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: UNIPROT:P08758 (annexin V)
9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The origin and the meaning of DNA fragmentation in ejaculated human spermatozoa are not yet clear, although some hypotheses have been proposed. In the present study, we used investigated sperm DNA fragmentation by terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick end labeling (TUNEL)-coupled flow cytometry to investigate DNA fragmentation in spermatozoa that were selected by the swim-up procedure and incubated long-term. In addition, using flow cytometry we detected annexin V binding assay and propidium iodide staining, and we also studied membrane phosphatidylserine translocation and the loss of membrane integrity in the same sperm populations that we used in the TUNEL investigation. We found that in vitro sperm DNA fragmentation 1) occurs after ejaculation under experimental conditions without the involvement of any external factor, 2) is not affected by treatment with the nuclease inhibitor aurintricarboxylic acid, 3) is increased by treatment with the glutathione peroxidase inhibitor mercaptosuccinate, 4) correlates with basal values (ie, just after swim-up selection) of DNA fragmentation in teratozoospermic but not in normospermic semen samples, 5) develops in a sharply associated manner with the in vitro occurrence of sperm necrosis, and 6) is predicted by the basal value of annexin V binding in viable spermatozoa. These findings suggest an involvement of endogenously produced reactive oxygen species as the possible cause of in vitro sperm DNA fragmentation.
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PMID:Spontaneous DNA fragmentation in swim-up selected human spermatozoa during long term incubation. 1263 13

Myocardial cell death is an important cellular event of heart failure. Tumor necrosis factor-alpha (TNF) accumulates in the failing heart and causes myocyte apoptosis, but the mechanism of this action is unclear. This study was undertaken to examine the relationship between TNF-induced cardiomyocyte apoptosis and activation of p38 mitogen-activated protein kinase (MAPK) through oxidative stress. Primary cultures of neonatal cardiomyocytes isolated from transgenic mouse hearts that overexpress metallothionein (MT) as well as cardiomyocytes isolated from wild-type mice were used. The treatment of wildtype cardiomyocytes with TNF at 10 ng/mL induced apoptosis, as detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and confirmed by Annexin V-fluorescein isothiocyanate binding. The apoptotic effect of TNF was significantly inhibited in the MT-overexpressing cardiomyocytes. Corresponding to the apoptotic effect, TNF at 10 ng/mL caused rapid phosphorylation of p38 MAPK in wild-type cardiomyocytes. The activation of p38 MAPK was further confirmed by an in vivo experiment treating the mice with TNF and measuring p38 MAPK activity using an immune complex kinase assay. The activation of p38 MAPK was not observed in the MT-overexpressing cardiomyocytes either in vitro or in vivo. Importantly, TNF-induced accumulation of reactive oxygen species was dramatically reduced in the MT-overexpressing cardiomyocytes as determined by a carboxy-H(2)-DCFDA staining method. This study thus suggests that p38 MAPK activation is likely involved in TNFinduced cardiomyocyte apoptosis, which is also related to reactive oxygen species accumulation.
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PMID:Inhibition of tumor necrosis factor-alpha-dependent cardiomyocyte apoptosis by metallothionein. 1266 66

Accumulation of delta-aminolevulinic acid (ALA), as it occurs in acute intermittent porphyria (AIP), is the origin of an endogenous source of reactive oxygen species (ROS), which can exert oxidative damage to cell structures. In the present work we examined the ability of different antioxidants to revert ALA-promoted damage, by incubating mouse astrocytes with 1.0 mM ALA for different times (1-4 hr) in the presence of melatonin (2.5 mM), superoxide dismutase (25 units/mL), catalase (200 units/mL) or glutathione (0.5 mM). The defined relative index [(malondialdehyde levels/accumulated ALA) x 100], decreases with incubation time, reaching values of 76% for melatonin and showing that the different antioxidants tested can protect astrocytes against ALA-promoted lipid peroxidation. Concerning porphyrin biosynthesis, no effect was observed with catalase and superoxide dismutase whereas increases of 57 and 87% were obtained with glutathione and melatonin, respectively, indicating that these antioxidants may prevent the oxidation of porphobilinogen deaminase, reactivating so that the AIP genetically reduced enzyme. Here we showed that ALA induces cell death displaying a pattern of necrosis. This pattern was revealed by loss of cell membrane integrity, marked nuclear swelling and double labeling with annexin V and propidium iodide. In addition, no caspase 3-like activity was detected. These findings provide the first experimental evidence of the involvement of ALA-promoted ROS in the damage of proteins related to porphyrin biosynthesis and the induction of necrotic cell death in astrocytes. Interestingly, melatonin decreases the number of enlarged nuclei and shows a protective effect on cellular morphology.
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PMID:Necrotic cell death induced by delta-aminolevulinic acid in mouse astrocytes. Protective role of melatonin and other antioxidants. 1282 7

Mercury is a highly toxic heavy metal; exposure to mercury in humans and animals causes damage in several organs or systems including the immune system. To characterize the toxicity of mercury in the immune cells, the cytotoxic effects of inorganic mercury were studied in two distinct lymphoma lines, the murine T lymphoma (EL4) and B lymphoma (A20) cells. Mercury concentration-dependently decreased cell viability, membrane integrity, and proliferation in both EL4 and A20 cells. Mercury increased the reactive oxygen species (ROS) production in both EL4 and A20 cells, and pretreatment with antioxidants reversed mercury-induced ROS generation. Pretreatment of cells with antioxidants N-acetylcysteine (NAC) and silymarin decreased mercury-induced lactate dehydrogenase (LDH) release in both types of cells; however, Ca(2+) channel blocker lanthanum (La(2+)) decreased it only in A20 cells. The mode of cytotoxicity was a mixture of both apoptosis and necrosis. Mercury-induced apoptosis and necrosis in the two cell lines were indicated by staining with Hoechst 33258, propidium iodide, and co-staining with annexin V and propidium iodide. Both mercury-induced apoptosis and necrosis were attenuated by antioxidants. Mercury increased gene expression of IL-4 and TNFalpha in EL4 cells; these cytokines were not expressed in A20 cells. Data suggested different pathways of mercury-induced cytotoxicity in T and B lymphoma cells and involvement of ROS, Ca(2+) homeostasis, and inflammatory cytokine gene expression.
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PMID:Cytotoxicity of inorganic mercury in murine T and B lymphoma cell lines: involvement of reactive oxygen species, Ca(2+) homeostasis, and cytokine gene expression. 1284 21

We evaluated neutrophil activation by measuring its phagocytic ability and oxidative burst activity in 16 patients with sepsis and 16 healthy volunteers. We also focused on neutrophil apoptosis as a regulatory mechanism of the inflammatory response. Neutrophil phagocytosis was evaluated by the detection of propidium iodide (PI)-labeled Staphylococcus aureus added to whole blood. Reactive oxygen species (ROS) formation was quantified by measuring the oxidation of 2',7' dichlorofluorescein diacetate (DCFH-DA) at baseline and after cell stimulation with phorbol myristate acetate (PMA), and bacterial cells (killed S. aureus) or products (lipopolysaccharide [LPS] and N-formyl-methionyl-leucyl-phenylalanine [FMLP]). Apoptosis was assessed in neutrophils stained with annexin V and PI. Neutrophil phagocytic ability was increased in patients with sepsis compared with healthy controls (median geometric mean fluorescence intensity [GMFI] was 101.9 and 54.7, respectively; P = 0.05). ROS formation was enhanced in patients with sepsis compared with healthy volunteers at baseline (median GMFI 275.6 and 52.1, respectively; P < 0.001), and after stimulation with S. aureus (median GMFI 2395.8 and 454.9, respectively; P < 0.001), PMA (median GMFI 1120.6 and 307.5, respectively; P = 0.003), FMLP (median GMFI 792.4 and 123.2, respectively; P < 0.001), and LPS (median GMFI 624.8 and 144.8, respectively; P < 0.001). Early neutrophil apoptosis was increased in patients with sepsis compared with healthy volunteers (median 11.3% and 9.1%, respectively; P = 0.03). These data demonstrate that neutrophil function is enhanced in patients with sepsis. Additionally, circulating neutrophils from patients with sepsis presented with increased early apoptosis, which may be consequence of a regulatory mechanism of the inflammatory response.
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PMID:Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. 1292 90

The clinically approved antioxidant cardioprotective agent dexrazoxane (ICRF-187) was examined for its ability to protect neonatal rat cardiac myocytes from doxorubicin-induced damage. Doxorubicin is thought to induce oxidative stress on the heart muscle, both through reductive activation to its semiquinone form, and by the production of hydroxyl radicals mediated by its complex with iron. Hydrolyzed dexrazoxane metabolites prevent site-specific iron-based oxygen radical damage by displacing iron from doxorubicin and chelating free and loosely bound iron. The mitochondrial stain MitoTracker Green FM and doxorubicin were shown by epifluorescence microscopy to accumulate in the myocyte mitochondria. An epifluorescence microscopic image analysis method to measure mitochondrial damage was developed using the mitochondrial membrane potential sensing ratiometric dye JC-1. This method was used to show that dexrazoxane protected against doxorubicin-induced depolarization of the myocyte mitochondrial membrane. Dexrazoxane also attenuated doxorubicin-induced oxidation of intracellular dichlorofluorescin. Annexin V-FITC/propidium iodide staining of myocytes was used to demonstrate that, depending on the concentration, doxorubicin caused both apoptotic and necrotic damage. These results suggest that doxorubicin may be cardiotoxic by damaging the mitochondria and dexrazoxane may be protective by preventing iron-based oxidative damage.
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PMID:Dexrazoxane (ICRF-187) protects cardiac myocytes against doxorubicin by preventing damage to mitochondria. 1450 Oct 28

G3139 is an 18-mer phosphorothioate oligodeoxyribonucleotide, which is targeted to the initiation codon region of the bcl-2mRNA. Although treatment of PC3 prostate cancer cells with G3139, which contains two CpG motifs, causes a dramatic decrease in bcl-2 protein expression after 3 days, it did not result in significant cellular apoptosis, as it does in many other cell lines. The absence of apoptosis was demonstrated by the absence of pro-caspase 3 cleavage products and of Annexin V cell surface expression. In addition, ATP production and the mitochondrial membrane potential DeltaPsim were preserved. Despite this, G3139 significantly inhibited the rate of cellular proliferation in complete media and blocked cloning in soft agar. G4232, a variant of G3139 that down-regulates bcl-2 expression to the same extent but has both CpG cytidines C5 methylated, was only minimally antiproliferative. A series of mismatched G3139-related oligomers were synthesized that could also substantially down-regulate bcl-2 protein expression, but only if the CpG motifs were preserved, demonstrating the presence of additional non-antisense mechanisms. G3139 caused production of reactive oxygen species in growth-arrested cells and oxidation of nuclear guanosine to 8-hydroxy-2'-deoxyguanosine, as determined by 1F7 monoclonal antibody staining. Bromodeoxyuridine incorporation studies demonstrated that G3139 induced a G1-S entry block and an intra-S-phase block in PC3 cells that persisted as long as 3 days. This finding coincides with the observation that expression of several proteins encoded by S-phase genes, including c-myb and poly(ADP-ribose) polymerase, were significantly reduced. These results illustrate the complexity of the mechanism of action of G3139 in PC3 cells.
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PMID:G3139 (oblimersen) may inhibit prostate cancer cell growth in a partially bis-CpG-dependent non-antisense manner. 1457 68

In utero ethanol exposure elicits apoptotic cell death in the fetal brain, and this may be mediated by oxidative stress. Our studies utilize cultured fetal rat cortical neurons and illustrate that ethanol elicits a rapid onset of oxidative stress, which culminates in mitochondrially mediated apoptotic cell death. Cells exposed to ethanol (2.5 mg/ml) remained attached to their polylysine matrix during a 24-hr exposure, but they exhibited distinct signs of oxidative stress, decreased viability, and apoptosis. Confocal microscopy of live cortical neurons pretreated with dichlorodihydrofluorescein diacetate demonstrated an increase in reactive oxygen species (ROS) within 5 min of ethanol exposure. The levels of ROS further increased by 58% within 1 hr (P <.05) and by 82% within 2 hr (P <.05), accompanied by increases of mitochondrial 4-hydroxynonenal (HNE). These early events were followed by decreased trypan blue exclusion of 10% to 32% (P <.05) at the 6- to 24-hr time points, respectively. This culminates in apoptotic death, with increases of Annexin V binding of 43%, 89%, 123%, and 238%, at 2, 6, 12, and 24 hr of ethanol treatment, respectively, as well as DNA fragmentation increases of 50% and 65% by 12 and 24 hr, respectively. Release of cytochrome c by mitochondria increased by 53% at 6 hr of exposure (P <.05), concomitant with activation of caspase 3 (52% at 12 hr, P <.05). Pretreatment with N-acetylcysteine increased cellular glutathione and prevented apoptosis. These studies provide a time line illustrating that oxidative stress and formation of a proapoptotic lipid peroxidation product, HNE, precede a cascade of mitochondrially mediated events in cultured fetal cortical neurons, culminating in apoptotic death. The prevention of apoptosis by augmentation of glutathione stores also strongly supports a role for oxidative stress in ethanol-mediated apoptotic death of fetal cortical neurons.
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PMID:Ethanol-induced oxidative stress precedes mitochondrially mediated apoptotic death of cultured fetal cortical neurons. 1459 2

Suspension-cultured apple fruit cells (Malus pumila Mill. cv. Braeburn) were exposed to a low oxygen atmosphere to test whether programmed cell death (PCD) has a role in cell dysfunction and death under hypoxic conditions. Protoplasts were prepared at various times after low oxygen conditions were established, and viability tested by triple staining with fluorescein diacetate (FDA), propidium iodide (PI) and Hoechst33342 (HO342). DNA breakdown and phosphatidylserine exposure on the plasma membrane were observed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and annexin V binding. About 30% of protoplasts from cells after 48 h under low oxygen showed an increased accumulation of HO342, indicating increased membrane permeability. Positive TUNEL and annexin V results were also only obtained with protoplasts from cells under low oxygen. The results suggest that apple cell death under low oxygen is at least partially PCD mediated, and may explain tissue breakdown under controlled atmosphere (low oxygen) conditions in apple fruit.
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PMID:Programmed cell death features in apple suspension cells under low oxygen culture. 1467 23

Reactive oxygen species (ROS) are important mediators for several biologic responses, including apoptosis. The present study evaluated the time course of changes in intracellular ROS production and apoptosis-related proteins, as well as apoptotic changes in human tubular proximal cells (HK-2 cells) exposed to hyperglycemia. Apoptosis (annexin V binding), ROS formation (fluorescence probe dichlorofluorescin diacetate and FACScan flow cytometry), and X chromosome-linked protein (XIAP; Western blot) were studied in HK-2 cells grown in a medium containing normal (NG) or high glucose (HG) concentrations (5.5 or 30 mM, respectively) for 18 to 48 h. HG promoted an increase (65% at 18 h and 73% at 24 h; P < 0.05 versus NG) in intracellular ROS generation. At 18 h, the NF-kB binding activity (evaluated by electrophoretic mobility-shift assay) was suppressed by HG. At the same time, the expression of NF-kB-induced antiapoptotic XIAP was reduced in HG-treated cells. Apoptotic changes were observed at 48 h (34 +/- 7% in HG versus 10 +/- 3% in NG; P < 0.001). Changes in ROS production at 24 h predicted changes in the apoptotic index at 48 h (r = 0.96, P < 0.0001). These results suggest that hyperglycemia induces apoptotic changes in human tubular cells via an increase in oxidative stress and that a downregulation of antiapoptotic protein XIAP is a component of this response.
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PMID:Oxidative stress mediates apoptotic changes induced by hyperglycemia in human tubular kidney cells. 1468 80


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