Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The catechins, a family of polyphenols found in tea, can evoke various responses, including cell death. However, the precise molecular mechanisms of these effects are unknown. Here, we demonstrate that treatment of human MCF-7 cells with 50 microM (-)-Epigallocatechin-3-gallate (EGCG), a catechin that is highly abundant in green tea, can induce apoptotic changes, including mitochondrial membrane potential changes and activation of c-Jun N-terminal kinase (JNK), caspase-9, and caspase-3. In contrast, higher concentrations of EGCG (100-400 microM) do not induce apoptosis, but rather trigger necrotic cell death in MCF-7 cells. Investigations of the possible mechanisms underlying these differences revealed that treatment with lower concentrations of EGCG (10-50 microM) directly increased intracellular oxidative stress, while higher concentrations (100-400 microM) did not. Immunoblotting revealed that treatment of MCF-7 cells with 10-50 microM EGCG caused increases in Bax protein levels and decreases in Bcl-2 protein levels, shifting the Bax-Bcl-2 ratio to favor apoptosis, while treatment with 100-400 microM EGCG had no such effect. Moreover, we observed a dose-dependent decrease in intracellular ATP levels in cells treated with high-dose EGCG. Blockade of reactive oxygen species (ROS) generation and ATP synthesis using antioxidants and ATP synthesis inhibitors revealed that ROS and ATP play important roles to switch cell death types with apoptosis or necrosis. Collectively, these results indicate for the first time that EGCG treatment has a dose-dependent effect on ROS generation and intracellular ATP levels in MCF-7 cells, leading to either apoptosis or necrosis, and that the apoptotic cascade involves JNK activation, Bax expression, mitochondrial membrane potential changes, and activation of caspase-9 and caspase-3.
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PMID:Epigallocatechin gallate dose-dependently induces apoptosis or necrosis in human MCF-7 cells. 1740 55

Hemorrhage has been shown to increase inducible nitric oxide synthase (iNOS) and deplete ATP levels in tissues and geldanamycin limits both processes. Moreover, it is evident that inhibition of iNOS reduces caspase-3 and increases survival. Thus we sought to identify the molecular events responsible for the beneficial effect of geldanamycin. Hemorrhage in mice significantly increased caspase-3 activity and protein while treatment with geldanamycin significantly limited these increases. Similarly, geldanamycin inhibited increases in proteins forming the apoptosome (a complex of caspase-9, cytochrome c, and Apaf-1). Modulation of the expression of iNOS by iNOS gene transfection or siRNA treatment demonstrated that the level of iNOS correlates with caspase-3 activity. Our data indicate that geldanamycin limits caspase-3 expression and protects from organ injury by suppressing iNOS expression and apoptosome formation. Geldanamycin, therefore, may prove useful as an adjuvant in fluids used to treat patients suffering blood loss.
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PMID:Geldanamycin inhibits hemorrhage-induced increases in caspase-3 activity: role of inducible nitric oxide synthase. 1752 98

We have previously shown that the activity and the expression of caspase-9 and caspase-3 were increased during hypoxia in the cerebral cortex of newborn piglets. The present study was conducted to test the hypothesis that the hypoxia-induced activation of caspase-3 in the cerebral cortex of newborn piglets is mediated by caspase-9. Twenty-two newborn piglets were randomly assigned to four groups: normoxic (Nx), normoxic pretreated with a selective caspase-9 inhibitor, Z-Leu-Glu(OMe)-His-Asp(OMe)-Fluoromethyl ketone (Z-LEHD-FMK) (Nx+LEHD), hypoxic (Hx), and hypoxic pretreated with Z-LEHD-FMK (Hx+LEHD). Cerebral tissue hypoxia was confirmed biochemically by measuring ATP and phosphocreatine. Caspase-9 and -3 activities were determined spectrofluorometrically. The expression of caspase-9 and -3 proteins was measured by Western blot analysis using active enzyme specific antibodies. Cytosolic caspase-9 activity (nmol/mg protein/h) was 3.70+/-0.40 in Nx, 3.56+/-0.31 in Nx+LEHD (p=NS versus Nx), 4.99+/-0.64 in Hx (p<0.05 versus Nx), and 3.73+/-0.80 in Hx+LEHD (p<0.05 versus Hx, p=NS versus Nx). Cytosolic caspase-3 activity (nmol/mg protein/h) was 7.80+/-1.17 in Nx, 8.15+/-0.87 in Nx+LEHD (p=NS versus Nx), 13.07+/-0.78 in Hx (p<0.05 versus Nx), and 10.05+/-2.09 in Hx+LEHD (p<0.05 versus Hx) The density (ODxmm(2)) of active caspase-9 protein was 18.52+/-1.89 in Nx, 20.53+/-1.12 in Nx+LEHD (p=NS versus Nx), 32.36+/-5.03 in Hx (p<0.05 versus Nx), and 19.94+/-3.59 in Hx+LEHD (p<0.05 versus Hx, p=NS versus Nx). The density (ODxmm(2)) of active caspase-3 protein was 55.87+/-8.73 in Nx, 55.69+/-8.18 in Nx+LEHD (p=NS versus Nx), 94.10+/-12.05 in Hx (p<0.05 versus Nx), and 56.12+/-14.56 in Hx+LEHD (p<0.05 versus Hx, p=NS versus Nx). These data show that administration of a selective caspase-9 inhibitor, Z-LEHD-FMK, prior to hypoxia prevents the hypoxia-induced increase in caspase-3 activity and the expression of active caspase-3 protein. We conclude that the hypoxia-induced activation of caspase-3 during hypoxia in the cerebral cortex of newborn piglets is mediated by caspase-9.
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PMID:Mechanism of caspase-3 activation during hypoxia in the cerebral cortex of newborn piglets. 1755 17

Hyperglycemia and elevation of methylglyoxal (MG) are symptoms of diabetes mellitus (DM). We previously showed that high glucose (HG; 30 mM) or MG (50-400 microM) could induce apoptosis in mammalian cells, but these doses are higher than the physiological concentrations of glucose and MG in the plasma of DM patients. The physiological concentration of MG and glucose in the normal blood circulation is about 1 microM and 5 mM, respectively. Here, we show that co-treatment with concentrations of MG and glucose comparable to those seen in the blood circulation of DM patients (5 microM and 15-30 mM, respectively) could cause cell apoptosis or necrosis in human umbilical vein endothelial cells (HUVECs) in vitro. HG/MG co-treatment directly increased the reactive oxygen species (ROS) content in HUVECs, leading to increases in intracellular ATP levels, which can control cell death through apoptosis or necrosis. Co-treatment of HUVECs with 5 microM MG and 20 mM glucose significantly increased cytoplasmic free calcium levels, activation of nitric oxide synthase (NOS), caspase-3 and -9, cytochrome c release, and apoptotic cell death. In contrast, these apoptotic biochemical changes were not detected in HUVECs treated with 5 microM MG and 30 mM glucose, which appeared to undergo necrosis. Pretreatment with nitric oxide (NO) scavengers could inhibit 5 microM MG/20 mM glucose-induced cytochrome c release, decrease activation of caspase-9 and caspase-3, and increase the gene expression and protein levels of p53 and p21, which are known to be involved in apoptotic signaling. Inhibition of p53 protein expression using small interfering RNA (siRNA) blocked the activation of p21 and the cell apoptosis induced by 5 microM MG/20 mM glucose. In contrast, inhibition of p21 protein expression by siRNA prevented apoptosis in HUVECs but had no effect on p53 expression. These results collectively suggest that the treatment dosage of MG and glucose could determine the mode of cell death (apoptosis vs. necrosis) in HUVECs, and both ROS and NO played important roles in MG/HG-induced apoptosis of these cells.
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PMID:Methylglyoxal and high glucose co-treatment induces apoptosis or necrosis in human umbilical vein endothelial cells. 1772 90

In previous studies, we have shown that cerebral hypoxia results in increased activity of caspase-9, the initiator caspase, and caspase-3, in the cytosolic fraction of the cerebral cortex of newborn piglets. The present study examines the mechanism of caspase-9 activation during hypoxia and tests the hypothesis that the ATP and cytochrome c-dependent activation of caspase-9 increases in the cytosol of the cerebral cortex of newborn piglets. Newborn piglets were divided into normoxic (Nx, n=4), and hypoxic (Hx, n=4) groups. Anesthetized, ventilated animals were exposed to an FiO(2) of 0.21 (Nx) or 0.07 (Hx) for 60 min. Cerebral tissue hypoxia was documented biochemically by determining levels of ATP and phosphocreatine (PCr). Cytosolic fraction was isolated and passed through a G25-Sephadex column to remove endogenous ATP and cytochrome c. Fractions were collected and protein determined by UV spectrophotometry at 280 nm. Eluted high-molecular weight samples from normoxic and hypoxic animals were divided into four subgroups: subgroup 1 (control), incubated without added ATP and cytochrome c; subgroup 2, incubated with added ATP; subgroup 3, incubated with added cytochrome c; and subgroup 4, incubated with added ATP and cytochrome c. The incubation was carried out at 37 degrees C for 30 min. Following incubation, the protein was separated by 12% SDS-PAGE and active caspase-9 was detected using specific active caspase-9 antibody. Protein bands were detected by enhanced chemiluminescence. Protein density was determined by imaging densitometry and expressed as absorbance (OD x mm(2)). ATP (mumol/g brain) level was 4.7 +/- 0.18 in normoxic, as compared to 1.53 +/- 0.16 in hypoxic (p < 0.05 vs. Nx). PCr (mumol/g brain) level was 4.03 +/- 0.11 in the normoxic and 1.1 +/- 0.3 in the hypoxic brain (p < 0.05 vs. Nx). In the normoxic preparations, active caspase-9 density increased by 9, 4 and 20% in the presence of ATP, cytochrome c and ATP+cytochrome c, respectively. In the hypoxic preparations, active caspase-9 density increased by 30, 45 and 60% in the presence of ATP, cytochrome c and ATP+cytochrome c, respectively. These results show that incubation with ATP, cytochrome c and ATP+cytochrome c result in a significantly increased activation of caspase-9 in the hypoxic group (p < 0.05). We conclude that the ATP and cytochrome c dependent activation of caspase-9 is increased during hypoxia. We propose that the ATP and cytochrome c sites of apoptotic protease activating factor I that mediate caspase-9 activation are modified during hypoxia.
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PMID:ATP and cytochrome c-dependent activation of caspase-9 during hypoxia in the cerebral cortex of newborn piglets. 1797 8

We have shown that hypoxia results in increased influx of nuclear Ca++ and increased expression of nuclear apoptotic proteins. The present study tests the hypothesis that hypoxia alters the distribution of pro-apoptotic proteins Bad and Bax, and the anti-apoptotic proteins Bcl-xl, and Bcl-2 in the nuclear, mitochondrial and cytosolic compartments of the cerebral cortex of newborn piglets and the administration of Clonidine, an inhibitor of high affinity nuclear Ca++ -ATPase, will prevent the hypoxia-induced increase in apoptotic proteins' expression. Studies were conducted in 19 newborn piglets, 6 normoxic (Nx), 7 hypoxic and 6 Clonidine-treated hypoxic (Hx-Clo). Tissue hypoxia was documented biochemically by measuring cerebral tissue ATP and phosphocreatine (PCr) levels. Bax and Bad protein expression increased in all the three compartments during hypoxia, while there was no significant change in the expression of anti-apoptotic proteins Bcl-2 and Bcl-xl. In Clonidine pretreated hypoxic group, the hypoxia-induced increased expression of pro-apoptotic proteins Bad and Bax was prevented in all the three fractions. We conclude that hypoxia results in increased expression of pro-apoptotic proteins in nuclear, mitochondrial and cytosolic compartments and that the increased expression of pro-apoptotic proteins during hypoxia is nuclear Ca++ -influx-dependent. We propose that during hypoxia the increased ratio of (pro-apoptotic Bad and Bax/anti-apoptotic Bcl-xl and Bcl-2) in all the three compartments, will lead to altered mitochondrial and nuclear membrane permeability as well as caspase-9 activation in the cytosolic compartment.
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PMID:Effect of hypoxia on expression of apoptotic proteins in nuclear, mitochondrial and cytosolic fractions of the cerebral cortex of newborn piglets: the role of nuclear Ca++ -influx. 1829 86

Nitric oxide (NO) can regulate chondrocyte activities. This study was aimed to evaluate the molecular mechanisms of NO donor sodium nitroprusside (SNP)-induced insults to human chondrocytes. Exposure of human chondrocytes to SNP increased cellular NO levels but decreased cell viability in concentration- and time-dependent manners. SNP time dependently induced DNA fragmentation and cell apoptosis. Treatment with 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl 3-oxide, an NO scavenger, significantly lowered SNP-induced cell injuries. Administration of SNP interrupted F-actin and microtubule cytoskeletons and stimulated phosphorylation of mitogen-activated protein kinase kinase kinase-1 (MEKK1) and c-Jun N-terminal kinase (JNK). Similar to SNP, cytochalasin D, an inhibitor of F-actin formation, disturbed F-actin polymerization and increased MEKK1 and JNK activations. Overexpression of a dominant negative mutant of MEKK1 (dnMEK1) in human chondrocytes significantly ameliorated SNP-induced cell apoptosis. Exposure to SNP promoted Bax translocation from the cytoplasm to mitochondria, but application of dnMEKK1 lowered the translocation. SNP time dependently decreased the mitochondrial membrane potential, complex I NADH dehydrogenase activity, and cellular ATP levels, but increased the release of cytochrome c from mitochondria to the cytoplasm. Activities of caspase-9, -3, and -6 were sequentially increased by SNP administration. This study shows that SNP can induce apoptosis of human chondrocytes through sequential events, including cytoskeletal remodeling, activation of MEKK1/JNK, Bax translocation, mitochondrial dysfunction, cytochrome c release, caspase activation, and DNA fragmentation.
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PMID:Apoptotic insults to human chondrocytes induced by sodium nitroprusside are involved in sequential events, including cytoskeletal remodeling, phosphorylation of mitogen-activated protein kinase kinase kinase-1/c-Jun N-terminal kinase, and Bax-mitochondria-mediated caspase activation. 1830 5

Amiodarone is an effective class III antiarrhythmic drug, however, the pulmonary toxicity is one of the most life-threatening complications of its use. The present study was designed to determine the mechanisms underlying pulmonary toxicity of amiodarone. In cultured human lung epithelial cells A549, amiodarone caused cell injury characterized by mitochondrial membrane depolarization, ATP depletion, enhanced propidium iodide (PI) uptake and increase in the number of Annexin-V positive cells, although the population of PI-stained cells appeared earlier and was not identical to that of Annexin-V stained cells, suggesting that the apoptosis and necrosis appeared in different cells. The apoptosis was accompanied with the activation of caspase-2, -3 and -8 but not caspase-9, and reversed by these caspase inhibitors. However, the caspase inhibitors had no influence on mitochondrial membrane potential or PI uptake after exposure of A549 cells to amiodarone. In contrast, mitochondrial cofactors such as L-carnitine and acetyl-L: -carnitine attenuated mitochondrial membrane depolarization, abrogated cellular ATP depletion and reversed PI uptake without affecting Annexin-V positive cells. These finding suggest that different intracellular events operate to cause apoptosis and necrosis after exposure of pulmonary epithelial cells to amiodarone.
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PMID:Combined treatment with L-carnitine and a pan-caspase inhibitor effectively reverses amiodarone-induced injury in cultured human lung epithelial cells. 1830 45

Lipopolysaccharide (LPS), the endotoxin of Gram-negative bacteria, is capable of eliciting a wide variety of pathophysiological effects, including endotoxin shock, tissue injury and lethality in both humans and animals. It is also a potent stimulant to initiate the proliferation, differentiation and activation of B lymphocytes and macrophages, resulting in changes of inflammatory cytokines, such as TNF-alpha, IL1-beta, IL6, IL-8 and IL-12, and enhancement of immune responses. However, little is known about its effect on the induction of apoptosis in lymphocytes. In the present study, the lymphocytes from Carassius auratus were employed for this purpose. The cells were exposed to LPS at various doses for different time periods. By careful apoptotic characteristic analysis, such as condensation of nuclear chromatin, fragmentation of genomic DNA and formation of apoptotic bodies, it provided the first evidence that LPS had apoptotic-inducing effect on fish lymphocytes in a time- and dose-dependent manner. LPS exposure induced significant increase of intracellular reactive oxygen species (ROS), loss of mitochondrial transmembrane potential (DeltaPsi), depletion of ATP production, down-regulation of Bcl-2 expression, up-regulation of Bax and mitochondrial NO-synthase (mNOS) expression, and selective activation of caspase-9 rather than caspase-8. Each of these observations suggests that the LPS-induced apoptosis in C. auratus lymphocytes occurs largely via the mitochondrial apoptotic pathway. This observation was different from the mechanism behind the LPS-induced apoptosis in mammalian macrophages/thymocytes that occurs via the TNF-alpha-mediated death-receptor pathway. Our study suggested the existence of a possible novel role in the pathogenesis of Gram-negative bacterial infection in fish and even in mammals, which may contribute to the therapy of bacterial diseases. Also, it will help to gain more insights into the mechanisms of septic shock and of LPS-induced immunosuppression and autoimmunity.
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PMID:Lipopolysaccharide induces apoptosis in Carassius auratus lymphocytes, a possible role in pathogenesis of bacterial infection in fish. 1832 87

The epidemiological studies and recent data have provided convinced evidence that green tea and its major constituent epigallocatechin gallate (EGCG) might have the potential to lower the risk of cancers in humans. Metal ions, such as zinc and cadmium, which are necessary to our health, are important factors inducing many diseases including prostate cancer in the condition of absence or excess. EGCG can satisfactorily exhibit complex chemistry with metal ions because of multiple hydroxyl states, which in turn changes their bioactivities and metabolism pathways. This paper presents the results of an investigation of the cytotoxicity of EGCG against PC-3 prostate cancer cells in the presence and absence of Cd2+ in vitro. The results showed that both EGCG and Cd2+ suppressed viability and clonegenecity of PC-3 cells, and the suppression effect was enhanced when EGCG added with Cd2+. Although Cd2+ up-regulated the 67 kDa laminin receptor (67LR), which is a migration-associated protein, the cell migration ability was not significantly increased after each treatment. We also found that EGCG and Cd2+ directly interacted with mitochondrial, and the mixture of EGCG and Cd2+ (EGCG+Cd2+) significantly caused loss of the mitochondrial membrane potential, decrease of the ATP content and activation of caspase-9 compared with EGCG treated alone. Taken together, these findings suggest that Cd2+ enhanced the cytotoxicity of EGCG to PC-3 cells by up-regulating the 67LR and the mitochondria-mediated apoptosis pathway.
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PMID:Investigations of the cytotoxicity of epigallocatechin-3-gallate against PC-3 cells in the presence of Cd2+ in vitro. 1835 84


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