Research paper Review about the multi-target profile of resveratrol and its implication in the SGK1 inhibition Giada Catalogna a, 1 , Federica Moraca b, c, d, 1 , Lucia D'Antona a , Vincenzo Dattilo a , Giuseppe Perrotti a , Antonio Lupia b, d , Giosu  e Costa b, d , Francesco Ortuso b, d , Rodolfo Iuliano a , Francesco Trapasso a , Rosario Amato a , Stefano Alcaro b, d, * , Nicola Perrotti a, ** a Dipartimento di Medicina Sperimentale e Clinica, University “Magna Græcia” of Catanzaro, Viale Europa, 88100, Catanzaro, Italy b Dipartimento di Scienze Della Salute, University “Magna Græcia” of Catanzaro, Viale Europa, 88100, Catanzaro, Italy c Department of Pharmacy, University of Napoli “Federico II”, Via D. Montesano 49, I-80131 Napoli, Italy d Net4Science Srl, Universit a “Magna Græcia”, Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy article info Article history: Received 27 June 2019 Received in revised form 30 August 2019 Accepted 2 September 2019 Available online 5 September 2019 Keywords: Resveratrol Multi-target SGK1 HCC Homology modeling Docking abstract Resveratrol (trans-3,4’,5-trihydroxystilbene) is a polyphenolic natural product with a well-known poly- pharmacological profile that places it among the multi-target-directed ligands (MTDLs). Given its pro- tective action against a wide number of chronic diseases, in this review, we introduce a general overview about the cardioprotective and antioxidant effects, the antidiabetic, neuroprotective and anti- inflammatory effects of this polyphenol. In the second part of the manuscript, we focused our atten- tion on the anticancer activity of Resveratrol, given the alteration of many different signaling pathways, leading to suppression of tumor cell proliferation in numerous cancer types. Among the several anti- cancer targets involved in the mechanism of action of Resveratrol, here we introduce experimental and molecular modeling studies performed against the SGK1 protein as a novel anticancer target of Resveratrol. SGK1 inhibitors have been demonstrated to inhibit cell growth of different cancer cells. We demonstrated that resveratrol inhibits SGK1 in vitro and in intact cells, affecting proliferation and survival of HUH7 human hepatoma cells. Our findings demonstrate that resveratrol may function as a SGK1 inhibitor, suggesting possible applications in sodium retention and cancer. © 2019 Elsevier Masson SAS. All rights reserved. 1. Introduction Trans-Resveratrol (trans-3,4,5-trihydroxystilbene) (RSV) is a polyphenolic natural product found in more than 70 species of plants. It was first described in 1940 as a phenolic component of the medicinal herb hellebore and then in 1963 in the Japanese Polyg- onum cuspidatum. It is found also, in the glycosylated form, in fruit such as berries, raw peanuts, red currant and especially in the skin of red grapes (Vitis vinifera L.), indeed RSV is one of the major components responsible for the potential benefits of red wine [1]. Structurally, the two phenolic rings of RSV are connected through a double bond that allow the existence of cis and trans isomeric forms (Fig. 1), with trans to cis isomerization facilitated by UV exposure. The trans-isomer is the most stable natural form and it is of considerable biological interest because of its greater beneficial health effects [2]. RSV has always attracted a lot of attention in the last three de- cades [3], given its capability to mediate a wide number of bio- logical responses, such as cardio and neuroprotective effects, anticancer, antioxidant, antiinflammatory and antidiabetic activ- ities. Indeed, it has been the focus of a lot of scientific articles describing its mechanism of action [4]. Currently, in 2019, it has been counted that about 244 clinical trials proves the efficacy, safety, and pharmacokinetics of RSV [5]. However, although RSV has several benefits, its rapid metabolism in the small intestine does not allow its clinical use [5]. In this review, we aim to give a general overview of both the * Corresponding author. Dipartimento di Scienze della Salute, University “Magna Graecia” of Catanzaro, Viale Europa, 88100, Catanzaro, Italy. ** Corresponding author. Dipartimento di Medicina Sperimentale e Clinica, Uni- versity “Magna Graecia” of Catanzaro, Viale Europa, 88100, Catanzaro, Italy. E-mail addresses: alcaro@unicz.it (S. Alcaro), perrotti@unicz.it (N. Perrotti). 1 These authors contributed equally. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech https://doi.org/10.1016/j.ejmech.2019.111675 0223-5234/© 2019 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 183 (2019) 111675