Serum Plasminogen Activator Inhibitor-1 Levels Research Articles

Impact of Plasminogen Activator Inhibitor-1 Serum Levels and the -675 4G/5G Variant in the SERPINE1 Gene on Systemic Sclerosis in a Mexican Population.

Systemic sclerosis (SSc) is characterized by a complex interplay of vascular damage, inflammation, and fibrosis, affecting the skin and internal organs. Plasminogen activator inhibitor-1 (PAI-1), a protein encoded by the SERPINE1 gene, is a potential biomarker of SSc because it is primarily involved in fibrinolysis and is associated with the severity of some autoimmune diseases. This study aimed to determine the association between SERPINE1 variant -675 4G/5G and soluble PAI-1 (sPAI-1) levels with the clinical characteristics and risk of SSc in a Mexican population. This cross-sectional study included 56 SSc patients and 114 control subjects (CSs). The variant was genotyped via the PCR-RFLP method and the levels of sPAI-1 were determined using enzyme-linked immunosorbent assays (ELISAs). The -675 4G/5G variant was not associated with SSc risk or sPAI-I levels. However, higher sPAI-1 levels were observed in SSc patients than in CSs (p = 0.045); these levels were significantly correlated with age, platelets, glucose, and serum levels of transforming growth factor (TGF)-β1, 2, and 3. The SERPINE1 -675 4G/5G variant did not show any association with SSc risk or sPAI-I levels. However, our study shows a possible alteration of sPAI-1 in this disease, which could be associated with the fibrotic and thrombotic processes in SSc.

Serum Levels of Plasminogen Activator Inhibitor-1 in Patients with Parkinson's Disease.

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. 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 Unified PD Rating Scale (UPDRS). PAI-1 level analysis was performed by enzyme-linked immunosorbent assay. Patients with PD had significantly lower serum PAI-1 levels than healthy controls (p < 0.001). Correlations with clinical findings showed only 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. 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.

Adipokines-A Cohort Prospective Study in Children with Severe Burns.

Burns generate every year an important burden of morbidity, being a major global public health problem through prolonged hospitalization, complications, and increased mortality. This study's purpose was to evaluate the serum levels of three adipokines and to establish significant correlations with other circulating molecules and with some clinical parameters. We evaluated 32 children with severe burns (over 25% total burned surface area-TBSA) at 48 h, day 10, and day 21 post burn, and 21 controls. The serum levels of adiponectin, resistin, leptin, tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein (CRP) (among nine other biochemical parameters) were detected by Multiplex technique. Significant statistical differences were obtained for resistin and leptin compared to the control group, in different moments of measurements. Adiponectin serum levels presented statistically significant correlations with hot liquid mechanism of burn, the Revised Baux score, TBSA, resistin, PAI-1, CRP, TNF-α, and triglycerides (TGLs) serum levels. Resistin serum levels presented statistically significant correlations with adiponectin, CRP, PAI-1, leptin, and TNF-α. Additionally, we found statistically significant correlations between leptin serum levels and length of hospitalization, TNF-α, resistin, adiponectin, and PAI-1 serum levels. In severely burned children, adiponectin, resistin, and leptin specifically correlate with clinical parameters and with proteins involved in the systemic inflammatory response and the hypermetabolic response.

Association between sex hormones and erectile dysfunction in men without hypoandrogenism

In addition to testosterone, various endocrine hormones, such as dehydroepiandrosterone sulfate (DHEA-S) and estradiol, may be involved in erectile function. However, the role of these sex hormones in the erectile function of men without hypoandrogenism remains unclear. This cross-sectional study included 398 community-dwelling men without hypoandrogenism. The participants were categorized into the non-ED and ED groups. Multivariable logistic regression analyses were performed to investigate the relationship between ED and serum sex hormone levels, including total testosterone, DHEA-S, estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin. Among the 398 men, 66 (17%) and 332 (83%) were categorized into the non-ED and ED groups, respectively. In the multivariable analyses, serum DHEA-S and estradiol levels were significantly associated with ED (odds ratio [OR]: 0.996, P = 0.030; OR: 1.082, P = 0.002; respectively), whereas serum total testosterone, LH, FSH, and prolactin levels did not demonstrate significant association. After adjusting for age, none of neutrophil-to-lymphocyte ratio, serum plasminogen activator inhibitor-1 levels, and skin advanced glycation end-products levels demonstrated significant correlation with serum DHEA-S and estradiol levels. In conclusion, lower testosterone levels did not affect ED in men with normal testosterone levels, whereas serum DHEA-S and estradiol levels were significantly associated with ED.

Serum Plasminogen Activator Inhibitor-1, α 1-Acid Glycoprotein, C-Reactive Protein, and Platelet Factor 4 Levels-Promising Molecules That Can Complete the "Puzzle" of the Biochemical Milieu in Severe Burns: Preliminary Results of a Cohort Prospective Study.

Background: Burns represent a serious health problem, associated with multiple-organ failure, prolonged hospitalization, septic complications, and increased rate of mortality. The main aim of our study was to evaluate the levels of various circulating molecules in children with severe burns (more than 25% TBSA), in three different moments: 48 h, day 10, and day 21 post-burn. Materials and Methods: This study included 32 children with burns produced by flame, hot liquid, and electric arc and 21 controls. Serum plasminogen activator inhibitor-1 (PAI-1), α 1-acid glycoprotein (AGP), C-reactive protein (CRP), and platelet factor 4 (PF4) were detected using the Multiplex technique. Several parameters, such as fibrinogen, leucocyte count, thrombocyte count, triiodothyronine, thyroxine, and thyroid-stimulating hormone were also determined for each patient during hospitalization. Results: Significant statistical differences were obtained for CRP, AGP, and PF4 compared to the control group, in different moments of measurements. Negative correlations between CRP, AGP, and PF4 serum levels and burned body surface, and also the hospitalization period, were observed. Discussions: CRP levels increased in the first 10 days after burn trauma and then decreased after day 21. Serum PAI-1 levels were higher immediately after the burn and started decreasing only after day 10 post-burn. AGP had elevated levels 48 h after the burn, then decreased at 7-10 days afterwards, and once again increased levels after 21 days. PF4 serum levels increased after day 10 since the burning event. Conclusions: Serum CRP, AGP, PAI-1, and PF4 seem to be promising molecules in monitoring patients with a burn within the first 21 days.

Plasminogen activator inhibitor-1 serum levels in frontotemporal lobar degeneration.

Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aβ) in Alzheimer's disease (AD). Since plasmin also regulates the synaptic activity, it is possible that altered PAI-1 is present in other neurodegenerative disorders. We investigated whether PAI-1 and its counter-regulatory tissue plasminogen activator (tPA) are altered in serum of patients with dementia due to frontotemporal lobar degeneration (FTLD). Thirty five FTLD patients (21 in mild cognitive impairment stage (MCI) and 14 in dementia stage) and 10 cognitively healthy controls were recruited. Serum tPA and PAI-1 protein levels were measured by anova. Correlation between biochemical and demographic data were explored by measuring Pearson correlation coefficient. Serum PAI-1 levels were elevated in the FTLD dementia group as compared to FTLD MCI and controls. tPA serum levels and PAI-1/tPA ratio did not significantly differ among groups. There was a negative correlation between PAI-1 serum levels and disease severity measured by MMSE score. No correlations of tPA serum levels and PAI-1/tPA ratio with MMSE were found. Increased PAI-1 serum levels may serve as a marker of dementia in FTLD, suggesting that, besides Aβ pathway, the plasmin system may affect cognition through synaptic activity.

Correlation of Serum Plasminogen Activator Inhibitor-1 with Body Mass Index and Blood Pressure among Newly Diagnosed Primary Hypertensive Patients: A Cross-sectional Study

Introduction: Plasminogen Activator Inhibitor-1 (PAI-1), a serine protease inhibitor expressed in adipose tissue, causes inflammation in hypertension and vice versa. The excess adipose tissue increases the production of PAI-1. There have been no relevant studies conducted on PAI-1 in southern Odisha in relation to Body Mass Index (BMI) and hypertension. Aim: To compare the BMI, Waist Hip Ratio (WHR), Waist Circumference (WC), and serum levels of PAI-1 in hypertensive cases with controls, and also to correlate the serum level of PAI-1 with BMI and blood pressure. Materials and Methods: This cross-sectional study was conducted in the Department of Biochemistry in collaboration with the Department of Medicine of MKCG Medical College and Hospital, Berhampur, Odisha, India from November 2020 to August 2021. A total of 45 newly diagnosed primary hypertensive patients and 43 healthy age and sex-matched individuals between the ages of 18 to 60 years were enrolled in the study. Serum PAI-1 was measured by Enzyme-Linked Immunosorbent Assay (ELISA). BMI, WC, hip circumference, WHR, and blood pressures of the controls as well as cases were recorded. Data were statistically analysed using the Student’s t-test and Pearson’s correlation coefficient. Results: The proportion of males was higher (56%) than females (44%). The cases had a significantly higher level of serum PAI-1 (203.36 ng/mL) compared to the control group (60.11 ng/mL) (p-value<0.001). The cases had a higher BMI, WC (meters), and WHR compared to the control group. The serum PAI-1 level positively correlated with Systolic Blood Pressure (SBP) (r-value=0.852, p-value<0.001), Diastolic Blood Pressure (DBP) (r-value=0.726, p-value=0.000), BMI (r-value=0.620, p-value=0.001), WC (r-value=0.444, p-value=0.002), and WHR (r-value=0.593, p-value<0.001). Conclusion: A high serum PAI-1 level was found in the newly diagnosed hypertensive cases, and a significant positive correlation was observed between PAI-1 and systolic and diastolic blood pressure, along with BMI, WC, and WHR.

Combination of neuromuscular electrical stimulation and ibuprofen to reduce pain in femoral head necrosis.

The combinative effects of neuromuscular electrical stimulation and ibuprofen on pain in patients with femoral head necrosis were discussed and analyzed. This retrospective study analyzed data of 60 patients with femoral head necrosis hospitalized during Oct. 2020 to Oct. 2021. According to different treatment methods, the patients were divided into an observation group and a control group (30 cases in each group). The control group took oral ibuprofen sustained-release capsules, and the observation group was treated with neuromuscular electrical stimulation in addition to ibuprofen. Both groups received a 4-week treatment course. The therapeutic efficacy, Harris scale scores, Visual Analogue Scale (VAS) score, MRI hip imaging stage, SF-36 scale score, serum plasminogen activator inhibitor 1 (PAI-1), leptin and osteopontin levels before and after treatment were compared between the two groups. After treatment, the overall response rate in the observation group was higher than that in control group (P<0.05). The post-treatment scores of Harris scale were higher in both groups than those pre-treatment (P<0.05), and were higher in the observation group than in the control group (P<0.05). The VAS scores were decreased in both groups (P<0.05), and the decrease was more significant in the observation group than in the control group (P<0.05). After treatment, there were more patients with 0-I MRI hip imaging stage in the two groups than before treatment (P<0.05), and more in the observation group than in the control group (P<0.05). The SF-36 scores in both groups were increased (P<0.05), and the increase was more significant in the observation group than in the control group (P<0.05). The serum levels of PAI-1, leptin and osteopontin were decreased in both groups (P<0.05), and the decreases were more significant in the observation group than in the control group (P<0.05). The combinative treatment of neuromuscular electrical stimulation and ibuprofen has a significant effect on patients with femoral head necrosis. The treatment can remarkably reduce patients' pain, improve their hip function and quality of life, and decrease the PAI-1, leptin and osteopontin levels.

Pharmacologic Reduction of Platelet Count Attenuates Whole Blood Hypofibrinolysis in a Mouse Model of Sickle Cell Disease

Increased risk of venous thrombosis is a hallmark of sickle cell disease (SCD). We previously reported that SCD dramatically alters the properties of venous clots, including resistance to tissue plasminogen activator (tPA)-mediated fibrinolysis. Using an internal fibrinolysis assay (tPA added to whole blood before clot formation), clot lysis time (CLT) was significantly (p&amp;lt;0.01) prolonged in clots formed ex vivo from whole blood of SCD patients (SS) (651±34 min) compared to race-matched controls (AA) (370±75). We then investigated how therapeutic RBC exchange affects CLT in SCD patients. Interestingly, despite hemoglobin A levels of approximately 50%, CLT for the pre-exchange SS clots (639±81 min) was similar to CLT recorded for blood clots from SS patients who did not undergo RBC exchange (see above). However, CLT for post-exchange SS clots was significantly shortened (240±34; p&amp;lt;0.05 vs pre-exchange) to the level observed for clots from AA controls. We noticed that the RBC exchange procedure not only changes the proportion of AA and SS RBCs, but also reduces both platelet counts and serum plasminogen activator inhibitor-1 (PAI-1) levels by approximately 50-60%. Importantly, exvivo restoration of the platelet number in post-exchange samples to the level observed in pre-exchange blood resulted in restoration of the hypofibrinolytic phenotype and a partial restoration of serum PAI-1 levels. Changes in platelet count after RBC exchange are quickly normalized. Therefore, in the current study, we investigated the effect of sustained reduction of platelet count on whole blood hypofibrinolysis in SCD mice. Using an external fibrinolysis assay (2.5 nM tPA added after clot formation) as described by Bonnard et al. (Sci Rep, 2017) we determined if hypofibrinolysis is also observed in Townes sickle cell mice (SS). Consistent with human SCD, the CLT was profoundly increased in ex vivo clots formed from whole blood of SS mice (n=13) compared to non-sickle (AA) control mice (n=12) (Figure 1A; first two bars). Next, we demonstrated that the cellular fraction of SS blood was responsible for resistance of the clots to tPA-mediated fibrinolysis, regardless of whether the plasma was from SS or AA mice (Figure 1A; last four bars). We then used a pharmacologic strategy to reduce platelet counts. Thrombopoietin (TPO) is a growth factor that promotes maturation of hematopoietic stem cells into megakaryocytes and thereby increases platelet production. We previously showed that silencing liver TPO expression using a liver-specific antisense oligonucleotide (TPO-ASO) resulted in a sustained 50% reduction in both plasma TPO levels and platelet counts without affecting hemostasis in both baboons and mice. In the present study, TPO-ASO (20 mg/kg subcutaneous) or vehicle control were administered to 3-month old AA and SS mice (n=3-6) on days 0, 3, 5 and 7, followed by weekly maintenance injections for the next 3 weeks. 4 weeks after initiation of treatment, mice were euthanized, and blood was collected to evaluate plasma levels of TPO and external whole blood fibrinolysis. Platelet, but no other cell count was significantly reduced in both AA (by 62%, p&amp;lt;0.05) and SS (by 47%, P&amp;lt;0.05) mice treated with TPO-ASO. Baseline plasma levels of TPO were reduced in SS mice (101±20 pg/ml) compared to AA controls (182±10; p&amp;lt;0.05). TPO-ASO treatment resulted in significant reduction of TPO plasma levels in both AA (21±16; p&amp;lt;0.01) and SS (17±9; p&amp;lt;0.05) mice. Interestingly, TPO-ASO-mediated reduction of platelet count did not affect CLT of ex vivo clots formed from whole blood of AA mice (Figure 1B). In contrast, TPO-ASO treatment dramatically reduced CLT in SS clots (p&amp;lt;0.05) (Figure 1B). In conclusion, we demonstrated that: (i) the resistance of ex vivo formed clots to tPA-mediated fibrinolysis observed in SCD patients can be reproduced in a mouse model of the disease; (i) the external fibrinolysis assay provides a robust and reliable model for studying whole blood hypofibrinolysis in SCD; (iii) hypofibrinolysis in SCD appears to be predominantly driven by the cellular fraction of blood; and (iv) platelets play an important role in the hypofibrinolytic phenotype in SCD, demonstrated by mitigation of the hypofibrinolytic phenotype in SS mice subjected to long-term reduction of platelet count. Further studies investigating the effect of platelet count reduction on venous thrombosis and vascular stasis in SS mice are currently ongoing.

Salivary expression of novel inflammatory marker Plasminogen Activator Inhibitor-1 in health and disease: an interventional study

Objective: To assess levels of the biomarkers Plasminogen Activator Inhibitor-1 (PAI-1) and alpha 2-macroglobulin (2MG) in saliva and serum in healthy individuals and patients with and without type 2 diabetes mellitus (T2DM) before and after periodontal therapy. Materials and Methods: The 90 recruited subjects were divided into the three following groups: Group 1, with 30 healthy subjects; Group 2, with 30 systemically healthy subjects with stage II and III periodontitis; and Group 3, with 30 patients with periodontitis and well-controlled T2DM (PDM). Salivary and serum PAI-1 and α2MG levels were estimated by enzyme-linked immunosorbent assay and correlated with clinical parameters before and three months after periodontal therapy, and the data obtained was statistically analyzed. Results: There was an improvement in clinical parameters in both groups that underwent initial periodontal therapy. Salivary and serum PAI-1 and α2MG levels were upregulated in PDM group, compared to periodontitis alone at baseline. A significant reduction in the levels of the biomarkers was observed three months after periodontal therapy, and an improvement in glycaemic control was also seen in the PDM group. Conclusion: PAI-1 was expressed in saliva and serum in healthy patients, and increased in periodontitis and diabetes patients, thus evidencing its possible role in periodontal inflammation and glucose regulation, and its levels decreased after periodontal therapy.

PAI-1 genetic polymorphisms influence septic patients' outcomes by regulating neutrophil activity.

Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathophysiology of sepsis, but the exact mechanism remains debatable. In this study, we investigated the associations among the serum levels of PAI-1, the incidence of 4G/5G promoter PAI-1 gene polymorphisms, immunological indicators, and clinical outcomes in septic patients. A total of 181 patients aged 18-80 years with sepsis between November 2016 and August 2018 in the intensive care unit in the Xinhua Hospital were recruited in this retrospective study, with 28-day mortality as the primary outcome. The initial serum level of PAI-1 and the presence of rs1799768 single nucleotide polymorphisms (SNPs) were examined. Univariate logistic regression and multivariate analyses were performed to determine the factors associated with different genotypes of PAI-1, serum level of PAI-1, and 28-day mortality. The logistic analysis suggested that a high serum level of PAI-1 was associated with the rs1799768 SNP of PAI-1 (4G/4G and 4G/5G) (Odds ratio [OR]: 2.49; 95% confidence interval [CI]: 1.09, 5.68). Furthermore, a high serum level of PAI-1 strongly influenced 28-day mortality (OR 3.36; 95% CI 1.51, 7.49). The expression and activation of neutrophils (OR 0.96; 95% CI 0.93, 0.99), as well as the changes in the expression patterns of cytokines and chemokine-associated neutrophils (OR: 1.00; 95% CI: 1.00, 1.00), were both regulated by the genotype of PAI-1. Genetic polymorphisms of PAI-1 can influence the serum levels of PAI-1, which might contribute to mortality by affecting neutrophil activity. Thus, patients with severe sepsis might clinically benefit from enhanced neutrophil clearance and the resolution of inflammation via the regulation of PAI-1 expression and activity.

The cardioprotective effects of secoisolariciresinol diglucoside (flaxseed lignan) against cafeteria diet-induced cardiac fibrosis and vascular injury in rats: an insight into apelin/AMPK/FOXO3a signaling pathways.

Introduction: Fast food is a major risk factor for atherosclerosis, a leading cause of morbidity and mortality in the Western world. Apelin, the endogenous adipokine, can protect against cardiovascular disease via activating its receptor, APJ. Concurrently, secoisolariciresinol diglucoside (SDG), a flaxseed lignan extract (FLE), showed a therapeutic impact on atherosclerosis. The current study aimed to examine the effect of SDG on cafeteria diet (CAFD)-induced vascular injury and cardiac fibrosis via tracking the involvement of the apelin/APJ pathway. Methods: Thirty male rats were allocated into control, FLE-, CAFD-, CAFD/FLE-, and CAFD/FLE/F13A-treated rats, where F13A is an APJ blocker. All treatments lasted for 12weeks. Results and discussion: The CAFD-induced cardiovascular injury was evidenced by histological distortions, dyslipidemia, elevated atherogenic indices, cardiac troponin I, collagen percentage, glycogen content, and apoptotic markers. CAFD increased both the gene and protein expression levels of cardiac APJ, apelin, and FOXO3a, in addition to increasing endothelin-1, VCAM1, and plasminogen activator inhibitor-1 serum levels and upregulating cardiac MMP-9 gene expression. Moreover, CAFD reduced serum paraoxonase 1 and nitric oxide levels, cardiac AMPK, and nuclear Nrf2 expression. FLE attenuated CAFD-induced cardiovascular injury. Such effect was reduced in rats receiving the APJ blocker, implicating the involvement of apelin/APJ in FLE protective mechanisms. Conclusion: FLE supplementation abrogated CAFD-induced cardiac injury and endothelial dysfunction in an apelin/APJ-dependent manner.

Metformin Effects on Plasminogen Activator Inhibitor-1 in Polycystic Ovarian Women

Background: Polycystic ovary syndrome (PCOS) is a widespread complex endocrine disorder of women in the reproductive age group. Plasminogen activator inhibitor-1(PAI-1) has been shown to be associated with the regulation of inflammation and ovulation. Objectives: The aim of this study was to evaluate serum PAI-1 level and to determine the effects of metformin treatment on serum PAI-1 levels in patients with PCOS. Patients and Methods: This study was conducted on sixty women with PCOS, while 30 healthy women matched for age with the PCOS patients were selected as the control group, only 30 patients of them complete the follow up study and they agree to continue on metformin treatment during three months, the duration of the follow up. Study Design: A cross sectional study is done in Salah Al-Deen general hospital/gynecology and obstetrics department in Tikrit city from 1st November 2022-30th January 2023. Patients diagnosed with PCOs depending based on the Rotterdam criteria. Participants were enrolled after all eligibility criteria were confirmed and informed consent completed. The body mass index is determined before and after therapy. Homeostatic model assessment for insulin resistance is determined according to the following formula: (fasting insulin multiplied by fasting glucose) divided by 405. Fasting serum PAI-1 was measured by Enzyme-Linked Immunosorbent Assay method. Data were analyzed using SPSS for Windows 7. Results: Compared with the control group, the levels of PAI1, fasting blood glucose (FBG), Insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) While the levels of follicle stimulating hormone (FSH) were significantly decreased (P&lt;0.05). In the PCOS group were significantly increased (P&lt;0.05). Serum levels of testosterone in PCOS group was significantly increased (P&lt;0.05). In PCOS women treated with metformin for three months, all patients showed significant in decrease in PAI1, and testosterone concentration at p-values 0.05, when compared to pre-treatment. Treatment resulted a significant decrease in in body mass index, Blood glucose, Insulin, HOMA-IR, and LH at p-values 0.05. Conclusion: Plasminogen activator inhibitor-1 level decreased significantly after 3 months of treatment with 850 mg per day with metformin in women with PCOS.

Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.

Plasminogen Activator Inhibitor-1 Potentiates Neutrophil Infiltration and Tissue Injury in Colitis.

The mechanism underlying inflammatory bowel disease (IBD) remains unclear. We aimed to identify early diagnostic biomarkers and understand their roles in the pathogenesis of IBD. Methods: We identified plasminogen activator inhibitor-1 (PAI-1) as a potential key gene that is upregulated in IBD based on published transcriptomic datasets. To further determine the role of PAI-1 in disease pathogenesis, we induced colitis in wild-type (WT) and PAI-1 knockout (KO) mice by administering dextran sulfate sodium (DSS). We used an RNA array of genes and 16S rRNA sequencing of the microbiome to analyze PAI-1 function. The colon and serum PAI-1 levels in humans were further evaluated for their diagnostic value. Results: PAI-1 expression was significantly increased in patients and DSS-induced WT mice but reduced in PAI-1 KO mice. These changes were associated with significantly decreased neutrophil infiltration in colonic tissues. The RNA array revealed that the CXC chemokines CXCL1 and CXCL5 and their common receptor CXCR2 were among the most significantly different genes between the PAI-1 KO mice with DSS-induced colitis and the WT mice. Mechanistically, PAI-1 deficiency led to blunted activation of the NF-κB pathway in the colon epithelium. The gut microbiome was altered in the PAI-1 KO mice, which showed enriched abundances of short-chain fatty acid-producing genera and diminished abundances of pathogenic genera. Receiver operating characteristic (ROC) curve analysis revealed the diagnostic value of PAI-1. Conclusions: Our data suggest a previously unknown function of PAI-1 inducing neutrophil-mediated chemokine expression by activating the NF-κB pathway and affecting the function of the gut microbiome. PAI-1 could be a potential diagnostic biomarker and a therapeutic target in IBD.

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis.

Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD. We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis. Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I² = 72%) and the chi-square test (χ² = 18.32; p = 0.003). This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

PSUN171 CORRELATIONS BETWEEN SERUM AND TEAR PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) AND TISSUE PLASMINOGEN ACTIVATOR (tPA) IN PATIENTS WITH DIABETIC RETINOPATHY

Abstract Introduction Diabetic retinopathy (DR) is a leading cause of blindness and visual disability, worldwide. The aim of the study was to investigate the correlation between tears and plasma levels of activity of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in patients with diabetic retinopathy. Method Patients with T2DM and DR (n=26) were enrolled in this study. Blood and tears samples were obtained from both groups and analysed for PAI-1 and tPA activities. Anthropometric measurements were also obtained. Results There was no correlation between serum and tear PAI-1 levels with a Spearman's coefficient of 0.028 (p=0.928). We were also unable to detect significant correlations between serum and tear tPA levels. However, there was a significant positive correlation between levels of tears PAI-1 and BMI (r=0.555, p=0.026). Conclusion This present study demonstrated no significant correlations between tears and serum PAI-1 and tPA, which was most likely due to the small sample size. However, the significant correlation between tear PAI-1 levels with BMI could indicate the potential role of tear biomarkers in diabetic retinopathy in obese patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

The relationship between plasminogen activator inhibitor-1 levels and the course of disease in COVID-19 patients

Abstract Objectives Studies have shown that fibrinolysis activity is insufficient in COVID-19 patients. Plasminogen activator inhibitor-1 (PAI-1) is an important antifibrinolytic molecule that plays a key role in the fibrinolytic system. In our study; we aimed to evaluate serum PAI-1 and other biochemical parameters of COVID-19 patients in terms of disease course and mortality. Methods A total of 40 COVID-19 patients were hospitalized in the service and intensive care unit (ICU) of our hospital from October to December 2020 and 20 healthy volunteers were included in our study. The patients were grouped as those who transferred to the ICU from the service and transferred to service from the ICU. The first and second values of the same patients in both the service and the ICU were analyzed by SPSS. Results The PAI-1 levels of the patients in the ICU were significantly higher than the levels of the same patients in the service and the healthy control group (p&lt;0.001). IL-6, ferritin, and D-dimer levels in the ICU of the same patients were significantly higher than the levels of service and healthy control group (p&lt;0.001). A positive correlation was found between initial serum PAI-1 and D-dimer levels in patients hospitalized in the service (p=0.039) and initial serum ferritin and IL-6 levels in the ICU (p=0.031). Conclusions In our study, we found that PAI-1 levels increased significantly with the increase in mortality in COVID-19 patients.

Association of Body Mass Index, Blood Pressure, and Interictal Serum Levels of Cytokines in Migraine with and without Aura.

The aim of the study was to clarify correlations between body mass index (BMI), blood pressure (BP), and serum levels of cytokines in female migraine patients. A total of 14 migraineurs with aura, and 12 without aura during their interictal period were compared with 25 controls. Interleukin-8 (IL-8), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), matrix metalloproteinase-9 (MMP-9), interferon gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-α), and plasminogen activator inhibitor-1 (PAI-1) were measured. Migraineurs have elevated levels of IL-8, but decreased serum levels of PAI-1 and sICAM-1 during the interictal period, regardless of aura. BMI correlates with BP, and also with IFN-γ and MMP-9 only in patients with aura. There are three correlations in migraine patients with aura that are absent in patients without aura: between IL-8 and PAI-1; MMP-9 and IL-8; and IL-8 and sICAM-1. Migraineurs without aura, on the other hand, have correlations that patients with aura do not have (between PAI-1 and MCP-1, sICAM-1; between MMP-9 and sICAM-1, MCP-1; between TGF-α and PAI-1, MMP-9, sICAM-1; between sICAM-1 and MMP-9, PAI-1, MCP-1; as well as between sVCAM-1 and MCP-1). PAI-1, TGF, and MMP-9 could be used as biomarkers to distinguish migraineurs from healthy individuals.

Relationship between serum and tear levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in diabetic retinopathy

BackgroundDiabetic retinopathy (DR) is a serious complication of longstanding type 2 diabetes mellitus (T2DM), a leading cause of blindness and visual disability in the world. The aim of this study is to compare the activity of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in tears and serum of patients with DR and those without DR.MethodAmong the T2DM patients enrolled in this study, 26 patients had DR (n = 26) while 29 were without DR (n = 29). The blood and tear samples were obtained from all participants. The level of PAI-1 and tPA were measured in both the serum and tears. Anthropometric measurements, HbA1c, renal and lipid profile were also obtained.ResultsPatients with DR had significantly longer disease duration and higher systolic blood pressure compared to those without DR. Serum PAI-1 level was significantly higher in patients with DR compared to those without DR, 32.72 (IQR 32.52) vs 21.37 (IQR 14.93) ng/mL, respectively (p < 0.05). However, tear PAI-1 were comparable in both groups. Serum and tear tPA levels in both groups were also comparable (p > 0.05). Among patients with DR, there were no significant correlations between tear and serum of both biomarkers. Patients without DR showed a moderate positive correlation between serum and tear tPA levels with a coefficient of 0.363, albeit no statistical significance. Patients with DR demonstrated a significant positive correlation between levels of tears PAI-1 and BMI (r = 0.555, p = 0.026). In the group without DR, there was a statistically significant positive correlation between serum level of PAI-1 with urine albumin creatinine ratio (UACR) (r = 0.501, p = 0.013).ConclusionThe present study demonstrated a significantly greater serum PAI-1 levels in patients with DR compared to those without DR. No significant correlations between tears and serum PAI-1 and tPA were observed. Thus, the role of tear biomarkers remains relevant for further investigations.