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)

Endoplasmic reticulum (ER) stress mechanisms have been found to play critical roles in a number of diseases states, such as diabetes mellitus and Alzheimer disease, but whether they are involved in acute pancreatitis is unknown. Here we show for the first time that all major ER stress sensing and signaling mechanisms are present in exocrine acini and are activated early in the arginine model of experimental acute pancreatitis. Pancreatitis was induced in rats by intraperitoneal injection of 4.0 g/kg body wt arginine. Pancreatitis severity was assessed by analysis of serum amylase, pancreatic trypsin activity, water content, and histology. ER stress-related molecules PERK, eIF2alpha, ATF6, XBP-1, BiP, CHOP, and caspase-12 were analyzed. Arginine treatment induced rapid and severe pancreatitis, as indicated by increased serum amylase, pancreatic tissue edema, and acinar cell damage within 4 h. Arginine treatment also caused an early activation of ER stress, as indicated by phosphorylation of PERK and its downstream target eIF2alpha, ATF6 translocation into the nucleus (within 1 h), and upregulation of BiP (within 4 h). XBP-1 splicing and CHOP expression were observed within 8 h. After 24 h, increased activation of the ER stress-related proapoptotic molecule caspase-12 was observed along with an increase in caspase-3 activity and TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL) staining in exocrine acini. These results indicate that ER stress is an important early acinar cell event that likely contributes to the development of acute pancreatitis in the arginine model.
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PMID:Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis. 1657 87

Ocular adnexa B-cell lymphomas are a relatively rare group of extranodal lymphomas, marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) being the most frequent type at this location. As with other nongastrointestinal MALT lymphomas, ocular adnexa MALT lymphomas have distinct characteristics from those of the gastric MALT model, implying specific pathogenic events, which could be of interest in the prediction of clinical behavior and the choice between therapeutic options. In a series of 39 cases of ocular adnexa MALT lymphomas, studied using a tissue microarray, we observed that the most frequent alteration was related to apoptosis regulation. Thus, caspase 3 activity was completely abolished, and phosphorylated IkappaBalpha, a marker of NF-kappaB activation, showed increased expression, while cases with an increased number of large cells displayed increased expression of survivin and other cell-cycle-related proteins, such as cyclin A, cyclin E and Ki67, and p16 expression was reduced. There were no occurrences of t(11;18)(q21,q21), while 5/37 cases exhibited t(14;18)(q32;q21). Aberrant nuclear expression of bcl10 was observed in 11 cases, independently of the presence of translocations, and was significantly associated with phosphorylated IkappaBalpha expression and a reduced TdT-mediated biotin-dUTP nicked-end labeling apoptotic index. Moreover, patients with tumoral bcl10 nuclear expression showed shorter failure-free survival.
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PMID:Nuclear bcl10 expression characterizes a group of ocular adnexa MALT lymphomas with shorter failure-free survival. 1664 71

Anaplastic thyroid carcinoma (ATC) is one of the most malignant tumors in humans, and currently there is no effective treatment. In the present study we investigated the effect of an endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), on the growth of human ATC cells. 2-ME treatment had a strong growth inhibitory effect on five human ATC cell lines (HTh7, HTh 74, HTh83, C643, and SW1736), but showed no effect on one cell line (KAT-4). Cell cycle analysis of the growth-inhibited cells showed that 2-ME induced a G2/M-arrest, followed by an increased fraction of cells in sub-G1. Analysis of internucleosomal DNA laddering as well as DNA fragmentation in a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay demonstrated a high number of cells undergoing apoptosis after 2-ME treatment. An increased activation of caspase-3 and caspase-8 by 2-ME was observed, and inhibition of caspase-3 decreased the apoptotic effect. Addition of 2-ME increased activity of p38 mitogen-activated protein kinase (MAPK) in the sensitive HTh7 as well as the refractory KAT-4 cells, however, activation of stress-activated protein kinase/c-jun aminoterminal kinase (SAPK/JNK) was seen only in the HTh7 cells. Inhibitors of p38 MAPK and SAPK/JNK significantly attenuated the 2-ME effect. Taken together, our data demonstrate an antiproliferative and apoptotic effect of 2-ME on ATC cells involving activation of MAPKs.
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PMID:2-methoxyestradiol induces apoptosis in cultured human anaplastic thyroid carcinoma cells. 1667 99

Low dietary folate and deficiency of methylenetetrahydrofolate reductase (Mthfr) were reported to increase the risk for congenital heart defects, but contributory mechanisms have not been elucidated. Because low folate and absent MTHFR activity were shown to affect proliferation and apoptosis in developing neural tissue, we examined these processes in the myocardium of embryos from Mthfr +/+ and Mthfr +/- mice fed control diets (CD) or folic acid-deficient diets (FADD). Mice consumed the designated diets for 8 wk, from weaning and through pregnancy until they were killed. Embryos were assessed on gestational day 12.5 for myocardial proliferation by 5-bromo-2'-deoxyuridine (BrdU) labeling and for apoptosis by TdT-mediated dUTP nick end labeling staining and caspase 3/7 activity assays. FADD-treated dams had significantly higher resorption rates than CD-treated dams. Embryonic lengths and weights from FADD-treated dams were significantly lower than those from CD-treated dams; the smallest embryos were those of the Mthfr +/- dams that consumed the FADD, with effect of genotype tending to be significant (P = 0.09). The thickness of cardiac ventricular compact walls of embryos from FADD-treated dams was significantly reduced, and embryonic myocardium from FADD-treated dams had significantly fewer BrdU-labeled cells compared with CD-treated dams, with no differences in apoptosis due to the diets. Genotype did not affect proliferation or apoptosis. Our results suggest that proliferation of embryonic myocardium is sensitive to maternal dietary folate and that folate supplementation during pregnancy is important for normal heart development and prevention of heart defects.
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PMID:Maternal folate deficiency affects proliferation, but not apoptosis, in embryonic mouse heart. 1677 36

Thyroid hormone insufficiency adversely affects cortical development; however, its effect on apoptosis modulation during cerebral cortex development is not understood. We investigated the effect of perinatal hypothyroidism on apoptosis and its mechanisms during rat cerebral cortex development. Primary hypothyroidism was induced by feeding methimazole (0.025% wt/vol) in the drinking water to pregnant and lactating rats and continued until the animals were killed (hypothyroid group). Cerebral cortices from pups were harvested at different postnatal ages (postnatal d 0, 8, 16, and 24 and adult), and apoptosis was quantitated by terminal deoxynucleotide transferase-mediated dUTP nick end labeling and cleaved caspase-3 immunoreactivity. Compared with the euthyroid, primary somatosensory cortex (S1) in the hypothyroid group exhibited enhanced apoptosis. In S1 of euthyroid rats, apoptotic cells were mostly found in cortical layers I-III and the proportion of apoptotic cells enhanced significantly in the hypothyroid group (P < 0.001). Most of the apoptotic cells were neurons, as assessed by double immunolabeling. A significantly increased activation of caspase-3 and -7, decreased levels of antiapoptotic proteins Bcl-2 and Bcl-x(L), and increased levels of proapoptotic protein Bax was observed in the developing cerebral cortex of hypothyroid rats, compared with the euthyroid (P < 0.001). In addition, hypothyroidism significantly elevated the levels of 53-kDa pro-nerve growth factor (P < 0.001) and p75 neurotrophin receptor (P < 0.001) and decreased TrkA expression. Taken together, we provide evidence for the possible contribution of pro-nerve growth factor/p75 neurotrophin receptor pathway in hypothyroidism-enhanced apoptosis during rat cortical development. Thus, the present study may help in explaining the mechanism of the deleterious effect of thyroid hormone deficiency on cerebral cortex development in children.
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PMID:Increased pro-nerve growth factor and p75 neurotrophin receptor levels in developing hypothyroid rat cerebral cortex are associated with enhanced apoptosis. 1679 16

Fatty acid-induced apoptosis occurs in pancreatic beta-cells and contributes to the metabolic syndrome. Skeletal muscle insulin resistance is mediated by fatty acid oversupply, which also contributes to the metabolic syndrome. Therefore, we examined whether fatty acids induce apoptosis in skeletal muscle myotubes, the proapoptotic signaling involved, and the effects on insulin sensitivity. Exposure of L6 myotubes to palmitate induced apoptosis, as demonstrated by increased caspase-3 activation, phosphatidylserine exposure on the plasma membrane, and terminal deoxynucleotide transferase dUTP nick end labeling and DNA laddering, both markers of DNA fragmentation. Ceramide content was concomitantly increased, indicating a potential role for ceramides in palmitate-induced apoptosis. Supporting this notion, reducing stearoyl-CoA desaturase-1 (SCD-1) protein content with short interfering RNA resulted in ceramide accumulation and was associated with increased apoptosis in the absence of palmitate. Furthermore, the membrane-permeable C(2)-ceramide enhanced apoptosis in myotubes, whereas the ceramide synthase inhibitor, fumonisin B(1), abrogated the proapoptotic effects of palmitate. Insulin-stimulated glucose uptake was inhibited by palmitate treatment, whereas the addition of effector caspase inhibitors [Ac-DEVD-aldehyde (DEVD-CHO), Z-DQMD-FMK] independently restored >80% of the insulin-stimulated glucose uptake. These effects were observed independently from changes in the protein content of insulin signaling proteins, suggesting that proteosomal degradation is not involved in this process. We conclude that lipoapoptosis occurs in skeletal muscle myotubes, at least partially via de novo ceramide accumulation, and that inhibiting downstream apoptotic signaling improves glucose uptake in vitro.
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PMID:Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance. 1684 30

The chick optic tectum displays an alternating pattern of cellular and plexiform layers and at embryonic day (ED) 12 there are mainly four cellular layers: transient cell compartment 3 (TCC3), compartment "h-i-j"(C"h-i-j"), stratum griseum centrale (SGC) and subventricular zone (SvZ). In the present work we characterized the programmed cell death (PCD) of these layers and their vulnerability to acute hypoxia at ED12, and also identified the main cellular type involved in hypoxic cell death. The colocalization of three independent markers of cell degeneration: pyknotic nuclei by Hoechst staining, fragmented DNA by TdT-mediated dUTP nick-end labeling (TUNEL), and presence of active caspase-3 by immunofluorescence, was analyzed in embryos that developed in normoxic conditions (control embryos) and embryos that were subjected to hypoxia (8% O(2)/92% N(2)) for 60 min (hypoxic embryos), followed by 0-12 h of normoxic recovery. In control embryos cell death rate within each layer was constant through time, but there were significant differences (P<0.01) in cell death rates among the different layers. In contrast, in hypoxic embryos, a significant increase (P<0.01) in cell death rate was observed in layers TCC3, C"h-i-j" and SGC. This change was evident only at 6 h post-hypoxia, and at later time points cell death rate was similar to control values. Each of these layers had a different vulnerability to the hypoxic event while the SvZ layer was not affected. In addition, the significant colocalization between the neuron specific nuclear protein (NeuN) and TUNEL signal showed that hypoxia affected primarily neurons. In conclusion, our findings demonstrate that in the chick optic tectum at ED12, PCD is layer dependent and that acute hypoxia causes a transient increase in neuronal death in a delayed fashion, which is also layer dependent. The morphological features of the neuronal death process at the light microscope level resembled apoptosis.
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PMID:Acute hypoxia and programmed cell death in developing CNS: Differential vulnerability of chick optic tectum layers. 1690 33

Previously, we found a significantly greater number of surviving CA1 neurons to global ischemia in the aged (24-month-old) F344 rats than in young (4-month-old) rats. The present study tests the hypothesis that aging retards neuronal death in the hippocampal CA1 region following cerebral ischemia. The CA1 "living cell ratio" was significantly greater in aged than in young rats at three days (62+/-8% vs. 30+/-8%) and at eight days (36+/-6% vs. 17+/-5%), but not at 14 days (15+/-12% vs. 18+/-12%) following ischemia. The number of the CA1 cells exhibiting co-localized TdT-mediated X-dUTP nick end labeling reaction and caspase-3 active peptide (C3AP) immunoreactivity was greater in aged than young animals at three and eight days following ischemia (36+/-8/mm vs. 3+/-1/mm and 36+/-14 vs. 0+/-0, p<0.05 respectively). Also, the total number of C3AP-positive cells in the CA1 region in the aged group was significantly greater than in the young group at three and eight days post-ischemia (p<0.05). Aging appears to delay caspase-3-dependent apoptotic cell death induced by global ischemia in the CA1 region of the hippocampus, consistent with an age-induced neuroprotective process.
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PMID:Aging is neuroprotective during global ischemia but leads to increased caspase-3 and apoptotic activity in hippocampal neurons. 1691 82

The aim of this study was to investigate the radiofrequency (RF) electromagnetic fields (EMF) effects on neuronal apoptosis in vitro. Primary cultured neurons from cortices of embryonic Wistar rats were exposed to a 900-MHz global system for mobile communication (GSM) RF field for 24 h in a wire-patch cell. The average-specific absorption rate (SAR) used was 0.25 W/kg. Apoptosis rate was assessed immediately or 24 h after exposure using three methods: (i) DAPI staining; (ii) flow cytometry using double staining with TdT-mediated dUTP nick-end labeling (TUNEL) and propidium iodide (PI); and (iii) measurement of caspase-3 activity by fluorimetry. No statistically significant difference in the apoptosis rate was observed between controls and 24 h GSM-exposed neurons, either 0 h or 24 h post-exposure. All three methods used to assess apoptosis were concordant. These results showed that, under the conditions of experiment used, GSM-exposure does not significantly increase the apoptosis rate in rat primary neuronal cultures. This work is in accordance with other studies performed on cell lines and, to our knowledge, is the first one performed on cultured cortical neurons.
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PMID:No apoptosis is induced in rat cortical neurons exposed to GSM phone fields. 1700 38

Resveratrol (Res) has been reported to inhibit tumor initiation, promotion, and progression in a variety of cell culture systems depending on the specific cell type and cellular environment. In the present study, we determined the effect of Res on the cell growth and apoptosis of rat glioma C6 cell line as well as mouse fibroblast 3T3 cell line, in vitro. Concurrently, we investigated whether caspase-3 is involved in the Res-induced apoptosis of rat glioma cells. Exposure to Res exhibits a significant anti-proliferative effect and induces an increase in the population of apoptotic cells on C6 cells in a concentration- and time-dependent manner, but not for normal 3T3 fibroblast cells, as measured by methyl thiazolyl tetrazolium assay and flow cytometer. Distinguished increase of C6 cells in S phase is observed after the treatment of Res as compared to insignificant change in cell cycle distribution of 3T3 cells. TdT-mediated dUTP nick end labeling fluorescence staining, HE staining, and scanning electron microscope revealed abnormal morphology and ultrastructure in C6 cells treated with Res. Our data showed that Res can increase the expression and induced the activation of caspase-3 in rat glioma C6 cells. These results suggest that Res has significant apoptosis-inducing effect on C6 glioma cells other than normal fibroblast 3T3 cells in vitro and caspase-3 may act as a potential mediator in the process.
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PMID:Resveratrol inhibits cell growth and induces apoptosis of rat C6 glioma cells. 1703 60


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