis in vivo. The immunological effect of dvHSV/MulFN-gamma was also examined in a mouse glioma RSV cell implantation model. A subcutaneous (s.c.) implant of 1 x 10(6) mouse glioma RSV cells after treatment with dvHSV/MulFN-gamma was rejected. However, the implant after treatment with an engineered HSV-defective vector containing an antisense nucleotide sequence of the murine IFN-gamma gene was not rejected. In addition, in another group of mice in which RSV cells treated with dvHSV/MulFN-gamma were implanted into a femoral (s.c.) region and nontreated RSV cells were implanted into a contralateral femoral (s.c.) region, the implanted RSV cells were rejected. The rejection of the implanted mouse glioma RSV was blocked by anti-asialo GM1, which was known to inhibit natural killer cell activity. These results revealed that the HSV-defective vector could realize a high efficiency of transfection to glioma cells through short-time treatment, and that the IFN-gamma gene transferred to the cells had the effect of tumor vaccination, which was suggested be related to natural killer cells. In conclusion, dvHSV/MulFN-gamma may be useful for the gene therapy of malignant glioma through either i.t. local injection or a practical tumor vaccination with ex vivo gene transfer.
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PMID:Experimental gene therapy against subcutaneously implanted glioma with a herpes simplex virus-defective vector expressing interferon-gamma. 1019 81

Calpain, a Ca2+-activated cysteine protease, has been implicated in apoptosis of immune cells. Since central nervous system (CNS) is abundant in calpain, the possible involvement of calpain in apoptosis of CNS cells needs to be investigated. We studied calpain expression in rat C6 glioma cells exposed to reactive hydroxyl radical (.OH) [formed via the Fenton reaction (Fe2++H2O2+H+-->Fe3++H2O+.OH)], interferon-gamma (IFN-gamma), and calcium ionophore (A23187). Cell death, cell cycle, calpain expression, and calpain activity were examined. Diverse stimuli induced apoptosis in C6 cells morphologically (chromatin condensation as detected by light microscopy) and biochemically [DNA fragmentation as detected by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay]. Oxidative stress arrested a population of C6 cells at the G2/M phase of cell cycle. The levels of mRNA expression of six genes were analyzed by the reverse transcriptase-polymerase chain reaction (RT-PCR). Diverse stimuli did not alter beta-actin (internal control) expression, but increased calpain expression, and the upregulated bax (pro-apoptotic)/bcl-2 (anti-apoptotic) ratio. There was no significant increase in expression of calpastatin (endogenous calpain inhibitor). Western blot analysis showed an increase in calpain content and degradation of myelin-associated glycoprotein (MAG), a calpain substrate. Pretreatment of C6 cells with calpeptin (a cell-permeable calpain inhibitor) blocked calpain overexpression, MAG degradation, and DNA fragmentation. We conclude that calpain overexpression due to.OH stress, IFN-gamma stimulation, or Ca2+ influx is involved in C6 cell death, which is attenuated by a calpain-specific inhibitor.
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PMID:Diverse stimuli induce calpain overexpression and apoptosis in C6 glioma cells. 1035 May 26

1 The effects of nepalolide A on the expression of inducible nitric oxide synthase (iNOS) caused by incubation with lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) or tumour necrosis factor-alpha/interleukin-1beta/IFN-gamma (TNF-alpha/IL-1beta/IFN-gamma, mixed cytokines) in C6 glioma cells and primary astrocytes of rat were investigated. The mechanisms by which nepalolide A confers its effect on iNOS expression were also elucidated. 2 Treatment with LPS/IFN-gamma and mixed cytokines for 24 h elicited the induction of iNOS activity as determined by nitrite accumulation in the culture medium and assay of enzyme activity. Nepalolide A at 10 microM abrogated the LPS/IFN-gamma- and mixed cytokines-mediated induction of iNOS by more than 90% in C6 glioma cells, and by 80% for mixed cytokines-induced induction of iNOS in primary astrocytes. The effect of nepalolide A (2-10 microM) was concentration-dependent. 3 The inhibition of iNOS induction by nepalolide A was attributed to decreases in the content of iNOS protein and the level of iNOS mRNA, as measured by immunoblotting and reverse transcriptase-polymerase chain reaction. 4 Electrophoretic mobility shift assay was used to evaluate the effect of nepalolide A on the activation of nuclear factor-kappaB (NF-kappaB). Results showed that nepalolide A diminished the LPS/IFN-gamma-mediated association of NF-kappaB with consensus oligonucleotide in a concentration-dependent manner. The activation of NF-kappaB by mixed cytokines was modulated both in the extent of activation and in its time-course by nepalolide A. 5 The ability of nepalolide A to inhibit NF-kappaB activation was further confirmed by studies on the degradation of the inhibitor of NF-kappaB, IkappaB, as measured by immunoblotting. 6 The present study demonstrates that the attenuation of NF-kappaB activation by nepalolide A was mediated by blockade of the degradation of IkappaB, leading to suppression of the expression of iNOS.
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PMID:Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IkappaB-alpha and IkappaB-beta in C6 glioma cells and rat primary astrocytes. 1051 Apr 44

We have examined the neuroimmunoregulatory function of prolactin (PRL) on astrocytic inducible nitric oxide synthase (iNOS) expression in the C6 glioma cell line. After 24 h of PRL (5-100 nM) stimulation, a concentration-dependent increase of NO release, evaluated as nitrite, was observed in C6 culture medium. Moreover, both NO release and iNOS expression induced by interferon-gamma (250 U/ml) were enhanced by PRL (18-100 nM). PRL-induced NO release was inhibited by dexamethasone, an inhibitor of de novo iNOS synthesis. We used erbstatin (5 microg/ml), a potent inhibitor of protein tyrosine kinases, to test whether these proteins were required for signaling events evoked by PRL in these cells. This inhibitor was able to inhibit completely the PRL-induced NO production and iNOS expression. In conclusion, we provide evidence that NO production in glial cells can be regulated not only by cytokines but also by neuroimmunoregulatory hormones such as PRL, which is present in normal brain but may be elevated in several pathological states.
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PMID:Prolactin induction of nitric oxide synthase in rat C6 glioma cells. 1058 84

P11 cells, derived from the transplantahle rat pituitary tumor 7315a, have been used previously ias a model system to study the regulation of serotonin2A (5-HT2A) receptor expression. As our laboratory has been interested in characterizing the interactions between the 5-HT2A receptor and inducible nitric oxide synthase (iNOS), we have analyzed the Pl I cell line for iNOS expression. Treatment of P ll cells with interferon-gamma and lipopolysaccharide resulted in a 23-fold increase in nitrite production and induced expression of iNOS protein. The increase in nitrite levels was attenuated by the non-selective nitric oxide synthase (NOS) inhibitor N i-nitro-L-arginine methyl ester, hut not the neuronal NOS inhibitor 7-nitroindazole. Typically, Pl 11 cells have been grown in either charcoal-stripped or dialyzed serum-containing medium. We have observed that Pl 1 cells grown under these culture conditions express basal iNOS activity, as evidenced by a 5-fold increase in nitrite accumulation over a 48-hr period, compared with that in cells grown in non-modified serum, which was inhibited by the selective iNOS inhibitor L.N6-(1-iminoethyl)-lysine. Conditioned medium from Pll cells was ahle to stimulate nitrite accumulation in C6 glioma cells, suggesting that the Pl I cells may produce a pro-inflammatory-like factor. As pro-inflammatory cytokines have been shown to modify hormone secretion from the anterior pituitary, the P11 cell line may be a useful in vitro model by which to characterize the function of cells from this organ. In addition, our data suggest that alteration of the microenvironment of the anterior pituitary may result in iNOS expression, possibly altering the function of the hypothalamic-pituitary-adrenal axis.
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PMID:Inducible nitric oxide synthase in P11 cells: expression in the presence of interferon-gamma, lipopolysaccharide, and modified serum. 1066 Jan 17

Activation of microglia by interferon-gamma (IFN-gamma) has been implicated in a number of central nervous system (CNS) inflammatory disease processes. Because IFN-gamma has also been shown to play a role in programmed cell death, we investigated its cytotoxicity and its effect on the Fas apoptotic pathway in microglia. Flow cytometry was used to quantify the IFN-gamma-mediated apoptotic response and Fas and Fas ligand (FasL) expression in two well-characterized murine microglia cell lines (BV-2 and N9). Nuclear fragmentation, suggestive of apoptosis, was noted within 24 h of incubation of microglia with IFN-gamma (10 U/ml). After a 72-h incubation, almost every BV-2 and N9 microglia, but not GL261 glioma cells, underwent cell death and detached from the culture plates. This cytotoxicity occurred even at low IFN-gamma concentrations (1 U/ml) and was inhibited by BAF, a pan-caspase inhibitor. Incubation of BV-2 and N9 microglia, but not GL261 glioma cells, with IFN-gamma also potentiated the expression of Fas and FasL in a similar dose-response and time-course manner, as seen for the apoptotic response. Whereas Fas expression increased by 100% in both microglia cells, FasL upregulation was more pronounced and increased by as much as 200% in the N9 cells. These findings suggest that in addition to its role as a microglia activator, IFN-gamma may also induce apoptosis of microglia, possibly through simultaneous upregulation of Fas and FasL. Interferon-gamma modulation of the Fas pathway and apoptosis in microglia may be important in the pathogenesis of inflammatory CNS disease processes.
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PMID:Interferon-gamma induces apoptosis and augments the expression of Fas and Fas ligand by microglia in vitro. 1073 35

Interleukin-18 (IL-18) exhibits antitumor activity in various laboratory models. In the current study, brain tumors in naive mice regressed after an intratumoral injection of a single dose of recombinant IL-18 (rIL-18). Intraperitoneal rIL-18 substantially delayed the growth of subcutaneously inoculated gliomas but not gliomas located in the brain. Efficacy was reduced when studies were performed in mice depleted of natural killer cells. Although intracerebral administration of rIL-18 increased the serum interferon-gamma concentration, the antitumor effect of IL-18 was not mediated by interferon-gamma. These data suggest the therapeutic potential for control of tumor growth by intratumoral administration of rIL-18 in patients with glioma.
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PMID:Antitumor activity of interleukin-18 on mouse glioma cells. 1074 44

The production of superoxide and nitric oxide induced in U87 glioma treated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was examined by electron spin resonance (ESR) spectroscopy using a newly designed flow-type quartz cuvette without detaching cells from the culture plate. ESR spectra of 2,2,6, 6-tetramethyl-4-hydroxy-1-piperidinyloxy (TEMPOL) with U87 cells on a quartz culture plate were measured at 15 min intervals. The signal intensity of TEMPOL decreased in the presence of U87 cells at the pseudo-first order rate. The signal decay was accelerated in the U87 cells treated with LPS/IFN-gamma for 24 h, and was suppressed in the presence of superoxide dismutase and catalase. By the spin-trapping method, nitric oxide from U87 cells pretreated with LPS/IFN-gamma for 24 h was measured by the ESR, but only a weak signal of nitric oxide adducts was detected. Further, the nitrite and nitrate levels in the medium did not increase for 24 h. By the ESR measurement of cells on culture plates without detachment stress, it was found that the production of superoxide was induced by LPS/IFN-gamma, but that of nitric oxide was not, in U87 glioma cells.
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PMID:Induction of superoxide in glioma cell line U87 stimulated with lipopolysaccharide and interferon-gamma: ESR using a new flow-type quartz cell. 1076 20


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