antioxidants Review Vitamin E beyond Its Antioxidant Label Anca Ungurianu 1 , Anca Zanfirescu 2 , Georgiana Nit , ulescu 3 and Denisa Margină 1, *   Citation: Ungurianu, A.; Zanfirescu, A.; Nit , ulescu, G.; Margin˘ a, D. Vitamin E beyond Its Antioxidant Label. Antioxidants 2021, 10, 634. https://doi.org/10.3390/ antiox10050634 Academic Editors: Silvana Hrelia and Cristina Angeloni Received: 1 April 2021 Accepted: 19 April 2021 Published: 21 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Biochemistry, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; anca.ungurianu@umfcd.ro 2 Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; anca.zanfirescu@umfcd.ro 3 Department Pharmaceutical Technology, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; georgiana.nitulescu@umfcd.ro * Correspondence: denisa.margina@umfcd.ro Abstract: Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal- based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component. Keywords: tocopherols; tocotrienols; inflammation; cancer 1. Introduction Lipids greatly vary in structure and function, and some, such as liposoluble vitamins (A, D, E, and K) and polyunsaturated fatty acids (PUFAs), constitute essential nutrients because they cannot be synthesized in the human body [1,2]. They and their metabolites can exert direct cellular effects, participate in various cell processes, or yield numerous regulatory functions like signal transduction modulation or gene expression [2,3]. Vitamin E, comprising eight vitamers (four tocopherols (TFs) and four tocotrienols (TTs)), is the most abundant liposoluble antioxidant compound in the human body, and its modulatory effects regarding signal transduction, cellular pathways (e.g., NF-κB signaling), and gene expression (e.g., pro-inflammatory cytokines) have recently gained notoriety [3–5]. Though several in vitro and in vivo preclinical studies have reported numerous cellu- lar pathways modulated and beneficial effects exerted by vitamin E, human clinical studies have shown sometimes-conflicting results, skewing towards beneficial and protective ac- tion of these molecules; notable differences have been found among them, with some of the 8 vitamers proving to be more efficient than others [5]. The inadequate intake of vitamin E is associated with a higher risk of the develop- ment of several low-grade inflammation-associated diseases [5]. Low-grade inflammation represents a prolonged inflammatory state characterized by a modest increase of pro- inflammatory molecules (e.g., C reactive protein (CRP)) without the well-known signs Antioxidants 2021, 10, 634. https://doi.org/10.3390/antiox10050634 https://www.mdpi.com/journal/antioxidants