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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 -
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 -
American Journal of Physiology. Cell... Oct 2021Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are serine proteases and major activators of fibrinolysis in mammalian systems.... (Review)
Review
Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are serine proteases and major activators of fibrinolysis in mammalian systems. Because fibrinolysis is an essential component of the response to tissue injury, diverse cells, including cells that participate in the response to injury, have evolved receptor systems to detect tPA and uPA and initiate appropriate cell-signaling responses. Formation of functional receptor systems for the plasminogen activators requires assembly of diverse plasma membrane proteins, including but not limited to: the urokinase receptor (uPAR); integrins; -formyl peptide receptor-2 (FPR2), receptor tyrosine kinases (RTKs), the -methyl-d-aspartate receptor (NMDA-R), and low-density lipoprotein receptor-related protein-1 (LRP1). The cell-signaling responses elicited by tPA and uPA impact diverse aspects of cell physiology. This review describes rapidly evolving knowledge regarding the structure and function of plasminogen activator receptor assemblies. How these receptor assemblies regulate innate immunity and inflammation is then considered.
Topics: Animals; Enzyme Activation; Fibrinolysis; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Ligands; Plasminogen; Protein Conformation; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Structure-Activity Relationship; Tissue Plasminogen Activator
PubMed: 34406905
DOI: 10.1152/ajpcell.00269.2021 -
Cellular Signalling Nov 2020A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen... (Review)
Review
A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.
Topics: Animals; Blood Coagulation; COVID-19; Complement Activation; Coronavirus Infections; Cytokine Release Syndrome; Cytokines; Humans; Immune System; Inflammation; Low Density Lipoprotein Receptor-Related Protein-1; NF-kappa B; Pandemics; Plasminogen; Pneumonia, Viral; Tissue Plasminogen Activator
PubMed: 32861744
DOI: 10.1016/j.cellsig.2020.109761 -
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 -
Cellular and Molecular Neurobiology Jan 2023As the second-leading cause of death, stroke faces several challenges in terms of treatment because of the limited therapeutic interventions available. Previous studies... (Review)
Review
As the second-leading cause of death, stroke faces several challenges in terms of treatment because of the limited therapeutic interventions available. Previous studies primarily focused on metabolic and blood flow properties as a target for treating stroke, including recombinant tissue plasminogen activator and mechanical thrombectomy, which are the only USFDA approved therapies. These interventions have the limitation of a narrow therapeutic time window, the possibility of hemorrhagic complications, and the expertise required for performing these interventions. Thus, it is important to identify the contributing factors that exacerbate the ischemic outcome and to develop therapies targeting them for regulating cellular homeostasis, mainly neuronal survival and regeneration. Glial cells, primarily microglia, astrocytes, and oligodendrocytes, have been shown to have a crucial role in the prognosis of ischemic brain injury, contributing to inflammatory responses. They play a dual role in both the onset as well as resolution of the inflammatory responses. Understanding the different mechanisms driving these effects can aid in the development of therapeutic targets and further mitigate the damage caused. In this review, we summarize the functions of various glial cells and their contribution to stroke pathology. The review highlights the therapeutic options currently being explored and developed that primarily target glial cells and can be used as neuroprotective agents for the treatment of ischemic stroke.
Topics: Humans; Brain Ischemia; Tissue Plasminogen Activator; Stroke; Neuroglia; Astrocytes
PubMed: 35066715
DOI: 10.1007/s10571-021-01183-3 -
Biomaterials Nov 2020Thrombotic occlusions of blood vessels are responsible for life-threatening cardiovascular disorders such as myocardial infarction, ischemic stroke, and venous... (Review)
Review
Thrombotic occlusions of blood vessels are responsible for life-threatening cardiovascular disorders such as myocardial infarction, ischemic stroke, and venous thromboembolism. Current thrombolytic therapy, the injection of Plasminogen Activators (PA), is yet limited by a narrow therapeutic window, rapid drug elimination, and risks of hemorrhagic complications. Nanomedicine-based vectorization of PA protects the drug from the enzymatic degradation, improves the therapeutic outcomes, and diminishes adverse effects in preclinical models. Herein, we review the pathophysiology of arterial and venous thrombosis and summarize clinically approved PA for the treatment of acute thrombotic diseases. We examine current challenges and perspectives in the recent key research on various (lipid, polymeric, inorganic, biological) targeted nanocarriers intended for the site-specific delivery of PA. Microbubbles and ultrasound-assisted sonothrombolysis that demonstrate thrombolysis enhancement in clinical trials are further discussed. Moreover, this review features strategies for the rational design of nanocarriers for targeted thrombolysis and effective PA encapsulation in view of interactions between nanomaterials and biological systems. Overall, nanomedicine represents a valued approach for the precise treatment of acute thrombotic pathologies.
Topics: Fibrinolysis; Fibrinolytic Agents; Humans; Nanomedicine; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 32818824
DOI: 10.1016/j.biomaterials.2020.120297 -
ACS Chemical Neuroscience Jul 2023Stroke is a disease with high disability and high mortality in the world. Due to the existence of the blood-brain barrier (BBB), complex brain structure, and numerous... (Review)
Review
Stroke is a disease with high disability and high mortality in the world. Due to the existence of the blood-brain barrier (BBB), complex brain structure, and numerous neural signal pathways, the treatment methods are limited, so new drugs and new treatments need to be developed urgently. Thankfully, the advent of nanotechnology offered a new opportunity for biomedical development because of the unique properties of nanoparticles that give them the ability to traverse the BBB and accumulate in relevant regions of the brain. More importantly, nanoparticles could be modified on the surface to meet a variety of specific properties that people need. Some could be used for effective drug delivery, including tissue plasminogen activator (tPA), neuroprotective agents, genes, and cytokines; some nanoparticles were used as contrast agents and biosensors in medical imaging for further diagnosis of stroke; some were used to track target cells for prognosis of stroke; and some were used to detect pathological markers of stroke that appear at different stages. This Review looks at the application and research progress of nanoparticles in the diagnosis and treatment of stroke, hoping to bring some help to researchers.
Topics: Humans; Tissue Plasminogen Activator; Stroke; Brain; Blood-Brain Barrier; Brain Ischemia; Nanotechnology
PubMed: 37310096
DOI: 10.1021/acschemneuro.2c00804 -
Stroke Mar 2021
Topics: Brain Ischemia; Fibrinolytic Agents; Humans; Tenecteplase; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 33588587
DOI: 10.1161/STROKEAHA.120.033593 -
Current Pharmaceutical Biotechnology 2022Cardiovascular diseases, like coronary heart disease or artery disorders (arteriosclerosis, including artery solidification), heart failure (myocardial infarction),... (Review)
Review
Cardiovascular diseases, like coronary heart disease or artery disorders (arteriosclerosis, including artery solidification), heart failure (myocardial infarction), arrhythmias, congestive heart condition, stroke, elevated vital signs (hypertension), rheumatic heart disorder, and other circulatory system dysfunctions are the most common causes of death worldwide. Cardiovascular disorders are treated with stenting, coronary bypass surgery grafting, anticoagulants, antiplatelet agents, and other pharmacological and surgical procedures; however, these have limitations due to their adverse effects. Fibrinolytic agents degrade fibrin through enzymatic and biochemical processes. There are various enzymes that are currently used as a treatment for CVDs, like streptokinase, nattokinase, staphylokinase, urokinase, etc. These enzymes are derived from various sources, like bacteria, fungi, algae, marine organisms, plants, snakes, and other organisms. This review deals with the fibrinolytic enzymes, their mechanisms, sources, and their therapeutic potential.
Topics: Fibrinolytic Agents; Humans; Myocardial Infarction; Streptokinase; Thrombolytic Therapy; Urokinase-Type Plasminogen Activator
PubMed: 34983344
DOI: 10.2174/1389201023666220104143113