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Translational Stroke Research Aug 2023Circulating neutrophils are activated shortly after stroke and in turn affect the fate of ischemic brain tissue, and microRNAs (miRNA) participate in regulating...
Circulating neutrophils are activated shortly after stroke and in turn affect the fate of ischemic brain tissue, and microRNAs (miRNA) participate in regulating neuroinflammation. We probed the role of neutrophilic miRNA in ischemic stroke. miR-193a-5p was decreased in circulating neutrophils of acute ischemic stroke (AIS) patients and healthy controls. In another set of AIS patients treated with recombinant tissue plasminogen activator, higher neutrophilic miR-193a-5p levels were associated with favorable outcomes at 3 months and non-symptomatic intracerebral hemorrhage. An experimental stroke model and human neutrophil-like HL-60 cells were further transfected with agomiR-193a-5p/antagomiR-193a-5p or ubiquitin-conjugating enzyme V2 (UBE2V2)-siRNA prior to model induction for in vivo and in vitro studies. Results of 2,3,5-triphenyl tetrazolium chloride staining and neurological function evaluations at post-experimental stroke showed that intravenous agomiR-193a-5p transfusion protected against ischemic cerebral injury in the acute stage and promoted neurological recovery in the subacute stage. This protective role was suggested to correlate with neutrophil N2 transformation based on the N2-like neutrophil proportions in the bone marrow, peripheral blood, and spleen of the experimental stroke model and the measurement of neutrophil phenotype-associated molecule levels. Mechanistically, analyses indicated that UBE2V2 might be a target of miR-193a-5p. Cerebral injury and neuroinflammation aggravated by miR-193a-5p inhibition were reversed by UBE2V2 silencing. In conclusion, miR-193a-5p protects against cerebral ischemic injury by restoring neutrophil N2 phenotype-associated neuroinflammation suppression, likely, in part, via UBE2V2 induction.
Topics: Humans; Neutrophils; Ischemic Stroke; Neuroinflammatory Diseases; Tissue Plasminogen Activator; MicroRNAs
PubMed: 35906328
DOI: 10.1007/s12975-022-01071-y -
The Cochrane Database of Systematic... Jan 2023Acute non-arteritic central retinal artery occlusion (CRAO) occurs as a sudden interruption of the blood supply to the retina and typically results in severe loss of... (Review)
Review
BACKGROUND
Acute non-arteritic central retinal artery occlusion (CRAO) occurs as a sudden interruption of the blood supply to the retina and typically results in severe loss of vision in the affected eye. Although many therapeutic interventions have been proposed, there is no generally agreed upon treatment regimen.
OBJECTIVES
To assess the effects of treatments for acute non-arteritic CRAO.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 February 2022.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) comparing any interventions with another treatment in participants with acute non-arteritic CRAO in one or both eyes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and graded the certainty of the body of evidence for primary (mean change in best-corrected visual acuity [BCVA]) and secondary (quality of life and adverse events) outcomes using the GRADE classification.
MAIN RESULTS
We included six RCTs with 223 total participants with acute non-arteritic CRAO; the studies ranged in size from 10 to 84 participants. The included studies varied geographically: one in Australia, one in Austria and Germany, two in China, one in Germany, and one in Italy. We were unable to conduct any meta-analyses due to study heterogeneity. None of the included studies compared the same pair of interventions: 1) tissue plasminogen activator (t-PA) versus intravenous saline; 2) t-PA versus isovolemic hemodilution, eyeball massage, intraocular pressure reduction, and anticoagulation; 3) nitroglycerin, methazolamide, mecobalamin tablets, vitamin B and B injections, puerarin and compound anisodine (also known as 654-2) along with oxygen inhalation, eyeball massage, tube expansion, and anticoagulation compared with and without intravenous recombinant tissue plasminogen activator (rt-PA); 4) transcorneal electrical stimulation (TES) with 0 mA versus with 66% of the participant's individual electrical phosphene threshold (EPT) at 20 Hz (66%) versus with 150% of the participant's individual EPT (150%) at 20 Hz; 5) ophthalmic artery branch retrograde thrombolysis versus superselective ophthalmic artery thrombolysis; and 6) pentoxifylline versus placebo. There was no evidence of an important difference in visual acuity between participants treated with t-PA versus intravenous saline (mean difference [MD] at 1 month -0.15 logMAR, 95% confidence interval [CI] -0.48 to 0.18; 1 study, 16 participants; low certainty evidence); t-PA versus isovolemic hemodilution, eyeball massage, intraocular pressure reduction, and anticoagulation (MD at 1 month -0.00 logMAR, 95% CI -0.24 to 0.23; 1 study, 82 participants; low certainty evidence); and TES with 0 mA versus TES with 66% of EPT at 20 Hz versus TES with 150% of EPT at 20 Hz. Participants treated with t-PA experienced higher rates of serious adverse effects. The other three comparisons did not report statistically significant differences. Other studies reported no data on secondary outcomes (quality of life or adverse events). AUTHORS' CONCLUSIONS: The current research suggests that proposed interventions for acute non-arteritic CRAO may not be better than observation or treatments of any kind such as eyeball massage, oxygen inhalation, tube expansion, and anticoagulation, but the evidence is uncertain. Large, well-designed RCTs are necessary to determine the most effective treatment for acute non-arteritic CRAO.
Topics: Humans; Tissue Plasminogen Activator; Retinal Artery Occlusion; Anticoagulants; China
PubMed: 36715340
DOI: 10.1002/14651858.CD001989.pub3 -
Frontiers in Immunology 2023Patients with coronavirus disease-2019 (COVID-19) have an increased risk of thrombosis and acute respiratory distress syndrome (ARDS). Thrombosis is often attributed to...
Patients with coronavirus disease-2019 (COVID-19) have an increased risk of thrombosis and acute respiratory distress syndrome (ARDS). Thrombosis is often attributed to increases in plasminogen activator inhibitor-1 (PAI-1) and a shut-down of fibrinolysis (blood clot dissolution). Decreased urokinase-type plasminogen activator (uPA), a protease necessary for cell-associated plasmin generation, and increased tissue-type plasminogen activator (tPA) and PAI-1 levels have been reported in COVID-19 patients. Because these factors can occur in free and complexed forms with differences in their biological functions, we examined the predictive impact of uPA, tPA, and PAI-1 in their free forms and complexes as a biomarker for COVID-19 severity and the development of ARDS. In this retrospective study of 69 Japanese adults hospitalized with COVID-19 and 20 healthy donors, we found elevated free, non-complexed PAI-1 antigen, low circulating uPA, and uPA/PAI-1 but not tPA/PAI-1 complex levels to be associated with COVID-19 severity and ARDS development. This biomarker profile was typical for patients in the complicated phase. Lack of PAI-1 activity in circulation despite free, non-complexed PAI-1 protein and plasmin/α2anti-plasmin complex correlated with suPAR and sVCAM levels, markers indicating endothelial dysfunction. Furthermore, uPA/PAI-1 complex levels positively correlated with TNFα, a cytokine reported to trigger inflammatory cell death and tissue damage. Those levels also positively correlated with lymphopenia and the pro-inflammatory factors interleukin1β (IL1β), IL6, and C-reactive protein, markers associated with the anti-viral inflammatory response. These findings argue for using uPA and uPA/PAI-1 as novel biomarkers to detect patients at risk of developing severe COVID-19, including ARDS.
Topics: Adult; Humans; Urokinase-Type Plasminogen Activator; Plasminogen Activator Inhibitor 1; Retrospective Studies; Fibrinolysin; COVID-19; Biomarkers; Respiratory Distress Syndrome; Thrombosis
PubMed: 38313435
DOI: 10.3389/fimmu.2023.1299792 -
BMC Ophthalmology Oct 2022To evaluate anatomical and functional outcomes of patients with large submacular hemorrhage (SMH) who treated by pars plana vitrectomy (PPV) in combination with...
BACKGROUND
To evaluate anatomical and functional outcomes of patients with large submacular hemorrhage (SMH) who treated by pars plana vitrectomy (PPV) in combination with subretinal tissue plasminogen activator (TPA) injection, intraocular gas tamponade, and with additional post-operative interventions.
METHODS
Medical records of 9 patients who presented with large SMH secondary to age-related macular degeneration (AMD) and underwent PPV, subretinal TPA injection, and gas tamponade at Chiang Mai university hospital between January 2012 and January 2020 were reviewed. Collected data included preoperative visual acuity (VA), SMH extent and duration, intraoperation and post-operation complications, post-operative anatomical and VA responses, and the need for administer post-operation additional treatments.
RESULTS
Overall, five patients were male and four patients were female with a mean (SD) age of 66.9 (7.7) years and a mean (SD) follow-up of 21.1 (16.1) months. A mean (SD) duration of SMH was 15.1 (10.9) days with a mean (SD) extent of SMH was 6.2 (3.4) disc diameters. At 1-month post-operation, complete SMH displacement was noted in eight (88.9%) patients. The mean (SD) VA significantly improved from LogMAR 1.9 (0.4) to 1.1 (0.4), (P = 0.004). During follow-up, eight patients (88.9%) were given additional therapy (anti-vascular endothelial growth factor (anti-VEGF) monotherapy, photodynamic therapy, or in combination). At final follow-up, a mean (SD) LogMAR VA of 0.9 (0.4) was significantly improved compared to baseline (P = 0.004). For intra- and post-operation complications, none developed intraoperative retinal break and retinal detachment.
CONCLUSIONS
Vitrectomy with subretinal TPA injection, intraocular gas tamponade, and additional post-operation treatments provide benefit for anatomical and visual outcomes for patients with large SMH. It may consider as one of effective treatment in this group of patients.
Topics: Aged; Female; Humans; Male; Endotamponade; Fibrinolytic Agents; Fluorescein Angiography; Follow-Up Studies; Retinal Hemorrhage; Retrospective Studies; Tissue Plasminogen Activator; Vitrectomy; Middle Aged
PubMed: 36303103
DOI: 10.1186/s12886-022-02639-w -
International Journal of Molecular... Dec 2022Stem cell transplantation is historically understood as a powerful preclinical therapeutic following stroke models. Current clinical strategies including clot... (Review)
Review
Stem cell transplantation is historically understood as a powerful preclinical therapeutic following stroke models. Current clinical strategies including clot busting/retrieval are limited by their time windows (tissue plasminogen activator: 3-4 h) and inevitable reperfusion injuries. However, 24+ h post-stroke, stem cells reduce infarction size, improve neurobehavioral performance, and reduce inflammatory agents including interleukins. Typically, interleukin-6 (IL-6) is regarded as proinflammatory, and thus, preclinical studies often discuss it as beneficial for neurological recuperation when stem cells reduce IL-6's expression. However, some studies have also demonstrated neurological benefit with upregulation of IL-6 or preconditioning of stem cells with IL-6. This review specifically focuses on stem cells and IL-6, and their occasionally disparate, occasionally synergistic roles in the setting of ischemic cerebrovascular insults.
Topics: Humans; Interleukin-6; Tissue Plasminogen Activator; Stroke; Stem Cell Transplantation; Interleukins
PubMed: 36555094
DOI: 10.3390/ijms232415453 -
Journal of Thrombosis and Haemostasis :... Feb 2022To reestablish blood flow in vessels occluded by clots, tissue plasminogen activator (tPA) can be used; however, its efficacy is limited by transport to and into a clot...
BACKGROUND
To reestablish blood flow in vessels occluded by clots, tissue plasminogen activator (tPA) can be used; however, its efficacy is limited by transport to and into a clot and by the depletion of its substrate, plasminogen.
OBJECTIVES
To overcome these rate limitations, a platform was designed to co-deliver tPA and plasminogen based on microwheels (µwheels), wheel-like assemblies of superparamagnetic colloidal beads that roll along surfaces at high speeds.
METHODS
The biochemical speed limit was determined by measuring fibrinolysis of plasma clots at varying concentrations of tPA (10-800 nM) and plasminogen (1-6 µM). Biotinylated magnetic mesoporous silica nanoparticles were synthesized and bound to streptavidin-coated superparamagnetic beads to make studded beads. Studded beads were loaded with plasminogen and tPA was immobilized on their surface. Plasminogen release and tPA activity were measured on the studded beads. Studded beads were assembled into µwheels with rotating magnetic fields and fibrinolysis of plasma clots was measured in a microfluidic device.
RESULTS
The biochemical speed limit for plasma clots was ~15 µm/min. Plasminogen-loaded, tPA-immobilized µwheels lyse plasma clots at rates comparableto the biochemical speed limit. With the addition of a corkscrew motion, µwheels penetrate clots, thereby exceeding the biochemical speed limit (~20 µm/min) and achieving lysis rates 40-fold higher than 50 nM tPA.
CONCLUSIONS
Co-delivery of an immobilized enzyme and its substrate via a microbot capable of mechanical work has the potential to target and rapidly lyse clots that are inaccessible by mechanical thrombectomy devices or recalcitrant to systemic tPA delivery.
Topics: Drug Delivery Systems; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Magnetic Iron Oxide Nanoparticles; Plasminogen; Thrombosis; Tissue Plasminogen Activator
PubMed: 34882946
DOI: 10.1111/jth.15617 -
International Journal of Molecular... Jul 2023Macrophage infiltration and accumulation is a hallmark of chronic kidney disease. Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of... (Review)
Review
Macrophage infiltration and accumulation is a hallmark of chronic kidney disease. Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of blood coagulation, fibrinolysis, and matrix degradation, and has been shown to act as a cytokine to trigger various receptor-mediated intracellular signal pathways, modulating macrophage function in response to kidney injury. In this review, we discuss the current understanding of tPA-modulated macrophage function and underlying signaling mechanisms during kidney fibrosis and inflammation.
Topics: Mice; Animals; Tissue Plasminogen Activator; Signal Transduction; Kidney Diseases; Macrophages; Kidney
PubMed: 37446244
DOI: 10.3390/ijms241311067 -
American Journal of Physiology. Cell... Jul 2022Corneal fibroblasts are embedded within an extracellular matrix composed largely of collagen type 1, proteoglycans, and other proteins in the corneal stroma, and their...
Corneal fibroblasts are embedded within an extracellular matrix composed largely of collagen type 1, proteoglycans, and other proteins in the corneal stroma, and their morphology and function are subject to continuous regulation by collagen. During wound healing and in various pathological conditions, corneal fibroblasts differentiate into myofibroblasts characterized by the expression of α-smooth muscle actin (α-SMA). Endo180, also known as urokinase-type plasminogen activator (uPA) receptor-associated protein (uPARAP), is a collagen receptor. Here we investigated whether targeting of Endo180 and the uPA receptor (uPAR) by uPA might play a role in the regulation of α-SMA expression by culturing corneal fibroblasts derived from uPA-deficient () or wild-type () mice in a collagen gel or on plastic. The expression of α-SMA was upregulated, the amounts of full-length Endo180 and uPAR were increased, and the levels of both transforming growth factor-β (TGF-β) expression and Smad3 phosphorylation were higher in corneal fibroblasts compared with cells under the collagen gel culture condition. Antibodies to Endo180 inhibited these effects of uPA deficiency on α-SMA and TGF-β expression, whereas a TGF-β signaling inhibitor blocked the effects on Smad3 phosphorylation and α-SMA expression. Our results suggest that uPA deficiency might promote the interaction between collagen and Endo180 and thereby increase α-SMA expression in a manner dependent on TGF-β signaling. Expression of α-SMA is thus negatively regulated by uPA through targeting of Endo180 and uPAR.
Topics: Actins; Animals; Collagen; Fibroblasts; Mice; Muscle, Smooth; Receptors, Mitogen; Transforming Growth Factor beta; Urokinase-Type Plasminogen Activator
PubMed: 35649252
DOI: 10.1152/ajpcell.00432.2021 -
Scandinavian Journal of Trauma,... Apr 2022Accurate triage of the undifferentiated patient is a critical task in prehospital emergency care. However, there is a paucity of literature synthesizing currently... (Review)
Review
BACKGROUND
Accurate triage of the undifferentiated patient is a critical task in prehospital emergency care. However, there is a paucity of literature synthesizing currently available prehospital triage tools. This scoping review aims to identify published tools used for prehospital triage globally and describe their performance characteristics.
METHODS
A comprehensive search was performed of primary literature in English-language journals from 2009 to 2019. Papers included focused on emergency medical services (EMS) triage of single patients. Two blinded reviewers and a third adjudicator performed independent title and abstract screening and subsequent full-text reviews.
RESULTS
Of 1521 unique articles, 55 (3.6%) were included in the final synthesis. The majority of prehospital triage tools focused on stroke (n = 19; 35%), trauma (19; 35%), and general undifferentiated patients (15; 27%). All studies were performed in high income countries, with the majority in North America (23, 42%) and Europe (22, 40%). 4 (7%) articles focused on the pediatric population. General triage tools aggregate prehospital vital signs, mental status assessments, history, exam, and anticipated resource need, to categorize patients by level of acuity. Studies assessed the tools' ability to accurately predict emergency department triage assignment, hospitalization and short-term mortality. Stroke triage tools promote rapid identification of patients with acute large vessel occlusion ischemic stroke to trigger timely transport to diagnostically- and therapeutically-capable hospitals. Studies evaluated tools' diagnostic performance, impact on tissue plasminogen activator administration rates, and correlation with in-hospital stroke scales. Trauma triage tools identify patients that require immediate transport to trauma centers with emergency surgery capability. Studies evaluated tools' prediction of trauma center need, under-triage and over-triage rates for major trauma, and survival to discharge.
CONCLUSIONS
The published literature on prehospital triage tools predominantly derive from high-income health systems and mostly focus on adult stroke and trauma populations. Most studies sought to further simplify existing triage tools without sacrificing triage accuracy, or assessed the predictive capability of the triage tool. There was no clear 'gold-standard' singular prehospital triage tool for acute undifferentiated patients.
TRIAL REGISTRATION
Not applicable.
Topics: Adult; Child; Emergency Medical Services; Humans; Stroke; Tissue Plasminogen Activator; Trauma Centers; Triage
PubMed: 35477474
DOI: 10.1186/s13049-022-01019-z -
The Journal of Biological Chemistry Jul 2022Plasmin is a broad-spectrum protease and therefore needs to be tightly regulated. Active plasmin is formed from plasminogen, which is found in high concentrations in the...
Plasmin is a broad-spectrum protease and therefore needs to be tightly regulated. Active plasmin is formed from plasminogen, which is found in high concentrations in the blood and is converted by the plasminogen activators. In the circulation, high levels of α2-antiplasmin rapidly and efficiently inhibit plasmin activity. Certain myeloid immune cells have been shown to bind plasmin and plasminogen on their cell surface via proteins that bind to the plasmin(ogen) kringle domains. Our earlier work showed that T cells can activate plasmin but that they do not themselves express plasminogen. Here, we demonstrate that T cells express several known plasminogen receptors and that they bind plasminogen on their cell surface. We show T cell-bound plasminogen was converted to plasmin by plasminogen activators upon T cell activation. To examine functional consequences of plasmin generation by activated T cells, we investigated its effect on the chemokine, C-C motif chemokine ligand 21 (CCL21). Video microscopy and Western blotting confirmed that plasmin bound by human T cells cleaves CCL21 and increases the chemotactic response of monocyte-derived dendritic cells toward higher CCL21 concentrations along the concentration gradient by increasing their directional migration and track straightness. These results demonstrate how migrating T cells and potentially other activated immune cells may co-opt a powerful proteolytic system from the plasma toward immune processes in the peripheral tissues, where α2-antiplasmin is more likely to be absent. We propose that plasminogen bound to migrating immune cells may strongly modulate chemokine responses in peripheral tissues.
Topics: Antifibrinolytic Agents; Chemokine CCL21; Chemokines; Dendritic Cells; Fibrinolysin; Humans; Ligands; Plasminogen; Plasminogen Activators; T-Lymphocytes; alpha-2-Antiplasmin
PubMed: 35690148
DOI: 10.1016/j.jbc.2022.102112