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This study investigated the in vitro antimicrobial and anthelmintic effect of copper nanoparticles (CuNPs) against the bacterium Aeromonas hydrophila, the monogeneans Dactylogyrus minutus, Dactylogyrus extensus, Gyrodactylus cyprini, and the cestode Schyzocotyle acheilognathi, as well as their toxicity to Cyprinus carpio Koi. In the antimicrobial in vitro test, the inhibition zone method and minimum inhibitory concentration (MIC) were performed. In order to determine the time and efficacy of monogenean parasite mortality, the parasites were exposed to CuNP concentrations of 20, 50, 100, 150, 200, and 300 mg L -1 , and a control group with tank water and one with copper sulphate pentahydrate (CuSO 4 . 5 H 2 O) at a concentration of 0.3 mg L -1 , performed in triplicate. The parasites were observed every 10 min for 300 min, and mortality was recorded. For the cestodes, parasites were immersed in CuNP concentrations of 50, 100, 150, and 300 mg L -1 . At the end of the in vitro tests, the anthelmintic efficacy of each treatment was calculated. To assess the tolerance and toxicity in fish, they were exposed to CuNP concentrations of 0.6, 1.25, 2.5, 5, 10, 20, and 50 mg L -1 for 12 h. The MIC demonstrated that CuNPs effectively inhibited the growth of A. hydrophila up to a dilution of 12,500 mg L -1 and showed an inhibition zone of 14.0 ± 1.6 mm for CuNPs. The results of anthelmintic activity showed a dose-dependent effect of concentration for both groups of parasites, with the most effective concentration being 300 mg L -1 in 120 min. In the toxicity test, the carps showed tolerance to lower concentrations. The study indicated that CuNPs were effective against the studied pathogens. However, it proved to be toxic to fish at high concentrations. The use of low concentrations is recommended still requires further investigation., (© 2024 John Wiley & Sons Ltd.)

Purpose: To report optical coherence tomography findings of presumed veterinary anthelmintic drugs (VADs)-induced retinal toxicity that may aid in understanding potential pathogenic mechanisms., Methods: This is a retrospective observational case series analysis of patients with vision abnormalities following the accidental or intentional consumption of veterinary anthelmintic drugs. All cases underwent a thorough ophthalmological examination. Moreover, medical records, as well as the initial and follow-up optical coherence tomography images, were thoroughly scrutinized., Results: Four patients were identified (3 men; mean [range] age, 36.5 [22-52] years). Each patient overdosed on one or two of the following VADs: closantel, triclabendazole, praziquantel, pyrantel pamoate, and niclofolan. The most characteristic optical coherence tomography finding was diffuse, granular, hyperreflective lesions throughout the outer retina, which were initially identified in the ellipsoid zone in two cases. At follow-up, optical coherence tomography exhibited regression of hyperreflective lesions and extensive loss of the outer retinal elements in two patients. In addition, the subfoveal outer retinal layers may be partially preserved., Conclusion: Some veterinary anthelmintic drugs could be detrimental to the human retina if overdosed, resulting in visual disturbances. Optical coherence tomography revealed the mitochondria-enriched ellipsoid zone where outer retinal damage first appeared on, implying that these medications may harm the retina by inhibiting mitochondrial energy metabolism, as they do to eliminate parasites.

The sustainability of the traditional extensive livestock sector will only be possible if healthy dung-decomposing insect communities are preserved. However, many current pharmaceutical anthelmintics are harmful to dung beetles, their presence can have a negative impact on biological systems. Phytochemical anthelmintics are an alternative to ecotoxic synthetic pharmaceutical anthelmintics, although ecotoxicological tests of their possible indirect effects on dung beetles are required to demonstrate their viability. In this study, the potential ecotoxicity of thymol, carvacrol, cinnamaldehyde and garlic oil (diallyl disulfide and diallyl trisulfide) were tested for the first time. Inhibition of antennal response was measured as a relevant parameter by obtaining relevant toxicity thresholds derived from concentration‒response curves, such as the IC50. All phytochemical compounds tested were demonstrated to be suitable alternative candidates to the highly ecotoxic compound ivermectin, considering their non-toxicity to nontarget organisms. Residues of the phytochemical antiparasitics found in cattle droppings were extremely low, even undetectable in the case of diallyl disulfide and diallyl trisulfide. Furthermore, our results showed that none of the phytochemical compounds have ecotoxic effects, even at extremely high concentrations, including those almost 1000 times higher than what is most likely to be found in dung susceptible to ingestion by dung beetles in the field. We can conclude that the four selected phytochemical compounds meet the requirements to be considered reliable alternatives to ecotoxic veterinary medicinal products, such as ivermectin., Competing Interests: The authors declare no competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright: © 2023 Verdú et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Anthelmintics are drugs used for the treatment and prevention of diseases caused by parasitic worms (helminths). While the importance of anthelmintics in human as well as in veterinary medicine is evident, they represent emerging contaminants of the environment. Human anthelmintics are mainly used in tropical and sub-tropical regions, while veterinary anthelmintics have become frequently-occurring environmental pollutants worldwide due to intensive agri- and aquaculture production. In the environment, anthelmintics are distributed in water and soil in relation to their structure and physicochemical properties. Consequently, they enter various organisms directly (e.g. plants, soil invertebrates, water animals) or indirectly through food-chain. Several anthelmintics elicit toxic effects in non-target species. Although new information has been made available, anthelmintics in ecosystems should be more thoroughly investigated to obtain complex knowledge on their impact in various environments. This review summarizes available information about the occurrence, behavior, and toxic effect of anthelmintics in environment. Several reasons why anthelmintics are dangerous contaminants are highlighted along with options to reduce contamination. Negative effects are also outlined., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Anthelmintic (AH) compounds are used to control gastrointestinal nematodes (GINs) in livestock production. They are only partially metabolized in animals ending in animal excreta whose use as manures leads to AH dispersal in agricultural soils. Once in soil, AHs interact with soil microorganisms, with the outcome being either detrimental, or beneficial. We aimed to disentangle the mechanisms of these complex interactions. Two soils previously identified as « fast » or « slow», regarding the degradation of albendazole (ABZ), ivermectin (IVM), and eprinomectin (EPM), were subjected to repeated applications at two dose rates (1, 2 mg kg -1 and 10, 20 mg kg -1 ). We hypothesized that this application scheme will lead to enhanced biodegradation in «fast » soils and accumulation and toxicity in «slow » soils. Repeated application of ABZ resulted in different transformation pathways in the two soils and a clear acceleration of its degradation in the «fast » soil only. In contrast residues of IVM and EPM accumulated in both soils. ABZ was the sole AH that induced a consistent reduction in the abundance of total fungi and crenarchaea. In addition, inhibition of nitrification and reduction in the abundance of ammonia-oxidizing bacteria (AOB) and archaea (AOA) by all AHs was observed, while commamox bacteria were less responsive. Amplicon sequencing analysis showed dose-depended shifts in the diversity of bacteria, fungi, and protists in response to AHs application. ABZ presented the most consistent effect on the abundance and diversity of most microbial groups. Our findings provide first evidence for the unexpected toxicity of AHs on key soil microbial groups that might have to be considered in a regulatory context., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to characterise compounds with activity against carbapenemase-expressing Gram-negative bacteria and nematodes and evaluate their cytotoxicity to non-cancerous human cells., Methods: The antimicrobial activity and toxicity of a series of phenyl-substituted urea derivatives were evaluated using broth microdilution, chitinase, and resazurin reduction assays., Results: The effects of different substitutions present on the nitrogen atoms of the urea backbone were investigated. Several compounds were active against Staphylococcus aureus and Escherichia coli control strains. Specifically, derivatives 7b, 11b, and 67d exhibited antimicrobial activity against Klebsiella pneumoniae 16, a carbapenemase-producing Enterobacteriaceae species, with minimum inhibitory concentration (MIC) values of 100, 50, and 72 µM (32, 64, and 32 mg/L), respectively. In addition, the MICs obtained against a multidrug-resistant E. coli strain were 100, 50, and 36 µM (32, 16, and 16 mg/L) for the same compounds, respectively. Furthermore, the urea derivatives 18b, 29b, 50c, 51c, 52c, 55c-59c, and 62c were very active towards the nematode Caenorhabditis elegans., Conclusions: Testing on non-cancerous human cell lines suggested that some of the compounds have the potential to affect bacteria, especially helminths, with limited cytotoxicity to humans. Given the simplicity of synthesis for this class of compounds and their potency against Gram-negative, carbapenemase-expressing K. pneumoniae, aryl ureas possessing the 3,5-dichloro-phenyl group certainly warrant further investigation to exploit their selectivity., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Haemonchus contortus is a highly pathogenic and prevalent helminth that causes many deaths in sheep herds. Anthelmintics are usually employed to overcome this issue; however, they do not guarantee immediate and lasting efficacy because of the occurrence of drug-resistant parasites. Among substances that are used in scientific studies for parasitic control, essential oils are known to have different pharmacological properties. However, they demonstrate instability owing to several factors, and therefore, nanoemulsification is considered an alternative to control the instability and degradability of these compounds. The objective of this study was to evaluate the cytotoxicity of nanoemulsions containing essential oil of Eucalyptus globulus against the blood of healthy sheep and to verify their activity against the parasite H. contortus in sheep. The results presented adequate nanotechnological characteristics (diameter 72 nm, PDI 0.2, zeta -11 mV, and acidic pH) and adequate morphology. Further, the corona effect and cytotoxic profiles of the free oil and nanoemulsion against blood cells from healthy sheep were evaluated. The tests results did not present a toxicity profile. For evaluating efficacy, we observed an important anthelmintic action of the nanoemulsion containing oil in comparison to the free oil; the results demonstrate a potential role of the nanoemulsion in the inhibition of egg hatchability and the development of larvae L1 to L3 (infective stage). Based on these results, we developed an important and potential anthelmintic alternative for the control of the parasite H. contortus., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Haemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing., (© 2021. The Author(s).)

In continuation of the search for new anthelmintic natural products, the study at hand investigated the nematicidal effects of the two naturally occurring quassinoids ailanthone and bruceine A against the reproductive system of the model nematode Caenorhabditis elegans to pinpoint their anthelmintic mode of action by the application of various microscopic techniques. Differential Interference Contrast (DIC) and the epifluorescence microscopy experiments used in the presented study indicated the genotoxic effects of the tested quassinoids (c ailanthone = 50 µM, c bruceine A = 100 µM) against the nuclei of the investigated gonadal and spermathecal tissues, leaving other morphological key features such as enterocytes or body wall muscle cells unimpaired. In order to gain nanoscopic insight into the morphology of the gonads as well as the considerably smaller spermathecae of C. elegans , an innovative protocol of polyethylene glycol embedding, ultra-sectioning, acridine orange staining, tissue identification by epifluorescence, and subsequent AFM-based ultrastructural data acquisition was applied. This sequence allowed the facile and fast assessment of the impact of quassinoid treatment not only on the gonadal but also on the considerably smaller spermathecal tissues of C. elegans . These first-time ultrastructural investigations on C. elegans gonads and spermathecae by AFM led to the identification of specific quassinoid-induced alterations to the nuclei of the reproductive tissues (e.g., highly condensed chromatin, impaired nuclear membrane morphology, as well as altered nucleolus morphology), altogether implying an apoptosis-like effect of ailanthone and bruceine A on the reproductive tissues of C. elegans .

Recently, emerging pollutants, such as anthelmintics have attracted an increasing attention worldwide due to their extensive use and notable stability. However, the information on anthelmintics in the environment of southwest China is scarce. Thus, the occurrence, ecological risk and exposure evaluation of nineteen anthelmintics in Tuojiang River, which is one of the largest tributaries of Yangtze River, and drinking water source of Sichuan, southwest China, were investigated. The result showed that the detection frequency of anthelmintics was relatively high in Tuojiang River, ranging from 65% to 100% in river water. Among the seven kinds of anthelmintics, benzimidazoles are the primary anthelmintics, with concentrations up to 61.12 ng/L and 596.06 ng/g in water and sediment of the Tuojiang river, respectively. The total concentration of 19 anthelmintics in sediment samples from non-agricultural area was higher than that in agricultural area(p = 0.000 < 0.05). This could be attributed to anthropogenic activities, which lead to greater discharge and accumulation of anthelmintics in residential area along the river. It's worth to mention that the highest total concentrations of anthelmintics (109.28 ng/L) was found at the junction of rivers in R31 site. The results could be ascribed to the complexity of junction of Tuojiang River and Yangtze River, which could influence the distribution of pollutant. Besides, the ecological risk assessment showed that the macrocyclic lactones rather than benzimidazoles had relatively high toxicity to non-target organisms in aquatic environment (p = 0.000 < 0.05), with the highest RQ Ecotox value of 101 for Daphnia magna, while benzimidazoles had relatively high concentrations. The exposure risk could be ignored for both children and adults because the daily intake of anthelmintics via water ingestion were below 10 ng/kg/d. In addition, strong correlations were found between sucralose and most of the selected anthelmintics in Tuojiang River, indicating that sucralose might be a good tracer to evaluated the source of anthelmintics in surface water. This study provides the levels, risks and even some tracer information of pollutants for better understanding of anthelmintics in southwest China., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

This study assessed the in vitro anthelmintic activity of the alkaloids berberine, harmaline and piperine on gastrointestinal nematodes (GIN) of goat and their possible cytotoxic effects in Vero cells. The anthelmintic evaluation was performed using the egg hatch (EHA) and larval motility (LMA) assays. Cytotoxicity was determined using the 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide (MTT) assay. The alkaloids berberine and piperine inhibited the hatching of GIN eggs in more than 90 %. Piperine was the most active compound against goat GIN eggs with an EC 50 (effective concentration 50 %) of 0.0074 mM (0.0021 mg/mL), while the EC 50 of berberine was 1.32 mM (0.49 mg/mL). Harmaline (EC 50  = 1.6 mM - 0.34 mg/mL) showed moderate ovicidal action (80.30 %). In LMA, piperine and harmaline reduced larval motility in 2.75 and 25.29 %, respectively. Larvicidal efficacy was evidenced only with the alkaloid berberine, which showed a percentage of inhibition of larval motility of 98.17 % (2.69 mM =1.0 mg/mL). In the MTT assay, all alkaloids showed low toxicity to Vero cells, with a percentage of cell viability greater than 50 % in all concentrations tested. These results suggest that berberine and piperine have anthelmintic potential on goat gastrointestinal nematodes with low toxicity to mammalian cells., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: "Dogel ebs" was known as Sophora flavescens Ait., which has been widely utilized in the clinical practice of traditional Chinese Mongolian herbal medicine for thousands of years. Shen Nong's Materia Medica (Shen Nong Ben Cao Jing in Chinese pinyin) recorded that it is bitter in taste and cold in nature with the effect of clearing heat and eliminating dampness, insecticide, diuresis. Due to its extensive application in the fields of ethnopharmacological utilization, the pharmaceutical researches of Sophora flavescens Ait.s keeps deepening. Modern pharmacological studies have exhibited that matrine, which is rich in this traditional herbal medicine, mediates its main biological properties., Aims of the Review: This review aimed at summarizing the latest and comprehensive information of matrine on the pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches to explore the therapeutic potential of this natural ingredient. In addition, outlooks and perspective for possible future researches that related are also discussed., Materials and Methods: Related information concerning matrine was gathered from the internet database of Google scholar, Pubmed, ResearchGate, Web of Science and Wiley Online Library with the keywords including "matrine", "pharmacology", "toxicology" and "pharmacokinetics", "clinical application", etc. RESULTS: Based on literatures, matrine has a variety of pharmacological effects, including anti-cancer, anti-inflammatory, anti-microbial, detoxification and so on. Nevertheless, there are still some doubts about it due to the toxicity and questionable bioavailability that does exist., Conclusions: Future researches directions probably include elucidate the mechanism of its toxicity and accurately tracing the in vivo behavior of its drug delivery system. Without doubt, integration of toxicity and efficiency and structure modification based on it are also pivotal methods to enhance pharmacological activity and bioavailability., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Collagen-enriched cuticle forms the outermost layer of skin in nematode Caenorhabditis elegans. The nematode's genome encodes 177 collagens, but little is known about their role in maintaining the structure or barrier function of the cuticle. In this study, we found six permeability determining (PD) collagens. Loss of any of these PD collagens-DPY-2, DPY-3, DPY-7, DPY-8, DPY-9, and DPY-10-led to enhanced susceptibility of nematodes to paraquat (PQ) and antihelminthic drugs- levamisole and ivermectin. Upon exposure to PQ, PD collagen mutants accumulated more PQ and incurred more damage and death despite the robust activation of antioxidant machinery. We find that BLMP-1, a zinc finger transcription factor, maintains the barrier function of the cuticle by regulating the expression of PD collagens. We show that the permeability barrier maintained by PD collagens acts in parallel to FOXO transcription factor DAF-16 to enhance survival of insulin-like receptor mutant, daf-2. In all, this study shows that PD collagens regulate cuticle permeability by maintaining the structure of C. elegans cuticle and thus provide protection against exogenous toxins., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Ethnopharmacological Relevance: The leaf of Sarcocephalus latifolius is known to be used traditionally by the Fulanis in Nigeria to deworm animals. As helminthosis remains a major constraint to profitable livestock production worldwide, a precarious situation aggravated by the advent of resistant parasites, the discovery of new anthelmintics is a priority, necessitating exploration of medicinal plants for their anthelmintic principles., Aim of the Study: To identify and characterise compounds with anthelmintic activity from the leaf of Sarcocephalus latifolius., Materials and Methods: Powdered S. latifolius leaves were extracted by successive maceration with n-hexane, chloroform and acetone. The dried extracts were evaluated for anthelmintic activity against Haemonchus placei adult worms, and the most active extract was subjected to bioassay-guided chromatographic separations. The isolated compounds were evaluated for cytotoxicity against the mammalian HeLa and MC3T3-E1 cell lines, using alamar blue and CellTitreGlo TM to quantify cell viability. LC 50 values were computed from the in vitro anthelmintic activity data by fitting to a non-linear regression equation (variable slope). Isolated compounds were characterized using spectroscopic and mass spectrometric analyses., Results: Anthelmintic activity LC 50 values for n-hexane, chloroform and acetone extracts were 47.85, 35.76 and 5.72 (mg/mL), respectively. Chromatographic separation of acetone extract afforded two bioactive epimers, identified as vincosamide (LC 50 14.7 mg/mL) and strictosamide (LC 50 12.8 mg/mL). Cytotoxicity evaluation showed that, below 200 μg/mL (400 μM), neither compound was toxic to the HeLa or MC3T3-E1 cells., Conclusion: Vincosamide and strictosamide could serve as novel scaffolds for the development of anthelmintic derivatives with improved potency and helminth selectivity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Schistosomiasis is a prevalent neglected tropical disease that affects approximately 300 million people worldwide. Its treatment is through a single class chemotherapy, praziquantel. Concerns surrounding the emergence of praziquantel insensitivity have led to a need for developing novel anthelmintics., Methodology/principle Findings: Through evaluating and screening fourteen compounds (initially developed for anti-cancer and anti-viral projects) against Schistosoma mansoni, one of three species responsible for most cases of human schistosomiasis, a racemic N-acyl homoserine (1) demonstrated good efficacy against all intra mammalian lifecycle stages including schistosomula (EC50 = 4.7 μM), juvenile worms (EC50 = 4.3 μM) and adult worms (EC50 = 8.3 μM). To begin exploring structural activity relationships, a further 8 analogues of this compound were generated, including individual (R)- and (S)- enantiomers. Upon anti-schistosomal screening of these analogues, the (R)- enantiomer retained activity, whereas the (S)- lost activity. Furthermore, modification of the lactone ring to a thiolactone ring (3) improved potency against schistosomula (EC50 = 2.1 μM), juvenile worms (EC50 = 0.5 μM) and adult worms (EC50 = 4.8 μM). As the effective racemic parent compound is structurally similar to quorum sensing signaling peptides used by bacteria, further evaluation of its effect (along with its stereoisomers and the thiolactone analogues) against Gram+ (Staphylococcus aureus) and Gram- (Escherichia coli) species was conducted. While some activity was observed against both Gram+ and Gram- bacteria species for the racemic compound 1 (MIC 125 mg/L), the (R) stereoisomer had better activity (125 mg/L) than the (S) (>125mg/L). However, the greatest antimicrobial activity (MIC 31.25 mg/L against S. aureus) was observed for the thiolactone containing analogue (3)., Conclusion/significance: To the best of our knowledge, this is the first demonstration that N-Acyl homoserines exhibit anthelmintic activities. Furthermore, their additional action on Gram+ bacteria opens a new avenue for exploring these molecules more broadly as part of future anti-infective initiatives., Competing Interests: The authors have declared that no competing interests exist.

It was developed a material to act as an antimicrobial and antiparasitic agent through a modification reaction in the gum structure extracted from the plant Sterculia striata. This material was characterized, the oxidant activity was evaluated and the antimicrobial activity against Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Salmonella Typhimurium and Klebsiella pneumoniae was investigated, in addition to the effect against Leishmania amazonensis, testing its acute toxicity and its cytotoxicity in human cells. Characterization techniques proved the success of chemical modification. The modification led to an increase in antioxidant activity, with excellent antibacterial activity, reaching almost 100% inhibition for P. aeruginosa and S. Typhimurium, and inhibitory effect above 70% against L. amazonensis, with an affinity far superior to the parasite than macrophages. The derivative showed no acute toxicity, it was non-hemolytic, increased cell viability in macrophages and fibroblasts, and stimulated cell proliferation of keratinocytes, thus being a strong candidate to be used as an antimicrobial and antiparasitic agent in biomedical applications., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The present study explored the protective role of dietary the extract of Angelica sinensis (EAs) on high density, CuSO 4 , or trichlorfon-treated Crucian carp (Carassius auratus auratus). Firstly, the study showed that the optimum density for growth and growth inhibition was 0.49 and 0.98 fish L -1 water, respectively. Dietary EAs relieved the high density-induced growth inhibition in Crucian carp. The appropriate concentration of EAs for recovery of growth was estimated to be 4.30 g kg -1 diet in high-density fish. Moreover, high density decreased both digestive and absorptive enzyme activities and increased lipid oxidation in digestive organs, suggesting the ability of high density to induce oxidative damage. However, dietary EAs inhibited the oxidative damage through elevating ROS scavenging ability and enzymatic antioxidant activity in digestive organs. Secondly, our data demonstrated that the appropriate concentration of CuSO 4 to induce the decrease in feed intake (FI) was 0.8 mg Cu L -1 water. Dietary EAs returned to FI of Crucian carp treated with CuSO 4 . The appropriate concentration of EAs for recovery of FI was estimated to be 4.25 g kg -1 diet. Moreover, dietary EAs suppressed the CuSO 4 -induced decrease in digestion and absorption capacity and increase in protein metabolism in digestive organs of Crucian carp. Finally, the present results suggested that dietary EAs inhibited the trichlorfon-induced rollover (loss of equilibrium) in Crucian carp. The appropriate concentration of EAs for inhibition of rollover was estimated to be 4.18 g kg -1 diet. Moreover, trichlorfon stimulated not only the decrease in energy metabolism but also lipid and protein oxidation, suggesting that trichlorfon caused loss of function and oxidative damage in muscles of fish. However, dietary EAs improved muscular function and inhibited oxidative damage via quenching ROS and elevating non-enzymatic and enzymatic antioxidant activity in muscles of trichlorfon-induced fish. So, EAs could be used as an inhibitor of high density, CuSO 4 , and trichlorfon stress in fish.

The mechanisms of action of silver nanoparticles (AgNPs) in monogenean parasites of the genus Cichlidogyrus were investigated through a microarray hybridization approach using genomic information from the nematode Caenorhabditis elegans . The effects of two concentrations of AgNPs were explored, low (6 µg/L Ag) and high (36 µg/L Ag). Microarray analysis revealed that both concentrations of AgNPs activated similar biological processes, although by different mechanisms. Expression profiles included genes involved in detoxification, neurotoxicity, modulation of cell signaling, reproduction, embryonic development, and tegument organization as the main biological processes dysregulated by AgNPs. Two important processes (DNA damage and cell death) were mostly activated in parasites exposed to the lower concentration of AgNPs. To our knowledge, this is the first study providing information on the sub-cellular and molecular effects of exposure to AgNPs in metazoan parasites of fish.

The objective of the present study was to determine the susceptibility of entomopathogenic nematodes to ivermectin and thiabendazole. Soil samples collected from the municipalities of Irapuato and León, Guanajuato, Mexico, were obtained, from which the entomopathogenic nematodes (EPNs) of the Steinernematidae and Heterorhabditidae families were isolated. The samples were classified from livestock and nonlivestock soils, and the susceptibility of EPNs to anthelmintics was determined with the larval motility assay (LMA, 24 h) and the larval migration inhibition assay (LMI assay, 48 h). Sterile distilled water (T1) and treatments with 1% ivermectin diluted in 5% DMSO (dimethyl sulfoxide) (T2) and 5% thiabendazole diluted in 5% DMSO (T3) were applied to infective juvenile larvae. Analysis of variance was performed with a factorial design and Tukey's test at 0.05 probability. In addition, different concentrations of ivermectin (0.1, 0.5, 1, 1.2, 1.5, and 2 μg) and thiabendazole (1, 5, 10, 12, 15, and 20 mg) were evaluated to perform a Probit analysis to determine their LC50. All strains of EPNs were susceptible to ivermectin in both the LMA and LMI assay. The results show that EPNs are susceptible to ivermectin and thiabendazole, and the degree depends on the type of test performed, the chemical product used, and the origin of the strain of EPN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Abamectin is widely utilized in both agricultural and aquaculture areas in China for pest control. However, information about toxic effects of abamectin on non-target aquatic organisms is still incomplete. The Chinese mitten crab, Erocheir sinensis has been extensively bred in the rice-crab co-culture system for years, resulting in the frequent exposure to pesticides including abamectin. In the present study, a primary haemocyte culture model was established to investigate the immune response under exposure of abamectin. The results showed that medium osmolarity ranging from 360 to 480 mOsM/Kg was optimal for primary haemocyte culture from E. sinensis. Abamectin could induce significant decrease of cell viability, inhibition of phagocytic activity, as well as decline of acid phosphatase (ACP) and alkaline phosphatase (AKP) activities. All parameters decreased in time- and dose- dependent manners throughout the experiment, indicating the remarkable immunosuppression of abamectin on E. sinensis and also the sensitivity of the cytotoxicology model of haemocytes in vitro under abamectin exposure. In addition, a dose dependent increase of intracellular reactive oxygen species (ROS) was found after 6 h exposure. It revealed that excessive generation of ROS may a main reason to the degradation of cell viability, and moreover, the decrease in immune function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Leishmaniasis ( Leishmania species), sleeping sickness ( Trypanosoma brucei ), and Chagas disease ( Trypanosoma cruzi ) are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technological advances in parasitology, chemistry, and genomics have unlocked new possibilities for novel drug concepts and compound screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biological context, as well as different examples of recently discovered lead compounds., Competing Interests: The authors declare no conflicts of interest.

Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC 50  = 0.78-22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The objective of this study was to evaluate the efficacy of carvacryl acetate (CVA) and nanoencapsulated CVA (nCVA) on gastrointestinal nematodes of sheep. The CVA was nanoencapsulated with chitosan/gum arabic and the efficacy of nanoencapsulation (EE), yield, zeta potential, nanoparticle morphology and release kinetics at pH 3 and 8 were analyzed. Acute and subchronic toxicity were evaluated in rodents and reduction of egg counts in the faeces (FECRT) of sheep. The sheep were divided into four groups (n = 10): G1, 250 mg/kg CVA; G2, 250 mg/kg nCVA; G3, polymer matrix and G4: 2.5 mg/kg monepantel. EE and nCVA yield were 65% and 57%, respectively. The morphology of the nanoparticles was spherical, size (810.6±286.7 nm), zeta potential in pH 3.2 (+18.3 mV) and the 50% release of CVA at pHs 3 and 8 occurred at 200 and 10 h, respectively. nCVA showed LD50 of 2,609 mg/kg. CVA, nCVA and monepantel reduced the number of eggs per gram of faeces (epg) by 57.7%, 51.1% and 97.7%, respectively. The epg of sheep treated with CVA and nCVA did not differ from the negative control (P>0.05). Nanoencapsulation reduced the toxicity of CVA; however, nCVA and CVA presented similar results in the FECRT.

Ethnopharmacological Relevance: Arecae semen has been used as vermifuge and digestant in traditional Chinese medicine (TCM) for more than one thousand years. However, the toxicity effect of areca semen and its underlying mechanism are still unclear., The Aim of the Study: This study was aimed to investigate the toxicity of arecae semen and to explore its mechanisms by serum metabolomics., Materials and Methods: The male Wistar rats were divided into the control group and treated group (n = 6 in each group), which were given by gavage with distill water or arecae semen aqueous extract (ASAE) once a day for 30 days, respectively. Serum samples were collected from all the rats after treatment of 7-day, 14-day and 30-day for metabolomics analysis. Moreover, biochemistry analysis and histopathological examination were performed at the end of study., Results: The phenomenon of diarrhea, less physical activity, tremors and body curl up were observed in the treated group. Additionally, the body weights of treated rats were significantly decreased compared with control rats from the 8th day after oral administration. Except the level of creatinekinase (CK) in the treated group significantly increased compared with the control group, there were no differences on biochemistry parameters and histopathological test in the two groups. Combined with the methods of principal component analysis (PCA), orthogonal projection to latent structure-discrimination analysis (OPLS-DA) and available databases, the treated and control rats were clearly distinguished from each other and 19 metabolites were identified as the potential biomarkers in the arecae semen treated rats. The identified biomarkers indicated that there were perturbations of the phospholipid metabolism, amino acid metabolism and fat acid metabolism in the treated group., Conclusions: This indicated that arecae semen possessed certain cardiotoxicity and inhibited the normal growth in Wistar male rats. In addition, the metabolomics approach is a useful tool to study the toxicity in TCM., (Copyright © 2019. Published by Elsevier B.V.)

Drugs are potentially dangerous environmental contaminants, as they are designed to have biological effects at low concentrations. Monepantel (MOP), an amino-acetonitrile derivative, is frequently used veterinary anthelmintics, but information about MOP environmental circulation and impact is almost non-existent. We studied the phytotoxicity, uptake and biotransformation of MOP in two fodder plants, Plantago lanceolata and Medicago sativa. The seeds and whole plant regenerants were cultivated with MOP. The plant roots and the leaves were collected after 1, 2, 3, 4, 5 and 6 weeks of cultivation. The lengths of roots and proline concentrations in the roots and leaves were measured to evaluate MOP phytotoxicity. The UHPLC-MS/MS technique with a Q-TOF mass analyser was used for the identification and semi-quantification of MOP and its metabolites. Our results showed no phytotoxicity of MOP. However, both plants were able to uptake, transport and metabolize MOP. Comparing both plants, the uptake of MOP was much more extensive in Medicago sativa (almost 10-times) than in Plantago lanceolate. Moreover, 9 various metabolites of MOP were detected in Medicago sativa, while only 7 MOP metabolites were found in Plantago lanceolata. Based on metabolites structures, scheme of the metabolic pathways of MOP in both plants was proposed. MOP and its main metabolite (MOP sulfone), both anthelmintically active, were present not only in roots but also in leaves that can be consumed by animals. This indicates the potential for undesirable circulation of MOP in the environment, which could lead to many pharmacological and toxicological consequences., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Schistosomiasis is caused by a trematode of the genus Schistosoma and affects over 200 million people worldwide. The only drug recommended by the World Health Organization for treatment and control of schistosomiasis is praziquantel. Development of new drugs is therefore of great importance. Thiazoles are regarded as privileged structures with a broad spectrum of activities and are potential sources of new drug prototypes, since they can act through interactions with DNA and inhibition of DNA synthesis. In this context, we report the synthesis of a series of thiazole derivatives and their in vitro schistosomicidal activity by testing eight molecules (NJ03-08; NJ11-12) containing thiazole structures. Parameters such as motility and mortality, egg laying, pairing and parasite viability by ATP quantification, which were influenced by these compounds, were evaluated during the assays. Scanning electron microscopy (SEM) was utilized for evaluation of morphological changes in the tegument. Schistosomula and adult worms were treated in vitro with different concentrations (6.25 to 50 μM) of the thiazoles for up to 5 and 3 days, respectively. After in vitro treatment for five days with 6.25 μM NJ05 or NJ07 separately, we observed a decrease of 30% in schistosomula viability, whilst treatment with NJ05+NJ07 lead to a reduction of 75% in viability measured by ATP quantitation and propidium iodide labeling. Adult worms' treatment with 50 μM NJ05, NJ07 or NJ05 + NJ07 showed decreased motility to 30-50% compared with controls. Compound NJ05 was more effective than NJ07, and adult worm viability after three days was reduced to 25% in parasites treated with 50 μM NJ05, compared with a viability reduction to 40% with 50 μM NJ07. SEM analysis showed severe alterations in adult worms with formation of bulges and blisters throughout the dorsal region of parasites treated with NJ05 or NJ07. Oviposition was extremely affected by treatment with the NJ series compounds; at concentrations of 25 μM and 50 μM, oviposition reached almost zero with NJ05, NJ07 or NJ05 + NJ07 already at day one. Tested genes involved in egg biosynthesis were all confirmed by qPCR as downregulated in females treated with 25 μM NJ05 for 2 days, with a significant reduction in expression of p14, Tyrosinase 2, p48 and fs800. NJ05, NJ07 or NJ05+NJ07 treatment of HEK293 (human embryonic cell line) and HES (human epithelial cell line) showed EC50 in the range of 18.42 to 145.20 μM. Overall, our results demonstrate that those molecules are suitable targets for further development into new drugs for schistosomiasis treatment, although progress is needed to lessen the cytotoxic effects on human cells. According to the present study, thiazole derivatives have schistosomicidal activities and may be part of a possible new arsenal of compounds against schistosomiasis., Competing Interests: The authors have declared that no competing interests exist.

The production of tambaqui Colossoma macropomum has been undergoing financial losses due to parasitic infection by the acanthocephalan Neoechinorhynchus buttnerae, raising an alert for aquaculture in South America. The lack of adequate treatment and use of unlicensed chemicals encourages research for alternative solutions with minimal side effects. The objectives of this study were to evaluate the in vitro antiparasitic potential of commercial nutraceutical products (Natumix® and BioFish®) against N. buttnerae and to assess the respective in vivo toxic effects on the host tambaqui. For in vitro assays, parasitized fish were necropsied for acanthocephalans sampling. The parasites were exposed to three concentrations (0.078, 0.313 and 1.25 mg/ml) of each product, as well as controls (one without product and another with a solubilizer). For the in vivo acute toxicity test, juvenile fish (<0.1 g) were exposed to five increasing concentrations of each product. Mortality of tambaqui was recorded at 24, 48, 72 and 96 h. The estimated lethal concentration (LC) for 10, 50, 90 and 99% of fish was determined to classify the toxicity of the products on the target species. After in vitro efficacy tests, the highest concentrations (1.25 mg/ml) caused 100% mortality of the parasites in both products, but only Natumix® caused 100% mortality using the intermediate concentration (0.313 mg/ml) after 24 h. According to the acute toxicity result, the LC50 classified the nutraceutical products as slightly toxic for tambaqui. The tested products had a parasiticidal effect on N. buttnerae, and the toxicity test showed that both products have therapeutic potential when added to the diet.

Niclosamide is an antihelminthic drug used worldwide for the treatment of tapeworm infections. Recent drug repurposing screens have highlighted the broad bioactivity of niclosamide across diverse mechanisms of action. As a result, niclosamide is being evaluated for a range of alternative drug-repurposing applications, including the treatment of cancer, bacterial infections, and Zika virus. As new applications of niclosamide will require non-oral delivery routes that may lead to exposure in utero, it is important to understand the mechanism of niclosamide toxicity during early stages of embryonic development. Previously, we showed that niclosamide induces a concentration-dependent delay in epiboly progression in the absence of effects on oxidative phosphorylation - a well-established target for niclosamide. Therefore, the overall objective of this study was to further examine the mechanism of niclosamide-induced epiboly delay during zebrafish embryogenesis. Based on this study, we found that (1) niclosamide exposure during early zebrafish embryogenesis resulted in a decrease in yolk sac integrity with a concomitant decrease in the presence of yolk sac actin networks and increase in cell size; (2) within whole embryos, niclosamide exposure did not alter non-polar metabolites and lipids, but significantly altered amino acids specific to aminoacyl-tRNA biosynthesis; (3) niclosamide significantly altered transcripts related to translation, transcription, and mRNA processing pathways; and (4) niclosamide did not significantly alter levels of rRNA and tRNA. Overall, our findings suggest that niclosamide may be causing a systemic delay in embryonic development by disrupting the translation of maternally-supplied mRNAs, an effect that may be mediated through disruption of aminoacyl-tRNA biosynthesis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Toxocara spp. are responsible for causing toxocariasis, a zoonotic disease of global importance, which is difficult to treat as the available drugs have moderate efficacy in the clinical resolution of the disease. A promising alternative to the existing drugs is Propolis, which is known for having biological and pharmacological properties such as antiparasitic, antioxidant, and antitumor activities. In this study, we report the in vitro anthelmintic activity of essential oil from Brazilian Red Propolis (EOP) against larvae of Toxocara cati. Approximately 100 larvae per well were cultivated in microplates containing RPMI-1640 medium and incubated in the presence of EOP (18.75, 37.5, 75, 150, 300 and 600 μg/mL) to determine the Minimum Inhibitory Concentration (MIC) and IC 50 (concentration required to inhibit 50% of the population) values. Then, T. cati larvae treated with the MIC of EOP were inoculated in mice to evaluate their progression in vivo. A concentration of 600 μg/mL of EOP showed 100% larvicidal activity after exposure for 48 h, while 300 μg/mL represented the IC 50 and CC 50 . The anthelmintic activity of EOP was confirmed by the inability of the treated T. cati larvae to infect the mice. Our findings demonstrate the potential of EOP as an anthelmintic., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Effects of the antiparasitic drug eprinomectin were studied on the dung beetles, Onthophagus lenzii Harold and the rare species, Copris ochus Motschulsky by pour-on administrations (500 µg kg-1) in Japan. Eprinomectin was detected in cattle dung from 1 to 7 or 14 days after treatment, with a peak at 1 day after treatment in two experiments. In O. lenzii, adult survivals and numbers of brood balls constructed were significantly reduced in dung from eprinomectin-treated cattle at 1 and 3 days post-treatment in experiment 1, and adult emergence rates were extremely reduced in dung at 1, 3, and 7 days post-treatment. In C. ochus, adult survivals were significantly reduced in dung at 3 days post-treatment (experiment 1), and equivalent levels to the control were restored in dung at 7 and 14 days post-treatment (experiment 2). Numbers of brood balls of C. ochus were nil in dung at 3 days (experiment 1), and significantly reduced in dung at 7 days (experiment 2) post-treatment compared with control. Adult emergence rates of C. ochus were 100 and 71.6% in dung from control cattle in experiments 1 and 2, respectively. However, no oviposition was observed in dung at 3 days post-treatment, and all offspring died at egg or the first instar larval stage in dung from 7 and 14 days post-treatment. Feeding activities of O. lenzii and C. ochus were significantly inhibited in dung from treated cattle at 1-3 days and 3 days post-treatment, respectively, returning to levels of the control at 7 days post-treatment.

Ivermectin (IVM), a macrocylic lactone from the avermectin family, is a potent broad-spectrum anthelmintic drug widely used in veterinary as well as human medicine. Although the health benefits of IVM treatment are particularly important, this drug also represents an environmental pollutant with potentially negative effects on many non-target species. To evaluate the ecotoxicological risk of IVM administration to livestock, information evaluating achievable environment-reaching concentration is needed. Therefore, the present study was designed to determine the excretion profile of subcutaneously administered IVM in sheep. The standard recommended dose of IVM (0.2 mg kg -1 b.w.) was used. UHPLC/MS/MS was used for the analysis of IVM faecal concentration. In addition, the effect of IVM on seed germination and early roots growth of white mustard (Sinapis alba L.) was evaluated in order to estimate the potential phytotoxic effect of IVM. Based on the obtained results, the parameters of IVM pharmacokinetics (maximum concentration (c max ), time to achieve maximum concentration (t max ), mean residence time (MRT), area under the curve (AUC)) were calculated. IVM elimination in sheep was slow, but faster than the elimination reported previously in cattle. Great interindividual differences were also observed. A two-peak profile of concentration curves indicate the importance of the active efflux of IVM via enterocytes. A "seed germination and early roots growth" test revealed significant IVM phytotoxicity (20% inhibition of root growth) even at 50 nM concentration, a level which may be found in the environment. This newly demonstrated phytotoxicity of IVM together with its well-known toxicity to invertebrates should be taken into account, and thus animals treated with IVM should not be kept in pastures, especially not in sites with high ecological value., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Schistosomiasis, a chronic neglected tropical disease caused by the Schistosoma spp. parasite, is associated with disabling patient symptoms. The new focus of the WHO roadmap on 'transmission control, wherever possible' offers drug development opportunities for intermediate-host control to prevent human-to-snail-to-human parasite transmission. Reports on the analysis of the impact of 'chemical-based mollusciciding' have concluded that constant application of molluscicides may contribute significantly towards the elimination of schistosomiasis in endemic areas. In South-Western Nigeria, Tetrapleura tetraptera is a tree whose fruit has been widely used in snail vector control. The presence of molluscicidal N-acetyl triterpene glycosides in the fruit has been reported. In this study, a bioactivity-directed fractionation of the fruit extract was performed to isolate the most potent molluscicidal saponin from the fruit. In an attempt to provide mechanistic insight into the observed activity, in silico screening was performed, profiling the molluscicidal N-acetyl triterpene glycosides reported from the fruit against two potential therapeutic targets in the mollusk used, NADH-ubiquinone oxidoreductase (NAD1) and retinoid X receptor. The docking predicted binary complexes of the saponins, which were subjected to explicit solvent conformational sampling from which patterns of structural stability were obtained. The binding energies alone did not account for the potency of the saponins indicating the influence of other factor like pharmacokinetic parameters. The study concluded that there is a preferential suitability of ND1's MWFE site for the rational design and development of novel molluscicidal agents., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Overdoses of macrocyclic lactones in dogs and cats can result in such signs as tremors, ataxia, seizures, coma, and blindness. Dogs with the ABCB1-1Δ gene defect are predisposed to macrocyclic lactone toxicosis at lower dosages than dogs without the defect. Intravenous lipid emulsion therapy has been suggested for treatment of macrocyclic lactone toxicosis but evidence of efficacy is limited. Initial decontamination and supportive care remain the mainstays of therapy for macrocyclic lactone toxicosis., (Published by Elsevier Inc.)

This study describes the effects of extracts and fractions of Persea willdenovii leaves against goat gastrointestinal nematodes and their cytotoxicity on Vero cells. The in vitro ovicidal and larvicidal activities of the crude ethanolic, hexane, ethyl acetate (EAE), butanolic and residual hydroethanolic extracts were assessed through the inhibition of egg hatching and larval motility assays. The most active extract (EAE) was then fractionated by chromatography in an open column containing silica gel, to furnish six fractions (Fr1-Fr6), which were also tested. The cytotoxicity of active extracts and fractions was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue exclusion assay. The EAE and two fractions (Fr1 and Fr2) showed inhibitory activity in the egg hatching of gastrointestinal nematodes of goats in a concentration-dependent manner. The effective concentrations for 50% inhibition (EC50) of egg hatching were 2.3, 0.12 and 2.94 mg/ml for EAE, Fr1 and Fr2, respectively. All extracts and fractions were not effective in inhibiting 50% of motility of infective larvae. EAE and Fr2 had IC50 values (50% inhibitory concentration) of 4.95 and 2.66 mg/ml, respectively. Fr1 showed a slight cytotoxic effect (cellular inviability <30%) only after 48 h of treatment (MTT test). Gas chromatography-mass spectrometry (GC-MS) analysis showed the presence of six fatty acid ethyl esters, a fatty acid methyl ester and a long-chain ketone in the most active fraction. These constituents identified in P. willdenovii can be related to the high ovicidal activity and relatively non-toxic effect of the extracts.

Ivermectin (IVM) is widely used in human and veterinary medicine for the control of parasitic infections. Researches revealed new avenues of medicinal applications of IVM as an antiviral and an anticancer agent. Very little is known about the genotoxic potential of IVM and the available literature is contradictory. The objective of this study was to evaluate the possible genetic damage caused by IVM. Male Sprague Dawley rats were intraperitoneally given IVM at doses between 0.2 mg and 3.2 mg/kg body weight (b. w). Percentages of mitotic and aberrant bone marrow cells were followed. The results indicated that IVM by itself, at doses higher than the recommended dose, induced significant levels of cytogenetic toxicity. To this end, we decided to investigate the potential use of combination of varying doses of aged garlic extract (AGE); 300, 600 and 1200 mg/kg b w and the minimum detectable toxic (MDT) dose of IVM; 0.4 mg/kg. A powerful capacity of AGE to reduce IVM cytogenetic effects was demonstrated. Overall, the data prove the safety of IVM at the recommended dose and provide a strong scientific evidence for superior protection of AGE against possible cytogenotoxic side effects of IVM, confirming the existence of a meaningful therapeutic window., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A quantitative structure-activity (QSAR) model has been developed for enriched tubulin inhibitors, which were retrieved from sequence similarity searches and applicability domain analysis. Using partial least square (PLS) method and leave-one-out (LOO) validation approach, the model was generated with the correlation statistics of [Formula: see text] and [Formula: see text] of 0.68 and 0.69, respectively. The present study indicates that topological descriptors, viz. BIC, CH&#95;3&#95;C, IC, JX and Kappa&#95;2 correlate well with biological activity. ADME and toxicity (or ADME/T) assessment showed that out of 260 molecules, 255 molecules successfully passed the ADME/T assessment test, wherein the drug-likeness attributes were exhibited. These results showed that topological indices and the colchicine binding domain directly influence the aetiology of helminthic infections. Further, we anticipate that our model can be applied for guiding and designing potential anthelmintic inhibitors.

Schistosomiasis, caused by helminth flatworms of the genus Schistosoma , is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify new antischistosomal drugs. Piplartine is an amide alkaloid found in several Piper species (Piperaceae) that exhibits antischistosomal properties. The aim of this study was to evaluate the structure–function relationship between piplartine and its five synthetic analogues (19A, 1G, 1M, 14B and 6B) against Schistosoma mansoni adult worms, as well as its cytotoxicity to mammalian cells using murine fibroblast (NIH-3T3) and BALB/cN macrophage (J774A.1) cell lines. In addition, density functional theory calculations and in silico analysis were used to predict physicochemical and toxicity parameters. Bioassays revealed that piplartine is active against S. mansoni at low concentrations (5⁻10 µM), but its analogues did not. In contrast, based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, piplartine exhibited toxicity in mammalian cells at 785 µM, while its analogues 19A and 6B did not reduce cell viability at the same concentrations. This study demonstrated that piplartine analogues showed less activity against S. mansoni but presented lower toxicity than piplartine.

Ethnopharmacological Relevance: Duranta erecta L. fruits have been reported to have in vitro anthelminthic properties. People living in the tropical South-Eastern part of Nigeria use the plant in folk medicine for the treatment of malaria, abscesses and as a vermifuge. Although there are a few reports about its in vitro anthelminthic activity against different worm categories, scientific reports regarding its in vivo anthelminthic activity are limited., Aim of the Study: This study was designed with the aim of determining the potential of the plant as an anthelminthic and to verify the claims made by its local users., Materials and Methods: Acute toxicity of the plant extract was determined using Lorke's method. Anthelminthic activity was investigated using adult male albino mice experimentally infected with Heligmosomoides bakeri infective L 3 . Graded ascending doses of the plant extract and Albendazole respectively were orally administered to the mice in the infected groups. Corprological and haematological parameters were recorded within the study period. Twenty-eight (28) days post-infection, all infected mice were humanely sacrificed and the Post-Mortem Adult Worm Burden (WB) was estimated and recorded., Results: The results showed that the extract had an LD 50 greater than 5000 mg/kg BW and therefore was not acutely toxic for oral use. It also showed that the plant extract was unable to eliminate the faecal egg output or adult worms in the gastrointestinal tract of infected animals even at the high doses used in the study. This was in contrast to Albendazole which significantly (p < .05) reduced faecal egg counts and worm burdens by 71% and 92% respectively in treated mice. Following infection, there was anaemia in all infected groups seen from results of erythrocytic parameters. Treatment with the plant extract, regardless of the dose, was unable to effectively reverse the effect of parasite infection on erythrocytic parameters. However, treatment with Albendazole positively reversed the anaemia, restoring the mice to pre-infection values by the end of the experiment. The results showed significant (p < .05) increase in WBC counts across all groups following infection with the parasite. Treatment with the plant extract and Albendazole respectively, significantly (p < .05) reduced the WBC counts to near pre-infection values in most treatment groups., Conclusion: As a result of the poor anthelminthic effects recorded in the study, it is therefore recommended that Duranta erecta L. fruits be explored for its other useful effects rather than as an anthelminthic., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study evaluated efficacy and toxicity of the pyrazinoisoquinoline anthelmintic praziquantel (PZQ) in barbel infected with metacercariae of Diplostomum spathaceum and adult Pomphorhynchus laevis, and assessed antioxidant biomarkers and the lipid peroxidation response in juvenile barbel post-treatment. The estimated 96-hr LC50 of PZQ was 28.6 mg/L. For evaluation of efficacy, barbel naturally infected with D. spathaceum were exposed to a 10 and 20 mg/L PZQ 4-day bath treatment. Both concentrations were 100% effective against D. spathaceum and significantly (p < .01) affected the activity of catalase, superoxide dismutase, glutathione reductase and glutathione-S-transferase as well as levels of reduced glutathione in liver and muscle. The efficacy of orally administered PZQ was assessed in adult barbel naturally infected with P. laevis. Fish were administered 10, 30 and 50 mg/kg of body weight and examined via gut dissection after 6 days. The 50 mg/kg dose significantly decreased the intensity of infection. Praziquantel is a feasible bath treatment for barbel infected with D. spathaceum and has potential for oral treatment of broodfish infected with P. laevis., (© 2018 John Wiley & Sons Ltd.)

Triclosan (TCS), 2,4,6-trichlorophenol (2,4,6-TCP) and 2,4-dichlorophenol (2,4-DCP) are the most prevalent chlorinated phenolic pollutants in aquatic environments. Our results showed LC 50 and EC 50 values of 0.51, 1.11, 2.45mg/L, and 0.36, 0.74, 1.53mg/L for TCS, 2,4,6-TCP and 2,4-DCP, respectively, to 120hpf zebrafish. The highest TCSD (the mixture of TCS, 2,4,6-TCP and 2,4-DCP) toxicity was observed at a TCS:2,4,6-TCP:2,4-DCP concentration ratio of 1:2:4. LC 50 and EC 50 values of TCSD mixtures for 120-hpf zebrafish were 2.28 and 1.16mg/L, respectively. Two toxicity assessment methods (Toxic Unit and Mixture Toxicity Index) indicated that TCSD interactions produced partly additive toxicity. TCSD exposure decreased zebrafish hatching rate and led to a series of malformations. Following alkaline phosphatase staining, a large area of vascular ablation was observed with almost complete disappearance of vascular branches and a smaller coverage range. Prominent reddening of the yolk sac and visceral mass after oil red O staining implied that TCSD exposure severely affected fat metabolism. Following acridine orange staining, cell death occurred in eyes while high TCSD concentrations (0.84mg/L) induced cardiovascular circulation dysfunction. Alcian blue staining increased the α angle between Meckel's cartilages and β angle between two ceratobranchial. Basihyal and palatoquadrate became shorter and developmental abnormality or defects occurred in the fifth ceratobranchial. Overall, these results provide a theoretical basis for systematically evaluating the combined toxicity of the prevalent chlorinated phenolic pollutants in real-world aquatic environments., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Avermectins are used worldwide as antiparasitic drugs in the field of veterinary medicine and as agricultural pesticides and insecticides. Carbonic anhydrase (CA, E.C. 4.2.1.1) is a zinc-containing metalloenzyme that catalyzes the reversible hydration of carbon dioxide (CO 2 ) to yield protons (H + ) and bicarbonate (HCO 3 - ). In this study, some avermectins, including abamectin, doramectin, eprinomectin, and moxidectin, were investigated for in vitro inhibitory effects on the CA enzyme purified from goat liver, which was purified (125.00-fold) using sepharose 4B-l-tyrosine-sulfanilamide affinity chromatography, with a yield of 68.27% and a specific activity of 21765.31 EU/mg proteins. The inhibition results obtained from this study showed K i values of 0.283, 0.153, 0.232, and 0.317 nM for abamectin, doramectin, eprinomectin, and moxidectin, respectively. On the other hand, acetazolamide, well-known clinically established CA inhibitor, possessed a K i value of 0.707 nM against goat liver CA., (© 2017 Wiley Periodicals, Inc.)

Although veterinary anthelmintics represent an important source of environmental pollution, the fate of anthelmintics and their effects in plants has not yet been studied sufficiently. The aim of our work was to identify metabolic pathways of the two benzimidazole anthelmintics fenbendazole (FBZ) and flubendazole (FLU) in the ribwort plantain (Plantago lanceolata L.). Plants cultivated as in vitro regenerants were used for this purpose. The effects of anthelmintics and their biotransformation products on plant oxidative stress parameters were also studied. The obtained results showed that the enzymatic system of the ribwort plantain was able to uptake FLU and FBZ, translocate them in leaves and transform them into several metabolites, particularly glycosides. Overall, 12 FLU and 22 FBZ metabolites were identified in the root, leaf base and leaf top of the plant. Concerning the effects of FLU and FBZ, both anthelmintics in the ribwort plantain cells caused significant increase of proline concentration (up to twice), a well-known stress marker, and significant decrease of superoxide dismutase activity (by 50%). In addition, the activities of four other antioxidant enzymes were significantly changed after either FLU or FBZ exposition. This could indicate a certain risk of oxidative damage in plants influenced by anthelmintics, particularly when they are under other stress conditions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Olfaction is a key sensory mechanism in humans. Deficits in this chemosensory function have wide-ranging impacts on overall health and quality of life. This study examines the role of environmental phenols as risk factors for olfactory dysfunction among a random sample of 839 middle-aged and older U.S. adults. Olfactory function assessment was carried out using a short 8-item test, scores on which were used to classify subjects into normal or impaired olfactory function groups. Logistic regression models were used to test for associations between olfactory impairment and creatinine-adjusted urinary levels of 8 common environmental phenols, adjusting for potentially confounding covariates. A statistically significant association between 2,4-dichlorophenol levels and olfactory impairment (OR = 1.02 [95 % CI: (1.003, 1.04)]; p = 0.02) was found. 2,4-dichlorophenol is a hazardous pollutant with widespread exposure via industrial and indoor air pollution, diet, and the use of pesticides and herbicides. This study is the first to reveal its role in olfactory impairment.

Praziquantel is the most effective anthelminthic drug for the treatment of schistosomiasis, an infectious disease caused by the platyhelminth Schistosoma mansoni. While praziquantel is known to trigger calcium influx into schisostomes, followed by spastic paralysis of the worms and tegumental disruption, the mechanism of action of the drug is not completely understood. Although relatively well tolerated, praziquantel has been reported to cause mild adverse effects, including nausea, abdominal pain and headaches. As a number of putative Transient Receptor Potential (TRP) channel genes have recently been predicted in S. mansoni, we sought to investigate the effect of praziquantel on three mammalian TRP channels, TRP melastatin type 8 (TRPM8), TRP vanilloid type 1 (TRPV1) and TRP ankyrin type 1 (TRPA1). Using calcium microfluorimetry and the patch clamp technique, we recorded the effect of praziquantel on HEK293T cells expressing recombinant TRPM8, TRPV1 or TRPA1, as well as on cultured dorsal root ganglion (DRG) neurons from wild type and TRPM8 null mutant mice. We discovered that praziquantel is a relatively potent and selective partial agonist of the mammalian and avian cold and menthol receptor TRPM8. The activation of cultured DRG neurons by clinically relevant concentrations of praziquantel is predominantly mediated by TRPM8. Our results may provide clues to a better understanding of praziquantel's mechanism of action and its adverse effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

2,4-Dichlorophenol (2,4-DCP) is considered a priority pollutant due to its high toxicity. Therefore, it is urgent to develop technologies for the disposal of this pollutant. Various remediation processes have been proposed for the elimination of 2,4-DCP in contaminated water, however, most of them involve high costs of operation and maintenance. This study aimed to determine the capacity of remediation of 2,4-DCP in water by Typha latifolia L. wild plants. For that, the tolerance, removal, accumulation and biotransformation of 2,4-DCP by T. latifolia were investigated. The plants were exposed to 2,4-DCP solutions with a concentration range from 1.5 to 300 mgL -1 for 10 days. They exhibited a reduction in chlorophyll levels and growth rate when 2,4-DCP solutions were ≥30 mgL -1 and ≥50 mgL -1 , respectively. The removal of contaminant was dose-depended, being 99.7% at 1.5-3 mgL -1 , 59-70% at 10-70 mgL -1 and 35-42% at 100-300 mgL -1 of 2,4-DCP in the solution. Studies indicated that 2,4-DCP was mainly accumulated in root tissue rather than in shoot tissue. Acid hydrolysis of biomass extracts suggests 2,4-DCP bioconjugates formation in root tissue as a response mechanism. Additionally, an increment in glutathione S-transferase (GST) activity could indicate a 2,4-DCP conjugation with glutathione as a detoxification mechanism of T. latifolia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The present study describes the isolation, characterization and in vitro cytotoxic effect of all forced degradation products of niclosamide (NCM) an anthelmintic class of drug used specifically to treat tapeworms. NCM was subjected to forced degradation involving hydrolysis (acidic, alkaline and neutral), oxidative, photolysis and thermal stress, as per ICH (Q1A (R2)) suggested conditions. The drug under hydrolytic (acidic and basic) conditions showed extensive degradation, while it was stable under neutral hydrolytic, oxidative, photolytic and thermal stress conditions. A total of four degradation products (DPs) were observed and chromatographic separation of drug and its degradation products were achieved on a reverse phase Fortis diphenyl column (150×4.6mm, 5μm) using 0.1% formic acid and acetonitrile as mobile phase in gradient mode. All the four degradation products were isolated by semi preparative LC and its structures were characterized and confirmed by high resolution MS and 1 H NMR spectroscopic techniques. In view of safety aspects, cytotoxicity assay were carried out for NCM and its four degradation products on human mononuclear cells and cell lines depicting the major organelle: neuronal (Neuro 2a), hepatic (HepG 2) and alveolar (A549). NCM was found to be non toxic on human mononuclear cells and cell lines at tested concentrations. However DP-1, DP-2, DP-3 and DP-4 showed significant increase in LDH release as compared to control at a concentration of 100μM. DP-1 and DP-3 exhibited toxicity on A549 cells with an IC 50 of 92.18±4.93μM and 65.42±6.29μM respectively. DP-2, DP-3 and DP-4 were cytotoxic to Neuro 2a cells with an IC 50 of 63.62±3.85μM, 86.09±6.19μM and 42.81±8.10μM respectively. The degradation products were found to be nontoxic on HepG 2 cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25-50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent.

In vivo and in vitro antiparasitic activity of the essential oil of Lippia sidoides and blood and histological alterations were assessed in Colossoma macropomum (tambaqui). Essential oil concentrations of 10, 20, 40, 80, 160 and 320mg/L were assayed in vitro against monogenoideans Anacanthorus spathulatus, Notozothecium janauachensis and Mymarothecium boegeri from fish gills. Lippia sidoides essential oil concentrations of 320 and 160mg/L were 100% effective against monogenoideans in 10min and 1h of exposure, respectively. However, the effectiveness of 100% concentrations of 80mg/L and 40mg/L occurred in 3 and 6h, respectively. In the in vivo tests, juvenile fish were submitted to 60min of baths with 10mg/L and 15min of baths with 20mg/L of the essential oil of L. sidoides. These therapeutic baths were not efficient against Ichthyophthirius multifiliis, and monogenoideans present in the gills of C. macropomum. In addition, 10 and 20mg/L of the essential oil of L. sidoides caused an anesthetic effect on the fish and did not influence total glucose and protein plasma levels; however, it decreased the number of total erythrocytes in fish exposed to the higher concentration of this essential oil. Severe alterations and irreversible damage were observed in the fish gills just after L. sidoides essential oil baths and after 24h of recovery. The most recurrent lesions found were hyperplasia and fusion of the lamellar epithelium, vasodilation, detachment of the gill epithelium and lamellar aneurism, epithelial breakdown with hemorrhage, congestion, edema and necrosis, proliferation of the mucous cells and chloride cells and lamellar hypertrophy. Therefore, since the essential oil of L. sidoides has in vitro antiparasitic activity and low concentrations of it have shown toxic effects, the bioactive potential of its main chemical components should be investigated, as well as more efficient forms of its administration in therapeutic baths in order to eliminate fish parasites., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Avermectin (AVM) has been widely used in agriculture and animal husbandry based on its broad spectrum of effective anthelmintic activity and specificity targets. However, AVM induction of cytotoxicity in human liver is largely unknown. In this study, we investigate the cytotoxic effects of AVM on HepG2 cells in vitro. The results revealed that AVM inhibited the viability of HepG2 cells and enhanced apoptosis. Established assays of cytotoxicity were performed to characterize the mechanism of AVM toxicity on HepG2 cells. Typical apoptosis morphological changes were shown in AVM-treatment cells including chromatin condensation and DNA fragmentation. We demonstrated that AVM-induced apoptosis of HepG2 cells were mediated by generated ROS. Moreover, a decrease in mitochondrial membrane potential (MMP) and up-regulating the Bax/Bcl-2 ratio, resulted in a release of cytochrome-c as well as activation of caspase-9/-3. In conclusion, our experimental results show that AVM has a potential threat to human health which may be induce apoptosis of human hepatocyte cells via caspase-dependent mitochondrial pathways., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Current scolicidal agents, which have been used for inactivation of protoscoleces during surgical procedures, are associated with adverse side effects including sclerosing cholangitis. This investigation aimed to evaluate the scolicidal effects of Bunium persicum (Boiss) essential oil against protoscoleces of hydatid cysts and also its toxicity in a mice model., Methods: Protoscoleces were aseptically aspirated from sheep livers having hydatid cysts. Various concentrations of the essential oil (3.125-50 mcL/mL) were used for 5-30 min. The viability of protoscoleces was confirmed using the eosin exclusion test (0.1% eosin staining). Further, 48 male NMRI mice were used to determine the acute and sub-acute toxicity of B. persicum essential oil., Results: The obtained results revealed that the B. persicum essential oil at the concentrations of 25 and 50 mcL/mL after 5 min of exposure killed 100% protoscoleces. The mean mortality rate of protoscoleces after 10 min of exposure to the concentration of 12.5 mcL/mL was 100%. Lower concentrations (6.25 and 3.125 mcL/mL) of B. persicum essential oil, however, indicated a delayed protoscolicidal effects. The LD 50 value of intra-peritoneal injection of the B. persicum essential oil was 1.96 mL/kg body wt. No significant difference (p > 0.05) was observed in the clinical chemistry and hematologic parameters after oral administrations of B. persicum essential oil at the doses 0.05, 0.1, 0.2, and 4 mL/kg for 14 d., Conclusion: Our findings demonstrated the potent scolicidal activity of B. persicum with no significant toxicity; it might be used as a natural scolicidal agent in hydatid cyst surgery.