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: EC:3.4.21.69 (APC)
16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in various hemostatic factor have been identified as risk factors for survival after acute myocardial infarction (AMI). However, these clinical data are primarily limited to observations made during the postinfarct stage. We assessed the effects of 50 minutes of left anterior descending artery occlusion on several hemostatic factors and analyzed their changes with outcome in 18 Yorkshire swine. Blood samples were obtained from the systemic circulation at base-line and at 25 and 50 minutes of occlusion. Platelet aggregability and plasma antithrombin-III protein C, protein S, fibronectin, endothelin-1, as well as the metabolites of thromboxane and prostacyclin were measured. Of the 18 swine, 7 survived the infarct and 11 animals developed fatal ventricular fibrillation. Both groups demonstrated significant decreases in platelet aggregation, and a decline in plasma protein S when compared with baseline. Thromboxane, prostacyclin, and ondothelin-1 plasma concentrations were also markedly reduced at the end of occlusion. There were significant changes in antithrombin-III, protein C, and fibronectin levels between surviving animals and those that died of ventricular fibrillation. Acute coronary artery occlusion is associated with substantial changes in the hemostatic factors in swine. Plasma levels of fibronectin, antithrombin-111, and protein C differed between survivors and nonsurvivors and thus might serve as predictors of mortality due to fatal ventricular fibrillation during AMI. The mechanisms of these changes during the acute phase of AMI are unclear. Immediately AMI prognosis may be related to hemostatic changes not only after thrombolysis or spontaneous reperfusion, but also during the occlusion phase as well.
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PMID:Survival in Acute Myocardial Infarction Induced by Coronary Ligation: Prognostic Relevance of Certain Hemostatic Factors During the Occlusion Phase. 1060 47

Myocardial stunning is characterized by transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. Platelet activation and hemostatic abnormalities have been described in patients with unstable angina and acute myocardial infarction, however, their role in the pathogenesis of myocardial stunning is unknown. The purpose of this study was to determine if platelet aggregation and certain hemostatic factors change during myocardial stunning following brief coronary arterial occlusion. Nine Yorkshire swine underwent left anterior descending coronary artery occlusion for 8 minutes followed by 90 minutes of reperfusion. Blood samples were obtained at baseline, at 4 and 8 minutes of occlusion, and at 60 and 90 minutes of reperfusion. Platelet aggregability and concentrations of antithrombin III, protein C, protein S, fibronectin, endothelin 1, and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1a) were measured in systemic circulation. The occlusion phase was associated with a decline of endothelin 1 (-13.6%), and TxB2 (-19.6%), and elevation of antithrombin III (+40.2%) and protein C (+22.9%). Mild myocardial stunning was associated with a significant increase in platelet aggregation (+33.7%), endothelin-1 (+24.7%), 6-keto-PGF1a (+41.5%), TxB2 (+11.9%), and protein C (+42.3%) during the reperfusion phase. There were no changes in plasma fibronectin and total protein S. Thus, mild myocardial stunning following brief coronary artery occlusion is associated with substantial dynamic changes in platelet aggregability and certain hemostatic factors. These results may be relevant to understanding the mechanisms determining myocardial stunning and coronary arterial patency following reperfusion.
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PMID:Mild myocardial stunning affects platelet aggregation and certain hemostatic factors in swine. 1072 20

Dendritic cells (DC) are highly specialized APC that are critical for the initiation of T cell-dependent immune responses. DC exert a sentinel function while immature and, after activation by inflammatory stimuli or infectious agents, mature and migrate into lymphoid organs to prime T cells. We have analyzed integrin expression on monocyte-derived DC (MDDC) and found that expression of CD49d integrins (CD49d/CD29 and CD49d/beta7) was induced/up-regulated during TNF-alpha- or LPS-initiated MDDC maturation, reflecting the induction/up-regulation of CD49d and beta7 mRNA. CD49d mRNA steady-state level increased more than 10 times during maturation, with the highest levels observed 24 h after TNF-alpha treatment. CD49d integrin expression conferred mature MDDC with an elevated capacity to adhere to the CS-1 fragment of fibronectin, and also mediated transendothelial migration of mature MDDC. Up-regulation of CD49d integrin expression closely paralleled that of the mature DC marker CD83. CD49d integrin expression was dependent on cell maturation, as its induction was abrogated by N:-acetylcysteine, which inhibits NF-kappaB activation and the functional and phenotypic maturation of MDDC. Moreover, CD49d integrin up-regulation and MDDC maturation were prevented by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase, but were almost unaffected by the mitogen-activated protein/extracellular signal-related kinase kinase 1/2 inhibitor PD98059. Our results support the existence of a link between functional and phenotypic maturation of MDDC and CD49d integrin expression, thus establishing CD49d as a maturation marker for MDDC. The differential expression of CD49d on immature and mature MDDC might contribute to their distinct motility capabilities and mediate mature DC migration into lymphoid organs.
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PMID:Maturation-dependent expression and function of the CD49d integrin on monocyte-derived human dendritic cells. 1103 69

Purified, resting peripheral blood T lymphocytes were previously reported to undergo beta(1) integrin-dependent activation when cultured with anti-CD3 mAb coimmobilized with fibronectin, but not type I collagen. However, the extravascular T cells that encounter immobilized extracellular matrix proteins and are involved in disease pathogenesis have different properties from resting peripheral blood cells. In this study, we confirm that resting CD4(+) and CD8(+) T cells from peripheral blood are costimulated by immobilized fibronectin, but not type I collagen. In contrast, Ag- or mitogen-stimulated CD4(+) and CD8(+) T cell lines, used as models of the effector cells involved in disease, are more potently costimulated by type I collagen than fibronectin. The collagen-induced effects are similar in assays with serum-free medium and in more physiological assays in which anti-CD3 mAb is replaced by a threshold concentration of Ag and irradiated autologous PBMC as APC. The responses are beta(1) integrin dependent and mediated largely by very late Ag (VLA) 1 and 2, as shown by their up-regulation on the T cell lines as compared with freshly purified resting PBL, and by the effects of blocking mAb. Reversed phase HPLC located the major costimulatory sequence(s) in the alpha1 chain of type I collagen, the structure of which was confirmed by amino acid sequencing. The results demonstrate the potential importance of type I collagen, an abundant extracellular matrix protein, in enhancing the activation of extravascular effector T cells in inflammatory disease, and point to a new immunotherapeutic target.
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PMID:Potent costimulation of effector T lymphocytes by human collagen type I. 1104 19

Histoplasma capsulatum (Hc) is a facultative, intracellular parasite of world-wide importance. As the induction of cell-mediated immunity to Hc is of critical importance in host defense, we sought to determine whether dendritic cells (DC) could function as a primary APC for this pathogenic fungus. DC obtained by culture of human monocytes in the presence of GM-CSF and IL-4 phagocytosed Hc yeasts in a time-dependent manner. Upon ingestion, the intracellular growth of yeasts within DC was completely inhibited compared with rapid growth within human macrophages. Electron microscopy of DC with ingested Hc revealed that many of the yeasts were degraded as early as 2 h postingestion. In contrast to macrophages, human DC recognized Hc yeasts via the fibronectin receptor, very late Ag-5, and not via CD18 receptors. DC stimulated Hc-specific lymphocyte proliferation in a concentration-dependent manner after phagocytosis of viable and heat-killed Hc yeasts, but greater proliferation was achieved after ingestion of viable yeasts. These data demonstrate that human DC can phagocytose and degrade a fungal pathogen and subsequently process the appropriate Ags for stimulation of lymphocyte proliferation. In vivo, such interactions between DC and Hc may facilitate the induction of cell-mediated immunity.
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PMID:Histoplasma capsulatum yeasts are phagocytosed via very late antigen-5, killed, and processed for antigen presentation by human dendritic cells. 1114 84

Hepatoblastoma (HBL) is the most common malignant liver tumor in young children. Recent reports have shown that the beta-catenin gene was frequently mutated or deleted in HBLS: To elucidate the role of beta-catenin abnormalities in HBLs, we searched for mutations of beta-catenin and APC as well as expression of the target genes, cyclin D1, c-myc, and fibronectin, in 68 primary HBLS: The mutation analysis revealed that 44 (65%) tumors carried missense mutations or deletions of beta-catenin, all of which were somatic and targeted to the exon 3 encoding the amino acid residues involved in its degradation. However, no loss of function mutation of the APC gene was detected by the yeast functional assay. Of interest, beta-catenin mutation was significantly correlated with overexpression of the target genes, cyclin D1 and fibronectin, but not with that of c-myc in HBLs as measured by quantitative real-time reverse transcription-PCR. The immunohistochemical studies in 15 HBLs demonstrated that the nuclear/cytoplasmic accumulation of beta-catenin was positive in 13 tumors, 9 of which had the deletion or mutation of the gene. The significant correlation between the beta-catenin gene abnormality and the positive staining of cyclin D1 was also confirmed. Furthermore, the nuclear accumulation of beta-catenin was strongly associated with the poorly differentiated tumor cell components as well as with the positive staining of cyclin D1 within the tumor. Thus, our present results suggested that the gain of function mutation of beta-catenin played a crucial role in the malignant progression of HBL in vivo.
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PMID:Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma. 1130 40

Blood monocytes of patients with thyroid autoimmune disease (TAID) display defects in rearranging their cortical actomyosin cytoskeleton ('polarize') in response to chemoattractants. Such rearrangements also take place after the adherence of monocytes to the extracellular matrix (ECM). It is therefore not surprising that monocytes are primed after fibronectin (FN) adherence, displaying an enhanced polarization toward chemoattractants. We investigated the integrin expression and chemoattractant-induced polarization of monocytes of TAID patients before and after FN adherence. Since cytoskeletal rearrangements are also required during the transition of monocytes into veiled antigen-presenting cells (VCs), we investigated such transition of FN-adherent monocytes of TAID patients. Adherent and nonadherent monocyte populations from TAID patients and healthy controls were subjected to a polarization test with the chemoattractant fMLP (or MCP-1), FACS analyses (FITC-labelled FN, CD29, CD49e, d, b and a) and tested for their capability to develop into veiled APC. Monocytes of healthy individuals showed an improved chemoattractant-induced cell polarization after FN adherence, not reflected by TAID monocytes, in which chemoattractant-induced polarization worsened. Monocytes of healthy individuals up-regulated CD49e and d integrins and their capability to bind FITC-labelled FN after adherence to a FN-coated plate, as well as enhancing their capability to generate T cell-stimulatory VCs. Monocytes of TAID patients did not. These data indicate that integrin- (and chemokine-) mediated functions are hampered in monocytes of TAID patients. Because integrin action is pivotal to processes such as monocyte adherence to endothelial cells, uropod formation, migration into tissues and differentiation into APC and macrophages, these defects might underly immune dysbalances important in thyroid autoimmune development.
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PMID:An abnormal adherence of monocytes to fibronectin in thyroid autoimmunity has consequences for cell polarization and the development of veiled cells. 1147 20

The pulmonary alveolar epithelium consists of alveolar type I (AT1) and alveolar type II (AT2) cells. Interactions between these two cell types are necessary for alveolar homeostasis and remodeling. These interactions have been difficult to study in vitro because current cell culture models of the alveolar epithelium do not provide a heterocellular population of AT1 and AT2 cells for an extended period of time in culture. In this study, a new method for obtaining heterocellular cultures of AT1- and AT2-like alveolar epithelial cells maintained for 7 d on a rat tail collagen-fibronectin matrix supplemented with laminin-5 is described. These cultures contain cells that appear by their morphology to be either AT1 cells (larger flattened cells without lamellar bodies) or AT2 cells (smaller cuboidal cells with lamellar bodies). AT1-like cells stain for the type I cell marker aquaporin-5, whereas AT2-like cells stain for the type II cell markers surfactant protein C or prosurfactant protein C. AT1/AT2 cell ratios, cell morphology, and cell phenotype-specific staining patterns seen in 7-d-old heterocellular cultures are similar to those seen in alveoli in situ. This culture system, in which a mixed population of phenotypically distinct alveolar epithelial cells are maintained, may facilitate in vitro studies that are more representative of AT1-AT2 cell interactions that occur in vivo.
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PMID:Heterocellular cultures of pulmonary alveolar epithelial cells grown on laminin-5 supplemented matrix. 1260 38

In contrast to skeletal muscle isoforms of myosin binding protein C (MyBP-C), the cardiac isoform has 11 rather than 10 fibronectin or Ig modules (modules are identified as C0 to C10, NH2 to COOH terminus), 3 phosphorylation sites between modules C1 and C2, and 28 additional amino acids rich in proline in C5. Phosphorylation between C1 and C2 increases maximum Ca-activated force (Fmax), alters thick filament structure, and increases the probability of myosin heads on the thick filament binding to actin on the thin filament. Unphosphorylated C1C2 fragment binds to myosin, but phosphorylation inhibits the binding. MyBP-C also binds to actin. Using two types of immunoprecipitation and cosedimentation, we show that fragments of MyBP-C containing C0 bind to actin. In low concentrations C0-containing fragments bind to skinned fibers when the NH2 terminus of endogenous MyBP-C is bound to myosin, but not when MyBP-C is bound to actin. C1C2 fragments bind to skinned fibers when endogenous MyBP-C is bound to actin but not to myosin. Disruption of interactions of endogenous C0 with a high concentration of added C0C2 fragments produces the same effect on contractility as extraction of MyBP-C, namely decrease in Fmax and increase in Ca sensitivity. These results suggest that cardiac contractility can be regulated by shifting the binding of the NH2 terminus of MyBP-C between actin and myosin. This mechanism may have an effect on diastolic filling of the heart.
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PMID:Effect of MyBP-C binding to actin on contractility in heart muscle. 1463 34

Pre-eclampsia is an extremely severe condition. It is associated with vasospasm, activation of the coagulation system and abnormal haemostasis. In pre-eclamptic patients increased plasmatic concentrations of fibronectin, laminin, von Willebrand factor (VWF) and endothelin are observed. Experimental studies on rats have also shown that the doses of antithrombin III (AT) needed to mediate anti-inflammatory processes are much higher than those required to obtain the anti-coagulant effect. The study aimed to evaluate the clinical efficacy of treatment with high AT doses (HD) in comparison with standard doses (SD). The primary endpoint was the prolongation of pregnancy defined as time (in days) from enrollment to delivery and to assess the maternal bleeding at and after delivery. The secondary endpoint was to demonstrate a role for AT in controlling haemostasis at conventional doses, and the inflammatory state at higher doses. The biochemical parameters assessed were: AT activity (%), Fibronectin (Fn), Fibrinogen, D-dimer, Uricemia, Proteinuria 24h, Protein C Reactive (PCR), Granulocyte Elastase and Endothelin. This study included 23 pre-eclamptic women. Patients were randomly subdivided into two groups: 10 patients ("cases") were treated with high doses of AT (6 vials: 3000 units) once daily for 5 days, or until delivery, while 13 women ("controls") were treated with doses of AT sufficient to maintain at least 80% of the activity. High-dose therapy was associated with prolongation of pregnancy by 2.5 days more when compared with controls (p = 0.03; Mann-Whitney test). The incidence of clinical significant bleeding was lower in cases than in controls (mean 550 mL vs. 650 mL, respectively). Preventive- and conservative-type treatment of moderate-severe pre-eclampsia, based on the administration high doses of AT, allows a significant prolongation of pregnancy, and thus a better neonatal outcome, as well as less maternal intra- and post-operative bleeding. Fn, PCR and elastase levels (markers of inflammation) decrease in the HD group in comparison with SD group. In the HD group, the AT plasma levels were obviously higher both at the end of the treatment (p < 0.0001) and after delivery (p = 0.03), in comparison with SD group. The fibrinogen and D-dimer levels were above the reference interval in both groups. TPA and PAI 1 were found to be significantly raised in the course of pre-eclampsia. In conclusion, the bio-chemical findings support a role for AT in controlling the haemostasis at conventional doses, and the inflammatory state at higher doses.
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PMID:Efficacy of AT in pre-eclampsia: a case-control prospective trial. 1496 Nov 55


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