nutrients Review Beneficial Outcomes of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on Human Health: An Update for 2021 Ivana Djuricic 1 and Philip C. Calder 2,3,* 1 Department of Bromatology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia; [email protected] 2 School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK 3 NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton SO16 6YD, UK * Correspondence: [email protected] Abstract: Oxidative stress and inflammation have been recognized as important contributors to the risk of chronic non-communicable diseases. Polyunsaturated fatty acids (PUFAs) may regulate the antioxidant signaling pathway and modulate inflammatory processes. They also influence hepatic lipid metabolism and physiological responses of other organs, including the heart. Longitudinal prospective cohort studies demonstrate that there is an association between moderate intake of the omega-6 PUFA linoleic acid and lower risk of cardiovascular diseases (CVDs), most likely as a result of lower blood cholesterol concentration. Current evidence suggests that increasing intake of arachidonic acid (up to 1500 mg/day) has no adverse effect on platelet aggregation and blood clotting, immune function and markers of inflammation, but may benefit muscle and cognitive performance. Many studies show that higher intakes of omega-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a lower incidence of chronic diseases characterized Citation: Djuricic, I.; Calder, P.C. by elevated inflammation, including CVDs. This is because of the multiple molecular and cellular Beneficial Outcomes of Omega-6 and actions of EPA and DHA. Intervention trials using EPA + DHA indicate benefit on CVD mortality and Omega-3 Polyunsaturated Fatty a significant inverse linear dose–response relationship has been found between EPA + DHA intake Acids on Human Health: An Update and CVD outcomes. In addition to their antioxidant and anti-inflammatory roles, omega-3 fatty acids for 2021. Nutrients 2021, 13, 2421. are considered to regulate platelet homeostasis and lower risk of thrombosis, which together indicate https://doi.org/10.3390/nu13072421 their potential use in COVID-19 therapy. Academic Editor: Katerina Vafeiadou Keywords: omega-6 fatty acids; omega-3 fatty acids; inflammation; oxidative stress; COVID-19 Received: 10 June 2021 Accepted: 13 July 2021 Published: 15 July 2021 1. Introduction Despite the COVID-19 pandemic with more than 3.4 million deaths in the last year Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in due to infection with severe acute respiratory syndrome coronavirus 2, chronic non- published maps and institutional affil- communicable diseases (NCDs) are still easily the most common global cause of mor- iations. bidity and mortality. The World Health Organization (WHO) estimated that 41 million deaths in 2018 were due to NCDs [1]. NCDs include cardiovascular diseases (CVDs), cancers, non-infectious respiratory diseases and metabolic diseases. Alongside other risk factors, oxidative stress and inflammation have been recognized as important contributors to risk of NCDs. Elevated levels of inflammatory markers, including several cytokines Copyright: © 2021 by the authors. and chemokines, are seen in those with NCDs [2]. Inflammation is an important part of Licensee MDPI, Basel, Switzerland. This article is an open access article host defense, firstly by creating a hostile environment for microbes and later by initiating distributed under the terms and tissue repair, recovery, and maintenance of homeostasis. However, prolonged (unresolved) conditions of the Creative Commons inflammation and continuous release of pro-inflammatory mediators can cause tissue dam- Attribution (CC BY) license (https:// age, metabolic changes and loss of function [3–5]. Thus, inflammation is a “double-edged creativecommons.org/licenses/by/ sword”. Likewise, in low or medium concentrations, free radicals (a term used to describe 4.0/). reactive oxygen species (ROS) and reactive nitrogen species (RNS)) have physiological roles Nutrients 2021, 13, 2421. https://doi.org/10.3390/nu13072421 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 24 (unresolved) inflammation and continuous release of pro‐inflammatory mediators can Nutrients 2021, 13, 2421 cause tissue damage, metabolic changes and loss of function [3–5]. Thus, inflammation2 of is 23 a “double‐edged sword”. Likewise, in low or medium concentrations, free radicals (a term used to describe reactive oxygen species (ROS) and reactive nitrogen species (RNS)) have physiologicalin protecting cellsroles from in variousprotecting harmful cells influences,from various including harmful microbes. influences, Furthermore, including free microbes.radicals have Furthermore, a regulatory free function radicals in have intracellular a regulatory signaling function cascades in intracellular in several signaling cell types, cascadessuch as endothelialin several cell cells, types, fibroblasts, such as endothelial cardiomyocytes, cells, andfibroblasts, thyroid cardiomyocytes, tissue [6]. However, and thyroidwhen production tissue [6]. of However, free radicals when exceeds production a particular of free concentration radicals exceeds and disturbs a particular the cell concentrationredox potential, and adverse disturbs effects the cell are redox manifested. potential, For adverse example, effects many are cellular manifested. structures For example,can be damaged many cellular as a resultstructures of oxidative can be damaged stress, including as a result membranes,of oxidative stress, proteins, including lipids, membranes,lipoproteins proteins, and DNA lipids, [6]. Inflammation lipoproteins and and DNA oxidative [6]. Inflammation stress are inter-related: and oxidative oxidative stress arestress inter can‐related: activate oxidative inflammatory stress signaling can activate pathways, inflammatory while inflammation signaling pathways, induces oxidative while inflammationstress (Figure 1induces[7]). oxidative stress (Figure 1 [7]). FigureFigure 1. 1. The bidirectionalbidirectional links links between between inflammation inflammation and and oxidative oxidative stress. stress. Reactive Reactive oxygen oxygen species species(ROS) can(ROS) act ascan inflammatory act as inflammatory trigger initiating trigger inflammation. initiating inflammation. On the other On hand, the inflammationother hand, inflammationinduces oxidative induces stress. oxidative Abbreviations stress. Abbreviations used: IkB, inhibitoryused: IkB, inhibitory subunit of subunit NFkB; of MAPK, NFkB; mitogen- MAPK, mitogenactivated‐activated protein kinase;protein NFkB,kinase; nuclear NFkB, nuclear factor kappa-light-chain-enhancer factor kappa‐light‐chain‐enhancer of activated of activated B cells; B P, cells;phosphate; P, phosphate; ROS, reactive ROS, reactive oxygen oxygen species. species. Reproduced Reproduced from [7 ].from [7]. FattyFatty acids acids are are an an integral integral component component of of cell cell membrane membrane phospholipids, phospholipids, with with specific specific functional,functional, metabolic, metabolic, andand signalingsignaling roles roles [ 8[8].]. Different Different cells cells have have different different fatty fatty acid acid com- compositionspositions that that influence influence membrane membrane fluidity fluidity and flexibility, and flexibility, and the functionand the offunction membrane of membraneproteins [8 proteins]. Different [8]. intakesDifferent of intakes polyunsaturated of polyunsaturated fatty acids fatty (PUFAs) acids (PUFAs) result in result different in differentlevels of levels PUFAs of inPUFAs cell membrane in cell membrane phospholipids phospholipids from where from theywhere exert they actions exert actions on cell onfunctions cell functions and cell and and cell tissue and tissue responsiveness responsiveness to signals to signals (Figure (Figure2). PUFAs2). PUFAs may may act act as asantioxidants antioxidants by by regulating regulating the the antioxidant antioxidant signaling signaling pathwaypathway [[9,10]9,10] and may modulate modulate inflammatoryinflammatory processes processes [10,11]. [10,11]. This This review review will will provide provide an an update update on on knowledge knowledge on on PUFAsPUFAs and and their their effects effects on on human human health. health. NutrientsNutrients 20212021,, 1313,, x 2421 FOR PEER REVIEW 3 3of of 24 23 Figure 2. Schematic overview of how polyunsaturated fatty acids (PUFAs) affect cell responses. Figure 2. Schematic overview of how polyunsaturated fatty acids (PUFAs) affect cell responses. 2.2. Omega Omega-6‐6 and and Omega Omega-3‐3 PUFAs PUFAs ThereThere are are two two main main families families of of PUFAs that are relevant toto humanhuman health,health, thethe omega-6omega‐ 6and and the the omega-3 omega‐3 PUFAs. PUFAs. InIn mostmost diets,diets, the PUFAs present in the highest amounts amounts are are linoleiclinoleic acid acid (LA, (LA, 18:2 18:2ω‐!-6)6) and and α‐α-linoleniclinolenic acid acid (ALA, (ALA, 18:3ω‐!-3).3). LA LA and and ALA ALA are are not not synthesizedsynthesized in in animals animals and and so so are are regarded regarded as essential fatty acids. Because Because they they are are synthesizedsynthesized in in plants, plants, LA LA and and ALA ALA are are