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- The Plasminogen Activation System Promotes Neurorepair in the Ischemic Brain. [Journal Article]
- CDCurr Drug Targets 2018 Dec 11
- The plasminogen activation (PA) system was originally thought to exclusively promote the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases: tis...
The plasminogen activation (PA) system was originally thought to exclusively promote the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). However, experimental evidence accumulated over the last 30 years indicates that tPA and uPA are also found in the central nervous system (CNS), where they have a plethora of functions that not always require plasmin generation or fibrin degradation. For example, plasminogen-dependent and -independent effects of tPA and uPA play a central role in the pathophysiological events that underlie one of the leading causes of mortality and disability in the world: cerebral ischemia. Indeed, recent work indicates that while the rapid release of tPA from the presynaptic compartment following the onset of cerebral ischemia protects the synapse from the deleterious effects of the ischemic injury, the secretion of uPA and its binding to its receptor (uPAR) during the recovery phase promotes the repair of synapses that have been lost to the acute ischemic insult. This restorative role of uPA has high translational significance because to this date there is no effective approach to induce neurorepair in the ischemic brain. Here we will discuss recent evidence that bridges the gap between basic research in the field of the PA system and the bedside of ischemic stroke patients, indicating that uPA and uPAR are potential targets for the development of therapeutic strategies to promote neurological recovery among ischemic stroke survivors.
- Idiopathic Pulmonary Fibrosis: Prospective, Case-Controlled Study of Natural History and Circulating Biomarkers. [Journal Article]
- ChestChest 2018; 154(6):1359-1370
- CONCLUSIONS: Several biomarkers, including CCL18, were associated with IPF, but none predicted disease progression. Two novel biomarkers, HE4 and prostasin, were identified and warrant further investigation.
- Probable Roles of Coagulation Cascade and Fibrinolysis System in the Development of Allergic Rhinitis. [Journal Article]
- AJAm J Rhinol Allergy 2018 Dec 06; :1945892418816015
- CONCLUSIONS: In AR, particular components of the coagulation cascade were increased and fibrinolysis system was decreased compared to normal control. This difference may be associated with the fibrin deposition in the mucosa of AR mouse model.
- Increased urokinase and consumption of α2 -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay. [Journal Article]
- JTJ Thromb Haemost 2018 Nov 19
- CONCLUSIONS: TXA protects fibrin but stimulates uPA activity and slows inhibition of plasmin by α2 -antiplasmin. Plasmin proteolytic activity digests fibrinogen and disrupts coagulation, exacerbated when α2 -antiplasmin is consumed by ongoing fibrinolysis. Additional direct inhibition of plasmin by aprotinin may prevent development of coagulopathy and extend the useful time window of TXA treatment. This article is protected by copyright. All rights reserved.
- Inhibiting the urokinase-type plasminogen activator receptor system recovers STZ-induced diabetic nephropathy. [Journal Article]
- JCJ Cell Mol Med 2018 Nov 13
- The urokinase-type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as so...
The urokinase-type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR -(s)uPAR- from circulation) is to regulate podocyte function through αvβ3 integrin/Rac-1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)-induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac-1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ-induced up-regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac-1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen-plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR-targeting approaches.
- Urokinase-type Plasminogen Activator Induces Neurorepair in the Ischemic Brain. [Journal Article]
- JNJ Neurol Exp Neurosci 2018; 4(2):24-29
- Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. Recent studies ind...
Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. Recent studies indicate that neurons but not astrocytes release uPA during the recovery phase from an ischemic injury, and that binding of uPA to uPAR promotes neurorepair in the ischemic brain by a mechanism that does not require plasmin generation. A combined approach of in vitro and in vivo studies has shown that uPA binding to uPAR induces the reorganization of the actin cytoskeleton in dendritic spines and axons that have suffered an ischemic injury. Furthermore, recent data indicate that uPA-uPAR binding induces astrocytic activation and a crosstalk between activated astrocytes and the injured neuron that triggers a sequence of biochemical events that promote the repair of synapses injured by the ischemic insult. The translational relevance of these observations is noteworthy because following its intravenous administrations recombinant uPA (ruPA) reaches the ischemic tissue, thus raising the question of whether treatment with ruPA is an effective therapeutic strategy to promote neurorepair functional recovery among ischemic stroke survivors.
- Follicle rupture during ovulation with an emphasis on recent progress in fish models. [Review]
- RReproduction 2018 Oct 01
- Ovulation, which is induced by the ovulatory luteinizing hormone (LH) surge, is a dynamic process that results in a discharge of one or more fertilizable oocytes from the ovarian follicle into the ov...
Ovulation, which is induced by the ovulatory luteinizing hormone (LH) surge, is a dynamic process that results in a discharge of one or more fertilizable oocytes from the ovarian follicle into the ovarian cavity or into the abdominal cavity. Follicle rupture is a core event of the ovulatory process and has been the subject of intensive investigation. Many studies have been performed in various vertebrate animals that focused on proteolysis during ovulation. Despite much effort, the proteases responsible for follicle rupture in ovulation have not yet been identified for mammalian species. However, studies conducted using the teleost medaka have recently provided valuable information about the follicle rupture process. Follicle rupture during medaka ovulation is accomplished by a two-step extracellular matrix (ECM) hydrolysis mechanism involving two distinct protease systems, the urokinase-type plasminogen activator-1 (Plau1)/plasmin and the matrix metalloproteinase (MMP) system. In the 24-h spawning cycle of the fish, the former protease system is activated first, and the latter subsequently becomes active. Proteolytic activities of these systems are regulated by their intrinsic inhibitors. The endocrine regulation of the rupture was examined by investigating the expression of matrix metalloproteinase 15 (Mmp15), which is the only LH-inducible protease among those involved in the rupture process. At least two transcription factors, classical nuclear progestin receptor and CCAAT/enhancer-binding protein β, play critical roles in the expression of the protease transcript. This review also summarizes studies addressing follicle rupture during ovulation conducted using other teleost models to understand the current status of teleost ovulation studies.
- Contribution of the TNF-α (Tumor Necrosis Factor-α)-TNF-Rp55 (Tumor Necrosis Factor Receptor p55) Axis in the Resolution of Venous Thrombus. [Journal Article]
- ATArterioscler Thromb Vasc Biol 2018; 38(11):2638-2650
- Objective- Deep vein thrombosis results from a combination of risk factors including genetic conditions, obesity, drugs, pregnancy, aging, and malignancy. We examined pathophysiological roles of the ...
Objective- Deep vein thrombosis results from a combination of risk factors including genetic conditions, obesity, drugs, pregnancy, aging, and malignancy. We examined pathophysiological roles of the TNF-α (tumor necrosis factor-α)-TNF-Rp55 (tumor necrosis factor receptor p55) axis in thrombus resolution using Tnfrp55-/- (TNF-Rp55-deficient) mice. Approach and Results- On ligating the inferior vena cava of wild-type (WT) mice, venous thrombi formed and grew progressively until 5 days but shrunk to <50% of the thrombus weight at day 14. Concomitantly, inferior vena cava ligation enhanced intrathrombotic gene expression of Tnfa and Tnfrp55, and intrathrombotic macrophages expressed both TNF-α and TNF-Rp55 proteins. In Tnfrp55-/- mice treated with the same manner, thrombus formed at a similar rate for 5 days, but shrinking was delayed compared with WT mice. Moreover, the blood flow recovery in thrombosed inferior vena cava was suspended in Tnfrp55-/- mice compared with WT mice. Intrathrombotic Plau (urokinase-type plasminogen activator), Mmp2 (matrix metalloproteinase 2), and Mmp9 (matrix metalloproteinase 9) mRNA expression was significantly reduced in Tnfrp55-/- mice, compared with WT ones. Supportingly, the administration of anti-TNF-α antibody or TNF-α inhibitor (etanercept) delayed the thrombus resolution in WT mice. Furthermore, TNF-α treatment enhanced gene expression of Plau, Mmp2, and Mmp9 in WT macrophages but not Tnfrp55-/- macrophages. These effects were significantly suppressed by ERK (extracellular signal regulated kinase) and NF-κB (nuclear factor-kappa B) inhibitors. Therefore, the lack of TNF-Rp55 has detrimental roles in the thrombus resolution by suppressing PLAU, MMP-2, and MMP-9 expression. In contrast, TNF-α administration accelerated thrombus resolution in WT but not Tnfrp55-/- mice. Conclusions- The TNF-α-TNF-Rp55 axis may have essential roles in the resolution of venous thrombus in mice.
- Fetal Renal Echogenicity Associated with Maternal Focal Segmental Glomerulosclerosis: The Effect of Transplacental Transmission of Permeability Factor suPAR. [Case Reports]
- JCJ Clin Med 2018 Oct 04; 7(10)
- We report a case of a pregnant woman with nephrotic syndrome due to biopsy-proven focal segmental glomerulosclerosis (FSGS) whose fetus developed echogenic kidneys and severe oligohydramnios by 27 we...
We report a case of a pregnant woman with nephrotic syndrome due to biopsy-proven focal segmental glomerulosclerosis (FSGS) whose fetus developed echogenic kidneys and severe oligohydramnios by 27 weeks of gestation. Maternal treatment with prednisone resulted in normalization of the amniotic fluid indices and resolution of fetal renal echogenicity. The newborn was noted to have transient renal dysfunction and proteinuria, resolving by 6 weeks postpartum. The transplacental passage of permeability factors is postulated to have caused both the fetal and newborn renal presentation, with significantly elevated levels of soluble urokinase-type plasminogen activator receptor (suPAR) noted in the cord blood. This case documents the transplacental maternal-fetal transmission of suPAR, demonstrating the potential for maternal-fetal transmission of deleterious, disease-causing entities, and adds to the differential diagnosis of fetal echogenic kidneys. Further, this is the first documentation of a fetal response to maternal systemic therapy.
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- Serum Urokinase-Type Plasminogen Activator Receptor Does Not Outperform C-Reactive Protein and Procalcitonin as an Early Marker of Severity of Acute Pancreatitis. [Journal Article]
- JCJ Clin Med 2018 Sep 27; 7(10)
- Severe acute pancreatitis (SAP) concerns 10⁻20% of acute pancreatitis (AP) patients and is associated with a poor prognosis and high mortality. An early prognosis of the unfavorable outcome, transfer...
Severe acute pancreatitis (SAP) concerns 10⁻20% of acute pancreatitis (AP) patients and is associated with a poor prognosis and high mortality. An early prognosis of the unfavorable outcome, transfer to an intensive care unit (ICU) and the introduction of an adequate treatment are crucial for patients' survival. Recently, the elevated circulating urokinase-type plasminogen activator receptor (uPAR) has been reported to predict SAP with a high diagnostic accuracy among patients in a tertiary center. The aim of the study was to compare the diagnostic utility of uPAR and other inflammatory markers as the predictors of the unfavorable course of AP in patients admitted to a secondary care hospital within the first 24 h of the onset of AP. The study included 95 patients, eight with a SAP diagnosis. Serum uPAR was measured on admission and in the two subsequent days. On admission, uPAR significantly predicted organ failure, acute cardiovascular failure, acute kidney injury, the need for intensive care, and death. The diagnostic accuracy of the admission uPAR for the prediction of SAP, organ failure, and ICU transfer or death was low to moderate and did not differ significantly from the diagnostic accuracy of interleukin-6, C-reactive protein, procalcitonin, D-dimer and soluble fms-like tyrosine kinase-1. In the secondary care hospital, where most patients with AP are initially admitted, uPAR measurements did not prove better than the currently used markers.