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

To detect the novel genes expressed uniquely in neutrophils and elucidate their function, the gene expression pattern was compared by using cDNA microarray containing 240 cytokine genes between the neutrophils and peripheral blood mononuclear cells (PBMCs) obtained from healthy human donors. Twenty-six genes, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were expressed in neutrophils at a level >10 times higher than that seen in phytohemagglutinin-stimulated PBMCs. The amounts of mRNA and protein of TRAIL were quantified by real-time reverse transcription-PCR and ELISA, respectively. TRAIL was expressed in resting neutrophils at the mRNA and protein levels, and its expression was enhanced after stimulation with IFN-gamma. Neutrophils expressed TRAIL on the cell surface and released it into the culture media. The cytotoxicity of neutrophil-derived TRAIL against Jurkat cells was determined by flow cytometry using FITC-conjugated annexin V. When Jurkat cells were cultured with neutrophils in the presence of IFN-gamma, the number of Jurkat cells undergoing apoptosis increased, and such increase depended on the effector:target ratio. This cytotoxicity was suppressed partially by adding anti-TRAIL antibody to the media. Neutrophils may exert their own antitumor effect by TRAIL. A microarray analysis was found to be a useful tool for detecting novel genes that are suggested to play unknown roles in the neutrophil function.
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PMID:Neutrophil-derived TNF-related apoptosis-inducing ligand (TRAIL): a novel mechanism of antitumor effect by neutrophils. 1487 35

Endothelial cells are the primary targets of circulating immune and inflammatory mediators. We hypothesize that interleukin-18, a proinflammatory cytokine, induces endothelial cell apoptosis. Human cardiac microvascular endothelial cells (HCMEC) were treated with interleukin (IL) 18. mRNA expression was analyzed by ribonuclease protection assay, protein levels by immunoblotting, and cell death by enzyme-linked immunosorbent assay and fluorescence-activated cell sorter analysis. We also investigated the signal transduction pathways involved in IL-18-mediated cell death. Treatment of HCMEC with IL-18 increases 1) NF-kappaB DNA binding activity; 2) induces kappaB-driven luciferase activity; 3) induces IL-1beta and TNF-alpha expression via NF-kappaB activation; 4) inhibits antiapoptotic Bcl-2 and Bcl-X(L); 5) up-regulates proapoptotic Fas, Fas-L, and Bcl-X(S) expression; 6) induces fas and Fas-L promoter activities via NF-kappaB activation; 7) activates caspases-8, -3, -9, and BID; 8) induces cytochrome c release into the cytoplasm; 9) inhibits FLIP; and 10) induces HCME cell death by apoptosis as seen by increased annexin V staining and increased levels of mono- and oligonucleosomal fragmented DNA. Whereas overexpression of Bcl-2 significantly attenuated IL-18-induced endothelial cell apoptosis, Bcl-2/Bcl-X(L) chimeric phosphorothioated 2'-MOE-modified antisense oligonucleotides potentiated the proapoptotic effects of IL-18. Furthermore, caspase-8, IKK-alpha, and NF-kappaB p65 knockdown or dominant negative IkappaB-alpha and dominant negative IkappaB-beta or kinase dead IKK-beta significantly attenuated IL-18-induced HCME cell death. Effects of IL-18 on cell death are direct and are not mediated by intermediaries such as IL-1beta, tumor necrosis factor-alpha, or interferon-gamma. Taken together, our results indicate that IL-18 activates both intrinsic and extrinsic proapoptotic signaling pathways, induces endothelial cell death, and thereby may play a role in myocardial inflammation and injury.
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PMID:Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. 1496 May 79

Insulin-like growth factor binding protein-3 (IGFBP-3) is emerging as a critical regulator of cell survival. There has been no study which directly examined the potential role for this major growth factor in the programmed cell death (apoptosis) of insulin-secreting cells. To determine whether IGFBP-3 mediates apoptosis in insulin-secreting cells, we performed a rigorous series of experiments with the rat insulinoma (RIN) cell line m5F and the hamster insulin-secreting tumor (HIT) T-15. Within 24 h exogenous IGFBP-3 induced significant DNA fragmentation in RIN and HIT cells, at doses ranging from 4.4 to 2000 ng/ml (P<0.05) without a classic dose-response relationship. DNA fragmentation induced by rhIGFBP-3 occurred in the presence of immunoglobulin to block the type 1 IGF receptor. As detected by flow cytometry for Annexin V exposure to the cell surface, rhIGFBP-3 treatment doubled the proportion of apoptotic HIT cells from 1.7 +/- 0.4% (serum-free control) to 3.4 +/- 0.2% (P<0.02), an effect completely reversed by co-treatment with 1000 ng/ml rhIGF-I. Immunofluorescent microscopy disclosed that pro-inflammatory Th1 cytokines increased intranuclear aggregation of endogenous IGFBP-3. Cytokine-induced DNA fragmentation was completely blocked by relatively brief pre-treatment with antisense IGFBP-3 phosphorothioate oligodeoxynucleotides. In conclusion, we have presented the first evidence that IGFBP-3 contributes to cytokine-mediated apoptosis in insulin-secreting cells.
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PMID:Insulin-like growth factor binding protein-3 is a novel mediator of apoptosis in insulin-secreting cells. 1512 83

Cytokines and growth factors that take part in the regulation of haematopoietic cell development activate many signalling pathways in target cells. The STAT5 (signal transducers and activators of transcription) proteins are members of a family of signal transducers and activators of transcription that can be activated after cytokine stimulation. Their binding to promoters of different genes influences cell proliferation, differentiation and survival. It is suggested that they play an important role in haematopoiesis, however, the question of the real function of STAT5 proteins requires further examination. The aim of our study was to investigate the role of STAT5 in the proliferation and apoptosis of normal haematopoietic bone marrow cells derived from heparinized cadaveric organ donors (HCOD). We applied antisense oligodeoxynucleotides (ODNs) to block STAT5A and STAT5B at the mRNA level and the reverse transcription polymerase chain reaction method to study STAT5 mRNA expression in the cells after incubation with ODNs. Moreover, we performed Western blot analysis of the STAT5A protein after exposure to antisense STAT5A. We analysed the clonogenicity of the colony-forming unit of granulocytes-macrophages and the burst-forming unit of erythrocytes in methylcellulose cultures according to the type and the dose of ODNs. We also examined apoptosis induced in bone marrow mononuclear and CD34(+) cells by employing annexin V staining and the TUNEL method using flow cytometry (FACScan). We found that the perturbation of STAT5 expression decreased the clonogenicity of bone marrow haematopoietic cells. However, we did not observe any significant increase in the percentage of apoptotic cells after incubation with antisense ODNs. It was concluded that the STAT5 proteins play a significant role in the proliferation of human bone marrow cells harvested from HCOD. These proteins might be critical in the regulation of haematopoiesis, especially under stress conditions.
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PMID:The influence of antisense oligonucleotides against STAT5 on the regulation of normal haematopoiesis in a bone marrow model. 1514

Dietary n-3 PUFAs have been shown to attenuate T-cell-mediated inflammation. To investigate whether dietary n-3 PUFAs promote activation-induced cell death (AICD) in CD4+ T-cells induced in vitro to a polarized T-helper1 (Th1) phenotype, C57BL/6 mice were fed diets containing either 5% corn oil (CO; n-6 PUFA control) or 4% fish oil (FO) plus 1% CO (n-3 PUFA) for 2 weeks. Splenic CD4+ T-cells were cultured with alpha-interleukin-4 (alphaIL-4), IL-12, and IL-2 for 2 days and then with recombinant (r) IL-12 and rIL-2 for 3 days in the presence of diet-matched homologous mouse serum (HMS) to prevent loss of cell membrane fatty acids, or with fetal bovine serum. After polarization, Th1 cells were reactivated and analyzed for interferon-gamma and IL-4 by intracellular cytokine staining and for apoptosis by Annexin V/propidium iodide. Dietary FO enhanced Th1 polarization by 49% (P = 0.0001) and AICD by 24% (P = 0.0001) only in cells cultured in the presence of HMS. FO enhancement of Th1 polarization and AICD after culture was associated with the maintenance of eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) in plasma membrane lipid rafts. In conclusion, n-3 PUFAs enhance the polarization and deletion of proinflammatory Th1 cells, possibly as a result of alterations in membrane microdomain fatty acid composition.
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PMID:Dietary n-3 polyunsaturated fatty acids promote activation-induced cell death in Th1-polarized murine CD4+ T-cells. 1514 80

Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disease, usually associated with cigarette smoking. Stimulated peripheral blood T cells from patients with COPD have an increased propensity to undergo apoptosis. The mitochondrial apoptotic pathway is regulated by pro-apoptotic proteins (including p53 and Bax) as well as anti-apoptotic proteins (e.g. Bcl-2) and cytokines (IL-2, IL-4 and IL-7). We hypothesized that alterations in expression of these apoptosis-related proteins, cytokines and cytokine receptors may be important in determining the susceptibility of T cells to undergoing apoptosis in COPD. We further hypothesized that inhaled corticosteroids (GCS) contribute to the increased rates of T-cell apoptosis observed in COPD. The process of apoptosis (assessed by Annexin V and ssDNA staining), as well as Bcl-2, Bax, p53, IL-2, IL-4 and receptors IL-7R, IL-4R and IL-2Rgamma were investigated in PHA-stimulated peripheral blood-derived T cells, using flow cytometry. Fifteen patients with COPD receiving inhaled GCS (four of who received additional prednisolone), eight patients with COPD receiving symptom control medication, and 16 control subjects were studied. T cells (CD4(+) and CD8(+)) from GCS-treated COPD patients showed an increased propensity to undergo apoptosis, associated with significantly decreased Bcl-2 and IL-7 receptor expression. No significant differences were observed for the COPD patients who were receiving symptom control medication. These findings may suggest a negative peripheral effect of inhaled GCS on the immune system in COPD, although the clinical significance of these effects remains uncertain.
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PMID:Increased peripheral blood T-cell apoptosis and decreased Bcl-2 in chronic obstructive pulmonary disease. 1574 12

Pollutant particles induce apoptosis and inflammation, but the relationship between these two biological processes is not entirely clear. In this study, we compared the proapoptotic and proinflammatory effects of four particles: residual oil fly ash (ROFA), St. Louis particles SRM 1648 (SL), Chapel Hill PM10 (CHP), and Mount St. Helens dust (MSH). Human alveolar macrophages (AM) were incubated with these particles at 100 microg/ml. Cell death was assessed by annexin V (AV) expression, histone release, nuclear morphology, caspase 3-like activity and release of caspase 1 for apoptosis, and propidium iodide (PI) for necrosis, and inflammation was measured by interleukin (IL)-1beta and IL-6. We found that particle effects on these cell death measurements varied, and ROFA affected most (four out of five) endpoints, including nuclear morphological changes. CHP and SL also caused necrosis. For cytokine release, the potency was CHP > SL > ROFA > MSH. The proapoptotic and proinflammatory effects induced by the whole particles were unaltered after the particles were washed with water. The water-soluble fraction was relatively inactive, as were individual soluble metals (V, Ni, Fe). ROFA-induced nuclear fragmentation was associated with upregulation and mitochondrial release of apoptosis-inducing factor (AIF), a caspase-independent chromatin condensation factor, and upregulation of DNase II, a lysosomal acid endonuclease. These results indicate that the potential for particles to induce apoptosis does not correlate with their proinflammatory properties, although active components for both processes reside in the water-insoluble core. Both apoptosis and inflammatory endpoints should be included when the toxicity of different pollutant particles is assessed.
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PMID:Apoptotic and inflammatory effects induced by different particles in human alveolar macrophages. 1576 74

The role of apoptosis/cell death in the inflammatory response at the implanted materials is unexplored. Two surfaces with different cytotoxic potential and in vivo outcomes, titanium (Ti) and copper (Cu) were incubated in vitro with human monocytes and studied using a method to discriminate apoptotic and necrotic cells (Annexin V/PI staining). Further, staurosporine, a potent inducer of apoptosis, was added to the surface adherent monocytes. Lactate dehydrogenase (a marker of cell membrane injury) and TNF-alpha and IL-10, cytokines, previously suggested to play a major role in the monocyte apoptosis, were assayed in the culture medium. The results demonstrated that Ti surfaces displayed enhanced monocyte survival and production of IL-10 and TNF-alpha. Cu adherent cells exhibited apoptotic signs as early as 1h after incubation. In contrast to Ti, after 48 h the predominance of apoptotic cells switched to apoptotic/necrotic cells on Cu surfaces. Staurosporine treatment of Ti adherent cells mediated similar type of cell death. LDH and cytokine contents were low around Cu surfaces, partly explained by interference between Cu ions and LDH and cytokines. This study suggests that material properties rapidly influence the onset of human monocyte apoptosis and progression to late apoptosis/necrosis. Early detection of apoptosis and cell death may be important for the understanding of the biological response to implanted materials.
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PMID:Monocyte viability on titanium and copper coated titanium. 1589 14

PANcreatic DERived factor (PANDER, FAM3B) is a recently discovered islet-specific cytokine. We have previously shown that, in vitro, truncated recombinant PANDER isoforms (20 and 21 kDa) are cytotoxic to beta-cell lines but the effects of full-length PANDER on islet biology remain unclear. In this study, we used adenovirus (Ad-PANDER) to overexpress full-length cDNA of PANDER in islets and betaTC3 cells. BetaTC3 cells were infected with Ad-PANDER or control vector. After 48 h, cell viability was significantly decreased as evaluated by MTT assay. The number of dead cells was significantly increased as indicated by the fluorescent intensity of the propidium iodide-stained cells (160 +/- 13 vs. control 100 +/- 7%, P = 0.001). Flow cytometric Tunel assay showed that overexpressing PANDER induced a significant fourfold increase in beta-cell apoptosis (19.4 +/- 6.3 vs. control 4.1 +/- 0.8%, P < 0.05). There was a significant increase in the number of annexin V-positive (apoptotic) cells and propidium iodide-positive (dead) cells in mouse islets infected with Ad-PANDER compared with control cells infected with Ad-LacZ. Addition of 4 nM recombinant PANDER protein to betaTC3 cells or infection of Ad-PANDER did not affect Akt and STAT1 phosphorylation, Bcl-2, Fas, and NF-kappaB protein levels. However, activation of caspase-3 was observed in betaTC3 and islets infected with Ad-PANDER. Overexpression of PANDER in mouse islets or addition of recombinant PANDER decreased insulin secretion induced by carbachol plus glucose or high potassium but not that by glucose alone. Culture with recombinant PANDER did not affect glucose-induced NAD(P)H elevation in mouse islets. In conclusion, Ad-PANDER infection is as effective as truncated recombinant PANDER to induce betaTC3 cell and mouse islet apoptosis.
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PMID:Effects of overexpression of pancreatic derived factor (FAM3B) in isolated mouse islets and insulin-secreting betaTC3 cells. 1592 25

Mesangial cells are critical for glomerular filtration. Mesangial cell dysfunction, the hallmark of diabetic nephropathy, results from disordered mesangial growth induced by cytokines, abnormal hemodynamic influence, and metabolic factors associated with chronic hyperglycemia. Insulin-like growth factors (IGFs) and their high affinity binding proteins (IGFBPs) exert major actions on mesangial cell survival, but their underlying mechanisms remain unclear. In light of emerging IGF-independent roles for IGFBP-3, we investigated IGFBP-3 actions during mesangial cell apoptosis induced by cytokine or high glucose concentration. Quantified by DNA fragmentation ELISA and Annexin V flow cytometry, apoptosis occurred in rat mesangial cells (RMC) exposed to 2 microg/mL IGFBP-3 for 24 h under high ambient or standard glucose. Anti-sense IGFBP-3 oligo at 10 microg/mL significantly inhibited apoptosis induced by 100 ng/mL TNF-alpha, serum-free conditions, or high (25 mM) glucose. Increased IGFBP-3 release associated with high ambient glucose or TNF-alpha was inhibited by pre-treatment with anti-sense oligo. Under serum-free conditions, recombinant human IGFBP-3 blocked Akt phosphorylation at threonine 308 (pThr308), whereas anti-sense oligo treatment was associated with enhanced pThr308 activity. In summary, these data support a novel mechanism for TNF-alpha-induced mesangial cell apoptosis mediated by IGFBP-3 and present regulation of pThr308 activity as a novel mechanism underlying IGFBP-3 action.
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PMID:Insulin-like growth factor binding protein-3 mediates cytokine-induced mesangial cell apoptosis. 1593 83


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