uPAR Research Articles

Determining biomarkers for evaluation and diagnosis of hereditary angioedema.

RationaleKallikrein‐bradykinin‐forming cascade is known to cause hereditary angioedema (HAE) acute angioedema (AE) attacks. Further research of HAE attacks is needed to explain disease heterogeneity, predict treatment response and identify biomarkers for monitoring HAE attacks. Differential expression of the microvascular endothelial cell‐surface receptors for example, g‐C1qR, cytokeratin‐1, and plasminogen‐activator‐urokinase‐receptor (PLAUR) were hypothesized as biomarkers of AE attacks.MethodTo understand HAE attacks, the differentially expressed genes (DEGs) in RNAseq and mi‐RNAseq data of total RNA extracted from skin biopsies of lesional versus non‐lesional skin collected during and between attacks in Type‐1 HAE patients (n = 11; F:M = 8:3) were compared. To understand the HAE variants, DEGs in skin biopsies from HAE with normal C1 inhibitor (n = 5, F:M = 5:0), and non‐HAE (n = 7; F:M = 3:4) patients were compared. Gene‐set enrichment analyses and regulator effects analysis of these DEGs identified biological pathways in HAE attacks and their regulators.ResultsPLAUR gene, encoding urokinase‐type plasminogen activator (u‐PAR), was constitutively over‐expressed in HAE‐Type‐1 versus non‐HAE controls suggestive of overactive u‐PAR‐mediated signaling via binding to Factor‐XII. Baseline PLAUR expression was associated with severe AE (p = 0.05). The 18 significant DEGs investigated between baseline and AE attack samples in Type1‐HAE were enriched in beta1/beta3‐integrin cell surface interactions and IL‐6‐mediated signaling. Regulator effects analysis suggests a role for IL‐1b in HAE flares. AKT2, the mRNA regulated by the differentially‐expressed miR‐184A, was also associated with HAE attacks.ConclusionAngiopoetin‐activated β1‐integrin signaling pathways causing endothelial destabilization, and avid binding of factor XII to u‐PAR are possible novel mechanisms for progression of the endothelial kinin‐bradykinin‐forming cascade in HAE attacks.

Evaluation of Serum Pentraxin-3 and suPAR Levels as Acute Phase Reactants in Patients with COVID-19

Coronavirus disease-2019 (COVID-19) is the most challenging health problem of our century, but our knowledge about the disease is limited. Most individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, have mild symptoms such as headache, sore throat, joint pain, loss of sense of taste and smell. However, infection also causes significant morbidity and mortality, especially in individuals over 65 years of age with comorbidities. However, it is not known exactly which patients will have a poor prognosis. In this study, it was aimed to determine serum Pentraxin-3 (PTX3) and soluble urokinase plasminogen activator receptor (suPAR) levels in COVID-19 patients, and to evaluate the relationship between PTX3 and suPAR levels and the clinical status of the disease. This study was conducted with 150 patients who were confirmed to have COVID-19 by microbiological or clinical/radiological methods between April 1 and December 31, 2020. Thirty people with no known history or symptoms of COVID-19 and negative reverse transcription-polymerase chain reaction (RT-PCR) results also constituted the control group. Patients admitted to inpatient services due to COVID-19 constituted the service group (n= 75) and patients admitted to the intensive care unit (ICU) constituted the ICU group (n= 75). Serum PTX3 and suPAR levels were analyzed by enzyme-linked immunoassay (ELISA) and the results were compared between the three groups. The patients' leukocyte, neutrophil, neutrophil/lymphocyte ratio (NLR), troponin, procalcitonin (PCT), D-dimer, C-reactive protein (CRP), lymphocyte and ferritin results were included in the analysis. The mean age of the patients was 67.2 ± 11.8, and 62.0 ± 8.4 in the control group. There was no significant difference between the groups in terms of female/male ratio (p= 0.582). The PTX3 and suPAR levels of the patients were higher than the controls (p= 0.001, p= 0.023, respectively). PTX3 and suPAR levels were higher in the service group than the ICU group (p<0.001, p= 0.004, respectively) and the control group (p<0.001, p= 0.001, respectively). However, PTX3 (p= 0.291) and suPAR (p= 0.411) concentrations did not differ between ICU and control groups. The most determining parameters in ICU admission were found to be leukocytes (AUC= 0.840), neutrophils (AUC= 0.840), and NLR (AUC= 0.835), respectively. The most predictive parameters for mortality were PCT (AUC= 0.712), NLR (AUC= 0.708) and D-dimer (AUC= 0.695), respectively. In our study, serum PTX3 and suPAR concentrations were found to be high in COVID-19 patients. In patients admitted to the ICU, PTX3 and suPAR levels were observed at low levels. Low levels of PTX3 and suPAR in COVID-19 patients were thought to be clinically important.

Perspectives on Drug Development in Early ADPKD.

Perspectives on Drug Development in Early ADPKD.

WITHDRAWN: Soluble urokinase plasminogen activator receptor and its complicated role in hemodialysis (HD) patients with Covid-19 infection

Soluble urokinase plasminogen receptor (suPAR) is a protein in the blood that has been described to reflect the severity status of systemic inflammation. We investigated the association between admission suPAR levels and severity and outcome of HD patients with Covid-19 infection. In an observational study of adult HD patients hospitalized for Covid-19, we measured suPAR levels in plasma samples. The time table for those measurements were as follows: at the beginning of admission, after a hemoperfusion (HP) session for those patients that received them, and just before discharge. Of the 17 patients (7 were male), 13 patients received HP (mean age: 74 years old). The median suPAR level was 12.94ng/ml. For those who undertook HP in HD unit the median suPAR level before the session was 12.95ng/mil and 6.2ng/ml at the end of each session (p<0.05). 3 patients had a suPAR level below 7ng/ml. 2 of them survived without developing pleural effusions. 7 patients were discharged from the hospital with median suPAR level 12.08ng/ml which did not differ significantly from the median suPAR level of the deceased ones (13.68ng/ml). Admission levels of suPAR in HD patients hospitalized for Covid-19 do not seem to be predictive for their clinical course in general. Chronic Kidney Disease and its relation to suPAR independently of patients' inflammation status may be the key component for our notice. Despite that, in patients where low levels of suPAR combined with absence of pleural effusions the prognosis was excellent.

The Pattern of Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels in Lupus Nephritis and Its Correlation with Renal Biopsy

The Pattern of Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels in Lupus Nephritis and Its Correlation with Renal Biopsy

Piptide Chemotypes for Perturbation of the Interaction of Urokinase with Its Receptor

Only a few small molecules that disrupt the uPA and uPA receptor (uPAR) interaction have been discovered despite decades of research in the area, and none have been approved in clinical trials. Research reported here features two new ways of considering the problem of discovering small molecules to disrupt uPA•uPAR, specifically in terms of chemotype design and method of evaluation. Chemotypes used in this work are piptides (Arancillo . Angew. Chem., Int. Ed., 2021, 60, 6653-6659) with side chains corresponding to the uPA loop that binds uPAR. Further, hybrids of 1 and another uPAR ligand developed in these labs (2), i.e., 3 and 4, were also designed and tested. All the piptide chemotypes bound uPAR at concentrations of 50 μM or less. Members of this series had Ki values <3 μM and showed favorable responses in cellular assays; these data are comparable with the best small molecule uPA•uPAR disruptors in the literature (from conventional screening).

Interleukin-1β and plasminogen activating system members in endometriotic stromal cell migration/invasion

To study the role of interleukin (IL)-1β and the plasminogen activating (PA) system members in endometriotic stromal cell (ESC) migration/invasion. Primary cultures of ESCs. Tertiary referral center for endometriosis and pelvic pain. Patients with surgically excised endometriosis. Interleukin-1β stimulation of primary cultures of ESCs and knockdown of the PA system members urokinase plasminogen activator (uPA), uPA receptor, and plasminogen activator inhibitor-1 (PAI-1). Invasion/migration assays. In primary cultures, IL-1β-stimulated ESC production of the PA system members uPA, uPA receptor, and PAI-1. Interleukin-1β also enhanced ESC migration and invasion, and these effects were inhibited by the IL-1 receptor-1 antagonist anakinra. Knockdown of each of the 3 PA system members also inhibited ESC migration and invasion. Knockdown of these PA system members further attenuated the impact of IL-1β on migration and invasion, suggesting that they mediated the promigration and proinvasion effects of IL-1β. To supplement the cell culture work, immunohistochemistry was performed on tissue sections of endometriotic epithelium/stroma: uPA, PAI-1, and IL-1β histoscores were not found to be correlated with each other. In primary cultures of ESCs, IL-1β induces migration and invasion, which is mediated by PA system members and inhibited by the drug anakinra. However, the immunohistochemistry expression of IL-1β, urokinase plasminogen inhibitor-1, and PAI-1 were not correlated, suggesting other regulatory mechanisms for PA system members. Inhibition of IL-1β (e.g., with anakinra) may have potential as a novel treatment approach for the migration/invasion of endometriosis.

Mast Cell Proteases Promote Diverse Effects on the Plasminogen Activation System and Wound Healing in A549 Alveolar Epithelial Cells.

Tissue damage, epithelial alterations, and intraepithelial presence of mast cells (MCs) are characteristics of asthma pathogenesis. Increased alveolar infiltration of MC populations has also been identified as a feature of asthma and other chronic respiratory diseases. The asthma associated receptor, urokinase plasminogen activator receptor (uPAR), has been shown to regulate bronchial epithelial repair responses. However, the impact of MC tryptase and chymase on functional properties and expression of uPAR in alveolar epithelial cells have not been fully investigated. Alveolar epithelial cell migration and wound healing were investigated using holographic live cell imaging of A549 cells in a wound scratch model post stimulation with tryptase or chymase. The expression of uPAR was investigated on the protein and gene level from cellular supernatants and in bronchoalveolar lavage fluid fractions from allergic asthmatics. We found that tryptase improved wound healing capacity, cellular migration and membrane bound uPAR expression. Chymase reduced gap closure capacity, cellular migration and membrane bound uPAR expression but increased soluble uPAR release. Our data suggest a dual regulatory response from the MC proteases in events related to uPAR expression and wound healing which could be important features in asthmatic disease.

Soluble Urokinase Plasminogen Activator Receptor Levels and Outcomes in Patients with Heart Failure

BackgroundSoluble urokinase-type plasminogen activator receptor (suPAR) is a marker of immune activation and pathogenic factor for kidney disease shown to predict cardiovascular outcomes including heart failure (HF) in various populations. We characterized suPAR levels in patients with HF and compared its ability to discriminate risk to that of B-type natriuretic peptide (BNP). Methods and ResultsWe measured plasma suPAR and BNP levels in 3,437 patients undergoing coronary angiogram and followed for a median of 6.2 years. We performed survival analyses for the following outcomes: all-cause death, cardiovascular death, and hospitalization for HF. We then assessed suPAR's ability to discriminate risk for the aforementioned outcomes. We identified 1116 patients with HF (age 65±12, 67.2% male, 20.0% Black, 67% with reduced ejection fraction). The median suPAR level was higher in HF compared to those without HF (3370 [IQR 2610-4371] vs. 2880 [IQR 2270-3670] pg/mL, respectively, P<0.001). In patients with HF, suPAR levels (log-base 2) were associated with outcomes including all-cause death (adjusted hazard ratio aHR 2.30, 95%CI[1.90-2.77]), cardiovascular death (aHR 2.33 95%CI[1.81-2.99]) and HF hospitalization (aHR 1.96, 95%CI[1.06-1.25]) independently of clinical characteristics and BNP levels. The association persisted across subgroups and did not differ between patients with reduced or preserved ejection fraction, or those with ischemic or non-ischemic cardiomyopathy. Addition of suPAR to a model including BNP levels significantly improved the C-statistic for death (Δ0.027), cardiovascular death (Δ0.017) and hospitalization for HF (Δ0.017). ConclusionsSuPAR levels are higher in HF compared to non-HF, are strongly predictive of outcomes, and combined with BNP, significantly improved risk prediction. Lay Summary•Soluble urokinase plasminogen activator receptor (suPAR) is a circulating protein of immune origin notorious for its involvement in kidney disease, and which levels have been found to predict the onset of heart failure.•Given the pathophysiologic link between heart failure and kidney disease, we sought to examine suPAR levels in patients with heart failure.•We measured suPAR in 1116 patients with heart failure, and found that levels were strongly predictive of outcomes independently of risk factors and above and beyond the myocardial marker BNP. SuPAR level may be useful as an adjunctive measure for risk stratification of patients with heart failure.

Assessment of clinical utility and predictive potential of pre-chemotherapy soluble urokinase plasminogen activator receptor: Observational single center study.

Alteration of urokinase plasminogen activator receptor (uPAR) in neoplasms is a prerequisite for invasiveness and metastatic ability. In the present study, we aimed to evaluate the relationship of pre-chemotherapy soluble uPAR (suPAR) with the odds for metastasis, lack of disease control, and its predictive ability for progression-free survival (PFS). Baseline plasma suPAR levels were measured by ELISA in 89 patients with various cancers prior to initiation of systemic treatment. Patients were followed prospectively until metastatic progression or death. TCGA Pan-Cancer dataset was mined for available RNAseq expression data of the PLAUR gene in patients with breast, colon, and lung cancer, and therelevant genomic and clinical data were extracted for further analysis. Pre-chemotherapy suPAR levels were significantly associated with white blood cell counts and fibrinogen and were significantly elevated both in patients with metastatic disease and in patients with progression. Increasing suPAR was significantly associated with odds for progression in the prespecified multivariate analysis (odds ratio 2.47, 95% confidence interval 1.3 - 5.11). In univariate Cox regression, suPAR was predictive of shortened progression-free survival (PFS) (hazard ratio 1.065, 95% confidence interval 1.002 - 1.13; p = 0.041). There was a trend towards shortened PFS in patients with higher baseline suPAR levels (cutoff 8.1 ng/mL). In the TCGA lung cancer cohort, PLAUR mRNA expression was significantly associated with shortened PFS in both univariate and multivariate analyses. High PLAUR gene expression conferred significant survival disadvantage only in patients with colon and lung cancer. SuPAR may bear predictive potential for adverse outcomes in cancer, but its utility as a biomarker seems to be more pronounced in cancers with associated inflammatory state.

Bioinformatics Analysis of Inflammation Gene Signature in Indicating Cholangiocarcinoma Prognosis

Aim We studied inflammatory response-related genes in cholangiocarcinoma by bioinformatics analysis. Methods The expression profiles and clinical information of cholangiocarcinoma patients were downloaded from the TCGA cohort and the Gene Expression Omnibus. The greatest absolute shrinking and selecting operator Cox analyses were utilized to build a multigene predictive signature. Results An inflammation response-related gene profile was generated using LASSO-Cox regression analysis of Homo sapiens bestrophin 1 (BEST1), Chemokine (C–C motif) ligand 2 (CCL2), and plasminogen activator, urokinase receptor (PLAUR). Individuals in the highest category had a significantly lower overall survival time than those from the low-risk group. A receiver operating curve analysis was used to demonstrate the predictive ability of the predictive gene signature. Through multivariate Cox analysis, the risk score was discovered to be a predictor of overall survival (OS). According to functional assessments, the immunological state and milieu of the two risk areas were significantly different. The expression levels of predictive genes were found to be strongly linked to the sensitivity of cancer cells to antitumor therapy. Conclusion A new signature made up of three respective response-relevant genes is found to be a promising indicator of prognosis by influencing the immune condition and tumor microenvironment.

Growth differentiation factor-15 as a biomarker of atherosclerotic coronary plaque: Value in people living with and without HIV.

BackgroundIncreased rates of cardiovascular diseases (CVD) and larger subclinical high-risk coronary plaques in coronary CT angiography have been observed in people living with HIV (PLWH) treated with antiretroviral therapy (ART) compared to HIV-uninfected people. Growth differentiation factor-15 (GDF-15) is a cytokine emerging as an optimal marker for CVD in the general population.MethodsWe cross-sectionally analyzed plasma of 95 PLWH on ART and 52 controls. We measured GDF-15, fibroblast growth factor-21 (FGF-21), glucagon-like peptide-2 (GLP-2), soluble urokinase plasminogen activator receptor (suPAR), CRP, and anti-CMV and anti-EBV IgG levels. All participants had no clinical CVD and underwent coronary CT angiography with the 3D reconstruction of coronary artery atherosclerotic plaques. Total plaque volume (TPV) and low attenuation plaque volume (LAPV, defined as density <30 Hounsfield Units) were calculated (mm3).ResultsIn both PLWH and controls, GDF-15 levels were increased in participants with presence of coronary plaque vs. without (p = 0.04 and p < 0.001, respectively) and correlated with TPV (r = 0.27, p = 0.009 and r = 0.62, p < 0.001, respectively) and LAPV (r = 0.28, p = 0.008, r = 0.60, p < 0.001, respectively). However, in a multivariate model, GDF-15 was independently associated with LAPV in controls only (adjusted OR 35.1, p = 0.04) and not in PLWH, mainly due to confounding by smoking. Other markers were not independently associated with plaque volume, except for anti-EBV IgGs in controls (adjusted OR 3.51, p = 0.02).ConclusionIn PLWH, GDF-15 and smoking seemed to synergistically contribute to coronary plaque volume. Conversely, increased GDF-15 levels were associated with the presence of coronary artery plaques in people without HIV, independently of CV risk factors.

Soluble urokinase Plasminogen Activator Receptor (suPAR) levels are predictive of COVID-19 severity: an Italian experience

BackgroundThe soluble urokinase Plasminogen Activator Receptor (suPAR) has been identified as a reliable marker of COVID-19 severity, helping in personalizing COVID-19 therapy. This study aims to evaluate the correlation between suPAR levels and COVID-19 severity, in relation to the traditional inflammatory markers. MethodsSera from 71 COVID-19 patients were tested for suPAR levels using Chorus suPAR assay (Diesse Diagnostica Senese SpA, Italy). suPAR levels were compared with other inflammatory markers: IL-1β, IL-6, TNF-α, circulating calprotectin, neutrophil and lymphocyte counts, and Neutrophil/Lymphocytes Ratio (NLR). Respiratory failure, expressed as P/F ratio, and mortality rate were used as indicators of disease severity. ResultsA positive correlation of suPAR levels with IL-6 (r = 0.479, p = 0.000), TNF-α (r = 0.348, p = 0.003), circulating calprotectin (r = 0.369, p = 0.002), neutrophil counts (r = 0.447, p = 0.001), NLR (r = 0.492, p = 0.001) has been shown. Stratifying COVID-19 population by suPAR concentration above and below 6 ng/mL, we observed higher levels of circulating calprotectin (10.1 μg/mL, SD 7.9 versus 6.4 μg/mL, SD 7.5, p < 0.001), higher levels of P/F ratio (207.5 IQR 188.3 vs 312.0 IQR 127.8, p = 0.013) and higher mortality rate. Median levels of suPAR were increased in all COVID-19 patients requiring additional respiratory support (Nasal Cannula, Venturi Mask, BPAP and CPAP) (6.5 IQR = 4.9) compared to the group at room air (4.6 IQR = 4.2). ConclusionsuPAR levels correlate with disease severity and survival rate of COVID-19 patients, representing a promising prognostic biomarker for the risk assessment of the disease.

Soluble Urokinase Plasminogen Activator Receptor and Venous Thromboembolism in COVID-19.

Background Venous thromboembolism (VTE) contributes significantly to COVID-19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID-19. Whether suPAR levels identify patients with COVID-19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID-19 with suPAR and D-dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine-Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D-dimer levels. There was a positive association between suPAR and D-dimer (β=7.34; P=0.002). Adjusted for clinical covariables, including D-dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51-4.75]; P<0.001). Findings were consistent when stratified by D-dimer levels and in survival analysis accounting for death as a competing risk. On the basis of predicted probabilities from random forest, a decision tree found the combined D-dimer <1 mg/L and suPAR <11 ng/mL cutoffs, identifying 41% of patients with only 3.6% VTE probability. Conclusions Higher suPAR was associated with incident VTE independently of D-dimer in patients hospitalized for COVID-19. Combining suPAR and D-dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Identification of a Novel Small RNA Encoded in the Mouse Urokinase Receptor uPAR Gene (Plaur) and Its Molecular Target Mef2d.

Urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored receptor of urokinase (uPA), which is involved in brain development, nerve regeneration, wound healing and tissue remodeling. We have recently shown that Plaur, which encodes uPAR, is an early response gene in murine brain. Assumingly, diverse functions of Plaur might be attributed to hypothetical, unidentified microRNAs encoded within introns of the Plaur gene. Using a bioinformatic approach we identified novel small RNAs within the Plaur gene and named them Plaur-miR1-3p and Plaur-miR1-5p. We confirmed Plaur-dependent expression of Plaur-miR1-3p and Plaur-miR1-5p in the mouse brain and mouse neuroblastoma Neuro2a cells. Utilizing an in silico MR-microT algorithm in DianaTools we selected two target genes – Mef2d and Emx2 with the highest binding scores to small RNAs selected from identified Plaur-Pre-miR1. Furthermore, sequencing of mouse brain samples for Plaur-miR1-5p target genes revealed two more genes—Nrip3 and Snrnp200. The expression of Emx2, Mef2d, and Snrnp200 in the mouse brain and Mef2d and Snrnp200 in Neuro2a cells correlated with expression of Plaur and small RNAs—Plaur-miR1-3p and Plaur-miR1-5p. Finally, we demonstrated elevated MEF2D protein expression in the mouse brain after Plaur induction and displayed activating effects of Plaur-miR1-5p on Mef2d expression in Neuro2a cells using Luciferase reporter assay. In conclusion, we have identified Plaur-miR1-3p and Plaur-miR1-5p as novel small RNAs encoded in the Plaur gene. This finding expands the current understanding of Plaur function in brain development and functioning.

Hypoxia Promotes Extravillous Trophoblast Cell Invasion through the Hypoxia-Inducible Factor Urokinase-Type Plasminogen Activator Receptor Pathway

Objectives: Hypoxia is a common feature of extravillous trophoblast (EVT) cells that promote invasion during the early stages of human placentation. This study aimed to examine whether hypoxia-induced an invasive phenotype in EVT cells in vitro and explore the underlying molecular mechanisms. Design: The invasiveness of primary EVT cells isolated from the first trimester placental tissues during weeks 5–8 of gestation was examined under hypoxic (5% O₂) and normoxic (20% O₂) conditions. Methods: Invasiveness was determined by transwell and wound-healing invasion assays using the IncuCyte ZOOM™ Live-Cell Imaging System. Protein expression of the urokinase plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor of hypoxia or normoxia-treated cells was measured using Western blot analysis. Knockdown of hypoxia-inducible factor-1 alpha (HIF-1α) was assessed using small interfering RNA (siRNA). Results: Hypoxia enhanced EVT cell invasion but did not affect apoptosis. The stimulatory effect of hypoxia on EVT cell invasiveness was associated with induction of the uPA-uPAR pathway. The synthetic inhibitor of uPAR significantly inhibited hypoxia-induced EVT cell invasion. Silencing of HIF-1α by siRNA abolished the stimulatory effect of hypoxia and inhibited the upregulation of uPAR expression, suggesting that the HIF-1α-uPAR signal is the key mediator for hypoxia-induced EVT cell invasion. Further experiments need to be performed to elucidate the HIF-1α-uPAR signal pathways. Conclusions: The low oxygen-regulated early events of EVT invasion may be mediated by the HIF-1α-uPAR pathway.

The role of soluble urokinase plasminogen activator receptor (suPAR) in patients with cancer: a review of the current literature.

Aim Several biomarkers are currently used as diagnostic and prognostic tools in patients with cancer. Soluble urokinase plasminogen activator receptor (suPAR) is elevated in acute and chronic inflammatory procedures and several observational studies during the last 20 years have investigated its role in oncology. The purpose of this article was to review the current literature regarding suPAR's role in clinical practice. Methods A systematic literature search of PubMed, Scopus, OpenGrey and Cochrane Library databases through September 2021 was conducted using the following search terms: "supar"or "soluble urokinase plasminogen receptor" and "cancer" or "malignancy". Original articles reporting on suPAR's role in the diagnosis, prognosis and prediction of therapeutic outcomes in patients with confirmed or suspected cancer were included. Results Among 45 found articles, the most were observational cohort studies. The included studies were further categorized by cancer site. SuPAR level was higher in patients with cancer compared to healthy controls, but its diagnostic and prognostic accuracy differs depending on the site of cancer. Conclusion SuPAR has promising aspects in the field of oncology and public health and future research should further investigate its use in clinical practice. As it is elevated in different types of cancer, it could potentially serve as an adjunctive tool for the mass screening of patients with non-specific signs of cancer, but larger cohort studies that support these findings must be conducted.

Identification of differentially expressed genes and pathways in diquat and paraquat poisoning using bioinformatics analysis

Objective: In this study, differentially expressed genes (DEGs) and signaling pathways involved in diquat (DQ) and paraquat (PQ) poisoning were identified via bioinformatics analysis, in order to inform the development of novel clinical treatments. Methods: Raw data from GSE153959 were downloaded from the Gene Expression Omnibus database. DEGs of the DQ vs. control (CON) and PQ vs. CON comparison groups were identified using R, and DEGs shared by the two groups were identified using TBtools. Subsequently, the shared DEGs were searched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, using the Database for Annotation, Visualization, and Integrated Discovery. A protein–protein interaction (PPI) network was constructed, and hub genes were identified using the cytoHubba plug-in in Cytoscape software. Finally, circos and contrast plots showing the DEGs shared between mouse and human chromosomes were constructed using TBtools. Results: Thirty-one DEGs shared by the DQ and PQ groups were identified. Enriched biological process terms included positive regulation of cell proliferation and translation. Enriched cellular component terms included extracellular region, intracellular membrane-bounded organelle and mitochondrion. Enriched molecular function terms included transcription factor activity and sequence-specific double-stranded DNA binding. Enriched KEGG pathways included the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and human T-cell leukemia virus 1 infection. The top 10 hub genes in the PPI network were prostaglandin-endoperoxide synthase 2 (Ptgs2), chemokine (C-X-C motif) ligand 2 (Cxcl2), colony-stimulating factor 2 (granulocyte-macrophage) (Csf2), matrix metallopeptidase 13 (Mmp13), amphiregulin (Areg), plasminogen activator, urokinase receptor (Plaur), fos-like antigen 1 (Fosl1), epiregulin (Ereg), activating transcription factor 3 (Atf3), and transferrin receptor (Tfrc). Cxcl2, Csf2, and Atf3 played important roles in the mitogen-activated protein kinase (MAPK) signaling pathway. Conclusions: These pathways and DEGs may serve as targets for gene therapy.

Curcumin intervention during progressive fibrosis controls inflammatory cytokines and the fibrinolytic system in pulmonary fibrosis

Persistent injuries and chronic inflammation paired with dysregulated healing process in the lungs leads to scarring and stiffening of the tissue leading to a condition called pulmonary fibrosis. There is no efficacious therapy against the condition because of the poorly understood pathophysiology of the disease. Curcumin is well known anti-inflammatory natural compound and is shown to have beneficial effects in many diseases. It is also reported to show antifibrotic activities in pulmonary fibrosis. There are evidences that fibrinolytic system plays a crucial role in the development of pulmonary fibrosis. We aimed to see whether curcumin could regulate inflammation and fibrinolysis in murine model of pulmonary fibrosis. We prepared BLM induced pulmonary fibrosis model by administering BLM at a dose of 2 mg/ kg bodyweight. Curcumin (75 mg/kg body wt) was instilled intraperitoneally on different time points. The effect of curcumin on inflammatory cytokines and fibrinolytic system was studied using molecular biology techniques like RT-PCR, western blot and immunohistochemistry/immunofluorescence. We observed that BLM brought changes in the expressions of components in the fibrinolytic system, i.e. BLM favoured fibrin deposition by increasing the expression of PAI-1 (plasminogen activator inhibitor) and decreasing the expression of uPA (Urokinase plasminogen activator) and uPAR (Urokinase plasminogen activator receptor). We also demonstrate that curcumin could restore the normal expression of fibrinolytic components, uPA, uPAR and PAI-1. Curcumin could also minimize the expression of key enzymes in tissue remodeling in pulmonary fibrosis, MMP-2 and MMP-9, which were elevated in the BLM treated group. Our data suggest that curcumin exerts an anti-inflammatory and antifibrotic effect in lungs. We highlight curcumin as a feasible adjuvant therapy option against pulmonary fibrosis.

SERPINA5 may promote the development of preeclampsia by disruption of the uPA/uPAR pathway

Preeclampsia (PE) is the leading cause of maternal and fetal morbidity or mortality but lacks reliable methods for early diagnosis. In a previous study, serum SERPINA5 levels were higher in women with PE before the clinical manifestation of the disease. This study aimed to evaluate the efficacy of SERPINA5 in predicting PE and investigate its role in trophoblast cell biology. A multicenter, 2-stage observational case-control study was performed to develop and validate an early predictive PE model based on SERPINA5, maternal characteristics, and inflammatory factors. To further understand the relationship between SERPINA5 and PE, SERPINA5 was overexpressed or knocked down in extravillous trophoblast cells (EVT) and a pregnant rat model. After development and initial validation, a model that combined SERPINA5 and inflammatory factors had a high predictive ability for PE before 20 weeks gestation with an AUC of 0.90 (95% CI 0.83-0.96). It also demonstrated that SERPINA5 inhibited primary EVT cell invasion by disrupting the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor (uPA/uPAR) pathway, in turn, is involved in the development of PE. In vivo experiments also proved that overexpression of SERPINA5 induced a PE-like syndrome (hypertension and proteinuria) in pregnant rats. Therefore, serum SERPINA5 is a promising early biomarker of PE, suggesting that it may be involved in placental development through its action on the uPA/uPAR system prior to the clinical manifestation of PE.