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Enzyme Catalysis
Published in Harvey W. Blanch, Douglas S. Clark, Biochemical Engineering, 1997
Harvey W. Blanch, Douglas S. Clark
The removal of blood clots (thrombi) is important in the treatment of several diseases. When a thrombus forms, blood flow in vessels is restricted and may lead to death of part of the heart muscle in the case of thrombi in the coronary artery (myocardial infarction), or strokes in the case of blood flow to the brain. Removal of clots is part of the wound healing process and is mediated by the serine protease plasmin, which is derived from its zymogen plasminogen. The activation of plasminogen is primarily a result of tissue plasminogen activator (tPA). Human tPA is a serine protease that is manufactured in murine cells, and it has found wide use in treatment of heart attacks.
Protein Secretion Systems in Microbial and Mammalian Cells
Published in Juan A. Asenjo, Separation Processes in Biotechnology, 2020
Human plasminogen activators are potential therapeutic agents for the treatment of thrombi in conditions such as myocardial infarct, pulmonary embolism, and deep vein thrombosis. Two types of plasminogen activator have been characterized extensively: a prourokinase or urinary type (uPA), and a tissue type (tPA). Transformed human cell lines are available that secrete uPA (Kohno et al., 1984) and tPA (Rijken and Collen, 1981); however, to supply the amounts projected for clinical use, it appears necessary to build cell lines that secrete higher levels of these proteins.
Fibrinolytic Enzymes for Thrombolytic Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Swaroop S. Kumar, Sabu Abdulhameed
Whenever an injury or trauma occurs, the blood flow through the vessels should be immediately arrested to prevent the loss. This is achieved by hemostasis, characterized by equilibrium between blood coagulation and fibrinolysis. The hemostatic system includes primary hemostasis (platelet plug formation), secondary hemostasis (coagulation), and tertiary hemostasis (fibrinolysis). Primary hemostasis initiates through vascular spasm or local vaso-constriction occurring immediately after injury and thereby reducing the blood flow through the vessel followed by platelet aggregation to form platelet plug. Coagulation factors normally exist as pro-enzymes and circulate through blood stream along with pro-coagulant and anticoagulant factors such as von Willebrand factor (vWF), tissue factor, platelet activating factors, tissue factor pathway inhibitor, endothelium-derived relaxing factor or nitric oxide (NO), tissue plasminogen activator (t-PA) and prostacyclin (Lane et al., 2005; Pearson, 1994). Once trauma occurs, the above factors get activated. Coagulation or secondary hemostasis usually referred as coagulation cascade initiates a series of enzyme reactions which consists of intrinsic and extrinsic pathways (Macfarlane, 1964). Chief coagulating enzyme thrombin, formed from Factor Xa initiates fibrin polymerization and thereby blood clotting (Kovalenko et al., 2017). However, removal of clot after wound healing is also important in order to ensure the proper blood circulation. Tertiary hemostasis is characterized by the dissolution of clot or fibrinolysis controlled by fibrinolytic system. Plasmin is the enzyme that degrades clot, and it is formed form plasminogen with the aid of plasminogen activators. However, this is regulated by plasminogen activator inhibitor 1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI), α2-antiplasmin and α2-macroglobulin, etc. (Stassen et al., 2004).
Fabrication of neuroprotective silk-sericin hydrogel: potential neuronal carrier for the treatment and care of ischemic stroke
Published in Journal of Experimental Nanoscience, 2022
Stroke is the world's fifth-most prominent cause of mortality, behind heart disease, cancer and respiratory diseases [1–3]. Nearly 75 to 80% of all strokes are ischemic, which occurs when blood flow to the brain is disrupted, depriving neurons of oxygen and glucose, resulting in cell death and behavioural impairment [4–7]. Ischemic stroke treatments are few despite their relevance. Intravenous tissue-type plasminogen activator (t-PA) revolutionized the management of acute ischemic stroke more than two decades ago, providing a new therapeutic intervention for a devastating neurological disorder [8–10]. However, the short treatment window can only assist a few patients because of the quick treatment window. Other therapies are essentially supportive, such as breathing, blood pressure management, reduction of cerebral oedema and infection prevention. Stroke-induced damage to brain tissue still cannot be reversed by any currently available therapy [11–14]. Approaches such as tissue engineering have been suggested as a viable option. It is usual to use hydrogels with various neuroprotective agents and stem cells to restore damaged neural tissue [15–17]. However, the low in vivo cell survival, limited encapsulation effectiveness and a considerable decrease in the activity of neurotrophic factors make this technique difficult to implement [18]. Identifying a biomaterial with inherent neurotrophic activity while also being appropriate for the fabrication of a hydrogel that improves in vivo cell survival may be a method to address these disadvantages [19–21].
Comparison of conventional and extractive fermentation using aqueous two-phase system to extract fibrinolytic proteases produced by Bacillus stearothermophilus DPUA 1729
Published in Preparative Biochemistry & Biotechnology, 2021
Raimundo Felipe da Cruz Filho, Januário Gama dos Santos, Rosana Antunes Palheta, Valéria Carvalho Santos-Ebinuma, Daniela de Araújo Viana Marques, Maria Francisca Simas Teixeira
Thrombolytic drugs such as tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and streptokinase are used in the treatment of cardiovascular diseases. In emergencies cases, activase® (serine protease), which is an activator of tissue plasminogen (t-PA) produced by recombinant DNA technology, is also used. All of these drugs have effective action in a short time but they are still expensive,[5,6] presented undesirable side effects, which include excessive bleeding, anaphylaxis and recurrence at the site of the residual thrombosis and have immunogenic effects.[7,8] In this way, alternative drugs and treatments are of great interest. In this sense, fibrinolytic enzymes, also known as nattokinase, which can reduce fibrinogen levels and degrade fibrin branched.[6,9] have gained attention due to their low cost of production and commercialization (three-time cheaper than conventional drugs), besides reduced side effects.[7,10] Fibrinolytic enzymes show the ability to dissolve the fibrin in blood clots represented by the fibrinolytic activity.[11]
Preparation and characterization of tissue plasminogen activator-loaded liposomes
Published in Soft Materials, 2022
Katsiaryna Dubatouka, Vladimir Agabekov
Liposomes are small, nontoxic, biodegradable and biocompatible self-organized spherical vesicles consisting of one or more phospholipid bilayers that closely resemble the structure of cell membranes.[1] Due to the amphiphilic character of lipids, hydrophobic and hydrophilic substances, such as drugs, proteins, enzymes, and nucleotides can be encapsulated into liposomes that can be used in medicine as drug delivery systems.[2,3] Alteplase (tissue plasminogen activator, tPA) is a serine protease with a molecular weight of ~68 kDa, which is used for treating thromboembolic conditions. Tissue plasminogen activator converts plasminogen into fibrinolytic enzyme plasmin that then degrades fibrin, leading to clot dissolution.[4,5] It is known that tPA acts only on plasminogen associated with a thrombus, has fibrin-specificity and low immunogenicity, making it possible to reduce the dosage of the drug and use it for the treatment of acute myocardial infarction effectively.[6] At the same time, there are some limitations in the use of TPA for the treatment of thrombosis: a narrow therapeutic window, a short half-life (4–6 minutes) and poor penetration into large blood clots.[7] Moreover, tissue plasminogen activator is very sensitive to changes in pH, ionic strength, temperature, the presence of detergents, metal ions and non-aqueous solvents, which leads to denaturation, aggregation, precipitation, nonspecific adsorption and decrease in the biological activity of the substance.[8] The incorporation of tPA into liposomes protects the drug against chemical and immunological breakdown in the circulation, maintains its activity and provides prolonged effect.[4,6,9–11]