Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For the past several years immunologists have been fascinated by a series of experiments showing that transforming growth factor beta (TGF beta) suppresses T- and B-lymphocyte growth as well as IgM and IgG production by B cells. Moreover, while exerting chemotactic activity on monocytes and inducing expression of interleukin-1 and interleukin-6 by these cells, TGF beta interferes with bacterially induced tumor necrosis factor alpha production, oxygen radical formation and the adhesiveness of granulocytes to endothelial cells. These mechanisms may provide the basis for the effect of TGF beta to prevent the microvascular changes associated with brain edema formation in bacterial meningitis. Given the potential of lymphocytes as well as macrophages to produce TGF beta 1, this cytokine may exert negative feedback signals on the immune response, provided the cytokine is processed from its latent form to the bioactive homodimer. Potent effects of TGF beta have been observed in experimental animals including the inhibition of the generation of virus-specific cytotoxic T cells and antiviral antibodies as well as the diminution of cellular infiltrates with decreased major histocompatibility complex class-II expression and CD8+ T cells in the tissue of virally infected animals. TGF beta may also be of importance in tumor immunology. By the production of bioactive TGF beta as detected in glioblastoma and acute T-cell leukemia, tumor cells may induce an immunodeficiency state and escape immune surveillance. In inflammation, monitoring of TGF beta in the tissue will bring light on the immune regulation in acute and chronic inflammatory diseases.
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PMID:Modulation of the immune response by transforming growth factor beta. 148 57

Using laser image cytometry and Indo-1 fluorescence, we investigated the intracellular free Ca2+ concentration ([Ca2+]i) of confluent A172 human glioblastoma cells stimulated by the BB homodimer of platelet-derived growth factor (PDGF-BB). The shape of the calcium transients and the delay time between stimulation and the beginning of the transient varied considerably. The percentage of responsive cells, the peak [Ca2+]i and the duration of the response were directly related to PDGF-BB dose, while the delay time was inversely related; the maximal response occurred at a PDGF-BB concentration of 20 ng/ml. Studies with EGTA and inorganic calcium-channel blockers (Ni2+, La3+) showed that the increase of [Ca2+]i resulted from initial release of intracellular stores and subsequent calcium influx across the plasma membrane. Opening of calcium channels in the plasma membrane, monitored directly by studying Mn2+ quenching of Indo-1 fluorescence, was stimulated by PDGF-BB and blocked by La3+; the opening occurred 55 +/- 10 s after the initial increase in [Ca2+]i. Therefore, in these tumor cells, intracellular release always occurs before channel opening in the plasma membrane. Depolarization of cells with high extracellular [K+] did not generally induce calcium transients but did decrease calcium influx. L-type calcium-channel blockers (verapamil, nifedipine, and diltiazem) had little or no effect on the calcium influx induced by PDGF-BB. These results indicate that PDGF-BB induces calcium influx by a mechanism independent of voltage-sensitive calcium channels in A172 human glioblastoma cells.
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PMID:Calcium channels in PDGF-stimulated A172 cells open after intracellular calcium release and are not voltage-dependent. 165 94

Recent studies using a rat model of pneumococcal meningitis have shown that nitric oxide synthase (NOS) inhibitors greatly attenuated microvascular changes and brain edema formation. The site of NO production during bacterial meningitis is unknown. In this study we tested whether primary astrocyte cultures from neonatal rat cortex can be induced to release NO upon stimulation with pneumococci. NO production was assessed by measuring nitrite in the cell culture supernatant using the Griess reaction. Stimulation with heat-killed unencapsulated pneumococci (HKP) increased nitrite concentrations in astrocyte culture supernatants in a dose-dependent fashion. Administration of N-nitro-L-arginine (L-NA), aminoguanidine, L-canavanine, cycloheximide, and dexamethasone prevented the increase in nitrite concentrations. Addition of L-arginine, but not of D-arginine, partially reversed the inhibitory effect of L-NA. Administration of SOD increased nitrite accumulation. Moreover, at 72 h after stimulation with heat-killed pneumococci (10(7) cfu/ml) astrocytes showed an inducible NOS-like immunoreactivity. Accumulation of nitrite was also observed when rat cerebellar neurons and microglia were stimulated with HKP, whereas there was only a slight increase of nitrite in media of rat C6 glioma cells, but no increase of nitrite when the human glioblastoma cell line LN-229 was stimulated with HKP. There was a stronger increase in nitrite levels when astrocytes from Lewis rats were used compared to that from Wistar rats. In conclusion, our study indicates that astrocytes, neurons and microglia are inducible for NO production upon stimulation with pneumococci.
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PMID:Production of nitrite by primary rat astrocytes in response to pneumococci. 764 48

Responses and susceptibility of 14 human glioblastoma cell lines to human natural tumor necrosis factor-alpha (TNF) were studied in vitro. Susceptibility of glioblastoma cells to TNF varied in experimental conditions applied. Most of glioblastoma cell lines were resistant to cytotoxic activity of TNF in a MTT assay at concentrations below 16 U/ml for 72 h exposure. However, TNF at higher dose, in prolonged exposure and against low density of target cells was antiproliferative for certain glioblastoma cultures. TNF exposure at 10 U/ml for 48 h suppressed DNA synthesis in 9 of 14 glioblastoma cultures, but increased in 3 cultures. In addition, colony forming assay showed anti-clonogenic activity of TNF in 5 of 6 glioblastoma cell lines tested. In spite of their low susceptibility to TNF, glioblastoma cells well responded to TNF stimulation at low dose (10 U/ml) for a short period in the absence of cell damage. Productions of Interleukin-6 (IL-6), IL-8-like activity, granulocyte-macrophage colony stimulating factor (GM-CSF), prostaglandin E2 (PGE2) and manganous superoxide dismutase (Mn-SOD) were enhanced or induced by the low-dose TNF stimulation. Mn-SOD, a protein protective against oxidative cell damage, was well induced in time- and dose-dependent manner, however did not correlate with TNF resistance. Whereas the levels of PGE2 in TNF-susceptible cell lines, H-4 and SF-188, were higher than those of other lines. In conclusion, most of glioblastoma cells are resistant to TNF cytotoxic effects, but highly responsive to TNF stimulation. Its effect on glioblastoma cells appears to modulate cell differentiation rather than to kill the cells.
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PMID:Responses of human glioblastoma cells to human natural tumor necrosis factor-alpha: susceptibility, mechanism of resistance and cytokine production studies. 836 Jul 7

Ciglitazone is the prototype of the thiazolidinedione class of compounds currently being developed for the treatment of insulin resistance and non-insulin-dependent diabetes. The effects of thiazolidinediones on blood pressure and cell calcium metabolism are not well defined. In the obese Zucker rat, a widely studied model of insulin resistance associated with mild hypertension, we investigated the effects of ciglitazone on plasma insulin levels and mean arterial pressure. We also evaluated the effects of ciglitazone on the changes in cytosolic calcium induced by platelet-derived growth factor in A172 human glioblastoma cells and rat A10 vascular smooth muscle cells. Oral administration of ciglitazone, approximately 45 mg/kg per day for 4 weeks, induced significant reductions in plasma insulin levels (p < 0.001) and blood pressure (p < 0.05). Ciglitazone was also found to significantly attenuate the capacity of platelet-derived growth factor BB homodimer to induce sustained increases in intracellular free calcium. These findings suggest that thiazolidinediones may offer a novel pharmacological approach to the treatment of hypertension, and raise the possibility that these compounds may affect blood pressure not only by affecting insulin metabolism but also by modifying the cell calcium response to pressor agents, growth factors, or both.
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PMID:Effects of ciglitazone on blood pressure and intracellular calcium metabolism. 850 86

The relationship between the degree of the expression of Cu/Zn SOD, GST-pi and bcl-2 in the initial and recurrent tumor tissue after radiotherapy and/or chemotherapy and the cellular heterogeneity obtained from DNA content by image cytometry was investigated. Subjects were 7 patients who had glial tumors which were surgically removed at onset and removed a second time at recurrence. Radiotherapy and chemotherapy were also administered after initial resection. Immunoreactivity for copper/zinc super oxide dismutase (Cu/Zn SOD), GST (glutathione-S-transferase)-pi, and bcl-2 were evaluated from routinely prepared tissue blocks. Tumors were classified into two groups by cytometric analysis of DNA ploidy in the G2M cell cycle phase. One tumor group consisted of single clonal cells in both the initial and recurrent tumors and the other group consisted of tumors with polyclonal cells in the initial and recurrent tumor. In this study, one patient (case 3) with single clonal cell glioblastoma at recurrence did not show high Cu/Zn SOD activity after radiotherapy and chemotherapy but showed a short survival time after recurrence. In three patients (cases 1, 2, 3) with single clonal-cell glioblastoma, the recurrent tumor cells showed high GST-pi immunoreactivity and survival time was short after recurrence. Tumor cells in two patients (cases 5, 7) with single clonal cell anaplastic glioma at recurrence, showed high GST-pi immunoreactivity and had a short survival time after recurrence. In three single clonal glioblastomas (cases 1, 2, 3), the recurrent tumor showed the increased bcl-2 immunoreactivity and showed a short survival time after recurrence. In two patients (case 5, 7) with single clonal cell anaplastic glioma at recurrence, tumor cells showed a high bcl-2 immunoreactivity and these patients showed a short survival time after recurrence. Although the number of subjects is very small, our study shows that the immunoreactivity of bcl-2 and GST-pi in malignant gliomas may be very important factors in radio- and chemosensitivity, and shows that GST-pi is induced by radiation and anti-cancer drugs.
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PMID:Expression of enzymes and oncogene induced after radiotherapy and/or chemotherapy in patients with brain tumors. 1143 58

We previously demonstrated that upstream stimulatory factor 1 (USF1) and USF2 regulate transcription of cathepsin B. Here, we have cloned a novel transcript variant of USF2 from a human DU145 prostate cancer cell line by reverse transcription-polymerase chain reaction (RT-PCR). This new transcript variant, designated USF2c, results from alternative splicing of the primary USF2 transcript using a cryptic splicing acceptor site within exon 6. As a consequence, USF2c is missing exons 4, 5, and part of exon 6. USF2c can be transcribed and translated to a protein of approximately 29 kDa in vitro, and the resulting USF2c protein can bind as a homodimer to the E-box of the cathepsin B promoter. USF2c is expressed in two other prostate cancer cell lines (LNCaP, PC3), and U87 human glioblastoma cells as are USF2a and USF2b, two previously identified isoforms of USF2. Cotransfection experiments in DU145 and U87 cells demonstrate that USF2c can down-regulate expression of cathepsin B. These results suggest that USF2c regulates expression of cathepsin B by binding to the E box element in the cathepsin B promoter as a repressor.
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PMID:Isolation of a novel USF2 isoform: repressor of cathepsin B expression. 1527 16

We previously demonstrated that the brain, pituitary, and C6 glioblastoma cells express leptin. To determine the physiological role of brain-derived leptin, we sought to selectively silence its expression using RNA interference (RNAi) in vitro. One of four potential targets, siRNA L7, reduced leptin mRNA by 50% (P < 0.05) and protein by 55% (P < 0.0001) in C6 cells. RNAi also induced a twofold increase in cell death as seen by ethidium homodimer-1 (P < 0.015) and TUNEL (P < 0.005) staining. These data suggest that endogenous leptin may be a critical factor promoting cell survival in the brain.
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PMID:RNAi-mediated silencing of leptin gene expression increases cell death in C6 glioblastoma cells. 1596 97

Multicellular tumor spheroids have been used to examine aspects of combined modality treatment since they often recreate the in vivo tumor environment much more closely than other models. The radioenhancement by gemcitabine (dFdC) on human glioma spheroids derived from cell lines (CLS) and biopsy tissue, grown as organotypic multicellular spheroids (OMS), was studied. CLS of GaMg and U87 and OMS of four glioblastoma patients were used. Radiochemosensitvity was determined using migration and proliferation assays on CLS. In OMS, histology and immunohistochemical studies of MIB-1, p53, and p21 expression were examined 24 and 48 h following treatment. Cell death (ethidium homodimer) was studied using a fluorescence cell viability assay. In CLS, combination treatment led to migration inhibition in GaMg and U87 of 85% and 62% (dFdC 46% and 52%, RT 21% and 43%) and proliferation inhibition of 83% and 85%, respectively. Following dFdC + RT in OMS (% of cases), apoptosis and p21 expression increased (50%), p53 expression increased (75%) and cell proliferation decreased (75%). Only minor morphological damage was observed. Confocal laser scanning microscopy identified an increased dead cell core after dFdC + RT (50%). In conclusion, dFdC can lead to an additively radioenhancement in CLS and individual OMS.
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PMID:Combined modality therapy of gemcitabine and irradiation on human glioma spheroids derived from cell lines and biopsy tissue. 1632 40

The role of placenta growth factor (PlGF) in pathologic angiogenesis is controversial. The effects of PlGF on growth, angiogenesis, and metastasis from orthotopic tumors are not known. To this end, we stably transfected three human cancer cell lines (A549 lung, HCT116 colon, and U87-MG glioblastoma) with human plgf-2 full-length cDNA. Overexpression of PlGF did not affect tumor cell proliferation or migration in vitro. The growth of PlGF-overexpressing tumors grown orthotopically or ectopically was impaired in all three tumor models. This decrease in tumor growth correlated with a decrease in tumor angiogenesis. The PlGF-overexpressing tumors had decreased vessel density and increased vessel diameter, but vessel permeability was not different from the parental tumors. Tumors overexpressing PlGF exhibited higher levels of PlGF homodimers and PlGF/vascular endothelial growth factor (VEGF) heterodimers but decreased levels of VEGF homodimers. Our study shows that PlGF overexpression decreases VEGF homodimer formation and inhibits tumor progression.
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PMID:Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. 1661 13


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