Urokinase Plasminogen Activator Research Articles

Occlusal trauma aggravates periodontitis through the plasminogen/plasmin system.

Periodontitis is a common oral disease that is aggravated by occlusal trauma. Fibrin is a protein that participates in blood clotting and is involved in several human diseases. The deposition of fibrin in periodontal tissues can induce periodontitis, while mechanical forces may regulate the degradation of fibrin. Our study investigated how occlusal trauma aggravating periodontitis through regulating the plasminogen/plasmin system and fibrin deposition. This study included 84 C57BL/6 mice in which periodontitis was induced with or without occlusal trauma. Micro-computed tomography was used to assess bone resorption. Fibrin, fibrinogen, plasminogen, plasmin, tissue plasminogen activator (t-PA), and urokinase plasminogen activator (u-PA) levels were measured using Frazer-Lendrum staining, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, immunofluorescence staining, and immunohistochemistry staining. Occlusal trauma aggravated inflammation and bone resorption. The periodontitis group showed significant fibrin deposition. Occlusal trauma increased fibrin deposition and neutrophil aggregation. The periodontitis with occlusal trauma group had decreased fibrinogen, t-PA, and u-PA expression and plasmin and fibrin degradation product levels, as well as increased plasminogen levels. Occlusal trauma promotes excessive fibrin deposition by suppressing the plasminogen/plasmin system, thus exacerbating periodontitis.

A characterization of patients with low soluble urokinase plasminogen activator receptor who died within 90 days of hospital discharge.

Soluble urokinase plasminogen activator receptor (suPAR) is a marker of systemic chronic inflammation. Elevated suPAR levels are associated with adverse clinical outcomes, but a small subset of patients with low suPAR also experience poor outcomes. Therefore, we aimed to characterize patients presenting to the emergency department with low suPAR (<3 ng/mL) who died within 90 days after discharge in a registry-based study. Compared to patients with low suPAR who survived (n = 15 122), those who died within 90 days (n = 87) had higher age (75.4 years), higher medication use (7.0; 71.3% with polypharmacy) and more blood tests outside reference intervals (5.0) (including C-reactive protein, neutrophils and albumin), and the most common diagnoses were chronic pulmonary disease (27.6%), cerebrovascular disease (18.4%) and dementia (11.5%). Patients with low suPAR were more morbid than what was reflected by suPAR alone. Future studies must determine which factors that contribute the most to potential algorithms when stratifying patients based on their risk of adverse clinical outcomes. These data indicate that inclusion of medication data could be relevant.

Biomarker-guided detection of acute kidney injury in abdominal aortic surgery: the new and the old.

Acute kidney injury (AKI) is a common complication in patients undergoing major vascular surgery. Despite significant research efforts in this area, the incidence of AKI remains high, posing a significant challenge to healthcare systems, especially in situations where resources are limited. Early prediction of AKI severity and individualized postoperative care is therefore essential. The primary objective of this exploratory study was to assess the diagnostic value of urine cell-cycle arrest biomarkers [(TIMP-2) × (IGFBP7)] and soluble urokinase plasminogen activator receptor (suPAR) for predicting moderate or severe AKI within 24 h after open aortic surgery, and compared to routine kidney biomarkers. Seventy-five patients undergoing elective aortic surgery were included. Clinical parameters, urine and blood samples were collected preoperatively, immediately postoperatively, and 24 h later. AKI was defined using KDIGO criteria. Individual and combined diagnostic performance of biomarkers were evaluated. Of the 75 patients, 61% developed AKI, of which 28% developed moderate or severe AKI within 24 h of surgery. Baseline demographics, comorbidities and kidney parameters did not differ between patients with moderate or severe AKI (AKI II/III) and none or mild AKI (AKI 0/I), except for higher preoperative suPAR levels in later AKI II/III patients. Urine osmolality, Cystatin C and serum creatinine had the highest predictive power for AKI II/III with AUCs of 0.75-0.72. (TIMP-2) × (IGFBP7), and neither (TIMP-2) × (IGFBP7) nor suPAR individually showed superior diagnostic value. Combining CysC or SCr with urine osmolality and 6 h urine output gave the best performance with AUCs of 0.86 (95% CI, 0.74-0.96) and 0.85 (95% CI, 0.75-0.95) respectively. Our study suggests that routine parameters like urine osmolality, CysC, SCr and 6 h urine output perform best in predicting postoperative AKI after aortic surgery compared to the new biomarkers (TIMP-2) × (IGFBP7) and suPAR. Combining biomarkers, particularly CysC or SCr with urine output, urine osmolality, may enhance diagnostic accuracy. Further validation in larger cohorts and clinical settings is warranted to establish their clinical utility.

Endothelial-specific Enhancer as a Cis Element of PLAUR Regulation by TNF-alpha, IL-1beta, and VEGF.

The expression of human PLAUR gene, which encodes the urokinase plasminogen activator receptor (uPAR), is cell- and process-specific, elevating inflammation, cancer and senescence. Its tight regulation is achieved by regulatory elements in the gene locus, such as the promoter and several enhancers. The promoter activity is not specific to a particular cell type and has been described earlier. The proximal enhancer is endothelial- specific and responsible for the PLAUR expression pattern in endothelial cells. In this study, we described the enhancer activity and its cis elements based on the published data. We showed a possible connection of the enhancer activity with known cellular phenotypes.

Targeting canine mammary neoplastic epithelial cells with a reengineered anthrax toxin: first study.

Mammary tumors are the most frequent type of neoplasms in intact female dogs. New therapies that target neoplastic cells without affecting normal cells are highly sought. The Bacillus anthracis toxin has been reengineered to target tumor cells that express urokinase plasminogen activators and metalloproteinases. In previous studies carried out in our laboratory, the reengineered anthrax toxin had inhibitory effects on canine oral mucosal melanoma and canine osteosarcoma cells. In this study, five canine neoplastic epithelial cell lines (four adenocarcinomas and one adenoma) and one non-neoplastic canine mammary epithelial cell line were treated with different concentrations of reengineered anthrax toxin components. Cell viability was quantified using an MTT assay and half-maximal inhibitory concentration (IC50) values. Cell lines were considered sensitive when the IC50 was lower than 5000ng/ml. One canine mammary adenocarcinoma cell line and one mammary adenoma cell line showed significantly decreased viability after treatment, whereas the non-neoplastic cell line was resistant. We conclude that the reengineered anthrax toxin may be considered a targeted therapy for canine mammary neoplasms while preserving normal canine mammary epithelial cells.

Multi-Marker Approach in Patients with Acute Chest Pain in the Emergency Department.

Chest pain is a prevalent reason for emergency room referrals and presents diagnostic challenges. The physician must carefully differentiate between cardiac and noncardiac causes, including various vascular and extracardiovascular conditions. However, it is crucial not to overlook serious conditions such as acute coronary syndrome (ACS). Diagnosis of acute myocardial infarction (AMI) and early discharge management become difficult when traditional clinical criteria, ECG, and troponin values are insufficient. Recently, the focus has shifted to a "multi-marker" approach to improve diagnostic accuracy and prognosis in patients with chest pain. This observational, prospective, single-center study involved, with informed consent, 360 patients presenting to the emergency department with typical chest pain and included a control group of 120 healthy subjects. In addition to routine examinations, including tests for hsTnI (Siemens TNIH kit), according to the 0-1 h algorithm, biochemical markers sST2 (tumorigenicity suppression-2) and suPAR (soluble urokinase plasminogen activator receptor) were also evaluated for each patient. A 12-month follow-up was conducted to monitor outcomes and adverse events. We identified two groups of patients: a positive one (112 patients) with high levels of hsTnI, sST2 > 24.19 ng/mL, and suPAR > 2.9 ng/mL, diagnosed with ACS; and a negative one (136 patients) with low levels of hsTnI, suPAR < 2.9 ng/mL, and sST2 < 24.19 ng/mL. During the 12-month follow-up, no adverse events were observed in the negative group. In the intermediate group, patients with hsTnI between 6 ng/L and the ischemic limit, sST2 > 29.1 ng/mL and suPAR > 2.9 ng/mL, showed the highest probability of adverse events during follow-up, while those with sST2 < 24.19 ng/mL and suPAR < 2.9 ng/mL had a better outcome with no adverse events at 12 months. Our data suggest that sST2 and suPAR, together with hsTnI, may be useful in the prognosis of cardiovascular patients with ACS, providing additional information on endothelial damage. These biomarkers could guide the clinical decision on further diagnostic investigations. In addition, suPAR and sST2 emerge as promising for event prediction in patients with chest pain. Their integration into the standard approach in PS could facilitate more efficient patient management, allowing safe release or timely admission based on individual risk.

#2307 Serum NGAL, MMP-9 and suPAR in the assessment of kidney impairment and cardiovascular risk in children and adolescents with type 1 diabetes or obesity

Abstract Background and Aims Type 1 diabetes mellitus (DM1) and obesity represent two chronic paediatric diseases with worryingly rising incidence, characterized by chronic inflammation, endothelial dysfunction and increased risk for kidney impairment and cardiovascular disease. The aim of this cross-sectional study was to explore the potential usefulness of serum Neutrophil Gelatinase-Associated Lipocalin (NGAL), Matrix Metalloproteinase-9 (MMP-9) and Soluble Urokinase Plasminogen Activator Receptor (suPAR) for predicting early kidney injury or increased cardiovascular risk in children and adolescents with DM1 or obesity. Method Serum samples were obtained from children and adolescents aged &amp;lt;18 years old with DM1 (n=35) or obesity (n=38) and normal renal function with no history of albuminuria, as well as from healthy controls (n=23). Serum NGAL, MMP-9 and suPAR concentrations were measured using commercially available sandwich ELISA kits (NGAL: (DY1757-05), MMP-9: (DMP900); suPAR: (DUP00); R&amp;D systems). All patients were evaluated for anthropometric indices (weight, height, BMI) while for different degrees of weight status we used the body mass index (BMI) z-score adjusted for age and sex. Estimated glomerular filtration rate (eGFR) was calculated according to the revised bedside Schwartz formula. Results Serum NGAL values were found significantly higher in patients with obesity but not in those with DM1. A positive correlation was found in patients with T1DM with diabetes duration (Spearman rho 0.364, p=0.044), and in all study participants with BMI z-score (Spearman rho 0.401, p=0.004). Furthermore, serum MMP-9 levels were significantly increased in patients with T1DM and in patients with obesity compared to controls. Mean serum suPAR levels were significantly higher in patients with obesity compared to patients with T1DM and controls, while children with T1DM had similar suPAR levels to controls (Table 1). Finally, serum suPAR levels showed a negative correlation with age (Spearman rho −0.359, p&amp;lt;0.001) and creatinine levels (Spearman rho −0.334, p=0.005), and a positive correlation with BMI z-score (Spearman rho 0.354, p=0.009). Conclusion Circulating NGAL, MMP-9 levels may prove useful as surrogate biomarkers to creatinine, GFR and albumin excretion rate for early detection of kidney injury, inflammation or endothelial dysfunction and cardiovascular complications in children and adolescents with T1DM or obesity. Children with obesity may have impaired inflammation status, kidney and endothelial function to a higher degree compared to children with T1DM, which may suggest that obesity may impose a greater health burden than T1DM, at least during childhood or the first years after T1DM diagnosis.

#2510 Urokinase plasminogen activator receptor upregulation in lupus nephritis associates with distinct interferon hub genes in stressed podocytes

Abstract Background and Aims Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease characterized by immune system dysfunction, leading to inflammation and damage in various organs and tissues. Renal involvement known as lupus nephritis is one of the most severe complications occurring in 60% of patients with SLE, significantly impacting patient morbidity and mortality. Understanding the intricate relationship between SLE and renal manifestations is crucial for effective management and improved patient outcomes. Recently, the cell surface urokinase plasminogen activator receptor (uPAR) has emerged as a significant player in the pathogenesis of lupus nephritis. However, the molecular mechanisms through which uPAR influences lupus nephritis remain an active area of investigation. Therefore, we here pursued a transcriptome array-based approach to identify molecular patterns in association with uPAR in lupus nephritis. Method PLAUR mRNA expression levels (encoding uPAR, reporter ID: 210845_s_at, platform: Affymetrix Human Genome U133 Plus 2.0 Array, altCDF v10) were extracted from microdissected control kidneys (glomerular compartment: n = 14) and lupus nephritis (glomerular: n = 32, tubulointerstitial: n = 32). Pathway analysis was performed for gene enrichment associated with PLAUR mRNA expression with a correlation threshold of ≥0.5 by using reactome (https://reactome.org), pathways with a predefined entities value of P ≤ .001 were included. Data was validated in cultured podocytes stressed with Adriamycin, protein expression profiling was performed by mass spectrometry in combination with stable isotope labelling by amino acids in cell culture (SILAC). Results We here identified a predominant glomerular expression of uPAR in lupus nephritis that was increased as compared to healthy controls. While glomerular uPAR expression was predominantly associated with interferon signaling, none of type I or type II interferons were induced. Interestingly, we identified distinct interferon hub genes that were associated with uPAR in lupus nephritis and enriched in stressed podocytes (GBP2: P &amp;lt; .0001, IFI30: P = .0006, IFIT1: P &amp;lt; .0001, IFITM3: P = .0308). Finally, uPAR and associated interferon hub genes correlated with proteinuria in lupus nephritis. Conclusion The therapeutic implications of targeting uPAR in lupus nephritis are promising, and ongoing research endeavors are aimed at unraveling the complexities of uPAR as a potential diagnostic marker and therapeutic target for this challenging renal pathology. We here expand our current knowledge and link uPAR upregulation in lupus nephritis to distinct interferon hub genes in stressed podocytes.

#2543 Complement receptor C5aR1 correlates with inflammatory responses driven by glomerular uPAR upregulation in renal vasculitides

Abstract Background and Aims Avacopan is a novel promising treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) targeting the complement system by blocking C5a receptor C5aR1. We here pursued a transcriptome array-based approach to dissect molecular signatures associated with C5aR1 in renal vasculitis. Method C5aR1 mRNA expression levels (reporter ID: 210845_s_at, platform: Affymetrix Human Genome U133 Plus 2.0 Array, altCDF v10) were extracted from microdissected samples of renal vasculitis (glomerular: n = 23, tubulointerstitial: n = 21). Pathway analysis was performed for gene enrichment associated with PLAUR mRNA expression with a correlation threshold of ≥0.5 by using reactome (http://reactome.org), pathways with a predefined entities value of p≤0.001 were included. Results We here identified a predominant glomerular expression of C5aR1 in renal vasculitis as compared to the tubulointerstitial compartment (p &amp;lt; 0.0001). Furthermore, glomerular C5aR1 induction correlated with impaired kidney function (eGFR: 0.0193). Gene set enrichment identified various inflammatory signatures including neutrophil degranulation and innate immunity, and particularly enrichment of urokinase plasminogen activator receptor (uPAR). uPAR itself also correlated with impairment of kidney function in renal vasculitis and particularly active glomerular lesions (cellular crescents and necrosis, p &amp;lt; 0.0001). Conclusion The therapeutic implications of targeting uPAR in renal vasculitis are promising, and ongoing research endeavors are aimed at unraveling the complexities of uPAR as a potential diagnostic marker and therapeutic target for this challenging renal pathology. We here expand our current knowledge and link C5aR1 to inflammatory responses driven by glomerular uPAR upregulation in renal vasculitis.

Association of suPAR, ST2, and galectin-3 with eGFR decline and mortality in patients with advanced heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble urokinase plasminogen activator receptor (suPAR), galectin-3, soluble suppression of tumorigenicity 2 (ST2), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are associated with CKD progression and mortality. The predictive value of these biomarkers in a population with HFrEF and kidney disease is relatively unknown. We sought to determine whether these biomarkers were associated with longitudinal trajectory of estimated glomerular filtration rate (eGFR) in HFrEF and assess their association with mortality using a joint model to account for competing risks of ventricular assist device (VAD) implantation and heart transplantation. We included participants from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with repeated eGFR measures over 2 years. Of 309 participants, mean age was 59 years, median eGFR 60 ml/min/1.73 m2, 45 participants died, 33 received VAD, and 25 received orthotopic heart transplantation. Higher baseline serum standardized suPAR (β coefficient = -0.36 √(ml/min/1.73 m2), 95% confidence interval (-0.48 to -0.24), p < 0.001), standardized galectin-3 (-0.14 √(ml/min/1.73 m2) (-0.27 to -0.02), p = 0.02), and log NT-proBNP (-0.23 √(ml/min/1.73 m2) (-0.31 to -0.15), p < 0.001) were associated with eGFR decline. ST2 and log NT-proBNP were associated with mortality. Higher baseline suPAR, galectin-3, and NT-proBNP are associated with eGFR decline in patients with HFrEF. Only ST2 and NT-proBNP are associated with greater mortality after controlling for other factors including change in eGFR. These biomarkers may provide prognostic value for kidney disease progression in HFrEF and inform candidacy for advanced heart failure therapies.

Molecular characterization of positively selected genes contributing aquatic adaptation in marine mammals.

Marine mammals, which have evolved independently into three distinct lineages, share common physiological features that contribute to their adaptation to the marine environment. To identify positively selected genes (PSGs) for adaptation to the marine environment using available genomic data from three taxonomic orders: cetaceans, pinnipeds, and sirenians. Based on the genomes within each group of Artiodactyla, Carnivora and Afrotheria, we performed selection analysis using the branch-site model in CODEML. Based on the branch-site model, 460, 614, and 359 PSGs were predicted for the cetaceans, pinnipeds, and sirenians, respectively. Functional enrichment analysis indicated that genes associated with hemostasis were positively selected across all lineages of marine mammals. We observed positive selection signals for the hemostasis and coagulation-related genes plasminogen activator, urokinase (PLAU), multimerin 1 (MMRN1), gamma-glutamyl carboxylase (GGCX), and platelet endothelial aggregation receptor 1 (PEAR1). Additionally, we found out that the sodium voltage-gated channel alpha subunit 9 (SCN9A), serine/arginine repetitive matrix 4 (SRRM4), and Ki-ras-induced actin-interacting protein (KRAP) are under positive selection pressure and are associated with cognition, neurite outgrowth, and IP3-mediated Ca2 + release, respectively. This study will contribute to our understanding of the adaptive evolution of marine mammals by providing information on a group of candidate genes that are predicted to influence adaptation to aquatic environments, as well as their functional characteristics.

Potential plasma biomarkers for the onset of heart and skeletal muscle inflammation from Piscine orthoreovirus-1 infection in Atlantic salmon (Salmo salar)

Biomarkers that give quantifiable information about disease development are valuable diagnostic indicators providing opportunities to thwart adverse outcomes through timely detection and initiation of countermeasures. Whereas human medicine already relies extensively on biomarker analysis, their application in the diagnostics of fish diseases is still at a tentative beginning. However, the increased utilisation of broad-range analytical approaches such as untargeted proteomics enhances the chances to discover changes in the levels of proteins, which are connected to fish health and could serve as novel biomarkers. In the present study, proteomic analysis accompanied by biostatistical data processing was employed with the aim of identifying plasma biomarker candidates for the onset of heart and skeletal muscle inflammation (HSMI) caused by Piscine orthoreovirus (PRV)-1 infection in Atlantic salmon. HSMI is a common viral disease and threat to fish welfare and productivity in Norwegian aquaculture, so that the early detection of HSMI development would allow a timely intervention to limit the damage. In the search for biomarker candidates, salmon plasma was sampled five and eight weeks after a PRV-1 cohabitation challenge experiment and from adequate control fish, and analysed by mass spectrometry-based proteomics. The proteome dataset contained 695 proteins with >90% probability of correct identification according to the set cut-off criteria for peptide quality. Time- and condition-related differences in protein abundance levels were revealed by multivariate analysis. Comparison of the proteins identified as significant using three different biostatistical models resulted in a short list of four potential biomarkers: galectin-3-binding protein (Gal-3BP), fucolectin-6, urokinase plasminogen activator surface receptor and ryanodine receptor 3. The physiological functions described for these proteins in mammals designate them as interesting indicators of inflammatory diseases also in other species, such as PRV-1 pathogenesis in salmon. In situ-hybridisation targeting Gal-3BP and PRV-1 mRNA in heart tissue sections from the same challenge trial showed a significant upregulation of Gal-3BP mRNA in infected salmon hearts as compared to controls, supporting the findings of the proteomic analysis and suggesting a role in the onset of heart- and skeletal muscle inflammation.

Soluble urokinase plasminogen activator receptor is associated with kidney disease and its progression in sickle cell anemia.

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Point-of-Care Serum Proenkephalin as an Early Predictor of Mortality in Patients Presenting to the Emergency Department with Septic Shock.

The aim of the present study is to investigate the prognostic utility of point-of-care (POC)-measured proenkephalin (PENK), a novel biomarker, in terms of predicting in-hospital mortality in patients presenting to the emergency department (ED) with septic shock. Bedside PENK was measured in consecutive patients presenting to the ED with septic shock according to the Sepsis-3 clinical criteria. The association of PENK with inflammatory and routine biomarkers, and its role as a predictor of in-hospital mortality, was examined. Sixty-one patients with septic shock [53% females, median age 83 years (IQR 71-88)] were evaluated. Median (IQR) values of creatinine, plasma lactate, soluble urokinase plasminogen activator receptor (SuPAR), procalcitonin and PENK were 1.7 (1.0-2.9) mg/dL, 3.6 (2.1-6.8) mmol/L, 13.1 (10.0-21.4) ng/mL, 2.06 (0.84-3.49) ng/mL, and 205 (129-425) pmol/L, respectively. LogPENK significantly correlated with LogLactate (rho = 0.369, p = 0.004), LogCreatinine (rho = 0.537, p < 0.001), LogProcalcitonin (rho = 0.557, p < 0.001), and LogSuPAR (rho = 0.327, p = 0.011). During hospitalization, 39/61 (64%) patients died. In a multivariable logistic regression model, logPENK was an independent predictor of in-hospital mortality (OR 11.9, 95% CI: 1.7-84.6, p = 0.013). POC PENK levels measured upon presentation to the ED strongly correlated with metabolic, renal and inflammatory biomarkers, and may serve as a predictor of in-hospital mortality in patients with septic shock.

PLAU, transcriptionally negatively regulated by GATA6, promotes lung squamous carcinoma cell proliferation and migration

BackgroundLung squamous cell carcinoma (LUSC) is associated with high mortality and has limited therapeutic treatment options. Plasminogen activator urokinase (PLAU) plays important roles in tumor cell malignancy. However, the oncogenic role of PLAU in the progression of LUSC remains unknown. GATA-binding factor 6 (GATA6), a key regulator of lung development, inhibits LUSC cell proliferation and migration, but the underlying regulatory mechanism remains to be further explored. Moreover, the regulatory effect of GATA6 on PLAU expression has not been reported. The aim of this study was to identify the role of PLAU and the transcriptional inhibition mechanism of GATA6 on PLAU expression in LUSC. MethodsTo identify the potential target genes regulated by GATA6, differentially expressed genes (DEGs) obtained from GEO datasets analysis and RNA-seq experiment were subjected to Venn analysis and correlation heatmap analysis. The transcriptional regulatory effects of GATA6 on PLAU expression were detected by real-time PCR, immunoblotting, and dual-luciferase reporter assays. The oncogenic effects of PLAU on LUSC cell proliferation and migration were evaluated by EdU incorporation, Matrigel 3D culture and Transwell assays. PLAU expression was detected in tissue microarray of LUSC via immunohistochemistry (IHC) assay. To determine prognostic factors for prognosis of LUSC patients, the clinicopathological characteristics and PLAU expression were subjected to univariate Cox regression analysis. ResultsPLAU overexpression promoted LUSC cell proliferation and migration. PLAU is overexpressed in LUSC tissues compared with normal tissues. Consistently, high PLAU expression, which acts as an independent risk factor, is associated with poor prognosis of LUSC patients. Furthermore, the expression of PLAU is transcriptionally regulated by GATA6. ConclusionIn this work, it was revealed that PLAU is a novel oncogene for LUSC and a new molecular regulatory mechanism of GATA6 in LUSC was unveiled. Targeting the GATA6/PLAU pathway might help in the development of novel therapeutic treatment strategies for LUSC.

Impaired endogenous fibrinolysis status: a potential prognostic predictor in ischemic stroke.

Stroke confers a severe global healthcare burden, hence exploring risk factors for stroke occurrence and prognosis is important for stroke prevention and post-stroke management strategies. Endogenous fibrinolysis is a spontaneous physiological protective mechanism that dissolves thrombus to maintain vascular patency. Recently, impaired endogenous fibrinolysis has been considered as a potential novel cardiovascular risk factor, but its link with ischaemic stroke in the past has been underappreciated. In this review, we summarize the latest mechanisms of endogenous fibrinolysis, review the current evidence and data on endogenous fibrinolysis in ischemic stroke. It includes the structure of thrombus in ischemic stroke patients, the effect of fibrin structure on the endogenous fibrinolytic efficiency, and the association between intravenous thrombolytic therapy and endogenous fibrinolysis in ischemic stroke. It also includes the single factors (tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, complement component 3, complement component 5, alpha-2-antiplasmin, plasmin-alpha-2-antiplasmin complex, and lipoprotein[a]), and the global assessments of endogenous fibrinolysis status (thromboelastography, rotational thromboelastometry, and global thrombosis test), and their potential as predictors to identify occurrence or unfavorable functional outcomes of ischemic stroke. All of these assessments present advantages and limitations, and we suggest that the global thrombosis test may be more appropriate for detecting impaired endogenous fibrinolysis status in ischemic stroke patients.

The Role of Soluble Urokinase Plasminogen Activator Receptor (suPAR) as an Early Indicator of Mortality in Pediatric Septic Shock.

Despite advancements in antibiotic therapy and resuscitation protocols, sepsis and septic shock remain major contributors to morbidity and mortality in children. We aimed to investigate the utility of soluble urokinase plasminogen activator receptor (suPAR) for the early detection of septic shock and to evaluate its accuracy in predicting mortality. A prospective study was conducted in a tertiary pediatric emergency department (ED), enrolling patients diagnosed with the sepsis, severe sepsis, or septic shock. In addition to assessing infection biomarkers such as C-reactive protein and procalcitonin, suPAR levels were quantified upon admission using enzyme-linked immunosorbent assay. The primary outcome measure was 30-day mortality. Overall 72 patients and 80 healthy children included. Plasma suPAR levels demonstrated a statistically significant elevation in the sepsis, severe sepsis, and septic shock groups compared with the control group (p < 0.001 for all). The septic shock group exhibited the highest suPAR levels upon admission, surpassing both the sepsis and severe sepsis groups (p = 0.009 and 0.042). ROC analysis underscored the promising potential of suPAR with an AUC of 0.832 for septic shock. Analysis of mortality prediction revealed significantly higher suPAR levels in nonsurvivors than survivors (9.7 ng/mL vs. 4.2 ng/mL; p < 0.001). Employing plasma suPAR levels to discriminate between mortality and survival, a threshold of ≥7.0 ng/mL demonstrated a sensitivity of 90.9% and specificity of 71.0%. Plasma suPAR levels have the potential as a biomarker for predicting mortality in children with septic shock. In pediatric septic shock, the presence of plasma suPAR ≥7 ng/mL along with an underlying disease significantly increases the risk of mortality.

Gene Association Study of the Urokinase Plasminogen Activator and Its Receptor Gene in Alzheimer's Disease.

The role of the innate immune system has long been associated with Alzheimer's disease (AD). There is now accumulating evidence that the soluble Urokinase Plasminogen Activator Receptor pathway, and its genes, PLAU and PLAUR may be important in AD, and yet there have been few genetic association studies to explore this. This study utilizes the DNA bank of the Brains for Dementia Research cohort to investigate the genetic association of common polymorphisms across the PLAU and PLAUR genes with AD. TaqMan genotyping assays were used with standard procedures followed by association analysis in PLINK. No association was observed between the PLAU gene and AD; however, two SNPs located in the PLAUR gene were indicative of a trend towards association but did not surpass multiple testing significance thresholds. Further genotyping studies and exploration of the consequences of these SNPs on gene expression and alternative splicing are warranted to fully uncover the role this system may have in AD.

Prognostic performance of soluble urokinase plasminogen activator receptor for heart failure or mortality in Western and Asian patients with acute breathlessness

AimsThe performance of circulating soluble urokinase plasminogen activator receptor (suPAR) for predicting the composite endpoint of subsequent heart failure (HF) hospitalisation and/or death at 1 year was assessed in (i) patients with undifferentiated breathlessness, and generalisability was compared in (ii) disparate Western versus Asian sub-cohorts, and in (iii) the sub-cohort adjudicated with HF. Methods and resultsPatients with acute breathlessness were recruited from the emergency departments in New Zealand (NZ, n = 612) and Singapore (n = 483). suPAR measured in the presentation samples was higher in patients incurring the endpoint (n = 281) compared with survivors (5.2 ng/mL vs 3.1 ng/mL, P < 0.0001). The discriminative power of suPAR for endpoint prediction was c-statistic of 0.77 in the combined population, but was superior in Singapore than NZ (c-statistic: 0.83 vs 0.71, P < 0.0001). Although the highest suPAR tertile (>4.37 ng/mL) was associated with risks of >4-fold in NZ, >20-fold in Singapore, and ≥3-fold in HF for incurring the outcome, there was no interaction between country and suPAR levels after adjustment. Multivariable analysis indicated suPAR to be robust in predicting HF/death at 1-year [hazard ratio: 1.9 (95% CI:1.7 to 2.0) per SD increase] and improved risk discrimination for outcome prediction in HF (∆0.06) and for those with NT-proBNP >1000 pg/mL (∆0.02). ConclusionsuPAR is a strong independent predictor of HF and/or death at 1 year in acutely breathless patients, in both Asian and Western cohorts, and in HF. suPAR may improve stratification of acutely breathless patients, and in acute HF, for risk of later onset of heart failure or mortality.

Obesity, Inflammation, and Clinical Outcomes in COVID-19: A Multicenter Prospective Cohort Study.

Obesity is a risk factor for coronavirus disease 2019 (COVID-19)-related outcomes; however, the mechanism remains unclear. The objective of this analysis was to determine whether inflammation mediates the association between obesity and COVID-19 outcomes. The International Study of Inflammation in Covid-19 (ISIC): A Prospective Multi-Center Observational Study Examining the Role of Biomarkers of Inflammation in Predicting Covid-19 Related Outcomes in Hospitalized Patients. Ten hospitals in the United States and Europe. Adults hospitalized specifically for COVID-19 between February 1, 2020, through October 19, 2022. Inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), were measured at admission. Associations were examined between body-mass index (BMI, kg/m2) and a composite of death, need for mechanical ventilation, and renal replacement therapy, stratified by pre- and post-Omicron variants. The contribution of inflammation to the relationship between obesity and outcomes was assessed. Among 4644 participants (mean age 59.3, 45.6% male, 21.8% BMI≥35), those with BMI>40 (n=485) had 55% higher odds of the composite outcome (95% CI[1.21 to 1.98]) compared to non-obese individuals (BMI<30, n=2358) in multivariable analysis. In multiple mediation analysis, only suPAR remained a significant mediator between BMI and composite outcome. Associations were amplified for participants younger than 65 years and with pre-Omicron variants. Obesity is associated with worse outcomes in COVID-19, notably in younger participants and in the pre-Omicron era. Inflammation, as measured by suPAR, is a significant mediator of the association between obesity and COVID-19 outcomes.