Plasminogen activator inhibitor 1 (PAI-1) is a crucial serine protease inhibitor that prevents plasminogen activation by inhibiting tissue- and urokinase-type plasminogen activators (tPA, uPA). PAI-1 is well-known for its role in modulating hemocoagulation or extracellular matrix formation by inhibiting plasmin or matrix metalloproteinases, respectively. PAI-1 is induced by pro-inflammatory cytokines across various tissues, yet its regulation by ligand-activated transcription factors is partly disregarded. Therefore, we have attempted to summarize the current knowledge on the transcriptional regulation of PAI-1 expression by the most relevant xenobiotic and endocrine receptors implicated in modulating PAI-1 levels. This review aims to contribute to the understanding of the specific, often tissue-dependent regulation of PAI-1 and provide insights into the modulation of PAI-1 levels beyond its direct inhibition.
BACKGROUND: The risk of acute ischemic stroke (AIS) associated with high estrogen states, including pregnant patients and those using oral contraceptives, has been well documented. We described the histological composition of thrombi collected in these cases. METHODS: From a prospective tissue registry (STRIP registry) of thrombi retrieved during mechanical thrombectomy for AIS, we identified 5 patients with high estrogen states: 1 post-partum patient, 1 undergoing hormone replacement therapy and 3 consuming oral contraceptive pills. Five male control patients were randomly chosen matched by age. Immunohistochemistry for CD42b (platelets), von Willebrand factor (vWF), thrombin-activatable fibrinolysis inhibitor (TAFI), fibrinogen and plasminogen activator inhibitor-1 (PAI-1) was performed. Expression was quantified using Orbit Image Software. Student's t-test was performed as appropriate. RESULTS: Mean TAFI content for the high estrogen state group was higher than controls (25.6 ± 11.9% versus 9.3 ± 9.0%, p = 0.043*). Mean platelet content for the high estrogen state group was lower than controls (41.7 ± 10.6% versus 61.8 ± 12.9%, p = 0.029*). No significant difference was found in vWF, fibrinogen and PAI-1 expression. Mean time to recanalize was higher in the high estrogen state group compared to the control group (57.8 ± 27.6 versus 22.6 ± 11.4 min, p = 0.0351*). The mean number of passes required was higher in the high estrogen group compared to controls 4.6 versus 1.2, p = 0.0261*). CONCLUSIONS: TAFI expression, a powerful driver of thrombosis, was significantly higher in stroke thrombi among patients with high estrogen states compared to controls.
- MeSH
- cévní mozková příhoda * MeSH
- estrogeny MeSH
- fibrinogen metabolismus MeSH
- fibrinolýza MeSH
- inhibitor aktivátoru plazminogenu 1 MeSH
- ischemická cévní mozková příhoda * MeSH
- karboxypeptidasa B2 * MeSH
- lidé MeSH
- trombóza * MeSH
- von Willebrandův faktor MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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.
- MeSH
- biologické markery krev MeSH
- frontotemporální lobární degenerace * krev MeSH
- inhibitor aktivátoru plazminogenu 1 * krev MeSH
- kognitivní dysfunkce krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- tkáňový aktivátor plazminogenu krev metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: Circulating insulin concentrations mediate vascular-inflammatory and prothrombotic factors. However, it is unknown whether interindividual differences in circulating insulin levels are associated with different inflammatory and prothrombotic profiles in type 1 diabetes (T1D). We applied an unsupervised machine-learning approach to determine whether interindividual differences in rapid-acting insulin levels associate with parameters of vascular health in patients with T1D. METHODS: We re-analyzed baseline pretreatment meal-tolerance test data from 2 randomized controlled trials in which 32 patients consumed a mixed-macronutrient meal and self-administered a single dose of rapid-acting insulin individualized by carbohydrate counting. Postprandial serum insulin, tumour necrosis factor (TNF)-alpha, plasma fibrinogen, human tissue factor (HTF) activity and plasminogen activator inhibitor-1 (PAI-1) were measured. Two-step clustering categorized individuals based on shared clinical characteristics. For analyses, insulin pharmacokinetic summary statistics were normalized, allowing standardized intraindividual comparisons. RESULTS: Despite standardization of insulin dose, individuals exhibited marked interpersonal variability in peak insulin concentrations (48.63%), time to peak (64.95%) and insulin incremental area under the curve (60.34%). Two clusters were computed: cluster 1 (n=14), representing increased serum insulin concentrations; and cluster 2 (n=18), representing reduced serum insulin concentrations (cluster 1: 389.50±177.10 pmol/L/IU h-1; cluster 2: 164.29±41.91 pmol/L/IU h-1; p<0.001). Cluster 2 was characterized by increased levels of fibrinogen, PAI-1, TNF-alpha and HTF activity; higher glycated hemoglobin; increased body mass index; lower estimated glucose disposal rate (increased insulin resistance); older age; and longer diabetes duration (p<0.05 for all analyses). CONCLUSIONS: Reduced serum insulin concentrations are associated with insulin resistance and a prothrombotic milieu in individuals with T1D, and therefore may be a marker of adverse vascular outcome.
- MeSH
- diabetes mellitus 1. typu * komplikace MeSH
- fibrinogen terapeutické užití MeSH
- hypoglykemika farmakologie terapeutické užití MeSH
- inhibitor aktivátoru plazminogenu 1 terapeutické užití MeSH
- injekce subkutánní MeSH
- inzulin terapeutické užití MeSH
- inzulinová rezistence * MeSH
- krátkodobě působící inzuliny terapeutické užití MeSH
- krevní glukóza analýza MeSH
- lidé MeSH
- postprandiální období MeSH
- strojové učení MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Background: To evaluate the association between hypertriglyceridemic waist (HTGW), a promising marker of visceral adiposity and cardiovascular (CV) risk, and different indicators of vascular damage in type 2 diabetes (T2D) patients. Methods: This case-control study included 161 patients with T2D (91 males, 70 females) and 40 healthy controls (24 males, 16 females). HTWG was defined as waist circumference >90 cm in men or >85 cm in women and triglyceride concentrations >2 mmol/L. In addition to anthropometric and metabolic parameters, markers of endothelial dysfunction, namely von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1), were assessed. Arterial stiffness parameters were examined using the SphygmoCor system. Results: Individuals with T2D and HTGW showed the highest elevation of PAI-1 levels and significantly increased vWF levels compared with healthy controls. No significant differences in arterial stiffness markers were observed between T2D individuals. Age and, for several markers, systolic and/or diastolic blood pressure were identified as the main predictors for arterial stiffness, whereas PAI-1 and vWF levels were predicted by metabolic parameters. Conclusions: HTGW represents increased CV risk in T2D patients, mainly due to endothelial damage. The presence of HTGW had no significant effect on arterial stiffness compared with other T2D individuals.
- MeSH
- biologické markery krev MeSH
- diabetes mellitus 2. typu * epidemiologie MeSH
- hypertriglyceridemický pas * epidemiologie MeSH
- inhibitor aktivátoru plazminogenu 1 krev MeSH
- kardiovaskulární nemoci * krev diagnóza epidemiologie MeSH
- lidé MeSH
- studie případů a kontrol MeSH
- von Willebrandův faktor analýza MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: To investigate the prognostic role of expression of urokinase-type plasminogen activator system members, such as urokinase-type activator (uPA), uPA-receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1), in patients treated with radical prostatectomy (RP) for prostate cancer (PCa). METHODS: Immunohistochemical staining for uPA system was performed on a tissue microarray of specimens from 3121 patients who underwent RP. Cox regression analyses were performed to investigate the association of overexpression of these markers alone or in combination with biochemical recurrence (BCR). Decision curve analysis was used to assess the clinical impact of these markers. RESULTS: uPA, uPAR, and PAI-1 were overexpressed in 1012 (32.4%), 1271 (40.7%), and 1311 (42%) patients, respectively. uPA overexpression was associated with all clinicopathologic characteristics of biologically aggressive PCa. On multivariable analysis, uPA, uPAR, and PAI-1 overexpression were all three associated with BCR (HR: 1.75, p < 0.01, HR: 1.22, p = 0.01 and HR: 1.20, p = 0.03, respectively). Moreover, the probability of BCR increased incrementally with increasing cumulative number of overexpressed markers. Decision curve analysis showed that addition of uPA, uPAR, and PAI-1 resulted in a net benefit compared to a base model comparing standard clinicopathologic features across the entire threshold probability range. In subgroup analyses, overexpression of all three markers remained associated with BCR in patients with favorable pathologic characteristics. CONCLUSION: Overexpression of uPA, uPAR, and PAI-1 in PCa tissue were each associated with worse BCR. Additionally, overexpression of all three markers is informative even in patients with favorable pathologic characteristics potentially helping clinical decision-making regarding adjuvant therapy and/or intensified follow-up.
- MeSH
- aktivátor plasminogenu urokinasového typu biosyntéza fyziologie MeSH
- inhibitor aktivátoru plazminogenu 1 biosyntéza fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru epidemiologie etiologie MeSH
- nádorové biomarkery biosyntéza fyziologie MeSH
- nádory prostaty epidemiologie etiologie metabolismus chirurgie MeSH
- prognóza MeSH
- prostatektomie * MeSH
- receptory urokinázového aktivátoru plazminogenu biosyntéza fyziologie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: the PAI-1 rs1799889 polymorphism has been reported to be associated with susceptibility to ischemic stroke. However, the results of previous studies have been inconsistent or controversial. Hence, we performed a systematic review and meta-analysis to evaluate the association of PAI-1 rs1799889 polymorphism with ischemic stroke risk. METHODS: A comprehensive literature search was performed on PubMed, Web of Science, Scopus, SciELO, CNKI, and CBD databases up to November 05, 2019. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to access the strength of this association in fixed- or random-effects model. RESULTS: A total of 44 case-control studies with 8,620 cases and 10,260 controls were selected. Pooled data showed a significant association between PAI-1 rs1799889 polymorphism and ischemic stroke risk in the overall populations (GG vs. AA: OR = 0.791, 95% CI 0.633-0.988, p = 0.039; GA vs. AA: OR = 0.807, 95% CI 0.683-0.953, p = 0.012; and GG+GA vs. AA: OR = 0.795, 95% CI 0.637-0.993, p = 0.043). Subgroup analysis by ethnicity revealed a significant association in Asian and Mixed populations, but not in Caucasians. Moreover, stratified analysis by country of origin revealed an increased risk of ischemic stroke in Chinese populations, but not among Dutch (Netherlands) and Swedish. CONCLUSIONS: This meta-analysis result suggested that PAI-1 rs1799889 polymorphism was associated with an increased risk of ischemic stroke, especially in Asian and Mixed populations.
PURPOSE: Urokinase-plasminogen activator (uPA), its receptor (uPAR), and the plasmin-activator inhibitor type 1 (PAI-1) have been associated with oncologic outcomes in various malignancies and could help identify bladder cancer (BC) patients treated with radical cystectomy (RC) who are likely to benefit from intensification of therapy to prevent disease progression. Our aim was to assess the value of uPA, uPAR, and PAI-1 for prognosticating survival outcomes of patients treated with RC for BC. MATERIALS AND METHODS: Tumor specimens from 272 consecutive patients treated with RC for advanced BC were assessed with immunohistochemical staining for uPA, uPAR, and PAI-1. Overexpression was assessed by pathological image analysis. Kaplan-Meier estimates and multivariable Cox-regression were used to analyze survival. Harrell's C-index was used to assess for clinical impact of the uPA system. RESULTS: uPA, uPAR, and PAI-1 were overexpressed in 48.2%, 51.1%, and 52.2% of patients, respectively. uPA overexpression was associated with lymphovascular invasion (P = 0.034) and nodal status (P = 0.013); PAI-1 overexpression was associated with primary muscle-invasive BC (P = 0.015) and lymphovascular invasion (P = 0.024). uPA, uPAR, and the number of overexpressed markers were all 3 significantly associated with shorter overall recurrence-free-, distant recurrence-free-, and cancer-specific survival. In multivariable analyses, uPA overexpression remained associated with shorter recurrence-free survival (hazard ratio [HR] = 1.79; P = 0.036) in the entire cohort, in patients without lymph node metastasis (HR = 1.98; P = 0.018) and those with nonorgan-confined disease (HR = 1.98; P = 0.022). uPAR overexpression was associated with shorter recurrence-free survival in patients without lymph node metastasis (HR = 2.01; P = 0.021) and those with organ-confined disease (HR = 4.11; P = 0.037). CONCLUSION: Members of the uPA system are associated with features of biologically aggressive BC and oncologic outcomes. However, their value beyond currently available information remains limited.
- MeSH
- aktivátor plasminogenu urokinasového typu analýza fyziologie MeSH
- cystektomie * metody MeSH
- inhibitor aktivátoru plazminogenu 1 analýza fyziologie MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- nádory močového měchýře chemie mortalita chirurgie MeSH
- prognóza MeSH
- receptory urokinázového aktivátoru plazminogenu analýza fyziologie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The serine proteases, tissue- and urokinase-type plasminogen activators (PLAT and PLAU) and their inhibitors SERPINE1/2 are regulators of plasminogen to plasmin conversion. They are widely expressed in ovarian tissues, including granulosa and cumulus cells, and their expression is regulated by gonadotropins. The aim of this work was to assess the effect of serine protease inhibitors (aprotinin and AEBSF) and SERPINE1/2 on FSH-induced cumulus cell expansion, the production of prostaglandin E2 (PGE2) and retention of hyaluronic acid (HA) in expanding cumulus. The serine protease activity proved to be essential for the production of PGE2 and also for the retention of HA; the inhibition of plasminogen activators by SERPINE1/2 had the same effect. Collectively, these data indicate that plasmin is required for proper function of expanding cumulus cells in vitro and presumably also in vivo in the pre-ovulatory follicles.
- MeSH
- aprotinin farmakologie MeSH
- dinoproston metabolismus MeSH
- folikuly stimulující hormon farmakologie MeSH
- inhibitor aktivátoru plazminogenu 1 farmakologie MeSH
- inhibitory serinových proteinas farmakologie MeSH
- kumulární buňky cytologie účinky léků metabolismus MeSH
- kyselina hyaluronová metabolismus MeSH
- oocyty cytologie účinky léků metabolismus MeSH
- prasata MeSH
- serpin E2 farmakologie MeSH
- sulfony farmakologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
To compare circulating pigment epithelium derived factor (PEDF) levels in type 2 diabetes patients (T2D) with and without metabolic syndrome (MetS+/-) to healthy controls and assess PEDF association with plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF) as markers of endothelial dysfunction. Fifty T2D individuals and forty healthy controls were included. PEDF, PAI-1, vWF, anthropological parameters, lipids, and markers of insulin resistance were investigated in all subjects. Compared to controls only MetS+ diabetics had higher PEDF levels [14.2 (10.2-16.0) mg/l vs. 11.1 (8.6-14.4) mg/l; p<0.05]. PEDF significantly correlated: positively with body mass index (rho=0.25), smoking (rho=0.21), C-reactive protein (rho=0.22), triglycerides (rho=0.38), non-HDL-cholesterol (rho=0.39), apolipoprotein B (rho=0.38), fasting glucose (rho=0.22), glycated hemoglobin (rho=0.24), C-peptide (rho=0.28), insulin (rho=0.26); and negatively with HDL-cholesterol (rho=-0.42) and apolipoprotein A1 (rho=-0.27). Independent association of PEDF with vWF in T2DMetS- subjects was found. Significantly elevated PEDF in T2DMet+ patients and its association with adverse metabolic profile confirmed PEDF as a marker of insulin resistance. Negative independent association of PEDF with vWF in T2DMetS- patients may reveal its angio-protective role.
- MeSH
- biologické markery krev MeSH
- diabetes mellitus 2. typu krev diagnóza MeSH
- dospělí MeSH
- inhibitor aktivátoru plazminogenu 1 krev MeSH
- inzulinová rezistence fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- neurotrofní faktory krev MeSH
- oční proteiny krev MeSH
- průřezové studie MeSH
- senioři MeSH
- serpiny krev MeSH
- von Willebrandův faktor metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
