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

{"title":"The first report of macrocyclic lactone resistant cyathostomins in the UK","authors":"K.E. Bull ,&nbsp;K.J. Allen ,&nbsp;J.E. Hodgkinson ,&nbsp;L.E. Peachey","doi":"10.1016/j.ijpddr.2023.03.001","DOIUrl":"10.1016/j.ijpddr.2023.03.001","url":null,"abstract":"<div><p>In recent years, resistance to the benzimidazole (BZ) and tetrahydropyrimidine (PYR) anthelmintics in global cyathostomin populations, has led to reliance on the macrocyclic lactone drugs (ML-of which ivermectin and moxidectin are licensed in horses) to control these parasites. Recently, the first confirmed case of resistance to both ivermectin (IVM) and moxidectin (MOX) was reported in the USA in yearlings imported from Ireland. This suggests that ML resistance in cyathostomins has emerged, and raises the possibility that regular movement of horses may result in rapid spread of ML resistant cyathostomins. Resistance may go undetected due to a lack of surveillance for ML efficacy. Here, we report anthelmintic efficacies in cyathostomins infecting UK Thoroughbreds on four studs. Faecal egg count reduction tests (FECRT) were performed to define resistance (resistance = FECR &lt;95% lower credible interval (LCI) &lt; 90%). Stud A yearlings had FECRs of 36.4–78.6% (CI:15.7–86.3) after three IVM treatments, 72.6% (CI: 50.8–85.2) after MOX, and 80.8% (CI: 61.9–90.0) after PYR. Mares on stud A had a FECR of 97.8% (CI: 93.3–99.9) and 98% (95.1–99.4) after IVM and MOX treatment, respectively. Resistance to MLs was not found in yearlings or mares on studs B, C or D with FECR after MOX OR IVM treatment ranging from 99.8 to 99.9% (95.4–100); although yearlings on studs B, C and D all had an egg reappearance period (ERP) of six weeks for MOX and stud C had a four-week ERP for IVM. This study describes the first confirmed case of resistance to both licensed ML drugs on a UK Thoroughbred stud and highlights the urgent need for a) increased awareness of the threat of ML resistant parasites infecting horses, and b) extensive surveillance of ML efficacy against cyathostomin populations in the UK, to gauge the extent of the problem.</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/a4/fb/main.PMC10036890.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9794165","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":"Proteomic characterization of Toxoplasma gondii ME49 derived strains resistant to the artemisinin derivatives artemiside and artemisone implies potential mode of action independent of ROS formation","authors":"Joachim Müller ,&nbsp;Carling Schlange ,&nbsp;Manfred Heller ,&nbsp;Anne-Christine Uldry ,&nbsp;Sophie Braga-Lagache ,&nbsp;Richard K. Haynes ,&nbsp;Andrew Hemphill","doi":"10.1016/j.ijpddr.2022.11.005","DOIUrl":"10.1016/j.ijpddr.2022.11.005","url":null,"abstract":"<div><p>The sesquiterpene lactone artemisinin and its amino-artemisinin derivatives artemiside (GC008) and artemisone (GC003) are potent antimalarials. The mode of action of artemisinins against <em>Plasmodium</em> sp is popularly ascribed to 'activation' of the peroxide group by heme-Fe(II) or labile Fe(II) to generate C-radicals that alkylate parasite proteins. An alternative postulate is that artemisinins elicit formation of reactive oxygen species by interfering with flavin disulfide reductases resposible for maintaining intraparasitic redox homeostasis. However, in contradistinction to the heme-activation mechanism, the amino-artemisinins are effective <em>in vitro</em> against non-heme-degrading apicomplexan parasites including <em>T. gondii</em>, with IC ₅₀ values of 50–70 nM, and induce distinct ultrastructural alterations. However, <em>T. gondii</em> strains readily adapted to increased concentrations (2.5 μM) of these two compounds within few days. Thus, <em>T. gondii</em> strains that were resistant against artemisone and artemiside were generated by treating the <em>T. gondii</em> reference strain ME49 with stepwise increasing amounts of these compounds, yielding the artemisone resistant strain GC003^R and the artemiside resistant strain GC008^R. Differential analyses of the proteomes of these resistant strains compared to the wildtype ME49 revealed that 215 proteins were significantly downregulated in artemisone resistant tachyzoites and only 8 proteins in artemiside resistant tachyzoites as compared to their wildtype. Two proteins, namely a hypothetical protein encoded by ORF TGME49_236950, and the rhoptry neck protein RON2 encoded by ORF TGME49_300100 were downregulated in both resistant strains. Interestingly, eight proteins involved in ROS scavenging including catalase and superoxide dismutase were amongst the differentially downregulated proteins in the artemisone-resistant strain. In parallel, ROS formation was significantly enhanced in isolated tachyzoites from the artemisone resistant strain and – to a lesser extent – in tachyzoites from the artemiside resistant strain as compared to wildtype tachyzoites. These findings suggest that amino-artemisinin derivatives display a mechanism of action in <em>T. gondii</em> distinct from <em>Plasmodium</em>.</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/PMC9763631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9495042","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":"The presence and relative frequency detection of the levamisole-resistance-associated S168T substitution in hco-acr-8 in Haemonchus contortus","authors":"Paulius Baltrušis ,&nbsp;Peter Halvarsson ,&nbsp;Claude L. Charvet ,&nbsp;Johan Höglund","doi":"10.1016/j.ijpddr.2023.02.002","DOIUrl":"10.1016/j.ijpddr.2023.02.002","url":null,"abstract":"<div><p>Parasitic sheep nematodes, among which <em>Haemonchus contortus</em> is often considered to be the most clinically important, exact a significant toll on the animals, not least because of their capacity to evolve drug resistance. Despite decades of research, our understanding of the mechanism of resistance to compounds such as levamisole is fairly limited, which therefore constrains our ability to develop sensitive and efficient molecular diagnostic tools for rapid and accurate resistance detection in field settings. Herein, we investigated the presence and frequency of the newly reported, levamisole-resistance-associated, mutation, yielding a S168T substitution in exon 4 of <em>hco-acr-8</em>, in six different phenotypically described isolates (three susceptible and three resistant), three Swedish field isolates and eight larvae culture samples, the latter two of which originated on farms where levamisole showed complete parasite elimination. For this purpose, we created both an allele-specific and droplet digital PCR approaches and found the mutated allele to be present only in the Kokstad isolate, whereas the other five as well as both the Swedish isolates and larvae cultures displayed only the non-mutated, serine-encoding, allele. While the finding of only the non-mutated allele in the phenotypically susceptible and Swedish isolate and larvae culture samples seemed sensible, we speculate that for the other two phenotypically resistant isolates, different (perhaps secondary) variants are responsible for conferring the resistance to levamisole phenotype, given the polygenic nature of levamisole resistance. All in all, despite the limited number of samples tested here, the mutation causing the S168T substitution in <em>hco-acr-8</em> represents a plausible levamisole resistance-associated variant in, at least, some isolates of <em>H. contortus</em>.</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/PMC9945773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9793634","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":"Exploration of the sensitivity to macrocyclic lactones in the canine heartworm (Dirofilaria immitis) in Australia using phenotypic and genotypic approaches","authors":"Rosemonde Isabella Power ,&nbsp;Jan Šlapeta","doi":"10.1016/j.ijpddr.2022.11.003","DOIUrl":"10.1016/j.ijpddr.2022.11.003","url":null,"abstract":"<div><p>Canine heartworm disease is a potentially deadly cardiopulmonary disease caused by the mosquito-borne filarial nematode <em>Dirofilaria immitis</em>. In Australia, the administration of macrocyclic lactone (ML) drugs has successfully reduced the prevalence of <em>D. immitis</em> infection. However, the recent re-emergence of <em>D. immitis</em> in dogs in Queensland, Australia and the identification of ML-resistant isolates in the USA poses an important question of whether ML-resistance has emerged in this parasite in Australia. The aim of this study was to utilise phenotypic and genotypic approaches to examine the sensitivity to ML drugs in <em>D. immitis</em> in Australia. To do this, we surveyed 45 dogs from Queensland and New South Wales across 3 years (2019–2022) for the presence of <em>D. immitis</em> infection using an antigen test, quantitative Modified Knott's test, and qPCR targeting both <em>D. immitis</em> and the <em>D. immitis</em> symbiont <em>Wolbachia</em>. A phenotype observed by utilising sequential quantification of microfilariae for 23/45 dogs was coupled with genetic testing of filtered microfilariae for SNPs previously associated with ML-resistance in isolates from the USA. Sixteen (16/45) dogs tested positive for <em>D. immitis</em> infection despite reportedly receiving ‘rigorous’ heartworm prevention for 12 months prior to the study, according to the owners' assessment. The phenotype and genotypic assays in this study did not unequivocally demonstrate the presence of ML-resistant <em>D. immitis</em> in Australia. Although the failure of 16 dogs to reduce microfilaremia by &gt;90% after ML treatment was considered a suspect phenotype of ML-resistance, no genotypic evidence was discovered using the genetic SNP analysis. The traditional quantitative Modified Knott's test can be substituted by qPCR targeting <em>D. immitis</em> or associated <em>Wolbachia</em> endosymbiont DNA for a more rapid measurement of microfilariae levels. More definitive phenotypic evidence of resistance is critically needed before the usefulness of SNPs for the detection of ML-resistance in Australia can be properly assessed.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9772245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10481241","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":"Genetic characterisation of the Theileria annulata cytochrome b locus and its impact on buparvaquone resistance in bovine","authors":"Qasim Ali ,&nbsp;Osama Zahid ,&nbsp;Moez Mhadhbi ,&nbsp;Ben Jones ,&nbsp;Mohamed Aziz Darghouth ,&nbsp;George Raynes ,&nbsp;Kiran Afshan ,&nbsp;Richard Birtles ,&nbsp;Neil D. Sargison ,&nbsp;Martha Betson ,&nbsp;Umer Chaudhry","doi":"10.1016/j.ijpddr.2022.08.004","DOIUrl":"10.1016/j.ijpddr.2022.08.004","url":null,"abstract":"<div><p>Control of tropical theileriosis, caused by the apicomplexan <em>Theileria annulata</em>, depends on the use of a single drug, buparvaquone, the efficacy of which is compromised by the emergence of resistance. The present study was undertaken to improve understanding of the role of mutations conferring buparvaquone resistance in <em>T. annulata</em>, and the effects of selection pressures on their emergence and spread. First, we investigated genetic characteristics of the cytochrome b locus associated with buparvaquone resistance in 10 susceptible and 7 resistant <em>T. annulata</em> isolates. The 129G (GGC) mutation was found in the Q₀₁ binding pocket and 253S (TCT) and 262S (TCA) mutations were identified within the Q₀₂ binding pocket. Next, we examined field isolates and identified cytochrome b mutations 129G (GGC), 253S (TCT) and 262S (TCA) in 21/75 buffalo-derived and 19/119 cattle-derived <em>T. annulata</em> isolates, providing evidence of positive selection pressure. Both hard and soft selective sweeps were identified, with striking differences between isolates. For example, 19 buffalo-derived and 7 cattle-derived isolates contained 129G (GGC) and 253S (TCT) resistance haplotypes at a high frequency, implying the emergence of resistance by a single mutation. Two buffalo-derived and 12 cattle-derived isolates contained equally high frequencies of 129G (GGC), 253S (TCT), 129G (GGC)/253S (TCT) and 262S (TCA) resistance haplotypes, implying the emergence of resistance by pre-existing or recurrent mutations. Phylogenetic analysis further revealed that 9 and 21 unique haplotypes in buffalo and cattle-derived isolates were present in a single lineage, suggesting a single origin. We propose that animal migration between farms is an important factor in the spread of buparvaquone resistance in endemic regions of Pakistan. The overall outcomes will be useful in understanding how drug resistance emerges and spreads, and this information will help design strategies to optimise the use and lifespan of the single most drug use to control tropical theileriosis.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/94/2c/main.PMC9529669.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10341916","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":"Diethylcarbamazine mediated potentiation of emodepside induced paralysis requires TRP-2 in adult Brugia malayi","authors":"Sudhanva S. Kashyap,&nbsp;Mark A. McHugh,&nbsp;Alan P. Robertson,&nbsp;Richard J. Martin","doi":"10.1016/j.ijpddr.2022.10.002","DOIUrl":"10.1016/j.ijpddr.2022.10.002","url":null,"abstract":"<div><p>Human and veterinary filarial nematode infections are a major health concern in tropical countries. They are transmitted by biting insects and mosquitoes. Lymphatic filariasis, a group of filarial infections caused by <em>Brugia</em> spp. and <em>Wucheria bancrofti</em> affect more than 120 million people worldwide. Infected individuals develop swollen limbs and disfigurement, leading to an inability to work and ostracization from society. Control and prophylaxis for these infections involve mass drug administration combinations of anthelmintics including diethylcarbamazine (DEC). DEC has actions on microfilariae, but its effects on adult worms are less pronounced. The SLO-1 (BK) channel activator, emodepside, kills adults of many filarial species. However, the <em>in vivo</em> efficacy of emodepside is suboptimal against <em>B. malayi,</em> possibly due to reduced bioavailability in the lymphatic system. Expressing different <em>slo-1</em> splice variants in <em>B. malayi</em> also affects sensitivity to emodepside. This study explores the potentiation of emodepside mediated paralysis by DEC in adult female <em>B. malayi</em>. Worminator motility measurements show that co-application of DEC and emodepside increases the potency of emodepside 4-fold. The potentiation of the emodepside effect persists even after the worms recover (desensitize) from the initial effects of DEC. RNAi knock-down demonstrates that the DEC-mediated potentiation of emodepside requires the presence of TRP-2 channels. Our study demonstrates that the addition of DEC could enhance the effect of emodepside where bioavailability or activity against a specific species may be low.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5f/59/main.PMC9772243.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9576089","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":"Sterol profiling of Leishmania parasites using a new HPLC-tandem mass spectrometry-based method and antifungal azoles as chemical probes reveals a key intermediate sterol that supports a branched ergosterol biosynthetic pathway","authors":"Mei Feng ,&nbsp;Yiru Jin ,&nbsp;Sihyung Yang ,&nbsp;Arline M. Joachim ,&nbsp;Yu Ning ,&nbsp;Luis M. Mori-Quiroz ,&nbsp;Jacob Fromm ,&nbsp;Chamani Perera ,&nbsp;Kai Zhang ,&nbsp;Karl A. Werbovetz ,&nbsp;Michael Zhuo Wang","doi":"10.1016/j.ijpddr.2022.07.003","DOIUrl":"10.1016/j.ijpddr.2022.07.003","url":null,"abstract":"<div><p>Human leishmaniasis is an infectious disease caused by <em>Leishmania</em> protozoan parasites. Current chemotherapeutic options against the deadly disease have significant limitations. The ergosterol biosynthetic pathway has been identified as a drug target in <em>Leishmania</em>. However, remarkable differences in the efficacy of antifungal azoles that inhibit ergosterol biosynthesis have been reported for the treatment of leishmaniasis. To better understand the sterol biosynthetic pathway in <em>Leishmania</em> and elucidate the mechanism underlying the differential efficacy of antifungal azoles, we developed a new LC-MS/MS method to study sterol profiles in promastigotes of three <em>Leishmania</em> species, including two <em>L. donovani</em>, one <em>L. major</em> and one <em>L. tarentolae</em> strains. A combination of distinct precursor ion masses and LC retention times allowed for specific detection of sixteen intermediate sterols between lanosterol and ergosterol using the newly developed LC-MS/MS method. Although both posaconazole and fluconazole are known inhibitors of fungal lanosterol 14α-demethylase (CYP51), only posaconazole led to a substantial accumulation of lanosterol in azole-treated <em>L. donovani</em> promastigotes. Furthermore, a key intermediate sterol accumulated by 40- and 7-fold when these parasites were treated with posaconazole and fluconazole, respectively, which was determined as 4α,14α-dimethylzymosterol by high resolution mass spectrometry and NMR spectroscopy. The identification of 4α,14α-dimethylzymosterol supports a branched ergosterol biosynthetic pathway in <em>Leishmania</em>, where lanosterol C4- and C14-demethylation reactions occur in parallel rather than sequentially. Our results suggest that selective inhibition of leishmanial CYP51 is insufficient to effectively prevent parasite growth and dual inhibitors of both CYP51 and the unknown sterol C4-demethylase may be required for optimal antiparasitic effect.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/75/96/main.PMC9418051.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10009813","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":"Anthelmintic resistance in equine nematodes: Current status and emerging trends","authors":"M.K. Nielsen","doi":"10.1016/j.ijpddr.2022.10.005","DOIUrl":"10.1016/j.ijpddr.2022.10.005","url":null,"abstract":"<div><p>Anthelmintic resistance is reported in equine nematodes with increasing frequency in recent years, and no new anthelmintic classes have been introduced during the past 40 years. This manuscript reviews published literature describing anthelmintic resistance in cyathostomins, <em>Parascaris</em> spp., and <em>Oxyuris equi</em> with special emphasis on larvicidal efficacy against encysted cyathostomin larvae and strongylid egg reappearance periods (ERP). Resistance to benzimidazoles and pyrimidines is highly prevalent in cyathostomin populations around the world, and macrocyclic lactone resistance has been documented in cyathostomins in recent years as well. Two recent studies have documented resistance to the larvicidal regimen of fenbendazole, whereas the larvicidal efficacy of moxidectin is variable, but with no evidence of a reduction from historic levels. In the 1990s, ERP estimates were 8–10 and 12–16 weeks for ivermectin and moxidectin, respectively, while several studies published after year 2000 found ERPs to be 5 weeks for both compounds. This is a clear change in anthelmintic performance, but it remains unclear if this is due to development of anthelmintic resistance or selection for other biological traits leading to a quicker resumption of strongylid egg shedding following anthelmintic treatment. Macrocyclic lactone resistance is common in <em>Parascaris</em> spp. around the world, but recent reports suggests that resistance to the two other classes should be monitored as well. Finally, <em>O. equi</em> has been reported resistant to ivermectin and moxidectin in countries representing four continents. In conclusion, multi-drug resistance is becoming the norm in managed cyathostomin populations around the world, and a similar pattern may be emerging in <em>Parascaris</em> spp. More work is required to understand the mechanisms behind the shortened ERPs, and researchers and veterinarians around the world are encouraged to routinely monitor anthelmintic efficacy against equine nematodes.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/18/5a/main.PMC9630620.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10412363","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":"In vitro evaluation of Resveratrol as a potential pre-exposure prophylactic drug against Trypanosoma cruzi infection","authors":"Matías E. Rodriguez,&nbsp;Valeria Tekiel,&nbsp;Vanina A. Campo","doi":"10.1016/j.ijpddr.2022.08.003","DOIUrl":"10.1016/j.ijpddr.2022.08.003","url":null,"abstract":"<div><p>Chagas' disease or American trypanosomiasis, caused by <em>Trypanosoma cruzi</em> infection, is an endemic disease in Latin America, which has spread worldwide in the past years. The drugs presently used for treatment have shown limited efficacy due to the appearance of resistant parasites and severe side effects. Some of the most recent studies on anti-parasitic drugs have been focused on protein acetylation, a reversible reaction modulated by Acetyl Transferases (KATs) and Deacetylases (KDACs). We have previously reported the anti-parasite activity of resveratrol (RSV), an activator of KDACs type III (or sirtuins), and showed that this drug can reduce the growth of <em>T. cruzi</em> epimastigotes and the infectivity of trypomastigotes. Since RSV is now widely used in humans due to its beneficial effects as an antioxidant, it has become an attractive candidate as a repurposing drug. In this context, the aim of the present study was to evaluate the ability of this drug to protect three different types of host cells from parasite infection. RSV treatment before parasite infection reduced the percentage of infected cells by 50–70% depending on the cell type. Although the mammalian cell lines tested showed different sensitivity to RSV, apoptosis was not significantly affected, showing that RSV was able to protect cells from infection without the activation of this process. Since autophagy has been described as a key process in parasite invasion, we also monitored this process on host cells pretreated with RSV. The results showed that, at the concentrations and incubation times tested, autophagy was not induced in any of the cell types evaluated. Our results show a partial protective effect of RSV <em>in vitro</em>, which justifies extending studies to an <em>in vivo</em> model to elucidate the mechanism by which this effect occurs.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/04/df/main.PMC9474288.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10341389","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":"Uncovering the antimalarial potential of toad venoms through a bioassay-guided fractionation process","authors":"Mathilde Wells ,&nbsp;Mathieu Fossépré ,&nbsp;Stéphanie Hambye ,&nbsp;Mathieu Surin ,&nbsp;Bertrand Blankert","doi":"10.1016/j.ijpddr.2022.10.001","DOIUrl":"10.1016/j.ijpddr.2022.10.001","url":null,"abstract":"<div><p>Malaria remains to date one of the most devastating parasitic diseases worldwide. The fight against this disease is rendered more difficult by the emergence and spread of drug-resistant strains. The need for new therapeutic candidates is now greater than ever. In this study, we investigated the antiplasmodial potential of toad venoms. The wide array of bioactive compounds present in <em>Bufonidae</em> venoms has allowed researchers to consider many potential therapeutic applications, especially for cancers and infectious diseases. We focused on small molecules, namely bufadienolides, found in the venom of <em>Rhinella marina (L.)</em>. The developed bio-guided fractionation process includes a four solvent-system extraction followed by fractionation using flash chromatography. Sub-fractions were obtained through preparative TLC. All samples were characterized using chromatographic and spectrometric techniques and then underwent testing on <em>in vitro Plasmodium falciparum</em> cultures. Two strains were considered: 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant). This strategy highlighted a promising activity for one compound named resibufogenin. With IC₅₀ values of (29 <span><math><mrow><mo>±</mo></mrow></math></span> 8) μg/mL and (23 <span><math><mrow><mo>±</mo></mrow></math></span> 1) μg/mL for 3D7 and W2 respectively, this makes it an interesting candidate for further investigation. A molecular modelling approach proposed a potential binding mode of resibufogenin to <em>Plasmodium falciparum</em> adenine-triphosphate 4 pump as antimalarial drug target.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9a/7d/main.PMC9772263.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10420900","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}