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International Journal of Molecular... May 2022The fibrinolytic system is composed of the protease plasmin, its precursor plasminogen and their respective activators, tissue-type plasminogen activator (tPA) and...
The fibrinolytic system is composed of the protease plasmin, its precursor plasminogen and their respective activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), counteracted by their inhibitors, plasminogen activator inhibitor type 1 (PAI-1), plasminogen activator inhibitor type 2 (PAI-2), protein C inhibitor (PCI), thrombin activable fibrinolysis inhibitor (TAFI), protease nexin 1 (PN-1) and neuroserpin. The action of plasmin is counteracted by α2-antiplasmin, α2-macroglobulin, TAFI, and other serine protease inhibitors (antithrombin and α2-antitrypsin) and PN-1 (protease nexin 1). These components are essential regulators of many physiologic processes. They are also involved in the pathogenesis of many disorders. Recent advancements in our understanding of these processes enable the opportunity of drug development in treating many of these disorders.
Topics: Fibrinolysin; Fibrinolysis; Plasminogen; Plasminogen Activator Inhibitor 1; Protease Nexins; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; alpha-2-Antiplasmin
PubMed: 35563651
DOI: 10.3390/ijms23095262 -
Frontiers in Immunology 2022Severe malaria (SM) is a leading cause of global morbidity and mortality, particularly in children in sub-Saharan Africa. However, existing malaria diagnostic tests do... (Review)
Review
Severe malaria (SM) is a leading cause of global morbidity and mortality, particularly in children in sub-Saharan Africa. However, existing malaria diagnostic tests do not reliably identify children at risk of severe and fatal outcomes. Dysregulated host immune and endothelial activation contributes to the pathogenesis of SM. Current research suggests that measuring markers of these pathways at presentation may have clinical utility as prognostic indicators of disease progression and risk of death. In this review, we focus on the available evidence implicating soluble urokinase-type plasminogen activator receptor (suPAR) as a novel and early predictor of severe and fatal malaria and discuss its potential utility for malaria triage and management.
Topics: Biomarkers; Child; Humans; Malaria; Prognosis; Receptors, Urokinase Plasminogen Activator; Triage
PubMed: 35757694
DOI: 10.3389/fimmu.2022.931321 -
Journal of Thrombosis and Haemostasis :... Dec 2019Fibrinolytic agents including plasmin and plasminogen activators improve outcomes in acute ischemic stroke and thrombosis by recanalizing occluded vessels. In the... (Review)
Review
Fibrinolytic agents including plasmin and plasminogen activators improve outcomes in acute ischemic stroke and thrombosis by recanalizing occluded vessels. In the decades since their introduction into clinical practice, several limitations of have been identified in terms of both efficacy and bleeding risk associated with these agents. Engineered nanoparticles and microparticles address some of these limitations by improving circulation time, reducing inhibition and degradation in circulation, accelerating recanalization, improving targeting to thrombotic occlusions, and reducing off-target effects; however, many particle-based approaches have only been used in preclinical studies to date. This review covers four advances in coupling fibrinolytic agents with engineered particles: (a) modifications of plasminogen activators with macromolecules, (b) encapsulation of plasminogen activators and plasmin in polymer and liposomal particles, (c) triggered release of encapsulated fibrinolytic agents and mechanical disruption of clots with ultrasound, and (d) enhancing targeting with magnetic particles and magnetic fields. Technical challenges for the translation of these approaches to the clinic are discussed.
Topics: Animals; Drug Carriers; Drug Compounding; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; High-Energy Shock Waves; Humans; Liposomes; Magnetite Nanoparticles; Nanomedicine; Nanoparticles; Plasminogen Activators; Thrombolytic Therapy
PubMed: 31529593
DOI: 10.1111/jth.14637 -
Frontiers in Immunology 2019Plasminogen activation is essential for fibrinolysis-the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation... (Review)
Review
Plasminogen activation is essential for fibrinolysis-the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation participates in a wide variety of inflammatory conditions. One of these conditions is hereditary angioedema (HAE), a rare disease with characteristic attacks of aggressive tissue swelling due to unregulated production and activity of the inflammatory mediator bradykinin. Plasmin was already implicated in this disease decades ago, but a series of recent discoveries have made it clear that plasmin actively contributes to this pathology. Collective evidence points toward an axis in which the plasminogen activation system and the contact system (which produces bradykinin) are mechanistically coupled. This is amongst others supported by findings in subtypes of HAE that are caused by gain-of-function mutations in the genes that respectively encode factor XII or plasminogen, as well as clinical experience with the antifibrinolytic agents in HAE. The concept of a link between plasminogen activation and the contact system helps us to explain the inflammatory side effects of fibrinolytic therapy, presenting as angioedema or tissue edema. Furthermore, these observations motivate the development and characterization of therapeutic agents that disconnect plasminogen activation from bradykinin production.
Topics: Angioedemas, Hereditary; Animals; Blood Coagulation; Bradykinin; Brain; Complement C1 Inhibitor Protein; Factor XII; Humans; Molecular Targeted Therapy; Plasminogen; Tissue Plasminogen Activator
PubMed: 31507620
DOI: 10.3389/fimmu.2019.02046 -
Biomolecules Nov 2020The Gram-negative bacterium causes plague, a fatal flea-borne anthropozoonosis, which can progress to aerosol-transmitted pneumonia. overcomes the innate immunity of... (Review)
Review
The Gram-negative bacterium causes plague, a fatal flea-borne anthropozoonosis, which can progress to aerosol-transmitted pneumonia. overcomes the innate immunity of its host thanks to many pathogenicity factors, including plasminogen activator, Pla. This factor is a broad-spectrum outer membrane protease also acting as adhesin and invasin. uses Pla adhesion and proteolytic capacity to manipulate the fibrinolytic cascade and immune system to produce bacteremia necessary for pathogen transmission via fleabite or aerosols. Because of microevolution, invasiveness has increased significantly after a single amino-acid substitution (I259T) in Pla of one of the oldest phylogenetic groups. This mutation caused a better ability to activate plasminogen. In paradox with its fibrinolytic activity, Pla cleaves and inactivates the tissue factor pathway inhibitor (TFPI), a key inhibitor of the coagulation cascade. This function in the plague remains enigmatic. Pla (or ) had been used as a specific marker of , but its solitary detection is no longer valid as this gene is present in other species of . Though recovering hosts generate anti-Pla antibodies, Pla is not a good subunit vaccine. However, its deletion increases the safety of attenuated strains, providing a means to generate a safe live plague vaccine.
Topics: Animals; Antigens, Bacterial; Humans; Plague; Plague Vaccine; Plasminogen Activators; Point Mutation; Protein Interaction Maps; Protein Structure, Secondary; Yersinia pestis
PubMed: 33202679
DOI: 10.3390/biom10111554 -
Journal of Thrombosis and Haemostasis :... Oct 2020Plg-R is a structurally unique transmembrane plasminogen receptor with both N- and C-terminal domains exposed on the extracellular face of the cell. Its C-terminal... (Review)
Review
Plg-R is a structurally unique transmembrane plasminogen receptor with both N- and C-terminal domains exposed on the extracellular face of the cell. Its C-terminal lysine functions to tether plasminogen to cell surfaces. Overexpression of Plg-R increases cell surface plasminogen binding capacity while genetic deletion of Plg-R decreases plasminogen binding. Plasminogen binding to Plg-R results in promotion of plasminogen activation to the broad spectrum serine protease plasmin. This function is promoted by the physical association of Plg-R with the urokinase receptor (uPAR). Plg-R is broadly expressed in cells and tissues throughout the organism and its sequence is remarkably conserved phylogenetically. Plg-R also is required for lactation and, thus, is necessary for survival of the species. This review provides an overview of established and emerging functions of Plg-R and highlights major roles for Plg-R in both the initiation and resolution of inflammation. While the roles for Plg-R in the inflammatory response are predominantly plasmin(ogen)-dependent, its role in lactation requires both plasminogen-dependent and plasminogen-independent mechanisms. Furthermore, the functions of Plg-R are dependent on sex. In view of the broad tissue distribution of Plg-R , its role in a broad array of physiological and pathological processes should provide a fruitful area for future investigation.
Topics: Cell Membrane; Female; Fibrinolysin; Humans; Inflammation; Plasminogen
PubMed: 32662180
DOI: 10.1111/jth.15014 -
European Journal of Drug Metabolism and... Mar 2022Desmoteplase is a bat (Desmodus rotundus) saliva-derived fibrinolytic enzyme resembling a urokinase and tissue plasminogen activator. It is highly dependent on fibrin... (Review)
Review
Desmoteplase is a bat (Desmodus rotundus) saliva-derived fibrinolytic enzyme resembling a urokinase and tissue plasminogen activator. It is highly dependent on fibrin and has some neuroprotective attributes. Intravenous administration of desmoteplase is safe and well tolerated in healthy subjects. Plasma fibrinolytic activity is linearly related to its blood concentration, its terminal elimination half-life ranges from 3.8 to 4.92 h (50 vs. 90 μg/kg dose). Administration of desmoteplase leads to transitory derangement of fibrinogen, D-dimer, alpha2-antiplasmin, and plasmin and antiplasmin complex which normalize within 4-12 h. It does not alter a prothrombin test, international normalized ratio, activated partial thromboplastin time, and prothrombin fragment 1.2. Desmoteplase was tested in myocardial infarction and pulmonary embolism and showed promising results versus alteplase. In ischemic stroke trials, desmoteplase was linked to increased rates of symptomatic intracranial hemorrhages and case fatality. However, data from "The desmoteplase in Acute Ischemic Stroke" Trials, DIAS-3 and DIAS-J, suggest that the drug is well tolerated and its safety profile is comparable to placebo. Desmoteplase is theoretically a superior thrombolytic because of high fibrin specificity, no activation of beta-amyloid, and lack of neurotoxicity. It was associated with better outcomes in patients with significant stenosis or occlusion of a proximal precerebral vessels. However, DIAS-4 was stopped as it might have not reached its primary endpoint. Due to its promising properties, desmoteplase may be added into treatment of ischemic stroke with extension of the time window and special emphasis on patients presenting outside the 4.5-h thrombolysis window, with wake-up strokes and strokes of unknown onset.
Topics: Fibrinolytic Agents; Humans; Ischemic Stroke; Plasminogen Activators
PubMed: 34893967
DOI: 10.1007/s13318-021-00743-8 -
International Journal of Molecular... Feb 2021Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere... (Review)
Review
Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere extracellular-matrix-degrading enzymes, fibrinolytic factors interfere with many processes during primary cancer growth and metastasis. Their many receptors give them access to cellular functions that tumor cells have widely exploited to promote tumor cell survival, growth, and metastatic abilities. They give cancer cells tools to ensure their own survival by interfering with the signaling pathways involved in senescence, anoikis, and autophagy. They can also directly promote primary tumor growth and metastasis, and endow tumor cells with mechanisms to evade myelosuppression, thus acquiring drug resistance. In this review, recent studies on the role fibrinolytic factors play in metastasis and controlling cell-death-associated processes are presented, along with studies that describe how cancer cells have exploited plasminogen receptors to escape myelosuppression.
Topics: Anoikis; Autophagy; Cell Survival; Cellular Senescence; Drug Resistance, Neoplasm; Exosomes; Extracellular Matrix; Humans; Neoplasm Metastasis; Neoplasms; Plasminogen; Plasminogen Inactivators; Signal Transduction
PubMed: 33669052
DOI: 10.3390/ijms22052304 -
International Journal of Molecular... Apr 2021The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A... (Review)
Review
The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A carefully coordinated interplay between these cellular and non-cellular components is required to maintain normal neuronal function, and in line with these observations, a growing body of evidence has linked NVU dysfunction to neurodegeneration. Plasminogen activators catalyze the conversion of the zymogen plasminogen into the two-chain protease plasmin, which in turn triggers a plethora of physiological events including wound healing, angiogenesis, cell migration and inflammation. The last four decades of research have revealed that the two mammalian plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), are pivotal regulators of NVU function during physiological and pathological conditions. Here, we will review the most relevant data on their expression and function in the NVU and their role in neurovascular and neurodegenerative disorders.
Topics: Animals; Cerebrovascular Disorders; Humans; Neurodegenerative Diseases; Plasminogen Activators; Receptors, Urokinase Plasminogen Activator
PubMed: 33922229
DOI: 10.3390/ijms22094380 -
Blood May 2022
Topics: Angioedemas, Hereditary; Bradykinin; Fibrinolysis; Glutamic Acid; Humans; Lysine; Plasminogen
PubMed: 35511189
DOI: 10.1182/blood.2022015610