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)

Most thymocytes are deleted by thymic selection. The mechanisms of cell death are far from being clear. Peroxynitrite is a powerful oxidant produced in vivo by the reaction of superoxide (O2*-) with nitric oxide (NO*) and is able to mediate apoptosis. The aim of this study was to analyze whether NO and peroxynitrite could play a role in human thymocyte apoptosis. The results indicate that 3-(4-morpholinyl)-sydnonimine (SIN-1, an O2*- and NO* donor) and chemically synthesized peroxynitrite, but not S-nitroso-N-acetyl-D,L-penicillamine (SNAP, an NO* donor), have a strong apoptotic effect on human thymocytes (annexin V staining and TUNEL reaction). This effect was inhibited by exogenous superoxide dismutase (SOD), which interacts with O2*- and inhibits the formation of peroxynitrite. Because peroxynitrite formation requires NO*, thymic stromal cells were investigated to determine if they produced NO*. Inducible NOS was synthesized in cultured thymic epithelial cells in certain conditions of cytokine stimulation, as shown by messenger RNA levels, protein analysis, and nitrite production in the supernatants. SIN-1-treated thymocytes had high levels of tyrosine nitration, abolished by the addition of exogenous SOD. Tyrosine nitration was also detected in thymus extracts and sections, suggesting the presence of peroxynitrite in situ. In thymus sections, clusters of nitrotyrosine-positive cells were found in the cortex and corticomedullary areas colocalized with cells positive in the TUNEL reaction. These data indicate an association between human thymocyte apoptosis and nitrotyrosine formation. Thus, the results support the notion of a physiologic role for peroxynitrite in human thymocyte apoptosis. (Blood. 2001;97:3521-3530)
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PMID:In vivo and in vitro apoptosis of human thymocytes are associated with nitrotyrosine formation. 1136 46

Nitric oxide (NO) attenuates hydrogen peroxide (H2O2)-mediated injury to H9C2 cardiomyoblasts. To examine the role of nitric oxide, cultured H9C2 cardiomyoblasts were treated with H2O2 for 2 h in the presence or absence of the NO donor, diethylamine nitric oxide (DEANO). DEANO (30 microM) attenuated H2O2-induced apoptosis in H9C2 cells. H2O2-exposed H9C2 cells resulted in apoptosis in a time-dependent manner estimated by DNA fragmentation assay, nuclear morphology stained with fluorescent dye, Hoechst 33258 and Annexin V staining. Pretreatment with z-VAD-FMK, a pancaspase inhibitor, or z-DEVD-CHO, a specific caspase-3 inhibitor, completely suppressed the DNA ladder in response to H2O2. An increase in caspase-3-like protease (DEVDase) activity was observed during apoptosis, but no caspase-1 activity (YVADase) was detected. Treatment of H9C2 cells with 100 microM H2O2, resulted in a strong activation of JNK/SAPK. However, the activation of JNK/ SAPK was clearly attenuated by 30 microM DEANO. Furthermore, the dominant negative JNK and SEK1-expressing cells displayed a marked decrease in a number of apoptotic cells. This inhibition of JNK1 in the system is involved in the protection of H2O2-induced apoptosis in H9C2 cardiomyoblasts.
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PMID:Signal transduction of nitric oxide donor-induced protection in hydrogen peroxide-mediated apoptosis in H9C2 cardiomyoblasts. 1141 47

Obesity is associated with insulin resistance and some reproductive abnormalities. Circulating FFAs are often elevated in obese subjects and are also closely linked to insulin resistance. In this study, we demonstrated that saturated FFAs, such as palmitic acid and stearic acid, markedly suppressed the granulosa cell survival in a time- and dose-dependent manner. Polyunsaturated FFA, arachidonic acid, had no effect on the cell survival, even at supraphysiological concentrations. The suppressive effect of saturated FFAs on cell survival was caused by apoptosis, as evidenced by DNA ladder formation and annexin V-EGFP/propidium iodide staining of the cells. The apoptotic effects of palmitic acid and stearic acid were unrelated to the increase of ceramide generation or nitric oxide production and were also completely blocked by Triacsin C, an inhibitor of acylcoenzyme A synthetase. In addition, acylcoenzyme A, pamitoylcoenzyme A, and stearylcoenzyme A markedly suppressed granulosa cell survival, whereas arachidonoylcoenzyme A had no such effect, and this finding was consistent with the effect of the respective FFA form. Surprisingly, arachidonic acid instead showed a protective effect on palmitic acid- and stearic acid-induced cell apoptosis. A Western blot analysis showed the apoptosis of the granulosa cells induced by palmitic acid to be accompanied by the down-regulation of an apoptosis inhibitor, Bcl-2, and the up-regulation of an apoptosis effector, Bax. These results indicate that saturated FFAs induce apoptosis in human granulosa cells caused by the metabolism of the respective acylcoenzyme A form, and the actual composition of circulating FFAs may thus play a critical role in the apoptotic events of human granulosa cells. These effects of FFAs on granulosa cell survival may be a possible mechanism for reproductive abnormalities, such as amenorrhea, which is frequently observed in obese women.
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PMID:Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells. 1145 7

Cytokines produced by immune system cells that infiltrate pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune (type 1) diabetes mellitus. Because the calcium binding protein, calbindin-D(28k), can prevent apoptotic cell death in different cell types, we investigated the possibility that calbindin-D(28k) may prevent cytokine-mediated islet beta-cell destruction. Using the expression vector BSRalpha, rat calbindin-D(28k) was stably expressed in the pancreatic islet beta-cell line, betaTC-3. Calbindin-D(28k) expression resulted in increased cell survival in the presence of the cytotoxic combination of the cytokines IL-1beta (30 U/ml), TNFalpha (10(3) U/ml), and interferon gamma (10(3) U/ml). The greatest protection was observed in the betaTC-3 cell clone expressing the highest concentration of calbindin-D(28k). Apoptotic cell death was detected by annexin V staining and by the TdT-mediated dUTP-X nick end labeling assay in vector-transfected betaTC-3 cells incubated with cytokines (14-15% apoptotic cells). The number of apoptotic cells was significantly decreased in calbindin-D(28k)-overexpressing betaTC-3 cells incubated with cytokines (5-6% apoptotic cells). To address the mechanism of the antiapoptotic effects of calbindin, studies were done to examine whether calbindin inhibits free radical formation. The stimulatory effects of the cytokines on lipid hydroperoxide, nitric oxide, and peroxynitrite production were significantly decreased in the calbindin-D(28k)-expressing betaTC-3 cells. Our findings indicate that calbindin-D(28k), by inhibiting free radical formation, can protect against cytokine-mediated apoptosis and destruction of beta-cells. These findings suggest that calbindin-D(28k) may be an important regulator of cell death that can protect pancreatic islet beta-cells from autoimmune destruction in type 1 diabetes.
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PMID:Expression of calbindin-D(28k) in a pancreatic islet beta-cell line protects against cytokine-induced apoptosis and necrosis. 1145 14

The endothelial layer of the myocardial vasculature serves as an important protective barrier between blood and myocardium. Ischemic reperfusion (I/R) of the endothelium has been shown to initiate a series of events that leads to ischemic reperfusion injury in the heart. At the onset of ischemic reperfusion, endothelial cells initiate apoptosis, a process whereby the cells self-destruct. Ischemic reperfusion was simulated to study its effects on the induction of apoptosis in cultured human endothelial cells (ECV 304). In addition, the cells were treated with nitric oxide (NO) to test its effect on induction of apoptosis. To mimic hypoxia, four ECV 304 cultures were placed in a medium that had been bubbled with pure nitrogen gas for 24 hours. A continuous flow of nitrogen gas was applied to the culture flasks during the course of the 2-hour ischemic period. After 2 hours, the nitrogen was removed from the hypoxic cultures to simulate reperfusion. Exposure to NO was achieved through the NO-donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) at 100 microM, Cell cultures were exposed to hypoxia only, hypoxia and SNAP, and SNAP only. One positive control was established by exposure to staurosporine. A second positive control was established by exposure to a 30-min heat treatment at 43 degrees C. Two cultures were left untreated to serve as negative controls. All cell cultures were incubated for 4 hours. Apoptosis was detected by the binding of annexin V-fluorescein isothiocyanate (annexin V-FITC). In addition, morphologic changes detected by electron microscopy were used. Apoptosis increased in all treated cultures, excluding SNAP only treated cells. It was concluded that I/R may lead to induction of apoptosis.
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PMID:Simulation of ischemic reperfusion in endothelial cell culture increases apoptosis. 1168 Jul 31

The endogenous viral superantigen 7 in DBA/2 mice serves as a target antigen on syngeneic ESb-MP lymphoma cells for allogeneic graft-vs-leukaemia reactive cells. Allogeneic viral superantigen 7 reactive Vbeta6+ T cells are able to transfer graft-vs-leukaemia reactivity and to kill specifically viral superantigen 7+ ESb-MP tumour cells in vitro. Here we elucidate the mechanism of this superantigen specific cell lysis. Already 10 min after co-incubation with in vitro stimulated Vbeta6+ T cells, viral superantigen 7+ ESb-MP tumour cells show an apoptotic phenotype (Annexin V-positivity, DNA-fragmentation). This extremely rapid type of cell death is not mediated by the death inducing ligands CD95L, TRAIL and TNF but by perforin and granzyme B. Surprisingly, neither mitochondria nor any of the known caspases appear to be involved in this type of tumour cell killing. In contrast, nitric oxide, released by activated macrophages and endothelial cells, induces in the same tumour cells another type of apoptosis which is much slower and involves mitochondria and caspase activation. A synergistic effect between the two different effector mechanisms of superantigen reactive donor cytotoxic T lymphocytes and nitric oxide releasing host macrophages and endothelial cells might explain the effective immune rejection of even advanced metastasised cancer in this graft-vs-leukaemia animal model.
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PMID:Superantigen reactive Vbeta6+ T cells induce perforin/granzyme B mediated caspase-independent apoptosis in tumour cells. 1187 49

Trans-resveratrol was analysed for its apoptotic and growth inhibitory activity in human B-cell lines derived from chronic B-cell malignancies (WSU-CLL and ESKOL), and in leukaemic lymphocytes from patients with B-cell chronic lymphocytic leukaemia (B-CLL). Resveratrol displayed antiproliferative activity on both B-cell lines, as estimated by the decrease in cell recovery and inhibition of thymidine uptake. Furthermore, resveratrol induced apoptosis in the two cell lines as well as in B-CLL patients' cells, as evidenced by the increase in annexin V binding, caspase activation, DNA fragmentation and decrease of the mitochondrial transmembrane potential DeltaPsim. We previously reported that nitric oxide (NO), endogenously released by an iNO synthase (iNOS) spontaneously expressed in these leukaemic cells, contributed to their resistance towards apoptosis. We show here that resveratrol inhibited both iNOS protein expression and in situ NO release in WSU-CLL, ESKOL and B-CLL patients'cells. In addition, Bcl-2 expression was also inhibited by resveratrol. Thus, downregulation of the two anti-apoptotic proteins iNOS and Bcl-2 can contribute to the apoptotic effects of resveratrol in leukaemic B cells from chronic leukaemia. Our data suggest that this drug is of potential interest for the therapy of B-CLL.
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PMID:Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia. 1206 Jan 19

Lipopolysaccharide (LPS) from gram-negative bacteria circulates in acute, subacute, and chronic conditions. It was hypothesized that LPS directly induces cardiac apoptosis. In adult rat ventricular myocytes (isolated with depyrogenated digestive enzymes to minimize tolerance), LPS (10 ng/ml) decreased the ratio of Bcl-2 to Bax at 12 h; increased caspase-3 activity at 16 h; and increased annexin V, propidium iodide, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining at 24 h. Apoptosis was blocked by the caspase inhibitor benzyloxycarbonyl-valine-alanine-aspartate fluoromethylketone (Z-VAD-fmk), captopril, and angiotensin II type 1 receptor (AT(1)) inhibitor (losartan), but not by inhibitors of AT(2) receptors (PD-123319), tumor necrosis factor-alpha (TNFRII:Fc), or nitric oxide (N(G)-monomethyl-L-arginine). Angiotensin II (100 nmol/l) induced apoptosis similar to LPS without additive effects. LPS in vivo (1 mg/kg iv) increased apoptosis in left ventricular myocytes for 1-3 days, which dissipated after 1-2 wk. Losartan (23 mg. kg(-1). day(-1) in drinking water for 3 days) blocked LPS-induced in vivo apoptosis. In conclusion, low levels of LPS induce cardiac apoptosis in vitro and in vivo by activating AT(1) receptors in myocytes.
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PMID:Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT(1) receptors. 1212 89

Inhaled nitric oxide (iNO) is used clinically to treat pulmonary hypertension in newborns, often in conjunction with hyperoxia (NO/O2). Prolonged exposure to NO/O2 causes synergistic lung injury and death of lung epithelial cells. To explore the mechanisms involved, oxygen-resistant HeLa-80 cells were exposed to NO +/- O2. Exposure to NO and O2 induced a synergistic cytotoxicity, accompanied with apoptotic characteristics, including elevated caspase-3-like activity, Annexin V incorporation, and nuclear condensation. This apoptosis was associated with a synergistic suppression of NF-kappaB activity. Cells lacking functional NF-kappaB p65 subunit were more sensitive to NO/O2 than their wild type counterparts. This injury was partially rescued by transfection with a p65 expression construct, suggesting an inverse relationship between NF-kappaB and susceptibility to the cytotoxicity of NO/O2. Despite the reduced NF-kappaB activity in cells exposed to NO +/- O2, IkappaBalpha was degraded, suggesting that pathways regulating the steady-state levels of IkappaB were not involved. However, exposure to NO/O2 caused a marked reduction in nuclear localization and an increase in protein carbonyl formation of NF-kappaB p65 subunit. These results suggest that NO/O2-induced apoptosis occurs by suppressing NF-kappaB activity.
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PMID:Suppression of nuclear factor-kappa B activity by nitric oxide and hyperoxia in oxygen-resistant cells. 1221 28

Ultraviolet radiation (UV) induces apoptosis in keratinocytes by both p53- and death receptor-dependent pathways. It also generates free radicals in keratinocytes, including the synthesis of nitric oxide (NO) by constitutive and inducible NO synthases (NOS). NO has both pro- and anti-apoptotic effects. We wished to determine which of these was predominant in keratinocytes. Human CCD1106 keratinocytes were irradiated with UVB in the presence and absence of several NOS antagonists. Apoptosis was measured by flow cytometry with annexin V binding. NOS antagonism consistently altered UVB-induced apoptosis measured 18 h after irradiation. In 9 of 13 experiments, NOS antagonism increased apoptosis. However, in 4 of 13 experiments, NOS antagonism reduced apoptosis. We postulated that the variable effects of NO might be due to a critical balance between UVB-induced NO and superoxide production. We predicted that NO would be anti-apoptotic in the presence of low O(-)(2), but pro-apoptotic when NO combined with O(-)(2) to form peroxynitrite. Though superoxide dismutase reduced apoptosis after UVB, addition of peroxynitrite did not affect apoptosis. We conclude that NO released by UV irradiation is anti-apoptotic; however, the levels of O(-)(2) may be a determinant of NO action.
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PMID:Pro- and anti-apoptotic effects of nitric oxide in irradiated keratinocytes: the role of superoxide. 1223 30


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