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)

Cadmium (Cd2+) is a potent toxic metal for both plants and animals. Chronic exposure to low doses of Cd2+ results in damage to several organs. We have previously reported that Cd2+ induces apoptosis in anterior pituitary cells by a caspase- and oxidative stress-dependent mechanism. Nitric oxide (NO) synthesis is affected by Cd2+ in several systems. NO has been shown to be either cytoprotective or cytotoxic in many systems. The aim of this study was to evaluate the possible participation of NO in the cytotoxic effect of Cd2+ on rat anterior pituitary cells. Cell viability was evaluated by mitochondrial dehydrogenase activity assay and confirmed by microscopy, studying nuclear morphology. Here we show that DETA NONOate ((Z)-1-[2 (2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate), a long-term NO donor, at concentrations below 0.5 mM, reduces nuclear condensation and fragmentation and reverses the decrease in cellular activity induced by Cd2+. Cd2+, by itself, induced NO synthesis, and inhibition of this synthesis enhanced Cd2+ cytotoxicity. NO also prevented caspase-3 activation and lipidic peroxidation induced by Cd2+. The NO/cGMP pathway does not seem to be involved in the cytoprotective effect of NO. These results indicate that NO has a cytoprotective role in Cd2+ -induced apoptosis, suggesting that endogenous NO could have a physiological role in protecting anterior pituitary cells.
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PMID:Nitric oxide protects anterior pituitary cells from cadmium-induced apoptosis. 1545 86

The body may be exposed simultaneously to more than one nephrotoxic substance and to measure the effects of the great number of possible combinations of nephrotoxins will rapidly become a great challenge when using the traditional methods. Therefore, we developed a rapid and cost-efficient method to screen the apoptotic potential of combinations of known cell- or nephrotoxic substances as ochratoxin A (OTA), cisplatin, cadmium, H(2)O(2), and amphotericin B on renal epithelial cell lines. The cells were seeded in 96-well plates and the apoptotic and necrotic potential of different combinations of nephrotoxins was determined. We found different results for the combinations used: depending on the concentrations of the various substances, antagonistic, additive, or potentiating effects on caspase-3 activity were found after co-exposure to OTA. We conclude that the co-exposure of renal cells to OTA with other substances can enhance or reduce the apoptotic potential of one substance alone depending on the substance, the concentration and on the cell line investigated. A "harmless" substance can thus convert to a potent cell toxic substance when combined with OTA or vice versa. The underlying mechanisms of the synergistic effects remain unknown.
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PMID:A rapid screening method to test apoptotic synergisms of ochratoxin A with other nephrotoxic substances. 1558 64

It is known that heavy metals can accumulate in tissues during aquatic organism growth (bioaccumulation) and often biomagnify up the food chain interfering with the health and reproduction of both wildlife and humans. Recently, cadmium (Cd) was included in the endocrine disruptors list, exerting its effect on gametes quality and reproductive functions; in addition, its role as apoptotic factor was evidenced in different cell types and tissues. In the present study, the effects of two different Cd doses on testis and liver of the black goby Gobius niger were analyzed. Cd concentration in the water and its uptake by the gills were measured by differential pulse anodic stripping voltammetry. Toxic, apoptotic, and stressor Cd effects were analyzed using metallothionein (MTT), caspase 3 and heath shock protein 70 (HSP70), respectively, as bioindicators. The results of the present study suggested that, in the gills, the saturation of all specific metal sites was reached only with the highest Cd dose exposure. Either testis and liver showed an increase of MTT gene expression and protein synthesis in addition to HSP70 gene expression, related with Cd concentration in the water indicating that both tissues were affected by Cd exposure. In conclusion, the present study, not only shows the toxic effect of Cd on hepatic tissue, but also indicates its potency as apoptotic factor in the testis. This is supported by the increase of caspase 3 gene expression and the presence of its active form in testis of exposed fish.
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PMID:Effects of cadmium exposure on testis apoptosis in the marine teleost Gobius niger. 1586 69

Mitochondria are believed to be integrators and coordinators of programmed cell death in addition to their respiratory function. Using mitochondrial DNA (mtDNA)-depleted osteosarcoma cells (rho0 cells) as a cell model, we investigated the apoptogenic signaling pathway of cadmium (Cd) under a condition of mitochondrial dysfunction. The apoptotic percentage was determined to be around 58.0% after a 24-h exposure to 25 microM Cd using flow cytometry staining with propidium iodine (PI). Pretreatment with Z-VAD-fmk, a broad-spectrum caspase inhibitor, failed to prevent apoptosis following Cd exposure. Moreover, Cd was unable to activate caspase 3 using DEVD-AFC as a substrate, indicating that Cd induced a caspase-independent apoptotic pathway in rho0 cells. JC-1 staining demonstrated that mitochondrial membrane depolarization was a prelude to apoptosis. On the other hand, the intracellular calcium concentration increased 12.5-fold after a 2-h exposure to Cd. More importantly, the apoptogenic activity of Cd was almost abolished by ruthenium red, a mitochondrial calcium uniporter blocker. This led us to conclude that mtDNA-depleted cells provide an alternative pathway for Cd to conduct caspase-independent apoptosis through a mitochondria-calcium mechanism.
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PMID:Cadmium toxicity toward caspase-independent apoptosis through the mitochondria-calcium pathway in mtDNA-depleted cells. 1596 96

Cadmium is a potent nephrotoxin that has been shown to induce apoptosis in some cells but also to prevent it under certain circumstances. In several clinical situations and experimental models of injury to the renal glomerulus, pathological proliferation of mesangial cells is followed by resolution involving mesangial cell apoptosis. We investigated the effects of Cd(2+) on rat mesangial cells induced to undergo apoptosis through either the extrinsic receptor-mediated pathway or the intrinsic mitochondrial-dependent pathway. Camptothecin initiated the intrinsic pathway with activation of caspase-9 and caspase-dependent cleavage of procaspase-3. Tumor necrosis factor-alpha (TNF-alpha) initiated caspase-8 activity and cleavage of pro-caspase-3 at the convergence point of the two pathways. However, pro-caspase-8 levels were low, and caspase-9 was also activated in response to TNF-alpha, characteristic of what have been termed type II cells. With both TNF-alpha and camptothecin, concurrent exposure to 10 microM CdCl(2) suppressed DNA laddering, nuclear condensation, and pro-caspase-3 cleavage. It also decreased activity of both caspase-8 and caspase-9, prevented caspase-8-dependent cleavage of the proapoptotic factor Bid, and suppressed release of cytochrome c from mitochondria. At this 10-microM concentration, Cd(2+) was unique among a number of metal ions in preventing DNA fragmentation. We conclude that Cd(2+) is anti-apoptotic in rat mesangial cells, acting by a mechanism that may involve general caspase inhibition. This may have consequences for the resolution of nephritis in situations of mesangial cell hyperproliferation.
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PMID:Cadmium inhibits both intrinsic and extrinsic apoptotic pathways in renal mesangial cells. 1626 7

Vimentin is an intermediate filament that regulates cell attachment and subcellular organization. In this study, vimentin filaments were morphologically altered, and its soluble subunits were rapidly reduced via cadmium chloride treatment. Cadmium chloride stimulated three major mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, and led apoptotic pathway via caspase-9 and caspase-3 activations. In order to determine whether MAPKs were involved in this cadmium-induced soluble vimentin disappearance, we applied MAPK-specific inhibitors (PD98059, SP600125, SB203580). These inhibitors did not abolish the cadmium-induced soluble vimentin disappearance. Caspase and proteosome degradation pathway were also not involved in soluble vimentin disappearance. When we observed vimentin levels in soluble and insoluble fractions, soluble vimentin subunits shifted to an insoluble fraction. As we discovered that heat-shock protein 27 (HSP27) was colocalized and physically associated with vimentin in unstressed cells, the roles of HSP27 with regard to vimentin were assessed. HSP27-overexpressing cells prevented morphological alterations of the vimentin filaments, as well as reductions of soluble vimentin, in the cadmium-treated cells. Moreover, HSP27 antisense oligonucleotide augmented these cadmium-induced changes in vimentin. These findings indicate that HSP27 prevents disruption of the vimentin intermediate filament networks and soluble vimentin disappearance, by virtue of its physical interaction with vimentin in cadmium-treated SK-N-SH cells.
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PMID:Heat shock protein 27 interacts with vimentin and prevents insolubilization of vimentin subunits induced by cadmium. 1626 67

Cadmium causes cellular damage but the exact mechanism of apoptosis in cadmium induced acute lung injury is not clear. We investigated the sequential expression of apoptotic nuclei and detected related molecules in tissue of cadmium-induced acute lung injury. Forty Sprague-Dawley rats were sacrificed at days 1, 3, 7 and 10 after intra-tracheal cadmium injection (2.5mg/kg). Light microscopic, ultrastructural terminal deoxyribonucleotidyl transferase mediated dUTP nick end labeling (TUNEL), and Western blot analysis for detection of FasL, Bid, cytochrome c, caspase 3 and PARP were carried out. Apoptosis occurred at day 1, and markedly decreased at days 3, 7 and 10 (11.8, 2.8, 0.9, 0.5%, respectively) determined by light microscopy and TUNEL assay. Ultrastructural TUNEL revealed two patterns of nuclear morphology according to the apoptotic stage. One pattern showed chromatin fragmentation and apoptotic nuclear body formation. The other pattern had bleb formation in the chromatin, budding with projection out to the nuclear membranes, fragmentation, segregation of chromatin clumps and apoptotic body formation. Western blot analysis showed prominent expression of FasL at days 1 and 3. Expression of Bid, cytochrome c and caspase 3 were prominent at day 1 compared to days 3, 7 and 10. PARP cleavage was prominent at day 1. In conclusion, intra-tracheal cadmium injection showed active alveolar cell apoptosis at day 1. Ultrastructural TUNEL showed various expressions according to the apoptotic nuclear stage. These studies suggest that cadmium-induced alveolar cell apoptosis is mediated by FasL and caspase-dependent mitochondrial apoptosis pathways.
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PMID:Expression of apoptotic nuclei by ultrastructural terminal deoxyribonucleotidyl transferase mediated dUTP nick end labeling and detection of FasL, caspases and PARP protein molecules in cadmium induced acute alveolar cell injury. 1632 65

We investigated the effects of various heavy metals such as copper, zinc and cadmium, as well as acute thermal stress, on the signalling mechanisms involved in the protection and/or apoptosis of Mytilus galloprovincialis mantle and gill tissues. The results of our studies revealed that mantle and gill tissues differentially respond to the stressful stimuli examined. In the mantle tissue, 1 micromol l(-1) Cu2+ and 50 micromol l(-1) Zn2+ induced a transient p38-MAPK activation, whereas 1 micromol l(-1) Cd2+ induced a biphasic profile of the kinase phosphorylation with maximal values at 15 and 120 min of treatment, respectively. Furthermore, 1 micromol l(-1) SB203580 abolished the Cu2+-induced kinase phosphorylation. In gills, both Cu2+ and Zn2+ induced a considerably higher p38-MAPK activation, which remained elevated for at least 60 min, whereas Cd2+ induced a maximal kinase activation within 60 min of treatment. Hypothermia (4 degrees C) induced a moderate kinase phosphorylation (maximised at 30 min), whereas hyperthermia (30 degrees C) induced a rapid (within 15 min) p38-MAPK phosphorylation that remained considerably above basal levels for at least 2 h. Our studies on the synergistic effect of hyperthermia and Cu2+ revealed that these two stressful stimuli are additive in the mantle tissue, inducing an almost double p38-MAPK activation. Further studies on the involvement of the p38-MAPK signalling pathway in tissue-specific pro- or anti-apoptotic events revealed that identical stressful stimuli possibly lead to apoptotic death via the caspase-3 activation in the mantle tissue and to anti-apoptotic events possibly via the induction of Hsp70 overexpression in the gill tissue.
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PMID:Acute thermal stress and various heavy metals induce tissue-specific pro- or anti-apoptotic events via the p38-MAPK signal transduction pathway in Mytilus galloprovincialis (Lam.). 1633 63

Cadmium being a potent immunotoxicant, affects both humoral and cell mediated immunity. However, its effect on spleen is not clearly understood. Hence, to delineate the action of Cd, mouse splenic lymphocytes were exposed to Cd (10, 25 and 50 microM) for 60 min, 1.5, 3, 6 and 18 h. At 6 h, apoptosis was reflected by DNA fragmentation, increased sub-G1 population (apoptotic DNA) and apoptotic cells (Annexin V binding assay). The early stage markers of apoptosis, i.e. decreased mitochondrial membrane potential and caspase-3 activation were observed as early as 1.5 h by the highest dose of Cd (50 microM). Significant ROS production by 25 and 50 microM Cd at 60 min occurred prior to the lowering of mitochondrial membrane potential, suggesting involvement of ROS in causing mitochondrial membrane damage. N-acetylcysteine and pyrrolidine dithiocarbamate (thiol antioxidants) lowered the sub-G(1) population, inhibited the ROS generation and raised the GSH levels induced by Cd. Buthionine sulfoximine (GSH depletor) on the other hand, enhanced the ROS production as well as the sub-G1 fraction. These results imply that ROS is a critical mediator of Cd-induced apoptosis and that cadmium may compromise splenic immune function by accelerating apoptosis.
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PMID:Oxidative stress and apoptotic changes in murine splenocytes exposed to cadmium. 1641 50

Cadmium is a nonessential heavy metal and a well-known persistent environmental pollutant. It causes a variety of toxic effects, including immunotoxicity. The exact mechanism of its cellular effects still is unclear. Cell-cycle regulation is an important factor that modulates cell death; however, cadmium-mediated cell-cycle arrest leading to cell death in murine macrophages has not been investigated. Cadmium at 20 microM induced both apoptotic and necrotic death in murine macrophage (J774A.1) cultures at 24 h. Cadmium at 20 microM triggered re-entry of G0/G1 to the next phase and increased the number of cells in the G2/M phase at 24 h. Phosphorylation of extracellular signal-regulated kinase (ERK) correlated with the cyclin-dependent kinase inhibitor p21WAF1/CIP1 induction. Inhibition of ERK activation by PD98059 resulted in G0/G1 arrest and partially released the cadmium-mediated G2/M arrest. Inhibition of ERK phosphorylation by PD98059 strongly attenuated cadmium-induced necrotic cell death, but did not prevent caspase-3 activation and DNA fragmentation. Necrosis rather than apoptosis was caused by cadmium-induced ERK signaling in J774A.1 cells. A scavenger of reactive oxygen species (ROS), N-acetylcystein, decreased cadmium-induced ERK activation and necrotic cell death, suggesting that cadmium induces the ROS-ERK-p21WAF1/CIP1 signaling pathway, leading to G2/M arrest and cell death. These findings may be important in further understanding the cellular mechanisms of cadmium toxicity to provide information to assess objectively risk for this metal.
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PMID:Extracellular signal-regulated kinase-signaling-dependent G2/M arrest and cell death in murine macrophages by cadmium. 1644 87


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