*Article* **Exploring Target Genes Involved in the E**ff**ect of Quercetin on the Response to Oxidative Stress in** *Caenorhabditis elegans*

**Begoña Ayuda-Durán 1, Susana González-Manzano 1, Antonio Miranda-Vizuete 2, Eva Sánchez-Hernández 1, Marta R. Romero 3, Montserrat Dueñas 1, Celestino Santos-Buelga 1,\* and Ana M. González-Paramás <sup>1</sup>**


Received: 15 November 2019; Accepted: 20 November 2019; Published: 25 November 2019

**Abstract:** Quercetin is one the most abundant flavonoids in the human diet. Although it is well known that quercetin exhibits a range of biological activities, the mechanisms behind these activities remain unresolved. The aim of this work is to progress in the knowledge of the molecular mechanisms involved in the biological effects of quercetin using *Caenorhabditis elegans* as a model organism. With this aim, the nematode has been used to explore the ability of this flavonoid to modulate the insulin/insulin-like growth factor 1(IGF-1) signaling pathway (IIS) and the expression of some genes related to stress response. Different methodological approaches have been used, i.e., assays in knockout mutant worms, gene expression assessment by RT-qPCR, and *C. elegans* transgenic strains expressing green fluorescent protein (GFP) reporters. The results showed that the improvement of the oxidative stress resistance of *C. elegans* induced by quercetin could be explained, at least in part, by the modulation of the insulin signaling pathway, involving genes *age-1, akt-1, akt-2, daf-18, sgk-1, daf-2*, and *skn-1*. However, this effect could be independent of the transcription factors DAF-16 and HSF-1 that regulate this pathway. Moreover, quercetin was also able to increase expression of *hsp-16.2* in aged worms. This observation could be of particular interest to explain the effects of enhanced lifespan and greater resistance to stress induced by quercetin in *C. elegans*, since the expression of many heat shock proteins diminishes in aging worms.

**Keywords:** quercetin; IIS pathway; *C. elegans*; oxidative stress
