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International Journal for Parasitology, Drugs and Drug Resistance

Reto Rufener, Luca Dick, Laura D'Ascoli, Dominic Ritler, Amani Hizem, Timothy N C Wells, Andrew Hemphill, Britta Lundström-Stadelmann
The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the lethal disease alveolar echinococcosis. Current chemotherapeutic treatment options are based on benzimidazoles (albendazole and mebendazole), which are insufficient and hence alternative drugs are needed. In this study, we screened the 400 compounds of the Medicines for Malaria Venture (MMV) Pathogen Box against E. multilocularis metacestodes. For the screen, we employed the phosphoglucose isomerase (PGI) assay which assesses drug-induced damage on metacestodes, and identified ten new compounds with activity against the parasite...
October 31, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Micah K Callanan, Sarah A Habibi, Wen Jing Law, Kristen Nazareth, Richard L Komuniecki, Sean G Forrester
The cys-loop superfamily of ligand-gated ion channels are well recognized as important drug targets for many invertebrate specific compounds. With the rise in resistance seen worldwide to existing anthelmintics, novel drug targets must be identified so new treatments can be developed. The acetylcholine-gated chloride channel (ACC) family is a unique family of cholinergic receptors that have been shown, using Caenorhabditis elegans as a model, to have potential as anti-parasitic drug targets. However, there is little known about the function of these receptors in parasitic nematodes...
October 27, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Helen L Whiteland, Anand Chakroborty, Josephine E Forde-Thomas, Alessandra Crusco, Alan Cookson, Jackie Hollinshead, Caroline A Fenn, Barbara Bartholomew, Peter A Holdsworth, Maggie Fisher, Robert J Nash, Karl F Hoffmann
Two economically and biomedically important platyhelminth species, Fasciola hepatica (liver fluke) and Schistosoma mansoni (blood fluke), are responsible for the neglected tropical diseases (NTDs) fasciolosis and schistosomiasis. Due to the absence of prophylactic vaccines, these NTDs are principally managed by the single class chemotherapies triclabendazole (F. hepatica) and praziquantel (S. mansoni). Unfortunately, liver fluke resistance to triclabendazole has been widely reported and blood fluke insensitivity/resistance to praziquantel has been observed in both laboratory settings as well as in endemic communities...
October 26, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Astra S Bryant, Elissa A Hallem
Infection with gastrointestinal parasitic nematodes is a major cause of chronic morbidity and economic burden around the world, particularly in low-resource settings. Some parasitic nematode species, including the human-parasitic threadworm Strongyloides stercoralis and human-parasitic hookworms in the genera Ancylostoma and Necator, feature a soil-dwelling infective larval stage that seeks out hosts for infection using a variety of host-emitted sensory cues. Here, we review our current understanding of the behavioral responses of soil-dwelling infective larvae to host-emitted sensory cues, and the molecular and cellular mechanisms that mediate these responses...
October 26, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Cristiana T Trinconi, Danilo C Miguel, Ariel M Silber, Christopher Brown, John G M Mina, Paul W Denny, Norton Heise, Silvia R B Uliana
Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmaniasis. Using a combination of metabolic labeling with [3 H]-sphingosine and myo-[3 H]-inositol, alkaline hydrolysis, HPTLC fractionations and mass spectrometry analyses, we observed a perturbation in the metabolism of inositolphosphorylceramides (IPCs) and phosphatidylinositols (PIs) after treatment of L...
October 24, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Medard Ernest, Carol Hunja, Yuka Arakura, Yohei Haraga, Hussein M Abkallo, Weiguang Zeng, David C Jackson, Brendon Chua, Richard Culleton
Both vaccine and therapeutic approaches to malaria are based on conventional paradigms; whole organism or single antigen epitope-based vaccines administered with or without an adjuvant, and chemotherapeutics (anti-malaria drugs) that are toxic to the parasite. Two major problems that limit the effectiveness of these approaches are i) high levels of antigenic variation within parasite populations rendering vaccination efficacy against all variants difficult, and ii) the capacity of the parasite to quickly evolve resistance to drugs...
October 23, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Anna C C Aguiar, Erika Murce, Wilian A Cortopassi, Andre S Pimentel, Maria M F S Almeida, Daniele C S Barros, Jéssica S Guedes, Mario R Meneghetti, Antoniana U Krettli
In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P...
October 13, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Josh Foster, Everett Cochrane, Mohammad Hassan Khatami, Sarah A Habibi, Hendrick de Haan, Sean G Forrester
The UNC-49 receptor is a unique nematode γ-aminobutyric acid (GABA)-gated chloride channel that may prove to be a novel target for the development of nematocides. Here we have characterized various charged amino acid residues in and near the agonist binding site of the UNC-49 receptor from the parasitic nematode Haemonchus contorts. Utilizing the Caenorhabditis elegans GluCl crystal structure as a template, a model was generated and various charged residues [D83 (loop D), E131 (loop A), H137 (pre-loop E), R159 (Loop E), E185 (Loop B) and R241 (Loop C)] were investigated based on their location and conservation...
October 6, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Jonathan S Marchant, Wayne W Harding, John D Chan
Serotonin (5-HT) is an important regulator of numerous aspects of flatworm biology, ranging from neuromuscular function to sexual maturation and egg laying. In the parasitic blood fluke Schistosoma mansoni, 5-HT targets several G-protein coupled receptors (GPCRs), one of which has been demonstrated to couple to cAMP and regulate parasite movement. This receptor, Sm.5HTRL , has been successfully co-expressed in mammalian cells alongside a luminescent cAMP-biosensor, enabling pharmacological profiling for candidate anti-schistosomal drugs...
September 28, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Laura M Alcântara, Thalita C S Ferreira, Fernanda R Gadelha, Danilo C Miguel
Tritryps diseases are devastating parasitic neglected infections caused by Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei subspecies. Together, these parasites affect more than 30 million people worldwide and cause high mortality and morbidity. Leishmaniasis comprises a complex group of diseases with clinical manifestation ranging from cutaneous lesions to systemic visceral damage. Antimonials, the first-choice drugs used to treat leishmaniasis, lead to high toxicity and carry significant contraindications limiting its use...
September 28, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Petra Matoušková, Lenka Lecová, Roz Laing, Diana Dimunová, Heiko Vogel, Lucie Raisová Stuchlíková, Linh Thuy Nguyen, Pavlína Kellerová, Ivan Vokřál, Jiří Lamka, Barbora Szotáková, Marián Várady, Lenka Skálová
UDP-glycosyltransferases (UGT), catalysing conjugation of UDP-activated sugar donors to small lipophilic chemicals, are widespread in living organisms from bacteria to fungi, plant, or animals. The progress of genome sequencing has enabled an assessment of the UGT multigene family in Haemonchus contortus (family Trichostrongylidae, Nematoda), a hematophagous gastrointestinal parasite of small ruminants. Here we report 32 putative UGT genes divided into 15 UGT families. Phylogenetic analysis in comparison with UGTs from Caenorhabditis elegans, a free-living model nematode, revealed several single member homologues, a lack of the dramatic gene expansion seen in C...
September 26, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Barbara J Reaves, Connor Wallis, Ciaran J McCoy, W Walter Lorenz, Balazs Rada, Adrian J Wolstenholme
Mass administration of macrocyclic lactones targets the transmission of the causative agents of lymphatic filariasis to their insect vectors by rapidly clearing microfilariae (Mf) from the circulation. It has been proposed that the anti-filarial action of these drugs may be mediated through the host immune system. We recently developed an in vitro assay for monitoring the attachment to and killing of B. malayi Mf by human neutrophils (PMNs) and monocytes (PBMCs), however, the levels of both cell to worm attachment and leukocyte mediated Mf killing varied greatly between individual experiments...
September 22, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Sarah A Habibi, Micah Callanan, Sean G Forrester
Nematode cys-loop ligand-gated ion channels (LGICs) have been shown to be attractive targets for the development of novel anti-parasitic drugs. The ACC-1 family of receptors are a unique group of acetylcholine-gated chloride channels present only in invertebrates, and sequence analysis suggests that they contain a novel binding site for acetylcholine. We have isolated a novel member of this family, Hco-ACC-2, from the parasitic nematode Haemonchus contortus and using site-directed mutagenesis, electrophysiology and molecular modelling examined how two aromatic amino acids in the binding site contributed to agonist recognition...
September 22, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Paulius Baltrušis, Peter Halvarsson, Johan Höglund
Anthelmintic resistance in gastrointestinal nematode (GIN) parasites of grazing ruminants is on the rise in countries across the world. Haemonchus contortus is one of most frequently encountered drug-resistant GINs in small ruminants. This blood-sucking abomasal nematode contributes to massive treatment costs and poses a serious threat to farm animal health. To prevent the establishment of resistant strains of this parasite, up-to-date molecular techniques need to be proposed which would allow for quick, cheap and accurate identification of individuals infected with resistant worms...
September 19, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Swarna Bais, Robert M Greenberg
Ion channels are membrane protein complexes that underlie electrical excitability in cells, allowing ions to diffuse through cell membranes in a regulated fashion. They are essential for normal functioning of the neuromusculature and other tissues. Ion channels are also validated targets for many current anthelmintics, yet the properties of only a small subset of ion channels in parasitic helminths have been explored in any detail. Transient receptor potential (TRP) channels comprise a widely diverse superfamily of ion channels with important roles in sensory signaling, regulation of ion homeostasis, organellar trafficking, and other functions...
September 8, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Daniel Yasur-Landau, Charles L Jaffe, Lior David, Adi Doron-Faigenboim, Gad Baneth
Leishmania infantum is one of the causative agents of visceral leishmaniasis (VL), a widespread, life-threatening disease. This parasite is responsible for the majority of human VL cases in Brazil, the Middle East, China, Central Asia and the Mediterranean basin. Its main reservoir are domestic dogs which, similar to human patients, may develop severe visceral disease and die if not treated. The drug allopurinol is used for the long-term maintenance of dogs with canine leishmaniasis. Following our report of allopurinol resistance in treated relapsed dogs, we investigated the mechanisms and markers of resistance to this drug...
August 23, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Marie Jalovecka, David Hartmann, Yukiko Miyamoto, Lars Eckmann, Ondrej Hajdusek, Anthony J O'Donoghue, Daniel Sojka
Babesiosis is a tick-transmitted zoonosis caused by apicomplexan parasites of the genus Babesia. Treatment of this emerging malaria-related disease has relied on antimalarial drugs and antibiotics. The proteasome of Plasmodium, the causative agent of malaria, has recently been validated as a target for anti-malarial drug development and therefore, in this study, we investigated the effect of epoxyketone (carfilzomib, ONX-0914 and epoxomicin) and boronic acid (bortezomib and ixazomib) proteasome inhibitors on the growth and survival of Babesia...
August 7, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Craig Wang, Paul R Torgerson, Ray M Kaplan, Melissa M George, Reinhard Furrer
The same anthelmintic treatment can have variable efficacy on individual animals even if the parasite population is homogenously susceptible. An extension of the R package eggCounts is proposed to take individual efficacy into account using a Bayesian hierarchical model. A simulation study is conducted to compare the performance of five different methods on estimating faecal egg count reduction and its uncertainty interval. Simulation results showed the individual efficacy model offered robust inference to two different data simulation procedures with low root mean squared error on the reduction estimate and appropriate uncertainty estimates...
August 3, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Shogo Furutani, Makoto Ihara, Kristin Lees, Steven D Buckingham, Frederick A Partridge, Jonathan A David, Rohit Patel, Scott Warchal, Ian R Mellor, Kazuhiko Matsuda, David B Sattelle
A novel L-glutamate-gated anion channel (IscaGluCl1) has been cloned from the black-legged tick, Ixodes scapularis, which transmits multiple pathogens including the agents of Lyme disease and human granulocytic anaplasmosis. When mRNA encoding IscaGluCl1 was expressed in Xenopus laevis oocytes, we detected robust 50-400 nA currents in response to 100 μM L-glutamate. Responses to L-glutamate were concentration-dependent (pEC50 3.64 ± 0.11). Ibotenate was a partial agonist on IscaGluCl1. We detected no response to 100 μM aspartate, quisqualate, kainate, AMPA or NMDA...
August 2018: International Journal for Parasitology, Drugs and Drug Resistance
Cristina Ballesteros, James F Geary, Charles D Mackenzie, Timothy G Geary
Lymphatic filariasis and onchocerciasis are neglected parasitic diseases which pose a threat to public health in tropical and sub-tropical regions. Strategies for control and elimination of these diseases by mass drug administration (MDA) campaigns are designed to reduce symptoms of onchocerciasis and transmission of both parasites to eventually eliminate the burden on public health. Drugs used for MDA are predominantly microfilaricidal, and prolonged rounds of treatment are required for eradication. Understanding parasite biology is crucial to unravelling the complex processes involved in host-parasite interactions, disease transmission, parasite immune evasion, and the emergence of drug resistance...
August 2018: International Journal for Parasitology, Drugs and Drug Resistance
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