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)

Cell death in the core of human brain tumors is triggered by hypoxia and lack of nutrients, but the mode of cell death whether necrosis or apoptosis is not clearly defined. To identify the role of apoptosis in brain tumor cell death, we investigated macromolecular (RNA and protein) synthesis and activity in the central to peripheral region of benign [desmoplastic infantile ganglioglioma (DIG) and transitional meningioma (TMG)] and malignant [ependymoma (END), anaplastic astrocytoma (APA), and glioblastoma multiforme (GBM)] brain tumors derived from five patients who had not received previously radiotherapy or chemotherapy. Normal brain tissue (NBT) served as control. RT-PCR analysis of tumor tissues covering central to peripheral regions detected mRNA overexpression of pro-apoptotic gene bax in malignant tumors, indicating a commitment to apoptosis. The mRNA expression of calpain (a Ca(2+)-dependent cysteine protease) and calpastatin (endogenous calpain inhibitor) was altered resulting in an elevated calpain/calpastatin ratio. Calpain content and activity were increased, suggesting a role for calpain in cell death. In the mitochondria-dependent death pathway, caspase-9 and caspase-3 were also overexpressed in tumors. The increased caspase-3 activity cleaved poly(ADP-ribose) polymerase (PARP). Agarose gel electrophoresis detected a mixture of random and internucleosomal DNA fragmentation in malignant brain tumors. Overexpression of pro-apoptotic bax, upregulation of calpain and caspase-3, and occurrence of internucleosomal DNA fragmentation are now presented indicating that one mechanism of cell death in malignant brain tumors is apoptosis, and that enhancement of this process therapeutically may promote decreased tumor growth.
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PMID:Molecular evidence of apoptotic death in malignant brain tumors including glioblastoma multiforme: upregulation of calpain and caspase-3. 1211 1

The aim of this study was to investigate the vagal motoneuronal degeneration after right vagotomy using in situ hybridization, RT-PCR, and immunohistochemistry methods. The morphology of the vagal motoneurons in dorsal motor nucleus of the vagus nerve (DMV) and nucleus of ambiguus (NA) after right vagotomy was examined by using Nissl staing and TUNEL. The expression of inducible nitric oxide synthase (iNOS), bcl-2, bax, and caspase-3 in DMV and NA of rats after right vagotomy was studied. Additionally, the involvement of the N-methyl-D-aspartate (NMDA) receptor-calcium-neuronal nitric oxide synthase (nNOS) pathway in the vagal motoneuronal degeneration was addressed by double-immunolabeling analysis of nNOS with NMDAR1 and calbindin D28K in right-vagotomized rats. The neurons in right DMV and NA displayed a darkly stained, shrunken morphology at 1 day and 5 days following right vagotomy as shown by Nissl staining. Quantitative analysis revealed that, at 1 day and 5 days following right vagotomy, the number of neurons in right DMV, but not NA, was significantly reduced in comparison with that of control rats. Occasional TUNEL-positive neurons were detected in right DMV of rat at 1 day after right vagotomy. The expression of iNOS protein and mRNA was absent in DMV and NA of control rats. However, the iNOS mRNA expression was induced bilaterally in DMV and NA at 1 day postoperation and continued to be up-regulated until 5 days after vagotomy as shown by in situ hybridization. Immunohistochemistry analysis also showed the increased expression of iNOS in bilateral DMV and NA of vagotomized rats. RT-PCR analysis revealed the enhanced bcl-2 and reduced bax mRNA levels and subsequent up-regulation of both bcl-2 and bax mRNA in right sides of the vagotomized brainstems at 1 day and 5 days postoperation, respectively. In situ hybridization analysis confirmed the up-regulation of bcl-2 and bax mRNA in right DMV and NA of the rats at 5 days following operation. Immunohistochemistry analysis showed up-regulated Bcl-2 immunoreactivity and undetectable changes in Bax immunoreactivity in DMV and NA of rats at 1 day after vagotomy, whereas enhancement of both Bcl-2 and Bax immunoreactivity was observed at 5 days postoperation. In addition, the caspase-3 mRNA level was elevated ipsilaterally in DMV and NA at 1 day and 5 days following right vagotomy. Double-immunofluorescence analysis showed complete colocalization of nNOS with NMDAR1 and with calbindin in ipsilateral DMV and NA at 10 days following right vagotomy. This study suggests that the signal pathway for NMDAR1-calcium-nNOS and the up-regulation of iNOS in DMV and NA may be involved in the vagal motor neurodgeneration after right vagotomy. Furthermore, our results imply that the apoptosis pathway mediated by Bcl-2, Bax, and caspase-3 may be activated in vagal motoneurons after right vagotomy.
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PMID:Molecular analysis of the vagal motoneuronal degeneration after right vagotomy. 1212 81

Injury of endothelial cells has been postulated to be an initial trigger of the progression of atherosclerosis in patients with diabetes. Previously, we demonstrated high D-glucose induced endothelial apoptosis through the bax-caspase pathway and the potential contribution of hepatocyte growth factor (HGF) to the pathogenesis of endothelial dysfunction. In this study, we analyzed the molecular mechanisms of the protective actions of HGF against endothelial cell death under high D-glucose conditions. High concentrations of D-glucose resulted in a significant increase in apoptosis and necrosis. In contrast, HGF attenuated high D-glucose-induced apoptosis and necrosis (P < 0.01). High D-glucose significantly increased bax protein, but not bcl-2, and activated caspase 3-like and 9, whereas HGF significantly increased bcl-2 expression without affecting bax level and attenuated the increase in caspase 3 and 9 activity. Interestingly, high D-glucose resulted in translocation of bax protein from cytosol to the mitochondrial membrane, whereas HGF inhibited the bax translocation. Importantly, this bax translocation was also completely blocked by overexpressed bcl-2. These findings suggest that HGF can activate bcl-2 expression and inhibit translocation of bax protein upstream of the mitochondria, thereby leading to the inhibition of caspase 3 and 9 activation. HGF may be an important factor in the maintenance of endothelial function.
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PMID:Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol to mitochondrial membrane. 1214 77

We tested the effects of hydroxychloroquine (HCQ), an anti-rheumatic drug, on the viability of chronic lymphocytic leukemia (CLL) cells. HCQ induced a decrease in cell viability in a dose- and time-dependent manner. The mean LC50 calculated for the cells of 20 patients was 32 +/- 7 microg/ml (range, 10-75 microg/ml). We observed a large increase in apoptotic cell number after 24 h of incubation with 50 microg/ml HCQ (55 +/- 6 vs. 23 +/- 3% in medium alone, p < 0.001). Indeed, HCQ in leukemic cells induced the features of apoptosis (cell shrinkage, decrease in mitochondrial transmembrane potential, phosphatidylserine externalization, chromatin condensation and DNA fragmentation). HCQ had marked selective cytotoxicity when compared with normal blood mononuclear cells, in which the LC50 was >100 microg/ml at 24 h. HCQ induced the proteolytic cleavage of poly(ADP(adenosine 5'-diphosphate)ribose) polymerase (PARP) and increased the activity of caspase-3. The expression of bcl-2 and bax proteins was significantly modified after incubation with the drug and HCQ activity against CLL cells occurred independently of the presence of IL-4, sCD40L and bone marrow stromal cells.
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PMID:Hydroxychloroquine-induced apoptosis of chronic lymphocytic leukemia involves activation of caspase-3 and modulation of Bcl-2/bax/ratio. 1214 91

To investigate whether ethanol induces apoptosis in Leydig cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, terminal deoxynuclotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay, 4,6-diamidino-2-phenylindole (DAPI) staining, DNA fragmentation assay, caspase-3 enzyme assay, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis were performed on TM3 mouse Leydig cells. Through morphological and biochemical analyses, it was demonstrated that TM3 cells treated with ethanol at concentrations of 50 and 100 mM exhibit classical apoptotic features. In addition, it was shown that ethanol induces increases in levels of bax and caspase-3 and a decrease in bcl-2 expression. Based on the results, alcohol appears to activate specific intracellular death-related pathways leading to bax-dependant caspase-3 activation and the induction of apoptosis in Leydig cells.
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PMID:Alcohol induces apoptosis in TM3 mouse Leydig cells via bax-dependent caspase-3 activation. 1216 4

A missense mutation (N1411) in Presenilin-2 (PS-2) gene is associated with early-onset familial Alzheimer's disease. In this study, SK-N-SH human neuroblastoma cells were transfected with wild-type and mutant PS-2 gene to examine presenilin-2 effects on apoptosis. Serum deprivation resulted in enhanced apoptosis in mutant PS-2 comparing with wild-type PS-2. Similarly, mutant PS-2 induced lactate dehydrogenase release to greater extent than wild-type PS-2. Time course experiment demonstrated that the increase in caspase-3-like activity was more pronounced and accelerated in mutant PS-2, compared to wild-type PS-2. While a significant decrease in bcl-2, an anti-apoptotic molecule, occurred in the cells overexpressing mutant PS-2, no significant change was observed in bax, a pro-apoptotic molecule, as compared with the cells overexpressing wild-type PS-2. Our study demonstrated that mutant PS-2 induces apoptosis accompanied by increased caspase-3-like activity and decreased bcl-2 expression in neuronal cells after serum-deprivation.
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PMID:N141I mutant presenilin-2 gene enhances neuronal cell death and decreases bcl-2 expression. 1217 18

Previous experimental studies have shown that high dietary fat intake is associated with mammary carcinogenesis. In the current study, the effect of 5-LOX or 12-LOX inhibitors on human breast cancer cell proliferation and apoptosis, as well as the possible mechanisms were investigated. The LOX inhibitors, NDGA, Rev-5901, and baicalein all inhibited proliferation and induced apoptosis in MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cell in vitro. In contrast, the LOX products, 5-HETE and 12-HETE had mitogenic effects, stimulating the proliferation of both cell lines. These inhibitors also induced cytochrome c release, caspase-9 activation, as well as downstream caspase-3, caspase-7 activation, and PARP cleavage. LOX inhibitor treatment also reduced the levels of anti-apoptotic proteins Bcl-2 and Mcl-1 and increased the levels of the pro-apoptotic protein bax. In conclusion, blockade of both 5-LOX and 12-LOX pathways induces apoptosis in breast cancer cells through the cytochrome c release and caspase-9 activation, with changes in the levels of Bcl-2 family proteins.
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PMID:The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. 1220 Jan 39

The aim of the present study was to investigate the action of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP-3) on steroidogenesis and apoptosis in human corpus luteum during the midluteal phase. Slices from corpora lutea were incubated for 4 h with IGF-I or IGFBP-3. Progesterone, oestradiol, androstenedione and testosterone concentrations were determined by radioimmunoassay; caspase 3 expression was assessed by immunohistochemistry; bcl-2, bax and P(450arom) expression were assessed by RT-PCR; and apoptosis was detected by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling. The results showed that addition of IGF-I stimulated progesterone production (150%, P < 0.01), oestradiol production (65%, P < 0.05) and bcl-2 gene expression (approximately 200%, P < 0.05), but decreased apoptosis (P < 0.05). In contrast, IGFBP-3 reduced steroid production and increased bax gene expression and the percentage of apoptotic cells (P < 0.05). Neither IGF-I nor IGFBP-3 had an effect on P(450arom) expression or on the concentrations of its substrates. However, maximum expression of caspase 3 was detected in corpus luteum during the midluteal phase. In conclusion, these results indicate that IGF-I and IGFBP-3 act as regulatory peptides of the function of the human corpus luteum during the midluteal phase. This action may be direct or mediated by steroid production or by bcl-2-bax expression.
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PMID:Regulation of steroid synthesis and apoptosis by insulin-like growth factor I and insulin-like growth factor binding protein 3 in human corpus luteum during the midluteal phase. 1236 68

We investigated the effect of a chronic exposure to high levels of free fatty acid (FFA; 2 mmol/L oleate/palmitate 2:1) or glucose (16.7 mmol/L) on islet cell apoptosis. Apoptosis was detected using 4 different methods: (1) cell staining with annexin-V fluorescien isothiocyanate (FITC) conjugate and propidium iodide (PI); (2) quantification of cytoplasmatic DNA fragments by an enzyme-linked immunosorbent assay (ELISA); (3) assay of caspase 3 activity; and (4) TdT-mediated dUTP nick-end labeling (TUNEL). Islet cells were also costained with an anti-insulin antibody to identify apoptotic beta cells. We also evaluated by reverse-transcriptase polymerase chain reaction (RT-PCR) the expression of bax, bcl-2, and caspas 3, genes involved in apoptosis. In islets cultured for 7 days in the presence of high FFA or for 3 days in the presence of high glucose levels, we observed: (1) a 2- to 3-fold increase of apoptotic cells conjugated with annexin-V FITC and PI; (2) a 4- to 6-fold increase of cytoplasmatic DNA fragments; (3) a 3- to 4-fold increase of caspase 3 activity; and (4) a significant increase of insulin positive apoptotic cells as detected with the TUNEL method. RT-PCR analysis indicated in islets exposed to high FFA or glucose levels an increase of bax (proapoptotic gene), a reduction of bcl-2 (antiapoptotic gene), and a slight (although not significant) increase in caspase 3 expression. Western blot analysis also showed an increase of Bax protein levels in islets exposed to high FFA or glucose. The simultaneous presence of both metabolic abnormalities did not further increase the amount of apoptotic cells, although the time-course of the cellular damage induced by FFA was accelerated by the contemporary presence of high glucose. To elucidate the mechanism by which FFA and glucose may induce pancreatic beta-cell damage, we examined whether nicotinamide prevents apoptosis in pancreatic islets cultured for 7 days with high FFA or for 3 days with high glucose. Nicotinamide was able to prevent beta-cell damage by significantly reducing apoptosis in both experimental conditions. Also, the increase of Bax protein level was prevented by nicotinamide. These data indicate that chronic exposure to elevated FFA or glucose levels increases apoptosis in rat pancreatic islets and these cytotoxic effects could be mediated by oxidative stress. This may contribute to the beta-cell failure that occurs in most in type 2 diabetic patients few years after clinical diabetes onset.
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PMID:Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets: possible role of oxidative stress. 1237 Aug 56

Few studies have characterised apoptosis in a brain injury model that causes a significant degree of diffuse axonal injury. Such characterisation is essential from a clinical viewpoint since diffuse axonal injury is a major component of human head injury. The present study therefore, examines the expression of active and proactive caspase-3, and the bax, bcl-2 and bcl-x members of the bcl-2 family, to characterise the temporal profile of apoptosis in a model of traumatic brain injury in rats that produces significant diffuse axonal injury. Pentobarbital anaesthetised male Sprague-Dawley rats were injured using the 2m impact-acceleration model of diffuse traumatic brain injury. After injury, diffuse trauma resulted in an increased bax expression followed by induction of caspase-3. The increase in caspase-3 was simultaneous with an increase in anti-apoptotic bcl-2 expression. Bcl-x levels were increased after induction of caspase-3 and the increased levels of bcl-x were sustained to the end of the 5-day observation period. Increased active caspase-3 expression was associated with the appearance of TUNEL positive cells. These cells were detected in different brain regions at different times, with some regions showing no apoptotic cells until 3 days after injury. No TUNEL positive cells were detected at 7 and 14 days after injury. DNA electrophoresis confirmed that DNA fragmentation was maximal at 3 days after injury. Increased active caspase-3 levels were also significantly correlated with increased bcl-2 levels (r=0.80; P<0.001) suggesting that the apoptotic cascade after diffuse traumatic brain injury is a carefully controlled cellular homeostatic response. Pharmacological manipulation of this balance may offer a therapeutic approach for preventing cell death and improving outcome after diffuse traumatic brain injury.
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PMID:Temporal characterisation of pro- and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats. 1238 17


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