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: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of p38 and c-jun-N-terminal kinases 1/2, members of the mitogen-activated protein kinase family, in mediating the toxic effects of human immunodeficiency virus-1 transactivator of transcription (Tat) and gp120 were explored in primary mouse striatal neurons in vitro. Both Tat and gp120 caused significant increases in p38 and c-jun-N-terminal kinase mitogen-activated protein kinase phosphorylation, caspase-3 activity, neurite losses and cell death in striatal neurons. Tat-induced increases in caspase-3 activity were significantly attenuated by an inhibitor of c-jun-N-terminal kinase (anthra[1,9-cd]pyrazol-6(2H)-one), but not by an inhibitor of p38 ([4-(4-fluorophenyl)-2-(4-methylsul-finylphenyl)-5-(4-pyridyl)1 H-imidazole]), mitogen-activated protein kinase. However, despite preventing increases in caspase-3 activity, c-jun-N-terminal kinase inhibition failed to avert Tat-induced neuronal losses suggesting that the reductions in caspase-3 activity were insufficient to prevent cell death caused by Tat. Alternatively, gp120-induced increases in caspase-3 activity, neurite losses and neuronal death were prevented by p38, but not c-jun-N-terminal kinase, mitogen-activated protein kinase inhibition. Our findings suggest that gp120 induces neuronal dysfunction and death through actions at p38 mitogen-activated protein kinase, while Tat kills neurons through actions that are independent of p38 or c-jun-N-terminal kinase mitogen-activated protein kinase, or through the concurrent activation of multiple proapoptotic pathways.
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PMID:Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons. 1611 29

Apoptotic loss of CD4+ T cells has been proposed as a mechanism of T cell depletion in human immunodeficiency virus (HIV) infections resulting in immunodeficiency. The Env glycoprotein has been implicated in apoptosis of uninfected bystander cells via gp120 binding to CD4/CXC chemokine receptor 4 as well as the fusion/hemifusion process mediated by gp41. Using an in vitro model of coculture of Env-expressing cells as effectors and CD4+ T cells as targets, we find that apoptosis mediated by Env glycoprotein in bystander cells in fact correlates with gp41-induced hemifusion. Further, the apoptotic pathway initiated by this interaction involves caspase-3-dependent mitochondrial depolarization and reactive oxygen species production. HIV gp41-induced mitochondrial depolarization is inhibited by protease inhibitor nelfinavir but not by other HIV protease inhibitors or inhibitors of calpain and cathepsin. This "kiss of death" (hemifusion) signaling pathway is independent of p38 mitogen-activated protein kinase and p53, making it distinct from the apoptosis seen in syncytia. We also show that virion-induced apoptosis is gp41-dependent. Our findings provide new insights into the mechanism via which HIV gp41 mediates apoptosis in bystander cells.
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PMID:HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir. 1633 May 30

The human immunodeficiency virus (HIV)-1 regulatory protein Vpr has been detected in the serum of HIV-seropositive individuals and in the cerebrospinal fluid of acquired immunodeficiency syndrome (AIDS) patients suffering from neurological disorders. Therefore, Vpr could play a critical role in the neuronal apoptosis observed postmortem in the brain of patients, often connected to a severe AIDS-related disease termed HIV-associated dementia (HAD). This suggests that the Vpr neurotoxicity already observed in vitro on hippocampal neurons could also occur in other brain structures. In this study the authors have investigated the ability of synthetic Vpr to induce apoptosis in primary cultures of rat cortical and striatal neurons. Moreover, the authors have explored the Vpr minimal proapoptotic region using synthetic Vpr fragments and mutants of the protein. Treatments of both neuronal types with Vpr, its C-terminal domain, Vpr(52-96), or a shorter fragment, Vpr(70-96), led to dose- and time-dependent cell death as determined by flow cytometry after propidium iodide labeling, phase-contrast microscopy, and TUNEL labeling. Taken together, these results support an apoptosis-induced death of these neurons. The (71-82) Vpr peptide, previously shown toxic to isolated mitochondria, was inactive on neurons. Vpr-induced neuronal apoptosis was associated with activation of caspase-3 beginning 3 h after Vpr extracellular addition and peaking 3 h later. Moreover, an hyperproduction of reactive oxygen species was observed. In addition to hippocampal neurons, the extension of the apoptotic property of Vpr to cortical and striatal neurons could account for several signs observed in HAD and is thus consistent with a possible involvement of Vpr in this syndrome.
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PMID:Critical implication of the (70-96) domain of human immunodeficiency virus type 1 Vpr protein in apoptosis of primary rat cortical and striatal neurons. 1633 43

The roles of methionine enkephalin, as an immunomodulator, on immunodeficiency virus-induced apoptosis of lymphocytes during prolonged infection are still unclear. In the present study, we evaluated the effects of methionine enkephalin on the viability, the profile of cell cycle and apoptosis, as well as the expression of apoptosis-related genes in CEM x 174 cells infected with simian immunodeficiency virus for 72 h. Our data demonstrated that methionine enkephalin maintains the viability of cells during the period of prolonged infection. Following co-incubation with the virus, CEM x 174 cells were arrested at S phase, with increased mortality as a result of apoptosis. Methionine enkephalin could abolish virus-induced over-expression of caspase-3. Taken together all findings, we conclude that methionine enkephalin may maintain the viability of SIV-infected cells via suppressing the expression of caspase-3, which may have clinical implications in opioid peptide therapy for AIDS.
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PMID:Involvement of caspase-3 pathway in anti-apoptotic action of methionine enkephalin on CEM x 174 cells in prolonged infection with simian immunodeficiency virus in vitro. 1645 26

Vpr of human immunodeficiency virus type 1 causes cell cycle arrest at the G(2)/M phase and induces apoptosis after G(2)/M arrest in primate cells. We have reported previously that Vpr also induces apoptosis independently of G(2)/M arrest in human HeLa cells. By contrast, Vpr does not induce G(2)/M arrest in rodent cells, but it retards cell growth. To clarify the relationship between cell cycle arrest and apoptosis, we expressed Vpr endogenously in rodent cells and investigated cell cycle profiles and apoptosis. We show here that Vpr induces cell cycle arrest at the G(1) phase and apoptosis in rodent cells. Vpr increased the activity of caspase-3 and caspase-9, but not of caspase-8. Moreover, Vpr-induced apoptosis could be inhibited by inhibitors of caspase-3 and caspase-9, but not by inhibitor of caspase-8. We also showed that Vpr induces the release of cytochrome c from mitochondria into the cytosol and disrupts the mitochondrial transmembrane potential. Finally, we showed that apoptosis occurred in HeLa cells through an identical pathway. These results suggest that disruption of mitochondrial functions by Vpr induces apoptosis via cell cycle arrest at G(1), but that apoptosis is independent of G(2)/M arrest. Furthermore, it appears that Vpr acts species-specifically with respect to induction of cell cycle arrest but not of apoptosis.
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PMID:Human immunodeficiency virus type 1 Vpr induces cell cycle arrest at the G(1) phase and apoptosis via disruption of mitochondrial function in rodent cells. 1648 Sep 11

Patients infected by human immunodeficiency virus type 1 (HIV-1) develop acquired immune deficiency syndrome-associated dementia complex (ADC), a disorder characterized by a broad spectrum of motor impairments and cognitive deficits. The number of cells in the brain that are productively infected by HIV-1 is relatively small and consists predominantly of macrophages and microglia, yet HIV-1 causes widespread neuronal loss. A better understanding of the pathogenic mechanisms mediating HIV-1 neurotoxicity is crucial for developing effective neuroprotective therapies against ADC. The HIV-1 envelope glycoprotein 120 (gp120), which is shed from the virus, is one of the agents causing neuronal cell death. However, the cellular mechanisms underlying its neurotoxic effect remain unclear. We report that gp120 injected into the rat striatum or hippocampus is sequestered by neurons and subsequently retrogradely transported to distal neurons that project to these brain areas. Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, hallmarks of apoptosis, were seen in neurons internalizing and transporting gp120. The retrograde transport of gp120 and apoptosis were mediated by the chemokine receptor CXCR4 because AMD3100, a selective CXCR4 inhibitor, blocked both events. Furthermore, colchicine or nocodazole, two inhibitors of intracellular trafficking, abolished gp120-mediated apoptosis in distal areas. These results indicate that axonal transport of gp120 might play a role in HIV-1-mediated widespread neuronal cell death.
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PMID:Axonal transport of human immunodeficiency virus type 1 envelope protein glycoprotein 120 is found in association with neuronal apoptosis. 1679 84

Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have progressive liver disease that frequently leads to cirrhosis and death. We previously showed that hepatocytes exposed to HCV and HIV envelope proteins undergo apoptosis via an innocent-bystander mechanism as a result of the cell surface binding of these proteins, independent of direct viral infection. Here, we have defined the mechanism of this hepatocytic apoptosis. We observed enhanced signal transducer and activator of transcription factor 1 (STAT1) activation and phosphorylation after costimulation with HCV-E2 and HIV-gp120. Moreover, inhibitor studies indicated that Lyn kinase, p38 mitogen-activated protein kinase, and protein kinase C delta might be involved in STAT1 phosphorylation. To elucidate the downstream STAT1-mediated signaling, we overexpressed wild-type STAT1 alpha and the C-terminal domain-deleted mutant STAT1 beta . STAT1 alpha overexpression increased cell apoptosis and Fas ligand expression, compared with STAT1 beta overexpression. STAT1 alpha also enhanced the release of cytochrome c from the mitochondria and caspase-3 activity. These studies indicate that the HCV/HIV envelope proteins cooperatively induce hepatocytic apoptosis by activating a novel downstream STAT1 signaling pathway.
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PMID:Signal transducer and activator of transcription factor 1 mediates apoptosis induced by hepatitis C virus and HIV envelope proteins in hepatocytes. 1719 63

The mechanisms of CD4(+) T-cell depletion during human immunodeficiency virus type 1 (HIV-1) infection remain incompletely characterized. Of particular importance is how CD4(+) T cells are depleted within the lymphoid organs, including the lymph nodes and thymus. Herein we characterize the pathogenic mechanisms of an envelope from a rapid progressor (R3A Env) in the NL4-3 backbone (NL4-R3A) which is able to efficiently replicate and deplete CD4(+) thymocytes in the human fetal-thymus organ culture (HF-TOC). We demonstrate that uninterrupted replication is required for continual thymocyte depletion. During depletion, NL4-R3A induces an increase in thymocytes which uptake 7AAD, a marker of cell death, and which express active caspase-3, a marker of apoptosis. While 7AAD uptake is observed predominantly in uninfected thymocytes (p24(-)), active caspase-3 is expressed in both infected (p24(+)) and uninfected thymocytes (p24(-)). When added to HF-TOC with ongoing infection, the protease inhibitor saquinavir efficiently suppresses NL4-R3A replication. In contrast, the fusion inhibitors T20 and C34 allow for sustained HIV-1 production. Interestingly, T20 and C34 effectively prevent thymocyte depletion in spite of this sustained replication. Apoptosis of both p24(-) and p24(+) thymocytes appears to be envelope fusion dependent, as T20, but not saquinavir, is capable of reducing thymocyte apoptosis. Together, our data support a model whereby pathogenic envelope-dependent fusion contributes to thymocyte depletion in HIV-1-infected thymus, correlated with induction of apoptosis in both p24(+) and p24(-) thymocytes.
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PMID:Fusion-induced apoptosis contributes to thymocyte depletion by a pathogenic human immunodeficiency virus type 1 envelope in the human thymus. 1695 34

Uninfected neurons of the substantia nigra (SN) degenerate in human immunodeficiency virus (HIV)-positive patients through an unknown etiology. The HIV envelope glycoprotein 120 (gp120) causes apoptotic neuronal cell death in the rodent striatum, but its primary neurotoxic mechanism is still under investigation. Previous studies have shown that gp120 causes neurotoxicity in the rat striatum by reducing brain-derived neurotrophic factor (BDNF). Because glial cell line-derived neurotrophic factor (GDNF) and BDNF are neurotrophic factors crucial for the survival of dopaminergic neurons of the SN, we investigated whether gp120 reduces GDNF and BDNF levels concomitantly to induce apoptosis. Rats received a microinjection of gp120 or vehicle into the striatum and were sacrificed at various time intervals. GDNF but not BDNF immunoreactivity was decreased in the SN by 4 days in gp120-treated rats. In these animals, a significant increase in the number of caspase-3- positive neurons, both tyrosine hydroxylase (TH)-positive and -negative, was observed. Analysis of TH immunoreactivity revealed fewer TH-positive neurons and fibers in a medial and lateral portion of cell group A9 of the SN, an area that projects to the striatum, suggesting that gp120 induces retrograde degeneration of nigrostriatal neurons. We propose that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor expression by gp120.
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PMID:Intrastriatal administration of human immunodeficiency virus-1 glycoprotein 120 reduces glial cell-line derived neurotrophic factor levels and causes apoptosis in the substantia nigra. 1696 4

Human immunodeficiency virus dementia (HIVD) is the most common form of dementia occurring among young adults. In HIVD, neuronal cell loss occurs in the absence of neuronal infection. With the advent of highly active anti-retroviral therapy (HAART), the incidence of HIVD has drastically reduced, though prevalence of milder forms of HIVD continues to rise. Though these agents have been used successfully in suppressing viral production, they have also been associated with a number of side effects. Here we examine the possible role of NRTIs, in particular 2',3'-dideoxycytidine (ddC), in the neuropathology of HIVD. Synaptosomes and isolated mitochondria treated and incubated for 6 h with CSF-achievable concentrations of ddC, i.e., 6-11 ng/ml, were found to show a significant increase in oxidative stress with 40 nM ddC as measured by protein carbonyls and 3-nitrotyrosine (3NT), effects that were not observed in the more tolerable NRTI, 3TC. Protection against protein oxidation induced by ddC was observed when brain mitochondria were isolated from gerbils 1 h after injection i.p. with the brain accessible antioxidant and glutathione mimetic, tricyclodecan-9-yl-xanthogenate (D609). In addition, there is a significant reduction in the levels of anti-apoptotic protein Bcl-2 and a significant increase in cytochrome c release and also a significant increase in the expression of pro-apoptotic protein caspase-3 after mitochondria were treated with 40 nM ddC. The results reported here show that ddC at 40 nM can induce oxidative stress, cause the release of cytochrome c, and in addition, reduce the levels of anti-apoptotic proteins, increase the levels of pro-apoptotic proteins, thereby increasing the possibility for induction of apoptosis. These findings are consistent with the notion of a possible role of the NRTIs, and in particular, ddC, in the mechanisms involved in HIVD.
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PMID:Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)--2',3'-dideoxycytidine (ddC): relevance to HIV-dementia. 1706 2


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