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)

Insulin resistance is followed by an islet adaptation resulting in a compensating increase in insulin secretion and hyperinsulinemia. The mechanism underlying this increased insulin secretion is not established. We studied whether islet phospholipase A(2) (PLA(2)) contributes by using C57BL/6J mice fed a high-fat diet, since we previously showed that the insulin responses to the two PLA(2)-activating insulin secretagogues carbachol and cholecystokinin (CCK) are enhanced in this model. CCK (100 nM) and carbachol (100 microM) stimulated [(3)H]AA efflux, reflecting PLA(2) activation, both in islets from mice after 12 weeks on high-fat diet and in controls. The efflux increase was more pronounced in islets from high-fat diet-fed mice during both CCK (by 93 +/- 46%; P = 0. 034) and carbachol (by 64 +/- 22%; P = 0.009) stimulation. Also a direct PLA(2) activation by mellitin (2 microg/ml) elicited a potentiated efflux in islets from the insulin-resistant mice (by 361 +/- 107%; P = 0.002). The results suggest that exaggerated non-glucose-induced PLA(2) activation contributes to the islet compensation in insulin resistance.
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PMID:Islet phospholipase A(2) activation is potentiated in insulin resistant mice. 1083 48

Obesity is associated with an increased risk of atherosclerotic coronary artery disease. Cytokines and oxygen-centered free radicals implicated in insulin resistance stimulate adipocyte and endothelial production of plasminogen activator inhibitor type-1 (PAI-1), the primary physiologic inhibitor of fibrinolysis, in vitro. In obese hyperinsulinemic animal models simulating insulin resistance, plasma PAI-1 activity is increased. As the cardiovascular risk profile in specific populations may differ, endogenous fibrinolysis in lean and obese subjects was characterized and the mechanisms underlying differences were identified. Obese subjects (body mass index > 26) exhibited increased blood levels of PAI-1 antigen compared with corresponding values in lean controls. Blood t-PA antigen differed as well, yet basal endogenous fibrinolytic activity was decreased because of the high PAI-1 activity. The increased PAI-1 level was associated with increased levels of immunoreactive insulin (IRI). In diabetic subjects, coronary atherectomy specimens exhibited strong positive PAI-1 immunostaining, suggesting that in the diabetic vascular wall, intramural fibrinolytic activity is diminished. Using the oral glucose tolerance test, patients with significant stenosis confirmed by coronary angiography exhibited increased sigmaIRI, sigmaBS, sigmaIRI/sigmaBS, and IRI at 120 min compared to subjects without significant stenosis. IRI at 120 min was closely correlated with the severity of coronary artery disease. These results indicate that adipocyte overproduction of PAI-1 by insulin induces decreased endogenous fibrinolytic activity and contributes to the accelerated coronary macroangiopathy in hyperinsulinemic obese subjects with insulin resistance.
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PMID:Diminished fibrinolysis and thrombosis: clinical implications for accelerated atherosclerosis. 1085 61

We investigated the age-related changes in blood coagulation, fibrinolysis, and platelet aggregation in male WBN/Kob rats, animals that exhibit spontaneously diabetes mellitus at more than 6 months of age. The rats aged 6 months or more showed significant hyperglycemia, hypoinsulinemia, and hyperlipidemia. As changes in coagulation parameters, the data indicated significant increases in factors II, V, VII, VIII, IX, X, and XII activities; a significant decrease in antithrombin III activity in rats more than 6 months of age; significant increases in fibrinogen level and factor XI activity; and significant decreases in prothrombin time and activated partial thromboplastin time in those more than 9 months of age. As changes in fibrinolytic parameters, the animals showed significant decreases in plasminogen and tissue-type plasminogen activator, and significant increases in alpha2-plasmin inhibitor and plasminogen activator inhibitor at more than 6 months of age. In addition, there were significant correlations between the plasma levels of coagulation/fibrinolytic markers and the 4-hour fasting glucose or lipids. Furthermore, they displayed significant increases in ADP- or collagen-induced platelet aggregation and in cholesterol/phospholipid molar ratio in platelets at more than 9 months of age. The increase in cholesterol/phospholipid ratio may be responsible for hyperaggregation of platelets in diabetic animals. These findings suggest that WBN/Kob rats are suitable for research on blood coagulation abnormalities in diabetes. However, further studies are needed to clarify the details of the mechanisms involved.
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PMID:Age-related changes in coagulation, fibrinolysis, and platelet aggregation in male WBN/Kob rats. 1089 50

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid, on the development of diabetes, insulin resistance, and abnormalities of blood coagulation in male WBN/Kob rats, a model of spontaneous diabetes mellitus. After 8-month oral EPA-E treatment, the incidence of diabetes at a dose of 0.1, 0.3, and 1.0 g/kg was 92%, 50%, and 17%, respectively. Its incidence was suppressed significantly and dose-dependently at a dose of 0.3 g/kg or higher compared with the rate (100%) for the vehicle control. Additionally, EPA-E significantly and dose-dependently decreased the elevation of plasma glucose after an oral glucose load and increased the glucose infusion rate (GIR) during the euglycemic insulin-glucose clamp test at a dose of 0.1 g/kg or higher compared with the vehicle control. Furthermore, EPA-E significantly and dose-dependently ameliorated coagulation-related parameters, including the prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen level, and factor II, V, VII, VIII, IX, X, XI, and XII and antithrombin III (AT III) activities, and fibrinolysis-related parameters, including plasminogen, tissue-type plasminogen activator (t-PA), alpha2-plasmin inhibitor (alpha2-PI), and plasminogen activator inhibitor (PAI), and also suppressed ADP- or collagen-induced platelet aggregation and the cholesterol to phospholipid (C/P) molar ratio in platelet membranes at a dose of 0.1 g/kg or higher. These data demonstrate multiple actions of the product in these laboratory animals. These include changes in platelet function, coagulation/fibrinolysis factors, plasma immunoreactive insulin secretion, and plasma glucose/insulin resistance.
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PMID:Long-term administration of highly purified eicosapentaenoic acid ethyl ester prevents diabetes and abnormalities of blood coagulation in male WBN/Kob rats. 1091 4

Fed-batch operation for the production of t-PA using Chinese Hamster Ovary (CHO) cells was optimized using serial and parallel experimentation. The feed, an isotonic concentrate, was improved to obtain 2- to 2.5-fold increases in integrated viable cell days versus batch. With a low glucose inoculum train, the viability index was further increased up to 4.5-fold. Hydrolysates were substituted for the amino acid portion of the concentrate with no significant change in fed-batch results. The concentrate addition rate was based on a constant 4 pmol/cell.day glucose uptake rate that maintained a relatively constant glucose concentration (approximately 3 mM). Increased viable cell indices did not lead to concomitant increases in t-PA concentrations compared to batch. The fed-batch concentrate and feeding strategy were shown to be effective in hybridoma culture, where a 4-fold increase in viable cell index yielded a 4-fold increase in antibody concentration. The half-life of t-PA decreased from 43 to 15 days with decreasing cell viability (from 92% to 71%), but this was not sufficient to explain the apparent t-PA threshold. Instead, the CHO results were explained by a reduction in t-PA production at higher extracellular t-PA concentrations that limited the fed-batch maximum at 35 mg/L for the cell line investigated. Analysis of both the total and t-PA mRNA levels revealed no response to increasing extracellular t-PA concentrations upon exogenous additions. Instead, intracellular t-PA levels were increased, revealing a possible secretory pathway limitation. A new reactor configuration was developed using an acoustic filter to retain the cells in the reactor while an ultrafiltration module stripped t-PA from the clarified medium before the permeate was returned to the reactor. By adding this harvesting step, the t-PA fed-batch production was increased over 2-fold, up to a yield of 80 mg/L.
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PMID:Increased t-PA yields using ultrafiltration of an inhibitory product from CHO fed-batch culture. 1102 71

The aim of this work was to study the influence of the concentration and molecular weight of poly(DL-lactide) (PLA) on the characteristics and in vivo biological activity of protein-loaded microspheres. At the same time, an attempt was made to achieve further optimization of the formulation. In the study, insulin was chosen as a model of protein drugs. Nine formulations of injectable insulin-loaded PLA microspheres were prepared using an emulsification and solvent evaporation process according to a factorial design. The trapping efficiency, drug loading, and the drop percentages of blood glucose levels at 24 hr and 72 hr in mice were used to evaluate the formulations. The results showed that PLA molecular weight and, especially, PLA concentration exerted influences on the characteristics and in vivo biological activity of insulin-loaded microspheres. The drug-trapping efficiency increased with the increase of the polymer concentration. The drug loading decreased with the increase of the polymer concentration and was not obviously affected by PLA molecular weight. The drop percentage of blood glucose level at 24 hr increased with the increase of polymer concentration and molecular weight. At 72 hr, the drop percentages of blood glucose levels were slightly increased with the increase of PLA concentration and then significantly decreased after the PLA concentration was above 150 mg/ml. An optimized formulation was prepared with PLA-10k at a concentration of 200 mg/ml. The experimental values of the response variables were close to the predicted values. The results suggest that the in vivo release behavior should be taken into consideration in the design of protein-loaded PLA microspheres.
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PMID:Preparation and evaluation of insulin-loaded polylactide microspheres using factorial design. 1114 33

We studied i) whether short-term weight loss alters plasminogen activator inhibitor-1 antigen (PAI-1-Ag) and tissue-type plasminogen activator antigen (tPA-Ag) in obese children, and ii) whether changes in body composition and/or abdominal adiposity are responsible for changes in PAI-1 and tPA-Ag. 20 obese boys (mean age 11.9 yr) and 40 obese girls (mean age 12 yr) were studied before and after three weeks of low-caloric diet and physical activity. Body composition was assessed by means of bioelectrical impedance, and the waist-to-hip ratio (WHR) was measured. Blood samples were determined for insulin, glucose, triglycerides, PAI-1-Ag, tPA-Ag, and the fasting insulin resistance index (FIRI) was calculated. Boys had a greater WHR, higher levels of glucose, and a slightly greater FIRI than girls. Estimates of adiposity, insulin, and triglycerides were correlated with PAI-1 and tPA-Ag. WHR was significantly correlated with fibrinolytic parameters only in girls. Insulin and tPA-Ag contributed to PAI-1 (adj. R2 = 0.36, p <0.0001), whereas percentage fat mass and triglycerides contributed to tPA-Ag (adj. R2 = 0.469, p <0.0001). The weight loss program significantly reduced adiposity, abdominal adiposity, and lowered fibrinolytic and metabolic parameters. Initial levels of PAI-1 and changes in body mass contributed to the fall in PAI-1 (adj. R2 = 0.18, p = 0.0016) and initial levels of tPA-Ag contributed significantly to changes in tPA-Ag (adj. R2 = 0.57, p <0.0001). The results suggest that changes in fibrinolytic parameters are associated with the loss in body mass but can occur independently of a concomitant reduction in fatness. Although initial PAI-1 and tPA-Ag predict the changes of these fibrinolytic parameters, the results do not exclude the possibility that the improvement in metabolic state and changes in unmeasured parameters related to physical activity and low-caloric diet could have influenced our findings.
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PMID:The influence of weight loss on fibrinolytic and metabolic parameters in obese children and adolescents. 1122 Jul 10

A characteristic feature of patients with heterozygous familial hypercholesterolemia (FH) is the premature occurrence of coronary artery disease because of elevated LDL cholesterol levels. Hyperinsulinemia and insulin resistance, important characteristics of the cardiovascular dysmetabolic syndrome (CDS), were found to be associated with coronary artery disease in FH subjects, as in the general population. We investigated whether hypofibrinolysis, as part of CDS, is independently associated with symptomatic coronary artery disease in these high-risk patients. Clinical examination (body mass index, waist circumference, blood pressure) and blood analysis (plasma tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PAI-1) antigen and activity, fibrinogen, serum lipids and lipoproteins, fasting glucose and insulin) were carried out in 39 male patients with heterozygous FH (aged 46.6 +/- 8.8 years). Insulin resistance was calculated using the homeostasis model assessment (HOMA) mathematical model. Thirteen of the patients had suffered a myocardial infarction (MI) 5 to 8 years ago (aged 47.8 +/- 6.1 years) and 26 were free of coronary artery disease (aged 45.9 +/- 9.9 years). There was no difference in total and LDL cholesterol between the two groups. Patients with previous myocardial infarction had significantly higher levels of insulin, insulin resistance, triglycerides, t-PA antigen, PAI-1 antigen and activity, and significantly lower values of HDL cholesterol. Other widely recognised risk factors for coronary artery disease, such as smoking, systolic and diastolic blood pressure, obesity and age, did not differ significantly between the groups. In the logistic regression model, PAI-1 antigen, as a marker of hypofibrinolysis, emerged as an independent risk factor for the occurrence of myocardial infarction (odds ratio 1.55; p = 0.02). In summary our results suggest that the impairment of fibrinolytic activity resulting from elevated levels of PAI-1 antigen and activity and t-PA antigen is an independent variable in CDS associated with the premature occurrence of myocardial infarction in male patients with FH.
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PMID:Fibrinolytic parameters and insulin resistance in young survivors of myocardial infarction with heterozygous familial hypercholesterolemia. 1125 36

Adiposity in childhood is often associated with metabolic abnormalities and accompanied by a dysregulation of the coagulation and fibrinolytic systems. We studied the interrelationship of metabolic and hemostatic parameters and explored their relationship with measures of adiposity and fat distribution in obese children. In 34 obese boys (mean age, 11.7 years) and 57 obese girls (12.1 years), blood samples were determined for insulin, glucose, triglycerides, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator-antigen (tPA-Ag). Body composition was assessed by means of impedance. Waist (Wc) and hip circumference were measured. The thickness of subcutaneous adipose tissue-layers (SAT-layers) was measured at 15 different body sites (from 1-neck to 15-calf) by means of the optical device, Lipometer. Overall subcutaneous fatness (SAT) was calculated and SAT-distribution was estimated by means of factor analysis. Significant correlations were found between different measures of adiposity and Wc with metabolic parameters. Fibrinogen was mainly associated with upper body subcutaneous fatness (factor 1) in boys. In girls, hemostatic parameters were associated with nearly all measures of adiposity and also with factor 1 and SAT. Regression analysis showed that factor 1 together with PAI-1 (both P <.0001) contribute to fibrinogen (adjusted [adj], R(2) =.30). PAI-1 together with trigylcerides (both P <.0001) and age (P <.04) were main determinants for tPA-Ag (adj, R(2) =.41). tPA-Ag (P <.0001) together with glucose (P <.001, negative slope), fibrinogen (P <.001, negative slope), and percentage fat mass (%FM) (P <.01) contributed to PAI-1 (adj, R(2) =.54). These results favor the concept of an interrelationship between metabolic and hemostatic parameters resulting from increased adiposity, perhaps influenced by pubertal development of children. Although upper body subcutaneous fatness was found to be a main correlate of metabolic and hemostatic parameters, it remains to be investigated whether this type of subcutaneous fat distribution is involved in the expression of metabolic and hemostatic risk factors and participates in the dysregulation of the hemostatic system in the state of childhood obesity.
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PMID:Interrelationship between estimates of adiposity and body fat distribution with metabolic and hemostatic parameters in obese children. 1139 45

Effect of tissue-type plasminogen activator (tPA) on oxygen-glucose deprivation (OGD) was studied in cultured cortical neurons prepared from tPA gene knockout (tPA-KO) and wild-type (Wt) mice. Three hours of OGD induced 45% and 23% of neuronal death in Wt and tPA-KO mice, respectively. Neuronal death in tPA-KO mice was increased to 42% by additional tPA. Six hours of OGD induced 80% and 40% of neuronal death in Wt and tPA-KO mice, respectively, whereas the addition of tPA increased to 62% in tPA-KO mice. These results suggest that tPA is directly involved in the process of neuronal death induced by ischemia-mimic stress without involving vascular or circulatory components.
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PMID:Tissue-type plasminogen activator is involved in the process of neuronal death induced by oxygen-glucose deprivation in culture. 1148 32


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