Caenorhabditis elegans
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ABSTRACT:
PROVIDER: PRJNA395200 | ENA |
REPOSITORIES: ENA
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Project description:Worldwide, more than 1 billion people are affected by infestations with soil-transmitted helminths and also in veterinary medicine helminthiases are a severe thread to livestock due to emerging resistances against the common anthelmintics. Proanthocyanidins have been increasingly investigated for their anthelmintic properties, however, except for an interaction with certain proteins of the nematodes, not much is known about their mode of action. To investigate the anthelmintic activity on a molecular level, a transcriptome analysis was performed in Caenorhabditis elegans after treatment with purified and fully characterized oligomeric procyanidins (OPC). The OPCs had previously been obtained from a hydro-ethanolic (1:1) extract from the leaves of Combretum mucronatum, a plant which is traditionally used in West Africa for the treatment of helminthiasis, therefore, also the crude extract was included in the study. Significant changes in differential gene expression were observed mainly for proteins related to the intestine, many of which were located extracellularly or within cellular membranes. Among the up-regulated genes, several hitherto undescribed orthologues of structural proteins in humans were identified, but also genes that are potentially involved in the worms’ defense against tannins. For example, T22D1.2, an orthologue of human basic salivary proline-rich protein (PRB) 2, and numr-1 (nuclear localized metal responsive) were found to be strongly up-regulated. Down-regulated genes were mainly associated with lysosomal activity, glycoside hydrolysis or the worms’ innate immune response. No major differences were found between the groups treated with purified OPCs versus the crude extract. Investigations using GFP reporter gene constructs of T22D1.2 and numr-1 corroborated the intestine as the predominant site of the anthelmintic activity.
2017-08-31 | GSE101680 | GEO
Project description:We have investigated how the model nematode Caenorhabditis elegans responds to and metabolizes albendazole; an important anthelmintic for human and animal parasite control. The transcriptional response of the mutant strain CB3474 ben-1(e1880)III, which is highly resistant to benzimidazoles due to a null mutation in the β-tubulin drug target, was examined. This approach was successful in minimizing transcriptional responses associated with non-specific stress or with the drug mode of action, resulting in only in a small subset of genes showing differential expression in response to drug exposure.
2010-06-14 | GSE21747 | GEO
Project description:Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, KM08948, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated KM08948’s potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and in the highly pathogenic, blood-feeding Haemonchus contortus (barber’s pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested a series of 25 KM08948 analogues for nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than KM08948, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a KM08948 analogue, 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with KM08948; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as targets of KM08948. Overall, the present study describes an evaluation of this anthelmintic candidate and highlights some challenges associated with early anthelmintic discovery.
2024-04-22 | PXD048945 | Pride
Project description:Quantitative high throughput screening (qHTS) pharmacologically evaluates libraries of drugs and investigational agents for potential therapeutic uses, toxicological risk assessment, and increasingly for academic chemical tool discovery. Phenotypic HTS assays aim to interrogate molecular pathways and networks, often relying on cell culture systems, historically with less emphasis on multicellular organisms. C. elegans has served as a powerful eukaryotic model organism for human biology and disease by virtue of genetic conservation and experimental tractability, as well as a surrogate for infectious parasitic nematodes. Here we describe a paradigm to enable C. elegans in qHTS using 384-well microtiter plate laser scanning cytometry for rapid signal acquisition with concurrent quantification of the fluorescent protein-encoded phenotype. E. coli ghost capsules are used as a non-replicating nutrient source to allow compound titration exposures over the full 7-day life cycle to mitigate complications from bacterial overgrowth. We demonstrate the method using 643 anti-infective biased agents tested in 7-pt titration to assess feasibility of nematode-based in vivo qHTS. A pharmacological profile from the primary screen confirmed the efficacy of known anti-parasitic molecules, such as ivermectin and levamisole as well as illuminating anthelmintic properties of general chemical classes, including -secretase, bromodomain and proteasome inhibitors. We anticipate a broader application of laser scanning cytometry-based qHTS will enable the analysis of C. elegans orthologous transgenic phenotypes of human pathologies to facilitate drug discovery for a range of therapeutic indications.
2023-05-30 | PXD027733 | Pride
Project description:We have investigated the transcriptomic response of the model nematode Caenorhabditis elegans to ivermectin (IVM); an important anthelmintic for human and animal parasite control. The transcriptomic response of the mutant strain DA1316 avr-14(ad1302); avr-15(ad1250); glc-1(pk54), which is highly resistant to ivermectin due to null mutations in three glutamate-gated chloride channel subunits, was examined. Despite the resistant nature of this strain, pharyngeal pumping rate was decreased following 4 hrs exposure to 100ng/ml and 1μg/ml ivermectin resulting in significant change in the expression level of genes associated with a fasting response.
2011-04-01 | GSE22660 | GEO
Project description:We have investigated how the model nematode Caenorhabditis elegans responds to and metabolizes albendazole; an important anthelmintic for human and animal parasite control. The transcriptional response of the mutant strain CB3474 ben-1(e1880)III, which is highly resistant to benzimidazoles due to a null mutation in the β-tubulin drug target, was examined. This approach was successful in minimizing transcriptional responses associated with non-specific stress or with the drug mode of action, resulting in only in a small subset of genes showing differential expression in response to drug exposure. Matched cultures of synchronised C. elegans were grown to young adult stage in liquid culture. The nematodes were then exposed to 300 ug/ml albendazole (ABZ) or exposed only to the DMSO excipient used to deliver the albendazole (CONT) for 4 hours. RNA was extracted from three biological replicates and hybridised to Affymetrix arrays.
2010-06-23 | E-GEOD-21747 | biostudies-arrayexpress
Project description:Global challenges with anthelmintic failure and resistance development lends impetus to the development of new nematocides (anthelmintics) with novel mechanism(s) of action. The free-living nematode Caenorhabditis elegans is as an important model organism used for drug discovery and a powerful tool for anthelmintic screening, evaluation and target deconvolution. Previously, we conducted a whole-organism phenotypic screen of the ‘Pandemic Response Box’ (from Medicines for Malaria Venture, MMV) and identified a hit compound, called ABX464, with activity against C. elegans. Here, we explored this nematocidal pharmacophore on C. elegans, and then tested a series of 46 analogues for human hepatoma (HepG2) toxicity, revealing five compounds whose potency was similar or greater than that of ABX464. Subsequently, we employed thermal proteome profiling (TPP), protein structure prediction and an in silico docking algorithm to identify prime ABX464-target candidates. Taken together, the findings from this study contribute significantly to the early-stage drug discovery of a new nematocide based on ABX464. Future work is aimed at validating the ABX464-protein interactions identified here, and at assessing of ABX464 and associated analogues against a panel of parasitic nematodes, towards the development of a new anthelmintic with a novel mechanism of action.
2024-01-29 | PXD042930 | Pride
Project description:We have investigated the transcriptomic response of the model nematode Caenorhabditis elegans to ivermectin (IVM); an important anthelmintic for human and animal parasite control. The transcriptomic response of the mutant strain DA1316 avr-14(ad1302); avr-15(ad1250); glc-1(pk54), which is highly resistant to ivermectin due to null mutations in three glutamate-gated chloride channel subunits, was examined. Despite the resistant nature of this strain, pharyngeal pumping rate was decreased following 4 hrs exposure to 100ng/ml and 1?g/ml ivermectin resulting in significant change in the expression level of genes associated with a fasting response. Matched cultures of synchronised C. elegans were grown to L4 stage on standard NGM plates with an OP50 bacterial lawn. The nematodes were then transferred to NGM plates containing 100ng/ml ivermectin, 1?g/ml ivermectin, or DMSO excipient only (control) for 4 hours. RNA was extracted from five biological replicates including controls for both the 100ng/ml ivermectin and 1?g/ml ivermectin experiments and hybridised to Affymetrix arrays.
2011-04-01 | E-GEOD-22660 | biostudies-arrayexpress
Project description:Gene Expression Profiling Reveals Molecular Patterns Underlying the Lifespan-Extending Effect of Tyrosol in Caenorhabditis elegans
| PRJNA247477 | ENA
Project description:Transcriptome analysis for the C. elegans modENCODE Project.
| PRJNA63457 | ENA