• Publikační typ
• abstrakt z konference MeSH

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as a result of natural cellular processes, intracellular signaling, or as adverse responses associated with diseases or exposure to oxidizing chemical and non-chemical stressors. The action of ROS and RNS, collectively referred to as reactive oxygen and nitrogen species (RONS), has recently become highly relevant in a number of adverse outcome pathways (AOPs) that capture, organize, evaluate and portray causal relationships pertinent to adversity or disease progression. RONS can potentially act as a key event (KE) in the cascade of responses leading to an adverse outcome (AO) within such AOPs, but are also known to modulate responses of events along the AOP continuum without being an AOP event itself. A substantial discussion has therefore been undertaken in a series of workshops named "Mystery or ROS" to elucidate the role of RONS in disease and adverse effects associated with exposure to stressors such as nanoparticles, chemical, and ionizing and non-ionizing radiation. This review introduces the background for RONS production, reflects on the direct and indirect effects of RONS, addresses the diversity of terminology used in different fields of research, and provides guidance for developing a harmonized approach for defining a common event terminology within the AOP developer community.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Antikoagulancia (hepariny, heparinoidy, ku mariny, přímé inhibitory trombinu a protid estičkové léky) patří k nejčastěji užívaným lékům. Všechny tyto léky mohou vyvolat reakce hypersenzitivity, které jsou založené na různých patogenetických mechanismech. Mezi nejvíce použ ívanou skupinu patří hepariny (nefrakcionované, ale i nízkomolekulární). Nejčastěji se vyskytujícími reakcemi jsou buňkami mediované reakce hy persenzitivity – kožní léze, avšak nejzávažnější reakci představuje heparinem indu kovaná trombocytopenie (HIT) s kožní manifestací heparinem i ndukované nekrózy. Příčinou této reakce je imunologická reakce II. typu podle Coombse a Gella, tj. tvorba protilátek ve třídě IgG proti k omplexu heparin – destičkový faktor 4 (PF4). Druhou nejčastěji používanou skupinou jsou kumariny (např. warfarin). Kumarinová nekróza není způs obena imunopatologickou reakcí, ale nedostatkem K vitamin-dependentních pr oteinů C a S. V článku jsou uvedeny možnosti diagnostiky a léčebné alternativy a naše zkušenosti s gravidními pacientkami s nežádoucími polékovými reakcemi po nízkomolekulárních (LMWH) heparinec h.

Anticoagulants (heparins, heparinoids, coumarins, direct trombin inhibitors, antiplatelet drugs) belong to the most widely used drugs. All of them may provoke hypersensitivity reactions based on various patogenetic pathways. The most used drugs are heparins (not only u nfractio- ned but also low molecular weight). The most common reactions in volve cell- mediated reactions hypersensitivity – skin lesions, but the most serious reaction is heparin necrosis as the cutaneous manifestation of the severe form of heparin induced trmobocytopenia (HIT) . The cause of HIT is II. type immunopathological reaction ie. production of IgG to complex heparin- platelet factor 4 (PF4). The next freq uently used are coumarins (warfarin). Coumarin necrosis is not based on immunopathological reactions, but on protein C and S deficiency. Diagno stic tools and treatment alternatives are disscused in this article. Our experience with pregnant women with adverse drug reactions to low -molecular weight heparins is mentioned.

• MeSH
• antikoagulancia imunologie   škodlivé účinky   terapeutické užití   MeSH
• embolie a trombóza diagnóza   farmakoterapie   MeSH
• eozinofilie farmakoterapie   prevence a kontrola   MeSH
• heparin nízkomolekulární škodlivé účinky   terapeutické užití   MeSH
• heparin škodlivé účinky   terapeutické užití   MeSH
• heparinoid škodlivé účinky   terapeutické užití   MeSH
• komplikace těhotenství farmakoterapie   imunologie   MeSH
• kumariny škodlivé účinky   terapeutické užití   MeSH
• léková alergie diagnóza   imunologie   MeSH
• lidé MeSH
• nekróza farmakoterapie   prevence a kontrola   MeSH
• trombocytopenie farmakoterapie   prevence a kontrola   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• přehledy MeSH

Mannose-binding lectin (MBL) is an important component of the innate immunity, and it is responsible not only for opsonization of micro-organisms, but also for efferocytosis. The aim of this study was to investigate whether MBL concentrations and lectin complement pathway activity are altered in non-pregnant women with previous adverse pregnancy outcomes. Patients were divided into four groups on the basis of their history of pregnancy complications, including control patients who had uncomplicated pregnancies and term deliveries (control, n = 33), and three groups of patients with a history of pregnancy complications, including preterm labour (n = 29), recurrent miscarriage (n = 19) or unexplained intrauterine foetal death (IUFD; n = 17). All women enrolled in the study had an interval of three to six months following their previous pregnancy, and they agreed to have a blood sample taken. We found significantly higher MBL concentrations and functional activity of the lectin complement pathway in healthy controls who had previous uneventful term pregnancies (1341 ng/mL; activity 100% (IQR: 62%-100%)), compared to women with the history of IUFD (684 ng/mL, P = .008; activity 8.5% (IQR: 0%-97.8%), P = .011), recurrent miscarriage (524 ng/mL, P = .022; activity 44% (IQR: 4%-83%), P = .011) or preterm labour (799 ng/mL, P = .022; activity 62.5% (IQR: 0%-83%), P = .003). Our results suggest that inadequate function of the complement lectin pathway is associated with a higher risk of preterm labour, recurrent miscarriage and unexplained intrauterine foetal death.

• MeSH
• dospělí MeSH
• komplikace těhotenství krev   epidemiologie   MeSH
• lektin vázající mannosu krev   MeSH
• lektinová dráha komplementu imunologie   MeSH
• lidé MeSH
• přirozená imunita imunologie   MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• těhotenství MeSH
• výsledek těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The presence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) is associated with adverse neonatal outcomes in pregnancies complicated by preterm prelabor rupture of membranes (pPROM). Therefore, there is an urgent need to identify new biomarkers revealing these conditions. The objective of this study is to identify possible biomarkers and their underlying biofunctions in pPROM pregnancies with and without MIAC and HCA. METHODS: A total of 72 women with pPROM were recruited. Only women with both MIAC and HCA (n = 19) and all women without these complications (n = 19) having the same range of gestational ages at sampling were included in the study. Samples of amniotic fluid were obtained by transabdominal amniocentesis, processed and analyzed using quantitative shotgun proteomics. Ingenuity pathway analysis was used to identify molecular networks that involve altered proteins. RESULTS: Network interaction identified by ingenuity pathway analysis revealed immunological disease and the inflammatory response as the top functions and disease associated with pPROM in the presence of MIAC and HCA. The proteins involved in these pathways were significantly altered between the groups with and without the presence of both MIAC and HCA. Proteins involved included histones H3, H4, H2B, cathelicidin antimicrobial peptide, myeloperoxidase, neutrophil gelatinase-associated lipocalin, matrix metalloproteinase-9, peptidoglycan recognition protein-1 and neutrophil defensin 1, all of which were found to be up-regulated in the presence of MIAC and HCA. CONCLUSION: Bioinformatic analysis of proteomics data allowed us to project likely biomolecular pathology resulting in pPROM complicated by MIAC and HCA. As inflammation is not a homogeneous phenomenon, we provide evidence for oxidative-stress-associated DNA damage and biomarkers of reactive oxygen species generation as factors associated with inflammation and proteolysis.

• MeSH
• biologické markery metabolismus   MeSH
• chorioamnionitida imunologie   metabolismus   MeSH
• dospělí MeSH
• histony metabolismus   MeSH
• kohortové studie MeSH
• lidé MeSH
• mediátory zánětu metabolismus   MeSH
• metabolické sítě a dráhy MeSH
• mladý dospělý MeSH
• novorozenec MeSH
• oxidační stres MeSH
• předčasný odtok plodové vody imunologie   metabolismus   MeSH
• proteomika MeSH
• studie případů a kontrol MeSH
• těhotenství MeSH
• výpočetní biologie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• biomedicínský výzkum MeSH
• cholelitiáza diagnóza   MeSH
• komplikace těhotenství diagnóza   MeSH
• těhotenství MeSH
• ultrazvuk diagnostické užití   MeSH
• Check Tag
• těhotenství MeSH

STUDY HYPOTHESIS: In women with preterm premature rupture of the membranes (PPROM), increased oxidative stress may accelerate premature cellular senescence, senescence-associated inflammation and proteolysis, which may predispose them to rupture. STUDY FINDING: We demonstrate mechanistic differences between preterm birth (PTB) and PPROM by revealing differences in fetal membrane redox status, oxidative stress-induced damage, distinct signaling pathways and senescence activation. WHAT IS KNOWN ALREADY: Oxidative stress-associated fetal membrane damage and cell cycle arrest determine adverse pregnancy outcomes, such as spontaneous PTB and PPROM. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Fetal membranes and amniotic fluid samples were collected from women with PTB and PPROM. Molecular, biochemical and histologic markers were used to document differences in oxidative stress and antioxidant enzyme status, DNA damage, secondary signaling activation by Ras-GTPase and mitogen-activated protein kinases, and activation of senescence between membranes from the two groups. MAIN RESULTS AND THE ROLE OF CHANCE: Oxidative stress was higher and antioxidant enzymes were lower in PPROM compared with PTB. PTB membranes had minimal DNA damage and showed activation of Ras-GTPase and ERK/JNK signaling pathway with minimal signs of senescence. PPROM had higher numbers of cells with DNA damage, prosenescence stress kinase (p38 MAPK) activation and signs of senescence. LIMITATIONS, REASONS FOR CAUTION: Samples were obtained retrospectively after delivery. The markers of senescence that we tested are specific but are not sufficient to confirm senescence as the pathology in PPROM. WIDER IMPLICATIONS OF THE FINDINGS: Oxidative stress-induced DNA damage and senescence are characteristics of fetal membranes from PPROM, compared with PTB with intact membranes. PTB and PPROM arise from distinct pathophysiologic pathways. Oxidative stress and oxidative stress-induced cellular damages are likely determinants of the mechanistic signaling pathways and phenotypic outcome. STUDY FUNDING AND COMPETING INTERESTS: This study is supported by developmental funds to Dr R. Menon from the Department of Obstetrics and Gynecology at The University of Texas Medical Branch at Galveston and funds to Dr M. Kacerovský from the Ministry of Health Czech Republic (UHHK, 001799906). The authors report no conflict of interest.

• MeSH
• dospělí MeSH
• extraembryonální obaly zranění   metabolismus   MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• lamin typ B genetika   metabolismus   MeSH
• lidé MeSH
• MAP kinasa-kinasa 4 genetika   metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 1 genetika   metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 3 genetika   metabolismus   MeSH
• mitogenem aktivované proteinkinasy p38 genetika   metabolismus   MeSH
• novorozenec nedonošený MeSH
• novorozenec MeSH
• oxidační stres genetika   MeSH
• poškození DNA MeSH
• předčasný odtok plodové vody genetika   metabolismus   patologie   MeSH
• předčasný porod MeSH
• regulace genové exprese MeSH
• signální transdukce genetika   MeSH
• stanovení celkové genové exprese MeSH
• stárnutí buněk MeSH
• superoxiddismutasa genetika   metabolismus   MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• diabetes mellitus 2. typu patofyziologie   MeSH
• dítě MeSH
• dospělí MeSH
• energetický metabolismus MeSH
• komplikace těhotenství metabolismus   MeSH
• mladiství MeSH
• nadměrná výživa MeSH
• obezita MeSH
• porucha glukózové tolerance MeSH
• selfmonitoring glykemie MeSH
• vývoj dítěte MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• mladiství MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• vnitřní lékařství

Humans are chronically exposed to the mycotoxins deoxynivalenol (DON) and fumonisin B1 (FB1), as indicated by their widespread presence in foods and occasional exposure in the workplace. This exposure is confirmed by human biomonitoring (HBM) studies on (metabolites of) these mycotoxins in human matrices. We evaluated the exposure-health relationship of the mycotoxins in humans by reviewing the available literature. Since human studies did not allow the identification of unequivocal chronic health effects upon exposure to DON and FB1, the adverse outcome pathway (AOP) framework was used to structure additional mechanistic evidence from in vitro and animal studies on the identified adverse effects. In addition to a preliminary AOP for DON resulting in the adverse outcome (AO) 'reduced body weight gain', we developed a more elaborated AOP for FB1, from the molecular initiating event (MIE) 'inhibition of ceramide synthases' leading to the AO 'neural tube defects'. The mechanistic evidence from AOPs can be used to support the limited evidence from human studies, to focus FB1- and DON-related research in humans to identify related early biomarkers of effect. In order to establish additional human exposure-health relationships in the future, recommendations are given to maximize the information that can be obtained from HBM.

• MeSH
• dráhy škodlivých účinků * MeSH
• fumonisiny * toxicita   MeSH
• lidé MeSH
• mykotoxiny * farmakologie   MeSH
• trichotheceny MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA.

• MeSH
• dráhy škodlivých účinků * MeSH
• hodnocení rizik metody   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH