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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 Pla (or ) had been used as a specific marker of , but its solitary detection is no longer valid as this gene is present in other species of .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 -
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 -
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 -
FEMS Microbiology Reviews Dec 2001Invasive bacterial pathogens intervene at various stages and by various mechanisms with the mammalian plasminogen/plasmin system. A vast number of pathogens express... (Comparative Study)
Comparative Study Review
Invasive bacterial pathogens intervene at various stages and by various mechanisms with the mammalian plasminogen/plasmin system. A vast number of pathogens express plasmin(ogen) receptors that immobilize plasmin(ogen) on the bacterial surface, an event that enhances activation of plasminogen by mammalian plasminogen activators. Bacteria also influence secretion of plasminogen activators and their inhibitors from mammalian cells. The prokaryotic plasminogen activators streptokinase and staphylokinase form a complex with plasmin(ogen) and thus enhance plasminogen activation. The Pla surface protease of Yersinia pestis resembles mammalian activators in function and converts plasminogen to plasmin by limited proteolysis. In essence, plasminogen receptors and activators turn bacteria into proteolytic organisms using a host-derived system. In Gram-negative bacteria, the filamentous surface appendages fimbriae and flagella form a major group of plasminogen receptors. In Gram-positive bacteria, surface-bound enzyme molecules as well as M-protein-related structures have been identified as plasminogen receptors, the former receptor type also occurs on mammalian cells. Plasmin is a broad-spectrum serine protease that degrades fibrin and noncollagenous proteins of extracellular matrices and activates latent procollagenases. Consequently, plasmin generated on or activated by Haemophilus influenzae, Salmonella typhimurium, Streptococcus pneumoniae, Y. pestis, and Borrelia burgdorferi has been shown to degrade mammalian extracellular matrices. In a few instances plasminogen activation has been shown to enhance bacterial metastasis in vitro through reconstituted basement membrane or epithelial cell monolayers. In vivo evidence for a role of plasminogen activation in pathogenesis is limited to Y. pestis, Borrelia, and group A streptococci. Bacterial proteases may also directly activate latent procollagenases or inactivate protease inhibitors of human plasma, and thus contribute to tissue damage and bacterial spread across tissue barriers.
Topics: Bacteria; Enzyme Precursors; Plasminogen Activators; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator
PubMed: 11742690
DOI: 10.1111/j.1574-6976.2001.tb00590.x -
Neuropharmacology Aug 2018In utero alcohol exposure can cause fetal alcohol spectrum disorders (FASD), characterized by structural brain abnormalities and long-lasting behavioral and cognitive...
In utero alcohol exposure can cause fetal alcohol spectrum disorders (FASD), characterized by structural brain abnormalities and long-lasting behavioral and cognitive dysfunction. Neuronal plasticity is affected by in utero alcohol exposure and can be modulated by extracellular proteolysis. Plasmin is a major extracellular serine-protease whose activation is tightly regulated by the plasminogen activator (PA) system. In the present study we explored the effect of ethanol on the expression of the main components of the brain PA system in sex-specific cortical astrocyte primary cultures in vitro and in the cortex and hippocampus of post-natal day (PD) 9 male and female rats. We find that ethanol alters the PA system in astrocytes and in the developing brain. In particular, the expression of tissue-type PA (tPA), encoded by the gene Plat, is consistently upregulated by ethanol in astrocytes in vitro and in the cortex and hippocampus in vivo. Astrocytes exhibit endogenous plasmin activity that is increased by ethanol and recombinant tPA and inhibited by tPA silencing. We also find that tPA is expressed by astrocytes of the developing cortex and hippocampus in vivo. All components of the PA system investigated, with the exception of Neuroserpin/Serpini1, are expressed at higher levels in astrocyte cultures than in the developing brain, suggesting that astrocytes are major producers of these proteins in the brain. In conclusion, astrocyte PA system may play a major role in the modulation of neuronal plasticity; ethanol-induced upregulation of tPA levels and plasmin activity may be responsible for altered neuronal plasticity in FASD.
Topics: Animals; Animals, Newborn; Astrocytes; Brain; Cells, Cultured; Central Nervous System Depressants; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Fibrinolysin; Homeostasis; International System of Units; Male; Plasminogen Activators; Rats, Sprague-Dawley; Recombinant Proteins
PubMed: 29885422
DOI: 10.1016/j.neuropharm.2018.06.004 -
Journal of Thrombosis and Haemostasis :... Jan 2017The cell surface orchestrates plasminogen activation through the concomitant binding of plasminogen and plasminogen activators to specific receptors. In this issue,...
The cell surface orchestrates plasminogen activation through the concomitant binding of plasminogen and plasminogen activators to specific receptors. In this issue, Miles and colleagues describe their detailed phenotypic characterization of mice deficient in Plg-R, a key plasminogen receptor expressed in numerous tissues, but highly expressed by proinflammatory macrophages. The analysis provides critical and surprising new insights into the biology of this receptor.
Topics: Amino Acid Sequence; Enzyme Activation; Humans; Plasminogen; Plasminogen Activators; Protein Processing, Post-Translational; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 27740735
DOI: 10.1111/jth.13541 -
Cellular and Molecular Life Sciences :... Mar 2011The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α(2)-antiplasmin are primarily responsible for a controlled and... (Review)
Review
The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α(2)-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α(2)-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polymers by plasmin, and urokinase-type plasminogen activator, which is primarily responsible for the generation of plasmin activity in the intercellular space. Both activators are multidomain serine proteases. Besides the main physiological inhibitor α(2)-antiplasmin, the plasmin-antiplasmin system is also regulated by the general protease inhibitor α(2)-macroglobulin, a member of the protease inhibitor I39 family. The activity of the plasminogen activators is primarily regulated by the plasminogen activator inhibitors 1 and 2, members of the serine protease inhibitor superfamily.
Topics: Antifibrinolytic Agents; Binding Sites; Blood Coagulation; Fibrinolysis; Humans; Models, Biological; Models, Molecular; Plasminogen; Plasminogen Activators; Plasminogen Inactivators; Protein Structure, Tertiary; Serine Proteases; Serine Proteinase Inhibitors; alpha-Macroglobulins
PubMed: 21136135
DOI: 10.1007/s00018-010-0566-5 -
Journal of the American College of... Dec 1986Streptokinase and urokinase have proved to be useful in a limited number of clinical conditions. Mainly because of the risk and unpredictability of bleeding with this... (Review)
Review
Streptokinase and urokinase have proved to be useful in a limited number of clinical conditions. Mainly because of the risk and unpredictability of bleeding with this first generation of thrombolytic agents, thrombolysis has not been ingrained in medical practice. In the interim, more fibrin-specific thrombolytic agents have been developed such as acylated streptokinase-human plasminogen complex, tissue-type plasminogen activator (t-PA) and single chain urokinase-type plasminogen activator (scu-PA or pro-urokinase). Only the latter two drugs do not induce major systemic fibrinogenolysis at thrombolytic effective doses. These two agents, obtained by recombinant techniques, as well as acylated streptokinase-plasminogen complex are available for clinical investigations. The first results of systemic administration of recombinant tissue-type plasminogen activation (t-PA) in patients with acute myocardial infarction were published and are promising. Continued experimentation with t-PA and pro-urokinase in evolving myocardial infarction and other thrombotic disorders is essential to better delineate their therapeutic index.
Topics: Drug Combinations; Fibrinolytic Agents; Humans; Plasminogen; Plasminogen Activators; Streptokinase; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 3097100
DOI: 10.1016/s0735-1097(86)80005-5 -
Clinical Cardiology Jun 1990Thrombotic disorders such as myocardial infarction and stroke are the leading causes of death and disability in industrialized nations. Timely institution of... (Review)
Review
Thrombotic disorders such as myocardial infarction and stroke are the leading causes of death and disability in industrialized nations. Timely institution of thrombolytic therapy can achieve a reduction of infarct size, a preservation of left ventricular function, and a reduction in mortality. The administration of streptokinase, urokinase, and acylated plasminogen-streptokinase activator complex (APSAC) can be associated with a complete breakdown of the hemostatic system. Tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA, prourokinase) are more fibrin specific; however, at the large dosages of activator needed for therapeutic efficacy, bleeding complications are still a problem. New approaches to optimizing the risk/benefit ratio for the patient by improving efficacy without sacrificing specificity include the use of synergistic combinations of plasminogen activators, mutants of t-PA and scu-PA, chimeric molecules, and antibody-targeted thrombolytic agents. The last approach opens the possibility of targeting several different components of the clot with either fibrinolytic or antiplatelet effector functions in one optimized molecule.
Topics: Animals; Antibodies, Monoclonal; Drug Synergism; Humans; Myocardial Infarction; Plasminogen Activators; Thrombolytic Therapy
PubMed: 2188764
DOI: 10.1002/clc.4960130602 -
Protein Science : a Publication of the... Jun 2014Bacterial plasminogen activators differ from each other in their mechanism of plasminogen activation besides their host specificity. Three-domain streptokinase (SK) and...
Bacterial plasminogen activators differ from each other in their mechanism of plasminogen activation besides their host specificity. Three-domain streptokinase (SK) and two-domain PauA generate nonproteolytic active site center in their cognate partner plasminogen but their binary activator complexes are resistant to α2-antiplasmin (a2AP) inhibition causing nonspecific plasminogen activation in plasma. In contrast, single-domain plasminogen activator, staphylokinase (SAK), requires proteolytic cleavage of human plasminogen into plasmin for the active site generation, and this activator complex is inhibited by a2AP. The single-domain plasminogen activator, PadA, from Streptococcus dysgalatiae, having close sequence and possible structure homology with SAK, was recently reported to activate bovine Pg in a nonproteolytic manner similar to SK. We report hereby that the binary activator complex of PadA with bovine plasminogen is inhibited by a2AP and PadA is recycled from this complex to catalyze the activation of plasminogen in the clot environment, where it is completely protected from a2AP inhibition. Catalytic efficiency of the activator complex formed by PadA and bovine plasminogen is amplified several folds in the presence of cyanogen bromide digested fibrinogen but not by intact fibrinogen indicating that PadA may be highly efficient at the fibrin surface. The present study, thus, demonstrates that PadA is a unique single-domain plasminogen activator that activates bovine plasminogen in a fibrin-targeted manner like SAK. The sequence optimization by PadA for acquiring the characteristics of both SK and SAK may be exploited for the development of efficient and fibrin-specific plasminogen activators for thrombolytic therapy.
Topics: Animals; Cattle; Fibrin; Plasminogen Activators; Protein Binding; Streptococcus; alpha-2-Antiplasmin
PubMed: 24639287
DOI: 10.1002/pro.2455