International Journal for Parasitology: Drugs and Drug Resistance最新文献

{"title":"Effect of geranylated dihydrochalcone from Artocarpus altilis leaves extract on Plasmodium falciparum ultrastructural changes and mitochondrial malate: Quinone oxidoreductase","authors":"Agriana Rosmalina Hidayati ,&nbsp;Melinda ,&nbsp;Hilkatul Ilmi ,&nbsp;Takaya Sakura ,&nbsp;Miako Sakaguchi ,&nbsp;Junko Ohmori ,&nbsp;Endah Dwi Hartuti ,&nbsp;Lidya Tumewu ,&nbsp;Daniel Ken Inaoka ,&nbsp;Mulyadi Tanjung ,&nbsp;Eri Yoshida ,&nbsp;Fuyuki Tokumasu ,&nbsp;Kiyoshi Kita ,&nbsp;Mihoko Mori ,&nbsp;Kazuyuki Dobashi ,&nbsp;Tomoyoshi Nozaki ,&nbsp;Din Syafruddin ,&nbsp;Achmad Fuad Hafid ,&nbsp;Danang Waluyo ,&nbsp;Aty Widyawaruyanti","doi":"10.1016/j.ijpddr.2022.12.001","DOIUrl":"10.1016/j.ijpddr.2022.12.001","url":null,"abstract":"<div><p>Nearly half of the world's population is at risk of being infected by <em>Plasmodium falciparum,</em> the pathogen of malaria. Increasing resistance to common antimalarial drugs has encouraged investigations to find compounds with different scaffolds. Extracts of <em>Artocarpus altilis</em> leaves have previously been reported to exhibit <em>in vitro</em> antimalarial activity against <em>P. falciparum</em> and <em>in vivo</em> activity against <em>P. berghei</em>. Despite these initial promising results, the active compound from <em>A. altilis</em> is yet to be identified. Here, we have identified 2-geranyl-2′, 4′, 3, 4-tetrahydroxy-dihydrochalcone (<strong>1</strong>) from <em>A. altilis</em> leaves as the active constituent of its antimalarial activity. Since natural chalcones have been reported to inhibit food vacuole and mitochondrial electron transport chain (ETC), the morphological changes in food vacuole and biochemical inhibition of ETC enzymes of (<strong>1</strong>) were investigated. In the presence of (<strong>1</strong>), intraerythrocytic asexual development was impaired, and according to the TEM analysis, this clearly affected the ultrastructure of food vacuoles. Amongst the ETC enzymes, (<strong>1</strong>) inhibited the mitochondrial malate: quinone oxidoreductase (<em>Pf</em>MQO), and no inhibition could be observed on dihydroorotate dehydrogenase (DHODH) as well as <em>bc</em>₁ complex activities. Our study suggests that (<strong>1</strong>) has a dual mechanism of action affecting the food vacuole and inhibition of <em>Pf</em>MQO-related pathways in mitochondria.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/56/main.PMC9798170.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9495054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and pharmacodynamic considerations for treating sarcoptic mange with cross-relevance to Australian wildlife","authors":"Kotaro Takano ,&nbsp;Lachlan de Hayr ,&nbsp;Scott Carver ,&nbsp;Robert J. Harvey ,&nbsp;Kate E. Mounsey","doi":"10.1016/j.ijpddr.2023.02.004","DOIUrl":"10.1016/j.ijpddr.2023.02.004","url":null,"abstract":"<div><p><em>Sarcoptes scabiei</em> is the microscopic burrowing mite responsible for sarcoptic mange, which is reported in approximately 150 mammalian species. In Australia, sarcoptic mange affects a number of native and introduced wildlife species, is particularly severe in bare-nosed wombats (<em>Vombatus ursinus</em>) and an emerging issue in koala and quenda. There are a variety of acaricides available for the treatment of sarcoptic mange which are generally effective in eliminating mites from humans and animals in captivity. In wild populations, effective treatment is challenging, and concerns exist regarding safety, efficacy and the potential emergence of acaricide resistance. There are risks where acaricides are used intensively or inadequately, which could adversely affect treatment success rates as well as animal welfare. While reviews on epidemiology, treatment strategies, and pathogenesis of sarcoptic mange in wildlife are available, there is currently no review evaluating the use of specific acaricides in the context of their pharmacokinetic and pharmacodynamic properties, and subsequent likelihood of emerging drug resistance, particularly for Australian wildlife. This review critically evaluates acaricides that have been utilised to treat sarcoptic mange in wildlife, including dosage forms and routes, pharmacokinetics, mode of action and efficacy. We also highlight the reports of resistance of <em>S. scabiei</em> to acaricides, including clinical and <em>in vitro</em> observations.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ea/68/main.PMC10023865.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9440544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments","authors":"Katalin Toth ,&nbsp;Sevan Alwan ,&nbsp;Susan Khan ,&nbsp;Stanton F. McHardy ,&nbsp;Philip T. LoVerde ,&nbsp;Michael D. Cameron","doi":"10.1016/j.ijpddr.2023.01.003","DOIUrl":"10.1016/j.ijpddr.2023.01.003","url":null,"abstract":"<div><p>The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an <em>in vitro-in vivo</em> paradox with the maximal clinical plasma concentrations five-to ten-times lower than the efficacious concentration for <em>in vitro</em> schistosomal killing. The parasite resides in the vasculature between the intestine and the liver, and modeling the PK data to determine portal concentrations fits with <em>in vitro</em> studies and explains the required human dose. <em>In silico</em> models were used to predict murine dosing to recapitulate human conditions for OXA portal concentration and time course. Follow-up PK studies verified in mice that a 50–100 mg/kg oral gavage dose of OXA formulated in acetate buffer recapitulates the 20–40 mg/kg dose common in patients. OXA was rapidly cleared through a combination of metabolism and excretion into bile. OXA absorbance and tissue distribution were similar in wild-type and P-gp efflux transporter knockout mice. The incorporation of <em>in vitro</em> efficacy data and portal concentration was demonstrated for an improved OXA-inspired analog that has been shown to kill <em>S. mansoni, S. haematobium,</em> and <em>S. japonicum</em>, whereas OXA is only effective against <em>S. mansoni.</em> Second-generation OXA analogs should optimize both <em>in vitro</em> killing and physiochemical properties to achieve high portal concentration via rapid oral absorption, facilitated by favorable solubility, permeability, and minimal intestinal metabolism.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6a/a7/main.PMC9929523.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9830092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergence of Ancylostoma caninum parasites with the benzimidazole resistance F167Y polymorphism in the US dog population","authors":"Christian M. Leutenegger ,&nbsp;Cecilia E. Lozoya ,&nbsp;Jeffrey Tereski ,&nbsp;Christian Savard ,&nbsp;Jennifer Ogeer ,&nbsp;Rene Lallier","doi":"10.1016/j.ijpddr.2023.01.001","DOIUrl":"10.1016/j.ijpddr.2023.01.001","url":null,"abstract":"<div><h3>Background</h3><p>Anthelmintic resistance to benzimidazole has been detected in the canine hookworm, <em>Ancylostoma caninum</em>. Benzimidazole resistance is believed to have developed originally in greyhounds, but has also been detected in non-greyhound pet dogs. The aim of this study was to validate a probe-based allele-specific real-time PCR tests for the F167Y polymorphism on the β-tubulin isotype-1 gene and to determine the geographic distribution.</p></div><div><h3>Methods</h3><p>Allele-specific real-time PCR tests were established and validated to detect the codon 167 polymorphism in the <em>Ancylostoma caninum</em> β-tubulin isotype-1gene. Additionally, real-time PCR tests were validated for <em>Ancylostoma</em> spp. and <em>Uncinaria stenocephala</em>. Two nucleic acid extraction protocols were validated including mechanical disruption of parasite structures in stool. The frequency of the F167Y single nucleotide polymorphism (SNP) was determined in hookworm confirmed stool samples. Samples with the resistant 167Y genotype were confirmed by β-tubulin gene sequencing and allele frequencies were determined.</p></div><div><h3>Results</h3><p>The <em>Ancylostoma</em> spp. and <em>A. caninum</em> F167Y allele-specific real-time PCR tests were highly sensitive and specific when tested against synthetic DNA, spiked samples, and characterized parasites. Using an optimized total nucleic acid extraction protocol, 54 of 511 (10.6%) were found to contain the benzimidazole resistance allele. All 55 samples containing hookworms with the resistance mutation were confirmed by β-tubulin gene sequencing. The majority of resistant hookworms (44 resistant, 183 tested; 24.4%) originated from Florida, five from California (103 tested, 4.9%), three from Idaho (40 tested, 7.5%), two from Nevada (22 tested, 9.1%), and one sample from Hawaii (13 tested, 7.7%). Resistant genotypes were found in 14 different dog breeds including eight in Greyhounds. Allele-frequency determination revealed resistance allele frequencies between 1 and 100% with 58% above 50%.</p></div><div><h3>Conclusions</h3><p>This data strongly supports recent findings of benzimidazole resistant canine hookworms present throughout the general US pet dog population.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068012/pdf/main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9794171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OBITUARY- Ian Fairweather","authors":"Mark W. Robinson ,&nbsp;Bob Hanna ,&nbsp;Philip Skuce ,&nbsp;Gerry Brennan","doi":"10.1016/j.ijpddr.2023.02.003","DOIUrl":"10.1016/j.ijpddr.2023.02.003","url":null,"abstract":"","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42453788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of the pseudomonas metabolites HQNO on the Toxoplasma gondii RH strain in vitro and in vivo","authors":"Jiao Mo ,&nbsp;Hongfei Si ,&nbsp;Siyang Liu ,&nbsp;Qingyuan Zeng ,&nbsp;Minghao Cai ,&nbsp;Zhendi Liu ,&nbsp;Jiyu Zhang ,&nbsp;Jingjing Fang ,&nbsp;Jili Zhang","doi":"10.1016/j.ijpddr.2023.02.001","DOIUrl":"10.1016/j.ijpddr.2023.02.001","url":null,"abstract":"<div><p>Toxoplasmosis is a widespread disease in humans and animals. Currently, toxoplasmosis chemotherapy options are limited due to severe side effects. There is an urgent need to develop new drugs with better efficacy and few side effects. HQNO, a cytochrome <em>bc</em>1 and type II NADH inhibitor in eukaryotes and bacteria, possesses extensive bioactivity. In this study, the cytotoxicity of HQNO was evaluated in Vero cells. The <em>in vitro</em> effects of HQNO were determined by plaque assay and qPCR assay. To determine the <em>in vivo</em> effect of HQNO, pharmacokinetic experiments and <em>in vivo</em> infection assays were performed in mice. The changes in tachyzoites after HQNO exposure were examined by transmission electron microscopy (TEM), MitoTracker Red CMXRos staining, ROS detection and ATP detection. HQNO inhibited <em>T. gondii</em> invasion and proliferation with an EC₅₀ of 0.995 μM. Pharmacokinetic experiments showed that the C_max of HQNO (20 mg/kg·bw) was 3560 ± 1601 ng/mL (13.73 μM) in healthy BALB/c mouse plasma with no toxicity <em>in vivo</em>. Moreover, HQNO induced a significant decrease in the parasite burden load of <em>T. gondii</em> in mouse peritoneum. TEM revealed alterations in the mitochondria of <em>T. gondii</em>. Further assays verified that HQNO also decreased the mitochondrial membrane potential (ΔΨm) and ATP levels and enhanced the level of reactive oxygen species (ROS) in <em>T. gondii</em>. Hence, HQNO exerted <em>anti-T. gondii</em> activity, which may be related to the damage to the mitochondrial electron transport chain (ETC).</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/67/b8/main.PMC9929485.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9433828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poor adherence is a major barrier to the proper treatment of cutaneous leishmaniasis: A case-control field assessment in Iran","authors":"Mehdi Bamorovat ,&nbsp;Iraj Sharifi ,&nbsp;Setareh Agha Kuchak Afshari ,&nbsp;Ali Karamoozian ,&nbsp;Amirhossein Tahmouresi ,&nbsp;Amireh Heshmatkhah ,&nbsp;Ehsan Salarkia ,&nbsp;Ahmad Khosravi ,&nbsp;Maryam Hakimi Parizi ,&nbsp;Maryam Barghi","doi":"10.1016/j.ijpddr.2022.11.006","DOIUrl":"10.1016/j.ijpddr.2022.11.006","url":null,"abstract":"<div><p>Leishmaniasis is an overlooked, poverty-stricken, and complex disease with growing social and public health problems. In general, leishmaniasis is a curable disease; however, there is an expansion of unresponsive cases to treatment in cutaneous leishmaniasis (CL). One of the effective and ignored determinants in the treatment outcome of CL is poor treatment adherence (PTA). PTA is an overlooked and widespread phenomenon to proper <em>Leishmania</em> treatment. This study aimed to explore the effect of poor adherence in unresponsiveness to treatment in patients with anthroponotic CL (ACL) by comparing conventional statistical modalities and machine learning analyses in Iran. Overall, 190 cases consisting of 50 unresponsive patients (case group), and 140 responsive patients (control group) with ACL were randomly selected. The data collecting form that included 25 queries (Q) was recorded for each case and analyzed by R software and genetic algorithm (GA) approaches. Complex treatment regimens (Q11), cultural and lay views about the disease and therapy (Q8), life stress, hopelessness and negative feelings (Q22), adverse effects of treatment (Q13), and long duration of the lesion (Q12) were the most prevalent significant variables that inhibited effective treatment adherence by the two methods, in decreasing order of significance. In the inherent algorithm approach, similar to the statistical approach, the most significant feature was complex treatment regimens (Q11). Providing essential knowledge about ACL and treatment of patients with chronic diseases and patients with misconceptions about chemical drugs are important issues directly related to the disease's unresponsiveness. Furthermore, early detection of patients to prevent the long duration of the disease and the process of treatment, efforts to minimize side effects of treatment, induction of positive thinking, and giving hope to patients with stress and anxiety by medical staff, and family can help patients adhere to the treatment.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9791244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9445251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Egg reappearance periods of anthelmintics against equine cyathostomins: The state of play revisited","authors":"Stephanie L. Macdonald ,&nbsp;Ghazanfar Abbas ,&nbsp;Abdul Ghafar ,&nbsp;Charles G. Gauci ,&nbsp;Jenni Bauquier ,&nbsp;Charles El-Hage ,&nbsp;Brett Tennent-Brown ,&nbsp;Edwina J.A. Wilkes ,&nbsp;Anne Beasley ,&nbsp;Caroline Jacobson ,&nbsp;Lucy Cudmore ,&nbsp;Peter Carrigan ,&nbsp;John Hurley ,&nbsp;Ian Beveridge ,&nbsp;Kristopher J. Hughes ,&nbsp;Martin K. Nielsen ,&nbsp;Abdul Jabbar","doi":"10.1016/j.ijpddr.2022.12.002","DOIUrl":"10.1016/j.ijpddr.2022.12.002","url":null,"abstract":"<div><p>Cyathostomins are the most common and highly prevalent parasites of horses worldwide. Historically, the control of cyathostomins has mainly relied on the routine use of anthelmintic products. Increasing reports on anthelmintic resistance (AR) in cyathostomins are concerning. A potential method proposed for detecting emerging AR in cyathostomins has been estimating the egg reappearance period (ERP). This paper reviews the data available for the ERP of cyathostomins against the three major classes of anthelmintics, macrocyclic lactones, tetrahydropyrimidines, and benzimidazoles. Published peer-reviewed original research articles were obtained from three databases (PubMed, CAB Direct and Web of Science) and were evaluated for their inclusion in a systematic review. Subsets of articles were then subjected to a review of ERP data. A total of 54 (of 134) studies published between 1972 and 2022 met the criteria for inclusion in the systematic review. Until the beginning of 2022, there was no agreed definition of the ERP; eight definitions of ERP were identified in the literature, complicating the comparison between studies. Additionally, potential risk factors for the shortening of the ERP, including previous anthelmintic use and climate, were frequently not described. Reports of shortened ERP for moxidectin and ivermectin are frequent: 20 studies that used comparable ERP definitions reported shortened moxidectin and ivermectin ERPs of 35 and 28 days, respectively. It is unclear whether the ERPs of these anthelmintics reduced to such levels are due to the development of AR or some biological factors related to horses, cyathostomin species, and/or the environment. The ERPs for other anthelmintics, such as fenbendazole and pyrantel, were frequently not reported due to established resistance against these drugs. Future research in horses is required to understand the mechanism(s) behind the shortening of ERP for cyathostomins. Based on this systematic review, we propose recommendations for future ERP studies.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105024/pdf/main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9793052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular characterization and analysis of drug resistance-associated protein enolase 2 of Eimeria tenella","authors":"Yu Yu ,&nbsp;Wenhao Huang ,&nbsp;Qingjie Wang,&nbsp;Hui Dong,&nbsp;Qiping Zhao,&nbsp;Shunhai Zhu,&nbsp;Bing Huang,&nbsp;Hongyu Han","doi":"10.1016/j.ijpddr.2023.01.004","DOIUrl":"10.1016/j.ijpddr.2023.01.004","url":null,"abstract":"<div><p><em>Eimeria tenella</em>, an intestinal parasite, has brought huge economic losses to the poultry industry. The prevalence and severity of the development of drug resistance has increased the challenge of coccidiosis control. We previously identified the enolase 2 of <em>E. tenella</em> (<em>Et</em>ENO2) was differentially expressed in drug-sensitive (DS) and drug-resistant strains using RNA-seq. In this study, the expression of <em>Et</em>ENO2 in diclazuril-resistant (DZR), maduramicin-resistant (MRR), and salinomycin-resistant (SMR) strains was analyzed by quantitative real-time PCR (qRT-PCR) and western blots. <em>Et</em>ENO2 was highly expressed in several drug-resistant strains compared with the DS strain. The qRT-PCR showed that the transcription level of <em>Et</em>ENO2 in the field-isolated resistant strains was upregulated compared with the DS strain. The enzyme activity results indicated that the catalytic activity of <em>Et</em>ENO2 in the drug-resistant strains was higher than in the DS strain. In addition, qRT-PCR and western blots showed that the expression level of <em>Et</em>ENO2 was higher in second generation merozoites (SM) and unsporulated oocysts (UO) than that in sporozoites (SZ) and sporulated oocysts (SO). Immunofluorescence localization revealed that <em>Et</em>ENO2 was distributed throughout SZ and SM and on the surface of the parasites. After the SZ invasion DF-1 cells, it was also observed on the parasitophorous vacuole membrane. Our secretion experiments found that <em>Et</em>ENO2 could be secreted outside the SZ. This study indicated that <em>Et</em>ENO2 might be related to the interaction between <em>E. tenella</em> and host cells and be involved in the development of <em>E. tenella</em> resistance to some anticoccidial drugs.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/51/43/main.PMC9929201.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9810601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis","authors":"Roman Memedovski ,&nbsp;Matías Preza ,&nbsp;Joachim Müller ,&nbsp;Tobias Kämpfer ,&nbsp;Reto Rufener ,&nbsp;Marcus Vinicius Nora de Souza ,&nbsp;Emerson Teixeira da Silva ,&nbsp;Gabriel Fernandes de Andrade ,&nbsp;Sophie Braga ,&nbsp;Anne-Christine Uldry ,&nbsp;Natasha Buchs ,&nbsp;Manfred Heller ,&nbsp;Britta Lundström-Stadelmann","doi":"10.1016/j.ijpddr.2023.03.002","DOIUrl":"10.1016/j.ijpddr.2023.03.002","url":null,"abstract":"<div><p>Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm <em>E. multilocularis</em>. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-parasiticidal benzimidazoles. Thus, they are only limitedly curative and can cause severe side effects. Therefore, novel and improved treatment options for AE are needed.</p><p>Mefloquine (MEF), an antimalarial agent, was previously shown to be effective against <em>E. multilocularis in vitro</em> and in experimentally infected mice. However, MEF is not parasiticidal and needs improvement for successful treatment of patients, and it can induce strong neuropsychiatric side-effects. In this study, the structure-activity relationship and mode of action of MEF was investigated by comparative analysis of 14 MEF derivatives. None of them showed higher activity against <em>E. multilocularis</em> metacestodes compared to MEF, but four compounds caused limited damage. In order to identify molecular targets of MEF and effective derivatives, differential affinity chromatography combined with mass spectrometry was performed with two effective compounds (MEF, MEF-3) and two ineffective compounds (MEF-13, MEF-22). 1′681 proteins were identified that bound specifically to MEF or derivatives. 216 proteins were identified as binding only to MEF and MEF-3. GO term enrichment analysis of these proteins and functional grouping of the 25 most abundant MEF and MEF-3 specific binding proteins revealed the key processes energy metabolism and cellular transport and structure, as well as stress responses and nucleic acid binding to be involved. The previously described ferritin was confirmed as an exclusively MEF-binding protein that could be relevant for its efficacy against <em>E. multilocularis</em>. The here identified potential targets of MEF will be further investigated in the future for a clear understanding of the pleiotropic effects of MEF, and improved therapeutic options against AE.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9811108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}