dictyNews
Electronic Edition
Volume 47, number 23
November 19, 2021
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Abstracts
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Derivatives of Dictyostelium differentiation-inducing factors
suppress the growth of Plasmodium parasites in vitro and in vivo.
Toshihiro Mita 1, Makoto Hirai 1, Yoshiko Maki 1, Saifun Nahar 1,
Naoko Yoshida 1, Yoshiteru Oshima 2, Haruhisa Kikuchi 3,
Yuzuru Kubohara 4
1 Department of Tropical Medicine and Parasitology, Faculty of
Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku,
Tokyo 113-8421, Japan
2 Head Office for Open Innovation Strategy, Tohoku University,
2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
3 Laboratory of Natural Product Chemistry, Graduate School of
Pharmaceutical Sciences, Tohoku University, 6-3, Aza-Aoba,
Aoba-ku, Sendai 980-8578, Japan
4 Laboratory of Health and Life Science, Graduate School of
Health and Sports Science, Juntendo University, Inzai,
Chiba 270-1695, Japan
Biochemical Pharmacology, in press.
Malaria, which is caused by protozoa of the genus Plasmodium ,
remains a major endemic public health problem worldwide.
Since artemisinin combination therapies are used as a first-line
treatment in all endemic regions, the emergence of parasites
resistant to these regimens has become a serious problem.
Differentiation-inducing factor 1 (DIF-1) is a chlorinated
alkylphenone originally found in the cellular slime mold
Dictyostelium discoideum . DIF-1 and its derivatives exhibit a
range of biological activities. In the present study, we investigated
the effects of 41 DIF derivatives on the growth of Plasmodium
falciparum in vitro using four laboratory strains and 12 field
isolates. Micromolar concentrations of several DIF derivatives
strongly suppressed the growth of the four laboratory strains,
including strains that exhibited resistance to chloroquine and
artemisinin, as well as strains that were susceptible to these
drugs. In addition, DIF-1(+2), the most potent derivative, strongly
suppressed the growth of 12 field isolates. We also examined the
effects of DIF-1(+2) on the activity of the rodent malarial parasite
Plasmodium berghei in mice. Intraperitoneal administration of
DIF-1(+2) over 7 days (50 or 70 mg/kg / day) significantly
suppressed the growth of the parasite in the blood with no
apparent adverse effects, and a dose of 70 mg/kg / day
significantly prolonged animal survival. These results suggest
that DIF derivatives, such as DIF-1(+2), could serve as new
lead compounds for the development of antimalarial agents.
Submitted by Yuzuru Kubohara [[log in to unmask]]
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Moving the research forward: The best of British biology using the
tractable model system Dictyostelium discoideum
Robin S.B. Williams1, Jonathan R. Chubb2*, Robert Insall3*,
Jason S. King4*, Catherine J. Pears5*, Elinor Thompson6* and
Cornelis J. Weijer7*
1 Centre for Biomedical Sciences, School of Biological Sciences,
Royal Holloway University of London, Eg-ham, TW20 0EX, UK;
[log in to unmask]
2 MRC Laboratory for Molecular Cell Biology, University College
London, Gower Street, London, WC1E 6BT, UK; [log in to unmask]
3 Institute of Cancer Sciences, University of Glasgow Switchback
Road, Bearsden, Glasgow G61 1QH, UK; [log in to unmask]
4. School of Biosciences, University of Sheffield, Firth Court,
Western Bank, Sheffield, S10 2TN, UK; [log in to unmask]
5 Department of Biochemistry, University of Oxford, South Parks
Road, Oxford, OX1 3QU, UK; [log in to unmask]
6 School of Science, University of Greenwich, Chatham Maritime,
ME4 4TB, UK; [log in to unmask]
7 Division of Cell and Developmental Biology, School of Life
Sciences, University of Dundee, DD1 5EH, UK; [log in to unmask]
* These authors contributed equally to the work
Cells, 10, 3036. https://doi.org/10.3390/cells10113036
The social amoeba Dictyostelium discoideum provides an excellent model
for research in a broad range of disciplines within biology. The organism
diverged from the plant, yeast, fungi and animal kingdoms around 1 billion
years ago, but retains common aspects found in these kingdom.
Dictyostelium has a low level of genetic complexity and provides a range
of molecular, cellular, biochemical and developmental biology experimental
techniques that enables a wide range of research in disparate areas, and
thus multidisciplinary studies leading to research breakthroughs. Numerous
laboratories within the United Kingdom employ Dictyostelium as their core
research model. This review will introduce Dictyostelium, and then highlight
research from several leading British research laboratories, covering their
distinct areas of research, the benefits of using the model, and the
breakthroughs that have arisen due to the use of Dictyostelium as a
tractable model system.
Submitted by Robin Williams [[log in to unmask]]
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Decanoic Acid Stimulates Autophagy in D. discoideum
Eleanor C. Warren, Pavol Kramár, Katie Lloyd-Jones and
Robin S.B. Williams*
Centre for Biomedical Sciences, Department of Biological Sciences,
Royal Holloway University of London, Egham TW20 0EX, UK
Cells, 10(11), 2946, https://doi.org/10.3390/cells10112946
Ketogenic diets, used in epilepsy treatment, are considered to work through
reduced glucose and ketone generation to regulate a range of cellular
process including autophagy induction. Recent studies into the medium-chain
triglyceride (MCT) ketogenic diet have suggested that medium-chain fatty
acids (MCFAs) provided in the diet, decanoic acid and octanoic acid, cause
specific therapeutic effects independent of glucose reduction, although a role
in autophagy has not been investigated. Both autophagy and MCFAs have
been widely studied in Dictyostelium, with findings providing important
advances in the study of autophagy-related pathologies such as
neurodegenerative diseases. Here, we utilize this model to analyze a role
for MCFAs in regulating autophagy. We show that treatment with decanoic
acid but not octanoic acid induces autophagosome formation and modulates
autophagic flux in high glucose conditions. To investigate this effect,
decanoic acid, but not octanoic acid, was found to induce the expression of
autophagy-inducing proteins (Atg1 and Atg8), providing a mechanism for
this effect. Finally, we demonstrate a range of related fatty acid derivatives
with seizure control activity, 4BCCA, 4EOA, and Epilim (valproic acid), also
function to induce autophagosome formation in this model. Thus, our data
suggest that decanoic acid and related compounds may provide a
less-restrictive therapeutic approach to activate autophagy.
Submitted by Robin Williams [[log in to unmask]]
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Evolution of a novel cell type in Dictyostelia required gene duplication of
a cudA-liketranscription factor
Koryu Kin1,2a, Zhi-Hui Chen1a, Gillian Forbes1, and Pauline Schaap1*
1 University of Dundee, School of Life Sciences, Dow Street, Dundee,
DD1 5EH, United Kingdom
2Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Passeig
Marítim de la Barceloneta 37-49, 08003 Barcelona, Spain
Current Biology, in press
The evolution of novel cell types has been proposed to result from
duplication of gene regulatory networks, but proven examples are rare.
In addition to stalk cells and spores that make up the fruiting bodies of
three major groups of Dictyostelia, those in Group 4 additionally evolved
basal disc and cup cells that respectively anchor the stalk to the
substratum and the spore mass to the stalk. We noted a putative Group
4 specific duplication of a cudA-like transcription factor (TF) in a
comparative analysis of group-representative genomes. Using increased
taxon sampling, we here confirmed that this TF, cdl1, duplicated into
cdl1a and cdl1b in the common ancestor to Group 4. cdl1a but not cdl1b
showed signatures of positive selection, indicative of functional innovation.
Deletion of cdl1a in Dictyostelium discoideum resulted in fruiting bodies
with sagging spore heads that lacked the supporting cup cells and
expression of cup-specific genes. Deletion of cdl1b resulted in thinner
fruiting body stalks, while a cdl1b-cdl1a- double knock-out showed more
severe stalk defects, suggesting an ancestral role of cdl1 in stalk
formation. This was confirmed in a closely related non-Group 4 species,
Polysphondylium violaceum, where cdl1 knock-out caused defective
stalk formation. These data indicate that the group-specific duplication
of cdl1 and subsequent diversification of cdl1a played a pivotal role in
the evolution of a novel somatic cell type in Group 4 Dictyostelia.
submitted by: Pauline Schaap [[log in to unmask]]
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[End dictyNews, volume 47, number 23]
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