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International Journal of Molecular... Jan 2021triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus . SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that... (Review)
Review
triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus . SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that alters plasminogen conformation to enhance its binding to fibrin and subsequent fibrinolysis. Certain SMTP congeners exert anti-inflammatory effects by targeting soluble epoxide hydrolase. SMTP congeners with both plasminogen modulation activity and anti-inflammatory activity ameliorate various aspects of ischemic stroke in rodents and primates. A remarkable feature of SMTP efficacy is the suppression of hemorrhagic transformation, which is exacerbated by conventional thrombolytic treatments. No drug with such properties has been developed yet, and SMTP would be the first to promote thrombolysis but suppress disease-associated bleeding. On the basis of these findings, one SMTP congener is under clinical study and development. This review summarizes the discovery, mechanism of action, pharmacological activities, and development of SMTP.
Topics: Animals; Anti-Inflammatory Agents; Benzopyrans; Brain Ischemia; Epoxide Hydrolases; Fibrinolysis; Fibrinolytic Agents; Humans; Inflammation; Ischemic Stroke; Plasminogen; Pyrrolidinones; Stachybotrys; Thrombolytic Therapy
PubMed: 33477998
DOI: 10.3390/ijms22020954 -
Veterinary Immunology and... Aug 2016Leptospirosis is a widespread zoonosis caused by pathogenic Leptospira spp. It is an important infectious disease that affects humans and animals. The disease causes... (Review)
Review
Leptospirosis is a widespread zoonosis caused by pathogenic Leptospira spp. It is an important infectious disease that affects humans and animals. The disease causes economic losses as it affects livestock, with decreased milk production and death. Our group is investigating the genome sequences of L. interrogans targeting surface-exposed proteins because, due to their location, these proteins are capable to interact with several host components that could allow establishment of the infection. These interactions may involve adhesion of the bacteria to extracellular matrix (ECM) components and, hence, help bacterial colonization. The bacteria could also react with the host fibrinolytic system and/or with the coagulation cascade components, such as, plasminogen (PLG) and fibrinogen (Fg), respectively. The binding with the first system generates plasmin (PLA), increasing the proteolytic power of the bacteria, while the second interferes with clotting in a thrombin-catalyzed reaction, which may promote hemorrhage foci and increase bacterial dissemination. Interaction with the complement system negative regulators may help bacteria to evade the host immune system, facilitating the invasion. This work compiles the main described leptospiral proteins that could act as adhesins, as PLG and fibrinogen receptors and as complement regulator binding proteins. We present models in which we suggest possible mechanisms of how leptospires might colonize and invade host tissues, causing the disease. Understanding leptospiral pathogenesis will help to identify antigen candidates that would contribute to the development of more effective vaccines and diagnostic tests.
Topics: Adhesins, Bacterial; Animals; Complement System Proteins; Extracellular Matrix Proteins; Fibrinogen; Host-Pathogen Interactions; Humans; Immune Evasion; Leptospira; Plasminogen
PubMed: 26727033
DOI: 10.1016/j.vetimm.2015.12.004 -
Trends in Parasitology Feb 2022Plasmodium and other vector-borne pathogens have evolved mechanisms to hijack the mammalian fibrinolytic system to facilitate infection of the human host and the... (Review)
Review
Plasmodium and other vector-borne pathogens have evolved mechanisms to hijack the mammalian fibrinolytic system to facilitate infection of the human host and the invertebrate vector. Plasmin, the effector protease of fibrinolysis, maintains homeostasis in the blood vasculature by degrading the fibrin that forms blood clots. Plasmin also degrades proteins from extracellular matrices, the complement system, and immunoglobulins. Here, we review some of the mechanisms by which vector-borne pathogens interact with components of the fibrinolytic system and co-opt its functions to facilitate transmission and infection in the host and the vector. Further, we discuss innovative strategies beyond conventional therapeutics that could be developed to target the interaction of vector-borne pathogens with the fibrinolytic proteins and prevent their transmission.
Topics: Animals; Fibrinolysin; Fibrinolysis; Humans; Malaria; Mammals; Plasminogen; Vector Borne Diseases
PubMed: 34649773
DOI: 10.1016/j.pt.2021.09.008 -
Biomolecules Mar 2022The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly...
The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly appreciated as key players in modulation of the tumor microenvironment. The interaction of plasminogen with cells to promote plasminogen activation requires the presence of proteins exposing C-terminal lysines on the cell surface. Plg-R is a structurally unique plasminogen receptor because it is an integral membrane protein that is synthesized with and binds plasminogen via a C-terminal lysine exposed on the cell surface. Here, we have investigated the expression of Plg-R in human breast tumors and human breast cancer cell lines. Breast cancer progression tissue microarrays were probed with anti-Plg-R mAB and we found that Plg-R is widely expressed in human breast tumors, that its expression is increased in tumors that have spread to draining lymph nodes and distant organs, and that Plg-R expression is most pronounced in hormone receptor (HR)-positive tumors. Plg-R was detected by Western blotting in human breast cancer cell lines. By flow cytometry, Plg-R cell surface expression was highest on the most aggressive tumor cell line. Future studies are warranted to address the functions of Plg-R in breast cancer.
Topics: Breast Neoplasms; Cell Membrane; Female; Humans; Plasminogen; Receptors, Cell Surface; Serine Proteases; Tumor Microenvironment
PubMed: 35454092
DOI: 10.3390/biom12040503 -
Critical Reviews in Microbiology Nov 2016Both coagulation and fibrinolysis are tightly connected with the innate immune system. Infection and inflammation cause profound alterations in the otherwise... (Review)
Review
Both coagulation and fibrinolysis are tightly connected with the innate immune system. Infection and inflammation cause profound alterations in the otherwise well-controlled balance between coagulation and fibrinolysis. Many pathogenic bacteria directly exploit the host's hemostatic system to increase their virulence. Here, we review the capacity of bacteria to activate plasminogen. The resulting proteolytic activity allows them to breach tissue barriers and evade innate immune defense, thus promoting bacterial spreading. Yersinia pestis, streptococci of group A, C and G and Staphylococcus aureus produce a specific bacterial plasminogen activator. Moreover, surface plasminogen receptors play an established role in pneumococcal, borrelial and group B streptococcal infections. This review summarizes the mechanisms of bacterial activation of host plasminogen and the role of the fibrinolytic system in infections caused by these pathogens.
Topics: Animals; Bacteria; Bacterial Infections; Bacterial Proteins; Humans; Immunity, Innate; Plasminogen; Plasminogen Activators
PubMed: 26485450
DOI: 10.3109/1040841X.2015.1080214 -
MBio Jun 2021Expression of bacteriophage lysin by Streptococcus oralis strain SF100 is thought to be important for the pathogenesis of infective endocarditis, due to its ability to...
Expression of bacteriophage lysin by Streptococcus oralis strain SF100 is thought to be important for the pathogenesis of infective endocarditis, due to its ability to mediate bacterial binding to fibrinogen. To better define the lysin binding site on fibrinogen Aα, and to investigate the impact of binding on fibrinolysis, we examined the interaction of lysin with a series of recombinant fibrinogen Aα variants. These studies revealed that lysin binds the C-terminal region of fibrinogen Aα spanned by amino acid residues 534 to 610, with an affinity of equilibrium dissociation constant () of 3.23 × 10 M. This binding site overlaps the known binding site for plasminogen, an inactive precursor of plasmin, which is a key protease responsible for degrading fibrin polymers. When tested , lysin competitively inhibited plasminogen binding to the αC region of fibrinogen Aα. It also inhibited plasminogen-mediated fibrinolysis, as measured by thromboelastography (TEG). These results indicate that lysin is a bi-functional virulence factor for streptococci, serving as both an adhesin and a plasminogen inhibitor. Thus, lysin may facilitate the attachment of bacteria to fibrinogen on the surface of damaged cardiac valves and may also inhibit plasminogen-mediated lysis of infected thrombi (vegetations) on valve surfaces. The interaction of streptococci with human fibrinogen and platelets on damaged endocardium is a central event in the pathogenesis of infective endocarditis. Streptococcus oralis can bind platelets via the interaction of bacteriophage lysin with fibrinogen on the platelet surface, and this process has been associated with increased virulence in an animal model of endocarditis. We now report that lysin binds to the αC region of the human fibrinogen Aα chain. This interaction blocks plasminogen binding to fibrinogen and inhibits fibrinolysis. , this inhibition could prevent the lysis of infected vegetations, thereby promoting bacterial persistence and virulence.
Topics: Binding Sites; Endocarditis; Fibrin; Fibrinogen; Fibrinolysis; Humans; Plasminogen; Protein Binding; Streptococcus; Streptococcus Phages; Virulence
PubMed: 34154404
DOI: 10.1128/mBio.00746-21 -
Frontiers in Immunology 2019Inflammation resolution is an active process that functions to restore tissue homeostasis. Clearance of apoptotic leukocytes by efferocytosis at inflammatory sites plays...
Inflammation resolution is an active process that functions to restore tissue homeostasis. Clearance of apoptotic leukocytes by efferocytosis at inflammatory sites plays an important role in inflammation resolution and induces remarkable macrophage phenotypic and functional changes. Here, we investigated the effects of deletion of either plasminogen (Plg) or the Plg receptor, Plg-R, on the resolution of inflammation. In a murine model of pleurisy, the numbers of total mononuclear cells recruited to the pleural cavity were significantly decreased in both Plg and Plg-R mice, a response associated with decreased levels of the chemokine CCL2 in pleural exudates. Increased percentages of M1-like macrophages were determined in pleural lavages of Plg and Plg-R mice without significant changes in M2-like macrophage percentages. , Plg and plasmin (Pla) increased CD206/Arginase-1 expression and the levels of IL-10/TGF-β (M2 markers) while decreasing IFN/LPS-induced M1 markers in murine bone-marrow-derived macrophages (BMDMs) and human macrophages. Furthermore, IL4-induced M2-like polarization was defective in BMDMs from both Plg and Plg-R mice. Mechanistically, Plg and Pla induced transient STAT3 phosphorylation, which was decreased in Plg and Plg-R BMDMs after IL-4 or IL-10 stimulation. The extents of expression of CD206 and Annexin A1 (important for clearance of apoptotic cells) were reduced in Plg and Plg-R macrophage populations, which exhibited decreased phagocytosis of apoptotic neutrophils (efferocytosis) and . Taken together, these results suggest that Plg and its receptor, Plg-R, regulate macrophage polarization and efferocytosis, as key contributors to the resolution of inflammation.
Topics: Animals; Cell Movement; Humans; Macrophages; Male; Mice, Transgenic; Neutrophils; Phagocytosis; Phenotype; Plasminogen; Pleurisy; Receptors, Cell Surface
PubMed: 31316511
DOI: 10.3389/fimmu.2019.01458 -
Croatian Medical Journal Dec 2023Soluble fibrin is composed mainly of desA fibrin and fibrinogen oligomers consisting of fewer than 16 monomers partially cross-linked by factor XIIIa. Soluble fibrin... (Review)
Review
Soluble fibrin is composed mainly of desA fibrin and fibrinogen oligomers consisting of fewer than 16 monomers partially cross-linked by factor XIIIa. Soluble fibrin cannot stimulate Glu-plasminogen activation by tissue plasminogen activator (t-PA); therefore, it may not be a direct predecessor of D-dimer. However, within the microcirculatory system, soluble fibrin oligomers may form microclots. Fibrin microclots stimulate Glu-plasminogen activation by t-PA, a process resulting in the formation of Glu-plasmin. Glu-plasmin dissolves the microclots, forming D-dimer. In normal and pathological blood plasma samples, soluble fibrin levels are substantially higher than those of D-dimer. Their concentrations in the plasma are also regulated by transendothelial transfer, absorption by blood macrophages, and binding and internalization with low-density lipoprotein receptors of the cells of the reticuloendothelial system. Therefore, the exact mechanisms of fibrin clots formation and elimination in normal and pathological conditions remain unclear. In this study, we reviewed findings on the molecular mechanisms of the formation and dissolution of fibrin clots, fibrin-dependent activation of Glu-plasminogen by t-PA, and blood plasma behavior in the microcirculatory system. Finally, we proposed a model that explains the relations of D-dimer and soluble fibrin underlying the common and separate mechanisms of their formation and elimination.
Topics: Humans; Tissue Plasminogen Activator; Fibrinolysin; Microcirculation; Plasminogen; Fibrin
PubMed: 38168523
DOI: 10.3325/cmj.2023.64.421 -
Circulation Mar 2017
Topics: Antifibrinolytic Agents; Fibrinolytic Agents; Humans; Plasminogen; Pulmonary Embolism; Thrombolytic Therapy; Tissue Plasminogen Activator; alpha-2-Antiplasmin
PubMed: 28289005
DOI: 10.1161/CIRCULATIONAHA.117.026884 -
Cells Jan 2023The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major... (Review)
Review
The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity.
Topics: Humans; COVID-19; Fibrinolysin; Inflammation; Mouth; Plasminogen; Tissue Plasminogen Activator
PubMed: 36766787
DOI: 10.3390/cells12030445