An animal's stress response requires different adaptive strategies depending on the nature and duration of the stressor. While acute stressors, like predation, induce a rapid and energydemanding fight or flight response, long-term environmental stressors induce the gradual and long-lasting activation of highly conserved cytoprotective processes 1-3 . In animals across the evolutionary spectrum the continued activation of the fight-or-flight response weakens the animal's resistance to environmental challenges 4,5 . However, the molecular and cellular mechanisms that regulate the trade-off between flight response and long-term stressors are poorly understood. Here we show that repeated induction of the C. elegans flight response shortens lifespan and inhibits conserved cytoprotective mechanisms. The flight response activates neurons that release tyramine, the invertebrate analog of adrenaline/noradrenaline. Tyramine stimulates the DAF-2/Insulin/IGF-1 pathway and precludes the induction of stress response genes by activating an adrenergic-like receptor in the intestine. In contrast, long-term environmental stressors, such as heat or oxidative stress, reduce tyramine release allowing the induction of cytoprotective genes. These findings demonstrate that a neural stress-hormone supplies a state-dependent neural switch between acute flight and long-term environmental stress responses and provides mechanistic insights into how the flight response impairs cellular defense systems and accelerates aging.

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.

The role Beta-cyclodextrin (βCD) on improving biocompatibility on healthy cellular and animal models was studied upon a formulation obtained from the development of a simple coating procedure. The obtained nanosystems were thoroughly characterized by FTIR, TGA, atomic absorption spectroscopy, dynamic light scattering and zeta potential, TEM/HR-TEM and magnetic properties. βCD might interact with the magnetic core through hosting OA. It is feasible that the nanocomposite is formed by nanoparticles of MG@OA dispersed in a βCD matrix. The evaluation of βCD role on biocompatibility was performed on two healthy models. To this end, in vivo studies were carried out on Caenorhabditis elegans. Locomotion and progeny were evaluated after exposure animals to MG, MG@OA, and MG@OA-βCD (10 to 500 µg/mL). The influence of βCD on cytotoxicity was explored in vitro on healthy rat aortic endothelial cells, avoiding alteration in the results derived from the use of transformed cell lines. Biological studies demonstrated that βCD attaching improves MG biocompatibility.