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Honeybees are important insects, both economically and as pollinators. While foraging, bees can come in contact with environmental pollutants such as pesticides, possibly in combination with other xenobiotic compounds that may compromise bee health. Our current study investigated the acute exposure to nanosized titanium dioxide, a common additive in food, cosmetics, paints and agricultural products, along with deltamethrin (DLT), a well‐known pyrethroid pesticide. The effects of binary exposure to titanium dioxide nanoparticles (TiO2‐NPs) nanoparticles at concentrations of 25, 50, 75 and 100 μg/mL with DLT were noted on Apis mellifera brain histology along with their possible synergism. In DLT‐ and combined TiO2‐NP‐DLT treated bees, survival rates were lowered and several histological alterations were observed including an increased number of cells with pyknotic nuclei, along with cytoplasmic vacuolization, chromatin compaction and degeneration indicating autophagic activity and a decrease in the cross‐sectional area of nanoparticle‐treated mushroom body calyces. A synergistic relationship between TiO2‐NPs and DLT was revealed, while LD50 for combined TiO2‐NP‐DLT treatment was 0.101, 0.09 and 0.02 μg/bee at 24, 48 and 72 h, respectively. In summary, results demonstrate that TiO2‐NP and DLT co‐exposure can induce damage in bee brain structures at higher concentrations, which indicates an additional risk factor for bee health in the field. [ABSTRACT FROM AUTHOR]

Urban soil and water contamination by xenobiotics is an increasing hazard to ecosystem health and human well-being. Xenobiotics including synthetic chemicals and contaminants from industrial, agricultural, and urban activities are renowned for accumulating in the environment. As urbanization expands, the detrimental impacts of xenobiotics on ecosystems and public health will intensify, making it more necessary than ever to learn about and implement appropriate remediation methods. This review article is focused on diverse categories of xenobiotics, their health impacts, and a range of xenobiotic removal methods from urban soils and water sources. We also explored extensive literature based on established and novel technological and natural approaches, spanning the physical, chemical, and biological sciences. Physicochemical methods including soil cleaning, electrokinetics, and adsorption may decontaminate xenobiotic-contaminated sites. Bioremediation using bacteria and plants degrades and detoxifies several xenobiotics. Advanced oxidation methods can also degrade persistent water pollutants very effectively. Nanoremediation, phytoremediation, and microbial-assisted remediation are some of the emerging technologies that effectively remove persistent pollutants and preserve ecological balance. Nature-based solutions like artificial wetlands and biofiltration can lessen xenobiotic impacts and sustainably increase urban ecosystem services. These methods have been tested in several urban locations. We also explored the hybrid approaches for the removal of xenobiotics and secondary pollution. A combination of techniques may be effective for efficient cleanup thereby promoting sustainable cleanup solutions for urban expansion and safeguarding the environment and residents from emerging contaminants. [ABSTRACT FROM AUTHOR]

For successful management of pollution problems, the use of bacteria is now a popular and widespread technique. Alcaligenes faecalis, an inhabitant of the natural environment, is equipped with machinery for cleaning up different types of contaminants, including heavy metals and xenobiotics. A. faecalis, a gram‐negative, flagellated, nonfermentive, aerobic member of the subgroup proteobacteria, often shows anaerobic respiration using nitrate or nitrite as terminal electron acceptors. It is also gifted with the power of nitrogen fixation and thereby could be used as a biofertilizer. The bacterium also has the unique ability to act as a probiotic and can often be used as a biocontrol agent due to its antimicrobial properties. Hence, for sustainable management of the environment, various strains of this bacterium as active bio‐remediators, bio‐pesticides, biofertilizers, and probiotics are being increasingly applied. [ABSTRACT FROM AUTHOR]

AbstractCytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20–30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics.Cytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20–30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics. [ABSTRACT FROM AUTHOR]

enviPath is a widely used database and prediction system for microbial biotransformation pathways of primarily xenobiotic compounds. Data and prediction system are freely available both via a web interface and a public REST API. Since its initial release in 2016, we extended the data available in enviPath and improved the performance of the prediction system and usability of the overall system. We now provide three diverse data sets, covering microbial biotransformation in different environments and under different experimental conditions. This also enabled developing a pathway prediction model that is applicable to a more diverse set of chemicals. In the prediction engine, we implemented a new evaluation tailored towards pathway prediction, which returns a more honest and holistic view on the performance. We also implemented a novel applicability domain algorithm, which allows the user to estimate how well the model will perform on their data. Finally, we improved the implementation to speed up the overall system and provide new functionality via a plugin system. Scientific contribution: The main scientific contributions are the development of a pathway prediction model applicable to diverse chemicals, a specialized evaluation method for holistic performance assessment, and a novel applicability domain algorithm for user-specific performance estimation. The introduction of two new data sets, and the creation of links to EC classes make enviPath a unique resource in microbial biotransformation research. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) have become internationally recognized over the past three decades as persistent organic pollutants used in the production of various consumer and industrial goods. Research efforts continue to gauge the risk that historically used, and newly produced, PFAS may cause to human health. Numerous studies report toxic effects of PFAS on the human liver as well as increased serum cholesterol levels in adults. A major concern with PFAS, also dubbed "forever chemicals," is that they accumulate in the liver and kidney and persist in serum. The mechanisms responsible for their disposition and excretion in humans are poorly understood. A better understanding of the interaction of PFAS with liver transporters, as it pertains to the disposition of PFAS and other xenobiotics, could provide mechanistic insight into human health effects and guide efforts toward risk assessment of compounds in development. This review summarizes the current state of the literature on the emerging relationships (eg, substrates, inhibitors, modulators of gene expression) between PFAS and specific hepatic transporters. The adaptive and toxicological responses of hepatocytes to PFAS that reveal linkages to pathologies and epidemiological findings are highlighted. The evidence suggests that our understanding of the molecular landscape of PFAS must improve to determine their impact on the expression and function of hepatocyte transporters that play a key role in PFAS or other xenobiotic disposition. From here, we can assess what role these changes may have in documented human health outcomes. [ABSTRACT FROM AUTHOR]

The microsomal metabolism of phenol (11 °C) over an annual reproductive cycle from June to December was studied using fall spawning adult brook trout (Salvelinus fontinalis). Hepatic microsomes were isolated from three male and three female fish each month. Incubations were optimized for time, cofactor concentration, pH, and microsomal protein concentration. The formation of phase I ring-hydroxylation metabolites, i.e., hydroquinone (HQ) and catechol (CAT), was quantified by HPLC with dual-channel electrochemical detection. Sample preparation and chromatographic conditions were optimized to achieve the separation and sensitivity required for the analysis of these labile products. Biotransformation of phenol over a range of substrate concentrations (1 to 150 mM) was quantified for the calculation of Michaelis–Menten constants (Km and Vmax) for each month. Results indicate a nearly equal production of HQ and CAT among males and females in late June. At the peak of maturity in October, there was an approximate ten-fold greater production of ring-hydroxylation metabolites noted in females in comparison with males on a total liver basis. In vitro phase II biotransformation of phenol glucuronidation was assessed by determining the Michaelis–Menten constants (Km, Vmax) using brook trout hepatic microsomes over a range of substrate concentrations (1 to 60 mM). Initially, there were no significant differences in the glucuronide rate of formation (pmol/min/mg protein) or total capacity (nmol/min/liver) between females and males. At the peak of maturation, the maximum rate of glucuronide formation was 4-fold less in females; however, the total capacity was 2-fold less in females due to the increased liver size in the females. The alterations in biotransformation coincided with increases in the hepatic and gonadal somatic indices and with changes in plasma hormone concentrations. These experiments provide insight into the metabolic deactivation of xenobiotics and to provide data for the prediction of altered hepatic biotransformation rates and pathways during the reproductive cycle. [ABSTRACT FROM AUTHOR]

Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes. While pharmacogenetics and pharmacogenomics have long been considered the primary causes of such heterogeneous responses, pharmacomicrobiomics has recently gained attention. The microbiome, a community of microorganisms living in or on the human body, is a critical determinant of drug response and toxicity. Factors such as diet, lifestyle, exposure to xenobiotics, antibiotics use, illness, and genetics can influence the composition of the microbiota. Changes in the intestinal microbiota are particularly influential in drug responsiveness, especially in cancer chemotherapy. The microbiota can modulate an individual's response to a drug, affecting its bioavailability, clinical effect, and toxicity, affecting treatment outcomes and patient quality of life. For instance, the microbiota can convert drugs into active or toxic metabolites, influencing their efficacy and side effects. Alternatively, chemotherapy can also alter the microbiota, creating a bidirectional interplay. Probiotics have shown promise in modulating the microbiome and ameliorating chemotherapy side effects, highlighting the potential for microbiota-targeted interventions in improving cancer treatment outcomes. This opinion paper addresses how environmental factors and chemotherapy-induced dysbiosis impact cancer chemotherapy gastrointestinal toxicity. [ABSTRACT FROM AUTHOR]

One method of crop protection is the application of a widely used group of pesticides—pyrethroids. As xenobiotics, sub-lethal doses of insecticides cause stress in pests, resulting in a change in the shape and size of their organs or bodies. The stress caused by pesticides may lead to acute destabilization of development, but also to transgenerational canalization through the process of genetic assimilation. Fluctuating asymmetry (FA), small random deviations between the right and left sides of bilaterally symmetrical traits, is an outcome of developmental instability and is a measurable indicator of phenotypic response to stress. We exposed four populations of the seed beetle Acanthoscelides obtectus to sub-lethal doses of cypermethrin for ten generations in a laboratory evolution experiment. Using geometric morphometrics, we analyzed size and shape changes and the level of fluctuating asymmetry in untreated beetles and in samples from the fifth and tenth generation. Exposure over ten generations led to an increase in the body size of the beetles, shortening of their pronotum and elongation of their thorax and abdomen. After ten generations of exposure to cypermethrin, FA levels decreased, indicating a canalization of development. This study provides new insights into the phenotypic markers of environmental pollution from agricultural activities. [ABSTRACT FROM AUTHOR]

Cytochrome P450 enzymes are a superfamily of enzymes responsible for the metabolism of a variety of medicines and xenobiotics. Among the Cytochrome P450 family, five isozymes that include 1A2, 2C9, 2C19, 2D6, and 3A4 are most important for the metabolism of xenobiotics. Inhibition of any of these five CYP isozymes causes drug-drug interactions with high pharmacological and toxicological effects. So, the inhibition or non-inhibition prediction of these isozymes is of great importance. Many techniques based on machine learning and deep learning algorithms are currently being used to predict whether these isozymes will be inhibited or not. In this study, three different molecular or substructural properties that include Morgan, MACCS and Morgan (combined) and RDKit of the various molecules are used to train a distinct SVM model against each isozyme (1A2, 2C9, 2C19, 2D6, and 3A4). On the independent dataset, Morgan fingerprints provided the best results, while MACCS and Morgan (combined) achieved comparable results in terms of balanced accuracy (BA), sensitivity (Sn), and Mathews correlation coefficient (MCC). For the Morgan fingerprints, balanced accuracies (BA), Mathews correlation coefficients (MCC), and sensitivities (Sn) against each CYPs isozyme, 1A2, 2C9, 2C19, 2D6, and 3A4 on an independent dataset ranged between 0.81 and 0.85, 0.61 and 0.70, 0.72 and 0.83, respectively. Similarly, on the independent dataset, MACCS and Morgan (combined) fingerprints achieved competitive results in terms of balanced accuracies (BA), Mathews correlation coefficients (MCC), and sensitivities (Sn) against each CYPs isozyme, 1A2, 2C9, 2C19, 2D6, and 3A4, which ranged between 0.79 and 0.85, 0.59 and 0.69, 0.69 and 0.82, respectively. [ABSTRACT FROM AUTHOR]

Humans are exposed to a cocktail of food-related and environmental contaminants, potentially contributing to the etiology of chronic diseases. Better characterizing the "exposome" is a challenging task and requires broad human biomonitoring (HBM). Veterinary drugs (VDs)/antibiotics, widely used and regulated in food and animal production, however, are typically not yet included in exposomics workflows. Therefore, in this work, a previously established multianalyte liquid chromatography-tandem mass spectrometry (LC-MS/MS) method covering >80 diverse xenobiotics was expanded by >40 VDs/antibiotics and pesticides. It was investigated if the generic workflow allowed for the successful integration of a high number of new analytes in a proof-of-principle study. The expanded method was successfully in-house validated and specificity, matrix effects, linearity, intra- and inter-day precision, accuracy, limits of quantification, and detection were evaluated. The optimized method demonstrated satisfactory recovery (81–120%) for most of the added analytes with acceptable RSDs (<20%) at three spiking levels. The majority of VDs/antibiotics and pesticides (69%) showed matrix effects within a range of 50–140%. Moreover, sensitivity was excellent with median LODs and LOQs of 0.10 ng/mL and 0.31 ng/mL, respectively. In total, the expanded method can be used to detect and quantify more than 120 highly diverse analytes in a single analytical run. To the best of the authors' knowledge, this work represents the first targeted biomonitoring method integrating VDs with various other classes of pollutants including plasticizers, PFAS, bisphenols, mycotoxins, and personal care products. It demonstrates the potential to expand targeted multianalyte methods towards additional groups of potentially toxic chemicals. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications The ATP‐dependent biliary efflux transporter ABCC2, also known as multidrug resistance protein 2 (MRP2), is essential for the cellular disposition and detoxification of various xenobiotics including drugs as well as endogenous metabolites. Common functionally relevant ABCC2 genetic variants significantly alter drug responses and contribute to side effects. The aim of this study was to determine functional consequences of rare variants identified in subjects with European ancestry using in silico tools and in vitro analyses.Targeted next‐generation sequencing of the ABCC2 gene was used to identify novel variants in European subjects (n = 143). Twenty‐six in silico tools were used to predict functional consequences. For biological validation, transport assays were carried out with membrane vesicles prepared from cell lines overexpressing the newly identified ABCC2 variants and estradiol β‐glucuronide and carboxydichlorofluorescein as the substrates.Three novel rare ABCC2 missense variants were identified (W227R, K402T, V489F). Twenty‐five in silico tools predicted W227R as damaging and one as potentially damaging. Prediction of functional consequences was not possible for K402T and V489F and for the common linked variants V1188E/C1515Y. Characterisation in vitro showed increased function of W227R, V489F and V1188E/C1515Y for both substrates, whereas K402T function was only increased for carboxydichlorofluorescein.In silico tools were unable to accurately predict the substrate‐dependent increase in function of ABCC2 missense variants. In vitro biological studies are required to accurately determine functional activity to avoid misleading consequences for drug therapy. [ABSTRACT FROM AUTHOR]

Microplastics generated from diverse categories of plastic wastes primarily accumulate in terrestrial ecosystems and subsequently find their way to aquatic ecosystems. As the use of plastic goods has been increasing globally during the last few decades, it is likely that the amount of microplastics too would increase significantly and get accumulated in the soil. An increased level of microplastics might have deleterious effects on soil properties and microbiota. Microplastics being small (< 5 mm), could be easily consumed by pedophagous soil fauna such as earthworms and get dispersed widely in soil and might even reach the groundwater table. It has been reported that microplastics such as polyvinyl chloride, polypropylene etc., can bind to toxic compounds, including pesticides and transfer these into the gut of earthworms, adversely impacting their growth, ecological functions, and reproduction. It is apprehended that earthworms and other soil fauna could accelerate the degradation of microplastics into nano forms which could enhance environmental risk not only for these animals but also for other beneficial soil biotas. [ABSTRACT FROM AUTHOR]

The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol‐reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38MAPK, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE‐induced activation of FOXO‐dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling. [ABSTRACT FROM AUTHOR]

Background Phthalates are additives used as plasticizers among other uses, classified as endocrine disruptors and may contribute to some metabolic disorders. The aim of this work was to determine the effect of the exposure of diethyl phthalate (DEP) and dibutyl phthalate (DBP) on cell viability and reactive oxygen species (ROS) production, as well as the regulation of sirloins in HepG2 cells. Methods HepG2 cells were exposed to DEP or DBP at 0.1, 1, 10 and 100 μg/mL, and after 48 or 72 h the gene and protein expression of sirtuins was quantified by qRT-PCR and Western-Blot, respectively. Results Results showed that even at a low concentration of 0.1 μg/mL DEP affected the expression of Sirt3 and Sirt4, whereas DBP at 0.1 μg/mL affected Sirt3 and Sirt5 gene expression. Protein analysis showed a reduction in Sirt1 levels at a DEP concentration of 1 μg/mL and higher, while DBP at higher dose (100 μg/mL) decreased Sirt3 protein levels. Cell viability decreased by 20% only at higher dose (100 μg/mL) and ROS production increased at 10 and 100 μg/mL for both phthalates. Conclusion These findings indicate that exposure to low concentrations (0.1 μg/mL) of DEP or DBP can negatively influence the expression of some sirtuins. [ABSTRACT FROM AUTHOR]

The vast majority of gastric cancer (GC) cases are adenocarcinomas including intestinal and diffuse GC. The incidence of diffuse GC, often associated with poor overall survival, has constantly increased in Western countries. Epidemiological studies have reported increased mortality from GC after occupational exposure to pro-carcinogens that are metabolically activated by cytochrome P450 enzymes through aryl hydrocarbon receptor (AhR). However, little is known about the role of AhR and environmental AhR ligands in diffuse GC as compared to intestinal GC in Western patients. In a cohort of 29, we demonstrated a significant increase in AhR protein and mRNA expression levels in GCs independently of their subtypes and clinical parameters. AhR and RHOA mRNA expression were correlated in diffuse GC. Further, our study aimed to characterize in GC how AhR and the AhR-related genes cytochrome P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) affect the mRNA expression of a panel of genes involved in cancer development and progression. In diffuse GC, CYP1A1 expression correlated with genes involved in IGF signaling, epithelial–mesenchymal transition (Vimentin), and migration (MMP2). Using the poorly differentiated KATO III epithelial cell line, two well-known AhR pollutant ligands, namely 2-3-7-8 tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (BaP), strongly increased the expression of CYP1A1 and Interleukin1β (IL1B), and to a lesser extend UGT1, NQO1, and AhR Repressor (AhRR). Moreover, the increased expression of CYP1B1 was seen in diffuse GC, and IHC staining indicated that CYP1B1 is mainly expressed in stromal cells. TCDD treatment increased CYP1B1 expression in KATO III cells, although at lower levels as compared to CYP1A1. In intestinal GC, CYP1B1 expression is inversely correlated with several cancer-related genes such as IDO1, a gene involved in the early steps of tryptophan metabolism that contributes to the endogenous AhR ligand kynurenine expression. Altogether, our data provide evidence for a major role of AhR in GC, as an environmental xenobiotic receptor, through different mechanisms and pathways in diffuse and intestinal GC. Our results support the continued efforts to clarify the identity of exogenous AhR ligands in diffuse GC in order to define new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: The genus Geobacillus and its associated taxa have been the focal point of numerous thermophilic biotechnological investigations, both at the whole cell and enzyme level. By contrast, comparatively little research has been done on its recently delineated sister genus, Parageobacillus. Here we performed pan-genomic analyses on a subset of publicly available Parageobacillus and Saccharococcus genomes to elucidate their biotechnological potential. Results: Phylogenomic analysis delineated the compared taxa into two distinct genera, Parageobacillus and Saccharococcus, with P. caldoxylosilyticus isolates clustering with S. thermophilus in the latter genus. Both genera present open pan-genomes, with the species P. toebii being characterized with the highest novel gene accrual. Diversification of the two genera is driven through the variable presence of plasmids, bacteriophages and transposable elements. Both genera present a range of potentially biotechnologically relevant features, including a source of novel antimicrobials, thermostable enzymes including DNA-active enzymes, carbohydrate active enzymes, proteases, lipases and carboxylesterases. Furthermore, they present a number of metabolic pathways pertinent to degradation of complex hydrocarbons and xenobiotics and for green energy production. Conclusions: Comparative genomic analyses of Parageobacillus and Saccharococcus suggest that taxa in both of these genera can serve as a rich source of biotechnologically and industrially relevant secondary metabolites, thermostable enzymes and metabolic pathways that warrant further investigation. [ABSTRACT FROM AUTHOR]

Summary: Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway in Saccharomyces cerevisiae results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar morphology and drug detoxification. The drug potentiation mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies. The PCA pathway, essential for synthesizing CoA and AcCoA from vitamin B5, plays a crucial role in fungal cellular processes. Targeting this pathway could enhance antifungal drug efficacy by affecting vacuolar morphology and drug detoxification. [ABSTRACT FROM AUTHOR]

Simple Summary: Substances that are absent in the biosphere, but have been synthesized by humans in recent decades, are called xenobiotics. They are released into the environment in large volumes and can actively affect invertebrates and their intestinal parasites or commensals. Such an influence of xenobiotics on parasite–host relationships remained poorly studied until recently. In this article, the host–parasite system "larva of Tenebrio molitor—Gregarina polymorpha" under the influence of 24 organic compounds is investigated. We found that several substances increase the mortality of T. molitor larvae, and substances such as diphenyl ether, benzyl alcohol, catechol, and 3-aminobenzoic acid, on the contrary, reduce the number of parasites (G. polymorpha) without significantly affecting host insects (larva of T. molitor). Thus, various xenobiotics can destroy the parasite–host relationship, having a greater effect on the host in some cases and on the parasite in other cases. Environmental contamination with xenobiotics affects organisms and the symbiotic relations between them. A convenient object to study relationships between parasites and their hosts is the host–parasite system "Tenebrio molitor Linnaeus, 1758 (Coleoptera, Tenebrionidae)—Gregarina polymorpha (Hammerschmidt, 1838) Stein, 1848 (Eugregarinorida, Gregarinidae)". For this experiment, we took 390 T. molitor larvae and 24 organic compounds. Groups of mealworms, 15 in each, were subjected to those compounds for 10 days. Then, we recorded the vitality of both the larvae of T. molitor and G. polymorpha. To assess how G. polymorpha had affected the hosts' wellbeing, we looked for changes in the larvae's body mass and compared them to the number of gregarines in their intestines. The vitality of the larvae was inhibited by cyclopentanol and 2-naphthol. The intensity of gregarine invasion was reduced by diphenyl ether, benzyl alcohol, catechol, and 3-aminobenzoic acid. No effect on the number of gregarines was produced by 3,4,5-trihydroxybenzoic acid, cyclohexanemethanol, phenol, benzalkonium chloride, maleic anhydride, cyclohexanol, resorcin, benzoic acid, 2-methylfuran, terpinen-4-ol, 1-phenylethylamine, dibutyl phthalate, 3-furancarboxylic acid, 5-methyl furfural, 6-aminohexanoic acid, succinic anhydride, o-xylene, and benzaldehyde. In the infected T. molitor individuals, the mean number of G. polymorpha equaled 45 specimens per host. The groups of smaller mealworms had fewer gregarines. Positive correlation was seen between growth rates of T. molitor larvae and the intensity of invasion by gregarines. [ABSTRACT FROM AUTHOR]

Flavin‐containing monooxygenases (FMOs), traditionally known for detoxifying xenobiotics, are now recognized for their involvement in endogenous metabolism. We recently discovered that an isoform of FMO, fmo‐2 in Caenorhabditis elegans, alters endogenous metabolism to impact longevity and stress tolerance. Increased expression of fmo‐2 in C. elegans modifies the flux through the key pathway known as One Carbon Metabolism (OCM). This modified flux results in a decrease in the ratio of S‐adenosyl‐methionine (SAM) to S‐adenosyl‐homocysteine (SAH), consequently diminishing methylation capacity. Here we discuss how FMO‐2‐mediated formate production during tryptophan metabolism may serve as a trigger for changing the flux in OCM. We suggest formate bridges tryptophan and OCM, altering metabolic flux away from methylation during fmo‐2 overexpression. Additionally, we highlight how these metabolic results intersect with the mTOR and AMPK pathways, in addition to mitochondrial metabolism. In conclusion, the goal of this essay is to bring attention to the central role of FMO enzymes but lack of understanding of their mechanisms. We justify a call for a deeper understanding of FMO enzyme's role in metabolic rewiring through tryptophan/formate or other yet unidentified substrates. Additionally, we emphasize the identification of novel drugs and microbes to induce FMO activity and extend lifespan. [ABSTRACT FROM AUTHOR]

Benzene is used worldwide as a major raw material in a number of industrial processes and also a potent airborne pollutant emitted from traffic exhaust fume. The present systematic review aimed to identify potential associations between genetic polymorphisms and occupational benzene-induced genotoxicity. For this purpose, a total of 22 selected studies were carefully analysed. Our results revealed a positive relation between gene polymorphism and genotoxicity in individuals exposed to benzene, since 17 studies (out of 22) observed positive relations between genotoxicity and polymorphisms in xenobiotics metabolizing genes influencing, therefore, individuals' susceptibility to genomic damage induced by benzene. In other words, individuals with some genotypes may show increase or decrease DNA damage and/or higher or lower DNA-repair potential. As for the quality assessment, 17 studies (out of 22) were categorized as Strong or Moderate and, therefore, we consider our findings to be trustworthy. Taken together, such findings are consistent with the notion that benzene induces genotoxicity in mammalian cells being strongly dependent on the genetic polymorphism. Certainly, such findings are important for clarifying the role of biomarkers related to genotoxicity in human biomonitoring studies. [ABSTRACT FROM AUTHOR]

This study focuses on the comparative metabolic profiling and effects of two steroid types: natural and synthetic, specifically 17α-methyl testosterone (17α-MT) at varying concentrations (1.5, 2, and 3 mg/kg) in rainbow trout (Oncorhynchus mykiss). Over a 75-day feeding trial, growth metrics, such as feed efficiency, daily specific growth, live weight gain, total weight gain, and survival rate were systematically monitored every 15 days. At the end of the feeding trial, histopathology, immunohistochemistry, and metabolome analyses were performed in the high-concentration groups (3 mg/kg natural and 3 mg/kg synthetic), in which the lowest survival rate was determined. Key findings reveal that the type of hormone significantly influences growth parameters. While some natural steroids enhanced certain growth aspects, synthetic variants often yielded better results. The metabolomic analysis highlighted significant shifts in the metabolism of tryptophan, purine, folate, primary bile acids, phosphonates, phosphinates, and xenobiotics via cytochrome P450 pathways. Histopathologically, the natural hormone groups showed similar testicular, hepatic, muscular, gill, cerebral, renal, and intestinal tissue structures to the control, with minor DNA damage and apoptosis observed through immunohistochemistry. Conversely, the synthetic hormone groups exhibited moderate DNA damage and mild degenerative and necrotic changes in histopathology. [ABSTRACT FROM AUTHOR]

Cytosolic sulfotransferases (SULTs) are Phase 2 drug-metabolizing enzymes that catalyze the conjugation of sulfonate to endogenous and xenobiotic compounds, increasing their hydrophilicity and excretion from cells. To date, 13 human SULTs have been identified and classified into five families. SULT4A1 mRNA encodes two variants: (1) the wild type, encoding a 284 amino acid, ~33 kDa protein, and (2) an alternative spliced variant resulting from a 126 bp insert between exon 6 and 7, which introduces a premature stop codon that enhances nonsense-mediated decay. SULT4A1 is classified as an SULT based on sequence and structural similarities, including PAPS-domains, active-site His, and the dimerization domain; however, the catalytic pocket lid 'Loop 3' size is not conserved. SULT4A1 is uniquely expressed in the brain and localized in the cytosol and mitochondria. SULT4A1 is highly conserved, with rare intronic polymorphisms that have no outward manifestations. However, the SULT4A1 haplotype is correlated with Phelan–McDermid syndrome and schizophrenia. SULT4A1 knockdown revealed potential SULT4A1 functions in photoreceptor signaling and knockout mice display hampered neuronal development and behavior. Mouse and yeast models revealed that SULT4A1 protects the mitochondria from endogenously and exogenously induced oxidative stress and stimulates cell division, promoting dendritic spines' formation and synaptic transmission. To date, no physiological enzymatic activity has been associated with SULT4A1. [ABSTRACT FROM AUTHOR]

Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized. Supplementary Material Supplementary Material File [ABSTRACT FROM AUTHOR]

Insects are the most diverse form of life, and as such, they interact closely with humans, impacting our health, economy, and agriculture. Beneficial insect species contribute to pollination, biological control of pests, decomposition, and nutrient cycling. Pest species can cause damage to agricultural crops and vector diseases to humans and livestock. Insects are often exposed to toxic xenobiotics in the environment, both naturally occurring toxins like plant secondary metabolites and synthetic chemicals like herbicides, fungicides, and insecticides. Because of this, insects have evolved several mechanisms of resistance to toxic xenobiotics, including sequestration, behavioral avoidance, and enzymatic degradation, and in many cases had developed symbiotic relationships with microbes that can aid in this detoxification. As research progresses, the important roles of these microbes in insect health and function have become more apparent. Bacterial symbionts that degrade plant phytotoxins allow host insects to feed on otherwise chemically defended plants. They can also confer pesticide resistance to their hosts, especially in frequently treated agricultural fields. It is important to study these interactions between insects and the toxic chemicals they are exposed to in order to further the understanding of pest insect resistance and to mitigate the negative effect of pesticides on nontarget insect species like Hymenopteran pollinators.

The work porpose was to conduct biotesting for the presence of antibiotics in several lakes of the Akmola region, located in the zone of possible ingress of antimicrobial drugs into them. Research method: the modified disk diffusion method to determine the microorganisms’ sensitivity to the used antibiotics. As a result of the study, sensitivity to antibiotics remained in the main control lakes. Antibiotics that have not been found to be resistant to microorganisms in lakes: enronite, furagin, cefuroxime, cefoperazone, amikacin. The most common resistance of microorganisms 90-100% was in antibiotics -benzylpenicillin, kanamycin, streptomycin, tylosin, trimethoprim/sulfamethoxazole, metronidazole, amikacin, spectinomycin.

OATP1B facilitates the uptake of xenobiotics into hepatocytes and is a prominent target for drug–drug interactions (DDIs). Reduced systemic exposure of OATP1B substrates has been reported following multiple‐dose rifampicin; one explanation for this observation is OATP1B induction. Non‐uniform hepatic distribution of OATP1B may impact local rifampicin tissue concentrations and rifampicin‐mediated protein induction, which may affect the accuracy of transporter‐ and/or metabolizing enzyme‐mediated DDI predictions. We incorporated quantitative zonal OATP1B distribution data from immunofluorescence imaging into a PBPK modeling framework to explore rifampicin interactions with OATP1B and CYP substrates. PBPK models were developed for rifampicin, two OATP1B substrates, pravastatin and repaglinide (also metabolized by CYP2C8/CYP3A4), and the CYP3A probe, midazolam. Simulated hepatic uptake of pravastatin and repaglinide increased from the periportal to the pericentral region (approximately 2.1‐fold), consistent with OATP1B distribution data. Simulated rifampicin unbound intracellular concentrations increased in the pericentral region (1.64‐fold) compared to simulations with uniformly distributed OATP1B. The absolute average fold error of the rifampicin PBPK model for predicting substrate maximal concentration (Cmax) and area under the plasma concentration–time curve (AUC) ratios was 1.41 and 1.54, respectively (nine studies). In conclusion, hepatic OATP1B distribution has a considerable impact on simulated zonal substrate uptake clearance values and simulated intracellular perpetrator concentrations, which regulate transporter and metabolic DDIs. Additionally, accounting for rifampicin‐mediated OATP1B induction in parallel with inhibition improved model predictions. This study provides novel insight into the effect of hepatic OATP1B distribution on site‐specific DDI predictions and the impact of accounting for zonal transporter distributions within PBPK models. [ABSTRACT FROM AUTHOR]

The pregnane X receptor (PXR) is a nuclear hormone receptor that plays a pivotal role in regulating gene expression in response to various ligands, particularly xenobiotics. In this context, the aim of this study was to shed light on the ligand affinity and functions of four NR1J1 paralogs identified in the marine mussel Mytilus galloprovincialis, employing a dual-luciferase reporter assay. To achieve this, the activation patterns of these paralogs in response to various toxins, including freshwater cyanotoxins (Anatoxin-a, Cylindrospermopsin, and Microcystin-LR, -RR, and -YR) and marine algal toxins (Nodularin, Saxitoxin, and Tetrodotoxin), alongside natural compounds (Saint John's Wort, Ursolic Acid, and 8-Methoxypsoralene) and microalgal extracts (Tetraselmis, Isochrysis, LEGE 95046, and LEGE 91351 extracts), were studied. The investigation revealed nuanced differences in paralog response patterns, highlighting the remarkable sensitivity of MgaNR1J1γ and MgaNR1J1δ paralogs to several toxins. In conclusion, this study sheds light on the intricate mechanisms of xenobiotic metabolism and detoxification, particularly focusing on the role of marine mussel NR1J1 in responding to a diverse array of compounds. Furthermore, comparative analysis with human PXR revealed potential species-specific adaptations in detoxification mechanisms, suggesting evolutionary implications. These findings deepen our understanding of PXR-mediated metabolism mechanisms, offering insights into environmental monitoring and evolutionary biology research. [ABSTRACT FROM AUTHOR]

AbstractThe herbicide triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) is already considered an environmental problem due to damage caused by incorrect disposal, leaching, and aerial dispersion, which may pose risks to the environment and human health. Studies have evaluated metabolism, absorption, excretion, and active transport but there is no clear information about its mode of action (MoA) and its cytotoxic action potential remains unknown. In this context, mitochondria have been used to assess the toxicity of xenobiotics, for this reason, to identify the toxic mechanism of triclopyr, hepatic mitochondria from Wistar rats were exposed in vitro to different concentrations of triclopyr (0.5–500 µM). There was neither formation/accumulation of reactive oxygen and nitrogen species, nor lipid peroxidation or changes in the mitochondrial antioxidant system, in addition to proper functioning of oxidative phosphorylation and ATP production. Changes were found in NAD(P)H oxidation, membrane potential dissipation and mitochondrial calcium gradient. These results demonstrate that mitochondria suffer damage related to their bioenergetics and redox status but not to their structure when exposed to concentrations of triclopyr considered higher than those described as found in the environment so far.HighlightsTriclopyr has a low mitochondrial uncoupling potential.The damage caused to the bioenergetics and redox state of the mitochondria is related to concentrations considered higher than those found in the environment.Even at high concentrations, triclopyr was not able to change the structure of the organelle after exposure.Oxidative phosphorylation and ATP production were not impaired after exposure.NAD(P)H oxidation resulted in potential membrane dissipation and mitochondrial calcium gradient dissipation.Triclopyr does not have RONS-forming properties, as well as it does not peroxide membrane lipids, it preserves membrane sulfhydryl groups and maintains the normality of the GSH/GSSG ratio.Triclopyr has a low mitochondrial uncoupling potential.The damage caused to the bioenergetics and redox state of the mitochondria is related to concentrations considered higher than those found in the environment.Even at high concentrations, triclopyr was not able to change the structure of the organelle after exposure.Oxidative phosphorylation and ATP production were not impaired after exposure.NAD(P)H oxidation resulted in potential membrane dissipation and mitochondrial calcium gradient dissipation.Triclopyr does not have RONS-forming properties, as well as it does not peroxide membrane lipids, it preserves membrane sulfhydryl groups and maintains the normality of the GSH/GSSG ratio. [ABSTRACT FROM AUTHOR]

Background: The recent exponential increase in legalized medical and recreational cannabis, development of medical cannabis programs, and production of unregulated over-the-counter products (e.g., cannabidiol (CBD) oil, and delta-8-tetrahydrocannabinol (delta-8-THC)), has the potential to create unintended health consequences. The major cannabinoids (delta-9- tetrahydrocannabinol and cannabidiol) are metabolized by the same cytochrome P450 (CYP) enzymes that metabolize most prescription medications and xenobiotics (CYP3A4, CYP2C9, CYP2C19). As a result, we predict that there will be instances of drug-drug interactions and the potential for adverse outcomes, especially for prescription medications with a narrow therapeutic index. Methods: We conducted a systematic review of all years to 2023 to identify real world reports of documented cannabinoid interactions with prescription medications. We limited our search to a set list of medications with predicted narrow therapeutic indices that may produce unintended adverse drug reactions (ADRs). Our team screened 4,600 reports and selected 151 full-text articles to assess for inclusion and exclusion criteria. Results: Our investigation revealed 31 reports for which cannabinoids altered pharmacokinetics and/or produced adverse events. These reports involved 16 different Narrow Therapeutic Index (NTI) medications, under six drug classes, 889 individual subjects and 603 cannabis/cannabinoid users. Interactions between cannabis/cannabinoids and warfarin, valproate, tacrolimus, and sirolimus were the most widely reported and may pose the greatest risk to patients. Common ADRs included bleeding risk, altered mental status, difficulty inducing anesthesia, and gastrointestinal distress. Additionally, we identified 18 instances (58%) in which clinicians uncovered an unexpected serum level of the prescribed drug. The quality of pharmacokinetic evidence for each report was assessed using an internally developed ten-point scale. Conclusion: Drug-drug interactions with cannabinoids are likely amongst prescription medications that use common CYP450 systems. Our findings highlight the need for healthcare providers and patients/care-givers to openly communicate about cannabis/cannabinoid use to prevent unintended adverse events. To that end, we have developed a free online tool (www.CANN-DIR.psu. edu) to help identify potential cannabinoid drug-drug interactions with prescription medications. [ABSTRACT FROM AUTHOR]

Insects are the most diverse form of life, and as such, they interact closely with humans, impacting our health, economy, and agriculture. Beneficial insect species contribute to pollination, biological control of pests, decomposition, and nutrient cycling. Pest species can cause damage to agricultural crops and vector diseases to humans and livestock. Insects are often exposed to toxic xenobiotics in the environment, both naturally occurring toxins like plant secondary metabolites and synthetic chemicals like herbicides, fungicides, and insecticides. Because of this, insects have evolved several mechanisms of resistance to toxic xenobiotics, including sequestration, behavioral avoidance, and enzymatic degradation, and in many cases had developed symbiotic relationships with microbes that can aid in this detoxification. As research progresses, the important roles of these microbes in insect health and function have become more apparent. Bacterial symbionts that degrade plant phytotoxins allow host insects to feed on otherwise chemically defended plants. They can also confer pesticide resistance to their hosts, especially in frequently treated agricultural fields. It is important to study these interactions between insects and the toxic chemicals they are exposed to in order to further the understanding of pest insect resistance and to mitigate the negative effect of pesticides on nontarget insect species like Hymenopteran pollinators. [ABSTRACT FROM AUTHOR]

Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome b5 (cyt b5)'s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1's involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI). [ABSTRACT FROM AUTHOR]

Glyphosate, a widely used herbicide, is linked to a plethora of deleterious effects in both clinical and preclinical studies. Nevertheless, the effects of its main metabolite, aminomethylphosphonic acid (AMPA), whose half-life in soil is even longer than that of glyphosate, have been little explored. On this basis, as a first approach, in this work, we report that intraperitoneal (i.p.) administration of AMPA or glyphosate (at 10, 56, and 100 mg/kg) decreased, to a similar extent, plasma cholinesterase (ChE) activity in acutely exposed rats. Moreover, we designed an experimental protocol to analyze and compare the effects of AMPA and glyphosate on human plasma ChE activity; this protocol consisted of adding these compounds to human plasma to subsequently test the effects of this plasma on the contraction to acetylcholine (ACh) in the frog rectus abdominis muscle (an indirect estimate of ChE activity). Accordingly, this muscular contraction to ACh was evaluated before and after pre-incubation of ACh with (i) plasma alone, (ii) plasma with AMPA, and (iii) plasma with glyphosate. Our results indicate that AMPA, like glyphosate, decreased ChE activity in the plasma of rats (when given i.p.) and humans (when added in vitro), suggesting that both xenobiotics may exert similar toxicological effects. [ABSTRACT FROM AUTHOR]

Glutathione-S-transferase enzymes (GSTs) are essential components of the phase II detoxification system and protect organisms from oxidative stress induced by xenobiotics and harmful toxins such as 1-chloro-2,4-dinitrobenzene (CDNB). In Tetrahymena thermophila, the TtGSTm34 gene was previously reported to be one of the most responsive GST genes to CDNB treatment (LD50 = 0.079 mM). This study aimed to determine the kinetic features of recombinantly expressed and purified TtGSTm34 with CDNB and glutathione (GSH). TtGSTm34-8xHis was recombinantly produced in T. thermophila as a 25-kDa protein after the cloning of the 660-bp full-length ORF of TtGSTm34 into the pIGF-1 vector. A three-dimensional model of the TtGSTm34 protein constructed by the AlphaFold and PyMOL programs confirmed that it has structurally conserved and folded GST domains. The recombinant production of TtGSTm34-8xHis was confirmed by SDS‒PAGE and Western blot analysis. A dual-affinity chromatography strategy helped to purify TtGSTm34-8xHis approximately 3166-fold. The purified recombinant TtGSTm34-8xHis exhibited significantly high enzyme activity with CDNB (190 µmol/min/mg) as substrate. Enzyme kinetic analysis revealed Km values of 0.68 mM with GSH and 0.40 mM with CDNB as substrates, confirming its expected high affinity for CDNB. The optimum pH and temperature were determined to be 7.0 and 25 °C, respectively. Ethacrynic acid inhibited fully TtGSTm34-8xHis enzyme activity. These results imply that TtGSTm34 of T. thermophila plays a major role in the detoxification of xenobiotics, such as CDNB, as a first line of defense in aquatic protists against oxidative damage. [ABSTRACT FROM AUTHOR]

The characterization of compost compositions on the basis of sewage sludge and structural materials (straw, sawdust, bark) composting is described. A comparison of the methods most often used for composting and characterization of structural materials is also presented. Sewage sludge and structural materials were mixed in different ratios and composted in piles (laboratory scale) for 3 months. During this time, the composting process was controlled using standard methods. The bioavailability of some xenobiotics in an agriculture experiment (using beans) was also investigated. [ABSTRACT FROM AUTHOR]

The purpose of the work was to conduct biotesting for the presence of antibiotics in several lakes of the Akmola region, located in the zone of possible ingress of antimicrobial drugs into them. The adopted research method was the modified disk diffusion method, employed to determine the microorganisms' sensitivity to the used antibiotics. As a result of the study, sensitivity to antibiotics remained in the main control lakes. The antibiotics that have not been found to be resistant to microorganisms in lakes included: enronite, furagin, cefuroxime, cefoperazone, and amikacin. The most common resistance of microorganisms 90-100% was in such antibiotics as benzylpenicillin, kanamycin, streptomycin, tylosin, trimethoprim/sulfamethoxazole, metronidazole, amikacin, and spectinomycin. [ABSTRACT FROM AUTHOR]

The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes, which are widely expressed in the liver and mainly mediate the sulfation of numerous xenobiotics and endogenous compounds. However, the role of various SULTs genes has not been reported in hepatocellular carcinoma (HCC). This study aims to analyze the expression and potential functional roles of SULTs genes in HCC and to identify the role of SULT2A1 in HCC stemness as well as the possible mechanism. We found that all of the 12 SULTs genes were differentially expressed in HCC. Moreover, clinicopathological features and survival rates were also investigated. Multivariate regression analysis showed that SULT2A1 and SULT1C2 could be used as independent prognostic factors in HCC. SULT1C4, SULT1E1, and SULT2A1 were significantly associated with immune infiltration. SULT2A1 deficiency in HCC promoted chemotherapy resistance and stemness maintenance. Mechanistically, silencing of SULT2A1 activated the AKT signaling pathway, on the one hand, promoted the expression of downstream stemness gene c-Myc, on the other hand, facilitated the NRF2 expression to reduce the accumulation of ROS, and jointly increased HCC stemness. Moreover, knockdown NR1I3 was involved in the transcriptional regulation of SULT2A1 in stemness maintenance. In addition, SULT2A1 knockdown HCC cells promoted the proliferation and activation of hepatic stellate cells (HSCs), thereby exerting a potential stroma remodeling effect. Our study revealed the expression and role of SULTs genes in HCC and identified the contribution of SULT2A1 to the initiation and progression of HCC. [ABSTRACT FROM AUTHOR]

Yeast metabolism can be engineered to produce xenobiotic compounds, such as cannabinoids, the principal isoprenoids of the plant Cannabis sativa, through heterologous metabolic pathways. However, yeast cell factories continue to have low cannabinoid production. This study employed an integrated omics approach to investigate the physiological effects of cannabidiol on S. cerevisiae CENPK2-1C yeast cultures. We treated the experimental group with 0.5 mM CBD and monitored CENPK2-1C cultures. We observed a latent-stationary phase post-diauxic shift in the experimental group and harvested samples in the inflection point of this growth phase for transcriptomic and metabolomic analysis. We compared the transcriptomes of the CBD-treated yeast and the positive control, identifying eight significantly overexpressed genes with a log fold change of at least 1.5 and a significant adjusted p-value. Three notable genes were PDR5 (an ABC-steroid and cation transporter), CIS1, and YGR035C. These genes are all regulated by pleiotropic drug resistance linked promoters. Knockout and rescue of PDR5 showed that it is a causal factor in the post-diauxic shift phenotype. Metabolomic analysis revealed 48 significant spectra associated with CBD-fed cell pellets, 20 of which were identifiable as non-CBD compounds, including fatty acids, glycerophospholipids, and phosphate-salvage indicators. Our results suggest that mitochondrial regulation and lipidomic remodeling play a role in yeast's response to CBD, which are employed in tandem with pleiotropic drug resistance (PDR). We conclude that bioengineers should account for off-target product C-flux, energy use from ABC-transport, and post-stationary phase cell growth when developing cannabinoid-biosynthetic yeast strains. [ABSTRACT FROM AUTHOR]

Cytochrome P450 (CYP) enzymes are crucial for the detoxification of xenobiotics, cellular metabolism, and homeostasis. This study investigated the molecular characterization of CYP enzymes in the black-spotted frog, Pelophylax nigromaculatus, and examined the regulation of CYP expression in response to chronic exposure to the antibiotic sulfamethoxazole (SMX) at various environmental concentrations (0, 1, 10, and 100 μg/L). The full-length cDNA of Pn-CYP26B1 was identified. The sequence included open reading frames of 1,536 bp, encoding proteins comprising 511 amino acids. The signature motif, FxxGxxxCxG, was highly conserved when compared with a number of selected animal species. SMX significantly upregulated the expression of the protein CYP26B1 in frog livers at concentrations of 1 and 10 μg/L. SMX showed an affinity for CYP26B1 of -7.6 kcal/mol, indicating a potential mechanism for SMX detoxification or adaptation of the frog. These findings contributed to our understanding of the environmental impact of antibiotics on amphibian species and underscored the importance of CYP enzymes in maintaining biochemical homeostasis under exposure to xenobiotic stress. [ABSTRACT FROM AUTHOR]

Bacillus subtilis ferredoxin:NADP+ oxidoreductase (BsFNR) is a thioredoxin reductase-type FNR whose redox properties and reactivity with nonphysiological electron acceptors have been scarcely characterized. On the basis of redox reactions with 3-acetylpyridine adenine dinucleotide phosphate, the two-electron reduction midpoint potential of the flavin adenine dinucleotide (FAD) cofactor was estimated to be −0.240 V. Photoreduction using 5-deazaflavin mononucleotide (5-deazaFMN) as a photosensitizer revealed that the difference in the redox potentials between the first and second single-electron transfer steps was 0.024 V. We examined the mechanisms of the reduction of several different groups of non-physiological electron acceptors catalyzed by BsFNR. The reactivity of quinones and aromatic N-oxides toward BsFNR increased when increasing their single-electron reduction midpoint redox potentials. The reactivity of nitroaromatic compounds was lower due to their lower electron self-exchange rate, but it exhibited the same trend. A mixed single- and two-electron reduction reaction was characteristic of quinones, whereas reactions involving nitroaromatics proceeded exclusively via the one-electron reduction reaction. The oxidation of FADH• to FAD is the rate-limiting step during the oxidation of fully reduced FAD. The calculated electron transfer distances in the reaction with nitroaromatics were close to those of other FNRs including the plant-type enzymes, thus demonstrating their similar active site accessibility to low-molecular-weight oxidants despite the fundamental differences in their structures. [ABSTRACT FROM AUTHOR]

AbstractEvery year, a huge amount of lethal compounds, such as synthetic dyes, pesticides, pharmaceuticals, hydrocarbons, etc. are mass produced worldwide, which negatively affect soil, air, and water quality. At present, pesticides are used very frequently to meet the requirements of modernized agriculture. The Food and Agriculture Organization of the United Nations (FAO) estimates that food production will increase by 80% by 2050 to keep up with the growing population, consequently pesticides will continue to play a role in agriculture. However, improper handling of these highly persistent chemicals leads to pollution of the environment and accumulation in food chain. These effects necessitate the development of technologies to eliminate or degrade these pollutants. Degradation of these compounds by physical and chemical processes is expensive and usually results in secondary compounds with higher toxicity. The biological strategies proposed for the degradation of these compounds are both cost-effective and eco-friendly. Microbes play an imperative role in the degradation of xenobiotic compounds that have toxic effects on the environment. This review on the fate of xenobiotic compounds in the environment presents cutting-edge insights and novel contributions in different fields. Microbial community dynamics in water bodies, genetic modification for enhanced pesticide degradation and the use of fungi for pharmaceutical removal, white-rot fungi’s versatile ligninolytic enzymes and biodegradation potential are highlighted. Here we emphasize the factors influencing bioremediation, such as microbial interactions and carbon catabolism repression, along with a nuanced view of challenges and limitations. Overall, this review provides a comprehensive perspective on the bioremediation strategies. [ABSTRACT FROM AUTHOR]

P-glycoprotein acts as a protective barrier against xenobiotics and cellular toxicants in the human body while playing an important role in drug transportation in many organs. Overexpression of p-glycoprotein can lead to a decrease in the absorption of many drugs. After screening, 33 phytochemicals from 25 spices were selected for docking with p-glycoprotein to detect some naturally occurring p-glycoprotein inhibitors to modulate multidrug resistance. Absorption, distribution, metabolism, excretion, and toxicity prediction and drug-like properties of those ligands were investigated from pkCSM, Molinspiration, and SwissADME software, followed by molecular docking study and molecular dynamic simulation on BIOVIA Discovery Studio. These 33 phytochemicals met the criteria of p-glycoprotein inhibitor as much as the reference drug verapamil. Pandamarilactone-31 showed the highest binding affinity for p-glycoprotein, acting as the lead p-glycoprotein inhibitor, followed by α-D-fructofuranoside methyl, sesamolinol, and nigellidine. [ABSTRACT FROM AUTHOR]

Nanocomposite microbeads (average diameter = 10–100 µm) were prepared by a microemulsion-solidification method and applied to the magnetic solid-phase extraction (m-SPE) of fourteen analytes, among pesticides, drugs, and hormones, from human urine samples. The microbeads, perfectly spherical in shape to maximize the surface contact with the analytes, were composed of magnetic nanoparticles dispersed in a polylactic acid (PLA) solid bulk, decorated with multi-walled carbon nanotubes (mPLA@MWCNTs). In particular, PLA was recovered from filters of smoked electronic cigarettes after an adequate cleaning protocol. A complete morphological characterization of the microbeads was performed via Fourier-transform infrared (FTIR) spectroscopy, UV–Vis spectroscopy, thermogravimetric and differential scanning calorimetry analysis (TGA and DSC), scanning electron microscopy (SEM) and X-ray diffraction analysis (XRD). The recovery study of the m-SPE procedure showed yields ≥ 64%, with the exception of 4-chloro-2-methylphenol (57%) at the lowest spike level (3 µg L−1). The method was validated according to the main FDA guidelines for the validation of bioanalytical methods. Using liquid chromatography-tandem mass spectrometry, precision and accuracy were below 11% and 15%, respectively, and detection limits of 0.1–1.8 µg L−1. Linearity was studied in the range of interest 1–15 µg L−1 with determination coefficients greater than 0.99. In light of the obtained results, the nanocomposite microbeads have proved to be a valid and sustainable alternative to traditional sorbents, offering good analytical standards and being synthetized from recycled plastic material. One of the main objectives of the current work is to provide an innovative and optimized procedure for the recycling of a plastic waste, to obtain a regular and reliable microstructure, whose application is here presented in the field of analytical chemistry. The simplicity and greenness of the method endows the procedure with a versatile applicability in different research and industrial fields. [ABSTRACT FROM AUTHOR]

Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses. It poses a significant threat to the physiological function of reproductive cells. Factors such as xenobiotics and heat can worsen this stress, leading to cellular damage and apoptosis, ultimately decreasing reproductive efficiency. The nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway plays a crucial role in defending against oxidative stress and protecting reproductive cells via enhancing antioxidant responses. Dysregulation of Nrf2 signaling has been associated with infertility and suboptimal reproductive performance in mammals. Recent advancements in therapeutic interventions have underscored the critical role of Nrf2 in mitigating oxidative damage and restoring the functional integrity of reproductive cells. In this narrative review, we delineate the harmful effects of heat and xenobiotic-induced oxidative stress on reproductive cells and explain how Nrf2 signaling provides protection against these challenges. Recent studies have shown that activating the Nrf2 signaling pathway using various bioactive compounds can ameliorate heat stress and xenobiotic-induced oxidative distress and apoptosis in mammalian reproductive cells. By comprehensively analyzing the existing literature, we propose Nrf2 as a key therapeutic target for mitigating oxidative damage and apoptosis in reproductive cells caused by exposure to xenobiotic exposure and heat stress. Additionally, based on the synthesis of these findings, we discuss the potential of therapies focused on the Nrf2 signaling pathway to improve mammalian reproductive efficiency. [ABSTRACT FROM AUTHOR]

Nitrophenols are environmental pollutants and xenobiotics, the main sources of which are diesel exhaust fumes and pesticides. The biotransformation processes that take place in the liver are defence mechanisms against xenobiotics, such as nitrophenols. Our previous study showed that the chicken ovary is an additional xenobiotic detoxification place and that nitrophenols disrupt steroidogenesis in chicken ovarian follicles. Therefore, the present study aimed to determine the in vivo and in vitro effects of 4‐nitrophenol (PNP) and 3‐methyl‐4‐nitrophenol (PNMC) on the expression and activity of phase I (CYP3A) and phase II (COMT) biotransformation enzymes in chicken ovary. In an in vivo study, hens were treated with a vehicle or 10 mg PNP or PNMC/kg b.wt. per day for 6 days. In an in vitro study, prehierarchical white and yellowish follicles, as well as the granulosa and theca layers of the three largest preovulatory follicles (F3, F2 and F1), were isolated and then incubated in a control medium or medium supplemented with PNP (10−6 M) or PNMC (10−6 M) for 24 or 48 h. Both in vivo and in vitro studies showed that nitrophenols exert tissue‐ and compound‐dependent (PNP or PNMC) effects on CYP3A and COMT gene (real‐time PCR) protein (Western blot) expression and their activity (colorimetric methods). The inhibitory effect of nitrophenols in vivo on the activity of biotransformation enzymes suggest that the ovary has the capacity to metabolise PNP and PNMC. This study aimed to determine the in vivo and in vitro effects of 4‐nitrophenol (PNP) and 3‐methyl‐4‐nitrophenol (PNMC) on the expression and activity of phase I (CYP3A) and phase II (COMT) biotransformation enzymes in chicken ovary. The results revealed that nitrophenols have a tissue‐ and compound‐dependent (PNP or PNMC) effect on CYP3A and COMT expression and activity, indicating that they can disrupt endogenous compounds and xenobiotic metabolism. Additionally, nitrophenols may lead to ovarian cancer by COMT inhibition. [ABSTRACT FROM AUTHOR]