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)

Acute myocardial infarction (AMI) is more frequent in winter months than in summer months. The aetiologic mechanisms underlying this seasonal pattern are poorly understood. We investigate whether seasonal variation of metabolic and haemostatic coronary risk factors exists, and whether this variation is more pronounced in subjects with coronary artery disease (CAD). In 82 subjects (47 free of clinical signs of CAD and in 35 survivors of AMI), measurements of body mass index (BMI), lipoproteins, glucose, insulin, plasminogen activator inhibitor-1, tissue-type plasminogen activator (t-PA), euglobulin clot lysis time, fibrinogen, and platelet count were performed twice in the cold months (December and March) and twice in the warm months (June and September). Significantly higher BMI (26.8 versus 26.2 kg/m2, P < 0.01), glucose (5.5 versus 5.1 mmol/l, P < 0.01), total cholesterol (5.61 versus 5.32 mmol/l, P < 0.05), low-density lipoprotein cholesterol (3.63 versus 3.34 mmol/l, P < 0.05), triglycerides (1.79 versus 1.61 mmol/l, P < 0.01), Lp(a) (270.7 versus 237.5 mg/l, P < 0.01), fibrinogen level (3.50 versus 2.95 g/l, P < 0.00001), platelet count (212 x 10(9) versus 173 x 10(9)/l, P < 0.01) and significantly lower high-density lipoprotein cholesterol level (1.22 versus 1.28 mmol/l, P < 0.05) were observed in the cold months compared with the warm months. Significant seasonal variation of t-PA activity (1.19 versus 0.87 IU/ml, P = 0.015) and t-PA antigen (8.5 versus 7.3 ng/ml, P = 0.05) was demonstrated only in subjects with CAD. Clustering of peak values of several metabolic and haemostatic coronary risk factors was observed in winter months. This variation might be of aetiopathogenetic importance for the seasonal pattern of acute myocardial infarction.
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PMID:Seasonal variation of some metabolic and haemostatic risk factors in subjects with and without coronary artery disease. 1150 78

A protease-deficient strain of Aspergillus niger has been used as a host for the production of human tissue plasminogen activator (t-PA). In defined medium, up to 0.07 mg t-PA (g biomass)(-1) was produced in batch and fed-batch cultures and production was increased two- to threefold in two-phase batch cultures in which additional glucose was provided as a single pulse at the end of the first batch growth phase. Production was increased [up to 1.9 mg t-PA (g biomass)(-1)] by the addition of soy peptone to the defined medium. The rate of t-PA production in batch cultures supplemented with soy peptone (0.2 to 0.6 mg t-PA L(-1) h(-1)) was comparable to rates observed previously in high-producing mammalian or insect cell cultures. In glucose-limited chemostat culture supplemented with soy peptone, t-PA was produced at a rate of 0.7 mg t-PA L(-1) h(-1). Expression of t-PA in A. niger resulted in increased expression of genes (bipA, pdiA, and cypB) involved in the unfolded protein response (UPR). However, when cypB was overexpressed in a t-PA-producing strain, t-PA production was not increased. The t-PA produced in A. niger was cleaved into two chains of similar molecular weight to two-chain human melanoma t-PA. The two chains appeared to be stable for at least 16 h in culture supernatant of the host strain. However, in general, <1% of the t-PA produced in A. niger was active, and active t-PA disappeared from the culture supernatant during the stationary phase of batch cultures, suggesting that the two-chain t-PA may have been incorrectly processed or that initial proteolytic cleavage occurred within the proteolytic domain of the protein. Total t-PA (detected by enzyme-linked immunoassay) also eventually disappeared from culture supernatants, confirming significant extracellular proteolytic activity, even though the host strain was protease-deficient.
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PMID:Production of tissue plasminogen activator (t-PA) in Aspergillus niger. 1150 86

An association between an increase in plasminogen activator inhibitor type 1 (PAI-1) and obesity, and also between elevated levels of PAI-1 and the presence of PAI-1 promoter 4G allele has been described in adults and can contribute to increased risk of cardiovascular disease. It has also been suggested that in adults a decrease in adiposity has beneficial effects on the haemostatic system. However, less information is available regarding adiposity and fibrinolysis in children. The aim of the present study is to evaluate the effect of weight loss and the influence of the PAI-1 promoter 4G/5G genotype on the fibrinolytic system and lipid parameters in obese children. The clinical groups included 102 obese children and 105 controls of similar age and sex distribution. A significant decrease in fibrinolytic activity due to a significant increase in PAI-1 antigen and activity levels was observed in the obese children in comparison with the control group. In obese children, no significant differences in PAI-1 levels between the PAI-1 4G/5G genotypes were obtained. A significant correlation was observed between PAI-1 antigenic and functional levels and body mass index (BMI), as well as between PAI-1 levels and both triglyceride and insulin levels. No correlation between PAI-1 levels and either cholesterol or glucose levels was observed. After a three-month period of treatment to reduce weight, an increase in fibrinolytic activity due to a decrease in PAI- levels was observed in the obese children who had reduced their BMI in comparison with the group of obese children who did not show a decrease in their BMI. No significant differences between the two groups with respect to the variations in tissue type plasminogen activator and fibrinogen levels were obtained after three months of intervention to reduce weight. A significant correlation was observed between variations in BMI and variations in PAI-1 levels, and a significant inverse correlation was also observed between previous PAI-1 levels and variation in PAI-1 levels. Therefore, the largest decrease in PAI-1 levels was observed in the obese children with the highest previous PAI-1 levels. In conclusion, a decrease in BMI in obese children shows a favourable effect on the fibrinolytic system due to a decrease in PAI-1 levels. However, no influence of 4G/5G genotype on PAI-1 levels was observed.
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PMID:Plasma PAI-1 levels in obese children--effect of weight loss and influence of PAI-1 promoter 4G/5G genotype. 1152 17

Perfusion cultures of CHO cells producing t-PA were performed using acoustic filter cell retention. A robust off-line glucose analysis and predictive control protocol was developed to maintain the process within approximately 0.5 mM of the glucose set point, without the need for a more fallible on-line sensor. Glucose usage (the difference between the inlet and reactor glucose concentrations) provided an easily measured indicator of overall medium utilization for mapping acceptable ranges of operation, including the edge of failure. Earlier onset of perfusion with a ramping glucose set point (1.5 mM/d) resulted in improved growth and consistency during the perfusion culture start-up. At steady state, the t-PA concentration variability increased gradually with increasing glucose usage up to approximately 22 mM, then up to 24 mM the variability increased threefold. Peak t-PA concentrations of over 90 mg/L were obtained by controlling at a glucose usage of approximately 24 mM, but these t-PA levels were not sustainable for more than 3 days. A consistent t-PA concentration of 40 mg/L was obtained at a glucose usage of 21.5 mM.
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PMID:Glucose-based optimization of CHO-cell perfusion cultures. 1153 49

Cell proliferation, tissue plasminogen activator (t-PA) production and metabolic changes of Hamster Kidney cells (HaK) grown on microcarriers in an automatic Dynamic Cell Culture System (DCCS) were determined on the first International Microgravity Mission (IML-1) Spacelab (22-30 January 1992). The DCCS was designed for two cell culture chambers (volume: 200 microliters each), one operating as a hatch system, the other as a perfusion system. Medium exchange was achieved with an osmotic pump (flow rate 1 microliter h-1). Two major items were investigated: the biological performance of the DCCS in space and the effect of microgravity on HaK cells. The results obtained demonstrated that (1) the DCCS can be used for biological experiments on long term Spacelab missions. In fact, higher cell densities and higher concentration of glucose but lower concentration of lactate in the perfusion chambers than in the batch chambers were measured. The concentration of t-PA, glutamine and ammonia was similar in all chambers. (2) Microgravity had no effect on cell growth and metabolism of HaK cells.
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PMID:Cultivation of hamster kidney cells in a dynamic cell culture system in space (Spacelab IML-1 Mission). 1154 89

Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic nerve endings during the preabsorptive and absorptive phases of feeding. In beta-cells, ACh binds to muscarinic M(3) receptors and exerts complex effects, which culminate in an increase of glucose (nutrient)-induced insulin secretion. Activation of PLC generates diacylglycerol. Activation of PLA(2) produces arachidonic acid and lysophosphatidylcholine. These phospholipid-derived messengers, particularly diacylglycerol, activate PKC, thereby increasing the efficiency of free cytosolic Ca(2+) concentration ([Ca(2+)](c)) on exocytosis of insulin granules. IP3, also produced by PLC, causes a rapid elevation of [Ca(2+)](c) by mobilizing Ca(2+) from the endoplasmic reticulum; the resulting fall in Ca(2+) in the organelle produces a small capacitative Ca(2+) entry. ACh also depolarizes the plasma membrane of beta-cells by a Na(+)- dependent mechanism. When the plasma membrane is already depolarized by secretagogues such as glucose, this additional depolarization induces a sustained increase in [Ca(2+)](c). Surprisingly, ACh can also inhibit voltage-dependent Ca(2+) channels and stimulate Ca(2+) efflux when [Ca(2+)](c) is elevated. However, under physiological conditions, the net effect of ACh on [Ca(2+)](c) is always positive. The insulinotropic effect of ACh results from two mechanisms: one involves a rise in [Ca(2+)](c) and the other involves a marked, PKC-mediated increase in the efficiency of Ca(2+) on exocytosis. The paper also discusses the mechanisms explaining the glucose dependence of the effects of ACh on insulin release.
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PMID:Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. 1158 41

The effect of glutamine replacement by glutamate and the balance between glutamate and glucose metabolism on the redistribution of t-PA-producing recombinant CHO cells metabolism is studied in a series of glucose shift down and shift up experiments in continuous culture. These experiments reveal the existence of multiple steady states, and experimental data are used to perform metabolic flux analysis to gain a better insight into cellular metabolism and its redistribution. Regulation of glucose feed rate promotes a higher efficiency of glucose and nitrogen source utilization, with lower production of metabolic byproducts, but this reduces t-PA specific production rate. This reduction under glucose limitation can be attributed to the fact that the cells are forced to efficiently utilize the carbon and energy source for growth, impairing the production of dispensable metabolites. It is, therefore, the combination of growth rate and carbon and energy source availability that determines the level of t-PA production in continuous culture.
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PMID:Analysis of CHO cells metabolic redistribution in a glutamate-based defined medium in continuous culture. 1173 37

The development of a strategy for the culture of Chinese hamster ovary (CHO) cells producing tissue plasminogen activator (t-PA) is investigated. This strategy is based on the replacement of the main carbon source, glucose, by another compound that is slowly metabolizable, particularly galactose. The introduction of this change allows for acute change in cell behavior at various levels. Cell growth is stopped after this nutrient shift, and the cells can be kept in long-duration culture at a low growth rate and high viability as compared with a culture strategy based solely on glucose utilization. Moreover, the capability of cells to produce recombinant proteins (t-PA in this work) can be maintained over the entire period of galactose feeding. From the metabolic point of view, use of a slowly metabolizable carbon source (galactose) introduces important changes in the production of lactate, ammonia, and some amino acids. The use of this metabolic shift enables the generation of biphasic processes, with a first phase with cell growth on glucose and a second stationary phase on galactose, which is particularly suited to perfusion systems.
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PMID:Decoupling cell growth and product formation in Chinese hamster ovary cells through metabolic control. 1174 63

Hypoxia is a common denominator of many vascular disorders, especially those associated with ischemia. To study the effect of oxygen depletion on endothelium, we developed an in vitro model of hypoxia on human umbilical vein endothelial cells (HUVEC). Hypoxia strongly activates HUVEC, which then synthesize large amounts of prostaglandins and platelet-activating factor. The first step of this activation is a decrease in ATP content of the cells, followed by an increase in the cytosolic calcium concentration ([Ca(2+)](i)) which then activates the phospholipase A(2) (PLA(2)). The link between the decrease in ATP and the increase in [Ca(2+)](i) was not known and is investigated in this work. We first showed that the presence of extracellular Na(+) was necessary to observe the hypoxia-induced increase in [Ca(2+)](i) and the activation of PLA(2). This increase was not due to the release of Ca(2+) from intracellular stores, since thapsigargin did not inhibit this process. The Na(+)/Ca(2+) exchanger was involved since dichlorobenzamil inhibited the [Ca(2+)](i) and the PLA(2) activation. The glycolysis was activated, but the intracellular pH (pH(i)) in hypoxic cells did not differ from control cells. Finally, the hypoxia-induced increase in [Ca(2+)](i) and PLA(2) activation were inhibited by phlorizin, an inhibitor of the Na(+)-glucose cotransport. The proposed biochemical mechanism occurring under hypoxia is the following: glycolysis is first activated due to a requirement for ATP, leading to an influx of Na(+) through the activated Na(+)-glucose cotransport followed by the activation of the Na(+)/Ca(2+) exchanger, resulting in a net influx of Ca(2+).
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PMID:Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: role of the Na(+)-glucose cotransporter. 1174 21

In both obese and nonobese women, polycystic ovary syndrome (PCOS) is essentially a disorder of hyperinsulinemic insulin resistance, and it may be heralded by precocious pubarche (PP; appearance of pubic hair in girls aged <8 y). The risk of progression from PP to PCOS is related to low birth weight, but there are no early biochemical markers of this risk. As increased plasminogen activator-inhibitor type 1 (PAI-1) activity (act) is an early marker of cardiovascular risk in PCOS, we have sought abnormalities in young girls with PP. In 33 young PP girls (age range 6-11 y), PAI-1-act was increased (mean + SEM: 15.6 +/- 1.5 IU/mL) compared with age-, sex-, and pubertal stage-matched controls (n = 13, 10.7 +/- 1.9, p < 0.05). PAI-1-act levels were inversely related to birth weight SD score (r = -0.33, p < 0.05), and PAI-1-act levels were therefore higher in PP girls with low birth weights (n = 14, 19.5 +/- 2.5 IU/mL) than normal birth weights (n = 19, 12.8 +/- 1.5, p < 0.01). During longitudinal observation in 10 PP girls (mean time interval 2.7 y), PAI-1-act levels in early puberty were positively related to postmenarcheal insulin levels (mean serum insulin SDS postoral glucose, r = 0.65, p < 0.05), and showed a similar relationship to postmenarcheal testosterone levels (r = 0.61, p = 0.06). Together with low birth weight, increased plasma PAI-1-act levels in early pubertal PP girls may indicate those girls with greater risk of developing hyperinsulinemic-hyperandrogenism features of PCOS.
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PMID:Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome? 1180 21


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