Edibles are the only source of nutrients and energy for humans. However, ingredients of edibles have undergone many physicochemical changes during preparation and storage. Aging, hydrolysis, oxidation, and rancidity are some of the major changes that not only change the native flavor, texture, and taste of food but also destroy the nutritive value and jeopardize public health. The major reasons for the production of harmful metabolites, chemicals, and toxins are poor processing, inappropriate storage, and microbial spoilage, which are lethal to consumers. In addition, the emergence of new pollutants has intensified the need for advanced and rapid food analysis techniques to detect such toxins. The issue with the detection of toxins in food samples is the nonvolatile nature and absence of detectable chromophores; hence, normal conventional techniques need additional derivatization. Mass spectrometry (MS) offers high sensitivity, selectivity, and capability to handle complex mixtures, making it an ideal analytical technique for the identification and quantification of food toxins. Recent technological advancements, such as high-resolution MS and tandem mass spectrometry (MS/MS), have significantly improved sensitivity, enabling the detection of food toxins at ultralow levels. Moreover, the emergence of ambient ionization techniques has facilitated rapid in situ analysis of samples with lower time and resources. Despite numerous advantages, the widespread adoption of MS in routine food safety monitoring faces certain challenges such as instrument cost, complexity, data analysis, and standardization of methods. Nevertheless, the continuous advancements in MS-technology and its integration with complementary techniques hold promising prospects for revolutionizing food safety monitoring. This review discusses the application of MS in detecting various food toxins including mycotoxins, marine biotoxins, and plant-derived toxins. It also explores the implementation of untargeted approaches, such as metabolomics and proteomics, for the discovery of novel and emerging food toxins, enhancing our understanding of potential hazards in the food supply chain.

• MeSH
• analýza potravin MeSH
• lidé MeSH
• mořské toxiny MeSH
• mykotoxiny * MeSH
• referenční standardy MeSH
• tandemová hmotnostní spektrometrie * metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Oxime reactivators of acetylcholinesterase (AChE) are used as causal antidotes for intended and unintended poisoning by organophosphate nerve agents and pesticides. Despite all efforts to develop new AChE reactivators, none of these drug candidates replaced conventional clinically used oximes. In addition to the therapeutic efficacy, determining the safety profile is crucial in preclinical drug evaluation. The exact mechanism of oxime toxicity and the structure-toxicity relationship are subjects of ongoing research, with oxidative stress proposed as a possible mechanism. In the present study, we investigated four promising bispyridinium oxime AChE reactivators, K048, K074, K075, and K203, and their ability to induce oxidative stress in vitro. Cultured human hepatoma cells were exposed to oximes at concentrations corresponding to their IC50 values determined by the MTT assay after 24 h. Their potency to generate reactive oxygen species, interfere with the thiol antioxidant system, and induce lipid peroxidation was evaluated at 1, 4, and 24 h of exposure. Reactivators without a double bond in the four-carbon linker, K048 and K074, showed a greater potential to induce oxidative stress compared with K075 and K203, which contain a double bond. Unlike oximes with a three-carbon-long linker, the number of aldoxime groups attached to the pyridinium moieties does not determine the oxidative stress induction for K048, K074, K075, and K203 oximes. In conclusion, our results emphasize that the structure of oximes plays a critical role in inducing oxidative stress, and this relationship does not correlate with their cytotoxicity expressed as the IC50 value. However, it is important to note that oxidative stress cannot be disregarded as a potential contributor to the side effects associated with oximes.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• buňky Hep G2 MeSH
• cholinesterasové inhibitory toxicita   MeSH
• lidé MeSH
• organofosfáty toxicita   MeSH
• oxidační stres MeSH
• oximy farmakologie   chemie   MeSH
• pyridinové sloučeniny farmakologie   chemie   MeSH
• reaktivátory cholinesterázy * farmakologie   chemie   MeSH
• uhlík MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

In this work, we carried out neurochemical and behavioral analysis of zebrafish (Danio rerio) treated with rotenone, an agent used to chemically induce a syndrome resembling Parkinson's disease (PD). Dopamine release, measured with fast-scan cyclic voltammetry (FSCV) at carbon-fiber electrodes in acutely harvested whole brains, was about 30% of that found in controls. Uptake, represented by the first order rate constant (k) and the half-life (t1/2) determined by nonlinear regression modeling of the stimulated release plots, was also diminished. Behavioral analysis revealed that rotenone treatment increased the time required for zebrafish to reach a reward within a maze by more than 50% and caused fish to select the wrong pathway, suggesting that latent learning was impaired. Additionally, zebrafish treated with rotenone suffered from diminished locomotor activity, swimming shorter distances with lower mean velocity and acceleration. Thus, the neurochemical and behavioral approaches, as applied, were able to resolve rotenone-induced differences in key parameters. This approach may be effective for screening therapies in this and other models of neurodegeneration.

• MeSH
• dánio pruhované metabolismus   MeSH
• dopamin metabolismus   MeSH
• kognice MeSH
• modely nemocí na zvířatech MeSH
• Parkinsonova nemoc * MeSH
• rotenon * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Skin sensitization potential or potency is an important end point in the safety assessment of new chemicals and new chemical mixtures. Formerly, animal experiments such as the local lymph node assay (LLNA) were the main form of assessment. Today, however, the focus lies on the development of nonanimal testing approaches (i.e., in vitro and in chemico assays) and computational models. In this work, we investigate, based on publicly available LLNA data, the ability of aggregated, Mondrian conformal prediction classifiers to differentiate between non- sensitizing and sensitizing compounds as well as between two levels of skin sensitization potential (weak to moderate sensitizers, and strong to extreme sensitizers). The advantage of the conformal prediction framework over other modeling approaches is that it assigns compounds to activity classes only if a defined minimum level of confidence is reached for the individual predictions. This eliminates the need for applicability domain criteria that often are arbitrary in their nature and less flexible. Our new binary classifier, named Skin Doctor CP, differentiates nonsensitizers from sensitizers with a higher reliability-to-efficiency ratio than the corresponding nonconformal prediction workflow that we presented earlier. When tested on a set of 257 compounds at the significance levels of 0.10 and 0.30, the model reached an efficiency of 0.49 and 0.92, and an accuracy of 0.83 and 0.75, respectively. In addition, we developed a ternary classification workflow to differentiate nonsensitizers, weak to moderate sensitizers, and strong to extreme sensitizers. Although this model achieved satisfactory overall performance (accuracies of 0.90 and 0.73, and efficiencies of 0.42 and 0.90, at significance levels 0.10 and 0.30, respectively), it did not obtain satisfying class-wise results (at a significance level of 0.30, the validities obtained for nonsensitizers, weak to moderate sensitizers, and strong to extreme sensitizers were 0.70, 0.58, and 0.63, respectively). We argue that the model is, in consequence, unable to reliably identify strong to extreme sensitizers and suggest that other ternary models derived from the currently accessible LLNA data might suffer from the same problem. Skin Doctor CP is available via a public web service at https://nerdd.zbh.uni-hamburg.de/skinDoctorII/.

• MeSH
• databáze faktografické MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• kožní testy * MeSH
• kůže účinky léků   MeSH
• molekulární struktura MeSH
• myši MeSH
• organické látky chemie   farmakologie   MeSH
• test regionální lymfatické uzliny MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Predicting the structures of metabolites formed in humans can provide advantageous insights for the development of drugs and other compounds. Here we present GLORYx, which integrates machine learning-based site of metabolism (SoM) prediction with reaction rule sets to predict and rank the structures of metabolites that could potentially be formed by phase 1 and/or phase 2 metabolism. GLORYx extends the approach from our previously developed tool GLORY, which predicted metabolite structures for cytochrome P450-mediated metabolism only. A robust approach to ranking the predicted metabolites is attained by using the SoM probabilities predicted by the FAME 3 machine learning models to score the predicted metabolites. On a manually curated test data set containing both phase 1 and phase 2 metabolites, GLORYx achieves a recall of 77% and an area under the receiver operating characteristic curve (AUC) of 0.79. Separate analysis of performance on a large amount of freely available phase 1 and phase 2 metabolite data indicates that achieving a meaningful ranking of predicted metabolites is more difficult for phase 2 than for phase 1 metabolites. GLORYx is freely available as a web server at https://nerdd.zbh.uni-hamburg.de/ and is also provided as a software package upon request. The data sets as well as all the reaction rules from this work are also made freely available.

• MeSH
• biotransformace * MeSH
• lidé MeSH
• molekulární struktura MeSH
• strojové učení * MeSH
• testy toxicity * MeSH
• xenobiotika chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Oxime cholinesterase reactivators (oximes) are used to counteract organophosphate intoxication. Charged oximes are administered via intramuscular or intravenous injection when the majority of dose is unmetabolized and is excreted as urine. In this study, the effects of selected double charged oximes were determined in the HK-2 cell line as a model for renal toxicity screening. Some effects on dehydrogenase activity were found for obidoxime, asoxime (syn. HI-6), K027, and K203. The effects of K868 and K869 were found to be unreliable due to rapid degradation of both chlorinated oximes in the assay medium, resulting for K868 in an isoxazole-pyridinium product.

• MeSH
• buněčné linie MeSH
• ledviny účinky léků   metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• oximy aplikace a dávkování   škodlivé účinky   chemie   MeSH
• reaktivátory cholinesterázy aplikace a dávkování   škodlivé účinky   chemie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The plant extract aristolochic acid (AA), containing aristolochic acid I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy and Balkan endemic nephropathy, unique renal diseases associated with upper urothelial cancer. Differences in the metabolic activation and detoxification of AAI and AAII and their effects on the metabolism of AAI/AAII mixture in the plant extract might be of great importance for an individual's susceptibility in the development of AA-mediated nephropathies and malignancies. Here, we investigated in vivo metabolism of AAI and AAII after ip administration to Wistar rats as individual compounds and as AAI/AAII mixture using high performance liquid chromatography/electrospray ionization mass spectrometry. Experimental findings were supported by theoretical calculations using density functional theory. We found that exposure to AAI/AAII mixture affected the generation of their oxidative and reductive metabolites formed during Phase I biotransformation and excreted in rat urine. Several Phase II metabolites of AAI and AAII found in the urine of exposed rats were also analyzed. Our results indicate that AAI is more efficiently metabolized in rats in vivo than AAII. Whereas AAI is predominantly oxidized during in vivo metabolism, its reduction is the minor metabolic pathway. In contrast, AAII is mainly metabolized by reduction. The oxidative reaction only occurs if aristolactam II, the major reductive metabolite of AAII, is enzymatically hydroxylated, forming aristolactam Ia. In AAI/AAII mixture, the metabolism of AAI and AAII is influenced by the presence of both AAs. For instance, the reductive metabolism of AAI is increased in the presence of AAII while the presence of AAI decreased the reductive metabolism of AAII. These results suggest that increased bioactivation of AAI in the presence of AAII also leads to increased AAI genotoxicity, which may critically impact AAI-mediated carcinogenesis. Future studies are needed to explain the underlying mechanism(s) for this phenomenon.

• MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• injekce intraperitoneální MeSH
• krysa rodu rattus MeSH
• kyseliny aristolochové aplikace a dávkování   metabolismus   moč   MeSH
• potkani Wistar MeSH
• teorie funkcionálu hustoty MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Arsenic is one of the inorganic pollutants typically found in natural waters, and its toxic effects on the human body are currently of great concern. For this reason, the search for detoxifying agents that can be used in a so-called "chelation therapy" is of primary importance. However, to the aim of finding the thermodynamic behavior of efficient chelating agents, extensive speciation studies, capable of reproducing physiological conditions in terms of pH, temperature, and ionic strength, are in order. Here, we report on the acid-base properties of meso-2,3-dimercaptosuccinic acid (DMSA) at different temperatures (i.e., T = 288.15, 298.15, 310.15, and 318.15 K). In particular, its capability to interact with As(III) has been investigated by experimentally evaluating some crucial thermodynamic parameters (ΔH and TΔS), stability constants, and its speciation model. Additionally, in order to gather information on the microscopic coordination modalities of As(III) with the functional groups of DMSA and, at the same time, to better interpret the experimental results, a series of state-of-the-art ab initio molecular dynamics simulations have been performed. For the sake of completeness, the sequestering capabilities of DMSA-a simple dithiol ligand-toward As(III) are directly compared with those recently emerged from similar analyses reported on monothiol ligands.

• MeSH
• arsen chemie   izolace a purifikace   MeSH
• chelátory chemie   MeSH
• koncentrace vodíkových iontů MeSH
• kyselina dimerkaptojantarová chemie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• simulace molekulární dynamiky MeSH
• tělesné tekutiny chemie   MeSH
• termodynamika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Salicylaldehyde isonicotinoyl hydrazone (SIH) is a small molecule and lipophilic chelating agent that firmly binds ferric ions from the cellular labile iron pool and is able to protect various tissues against oxidative damage. Previously, SIH possessed the best ratio of cytoprotective efficiency to toxicity among various iron chelators, including the desferrioxamine, deferiprone, and deferasirox used in clinical practice. Here, we prepared a series of 2,6-dihydroxybenzaldehyde aroylhydrazones as SIH analogues with an additional hydroxyl group that can be involved in the chelation of metal ions. Compound JK-31 (2,6-dihydroxybenzaldehyde 4-chlorobenzohydrazone) showed the best cytoprotective efficiency among the studied compounds including SIH. This compound significantly protected H9c2 cardiomyoblast cells against oxidative stress induced by various pro-oxidants, such as hydrogen peroxide, tert-butyl hydroperoxide, paraquat, epinephrine, N-acetyl- p-benzoquinone imine (a toxic metabolite of paracetamol), and 6-hydroxydopamine. The exceptional cytoprotective activity of JK-31 was confirmed using epifluorescence microscopy, where JK-31-treated H9c2 cells maintained a higher mitochondrial inner membrane potential in the presence of a lethal dose of hydrogen peroxide than was observed with cells treated with SIH. Hence, this study demonstrates the deleterious role of free iron ions in oxidative injury and the potential of 2,6-dihydroxybenzaldehyde aroylhydrazones in the prevention of various types of cardiac injuries, highlighting the need for further investigations into these compounds.

• MeSH
• aldehydy chemie   farmakologie   MeSH
• benzaldehydy chemie   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• hydrazony chemie   farmakologie   MeSH
• hydrolýza MeSH
• kardiomyocyty cytologie   účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• ochranné látky chemie   farmakologie   MeSH
• oxidační stres * účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• stabilita léku MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mosquito-borne diseases (including malaria) belong among the leading causes of death in humans. Vector control is a crucial part of the global strategy for management of mosquito-associated diseases, when insecticide use is the most important component in this effort. However, drug and insecticide resistance threaten the successes made with existing methods. Reduction or elimination of malaria is not possible without effective mosquito control. This article reviews current strategies of intervention in vector control to decrease transmission of disease and covers current relevant knowledge in molecular biology, biochemistry, and medicinal chemistry.

• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• Anopheles parazitologie   MeSH
• insekticidy chemie   farmakologie   MeSH
• komáří přenašeči účinky léků   MeSH
• lidé MeSH
• malárie parazitologie   patologie   MeSH
• racionální návrh léčiv MeSH
• rezistence k insekticidům * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH