Bacterial β sliding clamp (β-clamp) is an emerging drug target currently lacking small-molecule inhibitors with good in vivo activity. Thus, there is a need for fast and simple screening methods for identifying inhibitor candidates. Here we demonstrate the use of nuclear magnetic resonance spectroscopy (NMR) for evaluating compound binding to the E. coli β-clamp. To identify suitable molecular probes, a series of tetrahydrocarbazoles were synthesized, some of which contain fluorine. Key challenges in the synthesis were formation of regioisomers during the Fischer indole reaction and reducing racemization at the stereogenic center. The tetrahydrocarbazoles were assayed against the E. coli β-clamp by saturation-transfer difference (STD) NMR, waterLOGSY and T1ρ. Analysis by isothermal titration calorimetry gave KD-values of 1.7-14 μM for three fluorinated probe candidates, and NMR chemical shift perturbation experiments confirmed these molecules to directly interact with the β-clamp binding pocket. Binding of the fluorinated molecules to β-clamp was easily observed with 19F-observed T2-based binding experiments, and proof of concept for a fluorine-based binding assay for E. coli β-clamp binders is provided.

• MeSH
• Escherichia coli * účinky léků   MeSH
• halogenace MeSH
• karbazoly * chemie   chemická syntéza   farmakologie   metabolismus   MeSH
• magnetická rezonanční spektroskopie * MeSH
• molekulární sondy chemie   chemická syntéza   metabolismus   MeSH
• molekulární struktura MeSH
• proteiny z Escherichia coli metabolismus   antagonisté a inhibitory   chemie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH

Chlorinated paraffins (CPs) are environmental pollutants extensively used in industries. While the use of short-chain chlorinated paraffins (SCCPs) has been restricted since 2017, the use of medium-chain chlorinated paraffins (MCCPs) has risen as their replacement. Due to lipophilic character, it can be expected that CPs enter the cells; however, the in vitro accumulation potential of CPs remains poorly understood. In this study, we aimed to explore the ability of SCCPs and MCCPs to accumulate in fat cells. We utilized an in vitro model of mouse 3T3-L1 preadipocytes and adipocytes. Using gas chromatography coupled with high-resolution mass spectrometry operated in negative chemical ionization mode, we determined the intracellular amounts of CPs. These compounds accumulated at rates of 8.5 ± 0.1 μg/gcells/h for SCCPs and 7.8 ± 0.3 μg/gcells/h for MCCPs when an initial concentration of 120 ng/ml was present in the medium. This rate increased approximately tenfold when the concentration of CPs was raised to 1200 ng/ml. CPs content in adipocytes steadily increased over 5 days, whereas preadipocytes accumulated 15-20 times less CPs. This highlights the importance of cellular lipid content, which was about 12 times higher in adipocytes. Furthermore, we found that the level of chlorine content in the CPs molecules significantly influenced their accumulation. Our results demonstrate that MCCPs exhibit a similar accumulation potential to SCCPs, with lipid content playing a crucial role. As with SCCPs, restrictions on the use of MCCPs in industry should be considered to mitigate their environmental and health impacts.

• MeSH
• buňky 3T3-L1 * MeSH
• chlorované uhlovodíky * metabolismus   toxicita   MeSH
• halogenace * MeSH
• látky znečišťující životní prostředí toxicita   metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• myši MeSH
• parafín * MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• tukové buňky * metabolismus   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.

• MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• halogenace MeSH
• indoly * chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• receptory aromatických uhlovodíků * metabolismus   chemie   MeSH
• simulace molekulového dockingu * MeSH
• transkripční faktory bHLH MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Electronic waste (e-waste) poses significant environmental and health risks in Thailand due to both domestic production and international imports. A notable portion of this waste is processed in small-scale, community-based workshops, often located in poorer regions, where safety regulations are improperly enforced or entirely ignored. This study focuses on the Kalasin province in Northern Thailand, a region with numerous such workshops, where no comprehensive analysis of exposure to polybrominated diphenyl ethers (PBDEs) and dechlorane plus (DP) has been conducted. The study's objective was to quantify these toxic substances in environmental and biological samples to assess its contamination and human health risks. Environmental samples, including soil, dust, sediment, ash, eggs, crabs, snails, fish, and rice, were collected from e-waste processing sites and compared with control areas. Blood samples from e-waste workers and a control group were also analysed. Gas chromatography coupled with mass spectrometry operated in negative ion chemical ionization (GC-NCI-MS) was used to quantify PBDEs and DP isomers. Results showed significantly higher concentrations of these toxic compounds in e-waste sites compared to control areas. E-waste workers also had elevated levels of these substances in their blood, suggesting exposure through contaminated dust and food. These findings underscore the severe environmental contamination and health risks associated with improper e-waste management, highlighting the urgent need for regulatory measures and improved recycling practices to safeguard both environmental and public health.

• MeSH
• chlorované uhlovodíky * analýza   krev   MeSH
• elektronický odpad * analýza   MeSH
• halogenované difenylethery * analýza   toxicita   krev   MeSH
• hodnocení rizik MeSH
• látky znečišťující životní prostředí analýza   krev   MeSH
• lidé MeSH
• monitorování životního prostředí metody   MeSH
• polycyklické sloučeniny * analýza   MeSH
• prach analýza   MeSH
• pracovní expozice analýza   MeSH
• recyklace * MeSH
• vystavení vlivu životního prostředí škodlivé účinky   analýza   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Thajsko MeSH

Magnetic resonance imaging (MRI) relies on appropriate contrast agents, especially for visualizing transplanted cells within host tissue. In recent years, compounds containing fluorine-19 have gained significant attention as MRI probe, particularly in dual 1H/19F-MR imaging. However, various factors affecting probe sensitivity, such as fluorine content and the equivalency of fluorine atoms, must be considered. In this study, we synthesized fluorinated micelles with adjustable surface positive charge density and investigated their physicochemical properties and MRI efficacy in phantoms and labeled cells. While the micelles exhibited clear signals in 19F-MR spectra and imaging, the concentrations required for MRI visualization of labeled cells were relatively high, adversely affecting cell viability. Despite their favourable physicochemical properties, achieving higher labeling rates without compromising cell viability during labeling remains a challenge for potential in vivo applications.

• MeSH
• barvení a značení metody   MeSH
• fantomy radiodiagnostické MeSH
• fluor chemie   MeSH
• halogenace MeSH
• kationty * chemie   MeSH
• kontrastní látky chemie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• micely * MeSH
• myši MeSH
• viabilita buněk * účinky léků   MeSH
• zobrazování fluorovou magnetickou rezonancí metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Theranostics is a novel paradigm integrating therapy and diagnostics, thereby providing new prospects for overcoming the limitations of traditional treatments. In this context, perfluorocarbons (PFCs) are the most widely used tracers in preclinical fluorine-19 magnetic resonance (19F MR), primarily for their high fluorine content. However, PFCs are extremely hydrophobic, and their solutions often display reduced biocompatibility, relative instability, and subpar 19F MR relaxation times. This study aims to explore the potential of micellar 19F MR imaging (MRI) tracers, synthesized by polymerization-induced self-assembly (PISA), as alternative theranostic agents for simultaneous imaging and release of the non-steroidal antileprotic drug clofazimine. In vitro, under physiological conditions, these micelles demonstrate sustained drug release. In vivo, throughout the drug release process, they provide a highly specific and sensitive 19F MRI signal. Even after extended exposure, these fluoropolymer tracers show biocompatibility, as confirmed by the histological analysis. Moreover, the characteristics of these polymers can be broadly adjusted by design to meet the wide range of criteria for preclinical and clinical settings. Therefore, micellar 19F MRI tracers display physicochemical properties suitable for in vivo imaging, such as relaxation times and non-toxicity, and high performance as drug carriers, highlighting their potential as both diagnostic and therapeutic tools.

• MeSH
• biokompatibilní materiály chemie   MeSH
• fluor chemie   MeSH
• fluorokarbony chemie   MeSH
• halogenace MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• micely MeSH
• myši MeSH
• nanočástice * chemie   terapeutické užití   MeSH
• teranostická nanomedicína * MeSH
• zobrazování fluorovou magnetickou rezonancí * metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Many legacy and emerging flame retardants (FRs) have adverse human and environmental health effects. This study reports legacy and emerging FRs in children from nine European countries from the HBM4EU aligned studies. Studies from Belgium, Czech Republic, Germany, Denmark, France, Greece, Slovenia, Slovakia, and Norway conducted between 2014 and 2021 provided data on FRs in blood and urine from 2136 children. All samples were collected and analyzed in alignment with the HBM4EU protocols. Ten halogenated FRs were quantified in blood, and four organophosphate flame retardants (OPFR) metabolites quantified in urine. Hexabromocyclododecane (HBCDD) and decabromodiphenyl ethane (DBDPE) were infrequently detected (<16% of samples). BDE-47 was quantified in blood from Greece, France, and Norway, with France (0.36 ng/g lipid) having the highest concentrations. BDE-153 and -209 were detected in <40% of samples. Dechlorane Plus (DP) was quantified in blood from four countries, with notably high median concentrations of 16 ng/g lipid in Slovenian children. OPFR metabolites had a higher detection frequency than other halogenated FRs. Diphenyl phosphate (DPHP) was quantified in 99% of samples across 8 countries at levels ∼5 times higher than other OPFR metabolites (highest median in Slovenia of 2.43 ng/g lipid). FR concentrations were associated with lifestyle factors such as cleaning frequency, employment status of the father of the household, and renovation status of the house, among others. The concentrations of BDE-47 in children from this study were similar to or lower than FRs found in adult matrices in previous studies, suggesting lower recent exposure and effectiveness of PBDE restrictions.

• MeSH
• dítě MeSH
• dospělí MeSH
• halogenované difenylethery MeSH
• lidé MeSH
• lipidy MeSH
• retardanty hoření * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Evropa MeSH

We performed a mixture risk assessment (MRA) case study of dietary exposure to the food contaminants lead, methylmercury, inorganic arsenic (iAs), fluoride, non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs), all substances associated with declines in cognitive abilities measured as IQ loss. Most of these chemicals are frequently measured in human biomonitoring studies. A component-based, personalised modified reference point index (mRPI) approach, in which we expressed the exposures and potencies of our chosen substances as lead equivalent values, was applied to perform a MRA for dietary exposures. We conducted the assessment for four different age groups (toddlers, children, adolescents, and women aged 18-45 years) in nine European countries. Populations in all countries considered exceeded combined tolerable levels at median exposure levels. NDL-PCBs in fish, other seafood and dairy, lead in grains and fruits, methylmercury in fish and other seafoods, and fluoride in water contributed most to the combined exposure. We identified uncertainties for the likelihood of co-exposure, assessment group membership, endpoint-specific reference values (ESRVs) based on epidemiological (lead, methylmercury, iAs, fluoride and NDL-PCBs) and animal data (PBDE), and exposure data. Those uncertainties lead to a complex pattern of under- and overestimations, which would require probabilistic modelling based on expert knowledge elicitation for integration of the identified uncertainties into an overall uncertainty estimate. In addition, the identified uncertainties could be used to refine future MRA for cognitive decline.

• MeSH
• arsen * MeSH
• dioxiny * MeSH
• fluoridy MeSH
• halogenované difenylethery MeSH
• lidé MeSH
• methylortuťné sloučeniny * MeSH
• mladiství MeSH
• olovo MeSH
• polybrombifenylové sloučeniny * MeSH
• polychlorované bifenyly * MeSH
• polychlorované dibenzodioxiny * MeSH
• rtuť * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants in building materials, electronics, furnishings, vehicles, airplanes, plastics, polyurethane foams, and textiles for many years. Currently, the primary commercial mixtures, penta-, octa-, and deca-BDE, are globally restricted. Still, products containing PBDEs are expected to impact waste management and the environment for many years. In January 2016, an open fire in the Santa Marta landfill close to Santiago de Chile affected the city and surroundings. The fire caused several acute health effects and an increase in emergency hospitalizations. We measured PBDE levels in the areas affected by the fire in the air (gaseous and particulate) and soil, and PBDE emissions were estimated using a dispersion model. The results showed an increase in PBDE concentrations by a factor of 2-4 one day after the start of the fire. However, PBDE concentrations measured after the fire in PM10 and the gas phase were considered low compared to other regions. Interestingly, PBDEs' patterns differed across the sites; however, BDE209 was the dominant congener for all environmental matrices. A preliminary risk assessment was conducted using the daily exposure dose (DED) by air inhalation estimation. The results showed low DED values for adults and children and suggested no direct health risk due to PBDE exposure. This study brings new data useful for future solid waste management initiatives in the country.

• MeSH
• dítě MeSH
• dospělí MeSH
• halogenované difenylethery * analýza   MeSH
• hodnocení rizik MeSH
• lidé MeSH
• monitorování životního prostředí metody   MeSH
• retardanty hoření * analýza   MeSH
• skládková zařízení MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Chile MeSH

The greatest threat and medicinal impact within gram-positive pathogens are posed by two bacterial genera, Staphylococcus and Enterococcus. Chalcones have a wide range of biological activities and are recognized as effective templates in medicinal chemistry. This study provides comprehensive insight into the anti-staphylococcal and anti-enterococcal activities of two recently published brominated and chlorinated pyrazine-based chalcones, CH-0y and CH-0w. Their effects against 4 reference and 12 staphylococcal and enterococcal clinical isolates were evaluated. Bactericidal action, the activity in combination with selected conventional antibiotics, the study of post-antimicrobial effect (PAE, PAE/SME), and in vitro and in vivo toxicity, were included. In CH-0y, anti-staphylococcal activity ranging from MIC = 15.625 to 62.5 μM, and activity against E. faecium from 31.25 to 62.5 μM was determined. In CH-0w, anti-staphylococcal activity ranging from 31.25 to 125 μM, and activity against E. faecium and E. faecalis (62.5 μM) was revealed. Both CH-0y and CH-0w showed bactericidal action, beneficial impact on bacterial growth delay within PAE and PAE/SME studies, and non/low toxicity in vivo. Compared to CH-0w, CH-0y seems to have higher anti-staphylococcal and less toxic potential. In conclusion, chalcones CH-0y and CH-0w could be considered as structural pattern for future adjuvants to selected antibiotic drugs.

• Publikační typ
• časopisecké články MeSH