scholarly journals Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside

2021 ◽  
Author(s):  
Janneke Wit ◽  
Steffen R. Hahnel ◽  
Briana C. Rodriguez ◽  
Erik Andersen
Keyword(s):  
Caenorhabditis Elegans ◽  
Mode Of Action ◽  
Natural Variation ◽  
Treatment Strategies ◽  
Parasitic Nematodes ◽  
Anthelmintic Drug ◽  
C Elegans ◽  
Hormetic Effect ◽  
Filarial Nematodes

Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and genetic selection and in vitro experiments implicated slo-1, a BK potassium channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some variation in emodepside responses can be explained by natural differences in slo-1. This result suggests that other genes in addition to slo-1 underlie emodepside resistance in wild C. elegans strains. Additionally, all assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect), which could impact treatment strategies. We find that natural variation affects emodepside sensitivity, supporting the suitability of C. elegans as a model system to study emodepside responses across parasitic nematodes.

scholarly journals In Vitro Efficacy of Aqueous and Methanol Extract of Cassia siamea Against the Motility of Caenorhabditis elegans

2020 ◽  
Vol 31 (3) ◽  
pp. 145-159
Author(s):  
Haladu Ali Gagman ◽  
Nik Ahmad Irwan Izzauddin Nik Him ◽  
Hamdan Ahmad ◽  
Shaida Fariza Sulaiman ◽  
Rahmad Zakaria ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Methanol Extract ◽  
Anthelmintic Resistance ◽  
Gastrointestinal Nematode ◽  
Parasitic Nematodes ◽  
Cassia Siamea ◽  
Methanol Extracts ◽  
C Elegans ◽  
Significant Difference

Gastrointestinal nematode infections can cause great losses in revenue due to decrease livestock production and animal death. The use of anthelmintic to control gastrointestinal nematode put a selection pressure on nematode populations which led to emergence of anthelmintic resistance. Because of that, this study was carried out to investigate the efficacy of aqueous and methanol extract of Cassia siamea against the motility of C. elegans Bristol N2 and C. elegans DA1316. Caenorhabditis elegans Bristol N2 is a susceptible strain and C. elegans DA1316 is an ivermectin resistant strain. In vitro bioassay of various concentrations of (0.2, 0.6, 0.8, 1.0 and 2.0 mg mL–1) aqueous and methanol extracts of C. siamea was conducted against the motility of L4 larvae of C. elegans Bristol N2 and C. elegans DA1316. The L4 larvae were treated with 0.02 μg mL–1 of ivermectin served as positive control while those in M9 solution served as negative control. The activity of the extracts was observed after 24 h and 48 h. A significant difference was recorded in the extract performance compared to control at (P < 0.001) after 48 h against the motility of the larvae of both strains. The methanol extracts inhibited the motility of C. elegans Bristol N2 by 86.7% as well as DA1316 up to 84.9% at 2.0 mg mL–1 after 48 h. The methanol extract was more efficient than aqueous extract (P < 0.05) against the motility of both strains of C. elegans. Cassia siamea may be used as a natural source of lead compounds for the development of alternative anthelmintic against parasitic nematodes as well ivermectin resistant strains of nematodes.

scholarly journals Functional investigation of conserved glutamate receptor subunits reveals a new mode of action of macrocyclic lactones in nematodes

2020 ◽  
Author(s):  
Nicolas Lamassiaude ◽  
Elise Courtot ◽  
Angélique Corset ◽  
Claude L. Charvet ◽  
Cédric Neveu
Keyword(s):  
Caenorhabditis Elegans ◽  
Mode Of Action ◽  
Chloride Channels ◽  
Parasitic Nematode ◽  
Expression System ◽  
Molecular Targets ◽  
Parasitic Nematodes ◽  
Pharmacological Properties ◽  
Macrocyclic Lactones ◽  
C Elegans

AbstractGlutamate-gated chloride channels receptors (GluCls) are involved in the inhibition of neurotransmission in invertebrates and represent major molecular targets for therapeutic drugs. Among these drugs, macrocyclic lactones (MLs) are widely used as anthelmintic to treat parasitic nematodes impacting both human and animal health. Despite massive use of MLs since the 80’s, the exact molecular targets of these drugs are still unknown in many important parasite species. Among the GluCl subunit encoding genes, avr-14, glc-2, glc-3 and glc-4 are highly conserved throughout the nematode phylum. Using the Xenopus oocyte as an expression system, we pharmacologically characterized these GluCl subunits from the model nematode Caenorhabditis elegans, the human filarial nematode Brugia malayi and the horse parasitic nematode Parascaris univalens. In contrast with C. elegans, expression of parasitic nematode subunits as homomeric receptors was not reliable and needed glutamate application at the mM range to induce low currents at the nA range. However, the co-expression of GLC-2 and AVR-14B lead to the robust expression of ML-sensitive receptors for the three nematode species. In addition, we demonstrated that for C. elegans and P. univalens, GLC-2 co-assembled with GLC-3 to form a new GluCl subtype with distinct pharmacological properties. Whereas 1μM ivermectin, moxidectin and eprinomectin acted as agonist of the GLC-2/GLC-3 receptor from C. elegans, they did not directly activate GLC-2/GLC-3 of P. univalens. In contrast, these MLs potentialized glutamate elicited currents thus representing a unique pharmacological property. Our results highlight the importance of GLC-2 as a key subunit in the composition of heteromeric channels in nematodes and demonstrate that MLs act on novel GluCl subtypes that show unusual pharmacological properties, providing new insights about MLs mode of action.Author summaryThe filarial and ascarid parasitic nematodes include some of the most pathogenic or invalidating species in humans, livestock and companion animals. Whereas the control of these worms is critically dependent on macrocyclic lactones (MLs) such as ivermectin, the mode of action of this anthelmintic class remains largely unknown in these parasites. In the model nematode Caenorhabditis elegans, MLs target GluCl pentameric glutamate-sensitive chloride channels (GluCl). Because MLs are potent anthelmintics on C. elegans, ascarid and filarial nematodes, in the present study we investigated GluCl subunits highly conserved between these distantly related worms. Using the Xenopus oocyte as a heterologous expression system, we identified and performed the pharmacological characterization of novel GluCl receptors from C. elegans, the human filarial parasite Brugia malayi and the horse parasite Parascaris univalens. Our results highlight heteromeric GluCls from parasites as molecular targets for a wide range of MLs. We report an original mode of action of MLs on a new GluCl subtype made of the GLC-2/GLC-3 subunit combination. This study brings new insights about the diversity of GluCl subtypes in nematodes and opens the way for rational drug screening for the identification of next generation anthelmintic compounds.

Streblus asper Lour. exerts MAPK and SKN-1 mediated anti-aging, anti-photoaging activities and imparts neuroprotection by ameliorating Aβ in Caenorhabditis elegans

2021 ◽  
pp. 1-17
Author(s):  
Mani Iyer Prasanth ◽  
James Michael Brimson ◽  
Dicson Sheeja Malar ◽  
Anchalee Prasansuklab ◽  
Tewin Tencomnao
Keyword(s):  
Oxidative Stress ◽  
Caenorhabditis Elegans ◽  
Stress Resistance ◽  
Vital Role ◽  
Transgenic Strain ◽  
Wild Type ◽  
Neuroprotective Effects ◽  
C Elegans ◽  
Streblus Asper

BACKGROUND: Streblus asper Lour., has been reported to have anti-aging and neuroprotective efficacies in vitro. OBJECTIVE: To analyze the anti-aging, anti-photoaging and neuroprotective efficacies of S. asper in Caenorhabditis elegans. METHODS: C. elegans (wild type and gene specific mutants) were treated with S. asper extract and analyzed for lifespan and other health benefits through physiological assays, fluorescence microscopy, qPCR and Western blot. RESULTS: The plant extract was found to increase the lifespan, reduce the accumulation of lipofuscin and modulate the expression of candidate genes. It could extend the lifespan of both daf-16 and daf-2 mutants whereas the pmk-1 mutant showed no effect. The activation of skn-1 was observed in skn-1::GFP transgenic strain and in qPCR expression. Further, the extract can extend the lifespan of UV-A exposed nematodes along with reducing ROS levels. Additionally, the extract also extends lifespan and reduces paralysis in Aβ transgenic strain, apart from reducing Aβ expression. CONCLUSIONS: S. asper was able to extend the lifespan and healthspan of C. elegans which was independent of DAF-16 pathway but dependent on SKN-1 and MAPK which could play a vital role in eliciting the anti-aging, anti-photoaging and neuroprotective effects, as the extract could impart oxidative stress resistance and neuroprotection.

scholarly journals Caenorhabditis elegans as an in vivo Model to Assess Amphetamine Tolerance

2021 ◽  
pp. 1-9
Author(s):  
Dayana Torres Valladares ◽  
Sirisha Kudumala ◽  
Murad Hossain ◽  
Lucia Carvelli
Keyword(s):  
Caenorhabditis Elegans ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Genetic Model ◽  
In Vivo Model ◽  
C Elegans ◽  
Hyperactivity Disorder ◽  
In Vitro Data

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in <i>Caenorhabditis elegans</i> to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that <i>C. elegans</i> is a suitable system to study tolerance to drugs of abuse such as amphetamines.

scholarly journals Microtubules and microtubule-associated proteins from the nematode Caenorhabditis elegans: periodic cross-links connect microtubules in vitro.

1986 ◽  
Vol 103 (1) ◽  
pp. 23-31 ◽  
Author(s):  
E J Aamodt ◽  
J G Culotti
Keyword(s):  
Caenorhabditis Elegans ◽  
Apparent Molecular Weight ◽  
Cross Link ◽  
Nematode Caenorhabditis Elegans ◽  
Microtubule Associated Proteins ◽  
C Elegans ◽  
Associated Proteins ◽  
Cross Links ◽  
The Cross

The nematode Caenorhabditis elegans should be an excellent model system in which to study the role of microtubules in mitosis, embryogenesis, morphogenesis, and nerve function. It may be studied by the use of biochemical, genetic, molecular biological, and cell biological approaches. We have purified microtubules and microtubule-associated proteins (MAPs) from C. elegans by the use of the anti-tumor drug taxol (Vallee, R. B., 1982, J. Cell Biol., 92:435-44). Approximately 0.2 mg of microtubules and 0.03 mg of MAPs were isolated from each gram of C. elegans. The C. elegans microtubules were smaller in diameter than bovine microtubules assembled in vitro in the same buffer. They contained primarily 9-11 protofilaments, while the bovine microtubules contained 13 protofilaments. The principal MAP had an apparent molecular weight of 32,000 and the minor MAPs were 30,000, 45,000, 47,000, 50,000, 57,000, and 100,000-110,000 mol wt as determined by SDS-gel electrophoresis. The microtubules were observed, by electron microscopy of negatively stained preparations, to be connected by stretches of highly periodic cross-links. The cross-links connected the adjacent protofilaments of aligned microtubules, and occurred at a frequency of one cross-link every 7.7 +/- 0.9 nm, or one cross-link per tubulin dimer along the protofilament. The cross-links were removed when the MAPs were extracted from the microtubules with 0.4 M NaCl. The cross-links then re-formed when the microtubules and the MAPs were recombined in a low salt buffer. These results strongly suggest that the cross-links are composed of MAPs.

scholarly journals Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

2015 ◽  
Vol 112 (13) ◽  
pp. 3955-3960 ◽  
Author(s):  
Xinxing Zhang ◽  
Likui Feng ◽  
Satya Chinta ◽  
Prashant Singh ◽  
Yuting Wang ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Environmental Conditions ◽  
Side Chain ◽  
Side Chains ◽  
Activity Assay ◽  
C Elegans ◽  
Substrate Preferences ◽  
Acyl Coa Oxidase ◽  
Coa Thioesters

Caenorhabditis elegans uses ascaroside pheromones to induce development of the stress-resistant dauer larval stage and to coordinate various behaviors. Peroxisomal β-oxidation cycles are required for the biosynthesis of the fatty acid-derived side chains of the ascarosides. Here we show that three acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, form different protein homo- and heterodimers with distinct substrate preferences. Mutations in the acyl-CoA oxidase genes acox-1, -2, and -3 led to specific defects in ascaroside production. When the acyl-CoA oxidases were expressed alone or in pairs and purified, the resulting acyl-CoA oxidase homo- and heterodimers displayed different side-chain length preferences in an in vitro activity assay. Specifically, an ACOX-1 homodimer controls the production of ascarosides with side chains with nine or fewer carbons, an ACOX-1/ACOX-3 heterodimer controls the production of those with side chains with seven or fewer carbons, and an ACOX-2 homodimer controls the production of those with ω-side chains with less than five carbons. Our results support a biosynthetic model in which β-oxidation enzymes act directly on the CoA-thioesters of ascaroside biosynthetic precursors. Furthermore, we identify environmental conditions, including high temperature and low food availability, that induce the expression of acox-2 and/or acox-3 and lead to corresponding changes in ascaroside production. Thus, our work uncovers an important mechanism by which C. elegans increases the production of the most potent dauer pheromones, those with the shortest side chains, under specific environmental conditions.

Cuticular disruption and mortality of Caenorhabditis elegans exposed to culture filtrate of Byssochlamys nivea Westling

Nematology ◽  
2001 ◽  
Vol 3 (4) ◽  
pp. 355-363 ◽  
Author(s):  
Ja-On Park ◽  
Krishnapillai Sivasithamparam ◽  
Emile Ghisalberti ◽  
Jaih Hargreaves ◽  
Walter Gams ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Culture Filtrate ◽  
Structural Changes ◽  
Phytophthora Cinnamomi ◽  
Pathogenic Fungi ◽  
Gaeumannomyces Graminis ◽  
Pythium Irregulare ◽  
Potato Dextrose Broth ◽  
C Elegans

AbstractA strain of a Byssochlamys nivea, isolated from saline mud in Western Australia as a part of statewide survey of soil fungi for nematophagous activity, was evaluated for its effect on nematodes. Culture filtrate of the fungus grown on potato dextrose broth for 7 days caused structural changes in the cuticle, aggregation of individuals, and mortality of Caenorhabditis elegans. In addition, the culture filtrate completely inhibited hatching of C. elegans eggs. Exudates from agar colonies also caused cuticular disruption and mortality of C. elegans. The cuticular disruption observed, not reported in nematodes before, was initiated in the labial region and spread towards the posterior region of the nematode within 10 min of application. This reaction occurred only in live nematodes. Cuticular disruption and mortality caused by the culture filtrate varied according to growth conditions. The active compound(s) in the culture filtrate were thermostable (100°C for 1 h); however freezing the culture filtrate (-20°C for 2 days) eliminated the activities, as did dialysis (<14 000 molecular weight). Cuticular disruption and mortality were also observed when the nematode was exposed to culture filtrates of two other strains of B. nivea supplied by CBS, The Netherlands. The culture filtrate also inhibited in vitro growth of the plant-pathogenic fungi Fusarium oxysporum, Gaeumannomyces graminis var. tritici, Phytophthora cinnamomi, Pythium irregulare and Rhizoctonia solani.

scholarly journals Identification of gmhA, a Yersinia pestis Gene Required for Flea Blockage, by Using a Caenorhabditis elegans Biofilm System

2005 ◽  
Vol 73 (11) ◽  
pp. 7236-7242 ◽  
Author(s):  
Creg Darby ◽  
Sandya L. Ananth ◽  
Li Tan ◽  
B. Joseph Hinnebusch
Keyword(s):  
Caenorhabditis Elegans ◽  
Yersinia Pestis ◽  
Biofilm Formation ◽  
Yersinia Pseudotuberculosis ◽  
C Elegans ◽  
Transposon Insertion ◽  
Insertion Mutants ◽  
Random Screening

ABSTRACT Yersinia pestis, the cause of bubonic plague, blocks feeding by its vector, the flea. Recent evidence indicates that blockage is mediated by an in vivo biofilm. Y. pestis and the closely related Yersinia pseudotuberculosis also make biofilms on the cuticle of the nematode Caenorhabditis elegans, which block this laboratory animal's feeding. Random screening of Y. pseudotuberculosis transposon insertion mutants with a C. elegans biofilm assay identified gmhA as a gene required for normal biofilms. gmhA encodes phosphoheptose isomerase, an enzyme required for synthesis of heptose, a conserved component of lipopolysaccharide and lipooligosaccharide. A Y. pestis gmhA mutant was constructed and was severely defective for C. elegans biofilm formation and for flea blockage but only moderately defective in an in vitro biofilm assay. These results validate use of the C. elegans biofilm system to identify genes and pathways involved in Y. pestis flea blockage.

scholarly journals The noncanonical small heat shock protein HSP-17 from Caenorhabditis elegans is a selective protein aggregase

2020 ◽  
Vol 295 (10) ◽  
pp. 3064-3079 ◽  
Author(s):  
Manuel Iburg ◽  
Dmytro Puchkov ◽  
Irving U. Rosas-Brugada ◽  
Linda Bergemann ◽  
Ulrike Rieprecht ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Heat Shock ◽  
Small Heat Shock Protein ◽  
Independent Manner ◽  
C Elegans ◽  
Higher Eukaryotes ◽  
Prolonged Heat ◽  
Shock Proteins ◽  
Excretory Organs

Small heat shock proteins (sHsps) are conserved, ubiquitous members of the proteostasis network. Canonically, they act as “holdases” and buffer unfolded or misfolded proteins against aggregation in an ATP-independent manner. Whereas bacteria and yeast each have only two sHsps in their genomes, this number is higher in metazoan genomes, suggesting a spatiotemporal and functional specialization in higher eukaryotes. Here, using recombinantly expressed and purified proteins, static light-scattering analysis, and disaggregation assays, we report that the noncanonical sHsp HSP-17 of Caenorhabditis elegans facilitates aggregation of model substrates, such as malate dehydrogenase (MDH), and inhibits disaggregation of luciferase in vitro. Experiments with fluorescently tagged HSP-17 under the control of its endogenous promoter revealed that HSP-17 is expressed in the digestive and excretory organs, where its overexpression promotes the aggregation of polyQ proteins and of the endogenous kinase KIN-19. Systemic depletion of hsp-17 shortens C. elegans lifespan and severely reduces fecundity and survival upon prolonged heat stress. HSP-17 is an abundant protein exhibiting opposing chaperone activities on different substrates, indicating that it is a selective protein aggregase with physiological roles in development, digestion, and osmoregulation.

scholarly journals Rosemary Flowers as Edible Plant Foods: Phenolic Composition and Antioxidant Properties in Caenorhabditis elegans

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 811
Author(s):  
Cristina Moliner ◽  
Víctor López ◽  
Lillian Barros ◽  
Maria Inês Dias ◽  
Isabel C. F. R. Ferreira ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Antioxidant Properties ◽  
Ethanolic Extract ◽  
Food Ingredient ◽  
Edible Plant ◽  
Phenolic Profile ◽  
C Elegans ◽  
Rosmarinus Officinalis L

Rosmarinus officinalis L., commonly known as rosemary, has been largely studied for its wide use as food ingredient and medicinal plant; less attention has been given to its edible flowers, being necessary to evaluate their potential as functional foods or nutraceuticals. To achieve that, the phenolic profile of the ethanolic extract of R. officinalis flowers was determined using LC-DAD-ESI/MSn and then its antioxidant and anti-ageing potential was studied through in vitro and in vivo assays using Caenorhabditis elegans. The phenolic content was 14.3 ± 0.1 mg/g extract, trans rosmarinic acid being the predominant compound in the extract, which also exhibited a strong antioxidant capacity in vitro and increased the survival rate of C. elegans exposed to lethal oxidative stress. Moreover, R. officinalis flowers extended C. elegans lifespan up to 18%. Therefore, these findings support the potential use of R. officinalis flowers as ingredients to develop products with pharmaceutical and/or nutraceutical potential.

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