Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human Topoisomerase II is present in two isoforms, 170KDa alpha and 180KDa beta. Both the isoforms play a crucial role in maintenance of topological changes during DNA replication and recombination. It has been shown that Topoisomerase II activity is required for HIV-1 replication and the enzyme is phosphorylated during early time points of HIV-1 replication. In the present study, we have studied the molecular action of Topoisomerase II inhibitors, azalactone ferrocene (AzaFecp), Thiomorpholide amido methyl ferrocene (ThioFecp), and Ruthenium benzene amino pyridine (Ru(ben)Apy) on cell proliferation and also on various events of HIV-1 replication cycle. The Topoisomerase II beta over-expressing neuroblastoma cell line shows a higher sensitivity to these compounds compared to the Sup-T1 cell line. All the three Topoisomerase II inhibitors show significant anti-HIV activity at nanomolar concentrations against an Indian isolate of HIV-1(93IN101) in Sup-T1 cell line. An analysis of action of these compounds on proviral DNA synthesis at 5h of post-infection shows that they inhibit proviral DNA synthesis as well as the formation of pre-integration complexes completely. Further analysis, using polymerase chain reaction and western blot, showed that both the Topoisomerase II alpha and beta isoforms are present in the pre-integration complexes, suggesting their significant role in HIV-1 replication.
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PMID:A study of the topoisomerase II activity in HIV-1 replication using the ferrocene derivatives as probes. 1671 76

Examination of signal transduction pathways that modulate neuronal cell differentiation and protection against apoptosis has revealed a central role for the MAPK/Erk cascade. The activation of MAPK/Erk through the TrkA NGF signaling pathway is critical for growth and survival of neuronal cells. Here, we investigate the impact of HIV-1 Tat on the NGF-signaling pathway in SK-N-MC neuroblastoma cells. Expression of Tat decreased cell growth and induced apoptosis. Our results revealed dysregulation of various steps involved in the NGF pathway including suppression of MAPK, and inhibition of the promoter activity of Egr-1, a key pleiotropic mediator of the expression of genes involved in cell growth upon expression of Tat in SK-N-MC cells. Similarly, exposure of SK-N-MC to conditioned media derived from cells expressing Tat decreased phosphorylation of MAPK and reduced the level of Egr-1 protein expression in SK-N-MC cells. Furthermore, MAPK was able to phosphorylate Puralpha, a cellular protein that plays an important role in neuronal cell function and differentiation, and this was inhibited by Tat. The ability of Puralpha to interact with a GA/GC-rich sequence positioned upstream from the transcription start site of the Egr-1 promoter provided a rationale to examine Egr-1 expression. Expression of Tat decreased NGF-induced Egr-1 levels in SK-N-MC cells and reduced binding of Puralpha to the Egr-1 promoter. All of these observations support a model where the interplay between Tat and Puralpha dysregulates the NGF pathway including the MAPK/Erk network, resulting in reduced expression and activity of Egr-1 in neuronal cells.
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PMID:Dysregulation of NGF-signaling and Egr-1 expression by Tat in neuronal cell culture. 1674 63

Varying degrees of neurological dysfunction are observed in AIDS patients who develop AIDS dementia complex (ADC). Data from a large number of in vivo and in vitro rodent studies have suggested a role for the HIV envelope glycoprotein gp 120 in this process. These studies were initiated to clarify possible effects of recombinant gp120 on signal transduction systems and the synthesis of specific ADC-related cytokines in human neuroblastoma cells. Out results indicate that gp120 on signal transduction systems and the synthesis of specific ADC-related cytokines in human neuroblastoma cells. Our results indicate that gp120 did not induce the synthesis of cAMP, IPs or NO, nor did it alter agonist-induced synthesis of these molecules. In addition, it did not induce the synthesis of IL-6 and TNFα. However, it did activate a src-family protein tyrosine kinase which phosphorylates several substrates, including prominent proteins in the 115 and 60 kDa range. This gp120-induced tyrosine phosphorylation may contribute to neurological dysfunction since protein tyrosine kinases are known to be involved in processes important for pre- and post-synaptic neuronal function.
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PMID:HIV-1 gp120 Effects on Signal Transduction Processes and Cytokines: Increased src-Family Protein Tyrosine Kinase Activity. 1687 71

Despite HAART, a significant number of HIV-1-infected patients develop neurological complications. However, the presence of specific neurotropic HIV-1 strains, the extent of viral replication in the brain, and the type of cells infected remain controversial issues. To address this controversy we have analyzed different V3 loop sequences of viral isolates from four vertically HIV-1-infected children who developed HIV-1-related encephalopathy. Moreover, we have determined that some biological and molecular properties of HIV-1 might contribute to AIDS neurological dysfunctions. We detected very different HIV-1 isolates (X4 and R5) in the brain despite no great differences in clinical, pathological, or immunological parameters. In vitro, no differences in replicative competence in glial or neuroblastoma cells were observed between virus isolated from the blood of children with or without clinical neurological symptoms. The expression of both CXCR4 and CCR5 RNAs was observed in the brain independently of HIV-1 infection and viral strain predominant in this location. Our results failed to show a particular phenotypic property of the HIV-1 virus that might explain its neurovirulence and/or neurotropism.
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PMID:Lack of association of HIV-1 biological or molecular properties with neurotropism for brain cells. 1695 3

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

(1) HIV-1 and viral proteins-evoked chronic brain inflammation, which is characterized by microglial activation, is the pivotal neuropathogenesis of HIV-1-associated dementia (HAD). Platelet-activating factor (PAF), mainly released from activated microglia and acts as a high potent inflammatory mediator and a neurotoxin, is indicated to be a principle initiator of neuroinflammation, neuronal dysfunction, and apoptosis related to HAD. Thus, bis-interacting ligands of acetylcholinesterase (AChE) inhibition and PAF receptor antagonism would be of great interest in the therapeutic potential of HAD not only for improvement of cognitive performance, but also for disease-modifying. (2). We have previously reported that a novel tetrahydrofuran-derived bis-interacting ligand PMS777 had satisfying potencies for PAF receptor blockade and AChE inhibition, and markedly improved cholinergic dysfunction-induced cognitive impairment in mice. Continuing with our research, we further investigated the neuroprotective activities of PMS777 on PAF-triggered neuronal injury in human neuroblastoma SH-SY5Y cells. (3) The bis-interacting ligand PMS777 (10 muM) obviously alleviated PAF-induced cell apoptosis in SH-SY5Y cells. Pretreatment with PMS777 also markedly inhibited intracellular Ca(2+) overload, down-regulation of anti-apoptotic bcl-2 mRNA, stimulation of pro-apoptotic bax mRNA expression and activation of caspase-3 pathway. Also, PMS777 could fine-tune pro-inflammatory cyclooxygenase-2 (cox-2) mRNA expression in PAF-treated cells. (4) These results suggest that PMS777 possesses a neuroprotective profile via anti-apoptotic/inflammatory signaling and warrant further investigations in connection with the potential value of this compound in HAD treatment.
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PMID:PMS777, a bis-interacting ligand for PAF receptor antagonism and AChE inhibition, attenuates PAF-induced neurocytotoxicity in SH-SY5Y cells. 1771 22

Neuroblastoma (NB) is a neural crest precursor cell-derived extracranial solid tumor in children. Patients with a poor prognosis are often resistant to chemotherapy and have tumors that express the neuronal growth/survival factor brain-derived neurotrophic factor and its tyrosine kinase receptor, TrkB. In this article, the authors discuss a growth/survival factor-stimulated mechanism leading to chemoresistance in NB that is mediated by the PI3K/Akt signaling pathway. Besides brain-derived neurotrophic factor/TrkB, other growth/survival factors and their receptors also activate the PI3K/Akt pathway and have the potential to mediate chemoresistance in NB. These findings raise the possibility of a new therapeutic approach in NB that would target Akt, the common downstream mediator of multiple growth/survival factor signaling pathways, to enhance the efficacy of chemotherapeutics. Several classes of Akt inhibitors, including phosphatidylinositol ether lipid analogs, alkylphospholipid analogs, allosteric Akt kinase inhibitors, HSP90 inhibitor and HIV protease inhibitors are discussed.
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PMID:Targeting Akt to increase the sensitivity of neuroblastoma to chemotherapy: lessons learned from the brain-derived neurotrophic factor/TrkB signal transduction pathway. 1802 Sep 81

Monocytes/macrophages (M/M) are strategic reservoirs of HIV-1, spreading the virus to other cells and inducing apoptosis in T-lymphocytes, astrocytes and neurons. M/M are commonly infected by R5 HIV-1 strains, which use the chemokine receptor CCR5. D-Ala-peptide T-amide (DAPTA), or Peptide T, named for its high threonine content (ASTTTNYT), is a synthetic peptide comprised of eight amino acids (185-192) of the gp120 V2 region and functions as a viral entry inhibitor by targeting selectively CCR5. The anti-HIV-1 activity of DAPTA was evaluated in M/M infected with R5 HIV-1 strains. DAPTA at 10(-9) M inhibited HIV-1 replication in M/M by > 90%. PCR analysis of viral cDNA in M/M showed that DAPTA blocks HIV entry and in this way prevents HIV-1 infection. Moreover, DAPTA acts as a strong inhibitor and was more active than the non-peptidic CCR5 antagonist TAK-779 in inhibiting apoptosis (mediated by RS HIV-1 strains produced and released by infected M/M) on a neuroblastoma cell line. Our results suggest that antiviral compounds which interfere with receptor mechanisms such as CCR5 could be important, either alone or in combination with other antiretroviral treatments, in preventing HIV infection in the central nervous system and the consequential neuronal damage that leads to neuronal AIDS.
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PMID:Profound anti-HIV-1 activity of DAPTA in monocytes/macrophages and inhibition of CCR5-mediated apoptosis in neuronal cells. 1804 61

Parkinson's disease is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. The heat-shock protein 70 (Hsp70) reduces protein misfolding and aggregation. It has been shown to protect cells against oxidative stress and apoptotic stimuli in various neurodegenerative disease models. To deliver Hsp70 across cellular membranes and into the brain, we linked it to a cell-penetrating peptide derived from the HIV trans-activator of transcription (Tat) protein. In vitro, Tat-Hsp70 transduced neuroblastoma cells and protected primary mesencephalic DA neurons and their neurites against MPP+-mediated degeneration. In vivo, the systemic application of cell-permeable Hsp70 protected DA neurons of the substantia nigra pars compacta against subacute toxicity of MPTP. Furthermore, Tat-Hsp70 diminished the MPTP induced decrease in DA striatal fiber density. Thus, we demonstrate that systemically applied Tat-Hsp70 effectively prevents neuronal cell death in in vitro and in vivo models of Parkinson's disease. The use of Tat-fusion proteins might therefore be a valuable tool to deliver molecular chaperones like Hsp70 into the brain and may be the starting point for new protective strategies in neurodegenerative diseases.
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PMID:Tat-Hsp70 protects dopaminergic neurons in midbrain cultures and in the substantia nigra in models of Parkinson's disease. 1818 47

Microglia are innate immune cells in the central nervous system. Activation of microglia plays an important role in the processes of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated microglia can produce various proinflammatory cytokines and nitric oxide (NO), which may exert neurotoxic effects. Inhibition of microglia activation may alleviate neurodegeneration under these conditions. To search for the novel therapeutic agents against neuroinflammatory diseases, we have screened a series of flavonoid compounds using a cell-based assay. Our studies showed that fisetin markedly suppressed the production of tumor necrosis factor (TNF)-alpha, NO, and prostaglandin (PG) E2 in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells or primary microglia cultures. Fisetin also inhibited the gene expression of TNF-alpha, interleukin (IL)-1 beta, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) at both mRNA and protein levels. Fisetin significantly suppressed I kappa B degradation, nuclear translocation of NF-kappa B, and phosphorylation of p38 mitogen-activated protein kinase (MAPKs) in the LPS-stimulated BV-2 microglia cells. In addition, fisetin reduced cytotoxicity of LPS-stimulated microglia toward B35 neuroblastoma cells in a co-culture system. These results indicate that fisetin has a strong anti-inflammatory activity in brain microglia, and could be a potential therapeutic agent for the treatment of neuroinflammatory diseases.
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PMID:Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. 1827 3


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