C. elegans: a prominent platform for modeling and drug screening in neurological disorders.

INTRODUCTION: Human neurodevelopmental and neurodegenerative diseases (NDevDs and NDegDs, respectively) encompass a broad spectrum of disorders affecting the nervous system with an increasing incidence. In this context, the nematode C. elegans, has emerged as a benchmark model for biological research, especially in the field of neuroscience. AREAS COVERED: The authors highlight the numerous advantages of this tiny worm as a model for exploring nervous system pathologies and as a platform for drug discovery. There is a particular focus given to describing the existing models of C. elegans for the study of NDevDs and NDegDs. Specifically, the authors underscore their strong applicability in preclinical drug development. Furthermore, they place particular emphasis on detailing the common techniques employed to explore the nervous system in both healthy and diseased states. EXPERT OPINION: Drug discovery constitutes a long and expensive process. The incorporation of invertebrate models, such as C. elegans, stands as an exemplary strategy for mitigating costs and expediting timelines. The utilization of C. elegans as a platform to replicate nervous system pathologies and conduct high-throughput automated assays in the initial phases of drug discovery is pivotal for rendering therapeutic options more attainable and cost-effective.

The neurohormone tyramine stimulates the secretion of an Insulin-Like Peptide from the intestine to modulate the systemic stress response in C. elegans.

The DAF-2/insulin/insulin-like growth factor signaling (IIS) pathway plays an evolutionarily conserved role in regulating reproductive development, lifespan, and stress resistance. In C. elegans , DAF-2/IIS signaling is modulated by an extensive array of insulin-like peptides (ILPs) with diverse spatial and temporal expression patterns. However, the release dynamics and specific functions of these ILPs in adapting to different environmental conditions remain poorly understood. Here, we show that the ILP, INS-3, plays a crucial role in modulating the response to different types of stressors in C. elegans . ins-3 mutants display increased resistance to both heat and oxidative stress; however, under favorable conditions, this advantage is countered by slower reproductive development. ins-3 expression in both neurons and the intestine is downregulated in response to environmental stressors. Conversely, the neurohormone tyramine, which is released during the acute flight response, triggers an upregulation in ins-3 expression. Moreover, we found that tyramine negatively impacts environmental stress resistance by stimulating the release of INS-3 from the intestine. The subsequent release of INS-3 systemically activates the DAF-2 pathway, resulting in the inhibition of cytoprotective mechanisms mediated by DAF-16/FOXO and HSF-1. These studies offer mechanistic insights into the brain-gut communication pathway that weighs adaptive strategies to respond to acute and long-term stress scenarios.

Drug discovery: Insights from the invertebrate Caenorhabditis elegans.

Therapeutic drug development is a long, expensive, and complex process that usually takes 12-15 years. In the early phases of drug discovery, in particular, there is a growing need for animal models that ensure the reduction in both cost and time. Caenorhabditis elegans has been traditionally used to address fundamental aspects of key biological processes, such as apoptosis, aging, and gene expression regulation. During the last decade, with the advent of large-scale platforms for screenings, this invertebrate has also emerged as an essential tool in the pharmaceutical research industry to identify novel drugs and drug targets. In this review, we discuss the reasons why C. elegans has been positioned as an outstanding cost-effective option for drug discovery, highlighting both the advantages and drawbacks of this model. Particular attention is paid to the suitability of this nematode in large-scale genetic and pharmacological screenings. High-throughput screenings in C. elegans have indeed contributed to the breakthrough of a wide variety of candidate compounds involved in extensive fields including neurodegeneration, pathogen infections and metabolic disorders. The versatility of this nematode, which enables its instrumentation as a model of human diseases, is another attribute also herein underscored. As illustrative examples, we discuss the utility of C. elegans models of both human neurodegenerative diseases and parasitic nematodes in the drug discovery industry. Summing up, this review aims to demonstrate the impact of C. elegans models on the drug discovery pipeline.

A journey to 'tame a small metazoan organism', ‡ seen through the artistic eyes of C. elegans researchers.

In the following pages, we share a collection of photos, drawings, and mixed-media creations, most of them especially made for this JoN issue, manifesting C. elegans researchers' affection for their model organism and the founders of the field. This is a celebration of our community's growth, flourish, spread, and bright future. Descriptions provided by the contributors, edited for space. 1.

Diisopropylphenyl-imidazole (DII): A new compound that exerts anthelmintic activity through novel molecular mechanisms.

Nematode parasites cause substantial morbidity to billions of people and considerable losses in livestock and food crops. The repertoire of effective anthelmintic compounds for treating these parasitoses is very limited, as drug development has been delayed for decades. Moreover, resistance has become a global concern in livestock parasites and is an emerging issue for human helminthiasis. Therefore, anthelmintics with novel mechanisms of action are urgently needed. Taking advantage of Caenorhabditis elegans as an established model system, we here screened the nematicidal potential of novel imidazolium and imidazole derivatives. One of these derivatives, diisopropylphenyl-imidazole (DII), is lethal to C. elegans at both mature and immature stages. This lethal effect appears to be specific because DII concentrations which prove to be toxic to C. elegans do not induce significant lethality on bacteria, Drosophila melanogaster, and HEK-293 cells. Our analysis of DII action on C. elegans mutant strains determined that, in the adult stage, null mutants of unc-29 are resistant to the drug. Muscle expression of this gene completely restores DII sensitivity. UNC-29 has been largely reported as an essential constituent of the levamisole-sensitive muscle nicotinic receptor (L-AChR). Nevertheless, null mutants in unc-63 and lev-8 (essential and non-essential subunits of L-AChRs, respectively) are as sensitive to DII as the wild-type strain. Therefore, our results suggest that DII effects on adult nematodes rely on a previously unidentified UNC-29-containing muscle AChR, different from the classical L-AChR. Interestingly, DII targets appear to be different between larvae and adults, as unc-29 null mutant larvae are sensitive to the drug. The existence of more than one target could delay resistance development. Its lethality on C. elegans, its harmlessness in non-nematode species and its novel and dual mechanism of action make DII a promising candidate compound for anthelmintic therapy.