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)

Electrophiles generated endogenously, or via the metabolic bioactivation of drugs and other environmental chemicals, are capable of binding to a variety of nucleophilic sites within proteins. Factors that determine site selective susceptibility to electrophile-mediated post-translational modifications, and the consequences of such alterations, remain largely unknown. To identify and characterize chemical-mediated protein adducts, electrophiles with known toxicity were utilized. Hydroquinone, and its mercapturic acid pathway metabolites, cause renal proximal tubular cell necrosis and nephrocarcinogenicity in rats. The adverse effects of HQ and its thioether metabolites are in part a consequence of their oxidation to the corresponding electrophilic 1,4-benzoquinones (BQ). We now report that BQ and 2-(N-acetylcystein-S-yl)benzoquinone (NAC-BQ) preferentially bind to solvent-exposed lysine-rich regions within cytochrome c. Furthermore, we have identified specific glutamic acid residues within cytochrome c as novel sites of NAC-BQ adduction. The microenvironment at the site of adduction governs both the initial specificity and the structure of the final adduct. The solvent accessibility and local pKa of the adducted and neighboring amino acids contribute to the selectivity of adduction. Postadduction chemistry subsequently alters the nature of the final adduct. Using molecular modeling, the impact of BQ and NAC-BQ adduction on cytochrome c was visualized, revealing the spatial rearrangement of critical residues necessary for protein-protein interactions. Consequently, BQ-adducted cytochrome c fails to initiate caspase-3 activation in native lysates and also inhibits Apaf-1 oligomerization into an apoptosome complex in a purely reconstituted system. In summary, a combination of mass spectroscopic, molecular modeling, and biochemical approaches confirms that electrophile-protein adducts produce structural alterations that influence biological function.
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PMID:Quinone electrophiles selectively adduct "electrophile binding motifs" within cytochrome c. 1782 17

Tributyltin (TBT), an environmental pollutant, debilitates immune responses via induction of apoptosis in CD4(+) T cells through an undefined mechanism of action. Accumulating evidence indicates that the susceptibility of Th1 and Th2 cells to TBT-induced apoptosis differs. In this study, by using HL-60 cell model, we show that hydrogen peroxide (H(2)O(2)) plays a critical role in TBT-induced apoptosis. Generation of H(2)O(2) induced by TBT resulted in a change in mitochondrial membrane potential that proceed apoptotic pathway where, at least in part, involved activation of caspase-3. We also demonstrated that Th1 clones appear to be more vulnerable to apoptosis induction than Th2 clones following exposure to TBT, which was well correlated with increased H(2)O(2) generation in Th1 clones than Th2 clones. There was an inverse correlation between TBT-induced apoptosis and the basal levels of intracellular GSH, a major cellular antioxidant. Furthermore, the addition of NAC that replenish intracellular GSH levels inhibited generation of H(2)O(2) and apoptosis in Th1 clones. These results suggest that TBT selectively induces apoptosis via generation of H(2)O(2) in Th1 cells because of their low GSH levels, which may contribute to the Th2 predominance induced by TBT.
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PMID:Critical role of hydrogen peroxide in the differential susceptibility of Th1 and Th2 cells to tributyltin-induced apoptosis. 1797 19

Sanguinarine is a benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis and other poppy-fumaria species, possessing potent antibacterial, antifungal, and anti-inflammatory activities. In this study, we investigated the underling mechanisms by which sanguinarine induce apoptosis in human breast cancer MDA-231 cells. Treatment of MDA-231 cells with sanguinarine induced remarkable apoptosis accompanying the generation of ROS. Consistently, sanguinarine-induced apoptosis was mediated by the increased reproductive cell death. Pretreatment with NAC or GSH attenuated sanguinarine-induced apoptosis, suggesting the involvement of ROS in this cell death. During sanguinarin-induced apoptosis, protein levels of pro-caspase-3, Bcl-2, cIAP2, XIAP, and c-FLIPs were reduced. Sanguinarine-mediated apoptosis was substantially blocked by ectopic expression of Bcl-2 and cFLIPs. Additionally, we found that sub-lethal doses of sanguinarine remarkably sensitized breast cancer cells to TRAIL-mediated apoptosis, but the cell death induced by sanguinarine and TRAIL in combination was not blocked by overexpression of Bcl-2 or Akt. Therefore, combinatory treatment of sanguinarine and TRAIL may overcome the resistance of breast cancer cells due to overexpression of Akt or Bcl-2.
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PMID:Sanguinarine-induced apoptosis: generation of ROS, down-regulation of Bcl-2, c-FLIP, and synergy with TRAIL. 1818 68

The molecular mechanisms whereby hyperbaric oxygen (HBO) improves ischemic wound healing remain elusive. In this study, a rat model of wound ischemia was used to test the hypothesis that HBO enhances wound healing by modulating hypoxia-inducible factor-1alpha (HIF-1alpha) signaling. Male Sprague-Dawley rats underwent creation of a previously validated ischemic flap. Three groups underwent daily treatment: HBO (90 minutes, 2.4 atm); systemic administration of the free radical scavenger, N-acetylcysteine (NAC 150 mg kg(-1) intraperitoneal); control (neither HBO nor NAC). HBO treatment improved healing of the ischemic wounds. Analysis of ischemic wound tissue extracts demonstrated significantly reduced expression of HIF-1alpha, p53, and BNip3. Additionally, HBO increased expression of Bcl-2 while decreasing cleaved caspase-3. DNA fragmentation was abolished and the number of TUNEL-positive cells was reduced compared to the other groups. Vascular endothelial growth factor, cyclooxygenase-2, and neutrophil infiltration were reduced in ischemic wounds treated with HBO. These results indicate that HBO improves ischemic wound healing by downregulation of HIF-1alpha and subsequent target gene expression with attenuation of cell apoptosis and reduction of inflammation.
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PMID:Hyperbaric oxygen attenuates apoptosis and decreases inflammation in an ischemic wound model. 1833 31

Mutation of Bcr-Abl is an important mechanism by which chronic myelogenous leukemia (CML) cells become resistant to Gleevec. The T315I mutation is clinically significant since CML cells harboring this mutation are insensitive to Gleevec and other Bcr-Abl-targeted drugs. Identification of new agents capable of effectively killing CML cells with T315I mutation would have important therapeutic implications in Gleevec-resistant CML. Here, we showed that beta-phenylethyl isothiocyanate (PEITC), a natural compound found in vegetables, is effective in killing CML cells expressing T315I BCR-ABL. Treatment of leukemia cell lines harboring wild-type or mutant Bcr-Abl with 10 microM PEITC resulted in an elevated ROS stress and a redox-mediated degradation of the BCR-ABL protein, leading to massive death of the leukemia cells. Antioxidant NAC attenuated the PEITC-induced oxidative stress in CML cells and prevented the degradation of BCR-ABL, caspase-3 activation and cell death. We further showed that the ROS-induced degradation of BCR-ABL was mediated partially by caspase-3 and the proteasome pathway. The ability of PEITC to effectively kill T315I-positive CML cells was further confirmed using primary leukemia cells isolated from CML patients. Our results suggest that PEITC is a promising compound capable of killing Gleevec-resistant CML cells through a ROS-mediated mechanism and warrants further investigations.
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PMID:Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism. 1838 54

Organosulfur compounds have been established to possess anticancer effects. To provide a better understanding of the biological function of dimethyl sulfides, dimethyl monosulfide (Me(2)S), dimethyl disulfide (Me(2)S(2)), dimethyl trisulfide (Me(2)S(3)) and dimethyl tetrasulfide (Me(2)S(4)) were used as experimental materials to investigate their effects on apoptosis induction in human leukemia Jurkat cells and HL-60 cells. Treatment with 20 muM dimethyl sulfides for 24 h decreased the viability of both cells. The cell viability-reducing effect of these sulfides was in the following order: Me(2)S(4) asymptotically equal to Me(2)S(3) > Me(2)S(2) asymptotically equal to Me(2)S for Jurkat cells and Me(2)S(4) > Me(2)S(3) > Me(2)S(2) asymptotically equal to Me(2)S for HL-60 cells. Me(2)S(3) and Me(2)S(4) significantly induced DNA fragmentation and caspase-3 activation. The addition of GSH or NAC completely suppressed the sulfide-induced apoptosis. Our results indicate that dimethyl sulfides with a larger number of sulfur atoms more strongly induced apoptosis in both human leukemia cells via ROS production and caspase-3 activation.
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PMID:Effect of dimethyl sulfides on the induction of apoptosis in human leukemia Jurkat cells and HL-60 cells. 1899 6

This study was conducted to evaluate the possible involvement of mitochondrial pathway in NaAsO2-induced apoptosis and the role of reactive oxygen species (ROS) and reduced glutathione (GSH) in the apoptotic effect in Chang human hepatocytes. The MTT assay demonstrated that sodium arsenite (NaAsO2) treatment for 24 h caused a dose-dependent decrease of cell viability. NaAsO2 treatment (0-30 microM) was also found to induce phosphatidylserine externalization, a hallmark of apoptosis; to disrupt the mitochondrial membrane potential (Deltapsi ( m )); to cause the release of cytochrome c into the cytosol, and to trigger cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in a dose-dependent manner. All these changes were accompanied with the enhanced generation of intracellular ROS and malondialdehyde (MDA). Increase of intracellular GSH also coincided unexpectedly. Moreover, the extracellular addition of N-acetyl-L-cysteine (NAC, 5 mM) effectively reduced the generation of ROS and MDA, and rescued the cells from NaAsO2 induced apoptosis and related alteration of mitochondria. These data suggest that the arsenic-induced cell apoptosis occurs though the mitochondrial pathway, and is mostly dependent on generation of ROS rather than GSH depletion in Chang human hepatocytes.
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PMID:Arsenic induces mitochondria-dependent apoptosis by reactive oxygen species generation rather than glutathione depletion in Chang human hepatocytes. 1953 24

Diabetic retinopathy and retinopathy of prematurity are blinding disorders that follow a pathological pattern of ischemic retinopathy and affect premature infants and working-age adults. Yet, the treatment options are limited to laser photocoagulation. The goal of this study is to elucidate the molecular mechanism and examine the therapeutic effects of inhibiting tyrosine nitration on protecting early retinal vascular cell death and late neovascularization in the ischemic retinopathy model. Ischemic retinopathy was developed by exposing neonatal mice to 75% oxygen [postnatal day (p) 7-p12] followed by normoxia (21% oxygen) (p12-p17). Peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTPPS) (1 mg/kg), the nitration inhibitor epicatechin (10 mg/kg) or the thiol donor N-acetylcysteine (NAC, 150 mg/kg) were administered (p7-p12) or (p7-p17). Vascular endothelial cells were incubated at hyperoxia (40% oxygen) or normoxia (21% oxygen) for 48 h. Vascular density was determined in retinal flat mounts labeled with isolectin B4. Expression of vascular endothelial growth factor, caspase-3, and poly(ADP ribose) polymerase (PARP), activation of Akt and p38 mitogen-activated protein kinase (MAPK), and tyrosine nitration of the phosphatidylinositol (PI) 3-kinase p85 subunit were analyzed by Western blot. Hyperoxia-induced peroxynitrite caused endothelial cell apoptosis as indicated by expression of cleaved caspase-3 and PARP leading to vaso-obliteration. These effects were associated with significant tyrosine nitration of the p85 subunit of PI 3-kinase, decreased Akt activation, and enhanced p38 MAPK activation. Blocking tyrosine nitration of PI 3-kinase with epicatechin or NAC restored Akt phosphorylation, and inhibited vaso-obliteration at p12 and neovascularization at p17 comparable with FeTPPS. Early inhibition of tyrosine nitration with use of epicatechin or NAC can represent safe and effective vascular-protective agents in ischemic retinopathy.
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PMID:Early intervention of tyrosine nitration prevents vaso-obliteration and neovascularization in ischemic retinopathy. 1981 13

Berberine (BBR) has indicated significant antimicrobial activity against a variety of organisms including bacteria, viruses, and fungi. The mechanism by which BBR initiates apoptosis remains poorly understood. In the present study, we demonstrated that BBR exhibited significant cytotoxicity in human hepatoma HepG2 cells. Herein, we investigated cytotoxicity mechanism of BBR in HepG2 cells. The results showed that the induction of apoptosis in HepG2 cells by BBR was characterized by DNA fragmentation, an increased percentage of annexin V, and the activation of caspase-3. The expressions of Bcl-2 protein and pro-caspase-3 were reduced by BBR in HepG2 cells. However, Bax protein was increased in the cells. BBR-induced apoptosis was preceded by increased generation of reactive oxygen species (ROS). NAC treatment, a scavenger of ROS, reversed BBR-induced apoptosis effects via inhibition of Bax activation and Bcl-2 inactivation. BBR-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of MAP Kinases (JNK and p38 MAPK), ASK1, Akt, and p53. Furthermore, SB203580, p38 inhibitor, reduced the apoptotic effect of BBR, and blocks the generation of ROS and NO as well as activation of Bax. We found that the treatment of HepG2 cells with BBR triggers generation of ROS through Akt phosphorylation, resulting in dissociation of the ASK1-mediated activation of JNK and p38 pathways.
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PMID:BBR induces apoptosis in HepG2 cell through an Akt-ASK1-ROS-p38MAPKs-linked cascade. 1995 Feb 6

In solid tumours, necrosis is commonly found in the core region in response to metabolic stress that results from oxygen and glucose depletion (OGD) due to insufficient vascularization and has been implicated in tumour progression. We have previously shown that metabolic stress due to glucose depletion (GD) induces necrosis and HMGB1 release through mitochondrial ROS production in A549 lung adenocarcinoma cells. In this study, we examined the effects of hypoxia on GD-induced necrosis and show that hypoxia prevented GD-induced mitochondrial ROS production, HMGB1 release, and necrosis and switched the cell death mode to apoptosis that is dependent on caspase-3 and -9. We further found that inhibition of ERK1/2 by U0126 abolished the effects of hypoxia to switch the cell death mode and to suppress mitochondrial ROS production, indicating an important role(s) of the ERK pathway in cell death mode determination. We also found that during OGD-induced apoptosis the prosurvival protein kinase Akt is activated and inhibition of Akt by the phosphoinositide 3-kinase (PI3K) inhibitors LY294002 and wortmannin prevent OGD-induced apoptosis, caspase-3 and -9 activation, and nuclear translocation of AIF and EndoG. Similar inhibitory effects of PI3K inhibitors were observed in A549 cells that underwent apoptosis when treated with GD in the presence of NAC (a general antioxidant) or catalase (a H(2)O(2) scavenger), or in the presence of active PKC by treatment with phorbol-12-myristate-13-acetate, indicating a crucial role(s) of the PI3K-Akt pathway in OGD-indcued apoptosis. In conclusion, our results demonstrate that hypoxia switches GD-induced necrosis to apoptosis and ERK1/2 and PI3K-Akt exert anti-necrotic and pro-apoptotic activities in the cell death, respectively.
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PMID:Hypoxia switches glucose depletion-induced necrosis to phosphoinositide 3-kinase/Akt-dependent apoptosis in A549 lung adenocarcinoma cells. 1995 40


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