Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of intracellular free zinc and its chelation by TPEN (N,N,N',N'- tetrakis(2-pyridylmethyl)ethylene-diamine) was studied in Bowes human melanoma cells. The content of free Zn pools was determined by fluorescent probe Zinquin. Depletion of zinc triggered apoptosis confirmed by cell blebbing, changes in mitochondrial transmembrane potential and GSH levels, caspase-3 activation and nuclear fragmentation. Apoptosis was only partially prevented by cyclosporin A or N-acetylcystein, suggesting various independent but likely interrelated mechanisms participating in this process.
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PMID:Depletion of endogenous zinc stores induces oxidative stress and cell death in human melanoma cells. 1544 56

The programmed cell death-so-called apoptosis-is a physiological process occurring in all multicellular organisms to control cell-number homeostasis. Nevertheless, increase of apoptotic cell death in different organs can lead to pathological alterations. As zinc is a potent inhibitor of apoptosis, we investigated the influence of zinc deficiency on mRNA expression levels of caspase-3 and Fas in adult rats. For this purpose, 24 adult rats fed a Zn-deficient diet for up to 29 days were compared to seven animals in the control group. After 1, 2, 4, 7, 11, 16, 22 and 29 days of treatment three animals were sacrificed (n = 24). Total RNA extraction from thymus, liver, jejunum and colon was carried out. Samples were reverse transcribed and subjected to real-time PCR. Relative quantification of caspase-3 and Fas mRNA expression was achieved on the basis of normalisation by glycerolaldehyd-3-phosphate-dehydrogenase mRNA expression levels in all samples. In jejunum, up to day 11 the relative mRNA expression of the respective genes decreased. A significant increase in caspase-3 and Fas expression was found from day 11 of zinc deficiency onward. In contrast, mRNA expression in liver and colon remained unaffected, whereas thymus showed a slight but not significant increase in the expression of these genes. This study provides the first evidence that even moderate zinc deficiency in an adult, non-growing rat model is able to elevate mRNA expression levels of factors involved in early stages of apoptosis.
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PMID:Elevated caspase-3 and Fas mRNA expression in jejunum of adult rats during subclinical zinc deficiency. 1548 62

The levels of zinc in the brain are directly affected by dietary zinc and deficiency has been associated with alcohol withdrawal seizures, excitotoxicity, impaired learning and memory and an accelerated rate of dysfunction in aged brain. Although zinc is essential for a healthy nervous system, high concentrations of zinc are neurotoxic, thus it is important to identify the most effective forms of zinc for treatment of conditions of the central nervous system. Accumulating evidence suggests that zinc-histidine complex (Zn(His)(2)) has greater biological potency and enhanced bioavailability compared with other zinc salts and also has antioxidant potential. Therefore, in this study we investigated the ability of zinc-histidine to protect cultured cortical neurons against hydrogen peroxide-induced damage. Pre-treating neurons for 18 h with subtoxic concentrations of zinc-histidine (5-25 microM) improved neuronal viability and strongly inhibited hydrogen peroxide-induced (75 microM, 30 min) cell damage as assessed by MTT turnover and morphological analysis 24h later. Low concentrations of zinc-histidine were more neuroprotective than zinc chloride. There was evidence of an anti-apoptotic mechanism of action as zinc-histidine inhibited hydrogen peroxide-induced caspase-3 activation and c-jun-N-terminal kinase phosphorylation. In summary, zinc supplementation with zinc-histidine protects cultured neurons against oxidative insults and inhibits apoptosis which suggests that zinc-histidine may be beneficial in the treatment of diseases of the CNS associated with zinc deficiency.
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PMID:Zinc-histidine complex protects cultured cortical neurons against oxidative stress-induced damage. 1551 38

Transient global ischemia induces a delayed rise in intracellular Zn2+, which may be mediated via glutamate receptor 2 (GluR2)-lacking AMPA receptors (AMPARs), and selective, delayed death of hippocampal CA1 neurons. The molecular mechanisms underlying Zn2+ toxicity in vivo are not well delineated. Here we show the striking finding that intraventricular injection of the high-affinity Zn2+ chelator calcium EDTA (CaEDTA) at 30 min before ischemia (early CaEDTA) or at 48-60 hr (late CaEDTA), but not 3-6 hr, after ischemia, afforded robust protection of CA1 neurons in approximately 50% (late CaEDTA) to 75% (early CaEDTA) of animals. We also show that Zn2+ acts via temporally distinct mechanisms to promote neuronal death. Early CaEDTA attenuated ischemia-induced GluR2 mRNA and protein downregulation (and, by inference, formation of Zn2+-permeable AMPARs), the delayed rise in Zn2+, and neuronal death. These findings suggest that Zn2+ acts at step(s) upstream from GluR2 gene downregulation and implicate Zn2+ in transcriptional regulation and/or GluR2 mRNA stability. Early CaEDTA also blocked mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with low pI), caspase-3 activity (but not procaspase-3 cleavage), p75NTR induction, and DNA fragmentation. These findings indicate that CaEDTA preserves the functional integrity of the mitochondrial outer membrane and arrests the caspase death cascade. Late injection of CaEDTA at a time when GluR2 is downregulated and caspase is activated inhibited the delayed rise in Zn2+, p75NTR induction, DNA fragmentation, and cell death. The finding of neuroprotection by late CaEDTA administration has striking implications for intervention in the delayed neuronal death associated with global ischemia.
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PMID:Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death. 1552 75

Infection of cattle or bovine cells with bovine herpesvirus 1 (BHV-1) leads to increased apoptosis. Previous studies indicated that BHV-1 infected cell protein 0 (bICP0), the major transcriptional regulatory protein of BHV-1, is toxic in transiently transfected cells. Point mutations within the zinc RING finger of bICP0 reduced toxicity and eliminated the ability of bICP0 to activate viral gene expression. In mouse neuroblastoma cells (neuro-2A) and bovine turbinate cells, bICP0 activated caspase 3, a key regulatory protein in the apoptotic pathway. A pro-apoptotic gene (Bax), but not bICP0, induced caspase 3 cleavage and activation by 8 h after transfection of neuro-2A cells. Conversely, bICP0 or the N-terminal 356 aa of bICP0 did not induce caspase 3 cleavage in neuro-2A cells until 30 h after transfection, suggesting that bICP0 stimulates caspase 3 cleavage by an indirect mechanism. These studies indicate that the toxic functions of bICP0 correlate with caspase 3 cleavage and activation.
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PMID:Infected cell protein 0 encoded by bovine herpesvirus 1 can activate caspase 3 when overexpressed in transfected cells. 1555 24

Peroxynitrite toxicity is a major cause of neuronal injury in stroke and neurodegenerative disorders. The mechanisms underlying the neurotoxicity induced by peroxynitrite are still unclear. In this study, we observed that TPEN [N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine], a zinc chelator, protected against neurotoxicity induced by exogenous as well as endogenous (coadministration of NMDA and a nitric oxide donor, diethylenetriamine NONOate) peroxynitrite. Two different approaches to detecting intracellular zinc release demonstrated the liberation of zinc from intracellular stores by peroxynitrite. In addition, we found that peroxynitrite toxicity was blocked by inhibitors of 12-lipoxygenase (12-LOX), p38 mitogen-activated protein kinase (MAPK), and caspase-3 and was associated with mitochondrial membrane depolarization. Inhibition of 12-LOX blocked the activation of p38 MAPK and caspase-3. Zinc itself induced the activation of 12-LOX, generation of reactive oxygen species (ROS), and activation of p38 MAPK and caspase-3. These data suggest a cell death pathway triggered by peroxynitrite in which intracellular zinc release leads to activation of 12-LOX, ROS accumulation, p38 activation, and caspase-3 activation. Therefore, therapies aimed at maintaining intracellular zinc homeostasis or blocking activation of 12-LOX may provide a novel avenue for the treatment of inflammation, stroke, and neurodegenerative diseases in which the formation of peroxynitrite is thought to be one of the important causes of cell death.
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PMID:Peroxynitrite-induced neuronal apoptosis is mediated by intracellular zinc release and 12-lipoxygenase activation. 1556 77

Monocyte activation, apoptosis and differentiation are hallmarks of most inflammatory vascular disorders. We studied the effects of heme oxygenase-1 (HO-1) induced by its substrate hemin on apoptosis, caspase-3 expression and the differentiation of freshly isolated human monocytes. Hemin induced HO-1 in a dose- and time-dependent fashion as measured by semi-quantitative RT-PCR and flow cytometry. Apoptosis was markedly suppressed by hemin in cells rendered apoptotic by serum deprivation or dexamethasone as determined by flow cytometric detection of annexin V binding or transmission electron microscopy (TEM). The specific HO-1 inhibitor zinc protoporphyrin (ZnPP) reversed the effects of hemin on monocyte apoptosis and diminished cell lifespan. Surprisingly, the cytoprotective effects of hemin were positively correlated with caspase-3 up-regulation. Hemin-induced apoptosis suppression was enhanced by the caspase-3 inhibitor DEVD-CHO, indicating that caspase-3 was active in a pro-apoptotic fashion. Hemin inhibited CD95 as a putative cytoprotective mechanism. Morphological studies and detection of CD86 showed that monocytes differentiated into macrophages in response to hemin after relatively long incubation times, a phenomenon that might be provoked by caspase-3-regulated pathways. Our results confirm a similar cytoprotective effect of hemin/HO-1 for monocytes as has been shown for other cells, despite caspase-3 up-regulation. The fact that HO-1 may adversely affect monocyte survival and differentiation could be of particular significance in future therapies for occlusive vascular diseases or transplant rejection.
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PMID:Heme-induced heme oxygenase-1 (HO-1) in human monocytes inhibits apoptosis despite caspase-3 up-regulation. 1561 19

Accumulation of cytoplasmic zinc is linked with a cascade of events leading to neuronal death. In many in vivo models of zinc-induced cell death, toxic concentrations of synaptically released zinc enter vulnerable neurons via neurotransmitter- or voltage-gated ion channels. In vitro studies demonstrate, in addition, that zinc can be liberated from intracellular stores following oxidative stress and contribute to cell death processes, including apoptosis. Here we describe accumulation of intracellular zinc in an in vivo model of cell death in the absence of presynaptic zinc release. We focused on the lateral geniculate nucleus (LGN) because LGN neurons undergo apoptosis when separated from their target, the primary visual cortex (V1), and the LGN is mostly devoid of zinc-containing presynaptic terminals. Infant and adult rats and adult mice received unilateral ablation of V1, either by aspiration or kainate injection. One to 14 days later, brain sections were stained with selenium autometallography or fluorescently labeled to localize zinc, or stained immunochemically for activated caspase-3. V1 lesions led to zinc accumulation in LGN neurons in infant and adult subjects. Zinc-containing neurons were evident 1-3 days after aspiration lesions, depending on age, but not until 14 days after kainate injection. Zinc accumulation was followed rapidly by immunostaining for activated caspase-3. Our data indicate that like neurotrauma and excitotoxicity, target deprivation leads to accumulation of zinc in apoptotic neurons. Moreover, zinc accumulation in vivo can occur in the absence of presynaptic zinc release. Together these findings suggest that accumulation of intracellular zinc is a ubiquitous component of the cell death cascade in neurons.
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PMID:Zinc accumulation after target loss: an early event in retrograde degeneration of thalamic neurons. 1573 83

The transition metal zinc (Zn) is an endogenous regulator of apoptosis. The ability of Zn to modulate apoptosis is believed to be mediated by the regulation of caspase activity. Previously, we reported that an acute influx of labile Zn induced apoptosis via activation of caspase in human leukemia HL-60 cells treated with a Zn ionophore (Py, pyrithione) and Zn at 1 and 25 microM, respectively. In the present study, we investigated the involvement of caspase-3 in Py (1 microM)/Zn (25 microM)-induced apoptosis in HL-60 cells. Pro-caspase-3 is an inactive form of caspase-3. The processing of pro-caspase-3, a sign of caspase-3 activation, occurred 6 h after treatment with Py/Zn. Proteolysis of poly (ADP-ribose) polymerase (PARP), a substrate of caspase-3, was also observed 6 h after treatment with Py/Zn. We also confirmed the elevation of caspase-3 activity as an index of the cleavage of amino acid sequences recognized by activated caspase-3. An inhibitor of caspase-3 attenuated the appearance of the DNA ladder. Taken together, these results indicate that the activation of caspase-3 is partly responsible for the induction of apoptosis in Py/Zn-treated HL-60 cells.
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PMID:Activation of caspase-3 in HL-60 cells treated with pyrithione and zinc. 1580 26

We demonstrate herein that zinc pyrithione can induce apoptosis at nanomolar concentrations. Zinc pyrithione was a potent inducer of cell death causing greater than 40-60% apoptosis among murine thymocytes, murine splenic lymphocytes and human Ramos B and human Jurkat T cells. Conversely, the addition of a zinc chelator protected thymocytes against zinc pyrithione induced apoptosis indicating these responses were specific for zinc. Zinc-induced apoptosis was dependent on transcription and translation which suggested possible regulation by a proapoptotic protein. Indeed, zinc induced a 1.9 and 3.4 fold increase respectively in expression of the BimEL and BimL isoforms and also stimulated production of the most potent isoform, BimS. This increase in Bim isoform expression was dependent on transcription being blocked by treatment with actinomycin D. Overexpression of Bcl-2 or Bcl-xL provided substantial protection of Ramos B and Jurkat T cells against zinc-induced apoptosis. Zinc also activated the caspase cascade demonstrated by cleavage of caspase 9. Addition of specific inhibitors for caspase 9 and caspase 3 also blocked zinc-induced apoptosis. The data herein adds to the growing evidence that free or unbound zinc could be harmful to cells of the immune system.
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PMID:Zinc pyrithione induces apoptosis and increases expression of Bim. 1584 98


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