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)

A fish cell line, fathead minnow (FHM) cell, was used to investigate the alteration of mitochondrial dynamics and the mechanism of apoptosis under Rana grylio virus (RGV) infection. Microscopy observations, flow-cytometry analysis and molecular marker detection revealed the apoptotic fate of the RGV-infected cells. Some typical apoptotic characteristics, such as chromatin condensation, DNA fragmentation and mitochondrial fragmentation, were observed, and significantly morphological changes of mitochondria, including size, shape, internal structure and distribution, were revealed. The mitochondria in RGV-infected cells were aggregated around the viromatrix, and the aggregation could be blocked by colchicine. Moreover, the Deltapsim collapse was induced, and caspase-9 and caspase-3 were activated in the RGV-infected cells. In addition, NF-kappaB activation and intracellular Ca(2+) increase were also detected at different times after infection. The data revealed the detailed dynamics of mitochondrion-mediated apoptosis induced by an iridovirus, and provided the first report on mitochondrial fragmentation during virus-induced apoptosis in fish cells.
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PMID:Mitochondrion-mediated apoptosis induced by Rana grylio virus infection in fish cells. 1755 38

Elevated plasma levels of the acute-phase reactant serum amyloid A (SAA) have been used as a marker and predictor of inflammatory diseases. SAA regulates leukocyte activation; however, it is not known whether it also modulates neutrophil apoptosis, which is critical to the optimal expression and resolution of inflammation. Culture of human neutrophils with SAA (0.1-20 microg/ml) markedly prolonged neutrophil longevity by delaying constitutive apoptosis. SAA evoked concurrent activation of the ERK and PI3K/Akt signaling pathways, leading to phosphorylation of BAD at Ser(112) and Ser(136), respectively, and to prevention of collapse of mitochondrial transmembrane potential, cytochrome c release, and caspase-3 activation. These actions were abrogated by pharmacological inhibition of the formyl peptide receptor, ERK or PI3K. Furthermore, aspirin-triggered 15-epi-lipoxin A(4) (15-epi-LXA(4)) and its stable analog 15-epi-16-p-fluorophenoxy-LXA(4), which binds to the same receptor as SAA, effectively overrode the antiapoptosis signal from SAA even when neutrophils were treated with 15-epi-LXA(4) at either 1 or 4 h postculture with SAA. 15-Epi-LXA(4) itself did not affect neutrophil survival and apoptosis. Our results indicate that SAA at clinically relevant concentrations promotes neutrophil survival by suppressing the apoptotic machinery, an effect that can be opposed by 15-epi-LXA(4). The opposing actions of SAA and aspirin-triggered 15-epi-LXA(4) may contribute to the local regulation of exacerbation and resolution of inflammation, respectively.
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PMID:Aspirin-triggered lipoxins override the apoptosis-delaying action of serum amyloid A in human neutrophils: a novel mechanism for resolution of inflammation. 1757 83

Cremanthodium humile (C. humile) is a traditional herbal medicine for treatment of inflammation. Based on initial screening results, the purpose of this study was to evaluate the cytotoxic effect on four human cancer cell lines and one non-cancer cell line (293), then to determine the possible mechanisms of cell death elicited by the extract of C. humile on Hela cells. We have found the ether extract of C. humile (CH-EE) strongly decreased the survival rate of the four human tumor cell lines: Hela, A549, HepG2 and SW480. The cytotoxic effect of CH-EE on 293 was smaller than on tumor cell lines. Flow cytometry assays and nuclear staining showed that CH-EE induced apoptosis in Hela cells. This process was accompanied by the collapse of mitochondrial membrane potential, the release of cytochrome c and the activation of caspase-3/7 and -9. Furthermore, CH-EE generated reactive oxygen species (ROS) in Hela cells. These results indicate that CH-EE induces apoptosis in Hela cells through a ROS-mediated mitochondrial dysfunction pathway.
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PMID:Apoptosis of Hela cells induced by extract from Cremanthodium humile. 1759 78

Bioassay-guided phytochemical study of Androsace umbellata led to the successful isolation of saxifragifolin B (SB) for the first time. The anti-tumor effect of SB was firstly reported that it was shown to have potent cytotoxicity on human hepatoma HepG2 cells with IC50 value of 11.9 microM at 24 h. Mechanistic studies were conducted, the accumulation of sub-G1 population and the externalization of phosphatidylserine suggested that SB exerted its cytotoxic effect by induction of programmed cell death, which was confirmed by activation of PARP and caspase-3. Furthermore, SB-induced apoptosis on HepG2 cells was mediated by activation of caspase-8 and -9, mitochondrial membrane potential (Deltapsim) collapse and the leakage of cytochrome c. In summary, this study provided evidence that SB isolated from A. umbellata could induce apoptosis on human hepatoma HepG2 cells and described the molecular mechanism. Our finding revealed the potential of SB as new chemotherapeutic agent for human hepatoma.
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PMID:Saxifragifolin B from Androsace umbellata induced apoptosis on human hepatoma cells. 1776 1

The oxidative modification of low-density lipoprotein (LDL) is thought to have a central role in the pathogenesis of atherogenesis. Berberine, a natural constituent of plants of the genera Coptis and Berberis, has several anti-inflammation and anticancer biological effects. However, its protective effects on LDL oxidation and endothelial injury induced by oxLDL remain unclear. In this study, we evaluated the antioxidative activity of berberine and how berberine rescues human umbilical vein endothelial cells (HUVECs) from oxidized LDL (oxLDL)-mediated dysfunction. The antioxidative activity of berberine was defined by the relative electrophoretic mobility of oxLDL, fragmentation of ApoB, and malondialdehyde production via the Cu(2+)-mediated oxidation of LDL. Berberine also inhibited the generation of ROS and the subsequent mitochondrial membrane potential collapse, chromosome condensation, cytochrome C release, and caspase-3 activation induced by oxLDL in HUVECs. Our results suggest that berberine may protect LDL oxidation and prevent oxLDL-induced cellular dysfunction.
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PMID:Protective effects of berberine against low-density lipoprotein (LDL) oxidation and oxidized LDL-induced cytotoxicity on endothelial cells. 1800 Oct 34

Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while anti-apoptotic protein Bcl-2 has been found to prevent this process. The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro- and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.
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PMID:Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease. 1807 76

Ursolic acid (UA) is a pentacyclic triterpenoid compound which exists widely in nature and is known to have a pleitropic biological activity profile. For the last few decades, extensive work has been carried out to establish its biological activities and pharmacological actions. It is described as a promising chemopreventive agent with an antiproliferative effect on cancer cells that stems from its ability to induce apoptosis. We investigated and compared the role played by mitochondria during the apoptotic process induced by UA in human HaCaT-derived keratinotic cells and M4Beu human melanoma cells. In both cell lines, UA induced significant caspase-3 activation, the downstream central effector of apoptosis. Subsequent JC-1/TOTO-3 double staining clearly demonstrated that UA induces strong mitochondrial-transmembrane potential collapse in M4Beu cells, while mitochondria from HaCaT-treated cells remain largely unstimulated. This was confirmed by Western blot analysis, which revealed a Bax/Bcl-2-balance change in favor of Bax, the proapoptotic member, in UA-treated M4Beu cells. It can be concluded that UA induces apoptosis in M4Beu through the mitochondrial pathway, while other mechanisms are activated in the case of HaCaT cells.
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PMID:Differential involvement of mitochondria during ursolic acid-induced apoptotic process in HaCaT and M4Beu cells. 1809 88

In this study, the release of mitochondrial proapoptotic intermembrane space proteins induced by exogenous C(2)-ceramide in human colon carcinoma (HT-29) cell line was investigated. HT-29 cells were treated with 12.5, 25 and 50 micromol/L C(2)-ceramide in vitro. Flow cytometer was used to detect the mitochondrial membrane potential (DeltaPhi(m)). Subcellular fractions were extracted by Mitochondrial/Cytosol Fractionation Kit after C(2)-ceramide treatment for 24 h. SDS-PAGE was used to determine the level of cytochrome c (Cyt c), high temperature requirement A2 (HtrA2) and second mitochondrial-derived activator of caspases (Smac) released from mitochondria, the expression of X-linked inhibitor of apoptosis protein (XIAP) and caspase-3 for 24 h. The results showed that DeltaPhi(m) began to decrease from 6 h after 25 and 50 micromol/L C(2)-ceramide treatment (P<0.05) and cyclosporin A (CsA) could inhibit the collapse of DeltaPhi(m) through regulating mitochondrial membrane permeability transition pore. There was no effect of C(2)-ceramide on the expression of Cyt c, HtrA2 and Smac in the total levels. 12.5, 25 and 50 micromol/L C(2)-ceramide could induce Cyt c, HtrA2 and Smac to release from mitochondria to cytosol and down-regulate the expression of XIAP (P<0.05). Also there was expression of cleaved caspase-3 with C(2)-ceramide treatment. After the treatment with caspase inhibitor, C(2)-ceramide still induced the release of Cyt c and HtrA2, but Smac did not. Therefore, C(2)-ceramide could induce apoptosis of HT-29 cells through the mitochondria pathway. The release of Cyt c, HtrA2 and Smac from mitochondria did not occur via the same mechanism, the release of Cyt c and HtrA2 was caspase-independent and the release of Smac was caspase-dependent.
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PMID:Ceramide induces release of mitochondrial proapoptotic proteins in caspase-dependent and -independent manner in HT-29 cells. 1817 93

Anisomycin is known as a potent apoptosis inducer by activating JNK/SAPK and inhibiting protein synthesis during translation. However, only few details are known about the mechanism of apoptosis induced by this compound. The present study was undertaken to further elucidate the molecular mechanism of apoptosis and the changes of gene expression elicited by anisomycin using DNA microarrays and computational gene-expression analysis tools in human lymphoma U937 cells. Anisomycin was found to induce apoptosis in time- and concentration-dependent manner as confirmed by phosphatidylserine externalization and DNA fragmentation analysis. Furthermore, anisomycin-treated cells also showed caspase-8 activation, mitochondrial membrane potential collapse, Bid activation, caspase-3 cleavage and cytochrome c release into the cytosol. In the gene-expression analysis, six gene clusters were detected. From clusters I and II, three significant genetic networks were identified. Interestingly, many bZIP family transcription factors were observed in the up-regulated genetic networks. Moreover, the expression of protein-synthesis-related genes, such as EIF4 family proteins and ribosomal proteins, were inhibited. This finding could explain the reason why anisomycin inhibits the protein synthesis at the translation steps. These results provide novel information for understanding the molecular mechanism of apoptosis induced by anisomycin.
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PMID:Molecular mechanism of apoptosis and gene expressions in human lymphoma U937 cells treated with anisomycin. 1824 49

NO is known to suppress mast cell activation, but the role of NO in mast cell survival is unclear. Ligation of the high-affinity receptor for IgE (FcepsilonRI) resulted in NO production in mast cells within minutes. This NO production was largely dependent on NO synthase (NOS) activity and extracellular Ca(2+). The NO production required an aggregation of FcepsilonRI and was accompanied by increased phosphorylation of endothelial NOS (eNOS) at Ser1177 and Akt at Ser473. The phosphorylation of eNOS and Akt and the production of NO were abolished by the PI-3K inhibitor wortmannin. Although thapsigargin (TG) induced NO production as well, this response occurred with a considerable lag time (>10 min) and was independent of FcepsilonRI aggregation and PI-3K and NOS activity. Mast cells underwent apoptosis in response to TG but not upon FcepsilonRI ligation. However, when the NOS-dependent NO production was blocked, FcepsilonRI ligation caused sizable apoptosis, substantial mitochondrial cytochrome c release, caspase-3/7 activation, and collapse of the mitochondrial membrane potential, all of which were inhibited by the caspase-3 inhibitor z-Asp-Glu-Val-Asp-fluoromethylketone. The data suggest that the NO produced by the PI-3K-Akt-eNOS pathway is involved in protecting mast cells from cell death.
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PMID:Nitric oxide protects mast cells from activation-induced cell death: the role of the phosphatidylinositol-3 kinase-Akt-endothelial nitric oxide synthase pathway. 1828 1


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