UNIPROT:P08758 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heavy metals are well known to be able to induce immunotoxicity, but comparative metal studies related to apoptosis have not been conducted. In the present study, the effects of arsenic, cadmium, gold, lead, manganese, and mercury on thymocytes from BALB/c mice were analyzed. Thymic cells were cultured for 3-24 h in vitro in the absence or presence of metal, and markers of apoptosis or cell death, including annexin V binding, DNA loss/oligonucleosomal fragmentation, 7-amino-actinomycin D uptake (loss of impermeance), changes of the mitochondrial membrane potential (JC-1 fluorescence), and Western analysis of cellular thiols, were assayed. Mercury (Hg) was the only metal shown to be consistently toxic with the dose and times utilized. Cadmium (Cd) was the only other metal tested that also produced some significant level of DNA loss; however, the induction of apoptosis by Cd was not as consistent as that observed with Hg. When Hg was added with 2-mercaptoethanol (2-ME), Hg produced greater toxicity. Endogenous DNA synthesis by thymocytes was immediately inhibited by Hg and Hg + 2-ME. The Hg + 2-ME-induced apoptosis appeared to be associated with altered levels of cellular thiols, in that glutathione (GSH) depletion was significant in comparison to the non-metal control and Hg alone. The increased Hg-induced toxicity in the presence of 2-ME likely was due to the ability of 2-ME to enhance (10- to 20-fold) the cellular uptake of Hg. Western analysis with biotin maleimide demonstrated that Hg + 2-ME and to a lesser extent the positive control dexamethasone eliminated many reactive thiols; the major thiol-reactive protein still reactive with the maleimide probe had an approximate Molecular Mass of 45 kD. Surprisingly, Hg alone enhanced the expression of this thiol-expressing protein, which by Mass Spectrometry (MS)/MS analysis was shown to be beta-actin. Hg also produced the appearance of yet to be identified new proteins. Based on the results with Hg + 2-ME, it is suggested that numerous protein thiols participate in maintenance of cell survival and their loss is associated with apoptosis. The increased expression of new thiol-reactive proteins or thiol-reactive proteins with altered electrophoretic profiles needs to be further investigated. However, the enhanced toxicity attributed to Hg + 2-ME suggests that increased intracellular oxidative stress, observed as increased depletion of GSH, is responsible for the accelerated cell death.
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PMID:Mercury impairment of mouse thymocyte survival in vitro: involvement of cellular thiols. 1580 47

Ethanol induces oxidative stress in cultured fetal rat cortical neurons and this is followed by apoptotic death, which can be prevented by normalization of cell content of reduced glutathione (GSH). Because astrocytes can play a central role in maintenance of neuron GSH homeostasis, the following experiments utilized cocultures of neonatal rat cortical astrocytes and fetal cortical neurons to determine if astrocytes could protect neurons from ethanol-mediated apoptotic death via this mechanism. In cortical neurons cultured in the absence of astrocytes, ethanol (2.5 and 4 mg/ml; 6-, 12-, and 24-hr exposures) decreased trypan blue exclusion and the MTT viability measures by up to 45% (P < 0.05), increased levels of reactive oxygen species (ROS) by up to 81% (P < 0.05), and decreased GSH within 1 hr of treatment by 49 and 51% for 2.5 and 4 mg/ml, respectively (P < 0.05). This was followed by onset of apoptotic cell death as determined by increased Annexin V binding and DNA fragmentation by 12 hr of ethanol exposure. Coculturing neurons with astrocytes prevented GSH depletion by 2.5 mg/ml ethanol, whereas GSH content was increased over controls in neurons exposed to 4 mg/ml ethanol (by up to 341%; P < 0.05). Ethanol generated increases in neuron ROS and apoptosis; decreases in viability were also prevented by coculture. Astrocytes were largely insensitive to ethanol, using the same measures. Only exposure to 4.0 mg/ml ethanol decreased GSH content in astrocytes, concomitant with a 204% increase in GSH efflux (P < 0.05). These studies illustrate that astrocytes can protect neurons from ethanol-mediated apoptotic death and that this may be related to maintenance of neuron GSH.
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PMID:Astrocytes protect neurons from ethanol-induced oxidative stress and apoptotic death. 1588 May 62

Hypothermia induces injury in its own right, but the mechanisms involved in the cell damage are still unclear. The aim of this study was to test the effects that glutathione (GSH) depletion induces on cell death in isolated rat hepatocytes, kept at 4 degrees C for 20 h, by modulating intracellular GSH concentration with diethylmaleate and buthionine sulfoximine (DEM and BSO). Untreated hepatocytes showed Annexin V stained cells (AnxV(+)), scarce propidium iodide stained cells (PI(+)) and presented a low level of lactate dehydrogenase (LDH) leakage after 20 h at 4 degrees C and rewarming at 37 degrees C. When DEM and BSO were added before cold storage, we observed a few AnXV(+) cells and an increase in PI(+) cells associated with LDH release in the incubation medium. Conversely, the addition of DEM and BSO only during rewarming caused a marked increase in cell death by apoptosis. Production of reactive oxygen species (ROS) and thiobarbituric acid species (TBARS), associated with a decrease in GSH concentrations, was higher when DEM and BSO were added before cold storage. Cells treated with DEM and BSO before cold storage showed lower ATP energy stores than hepatocytes treated with DEM and BSO only during rewarming. Pretreatment of hepatocytes with deferoxamine protected against apoptotic and necrotic morphology in conditions of GSH depletion. These results suggest that pretreatment of hepatocytes with DEM and BSO before cold storage induces necrosis, while the treatment of hepatocytes only during rewarming increases apoptosis. In both conditions, iron represents a crucial mediator of cell death.
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PMID:Apoptosis vs. necrosis: glutathione-mediated cell death during rewarming of rat hepatocytes. 1594 4

Various physical and psychological stressors can cause thymocyte apoptosis and cell loss in rodents. Although glucocorticoids (GC) are commonly implicated, oxidative stress may also play a role. The purpose of this study was to examine the effect of an acute bout of strenuous treadmill running, and the antioxidant N-acetyl-L-cysteine (NAC) on thymocyte loss and apoptosis. Eighty-eight female C57BL/6 mice were given NAC (1 g/kg, i.p.) or saline (SAL) 30 min before 90 min of treadmill exercise at a 2 degrees slope (EX; 30 min at 22 m/min; 30 min at 25 m/min; and 30 min at 28 m/min) and sacrificed immediately (Imm) or 24 h following EX. Control mice (NonEX) were exposed to treadmill noise and vibration without running. Thymocytes were isolated and analyzed for phosphatidylserine (PS) externalization (Annexin V), loss of membrane integrity, mitochondria membrane depolarization, intracellular hydrogen peroxide (H(2)O(2)) production, and intracellular glutathione (GSH) as well as protein levels of caspase 3, Bcl-2, and cytosolic cytochrome c. Blood was analyzed for corticosterone (CORT) concentrations by radioimmunoassay. Exercise stress caused a significant increase in plasma CORT concentrations in EX + SAL + Imm and EX + NAC + Imm groups compared to NonEX mice. Relative to NonEX mice, thymocytes isolated from EX + SAL + Imm mice showed signs of an early apoptotic profile as indicated by decreased GSH stores and increased mitochondrial membrane depolarization. These effects were followed by a 50% reduction in thymocyte numbers 24 h post-exercise (EX + SAL + 24 h). Alterations in GSH levels, mitochondrial membrane depolarization, and thymocyte loss were not observed in mice receiving NAC. These results suggest that exercise-induced thymocyte apoptosis and cell loss may be mediated via an oxidative stress pathway.
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PMID:Mouse thymocyte apoptosis and cell loss in response to exercise and antioxidant administration. 1606 Nov 51

The aim was to exploit simultaneous inhibition of glycolytic and pentose phosphate pathways of energy production for radiosensitization using 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) in transformed mammalian cells. Two human tumour cell lines (cerebral glioma, BMG-1 and squamous carcinoma cells 4197) were investigated. 2-DG and/or 6-AN added at the time of irradiation were present for 4 h after radiation. Radiation-induced cell death (macrocolony assay), cytogenetic damage (micronuclei formation), cell cycle delay (bromodeoxyuridne (BrdU) pulse chase), apoptosis (externalization of phosphotidylserine (PS) by annexin V), chromatin-bound proliferation cell nuclear antigen (PCNA) and cellular glutathione (GSH) levels were investigated as parameters of radiation response. The presence of 2-DG (5 mM) during and for 4 h after irradiation increased the radiation-induced micronuclei formation and cell death, and caused a time-dependent decrease in GSH levels in BMG-1 cells while no significant effects could be observed in 4197 cells. 6-AN (5 microM) enhanced the radiosensitivity of both cell lines and reduced the GSH content by nearly 50% in gamma-irradiated 4197 cells. Combining 2-DG and 6-AN caused a profound decrease in the GSH content and enhanced the radiation damage in both the cell lines by increasing mitotic and apoptotic cell death. Further, the combination (2-DG + 6-AN) enhanced the radiation-induced G2 block, besides arresting cells in S phase and inhibited the recruitment of PCNA. The combination of 2-DG and 6-AN enhances radiation damage by modifying damage response pathways and has the potential for improving radiotherapy of cancer.
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PMID:Radiosensitization by 6-aminonicotinamide and 2-deoxy-D-glucose in human cancer cells. 1607 55

The effects of antioxidants on the apoptosis of Chinese hamster ovary (CHO) 1-15,500 cells and production of tissue plasminogen activator (tPA) in suspension culture were investigated. After cell growth to 2 x 10(5) cells/ml in Ham's F12 medium containing 10% newborn bovine serum (NBS) in a spinner bottle, CHO cells were maintained for 6 d in Ham's F12 medium containing 0 or 0.4% NBS and 10 mM antioxidants, namely, l-ascorbic acid 2-phosphate (VCP) or the reduced form of glutathione (GSH). The viable cell concentrations at day 6 in the serum-free culture with GSH and in the low-serum culture wiht VCP or GSH were 0.57, 1.04 and 1.69 x 10(5) cells/ml, respectively, while those in the serum-free and low-serum cultures without the antioxidants were only 2.33 and 1.17 x 10(3) cells/ml, respectively. The percentages of apoptotic cells in the serum-free and low-serum cultures with VCP (73.2, 44.6%) and GSH (76.9, 38.6%) measured using a flowcytometer after annexin V-FITC/propidium iodide staining were markedly lower than those in the cultures without antioxidants (96.3, 92.5%). The percentage of cells having a high mitochondrial membrane potential among the viable cells in the cultures with antioxidants determined using a flowcytometer after 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide staining was clearly higher than those in the cultures without the antioxidants. The production of tPA in the serum-free and low-serum media with VCP (0.282, 2.92 mg/l) or GSH (1.01, 1.61 mg/l) was markedly higher than that in the cultures without the antioxidants (0.275, 0.689 mg/l). Consequently, the suppression of apoptosis through the maintenance of the membrane potential of mitochondria by VCP or GSH resulted in a marked increase in tPA production by CHO cells in the serum-free and low-serum cultures.
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PMID:Effect of antioxidants on the apoptosis of CHO cells and production of tissue plasminogen activator in suspension culture. 1623 43

Curcumin is the main biologically active phytochemical compound in turmeric. It has been shown to have anticarcinogenic activity. The aims of the study were to identify the mechanism of apoptosis of HL-60 human promyelocytic leukemic cells induced by curcumin and to determine the effects of water-soluble antioxidants, ascorbic acid, Trolox (a water-soluble form of vitamin E), glutathione (GSH) and N-acetylcysteine (NAC) on this process. HL-60 cells were incubated with curcumin for 24 h and apoptotic cells were quantitated by flow cytometry following staining with annexin V-FITC and propidium iodide. Curcumin-treated HL-60 cells produced reactive oxygen species as detected by the dichlorofluorescein fluorescent assay. Apoptosis occurred via the mitochondria pathway as curcumin reduced mitochondrial membrane potential in a dose-dependent manner. In the presence of 10 microM curcumin, vitamin C (56 nM-5.6 microM) inhibited apoptosis of HL-60 cells; GSH at low concentration (1 microM) reduced apoptosis but had no effect at higher concentrations (10, 100 microM); and Trolox and NAC at 10 and 100 microM, respectively, enhanced apoptosis, but this effect was abolished at higher concentration (1 mM) of NAC. MAPKK/MEK inhibitor PD98059, enhanced curcumin-induced HL-60 apoptotic cell death.
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PMID:Effects of water-soluble antioxidants and MAPKK/MEK inhibitor on curcumin-induced apoptosis in HL-60 human leukemic cells. 1623 87

Fungicide thiram, which is also known as an inducer of allergic contact dermatitis (ACD), was used as a model compound of thiuram chemicals, and its cellular effects were investigated in cultured Chinese hamster V79 cells. The level of intracellular reduced glutathione (GSH), protein sulfhydryl (PSH) groups, protein carbonyls (PC), membrane lipid peroxidation reflected by enhanced thiobarbituric acid reactive substrates (TBARS) production, as well as apoptotic effect were determined. The apoptosis induction was determined by assessing DNA fragmentation by TUNEL, annexin V binding, and caspases activation assays, using fluorescent microscope or flow cytometry, respectively. The concentrations of thiram required to induce cellular GSH depletion (by 40-50%), protein, and membrane lipid peroxidation (2-fold, and 1.7-fold, respectively), as well as to induce apoptosis in V79 Chinese hamster fibroblasts without causing necrosis through cytotoxic effects were between 50-100 microM. To investigate the role of decreased GSH content in the toxicity of thiram, GSH level was modified prior to exposure. Pretreatment of V79 cells with N-acetyl-L-cysteine (NAC), a GSH biosynthesis precursor, prevented GSH decrease, PC and TBARS production, as well as caspases activation induced by thiram exposure. On the other hand, thiram effects were enhanced by the previous depletion of cellular GSH by L-buthionine-(S,R)-sulfoximine (BSO).
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PMID:Effect of glutathione depletion on apoptosis induced by thiram in Chinese hamster fibroblasts. 1627 29

Cytotoxici and alpha-diisoeugenol were investigated. The cytotoxicity of curcumin and a-diisoeugenol against human promyelocytic leukemia cells (HL-60 cells) and human submandibular cancer cells (HSG cells) was similar (CC50 1-3 microM). However, curcumin induced much more apoptosis, particularly in HL-60 cells compared with HSG cells, as revealed by measurement of the sub-G1/G0 DNA fraction in flow cytometric histograms. Treatment with 15 microM curcumin increased the number of cells with a sub-G1/G0 DNA fraction from control levels of <5% to 55% in HL-60 cells and 30% in HSG cells. Flow cytometry, after staining with annexin V-FITC/PI (the exposure of phosphatidylserine (PS) on the surface of apoptotic cells), showed a dose-dependent induction of early apoptosis by curcumin, which reached about 65% in HL-60 cells and about 20% in HSG cells after treatment with 10 microM curcumin. In contrast, alpha-diisoeugenol failed to induce apoptosis in either cell type. For both cell types, the proportion of late apoptotic/necrotic cells increased rapidly at concentrations of curcumin and a-diisoeugenol greater than 10 microM. The generation of intracellular reactive oxygen species (ROS) in curcumin-treated HL-60 cells was greater than that in HSG cells, as judged by CDFH-DA staining. In both cell types, ROS generation by a-diisoeugenol was at control levels. ROS generation by curcumin was suppressed by antioxidants such as N-acetyl-L-cysteine (NAC) and glutathione (GSH) and by scavengers of hydroxy radicals such as mannitol, but, conversely, was promoted by prooxidants such as the transition metal ions Cu(II) and Zn(II). ROS generation may play a part in the exposure of PS. Curcumin, but not a-diisoeugenol, at 10 microM inhibited LPS (lipopolysaccharide)-induced COX-2 gene expression in RAW 264.7 cells. Semiempirical PM 3 calculations suggested that this activity of curcumin, in which it behaves as a non-steroidal anti-inflammatory drug (NSAID)-like compound, is dependent on its phenolic function, which is more pronounced than that of alpha-diisoeugenol. Taken together, our results suggest that the bioactivity of curcumin is a result of its ability to act as both a prooxidant and an antioxidant.
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PMID:Induction of cytotoxicity and apoptosis and inhibition of cyclooxygenase-2 gene expression, by curcumin and its analog, alpha-diisoeugenol. 1630 95

Cadmium being a potent immunotoxicant, affects both humoral and cell mediated immunity. However, its effect on spleen is not clearly understood. Hence, to delineate the action of Cd, mouse splenic lymphocytes were exposed to Cd (10, 25 and 50 microM) for 60 min, 1.5, 3, 6 and 18 h. At 6 h, apoptosis was reflected by DNA fragmentation, increased sub-G1 population (apoptotic DNA) and apoptotic cells (Annexin V binding assay). The early stage markers of apoptosis, i.e. decreased mitochondrial membrane potential and caspase-3 activation were observed as early as 1.5 h by the highest dose of Cd (50 microM). Significant ROS production by 25 and 50 microM Cd at 60 min occurred prior to the lowering of mitochondrial membrane potential, suggesting involvement of ROS in causing mitochondrial membrane damage. N-acetylcysteine and pyrrolidine dithiocarbamate (thiol antioxidants) lowered the sub-G(1) population, inhibited the ROS generation and raised the GSH levels induced by Cd. Buthionine sulfoximine (GSH depletor) on the other hand, enhanced the ROS production as well as the sub-G1 fraction. These results imply that ROS is a critical mediator of Cd-induced apoptosis and that cadmium may compromise splenic immune function by accelerating apoptosis.
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PMID:Oxidative stress and apoptotic changes in murine splenocytes exposed to cadmium. 1641 50

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