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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although silica has been documented to cause apoptotic cell death, the cellular pathways leading to caspase activation have not been extensively investigated. Here we demonstrate in a mouse macrophage cell line (MH-S cells) that alpha-quartz silica exposure (12.5 mug/cm2 to 50 mug/cm2) elicited activation of both caspase 3 and caspase 9, whereas anatase titanium dioxide (TiO2), a non-fibrogenic particle, did not. Silica exposure in vitro also induced apoptosis after 6 h, as measured by the appearance of subdiploid cell fragments in a flow cytometric analysis. Exposure to TiO 2 did not elicit significant apoptosis. Silica-induced apoptosis and caspase 3 activation were, in part, caspase 9 dependent, as determined by their sensitivity to either a general caspase inhibitor (Z-VAD-FMK) or a specific caspase 9 inhibitor (Z-LEHD-FMK). Silica exposure in vitro also elicited significant mitochondrial depolarization after 2 and 6 h of exposure. Cyclosporin A, an inhibitor of the mitochondrial permeability pore, partially decreased mitochondrial depolarization, caspase 3 activation, and caspase 9 activation, suggesting a role for mitochondrial dysfunction in these events. Pepstatin A, an inhibitor of cathepsin D, also decreased mitochondrial depolarization, caspase 3 activation, and caspase 9 activation, whereas leupeptin, an inhibitor of cathepsin B, had no effect. These data suggest that short-term silica exposure in vitro induces both caspase 3 and caspase 9 activity, which appears to participate in apoptosis. Activation of these caspases seems to be dependent, in part, on aspartic proteolysis and loss of mitochondrial integrity.
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PMID:Silica-induced caspase activation in mouse alveolar macrophages is dependent upon mitochondrial integrity and aspartic proteolysis. 1461 16

Advanced glycation end products (AGEs) irreversibly cross-link proteins with sugars and accumulate at a higher age and in diabetes, processes which can interfere with the integration of implants into the tissue. Glyoxal is a highly reactive glycating agent involved in the formation of AGEs and is known to induce apoptosis, as revealed by the upregulation of caspase-3 and fractin (caspase-3 being a key enzyme activated during the late stage of apoptosis and fractin being a caspase-cleaved actin fragment). In this study, we investigated the influence of collagen type I coating on the cytotoxic effect of glyoxal on rat calvarial osteoblastic cells and on human osteosarcoma cells (Saos-2) grown on titanium alloy, Ti6Al4V. Activation of caspase-3 and fractin was measured by counting immunohistochemically stained cells and by flow cytometry with propidium iodide (detection of the apoptosis indicating a sub-G1 peak). Our results showed an increased number of apoptotic osteoblasts after incubation with glyoxal on Ti6Al4V discs. However, the number of apoptotic cells on collagen-coated titanium was significantly smaller than on uncoated titanium after the same treatment. The present findings demonstrate that osteoblasts treated with glyoxal undergo apoptosis, whereas collagen type I coating of titanium alloys (used for implants) has an antiapoptotic function.
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PMID:Collagen type I prevents glyoxal-induced apoptosis in osteoblastic cells cultured on titanium alloy. 1523 93

As the applications of industrial nanoparticles are being developed, the concerns on the environmental health are increasing. Cytotoxicities of titanium dioxide nanoparticles of different concentrations (5, 10, 20 and 40 microg/ml) were evaluated in this study using a cultured human bronchial epithelial cell line, BEAS-2B. Exposure of the cultured cells to nanoparticles led to cell death, reactive oxygen species (ROS) increase, reduced glutathione (GSH) decrease, and the induction of oxidative stress-related genes such as heme oxygenase-1, thioredoxin reductase, glutathione-S-transferase, catalase, and a hypoxia inducible gene. The ROS increase by titanium dioxide nanoparticles triggered the activation of cytosolic caspase-3 and chromatin condensation, which means that titanium dioxide nanoparticles exert cytotoxicity by an apoptotic process. Furthermore, the expressions of inflammation-related genes such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), TNF-a, and C-X-C motif ligand 2 (CXCL2) were also elevated. The induction of IL-8 by titanium dioxide nanoparticles was inhibited by the pre-treatment with SB203580 and PD98059, which means that the IL-8 was induced through p38 mitogen-activated protein kinase (MAPK) pathway and/or extracellular signal (ERK) pathway. Uptake of the nanoparticles into the cultured cells was observed and titanium dioxide nanoparticles seemed to penetrate into the cytoplasm and locate in the peri-region of the nucleus as aggregated particles, which may induce direct interactions between the particles and cellular molecules, to cause adverse biological responses.
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PMID:Oxidative stress and apoptosis induced by titanium dioxide nanoparticles in cultured BEAS-2B cells. 1866 54

This study reports on an investigation into apoptotic and proliferation signals in leukocyte and membrane fibroblasts in periprosthetic membranes collected during revision surgery for loosened total hip joint arthroplasty. Cementless and cemented prosthesis were studied under both aseptic and septic conditions. Fluorescence colocalization immunohistochemistry and colorimetric immunohistochemistry were used to investigate cell death signals. In aseptic cementless prosthesis macrophages and membrane fibroblasts show high bax signal, implying the occurrence of toxic/oxidative cell death caused by the debris of titanium alloy metal implant. Instead in aseptic cemented prosthesis only a moderate number of apoptotic leukocytes were observed, whilst the fibroblasts were affected by a diffuse apoptotic-like cell death, the Co-Cr ions debris released from cemented stem, may be at basis of apoptotic cell death induction. Furthermore cement debris is recognized to induce macrophages to produce cytokine, that may be responsible for the cell death observed and implant failure. The septic environment seems to protect leukocytes cell death. Septic cementless prosthesis showed only a few apoptotic leukocytes, instead fibroblasts remain affected by cell death signals. Similarly in septic cemented prosthesis, scanty apoptotic leukocytes were detected, whereas membrane fibroblasts showed an increase in proliferation index (Ki-67) along with caspase-3 activation. These findings indicate some kind of caspase-3 involvement in tissue proliferation, rather than in cell death pathway. Apoptotic periprosthetic sites have been interpreted as signs of inflammation resolution and normal tissue turnover. Nevertheless apoptosis may also be a sign of cell renewal associated to tissue proliferation.
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PMID:Different apoptosis modalities in periprosthetic membranes. 1916 96

DNA double-strand breaks (DSBs) can result in cell death or genetic alterations when cells are subjected to radiation, exposure to toxins, or other environmental stresses. A complex DNA-damage-response pathway is activated to repair the damage, and the inability to repair these breaks can lead to carcinogenesis. One of the earliest responses to DNA DSBs is the phosphorylation of a histone, H2AX, at serine 139 (gamma-H2AX), which can be detected by a fluorescent antibody. A study was undertaken to compare the induction of DNA DSBs in normal (small airway epithelial) cells and cancer cells (A549) after exposure to asbestos (crocidolite), a proven carcinogen, silica, a suspected carcinogen, and titanium dioxide (TiO(2)), an inert particle recently reported to be carcinogenic in animals. The results indicate that crocidolite induced greater DNA DSBs than silica and TiO(2), regardless of cell type. DNA DSBs caused by crocidolite were higher in normal cells than in cancer cells. Silica and TiO(2) induced higher DNA DSBs in cancer cells than in normal cells. The production of reactive oxygen species was found to be highest in cells exposed to crocidolite, followed, in potency, by silica and TiO(2). The generation of reactive oxygen species was higher in normal cells than in cancer cells. Cell viability assay indicated that crocidolite caused the greatest cytotoxicity in both cell types. Apoptosis, measured by caspase 3/7 and poly (ADP-Ribose) polymerase activation, was highest in crocidolite-exposed cells, followed by TiO(2) and silica. The results of this study indicate that crocidolite has a greater carcinogenic potential than silica and TiO(2), judged by its ability to cause sustained genomic instability in normal lung cells.
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PMID:DNA double-strand breaks by asbestos, silica, and titanium dioxide: possible biomarker of carcinogenic potential? 1978 90

To understand the underlying mechanism for apoptosis induced by titanium dioxide nanoparticles (TNP), human airway epithelial cell line was cultured to investigate the relevant apoptosis pathways. Our results showed that the levels of reactive oxygen species and morphological apoptosis increased in a dose-dependent manner whereas cell viability decreased in a similar manner in response to TNP exposure in the BEAS-2B cells. The activities of caspase 3 and PARP were also increased in parallel to the morphological apoptosis. Levels of caspase 9 increased significantly whereas there were no detectable changes in caspase 8 and t-Bid in the TNP treated cells. Caspase 9 inhibition blocked the TNP-induced activation of caspase 3 significantly. The levels of bax, cytochrome C, p53 and bcl-2 also changed reflecting the activation of intrinsic apoptosis pathway. Our results provide solid evidence that apoptosis in BEAS-2B cells exposed to TNP occurred via a mitochondrial apoptosis pathway independent of caspase 8/t-Bid pathway.
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PMID:Titanium dioxide nanoparticles cause apoptosis in BEAS-2B cells through the caspase 8/t-Bid-independent mitochondrial pathway. 2036 50

Nanoparticulate titanium dioxide (TiO(2)) has been demonstrated to decrease immunity of mice, but very little is known about the injury of spleen involved immunomodulation and its molecular mechanism. In order to understand the spleen injury induced by intraperitoneal injection of TiO(2) nanoparticules (NPs) for consecutive 45 days, the spleen pathological changes, apoptosis, the expression levels of the apoptotic genes and their proteins, and oxidative stress in the mouse spleen were investigated. The results demonstrated that TiO(2) NPs had obvious accumulation in the mouse spleen, leading to congestion and lymph nodule proliferation of spleen tissue, and splenocyte apoptosis. TiO(2) NPs effectively activated caspase-3 and -9, decreased the Bcl-2 the levels of gene and protein, and increase the levels of Bax, and cytochrome c genes and their protein expression, promoted ROS accumulation. Taken together, this study indicated that TiO(2) NPs-induced apoptosis in the mouse splenocyte via mitochondrial-mediated pathway. These findings provide strong evidence that the TiO(2) NPs can induce the spleen pathological changes, apoptosis, leading to the reduction of immunity of mice.
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PMID:Spleen injury and apoptotic pathway in mice caused by titanium dioxide nanoparticules. 2038 95

Even though there have been some investigations into cellular responses induced by ultrafine titanium dioxide (TiO(2)) in vitro, the relationship between cellular responses and secondary particle size is still not clear. In this study, a stable and uniform TiO(2)-cell culture-medium dispersion was prepared, and cellular responses prompted by "ultrafine secondary particles" were examined. The TiO(2)-DMEM-FBS dispersion included secondary particles in which the secondary particle size was 100 nm or less. In the present study, a "secondary particle" was defined as a complex aggregate of TiO(2) primary particles, proteins from FBS and other medium components. Secondary particle size did not influence the cell viability. The TiO(2)-DMEM-FBS dispersion introduced to the human keratinocyte HaCaT cells caused weak intracellular oxidative stress and apoptosis. The cellular influence of ultrafine TiO(2)in vitro is caused by the following mechanisms: (1) Secondary particles are formed. Ultrafine TiO(2) particles dispersed in medium immediately form secondary particles with proteins and salts. (2) "Ultrafine" secondary particles are taken up by the cells. The secondary particles reach the cells by diffusion and/or sedimentation and are taken up by the cells, through endocytosis. (3) Intracellular reactive oxygen species (ROS) level increases. Internalized secondary particles induce an increase in intracellular reactive oxygen species levels, although the secondary particles do not break up in the cell. In the case of ultrafine TiO(2), the increase of the intracellular ROS level was minimal. Moreover, the antioxidation system of cells such as glutathione was working. (4) Apoptotic cell death is induced. An accumulation of oxidative stress activates the apoptotic pathway (such as the caspase-3) and subsequently induces apoptotic cell death. After 24h of exposure to TiO(2), the percentage of apoptotic cells was only 6-7%. As a result, although the ultrafine TiO(2) particles induce some cellular responses, these cellular responses to ultrafine TiO(2) are weaker than those of other cytotoxic ultrafine metal oxide particles, such as nickel oxide.
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PMID:Cellular responses by stable and uniform ultrafine titanium dioxide particles in culture-medium dispersions when secondary particle size was 100 nm or less. 2054 99

Gingival epithelial-like cells (GE-1) were cultured and used to examine the cellular responses of gingival tissues to varying concentrations of titanium (Ti) ions. Titanium ions at concentrations of more than 13 ppm significantly decreased the viability of GE-1 cells and increased LDH release from the cells into the supernatant, but had no significant effect on their caspase 3 activity. These data suggest that a high concentration of Ti ions induced necrosis of the GE-1 cells. Titanium ions at a concentration of 5 ppm significantly increased the level of CCL2 mRNA expression in GE-1 cells exposed to lipopolysaccharide derived from Porphyromonas gingivalis in a synergistic manner. Moreover, the mRNA expression levels of TLR-4 and ICAM-1 in GE-1 cells loaded with Ti ions at 9 ppm were significantly enhanced as compared with those in GE-1 cells without Ti stimulation. We suggest that Ti ions are in part responsible for monocyte infiltration in the oral cavity by elevating the sensitivity of gingival epithelial cells to microorganisms. Taken together, these data indicate that Ti ions may be involved in cytotoxicity and inflammation at the interfaces of dental implants and gingival tissue.
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PMID:Titanium ion induces necrosis and sensitivity to lipopolysaccharide in gingival epithelial-like cells. 2068 37

Previous studies demonstrate that the exposure to titanium dioxide nanoparticles (TiO(2) NPs) damages the central nervous system of mice; however, very little is known about the effects of TiO(2) NPs on hippocampal apoptosis or its molecular mechanism. The present study investigated the molecular mechanism associated with hippocampal apoptosis in mice induced by intragastric administration of TiO(2) NPs for consecutive 60 days. Our findings indicate that TiO(2) NPs accumulate in the mouse hippocampus, and this accumulation, in turn, led to hippocampal apoptosis and impairment in spatial recognition memory in mice. In addition, TiO(2) NPs significantly activated caspase-3 and -9, inhibited Bcl-2, and promoted the levels of Bax and cytochrome c. Furthermore, TiO(2) NPs induced accumulation of reactive oxygen species in the mouse hippocampus. These findings suggest that TiO(2) NP-induced apoptosis in the mouse hippocampus may result from an intrinsic pathway, and workers and consumers should take great caution when handling nanomaterials.
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PMID:Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles. 2157 Jan 77


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