Food and Chemical Toxicology 146 (2020) 111842 Available online 3 November 2020 0278-6915/© 2020 Elsevier Ltd. All rights reserved. Drimys winteri and isodrimeninol decreased foam cell formation in THP-1 derived macrophages Viviana Burgos a , Cristian Paz b , Kathleen Saavedra a, b , Nicol´ as Saavedra a, b , Mary Ann Foglio c , Iv´ an Gonz´ alez-Chavarría d , Luis A. Salazar a, b, * a Centro de Biología Molecular y Farmacogen´ etica, Núcleo de Desarrollo Científco y Tecnol´ ogico (BIOREN), Universidad de La Frontera, Temuco, 4811230, Chile b Departamento de Ciencias B´ asicas, Universidad de La Frontera, Av. Francisco Salazar, 01145, Temuco, Chile c Faculty of Pharmaceutical Sciences, University of Campinas (UNICAMP), Rua Cˆ andido Portinari, 200, Campinas, SP, 13083-871, Brazil d Departamento de Fisiopatología, Facultad de Ciencias Biol´ ogicas, Universidad de Concepci´ on, Concepci´ on, Chile A R T I C L E INFO Keywords: Drimys winteri Isodrimeninol Foam cell THP-1 PMA ABSTRACT Early stages of atherosclerosis are characterizated for the uptake of oxidate low-density lipoprotein (oxLDL) by infammatory macrophages in the arteries, promoting the foam cell formation. Drimys winteri is a native tree of Chile that produce drimane sesquiterpenoids, here it was evaluated the inhibitory foam cell formation by the total extract of barks of Drimys winteri and isodrimeninol, a sesquiterpenoid isolated from the tree. The results showed that Dw and isodrimeninol inhibited the foam cell formation on macrophage M1, by Oil Red O staining. Moreover, Dw reduced the gene expression of pro-infammatory cytokine TNF-α, in contrast to isodrimeninol that showed not effect on the gene expression of this cytokine, also Dw enhanced the expression of the anti- infammatory cytokine IL-10, in more signifcant manner than isodrimeninol at 20 μg/mL. While, Dw and iso- drimeninol signifcantly reduced the expression of IL1-β at concentrations of 20 μg/mL, but not affecting the MMP-9 levels, assessed by RT-qPCR. In conclusion, Drimys winteri and isodrimeninol induce anti-atherosclerotic effects, inhibiting foam cell formation, as well as promoting anti-infammatory responses. This study confrm the relevance of this tree as a medicinal source for the Mapuche people, and suggesting that Drimys winteri could be used in early stages of atherosclerosis. 1. Introduction Atherosclerosis is a chronic infammatory cardiovascular disease (Kasikara et al., 2018), which is the primary cause of heart disease and stroke, doing a serious threat to human health around the world (Virani et al., 2020). Atherosclerosis is characterized by arterial wall thickness due to formation of an atheromatous plaque, which is produced by the infltration of monocytes in the sub-endothelium and their differentia- tion into macrophages, playing a crucial role in the progression of the disease, because they produce pro-infammatory cytokines, matrix metalloproteinases as well as other species that contribute to the infammation (Gupta et al., 2020; Tabas and Lichtman, 2017). More- over, macrophages take up modifed low density lipoproteins as oxidized LDL particles (oxLDL) via their scavenger receptors, forming foam cells, which is considered a landmark of atherosclerotic disease (Estronca et al., 2012; Lara-guzm´ an et al., 2018). Macrophages have high plasticity; they can polarize to different phenotypes in response to the surrounding environment stimuli (Biswas et al., 2012). Macrophage phenotype M1 is characteristic pro-atherogenic because they overexpress phagocytic abilities, induce a pro-infammatory response and tissue damage, in contrast to an alter- native polarization M2, which promote wound healing, angiogenesis and anti-infammatory cytokines as interleukine-10 (IL-10) (Li et al., 2016). Human leukemic cell line (THP-1) is a classical cell for in vitro studies of primary human macrophage function (Hern´ andez et al., 2007). These cells acquire a phenotype and functional characteristic that mimic to functional primary human macrophages (M0), by exposition to phorbol 12-myristate 13-acetate (PMA) (Kohro et al., 2004; Lund et al., 2016). This primary differentiation can be polarized to a specifc phenotype, M1 or M2 state, according to a secondary environment stimulus. The classical activation to M1, is in response of pro-infammatory stimuli such as lipopolysaccharide (LPS), interferon-γ (INF-γ) and tumor ne- crosis factor-α (TNF-α). This classical phenotype is characterized by * Corresponding author. Departamento de Ciencias B´ asicas, Universidad de La Frontera, Av. Francisco Salazar, 01145, Temuco, Chile. E-mail address: luis.salazar@ufrontera.cl (L.A. Salazar). Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox https://doi.org/10.1016/j.fct.2020.111842 Received 9 September 2020; Received in revised form 6 October 2020; Accepted 29 October 2020