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

Apoptosis is a morphologically defined type of cell death initiated by various stimuli that results in the activation of caspases (cysteine-containing aspartate-specific proteases). In the present study, it was determined that caspases are present during, and play a role in, corpus luteum (CL) apoptosis in vitro. Pseudopregnancy was induced in rabbits with 100 IU human chorionic gonadotrophin. On Day 11 of pseudopregnancy, CL were isolated and cultured for 0, 2, 4, 6, and 8 h in the absence of trophic support to induce spontaneous apoptosis. Total RNA was extracted and analysed for caspase-I expression by Northern blot analysis. The results demonstrated caspase-I expression from 4 h. In the second part of the study, CL were incubated without trophic support for 4 h with increasing concentrations of three general caspase inhibitors, sodium aurothiomalate (SAM), iodoacetic acid (IAA) and N-tosyl-L-phenylalanylchloromethylketone (TPCK), and two specific caspase inhibitors, N-acetyl (Ac)-Tyr-Val-Ala-Asp (YVAD)-chloromethylketone (CMK) (Ac-YVAD-CMK) and Ac-Asp-Glu-Val-Asp (DEVD)-aldehyde (CHO) (Ac-DEVD-CHO). At completion, DNA was isolated and integrity assessed. Treatment of CL with SAM, IAA or Ac-DEVD-CHO effectively suppressed apoptotic DNA fragmentation. The final component of the study was to examine caspase-3 protein expression. Western blot analysis revealed a significant increase in caspase-3 expression over the experimental time-course. The results of the present study clearly demonstrate a time-dependent link between the caspases, specifically caspase-3 and spontaneous apoptosis in the rabbit CL.
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PMID:Inhibitors of caspase homologues suppress an apoptotic phenotype in cultured rabbit corpora lutea. 1183 36

Specific biochemical hallmarks of apoptosis, namely internucleosomal DNA fragmentation and caspase-3 activation, appear in the aftermath of status epilepticus (SE). This led us to hypothesize that caspase-activated DNase (CAD) is involved in DNA fragmentation and apoptotic neuronal cell death following SE. The present study aimed to determine whether SE is associated with an activation of CAD, as reflected in the degradation of the CAD inhibitor, ICAD. SE was induced in adult male Sprague-Dawley rats by kainic acid (12 mg/kg i.p.) and seizures were terminated with diazepam after 2 h. At 24, 48, or 72 h after SE termination, protein levels of CAD and ICAD were measured by Western blotting (after sodium dodecyl sulfate-polyacrylamide gel electrophoresis) using specific antibodies. At 48 and 72 h after SE termination, ICAD protein levels significantly decreased (by more than 60%) in rhinal cortex and hippocampus as compared with those in the same tissue from animals not experiencing SE. No changes were detected in total CAD protein levels at any time point, resulting in an increase in the ratio of CAD to its inhibitor. The loss of ICAD following SE is indicative of a disinhibition of CAD, leading to DNA fragmentation. Consistent with this, we observed that the decrease in ICAD between 24 and 48 h was accompanied by a marked increase in DNA fragmentation. Our results support the proposal that CAD participates in caspase-3-mediated internucleosomal DNA fragmentation in the aftermath of SE.
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PMID:Status epilepticus leads to the degradation of the endogenous inhibitor of caspase-activated DNase in rats. 1183 14

Energy deficiency and dysfunction of the Na+, K+-ATPase are common consequences of many pathological insults. The nature and mechanism of cell injury induced by impaired Na+, K+-ATPase, however, are not well defined. We used cultured cortical neurons to examine the hypothesis that blocking the Na+, K+-ATPase induces apoptosis by depleting cellular K+ and, concurrently, induces necrotic injury in the same cells by increasing intracellular Ca2+ and Na+. The Na+, K+-ATPase inhibitor ouabain induced concentration-dependent neuronal death. Ouabain triggered transient neuronal cell swelling followed by cell shrinkage, accompanied by intracellular Ca2+ and Na+ increase, K+ decrease, cytochrome c release, caspase-3 activation, and DNA laddering. Electron microscopy revealed the coexistence of ultrastructural features of both apoptosis and necrosis in individual cells. The caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-FMK) blocked >50% of ouabain-induced neuronal death. Potassium channel blockers or high K+ medium, but not Ca2+ channel blockade, prevented cytochrome c release, caspase activation, and DNA damage. Blocking of K+, Ca2+, or Na+ channels or high K+ medium each attenuated the ouabain-induced cell death; combined inhibition of K+ channels and Ca2+ or Na+ channels resulted in additional protection. Moreover, coapplication of Z-VAD-FMK and nifedipine produced virtually complete neuroprotection. These results suggest that the neuronal death associated with Na+, K+-pump failure consists of concurrent apoptotic and necrotic components, mediated by intracellular depletion of K+ and accumulation of Ca2+ and Na+, respectively. The ouabain-induced hybrid death may represent a distinct form of cell death related to the brain injury of inadequate energy supply and disrupted ion homeostasis.
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PMID:Ionic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured cortical neurons. 1185 Apr 62

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in neoplasms (CNS astrocytomas - glioblastoma multiforme and high grade non - Hodgkin's lymphoma). The following parameters were assessed-isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+-K+ ATPase activity, serum ubiquinone and magnesium levels. Serum tryptophan, serotonin, nicotine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulphate in the case of CNS astrocytomas), the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. HDL cholesterol showed a significant decrease and free fatty acids & triglycerides were increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of malondialdehyde (MDA), hydroperoxides, conjugated dienes and NO increased. The concentration of alpha tocopherol was unaltered. Membrane Na+-K+ ATPase inhibition due to elevated digoxin, altered membrane structure and digoxin related tyrosine / tryptophan transport defect leading to increased levels of depolarising tryptophan catabolites and decreased levels of hyperpolarising tyrosine catabolites can lead to alteration in intracellular calcium/magnesium ratios and oncogene activation. Intracellular magnesium deficiency can produce defective microtubule related spindle fibre dysfunction and chromosomal non-dysjunction contributing to neoplastic cellular polyploidy and aneuploidy. Digoxin induced tryptophan/tyrosine transport defect can alter neurotransmitter patterns with increased serotonin, quinolinic acid, nicotine & glutamatergic transmission and reduced dopamine, morphine and noradrenaline levels leading to oncogenesis. Glycoconjugate metabolism is altered by elevated dolichol levels and magnesium depletion consequent to Na+-K+ ATPase inhibition. There is a qualitative alteration in proteoglycans and glycoproteins, defective membrane formation and structure and reduced lysosomal stability leading to disordered contact inhibition and tumour antigen presentation contributing to oncogenesis. Digoxin induced alteration in intracellular calcium/magnesium ratios and low ubiquinone levels can lead to a mitochondrial dysfunction resulting in increased free radical generation and reduced scavenging & caspase-3 activation producing a P21 defect contributing to oncogenesis.
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PMID:Hypothalamic digoxin mediated model for oncogenesis. 1187 54

We examined the effects of 4,4'-diisothiocyano-2,2'-stilbenedisulfonate (DIDS), an inhibitor of the chloride-bicarbonate exchangers and chloride channels, on death in cultured cerebellar granule neurons. Various stimuli, such as reduction of extracellular K+ concentration, removal of growth factors, and staurosporine treatment, induced cell death. This death was blocked by DIDS in a dose dependent manner. In the presence of DIDS, the cells exposed to such stimuli did not show DNA fragmentation, but retained the ability to exclude trypan blue and to metabolize MTT to formazan. On the other hand, pretreatment of the cells with DIDS did not show any protective effects. The neuroprotective effect of DIDS was not influenced by extracellular Na+, Cl-, HCO3- or Ca2+ concentrations, although reduction of extracellular Cl- or Ca2+ concentrations per se induced neuronal death. Other chloride-bicarbonate exchange blockers like 4-acetamido-4'-isothiocyanatostilmene-2,2'-disulfonic acid (SITS) or 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS) showed no significant effects on neuronal survival under these death-inducing stimuli. Dimethylamiloride, an inhibitor of the Na+/H+ exchanger, did not influence neuronal death induced by these stimuli. Cells undergoing death showed gradual intracellular acidification, and DIDS did not inhibit this response, although DIDS (2 mM) per se induced transitory acidification followed by recovery within 10 min. DIDS did not influence intracellular Ca2+ or Cl-levels during the lethal process. DIDS suppressed the cleavage of caspase-3 in the cells exposed to the death-inducing stimuli. These findings suggest that the neuroprotective effect of DIDS is mediated by a novel mechanism other than by nonselective inhibition of transporters or channels, and that DIDS blocks the death program upstream of caspases and downstream of all of the activation processes triggered by various stimuli.
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PMID:4,4'-diisothiocyano-2 ,2'-stilbenedisulfonate protects cultured cerebellar granule neurons from death. 1188 2

Presenilins 1 and 2 are two homologous proteins that, when mutated, account for most early onset Alzheimer's disease. Several lines of evidence suggest that, among various functions, presenilins could modulate cell apoptotic responses. Here we establish that the overexpression of presenilin 2 (PS2) and its mutated form Asn-141-Ile-PS2 alters the viability of human embryonic kidney (HEK)293 cells as established by combined trypan blue exclusion, sodium 3'-[1-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay, and propidium iodide incorporation FACS analyses. The two parent proteins increase the acetyl-DEVD-al-sensitive caspase-3-like activity in both HEK293 cells and Telencephalon specific murine neurons, modulate Bax and bcl-2 expressions, and enhance cytochrome C translocation into the cytosol. We show that overexpression of both wild-type and mutated PS2 increases p53-like immunoreactivity and transcriptional activity. We also establish that wild-type- and mutated PS2-induced caspase activation is reduced by p53 antisense approach and by pifithrin-alpha, a chemical inhibitor of p53. Furthermore, mouse fibroblasts in which the PS2 gene has been knocked out exhibited strongly reduced p53-transcriptional activity. Finally, we establish that the overexpression of both wild-type and mutated PS2 is accompanied by a drastic reduction of endogenous presenilin 1 (PS1) expression. Interestingly, pifithrin-alpha diminished endogenous PS2 immunoreactivity, whereas the inhibitor increases PS1 expression. Altogether, our data demonstrate that wild-type and familial Alzheimer's disease-linked PS2 trigger apoptosis and down-regulate PS1 expression through p53-dependent mechanisms.
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PMID:Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons. 1190 48

The effects of sodium butyrate (SB) and trichostatin A (TSA) on cell proliferation andapoptosis against human glioma T98G, U251MG, and U877MG cells were investigated. Upon exposure to either SB or TSA, cell proliferation was reduced, and apoptosis detected by DNA fragmentation analysis and the cleavage of CPP32 was induced. Previously, we reported that SB increased the expression levels of p21 (WAF-1) and inhibited G1-S transition of the cell cycle. In this study, we showed that TSA also increased p21 expression, suggesting that histone deacetylase (HDAC) inhibitors may up-regulate p21 protein in common and thus arrest proliferation in the G1 phase of the cell cycle. To further determine the underlying molecular mechanisms of apoptosis with either SB or TSA treatment, we studied the expression levels of apoptosis-related proteins in human glioma cells. SB increased the expression of the Bad protein, although the expression of Bcl-2, Bcl-xL, Bax, and Fas was not changed by theaddition of SB. TSA treatment also up-regulated the expression of Bad protein. The results suggest that HDAC inhibitors such as SB and TSA induce apoptosis through an increase in Bad protein in human glioma cells in vitro.
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PMID:Histone deacetylase inhibitors such as sodium butyrate and trichostatin A induce apoptosis through an increase of the bcl-2-related protein Bad. 1190 66

Porcine pulmonary arterial endothelial cells accumulated myo-inositol and taurine, as well as betaine, during adaptation to hypertonic stress. The cells grew and maintained their normal morphology during culture in hypertonic (0.5 osmol (kg H(2)O)(-1)) medium that contained osmolytes such as betaine, myo-inositol or taurine at concentrations close to reported physiological values. The cells did not grow well in hypertonic medium depleted of potential compatible osmolytes. After a few days, cell density decreased by about 50 % and many cells rounded up and detached from the plates, their nuclei showing clear apoptotic morphology. The caspase-3 activity of the cells also increased dramatically under these conditions, but remained negligibly low when betaine and myo-inositol were added to the medium. Addition of betaine and myo-inositol to hypertonic medium depleted of compatible osmolytes increased the number of colonies remaining after 12 days of culture; with each solute at 30-100 micromol l(-1) the number increased about sixfold. In the absence of compatible osmolytes, increased mRNA levels and corresponding activities of betaine/gamma-aminobutyric acid transporter (BGT1) and sodium/myo-inositol transporter (SMIT) induced by hypertonicity remained high after 72 h incubation, whereas they were down regulated in the presence of betaine and myo-inositol. Similarly, the down regulation of the amino acid System A transporter (ATA2) was markedly slowed in the absence of compatible osmolytes. We conclude that these compatible osmolytes at concentrations close to physiological values enable the endothelial cells to adapt to hypertonic stress, protecting them from apoptosis, and also modulate the adaptation process.
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PMID:Compatible osmolytes modulate the response of porcine endothelial cells to hypertonicity and protect them from apoptosis. 1195 39

Xanthomonas campestris pv. glycines strain AM2 (XcgAM2), the aetiological agent of bacterial pustule disease of soybean, as well as some other strains of Xanthomonas including X. campestris pv. malvacearum NCIM 2310 and X. campestris NCIM 2961, exhibited post-exponential rapid cell death (RCD) in Luria-Bertani (LB) medium. RCD was not displayed by Xanthomonas strains while growing in starch medium. Addition of starch to LB culture of XcgAM2 at any point of incubation during the exponential growth was found to arrest the onset of RCD. RCD in this organism was found to be associated with the synthesis of an endogenous enzyme similar to human caspase-3, a known marker of apoptosis in eukaryotes. On sodium dodecyl sulphate polyacrylamide gel elecrophoresis (SDS-PAGE) the XcgAM2 caspase appeared to run along a 55 kDa protein molecular weight marker. The caspase-3-like protein was detected in all Xanthomonas strains tested. RCD was not detected in Escherichia coli cultures in LB medium. The caspase-3-like enzyme activity or pro-tein was also found to be absent in this bacterium. Caspase-3-like protein or Xanthomonas caspase was detected only in the cells of XcgAM2 growing in LB medium and not in those growing in starch medium. The Xanthomonas caspase protein appeared in cells at around 4 h of incubation, and peaked at around 24 h, before finally disappearing at around 54 h of incubation. However, caspase enzyme activity was detected only 12-13 h after incubation and peaked around 18-20 h. Addition of starch at the beginning or during the period of exponential growth in LB cultures of XcgAM2 terminated the synthesis of this protein. It is presumed that starch acted as the repressor of biosynthesis of the Xanthomonas caspase, thereby preventing the organism from undergoing RCD. The cells undergoing RCD also displayed the other markers of eukaryotic apoptosis. These included binding of annexin V to plasma membrane of cells undergoing RCD and the presence of nicked DNA in culture supernatant as evidenced by the TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labelling) assay. Caspase-negative mutants of XcgAM2 did not display post-exponential RCD. The importance of RCD in Xanthomonas life cycle is not yet clear, however the phenomenon appears to have similarities with eukaryotic apoptosis.
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PMID:Involvement of caspase-3-like protein in rapid cell death of Xanthomonas. 1197 78

Colchicine has been shown to prevent kidney injury in chronic cyclosporine nephrotoxicity; however, the mechanisms of its action are undetermined. The purpose of this study was to clarify whether colchicine prevents cyclosporine-induced kidney injury by decreasing kidney-cell apoptosis. We also sought to determine whether such an antiapoptotic effect was related to Bcl-2/Bax protein and caspase3 activity. Adult male Sprague-Dawley rats kept on a salt-depleted diet (0.05% sodium) were treated daily for 28 days with cyclosporine (15 mg/kg in 1 mL/kg olive-oil vehicle), colchicine (30 microg/kg in 100% ethanol, diluted with sterile saline solution to a final concentration of 30 microg/mL), or both cyclosporine and colchicine. Kidney function, histomorphologic findings, in situ terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end-labeling assay, expressions of Bcl-2 and Bax proteins, and caspase-3 enzymatic activity were compared for the different treatment groups. Compared with the vehicle-treated rats, rats given cyclosporine showed a decline in creatinine clearance rate, an increase in serum creatinine concentration, tubulointerstitial fibrosis, and an increase in the number of apoptotic cells (all P <.01). Concomitant administration of colchicine significantly reversed all the above parameters (all P <.05). The decreased expression of Bcl-2 and the ratio of Bcl-2 to Bax protein seen in cyclosporine-treated rat kidneys were significantly increased after colchicine treatment, accompanying a suppression of caspase-3 activity (P <.05). Furthermore, the decreased apoptotic cell death was closely correlated with improved renal tubulointerstitial fibrosis (r = 0.583, P <.05). These findings strongly suggest that a renoprotective effect of colchicine on cyclosporine-induced nephrotoxicity is coassociated with a decrease in apoptotic cells.
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PMID:Colchicine decreases apoptotic cell death in chronic cyclosporine nephrotoxicity. 1206 35


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