molecules Review A Review of the Health Protective Effects of Phenolic Acids against a Range of Severe Pathologic Conditions (Including Coronavirus-Based Infections) Sotirios Kiokias 1,* and Vassiliki Oreopoulou 2 1 European Research Executive Agency, Place Charles Rogier 16, 1210 Bruxelles, Belgium 2 Laboratory of Food Chemistry and Technology, School of Chemical Engineering, National Technical University of Athens, Iron Politechniou 9, 15780 Athens, Greece; [email protected] * Correspondence: [email protected]; Tel.: +32-49-533-2171 Abstract: Phenolic acids comprise a class of phytochemical compounds that can be extracted from various plant sources and are well known for their antioxidant and anti-inflammatory properties. A few of the most common naturally occurring phenolic acids (i.e., caffeic, carnosic, ferulic, gallic, p-coumaric, rosmarinic, vanillic) have been identified as ingredients of edible botanicals (thyme, oregano, rosemary, sage, mint, etc.). Over the last decade, clinical research has focused on a number of in vitro (in human cells) and in vivo (animal) studies aimed at exploring the health protective effects of phenolic acids against the most severe human diseases. In this review paper, the authors first report on the main structural features of phenolic acids, their most important natural sources and their extraction techniques. Subsequently, the main target of this analysis is to provide an overview of the most recent clinical studies on phenolic acids that investigate their health effects against a range Citation: Kiokias, S.; Oreopoulou, V. A Review of the Health Protective of severe pathologic conditions (e.g., cancer, cardiovascular diseases, hepatotoxicity, neurotoxicity, Effects of Phenolic Acids against a and viral infections—including coronaviruses-based ones). Range of Severe Pathologic Conditions (Including Keywords: phenolic acids; antioxidants; health properties Coronavirus-Based Infections). Molecules 2021, 26, 5405. https:// doi.org/10.3390/molecules26175405 1. Introduction Academic Editors: Maria Free radicals are mainly reactive oxygen species (ROS) (including hydroxyl-, superoxide- José Rodríguez-Lagunas and radicals and singlet oxygen) that are formed in tissue cells by various endogenous and Malen Massot-Cladera exogenous pathways. ROS normally exert an adverse impact on human health by inducing the so called “oxidative stress conditions” [1]. The ability of free radicals to structurally Received: 23 July 2021 modify cellular components and cause oxidative damage to biomolecules (LDL-low density Accepted: 12 August 2021 Published: 6 September 2021 lipoproteins, DNA, etc.) has revealed their involvement in a variety of health pathologies (i.e., inflammation, aging, types of cancer and cardiovascular diseases) [2,3]. Publisher’s Note: MDPI stays neutral Nature has generously offered several types of natural dietary antioxidants, among with regard to jurisdictional claims in which phenolic compounds can operate as scavengers of free radicals in vivo and can published maps and institutional affil- efficiently reduce the harmful health impacts of oxidative damage [4,5]. Phenolic acids iations. comprise a group of natural phenolic compounds that are present in a wide range of herbs and other species of the plant kingdom [6]. More specifically, thyme, oregano, rosemary, sage, and mint herbal preparations—all rich in various phenolics—have been reported to exert strong antioxidant biochemical and anti-inflammatory properties [7,8]. A few authors have reviewed the radical scavenging capacity of phenolic acids and their subsequent Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. beneficial effects against the development of cancer, cardiovascular diseases and other This article is an open access article health disorders (such as skin problems, inflammations, bacterial infections, etc.) [9]. The distributed under the terms and main biochemical pathways and mechanisms of phenolic actions against the development conditions of the Creative Commons of certain types of cancer include: free radical scavenging, enzyme induction, DNA damage Attribution (CC BY) license (https:// repair, cell proliferation depression, and apoptosis [10]. creativecommons.org/licenses/by/ In their recent publication, Kiokias et al. (2020) [11] focused on the in vitro antioxidant 4.0/). activities of a few common naturally occurring phenolic acids (caffeic, carnosic, ferulic, Molecules 2021, 26, 5405. https://doi.org/10.3390/molecules26175405 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 18 Molecules 2021, 26, 5405 2 of 18 In their recent publication, Kiokias et al. (2020) [11] focused on the in vitro antioxidant activities of a few common naturally occurring phenolic acids (caffeic, carnosic, ferulic, gallic,gallic, p-coumaric,p-coumaric, rosmarinic, vanillic) vanillic) against against the the oxidation oxidation of ofoil-in-water oil-in-water emulsions. emulsions. SuchSuch interfacialinterfacial lipid-based systems systems generally generally mimic mimic the the structure structure of ofbiological biological mem- mem- branesbranes andand biomoleculesbiomolecules that that when when attacked attacked by by free free radicals radicals are are prone prone to harmful to harmful in vivoin vivo oxidativeoxidative reactions.reactions. InIn this paper, paper, the the authors authors first first report report on the on main the mainstructural structural features features of phenolic of phenolicacids acidsas well as wellas on as a onfew a fewimportant important natural natural sources sources and their and theirextraction extraction techniques. techniques. Subse- Sub- sequently,quently, the the main main focus focus of this of thisanalysis analysis is to isprovide to provide an overview an overview of the most of the recent most clin- recent clinicalical studies studies on phenolic on phenolic acids acids that investigate that investigate their health their effects health against effects a against few severe a few path- severe pathologicologic disorders. disorders. 2.2. Structure,Structure, Herbal Sources and and Extraction Extraction of of the the Most Most Common Common Naturally Naturally Occurring Occurring PhenolicPhenolic AcidsAcids 2.1.2.1. StructuralStructural Classidication of of Natural Natural Phenolic Phenolic Acids Acids InIn termsterms ofof their chemical structure, structure, phenolic phenolic acids acids are are classified classified as: as: HydroxybenzoicHydroxybenzoic acids with with a a C C66-C-C1 1structure:structure: Among Among them them a trihydroxy a trihydroxy derivative derivative (gallic(gallic acid) acid) has has been been associated associated withwith teatea antioxidantantioxidant activity, whilewhile vanilic acid is a methoxy-meth- hydroxyoxy-hydroxy derivative derivative serving serving as a as well-known a well-known flavouring flavouring agent agent [12 [12].]. HydroxycinnamicHydroxycinnamic acids acids with with a a C C6-C6-C3 3structurestructure [13]. [13 ].These These are are abundant abundant in plant in plant sources,sources, withwith p-coumaric (4-hydroxy (4-hydroxy derivati derivative),ve), caffeic caffeic (3, (3,4-dihydroxy4-dihydroxy derivative) derivative) and and ferulicferulic (3-methoxy,(3-methoxy, 4-hydroxy4-hydroxy derivative) derivative) commo commonlynly present present in invarious various culinary culinary herbs. herbs. In In addition,addition, rosmarinicrosmarinic acid (an (an ester ester of of caffeic caffeic acid acid with with 3,4-dihydroxyphenyl 3,4-dihydroxyphenyl lactic lactic acid) acid) is is mainlymainly encounteredencountered in certain aromatic aromatic herbs herbs [14]. [14 ]. Phenylacetic acids with a C6-C2 structure. Phenylacetic acids are scarce in fruits and Phenylacetic acids with a C6-C2 structure. Phenylacetic acids are scarce in fruits andvegetables, vegetables, while while a dihydroxy a dihydroxy derivative derivative was detected was detected in strawberry in strawberry tree honey tree [15]. honey Car- [15]. Carnosicnosic acid acid belongs belongs to the to phenolic the phenolic diterpenes diterpenes that are thatusually are classified usually as classified hybrid phenol- as hybrid phenolicsics [13]. [13]. ThisThis reviewreview focuses on on the the most most common common hydroxybenzoic hydroxybenzoic and and hydroxycinnamic hydroxycinnamic phenolic acids, along with carnosic acid, the chemical structures of which are given in phenolic acids, along with carnosic acid, the chemical structures of which are given in Figure 1. Figure1. (a) Hydrocinnamic acids (b) Hydroxybenzoic acids Caffeic acid Gallic acid Ferulic acid Vanillic acid p-Coumaric acid Carnosic acid Rosmarinic acid (hybrid phenolic) Figure 1. Chemical structure of phenolic acids examined in this study. Molecules 2021, 26, 5405 3 of 18 2.2. Herbal Sources and Extraction of Phenolic Acids Caffeic acid (CA) is found at high levels in various herbs worldwide, including the South American herb yerba mate (1.5 g/kg) [16], the Japanese herbal leaf tea, the tea stem from Moringa oleifera L. [17], and thyme (1.7 mg/kg) [18]. Carnocic acid (CarA) can be found in a few species of the Lamiaceae family (such as rosemary and common salvia species). It has been reported to be present at a concentration of 1.5 to 2.5% in dried sage leaves [19,20]. Ferulic acid (FA) is present in black beans at an average concentration of 0.8 g/kg, while flaxseed has been reported as the richest natural source of FA glucoside (4.1 ± 0.2 g/kg), [21,22] . FA has been