BACKGROUND: Adverse cardiac remodeling is a major risk factor for the development of post myocardial infarction (MI) heart failure (HF). This study investigates the effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute ST-segment-elevation myocardial infarction (STEMI). METHODS: In this double-blind, randomized, placebo-controlled trial patients with first STEMI were eligible. To preferentially enrich patients at high risk of adverse remodeling, main inclusion criteria were a left-ventricular ejection fraction (LVEF) ≤45% and an infarct size >10% on day 5 to 9 post MI as measured by cardiac MRI. Patients were then randomized to 6 months treatment with either 25 mg fulacimstat (n = 54) or placebo (n = 53) twice daily on top of standard of care starting day 6 to 12 post MI. The changes in LVEF, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume index (LVESVI) from baseline to 6 months were analyzed by a central blinded cardiac MRI core laboratory. RESULTS: Fulacimstat was safe and well tolerated and achieved mean total trough concentrations that were approximately tenfold higher than those predicted to be required for minimal therapeutic activity. Comparable changes in LVEF (fulacimstat: 3.5% ± 5.4%, placebo: 4.0% ± 5.0%, P = .69), LVEDVI (fulacimstat: 7.3 ± 13.3 mL/m2, placebo: 5.1 ± 18.9 mL/m2, P = .54), and LVESVI (fulacimstat: 2.3 ± 11.2 mL/m2, placebo: 0.6 ± 14.8 mL/m2, P = .56) were observed in both treatment arms. CONCLUSION: Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on cardiac remodeling.

• MeSH
• chymasy antagonisté a inhibitory   MeSH
• dvojitá slepá metoda MeSH
• funkce levé komory srdeční fyziologie   MeSH
• infarkt myokardu s elevacemi ST úseků komplikace   farmakoterapie   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonance kinematografická MeSH
• remodelace komor účinky léků   MeSH
• srdeční komory diagnostické zobrazování   patofyziologie   MeSH
• srdeční selhání diagnóza   farmakoterapie   etiologie   MeSH
• tepový objem fyziologie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• MeSH
• aktivace komplementu * imunologie   MeSH
• anafylaxe * imunologie   metabolismus   MeSH
• bazofily imunologie   MeSH
• biologické markery * metabolismus   MeSH
• bradykinin imunologie   metabolismus   MeSH
• chymasy imunologie   metabolismus   MeSH
• cytokiny * imunologie   metabolismus   MeSH
• faktor aktivující destičky imunologie   metabolismus   MeSH
• fenotyp * MeSH
• histamin imunologie   metabolismus   MeSH
• imunoglobulin E imunologie   MeSH
• imunoglobulin G imunologie   MeSH
• individualizovaná medicína MeSH
• interleukin-6 imunologie   metabolismus   MeSH
• karboxypeptidasy A imunologie   metabolismus   MeSH
• lidé MeSH
• mastocyty imunologie   MeSH
• tryptasy imunologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Platelet aggregation and acute inflammation are key processes in vertebrate defense to a skin injury. Recent studies uncovered the mediation of 2 serine proteases, cathepsin G and chymase, in both mechanisms. Working with a mouse model of acute inflammation, we revealed that an exogenous salivary protein of Ixodes ricinus, the vector of Lyme disease pathogens in Europe, extensively inhibits edema formation and influx of neutrophils in the inflamed tissue. We named this tick salivary gland secreted effector as I ricinus serpin-2 (IRS-2), and we show that it primarily inhibits cathepsin G and chymase, while in higher molar excess, it affects thrombin activity as well. The inhibitory specificity was explained using the crystal structure, determined at a resolution of 1.8 Å. Moreover, we disclosed the ability of IRS-2 to inhibit cathepsin G-induced and thrombin-induced platelet aggregation. For the first time, an ectoparasite protein is shown to exhibit such pharmacological effects and target specificity. The stringent specificity and biological activities of IRS-2 combined with the knowledge of its structure can be the basis for the development of future pharmaceutical applications.

• MeSH
• agregace trombocytů genetika   imunologie   MeSH
• chymasy imunologie   metabolismus   MeSH
• exprese genu MeSH
• hmyzí proteiny genetika   imunologie   metabolismus   MeSH
• kathepsin G imunologie   metabolismus   MeSH
• klíště genetika   imunologie   metabolismus   MeSH
• krystalizace MeSH
• kvarterní struktura proteinů MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• molekulární sekvence - údaje MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• sekvence aminokyselin MeSH
• sekvenční analýza proteinů MeSH
• serpiny genetika   imunologie   metabolismus   MeSH
• slinné proteiny a peptidy genetika   imunologie   metabolismus   MeSH
• zánět imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Atopická dermatitída (AD) je multifaktoriálne ochorenie. V jej etiopatogenéze sa uplatňujú viaceré faktory – genetická predispozícia, vplyvy vonkajšieho prostredia, humorálna a imunologická dysbalancia a porušená epidermálna bariéra. Genómové skríningy rodín sAD ukazujú na chromozomálne úseky, ktoré sa prekrývajú s ostatnými kožnými ochoreniami, zápalovými a autoimunitnými chorobami. Tieto spolu so štúdiami kandidátskych génov poskytujú nové náhľady na patogenézu atopickej dermatitídy. Nové genetické vysokocitlivé metódy génovej identifikácie ako „DNA microarrays“ a celogenómové genotypizovanie pomôžu ďalej analyzovať tieto poznatky, čo zlepší definíciu kriterií AD a povedie k cielenejšej liečbe.

Atopic dermatitis (AD) is a multifactorial disease. In its etiopathogenesis play role various factors including: genetic and environmental factors, metabolic and immunologic mechanisms and defect of epidermal barier. Genome screenings of families with AD have implicated chromosomal regions that overlap with other skin diseases and with inflammatory and autoimmune diseases. These, together with candidate gene studies, provide novel insights into the pathogenesis of AD. Recent genetic advances with high-throughput methods for gene identification, such as DNAmicroarrays and whole-genome genotyping, will help further dissect this complex trait. This will aid disease-defining criteria and more targeted therapies for AD.

• MeSH
• atopická dermatitida etiologie   genetika   MeSH
• bronchiální astma genetika   MeSH
• chemokin CCL11 genetika   MeSH
• chemokin CCL5 genetika   MeSH
• chymasy genetika   MeSH
• cytokininy genetika   klasifikace   MeSH
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• sezónní alergická rýma genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH

Matrix metalloproteinases (MMPs) is a family of proteolytic enzymes involved in remodeling of extracellular matrix. Although proteolytic enzymes are produced by many cell types, mast cells seem to be more important than other types in remodeling of pulmonary arteries during hypoxia. Therefore, we tested in vitro production of MMPs and serine proteases in four cell types (mast cells, fibroblasts, vascular smooth muscle cells and endothelial cells) cultivated for 48 h under normoxic or hypoxic (3 % O2) conditions. MMP-13 was visualized by immunohistochemistry, MMP-2 and MMP-9 were detected by zymography in cell lysates. Enzymatic activities (MMPs, tryptase and chymase) were estimated in the cultivation media. Hypoxia had a minimal effect on total MMP activity in the cultivation media of all types of cells, but immunofluorescence revealed higher intensity of MMP-13 in the cells exposed to hypoxia except of fibroblasts. Tryptase activity was three times higher and chymase activity twice higher in mast cells cultivated in hypoxia than in those cultured in normoxia. Among all cell types studied here, mast cells are the most abundant source of proteolytic enzymes under normoxic and hypoxic conditions. Moreover, in these cells hypoxia increases the production of both specific serine proteases tryptase and chymase, which can act as MMPs activators.

• MeSH
• arteria pulmonalis cytologie   MeSH
• buněčné linie MeSH
• chymasy metabolismus   MeSH
• endoteliální buňky cytologie   enzymologie   MeSH
• fibroblasty cytologie   enzymologie   MeSH
• financování organizované MeSH
• hypoxie metabolismus   MeSH
• krysa rodu rattus MeSH
• kyslík farmakologie   MeSH
• mastocytom MeSH
• mastocyty cytologie   enzymologie   MeSH
• matrixová metaloproteinasa 13 metabolismus   MeSH
• matrixová metaloproteinasa 2 metabolismus   MeSH
• matrixová metaloproteinasa 9 metabolismus   MeSH
• myocyty hladké svaloviny cytologie   enzymologie   MeSH
• myši MeSH
• potkani Wistar MeSH
• proteasy metabolismus   MeSH
• skot MeSH
• svaly hladké cévní cytologie   MeSH
• tryptasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• skot MeSH
• zvířata MeSH