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International Journal of Molecular... Sep 2022Carotid atherosclerosis (CA) is an important risk factor for ischemic stroke. We described the miRNA and hemostasis profile of patients with moderate and advanced stages...
Carotid atherosclerosis (CA) is an important risk factor for ischemic stroke. We described the miRNA and hemostasis profile of patients with moderate and advanced stages of carotid atherosclerosis and elucidated potential correlations with hemostatic activation. A prospective case-control study included 61 patients with evidence of carotid atherosclerosis (via ultrasound). The study population was divided into groups depending on the degree of carotid artery stenosis: 60% or more (advanced) and <60% (moderate). All patients underwent the following blood tests: general blood test, hemostatic parameters and microRNA. Extraction of microRNA was performed using Leukocyte RNA Purification Kit (NORGEN Biotec Corp., Thorold, ON, Canada); miRNA quantification was performed via RT-PCR. Statistical analysis was performed in R programming language (v. 4.1.0) using RSudio. MicroRNA expression profile was different depending on CA degree. MiR-33a-5p/3p levels were higher in patients with ≥60% carotid stenosis (42.70 and 42.45 versus 38.50 and 38.50, respectively, p < 0.05). Almost complete separation can be visualized with the levels of miR-126-5p: 9.50 in the moderate CA group versus 5.25 in the advanced CA (p < 0.001). MiR-29-5p was higher in the moderate CA group: 28.60 [25.50;33.05] than in advanced CA group: 25.75 [24.38;29.50] (p = 0.086); miR-29-3p was also higher in the moderate CA group: 10.36 [8.60;14.99] than in advanced CA group: 8.46 [7.47;10.3] (p = 0.001). By-group pairwise correlation analyses revealed at least three clusters with significant positive correlations in the moderate CA group: miR-29-3p with factors V and XII (r = 0.53 and r = 0.37, respectively, p < 0.05); miR-21-5p with ADAMTS13, erythrocyte sedimentation rate and D-dimer (r = 0.42, r = 0.36 and r = 0.44, respectively, p < 0.05); stenosis degree with miR-33a-5p/3p and factor VIII levels (r = 0.43 (both) and r = 0.62, respectively, p < 0.05). Hemostasis parameters did not reveal significant changes in CA patients: the only statistically significant differences concerned factor VIII, plasminogen and (marginally significant) ADAMTS-13 and protein C. Down-regulation of miR-126-5p expression has been identified as a promising biomarker of advanced carotid atherosclerosis with high specificity and sensitivity. Correlation cluster analysis showed potential interplay between miRNAs and hemostatic activation in the setting of carotid atherosclerosis.
Topics: ADAMTS13 Protein; Biomarkers; Carotid Artery Diseases; Case-Control Studies; Factor VIII; Hemostasis; Hemostatics; Humans; MicroRNAs; Plasminogen; Protein C
PubMed: 36142883
DOI: 10.3390/ijms231810974 -
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 -
International Journal of Molecular... Jun 2023The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance.... (Review)
Review
The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance. Mesenchymal stromal cells and macrophages release tolerogenic cytokines and favor anti-apoptotic signaling pathway activation, while the urokinase plasminogen activator receptor (uPAR) system contributes to migration through an extracellular matrix. Here, we first summarized the role of macrophages and the uPAR system in MM pathogenesis, and then we reported the potential therapeutic effects of uPAR inhibitors in a case series of primary MM-derived adherent cells. Our preliminary results showed that after uPAR inhibitor treatments, interleukein-6 (mean ± SD, 8734.95 ± 4169.2 pg/mL vs. 359.26 ± 393.8 pg/mL, pre- vs. post-treatment; = 0.0012) and DKK-1 levels (mean ± SD, 7005.41 ± 6393.4 pg/mL vs. 61.74 ± 55.2 pg/mL, pre- vs. post-treatment; = 0.0043) in culture medium were almost completely abolished, supporting further investigation of uPAR blockade as a therapeutic strategy for MM treatment. Therefore, uPAR inhibitors could exert both anti-inflammatory and pro-immunosurveillance activity. However, our preliminary results need further validation in additional in vitro and in vivo studies.
Topics: Humans; Receptors, Urokinase Plasminogen Activator; Multiple Myeloma; Urokinase-Type Plasminogen Activator; Signal Transduction; Macrophages; Tumor Microenvironment
PubMed: 37445697
DOI: 10.3390/ijms241310519 -
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 -
International Journal of Molecular... May 2022Obstructive sleep apnea is a chronic and prevalent condition that is associated with endothelial dysfunction, atherosclerosis, and imposes excess overall cardiovascular... (Review)
Review
Obstructive sleep apnea is a chronic and prevalent condition that is associated with endothelial dysfunction, atherosclerosis, and imposes excess overall cardiovascular risk and mortality. Despite its high prevalence and the susceptibility of CVD patients to OSA-mediated stressors, OSA is still under-recognized and untreated in cardiovascular practice. Moreover, conventional OSA treatments have yielded either controversial or disappointing results in terms of protection against CVD, prompting the need for the identification of additional mechanisms and associated adjuvant therapies. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), is a key regulator of fibrinolysis and cell migration. Indeed, elevated PAI-1 expression is associated with major cardiovascular adverse events that have been attributed to its antifibrinolytic activity. However, extensive evidence indicates that PAI-1 can induce endothelial dysfunction and atherosclerosis through complex interactions within the vasculature in an antifibrinolytic-independent matter. Elevated PAI-1 levels have been reported in OSA patients. However, the impact of PAI-1 on OSA-induced CVD has not been addressed to date. Here, we provide a comprehensive review on the mechanisms by which OSA and its most detrimental perturbation, intermittent hypoxia (IH), can enhance the transcription of PAI-1. We also propose causal pathways by which PAI-1 can promote atherosclerosis in OSA, thereby identifying PAI-1 as a potential therapeutic target in OSA-induced CVD.
Topics: Antifibrinolytic Agents; Atherosclerosis; Cardiovascular System; Humans; Plasminogen Activator Inhibitor 1; Sleep Apnea, Obstructive
PubMed: 35628326
DOI: 10.3390/ijms23105516 -
Cancer Metastasis Reviews Sep 2019The paradoxical pro-tumorigenic function of plasminogen activator inhibitor 1 (PAI-1, aka Serpin E1) in cancer progression and metastasis has been the subject of an... (Review)
Review
The paradoxical pro-tumorigenic function of plasminogen activator inhibitor 1 (PAI-1, aka Serpin E1) in cancer progression and metastasis has been the subject of an abundant scientific literature that has pointed to a pro-angiogenic role, a growth and migration stimulatory function, and an anti-apoptotic activity, all directed toward promoting tumor growth, cancer cell survival, and metastasis. With uPA, PAI-1 is among the most reliable biomarkers and prognosticators in many cancer types. More recently, a novel pro-tumorigenic function of PAI-1 in cancer-related inflammation has been demonstrated. These multifaceted activities of PAI-1 in cancer progression are explained by the complex structure of PAI-1 and its multiple functions that go beyond its anti-fibrinolytic and anti-plasminogen activation activities. However, despite the multiple evidences supporting a pro-tumorigenic role of PAI-1 in cancer, and the development of several inhibitors, targeting PAI-1, has remained elusive. In this article, the various mechanisms responsible for the pro-tumorigenic functions of PAI-1 are reviewed with emphasis on its more recently described contribution to cancer inflammation. The challenges of targeting PAI-1 in cancer therapy are then discussed.
Topics: Animals; Biomarkers, Tumor; Disease Progression; Humans; Models, Molecular; Neoplasms; Plasminogen Activator Inhibitor 1; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic
PubMed: 31734763
DOI: 10.1007/s10555-019-09806-4 -
Nature Communications May 2022In mammals, the serine protease plasmin degrades extracellular proteins during blood clot removal, tissue remodeling, and cell migration. The zymogen plasminogen is...
In mammals, the serine protease plasmin degrades extracellular proteins during blood clot removal, tissue remodeling, and cell migration. The zymogen plasminogen is activated into plasmin by two serine proteases: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), a process regulated by plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor that specifically inhibits tPA and uPA. Plasmodium gametes and sporozoites use tPA and uPA to activate plasminogen and parasite-bound plasmin degrades extracellular matrices, facilitating parasite motility in the mosquito and the mammalian host. Furthermore, inhibition of plasminogen activation by PAI-1 strongly blocks infection in both hosts. To block parasite utilization of plasmin, we engineered Anopheles stephensi transgenic mosquitoes constitutively secreting human PAI-1 (huPAI-1) in the midgut lumen, in the saliva, or both. Mosquitoes expressing huPAI-1 strongly reduced rodent and human Plasmodium parasite transmission to mosquitoes, showing that co-opting plasmin for mosquito infection is a conserved mechanism among Plasmodium species. huPAI-1 expression in saliva induced salivary gland deformation which affects sporozoite invasion and P. berghei transmission to mice, resulting in significant levels of protection from malaria. Targeting the interaction of malaria parasites with the fibrinolytic system using genetically engineered mosquitoes could be developed as an intervention to control malaria transmission.
Topics: Animals; Animals, Genetically Modified; Anopheles; Fibrinolysin; Humans; Malaria; Mammals; Mice; Mosquito Vectors; Plasminogen; Plasminogen Activator Inhibitor 1; Plasmodium; Sporozoites
PubMed: 35618711
DOI: 10.1038/s41467-022-30606-y -
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 -
Indian Journal of Ophthalmology Feb 2022Sub-macular hemorrhage poses a potential threat to vision if left untreated. The preferred surgical technique to clear sub-macular hemorrhage includes vitrectomy...
Sub-macular hemorrhage poses a potential threat to vision if left untreated. The preferred surgical technique to clear sub-macular hemorrhage includes vitrectomy followed by retinotomy using a 41G needle with subsequent injection of recombinant tissue plasminogen activator (r-tPA) followed by air/SF6 injection into the sub-retinal space. A malleable nature, increased resistance, and the cost of the 41G needle limit its use. We evaluated the safety and efficacy of a 26G needle for retinotomy as a supplement for the 41G needle in a series of six subjects with sub-macular hemorrhage. A slight modification in the procedure was done by injecting air into the sub-retinal space prior to the r-tPA injection. We found that our technique of using the 26G needle for retinotomy is safe and effective due to its stable nature and self-sealing properties. An air injection prior to r-tPA allows for increased bioavailability of the drug by preventing efflux due to its tamponading effect.
Topics: Fibrinolytic Agents; Humans; Macular Degeneration; Minimally Invasive Surgical Procedures; Retinal Hemorrhage; Retrospective Studies; Tissue Plasminogen Activator; Visual Acuity; Vitrectomy
PubMed: 35086260
DOI: 10.4103/ijo.IJO_1726_21