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Introduction: Oral potentially malignant disorders impact the oral mucosa and elevate the risk of oral cancer. In India, the high prevalence of oral submucous fibrosis and leukoplakia is attributed to habits such as tobacco use and smoking. Plasminogen activator inhibitor-1 plays a crucial role in cancer progression. Single-nucleotide polymorphisms are the most widespread genetic variations associated with various diseases, including cancers. Aim: This study aimed to investigate the association between PAI-1 promoter rs2227631 (− 844G > A) and missense variant rs6092 (+ 43G > A) polymorphisms and the susceptibility to OSMF and leukoplakia in a South Indian cohort of chewers and smokers. Methods: The rs2227631 and rs6092 of PAI-1 were analysed using PCR- RFLP in 285 subjects including OSMF, leukoplakia and healthy controls, along with their habitual factors. The allele frequencies and genotypic associations were examined. The impact of these SNPs on mRNA secondary structure, gene–gene and protein–protein interactions was also analysed using in silico tools. Results: The habits of chewers and smokers were (79% and 72%) in OSMF and (62% and 75%) in leukoplakia and disease prevalent was (78% and 59%) males and (22% and 26%) females respectively. The G allele of rs2227631 and A allele of rs6092 were significantly associated with the diseases (P < 0.05). Conclusion: PAI-1 polymorphisms rs2227631 and rs6092 were associated with OSMF and leukoplakia of the south Indian cohort. [ABSTRACT FROM AUTHOR]

Bruton tyrosine kinase (BTK), which is highly expressed in immune cells, plays a critical role in regulating the function of macrophages. A growing body of evidence has demonstrated that the accumulation of macrophages in cardiac tissue after myocardial infarction (MI) significantly affects wound healing and ventricular remodeling during the early phase of repair after MI. However, the role of BTK in cardiac repair post-MI, especially in macrophage-mediated repair, remains unclear. MI was induced by permanent left anterior descending (LAD) artery ligation in wild-type (WT) mice and macrophage-specific BTK-knockout (BTKMAC−KO) mice. Expression of BTK and phosphorylated BTK were assessed by western blotting. Then, RNA sequencing and ChIP-qPCR assay were performed to explore potential BTK targets and transcriptional regulatory sites. BTK, which was mainly expressed in macrophages, was upregulated in mice after MI. Compared with WT mice, BTKMAC−KO mice had significantly greater mortality due to heart rupture, reduced wall thickness and severe impairment of left ventricular (LV) function after MI. In addition, increased matrix metalloproteinase-9 (MMP-9) expression and decreased α-SMA and collagen expression were observed in BTKMAC−KO mice after MI. Further experiments revealed that BTK deficiency in macrophages reduces the expression of VEGF and impairs angiogenesis after MI. By RNA sequencing, we found that Nf-kB family genes, as well as the urokinase-type plasminogen activator (uPA), were significantly upregulated in BTK-deficient macrophages. By ChIP-qPCR analysis, we confirmed that uPA was transcriptionally activated by the Nf-kB p65 subunit. Finally, the application of plasminogen activator inhibitor-1 (PAI-1), an uPA inhibitor, markedly protected against cardiac rupture, lowered the mortality rate, and improved cardiac function by increasing collagen deposition and promoting tissue healing in BTKMAC−KO mice after MI. The present study identifies PAI-1 as a novel cardioprotective agent for cardiac repair post-MI that increases collagen deposition and promotes tissue healing. A therapeutic strategy targeting BTK may be a promising treatment for cardiac repair post-MI. [Display omitted] • Bruton tyrosine kinase (BTK), which is highly expressed in immune cells, plays a critical role in regulating the function of macrophages. However, the role of BTK in cardiac repair post-MI, especially in macrophage-mediated repair, remains unclear. • BTK improves wound healing and reduces cardiac rupture after myocardial infarction in mice. BTK increases matrix metalloproteinase-9 (MMP-9) expression and decreased α-SMA and collagen expression by inhibiting the transcription of u-PA. The uPA inhibitor, PAI-1, markedly reduces cardiac rupture and improves cardiac function after myocardial infarction in mice. • The present study identifies PAI-1 as a novel cardioprotective agent for cardiac repair post-MI that increases collagen deposition and promotes tissue healing. A therapeutic strategy targeting BTK may be a promising treatment for cardiac repair post-MI. [ABSTRACT FROM AUTHOR]

Radiopharmaceutical approaches to genitourinary cancers continue to expand. Nuclear medicine is broadening the search for new targets, renewing existing molecules to improve their specificity, biodistribution, and binding, and exploring "novel" isotopes. Interests focus on diagnostic tracers, theranostics, and combination treatments. This review aims to provide an overview of novel diagnostic and therapeutic radiopharmaceuticals tested recently or used currently in genitourinary cancers within prospective phase 1–2 clinical trials, summarizing progresses and future directions. A systematic search was conducted using the PubMed/MEDLINE and ClinicalTrials.gov databases for original prospective research studies following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Forty-six papers were systematically reviewed; 74 ongoing clinical trials were identified. The results of 27 novel radiopharmaceuticals (ie, not approved by the Food and Drug Administration/European Medicines Agency and not listed in the Pharmacopeia) prospectively investigated in genitourinary cancers, mostly prostate, for diagnostic, theranostic, or therapeutic purposes (21, one, and five of the 27 radiopharmaceuticals, respectively) over the past 5 yr were presented. Most were prostate-specific membrane antigen–targeting agents (17/27); other targets included gastrin-releasing peptide receptor, carbonic anhydrase IX, Cu, six transmembrane epithelial antigen of the prostate 1, tumor-associated glycoprotein 42, and urokinase-type plasminogen activator receptor. Ongoing research confirms the same trend. Fibroblast activation protein inhibitor, PD-L1, CD8, nectin-4, and HER2 are other targets under investigation. Among the 22 ongoing therapeutic trials (out of the 74 ongoing clinical trials), targeted alpha therapy is being explored in 12, and five are evaluating combinations of radioligand therapy with other treatments. We confirmed the safety of radiopharmaceuticals (regardless of the diagnostic/therapeutic purpose) and showed promising results in terms of diagnostic accuracy and therapeutic efficacy in genitourinary cancers. There continues to be expansion in radiopharmaceutical approaches to genitourinary cancers, reflecting a strong emphasis on improving tumor detection and treatment, which will likely impact future management across the disease spectrum, with the potential for improved patient care and outcomes. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored the urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression in this stroma-dense tumor. We generated a site-specific ADC offering high-affinity, cross-species reactivity, and efficient internalization of the anti-uPAR monoclonal antibody, FL1, carrying a potent anthracycline derivative (PNU-158692). In vitro, FL1-PNU exhibited potent and specific cytotoxicity against uPAR-expressing PDAC cell lines, stromal and immune cells, and bystander killing of uPAR-negative cells. In vivo, the ADC induced remission or sustained tumor regression and extended survival in xenograft models. In syngeneic orthotopic models, the antitumor effect promoted immunomodulation by enhancing infiltrating immune effectors and decreasing immunosuppressive cells. This study lays grounds for further exploring FL1-PNU as a putative clinical ADC candidate, potentially providing a promising therapeutic avenue for PDAC as a monotherapy or in combinatorial regimens. [ABSTRACT FROM AUTHOR]

The role of the plasminogen activation system is to regulate the activity of the extracellular protease plasmin. It comprises the urokinase plasminogen activator (uPA), a specific extracellular protease which activates plasminogen, its inhibitor PAI1, and the urokinase plasminogen activator receptor, uPAR, which localizes the urokinase activity. The plasminogen activation system is involved in tissue remodeling through extracellular matrix degradation, and therefore participates in numerous physiological and pathological processes, which make it a potential biomarker. To investigate the role of these molecules in the cellular processes, we cloned human uPA, PAI1, and uPAR and overexpressed them in two cell lines, the glioblastoma line A1235 and the transformed human embryonal kidney cells HEK 293. We analyzed the urokinase activity and the expression of plasminogen activation system elements on the protein and RNA level by Western blot analysis and RTqPCR. Cell proliferation was followed up by cell counting, cell migration and invasion by wound-healing and the transwell assays, respectively, and cell adhesion and dispersal by spheroid formation. The cells transfected with urokinase sequence had increased urokinase activity and uPA expression, while the PAI1-transfected cells decreased urokinase activity, increased PAI1 expression, and decreased cell migration. HEK 293 cells expressing PAI formed only small spheroids. The effects of the uPA system molecules depended on their interactions with each other and with other molecules in the microenvironment, as well as on the cell-type-specific signaling. [ABSTRACT FROM AUTHOR]

Circadian misalignment, due to shiftwork and/or individual chronotype and/or social jetlag (SJL), quantified as the difference between internal and social timing, may contribute to cardiovascular disease. Markers of endothelial dysfunction and activation of the coagulation system may predict cardiovascular pathology. The present study aim was to investigate the effects of shift work, SJL, and chronotype on endothelial function and coagulation parameters. One hundred female nurses underwent endothelial function testing using the EndoPAT and blood sampling for coagulation markers, repeated at 06:00–9:00 and 18:00–21:00. We found that compared with day workers, endothelial function and fibrinogen levels were lower (p = 0.001, p = 0.005, respectively) and the procoagulant parameters of plasminogen activator inhibitor-1 (PAI-1) and heparanase level and activity were higher amongst shift workers (p = 0.009, p = 0.03, p = 0.029, respectively). High SJL was associated with lower endothelial function (p = 0.002) and higher PAI-1, heparanase procoagulant activity, heparanase level, and D-Dimer level (p = 0.004, p = 0.003, p = 0.021, p = 0.006, respectively). In the late chronotype, PAI-1 and heparanase procoagulant activity were higher than in the early chronotype (p = 0.009, p = 0.007, respectively). Diurnal variation was found for PAI-1, von-Willebrand factor (vWF), heparanase, and heparan-sulfate with higher levels in the mornings. The correlation between shift/day workers and SJL or chronotype was moderately strong, indicating that SJL and chronotype are independent factors. In conclusion, findings suggest endothelial impairment and increased thrombotic risk in nurses working in shifts or with high SJL or late chronotype. The thrombotic risk is increased in the morning independent of circadian misalignment cause. These findings strengthen the importance of the alliance to the biological daily rhythm in daily life. Further research is needed to evaluate inhibitors of heparanase to attenuate the thrombotic risk in individuals with circadian misalignment. [ABSTRACT FROM AUTHOR]

We investigated the sex-dependent effects of inflammatory responses in visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT), as well as hematological status, in relation to cardiovascular disorders associated with prediabetes. Using male and female hereditary hypertriglyceridemic (HHTg) rats—a nonobese prediabetic model featuring dyslipidemia, hepatic steatosis, and insulin resistance—we found that HHTg females exhibited more pronounced hypertriglyceridemia than males, while HHTg males had higher non-fasting glucose levels. Additionally, HHTg females had higher platelet counts, larger platelet volumes, and lower antithrombin inhibitory activity. Regarding low-grade chronic inflammation, HHTg males exhibited increased serum leptin and leukocyte levels, while females had increased serum interleukin-6 (IL-6). Both sexes had increased circulating plasminogen activator inhibitor-1 (PAI-1), higher PAI-1 gene expression in VAT and PVAT, and elevated intercellular adhesion molecule-1 (ICAM-1) gene expression in the aorta, contributing to endothelial dysfunction in the HHTg strain. However, HHTg females had lower tumor necrosis factor alpha (TNFα) gene expression in the aorta. Severe dyslipidemia in this prediabetic model was associated with hypercoagulation and low-grade chronic inflammation. The increase in PAI-1 expression in both VAT and PVAT seems to indicate a link between inflammation and vascular dysfunction. Despite the more pronounced dyslipidemia and procoagulation status in females, their milder inflammatory response may reflect an association between reduced cardiovascular damage and prediabetes. [ABSTRACT FROM AUTHOR]

Objective: It is necessary to identify appropriate clinical, biochemical, epidemiological and genetic biomarkers to elucidate the underlying mechanisms of the coronavirus disease-2019 (COVID-19) disease. The study focused on not only the link between disease severity (non-intense unit care (non-ICU) versus intensive unit care (ICU) and genetic susceptibility in COVID-19 patients but also the connection between comorbidity and genetic susceptibility affecting the severity of COVID-19. Subject and methods: One hundred and sixty-two COVID-19 patients treated in the non-ICU and ICU in Kayseri City Hospital were included. All volunteers underwent a physical examination and biochemical evaluation. Angiotensin-converting enzyme (ACE p.T776T G > A(rs4343) and g.16471_16472delinsALU (also referred to as I/D polymorphism; rs1799752), angiotensin II receptor type-1 (AGTR1) c.*86A > C (also referred to as A1166C; rs5186), and plasminogen activator inhibitor-1 (PAI-1-844 G > A (rs2227631) polymorphisms were analysed as well. Results: To have ACE "ID" genotype did not change the severity of the disease (OR: 0.92, 95% CI: 0.41–2.1, p = 0.84), but decreased the mortality risk 2.9-fold (OR: 2.9, 95% CI: 1.1–7.0, p = 0.03). In PAI-1-844 G > A, having the "AA" genotype in the "A" recessive model increased the risk of the diabetes mellitus (DM) 2.3-fold (OR: 2.3 95%, CI: 1.16–4.66, p = 0.018). In the "G" recessive model, to have the GG genotype increased the risk of chronic kidney disease (CKD) 4.8-fold (OR:4.8, 95% CI: 1.5–15.5, p = 0.008). "GG" genotype in the DM group had a higher fibrinogen level compared to those with the "AG" genotype (AG:4847.2 mg/L (1704.3) versus GG:6444.67 mg/L (1861.62) p = 0.019) and "AA" genotype in the CKD group had lower platelet levels and those with "GG" had higher platelet levels (AA:149 µL (18–159) versus GG: 228 µL (146–357) p = 0.022). Conclusion: This study was shown that genetic predispositions that causes comorbidities were also likely to affect the prognosis of COVID-19. [ABSTRACT FROM AUTHOR]

Revascularization procedures are used over apexification to treat teeth with necrotic pulp tissues and incomplete root formation. Clinically, inducing proliferation, migration, matrix deposition, and differentiation of stem cells from apical papilla (SCAPs) are critical for pulp regeneration. The study aimed to elucidate the impact of bone morphogenetic protein-4 (BMP-4) on plasminogen activation molecules and the osteogenic/odontogenic differentiation of SCAPs, as well as understand the related signaling mechanisms. SCAPs were exposed to BMP-4 with or without signal transduction inhibitors. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. mRNA levels were quantified using real-time PCR. Protein expression in SCAPs was analyzed through immunofluorescent staining or western blotting. Cellular protein production was measured with enzyme-linked immunosorbent assay. BMP-4 induced suppressor of mother against decapentaplegic (Smad)1/5/8 and Smad2/3 phosphorylation and activation. It also promoted higher expression of osteogenic and odontogenic markers, including Osterix, N-cadherin, and secreted protein acidic and rich in cysteine (SPARC), in SCAPs. Additionally, BMP-4 stimulated connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1), and urokinase plasminogen activator receptor (uPAR) expression, but inhibited uPA expression and production in SCAPs, indicating its role in matrix remodeling and cell migration. Inhibition of Smad2/3 with SB431542 and Smad1/5/8 with LDN193189 attenuated the BMP-4-induced expression Osx, N-cadherin, CTGF, SPARC, uPAR and PAI-1. These results indicate that BMP-4 stimulates the osteogenic and odontogenic differentiation of SCAPs by regulating matrix turnover and mineralization-related proteins. Furthermore, these processes are associated with the induction of Smad2/3 and Smad1/5/8 of SCAPs by BMP-4. [ABSTRACT FROM AUTHOR]

Introduction: In the last decades, the recombinant tissue plasminogen activator alteplase has been the standard fibrinolytic treatment of acute myocardial infarction, pulmonary embolism, and acute ischemic stroke. An optimized version of alteplase, tenecteplase, has been developed by exchanging six amino acids to increase half-life, achieve higher fibrin selectivity and increase resistance to plasminogen activator inhibitor-1. Meanwhile, several products containing tenecteplase exist. The aim of this study was to compare the fibrinolytic activity and overall product quality of the 25 mg/vial presentation of tenecteplase originator Metalyse® (Boehringer Ingelheim Pharma GmbH and Co., KG, Ingelheim, Germany) to the 16 mg/vial formulation of the tenecteplase copy Mingfule® (CSPC Recomgen Pharmaceutical, Guangzhou, Co., Ltd.). Methods: We have systematically analyzed and evaluated the biochemical and fibrinolytic differences between Metalyse® and Mingfule® using a wide range of routine quality testing assays, supplemented by mass spectrometry analysis and surface plasmon resonance assays. Additional host cell protein quantification and clot lysis testing following plasmin incubation over time were performed. Results: Several key differences in biochemical composition and clot lysis activity were observed between the two tenecteplase variants. Versus Metalyse®, Mingfule® exhibited lower clot lysis activity and contained less of the two-chain form of tenecteplase. In addition, there were differences in sialic acid content, galactosylation, and fucosylation patterns, with Mingfule® exhibiting more bi- and less tri- and tetra-antennary glycosylation, leading to a different charge and size heterogeneity profile. Furthermore, Mingfule® displayed highly dissimilar binding to the three clearance receptors (LRP-1, ASGR, and mannose receptor) compared with Metalyse®. Purity analysis showed that Mingfule® contained a lower monomer content and, in contrast to Metalyse®, substantial amounts of host cell protein. Discussion: Taken together, these data demonstrate that the tenecteplase copy Mingfule® has several meaningful fibrinolytic and biochemical differences compared with Metalyse®. This raises the question of whether data from clinical studies with one of the products can be generalized for all tenecteplase variants. [ABSTRACT FROM AUTHOR]

Thromboembolic disorders, including deep vein thrombosis (DVT) and pulmonary embolism (PE), are major global health concerns, causing significant morbidity and mortality. Early diagnosis is crucial for effective treatment and improved patient outcomes. Recent research has identified Apelin-13, a bioactive peptide in the apelin family, as a promising diagnostic biomarker for Thromboembolic disorders. Apelin-13 supports vascular health by regulating protease balance through plasminogen activator inhibitors and modulating endothelial cell function. Additionally, it plays a vital role in coagulation, with elevated levels associated with an increased risk of clot formation, suggesting its utility in predicting thrombosis risk, particularly in preoperative evaluations. Findings indicate that the Apelin-13 pathway shows significant promise as a biomarker for Thromboembolic disorders, underscoring its potential therapeutic applications and the need for further investigation. This review synthesizes current literature on thromboembolic disorders and associated laboratory biomarkers, with a particular focus on Apelin-13. It examines Apelin-13's role in disease mechanisms, its physiological functions, and its potential as a diagnostic biomarker in thromboembolic conditions. [ABSTRACT FROM AUTHOR]

Pentadecanoic acid (C15:0, PDA) is an odd and minor fatty acid that has been neglected in the literature until the last decade. Indeed, as a specific fatty acid of dairy fat, PDA was only used as a biomarker of dairy fat consumption. Lately, PDA was first correlated negatively with the incidence of metabolic syndrome disorder, then its physiological effects have been investigated as a protective fatty acid. PDA supplementation has been demonstrated as negatively correlated with elevated levels of leptin, plasminogen activator inhibitor-1 and insulin, and has been shown to exhibit sensitizing insulin effects with activation of AMPK pathway. PDA also reduced the severity of metabolic dysfunction-associated steatohepatitis (MASH), notably through reduced alanine transaminase and pro-inflammatory cytokines levels. The final effect described for PDA is its ability to display anti-inflammatory properties in several pathology models. Hence, considering these multiple effects, the presence of PDA could be associated with a healthier physiological state, this raises the question of whether the presence of PDA in the body, in adequate quantities, is needed to participate to health maintenance. PDA is not synthesized in sufficient quantities endogenously, so it must be provided by the diet, mainly through dairy fat, although other types of food can also contribute to the dietary intake of PDA. Essential fatty acids are described as not being endogenously synthesized in sufficient and required quantities to maintain physiological health. Thus, PDA might gather both conditions to be described as essential, yet further investigations on both criteria are needed to enhance knowledge on this odd chain fatty acid with promising impact as potential protective supplement nutrient. • Pentadecanoic acid is dietary fatty acid which must be supplied from the diet. • Dietary pentadecanoic acid was shown protective against metabolic syndrome. • Studies are now investigated into its potential nutritional essentiality. [ABSTRACT FROM AUTHOR]

Background/aims: Submacular haemorrhages (SMH) cause significant visual impairment. Until now, the comparative effectiveness of different treatment approaches remains inconclusive without clear treatment guidelines. The aim of our study was to evaluate the effectiveness of 5 surgical treatment modalities in terms of visual prognosis and success rate. Methods: This retrospective study included 201 patients with SMH. Primary endpoint was best corrected visual acuity (BCVA), secondary endpoints included haemorrhage size and complications. Group 1 was treated with pneumatic displacement and rtPA-injection. Group 2 followed the "Manchester protocol" with rtPA-injection and—if needed—a standardised secondary procedure with pars plana vitrectomy (ppV) and subretinal rtPA. Group 3 underwent vitrectomy with subretinal rtPA, group 4 vitrectomy only and group 5 received subretinal lavage. Results: Baseline characteristics were a mean age of 79 years and a follow-up of 4.6 months. Pre-intervention BCVA of 1.7 logMAR improved to 1.4 logMAR at follow-up. A gain of > 0.2 logMAR was achieved in 47% of patients, while 20% lost > 0.2 logMAR. Only group 2 achieved a statistically significant visual gain. While group 5 was statistically larger in haemorrhage size preoperatively (p < 0.05), all groups were statistically equal in SMH size at follow-up. Complications led to additional interventions in 20% of patients. Conclusions: No significant change in visual prognosis could be achieved depending on the intervention. As more invasive techniques seem to lack the benefit of a better postoperative prognosis while carrying higher risks, it may be beneficial considering a less invasive option first. [ABSTRACT FROM AUTHOR]

• ECM architecture is dynamically altered by serine proteases during carcinogenesis. • Protease-mediated proteolysis modulates activities of ECM components and integrins. • Degradation of ECM allows epithelial cancer cells to enter the blood circulation. • ECM remodeling causes the release of many ECM-associated growth factors. The extracellular matrix (ECM) serves as a physical scaffold for tissues that is composed of structural proteins such as laminins, collagens, proteoglycans and fibronectin, forming a three dimensional network, and a wide variety of other matrix proteins with ECM-remodeling and signaling functions. The activity of ECM-associated signaling proteins is tightly regulated. Thus, the ECM serves as a reservoir for water and growth regulatory signals. The ECM architecture is dynamically modulated by multiple serine proteases that process both structural and signaling proteins to regulate physiological processes such as organogenesis and tissue homeostasis but they also contribute to pathological events, especially cancer progression. Here, we review the current literature regarding the role of ECM remodeling by serine proteases (KLKs, uPA, furin, HtrAs, granzymes, matriptase, hepsin) in tumorigenesis. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests the serine protease, urokinase plasminogen activator (uPA), may play an important role in the modulation of mood and cognitive functions. Also, preliminary evidence indicates that uPA modulates BDNF activity that is known to be involved in the pathogenesis of mood disorders. However, the physiological functions of uPA in specific brain regions for mediating stress-related emotional behaviors remain to be elucidated. Therefore, the aim of this study was to assess the role of ectopic uPA expression on anxiety- and depression-like behaviors following social defeat stress in rats. For this purpose, we inspected the behavioral outcomes following bilateral stereotaxic delivery of uPA-overexpressing lentiviral vectors in the hippocampus using a series of behavioral tests. Results show that hippocampal uPA gain-of-function prevented stress-elicited anxiogenic-like effects, as determined in the marble burying, open field, and elevated plus maze tests, with no alterations in spontaneous locomotor activity. Also, ectopic uPA overexpression resulted in anti-depressant-like effects in the sucrose splash, tail suspension, and forced swim tests. Most importantly, uPA overexpression increased hippocampal BDNF levels, and a strong positive correlation was found using the Pearson test. Moreover, the same correlation analysis revealed a strong negative relationship between uPA mRNA and parameters of anxiety- and depression-like behaviors. Taken together, this work highlights the importance of considering uPA activation and provides new insights into the mechanisms involved in the pathophysiology of stress-elicited mood illnesses, which should help in the development of new approaches to tackle depression and anxiety disorders. [ABSTRACT FROM AUTHOR]

Statins are lipid-lowering agents with anti-inflammatory effects. Data surrounding the benefits of statins in patients with coronavirus disease 2019 (COVID-19) are conflicting. We sought to better understand the impact of statins in the context of COVID-19-related inflammation. We leveraged the International Study of Inflammation in COVID-19, a prospective multicenter cohort of patients hospitalized for COVID-19 between February 2020 and October 2022. Participants underwent systematic assessment of biomarkers of inflammation. We used logistic regression modeling and inverse probability-of-treatment weighting (IPTW) to examine the association between prior statin use and the composite outcome of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. A total of 4464 patients were included in the study, of whom 1364 (27.5%) were taking a statin prior to admission. There were 1061 primary outcome events, including 540 deaths, 854 mechanical ventilation and 313 renal replacement therapy. Amongst biomarkers of inflammation, statin use was associated solely with lower levels of soluble urokinase plasminogen activator receptor (suPAR) after adjusting for known confounders. In multivariable logistic regression analysis, statin use was associated with lower odds of the composite outcome (adjusted odds ratio (aOR) 0.63, 95% CI [0.53-0.76]) compared to patients not on statins. Findings were consistent with IPTW (aOR 0.92, 95% CI [0.89- 0.95]). The proportion of the effect of statin on the primary outcome mediated by suPAR was estimated at 31.5%. Prior-statin use is associated with improved outcomes and lower inflammation as measured by suPAR levels in patients hospitalized for COVID-19. [ABSTRACT FROM AUTHOR]

Sepsis-associated acute kidney injury (S-AKI) is a critical illness and is often associated with high morbidity and mortality rates. The soluble urokinase-type plasminogen activator receptor (suPAR) is an important immune mediator and is involved in kidney injury. However, its diagnostic value in S-AKI patients remains unclear. Therefore, we assessed the early predictive value of suPAR for S-AKI patients. We prospectively enrolled adult patients, immediately after fulfilling the sepsis-3 criteria. Plasma suPAR levels at 0-, 12-, 24-, and 48-h post-sepsis diagnosis were measured. S-AKI development was the primary outcome. S-AKI risk factors were analyzed using logistic regression, and the value of plasma suPAR for early S-AKI diagnosis was assessed using receiver operating characteristic (ROC) curves. Of 179 sepsis patients, 63 (35.2%) developed AKI during hospitalization. At 12-, 24-, and 48-h post-sepsis diagnosis, plasma suPAR levels were significantly higher in patients with S-AKI than in patients without S-AKI (p < 0.05). The plasma suPAR had the highest area under the ROC curve of 0.700 (95% confidence interval (CI), 0.621–0.779) at 24-h post-sepsis diagnosis, at which the best discrimination ability for S-AKI was achieved with suPAR of ≥6.31 ng/mL (sensitivity 61.9% and specificity 71.6%). Logistic regression analysis showed that suPAR at 24-h post-sepsis diagnosis remained an independent S-AKI risk factor after adjusting for mechanical ventilation, blood urea nitrogen, and pH. The findings suggest that plasma suPAR may be a potential biomarker for early S-AKI diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: Plasma proteins play essential roles in myocardial infarction (MI) and atrial fibrillation (AF) ; however, it remains unknown whether the two disorders share causal plasma proteins. Methods: The present study utilizes cis-protein quantitative trait loci (cis-pQTLs) for 4,719 plasma proteins to assess their causality on MI and AF. Results: Two-sample Mendelian randomization (MR) identifies 21 and 9 plasma proteins for MI and AF, respectively (FDR P < 0.05), with plasminogen (PLG) being a commonly protective factor against both diseases. Multi-trait MR suggests that PLG is also protective against coronary atherosclerosis. PheWAS analysis identifies associations of six c/s-pQTLs with both MI and AF, i.e., rs11751347 (PLG), rs11591147 (PCSK9), rs77347777 (ITIH4), rs936228 (ULK3), rs2261033 (AIF1V), and rs2711897 (BDH2). Furthermore, interactions exist among the causal plasma proteins, with PLG directly interacting with multiple others. Drug-gene databases suggest that PLG activators, such as Urokinase, Reteplase, Streptokinase, Alteplase, Anistreplase, Tenecteplase, Desmoteplase, and Defibrotide sodium may serve as common therapeutic drugs for MI and AF. Conclusion: Our study provides a causal inference of human plasma proteins in MI and AF. Several of the identified proteins and single nucleotide polymorphisms (sNPs) exert pleiotropic effects on other cardiometabolic phenotypes, indicating their crucial roles in the pathology of cardiovascular disease (CVD). Our study provides new insights into the shared causality and drugs for MI and AF. [ABSTRACT FROM AUTHOR]

Rationale: Growing evidence suggests that air pollution exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) that is associated with an increased prothrombotic state and adverse cardiovascular outcomes. However, much of this work is based on observational data or human exposure studies involving younger participants. The biological causality and mechanism of air pollution-induced prothrombotic response in patients with COPD remain to be explored. Objectives: The main aim of this work was to investigate the impact of short-term diesel exhaust (DE) exposure on circulating prothrombotic markers—fibrinogen and plasminogen activator inhibitor-1 (PAI-1)—and urinary eicosanoids in patients with COPD. Methods: Twenty-nine research participants were recruited in this randomized, double-blind, crossover, controlled human exposure study to DE. Participants included former smokers with and without mild or moderate COPD (ex-smokers [ES] and COPD group) and healthy never-smokers without COPD (nonsmoker [NS] group). Each participant was exposed to DE (300 μg/m3 of particulate matter with an aerodynamic diameter ≤2.5 μm) and filtered air for 2 hours on different occasions, in randomized order, separated by a 4-week washout. Blood and urine samples were collected before and 24 hours after each exposure. Plasma fibrinogen and serum PAI-1 concentrations were quantified using enzyme-linked immunosorbent assays. Urinary eicosanoid concentrations were quantified using ultraperformance liquid chromatography coupled to tandem mass spectrometry. Linear mixed-effects models were used for statistical comparisons. Results: Participants with COPD showed an increase in plasma fibrinogen (effect estimate, 1.27 [1.06–1.53]; P = 0.01) after DE relative to filtered air, but no significant DE-associated change in serum PAI-1 (0.95 [0.87–1.04]; P = 0.26). In never-smokers and ex-smokers without COPD, fibrinogen (NS group, 1.10 [0.99–1.23]; P = 0.08; ES group, 0.86 [0.68–1.09]; P = 0.08] and PAI-1 (NS group, 1.12 [0.96–1.32]; P = 0.15; ES group, 0.90 [0.79–1.03]; P = 0.13) were not changed after DE exposure. Participants with COPD showed a DE-attributable increase in urinary thromboxane B2 (TXB2) metabolite concentrations as follows: 11-dehydro-TXB2 (1.45 [1.02–2.08]; P = 0.04) and 2,3-dinor-TXB2 (1.45 [1.05–2.00]; P = 0.03). Conclusions: Participants with COPD had increased plasma fibrinogen and urinary TXB2 metabolites after short-term DE exposure, suggesting they may be more susceptible to a pollution-attributable prothrombotic response than healthy control subjects or ex-smokers without COPD. Clinical trial registered with (NCT 02236039). [ABSTRACT FROM AUTHOR]

A general decline in the osteogenic differentiation capacity of human bone marrow mesenchymal stem cells (hBMSCs) in the elderly is a clinical consensus, with diverse opinions on the mechanisms. Many studies have demonstrated that metformin (MF) significantly protects against osteoporosis and reduces fracture risk. However, the exact mechanism of this effect remains unclear. In this study, we found that the decreased miR-181a-5p expression triggered by MF treatment plays a critical role in recovering the osteogenic ability of aging hBMSCs (derived from elderly individuals). Notably, the miR-181a-5p expression in hBMSCs was significantly decreased with prolonged MF (1000 μM) treatment. Further investigation revealed that miR-181a-5p overexpression markedly impairs the osteogenic ability of hBMSCs, while miR-181a-5p inhibition reveals the opposite result. We also found that miR-181a-5p could suppress the protein translation process of plasminogen activator inhibitor-1 (PAI-1), as evidenced by luciferase assays and Western blots. Additionally, low PAI-1 levels were associated with diminished osteogenic ability, whereas high levels promoted it. These findings were further validated in human umbilical cord mesenchymal stem cells (hUCMSCs). Finally, our in vivo experiment with a bone defects rat model confirmed that the agomiR-181a-5p (long-lasting miR-181a-5p mimic) undermined bone defects recovery, while the antagomiR-181a-5p (long-lasting miR-181a-5p inhibitor) significantly promoted the bone defects recovery. In conclusion, we found that MF promotes bone tissue regeneration through the miR-181a-5p/PAI-1 axis by affecting MSC osteogenic ability, providing new strategies for the treatment of age-related bone regeneration disorders. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is a global health issue, with lipid metabolism and inflammation critically implicated in its progression. This study harnesses cutting‐edge, expanded genetic information for lipid and inflammatory protein profiles, employing Mendelian randomization (MR) to uncover genetic risk factors for HF. Methods: We assessed genetic susceptibility to HF across 179 lipidomes and 91 inflammatory proteins using instrumental variables (IVs) from recent genome‐wide association studies (GWASs) and proteome‐wide quantitative trait loci (pQTL) studies. GWASs involving 47 309 HF cases and 930 014 controls were obtained from the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) Consortium. Data on 179 lipids from 7174 individuals in a Finnish cohort and 91 inflammatory proteins from a European pQTL study involving 14 824 individuals are available in the HGRI‐EBI catalogue. A two‐sample MR approach evaluated the associations, and a two‐step mediation analysis explored the mediation role of inflammatory proteins in the lipid–HF pathway. Sensitivity analyses, including MR‐RAPS (robust adjusted profile score) and MR‐Egger, ensured result robustness. Results: Genetic IVs for 162 lipids and 74 inflammatory proteins were successfully identified. MR analysis revealed a genetic association between HF and 31 lipids. Among them, 18 lipids, including sterol ester (27:1/18:0), cholesterol, 9 phosphatidylcholines, phosphatidylinositol (16:0_20:4) and 6 triacylglycerols, were identified as HF risk factors [odds ratio (OR) = 1.037–1.368]. Cholesterol exhibited the most significant association with elevated HF risk [OR = 1.368, 95% confidence interval (CI) = 1.044–1.794, P = 0.023]. In the inflammatory proteome, leukaemia inhibitory factor receptor (OR = 0.841, 95% CI = 0.789–0.897, P = 1.08E‐07), fibroblast growth factor 19 (OR = 0.905, 95% CI = 0.830–0.988, P = 0.025) and urokinase‐type plasminogen activator (OR = 0.938, 95% CI = 0.886–0.994, P = 0.030) were causally negatively correlated with HF, whereas interleukin‐20 receptor subunit alpha (OR = 1.333, 95% CI = 1.094–1.625, P = 0.004) was causally positively correlated with HF. Mediation analysis revealed leukaemia inhibitory factor receptor (mediation proportion: 23.5%–25.2%) and urokinase‐type plasminogen activator (mediation proportion: 9.5%–10.7%) as intermediaries in the lipid–inflammation–HF pathway. No evidence of directional horizontal pleiotropy was observed (P > 0.05). Conclusions: This study identifies a genetic connection between certain lipids, particularly cholesterol, and HF, highlighting inflammatory proteins that influence HF risk and mediate this relationship, suggesting new therapeutic targets and insights into genetic drivers in HF. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to evaluate thrombophilic/hypofibrinolytic factors in two ocular vascular pathologies; retinal vein occlusion (RVO) and non-arteritic anterior ischemic optic neuropathy (NAION). Methods: Prospective study including patients with RVO (n=13), NAION (n=17), and age-sex matched control group (n=14). Clinical history for pre-existing hypertension and diabetes mellitus were recorded. Measured serological thrombophilic markers included Factor V Leiden (FVL) and methyltetrahydrofolate reductase (MTHFR) C677T mutations. Serum Protein C (PC) activity and plasminogen activator inhibitor-1 (PAI-1) levels were also evaluated. P<0.05 was considered statistically significant. Results: There was no statistically significant difference with demographics between groups. FVL mutation was positive for three patients with RVO (23.1%), two patients with NAION (11.8%), and one subject in the control group (9.1%). MTHFR C677T mutation was found in 12 patients with RVO (92.3%), 15 patients with NAION (88.2%), and three subjects in the control group (27.3%). Even though there was not a statistically significant difference between RVO and NAION groups, this mutation was significantly higher in the patient groups compared to controls (p=0.001). We did not observe a statistically significant difference in PC activity levels between groups (p=0.35). Plasma PAI-1 levels were higher in the patient groups than the control group, however, the difference was not statistically significant (p=0.168) between any of the groups. Conclusion: MTHFR C677T mutation was more common in both patient groups compared to controls, without a statistically significant difference between RVO and NAION groups. PAI-1 levels were also higher in the patient groups; however, the difference was not statistically significant. The findings of this study underscore the potential role of genetic and serological factors in ocular vascular pathologies. Understanding these associations better could lead to more targeted screening and management strategies for patients at risk of ocular vascular disorders. Further studies including larger cohorts are required to elucidate possible associations. [ABSTRACT FROM AUTHOR]

Objective: This study examines the association between traditional inflammatory biomarkers, soluble urokinase plasminogen activator receptor (suPAR) levels in elderly and young myocardial infarction patients, and coronary artery disease severity. Materials and Methods: In this study, 332 participants, including 227 acute myocardial infarction (AMI) patients and 107 controls, underwent evaluation through Syntax Score analysis, suPAR, and high-sensitivity C-reactive protein (hs-CRP) level assessments. AMI patients were divided into young and elderly groups based on age. Syntax Score was utilized to ascertain the severity of coronary artery disease. Results: suPAR plasma concentrations were significantly higher in AMI patients compared to controls, with values of 2.76 (2.32-3.56) in the young MI group and 3.33 (2.43-4.41) in the elderly MI group, versus 2.33 (1.94-3.11) in the control group (p<0.001). Additionally, hs-CRP levels were notably elevated in the elderly MI groups (p<0.001). The ROC analysis identified threshold values for suPAR at 3.10 pg/mL and hs-CRP at 6.5 mg/dL to predict a Syntax Score of 23 or higher, with suPAR showing 74.7% sensitivity, 69.9% specificity, and an area under the curve (AUC) of 0.811 (p<0.001). The sensitivity of hs-CRP was 65.8%, the specificity was 60.2%, and the AUC was 0.700 (p<0.001). Conclusion: Our study reveals a pivotal relationship between inflammatory markers, particularly suPAR, and Syntax Score in MI patients, suggesting its potential in refining cardiovascular risk assessment and informing future diagnostic and therapeutic approaches for coronary artery disease management. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS) is a human-specific bacterial pathogen that can exploit the plasminogen-plasmin fibrinolysis system to dismantle blood clots and facilitate its spread and survival within the human host. In this study, we use affinity-enrichment mass spectrometry to decipher the host-pathogen protein-protein interaction between plasminogen and streptolysin O, a key cytolytic toxin produced by GAS. This interaction accelerates the conversion of plasminogen to plasmin by both the host tissue-type plasminogen activator and streptokinase, a bacterial plasminogen activator secreted by GAS. Integrative structural mass spectrometry analysis shows that the interaction induces local conformational shifts in plasminogen. These changes lead to the formation of a stabilised intermediate plasminogen-streptolysin O complex that becomes significantly more susceptible to proteolytic processing by plasminogen activators. Our findings reveal a conserved and moonlighting pathomechanistic function for streptolysin O that extends beyond its well-characterised cytolytic activity. Group A Streptococcus exploits the human fibrinolytic system to promote infection. Here, the authors reveal that the bacterial toxin streptolysin O binds to plasminogen and accelerates its conversion to plasmin, thereby dismantling blood clots and facilitating the spread within the human host. [ABSTRACT FROM AUTHOR]

Hepatic stellate cells (HSCs) are primary cells for development and progression of liver fibrosis. Mitophagy is an essential lysosomal process for mitochondrial homeostasis, which can be activated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP), a representative mitochondrial uncoupler. However, little information is available on the role of CCCP-mediated mitophagy in HSC activation and liver fibrogenesis. In this study, we showed that CCCP treatment in HSCs caused mitochondrial dysfunction proved by decreased mitochondrial membrane potential, mitochondrial DNA, and ATP contents and increased mitochondrial ROS. Moreover, CCCP induced mitophagy and impaired mitophagy flux at the later stage. This blockade of mitophagic flux effect was mediated by suppression of lysosomal activity; CCCP decreased expression of lysosomal markers and cathepsin B activity, and increased lysosomal pH. Intriguingly, CCCP treatment in LX-2 cells or primary HSCs elevated plasminogen activator inhibitor-1 (PAI-1), a typical fibrogenic marker of HSCs which was attenuated by mitochondrial division inhibitor 1, a mitophagy inhibitor. The up-regulation of PAI-1 by CCCP was not due to altered transcriptional activity but lysosomal dysfunction. In vivo acute or sub-chronic treatment of CCCP to mice induced mitophagy and fibrogenesis of liver. Hepatic fibrogenic marker (PAI-1) was incremented with mitophagy markers (parkin and PTEN-induced putative kinase 1) in the livers of CCCP injected mice. Furthermore, we found that 5-aminoimidazole-4-carboxyamide ribonucleoside reversed CCCP-mediated mitophagy and subsequent HSC activation. To conclude, CCCP facilitated HSC activation and hepatic fibrogenesis via mitochondrial dysfunction and lysosomal blockade, implying that attenuation of CCCP-related signaling molecules may contribute to treat liver fibrosis. [Display omitted] • CCCP enhances mitophagy as well as impairs autophagic flux in HSCs. • CCCP promotes PAI-1 induction via lysosomal dysfunction leading to liver fibrosis. • AICAR inhibits CCCP-mediated liver fibrosis in an AMPK-independent mechanism. [ABSTRACT FROM AUTHOR]

Background/Objectives: Heart failure (HF) remains a major therapeutic and diagnostic challenge nowadays. Albeit, acute decompensated HF is associated with several clinical signs such as dyspnea or edema, it remains a challenge to use easy accessible and suitable tools, such as biomarkers, to distinguish between patients at risk for an acute decompensation of their heart failure and compensated, stable HF patients. Existing biomarkers, such as natriuretic peptides or troponin, are not specific and can be elevated due to several other disease conditions, such as myocardial infarction, atrial fibrillation, or valve diseases. Therefore, the aim of this study was to analyze the predictive potential of four novel cardiovascular biomarkers—the soluble urokinase-type plasminogen activator receptor (suPAR), heart-type fatty acid binding protein (H-FABP), vascular cell adhesion molecule 1 (VCAM-1), and growth/differentiation factor 15 (GDF-15) for the detection of cardiac decompensation in patients with HF. Methods: In this study, 146 patients were prospectively enrolled and the serum biomarker concentrations were analyzed using Enzyme Linked Immunosorbent Assay (ELISA). We correlated the biomarker concentrations with clinical and biochemical parameters of all patients and the predictive value for detection of cardiac decompensation was assessed. Results: A significant increase in the levels of suPAR (1.6-fold-change, p < 0.0001), H-FABP (2.2-fold-change, p = 0.0458), VCAM-1 (1.6-fold-change, p < 0.0001), and GDF-15 (1.7-fold-change, p = 0.0009) was detected in all patients with acute decompensated HF in comparison to patients with compensated HF. Univariate logistic regression analysis revealed a significant association of biomarker plasma concentration with the risk for a cardiac decompensation (suPAR: p < 0.0001; VCAM-1: p < 0.0001, H-FABP: p = 0.0458; GDF-15: p = 0.0009). Conclusions: In conclusion, the investigated novel cardiovascular biomarkers suPAR, GDF-15, VCAM-1, and H-FABP could be a valuable tool to facilitate therapeutic decisions in patients with heart failure and suspicion of a cardiac decompensation. Parameters such as renal function should be taken into account. Further studies on novel biomarkers are required to find reliable, sensitive, and specific tools that will enable the early detection of patients with acute decompensation. [ABSTRACT FROM AUTHOR]

Plasminogen activator inhibitor-1 (PAI-1) is a vital regulator of the fibrinolytic mechanism and has been intricately involved in various physiological and clinical processes, including cancer, thrombosis, and wound healing. The PAI-1 signaling pathway is multifaceted, encompassing numerous signaling molecules and nodes. Recent studies have revealed a novel contribution of PAI-1 during cellular senescence. This review introduces a pathway resource detailing the signaling network events mediated by PAI-1. The literature curated on the PAI-1 system was manually compiled from various published studies, our analysis presents a signaling pathway network of PAI-1, which includes various events like enzyme catalysis, molecular association, gene regulation, protein expression, and protein translocation. This signaling network aims to provide a detailed analysis of the existing understanding of the PAI-1 signaling pathway in the context of cellular senescence across various research models. By developing this pathway, we aspire to deepen our understanding of aging and senescence research, ultimately contributing to the pursuit of effective therapeutic approaches for these complex chronic diseases. [ABSTRACT FROM AUTHOR]

We investigated serum concentrations of specific inflammatory parameters in patients with significant carotid artery stenosis (CAS) of 50–99%, with an additional focus on patients with moderate stenosis (50–69%), in terms of both symptomatic status and plaque morphology, to determine whether there are certain parameters that can be associated with plaque instability before the progression of CAS to a high degree. The study included 119 CAS patients, 29 of whom had moderate stenosis, and 46 controls. Ultrasonography of the carotid arteries was performed using color flow Doppler and B-mode duplex ultrasound, and serum inflammatory parameters were measured using commercially available enzyme immunoassays. When comparing patients with 50–99% stenosis, only serum amyloid A (SAA) was higher in symptomatic patients, while in the group of patients with 50–69% stenosis, myeloperoxidase (MPO) was higher and pentraxin-3 (PTX-3) was lower in symptomatic compared to asymptomatic patients, and soluble urokinase plasminogen activator receptor (suPAR) was higher in patients with carotid plaque of unstable compared to stable morphology. Our results suggest that the importance of different inflammatory parameters in patients with moderate CAS is not the same as in CAS patients in general, and therefore their separate investigation in patients with high and moderate stenosis may be beneficial. SAA has the potential to be further considered in research to predict CAS symptom risk. There is a possibility that MPO and PTX-3 play a role in the development of CAS symptoms originating from less stenotic plaques and that suPAR is involved in the destabilisation of such plaques. [ABSTRACT FROM AUTHOR]

Background/Objectives: This retrospective study analyzed soluble urokinase plasminogen activator receptor (suPAR) plasma levels alongside routine inflammatory markers, including the neutrophil-to-lymphocyte count ratio, C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), and D-dimers in COVID-19 patients hospitalized during the Omicron wave of the pandemic. Methods: We measured plasma suPAR levels using a suPARnostic® Quick Triage kit. We divided COVID-19 patients into two groups based on the severity of SARS-CoV-2 infection according to the National Institutes of Health (NIH) criteria. The logistic regression analysis tested the predictive value of the biomarkers. Results: We evaluated 160 consecutive COVID-19 patients hospitalized between January and August 2022. The cohort exhibited a high incidence of comorbidities, with an in-hospital mortality rate of 5.6%. Upon admission, the median suPAR plasma levels were not significantly different between patients with mild COVID-19 (n = 110) and those with moderate/severe disease (n = 50), with 7.25 ng/mL and 7.55 ng/mL, respectively. We observed significant differences (p < 0.01) between the groups for CRP and IL-6 levels that were higher in moderate/severe disease than in mild infection. Additionally, suPAR plasma levels were above the normal range (0–2.00 ng/mL) in all patients, with a significant positive correlation identified between suPAR levels and serum IL-6, PCT, and creatinine levels. Conclusions: These findings indicate that COVID-19 during the Omicron wave is strongly associated with elevated suPAR levels; however, these levels do not directly correlate with the severity of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Recent studies on viral diseases showed that neutrophils exist in various phenotypes and functional statuses, that may play a role either in viral clearance or in immunopathology. Emerging evidence suggests that dengue virus can activate neutrophils, leading to the release of myeloperoxidase and the formation of neutrophil extracellular traps; these were shown to enhance vascular permeability and mediate dengue-associated cardiac impairment, contributing to severe dengue. Neutrophils are recruited during early dengue virus infection, and they release soluble molecules such as olfactomedin 4 and soluble urokinase plasminogen activator receptor into the circulation; these may be useful biomarkers to predict disease progression in dengue. Given that neutrophils may mediate severe dengue, attenuating the neutrophil response can be an attractive pathway to ameliorate disease severity. Dengue is a mosquito-borne viral disease which causes significant morbidity and mortality each year. Previous research has proposed several mechanisms of pathogenicity that mainly involve the dengue virus and host humoral immunity. However, innate immune cells, such as neutrophils, may also play an important role in dengue, albeit a much less defined role. In this review, we discuss the emerging roles of neutrophils in dengue and their involvement in pathologies associated with severe dengue. We also describe the potential use of several neutrophil proteins as biomarkers for severe dengue. These studies suggest that neutrophils are important players in dengue, and a better understanding of neutrophil-dengue biology is urgently needed. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to investigate serum plasminogen activator inhibitor-1 (PAI-1) levels of patients with Parkinson's disease (PD) and their relationship with clinical findings and treatment of disease. Methods: The study included 125 PD patients and 48 healthy controls. Patients have been taking effective dopaminergic treatment regularly. The clinical severity of parkinsonism was assessed using the Hoehn and Yahr (HY) staging scale and the Unified PD Rating Scale (UPDRS). PAI-1 level analysis was performed by enzyme-linked immunosorbent assay. Results: Patients with PD had significantly lower serum PAI-1 levels than healthy controls (p < 0.001). Correlations with clinical findings showed only a marginally positive correlation between serum PAI-1 and HY score (r = 0.170, p = 0.05). In contrast, no significant correlation was demonstrated with the UPDRS score or other clinical parameters. Conclusion: This is the first comprehensive analysis of serum PAI-1 levels in patients with PD. The distribution of PAI-1 in PD appears to be complex. The study results implicate that the paradoxical effects of tissue plasminogen activator on the brain parenchyma can be important in the pathophysiology of PD. Future studies are needed to elucidate the role of fibrinolytic system components in PD. [ABSTRACT FROM AUTHOR]

• Plasma levels of BDNF, proBDNF, tPA and PAI-1 changed in MDD. • BDNF/proBDNF and tPA/PAI-1 were associated with MDD and antidepressive treatment. • Interaction of tPA and PAI-1 was important in MDD by regulating BDNF/proBDNF ratio. • The combination of tPA + PAI + BDNF showed the best diagnostic value for MDD. Increasing evidence demonstrates that brain-derived neurotrophic factor (BDNF) can be regarded as a biomarker for major depression. Our previous work found that the ratio of mature BDNF (mBDNF) to precursor-BDNF (proBDNF) was a pivotal factor in the pathogenesis of major depressive disorder (MDD). But the mechanism behind the ratio is still obscure. Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) both play essential roles in depression by regulating the ratio of BDNF/proBDNF. In present study, we analyzed BDNF, proBDNF, tPA and PAI-1 in the peripheral blood in 57 MDD patients pre- and post-treatment and in 57 healthy controls. We verified that BDNF and tPA levels were significantly decreased, whereas proBDNF and PAI-1 levels elevated obviously in MDD group pre-treatment. And after 4 weeks SSRIs treatment, the BDNF and tPA levels increased while the proBDNF and PAI-1 levels reduced. The MDD pre-treatment group had the lowest ratio of BDNF to proBDNF compared to MDD post-treatment group and control group. Though the ratio of tPA/PAI-1 in MDD pre-treatment had not reached the significance, it was still the lowest one among the three groups. The combination of tPA + PAI + BDNF showed the best diagnostic value for MDD. In summary, our data suggested that the interaction between tPA and PAI-1 implicated to the MDD and the antidepressant treatment which might through regulating the BDNF/proBDNF ratio. The combination of tPA, PAI-1 and BDNF might offer a helpful way for MDD diagnosis. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is one of the most common types of cardiovascular disease and can lead to a heart attack as plaque gradually builds up inside the coronary arteries, blocking blood flow. Previous studies have shown that polymorphisms in the PAI-1 gene are associated with CAD; however, studies of the PAI-1 3′-untranslated region, containing a miRNA binding site, and the miRNAs that interact with it, are insufficient. To investigate the association between miRNA polymorphisms and CAD in the Korean population based on post-transcriptional regulation, we genotyped five polymorphisms in four miRNAs targeting the 3′-untranslated region of PAI-1 using real-time PCR and TaqMan assays. We found that the mutant genotype of miR-30c rs928508 A > G was strongly associated with increased CAD susceptibility. In a genotype combination analysis, the combination of the homozygous mutant genotype (GG) of miR-30c rs928508 with the wild-type genotype (GG) of miR-143 rs41291957 resulted in increased risk for CAD. Also, in an allele combination analysis, the combination of the mutant allele (G) of miR-30c rs928508 and the wild-type allele (G) of miR-143 rs41291957 resulted in increased risk for CAD. Furthermore, metabolic syndrome and diabetes mellitus showed synergistic effects on CAD risk when combined with miR-30c rs928508. These results can be applied to identify CAD prognostic biomarkers among miRNA polymorphisms and various clinical factors. [ABSTRACT FROM AUTHOR]

There is little and conflicting data on the role of the plasminogen activator inhibitor-1 (PAI-1, SERPINE1) 4G/5G polymorphism in familial Mediterranean fever (FMF). Therefore this study aimed at evaluating the impact of this polymorphism on the disease course in a cohort of 303 Armenian FMF patients. Genotyping for 12 Mediterranean fever (MEFV) gene mutations and the PAI-1 4G/5G (rs1799762) polymorphism were performed by PCR/reverse-hybridization (StripAssay) and real-time PCR, respectively. PAI-1 genotypes 4G/4G, 4G/5G, and 5G/5G could be identified in 4 (5.88%), 30 (18.63%) and 9 (12.16%) patients with erysipelas-like erythema (ELE), while this was the case for 64 (94.12%), 131 (81.37%), and 65 (87.84%) patients without ELE, respectively (P < 0.033). We have identified a significant relationship between the PAI-1 4G/5G genotype and the occurence of ELE in a relatively large cohort of Armenian FMF patients. Because of conflicting results concerning the impact of this polymorphism on the clinical course of FMF in different populations, further studies are desirable to substantiate the findings reported here. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis, a debilitating lung disorder characterised by excessive fibrous tissue accumulation in lung parenchyma, compromises respiratory function leading to a life‐threatening respiratory failure. While its origins are multifaceted and poorly understood, the urokinase system, including urokinase‐type plasminogen activator (uPA) and its receptor (uPAR), plays a significant role in regulating fibrotic response, extracellular matrix remodelling, and tissue repair. Mesenchymal stem/stromal cells (MSCs) hold promise in regenerative medicine for treating pulmonary fibrosis. Our study aimed to investigate the potential of MSCs to inhibit pulmonary fibrosis as well as the contribution of uPAR expression to this effect. We found that intravenous MSC administration significantly reduced lung fibrosis in the bleomycin‐induced pulmonary fibrosis model in mice as revealed by MRI and histological evaluations. Notably, administering the MSCs isolated from adipose tissue of uPAR knockout mice (Plaur‐/‐ MSCs) attenuated lung fibrosis to a lesser extent as compared to WT MSCs. Collagen deposition, a hallmark of fibrosis, was markedly reduced in lungs treated with WT MSCs versus Plaur‐/‐ MSCs. Along with that, endogenous uPA levels were affected differently; after Plaur‐/‐ MSCs were administered, the uPA content was specifically decreased within the blood vessels. Our findings support the potential of MSC treatment in attenuating pulmonary fibrosis. We provide evidence that the observed anti‐fibrotic effect depends on uPAR expression in MSCs, suggesting that uPAR might counteract the uPA accumulation in lungs. [ABSTRACT FROM AUTHOR]

Background/Objectives: Besides a multitude of consequences patients on chronic renal replacement therapy have, anemia is one of the most prominent factors making a significant number of patients dependent on erythropoiesis-stimulating agent (ESA) therapy. The aim of this study was to examine the relationship between the levels of a broad spectrum of thrombo-inflammatory and oxidative stress-related biomarkers and the presence and level of ESA hyporesponsiveness in patients undergoing regular chronic hemodialysis. Methods: This cross-sectional study included 96 patients treated with chronic hemodialysis. Levels of several thrombo-inflammatory and oxidative stress-related biomarkers, as well as demographic, clinical, and laboratory analyses, were collected and analyzed based on the calculated value of the ESA-hyporesponsiveness index (EHRI). Results: In the analyzed sample, 58 patients received ESAs. Of all the investigated parameters, only body mass index (BMI), level of plasminogen activator inhibitor-1, and level of L-type fatty acid binding protein (L-FABP) were observed as significant predictors of EHRI. A significant diagnostic potential for ESA resistance has been observed in BMI and L-FABP between ESA-resistant and ESA-non-resistant groups of patients (p = 0.004, area under the curve 0.763 and p = 0.014, area under the curve 0.712, respectively) with the cut-off values of 25.46 kg/m2 and 5355.24 ng/mL, respectively. Having a BMI of 25.46 kg/m2 or less and an L-FABP level higher than 5355.24 ng/mL were observed as significant predictors of ESA resistance (odds ratio 9.857 and 6.125, respectively). Conclusions: EHRI was positively predicted by low BMI and high levels of plasminogen activator inhibitor-1 and L-FABP. High levels of L-FABP and low BMI have been observed as strong predictors of ESA resistance. [ABSTRACT FROM AUTHOR]

Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g. , anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases. [Display omitted] • Serpin secretion reduces brain interstitial plasmin to promote brain metastases. • L1CAM expression mediates tumor vessel co-option to resist anti-angiogenic therapy. • OMV-inspired nanocarriers cross the BBB and specially enter brain metastases. • Nanocarriers reduce serpin secretion to promote local plasmin production. • Restored plasmin degrades L1CAM and induces paracrine tumor apoptosis for therapy. [ABSTRACT FROM AUTHOR]

Gossypol, a natural polyphenolic compound, possesses antivirus activity and induces cell death of different types of tumors. However, the efficacy of gossypol on lung carcinoma metastases and epithelial to mesenchymal transition remains unknown. The aim of the present work was to determine the cellular and molecular mechanism of the anti‐cancer and anti‐metastatic efficacies of gossypol on human lung carcinoma cells. Gossypol showed a marked suppression of the viability, motility, and invasion in H1299 and A549 cells. Zymography assay showed that gossypol was sufficient to suppress the activities of urokinase‐type plasminogen activator and matrix metalloproteinase‐2. Gossypol reversed TGF‐β‐induced epithelial to mesenchymal transition. Gossypol reduced vimentin, p‐FAK, p‐Src and p‐paxillin. In vivo studies of gossypol were performed using subcutaneous inoculation and tail vein injection of A549 into immunodeficient BALB/c nude mice and severe combined immunodeficient mice. [ABSTRACT FROM AUTHOR]

Context Obesity is a risk factor for coronavirus disease 2019 (COVID-19)-related outcomes; however, the mechanism remains unclear. Objective The objective of this analysis was to determine whether inflammation mediates the association between obesity and COVID-19 outcomes. Methods 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, was conducted at 10 hospitals in the United States and Europe. Participants were 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. Results 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, 1.21-1.98) compared with nonobese 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. Conclusion 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. [ABSTRACT FROM AUTHOR]

Background: Treatment of patients with low-grade and high-grade gliomas is highly variable due to the large difference in survival expectancy. New non-invasive tools are needed for risk stratification prior to treatment. The urokinase plasminogen activator receptor (uPAR) is expressed in several cancers, associated with poor prognosis and may be non-invasively imaged using uPAR-PET. We aimed to investigate the uptake of the uPAR-PET tracer [68Ga]Ga-NOTA-AE105 in primary gliomas and establish its prognostic value regarding overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the proportion of uPAR-PET positive tumors to estimate the potential number of candidates for future uPAR-PRRT. Methods: In a prospective phase II clinical trial, 24 patients suspected of primary glioma underwent a dynamic 60-min PET/MRI following the administration of approximately 200 MBq (range: 83–222 MBq) [68Ga]Ga-NOTA-AE105. Lesions were considered uPAR positive if the tumor-to-background ratio, calculated as the ratio of TumorSUVmax-to-Normal-BrainSUVmean tumor-SUVmax-to-background-SUVmean, was ≥ 2.0. The patients were followed over time to assess OS and PFS and stratified into high and low uPAR expression groups based on TumorSUVmax. Results: Of the 24 patients, 16 (67%) were diagnosed with WHO grade 4 gliomas, 6 (25%) with grade 3, and 2 (8%) with grade 2. Two-thirds of all patients (67%) presented with uPAR positive lesions and 94% grade 4 gliomas. At median follow up of 18.8 (2.1–45.6) months, 19 patients had disease progression and 14 had died. uPAR expression dichotomized into high and low, revealed significant worse prognosis for the high uPAR group for OS and PFS with HR of 14.3 (95% CI, 1.8-112.3; P = 0.011), and HR of 26.5 (95% CI, 3.3–214.0; P = 0.0021), respectively. uPAR expression as a continuous variable was associated with worse prognosis for OS and PFS with HR of 2.7 (95% CI, 1.5–4.8; P = 0.0012), and HR of 2.5 (95% CI, 1.5–4.2; P = 0.00073), respectively. Conclusions: The majority of glioma patients and almost all with grade 4 gliomas displayed uPAR positive lesions underlining the feasibility of 68Ga-NOTA-AE105 PET/MRI in gliomas. High uPAR expression is significantly correlated with worse survival outcomes for patients. Additionally, the high proportion of uPAR positive gliomas underscores the potential of uPAR-targeted radionuclide therapy in these patients. Trail Registration: EudraCT No: 2016-002417-21; the Scientific Ethics Committee: H-16,035,303; the Danish Data Protection Agency: 2012-58-0004; clinical trials registry: NCT02945826, 26Oct2016, URL: https://classic.clinicaltrials.gov/ct2/show/NCT02945826. [ABSTRACT FROM AUTHOR]

Background/objective: To examine the cognitive benefits of 6  months of prescribed intermittent exercise (10-min bouts totaling 150 weekly minutes) in community-dwelling older adults, comparing effects of low-intensity movement (LIM) and moderate-intensity aerobic exercise (aerobic exercise; AE) training; and exploring biological mechanisms of exercise-related cognitive improvement. Method: Twenty-five adults (>60  years old) participated in a 6-month controlled trial and were randomized into LIM or AE intermittent training. Cognition was assessed using a neuropsychological test battery including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), California Verbal Learning Test, 2nd Edition (CVLT-II), and Delis-Kaplan Executive Function System (D-KEFS). Neuroimaging measures were collected using a 7  T human MRI scanner. Serologic neurotrophic and inflammatory factors were analyzed using Luminex multiplex assays [brain derived neurotrophic factor (BDNF); vascular endothelial growth factor (VEGF)]; interleukin-6 (IL-6), C-reactive protein (CRP), plasminogen activator inhibitor (PAI-1). Results: LIM and AE intermittent training had dissociable effects on cognition, with LIM resulting in improved learning and memory and AE resulting in improved executive functioning. Intervention groups differed on change in cognitive performance on CVLT-II learning and D-KEFS trail making test. Increase in right dorsolateral prefrontal cortex (DLPFC) surface area was linked to executive improvement (i.e., phonemic fluency) regardless of intervention group. A decline in circulating PAI-1 was linked to learning and memory improvement in response to LIM over 6 months. Conclusion: Moderate-intensity AE and LIM intermittent training likely have distinct cognitive benefits, though low-intensity activity is often included as a control group in exercise trials in aging. [ABSTRACT FROM AUTHOR]

This study investigates the expressions of ADAM9, CDCP1 and t-PA in OSCC and their impacts on patient prognosis. Previous research has demonstrated the overexpression of ADAM9 and activation of plasminogen activator in OSCC, but CDCP1's role remains unexplored. While these biomolecules are known to contribute to lung cancer metastasis, their concurrent expressions in OSCC have not been thoroughly examined. Our aim is to assess the expressions of ADAM9, CDCP1, and t-PA in OSCC specimens, compare them with normal oral tissues, and explore their correlation with OSCC's clinicopathological features and patient survival outcomes. [ABSTRACT FROM AUTHOR]

Background: We aimed to explore the predictive role of soluble urokinase plasminogen activator receptor (suPAR) in patients undergoing coronary angiography by systematically evaluating its association with adverse cardiovascular events at 10 years follow-up. Methods: The KORONEF study was a single-center, observational, prospective study with 492 subjects included. In the multivariable Cox regression model, we checked the impact of suPAR, neutrophil elastase, myeloperoxidase, and DNase 1 on long-term outcomes. Results: The mean study population age was 64.4 ± 9.9 years, and there were 37.2% women. We divided the population into tertiles of suPAR levels (T1 0.793–2.135 ng/mL; T2 2.136–2.868 ng/mL; and T3 2.872–8.677 ng/mL). Patients with higher suPAR concentrations were more often females (tertile 1 vs. tertile 3: 27.4% vs. 50.6%, p < 0.001) and older age (60.8 ± 8.7 years vs. 68.8 ± 9.5 years, p < 0.001). They also characterized higher incidence of diabetes (17.7% vs. 38.0%, p < 0.001), previous myocardial infarction (22% vs. 44.8%, p < 0.001), and chronic kidney disease (3% vs. 18.4%, p < 0.001), but lower incidence of dyslipidemia (54.3% vs. 35.6%). The 10-year all-cause death rates were 14.6% vs. 34.1%, HR 2.68, 95% CI 1.66–4.33, p < 0.001 for tertile 2, and 14.6% vs. 39.9%, HR 3.24, 95% CI 2.03–5.17, p < 0.001 for tertile 3. The optimal cut-off suPAR value of 2.39 ng/mL provided a sensitivity of 66.9% and a specificity of 54.6% in predicting all-cause death. Conclusions: The association of elevated suPAR with increased mortality risk suggests its potential relevance in predicting long-term outcomes and may help inform more individualized management strategies for high-risk patients. [ABSTRACT FROM AUTHOR]

Background: Endovascular therapy (EVT) is the treatment of choice for acute ischemic stroke (AIS) with large vessel occlusion. However, in many patients, successful EVT recanalization does not correspond to a clinical improvement, called futile recanalization (FR). We aimed to identify stroke risk factors and patient characteristics associated with FR in AIS with large core infarct (LCI). Methods: A total of 137 patients with AIS with LCI treated by EVT at a single stroke center were retrospectively included from January 2016 to June 2023. LCI was defined by Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECT) < 6. Patient age, sex, modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), time to treatment, risk factors, and radiologic findings were collected, and potential associations with FR were analyzed. FR was defined as successful reperfusion with modified Thrombolysis in Cerebral Infarction (mTICI) ≥ 2b but without functional independence at 90 days (mRS ≥ 3). A multivariate logistic regression analysis was conducted on the clinical characteristics of patients, based on the presence or absence of FR, and the factors influencing FR. Results: Of 137 patients, 120 showed successful recanalization (mTICI ≥ 2b). All patients were divided into FR (n = 80) and no FR (n = 40) groups. Older age (odds ratio [OR] 1.052, 95% confidence interval [CI] 1.002–1.105; p = 0.041), the higher the initial NIHSS score (OR 1.181, 95% CI 1.037–1.344; p = 0.012), and prior intravenous plasminogen activator (OR 0.310, 95% CI 0.118–0.813, p = 0.017) were independent influencing factors of FR. Conclusions: The older age, the higher the initial NIHSS, and not receiving intravenous plasminogen activator were independently associated with FR in AIS with LCI. These factors could identify poor responders to EVT recanalization. [ABSTRACT FROM AUTHOR]

Sepsis remains an important healthcare challenge. The lungs are often affected in sepsis, resulting in acute lung injury characterized by inflammation. Mechanisms involving lipopolysaccharide (LPS) stimulation of toll-like receptor (TLR) signaling with induction of proinflammatory pathways have been implicated in this process. To date, however, studies targeting these pathways have failed to improve outcomes. We have found that LPS may also promote lung injury through the activation of α4 nicotinic acetylcholine receptors (α4 nAChRs) in immune cells. We observed increased expression of α4 nAChRs in human THP-1 monocytic cells exposed to LPS (100 ng/mL, 24 h). We also observed that LPS stimulated the expression of other relevant genes, including tumor necrosis factor-α, interleukin-1β, plasminogen activator inhibitor-1, the solute carrier family 7 member 11, extracellular superoxide dismutase, and transforming growth factor-β1. Of interest, dihydro-β-erythroidine hydrobromide (DHβE), a specific chemical inhibitor of α4 nAChRs, inhibited the LPS-induced expression of these genes. We generated mice with a global knockout mutation of the α4 nAChR subunit in the C57BL/6 background using CRISPR/Cas9 technology. The lungs of these LPS-treated animals demonstrated a reduction in the expression of the above-mentioned genes when compared with the lungs of wild-type animals. In support of the role of oxidative stress, we observed that LPS induced expression of the cystine transporter Slc7a11 in both THP-1 cells and in wild-type mouse lungs. The effects of LPS on THP-1 cells were blocked by the thiol antioxidant N-acetylcysteine and mimicked by redox stress. Importantly, the induction of IL-1β by redox stress was inhibited by the α4 nAChR inhibitor DHβE. Finally, we showed that LPS stimulated calcium influx in THP-1 cells, which was blocked by the α4 nAChR inhibitor. Our observations suggest that LPS promotes lung injury by stimulating redox stress, which activates α4 nAChR signaling and drives proinflammatory cytokine expression. [ABSTRACT FROM AUTHOR]

Pulmonary congestion (PC) is common in hemodialysis (HD) patients. We explored the association of anemia and pulmonary congestion in HD patients. A prospective pilot observational study included 18 patients on maintenance HD. Individual B-lines scores (BLS; 8-sites method) were obtained by lung ultrasound, before and after the first two consecutive HD sessions of the week (HD1-HD2), with different inter-dialytic intervals (68 vs. 44 h). Bioimpedance spectroscopy body composition (BIS) was performed before each HD session. Hemoglobin (Hb) levels, in addition to circulating markers of chronic inflammation (soluble urokinase Plasminogen Activator Receptor [suPAR], soluble Suppression of Tumorigenicity 2 [sST2]) were obtained. Mean (±SD) BLS values were quite elevated at all time points: Pre-HD1 (16 ± 5.53), post-HD1 (15.3 ± 6.63), pre-HD2 (16.3 ± 5.26) and post-HD2 (13.6 ± 5.83), respectively. No direct significant correlation was found between inflammation markers levels and BLS. However, mean levels (±SD, ng/mL) of suPAR pre-HD1 (7.88 ± 3.07) and pre-HD2 (7.78 ± 3.02) remained significantly above the normal range (<4 ng/mL), and sST2 levels reached 2-fold the upper normal value in most patients (27.4 ± 17.8). Pulmonary congestion reflected by BLS was negatively correlated to Hb levels pre-HD1 (R² = 0.439, p = 0.003), and pre-HD2 (R² = 0.301, p = 0.018). In addition, Hb levels were negatively correlated to global volume status estimated by BIS (R² = 0.351, p = 0.009). Hemoglobin levels were negatively correlated to pulmonary congestion and to the global volume status evaluated by BIS. Chronic inflammation markers were increased in HD patients, suggesting a complex volume- and non-volume-dependent pathophysiology of pulmonary congestion in HD patients. [ABSTRACT FROM AUTHOR]

Endothelial injury indices, such as Endothelial Activation and Stress Index (EASIX), modified EASIX (m-EASIX), and simplified EASIX (s-EASIX) scores, have been previously associated with chimeric antigen receptor-T (CAR-T) cell immunotherapy complications. Soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor-15 (GDF-15), and soluble C5b-9 (sC5b-9) have been described as markers of endothelial injury post-hematopoietic stem cell transplantation. In the current study, we examined whether suPAR, GDF-15, and sC5b-9 levels were associated with endothelial injury indices in adult CAR-T cell recipients. The levels of these markers were measured in patients before CAR-T cell infusion and in healthy individuals with immunoenzymatic methods. We studied 45 CAR-T cell recipients and 20 healthy individuals as the control group. SuPAR, GDF-15, and sC5b-9 levels were significantly higher in the patients' group compared to the healthy control group (p < 0.001, in all comparisons). SuPAR levels at baseline were associated with the m-EASIX scores calculated at the same time point (p = 0.020), while suPAR and GDF-15 concentrations were correlated with EASIX scores at day 14 post-infusion (p < 0.001 in both comparisons). Moreover, sC5b-9 levels were correlated with the s-EASIX scores at infusion (p = 0.008) and the EASIX scores at day 14 (p = 0.005). In our study, sC5b9, suPAR, and GDF-15 levels were found to reflect endothelial injury in CAR-T cell recipients. [ABSTRACT FROM AUTHOR]

The study published in the International Journal of Laboratory Hematology explores the impact of preanalytical conditions on fibrin monomers (FMs) and D-dimer biomarkers. The research involved 20 healthy volunteers and compared nine simulated conditions to a reference condition. The study found that certain preanalytical conditions significantly affected FMs levels, while D-dimer levels remained consistent across all conditions. The findings suggest that FMs assays are sensitive to preanalytical artifacts, highlighting the importance of stringent guidelines for accurate measurements. [Extracted from the article]

Chronic kidney disease (CKD) is a significant global health issue and often involves CKD-mineral and bone disorder (MBD) and sarcopenia. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. PAI-1 has been implicated in the pathogenesis of osteoporosis and muscle wasting induced by inflammatory conditions. However, the roles of PAI-1 in CKD-MBD and sarcopenia remain unknown. Therefore, the present study investigated the roles of PAI-1 in bone loss and muscle wasting induced by adenine in PAI-1-deficient mice. CKD was induced in PAI-1+/+ and PAI-1-/- mice by administration of adenine for ten weeks. Muscle wasting was assessed by grip strength test, quantitative computed tomography (CT) analysis and muscle weight measurement. Osteoporosis was assessed by micro-CT analysis of femoral microstructural parameters. PAI-1 deficiency did not affect adenine-induced decreases in body weight and food intake or renal dysfunction in male or female mice. PAI-1 deficiency also did not affect adenine-induced decreases in grip strength, muscle mass in the lower limbs, or the tissue weights of the gastrocnemius, soleus, and tibialis anterior muscles in male or female mice. PAI-1 deficiency aggravated trabecular bone loss in CKD-induced male mice, but significantly increased trabecular bone in CKD-induced female mice. On the other hand, PAI-1 deficiency did not affect cortical bone loss in CKD-induced mice. In conclusion, PAI-1 is not critical for the pathophysiology of CKD-MBD or CKD-induced sarcopenia in mice. However, PAI-1 may be partly related to bone metabolism in trabecular bone in the CKD state with sex differences. [ABSTRACT FROM AUTHOR]