Anthelmintic drugs are widespread environmental contaminants, but their impact is still poorly understood. Although contact of parasitic nematode Haemonchus contortus with traces of anthelmintic drug albendazole (ABZ) altered the expression and activity of several UDP-glycosyl transferases (UGTs) and P-glycoproteins (Pgps, belonging to ABC-transporters), key enzymes in endogenous and xenobiotic metabolism, it is not known whether these changes will last during the life cycle and pass to the next generations. In the present study simulating the environmental-like exposure, free-living stages of H. contortus were exposed or unexposed to a sub-lethal dose of ABZ and its transformation products (ABZs) during L3 development. The L3 served for lambs' infection and obtaining of H. contortus adults and eggs, which were again exposed or unexposed to ABZs during L3 development. The expression pattern of UGTs and Pgps was analysed and compared in the first generation of L3, in the adults, and in the second generation of L3. The results showed that ABZs exposition during larvae development altered the expression of several ugt and pgp genes in L3 and adults. The intrageneration stability of ABZs-evoked changes was observed in the case of three genes, four genes maintained the intergeneration stability. Interestingly, ABZs-induced changes in the expression of some genes became apparent only in the second generation of L3. Taking together, contact of free-living stages of H. contortus with traces of ABZs in the environment evokes changes in the expression of certain UGTs and Pgps, with some of these changes being intra- and inter-generation stable.

• Klíčová slova
• Anthelmintics, Drug metabolizing enzymes, Drugs in environment, Helminths, Nematodes,
• MeSH
• ABC transportéry genetika   metabolismus   MeSH
• albendazol * MeSH
• anthelmintika * toxicita   MeSH
• glykosyltransferasy genetika   metabolismus   MeSH
• Haemonchus * účinky léků   MeSH
• ovce MeSH
• stadia vývoje účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• albendazol * MeSH
• anthelmintika * MeSH
• glykosyltransferasy MeSH

In all organisms, the biotransformation of xenobiotics to less toxic and more hydrophilic compounds represents an effective defense strategy. In pathogens, the biotransformation of drugs (used for their elimination from the host) may provide undesirable protective effects that could potentially compromise the drug's efficacy. Accordingly, increased drug deactivation via accelerated biotransformation is now considered as one of the mechanisms of drug resistance. The present study summarizes the current knowledge regarding the biotransformation of anthelmintics, specifically drugs used to treat mainly nematodes, a group of parasites that are a significant health concern for humans and animals. The main biotransformation enzymes are introduced and their roles in anthelmintics metabolism in nematodes are discussed with a particular focus on their potential participation in drug resistance. Similarly, the inducibility of biotransformation enzymes with sublethal doses of anthelmintics is presented in view of its potential contribution to drug resistance development. In the conclusion, the main tasks awaiting scientists in this area are outlined.

• MeSH
• anthelmintika * farmakologie   metabolismus   farmakokinetika   MeSH
• biotransformace MeSH
• hlístice * účinky léků   metabolismus   enzymologie   MeSH
• léková rezistence * MeSH
• lidé MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• anthelmintika * MeSH

The recent popularity of indoor farming has brought about problems with parasites spreading among pollinator colonies. The natural product callunene (1) can be used in the prophylaxis of bumblebees against Crithidia infection. Here, we report the synthesis of callunene (1), its enantioseparation, and a method for analyzing its optical purity. The approach was applied to determine the configuration of callunene extracted from heather honey. The proposed method is also applicable to the analysis of mixtures of diastereomers obtained during callunene synthesis, which allows the stereospecificity of individual reaction steps to be determined.

• MeSH
• antiparazitární látky chemie   farmakologie   MeSH
• biologické přípravky * chemie   MeSH
• med analýza   MeSH
• molekulární struktura MeSH
• stereoizomerie MeSH
• včely MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiparazitární látky MeSH
• biologické přípravky * MeSH

The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and an overall dearth of drug targets against Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. In vitro resistance selections using wildtype and mutator P. falciparum lines revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.

• MeSH
• antimalarika * farmakologie   MeSH
• chinoxaliny * farmakologie   MeSH
• léková rezistence účinky léků   MeSH
• lidé MeSH
• Plasmodium falciparum * účinky léků   MeSH
• protozoální proteiny metabolismus   genetika   MeSH
• Schistosoma účinky léků   MeSH
• schistosomóza farmakoterapie   MeSH
• tropická malárie farmakoterapie   parazitologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antimalarika * MeSH
• chinoxaliny * MeSH
• protozoální proteiny MeSH

Herein, we investigated the anti-amoebic activity of phosphonium-chloride-based deep eutectic solvents against pathogenic Acanthamoeba castellanii of the T4 genotype. Deep eutectic solvents are ionic fluids composed of two or three substances, capable of self-association to form a eutectic mixture with a melting point lower than each substance. In this study, three distinct hydrophobic deep eutectic solvents were formulated, employing trihexyltetradecylphosphonium chloride as the hydrogen bond acceptor and aspirin, dodecanoic acid, and 4-tert-butylbenzoic acid as the hydrogen bond donors. Subsequently, all three deep eutectic solvents, denoted as DES1, DES2, DES3 formulations, underwent investigations comprising amoebicidal, adhesion, excystation, cytotoxicity, and cytopathogenicity assays. The findings revealed that DES2 was the most potent anti-amoebic agent, with a 94% elimination rate against the amoebae within 24 h at 30 °C. Adhesion assays revealed that deep eutectic solvents hindered amoebae adhesion to human brain endothelial cells, with DES2 exhibiting 88% reduction of adhesion. Notably, DES3 exhibited remarkable anti-excystation properties, preventing 94% of cysts from reverting to trophozoites. In cytopathogenicity experiments, deep eutectic solvent formulations and dodecanoic acid alone reduced amoebae-induced human brain endothelial cell death, with DES2 showing the highest effects. Lactate dehydrogenase assays revealed the minimal cytotoxicity of the tested deep eutectic solvents, with the exception of trihexyltetradecylphosphonium chloride, which exhibited 35% endothelial cell damage. These findings underscore the potential of specific deep eutectic solvents in combating pathogenic Acanthamoeba, presenting promising avenues for further research and development against free-living amoebae.

• Klíčová slova
• Acanthamoeba castellanii, Cytotoxicity, Deep eutectic solvents, Excystment, Lactate dehydrogenase,
• MeSH
• Acanthamoeba castellanii * účinky léků   genetika   MeSH
• amébicidy * farmakologie   chemie   MeSH
• endoteliální buňky účinky léků   parazitologie   MeSH
• genotyp MeSH
• lidé MeSH
• organofosforové sloučeniny * farmakologie   chemie   MeSH
• rozpouštědla * farmakologie   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amébicidy * MeSH
• organofosforové sloučeniny * MeSH
• rozpouštědla * MeSH

BACKGROUND: This study evaluated in vitro antigiardial activity in four Indonesian plants (Archidendron fagifolium, Diospyros sumatrana, Piper betle and Shorea sumatrana) extracted in methanol, methanol-tetrahydrofuran, and water. These plants exhibiting promising anti-parasitic activity were selected on the basis of collected behavioral data and their ability to decrease parasite load in Sumatran orangutans. Extracts of Arabidopsis thaliana, a plant routinely used as a laboratory model in research, were used as a negative control. METHODS: Plant extracts of different concentrations (400, 100, 25 and 6.25 µg/ml) and metronidazole (100 µg/ml), a standard giardicidal drug, were incubated with 25,000 trophozoites per milliliter of growth medium in 12-well tissue culture plates under anaerobic conditions for 72 h. Cultures were counted in a hemocytometer using a light microscope and then statistically evaluated. The cytotoxicity of the extracts was determined by the MTT Cell Viability Assay. RESULTS: We recorded a statistically-significant decrease in giardia trophozoites in two extracts: the methanolic extract of A. fagifolium (Kruskal-Wallis: p = 0.013) and the aqueous extract of P. betle (Kruskal-Wallis: p = 0.002). Effective concentrations of 400 µg/ml and 100 µg/ml, respectively, were revealed. Cytotoxicity was not demonstrated. CONCLUSIONS: The results of our study show that extracts of A. fagifolium and P. betle have potential as an alternative treatment of G. intestinalis infection. This is the first scientific proof of the biological activity of A. fagifolium, confirming the assumption that orangutans use this plant (as well as P. betle) for self-medication.

• Klíčová slova
• Giardia intestinalis, Antigiardial activity, Drug of choice, Natural antiparasitic, Parasite,
• MeSH
• antiprotozoální látky farmakologie   MeSH
• Giardia lamblia * účinky léků   MeSH
• rostlinné extrakty * farmakologie   MeSH
• trofozoiti účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Indonésie MeSH
• Názvy látek
• antiprotozoální látky MeSH
• rostlinné extrakty * MeSH

A series of eighteen new 2-trifluoromethylcinnamanilides (1a-r) were synthesized by microwave synthesis and investigated for their antimycobacterial and antimalarial activities, along with the complementary (2E)-3-[3-(trifluoromethyl)phenyl]-N-arylprop-2-enanilides (2a-r) and (2E)-3-[4-(trifluoromethyl)phenyl]-N-arylprop-2-enanilides (3a-r) prepared earlier. All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102. The most active compounds against M. smegmatis (MIC values in the range of 1.17-11.1 µM, more effective than rifampicin) were anilides substituted by 3,5-CF3 (1q, 2q, 3q), 4-OCF3 (1k), and 4-CF3 (1j, 2j). The most effective agents against P. falciparum (IC50 values in the range of 0.32-4.5 µM, comparable to chloroquine) were anilides substituted by 3,5-CF3 (1q, 2q, 3q), 2-Br-4-OCF3 (1r), 4-CF3 (1j, 3j), 4-F (2d), 4-Cl (2g), 2-Cl (1e, 2e). A preliminary in vitro cytotoxicity screening was assessed using human leukemic cell lines and human dermal fibroblasts, revealing the toxic effect of 3,5-CF3 substituted anilides. On the other hand, the other investigated agents showed insignificant cytotoxic effects. Stability assays using rat liver microsomes demonstrated that compounds 1r (R = 2-Br-4-OCF3) and 1q (R = 3,5-CF3) are neither metabolized nor affect cytochrome P450 metabolizing capacity in vitro. Furthermore, complex in silico studies were performed - a combined approach (docking/MD simulations/QTAIM calculations) helped to define the molecular interactions that were applied during the binding of active agents and the subsequent inhibition of their molecular targets - InhA (activity against M. smegmatis) and arginase (activity against P. falciparum). In conclusion, promising active agents with dual antimycobacterial and antimalarial effects were identified.

• Klíčová slova
• Cinnamanilides, Cytotoxicity, Lipophilicity, M. smegmatis, Molecular modeling, P. falciparum, QTAIM calculations,
• MeSH
• anilidy farmakologie   chemie   chemická syntéza   MeSH
• antibakteriální látky farmakologie   chemie   chemická syntéza   MeSH
• antimalarika * farmakologie   chemie   chemická syntéza   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium smegmatis * účinky léků   MeSH
• parazitické testy citlivosti MeSH
• Plasmodium falciparum * účinky léků   MeSH
• simulace molekulového dockingu MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anilidy MeSH
• antibakteriální látky MeSH
• antimalarika * MeSH

Trichomoniasis, a globally distributed sexually transmitted infection, is caused by the urogenital parasite Trichomonas vaginalis Donné, 1836 affecting both women and men. The treatment of choice is metronidazole (MTZ). In the present study, 15 samples of vaginal discharge and urine were analysed by sequencing nitroreductase genes (ntr4 and ntr6). An in silico model was structured to illustrate the location of point mutations (PM) in the protein. The ntr4 gene presented four PMs: G76C (10/10), C213G (9/10), C318A (5/10) and G424A (1/10), while the ntr6 gene had eight PMs; G593A (13/13) the most frequent, G72T and G627C, both in 8/13. The PM C213G and A438T generated a stop codon causing a truncated nitroreductase 4 and 6 protein. Docking analysis demonstrated that some models had a decrease in binding affinity to MTZ (p < 0.0001). A high frequency of mutations was observed in the samples analysed that could be associated with resistance to MTZ in Chile.

• Klíčová slova
• clinical samples., dysfunctional enzyme, genital infection, protein polymorphism, refractory treatment, trichomoniasis,
• MeSH
• antiprotozoální látky farmakologie   MeSH
• bodová mutace * MeSH
• léková rezistence * MeSH
• lidé MeSH
• metronidazol * farmakologie   MeSH
• nitroreduktasy * genetika   metabolismus   MeSH
• protozoální proteiny genetika   metabolismus   MeSH
• trichomonádová vaginitida parazitologie   MeSH
• Trichomonas vaginalis * genetika   účinky léků   enzymologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Chile MeSH
• Názvy látek
• antiprotozoální látky MeSH
• metronidazol * MeSH
• nitroreduktasy * MeSH
• protozoální proteiny MeSH

BACKGROUND: Anthelmintic resistance (AR) is a global threat to grazing livestock farming. In Italy, anthelmintic efficacy remains high compared to other European countries, but many parts of the country haven't been investigated yet. Local veterinary practitioners from Trentino and Veneto regions reported suspected inefficacy towards anthelmintic drugs in some of their farms, prompting a study on AR in sheep and goat farms of northern Italy. The study aimed to assess anthelmintic effectiveness using genus-specific faecal egg count reduction tests (FECRT), to detect differences in treatment response among nematode genera involved in the infection. RESULTS: Twelve farms (6 sheep and 6 goat farms) were included based on clinical suspicion of AR. Treatments were carried out with either benzimidazoles (BZ) or macrocyclic lactones (ML) Treatment was effective in 3/6 goat trials, with reduced effectiveness to BZ in two farms and to ML the last one. In sheep farms (6/6), effectiveness was consistently and more severely insufficient. Ineffectiveness was particularly high towards Haemonchus contortus, while Oesophagostomum/Chabertia maintained susceptibility in nearly all trials. Trichostrongylus/Teladorsagia exhibited intermediate results. CONCLUSIONS: This study reveals diminished efficacy of both BZ and ML in small ruminant farms in north-eastern Italy, an area previously lacking data on the topic, except for goats in South Tyrol. Variability in treatment responses among nematode genera support suspicions of AR, and further concerns are raised by the prevalence of treatment ineffectiveness against the highly pathogenic Haemonchus contortus. This finding underscores the urgent need for comprehensive AR monitoring in the area and improved management practices to prevent further resistance development and protect livestock health.

• Klíčová slova
• Anthelmintic resistance, Control, Faecal egg count reduction test, Gastrointestinal nematodes, Small ruminants,
• MeSH
• anthelmintika * terapeutické užití   MeSH
• benzimidazoly terapeutické užití   farmakologie   MeSH
• feces parazitologie   MeSH
• Haemonchus * účinky léků   MeSH
• hemonchóza * veterinární   farmakoterapie   epidemiologie   MeSH
• kozy * MeSH
• léková rezistence * MeSH
• nemoci koz * farmakoterapie   parazitologie   epidemiologie   MeSH
• nemoci ovcí * farmakoterapie   epidemiologie   parazitologie   MeSH
• ovce MeSH
• počet parazitárních vajíček veterinární   MeSH
• prevalence MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Itálie epidemiologie   MeSH
• Názvy látek
• anthelmintika * MeSH
• benzimidazoly MeSH

Several Ranunculaceae species are used in folk medicine to eliminate pathologies associated with oxidative stress as well as parasitic infections; however, a number of studies confirming their pharmacological properties is limited. In this study, 19 ethanolic extracts obtained from 16 Ranunculaceae species were assayed for in vitro antioxidant, antiproliferative, and antiparasitic potential. The maximum antioxidant potential in both oxygen radical absorbance capacity (ORAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays was observed for Aconitum toxicum extract [half-maximal inhibitory concentration (IC50) 18.7 and 92.6 μg/mL]. Likewise, Anemone transsilvanica extract exerted the most promising antiproliferative activity against Caco-2 (IC50 46.9 μg/mL) and HT29 (IC50 70.2 μg/mL) cell lines in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Additionally, a dual antioxidant and cytotoxicity effect was demonstrated for Aconitum moldavicum and Caltha palustris extracts. Whilst the efficacy of extracts was modest against Trypanosoma brucei (IC50 ranging from 88.8 to 269.3 µg/mL), several extracts exhibited high potency against Leishmania infantum promastigotes (Aconitum vulparia IC50 18.8 µg/mL). We also tested them against the clinically relevant intracellular stage and found extract of A. vulparia to be the most effective (IC50 29.0 ± 1.1 µg/mL). All tested extracts showed no or low toxicity against FHs 74Int normal cell line (IC50 ranging from 152.9 to >512 µg/mL). In conclusion, we suggest the above-mentioned plant extracts as potential candidates for development of novel plant-based antioxidant and/or antiproliferative and/or antileishmanial compounds.

• Klíčová slova
• antileishmanial, antioxidants, antitrypanosomal, buttercup family, cytotoxicity, medicinal plants, plant extract,
• MeSH
• antioxidancia * farmakologie   chemie   MeSH
• antiparazitární látky farmakologie   chemie   MeSH
• buňky HT-29 MeSH
• Caco-2 buňky MeSH
• léčivé rostliny chemie   MeSH
• lidé MeSH
• proliferace buněk * účinky léků   MeSH
• Ranunculaceae chemie   MeSH
• rostlinné extrakty * farmakologie   chemie   MeSH
• tradiční lékařství MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Rumunsko MeSH
• Názvy látek
• antioxidancia * MeSH
• antiparazitární látky MeSH
• rostlinné extrakty * MeSH