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Process Affinity Chromatography
Published in Juan A. Asenjo, Separation Processes in Biotechnology, 2020
Tissue-type plasminogen activator (tPA) is a glycoenzyme that converts plasminogen to plasmin, which degrades the fibrin network associated with blood clots. Plasminogen activator from genetically manipulated human Bowes melanoma cells was purified in two successive charomatographic steps. The first column, zinc chelate-Sepharose CL-4B, was chosen because it is very effective in concentrating tPA from the harvest medium, whereas the second column, lysine-Sepharose CL-4B, was chosen because of its biospecificity for tPA. These adsorbents have also been selected among others because they can be autoclaved and thus the operation performed aseptically. A batch of 45 L of filtered harvest medium was loaded on the zinc chelate column (0.9 L), the unbound material was washed off, and adsorbed tPA was eluted in a buffer containing 0.05 M immidazole and directly applied to the lysine column (0.18 L). After washing the affinity adsorbent to remove unbound material, tPA was eluted in a buffer containing 0.5 M L-arginine. A total of 360 L of medium could be processed in eight cycles (Dodd et al., 1982).
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].
Purification and characterization of fibrinolytic protease from Bacillus amyloliquefaciens MCC2606 and analysis of fibrin degradation product by MS/MS
Published in Preparative Biochemistry & Biotechnology, 2018
Yogesh Devaraj, Savita Kumari Rajender, Prakash Motiram Halami
Cardio vascular diseases (CVDs) accounts largest number of deaths in the world, making world’s number one position as a cause of mortality. As an average, in every 40 s a person dies due to heart attack or any other cardiovascular related disorder.[1] Under normal healthy hemostasis condition of the body, the blood clots if so formed inside blood vessels are degraded by plasmin or fibrinolysin, a major inherent fibrinolytic enzyme in blood. However, under certain abnormal homeostasis condition blood clots remains and this condition aggravated by reduced concentration of plasmin in blood, accumulation of fibrinogen as risk factors and leading to deleterious condition called “thrombosis.”[2345] Thrombosis is one of the important CVDs and is defined by various pathological terms based on the site of formation of thrombus, such as deep vein thrombosis, coronary thrombosis, etc. The increasing percentage of cardiovascular cases and death due to thrombosis all over the world has attracted the researchers to look for newer agents to degrade thrombus. The commonly used thrombolytic drugs under usage including urokinase, tissue-type plasminogen activator (t-PA) and streptokinase, activates plasmin and converts plasminogen to plasmin that degrades fibrin. However, these agents have certain important limitations, such as higher cost, shorter half-life, immunogenicity, and intravenous administration of these agents are also known to cause hemorrhage.[6,7] These undesirable side effects have created interest in the field of thrombolytic agents, and motivated investigators to search for novel and effective fibrinolytic enzymes for safer use. Over the last decades, many thrombolytic agents have been identified, studied and characterized from various sources, such as earthworms,[8] snake venoms,[9] centipede venoms,[10] insects,[11] and leeches.[12] However, the microbial fibrinolytic enzymes, especially those from food grade microorganisms, have the potential to be developed as functional food additives and alternative drugs to prevent or cure cardiovascular diseases.
Diagnosis, treatment & management of prosthetic valve thrombosis: the key considerations
Published in Expert Review of Medical Devices, 2020
Sabahattin Gündüz, Macit Kalçık, Mustafa Ozan Gürsoy, Ahmet Güner, Mehmet Özkan
There is no consensus on the optimal TT strategy, the type of agent, and the dose or route of administration. The recombinant tissue-type plasminogen activator (rt-PA) is a naturally occurring serum protein with a high affinity for fibrin. It is currently one of the most frequently used thrombolytic agents for PHVT therapy [3,5,9,11,79]. Due to its high fibrin specificity, rt-PA is widely used in the management of PHVT [5,11,79]. On the other hand, despite its significant limitations, streptokinase remains the drug of choice instead of rt-PA particularly in low-income countries because of its relatively lower cost [77,78,80–82]. Fibrinolytic agents such as tenecteplase and urokinase have also been used in the management of PHVT; however, no difference has been identified regarding the efficacy and safety of these agents when compared with streptokinase [77,78,80–84]. Although accelerated protocols seem attractive as they may induce more rapid lysis. However, rapid thrombolysis is associated with higher bleeding and embolic complications and mortality rates [5,52,84]. In the TROIA Trial (182 patients, 220 episodes), we have reported a thrombolytic success rate of 83.2% without a significant difference between TT protocols. The comparison of complication rates between study groups showed a statistically lower combined complication rate in the slow infusion of low-dose t-PA group [5]. Based on our experience regarding TT [3,5,85], we have developed an ultra-slow infusion of low-dose t-PA (25 mg/25 h) strategy with the aim of reducing embolic and bleeding complications while keeping the success as high as possible. The ultra-slow PROMETEE Trial has demonstrated that ultra-slow (25 h) infusion of low dose (25 mg) t-PA without bolus appears to be associated with quite low non-fatal complications and mortality for PHVT patients without loss of effectiveness, except for those with NYHA class-IV [11]. To identify the underlying biological mechanism of failed thrombolysis, we investigated the effect of anti-tPA antibodies (ATA). Our study revealed that the infusion of rt-PA triggers the production of ATA, which may interfere with the success of TT, necessitating a higher dose of rt-PA for complete success [86]. Moreover, PHVT patients with elevated baseline ATA levels had also a higher risk of rethrombosis after initial successful TT. Recently, we have described how to perform and manage low-dose and slow/ultra-slow t-PA infusion regimens in patients with PHVT regarding the preparation and biological stabilization of reconstituted solution (rt-PA+sterile sodium chloride) during a 6 or 25-h infusion [9]. Patient suitability criteria for TT are described in Table 2 and the diagnostic and management strategies of PHVT are summarized in Figure 4.