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antioxidants
Review
Polyphenols in the Mediterranean Diet: From Dietary Sources
to microRNA Modulation
Roberto Cannataro 1,2 , Alessia Fazio 1, Chiara La Torre 1,2, Maria Cristina Caroleo 1, 2, * and Erika Cione 1,2
Citation: Cannataro, R.; Fazio, A.; La
Torre, C.; Caroleo, M.C.; Cione, E.
Polyphenols in the Mediterranean
Diet: From Dietary Sources to microRNA
Modulation. Antioxidants 2021,10, 328.
https://doi.org/10.3390/antiox10020328
Academic Editor: Maria
Cristina Albertini
Received: 1 February 2021
Accepted: 16 February 2021
Published: 23 February 2021
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4.0/).
1Department of Pharmacy, Health and Nutritional Sciences, Department of Excellence 2018-2022,
University of Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy; r.cannataro@gmail.com (R.C.);
alessia.fazio@unical.it (A.F.); latorre.chiara@libero.it (C.L.T.); erika.cione@unical.it (E.C.)
2GalaScreen Laboratories, Department of Pharmacy, Health and Nutrition Sciences, University of Calabria,
87036 Rende (CS), Italy
*Correspondence: mariacristina.caroleo@unical.it
Abstract:
It is now well established that polyphenols are a class of natural substance that offers
numerous health benefits; they are present in all plants in very different quantities and types. On
the other hand, their bioavailability, and efficacy is are not always well proven. Therefore, this
work aims to discuss some types of polyphenols belonging to Mediterranean foods. We chose
six polyphenols—(1) Naringenin, (2) Apigenin, (3) Kaempferol, (4) Hesperidin, (5) Ellagic Acid and
(6) Oleuropein—present in Mediterranean foods, describing dietary source and their chemistry, as
well as their pharmacokinetic profile and their use as nutraceuticals/supplements, in addition to the
relevant element of their capability in modulating microRNAs expression profile.
Keywords: polyphenols; nutraceutical; microRNA; epigenomic
1. Introduction
Angel Keys, a biologist and physiologist who based his conclusions on his studies
focusing on the dietary habits of people living in Southern Italy, was the first to present
the phrase “Mediterranean diet” to the popular imagination, investing it with a scientific
and cultural meaning. Now, following the joint candidacy of Italy, Spain, Greece and
Morocco, followed by Cyprus, Croatia and Portugal, it has the recognition of not only
UNESCO, but also of the WHO and FAO. The Mediterranean diet varies by country and
region, so it has a range of definitions. In general, however, it is high in vegetables, fruits,
legumes (such as beans), nuts, cereals, fish and unsaturated fats (such as olive oil). It
usually includes a low intake of meat and dairy foods. In particular, some plants are
characteristic of the Mediterranean vegetation; some have been present for thousands of
years, such as olive trees, walnuts, oregano, pomegranates, onions and others including
various citrus species [
1
]. The Mediterranean diet represents one of the first examples of
a positive correlation between diet and cardiovascular health; in fact, a diet that involves
the frequent eating of fruit and vegetables, possibly in season, in addition to seeds and
olive oil, has been shown to exhibit significant benefits in health terms, resulting not only
in preventing cardiovascular disease, but also diabetes, obesity and even various forms
of cancer [
2
–
5
], although the dietary polyphenol intake in Europe seems to be high in
the north [
6
]. This effect can be explained, at least in part, by the regular and varied
intake of food polyphenols that characterize the Mediterranean diet. Although there is
no set recommended daily dose, polyphenols have an important role in modulating and
preventing various diseases, such as cardiovascular [
6
], as well as inflammatory diseases
such as arthritis [
7
]. Probably the most important actions by polyphenols are carried out in
the regulation and management of reactive oxygen species (ROS) and immunomodulation.
The pathways that are influenced by much of them are those of nuclear factor kappa-light-
chain-enhancer of activated B cells (NF-
κ
B), mitogen-activated protein Kinase (MAPK) and
Antioxidants 2021,10, 328. https://doi.org/10.3390/antiox10020328 https://www.mdpi.com/journal/antioxidants
Antioxidants 2021,10, 328 2 of 24
arachidonic acids and phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT) as an
inhibitor. On the other hand, they upregulate superoxide dismutase (SOD), catalase and
glutathione peroxidase (GPx) expression: GPR40 [8–11].
Polyphenols are very often linked to the colors of the plants that contain them. They
are present in practically all plant species and in various parts of the plant itself, especially
in the leaves, fruits and roots [
12
]. On the other hand, while showing promising
in vitro
activity, they often present the obstacle of bioavailability, which does not always make
them so useful if tested directly on humans. Polyphenols have a typical molecular structure
with one or more aromatic rings, and one or more double bonds are present in the molecule.
This structure guarantees an antioxidant action for all classes, as there is delocalization
of the free radical itself, with consequent antioxidant activity. [
12
]. Together with this,
polyphenols have a genomic and epigenomic action, in fact there are numerous studies
that underline their regulatory action, among others, on NF-
κ
B, MAPK and nuclear factor
erythroid related factor 2 (Nrf2) [
11
,
13
,
14
]. In addition to that, they show epigenetic activity
in modulating microRNAs expression and from this point of view the microRNAs could
represent a useful evaluation tool to study polyphenols action in human. In this review, we
choose six polyphenols—(1) Naringenin, (2) Apigenin, (3) Kaempferol, (4) Hesperidin, (5)
Ellagic Acid and (6) Oleuropein—present in Mediterranean foods, as this dietetic lifestyle
is linked to better health status [2–5].
2. Dietary Sources
2.1. Naringenin
Naringenin is especially abundant in rosemary (55.1 mg/100 g) and present in grape-
fruit juice (37.76 mg/100 mL), red wine (0.75 mg/100 mL) and orange juice (
0.07 mg/100 mL
)
(Figure 1). Naringenin is a flavonoid belonging to the subclass of flavanones, also often
found in food in its glycosides form. [15].
Antioxidants2021,10,3282of24
chain‐enhancerofactivatedBcells(NF‐κB),mitogen‐activatedproteinKinase(MAPK)
andarachidonicacidsandphosphatidylinositide3‐kinases/proteinkinaseB(PI3K/AkT)
asaninhibitor.Ontheotherhand,theyupregulatesuperoxidedismutase(SOD),catalase
andglutathioneperoxidase(GPx)expression:GPR40[8–11].
Polyphenolsareveryoftenlinkedtothecolorsoftheplantsthatcontainthem.They
arepresentinpracticallyallplantspeciesandinvariouspartsoftheplantitself,especially
intheleaves,fruitsandroots[12].Ontheotherhand,whileshowingpromisinginvitro
activity,theyoftenpresenttheobstacleofbioavailability,whichdoesnotalwaysmake
themsousefuliftesteddirectlyonhumans.Polyphenolshaveatypicalmolecularstruc‐
turewithoneormorearomaticrings,andoneormoredoublebondsarepresentinthe
molecule.Thisstructureguaranteesanantioxidantactionforallclasses,asthereisdelo‐
calizationofthefreeradicalitself,withconsequentantioxidantactivity.[12].Together
withthis,polyphenolshaveagenomicandepigenomicaction,infacttherearenumerous
studiesthatunderlinetheirregulatoryaction,amongothers,onNF‐κB,MAPKandnu‐
clearfactorerythroidrelatedfactor2(Nrf2)[11,13,14].Inadditiontothat,theyshowepi‐
geneticactivityinmodulatingmicroRNAsexpressionandfromthispointofviewthemi‐
croRNAscouldrepresentausefulevaluationtooltostudypolyphenolsactioninhuman.
Inthisreview,wechoosesixpolyphenols—(1)Naringenin,(2)Apigenin,(3)Kaempferol,
(4)Hesperidin,(5)EllagicAcidand(6)Oleuropein—presentinMediterraneanfoods,as
thisdieteticlifestyleislinkedtobetterhealthstatus[2–5].
2.DietarySources
2.1.Naringenin
Naringeninisespeciallyabundantinrosemary(55.1mg/100g)andpresentingrape‐
fruitjuice(37.76mg/100mL),redwine(0.75mg/100mL)andorangejuice(0.07mg/100
mL)(Figure1).Naringeninisaflavonoidbelongingtothesubclassofflavanones,also
oftenfoundinfoodinitsglycosidesform.[15].
Figure1.Mainfoodsandbeveragesthatcontainnaringenin,accordingtothedatabasePhenol‐
Explore(http://phenol‐explorer.eu/)andUSDADatabasefortheflavonoidcontentofselected
foods(https://www.ars.usda.gov/).
2.2.Apigenin
ThenameapigeninderivesfromthegenusApiumintheApiaceaealsoknownas
Umbelliferaeandisfoundasauniqueingredientinchamomile(Matricariachamomilla),an
annualherbnativetowesternAsiaandEurope.Drinkspreparedfromchamomilecontain
from0.8%to1.2%ofapigenin.Apigeninisabundantinavarietyofotherdietarysources
[16],includingfruitsandvegetables(Figure2),suchasceleryseeds(78.65mg/100g),spin‐
ach(62.0mg/100g),parsley(45.04mg/100g),marjoram(4.40mg/100g),Italianoregano
(3.5mg/100g),sage(2.40mg/100g),chamomile(3to5mg/100g)andpistachio(0.03
mg/100g),buttherichestsourcesaretherespectivedriedsources.[17].
Figure 1.
Main foods and beverages that contain naringenin, according to the database Phenol-
Explore (http://phenol-explorer.eu/ accessed on 29 January 2021) and USDA Database for the
flavonoid content of selected foods (https://www.ars.usda.gov/ accessed on 13 February 2021).
2.2. Apigenin
The name apigenin derives from the genus Apium in the Apiaceae also known as
Umbelliferae and is found as a unique ingredient in chamomile (Matricaria chamomilla), an
annual herb native to western Asia and Europe. Drinks prepared from chamomile contain
from 0.8% to 1.2% of apigenin. Apigenin is abundant in a variety of other dietary sources [
16
],
including fruits and vegetables (Figure 2), such as celery seeds (7
8.65 mg/100 g)
, spinach
(62.0 mg/100 g), parsley (45.04 mg/100 g), marjoram (
4.40 mg/100 g)
, Italian oregano
(
3.5 mg/100 g
), sage (
2.40 mg/100 g)
, chamomile (3 to 5 mg/100 g) and pistachio
(0.03 mg/100 g)
,
but the richest sources are the respective dried sources. [17].
Antioxidants 2021,10, 328 3 of 24
Antioxidants2021,10,3283of24
Figure2.Mainfoodsthatcontainapigenin,accordingtothedatabasePhenol‐Explore(http://phenol‐explorer.eu/)and
USDADatabasefortheflavonoidcontentofselectedfoods(https://www.ars.usda.gov/).
2.3.Kaempferol
Therichestplantsourcesofkaempferolaregreenleafyvegetables,suchasspinach
(55mg/100g),cabbage(47mg/100g)andbroccoli(7.2mg/100g),butalsoinonions(4.5
mg/100g)andblueberries(3.17mg/100g).Regardingdrinks,kaempferolismainlypre‐
sentinblacktea(1.7mg/100mL)andredwine(0.23mg/100mL).Agoodpercentageis
alsopresentinspicessuchascapers(104.29mg/100g),cumin(38.6mg/100g)andcloves
(23.8mg/100g)(Figure3).
Figure3.Mainfoodsandbeveragesthatcontainkaempferol,accordingtothedatabasePhenol‐
Explore(http://phenol‐explorer.eu/)andUSDADatabasefortheflavonoidcontentofselected
foods(https://www.ars.usda.gov/).
Figure 2.
Main foods that contain apigenin, according to the database Phenol-Explore (http://phenol-
explorer.eu/ accessed on 29 January 2021) and USDA Database for the flavonoid content of selected
foods (https://www.ars.usda.gov/ accessed on 13 February 2021).
2.3. Kaempferol
The richest plant sources of kaempferol are green leafy vegetables, such as spinach
(55 mg/100 g), cabbage (47 mg/100 g) and broccoli (7.2 mg/100 g), but also in onions
(4.5 mg/100 g) and blueberries (3.17 mg/100 g). Regarding drinks, kaempferol is mainly
present in black tea (1.7 mg/100 mL) and red wine (0.23 mg/100 mL). A good percentage is
also present in spices such as capers (104.29 mg/100 g), cumin (38.6 mg/100 g) and cloves
(23.8 mg/100 g) (Figure 3).
Antioxidants2021,10,3283of24
Figure2.Mainfoodsthatcontainapigenin,accordingtothedatabasePhenol‐Explore(http://phenol‐explorer.eu/)and
USDADatabasefortheflavonoidcontentofselectedfoods(https://www.ars.usda.gov/).
2.3.Kaempferol
Therichestplantsourcesofkaempferolaregreenleafyvegetables,suchasspinach
(55mg/100g),cabbage(47mg/100g)andbroccoli(7.2mg/100g),butalsoinonions(4.5
mg/100g)andblueberries(3.17mg/100g).Regardingdrinks,kaempferolismainlypre‐
sentinblacktea(1.7mg/100mL)andredwine(0.23mg/100mL).Agoodpercentageis
alsopresentinspicessuchascapers(104.29mg/100g),cumin(38.6mg/100g)andcloves
(23.8mg/100g)(Figure3).
Figure3.Mainfoodsandbeveragesthatcontainkaempferol,accordingtothedatabasePhenol‐
Explore(http://phenol‐explorer.eu/)andUSDADatabasefortheflavonoidcontentofselected
foods(https://www.ars.usda.gov/).
Figure 3.
Main foods and beverages that contain kaempferol, according to the database Phenol-
Explore (http://phenol-explorer.eu/ accessed on 29 January 2021) and USDA Database for the
flavonoid content of selected foods (https://www.ars.usda.gov/ accessed on 13 February 2021).
Antioxidants 2021,10, 328 4 of 24
2.4. Hesperidin
Hesperidin and its aglycone, hesperetin, are two flavonoids, which together with rutin
and quercetin, are the main compounds of citrus fruits and, for this reason, this compound is
called “citroflavonoid”. It is present mainly in blood orange (
43.71 mg/100 mL
), mandarin
juice (36.11 mg/100 mL), blond orange juice (25.85 mg/100 mL), lemon (
17.81 mg/100 mL
)
and lime (13.41 mg/100 g) (Figure 4). The presence of this compound has also been detected
in plants; a high value is reported in peppermint (480.65 mg/100 g).
Antioxidants2021,10,3284of24
2.4.Hesperidin
Hesperidinanditsaglycone,hesperetin,aretwoflavonoids,whichtogetherwithru‐
tinandquercetin,arethemaincompoundsofcitrusfruitsand,forthisreason,thiscom‐
poundiscalled“citroflavonoid”.Itispresentmainlyinbloodorange(43.71mg/100mL),
mandarinjuice(36.11mg/100mL),blondorangejuice(25.85mg/100mL),lemon(17.81
mg/100mL)andlime(13.41mg/100g)(Figure4).Thepresenceofthiscompoundhasalso
beendetectedinplants;ahighvalueisreportedinpeppermint(480.65mg/100g).
Figure4.MainfoodsthatcontainhesperidinaccordingtothedatabasePhenol‐Explore(http://phe‐
nol‐explorer.eu/)andUSDADatabasefortheflavonoidcontentofselectedfoods
(https://www.ars.usda.gov/).
2.5.EllagicAcid
Ellagicacid,adilactoneofthedimergallicacid,isapolyphenolfoundinfruitand
vegetables.Somefoodscontainamorecomplexversioncalledellagitannin,whichwillbe
convertedintoellagicacidbyorganism.Ellagicacidisprevalentinberries(Figure5).
Foodshighinellagicacidarechestnut(735.44mg/100g),blackberries(43.67mg/100g),
blackraspberries(38mg/100g),walnuts(28.50mg/100g),cloudberries(15.30mg/100g),
pomegranatejuice(2.06mg/100mL),strawberries(1.24mg/100g),redraspberries(1.14
mg/100g)andmuscadinegrape(0.90mg/100g)[18].Ellagicacidissynthetizedbyplants
asadefensemechanismagainstinfectionsandparasites.
Figure5.Structureandmainfoodsthatcontainellagicacid,accordingtothedatabasePhenol‐
Explore(http://phenol‐explorer.eu/).ThereisnovaluereportedfortheUSDADatabaseforthe
flavonoidcontentofselectedfoods(https://www.ars.usda.gov/).
2.6.Oleuropein
Oleuropeinisthemoleculeresponsibleforthebittertasteofolivesandisthemost
commonphenoliccomponentintheleaves,seeds,pulpandskinofunripeolives.Alt‐
houghabundant,thiscompoundundergoeshydrolysisduringfruitripeningleadingto
Figure 4.
Main foods that contain hesperidin according to the database Phenol-Explore (http://
phenol-explorer.eu/ accessed on 29 January 2021) and USDA Database for the flavonoid content of
selected foods (https://www.ars.usda.gov/ accessed on 13 February 2021).
2.5. Ellagic Acid
Ellagic acid, a dilactone of the dimer gallic acid, is a polyphenol found in fruit and
vegetables. Some foods contain a more complex version called ellagitannin, which will
be converted into ellagic acid by organism. Ellagic acid is prevalent in berries
(Figure 5
).
Foods high in ellagic acid are chestnut (735.44 mg/100 g), blackberries (
43.67 mg/100 g
),
black raspberries (38 mg/100 g), walnuts (28.50 mg/100 g), cloudberries (1
5.30 mg/100 g
),
pomegranate juice (2.06 mg/100 mL), strawberries (1.24 mg/100 g), red raspberries
(
1.14 mg/100 g
) and muscadine grape (0.90 mg/100 g) [
18
]. Ellagic acid is synthetized by
plants as a defense mechanism against infections and parasites.
Antioxidants2021,10,3284of24
2.4.Hesperidin
Hesperidinanditsaglycone,hesperetin,aretwoflavonoids,whichtogetherwithru‐
tinandquercetin,arethemaincompoundsofcitrusfruitsand,forthisreason,thiscom‐
poundiscalled“citroflavonoid”.Itispresentmainlyinbloodorange(43.71mg/100mL),
mandarinjuice(36.11mg/100mL),blondorangejuice(25.85mg/100mL),lemon(17.81
mg/100mL)andlime(13.41mg/100g)(Figure4).Thepresenceofthiscompoundhasalso
beendetectedinplants;ahighvalueisreportedinpeppermint(480.65mg/100g).
Figure4.MainfoodsthatcontainhesperidinaccordingtothedatabasePhenol‐Explore(http://phe‐
nol‐explorer.eu/)andUSDADatabasefortheflavonoidcontentofselectedfoods
(https://www.ars.usda.gov/).
2.5.EllagicAcid
Ellagicacid,adilactoneofthedimergallicacid,isapolyphenolfoundinfruitand
vegetables.Somefoodscontainamorecomplexversioncalledellagitannin,whichwillbe
convertedintoellagicacidbyorganism.Ellagicacidisprevalentinberries(Figure5).
Foodshighinellagicacidarechestnut(735.44mg/100g),blackberries(43.67mg/100g),
blackraspberries(38mg/100g),walnuts(28.50mg/100g),cloudberries(15.30mg/100g),
pomegranatejuice(2.06mg/100mL),strawberries(1.24mg/100g),redraspberries(1.14
mg/100g)andmuscadinegrape(0.90mg/100g)[18].Ellagicacidissynthetizedbyplants
asadefensemechanismagainstinfectionsandparasites.
Figure5.Structureandmainfoodsthatcontainellagicacid,accordingtothedatabasePhenol‐
Explore(http://phenol‐explorer.eu/).ThereisnovaluereportedfortheUSDADatabaseforthe
flavonoidcontentofselectedfoods(https://www.ars.usda.gov/).
2.6.Oleuropein
Oleuropeinisthemoleculeresponsibleforthebittertasteofolivesandisthemost
commonphenoliccomponentintheleaves,seeds,pulpandskinofunripeolives.Alt‐
houghabundant,thiscompoundundergoeshydrolysisduringfruitripeningleadingto
Figure 5.
Structure and main foods that contain ellagic acid, according to the database Phenol-
Explore (http://phenol-explorer.eu/ accessed on 29 January 2021). There is no value reported for the
USDA Database for the flavonoid content of selected foods (https://www.ars.usda.gov/ accessed on
13 February 2021).
2.6. Oleuropein
Oleuropein is the molecule responsible for the bitter taste of olives and is the most
common phenolic component in the leaves, seeds, pulp and skin of unripe olives. Although
Antioxidants 2021,10, 328 5 of 24
abundant, this compound undergoes hydrolysis during fruit ripening leading to the pro-
duction of other important compounds such as hydroxytyrosol and ester derivatives [
19
].
It is important to underline that the oleuropein content may also depend on the variety of
the olive (in fact black and green olives contain 72.02 mg/100 mL and
55.58 mg/100 mL
,
respectively (Figure 6)), but also, and above all, on the processing techniques used to obtain
the oil [20].
Antioxidants2021,10,3285of24
theproductionofotherimportantcompoundssuchashydroxytyrosolandesterderiva‐
tives[19].Itisimportanttounderlinethattheoleuropeincontentmayalsodependonthe
varietyoftheolive(infactblackandgreenolivescontain72.02mg/100mLand55.58
mg/100mL,respectively(Figure6)),butalso,andaboveall,ontheprocessingtechniques
usedtoobtaintheoil[20].
Figure6.Oliveisthemainfoodthatcontainsoleuropien,accordingtothedatabasePhenol‐Ex‐
plore(http://phenol‐explorer.eu/).ThereisnovaluereportedfortheUSDADatabasefortheflavo‐
noidcontentofselectedfoods(https://www.ars.usda.gov/).
3.Chemistry
Polyphenolsarenaturalcompoundssynthesizedexclusivelybyplantsandcharac‐
terizedbytwophenylringsatleastandoneormorehydroxylsubstituents.Thisdescrip‐
tioncomprehendsalargenumberofheterogeneouscompoundswithreferencetotheir
complexity.Allphenoliccompoundsaresynthesizedthroughthephenylpropanoidpath‐
way(Figure7),startingfromtheaminoacidphenylalanine[21],whichis,inturn,aprod‐
uctoftheshikimatepathway;thelatterlinkscarbohydratemetabolismtothebiosynthesis
ofaromaticaminoacidsandsecondarymetabolitesshikimatepathway[22].
Figure 6.
Olive is the main food that contains oleuropien, according to the database Phenol-Explore
(http://phenol-explorer.eu/ accessed on 29 January 2021). There is no value reported for the USDA
Database for the flavonoid content of selected foods (https://www.ars.usda.gov/ accessed on
13 February 2021).
3. Chemistry
Polyphenols are natural compounds synthesized exclusively by plants and character-
ized by two phenyl rings at least and one or more hydroxyl substituents. This description
comprehends a large number of heterogeneous compounds with reference to their com-
plexity. All phenolic compounds are synthesized through the phenylpropanoid pathway
(Figure 7), starting from the amino acid phenylalanine [
21
], which is, in turn, a product
of the shikimate pathway; the latter links carbohydrate metabolism to the biosynthesis of
aromatic amino acids and secondary metabolites shikimate pathway [22].
The phenylpropanoid pathway leads to different classes of compounds which can
be can be simply classified into flavonoids and nonflavonoids, or be subdivided in many
subclasses depending on the structural diversity. This arises from the number of phenol
units within the structure, substituent groups, variations in hydroxylation pattern and/or
the linkage type between phenol units.
The flavonoid pathway (calchone synthase) leads to the synthesis of six major classes
of metabolites, such as flavonols, flavan-3-ols, anthocyanidins, proanthocyanidins and
anthocyanins. All these compounds share the basic structure of diphenyl propanes (C6-C3-
C6), in which phenolic rings (ring A and ring B) are usually linked by a heterocyclic ring
(ring C), which usually is a closed pyran, as shown in Figure 8[23].
Most flavonoids occur in edible plants and foods as
β
-glycosides, bound to one or
more sugar units with the exception of flavan-3-ols (catechins and proanthocyanidins) and
glycosylated isoflavones that are exposed to microbial
β
-glucosidases, which catalyze the
hydrolysis of the glycosidic bond.
3.1. Naringenin
Naringenin is a flavorless, colorless flavanone with three hydroxy groups at the 7, 5
and 4
0
carbons (Figure 9) [
24
]. It may be found both in the aglycol form, naringenin (a), or in
its glycosidic form, naringin (b), which has the addition of the disaccharide neohesperidose
attached via a glycosidic linkage at carbon.
Antioxidants 2021,10, 328 6 of 24
Entering the flavone synthesis pathway, enzyme chalcone synthase (CHS) catalyzes
consecutive condensations of three equivalents of malonyl CoA followed by aromatization
to convert starting p-coumaroyl-CoA to chalcone [
25
]. Chalcone isomerase (CHI) performs
stereospecific isomerization of tetrahydroxychalcone to (2S)-flavanone, which is the branch
point precursor of many important downstream flavonoids, including flavones (Figure 10).
Antioxidants2021,10,3286of24
Figure7.PhenylpropanoidPathway.Themetabolitesoftheshikimatepathwayandp‐coumaroyl
CoAareshadedingrey.
Thephenylpropanoidpathwayleadstodifferentclassesofcompoundswhichcanbe
canbesimplyclassifiedintoflavonoidsandnonflavonoids,orbesubdividedinmany
subclassesdependingonthestructuraldiversity.Thisarisesfromthenumberofphenol
unitswithinthestructure,substituentgroups,variationsinhydroxylationpatternand/or
thelinkagetypebetweenphenolunits.
Theflavonoidpathway(calchonesynthase)leadstothesynthesisofsixmajorclasses
ofmetabolites,suchasflavonols,flavan‐3‐ols,anthocyanidins,proanthocyanidinsandan‐
thocyanins.Allthesecompoundssharethebasicstructureofdiphenylpropanes(C6‐C3‐
C6),inwhichphenolicrings(ringAandringB)areusuallylinkedbyaheterocyclicring
(ringC),whichusuallyisaclosedpyran,asshowninFigure8[23].
Figure 7.
Phenylpropanoid Pathway. The metabolites of the shikimate pathway and p-coumaroyl
CoA are shaded in grey.
3.2. Kaempferol
Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one) is a natural
flavonol found in common foods derived from plants and fruits. It is biosynthesized from
naringenin via a 2-hydroxy intermediate (Figure 12).
Antioxidants 2021,10, 328 7 of 24
Antioxidants2021,10,3287of24
Figure8.Basicstructuresofflavonoidsubclasses.
Mostflavonoidsoccurinedibleplantsandfoodsasβ‐glycosides,boundtooneor
moresugarunitswiththeexceptionofflavan‐3‐ols(catechinsandproanthocyanidins)
andglycosylatedisoflavonesthatareexposedtomicrobialβ‐glucosidases,whichcatalyze
thehydrolysisoftheglycosidicbond.
3.1.Naringenin
Naringeninisaflavorless,colorlessflavanonewiththreehydroxygroupsatthe7,5
and4′carbons(Figure9)[24].Itmaybefoundbothintheaglycolform,naringenin(a),or
initsglycosidicform,naringin(b),whichhastheadditionofthedisaccharideneohesper‐
idoseattachedviaaglycosidiclinkageatcarbon.
Figure9.Structuresofnaringenin(a)andnaringin(b).
Enteringtheflavonesynthesispathway,enzymechalconesynthase(CHS)catalyzes
consecutivecondensationsofthreeequivalentsofmalonylCoAfollowedbyaromatiza‐
tiontoconvertstartingp‐coumaroyl‐CoAtochalcone[25].Chalconeisomerase(CHI)per‐
formsstereospecificisomerizationoftetrahydroxychalconeto(2S)‐flavanone,whichisthe
branchpointprecursorofmanyimportantdownstreamflavonoids,includingflavones
(Figure10).
Figure 8. Basic structures of flavonoid subclasses.
Antioxidants2021,10,3287of24
Figure8.Basicstructuresofflavonoidsubclasses.
Mostflavonoidsoccurinedibleplantsandfoodsasβ‐glycosides,boundtooneor
moresugarunitswiththeexceptionofflavan‐3‐ols(catechinsandproanthocyanidins)
andglycosylatedisoflavonesthatareexposedtomicrobialβ‐glucosidases,whichcatalyze
thehydrolysisoftheglycosidicbond.
3.1.Naringenin
Naringeninisaflavorless,colorlessflavanonewiththreehydroxygroupsatthe7,5
and4′carbons(Figure9)[24].Itmaybefoundbothintheaglycolform,naringenin(a),or
initsglycosidicform,naringin(b),whichhastheadditionofthedisaccharideneohesper‐
idoseattachedviaaglycosidiclinkageatcarbon.
Figure9.Structuresofnaringenin(a)andnaringin(b).
Enteringtheflavonesynthesispathway,enzymechalconesynthase(CHS)catalyzes
consecutivecondensationsofthreeequivalentsofmalonylCoAfollowedbyaromatiza‐
tiontoconvertstartingp‐coumaroyl‐CoAtochalcone[25].Chalconeisomerase(CHI)per‐
formsstereospecificisomerizationoftetrahydroxychalconeto(2S)‐flavanone,whichisthe
branchpointprecursorofmanyimportantdownstreamflavonoids,includingflavones
(Figure10).
Figure 9. Structures of naringenin (a) and naringin (b).
Antioxidants2021,10,3288of24
OH
O
S
CoA p-coumaroyl-CoA
OO
OHS
CoA
malonyl-CoA 2x
CHS
OOH
HO O
OH
naringenin
OOH
HO OH
OH
chalcone
CHI
Figure10.Biosyntheticpathwayofnaringenin.
3.2.Apigenin
Apigenin(4′,5,7‐trihydroxyflavone),isanaturalproductbelongingtotheflavone
classthatistheaglyconeofseveralnaturallyoccurringglycosides.Itisayellowcrystalline
solidthathasbeenusedtodyewool.Theapproximately650knownflavonesarisefrom
flavanonesbyoxidativeprocessescatalyzedbyaflavanonesynthase(FNS)enzyme(Fig‐
ure11)[26].TwotypesofFNShavepreviouslybeendescribed;FNSI,asolubleenzyme
thatuses2‐oxogluturate,Fe2+andascorbateascofactorsandFNSII,amembranebound,
NADPHdependentcytochromep450monooxygenase[27].
Figure11.Biosyntheticpathwayofapigenin.
3.3.Kaempferol
Kaempferol(3,5,7‐trihydroxy‐2‐(4‐hydroxyphenyl)‐4H‐chromen‐4‐one)isanatural
flavonolfoundincommonfoodsderivedfromplantsandfruits.Itisbiosynthesizedfrom
naringeninviaa2‐hydroxyintermediate(Figure12).
Figure12.Biosynthesisofkaempferol.
Figure 10. Biosynthetic pathway of naringenin.
Antioxidants 2021,10, 328 8 of 24
3.3. Apigenin
Apigenin (4
0
,5,7-trihydroxyflavone), is a natural product belonging to the flavone
class that is the aglycone of several naturally occurring glycosides. It is a yellow crystalline
solid that has been used to dye wool. The approximately 650 known flavones arise
from flavanones by oxidative processes catalyzed by a flavanone synthase (FNS) enzyme
(Figure 11)
[
26
]. Two types of FNS have previously been described; FNS I, a soluble enzyme
that uses 2-oxogluturate, Fe2+ and ascorbate as cofactors and FNS II, a membrane bound,
NADPH dependent cytochrome p450 monooxygenase [27].
Antioxidants2021,10,3288of24
OH
O
S
CoA p-coumaroyl-CoA
OO
OHS
CoA
malonyl-CoA 2x
CHS
OOH
HO O
OH
naringenin
OOH
HO OH
OH
chalcone
CHI
Figure10.Biosyntheticpathwayofnaringenin.
3.2.Apigenin
Apigenin(4′,5,7‐trihydroxyflavone),isanaturalproductbelongingtotheflavone
classthatistheaglyconeofseveralnaturallyoccurringglycosides.Itisayellowcrystalline
solidthathasbeenusedtodyewool.Theapproximately650knownflavonesarisefrom
flavanonesbyoxidativeprocessescatalyzedbyaflavanonesynthase(FNS)enzyme(Fig‐
ure11)[26].TwotypesofFNShavepreviouslybeendescribed;FNSI,asolubleenzyme
thatuses2‐oxogluturate,Fe2+andascorbateascofactorsandFNSII,amembranebound,
NADPHdependentcytochromep450monooxygenase[27].
Figure11.Biosyntheticpathwayofapigenin.
3.3.Kaempferol
Kaempferol(3,5,7‐trihydroxy‐2‐(4‐hydroxyphenyl)‐4H‐chromen‐4‐one)isanatural
flavonolfoundincommonfoodsderivedfromplantsandfruits.Itisbiosynthesizedfrom
naringeninviaa2‐hydroxyintermediate(Figure12).
Figure12.Biosynthesisofkaempferol.
Figure 11. Biosynthetic pathway of apigenin.
Antioxidants2021,10,3288of24
OH
O
S
CoA p-coumaroyl-CoA
OO
OHS
CoA
malonyl-CoA 2x
CHS
OOH
HO O
OH
naringenin
OOH
HO OH
OH
chalcone
CHI
Figure10.Biosyntheticpathwayofnaringenin.
3.2.Apigenin
Apigenin(4′,5,7‐trihydroxyflavone),isanaturalproductbelongingtotheflavone
classthatistheaglyconeofseveralnaturallyoccurringglycosides.Itisayellowcrystalline
solidthathasbeenusedtodyewool.Theapproximately650knownflavonesarisefrom
flavanonesbyoxidativeprocessescatalyzedbyaflavanonesynthase(FNS)enzyme(Fig‐
ure11)[26].TwotypesofFNShavepreviouslybeendescribed;FNSI,asolubleenzyme
thatuses2‐oxogluturate,Fe2+andascorbateascofactorsandFNSII,amembranebound,
NADPHdependentcytochromep450monooxygenase[27].
Figure11.Biosyntheticpathwayofapigenin.
3.3.Kaempferol
Kaempferol(3,5,7‐trihydroxy‐2‐(4‐hydroxyphenyl)‐4H‐chromen‐4‐one)isanatural
flavonolfoundincommonfoodsderivedfromplantsandfruits.Itisbiosynthesizedfrom
naringeninviaa2‐hydroxyintermediate(Figure12).
Figure12.Biosynthesisofkaempferol.
Figure 12. Biosynthesis of kaempferol.
3.4. Hesperidin
Hesperidin is a flavanone glycoside found in citrus isolated in 1828 by French chemist
Lebreton from the white inner layer of citrus peels (mesocarp, albedo) [
28
]. The structure
consists of a flavanone aglycone, hesperetin, similar to naringenin, which differs from it for
the different pattern of substitution on the B ring, which is functionalized with hydroxy
group on 3
0
carbon and methoxy group on 4
0
carbon, whereas the naringenin lacks the
methoxy group (Figure 13) [29].
Antioxidants2021,10,3289of24
3.4.Hesperidin
Hesperidinisaflavanoneglycosidefoundincitrusisolatedin1828byFrenchchem‐
istLebretonfromthewhiteinnerlayerofcitruspeels(mesocarp,albedo)[28].Thestruc‐
tureconsistsofaflavanoneaglycone,hesperetin,similartonaringenin,whichdiffersfrom
itforthedifferentpatternofsubstitutionontheBring,whichisfunctionalizedwithhy‐
droxygroupon3′carbonandmethoxygroupon4′carbon,whereasthenaringeninlacks
themethoxygroup(Figure13)[29].
Figure13.Structureofhesperidin.
3.5.EllagicAcid
Ellagicacidis2,3,7,8‐tetrahydroxy[l]benzo‐pyrano‐[5,4,3‐cde][1]benzopyran‐5,10‐
dione[30].Itisformedbydimerizationofgallicacidbyoxidativecouplingwithintramo‐
lecularlactonizationofbothcarboxylicacidgroups;thus,itisadilactoneofthedimerof
gallicacid(Figure14).
OH
HO
HO
O
OH
gallic acid
O
OH
O
HO
OH
HO
HO
OH
OH
OH
hexahydroxydiphenic acid
O
O
OH
OH
O
O
HO
HO
ellagic acid
Figure14.Gallicandellagicacids.
3.6.Oleuropein
Oleuropeinisaglycosylatedsecoiridoidproducedbysecondarymetabolismof
plantsandispresentinallolivetissues.Thetermoleuropeinisderivedfromthebotanical
nameoftheolivetree,Oleaeuropaea.Oleuropeinisanesterofelenolicacidwith3,4‐dihy‐
droxyphenylethanol(hydroxytyrosol),whichislinkedtoaunitofglucosebyaβ‐glyco‐
sidicbond(Figure15)[31].
O
O
O
O
HO
O
elenolic acid
OH
HO
HO
3,4-dihydroxyphenylet hanol
HO
HO O
O
O
H
OO
O
oleuropein
O
HO OH
OH
CH
2
OH
Figure15.Structureofoleuropein.
Figure 13. Structure of hesperidin.
Antioxidants 2021,10, 328 9 of 24
3.5. Ellagic Acid
Ellagic acid is 2,3,7,8-tetrahydroxy[l]benzo-pyrano-[5,4,3-cde] [
1
] benzopyran-5,10-
dione [
30
]. It is formed by dimerization of gallic acid by oxidative coupling with intramolec-
ular lactonization of both carboxylic acid groups; thus, it is a dilactone of the dimer of gallic
acid (Figure 14).
Antioxidants2021,10,3289of24
3.4.Hesperidin
Hesperidinisaflavanoneglycosidefoundincitrusisolatedin1828byFrenchchem‐
istLebretonfromthewhiteinnerlayerofcitruspeels(mesocarp,albedo)[28].Thestruc‐
tureconsistsofaflavanoneaglycone,hesperetin,similartonaringenin,whichdiffersfrom
itforthedifferentpatternofsubstitutionontheBring,whichisfunctionalizedwithhy‐
droxygroupon3′carbonandmethoxygroupon4′carbon,whereasthenaringeninlacks
themethoxygroup(Figure13)[29].
Figure13.Structureofhesperidin.
3.5.EllagicAcid
Ellagicacidis2,3,7,8‐tetrahydroxy[l]benzo‐pyrano‐[5,4,3‐cde][1]benzopyran‐5,10‐
dione[30].Itisformedbydimerizationofgallicacidbyoxidativecouplingwithintramo‐
lecularlactonizationofbothcarboxylicacidgroups;thus,itisadilactoneofthedimerof
gallicacid(Figure14).
OH
HO
HO
O
OH
galli c acid
O
OH
O
HO
OH
HO
HO
OH
OH
OH
hexahydroxydipheni c acid
O
O
OH
OH
O
O
HO
HO
ellagi c acid
Figure14.Gallicandellagicacids.
3.6.Oleuropein
Oleuropeinisaglycosylatedsecoiridoidproducedbysecondarymetabolismof
plantsandispresentinallolivetissues.Thetermoleuropeinisderivedfromthebotanical
nameoftheolivetree,Oleaeuropaea.Oleuropeinisanesterofelenolicacidwith3,4‐dihy‐
droxyphenylethanol(hydroxytyrosol),whichislinkedtoaunitofglucosebyaβ‐glyco‐
sidicbond(Figure15)[31].
O
O
O
O
HO
O
elenoli c acid
OH
HO
HO
3,4-dihydroxyphenylet hanol
HO
HO O
O
O
H
OO
O
oleuropein
O
HO OH
OH
CH
2
OH
Figure15.Structureofoleuropein.
Figure 14. Gallic and ellagic acids.
3.6. Oleuropein
Oleuropein is a glycosylated secoiridoid produced by secondary metabolism of plants
and is present in all olive tissues. The term oleuropein is derived from the botanical
name of the olive tree, Olea europaea. Oleuropein is an ester of elenolic acid with 3,4-
dihydroxyphenylethanol (hydroxytyrosol), which is linked to a unit of glucose by a
β
-
glycosidic bond (Figure 15) [31].
Antioxidants2021,10,3289of24
3.4.Hesperidin
Hesperidinisaflavanoneglycosidefoundincitrusisolatedin1828byFrenchchem‐
istLebretonfromthewhiteinnerlayerofcitruspeels(mesocarp,albedo)[28].Thestruc‐
tureconsistsofaflavanoneaglycone,hesperetin,similartonaringenin,whichdiffersfrom
itforthedifferentpatternofsubstitutionontheBring,whichisfunctionalizedwithhy‐
droxygroupon3′carbonandmethoxygroupon4′carbon,whereasthenaringeninlacks
themethoxygroup(Figure13)[29].
Figure13.Structureofhesperidin.
3.5.EllagicAcid
Ellagicacidis2,3,7,8‐tetrahydroxy[l]benzo‐pyrano‐[5,4,3‐cde][1]benzopyran‐5,10‐
dione[30].Itisformedbydimerizationofgallicacidbyoxidativecouplingwithintramo‐
lecularlactonizationofbothcarboxylicacidgroups;thus,itisadilactoneofthedimerof
gallicacid(Figure14).
OH
HO
HO
O
OH
galli c acid
O
OH
O
HO
OH
HO
HO
OH
OH
OH
hexahydroxydipheni c acid
O
O
OH
OH
O
O
HO
HO
ellagi c acid
Figure14.Gallicandellagicacids.
3.6.Oleuropein
Oleuropeinisaglycosylatedsecoiridoidproducedbysecondarymetabolismof
plantsandispresentinallolivetissues.Thetermoleuropeinisderivedfromthebotanical
nameoftheolivetree,Oleaeuropaea.Oleuropeinisanesterofelenolicacidwith3,4‐dihy‐
droxyphenylethanol(hydroxytyrosol),whichislinkedtoaunitofglucosebyaβ‐glyco‐
sidicbond(Figure15)[31].
O
O
O
O
HO
O
elenoli c acid
OH
HO
HO
3,4-dihydroxyphenylet hanol
HO
HO O
O
O
H
OO
O
oleuropei n
O
HO OH
OH
CH
2
OH
Figure15.Structureofoleuropein.
Figure 15. Structure of oleuropein.
Secoiridoid conjugates that contain an esterified phenolic moiety, such as oleuropein,
result from a branching in the mevalonic acid pathway in which terpene synthesis (oleoside
moiety) and phenylpropanoid metabolism (phenolic moiety) merge [
32
]. This is illustrated
schematically in Figure 16.
Antioxidants2021,10,32810of24
Secoiridoidconjugatesthatcontainanesterifiedphenolicmoiety,suchasoleuropein,
resultfromabranchinginthemevalonicacidpathwayinwhichterpenesynthesis(oleo‐
sidemoiety)andphenylpropanoidmetabolism(phenolicmoiety)merge[32].Thisisil‐
lustratedschematicallyinFigure16.
Figure16.Asimplifiedschemeoftheoleuropeinbiosynthesis.
4.microRNAs
MicroRNAs(miRs)areauniqueclassofshortendogenousRNAs.Theyaresingle‐
strandednon‐codingRNAsabletomodulategeneexpressionbybindingtothecomple‐
mentaryregionsof3′UTRsequenceofspecificmRNAtargets.Withthisbiochemistry,
miRsallowsmRNAdegradationorinhibitstranslation.Thepeculiarregulatorycapability
makesthemcrucialfornormaldevelopmentinplantsandanimals[33].Intheareaof
molecularbiology,itisgenerallyacceptedthatmiRNAshaveevolvedindependentlyin
distinctlineages.However,recentstudiesonmiRsinnon‐bilaterianmetazoans,plants
andseveralalgaeraisethepossibilitythatthelastcommonancestorofbothlineagesmight
haveemployedamiRspathwayforpost‐transcriptionalregulation[33].Antioxidantand
microRNAsareanemergingfieldofresearch,especiallyinregardtopolyphenolsepige‐
neticability[34].Todate,searchingPubMedwiththewords“polyphenolsandmi‐
croRNAs”showsthat209papersarecurrentlypresent(accessedon25January2021at
7:00p.m.).Focusingthesearchto“NaringeninandmicroRNAs”,“Apigeninandmi‐
croRNAs”,“KaempferolandmicroRNAs”,“HesperidinandmicroRNAs”,“EllagicAcid
andmicroRNAs”,and“OleuropeinandmicroRNA”producedsixpapersfornaringenin
andmicroRNAs,19onapigeninandmicroRNAs,22onkaempferolandmicroRNAs,six
onhesperidinandmicroRNAs,14onellagicacidandmicroRNAsandeightonoleuropein
andmicroRNAs.
Figure 16. A simplified scheme of the oleuropein biosynthesis.
Antioxidants 2021,10, 328 10 of 24
4. microRNAs
MicroRNAs (miRs) are a unique class of short endogenous RNAs. They are single-
stranded non-coding RNAs able to modulate gene expression by binding to the comple-
mentary regions of 3
0
UTR sequence of specific mRNA targets. With this biochemistry,
miRs allows mRNA degradation or inhibits translation. The peculiar regulatory capability
makes them crucial for normal development in plants and animals [
33
]. In the area of
molecular biology, it is generally accepted that miRNAs have evolved independently in
distinct lineages. However, recent studies on miRs in non-bilaterian metazoans, plants
and several algae raise the possibility that the last common ancestor of both lineages
might have employed a miRs pathway for post-transcriptional regulation [
33
]. Antioxidant
and microRNAs are an emerging field of research, especially in regard to polyphenols
epigenetic ability [
34
]. To date, searching PubMed with the words “polyphenols and
microRNAs” shows that 209 papers are currently present (accessed on 25 January 2021 at
7:00 p.m.). Focusing the search to “Naringenin and microRNAs”, “Apigenin and microR-
NAs”, “Kaempferol and microRNAs”, “Hesperidin and microRNAs”, “Ellagic Acid and
microRNAs”, and “Oleuropein and microRNA” produced six papers for naringenin and
microRNAs, 19 on apigenin and microRNAs, 22 on kaempferol and microRNAs, six on
hesperidin and microRNAs, 14 on ellagic acid and microRNAs and eight on oleuropein
and microRNAs.
4.1. Naringenin
The polyphenols naringenin was tested in diverse cell systems displaying epigenetic
property by regulating miRs, which in turn regulates the gene expression profile.
Naringenin treatment protects trophoblasts and endothelial cells from the harmful
high glucose environment by downregulating the miR-140-3p. In the interim, insulin
receptor alpha and insulin-like growth factor 1 receptor expression were upregulated
and the glucose uptake increased in naringenin treated trophoblasts and endothelial cells.
Therefore, naringenin was proposed by Zhao et al. as a treatment candidate, for gestational
diabetes [
35
]. Another evidence into the diabetes field by naringenin comes from its ca-
pability to ameliorated kidney injury through the let-7a. Yan et al. using mesangial cells
(MMCs) and diabetic rats as experimental models demonstrate that naringenin led to an
upregulation of let-7a under high glucose conditions affecting the expressions of fibronectin
and collagen VI in MMCs. In addition, let-7a upregulation in renal tissue diminished the
expression of transforming growth factor-
β
1 receptor 1 (TGFBR1), required for the regula-
tion of Let-7a/TGFBR1 signaling pathway in diabetic nephropathy [
36
]. Naringenin has
neuroprotective. In fact, in PC12 cells naringenin decreased the expression of miR-224-3p in
a dose-dependent manner and increased the expressions of SOD1 mRNA and protein [
37
].
Furthermore, in rats, after spinal cord injury, the protective effect of naringenin was exerted
through the repression of miR-223. This miR is a fine-tuner granulocyte production playing
a fundamental role on neutrophils activation of the inflammatory response [38].
In lung cancer, naringenin biochemical activity inhibits migration and invasion, as
well as tumor growth, through the regulation of the microRNA-3619-5p, which belong to
a regulating axis with circular RNA FOXM1 and sperm-associated antigen 5 [
39
]. Lastly,
Curti et al. recently demonstrate that naringenin is able to affect the miR-17-3p involved
in the control of antioxidant endogenous system [
40
]. Using a Caco cell, a well charac-
terized
in vitro
model which mimics the intestinal barrier, it is demonstrated that single
enantiomers of naringenin R and S have similar activity on this miR, while their equimolar
racemic mixture does not [41].
4.2. Apigenin
Apigenin in hepatocellular carcinoma cell line was noted to upregulate miR-520b
and miR-101 to inhibit tumor growth. The miRs miR-520b and miR-101 are involved
in Autophagy Related 7 protein (ATG7) and Nfr2 pathways, respectively, sensitize to
doxorubicin treatment [
42
,
43
]. In neuron derivative tumor, miR 16, miR-138 and miR-423
Antioxidants 2021,10, 328 11 of 24
were identified to be modulated by apigenin. In particular, miR-16 in glioma cells was
upregulated negatively influencing the cell B cell CLL/lymphoma 2 (BCL2)/NFkB/Matrix
Metallopeptidase 9 (MMP9) axis [
44
]. Similarly, in neuroblastoma cell, apigenin increased
the expression of miR-138, while in glioma, stem cells knockdown miR-423 enhances
sensitivity to apigenin involving the mitochondrial cell death pathways [45,46].
Apigenin could inhibit differentiation in TGF-
β
1-stimulated cardiac fibroblast, as well
the synthesis of extra cellular matrix (ECM) component. This mechanism might partly
be attributable to the reduction of miR-155-5p which control the c-Ski expression and the
axis in which is involved, which might result in the inhibition of small mother against
decapentaplegic (Smad)2/3 and p-Smad2/3 expressions [47].
Apigenin alleviates myocardial reperfusion injury (RI) in rats by downregulating
miR-15b. This miR was found to be increased during myocardial RI, determining a down-
regulation of JAK2 that promotes myocardial apoptosis and ROS production, aggravating
the myocardial injury. Apigenin treatment can downregulate miR-15b expression and
increase the expression of Janus kinase 2 (JAK2) and the activity of Signal transducer and
activator of transcription 3 (STAT3) pathway, reducing myocardial apoptosis and ROS
production and alleviating myocardial RI [
48
]. Lastly, in mice, apigenin improved glucose
intolerance by suppression of matured miR103 expression levels [
49
]. Apigenin normalized
let-7f expression in epididymal fat tissues preventing colonic inflammation, associated with
high fat diet-induced obesity [
50
]. Linked to lipids metabolism a liver-specific microRNA,
miR-122, is also an important factor for hepatitis C virus (HCV), replication. Apigenin,
in vitro
, significantly reduced mature miR122 expression levels in a dose-dependent man-
ner. Therefore, its intake, either via regular diet or supplements, may decrease HCV
replication in chronically infected patients [51].
4.3. Kaempferol
In human lung cancer cells, kaempferol was able to up-regulate miR-340, along
with the inactivation of the phosphatidylinositol-3-kinase (PI3K)/AKT pathways [
52
].
Likewise, in hepatocellular carcinoma cell line it remarkably reduces the expression of
miR-21 leading to the inactivation of the same PI3K/AKT pathway [
53
]. Kaempferol
is known to induce cardioprotective effects. In human aortic endothelial cells (HAECs),
kaempferol induced the upregulation of miR-26a-5p, which, targeting the toll-like receptor 4
(TLR4), was able to inactivate the TLR4/nuclear factor kappa B (NF-
κ
B) signaling pathway.
This biochemical mechanism improves the oxidized low-density lipoprotein-stimulated
HAECs [
54
]. In the same cell system, kaempferol increased miR-203 reversing the results
led by lipopolysaccharides (LPS)-induced inflammatory injury [
55
]. In vascular smooth
muscle cell (VSMC), kaempferol induces miR-21 expression inhibiting of cell migration [
56
].
The myocardial protective property of kaempferol was confirmed in ischemic heart disease
(IHD), using primary cardiomyocytes and myoblast cell line H9c2. Under oxygen-glucose
deprivation kaempferol exposure promoted the down-regulation of miR-15b, which target
Bcl-2 and TLR4 [
57
]. Furthermore, kaempferol enhanced miR-21 level in H9c2 cells exposed
to hypoxia/reoxygenation (H/R) and inhibition of miR-21 induced by transfection with
miR-21 inhibitor significantly blocked the protection of kaempferol against H/R-induced
H9c2 cell injury. Furthermore, kaempferol eliminated H/R-induced oxidative stress and
inflammatory response by the decreases in ROS generation and malondialdehyde content,
as well as the increase in antioxidant enzyme superoxide dismutase and glutathione
peroxidase activities [
58
]. Kaempferol exerts anti-inflammatory activities and has been
recognized as an effective agent for alleviating the clinical symptoms of osteoarthritis (OA)
by decreasing miR-146a in the chondrogenic cell line ATDC5 activated PI3K/AKT/mTOR
signaling pathway. In a rat model of OA, the expression of miR-146a in cartilage tissues
was repressed by kaempferol [59].
In osteoblast precursor cell line MC3T3-E1, kaempferol enhanced the expression level
of miR-101 promoting osteoblast proliferation, migration and differentiation [60].
Antioxidants 2021,10, 328 12 of 24
4.4. Hesperidin
Aberrant oxidative stress was implicated in the environmental contaminant Di-(2-
ethylhexyl) phthalate (DEHP)-induced testicular toxicity in which the miR-126-3p and the
miR-181a are overexpressed. Hesperidin administration normalized their levels beside to
other biochemical markers [
61
]. To the best of our knowledge, the present study demon-
strated for the first time that the administration of hesperidin decreased the expression
of ZEB2 by upregulating the expression of miR 132, which in turn promoted apopto-
sis and inhibited the proliferation of NSCLC cells [
62
]. Pre-treatment with hesperidin
(2
5, 50, 100 mg/kg
) for 7 days prevented these abnormalities induced by LPS injection.
In contrast, this effect of hesperidin was abolished by a miRNA-132 antagomir. Taken
together, these results suggest that the antidepressant-like mechanisms of hesperidin are at
least partially related to decreased pro-inflammatory cytokine levels via the miRNA-132
pathway in the brain [63].
4.5. Ellagic Acid
In high glucose-induced T2DM HepG2 cells, ellagic Acid (EA) was able to elevate
the miR-223 expression level, downregulating both, mRNA and protein levels of keap1.
This led to the upregulation of Nrf2, SOD1 and SOD2 protein levels. Therefore, EA
ameliorates oxidative stress and insulin resistance in the cell system used as model [
64
].
Another beneficial biochemical activity of EA was evident in ventricular remodeling after
myocardial infarction. EA improved ventricular remodeling by up-regulating miR-140-3p
expression and inhibiting MKK6 expression [65].
4.6. Oleuropein
In ovarian cancer was induced in xenograft mice model. Mice exposed to radiation
with the simultaneous administration of oleuropein. Oleuropein sensitized ovarian cells to
radiation altering the expression of miR-299. This miR was suppressed by a hypoxia in-
ducible factor and relieved in response to oleuropein, which in turn suppressed heparanase
1 expression and consequently led to increased sensitivity to radiation due to synergistic
effect of oleuropein with radiation [
66
]. Similarly, in nasopharyngeal carcinoma, oleuropein
strongly enhanced radio-sensitivity through the downregulation of miR-519d [67].
5. Pharmacokinetic Profile
Results from a growing number of studies unveiled polyphenols as promising thera-
peutic agents due to their broad spectrum of biological activities; however, the effectiveness
of these compounds in disease prevention and human health improvement is tightly related
and limited to their bioavailability [
68
]. The concept of bioavailability encompasses several
variables such as intestinal absorption, metabolism by gut microbiota, intestinal and liver
metabolism, biological properties of metabolites, distribution at tissues level and excretion
which in turn depend upon the chemical structure of xenobiotics. In addition, the various
chemical forms of polyphenols lead to high variability in their rate and extent of intestinal
absorption, as well as in the nature of circulating metabolites. Currently there is an increas-
ing interest in biological properties of apigenin owing to it proved relatively low toxicity
and effectiveness on cells with impaired biochemistry, such as cancer cells [
69
]. According
to biopharmaceutics classification system (BCS) that correlates
in vitro
dissolution with
in vivo
bioavailability, Apigenin is categorized as BCS class II drug due to its low solubility
and high permeability. Absorption of this compound occurs in the small intestine by both
passive and carrier-mediated saturable mechanism [
70
]; furthermore, the gastrointestinal
tract plays a crucial role in the metabolism and conjugation of apigenin before the entry
of the compound into the systemic circulation and the liver [
71
]. It is worth mentioning
that apigenin is naturally present in plants as glycosides. It has been hypothesized that
apigenin glucosides can be hydrolyzed into apigenin by cytosolic
β
-glucosidase (CBG) and
lactase-phlorizin hydrolase (LPH), which are enzymes produced by the liver, intestinal cells
or the gut microbiota [
70
,
72
,
73
]. LPH has been shown to hydrolyze flavonoid glycosides
Antioxidants 2021,10, 328 13 of 24
and the resulting aglycone may then enter epithelial cells by passive diffusion [
74
]. The
absorbed apigenin undergoes extensive Phase I and Phase II metabolism [75], accounting
for the low bioavailability of the compound.
5.1. Naringenin
The gut microbiota also plays a crucial role in the naringenin low availability as it
determines extensive pre-systemic metabolism of the compound leading to the formation
of degradation products such as phenolic acids [
76
]. As naringenin, hesperidin has limited
bioavailability due to the presence of the rutosin moiety. The removal of either rutinoside or
rhamnose from the molecule improves bioavailability and promotes a faster achievement
of the maximum plasma concentration [77].
5.2. Apigenin
In both rats and humans, apigenin has been documented to produce glucuronide,
sulfate conjugates or luteolin as major metabolites [
78
,
79
]. In addition, glucuronidation
reactions also occur in the intestine and intestinal disposition may be more important than
hepatic one in the first-pass metabolism of apigenin [
78
]. Of note, this natural flavone
modulates efflux proteins, especially P-glycoprotein (P-gp) and metabolic enzyme CYP3A4,
thus inducing clinically relevant drug-drug interactions by alteration of bioavailability
and distribution profiles of targeted drug such as TK inhibitors or paclitaxel [
72
]. The
elimination of Apigenin takes place through urine and feces and it is a slow process,
therefore an accumulation of the flavone in tissues seems possible [72].
5.3. Kaempeferol
Kaempferol shows up a more favorable bioavailability profile. Absorption of the
compound occurs in the small intestine through passive and facilitated diffusion or active
transport [
80
]. Following absorption phase kaempferol undergoes metabolic transforma-
tion in the glucuronides and sulfoconjugates forms at both liver [
81
] and small intestine
by enteric conjugation enzymes [
80
]. Kaempferol and its glycosides are also metabolized
in the colon by the bacterial microflora that releases the aglycones and broke aglycone C3
ring to form compounds (i.e., 4-methylphenol, phloroglucinol and 4-hydroxyphenylacetic
acid) that are either be absorbed and distributed to tissues by systemic circulation or be
excreted in feces and urine [
82
–
85
]. Of note, combination of kaempferol with quercetin
increase its bioavailability, thus improving its biological efficacy [86].
5.4. Hesperidin
Hesperidin bioavailability is also affected by various conditions including the health
status [
87
] and the concomitant administration of this compound with other flavonoids
such as quercetin, rutin, daidzein and chrysin [
88
]. Hesperidin requires deglycosylation
into hesperitin by gut microflora to be absorbed. The absorption phase occurs at the
level of colonocytes by proton-coupled active transport and transcellular passive diffu-
sion [
89
,
90
]. Hesperitin is then selectively metabolized into the liver to eriodictyol by both
the cytochrome P450 isoforms CYP1A and CYP1B1. Afterward, eriodictyol undergoes
methylation and it is transformed to homoeriodictyol (3
0
-O-methylated) or hesperitin
4
0
-O-methylated. The other hesperitin metabolites comprise hesperitin glucuronides (7-O-
glucuronide and 3
0
-O-glucuronide, hesperitin sulfates, 7-O- and 3
0
-O-sulfate, hesperitin
sulfoglucuronides and homoeriodictyol glucuronides. It is worth mentioning that the
first-pass metabolism of hesperitin occurs in intestinal cells leading to the formation of
hesperitin 7-O-glucuronide and 3
0
-O-glucuronide, which represents the major hesperitin
metabolites
in vivo
[
91
,
92
]. Hesperitin is also a selective inhibitor of cytochrome P450
CYP1B1 [
93
]. This observation provides a possible explanation of the compound anti-
tumor activity being the enzyme involved in facilitating carcinogenesis process. Moreover,
hesperitin enhances bioavailability of co-administered drugs such as diltiazem, verapamil
and vincristine through inhibition of CYP3A4 or P-gp efflux [
94
–
96
]. The metabolites of
Antioxidants 2021,10, 328 14 of 24
hesperidin/hesperitin are detected in urine but not in feces, thus suggesting a further
bacterial degradation to ring fission products and phenolic acids in the colon [97].
5.5. Ellagic Acid
The poor systemic bioavailability also affects the mechanism of action across condi-
tions and doses of ellagic acid (EA) as demonstrated by several
in vivo
studies [
98
]. In
fruits and nuts, EA exists in either its free form, as EA-glycosides, or bound as ellagitannin
(ET) [
99
,
100
]. However, only a small portion of free EA is absorbed in the stomach, since ET
are resistant to acidic pH. ET hydrolysis occurs in the small intestine, yielding to the release
of EA. This latter is absorbed mainly by passive diffusion, although the involvement of
a protein-mediated transport cannot be ruled out as suggested by
in vitro
experiment on
Caco-2 cells line model [
101
]. In the systemic circulation, EA undergoes a massive first pass
effect, being transformed in methyl esters, dimethyl esters or glucuronides, measurable
in human plasma from 1 to 5 h after ET ingestion [
102
]. In the meantime, unabsorbed ET
and EA fractions are mostly converted to a family of metabolites called urolithins by gut
microbiota. Urolithins contain a common lipophilic moiety, thus resulting in a net improve-
ment of bioavailability compared to EA [
103
]. However, the difference in gut microbiota
composition leads to a wide variability in microbial metabolism of EA among individuals.
Indeed, humans may produce no urolithins, highly active urolithins or less active urolithin,
hence EA consumption may not exert equal health benefits in all subjects [
104
–
106
]. The
low EA oral bioavailability was also confirmed in human pharmacokinetic studies demon-
strating the rapid metabolism of the compound and the existence in the absorption phase
of saturable mechanism [107].
5.6. Oleuropein
Poor data and often conflicting results exist on the oleuropein pharmacokinetic from
EVOO or olive leaves in humans [
108
–
111
]. This discrepancy may be due to several factors.
Indeed, the route of administration, genotype, age, sex, interaction with food and the
different extraction processes deeply affect oleuropein bioavailability [
112
]. It has been
reported that oral oleuropein ingestion is resistant to the stomach acidic pH and it is quickly
absorbed in the small intestine, reaching a maximum plasma concentration earlier than
conjugated metabolites of hydroxytyrosol in humans. Of note these latter represented the
major fraction of the oleuropein phenolic metabolites in plasma and urine after intake [
113
],
suggesting potential complete metabolization of oleuropein to hydroxytyrosol and other
catabolic products. Attention has also been payed to the gut microbiota.
In vitro
and
in vivo
approaches demonstrated that oleuropein was rapidly deglycosylated to oleuropeinA
by human fecal microbiota and then metabolized into elenolic acid and hydroxytyrosol
by microbial esterase activity [
114
]. Further studies have shown that the conversion of
oleuropein into hydroxytyrosol was performed by acid by Lactobacillus plantarum [
115
]
and based on this observation oral granules for the co-delivery of Lactobacillus plantarum
and a standardized olive leaf extract were developed in order to promote oleuropein
metabolism and ensure high levels of hydroxytyrosol [116].
6. Health Effects
6.1. Naringenin
Being present in foods known to be beneficial for health, such as citrus fruits and
tomatoes, naringenin boasts numerous studies, even if, as happens for all molecules of
plant origin, mainly
in vivo
and
in vitro
. In this sense, various studies show a favorable
action in oncology, as it acts by limiting the progression of the cell cycle and angiogenesis;
favoring apoptosis and acting directly on some carcinogens [
117
–
119
]. It also shows
interesting qualities in the management of type 2 diabetes, obesity and metabolic syndrome;
improving insulin sensitivity probably by regulating the action of AMPK, regulating
the action of amylases and modulating inflammation via inhibition of NF-
κ
B; beneficial
actions are reported on the prevention of liver diseases in particular with an interesting
Antioxidants 2021,10, 328 15 of 24
mechanism, according to which naringenin should be incorporated in cell membranes thus
providing a greater protective action [
120
,
121
]. Preventive action on neurodegenerative
diseases can also be explained with the mechanisms proposed above [
121
]. Possessing
immunomodulatory and antiviral activity, naringenin has also been proposed to support
therapies against COVID-19 [
122
]. As for almost all polyphenols, the main problem is
bioavailability, although many studies have used orange juice and not extracts or the
molecule as it is; for this reason, different strategies are evaluated to make the molecule
more bioavailable, as the doses that should be drawn from
in vitro
or
in vivo
studies
should be between 25 and 50 mg per kg of body weight [
123
,
124
], even if some studies
seem to confirm an absorption or at least a retention by the microbiota, with consequent
beneficial action on it, with doses ranging from 200 to 500 mg [
125
–
127
]. In a case report
by Murugesan et al., an improvement in insulin sensitivity is reported with an orange
juice dosage of 150 mg naringenin for eight weeks [
128
]. In one of the few human studies
48 postmenopausal women took 210 mg of naringenin from grapefruit juice for 6 months,
showing a clear benefit on arterial stiffness [129].
6.2. Apigenin
Like many substances of plant origin, apigenin has also been used for a long time
through sources that are part of traditional medicines or common uses, remembering, in
this regard, honey and chamomile [
130
,
131
]. There are many studies in which apigenin
shows a very promising potential as an antioxidant [
132
] and as an adjuvant for numerous
pathological states, such as diabetes, cancer, depression, amnesia and Alzheimer’s [
131
];
on the other hand, the studies on humans are few and the compound is extracted mainly
from chamomile. Zick et al. tested a standardized chamomile extract that provided
15 mg of apigenin on 34 patients in double blind versus placebo, evaluating the quality of
sleep and therefore the impact on insomnia, showing moderate positive effects: different
quantities should probably be tested, as there are no adverse effects [
133
]. In two other
papers
[134,135]
, the effect of apigenin, still supplied as chamomile extract, on anxiety dis-
orders was evaluated: the first followed a protocol with a variable dose from
8 to 13 mg
of
apigenin; in the second, a constant dose of 18mg of active ingredients, in both cases, showed
positive effects, justifying their use in support of any drug therapy. A very interesting
hypothesis comes from the work of Vollmer et al., from which it can be deduced that part
of the apigenin is excreted intact with the feces; therefore, it is able to reach the microbiota
present in the large intestine and thus positively influence the peculiar function [136].
6.3. Kaempeferol
Kaempferol is a polyphenol widespread in food, present in crucifers, but also in other
foods used quite commonly in various food cultures. For this reason, there are also evalua-
tions of epidemiological studies which positively correlate its intake with the prevention
and treatment of various diseases [
137
]. A review Kashyap et al. [
138
] shows conflicting
results from epidemiological studies: multiple positive results are highlighted, especially
in the chemopreventive action, but not all studies report the same effects [
139
]. Human
studies are not numerous, despite the promising results
in vitro
and
in vivo [140–143]
;
epidemiological studies show a protective effect from cardiovascular diseases and a de-
crease in IL6 (with consequent modulation of inflammation) from a dosage of kaempferol
included in a range of 2–12 mg per day, combined; however, with other polyphenols [
139
];
moreover, from an interesting study a protective effect on osteoporysis would result, ac-
cording to various mechanisms that would lead to a decrease in adipogenesis, an increase
in chondrogenesis and osteoblastogenesis [144].
6.4. Hesperidin
Hesperidin is the polyphenol most present in oranges and other citrus fruits, whose
beneficial effect is well known, but often related to vitamin C and not to polyphenols. The
beneficial effects demonstrated
in vivo
and
in vitro
are multiple, as for all polyphenols,
Antioxidants 2021,10, 328 16 of 24
thanks to their chemical structure, the antioxidant action is well present. In addition to
this, a neuroprotective action was highlighted, beneficial on the cardiovascular system,
bone health, on glycemic regulation and not least on the microbiota [
145
–
147
]; the dosages
of hesperidin used in human studies vary from a minimum of 200 mg to a maximum
of 500 mg, remaining, although largely in non-toxic or harmful dosages; some show
improved cardiovascular health (64 subjects for 6 weeks 500 mg/day); however, positive
effects are also shown in the management of hemorrhoids (70 subjects for 6 months of use),
in neuroprotection (more than one study with dosages ranging from 200 to 500 mg/day),
in the prevention and treatment of osteoporosis [
148
–
152
] and even in sports: 500 mg
of hesperidin seems to improve aerobic performance in cyclists, probably thanks to the
antioxidant action.
6.5. Ellagic Acid
This compound is very often linked to pomegranate; in fact, many papers refer to the
use of the juice of the fruit, which, however, contains various polyphenols. In fact, in some
cases the juice has proved more effective than the extract itself [
153
,
154
]. Common with
all polyphenols, ellagic acid also has an antioxidant activity, directly and as a regulator of
NF-
κ
B [
155
,
156
]. In addition,
in vitro
and
in vivo
, it has also shown a regulatory action on
inflammatory prostaglandins and on the onset of atherogenesis; many studies, however,
are performed
in vitro
or
in vivo
. As for humans, a point to be clarified is the bioavailability
and conversion of ellagic acid into urolithin, with relative efficacy of the latter [
157
,
158
]. It
is interesting to note how the suboptimal absorption at the gastrointestinal level makes
it available for the microbiota; from some papers, it seems that this favors some bacterial
strains favorable for health, such as the Firmicutes: Bacteroidetes ratio [
159
]. The last study
involved 20 subjects by administering 1000 mg of ellagic acid for four weeks. Another area
where ellagic acid seems to have a positive effect is that relating to the central nervous
system [
160
]; Ying et al. [
161
], administered to a group of 150 obese subjects, 50 mg of
ellagic acid for 12 weeks, a positive effect was recorded not only on the lipid profile, but
also on the BNDF, with improvement of the cognitive capacity of the subjects. Amma
et al. [
162
], evaluated the action of ellagic acid in promoting recovery after an intense
weightlifting workout; the study, carried out on nine subjects, showed a modulating effect
on all the parameters relating to the antioxidant state, although it should be emphasized,
however, that pomegranate juice was provided, and not ellagic acid alone. In the review of
Huang et al., no positive effects of glycemic control are evident.
6.6. Oleuropein
Oleuropein and its derivatives should represent the center of the Mediterranean diet,
as a characteristic of the olive tree and consequently of the olive oil; the benefits, proven
in vivo
and
in vitro
are multiple and attributable to various pathways, to mention the
antiatherogenic, cardioprotective, anticancer, neuroprotective, antidiabetic, anti-obesity,
regulating lipids, antimicrobial and antiviral effects [
163
], but also others less frequently
combined with polyphenols, such as the positive action on osteoarthritis [
164
] or in-
flammatory bowel diseases [
165
] and immunomodulation in general [
166
]; Somerville
et al. [
167
], tested a supplement containing 100 mg of oleuropein on 32 high school athletes
of good level, assessing their tendency to get sick and reported a positive correlation;
De Bock et al. [168]
demonstrated an improvement in insulin sensitivity by administer-
ing a supplement containing about 52 mg of oleuropein and 10mg of hydroxytyrosol to
46 obese subjects, in crossover versus placebo; with the same dosage, Lockyer et al. [
169
],
on 16 subjects, analyzed the action of inflammatory cytokines and cardiovascular health,
a modulating action was found in particular on IL8; overall, dosages of oleuropein from
5
0 to 150 mg
per day and/or hydroxytorosol between 10 and 50 mg seem to be safe and
effective to ensure an anti-inflammatory and antioxidant effect, which is beneficial in im-
proving various conditions, such as atherosclerosis. Similar to other polyphenols [
170
,
171
].
Antioxidants 2021,10, 328 17 of 24
7. Conclusions
Polyphenols certainly show great potential in assisting nutritionist or physician to co-
treat various pathologies with a marked inflammatory component. Indeed, the numerous
studies on the Mediterranean diet show how this eating style disfavors the onset of diseases
that are the major cause of death worldwide, such as cardiovascular diseases, diabetes and
cancer. The contemporary diet, in particular in the West, with the exception of north Europe,
is often lacking of fruit and vegetables, the main sources of polyphenols; therefore, the
consumption of these food categories should be strongly encouraged. On the other hand,
the use of polyphenols as supplements could also have a strong impact on health. Although
there are many
in vitro
and
in vivo
studies, those performed in humans are few and often
not organized in a systematic way. Often the vegetable extract in toto or the vegetable is
used, so it is difficult to understand which of the compounds had the predominant effect,
also because they often act in synergy. In the current state of knowledge, we strongly
recommend the use of fruit and vegetables in the diet and to consider the intake ranging
from 50 to 200 mg/day of polyphenols, an amount that can also be doubled in pathological
conditions, to ensure a beneficial action, at least from an anti-inflammatory and antioxidant
viewpoint. As shown, polyphenols have an epigenetic action in particular on miRNAs,
and this could also be a fascinating field of study to evaluate, in a clear and systematic way,
even in clinical trials, the action of polyphenols.
Author Contributions:
Conceptualization, R.C. and E.C., C.L.T. wrote the dietary sources section; A.F.
wrote the chemistry section; E.C. wrote the microRNAs section; M.C.C. wrote the pharmacokinetic
profile section; R.C wrote the health effects section; R.C. and E.C wrote the conclusion; M.C.C.
coordinated the study. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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