Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence in vitro has suggested that neuronal injury observed in the acquired immunodeficiency syndrome dementia complex may depend, at least in part, on toxic effects of the human immunodeficiency virus type 1 envelope protein, gp120. This laboratory previously reported that members of the dihydropyridine class of calcium channel antagonists, nimodipine and nifedipine, greatly attenuate the rise in intracellular calcium engendered by gp120 and prevent subsequent neuronal injury. The relatively low (nanomolar) concentrations of dihydropyridines that were effective suggested that their action might be exerted at the level of the L-type of voltage-dependent calcium channels. In the present study, I tested members of the three other major classes of Ca2+ channel antagonist drugs to determine if they too could prevent neurotoxicity induced by gp120. At the maximal dose that did not cause neuronal damage in and of itself, a diphenylalkylamine piperazine derivative (flunarizine, 10 microM) was the most effective, a phenylalkylamine (verapamil, 100 microM) was possibly effective, whereas a benzothiazepine (diltiazem, 1 microM) was ineffectual in protecting rat retinal ganglion cells from gp120-induced toxicity in vitro. To explain these results, previous work has shown that the various classes of Ca2+ channel antagonists may exhibit differential potency in blocking voltage-dependent Ca2+ current in neurons, with dihydropyridines and flunarizine being the most potent at neuronal calcium channels. Moreover, these channels on mammalian central neurons are relatively insensitive to agents such as verapamil and diltiazem compared with other cell types like muscle. The low micromolar concentrations necessary for potency of flunarizine is in keeping with that predicted by binding and electrophysiological studies for block of voltage-dependent calcium channels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium channel antagonists and human immunodeficiency virus coat protein-mediated neuronal injury. 165 45

Cell signaling events are known to affect human immunodeficiency virus type 1 (HIV-1) replication. Treatment of lymphoid CEM cells with the calcium channel blocker verapamil (25-75 microM) enhanced HIV-1 expression in acute, whole virus infection experiments, despite lowering intracellular calcium levels, ablating the acute rise in intracellular calcium normally seen with infection, and lengthening the doubling time of cell replication. Verapamil had no effect on cell surface CD4 expression. Transfection of CEM cells with plasmids containing the HIV-1 long terminal repeat linked to the chloramphenicol acetyltransferase reporter gene showed that verapamil enhanced expression of the HIV-1 long terminal repeat in a dose-dependent fashion. This effect was abolished by mutations in the binding sites for nuclear factor kappa-B. Electrophoretic mobility shift assays confirmed that verapamil induced nuclear factor kappa-B activity in CEM cells. Thus, verapamil, in high concentrations, can potentiate HIV-1 replication in lymphoid cells, and this effect may be mediated by induction of nuclear factor kappa-B.
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PMID:Effect of the calcium channel blocker verapamil on human immunodeficiency virus type 1 replication in lymphoid cells. 171 54

Many of the advances in the management of non-Hodgkin's lymphomas have been based on more precise understanding of the various cell types that constitute these disorders. During the past year, we have seen some dramatic changes in the therapeutic approach to low-grade lymphomas. Until recently, the usual approach to these disorders was a purely palliative one, but a number of publications from the past year describe a more intensive approach with the goal of developing a curative modality. The use of combination chemotherapy in addition to radiation therapy for the early Ann Arbor stages as well as the use of high-dose chemotherapy with bone marrow transplantation in patients with high-risk factors has been reported recently. In the area of intermediate-grade lymphomas, most of the recent publications have described prognostic factors associated with various chemotherapy protocols. One of the most interesting recent developments is related to the dose-intensity issue. A consensus appears to be developing in regard to the correlation of dose intensity with clinical outcome. Despite the fact that new third-generation regimens have been associated with cures in 50% to 66% of the patients, a significant fraction of patients require salvage chemotherapy. Some of the new salvage regimens are discussed, as is the use of calcium channel blockers to reverse multiple-drug resistance. Finally, management of the high-grade lymphomas, specifically the small noncleaved cell type, has been associated with a cure rate in the range of 50% in two recently published studies. Patients who are human immunodeficiency virus-positive with small noncleaved cell lymphoma can be cured of their underlying malignancy, but many of them later develop complications of acquired immunodeficiency syndrome, to which they usually succumb.
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PMID:Treatment of non-Hodgkin's lymphoma. 175 77

Coat protein gp120 from the human immunodeficiency virus type-1 (HIV-1) increased intracellular free calcium and injured rodent retinal ganglion cells and hippocampal neurons in culture. Highly purified recombinant gp120 envelope protein produced these effects in a dose-dependent fashion at picomolar concentrations. Immunoprecipitation with antibody to gp120, but not with control immunoglobulin-containing serum, depleted solutions of the viral envelope protein and also prevented both the rise in intracellular calcium and neuronal toxicity. The gp120-induced increase in intracellular calcium was abrogated by transiently lowering extracellular calcium or by adding the dihydropyridine calcium channel antagonist nimodipine (100 nM). Calcium channel antagonists also prevented gp120-induced neuronal injury. In addition, intracellular stores appeared to contribute substantially to the increase in calcium elicited by gp120. Since increases in intracellular calcium have been associated with neurotoxicity, it is possible that an injurious effect of gp120 on neurons might be related to this mechanism and that treatment with calcium channel antagonists may prove useful in mitigating HIV-1-related neuronal injury.
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PMID:HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. 232 43

The effects of human immunodeficiency virus type-1 (HIV-1) coat protein gp120 on levels of intrasynaptosomal calcium ([Ca2+]i) were determined in rat cortical synaptosomes. gp120 at concentrations of > or = 400 pM, significantly (P < 0.05) increased levels of [Ca2+]i. Treatment with 20 mM KCl, reduced the concentrations of gp120 necessary to produce significant (P < 0.001) increases in [Ca2+]i. gp120-evoked increases in [Ca2+]i were prevented either by treatment with dantrolene or by removal of extracellular calcium with BAPTA. The peak levels of gp120-induced increases in [Ca2+]i were not affected by calcium channel blockers lanthanum and nicardipine, by glutamate receptor antagonists MK-801 and NBQX, or by removal of endogenous glutamate with glutamate dehydrogenase. gp120-induced [Ca2+]i increases in presynaptic terminals may play a role in HIV-mediated effects in the central nervous system.
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PMID:HIV-1 coat protein gp120-induced increases in levels of intrasynaptosomal calcium. 762 Aug 88

Activation of CD4 positive T cells is a primary requirement for human immunodeficiency virus (HIV) entry, efficient HIV replication, and progression to AIDS, Utilizing CD4 positive T cell lines and purified T cells from normal individuals, we have demonstrated that native envelope glycoproteins of HIV, gp 160, can induce activation of transcription factor, activated protein-1 (AP-1). The stimulatory effects of gp160 are mediated through the CD4 molecule, since treatment of gp160 with soluble CD4-IgG abrogates its activity, and CD4 negative T cell lines fail to be stimulated with gp160. Immunoprecipitation of the gp 160-induced nuclear extracts with polyclonal antibodies to Fos and Jun proteins indicates that AP-1 complex is comprised of members of these family of proteins. The gp160-induced AP-1 complex is dependent upon protein tyrosine phosphorylation and is protein synthesis-independent. This stimulation can also be abolished by inhibitors of protein kinase C, but it is unaffected by calcium channel blocker or cyclosporine A. This gp160 treatment adversely affects the functional capabilities of T cells: pre-treatment of CD4+ T cells with gp160 for 4 h at 37 degrees C inhibited anti-CD3-induced interleukin-2 secretion. Effects similar to gp160 were seen with anti-CD4 mAb. The aberrant activation of AP-1 by gp160 in CD4 positive T cells could result in up-regulation of cytokines containing AP-1 sites, e.g. interleukin-3 and granulocyte macrophage colony-stimulating factor, and concurrently lead to T cell unresponsiveness by inhibiting interleukin-2 secretion.
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PMID:HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells. 764 15

We have studied the role of intracellular calcium sequestration on human immunodeficiency virus (HIV) production by latently infected T-lymphocytic cells. Inhibition of the sarco-endoplasmic reticulum-type calcium transport ATPases by thapsigargin or cyclopiazonic acid induced activation of HIV production in the CEM-derived ACH-2 cells. An approximately 50% depletion of the thapsigargin-sensitive calcium pools as measured fluorimetrically of Indo-loaded cells fully activated virus production. Viral activation was manifest by increases in soluble viral core p24 production, increases in cellular immunofluorescent staining for viral antigens, and increased viral transcription as measured by HIV long terminal repeat-directed expression of the chloramphenicol acetyltransferase reporter gene. Virus induction could be blocked in a dose-dependent manner by the calcium channel blocker econazole. Virus production by the Jurkat-derived HIV-1-inducible J1.1 cells was not significantly stimulated by thapsigargin. These data indicate that intracellular calcium pool function is involved in the control of the transcription of proviral HIV in a cell type-specific manner within the T-lymphoid lineage and that ACH-2 cells represent a useful model for the study of calcium dependent activation of the transcription of proviral HIV.
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PMID:Stimulation of HIV expression by intracellular calcium pump inhibition. 773 Mar 32

Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:AIDS-related dementia and calcium homeostasis. 784 72

Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. 799 15

The effects of a synthetic peptide fragment of human immunodeficiency virus gp120 (HIV gp120) on opioid (D-ala2-D-met5 enkephalinamide; DAMA) and interleukin-1 (IL-1) induced chemotactic responses in human granulocytes and monocytes and invertebrate (Mytilus edulis) immunocytes were studied. Both DAMA and IL-1 increased the velocity of cell migration from both species and the response is chemotactic (e.g. directed). Non-treated control cells move randomly or not at all. The addition of gp120 to DAMA or IL-1 treated human granulocytes or monocytes results in a slower movement which is chemokinetic (loss of directionality or random) in nature. A similar phenomenon occurs in the invertebrate immunocytes. If gp120 alone is added, it inhibits the movement of spontaneously active human granulocytes and Mytilus edulis immunocytes. In contrast, it stimulates chemokinesis of spontaneously active human monocytes. These responses occur immediately after addition of the peptide. Based on experiments with the selective calcium channel antagonist nimodipine, it appears that the gp120 causes its effects by irreversible binding to a calcium channel. Our results suggest a universal inhibitory mechanism is occurring since the invertebrate immunocytes must recognize HIV gp120 peptide to result in this effect, possibly through a CD4 or other type of surface determinant.
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PMID:HIV gp120 alteration of DAMA and IL-1 alpha induced chemotaxic responses in human and invertebrate immunocytes. 845 86


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