Tick saliva is a rich source of modulators of vascular biology. We have characterized Ixonnexin, a member of the "Basic-tail" family of salivary proteins from the tick Ixodes scapularis. Ixonnexin is a 104 residues (11.8 KDa), non-enzymatic basic protein which contains 3 disulfide bonds and a C-terminal rich in lysine. It is homologous to SALP14, a tick salivary FXa anticoagulant. Ixonnexin was produced by ligation of synthesized fragments (51-104) and (1-50) followed by folding. Ixonnexin, like SALP14, interacts with FXa. Notably, Ixonnexin also modulates fibrinolysis in vitro by a unique salivary mechanism. Accordingly, it accelerates plasminogen activation by tissue-type plasminogen activator (t-PA) with Km 100 nM; however, it does not affect urokinase-mediated fibrinolysis. Additionally, lysine analogue ε-aminocaproic acid inhibits Ixonnexin-mediated plasmin generation implying that lysine-binding sites of Kringle domain(s) of plasminogen or t-PA are involved in this process. Moreover, surface plasmon resonance experiments shows that Ixonnexin binds t-PA, and plasminogen (KD 10 nM), but not urokinase. These results imply that Ixonnexin promotes fibrinolysis by supporting the interaction of plasminogen with t-PA through formation of an enzymatically productive ternary complex. Finally, in vivo experiments demonstrates that Ixonnexin inhibits FeCl3-induced thrombosis in mice. Ixonnexin emerges as novel modulator of fibrinolysis which may also affect parasite-vector-host interactions.

• MeSH
• arteriální okluzní nemoci chemicky indukované   patologie   prevence a kontrola   MeSH
• chloridy toxicita   MeSH
• fibrinolýza účinky léků   MeSH
• klíšťata metabolismus   MeSH
• myši MeSH
• noxy toxicita   MeSH
• plazminogen metabolismus   MeSH
• slinné proteiny a peptidy farmakologie   MeSH
• sliny metabolismus   MeSH
• tkáňový aktivátor plazminogenu metabolismus   MeSH
• trombóza chemicky indukované   patologie   prevence a kontrola   MeSH
• železité sloučeniny toxicita   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• chloridy MeSH
• ferric chloride MeSH Prohlížeč
• noxy MeSH
• plazminogen MeSH
• slinné proteiny a peptidy MeSH
• tkáňový aktivátor plazminogenu MeSH
• železité sloučeniny MeSH

Haemodialysis (HD) is associated with stimulation of the fibrinolytic system. The increase of fibrinolytic activity seems to be primarily due to tissue-type plasminogen activator (t-PA) released from the vessel wall. The aim of our study was to determine whether the t-PA release is the consequence of uraemic intoxication adjustment, extracorporeal circulation effect, heparin administration, or whether a mere reflection of the circadian rhythm of fibrinolysis is involved. To identify the factor, fibrinolytic system parameters were determined during HD, sham HD (SD), after the administration of heparin alone outside HD, and during a control period (CP). The plasma concentrations of t-PA antigen indicate that HD is associated with the release of t-PA from the vessel wall; 3.70 ng/ml before HD, 4.35 (NS) at the 15th min, 4.88 (P less than 0.05) at the 20th min, and 5.09 (P less than 0.05) after HD (medians). The respective values for a CP are 4.05, 4.37 (NS), 4.40 (NS), and 4.22 (NS). The effect of heparin alone and SD was evaluated for 120 min only, with the following t-PA concentrations determined after heparin: 5.10, 6.22 (NS), 4.72 (NS), 4.72 (NS); during SD and 4.50, 5.14 (NS), 5.20 (P less than 0.05). We conclude that t-PA is released from the vessel wall during HD. A factor contributing to its release is the extracorporeal circulation system.

• MeSH
• cévy metabolismus   MeSH
• chronické selhání ledvin krev   terapie   MeSH
• dialýza ledvin škodlivé účinky   MeSH
• dospělí MeSH
• fibrinolýza MeSH
• lidé MeSH
• tkáňový aktivátor plazminogenu krev   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• tkáňový aktivátor plazminogenu 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.

• Klíčová slova
• dementia, frontotemporal lobar degeneration, plasminogen activator inhibitor‐1, tissue‐type plasminogen activator,
• 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
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• inhibitor aktivátoru plazminogenu 1 * MeSH
• SERPINE1 protein, human MeSH Prohlížeč
• tkáňový aktivátor plazminogenu MeSH

AIM: To establish whether the values of two key enzymes of fibrinolysis, tissue-type plasminogen activator (tPA) and its inhibitor (PAI-1), differ between patients treated with continuous ambulatory peritoneal dialysis (CAPD) and healthy volunteers and whether plasma and dialysate tPA and PAI-1 values vary during one exchange of dialysis solution. METHODS: A total of 11 patients with chronic renal failure, treated with CAPD during the peritoneal equilibration test (in addition with blood sampling at time 0), and a control group of 11 healthy volunteers were examined. To identify the factors involved in the changes in tPA and PAI-1, 9 CAPD patients were subsequently monitored, in a crossover manner, during dialysis with solutions of 1.36 and 3.86% dextrose and off dialysis. RESULTS: Compared with healthy individuals, CAPD-treated patients showed a significantly lower tPA activity (0.39 vs. 0.81 IU/ml, p < 0.05). Changes in plasma fibrinolysis during one exchange of dialysis solution were characterized mainly by a decrease in PAI-1 concentrations and activities caused by the circadian rhythm of fibrinolysis. To explain, in the crossover part of the study, the values of plasma PAI-1 antigen at time 0 (07.00 h) and at time 2 (09.00 h) were 9.4 versus 6.5 ng/ml with the 1.36% solution (p < 0.05), 8.2 versus 4.9 with the 3.86% solution (p < 0.05), and 14.1 versus 9.1 ng/ml off dialysis (p < 0.01). Compared to baseline (0 ng/ml with 1.36 as well as 3.86% solutions), the levels of PAI-1 antigen in dialysis solution rose, apparently due to local production in the peritoneal cavity, to 0.5 ng/ml (p < 0.05) with the 1.36% solution, to 0.7 (p < 0.05) with the 3.86% solution after a 2-hour dwell time, and to 1.6 (p < 0.05) and 1.3 ng/ml (p < 0.05) after a 4-hour dwell time, respectively. Hence, the different dextrose levels in the dialysis solutions had no effect on the monitored parameters of fibrinolysis. CONCLUSION: The lower activity of plasma tPA, and the increase in PAI-1 levels in dialysis solutions may contribute to the development of thromboses in CAPD patients and to fibrin formation on the peritoneal surface with consequences such as peritoneal fibrosis.

• MeSH
• chronické selhání ledvin krev   enzymologie   terapie   MeSH
• dospělí MeSH
• fibrinolýza * MeSH
• inhibitor aktivátoru plazminogenu 1 metabolismus   MeSH
• kontinuální ambulantní peritoneální dialýza * MeSH
• lidé středního věku MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• tkáňový aktivátor plazminogenu metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• inhibitor aktivátoru plazminogenu 1 MeSH
• tkáňový aktivátor plazminogenu MeSH

Several plasminogen activators (PAs) have been found effective in treating different thromboembolic diseases. However, administration of conventional thrombolytic therapy is limited by a low efficacy of present formulations of PAs. Conventional treatments using these therapeutic proteins are associated with several limitations including rapid inactivation and clearance, short half-life, bleeding complications or non-specific tissue targeting. Liposome-based formulations of PAs such as streptokinase, tissue-plasminogen activator and urokinase have been developed to improve the therapeutic efficacy of these proteins. Resulting liposomal formulations were found to preserve the original activity of PAs, promote their selective delivery and improve thrombus targeting. Therapeutic potential of these liposome-based PAs has been demonstrated successfully in various pre-clinical models in vivo. Reductions in unwanted side effects (e.g., hemorrhage or immunogenicity) as well as enhancements of efficacy and safety were achieved in comparison to currently existing treatment options based on conventional formulations of PAs. This review summarizes present achievements in: (i) preparation of liposome-based formulations of various PAs, (ii) development of PEGylated and targeted liposomal PAs, (iii) physico-chemical characterization of these developed systems, and (iv) testing of their thrombolytic efficacy. We also look to the future and the imminent arrival of theranostic liposomal formulations to move this field forward.

• Klíčová slova
• Fibrin, Liposomes, Platelets, Protein delivery, RGD peptide, Streptokinase, Stroke, Thrombus, Tissue plasminogen activator, Urokinase,
• MeSH
• aktivátor plazminogenu urokinázového typu aplikace a dávkování   terapeutické užití   MeSH
• fibrinolytika aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• liposomy chemie   ultrastruktura   MeSH
• metaloendopeptidasy aplikace a dávkování   terapeutické užití   MeSH
• nanostruktury chemie   ultrastruktura   MeSH
• plasmin aplikace a dávkování   terapeutické užití   MeSH
• streptokinasa aplikace a dávkování   terapeutické užití   MeSH
• tkáňový aktivátor plazminogenu aplikace a dávkování   terapeutické užití   MeSH
• tromboembolie farmakoterapie   MeSH
• trombolytická terapie metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• aktivátor plazminogenu urokinázového typu MeSH
• auR protein, Staphylococcus aureus MeSH Prohlížeč
• fibrinolytika MeSH
• liposomy MeSH
• metaloendopeptidasy MeSH
• plasmin MeSH
• streptokinasa MeSH
• tkáňový aktivátor plazminogenu MeSH

Biochemical markers of early changes that are characteristic for diabetic microangiopathy are not completely understood. We investigated activities of serum N-acetyl-beta-glucosaminidase (NAG), tissue plasminogen activator and erythrocyte superoxide dismutase in well defined groups of type 1 diabetic patients. Patients were selected on the basis of 4 year follow-up observation. Forty-two type 1 diabetic patients were subdivided into those without retinopathy (n = 13) throughout the study, those with newly developed or worsened retinopathy (n = 12) during 4 years and those with retinopathy already established at the beginning of the study and without evidence of its progression (n = 17). All diabetic patients had albustix-negative urine. A significant increase of the mean serum NAG activity during 4 years was found only in patients without retinopathy (P < 0.01) whereas no changes of the altered enzyme activities were present in patients with developing and established retinopathy. The mean activity of tissue plasminogen activator was elevated in all groups of diabetic patients compared with healthy subjects (P < 0.001). A significant positive correlation was found between plasminogen activator and serum NAG (r = 0.51, P < 0.01). Erythrocyte superoxide dismutase was higher in diabetic patients than in healthy persons (P < 0.01) but no differences were observed between the patients with or without retinopathy. Superoxide dismutase positively correlated with NAG (r = 0.57, P < 0.01). We conclude that early functional changes precede a morphological development of diabetic retinopathy as was evident from the altered enzyme activities.

• MeSH
• acetylglukosaminidasa krev   MeSH
• diabetes mellitus 1. typu enzymologie   MeSH
• diabetická retinopatie enzymologie   MeSH
• dospělí MeSH
• erytrocyty enzymologie   MeSH
• glykovaný hemoglobin metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• superoxiddismutasa krev   MeSH
• tkáňový aktivátor plazminogenu krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylglukosaminidasa MeSH
• glykovaný hemoglobin MeSH
• superoxiddismutasa MeSH
• tkáňový aktivátor plazminogenu 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.

• Klíčová slova
• Biochemical recurrence, Prostate cancer, Radical prostatectomy, Urokinase-type plasminogen activator,
• MeSH
• aktivátor plazminogenu urokinázového 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
• Názvy látek
• aktivátor plazminogenu urokinázového typu MeSH
• inhibitor aktivátoru plazminogenu 1 MeSH
• nádorové biomarkery MeSH
• PLAUR protein, human MeSH Prohlížeč
• receptory urokinázového aktivátoru plazminogenu MeSH
• SERPINE1 protein, human MeSH Prohlížeč

• Klíčová slova
• Editorial, reperfusion, stroke, ultrasonography, Doppler, transcranial,
• MeSH
• cévní mozková příhoda farmakoterapie   MeSH
• ischemie mozku farmakoterapie   MeSH
• lidé MeSH
• tkáňový aktivátor plazminogenu terapeutické užití   MeSH
• trombolytická terapie metody   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• komentáře MeSH
• práce podpořená grantem MeSH
• úvodníky MeSH
• Názvy látek
• tkáňový aktivátor plazminogenu MeSH

BACKGROUND: The safety and efficacy of low- and high-dose intravenous tissue plasminogen activator (t-PA) for the treatment of acute ischemic stroke are poorly understood. In this multicenter study, we examined the relationships between different doses of t-PA and outcome. METHODS: Between 2006 and 2010, patients were enrolled if they were treated with t-PA on the basis of estimated body weight and on the subsequent availability of actual body weight. Based on the actual weight, patients were divided into lower (<0.85 mg/kg), standard (0.85-0.95 mg/kg), and higher (>0.95 mg/kg) t-PA dose groups. Differences in the outcomes of these groups were compared in terms of functional recovery (modified Rankin Scale [mRS] 0-1) at 3 months and the incidence of parenchymal hemorrhages on follow-up computed tomographic scans. RESULTS: This cohort study included 272 patients: 171 (63%) patients received the standard t-PA dose, 62 (23%) a lower dose, and 39 (14%) a higher dose. At 3 months, 51% of the standard dose patients achieved a mRS score of 0 to 1, compared with 50% in the lower dose and 44% in the higher dose groups. Parenchymal hemorrhage occurred in 4.7%, 6.5%, and 7.7% of patients in standard, lower, and higher dose groups, respectively. Compared with standard dose groups, no significant differences in functional recovery and parenchymal hemorrhage were observed in the lower and higher dose groups. CONCLUSIONS: In clinical practice, the actual dose of t-PA often differs from the recommended dose of 0.9 mg/kg, but this has no significant impact on the outcome after t-PA treatment.

• Klíčová slova
• Acute ischemic stroke, efficacy of treatment, safety of treatment, thrombolysis, tissue plasminogen activator dose,
• MeSH
• cévní mozková příhoda farmakoterapie   MeSH
• dospělí MeSH
• fibrinolytika aplikace a dávkování   terapeutické užití   MeSH
• ischemie mozku farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• obnova funkce MeSH
• prospektivní studie MeSH
• retrospektivní studie MeSH
• senioři MeSH
• tkáňový aktivátor plazminogenu aplikace a dávkování   terapeutické užití   MeSH
• trombolytická terapie metody   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrinolytika MeSH
• tkáňový aktivátor plazminogenu MeSH

BACKGROUND: Fibrinogen (Fgb), the tissue activator of plasminogen (t-PA) and its inhibitor (PAI-1) are described as so-called cardiovascular risk factors. The objective of the present investigation was to assess the occurrence of the mentioned risk factors (Fbg, t-PA and PAI-1) in diabetes mellitus (DM) type 1 and 2, compare them with findings in a healthy control group and the two types of diabetes mutually. METHODS AND RESULTS: Fifty patients with type 1 DM were examined (mean BMI 23.8), 59 patients with type 2 DM (mean BMI 28) and 33 healthy subjects as controls (mean BMI 24.6). Both groups of diabetics were compensated. To assess the t-PA and PAI-1 concentration the ELISA test was used, Fbg was assessed by Clauss' method. The euglobulin fibrinolysis time (ECLT) was also examined. In both groups of patients with DM higher concentration of t-PA were found (DM type 7.06 +/- 2.4 ng/ml, p < 0.05, DM type 2 15.15 +/- 6.07 ng/mg, control 4.67 +/- 2.87 ng/ml, p < 0.05). In patients with DM type 1 a higher concentration of t-PA was found in patients with retinopathy (8.2 +/- 1.7 ng/ml than in patients with DM type 1 without retinopathy (6.9 +/- 1.3 ng/ml), p < 0.05). The PA-1 concentration was, as compared with controls, raised only in type 2 diabetics (DM type 2 124.57 +/- 47.22 ng/ml, control 88.57 +/- 15.7 ng/ml p < 0.05). Between the two groups also a difference in the PAI-1 level was found (DM type 179.25 +/- 17.95 ng/ml, vs. DM type 2, p < 0.05). With these findings corresponded the ECLT activation in DM type 1 (203.4 +/- 76.8 min. vs. ECLT in the control group 276.08 +/- 84.87 min., p < 0.05) and conversely a reduction of the euglobulin fibrinolysis in type 2 DM (448 +/- 117 min.), as compared with the controls (p < 0.05), as well as compared with DM type 1 (p < 0.05). The fibrinogen level was also elevated only in DM type 2 (3.619 +/- 0.69 g/l) as compared with the control group (2.42 +/- 0.42 g/l, p < 0.05) as well as compared with DM type 1 (2.53 +/- 0.47 g/l, p < 0.05). No difference was found in the fibrinogen level between DM type 1 and the control group. CONCLUSIONS: In both groups of patients with diabetes mellitus type 1 and 2 among the mentioned cardiovascular risk factors only a raised t-PA concentration was recorded. Concurrent elevation of PAI-1 and fibrinogen was found only in diabetes mellitus type 2.

• MeSH
• diabetes mellitus krev   MeSH
• dospělí MeSH
• fibrinogen analýza   MeSH
• inhibitor aktivátoru plazminogenu 1 krev   MeSH
• lidé MeSH
• tkáňový aktivátor plazminogenu krev   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• fibrinogen MeSH
• inhibitor aktivátoru plazminogenu 1 MeSH
• tkáňový aktivátor plazminogenu MeSH