Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.

• MeSH
• buňky A549 MeSH
• dioxiny toxicita   MeSH
• druhová specificita MeSH
• hlodavci MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• plíce účinky léků   metabolismus   patologie   MeSH
• potkani Sprague-Dawley MeSH
• testy akutní toxicity metody   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: The emergence and spread of antibiotic resistance among pathogenic bacteria drives the search for alternative antimicrobial therapies. Bacteriocins represent a potential alternative to antibiotic treatment. In contrast to antibiotics, bacteriocins are peptides or proteins that have relatively narrow spectra of antibacterial activities and are produced by a wide range of bacterial species. Bacteriocins of Escherichia coli are historically classified as microcins and colicins, and, until now, more than 30 different bacteriocin types have been identified and characterized. AREAS COVERED: We performed bibliographical searches of online databases to review the literature regarding bacteriocins produced by E. coli with respect to their occurrence, bacteriocin role in bacterial colonization and pathogenicity, and application of their antimicrobial effect. EXPERT OPINION: The potential use of bacteriocins for applications in human and animal medicine and the food industry includes (i) the use of bacteriocin-producing probiotic strains, (ii) recombinant production in plants and application in food, and (iii) application of purified bacteriocins.

• MeSH
• antibakteriální látky biosyntéza   izolace a purifikace   farmakologie   MeSH
• bakteriociny biosyntéza   izolace a purifikace   farmakologie   MeSH
• Escherichia coli metabolismus   MeSH
• koliciny biosyntéza   izolace a purifikace   farmakologie   MeSH
• lidé MeSH
• probiotika farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The neuroprotective effects of a newly developed oxime K203 and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with sarin were studied. The sarin-induced neurotoxicity was monitored using a functional observatory battery at 2 hr after sarin challenge. The results indicate that the potency of a novel bispyridinium oxime K203 to counteract sarin-induced neurotoxicity is relatively low and roughly corresponds to the neuroprotective efficacy of obidoxime. Among tested oximes, the oxime HI-6 seems to be significanlty more efficacious to counteract acute neurotoxicity of sarin than commonly used obidoxime and a newly developed oxime K203. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with sarin in comparison with the oxime HI-6 that should be considered to be the best oxime for antidotal treatment of acute sarin poisonings.

• MeSH
• antagonisté muskarinových receptorů terapeutické užití   MeSH
• antidota škodlivé účinky   terapeutické užití   MeSH
• atropin terapeutické užití   MeSH
• autonomní nervový systém účinky léků   patofyziologie   MeSH
• chemické bojové látky chemie   toxicita   MeSH
• cholinesterasové inhibitory chemie   toxicita   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• LD50 MeSH
• neurony účinky léků   MeSH
• neurotoxické syndromy farmakoterapie   patofyziologie   MeSH
• obidoxim chlorid škodlivé účinky   terapeutické užití   MeSH
• oximy škodlivé účinky   terapeutické užití   MeSH
• potkani Wistar MeSH
• psychomotorický výkon účinky léků   MeSH
• pyridinové sloučeniny škodlivé účinky   terapeutické užití   MeSH
• reaktivátory cholinesterasy škodlivé účinky   terapeutické užití   MeSH
• sarin antagonisté a inhibitory   toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika MeSH

Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine kinase-type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin and IGF-1 bind the noncognate receptor with substantially reduced affinity. We prepared [d-HisB24, GlyB31, TyrB32]-insulin, which binds all three receptors with high affinity (251 or 338% binding affinity to IR-A respectively to IR-B relative to insulin and 12.4% binding affinity to IGF-1R relative to IGF-1). We prepared other modified insulins with the aim of explaining the versatility of [d-HisB24, GlyB31, TyrB32]-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of [d-HisB24, GlyB31, TyrB32]-insulin to stimulate all three receptors is provided by structural changes caused by a reversed chirality at the B24 combined with the extension of the C terminus of the B chain by two extra residues. We assume that the structural changes allow the directing of the B chain C terminus to some extra interactions with the receptors. These unusual interactions lead to a decrease of dissociation rate from the IR and conversely enable easier association with IGF-1R. All of the structural changes were made at the hormones' Site 1, which is thought to interact with the Site 1 of the receptors. The results of the study suggest that merely modifications of Site 1 of the hormone are sufficient to change the receptor specificity of insulin.

• MeSH
• insulinu podobný růstový faktor I chemie   genetika   metabolismus   MeSH
• inzulin agonisté   metabolismus   MeSH
• kinetika MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• receptor inzulinu chemie   genetika   metabolismus   MeSH
• receptory somatomedinů chemie   genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Rhomboid intramembrane serine proteases have been implicated in several pathologies, and emerge as attractive pharmacological target candidates. The most potent and selective rhomboid inhibitors available to date are peptidyl α-ketoamides, but their selectivity for diverse rhomboid proteases and strategies to modulate it in relevant contexts are poorly understood. This gap, together with the lack of suitable in vitro models, hinders ketoamide development for relevant eukaryotic rhomboid enzymes. Here we explore the structure-activity relationship principles of rhomboid inhibiting ketoamides by medicinal chemistry and enzymatic in vitro and in-cell assays with recombinant rhomboid proteases GlpG, human mitochondrial rhomboid PARL and human RHBDL2. We use X-ray crystallography in lipidic cubic phase to understand the binding mode of one of the best ketoamide inhibitors synthesized here containing a branched terminal substituent bound to GlpG. In addition, to extend the interpretation of the co-crystal structure, we use quantum mechanical calculations and quantify the relative importance of interactions along the inhibitor molecule. These combined experimental analyses implicates that more extensive exploration of chemical space at the prime side is unexpectedly powerful for the selectivity of rhomboid inhibiting ketoamides. Together with variations in the peptide sequence at the non-prime side, or its non-peptidic alternatives, this strategy enables targeted tailoring of potent and selective ketoamides towards diverse rhomboid proteases including disease-relevant ones such as PARL and RHBDL2.

• MeSH
• amidy * chemie   farmakologie   chemická syntéza   MeSH
• inhibitory proteas farmakologie   chemie   chemická syntéza   metabolismus   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• hnací plyny analýza   MeSH
• látky znečišťující vzduch analýza   MeSH
• polycyklické aromatické uhlovodíky analýza   MeSH
• vysokoúčinná kapalinová chromatografie MeSH

BACKGROUND: Guidelines suggest that "upstream" P2Y12 receptor antagonists should be considered in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). HYPOTHESIS: Early use of ticagrelor in patients managed with an invasive strategy would be more effective than clopidogrel because of its more rapid onset of action and greater potency. METHODS: In the PLATO trial, 6792 NSTE-ACS patients were randomized to ticagrelor or clopidogrel (started prior to angiography) and underwent angiography within 72 hours of randomization. We compared efficacy and safety outcomes of ticagrelor vs clopidogrel as a function of "early" (<3h) vs "late" (≥3h) time to angiography. Adjusted Cox proportional hazards models evaluated interaction between randomized treatment and time from randomization to angiography on subsequent outcomes. RESULTS: Overall, a benefit of ticagrelor vs clopidogrel for cardiovascular death/myocardial infarction/stroke was seen at day 7 (hazard ratio [HR]: 0.67, P = 0.002), day 30 (HR: 0.81, P = 0.042), and 1 year (HR: 0.80, P = 0.0045). There were no significant interactions in the <3h vs ≥3h groups at any timepoint. For major bleeding, overall there was no significant increase (HR: 1.04, 95% confidence interval: 0.85-1.27); but there was a significant interaction with no difference between ticagrelor and clopidogrel in the early group (HR: 0.79), but higher bleeding risk with ticagrelor in the late angiography group, at 7 days (HR: 1.51, Pint = 0.002). Patterns were similar at 30 days and 1 year. CONCLUSIONS: The benefit of ticagrelor over clopidogrel was consistent in those undergoing early and late angiography, supporting upstream use of ticagrelor.

• MeSH
• adenosin aplikace a dávkování   analogy a deriváty   MeSH
• akutní koronární syndrom diagnóza   patofyziologie   terapie   MeSH
• antagonisté purinergních receptorů P2Y aplikace a dávkování   MeSH
• časové faktory MeSH
• dvojitá slepá metoda MeSH
• elektrokardiografie účinky léků   MeSH
• inhibitory agregace trombocytů aplikace a dávkování   MeSH
• koronární angiografie MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• revaskularizace myokardu * MeSH
• senioři MeSH
• tiklopidin aplikace a dávkování   analogy a deriváty   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: High-potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high-potency statins after acute coronary syndromes. METHODS AND RESULTS: The Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high-potency statin was defined as ≥40 mg atorvastatin, ≥20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high-potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high-potency statin. Selected patient factors associated with nonuse of high-potency statins included age ≥75 years (odds ratio 1.39, 95% CI 1.24-1.56), female sex (odds ratio 1.11, 95% CI 1.02-1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03-1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27-1.62). At 3 months after baseline, only 49% of patients had low-density lipoprotein cholesterol <70 mg/dL. Among the 5490 patients (59%) who were not on a high-potency statin at 3 months, lower low-density lipoprotein cholesterol was a predictor of nonuse of a high-potency statin after a median of 2.3 years (odds ratio 1.15 for 10 mg/dL decrease, 95% CI 1.11-1.19). CONCLUSION: Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high-potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01000727.

• MeSH
• akutní koronární syndrom farmakoterapie   MeSH
• atorvastatin aplikace a dávkování   MeSH
• benzaldehydy terapeutické užití   MeSH
• infarkt myokardu farmakoterapie   MeSH
• inhibitory fosfolipasy A2 terapeutické užití   MeSH
• lékařská praxe - způsoby provádění * MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• nestabilní angina pectoris farmakoterapie   MeSH
• odds ratio MeSH
• oximy terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• renální insuficience epidemiologie   MeSH
• rosuvastatin kalcium aplikace a dávkování   MeSH
• sekundární prevence MeSH
• senioři MeSH
• sexuální faktory MeSH
• simvastatin aplikace a dávkování   MeSH
• srdeční selhání epidemiologie   MeSH
• statiny aplikace a dávkování   MeSH
• věkové faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

This article deals with the issue of Relative Age Effect (RAE), which enables the exploration of differences and links between the expected and observed distribution of birth date of athletes based on their date of birth. It is expected that into the elite choice are chosen athletes, who were born in the beginning of the year. Therefore, athletes born in last months of year are disadvantaged. In this article, RAE was tes-ted by the means of chi-squared test in Goodness-of-fit test and Kolmogorov-Smirnov test. Afterwards, Cramer’s V was used for more accurate estimation of a potency of the association between expected and observed distribution. By the usage of methods previously mentioned it was found out that in selected sport clubs, the results of RAE are not statistically confirmed, however, different connections, which cannot be left unnoticed, were observed. In the conclusion, there is stated that even though it is not obvious on the fleeting glance, the junior category in more influenced by RAE than the senior category. This fact is as such affected also by the nature of shotgun shooting, it emphasizes overall physical condition and physique rather than separate physical and age details of a shooter.

• Klíčová slova
• střelba,
• MeSH
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• sportovci * statistika a číselné údaje   MeSH
• střelné zbraně MeSH
• věkové faktory * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Geografické názvy
• Česká republika MeSH