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Your search keyword '"Forde-Thomas, Josephine E."' showing total 2 results
Start Over Author "Forde-Thomas, Josephine E." Publisher elsevier
2 results on '"Forde-Thomas, Josephine E."'

1. Aberrant spindle dynamics and cytokinesis in Dictyostelium discoideum cells that lack glycogen synthase kinase 3☆

Author

Harwood, Adrian J., Forde-Thomas, Josephine E., Williams, Hazel, Samereier, Matthias, and Müller-Taubenberger, Annette

Subjects
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

2. An Abies procera-derived tetracyclic triterpene containing a steroid-like nucleus core and a lactone side chain attenuates in vitro survival of both Fasciola hepatica and Schistosoma mansoni.

Author

Whiteland HL, Chakroborty A, Forde-Thomas JE, Crusco A, Cookson A, Hollinshead J, Fenn CA, Bartholomew B, Holdsworth PA, Fisher M, Nash RJ, and Hoffmann KF

Subjects
Abies anatomy & histology, Animals, Anthelmintics chemistry, Fasciola hepatica physiology, Fascioliasis drug therapy, Fascioliasis parasitology, Female, Hep G2 Cells, Humans, Lactones chemistry, Life Cycle Stages drug effects, Male, Neglected Diseases drug therapy, Phytochemicals chemistry, Phytochemicals isolation & purification, Phytochemicals pharmacology, Plant Bark chemistry, Schistosoma mansoni physiology, Schistosomiasis drug therapy, Schistosomiasis parasitology, Triterpenes chemistry, Triterpenes isolation & purification, Abies chemistry, Anthelmintics pharmacology, Drug Discovery, Fasciola hepatica drug effects, Lactones pharmacology, Schistosoma mansoni drug effects, Triterpenes pharmacology
Abstract

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. Therefore, the identification of new anthelmintics is necessary for the sustainable control of these NTDs in both animal and human populations. Here, continuing our work with phytochemicals, we isolated ten triterpenoids from the mature bark of Abies species and assessed their anthelmintic activities against F. hepatica and S. mansoni larval and adult lifecycle stages. Full 1 H and 13 C NMR-mediated structural elucidation of the two most active triterpenoids revealed that a tetracyclic steroid-like nucleus core and a lactone side chain are associated with the observed anthelmintic effects. When compared to representative mammalian cell lines (MDBK and HepG2), the most potent triterpenoid (700015; anthelmintic EC 50 s range from 0.7 μM-15.6 μM) displayed anthelmintic selectivity (selectivity indices for F. hepatica: 13 for newly excysted juveniles, 46 for immature flukes, 2 for mature flukes; selectivity indices for S. mansoni: 14 for schistosomula, 9 for immature flukes, 4 for adult males and 3 for adult females) and induced severe disruption of surface membranes in both liver and blood flukes. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also severely inhibited by 700015. Together, our results describe the structural elucidation of a novel broad acting anthelmintic triterpenoid and support further investigations developing this compound into more potent analogues for the control of both fasciolosis and schistosomiasis., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2018
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