Plasminogen activator , production

Ziche M, Parenti A, Ledda F, Dell Era P, Granger HJ, Maggi CA, et al. Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Circ Res 1997 80 845-852. 

VI. Van Aswegen, C. H., The effect of essential fatty acids on growth and urokinase-type plasminogen activator production on human prostate DU-145 cells. Prostaglandins Leuk. Essent. Fatty Acids 55, 173-177 (1996). 

Wang, W. et al, Effects of S-dC28 on vascular smooth muscle cell adhesion and plasminogen activator production, Antisense Nucleic Acid Drug Dev., 7,101,1997. 

As of early 1992, the market for ceU culture-derived products approached 1 billion per year. The market is expected to grow substantially throughout the 1990s. CeU culture products include erythropoietin, 1991 sales of approximately 400 million, for the treatment of anemia associated with kidney dialysis, and tissue plasminogen activator, 1991 sales approximately 200 million, for treating heart attack victims with blocked arteries (see Cardiovascularagents). 

Plasmin, a serine protease (83 kDa), can degrade fibrin, and its degradation products (FDP) are soluble in the blood. Plasmin is formed from its proenzyme (zymogen, precursor), plasminogen (92 kDa), synthesized by the liver, and secreted into the blood circulation, where its concentration is 2 pM. Plasminogen is converted to plasmin by plasminogen activators (serine proteases). 

There are a number of disorders, including cancer and shock, in which the concentrations of plasminogen activators increase. In addition, the antiplasmin activities contributed by tti-antitrypsin and a2-antiplas-min may be impaired in diseases such as cirrhosis. Since certain bacterial products, such as streptokinase, are capable of activating plasminogen, they may be responsible for the diffuse hemotthage sometimes observed in patients with disseminated bacterial infections. 

Recent applications of HPAEC-PAD are many and varied. A representative list includes quantitation of polyglucose metabolites in plasma of dialysis patients,148 analysis of heat-treated milk,149 carbohydrate content in lipopolysaccharides,150 phosphorylated sugars in tissue samples,151 composition of soybean meal,152 carbohydrate composition of recombinant modified tissue plasminogen activator,153 analysis of cyclization products from an enzyme reaction,154 carbohydrate content of glycoconjugate vaccines,155 and monitoring of patients with rheumatoid arthritis.156... 

The procoagulant factors produced by endothelial cells are the coagulation factors von Willebrand factor (WF), F-V, F-VIII, tissue factor (TF), and plasminogen activator inhibitor (PAI), which blocks the activators u-PA and t-PA and counteracts fibrinolysis (G21, FI6). It has been shown that under the influence of complement activation (C9), in response to endotoxin in vitro (C24), in experimental E. coli sepsis in baboons (D30), and after stimulation with TNF (Al, N6), endothelial cells up-regulate the expression of TF, down-regulate TM and inhibit the production of t-PA and PAF. Thus, the balance may shift in the procoagulant direction with a large excess of PAI-1. 

N2. Nakashima, Y., Sueishi, K., and Tanaka, K Thrombin enhances production and release of tissue plasminogen activator from bovine venous endothelial cells. Fibrinolysis 2, 227-234 (1988). 

The first large-scale process to circumvent these limitations was one developed by Genentech, Inc. (South San Francisco, CA) for production of recombinant tissue plasminogen activator (tPA). This protein dissolves blood clots and can be used to treat heart attacks and strokes. This process was developed in the mid-1980s, resulting in final product licensure in 1987. The process required both regulatory and technical breakthroughs. 

Mammalian cell suspension cultures are the preferred choice for large-scale recombinant protein production in stirred-tank bioreactors. The most widely used systems are Chinese hamster ovary (CHO) cells and the murine myeloma fines NSO and SP2/0. In half of the biological license approvals from 1996-2000, CHO cells were used for the production of monoclonal antibodies and other recombinant glycosylated proteins, including tPA (tissue plasminogen activator) and an IgGl fusion with the tumor necrosis factor (TNF) receptor, the latter marketed as Enbrel [7]. 

Tissue paper products, 13 129-130 Tissue plasminogen activator (t-PA) bioseparation from mammalian cell culture, 3 821-826 peptide map, 3 841, 842 selling price, 3 817t Tissue reactions, to sutures, 24 218 Tissue-type plasminogen activator (t-PA) and hemostatic system, 4 89 human, use as thrombolytic agent,... 

The mechanisms of the influence of the SNS on the induction of CD8+ Tregs are likely directed towards both the activation and function of these cells (fig. 2). Sympathetic neurons are a source of (i) norepinephrine that has strong immunoregulatory effects [35] including the proliferation of liver NKT cells necessary for the initiation of contact sensitivity reactions (ii) immunomodulatory NPY [38] that may promote the production of IFN-y necessary for the function of CD8+ suppressor T cells (see below), and (hi) tissue plasminogen activator (t-PA) [41] that converts plasminogen to plasmin that in turn is an activator of immunosuppressive TGF-(3 [42]. 

Along with the production of insulin, many other medical uses have been achieved for recombinant DNA. This includes the production of erythropoetin, a hormone used to stimulate production of red blood cells in anemic people tissue plasminogen activator, an enzyme that dissolves blood clots in heart attack victims and antihemophilic human factor VIII, used to prevent and control bleeding for hemophiliacs. These three important genetically engineered proteins were all cloned in hamster cell cultures. 

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