- Effects of gestational hypertension and pre-eclampsia in mRNA expression of fibrinolysis genes in primary cultured human umbilical vein endothelial cells. [Journal Article]
- TRThromb Res 2018 May 17; 167:74-79
- Hypertension disorders (HD) and pre-eclampsia (PRE) are leading causes of maternal deaths worldwide. PRE is associated with vascular endothelial dysfunction and with deregulation of the fibrinolysis ...
Hypertension disorders (HD) and pre-eclampsia (PRE) are leading causes of maternal deaths worldwide. PRE is associated with vascular endothelial dysfunction and with deregulation of the fibrinolysis pathway genes. Fibrinolysis is the fibrin clot hydrolysis process catalyzed by plasmin, a proteolytic enzyme formed from plasminogen. Plasminogen is cleaved by tissue-type (tPA) and urokinase-type (uPA) activators and inhibited by the plasminogen activator inhibitors type-1 (PAI-1) and type-2 (PAI-2). The whole process maintains blood hemostasis. This study aims to assess PAI-1, PAI-2, tPA and uPA mRNA expression in primary cultured human umbilical vein endothelial cells (HUVEC) isolated and cultured from healthy, HD and PRE women. Results show that PAI-1 and PAI-2 mRNA decreased in HD-HUVEC, whereas PAI-1 and uPA decreased in PRE-HUVEC cultures compared to control ones. Notably, the expression ratio between pro- and anti-fibrinolytic actors remained unchanged among the studied groups. It seems that newborn's hemostasis is maintained balanced probably by a compensatory mechanism that involves changes in the fibrinolysis gene expression profile. The real impact of these changes in mRNA expression is unknown, however, it is suggested that these changes could be associated with an increased predisposition to vascular disease development in the progeny.
- The clinical pattern of nephrotic syndrome in children has no effect on the concentration of soluble urokinase receptor (suPAR) in serum and urine. [Journal Article]
- PMPol Merkur Lekarski 2018 Apr 23; 44(262):183-187
- CONCLUSIONS: Serum and urine concentration of suPAR did not different between different clinical patterns of nephrotic syndrome in children, regardless the immunosuppressive treatment used.
- Diagnostic value of decoy receptor 3 combined with procalcitonin and soluble urokinase-type plasminogen activator receptor for sepsis. [Journal Article]
- CMCell Mol Biol Lett 2018; 23:22
- The levels of decoy receptor 3 (DcR3), soluble urokinase type plasminogen activator receptor (suPAR) and procalcitonin (PCT) are significantly increased in sepsis. We investigated the diagnostic valu...
The levels of decoy receptor 3 (DcR3), soluble urokinase type plasminogen activator receptor (suPAR) and procalcitonin (PCT) are significantly increased in sepsis. We investigated the diagnostic value of DcR3 combined with suPAR and PCT in sepsis. Patients with sepsis, non-infectious systemic inflammatory response comprehensive syndrome (SIRS) and healthy controls were recruited according to the diagnostic standard. We measured DcR3, suPAR, PCT, interleukin-6 (IL-6) and C-reactive protein (CRP), and the diagnostic value was evaluated by receiver operating characteristics (ROC) curves. In our analysis, serum DcR3, suPAR and PCT levels of the sepsis group were significantly higher than those of the SIRS and control groups. However, IL-6, CRP and WBC showed no significant difference between the SIRS group and the sepsis group. The serum DcR3 level was positively correlated with the serum suPAR level (r = 0.37, p = 0.0022) and PCT level (r = 0.37, p = 0.0021). Using DcR3, suPAR and PCT to distinguish SIRS from sepsis, the area under the curve (AUC) values were 0.892, 0.778 and 0.692. When DcR3, suPAR and PCT combined were used for diagnosis of sepsis, the AUC was 0.933, at a cut-off point of 0.342. This combination improved the sensitivity and specificity of diagnosis of sepsis, suggesting that use of the combination of three indexes enhanced the efficiency of sepsis diagnosis.
- Enhancement of cutaneous wound healing by Dsg2 augmentation of uPAR secretion. [Journal Article]
- JIJ Invest Dermatol 2018 May 09
- In addition to playing a role in adhesion, desmoglein 2 (Dsg2) is an important regulator of growth and survival signaling pathways, cell proliferation, migration and invasion, and oncogenesis. While ...
In addition to playing a role in adhesion, desmoglein 2 (Dsg2) is an important regulator of growth and survival signaling pathways, cell proliferation, migration and invasion, and oncogenesis. While low-level Dsg2 expression is observed in basal keratinocytes and is downregulated in non-healing venous ulcers, overexpression has been observed in both melanomas and non-melanoma malignancies. Here, we show that transgenic mice overexpressing Dsg2 in basal keratinocytes primed the activation of mitogenic pathways, but did not induce dramatic epidermal changes or susceptibility to chemical-induced tumor development. Interestingly, acceleration of full-thickness wound closure and increased wound-adjacent keratinocyte proliferation was observed in these mice. As epidermal cytokines and their receptors play critical roles in wound healing, Dsg2-induced secretome alterations were assessed with an antibody profiler array and revealed increased release and proteolytic processing of the urokinase-type plasminogen activator receptor (uPAR). Dsg2 induced uPAR expression in the skin of transgenic compared to wild-type mice. Wound healing further enhanced uPAR in both epidermis and dermis with concomitant increase in the pro-healing laminin-332, a major component of the basement membrane zone, in transgenic mice. This study demonstrates that Dsg2 induces epidermal activation of various signaling cascades and accelerates cutaneous wound healing, in part, through uPAR-related signaling cascades.
- Soluble urokinase-type plasminogen activator receptor is associated with signs of periodontitis in adolescents. [Journal Article]
- EJEur J Oral Sci 2018 May 11
- Owing to its molecular stability in body fluids, soluble urokinase-type plasminogen activator receptor (suPAR) is used as a biomarker for the level of systemic inflammation. This study compares the s...
Owing to its molecular stability in body fluids, soluble urokinase-type plasminogen activator receptor (suPAR) is used as a biomarker for the level of systemic inflammation. This study compares the suPAR levels in serum with those in the saliva of adolescents and evaluates their association with the periodontal conditions. Adolescents identified as screen positive (n = 87) or screen negative (n = 73) for periodontitis had saliva and serum samples taken, along with subgingival plaque samples. The concentrations of suPAR were determined in saliva and serum, and 18 microbial species and the immunoglobulin response to them was evaluated. Factor analyses were used to reduce the number of variables within each of the domains of clinical, microbiological, and immunological findings. The median salivary suPAR concentration was 13.18 [(interquartile range (IQR): 6.20-23.36] μg l-1 and was not associated with the serum suPAR levels (median 2.05; IQR: 1.62-2.46 μg l-1 ). Linear regression analysis showed that the log10 (salivary suPAR concentration) was statistically significantly positively associated with the clinical phenotype 'Periodontitis Extent' (β = 0.28; 95% CI: 0.16-0.39) along with 'Putative periodontopathogens' (β = 0.65; 95% CI: 0.51-0.79). The study represents the first determination of salivary suPAR concentration in a larger well-defined adolescent population. Our results suggest the potential for clinical use of suPAR in saliva as an inflammatory risk indicator/biomarker of periodontitis.
- In vivo evaluation of urokinase-loaded hollow nanogels for sonothrombolysis on suture embolization-induced acute ischemic stroke rat model. [Journal Article]
- BMBioact Mater 2018; 3(1):102-109
- The urokinase-type plasminogen activator (uPA) loaded hollow nanogels (nUK) were synthesized by a one-step reaction of glycol chitosan and aldehyde capped poly (ethylene oxide). The resultant formula...
The urokinase-type plasminogen activator (uPA) loaded hollow nanogels (nUK) were synthesized by a one-step reaction of glycol chitosan and aldehyde capped poly (ethylene oxide). The resultant formulation is sensitive to diagnostic ultrasound (US) of 2 MHz. Herein, we evaluated the in vivo sonothrombolysis performance of the nUK on acute ischemic stroke rat model which was established by suture embolization of middle cerebral artery (MCA). Via intravenous (i.v.) administration, the experimental data prove a controlled release of the therapeutic protein around the clots under ultrasound stimulation, leading to enhanced thrombolysis efficiency of the nUK, evidenced from smaller infarct volume and better clinical scores when compared to the i.v. dose of free uPA no matter with or without US intervention. Meanwhile, the preservation ability of the nanogels not only prolonged the circulation duration of the protein, but also resulted in the better blood-brain barrier protection of the nUK formulation, showing no increased risk on the hemorrhagic transformation than the controls. This work suggests that the nUK is a safe sonothrombolytic formulation for the treatment of acute ischemic stroke.
- Tristetraprolin: A novel target of diallyl disulfide that inhibits the progression of breast cancer. [Journal Article]
- OLOncol Lett 2018; 15(5):7817-7827
- Diallyl disulfide (DADS), a volatile component of garlic oil, has various biological properties, including antioxidant, antiangiogenic and anticancer effects. The present study aimed to explore novel...
Diallyl disulfide (DADS), a volatile component of garlic oil, has various biological properties, including antioxidant, antiangiogenic and anticancer effects. The present study aimed to explore novel targets of DADS that may slow or stop the progression of breast cancer. First, xenograft tumor models were created by subcutaneously injecting MCF-7 and MDA-MB-231 breast cancer cells into nude mice. Subsequently, western blot analysis was performed to investigate the expression of tristetraprolin (TTP), urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in the xenograft tumors, and cell cultures. Tablet cloning, Transwell and wound healing assays revealed that DADS treatment significantly inhibited the proliferation, invasion and migration of breast cancer cells. In addition, DADS treatment led to significant downregulation of uPA and MMP-9 protein expression, but significantly upregulated TTP expression in vivo and in vitro. Knocking down TTP expression using small interfering RNA reversed the aforementioned effects of DADS, which suggests TTP is a key target of DADS in inhibiting the progression of breast cancer.
- Characteristics of fibrinolytic disorders in acute promyelocytic leukemia. [Journal Article]
- HHematology 2018 May 04; :1-9
- CONCLUSIONS: In APL, activated coagulation system activated fibrinolytic system, and increased uPAR levels could contribute to the hyperfibrinolysis. Annexin II might not be involved in the coagulopathy.
- Urokinase-type plasminogen activator (uPA) promotes ezrin-mediated reorganization of the synaptic cytoskeleton in the ischemic brain. [Journal Article]
- JBJ Biol Chem 2018 May 02
- Synaptic repair in the ischemic brain is a complex process that requires reorganization of the actin cytoskeleton. Ezrin, radixin and moesin (ERM) are a group of evolutionary conserved proteins that...
Synaptic repair in the ischemic brain is a complex process that requires reorganization of the actin cytoskeleton. Ezrin, radixin and moesin (ERM) are a group of evolutionary conserved proteins that link the plasma membrane to the actin cytoskeleton and act as scaffolds for signaling transduction. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface and activates intracellular signaling pathways. Early studies indicate that uPA and uPAR expression increase during the recovery phase from an ischemic stroke, and that uPA binding to uPAR promotes neurorepair in the ischemic brain. The in vitro and in vivo studies presented here show that either the release of neuronal uPA or treatment with recombinant uPA (ruPA) induces the local synthesis of ezrin in the synapse and the recruitment of β3-integrin to the postsynaptic density (PSD) of cerebral cortical neurons by a plasminogen-independent mechanism. We found that β3-integrin has a double effect on ezrin, inducing its recruitment to the PSD via the intercellular adhesion molecule-5 (ICAM-5), and its subsequent activation by phosphorylation at Thr567. Finally, our data indicate that by triggering the reorganization of the actin cytoskeleton in the postsynaptic terminal, active ezrin induces the recovery of dendritic spines and synapses that have been damaged by an acute ischemic stroke. In summary, our data show that uPA/uPAR binding promotes synaptic repair in the ischemic brain via ezrin-mediated reorganization of the actin cytoskeleton in the postsynaptic terminal.
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- Molecular Mechanisms of Proteinuria in Focal Segmental Glomerulosclerosis. [Review]
- FMFront Med (Lausanne) 2018; 5:98
- Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disease resulting in end-stage renal disease in the USA and is increasing in prevalence worldwide. It is a diverse clin...
Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disease resulting in end-stage renal disease in the USA and is increasing in prevalence worldwide. It is a diverse clinical entity with idiopathic, genetic, metabolic, infectious, and other causes that culminate in a characteristic histologic pattern of injury. Proteinuria is a hallmark of FSGS as well as other primary and secondary glomerular disorders. The magnitude of proteinuria at disease onset and during treatment has prognostic implications for renal survival as well as associated cardiovascular morbidity and mortality. Significant advances over the last two decades have shed light on the molecular architecture of the glomerular filtration barrier. The podocyte is the target cell for injury in FSGS. A growing list of disease-causing gene mutations encoding proteins that regulate podocyte survival and homeostasis has been identified in FSGS patients. Several pathogenic and regulatory pathways have been uncovered that result in proteinuria in rodent models and human FSGS. The recurrence of proteinuria and FSGS after kidney transplantation is supporting evidence for the role of a circulating permeability factor in disease pathogenesis. These advances reviewed herein have significant implications for disease classification and therapeutic drug development for FSGS.