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)

JC virus (JCV), the causative agent of a human demyelinating disease, progressive multifocal leukoencephalopathy, has a very narrow host range. Cells permissive for infection by JCV have been essentially limited to primary human fetal glial cells, which are difficult to obtain and maintain. In pilot studies, it was found that JCV can multiply in an established cell line of human neuroblastoma. JCV strains Mad-1 and Tokyo-1 were inoculated, respectively, into two cell lines, IMR-32 (neuroblastoma) and A-172 (glioblastoma). Viral infection with cytopathic effect was observed only in IMR-32 cells, and the most efficient viral proliferation was obtained in cells cultured in medium containing 2% fetal calf serum (FCS). Both Mad-1 and Tokyo-1 strains propagated well, with the former being more efficient than the latter. Viral replication was confirmed by immunofluorescence, electron microscopy, and a hemagglutination assay. Sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and Western blot analysis of the purified virus revealed the characteristic JCV protein profile. Thus, IMR-32 cells have been found to be permissive for JCV, which should provide a useful system for further studies of virus proliferation and viral tissue tropism.
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PMID:Propagation of JC virus in human neuroblastoma cell line IMR-32. 808 45

Increasing numbers of patients within the Mohave Valley region of the United States are reporting symptoms attributable to atypical neurological illness. Many of these patients have experienced an acute-onset gastrointestinal illness during the spring and summer of 1996. Stealth viral cultures performed on the blood of 40 of these patients have been uniformly positive, yielding unequivocal transmissible cytopathic effect (CPE) in both human- and monkey-derived cell lines. One patient has died from a stealth-CPE-positive glioblastoma, while another patient has developed a plemorphic adenoma of the parotid. Viral cultures and epidemiological data support human-to-human, and probable human-to-dog, transmission of the Mohave stealth virus infection.
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PMID:Stealth virus epidemic in the Mohave Valley. I. Initial report of virus isolation. 920 Jan 90

Apoptosis induced by H-1 parvovirus infection was investigated in C6 rat glioblastoma cells and in newborn rats. Apoptotic changes, such as chromatin condensation, the appearance of apoptotic nuclear bodies and oligonucleosomal DNA ladders, were observed in infected C6 cells 2 days after infection. Inhibitor assay results suggest that a caspase-3-dependent apoptosis activation pathway is induced by H-1 virus infection in C6 cells. Observations made in vivo revealed that the number of apoptotic cells increased in the infected cerebellum, coinciding with known virus infection sites.
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PMID:Induction of apoptosis in vitro and in vivo by H-1 parvovirus infection. 988 23

Cleavage of the hemagglutinin (HA) molecule by proteases is a prerequisite for the pathogenicity and even for the neurovirulence of influenza A viruses. WSN, a neurovirulent virus, adapted to mouse brain, grew in vitro in several types of cells including neuroblastoma cells in the absence of trypsin. When mice were intracerebrally inoculated with WSN, the viral antigen was found in the substantia nigra zona compacta and hippocampus. The mice inoculated with viruses isolated from children with acute encephalopathy associated with an influenza virus infection, on the other hand, showed no neurological symptoms. Furthermore, these viruses did not grow in the human neuroblastoma and glioblastoma cells. Since 1991, most of the human influenza A viruses have not agglutinated chicken erythrocytes. Whether this altered receptor binding specificity is related to the occurrence of influenza encephalitis and encephalopathy is now under investigation.
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PMID:[Influenza encephalopathy and encephalitis]. 1072 90

In human cytomegalovirus (HCMV) infection, both of the major immediate-early proteins IE1(IE68, UL123) and IE2(IE86, UL122) target to PML protein-associated nuclear bodies known as PODs or ND10 at very early times after infection. IE1 causes a redistribution of both PML and IE1 from the PODs into a nuclear diffuse form, whereas IE2 initially localizes adjacent to PODs but later associates with viral DNA replication compartments. The peripheries of PODs are also believed to be sites for initiation of both viral IE transcription and DNA replication. However, because IE1 is nonessential at high multiplicity of infection (m.o.i.) in HF cells, the exact role of these processes in viral infection has been enigmatic. Therefore, we investigated the effects of overexpression of PML in the presence or absence of IE1 on the intranuclear distribution of IE2 and formation of viral DNA replication compartments, as well as on the levels of delayed-early and late viral transcription and protein accumulation. Infection with wild-type HCMV(Towne) and the IE1-deleted derivative HCMV(CR208), which fails to disrupt PODs, was compared in a pair of related astrocytoma/glioblastoma cell lines, the U373-Neo control and a variant U373-PML that constitutively overexpresses PML(560) in much larger than normal PODs. IFA studies on the localization patterns for IE1, IE2, and PML showed that, although the numbers of IE2-positive cells were not significantly reduced in either the wild-type virus-infected U373-PML cell line or in DeltaIE1-infected control cells, POD disruption by IE1 in wild-type virus infection was delayed by up to 6 h in U373-PML cells compared to control cells. Furthermore, there was considerable enhancement of IE2 colocalization with PODs in Delta IE1-infected U373-PML cells. Formation of viral DNA replication compartments in the U373-PML cell line was also greatly delayed, measured at fivefold lower after wild-type virus infection and 12-fold lower after infection with Delta IE1 than in the control cell line at 48 h at an m.o.i. of 1.0. The levels of representative early and late viral proteins detected by Western blotting were suppressed by fivefold and 22-fold at 24 and 72 h, respectively, in the U373-PML cell line, even with high m. o.i. wild-type HCMV infection. Decreased viral protein levels also occurred when control cells were infected with the Delta IE1 virus and these two effects were additive in the U373-PML cell line. Similarly, when U373-PML cells were infected with recombinant HCMV expressing an extragenic luciferase reporter gene under the control of viral early (Pol) or late (pp28) promoters, their transcriptional activation was reduced up to fivefold at both high and low m.o.i. compared to that of the control cells. Overall, these results suggest that POD disruption by IE1 and subsequent redistribution of both PML and IE1 at very early times after infection may play an important role in the efficient utilization of cellular transcription and replication machinery by HCMV and contribute to rapid progression of the HCMV lytic cycle.
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PMID:Disruption of PML-associated nuclear bodies by IE1 correlates with efficient early stages of viral gene expression and DNA replication in human cytomegalovirus infection. 1093 87

Modulation of host immune responses has emerged as a common strategy employed by herpesviruses both to establish life-long infections and to affect recovery from infection. Herpes simplex virus 1 (HSV-1) blocks the major histocompatibility complex (MHC) class I antigen presentation pathway by inhibiting peptide transport into the endoplasmic reticulum. The interaction of viral gene products with the MHC class II pathway, however, has not been thoroughly investigated, although CD4(+) T cells play an important role in human recovery from infection. We have investigated the stability, distribution, and state of MHC class II proteins in glioblastoma cells infected with wild-type HSV-1 or mutants lacking specific genes. We report the following findings. (i) Wild-type virus infection caused a decrease in the accumulation of class II protein on the surface of cells and a decrease in the endocytosis of lucifer yellow or dextran conjugated to fluorescein isothiocyanate but no decrease in the total amount of MHC class II proteins relative to the levels seen in mock-infected cells. (ii) Although the total amount of MHC class II protein remained unchanged, the amounts of cell surface MHC class II proteins were higher in cells infected with the U(L)41-negative mutant, which lacks the virion host shutoff protein, and especially high in cells infected with the gamma(1)34.5-negative mutant. We conclude that infected cells attempt to respond to infection by increased acquisition of antigens and transport of MHC class II proteins to the cell surface and that these responses are blocked in part by the virion host shutoff protein encoded by the U(L)41 gene and in large measure by the direct or indirect action of the infected cell protein 34.5, the product of the gamma(1)34.5 gene.
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PMID:Cell surface major histocompatibility complex class II proteins are regulated by the products of the gamma(1)34.5 and U(L)41 genes of herpes simplex virus 1. 1207 98

The extremely poor prognosis of malignant gliomas requires the investigation of other than standard therapies, i.e., the application of oncolytic viruses. In our study, we evaluated the effects of the oncosuppressive parvovirus H-1 on different established glioblastoma cell lines of rat and human origin and on short-term/low-passage cultures of human glioblastoma cells. We observed an efficient and dose-dependent killing of all glioma cell cultures at low multiplicities of infectious particles (MOI) per cell. Southern blot analysis of viral DNA amplification, RT-PCR analysis of viral RNA expression and Western blot analysis of the expression of viral structural (VP-1/VP-2) and nonstructural (NS-1) proteins demonstrated the biosynthesis of these viral macromolecular components in all of the cultures. Moreover, all the glioma cells were proficient for the production of infectious H-1 virus particles. The amount of virus production differed between a several fold increase of the input virus titer in most of the short-term/low-passage cultures up to 1,000-fold in one short-term glioma and in the rat cells. Glioma cells lines and, more importantly, short-term/low-passage cultures of human glioblastomas were found to be highly susceptible target cells for H-1 virus mediated cytotoxicity. The formation of fully infectious progeny particles in infected glioma cells offers the chance for the induction of secondary rounds of infection resulting in an advanced cytotoxic effect. These advantageous characteristics of H-1 virus infection of glioma cells, combined with the known low toxicity of H-1 virus in nontransformed cells, make parvovirus H-1 a promising candidate for oncolytic glioma therapy.
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PMID:Parvovirus H-1 infection of human glioma cells leads to complete viral replication and efficient cell killing. 1473 71

During the past decade, numerous molecular mediators of neurodegenerative diseases and neurological disorders have been identified and validated, yet few novel therapies have emerged and the unmet medical needs remain high. These molecular mediators belong to target classes such as ion channels, neurotransmitters and neurotransmitter receptors, cytokines, growth factors, enzymes and other proteins. In some cases, substantial pre-clinical validation exists, but the molecular target has not been readily druggable with small molecules, proteins or antibodies. RNA interference represents a therapeutic approach applicable to such non-druggable targets. Both non-viral and viral delivery strategies are being undertaken for in vivo silencing of molecular targets by RNA interference, which has resulted in robust efficacy in animal models of Alzheimer's disease, ALS, Huntington's disease, spinocerebellar ataxia, anxiety, depression, neuropathic pain, encephalitis and glioblastoma. These proof-of-concept data in animal models, together with the commencement of clinical trials using RNA interference for macular degeneration and respiratory syncytial virus infection, point to the potential of direct RNA interference for neurological disorders and neurodegenerative diseases.
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PMID:Therapeutic potential of RNA interference for neurological disorders. 1681 77

The activity of Topoisomerase II alpha and beta isoforms is tightly regulated during different phases of cell cycle. In the present study, the action of anti-inflammatory agents, nordihydroguaretic acid (NDGA) is analyzed in HIV-1 infected CXCR4(+), CCR5(+) and CD4(-) SK-N-SH neuroblastoma, CXCR4(+), CCR5(+) and CD4(-) 1321N1 astrocytoma and CXCR4(+), CCR5(+/-) and CD4(-) GO-G-CCM glioblastoma cell lines. In SK-N-SH and 1321N1 the expression of Topoisomerase II alpha is concomitant with that of LOX-5 and is highly sensitive to NDGA, while the Topoisomerase II beta is expressed along with TNFalpha and exhibits low sensitivity to NDGA, suggesting distinct pathways of regulation for the two isoforms. HIV-1 infection in these cells enhanced the expression of Topo II alpha and beta. Further, the regulation of Topo II beta and TNFalpha in infected and uninfected SK cells is distinctly different. HIV-1 gp120 derived peptides could block HIV-1 mediated inflammation and Topoisomerase II alpha and beta expression, suggesting the viral mediated response. A combination of NDGA, gp-120 derived peptides and AZT has completely blocked the viral replication, suggesting the enhancement of potency of AZT under the suppression of inflammatory response. In contrast, the expression of Topo II alpha and beta was stimulated by NDGA in GO-G-CCM cells showing distinct regulatory pathway in these cells that was resistant to HIV-1 infection. This suggests the requirement of inflammatory response for productive viral infection. In summary, an induction of co-receptor mediated inflammatory response can distinctly enhance regulated expression of the cellular Topo II alpha and beta and promote productive infection in neurons and astrocytes.
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PMID:Regulation of topoisomerase II alpha and beta in HIV-1 infected and uninfected neuroblastoma and astrocytoma cells: involvement of distinct nordihydroguaretic acid sensitive inflammatory pathways. 1739 42

The eradication of brain tumor stem cells is essential for long-term brain tumor remission after treatment. In this study, we examined the therapeutic potential of an oncolytic adenovirus, Delta-24-RGD, targeted to the abnormal p16INK4/Rb pathway in brain tumor stem cells. Four brain tumor stem cell lines from surgical glioblastoma specimens expressed high levels of adenoviral receptors and allowed for efficient viral infection, replication, and oncolysis in an Rb-dependent manner. Delta-24-RGD induced autophagic cell death, as indicated by accumulation of Atg5 and LC3-II protein and autophagic vacuoles. Treatment of xenografts derived from brain tumor stem cells with Delta-24-RGD statistically significantly improved the survival of glioma-bearing mice (means: 38.5 versus 66.3 days, difference = 27.8 days, 95% confidence interval = 19.5 to 35.9 days, P <.001). Analyses of treated tumors showed that Atg5 expression colocalized with viral fiber protein and delineated a wave front of autophagic cells that circumscribed areas of virally induced necrosis. Our results show for the first time that brain tumor stem cells are susceptible to adenovirus-mediated cell death via autophagy in vitro and in vivo.
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PMID:Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. 1784 77


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