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Albendazole (ABZ) is an anthelmintic frequently used to treat haemonchosis, a common parasitosis of ruminants caused by the gastrointestinal nematode Haemonchus contortus. This parasite is able to protect itself against ABZ via the formation of inactive ABZ-glycosides. The present study was designed to deepen the knowledge about the role of UDP-glycosyltransferases (UGTs) in ABZ glycosylation in H. contortus. The induction effect of phenobarbital, a classical inducer of UGTs, as well as ABZ and ABZ-sulphoxide (ABZSO, the main active metabolite of ABZ) on UGTs expression and UGT activity toward ABZ was studied ex vivo in isolated adult nematodes. The effect of three potential UGT inhibitors (5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine and sulfinpyrazone) on ABZ glycosylation was tested. Pre-incubation of nematodes with ABZ and ABZSO led to increased expression of several UGTs as well as ABZ-glycosides formation in subsequent treatment. Phenobarbital also induced UGTs expression, but did not affect ABZ biotransformation. In the nematode's subcellular fraction, sulfinpyrazone inhibited UGT activity toward ABZ, although no effect of other inhibitors was observed. The inhibitory potential of sulfinpyrazone on the formation of ABZ-glycosides was also proved ex vivo in living nematodes. The obtained results confirmed the role of UGTs in ABZ biotransformation in H. contortus adults and revealed sulfinpyrazone as a potent inhibitor of ABZ glycosylation in this parasite. The possible use of sulfinpyrazone with ABZ in combination therapy merits further research. [Display omitted] • UDP-glycosyl transferases catalyse biotransformation of benzimidazole anthelmintics. • Gene expression of several UGTs in H. contortus is affected by albendazole. • The inhibition of UGTs leads to a decrease in the amounts of glycosylated metabolites. [ABSTRACT FROM AUTHOR]

Aldo-keto reductases (AKRs), a superfamily of NADP(H)-dependent oxidoreductases, catalyze the oxidoreduction of a wide variety of eobiotic and xenobiotic aldehydes and ketones. In mammals, AKRs play essential roles in hormone and xenobiotic metabolism, oxidative stress, and drug resistance, but little is known about these enzymes in the parasitic nematode Haemonchus contortus. In the present study, 22 AKR genes existing in the H. contortus genome were investigated and a phylogenetic analysis with comparison to AKRs in Caenorhabditis elegans , sheep and humans was conducted. The constitutive transcription levels of all AKRs were measured in eggs, larvae, and adults of H. contortus , and their expression was compared in a drug-sensitive strain (ISE) and a benzimidazole-resistant strain (IRE) previously derived from the sensitive strain by imposing benzimidazole selection pressure. In addition, the inducibility of AKRs by exposure of H. contortus adults to benzimidazole anthelmintic flubendazole in vitro was tested. Phylogenetic analysis demonstrated that the majority of AKR genes in H. contortus lack orthologues in the sheep genome, which is a favorable finding for considering AKRs as potential drug targets. Large differences in the expression levels of individual AKRs were observed, with AKR1, AKR3, AKR8, and AKR10 being the most highly expressed at most developmental stages. Significant changes in the expression of AKRs during the life cycle and pronounced sex differences were found. Comparing the IRE and ISE strains, three AKRs were upregulated, and seven AKRs were downregulated in adults. In addition, the expression of three AKRs was induced by flubendazole exposure in adults of the ISE strain. Based on these results, AKR1, AKR2, AKR3, AKR5, AKR10 and AKR19 in particular merit further investigation and functional characterization with respect to their potential involvement in drug biotransformation and anthelmintic resistance in H. contortus. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract UDP-glycosyltransferases (UGT), catalysing conjugation of UDP-activated sugar donors to small lipophilic chemicals, are widespread in living organisms from bacteria to fungi, plant, or animals. The progress of genome sequencing has enabled an assessment of the UGT multigene family in Haemonchus contortus (family Trichostrongylidae, Nematoda), a hematophagous gastrointestinal parasite of small ruminants. Here we report 32 putative UGT genes divided into 15 UGT families. Phylogenetic analysis in comparison with UGTs from Caenorhabditis elegans , a free-living model nematode, revealed several single member homologues, a lack of the dramatic gene expansion seen in C. elegans , but also several families (UGT365, UGT366, UGT368) expanded in H. contortus only. The assessment of constitutive UGT mRNA expression in H. contortus adults identified significant differences between females and males. In addition, we compared the expression of selected UGTs in the drug-sensitive ISE strain to two benzimidazole-resistant strains, IRE and WR, with different genetic backgrounds. Constitutive expression of UGT368B2 was significantly higher in both resistant strains than in the sensitive strain. As resistant strains were able to deactivate benzimidazole anthelmintics via glycosylation more effectively then the sensitive strain, UGT368B2 enhanced constitutive expression might contribute to drug resistance in H. contortus. Graphical abstract Image 1 Highlights • UDP-glycosyltransferase family contains 32 members in Haemonchus contortus. • Constitutive expression of UDP-glycosyltransferases differs between sexes. • UGT368B2 expression level is significantly higher in resistant strains. [ABSTRACT FROM AUTHOR]

Haemonchus contortus (family Trichostrongylidae, Nematoda) , a hematophagous gastrointestinal parasite found in small ruminants, has a great ability to develop resistance to anthelmintic drugs. We studied the biotransformation of the three benzimidazole anthelmintics: albendazole (ABZ), ricobendazole (albendazole S-oxide; RCB) and flubendazole (FLU) in females and males of H. contortus in both a susceptible ISE strain and resistant IRE strain. The ex vivo cultivation of living nematodes in culture medium with or without the anthelmintics was used. Ultrasensitive UHPLC/MS/MS analysis revealed 9, 7 and 12 metabolites of ABZ, RCB and FLU, respectively, with most of these metabolites now described in the present study for the first time in H. contortus . The structure of certain metabolites shows the presence of biotransformation reactions not previously reported in nematodes. There were significant qualitative and semi-quantitative differences in the metabolites formed by male and female worms. In most cases, females metabolized drugs more extensively than males. Adults of the IRE strain were able to form many more metabolites of all the drugs than adults of the ISE strain. Some metabolites were even found only in adults of the IRE strain. These findings suggest that increased drug metabolism may play a role in resistance to benzimidazole drugs in H. contortus. [ABSTRACT FROM AUTHOR]

Potentially invasive species can be identified before they start to spread by comparing their traits with those of successful invaders. A powerful tool for delimiting the traits associated with invasiveness are analyses of a number of species of the same genus, where it is more likely to detect relevant differences because of elimination of biases that constrain the search for such traits in whole floras. Since the influence of traits on invasion success may differ with respect to the stage of the plant's life cycle, comparative studies should address the whole life cycle, including early stages. Here we studied which biological traits are associated with the ability to naturalize within the genus Impatiens , how frequency of planting affects naturalization success, and whether naturalized species with biological traits similar to the native representative of this genus are more successful. The genus Impatiens includes a number of cultivated species popular in horticulture, among them several widespread invaders. We used one native and 10 alien annual taxa. This data set involved all commonly cultivated species, and representatives of different invasion status in Europe. In garden experiments and climatic chambers we measured seed mass, time to germination, percentage of seeds germinated, seedling growth rate, total seedling biomass, seedling root/total biomass ratio, adult biomass and fecundity. These traits and planting frequency were used to explain the invasion success of the species, expressed as (i) invasion status in Europe and (ii) the number of global temperate regions in which the species has been reported as naturalized. The frequency of planting was used as a proxy of propagule pressure to separate this potentially biasing factor known to affect plant invasiveness from the effect of plant traits. We found that both species traits and frequency of planting were correlated with naturalization. Species naturalized in many temperate regions of the world had heavier seeds, high seedling growth rate and allocated low proportion of seedling biomass to roots. Importantly, common planting was more strongly correlated with naturalization success than with biological traits. Impatiens species naturalized in Europe exhibited better seed germination in the common garden, and it took a longer time for the seeds to germinate. Species escaped from cultivation but occurring only as casuals in Europe had heavy seeds and invested more resources into shoots than roots, whereas species not escaping from cultivation were characterized by fast seed germination and light seed. In general, traits linked to early stages of the life cycle were more strongly associated with invasion success than those of the adults. Frequently planted species tend to naturalize more easily than those planted scarcely. The successful invaders share traits similar to the one native Impatiens species in Europe and those with traits distinct from it do not invade. Our results indicate that many Impatiens species represent potential invaders should their planting become more widespread; this prediction is supported by the fact that Impatiens species included in the experiment completed their life cycles in an experimental garden in central Europe. [ABSTRACT FROM AUTHOR]

The C-type lectin-like fold (CTL fold) is a building block of many proteins, including saccharide-binding lectins, natural killer cell receptors, macrophage mannose receptor, selectins, collectins, snake venoms and others. Some are important players in innate immunity and are involved in the first-line response to virally infected cells or cancer cells, some play a role in antimicrobial defense, and some are potential targets for fight against problems connected with allergies, obesity, and autoimmunity. The structure of a CTL domain typically contains two α-helices, two small β-sheets and a long surface loop, with two or three disulfide bridges stabilizing the structure. This small domain is often involved in interactions with a target molecule, however, utilizing varied parts of the domain surface, with or without structural modifications. More than 500 three-dimensional structures of CTL fold-containing proteins are available in the Protein Data Bank, including a significant number of complexes with their key interacting partners (protein:protein complexes). The amount of available structural data enables a detailed analysis of the rules of interaction patterns utilized in activation, inhibition, attachment, and other pathways or functionalities. Interpretation of known CTL receptor structures and all other CTL-containing proteins and complexes with described three-dimensional structures, complemented with sequence/structure/interaction correlation analysis, offers a comprehensive view of the rules of interaction patterns of the CTL fold. The results are of value for prediction of interaction behavior of so far not understood CTL-containing proteins and development of new protein binders based on this fold, with applications in biomedicine or biotechnologies. It follows from the available structural data that almost the whole surface of the CTL fold is utilized in protein:protein interactions, with the heaviest frequency of utilization in the canonical interaction region. The individual categories of interactions differ in the interface buildup strategy. The strongest CTL binders rely on interfaces with large interaction area, presence of hydrophobic core, or high surface complementarity. The typical interaction surfaces of the fold are not conserved in amino acid sequence and can be utilized in design of new binders for biotechnological applications. [ABSTRACT FROM AUTHOR]

• Population trends of the habitat-defined bird groups may reflect forest management. • In Czechia, forest bird populations showed a general increase from 1982 to 2019. • Increases concern habitat generalists and species of canopy and broad-leaved trees. • Both primary and secondary cavity nesters also showed a population increase. • Longer rotation period and change in tree species composition were likely drivers. In areas where forest is under long-term human influence, we can expect that forest bird populations will be affected by changes in forest management. Consequences of such forest management changes can be studied using long-term population trajectories of habitat-defined groups of bird species because various species are associated to different habitat types. Here we focused on 51 species of common forest birds in Czechia, a central European country, using data from a nation-wide breeding bird monitoring scheme collected from 1982 to 2019. Important changes in forest management took place over this time period in Europe and we asked whether the trends in Czech forest bird populations reflected these changes. For this purpose, we defined nine groups according to the species' habitat associations in respect of stand size, vegetation layers and tree species composition. We calculated annual population indices using log-linear models with Poisson distribution for every species and composed these annual indices into multispecies indicators (MSIs). MSI of all forest birds, as well as MSIs of three groups of habitat generalists showed significant increases over the focal period. The groups of more specialized species showed more variable population trajectories: birds of the shrub layer decreased, whereas birds of the forest canopy and birds of broad-leaved trees increased, and populations of birds of forest edges, forest interior and coniferous trees were stable. These patterns in forest bird populations are consistent with forest maturation and increasing wood volume that took place in Czech forests over several decades. Such changes in forest environment are likely consequences of the change in purposes of forest management from fuel wood to timber harvesting that took place in 20th century resulting in a longer rotation period. Increases in species associated with broad-leaved trees can be explained by replacement of coniferous stands by stands of broad-leaved trees indicating recovery of forest environment towards more natural conditions as majority of the forested area would be naturally covered by broad-leaved vegetation in Czechia. In addition, the occurrence of some broad-leaved trees within coniferous stands, a common practice in Czech forestry, may also provide benefits to populations of bird species associated with broad-leaved trees. Taken together, these results support suitability of current forest management for forest birds that corresponds to recent findings from several other European regions. However, we should take this conclusion with caution because the increases of generalist birds may be also driven by factors outside the forest environment. [ABSTRACT FROM AUTHOR]

Green tea represents a favourite beverage and green tea extracts are popular components of dietary supplements. The aim of present in vivo study was to report on the effect of defined green tea extract (Polyphenon) in various dosage schemes on drug-metabolizing enzymes in mice. The specific activities and expressions of a panel of drug-metabolizing enzymes (totally 16) were tested in liver and small intestine. Nine enzymes were significantly altered by Polyphenon treatment. The intestinal enzymes were more affected than the hepatic ones. The effects were mostly dose-dependent but short-term treatment had more pronounced impact than the long-term administration. Based on the results, normal consumption of green tea seems to be safe but extremely high doses of green tea extracts in dietary supplements could influence drugs metabolism and efficacy. [ABSTRACT FROM AUTHOR]

Benzimidazole anthelmintics, the drugs against parasitic worms, are widely used in human as well as veterinary medicine. Following excretion, these substances may persist in the environment and impact non-target organisms. In order to test phytoremediation as a possible tool for detoxification of anthelmintics in environment, the biotransformation pathways of albendazole (ABZ) and flubendazole (FLU) were studied in reed ( Phragmites australis ) in vitro . Reed cells were able to uptake and biotransform both anthelmintics. Ten ABZ metabolites and five FLU metabolites were found. Some atypical biotransformation reactions (formation of glucosylglucosides, acetylglucosides and xylosylglucosides), which have not been described previously, were identified. Based on the obtained results, the schemes of metabolic pathways of ABZ and FLU in reed were proposed. Most of ABZ and FLU metabolites can be considered as anthelmintically less active; therefore uptake and biotransformation of these anthelmintics by reed could be useful for decrease of their toxicity in environment. [ABSTRACT FROM AUTHOR]

Abstract: Invasion of some alien plants is considered to be associated with inter-population differentiation and adaptations to local conditions. To obtain an insight into these processes it is convenient to compare invasive plants with their native congeners. The intra-specific differentiation during invasion was studied using four Impatiens (Balsaminaceae) species in Central Europe: native Impatiens noli-tangere and three aliens (highly invasive Impatiens glandulifera, less invasive Impatiens parviflora and potentially invasive Impatiens capensis). Differentiation in traits important for the establishment (germination; seedling emergence; seedling frost resistance) was measured in a laboratory and an experimental garden using seed collected from five natural populations of each species. Frost resistance of I. capensis, currently invasive in Western Europe, was within the scope of other congeners and it does not seem to be a barrier to spread of the species into Central Europe. Among-population differences were found within all species except I. capensis. In I. noli-tangere, I. glandulifera and I. parviflora the differences were related to the climatic characteristics in early spring at the source localities, which indicates that individuals may be adapted to local conditions. The differences found between the populations of I. noli-tangere, I. glandulifera and I. parviflora are likely to reflect the frost sensitivity of the species. In the highly frost-sensitive I. parviflora differentiation was found both in germination and frost resistance of individual populations. In I. glandulifera the differences among populations in frost sensitivity depended on temperature at the seed source and corresponded to the pattern of emergence of seedlings in the garden. In the native I. noli-tangere, the differences among populations in the time of germination depended on temperature at the seed-source locality. Since local adaptations were indicated both in native and invasive species studied, they are unlikely to provide the invasive Impatiens species with an advantage against the native congener, at least in terms of the traits investigated. [Copyright &y& Elsevier]

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Benfluron (B, [5-(2-N-oxo-2-N′,N″-dimethylaminoethoxy)-7-oxo-7H-benzo[c]fluorene]) is a potential benzo[c]fluorene antineoplastic agent with high activity against a broad spectrum of experimental tumors in vitro and in vivo. The structure of B has been modified to repress its rapid deactivation through carbonyl reduction on C7. 3,9-Dimethoxybenfluron (D, [3,9-dimethoxy-5-(2-N-oxo-2-N′,N″-dimethylaminoethoxy)-7-oxo-7H-benzo[c]fluorene]) is one of the B derivatives developed. The present paper was designed to compare the C7 carbonyl reduction of B and D in microsomes, cytosol and hepatocytes from human liver. Two purified human enzymes, microsomal 11β-hydroxysteroid dehydrogenase 1 (11β-HSD 1) and cytosolic carbonyl reductase, were tested if they are responsible for B and D carbonyl reduction in the respective fractions. Indeed, carbonyl reduction of D in comparison to that of B was 4 and 6–10 times less extensive in human liver microsomes and cytosol, respectively. Moreover, about 10–20 times higher amounts of dihydro B than dihydro D were detected in primary culture of human hepatocytes. 11β-HSD 1 was shown to be able to reduce B and D. For this enzyme, about 10 times higher rates of carbonyl reduction were observed for B than for D. Likewise, CR participates in B and D carbonyl reduction, although smaller amounts of both reduced metabolites were detected. In summary, carbonyl reduction of D was significantly less extensive than that of B in all in vitro experiments. This lower rate of D inactivation was especially pronounced in hepatocytes which represent a close to in vivo situation. Our results clearly demonstrate that dimethoxy substitution protects the carbonyl group of the benzo[c]fluorene moiety against the deactivation by microsomal and cytosolic reductases. Detailed knowledge on the participating enzymes may serve as a basis for the co-application of specific inhibitors in chemotherapy to further improve the pharmacokinetics of benzo[c]fluorene derivatives. [Copyright &y& Elsevier]

Prenatal learning of speech rhythm and melody is well documented. Much less is known about the earliest acquisition of segmental speech categories. We tested whether newborn infants perceive native vowels, but not nonspeech sounds, through some existing (proto-)categories, and whether they do so more robustly for some vowels than for others. Sensory event-related potentials (ERP), and mismatch responses (MMR), were obtained from 104 neonates acquiring Czech. The ERPs elicited by vowels were larger than the ERPs to nonspeech sounds, and reflected the differences between the individual vowel categories. The MMRs to changes in vowels but not in nonspeech sounds revealed left-lateralized asymmetrical processing patterns: a change from a focal [a] to a nonfocal [ɛ], and the change from short [ɛ] to long [ɛ:] elicited more negative MMR responses than reverse changes. Contrary to predictions, we did not find evidence of a developmental advantage for vowel length contrasts (supposedly most readily available in utero) over vowel quality contrasts (supposedly less salient in utero). An explanation for these asymmetries in terms of differential degree of prior phonetic warping of speech sounds is proposed. Future studies with newborns with different language backgrounds should test whether the prenatal learning scenario proposed here is plausible. • Newborns' processing of native vowels and comparable nonspeech sounds differ. • Durational and spectral differences in stimuli were more clearly reflected by the ERPs to vowels, compared to tone complexes. • Directional asymmetries were detected in the mismatch responses to vowel deviants. • In the left hemisphere, a change in vowels from focal to nonfocal and from short to long resulted in a more negative MMR. • The findings may be explained by phonetic learning prior to the 3rd day after birth. [ABSTRACT FROM AUTHOR]

Anthelmintics, drugs against parasitic worms, are frequently used in livestock and might act as danger environmental microcontaminants. The present study was designed to monitor the possible circulation of common anthelmintic drug albendazole (ABZ) and its metabolites in the real agriculture conditions. The sheep were treated with the recommended dose of ABZ. Collected faeces were used for the fertilization of a field with fodder plants (alfalfa and clover) which served as feed for sheep from a different farm. The selective ultrasensitive mass spectrometry revealed surprisingly high concentrations of active ABZ metabolite (ABZ-sulphoxide) in all samples (dung, plants, ovine plasma, rumen content and faeces). Our results prove for the first time an undesirable permeation of ABZ metabolites from sheep excrement into plants (used as fodder) and subsequently to other sheep in real agricultural conditions. This circulation causes the permanent exposition of the ecosystems and food-chain to the drug and can promote the development of drug resistance in helminths. [Display omitted] • Veterinary anthelmintics are neglected but hazardous microcontaminants. • Anthelmintic albendazole (ABZ) enters via excrements to soil and fodder plants. • ABZ metabolites were detected in sheep fed with these fodder plants. • Proved undesired ABZ circulation causes permanent exposition of ecosystems. [ABSTRACT FROM AUTHOR]

• Gastrointestinal nematodes are resistant to available anthelmintics. • No new anthelmintic on the market for several years. • A target-based approach, drug repurposing or derivatives? • Chemical compounds, natural products or medicinal plants? • Each approach has certain advantages and disadvantages. The control of gastrointestinal nematodes (GINs), the most abundant and serious parasites of livestock, has become difficult because of the limited number of available drugs and fast development of drug resistance. Thus, considerable efforts have been devoted to developing new anthelmintics that are efficient against nematodes, especially resistant species. Here, we summarize the most recent results using various approaches: target-based or high-throughput screening (HTS) of compound libraries; the synthesis of new derivatives or new combinations of current anthelmintics; the repurposing of drugs currently approved for other indications; and lastly, the identification of active plant products. We also evaluate the advantages and disadvantages of each of these approaches. [ABSTRACT FROM AUTHOR]

High fructose intake from soft drinks and sweets is assumed to have a negative impact on human health. Yet in spite of intensive research, the molecular mechanisms of these effects have not been fully elucidated yet, for example, the effect of high fructose intake could be different in normal and obese individuals. Four groups of mice were used in this study: control groups of lean mice and mice with obesity induced by a high-fat diet, then both of these groups with or without fructose administration in drinks. In plasma of each group, triacylglycerol, cholesterol, free fatty acids, alanine aminotransferase, insulin and adiponectin were measured. The expression levels of selected microRNAs (miRNAs) in plasma, the liver, white adipose tissue, brown adipose tissue and subcutaneous adipose tissue were quantified. In both lean and obese mice, high fructose intake increased cholesterol amount in the liver, up-regulated hepatic miR-27a, down-regulated miR-33a in white adipose tissue and increased plasmatic level of miR-21. The effect of high fructose intake on other miRNAs in the liver, plasma and adipose tissues differed in normal and obese mice. Fructose intake led to hepatic hypercholesterolemia and aberrant expression of several miRNAs participating in lipid metabolism, adipocytes differentiation and nonalcoholic fatty liver disease promotion. The effect of fructose on miRNAs expression differed in normal and obese mice. Nevertheless, plasmatic miR-21, which was induced by fructose in both lean and obese mice, may be considered as a potential biomarker of excessive fructose intake. [ABSTRACT FROM AUTHOR]

The heme-based oxygen sensor histidine kinase AfGcHK is part of a two-component signal transduction system in bacteria. O2 binding to the Fe(II) heme complex of its N-terminal globin domain strongly stimulates autophosphorylation at His183 in its C-terminal kinase domain. The 6-coordinate heme Fe(III)-OH- and -CN- complexes of AfGcHK are also active, but the 5-coordinate heme Fe(II) complex and the heme-free apo-form are inactive. Here, we determined the crystal structures of the isolated dimeric globin domains of the active Fe(III)-CN- and inactive 5-coordinate Fe(II) forms, revealing striking structural differences on the heme-proximal side of the globin domain. Using hydrogen/deuterium exchange coupled with mass spectrometry to characterize the conformations of the active and inactive forms of full-length AfGcHK in solution, we investigated the intramolecular signal transduction mechanisms. Major differences between the active and inactive forms were observed on the heme-proximal side (helix H5), at the dimerization interface (helices H6 and H7 and loop L7) of the globin domain and in the ATP-binding site (helices H9 and H11) of the kinase domain. Moreover, separation of the sensor and kinase domains, which deactivates catalysis, increased the solvent exposure of the globin domain-dimerization interface (helix H6) as well as the flexibility and solvent exposure of helix H11. Together, these results suggest that structural changes at the heme-proximal side, the globin domain-dimerization interface, and the ATP-binding site are important in the signal transduction mechanism of AfGcHK.Weconclude that AfGcHKfunctions as an ensemble of molecules sampling at least two conformational states. [ABSTRACT FROM AUTHOR]

Benzimidazoles anthelmintics, which enter into environment primarily through excretion in the feces or urine of treated animals, can affect various organisms and disrupt ecosystem balance. The present study was designed to test the phytotoxicity and biotransformation of the three benzimidazole anthelmintics albendazole (ABZ), fenbendazole (FBZ) and flubendazole (FLU) in the harebell ( Campanula rotundifolia ). This meadow plant commonly grows in pastures and comes into contact with anthelmintics through the excrements of treated animals. Suspensions of harebell cells in culture medium were used as an in vitro model system. ABZ, FLU and FBZ were not found to be toxic for harebell cells, which were able to metabolize ABZ, FLU and FBZ via the formation of a wide scale of metabolites. Ultrahigh-performance liquid chromatography coupled with high mass accuracy tandem mass spectrometry (UHPLC-MS/MS) led to the identification of 24, 18 and 29 metabolites of ABZ, FLU and FBZ, respectively. Several novel metabolites were identified for the first time. Based on the obtained results, the schemes of the metabolic pathways of these anthelmintics were proposed. Most of these metabolites can be considered deactivation products, but a substantial portion of them may readily be decomposed to biologically active substances which could negatively affect ecosystems. [ABSTRACT FROM AUTHOR]

Veterinary drugs used for treatment and prevention of diseases in animals represent important source of environmental pollution due to intensive agri- and aquaculture production. The drugs can reach environment through the treatment processes, inappropriate disposal of used containers, unused medicine or livestock feed, and manufacturing processes. Wide scale of veterinary pharmaceuticals e.g. antibiotics, antiparasitic and antifungal drugs, hormones, anti-inflammatory drugs, anaesthetics, sedatives etc. enter the environment and may affect non-target organisms including plants. This review characterizes the commonly used drugs in veterinary practice, outlines their behaviour in the environment and summarizes available information about their toxic effect on plants. Significant influence of many antibiotics and hormones on plant developmental and physiological processes have been proved. However, potential phytotoxicity of other veterinary drugs has been studied rarely, although knowledge of phytotoxicity of veterinary drugs may help predict their influence on biodiversity and improve phytoremediation strategies. Moreover, additional topics such as long term effect of low doses of drugs and their metabolites, behaviour of mixture of veterinary drugs and other chemicals in ecosystems should be more thoroughly investigated to obtain complex information on the impact of veterinary drugs in the environment. [ABSTRACT FROM AUTHOR]

• Secretory carcinoma diagnosis is made by a combination of histologic features and immunohistochemical markers. • Secretory carcinoma may present an aggressive behavior and unfavorable prognosis. • The grading system of SC correlates with histologic findings and clinical behavior. A 56-year-old female was referred to our service for management of a malignant salivary gland neoplasm with compromised margins that had been biopsied previously at another service. The patient reported a twenty-year history of a lesion in the oral cavity with progressive and exuberant growth over the past two years, associated with local pain and dyspnea. Physical examination revealed an erythematous, ulcerated, and hemorrhagic lesion measuring approximately 3 cm on the left soft palate and tonsillar pillar. Computed tomography revealed an expansile lesion in the topography of the left soft palate, growing predominantly toward the lumen of the nasopharynx and partially invading the left wall of this region. The patient underwent surgery and histopathologic examination revealed an infiltrative and aggressive epithelial neoplasia with large vacuolated and eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. The neoplastic cells were arranged in a solid, microcystic, tubular, and follicular pattern with eosinophilic luminal secretion. Mitotic figures were frequent and all margins were affected by the neoplasia. Morphologic and immunohistochemical features supported the diagnosis of secretory carcinoma, and the patient is currently being followed for further therapeutic intervention. [ABSTRACT FROM AUTHOR]

Abstract: Benfluron (B) [5-(2-dimethylaminoethoxy)-7H-benzo[c]fluorene-7-one hydrochloride] is a potential antineoplastic agent. In the organism, B undergoes a rapid phase I biotransformation through oxidative and reductive metabolic pathways. The carbonyl reduction of B leads to reduced benfluron, red-B, this is one of the principal pathways for the deactivation of this compound. The structure of B was modified to suppress its rapid deactivation via the carbonyl reduction on C7. Dimefluron, D (3,9-dimethoxy-benfluron) is one of the derivatives of B, in which an alternative metabolic pathway (O-desmethylation) prevails over the carbonyl reduction. The goal of this study was to develop HPLC methods enabling chiral separations of the red-B and -D enantiomers. The separation of red-B enantiomers was successful done on a Chiralcel OD-R column (250mm×4.6mm ID, 5μm) using a mobile phase acetonitrile–1M NaClO4 (40:60, v/v). Another mobile phase, methanol–1M NaClO4 (75:25, v/v), had to be employed for the sufficient resolution of red-D enantiomers. Flow rate was 0.5mlmin−1 in both cases. Red-B was detected at 340nm, red-D at 370nm. The above chiral HPLC methods were used for the study of the biotransformation of B and D in the microsomal fractions of liver homogenates prepared from various species (rat, rabbit, pig, guinea pig, goat and human). The enantiospecificity of the respective carbonyl reductases was evaluated and discussed for both prochiral compounds, B and D. [Copyright &y& Elsevier]