Willian Goulart Salgueiro

Direct synthesis of 4-organylsulfenyl-7-chloro quinolines and their toxicological and pharmacological activities in Caenorhabditis elegans

We describe herein our results on the synthesis and biological properties in Caenorhabditis elegans of a range of 4-organylsulfenyl-7-chloroquinolines. This class of compounds have been easily synthesized in high yields by direct reaction of 4,7-dichloroquinoline with organylthiols using DMSO as solvent at room temperature under air atmosphere and tolerates a range of substituents in the organylsulfenyl moiety. We have performed a toxicological and pharmacological screening of the synthesized 4-organylsulfenyl-7-chloroquinolines in vivo in C. elegans acutely exposed to these compounds, under per se and stress conditions. Hence, we determined the lethal dose 50% (LD50), in order to choose a nonlethal concentration (10 μM) and verified that at that concentration some of the compounds depicted protective action against the induced damage inflicted by paraquat, a superoxide generator. Two compounds (3c and 3h) reduced the toxicity inflicted by paraquat above survival, reproduction and longevity of the worms, at least in part, by reducing the reactive oxygen species (ROS) generated by the toxicant exposure. Besides, these compounds increased the quantities of superoxide dismutase (SOD-3::GFP) and catalase (CTL-1,2,3::GFP), antioxidant enzymes. We concluded that the protective effects of the compounds observed in this study might have been a hormetic response dependent of the transcriptional factor DAF-16/FOXO, causing a non-lethal oxidative stress that protects against the subsequently damage induced by paraquat.

Ilex paraguariensis Extract Increases Lifespan and Protects Against the Toxic Effects Caused by Paraquat in Caenorhabditis elegans

Recent studies have shown that phenolic compounds present in yerba mate have antioxidant defense properties. To verify whether Ilex paraguariensis extracts are capable of increasing the lifespan of an organism, we have used the free-living nematode Caenorhabditis elegans. Notably, this is the first study that analyzes the effects of the extracts of yerba mate obtained from an extraction method that mimics the manner that the plant is consumed by the population by using a live organism. Yerba mate was purchased from commercial markets from Argentina, Brazil, and Uruguay. Ilex paraguariensis extracts significantly increased the life span of C. elegans. Moreover, the extracts reduced the ROS levels per se, and protected from the reduced survival and reproduction rate induced by paraquat exposure. Considering molecular aspects, we observed that the worms pretreated with the extracts depicted higher translocation of the transcription factor DAF-16::GFP to the nucleus. However, there was no increase in the levels of the DAF-16 target genes, SOD-3 and catalase. Our results suggest that the increase of lifespan caused by the different extracts is associated to the antioxidant potential of yerba mate, however this effect is not completely mediated by daf-16.

Seleno- and Telluro-xylofuranosides attenuate Mn-induced toxicity in C. elegans via the DAF-16/FOXO pathway

Organochalcogens are promising pharmacological agents that possess significant biological activities. Nevertheless, because of the complexity of mammalian models, it has been difficult to determine the molecular pathways and specific proteins that are modulated in response to treatments with these compounds. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging and in vivo live analysis of toxicity. Abundant evidence points to oxidative stress in mediating manganese (Mn)-induced toxicity. In this study we challenged worms with Mn, and investigated the efficacy of inedited selenium- and tellurium-xylofuranosides in reversing and/or protecting the worms from Mn-induced toxicity. In addition, we investigated their putative mechanism of action. First, we determined the lethal dose 50% (LD50) and the effects of the xylofuranosides on various toxic parameters. This was followed by studies on the ability of xylofuranosides to afford protection against Mn-induced toxicity. Both Se- and Te-xylofuranosides increased the expression of superoxide dismutase (SOD-3). Furthermore, we observed that the xylofuranosides induced nuclear translocation of the transcription factor DAF-16/FOXO, which in the worm is known to regulate stress responsiveness, aging and metabolism. These findings suggest that xylofuranosides attenuate toxicity Mn-induced, by regulating the DAF-16/FOXO signaling pathway.

Insights into the differential toxicological and antioxidant effects of 4-phenylchalcogenil-7-chloroquinolines in Caenorhabditis elegans

Abstract Organic selenium and tellurium compounds are known for their broad‐spectrum effects in a variety of experimental disease models. However, these compounds commonly display high toxicity and the molecular mechanisms underlying these deleterious effects have yet to be elucidated. Thus, the need for an animal model that is inexpensive, amenable to high‐throughput analyses, and feasible for molecular studies is highly desirable to improve organochalcogen pharmacological and toxicological characterization. Herein, we use Caenorhabdtis elegans (C. elegans) as a model for the assessment of pharmacological and toxicological parameters following exposure to two 4‐phenylchalcogenil‐7‐chloroquinolines derivatives (PSQ for selenium and PTQ for tellurium‐containing compounds). While non‐lethal concentrations (NLC) of PTQ and PSQ attenuated paraquat‐induced effects on survival, lifespan and oxidative stress parameters, lethal concentrations (LC) of PTQ and PSQ alone are able to impair these parameters in C. elegans. We also demonstrate that DAF‐16/FOXO and SKN‐1/Nrf2 transcription factors underlie the mechanism of action of these compounds, as their targets sod‐3, gst‐4 and gcs‐1 were modulated following exposures in a daf‐16‐ and skn‐1‐dependent manner. Finally, in accordance with a disturbed thiol metabolism in both LC and NLC, we found higher sensitivity of trxr‐1 worm mutants (lacking the selenoprotein thioredoxin reductase 1) when exposed to PSQ. Finally, our study suggests new targets for the investigation of organochalcogen pharmacological effects, reinforcing the use of C. elegans as a powerful platform for preclinical approaches. Graphical abstract Figure. No caption available. HighlightsPSQ and PTQ at LC induce oxidative damage and impair C. elegans physiology.PSQ and PTQ at NLC protect C. elegans from oxidative stress induced by PQ.daf‐16/FOXO and skn‐1/NRF2 modulations are involved in PSQ and PTQ effects.sod‐3, gcs‐1, gst‐4, and trxr‐1 expression are altered after PSQ and PTQ exposure.

Behavioral and dopaminergic damage induced by acute iron toxicity in Caenorhabditis elegans

Iron (Fe) is an important metal to organism homeostasis and exists abundantly in the environment. Moderate levels of Fe obtained from food are necessary for normal cell physiology; however, abnormally high levels of Fe may have toxic effects by reducing H2O2 to the highly cytotoxic hydroxyl radical (OH˙) (Fenton catalysis). Fe is a ubiquitous toxicant to the environment and also widely used in food products; however, its effects on the nervous system are not well understood. Herein, we evaluated the toxic effects of Fe using C. elegans and investigated various parameters in order to contribute to the understanding of Fe-induced toxicity and to validate this model. The Fe LD50 of acute exposure (30 min) was 1.2 mM, and we verified that worms readily take up this metal. Furthermore, sublethal Fe concentrations significantly decreased the worms’ lifespan and brood size compared to non-exposed worms. We also observed that animals exposed to Fe had decreased locomotor activity and decreased mechanical sensitivity, suggesting the possible dysfunction of the nervous system. In agreement, we found cholinergic and dopaminergic alterations in the worms. In summary, we suggest that Fe leads to selective neuronal damage, which might be the underlying cause of altered behavior and reproductive defects.