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 hypothesis was tested that treatment with allopurinol, a xanthine oxidase inhibitor, or deferoxamine, a chelator of nonprotein-bound iron, preserved cerebral energy metabolism, attenuated development of edema, and improved histologic outcome in the newborn piglet at 24 h after hypoxia-ischemia. Thirty-two newborn piglets were subjected to 1 h of hypoxia-ischemia by occluding both carotid arteries and reducing the fraction of inspired oxygen; five newborn piglets served as sham-operated controls. The depth of hypoxia-ischemia was controlled by phosphorous magnetic resonance spectroscopy. Upon reperfusion and reoxygenation, piglets received vehicle (n= 12), allopurinol (30 mg/kg/d, n = 10), or deferoxamine (12.5 mg/kg/d, n = 10). The cerebral energy status was determined with phosphorous magnetic resonance spectroscopy. The presence of vasogenic edema was assessed by T2-weighted magnetic resonance imaging. Brain cell injury was assessed with caspase-3 activity, histology, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end (TUNEL)-labeling. At 24 h after hypoxia-ischemia, the phosphocreatine/inorganic phosphate ratios were significantly decreased in vehicle-treated, but not in allopurinol- or deferoxamine-treated piglets. Water T2 values were significantly increased at 24 h after hypoxia-ischemia in cerebral cortex, thalamus, and striatum of vehicle-treated piglets, but not in allopurinol- and deferoxamine-treated piglets. No differences in caspase-3 activity, histologic outcome, or TUNEL-labeling were demonstrated between the three treatment groups. We suggest that allopurinol and deferoxamine may have an additional value in the treatment of perinatal hypoxia-ischemia with other neuroprotective agents or in combination with hypothermia.
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PMID:Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia. 1281 12

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta, and in other subcortical nuclei associated with a widespread occurrence of Lewy bodies. The causes of cell death in Parkinson's disease are still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative stress have been proposed. We have examined 3-morpholinosydnonimine (SIN-1)-induced apoptosis in control and metallothionein-overexpressing dopaminergic neurons, with a primary objective to determine the neuroprotective potential of metallothionein against peroxynitrite-induced neurodegeneration in Parkinson's disease. SIN-1 induced lipid peroxidation and triggered plasma membrane blebbing. In addition, it caused DNA fragmentation, alpha-synuclein induction, and intramitochondrial accumulation of metal ions (copper, iron, zinc, and calcium), and enhanced the synthesis of 8-hydroxy-2-deoxyguanosine. Furthermore, it down-regulated the expression of Bcl-2 and poly(ADP-ribose) polymerase, but up-regulated the expression of caspase-3 and Bax in dopaminergic (SK-N-SH) neurons. SIN-1 induced apoptosis in aging mitochondrial genome knockout cells, alpha-synuclein-transfected cells, metallothionein double-knockout cells, and caspase-3-overexpressed dopaminergic neurons. SIN-1-induced changes were attenuated with selegiline or in metallothionein-transgenic striatal fetal stem cells. SIN-1-induced oxidation of dopamine to dihydroxyphenylacetaldehyde was attenuated in metallothionein-transgenic fetal stem cells and in cells transfected with a mitochondrial genome, and enhanced in aging mitochondrial genome knockout cells, in metallothionein double-knockout cells and caspase-3 gene-overexpressing dopaminergic neurons. Selegiline, melatonin, ubiquinone, and metallothionein suppressed SIN-1-induced down-regulation of a mitochondrial genome and up-regulation of caspase-3 as determined by reverse transcription-polymerase chain reaction. The synthesis of mitochondrial 8-hydroxy-2-deoxyguanosine and apoptosis-inducing factors were increased following exposure to 1-methyl-4-phenylpyridinium ion or rotenone. Pretreatment with selegiline or metallothionein suppressed 1-methyl-4-phenylpyridinium ion-, 6-hydroxydopamine-, and rotenone-induced increases in mitochondrial 8-hydroxy-2-deoxyguanosine accumulation. Transfection of aging mitochondrial genome knockout neurons with mitochondrial genome encoding complex-1 or melanin attenuated the SIN-1-induced increase in lipid peroxidation. SIN-1 induced the expression of alpha-synuclein, caspase-3, and 8-hydroxy-2-deoxyguanosine, and augmented protein nitration. These effects were attenuated by metallothionein gene overexpression. These studies provide evidence that nitric oxide synthase activation and peroxynitrite ion overproduction may be involved in the etiopathogenesis of Parkinson's disease, and that metallothionein gene induction may provide neuroprotection.
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PMID:Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons. 1288 Apr 80

The actinomycin D (AD)-induced apoptosis in human leukemia CMK-7 cell line is greatly accelerated by microtubule disruption with colcemid (CL). We studied the effect of antioxidants on this apoptosis in order to learn how the universal signal mediators, reactive oxygen species (ROS), are involved. Caspase-3 activation and DNA fragmentation were both suppressed by vitamin E (VE), t-butylhydroxyanisole, and luteolin. The ROS formation in the AD treatment was evidenced by flow cytometry, and further supported by suppression of caspase-3 activation by superoxide radical-forming enzyme inhibitors (TTFA, rotenone, and DPI). The inhibition of apoptosis by VE was completed during the initial 1-h treatment with AD, but it did not appear when VE was added with CL to washed cells after AD treatment. Luteolin, an iron chelator PDTC, and a water-soluble VE analogue, trolox, inhibited the apoptosis when added with CL after the AD treatment. Western blot analysis showed that the proteolytic cleavage of procaspase-9 and procaspase-3 were both inhibited when VE was added with AD or when luteolin was added with CL, and that the cytochrome c liberation was suppressed by both antioxidants. This result implies that the ROS are initially formed in lipophilic environments (e.g. mitochondrial membrane) and then they diffuse into an aqueous environment (i.e. cytoplasm) where they promote the apoptotic process in combination with the cytoskeletal disruption. Thus, the different antioxidants are effective to scavenge ROS for preventing the apoptosis in its different phases.
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PMID:Differential effects of vitamin E and three hydrophilic antioxidants on the actinomycin D-induced and colcemid-accelerated apoptosis in human leukemia CMK-7 cell line. 1296 51

The mitochondrial permeability transition is recognized to be involved in toxic and oxidative forms of cell injury. In the present study, we investigated the effect of ambroxol against the cytotoxicity of bleomycin (BLM) by looking at the effect on the mitochondrial membrane permeability in alveolar macrophages and lung epithelial cells. Alveolar macrophages or lung epithelial cells exposed to BLM revealed the loss of cell viability and increase in caspase-3 activity. Ambroxol (10-100 microM) reduced the 75 mU/mL BLM-induced cell death and activation of caspase-3 in macrophages or epithelial cells. It reduced the condensation and fragmentation of nuclei caused by BLM in macrophages. Ambroxol alone did not significantly cause cell death. Treatment of alveolar macrophages with BLM resulted in the decrease in transmembrane potential in mitochondria, cytosolic accumulation of cytochrome c, increase in formation of reactive oxygen species (ROS) and depletion of GSH. Ambroxol (10-100 microM) inhibited the increase in mitochondrial membrane permeability, ROS formation and decrease in GSH contents due to BLM in macrophages. Ambroxol exerted a scavenging effect on hydroxyl radicals and nitric oxide and reduced the iron-mediated formation of malondialdehyde and carbonyls in liver mitochondria. It prevented cell death due to SIN-1 in lung epithelial cells. The results demonstrate that ambroxol attenuates the BLM-induced viability loss in alveolar macrophages or lung epithelial cells. This effect may be due to inhibition of mitochondrial damage and due to the scavenging action on free radicals.
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PMID:Inhibition of bleomycin-induced cell death in rat alveolar macrophages and human lung epithelial cells by ambroxol. 1450 9

Heme oxygenase-1 (HO-1), a stress-responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin, and iron, has previously been shown to protect grafts from ischemia/reperfusion injury and rejection. Here we investigated the protective potential of HO-1 in 5 models of immune-mediated liver injury. We found that up-regulation of endogenous HO-1 by cobalt-protoporphyrin-IX (CoPP) protected mice from apoptotic liver damage induced by anti-CD95 antibody (Ab) or d-galactosamine in combination with either anti-CD3 Ab, lipopolysaccharide (LPS), or tumor necrosis factor alpha (TNF-alpha). HO-1 induction prevented apoptotic liver injury, measured by inhibition of caspase 3 activation, although it did not protect mice from caspase-3-independent necrotic liver damage caused by concanavalin A (Con A) administration. In addition, overexpression of HO-1 by adenoviral gene transfer resulted in protection from apoptotic liver injury, whereas inhibition of HO-1 enzymatic activity by tin-protoporphyrin-IX (SnPP) abrogated the protective effect. HO-1-mediated protection seems to target parenchymal liver cells directly because CoPP treatment protected isolated primary hepatocytes from anti-CD95-induced apoptosis in vitro. Furthermore, depletion of Kupffer cells (KCs) did not interfere with the protective effect in vivo. Exogenous CO administration or treatment with the CO-releasing agent methylene chloride mimicked the protective effect of HO-1, whereas treatment with exogenous biliverdin or overexpression of ferritin by recombinant adenoviral gene transfer did not. In conclusion, HO-1 is a potent protective factor for cytokine- and CD95-mediated apoptotic liver damage. Induction of HO-1 might be of a therapeutic modality for inflammatory liver diseases.
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PMID:Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice. 1572 11

The signaling mechanisms that control apoptotic events evoked by iron chelators are largely unknown. We found that cAMP response element-binding protein (CREB) is cleaved during iron chelator deferoxamine (DFO)-induced apoptosis, and that the cleavage is largely prevented by the cell-permeable analog of cAMP, dibutyryl-cAMP (dbcAMP), a known CREB activator. In addition, dbcAMP profoundly reduced DFO-induced apoptosis along with significant suppression of caspase-3 and -8 activation and inhibition of loss of mitochondrial potential. These results led us to investigate whether CREB activation is functionally connected with the MAPK family members because we previously demonstrated that p38 kinase is involved in iron chelator-induced apoptosis of HL-60 cells. dbcAMP by itself rapidly induced CREB phosphorylation but dramatically inhibited DFO-induced phosphorylation of all three MAPK family members. However, disruption of CREB expression by antisense oligodeoxyribonucleotide (AS-ODN) only restored p38 kinase activation, and simultaneously attenuated dbcAMP-induced protection of HL-60 cells from DFO-induced cell death. Conversely, inhibition of p38 kinase activity by SB203580 significantly reduced DFO-induced CREB cleavage as well as apoptosis, indicating a cross-talk between CREB and p38 kinase. Collectively, these results demonstrate that cAMP-dependent CREB activation plays an important role in protecting HL-60 cells from iron chelator-induced apoptosis, presumably through downregulation of p38 kinase.
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PMID:Downregulation of p38 kinase pathway by cAMP response element-binding protein protects HL-60 cells from iron chelator-induced apoptosis. 1460 16

Recent studies in lymphohemopoietic cells show that transferrin (Tf), a pivotal component of iron transport and metabolism, also exerts cytoprotective functions. We show here in a murine model that Tf interferes with Fas-mediated hepatocyte death and liver failure. The mechanism involves the downregulation of apoptosis via BID, cytochrome c, caspase-3 and caspase-9, and upregulation of antiapoptotic signals via Bcl-xL. The results obtained with iron-saturated Tf, Apo-Tf and the iron-chelator salicylaldehyde isonicotinoyl hydrazone indicate that the observed antiapoptotic effect of Tf was not mediated by iron alone. In conclusion, the data suggest that Tf has broader functions than previously recognized and may serve as a cytoprotective agent.
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PMID:Prevention of Fas-mediated hepatic failure by transferrin. 1470 19

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin that causes Parkinson's disease in experimental animals and humans. Despite the fact that intracellular iron was shown to be crucial for MPP(+)-induced apoptotic cell death, the molecular mechanisms for the iron requirement remain unclear. We investigated the role of transferrin receptor (TfR) and iron in modulating the expression of alpha-synuclein (alpha-syn) in MPP(+)-induced oxidative stress and apoptosis. Results show that MPP(+) inhibits mitochondrial complex-1 and aconitase activities leading to enhanced H(2)O(2) generation, TfR expression and alpha-syn expression/aggregation. Pretreatment with cell-permeable iron chelators, TfR antibody (that inhibits TfR-mediated iron uptake), or transfection with glutathione peroxidase (GPx1) enzyme inhibits intracellular oxidant generation, alpha-syn expression/aggregation, and apoptotic signaling as measured by caspase-3 activation. Cells overexpressing alpha-syn exacerbated MPP(+) toxicity, whereas antisense alpha-syn treatment totally abrogated MPP(+)-induced apoptosis in neuroblastoma cells without affecting oxidant generation. The increased cytotoxic effects of alpha-syn in MPP(+)-treated cells were attributed to inhibition of mitogen-activated protein kinase and proteasomal function. We conclude that MPP(+)-induced iron signaling is responsible for intracellular oxidant generation, alpha-syn expression, proteasomal dysfunction, and apoptosis. Relevance to Parkinson's disease is discussed.
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PMID:Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. 1474 48

INTRODUCTION: Heme oxygenase-1 (HO-1) is a stress response enzyme, which catalyses the breakdown of heme into biliverdin-IX alpha, carbon monoxide and ferrous iron. Under situations of oxidative stress, heat stress, ischemia/reperfusion injury or endotoxemia, HO-1 has been shown to be induced and to elicit a protective effect. The mechanism of how this protective effect is executed is unknown. RESULTS: HO-1 induction with cobalt protoporphorin (Co-PP) dose-dependently protected against apoptotic cell death as well as neutrophil-mediated oncosis in the galactosamine/endotoxin (Gal/ET) shock model. Induction of HO-1 with Co-PP dose-dependently protected against neutrophil-mediated oncosis as indicated by attenuated ALT release and TNF-mediated apoptotic cell death as indicated by reduced caspase-3 activation. HO-1 induction did not attenuate Gal/ET-induced TNF-alpha formation. Furthermore, a similar protective effect with the high dose of Co-PP was observed when animals were treated with Gal/TNF-alpha. CONCLUSIONS: HO-1 induction attenuates apoptosis and neutrophil-mediated oncosis in the Gal/ET shock model. However, the protective effect is not due to the reduction of TNF-alpha release or the attenuation of neutrophil accumulation in the liver sinusoids.
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PMID:Heme oxygenase-1 induction in hepatocytes and non-parenchymal cells protects against liver injury during endotoxemia. 1496 Jan 94

Mutations in parkin are implicated in the pathogenesis of autosomal recessive juvenile parkinsonism (AR-JP) disease. We show that homozygote Cys212Tyr parkin mutation in AR-JP patients renders lymphocytes sensitive to dopamine, iron and hydrogen peroxide stimuli. Indeed, dopamine-induced apoptosis by four alternative mechanisms converging on caspase-3 activation and apoptotic morphology: (1) NF-kappaB-dependent pathway; mitochondrial dysfunction either by (2) H(2)O(2) or (3) hydroxyl exposure and (4) increase of unfolded-protein stress. We also demonstrate that 17beta-estradiol and testosterone prevent homozygote lymphocytes from oxidative stressors-evoked apoptosis. These results may contribute to understanding the relationship between genetic and environmental factors and iron in AR-JP.
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PMID:Autosomal recessive juvenile parkinsonism Cys212Tyr mutation in parkin renders lymphocytes susceptible to dopamine- and iron-mediated apoptosis. 1502 88


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