Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chelating and antioxidant effects of pyrrolidine dithiocarbamate (PDTC) have been investigated extensively for preventing cell death induced by different insults. However, the toxic effects of PDTC have been studied only recently and fewer studies on the toxic effects on astrocytes have been reported. In our study, we demonstrated that both PDTC and Cu(2+) alone were rated as only weakly toxic in inducing cell death in cortical astrocytes with IC(50) of 300 microM and 180 microM, respectively. However, PDTC and Cu(2+) in the complex form markedly potentiated with each other by about 1,000-fold with IC(50) of 0.3 microM PDTC plus 10 microM Cu(2+). Other metals at concentrations of 3-10 microM (VO(4)(5+), Cr(6+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Pb(2+), Bi(2+), Ba(2+), UO(2+), Cs(+), SeO(4)(2-), La(3+)) had no such potentiating effects on PDTC. Changes in morphology (nuclear condensation), apoptotic body formation, and hypodiploidity of DNA suggested that the PDTC-Cu(2+) complex induced cell death through an apoptotic process. Further studies showed that the PDTC-Cu(2+) complex decreased mitochondrial membrane potential, increased hydrogen peroxide production, and depleted GSH contents. After the increased oxidative stress, PDTC-Cu(2+) complex differentially activated JNKs, ERK, p38 and caspase 3, which caused PARP degradation in a time-dependent manner. All these effects were consistent with the increased cellular Cu contents. The nonpermeable copper-specific chelator bathocuproine disulfonate (BCPS), but not the permeable Cu(2+) chelator neocuproine, abolished all the observed effects. Antioxidants (N-acetylcysteine [NAC], vitamin C), catalase, and Cu(2+)-binding proteins (albumin, hemoglobin, and higher serum) reduced the cytotoxic effects of PDTC-Cu(2+) complex. We concluded that the death signaling pathway of PDTC-Cu(2+) complex was mediated by oxidative stress and subsequent JNK activation. These findings imply that PDTC, a widely used pesticide and medicine that is capable of penetrating the blood-brain barrier, may cause neurotoxicity through astrocyte dysfunction.
 ...
PMID:Death signaling pathway induced by pyrrolidine dithiocarbamate-Cu(2+) complex in the cultured rat cortical astrocytes. 1094 Nov 51

Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress and causing apoptosis. Our previous studies demonstrated that MG induced apoptosis in Jurkat cells by activating the c-Jun N-terminal kinase (JNK) signal transduction pathway, which induced an obvious decrease in mitochondrial membrane potential, followed by caspase-3 activation. Here, we observed that MG-induced apoptosis was associated with both rapid production of superoxide anion (O(2)(-)) followed by a marked increase in ROS and striking and temporal activation of ASK1. Overexpression of wild-type ASK1 could enhance the rate of apoptosis induced by MG, whereas the expression of the kinase-inactive form of ASK1 notably prevented cells from MG-induced death. NAC and PDTC blocked the activation of ASK1 and MG-induced apoptosis completely. Moreover, nonthiol antioxidants SOD-mimic MnTBAP and catalase together obviously inhibited MG-induced ASK1 activation and apoptosis induction. Correspondingly, MG-mediated ASK1 activation was enhanced by diethyldithiocarbamate (DDC). Addition of antioxidant into the culture of cells at a later stage (4-8 h after the initial MG treatment) failed to prevent their death. These results suggest that activating ASK1 at the early stage linking to production of O(2)(-) is crucial for subsequent progression of apoptosis in MG-treated Jurkat cells.
 ...
PMID:Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process. 1149 80

In women with premature ovarian failure, fertility may be preserved by ovarian tissue culture in vitro. However, techniques for tissue culture and follicle maturation have remained suboptimal. Our aim was to characterize ovarian tissue degeneration in cultures and to establish a model for cell death research in cultured ovarian tissue. Precise knowledge on the process resulting in cell death in cultured ovarian tissue will ultimately facilitate work aimed at improving long-term culture conditions. Ovarian tissue apoptosis was studied in a serum-free culture model in which nuclear DNA fragmentation was shown to occur within 24 h of the start of the culture. Activation of caspase-3 was detected in some stromal cells and a few oocytes. Since not all of the tissue exhibited signs of apoptosis and since DNA fragmentation increased over time, the tissue probably gradually dies by apoptosis. The antioxidant N-acetyl-L-cysteine (NAC; 25, 50 and 100 mmol/l) was found to inhibit this apoptosis. Thus, apoptosis appears to play a critical role in the degeneration of human ovarian cortical tissue cultures, and this cell death can be suppressed by NAC. The present tissue culture model can be used for identifying components capable of inhibiting cell death in vitro.
 ...
PMID:Cell death and its suppression in human ovarian tissue culture. 1187 Feb 30

We showed previously that homocysteine thiolactone (HcyT) is a potent inducer of apoptosis in HL-60 cells. In the present study, the role of some radical scavengers (N-acetylcysteine, vitamin C, vitamin E and folate) on the reduction of HcyT-induced apoptosis was investigated. Preincubation of HcyT-treated HL-60 cells with vitamin C (Vit C; 100 micro mol/L) or vitamin E (Vit E; 100 micro mol/L) for 2 h significantly reduced the proportion of apoptotic cells with hypodiploid DNA contents or with membrane phosphatidylserine exposure, and attenuated the apoptotic DNA fragmentation. Preincubation of cells with N-acetylcysteine (NAC; 5 mmol/L) for 2 h significantly reduced HcyT-promoted apoptosis measured by membrane phosphatidylserine exposure only. The reduction of HcyT-induced apoptosis by NAC, Vit C or Vit E occurred simultaneously with a significant decrease in intracellular H(2)O(2) levels and reduced caspase-3 enzymatic activity. In contrast, folate had no H(2)O(2) scavenging capacity and did not suppress caspase-3 activity 6 h after HcyT treatment, although folate exhibited antioxidant behavior toward superoxide anions, hydroxyl radicals and peroxynitrite. Preincubation of cells with folate (10 micro mol/L) for 3 d did not affect the extent of HcyT-promoted apoptotic damage. Taken together, our findings suggest that antioxidant pretreatment with NAC, Vit C or Vit E exerts more beneficial effects than folate on reducing apoptotic cell damage induced by homocysteine thiolactone.
 ...
PMID:N-Acetylcysteine, vitamin C and vitamin E diminish homocysteine thiolactone-induced apoptosis in human promyeloid HL-60 cells. 1216 54

Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in acute promyelocytic leukemia (APL), but little is known about the molecular mechanisms mediating these effects. In the present study, we determined the molecular pathways that lead to apoptosis after treatment of cells with arsenic trioxide. Arsenic trioxide treatment of U937 cells leads to apoptosis, which is accompanied by activation of caspase 3 (as measured by decreased levels of the 32 kDa inactive form and increased proteolytic cleavage of PLC-gamma1). The broad-range caspase inhibitor z-VAD-fmk inhibits this induction of apoptosis, supporting a direct link between caspase activation and arsenic trioxide induction of apoptosis. This activation of apoptosis is accompanied by release of cytochrome c, down-regulation of cIAP1, and inactivation of Akt. Bcl-2 overexpression attenuates arsenic trioxide-induced apoptosis in U937 cells by inhibition of caspase 3 activity, but not inhibition of Akt. In addition, arsenic trioxide-induced apoptosis was caused by the generation of reactive oxygen species, which was prevented by antioxidant NAC (N-acetyl-cysteine). Co-treatment with NAC markedly prevented dephosphorylation of Akt, activation of caspase 3, and down-regulation of cIAP1. These data indicate that arsenic trioxide can cause cell damage by inactivating the Akt-related cell survival pathway and generating the reactive oxygen species, providing a new mechanism for arsenic trioxide-induced apoptosis.
 ...
PMID:Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt. 1216 6

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an active constituent of Rheum palmatum, and showed inhibitory activity on lipopolysaccharide-induced NO production in our previous study. However, the apoptosis-inducing activity of emodin has remained undefined. Among three structurally related anthraquinones, including emodin, physcion, and chrysophanol, emodin showed the most potent cytotoxic effects on HL-60 cells, accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including an increase in DNA ladder intensity, morphological changes, appearance of apoptotic bodies, and an increase in hypodiploid cells. Emodin at apoptosis-inducing concentrations causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity, according to cleavage of caspase 3 substrates poly(ADP-ribose) polymerase and D4-GDI proteins, the appearance of cleaved caspase 3 fragments being detected in emodin- but not physcion- or chrysophanol-treated HL-60 cells. A decrease in the anti-apoptotic protein, Mcl-1, was detected in emodin-treated HL-60 cells, whereas other Bcl-2 family proteins including Bax, Bcl-2, Bcl-XL, and Bad remained unchanged. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated emodin-induced DNA ladders, associated with the blockage of PARP and D4-GDI cleavage. Free radical scavenging agents including NAC, catalase, SOD, ALL, DPI, L-NAME and PDTC showed no preventive effect on emodin-induced apoptotic responses, whereas NAC, CAT and PDTC prevented HL-60 cells from ROS (H(2)O(2))-induced apoptosis through inhibition of caspase 3 cascades. Induction of catalase, but not SOD, activity was detected in emodin-treated HL-60 cells by in gel activity assays, and H(2)O(2)-induced intracellular peroxide level was significantly reduced by prior treatment of emodin in HL-60 cells. Our experiments provide evidence that emodin is an effective apoptosis inducer in HL-60 cells through activation of the caspase 3 cascade, but that it is independent of ROS production.
 ...
PMID:Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase 3 cascade but independent of reactive oxygen species production. 1244 60

The neuroprotective mechanism of Rg1 was studied in this paper by means of its obvious anti-apoptotic effect on human SHSY5Y cells. SHSY5Y cells were treated with MPP+ (1-methyl-4-phenyl-pyridinium) for 72 hours to induce apoptosis. During the apoptosis, production of reactive oxygen species (ROS), activation of c-Jun N-terminal kinase (JNK) and activation of caspase-3 were observed. The results showed that the signal transduction pathway of MPP+-induced apoptosis might be ROS to JNK, then to caspase-3. MPP+-induced apoptosis in SHSY5Y cells was obviously inhibited in both NAC (N-acetylcysteine) pretreated groups and Rg1 pretreated groups. Meanwhile, compared to that of the controls, our results showed decreased level of ROS, less JNK activity and lower expression of cleaved caspase-3 in pretreated NAC groups and in Rg1 pretreated groups. The protection by Rg1 might be mediated by removing of ROS. The removal of ROS might inhibit the activity of JNK and the expression of cleaved caspase-3. These results suggest that ginsenoside Rg1 may take effect through its anti-apoptotic activity in neurodegenerative diseases.
 ...
PMID:Protective effect of ginsenoside Rg1 on MPP+-induced apoptosis in SHSY5Y cells. 1289 40

A microbial secondary metabolite, arisostatins A (As-A), was originally discovered as a substance carrying the antibiotic activity against Gram-positive bacteria and shown to possess potent anti-tumor properties. The mechanism by which arisostatins A initiates apoptosis remains poorly understood. In the present report we investigated the effect of arisostatins A on activation of the apoptotic pathway in HN-4 cells. Arisostatins A was shown to be responsible for the inhibition of HN-4 cell growth by inducing apoptosis. Treatment with 4 microM arisostatins A for 24h produced morphological features of apoptosis and DNA fragmentation in HN-4 cells. Arisostatins A caused dose-dependent apoptosis and DNA fragmentation of HN-4 cells used as a model. Treatment with caspase inhibitor significantly reduced the arisostatins A-induced caspase 3 activation. In addition, arisostatins A-induced apoptosis was associated with the generation of reactive oxygen species (ROS), which was prevented by an antioxidant NAC (N-acetyl-cysteine). These data indicate that cytotoxic effect of arisostatins A on HN-4 cells is attributable to the induced apoptosis and that arisostatins A-induced apoptosis is mediated by caspase-3 activation pathway, loss of mitochondrial transmembrane potential (DeltaPsi(m)), and release of cytochrome c into cytosol.
 ...
PMID:Arisostatins A induces apoptosis through the activation of caspase-3 and reactive oxygen species generation in AMC-HN-4 cells. 1295 Oct 70

Grape seed proanthocyanidin extract (GSPE), a polyphenolic compound with antioxidant properties, may protect against cardiac ischemia and reperfusion injury. However, its potential toxicity at higher doses is unknown. The authors tested the effects of GSPE on reactive oxygen species (ROS) generation, cell survival, lactate dehydrogenase (LDH) release, and caspase- 3 activity using chick cardiomyocytes incubated with GSPE at 5, 10, 50, 100, or 500 micrograms/mL in medium for 8 h. Exposure to increasing concentrations of GSPE (100 or 500 micrograms/mL) resulted in an increase in ROS generation and cell death as measured by propidium iodide uptake and LDH release. Caspase-3 activity was significantly increased fourfold in cells exposed to GSPE 500 micrograms/ mL compared to controls; this was abolished by the selective caspase-3 inhibitor Ac-Asp-Gln-Thr-Asp-H (50 microM), which also significantly reduced the cell death resulting from GSPE (500 micrograms/mL). The antioxidant N-acetylcysteine (NAC, 100 microM) reduced cell death induced by GSPE (500 micrograms/mL) but failed to attenuate caspase-3 activation. Collectively, the authors conclude that higher doses of GSPE could cause apoptotic cell injury via effector caspase-3 activation and subsequent induction of ROS generation. Consumers may take higher doses of dietary supplements in the belief that natural herbs have no major side effects. This study demonstrates that dosages of GSPE should be optimized to avoid potential harmful pro-oxidant effects.
 ...
PMID:Grape seed proanthocyanidins induce pro-oxidant toxicity in cardiomyocytes. 1473 30

Recently, we have reported that ultrasound (US)-induced apoptosis is due to inertial cavitation and that extracellular reactive oxygen species (ROS) generated by inertial cavitation are not directly correlated with the apoptosis (Honda et al. 2002). The molecular mechanism of apoptosis induced by US is not yet sufficiently clear. Here, we examine the role of intracellular calcium ions and the intracellular ROS on apoptosis induced by US. Human myelomonocytic lymphoma U937 cells were exposed to continuous 1-MHz US at an intensity of 4.9 W/cm(2) (I(SPTA)) in the presence of air, and changes of intracellular calcium ion concentration ([Ca(2+)]i) in individual cells by digital imaging, various flow cytometric analyses of endpoints of apoptosis (early apoptosis, secondary necrosis, loss of mitochondria membrane potential, superoxide formation, caspase-3 activation) and DNA fragmentation were explored. Furthermore, the effects of an intracellular calcium ion chelator (BAPTA-AM), an antioxidant (N-acetyl-L-cysteine, NAC), a calcium channel blocker (verapamil), Ca(2+)-free buffer and Levovist were also investigated. These results indicate that: 1. the mitochondria-caspase pathway and the Ca(2+)-dependent pathway play cardinal roles in apoptosis induced by US because BAPTA-AM partially inhibited DNA fragmentation, loss of mitochondria membrane potential and caspase-3 activation; 2. intracellular ROS generated from mitochondria, rather than extracellular ROS (which were directly produced by inertial cavitation in the medium), are involved in the regulation of apoptosis induced by US because addition of NAC after sonication showed effective suppression of the apoptosis; and 3. increase of [Ca(2+)]i appears to be due to nonspecific influx from outside the cells because verapamil is not effective and no increase of [Ca(2+)]i due to sonication could be observed in the Ca(2+)-free buffer.
 ...
PMID:Role of intracellular calcium ions and reactive oxygen species in apoptosis induced by ultrasound. 1518 35


1 2 3 4 5 6 7 8 9 10 Next >>