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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Models for human cytomegalovirus (HCMV) brain infection have been developed in a variety of brain-derived cells in which the factors governing virus infectivity might be studied in vitro. Studies were initiated with brain endothelial cells, the likely portal of entry for virus into the central nervous system. Primary explant cultures of brain endothelial cells, derived from homogenates of healthy human brain, supported complete viral gene expression and cytopathic effect (CPE). Endothelial cells do not appear to be a barrier for HCMV passage into the central nervous system. Astroglial lines (primary explant or tumor-derived) varied in their ability to support HCMV replication. Some (T98G) supported incomplete (immediate-early) gene expression while others (A-172) did not support any detectable gene expression. Some astroglial lines (HS-683) supported extensive virus replication with minimal viral CPE. Neuronal cell lines (SK-N-MC) were fully permissive. The more differentiated glial lines (astrocytoma) were fully permissive to HCMV infection; however, the less differentiated glial lines (glioblastoma) were partly or nonpermissive.
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PMID:Cytomegalovirus in the brain: in vitro infection of human brain-derived cells. 217

The vascular system of the central nervous system is derived from capillary endothelial cells, which have invaded the early embryonic neuroectoderm. This process is called angiogenesis and is probably regulated by brain-derived factors. Vascular endothelial cell growth factor (VEGF) is an angiogenic growth factor whose expression correlates with embryonic brain angiogenesis, i.e. expression is high in the embryonic brain when angiogenesis occurs and low in the adult brain when angiogenesis is shut off under normal physiological conditions. VEGF is also a vascular permeability factor (VPF) and, therefore, its expression is also consistent with the formation of the blood-brain barrier by brain endothelial cells, i.e. capillaries are leaky in the embryonic brain but are tight in the postnatal and adult brain. Thus, VEGF/VPF may be a key factor regulating endothelial cell growth and permeability. This notion is further supported by the observation that VEGF expression is induced and strongly upregulated in human malignant glioblastoma. This tumor is characterized by vascular proliferations, vascular leakage and edema. The differentiation of blood-brain barrier endothelial cells is probably regulated by astrocytes which form foot processes apposed to the abluminal vascular basement membrane. Blood-brain barrier endothelial cells express a set of cell surface proteins that are absent from permeable capillaries. We have characterized one such novel transmembrane glycoprotein which is a new member of the immunoglobulin superfamily. This protein and the analysis of the in vitro characteristics of brain endothelial cells may help to define the molecular mechanisms that are involved in blood-brain barrier induction and permeability.
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PMID:Molecular biology of blood-brain barrier ontogenesis and function. 752 21

Several transcription regulatory elements that interact with cellular DNA-binding proteins have been identified in the HIV-1 long terminal repeat (LTR). We have identified two sequence motifs in the U3 region of the LTR that are similar to the consensus 9-bp DNA-binding element of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors. One of the sequences (promoter-proximal) mapped immediately upstream of the NF-kappa B element, whereas the other (promoter-distal) completely overlapped the upstream stimulatory factor (USF) binding site. In this study, we investigated the role of the enhancer-proximal consensus C/EBP binding sequence in the expression of the HIV-1 LTR. In cotransfection assays we found that although this sequence is a functional C/EBP-responsive element, the regulation of the HIV promoter by C/EBP is very complex. C/EBP isoforms inhibited the phorbol 12-myristate 13-acetate (PMA)-stimulated HIV-1 promoter activity in human glioblastoma U138MG and neuroblastoma SHSY5Y cells, but not in HeLa epithelial cells, and this inhibition required the NF-kappa B element. C/EBP also downregulated the HIV NF-kappa B element-containing SV40 early promoter activity, regardless of the presence of the flanking C/EBP-binding sequences, in the two brain-derived cells. In electrophoretic mobility shift assays with nuclear extracts from HeLa and U138MG cells, purified C/EBP markedly increased the complex formation between endogenous proteins and the NF-kappa B DNA probe without detectable association with the complex. However, with extracts from U138MG cells but not from HeLa cells, a slow migrating complex was observed. Our data suggest that the C/EBP family of transcription factors can downregulate the HIV-1 promoter activity in CNS-derived cells through the NF-kappa B binding elements.
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PMID:NF-kappa B site-mediated negative regulation of the HIV-1 promoter by CCAAT/enhancer binding proteins in brain-derived cells. 757 67

To study the relevance of gamma delta T cells in multiple sclerosis (MS) we analyzed the T cell receptor (TCR) gamma delta repertoire and the antigen reactivity of gamma delta clones isolated from cerebrospinal fluid (CSF). In T cell cultures derived from CSF we found an increased percentage of V delta 1+ cells as compared to peripheral blood of the same donors. Phenotypic analysis of cells from MS CSF with V gamma- and V delta-specific monoclonal antibodies (mAb) showed that the V delta 1 chain is most frequently associated with gamma chains belonging to the V gamma 1 family. Sequence analysis of TCR genes revealed heterogeneity of junctional regions in both delta and gamma genes indicating polyclonal expansion. gamma delta clones were established and some recognized glioblastoma, astrocytoma or monocytic cell lines. Stimulation with these targets induced serine esterase release and lymphokine expression characteristic of the TH0-like phenotype. Remarkably, these tumor-reactive gamma delta cells were not detected in the peripheral blood using PCR oligotyping, but were found in other CSF lines independently established from the same MS patient. Altogether, these results demonstrate that in the CSF there is a skewed TCR gamma delta repertoire and suggest that gamma delta cells reacting against brain-derived antigens might have been locally expanded.
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PMID:T cell receptor gamma delta repertoire is skewed in cerebrospinal fluid of multiple sclerosis patients: molecular and functional analyses of antigen-reactive gamma delta clones. 787 96

Human cytomegalovirus (HCMV) is commonly found in the brains of patients with AIDS and in some cases can be detected in the same cells as can human immunodeficiency virus type 1 (HIV-1). In this study, we analyzed the patterns of replication of HIV-1 and HCMV in singly infected cells and the effects of dual infection in human brain-derived cell lines of three different origins: neuroblastoma cell lines SK-N-MC and SY5Y; astrocytoma/glioblastoma cell lines U373-MG and Hs 683; and undifferentiated glioblastoma cell lines A172 and T98G. To bypass the restriction at the adsorption/penetration step in these CD4-negative cells, we used HIV-1 (amphotropic retrovirus) pseudotypes. These HIV-1 pseudotypes infected the majority of the cells in the cultures and expressed high levels of HIV-1 gene products in all except the SY5Y cells. The cell lines differed in the ability to support HCMV infection, but coinfection with HIV-1 had no effect on HCMV replication. The A172 cells were completely nonpermissive for HCMV gene expression, while HCMV replication in the singly infected T98G and SK-N-MC cell lines was restricted at the level of some early gene products. This resulted in complete and partial inhibition, respectively, of viral DNA synthesis. Dual infection of the A172, T98G, and SK-N-MC cells had no effect on HIV-1 replication. The other three cell lines, U373-MG, Hs 683, and SY5Y, were fully permissive for HCMV replication. In the U373-MG and Hs 683 cells, HCMV markedly inhibited the synthesis of HIV-1 gene products. In contrast, a transient stimulation of HIV-1 production followed by a repression was observed in the dually infected SY5Y cells. We conclude from these results that under conditions in which both HIV-1 and HCMV can undergo fully permissive infection, HCMV can repress HIV-1 gene expression. In cells in which HCMV replication is limited but HIV-1 replicates well, there is no effect on HIV-1 gene expression. However, activation of HIV-1, at least transiently, may occur in cells in which HIV-1 gene expression is limited. These studies suggest that a threshold level of some HIV-1 gene product(s) may obscure activation or promote repression of HIV replication by HCMV.
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PMID:The effects of cytomegalovirus on human immunodeficiency virus replication in brain-derived cells correlate with permissiveness of the cells for each virus. 828 98

Previously, our laboratory showed that human cytomegalovirus (HCMV) activates human immunodeficiency virus type 1 (HIV-1) in brain-derived cells with limited HIV-1 gene expression but inhibits HIV-1 in cells fully permissive for replication of both viruses (F. M. Jault, S. A. Spector, and D. H. Spector, J. Virol. 68:959-973, 1994). To investigate these effects further, we developed a model system that uncouples HIV-1 gene expression from long terminal repeat (LTR) activity. Two monoclonal U373-MG astrocytoma/glioblastoma cell lines (LTRIG and LIGHIVDC) were generated, each containing an integrated copy of an LTR-chloramphenicol acetyltransferase (CAT) construct and the Escherichia coli lacI gene. LIGHIVDC also has an inducible HIV-1 genome controlled by a Rous sarcoma virus promoter with lac operator sequences. Basal LTR-mediated CAT activity is 65-fold higher in LIGHIVDC than in LTRIG, and this activity is further increased (20-fold) following incubation of LIGHIVDC with isopropyl-beta-D-thiogalactopyranoside (IPTG). Tat protein can be detected by immunostaining in LIGHIVDC. However, Rev-mediated transport and subsequent translation of the singly spliced and unspliced HIV-1 mRNAs is inefficient. In the absence of Tat, HCMV stimulated CAT activity approximately 20-fold, and this activation required HCMV gene expression but not viral DNA replication. LTR-directed transcription was unaffected by HCMV infection in LIGHIVDC but was inhibited in these cells when they contained increased Tat levels following IPTG induction. These results support the hypothesis that HCMV can induce the HIV-1 LTR when HIV-1 gene expression is minimal and that a threshold level of HIV-1 gene products is necessary for HCMV to inhibit this promoter.
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PMID:A model system for human cytomegalovirus-mediated modulation of human immunodeficiency virus type 1 long terminal repeat activity in brain cells. 909 43

Angiotensin peptides are potent vasoconstrictors, cell growth factors, and neuromodulators in normal and pathological situations. To assess the potential role of the angiotensins in brain tumor-associated vessels, the expression of the enzymes of the angiotensin cascade were evaluated in these tumors. The production of these bioactive peptides is dependent on the activities of exopeptidases, including several aminopeptidases and carboxypeptidases, producing angiotensin (Ang) I, II, III, IV and Ang 1-7. Human cerebral parenchymal and glioblastoma cells expressed renin, and tumor vasculature, but not glioblastoma cells, expressed angiotensin-converting enzyme. High aminopeptidase A (APA) activity, but no aminopeptidase N/B activity, was observed in human brain tumor vasculature, suggesting a predominant production of Ang III. Grafting of rat glioma cells in rat brains yielded tumors with high APA and low aminopeptidase N/B activities in tumor vessels, confirming human results. Tumor growth and APA activity in tumor vessels were not affected by chronic angiotensin-converting enzyme inhibition. The brain-derived EC219 endothelial cells expressed high APA activity, which was not involved in endothelial cell proliferation, but was down-regulated by exposure of cells to transforming growth factor-beta (TGF beta) or to TGF beta-secreting tumor cells, suggesting a role for this peptide in the control of APA activity in cerebral vasculature. Thus, APA is a potential marker of chronic dysfunction, involving loss of TGF beta function, of the metabolic blood-brain barrier, but not of neovascularization.
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PMID:Regulation of aminopeptidase A in human brain tumor vasculature: evidence for a role of transforming growth factor-beta. 1087 47

The hormone leptin is implicated in the regulation of appetite and body weight in rodents, primates and humans. We reported that the leptin gene (ob) is expressed in the brain, but the factors which control ob expression in the central nervous system are not known. We previously showed that brain-derived rat C6 glioblastoma cells express ob mRNA and protein. In the present study we examined the regulation of ob expression in C6 cells. Leptin and leptin receptor immunoreactivity was detected in C6 cells, suggesting a possible autocrine role for leptin. The identity of the leptin immunoreactivity (OB-ir) in C6 cells was confirmed by immunoprecipitation and Western blotting using two leptin specific polyclonal antibodies. Using RT-PCR analysis a product of the expected size for the short, but not the long, leptin receptor isoform was detected in C6 cells. Cells were maintained in serum-free (SF) media for 0-24 h in the presence of various regulators of leptin expression. Leptin mRNA levels were significantly higher in cells treated with dbcAMP (1 mM), IGF 1 (100 ng/ml) or insulin (5 microg/ml) compared to SF controls. In contrast, corticosterone (10(-7)M) reduced leptin mRNA. In the presence of dbcAMP, C6 cells undergo a dramatic alteration in morphology which is coincident with an apparent increase in the number of leptin-ir nuclei and an increase in leptin immunoreactivity. In contrast to C6 cells, glucocorticoids are reported to increase leptin levels in adipocytes/adipose tissue, while increases in intracellular cAMP levels are reported to reduce leptin levels. Overall, our in vitro data suggest that the regulation of leptin gene expression in C6 glioblastoma cells is different from that in adipocytes.
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PMID:The regulation of leptin gene expression in the C6 glioblastoma cell line. 1094 Apr 88

The effects of functionalized aryl beta-D-glycopyranosides (glycomers) on the proliferation, survival, and apoptosis of human glioblastoma cells in culture were evaluated as a way to control tumor progression. The results showed that inhibition of growth and/or induction of apoptosis can be achieved by these molecules in human glioblastoma cells. Inhibition of DNA synthesis precedes induction of apoptosis and growth inhibition. The substituents at C-1, C-2, C-3,C-4, and C-6 on the pyranosidic scaffold are important to modulate the action and the efficacy of these molecules. Human fibroblasts and brain-derived endothelial cells were less sensitive to glycomers than tumor cells. Thus, functionalized aryl beta-D-glycopyranosides represent a new class of molecules potentially able to control the progression of brain tumors.
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PMID:Functionalized glycomers as growth inhibitors and inducers of apoptosis in human glioblastoma cells. 1290 64

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


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