Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to investigate the in vivo effect of metals used in dentistry, we investigated the effect of direct contact with metal plates (20 x 20 x 0.5 mm3) made of gold (Au), silver (Ag), copper (Cu) or palladium (Pd) on human promyelocytic leukemic HL-60 cells grown in RPMI1640 medium supplemented with 10% fetal bovine serum. When 0.5 mL of cell suspension was applied to the metal plates, cells were precipitated on the surface of the metal plate within 10 min. Contact with Cu induced a rapid decline of cell viability, the smear pattern of DNA fragmentation, and only minor activation of caspase-3. These effects were accompanied by a progressive decrease in the extracellular concentration of methionine, cysteine and histidine, with a corresponding increase in the concentration of methionine sulfoxide. Electron microscopy showed that contact with Cu induced vacuolization and cytoplasmic damage, prior to nuclear damage, without affecting the cell surface microvilli or mitochondrial integrity. Contact with the other metals did not induce such changes during the 3 h incubation, nor was any hormetic response (beneficial action at lower concentration) observed in the cells with any metals. Addition of N-acetyl-L-cysteine (4-5 mM) almost completely abrogated the Cu-induced cytotoxicity, whereas sodium ascorbate (0.1-0.5 mM) and catalase (6,000(1)-30,000 units/mL) were ineffective. Numerous serum proteins were adsorbed to the Ag plate, while bovine serum albumin was the major protein adsorbed to other metal plates. The present study suggests that direct contact with Cu induced non-apoptotic cell death by an oxidation-involved mechanism. The present model system may be applicable to the study of the interaction between cells and dental restorative materials.
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PMID:Biological impact of contact with metals on cells. 1709 67

Neuronal ceroid lipofuscinosces/Batten disease (NCL) is a devastating group of neurodegenerative diseases caused by genetic disruptions in lysosomal function. Cathepsin D (CD) is a major lysosomal protease, and mutations in CD that render it enzymatically defective have been reported recently in subsets of NCL patients. The targeted deletion of CD in mice results in extensive neuropathology, including biochemical and morphological evidence of apoptosis and autophagic stress (aberrant autophagosome accumulation), effects that are similar to those observed in NCL. To determine the contribution of Bax-dependent apoptosis in this mouse model of NCL, combined Bax- and CD-deficient mice were generated. Morphological analysis of CD-deficient mouse brains indicated large numbers of pyknotic neurons and neurons with marked cytoplasmic swellings containing undigested lipofuscin. Cell death and apoptosis were evidenced by increases in terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactivity and activation of caspase-3, respectively. DeOlmos silver-positive neurons were abundant in CD-deficient brain and correlated with neuron loss, as indicated by significant decreases in NeuN (neuronal nuclear antigen)-positive neurons. Lysosome dysfunction and autophagic stress were apparent in CD-deficient brain as indicated by the accumulation of autofluorescent storage material and by increased levels of LC3-II (light chain 3-II, a selective autophagosome marker), respectively. Bax deletion significantly inhibited caspase-3 activation and hippocampal TUNEL reactivity but did not prevent the majority of CD deficiency-induced neuropathology, including the persistence of pyknotic neurons, elevated cortical TUNEL reactivity, lysosome dysfunction and autophagic stress, neurodegeneration, and neuron loss. Together, these results suggest that CD deficiency-induced neuropathology does not require Bax-dependent apoptosis and highlights the importance of caspase-independent neuron death and neurodegeneration resulting from the genetic disruption of lysosome function.
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PMID:Cathepsin D deficiency induces persistent neurodegeneration in the absence of Bax-dependent apoptosis. 1731 3

The goal of this study was to characterize the impact of induction or inhibition of the heme-HO system on renal apoptosis in clipped and non-clipped kidneys from 2K1C hypertensive rats. Male Sprague-Dawley rats had a 0.25 mm silver clip placed around the left renal artery. Four groups of rats were studied: sham operated animals, 2K1C control rats, 2K1C rats received weekly injections of CoPP (5 mg/100 g body wt, administered subcutaneously), and 2K1C rats pretreated with SnMP (5 mg/ 100g body wt, administered intraperitoneally three times a week). The animals were sacrificed three weeks after surgery. We measured systolic blood pressure, plasma renin activity, non-clipped and clipped kidney HO-1 and HO-2 protein expression, HO activity, heme content, nitrotyrosine levels, and activation of selected pro- and anti-apoptotic proteins. Systolic blood pressure and plasma renin activity were significantly higher in 2K1C rats compared to sham rats. Compared to kidneys from sham animals, clipped kidneys from 2K1C rats showed a significant increase in HO-1 expression with increases in HO activity (26%), heme content (47%) and nitrotyrosine levels (49%), accompanied by an increase in caspase-3 and caspase-9 activity. In contrast, non-clipped kidneys from 2K1C rats showed no differences in HO-1 expression, HO activity, heme content, nitrotyrosine levels and caspase activity compared to sham rats. In clipped kidneys from 2K1C rats, inhibition of HO activity by SnMP augmented caspase-3 and caspase-9 activity and decreased expression of the anti-apoptotic Bcl-2 protein, while induction of HO-1 with CoPP strongly inhibited the activity of both caspases and increased the induction of Bcl-2 and Bcl-xl proteins. These findings demonstrate that the clipped kidneys responded to decreased renal perfusion pressure and increased oxidative stress by activation of the heme-HO system, which exerts antiapoptotic action via mechanisms involving decreased caspase-3 and caspase-9 activity, and increased expression of antiapoptotic molecules.
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PMID:Induction of heme oxygenase-1 in renovascular hypertension is associated with inhibition of apoptosis. 1753 Nov 61

Under natural conditions and in some experimental models, rabies virus infection of the central nervous system causes relatively mild histopathological changes, without prominent evidence of neuronal death despite its lethality. In this study, the effects of rabies virus infection on the structure of neurons were investigated with experimentally infected transgenic mice expressing yellow fluorescent protein (YFP) in neuronal subpopulations. Six-week-old mice were inoculated in the hind-limb footpad with the CVS strain of fixed virus or were mock infected with vehicle (phosphate-buffered saline). Brain regions were subsequently examined by light, epifluorescent, and electron microscopy. In moribund CVS-infected mice, histopathological changes were minimal in paraffin-embedded tissue sections, although mild inflammatory changes were present. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and caspase-3 immunostaining showed only a few apoptotic cells in the cerebral cortex and hippocampus. Silver staining demonstrated the preservation of cytoskeletal integrity in the cerebral cortex. However, fluorescence microscopy revealed marked beading and fragmentation of the dendrites and axons of layer V pyramidal neurons in the cerebral cortex, cerebellar mossy fibers, and axons in brainstem tracts. At an earlier time point, when mice displayed hind-limb paralysis, beading was observed in a few axons in the cerebellar commissure. Toluidine blue-stained resin-embedded sections from moribund YFP-expressing animals revealed vacuoles within the perikarya and proximal dendrites of pyramidal neurons in the cerebral cortex and hippocampus. These vacuoles corresponded with swollen mitochondria under electron microscopy. Vacuolation was also observed ultrastructurally in axons and in presynaptic nerve endings. We conclude that the observed structural changes are sufficient to explain the severe clinical disease with a fatal outcome in this experimental model of rabies.
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PMID:Structural abnormalities in neurons are sufficient to explain the clinical disease and fatal outcome of experimental rabies in yellow fluorescent protein-expressing transgenic mice. 1794 40

A systematic study on the in vitro interactions of 7-20 nm spherical silver nanoparticles (SNP) with HT-1080 and A431 cells was undertaken as a part of an on-going program in our laboratory to develop a topical antimicrobial agent for the treatment of burn wound infections. Upon exposure to SNP (up to 6.25 microg/mL), morphology of both the cell types remained unaltered. However, at higher concentrations (6.25-50 microg/mL) cells became less polyhedral, more fusiform, shrunken and rounded. IC(50) values for HT-1080 and A431 as revealed by XTT assay were 10.6 and 11.6 microg/mL, respectively. When the cells were challenged with approximately 1/2 IC(50) concentration of SNP (6.25 microg/mL), clear signs of oxidative stress, i.e. decreased GSH ( approximately 2.5-folds in HT-1080, approximately 2-folds in A431) and SOD ( approximately 1.6-folds in HT-1080, 3-folds in A431) as well as increased lipid peroxidation ( approximately 2.5-folds in HT-1080, approximately 2-folds in A431) were seen. Changes in the levels of catalase and GPx in A431 cells were statistically insignificant in both cell types. DNA fragmentation in SNP-exposed cells suggested apoptosis. When the apoptotic thresholds of SNP were monitored with caspase-3 assay the concentrations required for the onset of apoptosis were found to be much lower (0.78 microg/mL in HT-1080, 1.56 microg/mL in A431) than the necrotic concentration (12.5 microg/mL in both cell types). These results can be used to define a safe range of SNP for the intended application as a topical antimicrobial agent after appropriate in vivo studies.
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PMID:Cellular responses induced by silver nanoparticles: In vitro studies. 1850 9

The development of the human insula was studied in the foetuses from 21 to 32 gestation weeks, using silver staining, immunohistochemistry of proliferative cell nuclear antigen (PCNA), activated caspase-3, and TdT-mediated dUTP-biotin nick end labeling (TUNEL) techniques. To test whether the insula also has a significant role in psychiatry behavior, we also mapped the major receptor of serotonin, 5HT-2A, in the developing insula as well. Opercular formation was evident by 21 weeks gestation. At this time, the cortical layers in the insula had started to organize, with silver impregnated pyramidal and stellate cells demonstrated various processes. By 25 gestation weeks, gyri in the insula were observed. PCNA positive cells decreased in density from 21 gestation weeks onwards while an increase of TUNEL positive cells was evident from 25 to 32 weeks of gestation. Activated capase-3 positive cells were detected in the insula, along with TUNEL positive cells, confirming possibly apoptosis. Serotonin 2A receptor appeared robustly in the 31/32 gestation week specimens. Our study showed early differentiation in the insula, when compared with other parts of the human cortex in the literature. In addition, proliferation as well as apoptosis were demonstration. Expression of 5HT (serotonin) 2A receptor positive cells in development was indicative of the insula as a significant psychiatric center.
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PMID:Development of the human insular cortex: differentiation, proliferation, cell death, and appearance of 5HT-2A receptors. 1876 64

The central objective of the current study was to investigate the potential in vitro anti-proliferative effect of 4-hydroxy-3-nitro-coumarin (hncH), and the mixed-ligand silver (I) complex of 4-oxy-3-nitro-coumarin-bis(phenanthroline), [Ag(hnc)(phen)(2)] using four human-derived model cell lines. In addition, selected mechanistic studies were carried out using the most sensitive of the four cell lines. Results obtained show that the complex could decrease the proliferation of all four cell lines including neoplastic renal and hepatic, namely A-498 and HepG(2) cells, respectively, along with two non-neoplastic renal and hepatic cell lines, HK-2 and Chang, respectively. Furthermore, non-neoplastic hepatic cells (Chang) appeared to be less sensitive to the effect of the complex, but this effect was not replicated in the non-neoplastic renal (HK-2) cells. Based on IC(50) values [Ag(hnc)(phen)(2)] was shown to be almost four times more potent than cisplatin, using HepG(2) cells. In addition, the observed anti-proliferative effect was shown to be both dose- and time-dependent. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Moreover, there was no evidence that P-glycoprotein-mediated multi-drug resistance was likely to decrease anti-proliferative activity. Cytological stains, analysis of genomic DNA, and biochemical assays [caspase-3 and -9 and cleaved poly(ADP-ribose)-polymerase protein] showed that cell death appeared to result from apoptosis, with the possibility of secondary necrosis. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Ag(hnc)(phen)(2)] has been shown to be a more potent anti-proliferative agent than cisplatin, capable of altering key biochemical events leading to cell death. Additional mechanistic studies are underway to probe more fully its mechanism of action.
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PMID:Role of cell cycle events and apoptosis in mediating the anti-cancer activity of a silver(I) complex of 4-hydroxy-3-nitro-coumarin-bis(phenanthroline) in human malignant cancer cells. 1904 61

The aims of the present study were to apply the AMG technique for localization of mercury at the light and electron microscopic level in the ovary of crucian carp after exposure to mercuric chloride and to find out if this heavy metal induces expression of caspase-3. Depending on the stage of ovarian follicle development, two patterns of mercury accumulation have been found in previtellogenic ovary of crucian carp. The first mercury accumulation pattern has been found in the early previtellogenic oocyte without zona radiata. In these oocytes, mercury accumulates into an ooplasmic region that seems to correspond to the Balbiani body (32-65 microm oocyte diameter), throughout the cytoplasm (84-116 microm oocyte diameter) and in the cortical cytoplasm (approximately 180 microm oocyte diameter). The second mercury accumulation pattern has been found in the late previtellogenic oocyte with cortical alveoli (229-330 microm oocyte diameter). Ultrastructural observations have shown grains of silver-enhanced mercury inside coated vesicles, the cortical lysosome-like bodies or multivesicular bodies and cortical alveoli. Immunohistochemistry reaction for caspase-3 was positive in nuclei of the early previtellogenic oocyte and Balbiani body.
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PMID:Tracing the accumulation and effects of mercury uptake in the previtellogenic ovary of crucian carp, Carassius auratus gibelio by autometallography and caspase-3 immunohistochemistry. 1908 30

Angiogenesis, the growth of new blood vessels from pre-existing vasculature is of physiological and pathological importance. We have investigated the anti-angiogenic potential of silver nanoparticles, produced by Bacillus licheniformis. Bovine retinal endothelial cells (BRECs) were treated with the different concentrations of silver nanoparticles for 24 h in the presence and absence of vascular endothelial growth factor (VEGF), where 500 nM (IC50) of silver nanoparticle concentration, was able to block the proliferation and migration of BRECs. The cells showed a clear enhancement in caspase-3 activity and formation of DNA ladders, evidence of induction of apoptosis. Here we report for the first time that silver nanoparticles inhibit cell survival via PI3K/Akt dependent pathway in Bovine retinal endothelial cells.
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PMID:Silver nanoparticles inhibit VEGF induced cell proliferation and migration in bovine retinal endothelial cells. 1948 8

Ketamine, a widely used pediatric anesthetic, has been associated with enhanced neuronal toxicity in the developing brain, but mechanisms and neuronal susceptibility to neurotoxic insult leading to neuronal cell death remain poorly defined. One of the main goals of this study was to determine whether there is a duration of ketamine-induced anesthesia below which no significant ketamine-induced neurodegeneration can be detected. Newborn rhesus monkeys (postnatal day 5 or 6) were administered ketamine intravenously for 3, 9 or 24h to maintain a steady anesthetic plane, followed by a 6-h withdrawal period. The 9- and 24-h durations were selected as relatively long and extremely long exposures, respectively, while the 3-h treatment more closely approximates a typical duration of pediatric general anesthesia. Animals were subsequently perfused under anesthesia and brain tissue was processed for analyses using silver and Fluoro-Jade C stains and caspase-3 immunostain. The results indicated that no significant neurotoxic effects occurred if the anesthesia duration was 3h. However, ketamine infusions for either 9 or 24h significantly increased neuronal cell death in layers II and III of the frontal cortex. Although a few caspase-3- and Fluoro-Jade C-positive neuronal profiles were observed in some additional brain areas including the hippocampus, thalamus, striatum and amygdala, no significant differences were detected between ketamine-treated and control monkeys in these areas after 3, 9 or 24h of exposure. These data show that treatment with ketamine up to 3h is without adverse effects as determined by nerve cell death. However, anesthetic durations of 9h or greater are associated with significant brain cell death in the frontal cortex. Thus, the threshold duration below which no neurotoxicity would be expected is somewhere between 3 and 9h.
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PMID:Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain. 1958 Aug 62


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