7 results on '"Forde-Thomas, Josephine E."'
Search Results
2. Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica.
- Author
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Chakroborty, Anand, Pritchard, Deiniol R., Bouillon, Marc E., Cervi, Anna, Kraehenbuehl, Rolf, Wild, Charlotte, Fenn, Caroline, Holdsworth, Peter, Capner, Colin, Padalino, Gilda, Forde-Thomas, Josephine E., Payne, Joseph, Smith, Brendan G., Fisher, Maggie, Lahmann, Martina, Baird, Mark S., and Hoffmann, Karl F.
- Subjects
FASCIOLA hepatica ,LIVER flukes ,ENGLISH ivy ,FASCIOLIASIS ,AGRICULTURE - Abstract
Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in bulk from Hedera helix. Thirty-six compounds were initially screened against F. hepatica newly excysted juveniles (NEJs) of the Italian strain. Eleven of these compounds were active against NEJs and were selected for further study, using adult F. hepatica derived from a local abattoir (provenance unknown). From these eleven compounds, six demonstrated activity and were further assessed against immature liver flukes of the Italian strain. Subsequently, the most active compounds (n = 5) were further evaluated in ex vivo dose response experiments against adult Italian strain liver flukes. Overall, MC042 was identified as the most active molecule and the EC
50 obtained from immature and adult liver fluke assays (at 24 h post co-culture) are estimated as 1.07 μM and 13.02 μM, respectively. When compared to the in vitro cytotoxicity of MDBK bovine cell line, MC042 demonstrated the highest anthelmintic selectivity (44.37 for immature and 3.64 for adult flukes). These data indicate that modified hederagenins display properties suitable for further investigations as candidate flukicides. [ABSTRACT FROM AUTHOR]- Published
- 2023
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3. Using ChEMBL to Complement Schistosome Drug Discovery.
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Padalino, Gilda, Coghlan, Avril, Pagliuca, Giampaolo, Forde-Thomas, Josephine E., Berriman, Matthew, and Hoffmann, Karl F.
- Subjects
DRUG discovery ,NEGLECTED diseases ,TRICHOSTATIN A ,VACCINE effectiveness ,FUNCTIONAL genomics - Abstract
Schistosomiasis is one of the most important neglected tropical diseases. Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel. The sustainability of this strategy is at substantial risk due to the possibility of praziquantel insensitive/resistant schistosomes developing. Considerable time and effort could be saved in the schistosome drug discovery pipeline if available functional genomics, bioinformatics, cheminformatics and phenotypic resources are systematically leveraged. Our approach, described here, outlines how schistosome-specific resources/methodologies, coupled to the open-access drug discovery database ChEMBL, can be cooperatively used to accelerate early-stage, schistosome drug discovery efforts. Our process identified seven compounds (fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474 and staurosporine) with ex vivo anti-schistosomula potencies in the sub-micromolar range. Three of those compounds (epoxomicin, CGP60474 and staurosporine) also demonstrated potent and fast-acting ex vivo effects on adult schistosomes and completely inhibited egg production. ChEMBL toxicity data were also leveraged to provide further support for progressing CGP60474 (as well as luminespib and TAE684) as a novel anti-schistosomal compound. As very few compounds are currently at the advanced stages of the anti-schistosomal pipeline, our approaches highlight a strategy by which new chemical matter can be identified and quickly progressed through preclinical development. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production.
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Hulme, Benjamin J., Geyer, Kathrin K., Forde-Thomas, Josephine E., Padalino, Gilda, Phillips, Dylan W., Ittiprasert, Wannaporn, Karinshak, Shannon E., Mann, Victoria H., Chalmers, Iain W., Brindley, Paul J., Hokke, Cornelis H., and Hoffmann, Karl F.
- Subjects
SCHISTOSOMA mansoni ,WORM eggs ,AMINO acid residues ,NEGLECTED diseases ,PARASITES ,PARASITIC diseases ,EGGS ,FEMALES - Abstract
α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni's α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290's female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds. Author summary: Schistosomiasis is a parasitic disease caused by infection with blood flukes, which leads to acute and chronic pathology in millions of infected individuals located in deprived tropical and subtropical regions. Elucidating the function of schistosome genes has provided a clearer view on their roles in various molecular pathways, which are critical to successful parasitism. This information is invaluable when progressing novel drug and vaccine candidates. Here, we add to the existing knowledge of the Schistosoma mansoni parasitic glycan processing and modification machinery by functionally characterising a glycosyl hydrolase (S. mansoni α-N-acetylgalactosaminidase, SmNAGAL). We demonstrate that this protein is enzymatically active and important in coordinating parasite movement in adult male and female schistosomes. Additionally, we provide evidence that this protein regulates pathways associated with egg production in female schistosomes, which is responsible for inducing pathological reactions. Developing drugs that inhibit SmNAGAL enzymatic activity could provide a novel approach for controlling schistosomiasis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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5. Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1) is an immunogenic antigen found in EVs released from pre-acetabular glands of invading cercariae.
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Gasan, Thomas A., Kuipers, Marije E., Roberts, Grisial H., Padalino, Gilda, Forde-Thomas, Josephine E., Wilson, Shona, Wawrzyniak, Jakub, Tukahebwa, Edridah M., Hoffmann, Karl F., and Chalmers, Iain W.
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EXTRACELLULAR vesicles ,SCHISTOSOMA mansoni ,CERCARIAE ,GLANDS ,TREMATODA ,SKIN absorption ,HUMORAL immunity ,HELMINTHS - Abstract
Extracellular Vesicles (EVs) are an integral component of cellular/organismal communication and have been found in the excreted/secreted (ES) products of both protozoan and metazoan parasites. Within the blood fluke schistosomes, EVs have been isolated from egg, schistosomula, and adult lifecycle stages. However, the role(s) that EVs have in shaping aspects of parasite biology and/or manipulating host interactions is poorly defined. Herein, we characterise the most abundant EV-enriched protein in Schistosoma mansoni tissue-migrating schistosomula (Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1)). Comparative sequence analysis demonstrates that lev1 orthologs are found in all published Schistosoma genomes, yet homologs are not found outside of the Schistosomatidae. Lifecycle expression analyses collectively reveal that smlev1 transcription peaks in cercariae, is male biased in adults, and is processed by alternative splicing in intra-mammalian lifecycle stages. Immunohistochemistry of cercariae using a polyclonal anti-recombinant SmLEV1 antiserum localises this protein to the pre-acetabular gland, with some disperse localisation to the surface of the parasite. S. mansoni—infected Ugandan fishermen exhibit a strong IgG
1 response against SmLEV1 (dropping significantly after praziquantel treatment), with 11% of the cohort exhibiting an IgE response and minimal levels of detectable antigen-specific IgG4 . Furthermore, mice vaccinated with rSmLEV1 show a slightly reduced parasite burden upon challenge infection and significantly reduced granuloma volumes, compared with control animals. Collectively, these results describe SmLEV1 as a Schistosomatidae-specific, EV-enriched immunogen. Further investigations are now necessary to uncover the full extent of SmLEV1's role in shaping schistosome EV function and definitive host relationships. Author summary: From the moment they start to penetrate the human skin, juvenile schistosomes secrete bioactive molecules to facilitate invasion, evade the host immune response, and establish a long-lived infection. One component of these secretions are pre-packaged, membrane-bound extracellular vesicles (EVs) capable of modulating the host immune response. Whilst EVs contain a subset of known biologically relevant molecules, many EV proteins remain uncharacterised. Here we investigate the most abundant protein found within EVs released by early skin-stage schistosomes—SmLEV1. We show that the lev1 gene is only found in the schistosomes and closely related species and is most abundantly expressed during the early stages of human infection. Localising the SmLEV1 protein to the pre-acetabular glands of the cercarial head, highlights this gland as a source of larval EVs. Vaccination with SmLEV1 had minimal effects on parasite burden, but significantly reduced the liver granuloma volume, implicating SmLEV1 as a potential anti-pathology target for schistosomiasis. Our collective findings are the first characterisation of SmLEV1 and provide essential data and resources for the ongoing study of schistosome EVs. [ABSTRACT FROM AUTHOR]- Published
- 2021
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6. Aberrant spindle dynamics and cytokinesis in Dictyostelium discoideum cells that lack glycogen synthase kinase 3☆
- Author
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Harwood, Adrian J., Forde-Thomas, Josephine E., Williams, Hazel, Samereier, Matthias, and Müller-Taubenberger, Annette
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Glycogen Synthase Kinase 3 ,Short Communication ,Chromosome Segregation ,Mitotic spindle ,Mutation ,Protozoan Proteins ,Mitosis ,Dictyostelium ,macromolecular substances ,Spindle Apparatus ,Cytokinesis ,Protein Binding - Abstract
Eukaryotic cell division requires the co-ordinated assembly and disassembly of the mitotic spindle, accurate chromosome segregation and temporal control of cytokinesis to generate two daughter cells. While the absolute details of these processes differ between organisms, there are evolutionarily conserved core components common to all eukaryotic cells, whose identification will reveal the key processes that control cell division. Glycogen synthase kinase 3 (GSK-3) is a major protein kinase found throughout the eukaryotes and regulates many processes, including cell differentiation, growth, motility and apoptosis. In animals, GSK-3 associates with mitotic spindles and its inhibition causes mis-regulation of chromosome segregation. Two suppressor screens in yeast point to a more general effect of GSK-3 on cell division, however the direct role of GSK-3 in control of mitosis has not been explored outside the animal kingdom. Here we report that the Dictyostelium discoideum GSK-3 orthologue, GskA, associates with the mitotic spindle during cell division, as seen for its mammalian counterparts. Dictyostelium possesses only a single GSK-3 gene that can be deleted to eliminate all GSK-3 activity. We found that gskA-null mutants failed to elongate their mitotic spindle and were unable to divide in shaking culture, but have no chromosome segregation defect. These results suggest further conservation for the role of GSK-3 in the regulation of spindle dynamics during mitosis, but also reveal differences in the mechanisms ensuring accurate chromosome segregation.
- Published
- 2013
7. Antischistosomal Properties of Sclareol and Its Heck-Coupled Derivatives: Design, Synthesis, Biological Evaluation, and Untargeted Metabolomics.
- Author
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Crusco, Alessandra, Whiteland, Helen, Baptista, Rafael, Forde-Thomas, Josephine E., Beckmann, Manfred, Mur, Luis A. J., Nash, Robert J., Westwell, Andrew D., and Hoffmann, Karl F.
- Published
- 2019
- Full Text
- View/download PDF
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