Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated 27 azulene derivatives for their relative cytotoxicity against three human normal cells and three human oral tumor cell lines. 2-Acetylaminoazulene [4], diethyl 2-chlorozulene-1,3-dicarboxylate [9] and methyl 7-isopropyl-2-methoxyazulene-1-carboxylate [24] showed higher tumor-specific cytotoxicity than azulene [1] and guaiazulene [2]. Four 1- and 3-halogenated compounds showed lower tumor specificity. The tumor-specific cytotoxic activity seems not to be related to the position of functional groups. All compounds showed no anti-HIV activity. Methyl 7-isopropyl-2-methoxyazulene-1-carboxylate [24] induced apoptotic cell death (characterized by internucleosomal DNA fragmentation and caspase 3 activation) in HL-60 cells. ESR spectroscopy showed that methyl 7-isopropyl-2-methoxyazulene-1-carboxylate [24] did not produce radical and less efficiently scavenged O2- (generated by HX-XOD reaction) and NO (generated from NOC-7). These data suggest that a radical-mediated oxidation mechanism may not be involved in the apoptosis induction by methyl 7-isopropyl-2-methoxyazulene-1-carboxylate [24].
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PMID:Cytotoxic activity of azulenes against human oral tumor cell lines. 1498 22

Death-associated protein kinase (DAP kinase) is a proapoptotic serine/threonine kinase that has been shown to play a role in both death-receptor signaling and mitochondrial signaling pathways of apoptosis. DAP kinase activates the p19ARF-p53 apoptotic checkpoint. In this study we report that the expression of DAP kinase, p19ARF, p53, and p21WAF1 was significantly down-regulated in the chronically HIV-1SF2-infected HUT78 T cells (HUT78/HIV-1SF2) as compared to uninfected HUT78 cells. An increased proportion of HUT78/HIV1SF2 cells was detected in S phase and a decreased proportion in G0/G1 phase indicating that more HUT78/HIV1SF2 cells progressed through the G1/S transition. Furthermore, HUT78/HIV-1SF2 cells showed increased resistance to CD95-mediated apoptosis as compared to HIV-1SF2-uninfected HUT78 cells and activation of caspase-3, -8, and -9 was significantly reduced in HUT78/HIV-1SF2 cells. These data suggest that down-regulation of DAP kinase and downstream signaling factors may be one of the mechanism that HIV-1 may employ to protect the infected host cells from cell death and to allow persistent HIV-1 replication.
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PMID:Chronic HIV type 1 infection down-regulates expression of DAP kinase and p19ARF-p53 checkpoint and is associated with resistance to CD95-mediated apoptosis in HUT78 T cells. 1501 6

CD8(+) T cells play a crucial role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. Recent data suggest that HIV-1-specific CD8(+) T cell subsets may differ in their ability to exert these effector functions. Here, we directly compared the cytokine secretion patterns and cytotoxic capacity of HIV-1-specific CD8(+) T cells, using a flow-cytometric cytotoxicity assay based on caspase-3 activation in dying target cells. These experiments revealed considerable intraindividual and interindividual differences among epitope-specific T-cell effector functions: while the frequency of HIV-1-specific CD8(+) T cells secreting interferon-gamma but no tumor necrosis factor-alpha (TNF-alpha) following antigenic stimulation was only weakly correlated to their cytotoxic activity (R = 0.05, P =.57), a subset of CD8(+) T cells secreting both inter-feron-gamma and TNF-alpha was substantially more strongly associated with cytotoxicity (R = 0.67, P <.001). This subset of CD8(+) T cells also exhibited stronger intracellular perforin expression and more pronounced direct ex vivo HIV-1-specific cytoxicity than CD8(+) T cells secreting solely interferon-gamma following sorting of these subpopulations according to their cytokine profile. These results suggest that HIV-1-specific cytotoxicity of CD8(+) T cells is preferentially mediated by a subset of CD8(+) T cells secreting both interferon-gamma and TNF-alpha.
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PMID:HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8(+) T cells producing both interferon-gamma and tumor necrosis factor-alpha. 1505 48

Patients infected with human immunodeficiency virus type 1 (HIV-1) develop a spectrum of B cell lymphoproliferative disorders ranging from polyclonal B cell activation to B cell lymphomas. While a direct role of Epstein-Barr virus (EBV) is well recognized for most of these lesions, recent findings have suggested that transactivator HIV-1 Tat protein might be involved in the pathogenesis of B cell lymphomas. Tat-expressing EBV-positive B cells were generated by transduction with a retroviral Tat-encoding vector. B(Tat+) cells expressed lower levels of anti-apoptotic protein Bcl-2 than parental and control B(Tat-) cells, generated by transduction with an empty retroviral vector, and were more prone to apoptosis upon serum withdrawal, as assessed by analysis of annexin V-stained cells and cleavage of poly-ADP-ribose-polymerase by caspase 3. Nevertheless, in serum starvation, B(Tat-) cells mainly exhibited the Rb hypo-phosphorylated form, underwent cell cycle arrest, and grew in single cell suspension, while B(Tat+) cells displayed the Rb hyper-phoshorylated form, progressed throughout the cell cycle, and retained the ability to grow in small clumps. Finding that B(Tat+) cells maintained proliferative capacity upon serum withdrawal suggests that cells expressing Tat have growth advantages among the EBV-driven cell proliferations and may originate B cell clones with more oncogenic potential.
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PMID:Human immunodeficiency virus type 1 Tat protein modulates cell cycle and apoptosis in Epstein-Barr virus-immortalized B cells. 1509 50

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system is associated with microglia activation and neuronal apoptosis, alterations that are also caused by the HIV-1 envelope glycoprotein 120 (gp120) alone. This study was undertaken to examine the onset of gp120 neurotoxicity, the type of cell death and which cells of the adult rat brain are more sensitive to the toxic action of gp120. Gp120 or vehicle were injected chronically (daily for 3 or 7 days) into the lateral ventricle. Magnetic resonance imaging revealed hypertensive areas in the cortical and hippocampal gray matter in gp120-treated rats 7-10 days after the first injection, suggesting vasogenic edema. This phenomenon was accompanied by an enlargement of the lateral and third ventricles. Immunohistochemical analyses were then carried out to examine the toxic effect of gp120 at a cellular level. Several markers of apoptosis, including activated caspase-3 were observed at both 3 and 7 days throughout brains of gp120-treated rats, especially in the cerebral cortex. In this area, most of the apoptotic cells exhibited a pyramidal shape and were Nissl positive, indicative of neurons. Few non-neuronal cells exhibited signs of apoptosis. The results of the present study support the notion that gp120 is neurotoxic in vivo and provide evidence that gp120 activates a caspase-dependent apoptotic pathway.
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PMID:Human immunodeficiency virus type 1 protein gp120 causes neuronal cell death in the rat brain by activating caspases. 1511 Dec 37

Human immunodeficiency virus-1 (HIV-1) infection affects the striatum, resulting in gliosis and neuronal losses. To determine whether HIV-1 proteins induce striatal neurotoxicity through an apoptotic mechanism, mouse striatal neurons isolated on embryonic day 15 and the effects of HIV-1 Tat(1-72) and gp120 on survival were assessed in vitro. Mitochondrial release of cytochrome c, caspase-3 activation, and neuron survival, as well as an alternative apoptotic pathway involving endonuclease G (endo G), were assessed at 4 h, 24 h, 48 h, and/or 72 h using enzyme assays and immunoblotting. Both HIV-1 Tat and gp120 significantly increased caspase-3 activation in a concentration-dependent manner in striatal neurons at 4 h following continuous exposure in vitro. Tat(1-72) and gp120 caused significant neuronal losses at 48 h and/or 72 h. Tat(1-72) increased cytochrome c release, and caspase-3 and endo G activation at 4 h, 24 h, and/or 72 h. By contrast, gp120 increased caspase-3 activation, but failed to increase cytochrome c or endo G levels in the cytoplasm at 4 h, 24 h, and/or 72 h. The cell permeant caspase inhibitor Z-DEVD-FMK significantly attenuated gp120-induced, but not Tat(1-72)-induced, neuronal death, suggesting that gp120 acts in large part through the activation of caspase(s), whereas Tat(1-72)-induced neurotoxicity was accompanied by activating an alternative pathway involving endo G. Thus, although Tat(1-72) and gp120 induced significant neurotoxicity, the nature of the apoptotic events preceding death differed. Collectively, our findings suggest that HIV-1 proteins are intrinsically toxic to striatal neurons and the pathogenesis is mediated through separate actions involving both caspase-3 and endo G.
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PMID:Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G. 1520 19

Human immunodeficiency virus (HIV)-1 infection can cause characteristic neural defects such as progressive motor dysfunction, striatal pathology and gliosis. Recent evidence suggests that HIV-induced pathogenesis is exacerbated by heroin abuse and that the synergistic neurotoxicity is a direct effect of heroin on the CNS, an alarming observation considering the high incidence of HIV infection with injection drug abuse. Although HIV infection results in neurodegeneration, neurons themselves are not directly infected. Instead, HIV affects microglia and astroglia, which subsequently contributes to the neurodegenerative changes. Opioid receptors are widely expressed by macroglia and macroglial precursors, and the activation of mu-opioid receptors can modulate programmed cell death, as well as the response of neural cells to cytotoxic insults. For this reason, we questioned whether opioid drugs might modify the vulnerability of macroglia and macroglial precursors to HIV-1 Tat protein. To address this problem, the effects of morphine and/or HIV Tat(1-72) on the viability of macroglia and macroglial precursors were assessed in mixed-glial cultures derived from mouse striatum. Our findings indicate that sustained exposure to morphine and Tat(1-72) viral protein induces the preferential death of glial precursors and some astrocytes. Moreover, the increased cell death is mediated by mu-opioid receptors and accompanied by the activation of caspase-3. Our results imply that opiates can enhance the cytotoxicity of HIV-1 Tat through direct actions on glial precursors and/or astroglia, suggesting novel cellular targets for HIV-opiate interactions.
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PMID:Preferential vulnerability of astroglia and glial precursors to combined opioid and HIV-1 Tat exposure in vitro. 1521 73

We examined heart tissues of AIDS patients with or without HIV cardiomyopathy (HIVCM) by immunohistochemistry, in situ polymerase chain reaction, in situ riboprobe hybridization, and the TUNEL technique for apoptosis. In HIVCM tissues, only inflammatory cells, but not endothelial cells or cardiomyocytes, displayed HIV-1 DNA and RNA. However, macrophages, lymphocytes, and--in a patchy fashion--cardiomyocytes and endothelial cells exhibited virus envelope protein gp120. Macrophages infiltrated the myocardium in a perivascular fashion and expressed tumor necrosis factor family ligands; adjacent cardiomyocytes suffered apoptosis. In vitro HIV-1 strongly invaded neonatal rat ventricular myocytes (NRVMs) and coronary artery endothelial cells (CAECs) and induced microvilli but did not replicate. HIV-1, gp120, or Tat induced Erk 1/2 phosphorylation, activation of caspase-3, and apoptosis of NRVMs and CAECs; all of these were inhibited by a MAPK/ERK-kinase (MEK) inhibitor U0126. The pathogenesis of HIVCM involves HIV-1 replication in inflammatory cells and induction of cardiomyocyte apoptosis by (1) the extrinsic pathway through apoptotic ligands and (2) the intrinsic pathway through direct virus entry and gp120- and Tat-proapoptotic signaling.
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PMID:HIV-1 induces cardiomyopathyby cardiomyocyte invasion and gp120, Tat, and cytokine apoptotic signaling. 1537 27

The mechanisms of neuronal apoptosis in prion diseases are unclear. Experimental studies suggest that it may result from 2 associated mechanisms: glutamate-mediated excitotoxicity and oxidative stress. Recent studies showed that activated macrophages/microglia (AMM) express excitatory amino acid transporters (EAATs) in HIV infection, suggesting that they may play a neuroprotective role by clearing extra-cellular glutamate and producing anti-oxidant glutathione. In order to test this hypothesis in prion diseases, samples from cerebral cortex, striatum, thalamus, and cerebellum from 14 patients with Creutzfeldt-Jakob disease (8 sporadic, 2 familial, 2 iatrogenic, and 2 variant), and 4 with fatal familial insomnia (3 homozygous Met/Met at codon 129 of the PRNP gene, 1 heterozygous Met/Val), and 3 controls were immunostained for EAAT-1, GFAP, HLA-DR, CD68, IL-1, caspase 3, and PrP. In prion diseases, EAAT-1 immunopositivity was found in affected areas. Only AMM, interstitial, perivascular, perineuronal (sometimes around apoptotic neurons), or close to reactive astrocytes, expressed EAAT-1. Astrocyte EAAT-1 expression was scarcely detectable in controls and was not detected in prion disease cases. The proportion of AMM expressing EAAT-1 did not correlate with the severity of neuronal apoptosis, spongiosis, astrocytosis, microgliosis, or PrP deposition, but only with disease duration. Occasional EAAT-1 expressing AMM were found in patients with short survival, whereas diffuse EAAT-1 expression by AMM was observed in cases with long survival (24 to 33 months) that most often were heterozygous for Met/Val at codon 129 of the PRNP gene. Our findings suggest that AMM may develop a partial neuroprotective function in long-lasting prion diseases, although it does not seem to efficiently prevent neurological and neuropathological deterioration. Whether this neuroprotective function of microglia is the cause or the effect of longer survival needs to be clarified.
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PMID:Expression of excitatory amino acid transporter-1 (EAAT-1) in brain macrophages and microglia of patients with prion diseases. 1553 33

Neuronal loss has been observed in post mortem brains of patients with human immunodeficiency virus type 1 (HIV-1). Experimental evidence has implicated HIV-1-derived envelope glycoprotein 120 (gp120) in the neuronal cell death observed in these patients. However, the intrinsic mechanisms by which gp120 causes neurotoxicity are still unknown. We have recently shown that the neurotoxic effect of gp120 in vitro is reduced by brain-derived neurotrophic factor (BDNF). We therefore tested the hypothesis that low levels of BDNF render neurons more sensitive to gp120. Gp120 was injected acutely into the striatum of BDNF heterozygous mice and wild-type littermates. BDNF heterozygous mice exhibited more apoptotic neurons in the striatum than wild-type mice, suggesting that BDNF is neuroprotective also in vivo. Because several neurodegenerative disorders are characterized by lack of trophic support, we tested the hypothesis that gp120 may cause apoptosis by reducing BDNF expression. Gp120 was injected acutely in the rat striatum and BDNF levels determined by a two-site immunoassay at various times after the injection. Gp120 elicited a dramatic decrease in BDNF protein levels by 24 h. Reduced BDNF levels were still present at 4 days. Cellular localization of BDNF immunoreactivity revealed that gp120 decreases BDNF immunoreactivity mainly in neuronal processes. This effect of gp120 precedes the peak of caspase-3 activation and neuronal cell death. We propose that one of the mechanisms whereby gp120 causes neurotoxicity is a reduction of the neurotrophic factor environment crucial for cell survival.
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PMID:Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death. 1557 39


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