Thyroid hormones (TH) are essential for vertebrate development, growth, and metabolism. The increasing prevalence of anthropogenic chemicals with TH-disrupting potential highlights the urgent need for advanced methods to assess their impact on TH homeostasis. Inhibition of the sodium-iodide symporter (NIS) has been identified as a key molecular initiating event disrupting the TH system across species, with significant relevance for diagnostic and therapeutic applications in various carcinomas. This study presents in vitro bioassays for evaluating the effects of compounds on iodide uptake into cells, a critical step in TH production mediated by NIS. Two novel stably transfected human cell lines overexpressing human NIS were employed along with a rat thyroid cell model FRTL-5, using colorimetric Sandell-Kolthoff (SK) reaction for iodide detection. The results from 23 model compounds demonstrate comparability across various in vitro models and radioactivity-based assays. To enhance physiological relevance, an external biotransformation system (BTS) was integrated and optimized for live-cell compatibility without inducing cytotoxicity or interfering with the assay. Compounds identified as NIS inhibitors were evaluated using the BTS-augmented assay, which revealed that metabolic activity mitigated the inhibitory effects of some chemicals. The augmented assay exhibited strong concordance with in vivo and in silico biotransformation data. Protein sequence alignment confirmed high conservation of NIS functional domains across vertebrates, reinforcing the cross-species applicability of the findings. The SK-based NIS assay, with optional BTS integration, represents a sensitive, robust, and high-throughput amendable alternative to radioactivity-based methods, for characterizing the impacts of individual compounds and complex environmental mixtures on TH homeostasis.

• Klíčová slova
• Biotransformation, NIS, Sandell–Kolthoff reaction, SeqAPASS, Thyroid hormone,
• MeSH
• biotest metody   MeSH
• biotransformace MeSH
• buněčné linie MeSH
• endokrinní disruptory * toxicita   MeSH
• hormony štítné žlázy metabolismus   MeSH
• jodidy * metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• štítná žláza metabolismus   účinky léků   cytologie   MeSH
• symportéry * antagonisté a inhibitory   metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endokrinní disruptory * MeSH
• hormony štítné žlázy MeSH
• jodidy * MeSH
• sodium-iodide symporter MeSH Prohlížeč
• symportéry * MeSH

Anthracycline anticancer agents, such as daunorubicin and doxorubicin, rank among the most effective and widely used anticancer drugs. However, their benefit is markedly reduced by the risk of severe cardiotoxicity. Anthracyclines undergo metabolic reduction of the side chain carbonyl group, producing hydroxy metabolites implicated in the cardiotoxicity. This study investigated toxicity, metabolism and cellular disposition of daunorubicin and its hydroxy metabolite, daunorubicinol, in isolated rat neonatal cardiomyocytes. Daunorubicin induced concentration-dependent cytotoxicity, whereas the toxicity of exogenously administered daunorubicinol was significantly lower despite induction of similar DNA damage. UHPLC-MS analyses revealed that daunorubicin rapidly penetrates cardiomyocytes and is metabolized to daunorubicinol, which is then released from the cells. The intracellular concentration of daunorubicinol was consistently lower than that of daunorubicin, indicating a reduced tendency for daunorubicinol to accumulate in cardiomyocytes. P-glycoprotein 1 has been shown to actively facilitate the efflux of both daunorubicin and daunorubicinol from cardiomyocytes. Dexrazoxane, the only approved agent for anthracycline cardiotoxicity prevention, did not affect the cellular metabolism or disposition of daunorubicin or its hydroxy metabolite, but it effectively reduced not only daunorubicin-induced cardiotoxicity, but also provided protection against the lower toxicity of daunorubicinol. Moreover, dexrazoxane reduced DNA damage induced by both daunorubicin and its hydroxy metabolite. These findings suggest that daunorubicin is the primary driver of cardiomyocyte cytotoxicity, while its hydroxy metabolite, daunorubicinol, plays a more limited role, challenging the notion that it serves as a significant toxic reservoir.

• Klíčová slova
• Anthracycline cardiotoxicity, DNA damage, Daunorubicin, Daunorubicinol, Dexrazoxane protection,
• Publikační typ
• časopisecké články MeSH

Organophosphorus compounds, including pesticides and nerve agents, irreversibly inhibit acetylcholinesterase, leading to an accumulation of acetylcholine that can cause a cholinergic crisis. Standard treatment of organophosphate poisoning relies on oxime-based reactivators, such as pralidoxime, obidoxime, or asoxime. However, these compounds have several limitations, including poor penetration through the blood-brain barrier and limited efficacy across a broad spectrum of organophosphorus compounds. For this reason, non-oxime reactivators were introduced as potential alternatives. The most promising non-oxime reactivators contain Mannich phenol moiety, imidazole group or combination of both. Some of the non-oxime derivatives demonstrated better efficacy than standard oximes during in vitro evaluation. Nevertheless, these structures have significant drawbacks such as high intrinsic acetylcholinesterase inhibition or high toxicity profile which make them unsuitable for further in vivo tests. In this review, the current progress in the development of non-oxime reactivators is summarized and their bioactivity as well as their limitations are critically discussed.

• Klíčová slova
• Acetylcholinesterase, Butyrylcholinesterase, Nerve agent, Non-oxime, Reactivator,
• Publikační typ
• časopisecké články MeSH

Recent events involving nerve agents of the A-Series, a once elusive class of chemical warfare agents, have provoked a great concern in the international community. In this paper, continuing our research efforts in Medicinal Chemistry at the Brazilian Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN) (an OPCW-designated Laboratory for environmental samples), we explore ANMP, an A-230 surrogate, in the search for new treatment options for intoxications caused by these chemicals. Five isatin-pyridine oxime hybrids were evaluated as acetylcholinesterase (AChE) reactivators using a modified Ellman's assay. Our results indicate that monocationic hybrids with five methylene units, as well as its oxa-analog, are promising compounds for the design of new AChE reactivators.

• Klíčová slova
• Acetylcholinesterase, Antidotes, Chemical Weapons Convention, Isatin hybrids, Nerve agents,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• chemické bojové látky * toxicita   chemie   MeSH
• cholinesterasové inhibitory * toxicita   chemie   MeSH
• isatin * chemie   farmakologie   analogy a deriváty   MeSH
• oximy * chemie   farmakologie   MeSH
• počítačová simulace MeSH
• pyridiny * chemie   farmakologie   MeSH
• reaktivátory cholinesterasy * farmakologie   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• chemické bojové látky * MeSH
• cholinesterasové inhibitory * MeSH
• isatin * MeSH
• oximy * MeSH
• pyridiny * MeSH
• reaktivátory cholinesterasy * 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.

• Klíčová slova
• 3T3-L1 cells, Adipocytes, Chlorinated paraffins, Persistent organic pollutants,
• MeSH
• buňky 3T3-L1 MeSH
• chlorované uhlovodíky * metabolismus   toxicita   MeSH
• halogenace MeSH
• látky znečišťující životní prostředí * metabolismus   toxicita   MeSH
• lipidy analýza   MeSH
• metabolismus lipidů * účinky léků   MeSH
• myši MeSH
• parafín * metabolismus   toxicita   chemie   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
• Názvy látek
• chlorované uhlovodíky * MeSH
• látky znečišťující životní prostředí * MeSH
• lipidy MeSH
• parafín * MeSH

Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.

• Klíčová slova
• Lipid metabolism, Liver, MASLD, Metabolism disrupting chemicals (MDCs), Nuclear receptors/PXR, Propiconazole,
• MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• inzulinová rezistence MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita * chemicky indukované   metabolismus   etiologie   MeSH
• pregnanový X receptor * metabolismus   genetika   MeSH
• průmyslové fungicidy * toxicita   aplikace a dávkování   MeSH
• triazoly * toxicita   aplikace a dávkování   MeSH
• triglyceridy krev   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• ztučnělá játra * chemicky indukované   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• pregnanový X receptor * MeSH
• propiconazole MeSH Prohlížeč
• průmyslové fungicidy * MeSH
• triazoly * MeSH
• triglyceridy MeSH

Heavy metals are naturally occurring components of the Earth's crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO·), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O2·-), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO-). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (Cd), arsenic (As), mercury (Hg), lead (Pb), and chromium (Cr) and their roles in the development of gastrointestinal, pulmonary, kidney, reproductive, neurodegenerative (Alzheimer's and Parkinson's diseases), cardiovascular, and cancer (e.g. renal, lung, skin, stomach) diseases are discussed. A short account is devoted to the detoxification of heavy metals by chelation via the use of ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propane sulfonic acid (DMPS), and penicillamine chelators.

• Klíčová slova
• Antioxidant enzymes, Heavy metals, Human disease, Oxidative stress, ROS, Toxicity,
• MeSH
• antioxidancia metabolismus   MeSH
• látky znečišťující životní prostředí * toxicita   farmakokinetika   MeSH
• lidé MeSH
• otrava těžkými kovy MeSH
• oxidační stres účinky léků   MeSH
• těžké kovy * toxicita   farmakokinetika   MeSH
• vystavení vlivu životního prostředí * škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia MeSH
• látky znečišťující životní prostředí * MeSH
• těžké kovy * MeSH

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

• Klíčová slova
• Antioxidant enzyme, Catalytic activity, Expression, Glutathione, Metabolic dysfunction-associated steatotic liver disease,
• MeSH
• antioxidancia * metabolismus   MeSH
• játra metabolismus   patologie   MeSH
• lidé MeSH
• oxidační stres účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ztučnělá játra * metabolismus   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia * MeSH
• reaktivní formy kyslíku MeSH

Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants.

• Klíčová slova
• Beta-cells, Diabetes, Insulin, Metabolic disease, TDCIPP, TPhP,
• MeSH
• beta-buňky * účinky léků   metabolismus   MeSH
• buněčné linie MeSH
• homeostáza * účinky léků   MeSH
• inzulin * metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• organofosfáty toxicita   MeSH
• organofosforové sloučeniny * toxicita   MeSH
• proinsulin metabolismus   MeSH
• retardanty hoření * toxicita   MeSH
• sekrece inzulinu účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inzulin * MeSH
• organofosfáty MeSH
• organofosforové sloučeniny * MeSH
• proinsulin MeSH
• retardanty hoření * MeSH
• triphenyl phosphate MeSH Prohlížeč
• tris(1,3-dichloro-2-propyl)phosphate MeSH Prohlížeč

The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.

• Klíčová slova
• A-230, Acetylcholinesterase, Antidotes, Chemical Weapons Convention, Nerve agent surrogates,
• MeSH
• acetylcholinesterasa * metabolismus   MeSH
• antidota farmakologie   MeSH
• chemické bojové látky * toxicita   MeSH
• cholinesterasové inhibitory * toxicita   MeSH
• nervová bojová látka * toxicita   MeSH
• organothiofosforové sloučeniny toxicita   MeSH
• oximy * farmakologie   MeSH
• pralidoximové sloučeniny farmakologie   MeSH
• pyridinové sloučeniny * farmakologie   MeSH
• reaktivátory cholinesterasy * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa * MeSH
• antidota MeSH
• chemické bojové látky * MeSH
• cholinesterasové inhibitory * MeSH
• nervová bojová látka * MeSH
• organothiofosforové sloučeniny MeSH
• oximy * MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• pyridinové sloučeniny * MeSH
• reaktivátory cholinesterasy * MeSH