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)

Monocrotaline (MCT) is a pyrrolizidine alkaloid (PA) plant toxin that produces sinusoidal endothelial cell (SEC) injury, hemorrhage, fibrin deposition, and coagulative hepatic parenchymal cell (HPC) oncosis in centrilobular regions of rat livers. Cells with apoptotic morphology have been observed in the livers of animals exposed to other PAs. Whether apoptosis occurs in the livers of MCT-treated animals and whether it is required for full manifestation of pathological changes is not known. To determine this, rats were treated with 300 mg MCT/kg, and apoptosis was detected by transmission electron microscopy and the TUNEL (TdT-mediated dUTP nick end labeling) assay. MCT produced significant apoptosis in the liver by 4 h after treatment. To determine if MCT kills cultured HPCs by apoptosis, HPCs were isolated from the livers of rats and exposed to MCT. MCT caused a concentration-dependent release of alanine aminotransferase (ALT), a marker of HPC injury. Furthermore, caspase 3 was activated and TUNEL staining increased in MCT-treated HPCs. MCT-induced TUNEL staining and release of ALT into the medium were completely prevented by the pancaspase inhibitors z-VAD.fmk and IDN-7314, suggesting that MCT kills cultured HPCs by apoptosis. To determine if caspase inhibition prevents MCT-induced apoptosis in the liver, rats were cotreated with MCT and IDN-7314. IDN-7314 reduced MCT-induced TUNEL staining in the liver and release of ALT into the plasma. Morphometric analysis confirmed that IDN-7314 reduced HPC oncosis in the liver by approximately 50%. Inasmuch as HPC hypoxia occurred in the livers of MCT-treated animals, upregulation of the hypoxia-regulated cell-death factor, BNIP3 (Bcl2/adenovirus EIB 19kD-interacting protein 3), was examined. BNIP3 was increased in the livers of mice treated 24 h earlier with MCT. Results from these studies show that MCT kills cultured HPCs by apoptosis but causes both oncosis and apoptosis in the liver in vivo. Furthermore, caspase inhibition reduces both apoptosis and HPC oncosis in the liver after MCT exposure.
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PMID:Modes of cell death in rat liver after monocrotaline exposure. 1460 Feb 77

Overexpression of the receptor tyrosine kinase HER-2/neu is associated with poor prognosis in patients with breast and ovarian cancer. Recent excitement has surrounded the therapeutic effects of HER-2-blocking therapy strategies and has rekindled interest on the molecular mechanisms of HER-2/neu in tumor biology. To study the role of HER-2/neu overexpression in vivo, we used a murine fibroblast cell line (NIH3T3-her2) conditionally expressing human HER-2/neu under control of a tetracycline-responsive promoter. Expression of HER-2 could be down-regulated below detection limit (>625-fold dilution) by exposure of NIH3T3-her2 cells to anhydrotetracycline (ATc). Subcutaneous injection of NIH3T3-her2 cells into nude mice resulted in rapid tumor growth. Mice with mean tumor volumes of 0.2, 0.8, 1.9, and 14.9 cm(3) were treated daily with 10 mg/kg ATc to switch off HER-2/neu expression, producing reductions in tumor size of 100, 98.1, 81.4, and 74.2%, respectively, by 7 days after onset of ATc administration (P = 0.005, Kruskal-Wallis test). Different long-term effects of HER-2 down-regulation were observed when mice with small (0.2 cm(3); n = 7), intermediate (0.8-1.2 cm(3); n = 10) and large (> or =1.9 cm(3); n = 11) tumors received ATc for up to 40 days. Complete remission was observed for 100, 40, and 18% of the small-, intermediate-, and large-sized tumors, respectively (P = 0.003). However, after 20-45 days of ATc administration, recurrent tumor growth was observed for all mice, even in those with previous complete remissions. The time periods for which mean tumor volume could be suppressed to volumes <0.1 cm(3) under ATc administration were 34, 22, 8, and 0 days for tumors with initial volumes of 0.2, 0.8, 1.9 and 14.9 cm(3), respectively (P = 0.005, Kruskal-Wallis test). Interestingly, HER-2 remained below the detection limit in recurrent tumor tissue, suggesting that initially HER-2-dependent tumors switched to HER-2 independence. The "second hits" leading to HER-2-independent tumor growth have not yet been identified. The rapid regression of tumors after down-regulation of HER-2 was explained by two independent mechanisms: (a) a block in cell cycle progression, as evidenced by a decrease in Ki-67 antigen expression from 40% before ATc treatment to 8.3% after 7 days of ATc treatment; and (b) induction of apoptosis as demonstrated by caspase-3 activation and by the terminal deoxynucleotidyltransferase (Tdt)-mediated nick end labeling assay (TUNEL). In conclusion, we have shown that switching off HER-2 may disturb the sensitive balance between cell proliferation and cell death, leading to apoptosis and tumor remission. Tumor remission was dependent on the volume of the tumors before down-regulation of HER-2/neu.
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PMID:Switching off HER-2/neu in a tetracycline-controlled mouse tumor model leads to apoptosis and tumor-size-dependent remission. 1461 17

Results of studies from our laboratory have shown that administration of 17beta-estradiol (E(2)) reduces cerebellar neuronal damage during ethanol withdrawal (EW). In the current study, we examined mechanisms underlying E(2) protection against EW-associated cerebellar damage by assessing apoptotic indicators: DNA fragmentation, caspase-3 activity, and protein kinase C (PKC) activity. Ovariectomized rats, implanted with E(2) or oil pellets, received ethanol [7.5% weight/volume (wt./vol.)] (EW/E(2) group and EW/Oil group, respectively) chronically (for 5 weeks) or control dextrin diet (Dextrin/Oil group). At day 14 of EW, cerebelli were collected for the terminal deoxynucleotidyltransferase (TdT)-mediated dUDP-biotin nick end labeling (TUNEL) assay to detect DNA fragmentation and for immunohistochemistry to detect caspase-3 activation. A separate group of rat cerebelli was prepared to assess for total PKC activity, as well as for activity of a specific PKC isozyme, epsilon (PKCepsilon), by using an in vitro [gamma-(32)P]ATP phosphorylation assay at days 1 and 14 of EW. Results indicated that rats in the EW/Oil group had more DNA fragments and caspase-3-positive neuronal cells than observed for control rats, and these effects were inhibited by E(2) treatment. For total PKC activity at day 1 of EW, rats in the EW/E(2) group had a lower cytosolic PKC activity than observed for either rats in the EW/Oil group or control rats. At day 14 of EW, both EW groups had a lower total PKC activity than observed for control rats. For PKCepsilon activity, rats in the EW/E(2) group had a lower cytosolic PKCepsilon activity than observed for rats in the EW/Oil group or for control rats at day 1, and they had a lower membrane PKCepsilon activity at day 14 of EW than observed for control rats. These findings support the suggestion that E(2) protects against cerebellar neuronal damage in ethanol-withdrawn rats by inhibition of DNA fragmentation and caspase-3 activation, and that reduced PKC activity may be involved in the protection.
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PMID:Role of protein kinase C in estrogen protection against apoptotic cerebellar cell death in ethanol-withdrawn rats. 1461 10

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 micromol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 micromol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.
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PMID:Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro. 1461 77

In this study, we investigated the involvement of reactive oxygen species (ROS) and calcium in staurosporine (STS)-induced apoptosis in cultured retinal neurons, under conditions of maintained membrane integrity. The antioxidants idebenone (IDB), glutathione-ethylester (GSH/EE), trolox, and Mn(III)tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly reduced STS-induced caspase-3-like activity and intracellular ROS generation. Endogenous sources of ROS production were investigated by testing the effect of the following inhibitors: 7-nitroindazole (7-NI), a specific inhibitor of the neuronal isoform of nitric oxide synthase (nNOS); arachidonyl trifluoromethyl ketone (AACOCF(3)), a phospholipase A(2) (PLA(2)) inhibitor; allopurinol, a xanthine oxidase inhibitor; and the mitochondrial inhibitors rotenone and oligomycin. All these compounds decreased caspase-3-like activity and ROS generation, showing that both mitochondrial and cytosolic sources of ROS are implicated in this mechanism. STS induced a significant increase in intracellular calcium concentration ([Ca(2+)](i)), which was partially prevented in the presence of IDB and GSH/EE, indicating its dependence on ROS generation. These two antioxidants and the inhibitors allopurinol and 7-NI also reduced the number of TdT-mediated dUTP nick-end labeling-positive cells. Thus, endogenous ROS generation and the rise in intracellular calcium are important inter-players in STS-triggered apoptosis. Furthermore, the antioxidants may help to prolong retinal cell survival upon apoptotic cell death.
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PMID:Cytosolic and mitochondrial ROS in staurosporine-induced retinal cell apoptosis. 1464 98

We have found that neuregulin-1beta (NRG-1beta) is expressed in the cardiac microvascular endothelium, and promotes the growth and survival of cardiac myocytes in culture through the activation of erbB2 and erbB4 receptor tyrosine kinases. In this study, we examined the role of NRG-1/erbB signaling in protection of cardiac myocytes from anthracycline-induced apoptosis in vitro to determine the coupling between erbB receptor subtypes and cytoprotective signaling. Treatment of neonatal rat ventricular myocytes with NRG-1beta inhibited daunorubicin-induced apoptosis as shown by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling staining for DNA fragmentation as well as flow cytometric quantification of apoptotic myocytes. Daunorubicin-induced activation of caspase-3 in cardiomyocytes was similarly inhibited by NRG-1beta. The phosphoinositol-3-kinase (PI3-kinase) inhibitor wortmannin prevented the effects of NRG-1beta on daunorubicin-induced apoptosis and activation of caspase-3. NRG-1beta treatment induced rapid activation of Akt/PKB that was inhibited by wortmannin, and adenoviral-mediated overexpression of a dominant-negative Akt prevented the protective effect of NRG-1beta. Akt activation by NRG-1beta was prevented by the tyrphostin AG1478, which we show inhibits erbB4 activation by NRG-1beta. In contrast, the erbB2-specific tyrphostin AG879 had no effect on NRG-1beta activation of Akt. Myocyte treatment with an activating antibody to erbB2 caused phosphorylation of erbB2, and led to activation of Erk but not Akt. Treatment with the erbB2 antibody had no effect on anthracycline-induced apoptosis. Thus, NRG-1beta protects against anthracycline-induced apoptosis via erbB4-dependent activation of the PI3-kinase/Akt pathway.
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PMID:Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt. 1465 73

The expression of c-jun, mitogen-activated protein kinase phosphatase-1 (mkp-1), caspase-3 and glial fibrillary acidic protein (gfap) was examined at 1, 3 and 7 days after cortical cold injury in rats by in situ hybridisation and immunocytochemistry. Alterations of gene expression were related to metabolic disturbances and delayed cell death, as revealed by cerebral protein synthesis autoradiography, ATP bioluminescence, pH fluorescence and terminal transferase biotinylated dUTP nick end labelling (TUNEL). Protein synthesis autoradiographies depicted sharply demarcated cortex lesions, which were almost congruent with areas exhibiting ATP depletion (lesion volume: 16.9+/-11.8 mm(3) after 7 days). Lesions were surrounded by a region of tissue alkalosis, which was most prominent 1 day after trauma. Delayed cell injury, as revealed by TUNEL, was noticed in a thin rim around the lesion border on day 1 (tissue volume: 1.7+/-0.8 mm(3)) and, to lesser extent, days 3 and 7 post-lesioning. However, only a small percentage of cells in this area were positive for activated caspase-3 protein. TUNEL(+) cells were further seen in the ventrobasal thalamus after 7 days. In the thalamus, the appearance of DNA-fragmented cells was closely accompanied by activated caspase-3 expression. In situ hybridisations revealed that cell injury both in the peri-lesion rim and ventrobasal thalamus was associated with increased c-jun and gfap, but not mkp-1 and caspase-3 mRNA levels. Gene responses were not confined to areas revealing irreversible cell death: mkp-1 mRNA was bilaterally upregulated in the lesion-remote entorhinal cortex, cingulate cortex and reticular thalamus at 7 days after trauma, and caspase-3 mRNA was slightly, but significantly downregulated in the entorhinal cortex after 3 and 7 days. Gfap mRNA was elevated in all regions exhibiting tissue alkalosis. Our data suggest that delayed cell injury after cortex trauma may be apoptotic in the ventrobasal thalamus, but not the peri-lesion rim. The dissociated responses of c-jun, mkp-1 and caspase-3 mRNAs may represent important factors influencing tissue viability.
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PMID:Expression of c-jun, mitogen-activated protein kinase phosphatase-1, caspase-3 and glial fibrillary acidic protein following cortical cold injury in rats: relationship to metabolic disturbances and delayed cell death. 1469 45

We have investigated the expression of P2X5, P2X7, P2Y1, and P2Y2 receptor subtypes in 8- to 11-wk-old human fetal epidermis in relation to markers of proliferation (proliferating cell nuclear antigen (PCNA) and Ki-67), keratinocyte differentiation (cytokeratin K10 and involucrin), and markers of apoptosis (TdT-mediated dUTP nick end labeling (TUNEL) and anti-caspase-3). Immunohistochemistry showed that each of the four receptors was expressed in spatially distinct zones of the developing epidermis: P2Y1 receptors were found in the basal layer, P2X5 receptors were predominantly in the basal and intermediate layers, and both P2Y2 and P2X7 receptors were in the periderm. Colocalization experiments suggested different functional roles for these receptors. P2Y1 receptors were found in fetal keratinocytes positive for PCNA and Ki-67, suggesting a role in proliferation. P2X5 receptors double labeled with differentiated fetal keratinocytes that were positive for cytokeratin K10, suggesting a role in differentiation. P2X7 receptors colocalized with anti-caspase-3 antibody and were also expressed in periderm cells positive for TUNEL, suggesting a role in periderm cell apoptosis. P2Y2 receptors were found only in periderm cells and may have a role in chloride and fluid secretion into the amniotic fluid.
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PMID:Purinergic receptors are part of a signaling system for keratinocyte proliferation, differentiation, and apoptosis in human fetal epidermis. 1470 18

Apoptosis and proliferation and the effect of exogenous surfactant on these processes were investigated in the lungs of mechanically ventilated/oxygen-treated preterm infants with respiratory distress syndrome and stillborn foetuses. Apoptotic and proliferation indices were determined in lung tissue sections from 27 ventilated/oxygen-treated preterm infants and 29 stillborn foetuses. The effect of exogenous surfactant on apoptosis and proliferation was studied in 16 ventilated preterm infants; 11 untreated infants served as control. Apoptotic and proliferating cells were identified by double labelling combining terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end-labelling or Ki-67 with cell marker proteins. Pathways to cell death were explored by immunolabelling of cleaved caspases-3, -8 and -9. In the lungs of ventilated/oxygen-treated preterm infants, the numbers of apoptotic and proliferating cells increased significantly compared to the respective numbers in the lungs of stillborn foetuses. Apoptosis was detected in alveolar epithelial cells, whereas epithelial, endothelial and smooth muscle cells proliferated. Surfactant treatment reduced apoptosis induced by ventilation/oxygen-treatment; however, the decrease was not significant. Caspases-8 and -9 do not contribute to ventilation-induced apoptosis, whereas caspase-3 is involved. In conclusion, ventilation/oxygen-treatment induces epithelial cell apoptosis and proliferation of epithelial, endothelial and smooth muscle cells in the lungs of preterm infants.
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PMID:Apoptosis and proliferation in lungs of ventilated and oxygen-treated preterm infants. 1473 42

Apoptosis plays an important role in atherosclerosis. The factors regulating this process are not well defined. We examined the relation of apoptotic cells with the terminal complement complex C5b-9 in human atherosclerotic lesions. The extent of apoptosis was determined using TdT dUTP nick-end labeling (TUNEL) and immunohistochemistry of apoptosis regulators caspase-3, caspase-9, Bax, and Bcl-2. C5b-9 was localized by immunohistochemistry and immunoelectron microscopy. The apoptotic index was higher in fibrous plaques when compared with intimal fatty streaks and intimal thickenings. Bax expression was present in TUNEL+ apoptotic cells, and Bcl-2 was rarely present in the atherosclerotic wall. Active caspase 9 and caspase 3 deposits were present in the same areas, suggesting an involvement of the mitochondrial pathway. C5b-9 deposits colocalized with TUNEL+ cells, and the percent of double-positive cells was 2% in fatty streaks, 12% in intimal thickenings, and 35% in fibrous plaques. Colocalization of apoptotic cells with C5b-9 was also confirmed by immunoelectron microscopy. In conclusion, some apoptotic cells carry C5b-9 deposits, suggesting that complement might be activated by apoptotic cells and involved in the promotion of apoptosis, contributing to the progression of atherosclerotic lesions.
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PMID:C5b-9 terminal complement complex assembly on apoptotic cells in human arterial wall with atherosclerosis. 1473 64


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