Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endothelial cells (ECs) are antithrombotic in the physiological states and maintains the integrity of blood circulation. However, ECs turn to be thrombotic upon being stimulated by various physiological mediators. These functions are mainly achieved by changing specific protein synthesis in ECs. Type 1 plasminogen activator inhibitor (PAI-1) is a serine protease inhibitor synthesized by ECs and thought to play a crucial role in the regulation of fibrinolysis. Basic research as well as clinical studies support this hypothesis. PAI-1 is a physiological inhibitor of both tissue-type plasminogen activator and urokinase-type plasminogen activator, key enzymes in the initiation of fibrinolysis. Thus PAI-1 regulates not only blood clot lysis but also a wide variety of biological reactions occurring in extracellular matrices such as tumor metastasis, neovascularization, inflammation, and cell migration. PAI-1 is a glycoprotein, of which molecular weight is approximately 50,000. Molecular biological analyses indicate that PAI-1 is synthesized as a single polypeptide composed of 402 amino acids containing a signal peptide. After post-translational modification, PAI-1 is secreted from ECs as a polypeptide composed of 379 amino acids and three N-linked carbohydrates. PAI-1 lacks Cys residues, indicating that PAI-1 may not be rigid and thus thermolabile. In fact, PAI-1 is unstable even at 37 degrees C decaying into an inactive form with a biological half life of 2-3 hours. PAI-1 binds to a cell adhesion molecule, vitronectin. The association of PAI-1 with vitronectin appears to stabilize PAI-1. PAI-1 in complex with vitronectin is still accessible to plasminogen activators.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Type 1 plasminogen activator inhibitor: its role in biological reactions]. 187 Feb 65

Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous disease in which oral lesions may be the initial and predominant manifestation. The disease is characterized by acantholysis in the immediately suprabasal layers of the stratified squamous epithelium, giving rise to blisters which readily rupture leaving erosions which show little tendency to heal. Immunogenetic studies indicate a marked genetic susceptibility to the disease, with the immune response-associated HLA-DR4 and DRw6 alleles being especially important. The trigger for autoantibody formation is unknown. The antigen in pemphigus vulgaris is probably a 130-140 kD cell adhesion molecule located in the cell membrane of basal and immediately suprabasal keratinocytes. Antibody binding to this antigen is likely to interfere with normal intercellular adhesion, leading to desmosomal detachment. Propagation of acantholysis and cell damage are attributable to complement activation, with deposition of the membrane attack complex on the keratinocyte cell membrane, and proteolysis due to increased plasminogen activator production. Steroid therapy is the treatment of choice, but significant mortality is still associated with the disease.
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PMID:Vesiculobullous mucocutaneous disease: pemphigus vulgaris. 269 19

During angiogenesis capillary endothelial cells undergo a coordinated set of modifications in their interactions with extracellular matrix components. In this study we have investigated the effect of the prototypical angiogenic factor basic fibroblast growth factor (bFGF) on the expression and function of several integrins in microvascular endothelial cells. Immunoprecipitation experiments with antibodies to individual subunits indicated that microvascular cells express at their surface several integrins. These include the alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 laminin/collagen receptors; the alpha 6 beta 1 laminin receptor; the alpha 5 beta 1 and alpha v beta 1 fibronectin receptors; the alpha 6 beta 4 basement membrane receptor; and the alpha v beta 3 and alpha v beta 5 vitronectin receptors. Treatment with bFGF caused a significant increase in the surface expression of the alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha 6 beta 1, alpha 6 beta 4, and alpha v beta 5 integrins. In contrast, the level of expression of the alpha 1 beta 1 and alpha v beta 3 integrins was decreased in bFGF-treated cells. Immunoprecipitation of metabolically labeled cells indicated that bFGF increases the biosynthesis of the alpha 3, alpha 5, alpha 6, beta 4, and beta 5 subunits and decreases the production of the alpha v and beta 3 subunits. These results suggest that bFGF modulates integrin expression by altering the biosynthesis of individual alpha or beta subunits. In accordance with the upregulation of several integrins observed in bFGF-treated cells, these cells adhered better to fibronectin, laminin, vitronectin, and type I collagen than did untreated cells. The largest differences in beta 1 integrin expression occurred approximately 72 h after exposure to bFGF, at a time when the expression of the endothelial cell-to-cell adhesion molecule endoCAM was also significantly upregulated. In contrast, a shorter exposure to bFGF (24-48 h) was required for the maximal induction of plasminogen activator production in the same cells. Taken together, these results show that bFGF causes significant changes in the level of expression and function of several integrins in microvascular endothelial cells.
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PMID:Basic fibroblast growth factor modulates integrin expression in microvascular endothelial cells. 829 94

Several components of blood, e.g. lipids, coagulation and fibrinolytic factors, are thought to be important risk factors in cardiovascular diseases. The aim of this study was to correlate these risk factors and the soluble adhesion proteins, soluble P-selection (sP-selectin) and soluble vascular cell adhesion molecule (sVCAM-1), in healthy men and women as well as to unravel any effects of smoking. One hundred and forty-two fasting men (median age 36 years) including 39 smokers, and 124 women (median age 34 years) including 35 smokers, were tested between 0800 h and 1000 h. Fibrinogen correlated positively with white blood cells (WBC) (r = 0.25), prothrombin fragment 1.2 (F1.2) (r = 0.21), cholesterol (r = 0.27), beta-thromboglobulin (r = 0.29), Factor VII clotting activity (FVIIc) (r = 0.27) (all P < 0.0001), tissue plasminogen activator antigen (t-PAag) (r = 0.22, P < 0.0005), plasminogen activator inhibitor-1 antigen (PAI-1ag) (r= 0.20) and VCAM-1 (r= 0.19) (both P< 0.002). Cholesterol and triacylglycerol (TG) correlated positively with t-PA antigen (t-PAag) (r = 0.36 and r = 0.38), PAI-1 antigen (PAI-1ag) (r = 0.35 and r = 0.50), P-selectin (r = 0.26 and r = 0.27) (all P < 0.0001) and WBC (r = 0.17, P < 0.007 and r = 0.18, P < 0.004). Cholesterol correlated also with F1.2 (r = 0.29) and TG (r= 0.44) (P< 0.0001). In addition to cholesterol and TG, sP-selectin correlated postively with PAI-1ag (r= 0.39), t-PAag (r= 0.27) and WBC (r = 0.25) (all P < 0.0001). Comparing the various test parameters in men and women, it was found that women had significantly higher levels of F 1.2 and high-density lipoprotein-cholesterol than men, whereas men had higher levels of t-PAag, PAI-lag and P-selectin than women. Smoking was associated with a rise in several of the test parameters. It can be concluded that there are correlations between several risk factors. Of particular interest is the positive correlation between sP-selectin and a number of established risk factors of cardiovascular diseases.
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PMID:Haemostatic parameters related to lipids and adhesion molecules. 1063 57

Two types of gastric adenocarcinoma can be distinguished histopathologically: the diffuse and the intestinal type. Molecular pathology supports this theory by showing differences in the genetic pathways of both tumor types. In addition to known pathomorphological factors of prognosis, e.g., depth of tumor infiltration, number of lymph node metastases and resection margins, a few genes have been suggested to have prognostic impact in gastric carcinoma. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1), the cell cycle regulator cyclin E, epidermal growth factor (EGF), the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-catenin. Gene amplification and protein overexpression of the growth factor receptors c-erbB-2 and K-sam may be prognostic factors for intestinal-type and diffuse-type gastric cancer, respectively. In addition, genetic instability is commonly seen. There has long been evidence for a genetic predisposition to gastric cancer by epidemiological studies and case reports. Very recently, germ line mutations of E-cadherin have been identified that are responsible for a dominantly inherited form of diffuse-type gastric cancer and could be used to identify individuals that are at high risk.
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PMID:Gastric adenocarcinoma: pathomorphology and molecular pathology. 1131 54

The investigation of molecular and genetic changes in gastric cancer has brought new insights into the pathogenesis of the disease. Knowledge of the genetic abnormalities and altered molecules could be used for differential diagnosis in case of an unknown primary tumor, allows their evaluation as prognostic factors, and could open novel avenues for more specific clinical interventions. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator and its inhibitor plasminogen activator inhibitor type 1, the cell cycle regulator cyclin E, epidermal growth factor, the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-Catenin. In addition, genetic instability is commonly seen. Gene amplification and protein overexpression of the growth factor receptors c-erbB2 and K-sam may be prognostic factors for intestinal- and diffuse-type gastric cancer, respectively. There has long been evidence for a genetic predisposition to gastric cancer by epidemiological studies and case reports. Very recently, germ line mutations of E-cadherin have been identified that are responsible for a dominantly inherited from of diffuse-type gastric cancer and could be used to identify individuals that are at high risk. The clinical implications of the recent findings for diagnosis, prognosis, therapy, and risk assessment are discussed.
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PMID:The use of molecular biology in diagnosis and prognosis of gastric cancer. 1152 6

The catalog of gene alterations in human cancer grows rapidly. Gastric cancer is no exception and displays gene changes in multiple oncogenes, suppressor genes, and DNA repair genes. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1), the cell-cycle regulator cyclin E, epidermal growth factor (EGF), the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-catenin. In addition, genetic instability is commonly seen. Gene amplification and protein overexpression of the growth factor receptors c-erbB2 and K-sam may be prognostic factors for intestinal-type and diffuse-type gastric cancer, respectively. The clinical implications of some of the recent findings for diagnosis and therapy are discussed.
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PMID:Molecular mechanisms of carcinogenesis in gastric cancer. 1279 Mar 21

Inflammatory processes play a role in the onset of acute cardiovascular events associated with activation of the coagulation system whereas the fibrinolytic system may prevent local thrombus formation. We compared 25 patients with premature coronary artery disease (CAD) (first ST-elevation myocardial infarction, < 55 years old) with 25 sex-matched patients older than 55 years at their first myocardial infarction. Six months after the acute event, patients with late onset of CAD showed a significantly higher increase of tissue-type plasminogen activator activity during venous occlusion compared with patients with premature CAD (P < 0.005). Prothrombin fragment 1+2 was higher in patients with late-onset CAD (P < 0.05), whereas the inflammatory markers C-reactive protein and soluble intercellular cell adhesion molecule-1 were not different in both groups. A multivariate analysis including cardiovascular risk factors showed that the tissue-type plasminogen activator response to venous occlusion was independently associated with patient age at onset of first ST-elevation myocardial infarction. Although in our series high age was associated with a prothrombotic state, a high fibrinolytic capacity might have some beneficial effect and contribute to a delayed onset of adverse cardiovascular events in these patients.
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PMID:Premature compared with late onset of coronary artery disease: young patients show a severe defect in fibrinolytic response to venous occlusion. 1728 34

Several food items of plant origin, and in particular red wine, have been reported to protect from cardiovascular disease (CVD) development, thanks to their polyphenol components. Polyphenols undergo complex metabolic transformation during digestion and intestinal absorption. Here we report a novel model to study the effects of complex food matrices, applied to red wine, on gene expression in cultured primary human endothelial cells that takes into account the polyphenol metabolic transformation. Red wine was administered to human volunteers acting as 'bio-reactors'. Serum (RWS) obtained after 40 min was utilized to enrich endothelial cell culture media. The expression of specific genes involved in cell adhesion (vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) and monocytes chemoattractant protein (MCP-1)) and fibrinolysis (tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2)) was considered as a molecular marker of cell function and related to the effects of RWS. The gene expression profile determined by RWS incubation was significantly different from that observed after the addition of red wine. Data obtained by this approach indicate the importance of taking into account the complex metabolic transformation of polyphenols that occurs during absorption when studying their effect on human health.
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PMID:A novel model to study the biological effects of red wine at the molecular level. 1739 52

Endothelial cells are the main sensors of changes in the biomechanical flow environment and play a pivotal role in vascular homeostasis. An in vitro perfusion model was developed to study the regulatory effect on gene expression by different flow and pressure profiles. Human umbilical vein endothelial cells were grown to confluence inside capillary microslides or silicone tubes. Thereafter, they were exposed to different levels of shear stress or different levels of static or pulsatile pressure. Genes representing various hemostasis functions of the endothelial cells were analyzed. Shear stress was a more effortful stimulus than static or pulsatile tensile stress. Although shear stress affected mRNA expression of all six studied genes (tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor [PAI]-1, Thrombomodulin [TM], urokinase-type plasminogen activator [u-PA], vascular cell adhesion molecule [VCAM-1], and endothelial nitric oxide synthase [eNOS]), none of the genes was found regulated by pressure. Shear stress down-regulated t-PA and VCAM-1 in a dose response-dependent way, and up-regulated TM. u-PA, eNOS, and PAI-1 were up-regulated by shear stress, but there was no obvious dose-response effect for these genes. These findings suggest that shear stress has a more powerful gene regulatory effect on endothelial gene expression than tensile stress. Low shear stress induced a more proatherogenic endothelial surface but preserved t-PA gene expression levels compared to high shear stress.
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PMID:Effects of two complex hemodynamic stimulation profiles on hemostatic genes in a vessel-like environment. 1906 14


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