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)

It has been previously shown that the HIV-1 envelope glycoprotein 120 (gp120) activates cell signaling by CXCR4, independently of CD4. The present study examines the involvement of different intracellular signaling pathways and their physiopathologic consequences following the CD4-independent interaction between CXCR4 or CCR5 and gp120 in different cell types: primary T cells, CD4(-)/CXCR4(+)/CCR5(+) T cells, or glioma cells. These interactions were compared with those obtained with natural ligands, stromal cell-derived factor 1 alpha (SDF-1alpha) (CXCL12) and macrophage inflammatory protein 1 beta (MIP-1beta) (CCL4) of their respective coreceptors. Thus, both p38 and SAPK/Jun N-terminal kinase mitogen-activated protein kinases (MAPKs) are activated on stimulation of these cells with either T- or M-tropic gp120, as well as with SDF-1alpha or MIP-1beta. In contrast, extracellular signal-related kinase 1 and 2 MAPKs are only activated by MIP-1beta but not by M-tropic gp120. Importantly, T- and M-tropic gp120 are able to induce the secretion of matrix metalloproteinase 9 (MMP-9), an extracellular metalloproteinase present in cerebrospinal fluid of patients with HIV-1 by T cells or glioma cells. Specific inhibition of MAPK p38 activation resulted in a complete abrogation of the induction of the MMP-9 pathogenic factor expression by gp120 or chemokines in both cell types. Because neurodegenerative features in acquired immune deficiency syndrome dementia may involve demyelinization by MMP-9, the specific targeting of p38 could provide a novel means to control HIV-induced cytopathogenic effects and cell homing to viral replication sites. (Blood. 2001;98:541-547)
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PMID:HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway. 1146 47

Reported are six cases of glioma, diagnosed in the last 10 years, arising in organ transplant recipients. Five transplant recipients developed glioblastoma, and one developed oligodendroglioma. None had other risk factors for glioma. Gliomas must be considered in the differential diagnosis of space-occupying lesions in transplant recipients. Although these cases may represent coincidence, the putative HIV-glioma association suggests a pathogenetic link to immunosuppression.
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PMID:Gliomas arising in organ transplant recipients: an unrecognized complication of transplantation? 1167 95

Cannabinoids modulate nitric oxide (NO) levels in cells of the central nervous system. Here we studied the effect of cannabinoid CB(1) and CB(2) receptor agonists on the release of NO and cell toxicity induced by the human immuno-deficiency virus-1 Tat protein (HIV-1 Tat) in rat glioma C6 cells. The CB(1) and CB(2) agonist WIN 55,212-2 inhibited the expression of inducible NO synthase (iNOS) and NO release caused by treatment of C6 cells with HIV-1 Tat and interferon-gamma (IFN-gamma). The effect of WIN 55,212-2 was uniquely due to CB(1) receptors, as shown by experiments carried out with selective CB(1) and CB(2) receptor agonists and antagonists. CB(1) receptor stimulation also inhibited HIV-1 Tat + IFN-gamma-induced and NO-mediated cell toxicity. Moreover, cell treatment with HIV-1 Tat + IFN-gamma induced a significant inhibition of CB(1), but not CB(2), receptor expression. This effect was mimicked by the NO donor GSNO, suggesting that the inhibition of CB(1) expression was due to HIV-1 Tat + IFN-gamma-induced NO overexpression. HIV-1 Tat + IFN-gamma treatment also induced a significant inhibition of the uptake of the endocannabinoid anandamide by C6 cells with no effect on anandamide hydrolysis. These findings show that the endocannabinoid system, through the modulation of the l-arginine/NO pathway, reduces HIV-1 Tat-induced cytotoxicity, and is itself regulated by HIV-1 Tat.
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PMID:The endocannabinoid system protects rat glioma cells against HIV-1 Tat protein-induced cytotoxicity. Mechanism and regulation. 1238 47

A variety of amine complexes with 1-boraadamatane were synthesized and subsequently evaluated for an antiproliferative effect on CD81-enriched cell lines to provide evidence for binding and activation of CD81. CD81 is a member of the tetraspanin family of membrane proteins found in all cell lineages in the liver. CD81 signals for antiproliferation when bound by antibodies. It is known that the HCV-E2 envelope glycoprotein binds to the CD81 protein. While it is unclear whether virus entry into host cells is directly linked to virus attachment via CD81 for HCV, this step in the viral life cycle has recently proven to be an effective point of attack for other viruses including HIV and rhinoviruses. The aim of the current study concerns the synthesis of amantidine analogues by appending primary amines to 1-boraadamantane to evaluate such compounds for CD81-dependent antiproliferation of CD81-enriched cell lines (astrocyte) vs CD81-deficient cell lines (C6 glioma). If the antiproliferative effect of these amantidine analogues proves to be an effect of binding and activating CD81, then these compounds may have the potential to prevent or treat HCV infections. Each compound's potential for preventive and therapeutic activity stems from the compound's potential to block viral attachment, virus-cell fusion, or virus entry into host cells or to counter potential mechanisms of HCV immune evasion. Out of a library of over 500 compounds, including randomly selected small molecules and rationally designed small molecules, only the 1-boraadamantaneamine compounds and structurally similar analogues display a significant antiproliferative effect on the CD81-enriched astrocytes relative to the CD81-deficient cell lines. In fact, 1-boraadamantane.l-phenylalanine methyl ester complex (5), 1-boraadamantane.ethanolamine complex (8), and (S)-2-[(adamantane-1-carbonyl)amino]-3-phenylpropionic acid (15) show a dose-dependent, astrocyte-selective antiproliferative activity in the concentration range 0.1-10 microM. This is consistent with the binding and activation of CD81 and represents a 2-fold improvement compared to the clinically prescribed anti-HCV agent, amantidine, in the same concentration range. Consequently, the 1-boraadamantaneamine derivatives present a promising lead in the development of small molecules with potential to bind to CD81 and treat HCV infections.
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PMID:Synthesis of 1-boraadamantaneamine derivatives with selective astrocyte vs C6 glioma antiproliferative activity. A novel class of anti-hepatitis C agents with potential to bind CD81. 1282 26

The characteristic properties of the blood-brain barrier (BBB) forming brain capillary endothelial cells (BCEC) are modulated by their microenvironment, but the cellular sources of the induction signals are still unclear. Apart from astrocytes, another cell type in close contact with cerebral blood vessels is the perivascular macrophages, which are known to be regularly replaced by blood-derived monocytic precursor cells. It is unknown if, and how, these cells may interact with the cerebral endothelium and modulate its BBB-specific functions. In the present study, a cell culture model of the BBB was used to investigate the effect of blood-derived human macrophages on the permeability of cultured bovine and human BCEC, determined by a transendothelial electrical resistance (TEER) measurement. We found that the TEER of postconfluent BCEC was considerably increased by a non-contact coculture with macrophages. After 24 h, we found a TEER augmentation of over 50% compared with the control without coculture, and this effect was comparable to the response of BCEC to a C6 glioma cells coculture. Stimulation or HIV-1 infection of the macrophages did not alter their effect on BCEC monolayer permeability. Investigation of signal transduction pathways showed that TEER increase of BCEC due to macrophage coculture was cAMP-independent and involves neither phospholipase C, protein kinase C nor calmodulin. Our findings demonstrate that macrophages are able to modulate BBB-specific functions in cultured BCEC. Thus, these cells or cerebral cells of monocytic origin (e.g. perivascular macrophages), may be part of the microenvironment of BCEC that modulates their specific properties in vivo.
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PMID:Human blood-derived macrophages enhance barrier function of cultured primary bovine and human brain capillary endothelial cells. 1282 21

Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.
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PMID:Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. 1498 53

L-Glutamate serves as a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and is stored in synaptic vesicles by an uptake system that is dependent on the proton electrochemical gradient (VGLUTs). Following its exocytotic release, glutamate activates fast-acting, excitatory ionotropic receptors and slower-acting metabotropic receptors to mediate neurotransmission. Na+-dependent glutamate transporters (EAATs) located on the plasma membrane of neurons and glial cells rapidly terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels. Thus far, five Na+-dependent glutamate transporters (EAATs 1-5) and three vesicular glutamate transporters (VGLUTs 1-3) have been identified. Examination of EAATs and VGLUTs in brain preparations and by heterologous expression of the various cloned subtypes shows these two transporter families differ in many of their functional properties including substrate specificity and ion requirements. Alterations in the function and/or expression of these carriers have been implicated in a range of psychiatric and neurological disorders. EAATs have been implicated in cerebral stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, Huntington's disease, amyotrophic lateral sclerosis (ALS) and malignant glioma, while VGLUTs have been implicated in schizophrenia. To examine the physiological role of glutamate transporters in more detail, several classes of transportable and non-transportable inhibitors have been developed, many of which are derivatives of the natural amino acids, aspartate and glutamate. This review summarizes the development of these indispensable pharmacological tools, which have been critical to our understanding of normal and abnormal synaptic transmission.
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PMID:Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. 1521 Mar 7

Human immunodeficiency virus 1 (HIV-1) downregulates cell surface expression of HLA-A and HLA-B but not HLA-C or HLA-E to ultimately escape immune defences. Here, it is shown that cell surface expression of the non-classical HLA-G1 is also downregulated by HIV-1, by using co-transfection experiments and infection with cell-free HIV-1 of HLA-G1-expressing U87 glioma cells or macrophages in primary culture. Moreover, co-transfection experiments using proviruses deleted in either nef or vpu or plasmids encoding HIV-1 Nef and Vpu mixed together with a HLA-G1-expressing construct demonstrated that HLA-G1 downregulation is Nef-independent and Vpu-dependent, contrasting with the Nef- and Vpu-dependent HLA-A2 downregulation. Together, these results show that the decrease of HLA-A2 and HLA-G1 caused by HIV-1 occurs through distinct mechanisms.
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PMID:Human immunodeficiency virus 1 downregulates cell surface expression of the non-classical major histocompatibility class I molecule HLA-G1. 1521 79

We presently describe the full-length cloning and functional characterization of an HIV-1-inducible gene, astrocyte elevated gene (AEG)-1. Additionally, a novel method is outlined for producing tag-free recombinant protein in a baculovirus system and its use in producing AEG-1 protein. AEG-1 mRNA is expressed ubiquitously with higher expression in tissues containing muscular actin and its expression is increased in astrocytes infected with HIV-1 or treated with gp120 or tumor necrosis factor (TNF)-alpha. The mRNA encodes a single pass transmembrane protein of predicted molecular mass of 64-kDa and pI 9.3 that predominantly localizes in the endoplasmic reticulum and perinuclear region. Ectopic expression of AEG-1 inhibits excitatory amino acid transporter 2 (EAAT2) promoter activity with the potential to promote glutamate excitotoxicity and consequently HIV-1-associated dementia (HAD). AEG-1 expression is elevated in subsets of breast carcinomas, malignant gliomas and melanomas and it synergizes with oncogenic Ha-ras to enhance soft agar colony forming ability of non-tumorigenic immortalized melanocytes, documenting its tumor promoting activity. AEG-1 may affect tumor progression in multiple cell lineages by augmenting expression of the transformed phenotype and/or by inducing glutamate excitotoxicity in malignant glioma. In these contexts, an HIV-1-inducible gene, AEG-1, may contribute to multiple brain abnormalities, including HAD and tumor formation, by both common and distinct mechanisms.
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PMID:Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. 1592 26

Protein transduction domain (PTD) from HIV-1 TAT protein has been reported to translocate across the mammalian cell membrane, also as a part of fusion proteins. However, the true nature of TAT-mediated intercellular spreading is still under debate because it has been claimed to be a fixation artifact. To study the spreading of TAT fusion proteins and their potency to enhance thymidine kinase/ ganciclovir (HSV-TK/GCV) cancer gene therapy, we constructed a novel triple fusion protein containing TAT PTD, HSV-TK and green fluorescent protein (TAT-TK-GFP). This fusion protein has three functional domains in the same polypeptide, allowing reliable determination of the relationship between transduction rate and cell killing efficiency. TAT-TK-GFP was cloned into a lentivirus vector and used for analyses of TAT-mediated protein translocation and enhancement of HSV-TK/GCV cytotoxicity. The triple fusion protein was expressed correctly in vitro, but cell-to-cell translocation was not observed in rat glioma cells (BT4C). However, TAT-TK-GFP made BT4C and SKOV3.ip1 (human ovarian carcinoma) cells significantly more sensitive to ganciclovir than TK-GFP, whereas the effect in PC-3 human prostate carcinoma cells was more subtle. It was also observed that growth in lower serum concentration (2.5-5%) abolished the enhancement in BT4C cells, suggesting that high proliferation rate is one of the factors that contribute to TAT PTD-mediated enhancement of cytotoxicity. In summary, our results indicate that TAT PTD fusion proteins do not translocate intercellularly at detectable levels, but enhancement of the HSV-TK/GCV cytotoxicity can be detected in rat and human tumor cell lines in vitro.
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PMID:HIV-1 TAT protein transduction domain mediates enhancement of enzyme prodrug cancer gene therapy in vitro: a study with TAT-TK-GFP triple fusion construct. 1594 61


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