Wine’s Phenolic Compounds and Health: A Pythagorean View

Review Wine’s Phenolic Compounds and Health: A Pythagorean View Francesco Visioli 1,2, * , Stefan-Alexandru Panaite 1 and Joao Tomé-Carneiro 2 1 2 * Department of Molecular Medicine, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy; stefan.panaite@outlook.it IMDEA-Food, CEI UAM + CSIC, 28049 Madrid, Spain; joao.estevao@imdea.org Correspondence: francesco.visioli@unipd.it Academic Editors: Paula Silva and Norbert Latruffe Received: 14 August 2020; Accepted: 5 September 2020; Published: 8 September 2020



 Abstract: In support of the J curve that describes the association between wine consumption and all-cause mortality, researchers and the lay press often advocate the health benefits of (poly)phenol consumption via red wine intake and cite the vast amount of in vitro literature that would corroborate the hypothesis. Other researchers dismiss such evidence and call for total abstention. In this review, we take a skeptical, Pythagorean stance and we critically try to move the debate forward by pointing the readers to the many pitfalls of red wine (poly)phenol research, which we arbitrarily treat as if they were pharmacological agents. We conclude that, after 30 years of dedicated research and despite the considerable expenditure, we still lack solid, “pharmacological”, human evidence to confirm wine (poly)phenols’ biological actions. Future research will eventually clarify their activities and will back the current recommendations of responsibly drinking moderate amounts of wine with meals. Keywords: wine; polyphenols; flavonoids; diet; clinical trials; metabolites 1. Introduction The association between alcohol consumption and health follows a J-shaped curve [1]. Moderate alcohol use is associated with better prognosis and lower all-cause death, whereas excessive intake is detrimental to human health [1]. The mechanisms underlying the protective effects of moderate alcohol consumption are under investigation and mostly involve reduced plasminogen levels and lower thrombogenicity observed in moderate drinkers vs. abstainers [1]. Some authors propose the superiority of wine, namely red wine over other alcoholic beverages and attribute such advantage to the (poly)phenolic components of red wine [2]. Even though this notion is not fully proven and is, conversely, often challenged [2], much research is being performed to elucidate the purported biochemical mechanisms through which wine (poly)phenols would afford better health, in particular by lowering cardiovascular risk. The debate on alcohol use and health is becoming heavily polarized: one party underscores a large amount of data in support of the J curve [1,3] whereas the other side dismisses such evidence and calls for total abstention [2,3]. In support of the former, researchers and the lay press often advocate the health benefits of (poly)phenol consumption via red wine intake and cite the vast amount of in vitro literature that would corroborate the hypothesis [4,5]. In this review, we take a skeptical, Pythagorean stance and we critically try to move the debate forward by pointing the readers to the many pitfalls of red wine (poly)phenol research, which we arbitrarily treat as if they were pharmacological agents. 2. Phenolic Compounds and Health Diet and nutrition are essential to promote and maintain good health throughout life and for many years they have been known to be of crucial importance as risk factors for chronic diseases, making Molecules 2020, 25, 4105; doi:10.3390/molecules25184105 www.mdpi.com/journal/molecules

them essential components of prevention activities [6]. The consumption of foods derived from plant products such as wine, fruits, vegetables, nuts, cereals, legumes, spices and others integrated into Molecules 2020, 25, PEER x FORREVIEW PEER REVIEW Molecules 2020, 25, x FOR 20 2 of 20 the Mediterranean or the DASH diets [7], is associated with beneficial health effects and 2aofprotective role against the development and progression ofpromote diseases, as cardiovascular disease (CVD) Dietnutrition and nutrition are essential to andsuch maintain throughout lifefor and for [8]. Diet and are essential to promote and maintain good good healthhealth throughout life and The ability ofmany some plant-derived foods to reduce disease risk has been associated with the presence many they have been known of crucial importance risk factors for chronic diseases, of years years they have been known to be to of be crucial importance as riskasfactors for chronic diseases, making them essential components of prevention activities [6]. The consumption of foods derived them essential components of prevention activities [6].aThe consumption of biological foods derived non-nutrientmaking secondary metabolites (phytochemicals) to which wide variety of activities from plant products such as wine, fruits, vegetables, nuts, cereals, legumes, spices and others from plant products such as wine, fruits, vegetables, nuts, cereals, legumes, spices and others are attributed [9,10]. These metabolites have moderate potency as bioactive compounds and low integrated intoMediterranean the Mediterranean the DASH dietsis[7], is associated with beneficial integrated into the or theorDASH diets [7], associated with beneficial healthhealth effectseffects bioavailability compared to drugs, but when ingested regularly and in significant amounts can have a protective role against the development and progression of diseases, such as cardiovascular and aand protective role against the development and progression of diseases, such as cardiovascular noticeable mid/long term effects. Phytochemicals in foods associated with a disease (CVD) [8].ability The ability of some plant-derived to present reduce disease riskbeen has been associated disease (CVD) [8].physiological The of some plant-derived foodsfoods to reduce disease risk has associated with theinclude presence of non-nutrient secondary metabolites which a wide variety with the presence of non-nutrient secondary metabolites (phytochemicals) to which a wide variety beneficial health effect glucosinolates, terpenoids and a(phytochemicals) large group oftophenolic compounds of biological activities are attributed metabolites moderate potency as bioactive of biological activities are attributed [9,10].[9,10]. TheseThese metabolites have have moderate potency as bioactive (anthocyanins, flavones, flavan-3-ol, stilbenes, etc.) collectively known as (poly)phenols [10,11]. compounds and bioavailability low bioavailability compared to drugs, but when ingested regularly and in compounds and low compared to drugs, but when ingested regularly and in significant amounts can noticeable have noticeable mid/long term physiological effects. Phytochemicals present significant amounts can have mid/long term physiological effects. Phytochemicals present 3. Classification in and Amounts of Wine Phenolic Compounds associated a beneficial include glucosinolates, terpenoids large group in foodsfoods associated with awith beneficial healthhealth effect effect include glucosinolates, terpenoids and a and largea group of phenolic compounds (anthocyanins, flavones, flavan-3-ol, stilbenes, etc.) collectively as of compounds phenolic compounds (anthocyanins, flavan-3-ol, stilbenes, etc.) collectively as Phenolic have as a common flavones, characteristic in their chemical structureknown the known presence of (poly)phenols [10,11]. (poly)phenols [10,11]. one or more hydroxyl groups attached to one or more aromatic or benzene rings. In general, phenolic 3. Classification and Amounts of Wine Phenolic compounds that contain more than oneofphenolic group areCompounds called polyphenols to distinguish them from 3. Classification and Amounts Wine Phenolic Compounds simple phenolics. Typically, thesehave compounds arecharacteristic found in ainconjugate form with one or sugar Phenolic compounds have as a common characteristic in chemical their chemical structure themore presence Phenolic compounds as a common their structure the presence one or more hydroxyl groups attached one more aromatic or rings. In general,ring of one or more hydroxyl groups attached to onetoor more aromatic or benzene rings.to Inangeneral, residues linked byofβ-glycosidic (O-glycosylated) bonds or byordirect linkages ofbenzene sugar aromatic phenolic compounds that contain one phenolic group are called polyphenols to compounds contain more more than than one group are called polyphenols to carbon atom phenolic (C-glycosides) [12].that Phenolic compounds are phenolic grouped according to their chemical structure distinguish from simple phenolics. Typically, compounds are found in a conjugate distinguish them them from simple phenolics. Typically, these these compounds are found in a conjugate form form into two main categories, flavonoids and non-flavonoids, each comprising several sub-groups. In wine, withorone or more residues by β-glycosidic (O-glycosylated) by direct linkages with one more sugarsugar residues linkedlinked by β-glycosidic (O-glycosylated) bondsbonds or by or direct linkages sub-groups of flavonoids compounds include flavonols, flavononols (also known as dihydroflavonols), of sugar to an aromatic ring carbon atom (C-glycosides) [12]. Phenolic compounds are grouped of sugar to an aromatic ring carbon atom (C-glycosides) [12]. Phenolic compounds are grouped according to chemical their chemical structure intomain twowhile main categories, flavonoids and non-flavonoids, according to their structure into two categories, flavonoids andcontain non-flavonoids, each each anthocyanins, flavan-3-ols, flavanones and flavones, non-flavonoids hydroxycinnamic comprising several sub-groups. In wine, sub-groups of flavonoids compounds include flavonols, comprising several sub-groups. In wine, sub-groups of flavonoids compounds include flavonols, and hydroxybenzoic acids, and stilbenes (Table 1). (Poly)phenolic composition varies among different flavononols (also known as dihydroflavonols), anthocyanins, flavan-3-ols, flavanones and flavones, flavononols (also known as dihydroflavonols), anthocyanins, flavan-3-ols, flavanones and flavones, wines according while to thenon-flavonoids type of grape used, vinification process used, type of yeast that participates in contain hydroxycinnamic and hydroxybenzoic and stilbenes while non-flavonoids contain hydroxycinnamic and hydroxybenzoic acids,acids, and stilbenes (Table(Table 1). 1). the fermentation, and whether grape solids are present in he maceration [13]. For (Poly)phenolic composition varies among different wines according totype the of type of grape used, (Poly)phenolic composition varies among different wines according to theprocess grape used,instance, vinification process used, type of yeast that participates the fermentation, andpulp, whether grape solids vinification process used, type of yeast that participates in thein fermentation, andi.e., whether grape solids in grapes, the composition in phenolic compounds is location-dependent, skin and seeds are present the maceration process [13].instance, For instance, in grapes, the composition phenolic aretypes present in proportions theinmaceration process [13]. For grapes, theare composition have different and of (poly)phenols); sinceinred wines exposed in to phenolic allingrape parts compounds is location-dependent, i.e., pulp, skinseeds and seeds have different and proportions of compounds is location-dependent, i.e., pulp, skin and have different types types and proportions of during the vinification process they (poly)phenols than white wines, whose contents (poly)phenols); redcontain wines aremore exposed all grape during the vinification process (poly)phenols); since since red wines are exposed to all to grape parts parts during the vinification process they they essentially originate from the pulp. than In this the minimum and essentially maximum levels ofpulp. total contain ore (poly)phenols thansense, white whose contents originate from the pulp. In contain more (poly)phenols white wines,wines, whose contents essentially originate from the Inphenolic this the minimum andof maximum of phenolic total phenolic contents reported in a representative this sense, minimum and maximum levelslevels of total reported in a representative contents reported in sense, athe representative set studies (expressed ascontents the median (Q25–Q75) in mg of gallic of studies the median (Q25–Q75) inofmg of gallic acid equivalents (GAE) per liter) set of set studies (expressed theasmedian in mg gallic acid equivalents (GAE) per(89–282) liter) acid equivalents (GAE) per (expressed liter)aswere 1531 (Q25–Q75) (983–1898) and 3192 (2700–3624), and 210 and 1531 (983–1898) and (2700–3624), 3192 (2700–3624), and(89–282) 210 (89–282) and(347–434) 402 (347–434) forand redwhite and white were were 1531 (983–1898) and 3192 and 210 and 402 for red 402 (347–434) forwines, red and white wines, respectively (Table 2). The content of polyphenols in rosé wine respectively 2).content The content of polyphenols inwine rosé wine is intermediate between wines, respectively (Table(Table 2). The of polyphenols in rosé is intermediate between red red is intermediate red and white wines [14,15]. and white wines [14,15]. and between white wines [14,15]. Table 1. Classification of phenolic compounds found in wine. 1. Classification of phenolic compounds found in in wine. Table 1. Table Classification of phenolic compounds found wine. Group Subgroup Subgroup Group Group Subgroup Main Parent and Representative Main Parent Compounds and Representative Derivatives Derivatives Main Parent Compounds and Compounds Representative Derivatives Flavonoids Flavonoids Flavonoids Molecules 2020, 25, x FOR PEER REVIEW Flavonols Flavonols Flavan-3-ols 3 of 20 Kaempferol Kaempferol R1 = R2 =R1H= R2 = H = R2 = OH Myricetin Myricetin R1 = R2 =R1OH (+)-Catechin R1 = R4 = R5 = OH, R2 = R3 = H 1 Quercetin R = H R2 = H Quercetin R1 = OH, R=2OH, (-)-Epicatechin R1 = R3 = R5 = OH, R2 = R4 = H R1 OH HO O HO HO HO O Molecules 2020, 25, x FOR2 PEER REVIEW Molecules 2020, 25, x FOR PEER REVIEW OH OH OH Procyanidin B1 O R3 R4 HO HOH (+)-Catechin R1 = R4 = R5 = OH, R2 = RHO3 = H (+)-Catechin R1 = R4 = R5 = OH, R2 = R3 = H OH Flavan-3-ols Flavan-3-ols R1 R1 1 = R3 = R5 = OH, R2 = R4 = H (-)-Epicatechin R Cyanidin R 1 = OH, R 2 = H OH (-)-Epicatechin R1 = R3 = R5 = OH, R2 = R4 = H OH Anthocyanins HO HO HO Delphinidin R1 = R2 = OH HO O HO R2 HO O R3=O-glycoside R2 R3 Malvidin R1 = R2 = OCH3 R3 R5 R4 R5 R5 R4 HO Peonidin R1 = OCH3, R2 = H 1 = OH, R2 = H OH, R2 =ROCH Petunidin R1 =Cyanidin Cyanidin R1 3= OH, R2 = H Anthocyanins Anthocyanins Delphinidin R1 = R2 = OH Delphinidin R1 = R2 = OH Naringenin R1 = H, R2 = OH Malvidin R1 = R2 = OCH3 Flavanones Malvidin R1 = R2 = OCH3 Hesperetin R1 = OH, R2 = OCH3 Peonidin R1 = OCH3, R2 = H Peonidin R1 = OCH3, R2 = H HO O Flavanones Flavanones HO O R1 R2 R3 O OH OH HO O O OH OH OH OH Procyanidin B1 Procyanidin B1 OH O Naringenin R1 = H, R2 = OH Naringenin R1 = H, R2 = OH Dihydromyricetin R1 = R2 = R3 = OH OH OH R3=O-glycoside R3=O-glycoside = OH, R2 = OCH3 Hesperetin Dihydroquercetin R1 = R2R=1OH Hesperetin R1 = OH, R2 = OCH3 OH O Petunidin R1 = OH, R2 = OCH3 Petunidin R1 = OH, R2 = OCH3 Flavanolols 3 of 20 3 of 20 OH OH

Molecules 2020, 25, x FOR PEER REVIEW 25, FOR PEER REVIEW Molecules 2020, 25, x FOR PEER Molecules 2020, 25, x FORREVIEW PEER REVIEW REVIEW Molecules 2020, 25, xx FOR PEER REVIEW Molecules 2020,25, 25, FOR PEER REVIEW Molecules 2020, 25, xx FOR PEER REVIEW Molecules 2020, 25, PEER Molecules 2020, xxxFOR Molecules 2020, 25, FOR PEER REVIEW Molecules 2020, 25,PEER xFOR FORREVIEW PEER REVIEW Molecules 2020, 25, 4105 2020, 25, x FOR PEER REVIEW Molecules Flavan-3-ols R1 Flavan-3-ols Flavan-3-ols Flavan-3-ols R1 Flavan-3-ols Flavan-3-ols Flavan-3-ols Flavan-3-ols R Flavan-3-ols Flavan-3-ols Flavan-3-ols RR111 HOFlavan-3-ols O HO O HO HO O H O HO O H O H HHO O O HO O HO Group R1 R11 R R OHR 11 OHR 1 OH OH OH O R1 R2 O O R2 O R 3 OO R2 R R232OH R R33 R RR433 R R 33 RR R R334 R R4443 R R R R 44 RR444 RR 42 HO (+)-Catechin R1 = R4 = R5 = OH, R2 = R3 = H HO (+)-Catechin R R R ==2OH, OH, R R H (+)-Catechin R R ==1111R ==4444OH, == R ==2222H (+)-Catechin R R R55555= OH, R R3333== HHHHOOO (+)-Catechin R == R == R =R R == R (+)-Catechin R1111====R R4444R R OH, 2OH, R3333R H (+)-Catechin ==5555R == R R =R22OH, == R R == H H (+)-Catechin = = = (+)-Catechin R =R =R =R (+)-Catechin R R =1R R =4OH, OH, R =R R =R2H (+)-Catechin R5R =R=OH, 2H = R33==H H 2 = R4 = H (-)-Epicatechin R1 = R3R=1 =R5R=4 =OH, R R ==2OH, OH, R R H (-)-Epicatechin R R ==1111R ==3333OH, =R ==2222H R OH(-)-Epicatechin R R5555= OH, R R4444== H (-)-Epicatechin R == R == R =R R == R (-)-Epicatechin R R3333R R OH, 2OH, R4444R H (-)-Epicatechin R1111====R H HO O ==5555R R == R R =R22OH, R == R R == H H (-)-Epicatechin R 1R = 3OH, = 2H = (-)-Epicatechin OH OH ===RR (-)-Epicatechin R OH =R R R =H (-)-Epicatechin R OH (+)-Catechin R 1 = RR 4 == 5= ===ROH, 3 == 1R 3OH, = R5R 5R =2 =OH, R 2H = R44==HH H (-)-Epicatechin R OHHO OH O R2 R22 R R R 2 R22 R555 R R R 55 R5 R3 Table 1. Cont. (-)-Epicatechin R1 = R3 = R5 = OH, R2 = R4 = H HO HO O HH O H O O HO O O OO HHH OOO HO HHOO HO H HO O Anthocyanins Flavanones Flavanones Flavanones Flavanones Flavanones Flavanones Flavanones Flavanones Flavanones Flavanones Flavanones Flavanones OH OH OH OH OH OH OH OH 3 of 18 OH OH OH OH OH OH HO OH HHO OO OH HHH OOO OH HO OH HO O H HHO OO OH HO O O OO OH OH OH OH B1 OH OH OH Procyanidin OH OH OH OH OH Procyanidin B1 Procyanidin B1 OH Procyanidin B1 Procyanidin B1 Procyanidin B1 Procyanidin B1 OH Procyanidin B1 OProcyanidin B1 Procyanidin B1 Procyanidin B1 O OH O OH O O OH HO O OH HO OH OH OH OH OH HHOO Cyanidin R1 = OH, R2 = H Cyanidin R ==2OH, OH, R H Cyanidin R OH, == H Cyanidin R11111= OH, R22222= H Cyanidin R =R R == Cyanidin R1111====OH, OH, 2OH, HR Cyanidin R =R22OH, R == H H Cyanidin R HO Cyanidin R =OH, Cyanidin R OH, R =H Cyanidin R21R R2 =H H == OH Delphinidin R1 = R 1OH = R 2 = OH Delphinidin R 1 = R 2 = Delphinidin R =R R2222= = OH OH R3=O-glycoside Delphinidin R 111OH = R = OH Delphinidin R 1 = R2R = Delphinidin R = R = OH Delphinidin R 1 = Delphinidin R =O-glycoside == R Delphinidin R22==ROH Delphinidin R=11OH, =O-glycoside Cyanidin 1R 21OH =H R2 = OH R Delphinidin R33333=O-glycoside =O-glycoside R R33=O-glycoside =O-glycoside R =O-glycoside 1 = R2 = OCH3 Malvidin RR R R R 33=O-glycoside =R =3 OCH Malvidin R R3=O-glycoside =O-glycoside R ==1111OCH Malvidin R R22222= OCH33333 Malvidin R = Malvidin R2222R OCH Malvidin R1111====R R OCH Malvidin ===2==R R ===3 OCH OCH Malvidin R =R OCH Malvidin R R =R1R Malvidin R 1= OH Delphinidin R 1OCH R 233= OCH3 Malvidin Peonidin R1 = OCH3, R2 = H Peonidin R ==3,OCH OCH 3, R2 = H R3=O-glycoside Peonidin R OCH R H Peonidin R11111= OCH 3, R R2222= H Peonidin R 3 Peonidin R1111====OCH OCH R2222====H H Peonidin R =33,,,OCH OCH H Peonidin 33,,, R R === H H Peonidin R Peonidin R OCH R RR 2R =1=3R OCH 3H Malvidin Peonidin = 2R OCH 3 , R2 = H = OCH 3 Petunidin RR11==OH, 1R = OH, R 2= OCH Petunidin R 1 = OH, 2 = OCH 3 Petunidin R = OH, OH, R2222= OCH33333 Petunidin R1111= R Petunidin R OH, 2OH, OCH Petunidin R111===OH, =R R ==3 OCH OCH Petunidin R =R OH, Petunidin R =OH, Petunidin R OH, ==2OCH OCH Petunidin R Peonidin 1 OCH 3=,22R =R H R2=33=OCH OCH3 Petunidin R1R Naringenin R11== OH, H, RR 2 = OH 2== OCH Petunidin R Naringenin R 12= H, R 2 =3OH Naringenin R 1 = H, R OH Naringenin RR = H, H, R2222= OH Naringenin R 11= R === OH Naringenin R111===H, H,R OH Naringenin R H, R OH Naringenin R Naringenin R R OH Naringenin R H, R11212=2=====H, OH Naringenin H, R2 =OH OH 2 = OCH3 Hesperetin R1 = OH,RR == 2OH, OH, R ==3 OCH OCH Hesperetin R 1 = OH, R == OCH Hesperetin R OH, R22222= OCH33333 Hesperetin R11111= = R = Hesperetin R 1 = OH, R 2OH, OCH 3 OCH Hesperetin R = R = Hesperetin R OH, R Hesperetin R OCH Hesperetin R 1= =1 =OH, OH, R=222==OH, =OH OCH Hesperetin R1R Naringenin H,RR 1R R233=OCH OCH3 Hesperetin Anthocyanins R4 Anthocyanins Anthocyanins Anthocyanins Anthocyanins RAnthocyanins Anthocyanins Anthocyanins 5 Anthocyanins Anthocyanins Anthocyanins 3 of 20 O O O O O O O OHOH OH OH OH OH OH OH OH OH OH HO OH HO Main Parent Compounds and Representative Derivatives Procyanidin OH B1 OH HO O OH HH OH HO OH OH O OH O Subgroup R R5 R5 R RR555 3 of 20 of 20 3 of 20 of 20 20 33 of of20 203 33 of of 20 333of of 20 3 of20 20 OH OH OH OH OH OH OH OH OH Hesperetin R1 = OH, R2 = OCH3 R1 Flavanolols Flavanolols Flavanolols FlavanololsRR11 Flavanolols Flavanolols Flavanolols Flavanolols Flavanolols Flavanolols FlavanololsRR11 O HO HO O HOFlavanolols HO O O H HO H O H O OO HHOO HO HO OH OH OH OH OH R2 RR R1 R R2RR1111 R RR222 1 R3 R3 R RR 3R2 O R O 1 O O O O 33 OH OH OH OH OH O OH OH OH O OH OH R3 OH OH OH O OH O OH OH O O O O O OO OH O OH OH O Flavones Flavones Flavones Flavones Flavones Flavones Flavones Flavones Flavones Flavones Flavones Flavones Dihydroquercetin R1 = R2 = OH Dihydroquercetin R =R == OH OH Dihydroquercetin R R ==1111OH Dihydroquercetin R R22222= OH Dihydroquercetin = Dihydroquercetin R1111====R R2222R OH Dihydroquercetin R = OH Dihydroquercetin R ====R R Dihydroquercetin R =R Dihydroquercetin R R =R1OH Dihydroquercetin 1OH R2==OH OH 1 = R2 = R3 = OH Dihydromyricetin R R2 R2 1R ==3R R 2OH == R R == OH OH Dihydromyricetin RR 1 = R2 R = = Dihydromyricetin R R 2 1 R 2 R33333= OH Dihydromyricetin R 1 = 2 = Dihydromyricetin R 2 R222R =1R =2OH Dihydromyricetin R111===R 1R =333R R 2OH =R R = OH Dihydromyricetin R = = Dihydromyricetin R2 2 = = Dihydromyricetin R R = R = OH Dihydromyricetin R Dihydroquercetin R 1 = R 2 = OH OH Dihydromyricetin R1 = R2 = R3==OH R3 R3 RR R 3 R333 Dihydromyricetin R1 = R2 = R3 = OH OH OH OH OH OHHO HO O HH O H O HO HO HO HHOO OH HO HO OH OH OH OH OH OH OH O OH O OH O O O OH O OH O O O O OH O O O O O OO H OO OO O OH O OHOH HO O O O OH H O OH OH O O O OH HHO OH O O OH OH O HOO OO OH O OO CH O 3 OHO CH CH3 HO O CH3 CH33 CH OHH H O CH HO CH 3 CH O33 OH OH CH33 OH HO CH 3 OH OH OH O OH OH OH OH OH HO O O O OO OH OH OH OH OH OH Dihydroquercetin 3-rhamnosideHHHHOOOO Dihydroquercetin 3-rhamnoside Dihydroquercetin 3-rhamnoside Dihydroquercetin 3-rhamnoside Dihydroquercetin 3-rhamnoside Dihydroquercetin 3-rhamnoside HO Dihydroquercetin 3-rhamnoside Dihydroquercetin 3-rhamnoside Dihydroquercetin 3-rhamnoside Dihydroquercetin 3-rhamnoside Dihydroquercetin 3-rhamnoside HO HO HHO OO H Dihydroquercetin 3-rhamnoside Apigenin R1 = H Apigenin R =H Apigenin R H Apigenin R11111= H Apigenin Apigenin R1111====H HR Apigenin R H Apigenin R === H H Apigenin R Apigenin R H LuteolinApigenin R1 = OH R1 = H 1 = OH Luteolin R 1 = OH Luteolin R OH Luteolin R111=== OH Luteolin R OH Luteolin R111===OH OH Luteolin R Luteolin Luteolin R Luteolin R Apigenin R1 OH = RR11==OH OH Luteolin HO CH3 OH Luteolin R1 = OH Non-flavonoids Non-flavonoids Non-flavonoids Non-flavonoids Non-flavonoids Non-flavonoids Non-flavonoids Non-flavonoids Non-flavonoids Caffeic acid R1 = R4 = H, R2 = R3 = OH Caffeic acid R =R 42==H, R =R == OH OH Caffeic acid R =R ==1111H, R ==2222OH Hydroxycinnamic acids Caffeic acid R RR 4 2= H, R R33333= OH = 4 = CaffeicCaffeic acidR R111acid 1acid R4444R H, R R3333R OH Caffeic R H, R = OH Caffeic acid R ====R R 4422= =====H, H, R ====R R Hydroxycinnamic acids Hydroxycinnamic acids Caffeic acid ===R =R R R =R Caffeic acid R R =1H, R R =R2OH Hydroxycinnamic acids Caffeic 1H, R 4= H, 2OH R3==OH OH Hydroxycinnamic Hydroxycinnamic acids acids Hydroxycinnamic acids Hydroxycinnamic acids R4 =RH, R 2 = OCH3, R3 = OH Ferulic acid R1 =acid Hydroxycinnamic acids Hydroxycinnamic acids Hydroxycinnamic acids 1H, = R 42==H, R 2= 3, R3 = OH Ferulic 1acid = R 4R = R OCH 3, OCH R 3 = OH Ferulic acid R 1 = R 4 = H, R 2 = OCH R3333= OH Ferulic acid R == R R 44 = =2===H, H, R =3=3,,OCH OCH 333,,,, R R === OH OH Ferulic acid R 1acid =R R444R =11H, R OCH R333===OH OH FerulicFerulic acidR R11acid 1H, R H, R222= OCH R OH Ferulic R = 4 R 3 = = R 2 OCH R Ferulic acid = R = H, R 2 = OCH 3 , R OH Ferulic acid R CaffeicFerulic acidacid Racid 1 = R4R RH, 3R =2ROH =2 R =3 =OCH =R4R=24==H, OH3, R3 = OH p-Coumaric R1 ==1RH, Hydroxycinnamic acids 1R = R 2H, = R 43==H, R 3 = OH p-Coumaric acid R 1 = R 2 = 4 = R OH p-Coumaric acid R R RR4444= = H, H, R3333= OH p-Coumaric acid R = = R p-Coumaric 1acid R222R =11R =22H, OH p-Coumaric acidR Racid 11R 22H, R H, R OH p-Coumaric ===4=44R R ====R R R === OH OH p-Coumaric R =R =R R OH p-Coumaric acid ==R R =R =R R3343=3,=====RH, OH p-Coumaric acid 4= H, RR 2= OCH 3=R OH Ferulic acidacid R1 =RR111acid 1R 2H, R H, 3 = OH p-Coumaric =acid OH, 2 = R3 = R4 = o-Coumaric ==2OH, OH, ==4R R == R R == H H o-Coumaric R 1acid == OH, R == R 3R ==2222R ==3333H o-Coumaric acid R OH, R R R44444= H o-Coumaric acid R11111= = = o-Coumaric acid R 1acid OH, R 2OH, R 3R R 4R H o-Coumaric acid R = R = R = R = H o-Coumaric R = OH, R 2 = 3 = R = o-Coumaric acid R Non-flavonoids 11= 33= 44== H o-Coumaric acid OH, R ==R R =RRR =ROH o-Coumaric acid R RR 1==OH, R2R=1R R H, 3= p-Coumaric =224=OH, 2R 3H = R4 =H H o-Coumaric acid 1 = H, R2 = R4 = OCH3, R3 = OH Sinapic acid Racid 12==H, 2OCH == R R 4= 3, R3 = OH Sinapic R 1acid = H, R R 4R = 3, OCH R 3 = OH Sinapic acid R 1 = H, R 2 R 4 = OCH 3 , R 3 = OH Sinapic acid R 1 = H, R 2 = 4 = OCH 3 , R 3 = Sinapic acid R 1 = H, R 2 = R 4 = OCH 3 , R 3 = OH Sinapic acid R 2= =R R4 = OCH R33== OH OH Sinapic acid RR1122====H, 33,, R OH Sinapic 11acid =acid =R R Sinapic acid = H, H, R44R =R2OCH R343== OH OH Sinapic acid R R 1R 2OCH = R434=3=3,,OCH H o-Coumaric acid RR =R OCH 3, R3 = OH Sinapic R=1 OH, 2,3-Dihydroxybenzoic acid R1 = R2 = H, R3 = R4 = OH 2,3-Dihydroxybenzoic acid R R 23==H, R R OH 2,3-Dihydroxybenzoic == R =3=,1111H, R, ==3333OH Hydroxybenzoic acids = R4 R =R1acid OCH R =R Sinapic acid R1 = H, R2acid 2,3-Dihydroxybenzoic acid R R H, R R4444== OH 2,3-Dihydroxybenzoic acid R == R 222OH =3===R R == R 2,3-Dihydroxybenzoic acid 1acid R2222R H, R R4444R OH 2,3-Dihydroxybenzoic ==3R R H, == R R == OH OH 2,3-Dihydroxybenzoic = 2 = Hydroxybenzoic acids Hydroxybenzoic acids 2,3-Dihydroxybenzoic acid R 11= =R 33== =R 2,3-Dihydroxybenzoic acid R =R R =1H, H, R = R, =R3OH Hydroxybenzoic acids 2,3-Dihydroxybenzoic =R R 3OH = R44==OH OH Hydroxybenzoic Hydroxybenzoic acids acids Hydroxybenzoic acids Hydroxybenzoic acids = R3 R = 1H, R24==H, OH 2-Hydroxybenzoic acid R1 = R2acid Hydroxybenzoic acids Hydroxybenzoic acids Hydroxybenzoic acids 1R = R 2H, = R 34==H, R 4 = OH 2-Hydroxybenzoic acid R 1 = R 2 = 3 = R OH 2-Hydroxybenzoic acid R =3R R =R RR ==H, H, R4444= = OH OH 2-Hydroxybenzoic acid R 111R = R 222H, = R 333= = H, R = OH 2-Hydroxybenzoic acid R 1acid = R 2R = = 4= OH 2-Hydroxybenzoic acid R = R = R H, R = OH 2-Hydroxybenzoic R 1 = 2 = 3 R 2-Hydroxybenzoic acid 323= H, R 4334= OH 2-Hydroxybenzoic acid R =R R212==RR OH 2-Hydroxybenzoic acid acid R11=acid 2,3-Dihydroxybenzoic = R = R 4= 1R= R 2H, = R = H, R 4OH = OH 2-Hydroxybenzoic 4-Hydroxybenzoic acid R1 = R3 = R4 = H, R2 = OH Hydroxybenzoic acids ==4R R == R R 42==H, R == OH OH 4-Hydroxybenzoic acid R == R ==1111R ==3333H, OH 4-Hydroxybenzoic acid R R RR 4 2= ==H, H, R22222= OH 4-Hydroxybenzoic acid R = = 4 R 4-Hydroxybenzoic 1acid R3333R R 4R H, R OH 4-Hydroxybenzoic acidR R111acid R H, R = OH 4-Hydroxybenzoic ==R ==H, 4422= R 4-Hydroxybenzoic =1acid =2R =3=R OH 4-Hydroxybenzoic acid ==R R =R=1R R OH 4-Hydroxybenzoic acid R RR =3H, R4==4===H, OH 2-Hydroxybenzoic Racid 1R =44R 3H, =RR R H, R2==OH OH 4-Hydroxybenzoic 3 = OH, R4 = H Gallic acid R1 = R2 = Racid 1R ==3R R 2OH, == R R 3R ==4OH, OH, R 4= H Gallic 1acid = R 2R = = = H Gallic acid R 1 R 2 R 3 OH, R 4 = H Gallic acid R 1 = 2 = 3 = R 4 = H Gallic acid R 1acid =R R222R =1R =2OH, 4OH, =H HR Gallicacid acid R11acid 1R =333R R 2OH, =R R33R =R44OH, R44== H H Gallic R = = = Gallic = = = = Gallic R = R = R = OH, R = Gallic acid R R4 R = 4H, R2 = OH 4-Hydroxybenzoic = R2R = 1R=3 = 3OH, =H Gallic R1acid 1 = R4 = OH, R3 = R2 = H Gentisic acid Racid =R ==3OH, OH, R =R == H H Gentisic acid R == R ==1111OH, R == R ==3333H Gentisic acid R R44444= OH, R R22222= H Gentisic acid R = = Gentisic 1acid R4444R OH, 3OH, R2222R H Gentisic acidR R111acid R =R33OH, R =H Gentisic ====R R =R R ====R R acid R =acid =R =R Gentisic acid =RR =R1OH, =RR =H Gentisic acid 1R= 2R= 31OH, OH, 4R= GallicGentisic acid R4R = =OH, R3H 3H R2==H H Gentisic 1 = R3 = OCH3, R2 = OH, R4 = H Syringic acidRR 1OCH = R 3= OCH 3 , R2 R = OH, R =H Syringic acid R 1 = R 3 = 3 , R 2 = OH, 4 = H Syringic acid R =R R3333= =3,OCH OCH R2222= = OH, OH, R44444= H Syringic acid R 111OCH = 333,,,, R Syringic acid 1acid = R 3R = R 2 = OH, R 4OH, = HR Syringic acid R = R = OCH R = R H Syringic R 1 = R = OCH 3 R = OH, R === H H Syringic acid R ,, R Syringic acid R ==R RR334==R=OCH R=22==ROH, R=44=OH, =H Syringic acid RR111=acid OH, R 3OCH 2OH, Gentisic acid 1OCH = R 333= 3=, H R 2R Syringic Protocatechuic acid R1 = H, R2 = R3 = OH, R4 = R4 = H 1 = H, R 2 = R 3 = OH, R 4= H Protocatechuic acid R 1acid == H, R ==H, R 3R ==222OH, R 4OH, == H Protocatechuic acid R 12= = H, = R 3= = R 4= =H H Protocatechuic R 1 R = R 3 OH, R 4 Protocatechuic acid R 1 H, R 2 R 3 OH, R 4 H Protocatechuic acid R 1 = H, R = R 3 = OH, R 4 H Protocatechuic acid R ==RR ===44OH, Protocatechuic 11acid =acid H, R 33R =OH, =OH, Protocatechuic acid =OCH H,RR R1321,2===R =H, =R2OH, = H RR44===H Protocatechuic acid = RR 3R= 2R= R33R 4R H Syringic acid Molecules 2020, 25, x FOR PEER REVIEW H, 2OH, H Protocatechuic R R 2 = OH, R3 = OCH3, R4 = H Vanillic acid R1R=1 H, 12==H, R 2R ==3OH, OH, R 3= 3, R4 = H Vanillic R 1acid = H, R OH, = OCH 3, OCH R 4= H Vanillic acid R 1 = H, R 2 OH, R 3 = OCH 3, R 4 = H Vanillic acid R 1 = H, R 2 = R 3 = OCH 3, R 4 = H Vanillic acid R 1acid =H, H,R R 2==H, OH, 3OH, =OCH OCH R444===H H Vanillic acidR R11acid Molecules 2020, 25, x FOR PEER REVIEW H, R22R =R33OH, R33=3,=3,3,OCH OCH 3, R R44== H H Vanillic R 1122= R = R 3, Vanillic = R = OH, = R Vanillic acid = H, R = OH, R = OCH R H Vanillic acid R 1 = H, R 2 = R 3 = OH, R 4 = H Protocatechuic acid R Vanillic acid R1 = H, R2 = OH, R3 = OCH3, R4 = H Resveratrol R1 = R2 = H, R3 = OH Vanillic acid R1 = H, R2 = OH, R3 = OCH3, R4 = H Resveratrol R1 = R2 = H, R3 = OH Piceatannol R1 = H, R3=R2 = OH Piceatannol R1 = H, R3=R2 = OH 4 of 20 4 of 20 Stilbenes Stilbenes Table 2. Range of total phenolic content in red and white wines in a representative set of studies. Table 2. Range of total phenolic content in red and white wines in a representative set of studies. Red Wine Total Phenolic Content a Red Wine Range Content a Total Phenolic Min. RangeMax. Min. Max. 1615 4177 1615 1313 1313 2193 4177 2389 2389 3183 2193 622 622 1724 3183 3200 3200 1936 1724 2340 2340 1460 n 7 n 16 7 White Wine Total Phenolic White Content Wine a Range Content a Total Phenolic Min. RangeMax. Min. Max. 216 854 407854 402407 n 7 n 17 7 6 16 20 6 89216 29289 - 292 5 20 282 - - 402 434 - 1936 3730 3730 3380 23 5 39 23 - 282 210 - - 434 390 - 1460 2082 2082 1402 3380 3184 3184 3180 3 39 24 3 213210 189213 277390 425277 1402 3200 3200 1788 3180 5900 5900 3070 8 24 - 189 - 425 11 5 - 11 4 8 1788 1012 3070 3264 11 4 55 - 55 370 - 370 20 - 20 4 17 - 4 5 - 5 47 5 47 Reference Reference [16] [16] [17] [17] [18] [18] [19] [19] [15] [15] [20] [20] [21] [21] [22] [22] [14] [14] [23] [23]

Table 2. Range of total phenolic content in red and white wines in a representative set of studies. Red Wine White Wine Total Phenolic Content a Total Phenolic Content a Range Range Min. Max. n Min. Max. n Reference 1615 4177 7 216 854 7 [16] 1313 2389 16 89 407 17 [17] 2193 3183 6 292 402 4 [18] 622 3200 20 - - - [19] 1724 1936 5 282 434 5 [15] 2340 3730 23 - - - [20] 1460 3380 39 210 390 47 [21] 2082 3184 3 213 277 5 [22] 1402 3180 24 189 425 11 [14] 3200 5900 8 - - - [23] 1788 3070 4 55 370 20 [24] 1012 3264 11 - - - [25] 554 2669 2 167 347 3 [26] 1181 3589 23 - - - [27] - - - 291 2103 14 [28] 860 2710 8 - - - [29] 1602 1968 7 - - - [30] 1837 3467 6 - - - [31] 38 2 [32] 896 6319 77 83 Mean ± SD 1538 ± 664 3406 ± 1139 189 ± 85 554 ± 545 Median (Q25–Q75) 1531 (983–1898) 3192 (2700–3624) 210 (89–282) 402 (347–434) a Data are expressed as gallic acid equivalents (GAE) in mg/L. 3.1. Flavonoids Flavonoids have a skeleton with 15 carbon atoms and are represented in a C6-C3-C6 type system, where a benzene ring (designated as B) is joined (in most cases) to the C2 position of a γ-pyran type ring (C) included in a chromane ring (Table 1) [33]. The structure of flavonoids is shaped by different levels of hydroxylation, prenylation, alkalization or glycosylation reactions, which give rise to different sub-groups [34]. In plants, most flavonoids exist as glycosides in combination with monosaccharides such as glucose and rhamnose (most common), followed by galactose, xylose and arabinose [35]. 3.2. Flavonols Flavonols are characterized by a hydroxyl group in C3 (Table 1) and are often named 3-hydroxyflavones. These compounds are known to play a wide range of biological activities and are considered the main active compounds within the flavonoids group [36,37]. Flavonols and their glycosides are present in red and in white wines, influencing their color, taste, and health properties [38]. Flavonols in red wine include aglycons such as myricetin, quercetin, kaempferol, and rutin and their respective glycosides (glucosides, glucuronides, galactosides and diglycosides). Quercetin 3-O-glucoside is the most representative flavonol in wines [39]. Flavonol levels in red wine can reach over 150 mg/L (Table 3).

Table 3. (Poly)phenol contents in red and white wines. Red Wine Phenol Explorer a Flavonoids Main representatives Anthocyanins Cyanidin c Delphinidin c Malvidin c Peodinin c Petunidin c Total Dihydroflavonols Dihydromyricetin 3-O-rhamnoside White Wine Phenol Explorer a USDA b USDA b mean min max mean min max mean min max mean min max 2.9 16.6 156 18.1 23.6 217 0.6 2.4 12.4 2.5 3.4 21.3 11.9 40.1 541 80.9 61.8 736 1.9 20.1 138 12.5 19.8 193 0.0 0.2 0.0 0.2 0.2 0.6 45.0 57.1 536 50.3 56.6 745 0.4 0.4 0.0 0.0 3.5 3.5 0.6 0.6 0.0 0.0 2.4 2.4 44.7 44.7 44.7 - - - 3.0 3.0 3.0 - - - 54.4 45.8 59.8 - - - 5.7 3.7 15.9 - - - (+)-Catechin (-)-Epicatechin Proanthocyanidins 68.1 37.8 355 470 13.8 0.0 99.7 114 390 165 560 1131 71.4 37.9 296 407 0.0 0.0 63.1 63.1 390 165 1354 1917 10.8 9.5 0.2 20.8 0.0 0.0 0.0 0.0 46.0 60.0 1.5 109 7.7 5.5 3.9 17.1 0.0 0.5 0.6 1.1 58.0 60.0 7.3 125 Flavanones Total Naringenin c 8.0 8.5 7.3 7.8 8.8 9.4 17.7 24.0 10.3 13.0 25.1 35.0 2.3 2.3 1.7 1.7 2.9 2.9 3.8 7.8 0.0 3.2 7.7 12.5 Flavones Total Apigenin - - - 1.3 1.7 0.0 0.0 4.7 8.7 - - - - - - Isorhamnetin c Kaempferol c Myricetin c Quercetin c 5.9 10.2 8.3 44.2 68.6 1.7 5.7 0.0 12.3 19.7 11.6 14.4 17.9 110 154 0.2 0.9 4.2 10.4 15.7 0.0 0.0 0.0 0.0 0.0 1.6 13.7 17.9 33.6 66.8 0.0 0.2 0.0 4.6 4.8 0.0 0.0 0.0 1.3 1.3 0.0 2.6 0.0 20.8 23.4 0.0 0.1 0.1 0.4 0.5 0.0 0.0 0.0 0.0 0.0 0.2 2.7 1.0 8.4 9.4 Total Flavanols Total Flavonols Total

Table 3. Cont. Red Wine Phenol Explorer a White Wine Phenol Explorer a USDA b USDA b mean min max mean min max mean min max mean min max Gallic Gentisic Protocatechuic Syringic Vanillic 35.9 4.6 1.7 2.7 3.2 70.1 0.0 0.0 0.0 0.0 0.0 13.7 126 8.0 9.6 23.3 7.5 221 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 2.2 18.2 3.3 0.5 0.4 24.8 0.0 0.0 0.1 0.0 0.1 0.4 11.0 20.0 13.0 0.2 1.2 46.8 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA Caffeic Caftaric Ferulic (o- and p-) Coumaric Sinapic 18.8 33.5 0.8 5.8 0.7 100 0.0 1.4 0.0 0.2 0.0 14.9 77.0 179 10.4 40.4 5.4 378 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 2.4 21.5 0.9 1.8 0.6 28.2 0.0 21.4 0.3 0.0 0.0 21.7 7.0 22.0 2.1 5.6 2.8 42.4 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA Resveratrol d Resveratrol 3-O-glucoside d Piceatannol c Viniferins (δ-. ε-) Pallidol 5.8 12.5 15.3 7.9 2.0 43.5 0.0 0.0 6.3 0.1 0.0 6.4 61.5 88.0 38.8 26.7 2.5 218 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 0.9 5.0 4.6 0.6 0.7 10.6 0.0 0.4 1.4 0.0 0.0 1.4 3.2 13.1 8.0 0.1 0.3 24.7 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA Hydroxybenzaldehydes Tyrosols 7.1 36.5 43.6 0.0 6.4 6.4 45.6 54.3 99.9 NA NA NA NA NA NA NA NA NA 4.1 4.2 8.3 2.4 2.7 5.1 5.8 5.7 11.5 NA NA NA NA NA NA NA NA NA Non-flavonoids Hydroxybenzoic acids Total Hydroxycinnamic acids Total Stilbenes Total Other polyphenols Total a Data are expressed as milligrams of gallic acid equivalent per litter (mg/GAE/L). b Data are expressed as milligrams of gallic acid equivalent per kilogram (mg/GAE/Kg). c Plus glucoside derivatives.d includes both cis and trans conformations. NA, data not available in the database.

3.3. Flavan-3-Ols Flavanols or flavan-3-ols are responsible for the astringency, bitterness, and structure of wines, and are found in important concentrations in red wine [40]. They are benzopyrans, having no double bond between C2 and C3, and no C4 carbonyl in Ring C. Furthermore, due to the hydroxylation at C3 flavanols have two chiral centers. (+)-Catechin (trans configuration) and (−)-epicatechin (cis configuration) are the two main flavan-3-ol isomers found in red wine, with average combined concentration over 100 mg/L (Table 3). Catechins usually occur as aglycones, or esterified with gallic acid, and can form polymers, which are often referred to as proanthocyanidins (or condensed tannins) because an acid-catalyzed cleavage of the polymeric chains produces anthocyanidins. Proanthocyanidins, which present an average concentration over 350 mg/L in red wine, include, for example, procyanidin dimers B1, B2, B3 and B4. Trimers such as procyanidin C1 (three epicatechins) have also been identified. 4. Anthocyanins Anthocyanic pigments (anthocyanidins and anthocyanins) have a structure based on the flavylium cation (2-phenylbenzopyrylium). In fact, anthocyanins are anthocyanidin glycosides, being the corresponding aglycons (anthocyanidins) obtained by hydrolysis. The great variety of anthocyanins found in nature (more than 500 anthocyanins have been described) is characterized by the different hydroxylated groups, conjugated sugars and acyl moieties they present [41,42]. The main anthocyanidins found in red wine are malvidin (most abundant), petunidin, peonidin, delphinidin and cyanidin. Often anthocyanins are found linked (mainly in position 3) to one or more sugar molecules, usually glucose, and also to acyl substituents bound to sugars, aliphatic acids, and cinnamic acids. Anthocyanins can be present in amounts higher than 700 mg/L in red wine, whereas in white wine they are essentially absent (Table 3). 4.1. Flavanones Flavanones, also known as dihydroflavones, lack the double bond between carbons 2 and 3 in the C-ring of the flavonoid skeleton. Some flavanones have unique substitution patterns, e.g., prenylated flavanones, furanoflavanones, pyranoflavanones, benzylated flavanones, resulting in a large number of derivatives of this subgroup. One of the main flavonones found in wine is naringenin at levels that can reach 25 mg/kg (Table 3). 4.2. Flavones Flavones are characterized by absence of a hydroxyl group in the C3 position and a conjugated double bond between C2 and C3 in the flavonoid skeleton. Flavones and their 3-hydroxy derivatives flavonols, including their glycosides, methoxides and other acylated products on all three rings, make this the largest subgroup among all polyphenols. These compounds were found in grape skin and wine in both aglycones and glycosides forms. Apigenin, for example, has been described in red wine only in trace amounts (Table 3). 5. Non-Flavonoids The non-flavonoid phenolic constituents in wine are divided into hydroxybenzoic acids and hydroxycinnamic acids, stilbenes and other miscellaneous compounds [43]. These phenolic compounds can reach levels that range from 60 to 566 mg/L [44]. 6. Hydroxycinnamic Acids Hydroxycinnamic acids are the foremost group of phenolic compounds in grapes and wine [45]. Caffeic, coumaric, and ferulic acids, essentially conjugated with tartaric acid esters or diesters, are some of the most important compounds in this polyphenol sub-class. For instance, caftaric acid, which is composed of caffeic acid esterified with tartaric acid, is found in the pulp and represents up to 50% of

total hydroxycinnamic acids [43,46]. The average amount of hydroxycinnamic acids present in red wine is around 100 and 30 mg/L in red and white wines, respectively (Table 3). 7. Hydroxybenzoic Acids In comparison with cinnamic acid derivatives, benzoates are present at lower levels in wine (Table 3). Hydroxybenzoic acids are phenolic metabolites with a general C6–C1 structure and occur mainly in their free forms in wine, mainly as p-hydroxybenzoic, gallic, vanillic, gentisic, syringic, salicylic, and protocatechuic acids [43], although ethyl and mehyl esters of these phenolic acids have been also identified [47]. Gallic acid, which is present in important levels in white and, especially, in red wine, is the precursor of all hydrolyzable tannins and is incorporated in condensed tannins [46]. 8. Stilbenes Stilbenes are widely distributed molecules in the Plant Kingdom. However, their presence in the diet is not very significant, being basically restricted to grapes, red wine and, to a lesser extent, peanuts and blueberries [48]. Chemically they are 1,2-diarilethenes and usually have two hydroxyl groups in the meta position of ring A, while ring B is substituted with hydroxyl groups and methoxyl groups in the meta and/or para positions (Table 1). Although its concentration in wine is much lower than other polyphenols, i.e., often traces, resveratrol has received much attention for its biological properties and potential therapeutic effects (see below). The levels of resveratrol aglycone, its piceid glycoside, and its dimeric and trimeric forms (e.g., pallidol, viniferins) combined may range from negligible up to more than 100 mg/L (Table 3) when grapes are exposed to fungi. 9. Effects on Human Health The Greek philosopher Pythagoras of Samos allegedly used to say “All is number” or “God is number” [49]. He meant that he only believed in what could be measured. This was echoed by William Thomson, 1st Baron Kelvin who, in his Popular Lectures and Addresses vol. 1 (1889) ‘Electrical Units of Measurement’, delivered 3 May 1883 notoriously said “When you can measure what you are speaking about, and express it in numbers, you know something about it, when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts advanced to the stage of science.” [50]. What both scientists meant was that we should base our knowledge on hard evidence. More recently, Dr. Archie L. Cochrane set out clearly the vital importance of randomized controlled trials (RCTs) in assessing the effectiveness of treatments [51]. How does this apply to wine (poly)phenols? We shall start by mentioning that there are thousands of papers published on this topic (a cursory PubMed search ran on August 14th, 2020 retrieved 2954 entries just by entering “wine polyphenols”). The near totality of such studies has been performed in vitro. Needless to say, in vitro studies are indispensable to address mechanisms of action and to propose new avenues of in vivo research. The case of wine (poly)phenols, however, is rather unique and presents us with a paradigmatic opportunity to underscore the current very limits of (poly)phenol research. In keeping with the above, we would like to discuss the case of resveratrol as an example of molecules for which there exists a strong dyscrasia between the lay public perception of health benefits and hard scientific data. Resveratrol became popular in 1991, when Drs. Michel de Lorgeril and Serge Renaud appeared in the “60 Minutes” CBS show to talk about the French Paradox and to attribute it to the French habit of drinking red wine, which would theoretically inhibit lipid peroxidation. Note that, back then the “free radical/antioxidant hypothesis” [52] was in full swing and it was commonplace to believe that eating and drinking (poly)phenols would scavenge free radicals and prevent their noxious effects, for example by inhibiting LDL oxidation [53]. This conjecture, now largely proven wrong [54], granted red wine (poly)phenols, namely resveratrol, immediate popularity and trigger the vast amount of well-funded research mentioned above.

Two major issues developed during the nearly three decades that separate the 60 min show from our current knowledge. The first problem is that we came to realize that (poly)phenols are very weak (if at all effective) in vivo direct antioxidants [55]. For kinetic reasons they do not scavenge free radicals and their bioavailability is generally so low that they contribute very little to the integrated cellular antioxidant machinery, which is mostly composed of enzymes [56–58]. Alas, plenty of investigators still perform research and publish papers on the in vitro antioxidant abilities of individual (poly)phenols or of some raw mixtures of them. Luckily, plenty of researchers correctly use (poly)phenols’ metabolites in their in vitro studies [59,60]. The hurdle then becomes the difficulty of synthesizing such metabolites, which are often produced by the organism in different forms. It is worth underscoring that we are making progress in the identification of metabolites, but—until recently—we mainly focused on the liver-derived ones [61]. The relatively recent discovery of microbiota-synthesized metabolites amplifies the list of potential biologically-active molecules produced by the body after the ingestion of (poly)phenol-rich foods [58,62,63]. In consonance with the above, the lay press often overlooks the bioavailability issue. As regards resveratrol, already in 1993 Soleas and Goldberg acted as the harbinger of the subsequent in vivo debacle of the molecule by calling it “a molecule whose time has come and gone” [64]. That conclusive title might have been a bit too harsh, but it’s a fact that many years of research and many million dollars invested in it did not yield major results [65,66]. Finally, animal studies often employ very high doses of grape (poly)phenols, e.g., resveratrol and their results cannot be readily transferred to humans, who would need to ingest several grams of extracts to replicate the same effects. Indeed, a discrepancy between animal and human effects has just been underscored [5] and resveratrol’s potential toxicity has been recently reviewed [67]. An often overlooked paper reported that resveratrol promoted atherosclerotic development in hypercholesterolemic rabbits, by a mechanism that is independent of observed differences in gross animal health, liver function, plasma cholesterol concentrations, or LDL oxidative status [68]. 10. Human Studies of Resveratrol and Red Wine (Poly)Phenols One of the fields where red wine (poly)phenols are most actively studied is that of weight control, namely obesity and its associated insulin sensitivity [69]. The rationale behind studying red wine (poly)phenols and, particularly, resveratrol is that type II diabetes is rampant in developed countries and that many researchers are looking for fasting mimetics, to approximate the beneficial effects of calorie restriction or intermittent fasting on insulin sensitivity [70]. The results are equivocal, to say the least, as most trials failed to report significant effects, e.g., [71]. The molecular rationale for studying it is the finding that resveratrol and, maybe, other wine (poly)phenols activate SIRT1, a modulator of pathways downstream of calorie restriction that produces beneficial effects on glucose homeostasis and insulin sensitivity [72,73]. This hypothesis is quite controversial for at least two reasons. One is the factual role of sirtuins as longevity promoters [74]. The other one is that several researchers question the reproducibility of those data, e.g., [75]. In summary, the jury is still out [76] and the quixotic search for a substance that would fix the cardiometabolic effects of inordinate diets is not over [77]. Rather than trying to single out individual molecules purportedly responsible for the beneficial effects of moderate wine use (which is a pharmacological approach), an alternative is to test the effects of the whole (poly)phenolic fraction. We retrieved 24 publications of human studies that employed dealcoholized wine (Table S1). Taken together, their results indicate that wine (poly)phenols do exert healthful effects, ranging from anti-inflammatory actions to modulation of the microbiota, which is now gaining traction from an industrial viewpoint [78,79] and might be one of the next applications of these compounds. The extent and precise nature of such activities, however, remains to be fully elucidated. For example, some publications stem from the same study; there are some contradictions between data and their discussion (e.g., LPS and LPB data in [80], fatty acid data in [81], inflammatory markers in [82], etc.); and the true clinical relevance of microbiota modification as related to, e.g., circulating

lipids (Table S1) [83–106]. In summary, there is indeed evidence that wine (poly)phenols modulate human physiology, but puffery should be avoided until we can clearly correlate such modifications with undisputable clinical outcomes. We also searched the literature for acute or short-term human effects of wine (poly)phenols (Table S2) [107–123]. Even though this might be seen as a more classic “pharmacological” approach, even small effects repeated over time might—in the end—affect human physiology and health. Some outcomes fall in the now-outdated “plasma antioxidant capacity” or “oxLDL” areas, i.e., are poor proxies of prognosis. Other data are more physiologically relevant and indicate, e.g., salubrious effects on endothelial function and related flow-mediated dilation. Anti-inflammatory effects have also been reported. Other studies focused on bioavailability, with scant indications of biological effects. It is worth noting that ethical reasons often impede research on alcohol in humans [1]. 11. Wine vs. Other Alcoholic Beverages: Does Digestion Make the Difference? Often miscategorized as direct antioxidants [124] (see above) wine (poly)phenols might act as such during digestion. Several pieces of evidence reveal that, during digestion, lipid peroxides are formed in the stomach at millimolar concentrations [125]. In addition, we eat pre-formed hydroperoxides, whose formation is unavoidable in fat-containing foods. Dr. Kanner called the stomach “a bioreactor” [125] where hydroperoxides are formed and subsequently absorbed. This is particularly noteworthy in the case of red meat (hypothetically because of its iron content [126]), but it is likely to happen with any animal food. Lipid peroxidation during digestion can be decreased by the consumption of (poly)phenol rich foods and beverages such as extra virgin olive oil [127] and—germane to this review—red wine [128,129]. In a wider context, these data experimentally explain the evolutionary-sound habit of eating fruit and vegetables, i.e., (poly)phenols with protein [130]. Further, most cultures have culinary routines that involve drinking (poly)phenols during or after meals, including tea [131], coffee [132,133], red wine [128], etc. Another place where wine (poly)phenols might act as indirect antioxidants is the liver, where ethanol is metabolized to acetaldehyde by the microsomal ethanol oxidizing system (MEOS), via cyp2E1 [134]. In doing, ROS are generated as by-products. Possibly, (poly)phenols might lessen this untoward effect of ethanol ingestion, through mechanisms that are yet to be elucidated. 12. Conclusions In this review, we took a pharma-nutritional approach to wine (poly)phenols. Epidemiological evidence describes the association between alcohol use and all-cause mortality as following a J-shaped curve. Many investigators claim the superiority of wine, namely red wine with respect to other alcoholic beverages and call for (poly)phenols to support their hypothesis. The result is that the lay public often believes in this premise, in part because there is plenty of in vitro and some animal data and in part due to wish bias [135]. Indeed, there appears to be a discrepancy between the strength of biochemical data and the scantiness of well-controlled human trials of individual molecules isolated from wine. This is commonplace in nutritional research [136,137] and there is no easy way out of it [138]. In a way, wine (poly)phenols are paradigmatic of the current tension between treating such compounds as non-essential nutritional agents and expecting pharmacological actions from them [139]. In the former case, we must accept the fact that the biological effects of wine (poly)phenols are minimal and very difficult to detect with current technologies and biomarkers [138,139]. The latter scenario involves the unavoidable acceptance of side effects and is not epistemologically applicable to human nutrition. Another limitation of wine (poly)phenol research is that we often use a reductionist approach and look for one single mechanism of action. In the case of wine (poly)phenols and particularly resveratrol, this involves their misclassification as in vivo free radical scavengers and antioxidants, even if their mechanisms of action are manifold and chiefly involve anti-inflammatory actions and, possibly, activation of nrf2 and its downstream pathways via xeno-hormesis [1]. In pharma-nutritional research we should look at a wider picture and acknowledge that phytochemicals contribute to health

5 of 20 even though, based on the definition of nutrients, they are not essential. Therefore, these molecules targets depending on their concentration, and do not have a univocal pharmacological mechanism of do not fit in the classic and rigorous pharmacological definitions; they can be modified by organisms action. before they interact with targets, can have different targets depending on their concentration, and do In conclusion, after 30 years of dedicated research and despite the considerable expenditure, we not have a univocal pharmacological mechanism of action. still lack solid, “pharmacological” human evidence to confirm wine (poly)phenols’ biological actions In conclusion, after 30 years of dedicated research and despite the considerable expenditure, (Figure 1). Future research [138] will eventually clarify their activities and will back the current we still lack solid, “pharmacological” human evidence to confirm wine (poly)phenols’ biological recommendations of responsibly drinking moderate amounts of wine with meals. actions (Figure 1). Future research [138] will eventually clarify their activities and will back the current recommendations of responsibly drinking moderate amounts of wine with meals. Figure 1. Schematic overview of current pitfalls in wine (poly)phenols research. Figure 1. Schematic overview of current pitfalls in wine (poly)phenols research. Supplementary Materials: The following are available online, Table S1: Human long-term studies with Supplementary The are or available online, Table Human long-term dealcoholized redMaterials: wine, Table S2: following Human acute short-term studies withS1: dealcoholized red wine.studies with dealcoholized red wine, Table S2: Human acute or short-term studies with dealcoholized red wine. Author Contributions: This is an Invited Review and all authors (F.V., S.-A.P., and J.T.-C.) contributed to drafting, revising, Contribution: and finalizing it. All is authors have read andand agreed the published versionand of the manuscript. Authors This an Invited Review all to authors (F.V., S.-A.P., J.T.-C.) contributed to drafting, revising, and finalizing it. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Acknowledgments: This publication was not funded. We thank Paula Silva for inviting us to contribute to this Funding: This research received no external funding. Special Issue. This manuscript forms part of S-A.P. dissertation to obtain his M.D. degree. Acknowledgments: This publication was not funded. We thank Paula Silva for inviting us to contribute to this Conflicts of Interest: The authors declare no conflict of interest. Special Issue. This manuscript forms part of S-A.P. dissertation to obtain his M.D. degree. Conflicts of Interest: The authors declare no conflict of interest. References 1. Poli, A.; Marangoni, F.; Avogaro, A.; Barba, G.; Bellentani, S.; Bucci, M.; Cambieri, R.; Catapano, A.L.; References 1. 2. 2. 3. 3. 4. 4. 5. 5. 6. 6. Costanzo, S.; Cricelli, C.; et al. Moderate alcohol use and health: A consensus document. Nutr. Metab. Poli, A.; Marangoni, A.; Barba, [PubMed] G.; Bellentani, S.; Bucci, M.; Cambieri, R.; Catapano, A.L.; Cardiovasc. Dis. 2013, F.; 23, Avogaro, 487–504. 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