Ligneous membranitis/conjunctivitis (LM, OMIM 217090) is a hereditary disorder caused by a congenital plasminogen (PLG) deficiency. In veterinary medicine, LM (OMIA 002020-9615) has rarely been reported in Golden Retrievers, Yorkshire Terriers, Doberman Pinschers and Scottish Terriers. In the latter breed, an A>T variation in an intron donor site of the PLG gene (PLG, c.1256+2T>A) has been found to be the sole causative molecular defect reported to date in dogs. Owing to the absence of plasmin enzymatic clearance which in turn depends on the lack of its proenzyme plasminogen, fibrin deposits tend to accumulate in viscous membranes on the eyes, triggering and sustaining an intense inflammatory response. A case of LM was diagnosed in a 7-month-old male Maltese dog. The dog was examined for severe recurrent conjunctivitis. A diagnosis of ligneous conjunctivitis was made by an ophthalmologist after a thorough eye examination and was confirmed by a complete lack of plasma activity of plasminogen. The main local signs were redness of the conjunctiva with persistent membranes having ligneous (wood-like) membranes on the eyes. The disease was associated with a complex rearrangement involving the plasminogen gene loci, causing the complete deletion of exon 1. This study provides a spontaneous animal model for LM associated with complete plasminogen deficiency and provides a method for detecting affected or carrier dogs.

• MeSH
• chov MeSH
• genetická onemocnění kůže genetika   veterinární   MeSH
• konjunktivitida genetika   veterinární   MeSH
• nemoci psů genetika   MeSH
• plazminogen nedostatek   genetika   MeSH
• psi genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• psi genetika   MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

AIM: We assessed various ways of tranexamic acid (TXA) administration on the fibrinolytic system. Blood loss, transfusions, drainage and haematoma were secondary outcomes. METHODS: In this prospective study, we examined 100 patients undergoing primary total knee arthroplasty (TKA) between June and November 2018. Patients were randomly assigned to 4 groups according to the following TXA regimens: 1) loading dose 15 mg TXA/kg single intravenous administration applied at initiation of anesthesia (IV1); 2) loading dose 15 mg TXA/kg + additional dose 15 mg TXA/kg 6 h after the first application of TXA (IV2); 3) IV1 regime in combination with a local wash of 2 g of TXA in 50 mL of saline (COMB); 4) topical administration of 2 g of TXA in 50 mL of saline (TOP). RESULTS: Systemic fibrinolysis interference was insignificant in all of the regimens; we did not detect significant differences between IV1, IV2 and COMB in the monitored parameters within the elapsed time after the TKA; IV regimes had the lowest total drainage blood loss; the lowest blood loss was associated with the IV1 and IV2 regimens (IV1, IV2 < COMB < TOP); the lowest incidence of haematomas was in patients treated with TXA topically (i.e., in COMB + TOP). CONCLUSION: The largest antifibrinolytic effect was associated with intravenous administration of TXA. In terms of blood loss, intravenously administered TXA can interfere with the processes associated with the formation of the fibrin plug more efficiently than the simple washing of wound surfaces with TXA.

• MeSH
• antifibrinolytika aplikace a dávkování   MeSH
• aplikace lokální MeSH
• artróza kolenních kloubů chirurgie   MeSH
• fibrin-fibrinogen - produkty degradace metabolismus   MeSH
• hematokrit MeSH
• hemoglobiny metabolismus   MeSH
• intravenózní podání MeSH
• krvácení při operaci * MeSH
• kyselina tranexamová aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• plazminogen metabolismus   MeSH
• pooperační krvácení epidemiologie   MeSH
• senioři MeSH
• totální endoprotéza kolene metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

Soluble oligomeric forms of amyloid beta (Aβ) play an important role in causing the cognitive deficits in Alzheimer's disease (AD) by targeting and disrupting synaptic pathways. Thus, the present research is directed toward identifying the neuronal pathways targeted by soluble forms and, accordingly, develops alternative therapeutic strategies. The neurotrophin brain-derived neurotrophic factor (BDNF) is synthesized as a precursor (pro-BDNF) which is cleaved extracellularly by plasmin to release the mature form. The conversion from pro-BDNF to BDNF is an important process that regulates neuronal activity and memory processes. Plasmin-dependent maturation of BDNF in the brain is regulated by plasminogen activator inhibitor-1 (PAI-1), the natural inhibitor of tissue-type plasminogen activator (tPA). Therefore, tPA/PAI-1 system represents an important regulator of extracellular BDNF/pro-BDNF ratio. In this review, we summarize the data on the components of the plasminogen activation system and on BDNF in AD. Moreover, we will hypothesize a possible pathogenic mechanism caused by soluble Aβ forms based on the effects on tPA/PAI-1 system and on the consequence of an altered conversion from pro-BDNF to the mature BDNF in the brain of AD patients. Translation into clinic may include a better characterization of the disease stage and future direction on therapeutic targets.

• MeSH
• Alzheimerova nemoc diagnóza   farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• extracelulární prostor účinky léků   metabolismus   MeSH
• lidé MeSH
• mozkový neurotrofický faktor metabolismus   MeSH
• plazminogen metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The plasminogen system is harnessed in a wide variety of physiological processes, such as fibrinolysis, cell migration, or efferocytosis; and accordingly, it is essential upon inflammation, tissue remodeling, wound healing, and for homeostatic maintenance in general. Previously, we identified a plasminogen receptor in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R, CD222). Here, we demonstrate by means of genetic knockdown, knockout, and rescue approaches combined with functional studies that M6P/IGF2R is up-regulated on the surface of macrophages, recognizes plasminogen exposed on the surface of apoptotic cells, and mediates plasminogen-induced efferocytosis. The level of uptake of plasminogen-coated apoptotic cells inversely correlates with the TNF-α production by phagocytes indicating tissue clearance without inflammation by this mechanism. Our results reveal an up-to-now undetermined function of M6P/IGF2R in clearance of apoptotic cells, which is crucial for tissue homeostasis.

• MeSH
• buněčná diferenciace účinky léků   MeSH
• fagocytóza účinky léků   MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• genový knockout MeSH
• Jurkat buňky MeSH
• lidé MeSH
• makrofágy cytologie   účinky léků   metabolismus   MeSH
• myši MeSH
• plazminogen farmakologie   MeSH
• receptor IGF typ 2 metabolismus   MeSH
• THP-1 buňky MeSH
• TNF-alfa metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• anafylaxe etiologie   MeSH
• angioedém * etiologie   MeSH
• bradykinin * škodlivé účinky   MeSH
• cévní mozková příhoda * farmakoterapie   MeSH
• fibrinolytika škodlivé účinky   MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• plazminogen škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• trombolytická terapie * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: Serine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). These proteases are recognized as antigens during host infection and may prove useful as anthelminthic vaccines, however their molecular characteristics are under-studied. Here, we characterize the structural and proteolytic attributes of serine protease 2 (SmSP2) from Schistosoma mansoni, one of the major species responsible for the tropical infectious disease, schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: SmSP2 comprises three domains: a histidine stretch, TSR-1 and a serine protease domain. The cleavage specificity of recombinant SmSP2 was determined using positional scanning and multiplex combinatorial libraries and the determinants of specificity were identified with 3D homology models, demonstrating a trypsin-like endopeptidase mode of action. SmSP2 displayed restricted proteolysis on protein substrates. It activated tissue plasminogen activator and plasminogen as key components of the fibrinolytic system, and released the vasoregulatory peptide, kinin, from kininogen. SmSP2 was detected in the surface tegument, esophageal glands and reproductive organs of the adult parasite by immunofluorescence microscopy, and in the excretory/secretory products by immunoblotting. CONCLUSIONS/SIGNIFICANCE: The data suggest that SmSP2 is secreted, functions at the host-parasite interface and contributes to the survival of the parasite by manipulating host vasodilatation and fibrinolysis. SmSP2 may be, therefore, a potential target for anti-schistosomal therapy.

• MeSH
• fibrinolýza účinky léků   MeSH
• hemokoagulace účinky léků   MeSH
• hemostatika antagonisté a inhibitory   MeSH
• krevní tlak účinky léků   MeSH
• molekulární modely MeSH
• plazminogen účinky léků   MeSH
• proteinové domény MeSH
• proteiny červů chemie   genetika   farmakologie   MeSH
• proteolýza účinky léků   MeSH
• rekombinantní proteiny MeSH
• Schistosoma mansoni enzymologie   MeSH
• schistosomiasis mansoni parazitologie   MeSH
• sekvence aminokyselin MeSH
• serinové endopeptidasy chemie   genetika   farmakologie   MeSH
• tkáňový aktivátor plazminogenu účinky léků   MeSH
• vazodilatace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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

Pseudomonas aeruginosa is one of the pathogenic bacteria which utilize binding of the host plasminogen (Plg) to promote their invasion throughout the host tissues. In the present study, we confirmed that P. aeruginosa exhibits binding affinity for human plasminogen. Furthermore, we showed that the protein detected on the cell wall of P. aeruginosa and binding human plasminogen is an enolase-like protein. The hypothesis that alpha-enolase, a cytoplasmatic glycolytic enzyme, resides also on the cell surface of the bacterium was supported by electron microscopy analysis. The plasminogen-binding activity of bacterial cell wall outer membrane enolase-like protein was examined by immunoblotting assay.

• MeSH
• fosfopyruváthydratasa metabolismus   MeSH
• imunoblotting MeSH
• imunoelektronová mikroskopie MeSH
• lidé MeSH
• plazminogen metabolismus   MeSH
• proteiny vnější bakteriální membrány metabolismus   MeSH
• Pseudomonas aeruginosa enzymologie   metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• fibrinolýza genetika   MeSH
• hydrocefalus diagnóza   chirurgie   terapie   MeSH
• konjunktivitida diagnóza   etiologie   terapie   MeSH
• lidé MeSH
• novorozenec MeSH
• plazminogen aplikace a dávkování   nedostatek   terapeutické užití   MeSH
• ventrikuloperitoneální zkrat metody   využití   MeSH
• vrozené, dědičné a novorozenecké nemoci a abnormality diagnóza   chirurgie   terapie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• Publikační typ
• kazuistiky MeSH

Cancer cell lines derived from hepatocytes have an altered phenotype and they lack hepatocyte-specific functions. It is at least partly due to the under-expression of transcription factors such as hepatocyte nuclear factor 4α (HNF4α), steroid receptor co-activator 1 (SRC1) etc. Recently, a strategy of transient transfection of human hepatic cells with HNF4α revealed improved hepatospecific functions, including the expression of drug-metabolizing enzymes. In the current study we established a human cell line derived from HepG2 cells stably transfected with human HNF4α, and we examined this line for hepatospecific markers. Of the 9 clones analyzed, we found an increased secretion of fibrinogen (9 clones), albumin (5 clones) and plasminogen (3 clones), while secretion of alpha1-antitrypsin was not changed. The expression of pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) proteins but not mRNAs was slightly increased. TCDD-dependent induction of CYP1A1 mRNA and protein was augmented in 50% of clones, but there was no correlation between the CYP1A1 inducibility and expression levels of AhR and HNF4α. Induction of CYP3A4 mRNA by rifampicin was about 1.5-2.5 fold (clones 2, 4, 6, 7) and it was not significantly different from CYP3A4 mRNA induction in parent HepG2. The basal expression of CYP3A4 protein was increased in all clones, but rifampicin-induced expression of CYP3A4 protein was in all clones lower than in parent HepG2. Overall, the stable over-expression of HNF4α in HepG2 cells restores some of the hepatospecific functions, but it has a minor effect on the expression of xenobiotic-metabolizing enzymes and their regulators.

• MeSH
• albuminy metabolismus   MeSH
• alfa-1-antitrypsin metabolismus   MeSH
• antiprotozoální látky farmakologie   MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• fibrinogen metabolismus   MeSH
• gentamiciny farmakologie   MeSH
• glyceraldehyd-3-fosfátdehydrogenasy metabolismus   MeSH
• hepatocytární jaderný faktor 4 genetika   metabolismus   MeSH
• hepatocyty metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie metabolismus   MeSH
• plazminogen metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• receptory aromatických uhlovodíků metabolismus   MeSH
• steroidní receptory metabolismus   MeSH
• transfekce MeSH
• viabilita buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH