molecules

Review
Therapeutic Potential of Phenolic Compounds in Medicinal
Plants—Natural Health Products for Human Health
Wenli Sun *,† and Mohamad Hesam Shahrajabian †

Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
* Correspondence: sunwenli@caas.cn; Tel.: +86-13-4260-83836
† These authors contributed equally to this work.

Abstract: Phenolic compounds and flavonoids are potential substitutes for bioactive agents in phar-
maceutical and medicinal sections to promote human health and prevent and cure different diseases.
The most common flavonoids found in nature are anthocyanins, flavones, flavanones, flavonols,
flavanonols, isoflavones, and other sub-classes. The impacts of plant flavonoids and other phenolics
on human health promoting and diseases curing and preventing are antioxidant effects, antibacterial
impacts, cardioprotective effects, anticancer impacts, immune system promoting, anti-inflammatory
effects, and skin protective effects from UV radiation. This work aims to provide an overview of
phenolic compounds and flavonoids as potential and important sources of pharmaceutical and
medical application according to recently published studies, as well as some interesting directions for
future research. The keyword searches for flavonoids, phenolics, isoflavones, tannins, coumarins,
lignans, quinones, xanthones, curcuminoids, stilbenes, cucurmin, phenylethanoids, and secoiridoids
medicinal plant were performed by using Web of Science, Scopus, Google scholar, and PubMed.
Phenolic acids contain a carboxylic acid group in addition to the basic phenolic structure and are
mainly divided into hydroxybenzoic and hydroxycinnamic acids. Hydroxybenzoic acids are based
on a C6-C1 skeleton and are often found bound to small organic acids, glycosyl moieties, or cell
structural components. Common hydroxybenzoic acids include gallic, syringic, protocatechuic,
p-hydroxybenzoic, vanillic, gentistic, and salicylic acids. Hydroxycinnamic acids are based on a
C6-C3 skeleton and are also often bound to other molecules such as quinic acid and glucose. The
main hydroxycinnamic acids are caffeic, p-coumaric, ferulic, and sinapic acids.
Citation: Sun, W.; Shahrajabian, M.H.
Therapeutic Potential of Phenolic
Keywords: phenolics; curcumin; protocatechuic; quinones; stilbenes; curcuminoids
Compounds in Medicinal
Plants—Natural Health Products for
Human Health. Molecules 2023, 28,
1845. https://doi.org/10.3390/
1. Introduction
molecules28041845
Medicinal plants are very important worldwide, both when used alone and as a
Academic Editor: Giovanni Ribaudo
supplement to traditional medication [1–5]. For many years, humans have employed
Received: 6 January 2023 plants as a source of food, flavoring, and medicines [6–10]. Various parts of medicinal
Revised: 11 February 2023 plants such as seeds, leaves, flowers, fruits, stems, and roots are rich sources of bioactive
Accepted: 13 February 2023 compounds [11–13]. Bioactive compounds should be considered as important dietary
Published: 15 February 2023 supplements [14–19]. Polyphenols are a group of secondary metabolites involved in the
hydrogen peroxide scavenging in plant cells [20]. Phenolic compounds are second only
to carbohydrates in abundance in higher plants, and they display a great variety of struc-
tures, varying from derivatives of simple phenols to complex polymeric materials such
Copyright: © 2023 by the authors.
as lignin [21–26]. Phenolic compounds are known for their notable potential activity
Licensee MDPI, Basel, Switzerland.
against various human viruses, and phenolic compounds also have immunomodulatory
This article is an open access article
and anti-inflammatory activity [27]. The most abundant phenolic compounds are phenolic
distributed under the terms and
monoterpenes (carvacrol and thymol) and diterpenes (carnosol, carnosic acid, and methyl
conditions of the Creative Commons
carnosate), hydroxybenzoic acids (p-hydroxybenzoic, protocatechuic, gallic, vanillic, cat-
Attribution (CC BY) license (https://
echol, and ellagic), phenylpropanoic acids (p-coumaric, caffeic, rosmarinic, chlorogenic,
creativecommons.org/licenses/by/
4.0/).
ferulic, cryptochlorogenic, and neochlorogenic), phenylpropenes (eugenol), coumarins

Molecules 2023, 28, 1845. https://doi.org/10.3390/molecules28041845 https://www.mdpi.com/journal/molecules

Molecules 2023, 28, 1845 2 of 43

(herniarin and coumarin), flavanoes (naringenin, eriocitrin, naringin, and hesperidin),

flavones (apigenin, apigetrin, genkwanin, luteolin, luteolin 7-glucuronide, cynaroside,
scolymoside, salvigenin, and cirsimaritin), and flavanols (catechin, astragalin, kaempferol,
methyl ethers, quercetin, hyperoside, isoquercetin, miquelianin, and rutin) [28,29].
Plant phenolics are considered promising antibiofilm and antifungal agents [30,31].
Diaz et al. [32] also reported that the levels of phenolic and flavonoid compounds were
correlated with the anti-inflammatory and antioxidant activities of medicinal plants.
Tukun et al. [33] reported that phenolic content is significantly connected to antioxi-
dant activity, and halophytes have high content of nutrients and phenolic metabolites.
Some of the most important phenolic compounds recognized from medicinal plants are
syringic acid and gallic acid from Moringa oleifera [34]; gallic acid, vanillic acid,
4-hydroxybenzoic acid, and syringic acid from Peganum harmala [35]; rosmarinic acid from
Rosmarinus officinalis L. and Mentha canadensis L. [36]; vanillin from Thymus vulgaris [37];
caffeic acid and p-coumaric acid from Ocimum basilicum L., Thymus vulgaris L., Salvia officinalis L.,
and Origanum vulgare L. [36]; piceatannol glucoside, resveratroloside, and piceid from
Polygonum cuspidatum [38]; trans-rhapontin, cis-rhapontin, and trans-desoxyrhaponticin
from Rheum tanguticum Maxim. Ex Balf. [39]; herniarin from Matricaria chamomilla [40];
kayeassamin I, mammeasin E, and mammeasin E from Mammea siamensis [41]; scopoletin,
fraxetin, aesculetin, fraxin, and aesculin from Fraxinus rhynchophylla [42]; phyllanthin,
niranthin, hypophyllanthin, nirtetralin, virgastusin, heliobuphthalmin lactone, and burse-
hernin from Phyllanthus amarus [43]; schisanchinin A, schisanchinin B, schisanchinin C, and
schisanchinin D from Schisandra chinensis [44]; 7-methyljuglone from Drosera rotundifolia [45],
rhein, physcion, chrysophanol, emodin, and aloe-emodin from Rheum palmatum and
Rheum hotaoense [46]; curcumin, demethoxycurcumin, and bis-demethoxycurcumin from
Curcuma longa [47]; luteolin, apigenin, orientin, apigenin-O-glucuronide, and luteolin-
O-glycoside from Origanum majorana [48]; glycitein, genistein, formononetin, daidzein,
prunetin, biochanin A and daidzin, and genistin from Medicago spp. [49]; kaempferol
3-O-glucoside and isorhamnetin 3-O-galactoside from Tephrosia vogelii [50]; rutin, kaempferol
3-O-rhamnoside, and quercetin 3-O-glucoside from M. oleifera [34]; gallocatechin and cate-
chin from Mentha pulegium [48]; taxifolin, taxifolin methyl ether, and dihydrokaempferide
from Origanum majorana [48]; hesperidin, naringenin-O-rhamnoglucoside, and isosakuranetin-
O-rutinoside from Mentha pulegium [48]; and punicalagin, pedunculagin I, granatin A,
ellagic acid, ellagic acid pentoside, ellagic acid glucoside, and punigluconin from
Punica granatum [51]. Phenolic phytochemicals include flavonoids, flavonols, flavanols,
flavanones, flavones, phenolic acids, chalcones, isoflavones, tannins, coumarins, lignans,
quinones, xanthones, curcuminoids, stilbenes, cucurmin, phenylethanoids, and several
other plant compounds, owing to the hydroxyl group bonded directly to an aromatic
hydrocarbon group [52]. The classes of phenolic compounds in plants are shown in Table 1.

Table 1. Classes of phenolic compounds in plants [53].

Class Structure
Simple phenolics, benzoquinones C6
Hydroxybenzoic acids C6 -C1
Acetophenones, phenylacetic acids C6 -C2
Hydroxycinnamic acids, phenylpropanoids (coumarins, isocoumarins,
C6 -C3
chromones, chromenes)
Napthoquinones C6 -C4
Xanthones C6 -C1 -C6
Stilbenes, anthraquinones C6 -C2 -C6
Flavonoids, isoflavonoids C6 -C3 -C6
Lignans, neolignans (C6 -C3 )2
Biflavonoids (C6 -C3 -C6 )2
Lignins (C6 -C3 )n
Condensed tannins (proanthocyanidins or flavolans) (C6 -C3 -C6 )n
Molecules 2023, 28, 1845 3 of 43

Phenolic acids include two subgroups, i.e., hydroxybenzoic and hydroxycinnamic

acids [53]. Hydroxybenzoic acids consist of gallic, p-hydroxybenzoic, vanillic, protocate-
chuic, and syringic acid, which, in common, have the C6 -C1 structure [53]. Hydroxycin-
namic acids, on the other hand, are aromatic compounds with a three-carbon side chain
(C6 -C3 ), with caffeic, p-coumaric, ferulic, and sinapic acids being the most common [52].
Gallic acid is present in cloves (Eugenia caryophyllata Thunb.), while protocatechuic acid
can be found in coriander (Coriandrum sativum L.), dill (Anethum graveolens L.), and
star anise (Illicium verum Hook. f.) [54]. Caffeic acid is found among others in parsley
(Petroselinum crispum L.), ginger (Zingiber officinale Rosc.), and sage (Salvia officinalis L.), and
p-coumaric acid is found in oregano (Origanum vulgare L.), basil (Ocimum basilicum L.), and
thyme (Thymus vulgaris L.) [54]. Some samples of hydroxybenzoic and hydrozycinnamic
acids are presented in Table 2.

Table 2. Examples of hydroxybenzoic and hydroxycinnamic acids.

Phenolic Acids Examples Molecular Formula

Gallic acid C7 H6 O5
Hydroxybenzoic acids
Protocatechuic acid C7 H6 O4
p-coumaric acid C9 H8 O3
Caffeic acid C9 H8 O4
Hydroxycinnamic acids
Ferulic acid C10 H10 O4
Sinapic acid C11 H12 O5
Other components
Umbelliferone C9 H6 O3
Coumarins Esculetin C9 H6 O4
Scopoletin C10 H8 O4
Resveratrol C14 H12 O3
Stilbenes Piceatannol C14 H12 O4
Pterostilbene C16 H16 O3
Curcumin C21 H20 O6
Curcuminoids Demethoxycurcumin C20 H18 O5
Bisdemethoxycurcumin C19 H16 O4
Condensed tannins or proanthocyanidins Procyanidin B1 C30 H26 O12
Lignan Sesamin C20 H18 O6

Flavonoids include the largest group of plant phenolics, responsible for over half of
the eight thousand naturally occurring phenolic constituents [55,56]. Flavonoids are low
molecular weight compounds, including fifteen carbon atoms, arranged in a C6 -C3 -C6
configuration [53]. The genetic structure of main classes of flavonoids are shown in Table 3.
Phenolic phytochemicals play a variety of protective roles against abiotic stresses,
such as UV light, or abiotic stresses, namely predator and pathogen attacks [57]. Pheno-
lic phytochemicals are utilized by humans to treat several ailments including bacterial,
protozoal, fungal, and viral infections, inflammation, diabetes, and cancer. Biosynthesis
and accumulation of polyphenol and other secondary metabolites in plants is consid-
ered as an evolutionary reaction of biochemical pathways under adverse environmen-
tal influences, i.e., biotic/abiotic limitations, including increased salinity and drought
stress [58–60]. Some of the extraction methodologies of phenolic components from medici-
nal and aromatic plants are maceration, digestion, infusion, decoction, Soxhlet extraction,
percolation, aqueous alcoholic extraction by fermentation, counter-current extraction, ultra-
sound extraction, supercritical fluid extraction, and phytonics stage. The principle factors
shaping the production of phenolic components are the water supplied to plants and
the time of stress exposure, and, among the various quantification methods, HPLC and
colorimetric tests are the most utilized to quantify the phenolic compounds analyzed [61].
Djeridane et al. [62] reported that the phenolics in medicinal plants provide substantial
antioxidant activity. A positive, significant linear connection between antioxidant activity
and total phenolic content revealed that phenolic components were the dominant antiox-
idant constituents in medicinal plants [63,64]. Various groups of tests on phenolics indi-
Molecules 2023, 28, 1845 4 of 43

cated significant mean alterations in radical scavenging activity; tannins demonstrated the
strongest activity, while most quinones, isoflavones, and lignans tested revealed the weakest
activity [65,66]. The most abundant flavone in Cytisus multiflorus is the chrysin derivative,
Kaempferol-3-O-rutinoside is the major flavonol in Malva sylvestris, and Quercetin-3-O-rutinoside
is the principle flavonol in Sambucus nigra [66]. Nepeta italica subsp. cadmea and Teucrium
sandrasicum are rich in phenolics, which indicated antioxidant and cytotoxic properties [67].
Through LC-ESI-MS analysis, five phenolic acids (quinic acid, syringic acid, gallic acid,
p-coumaric acid, and trans-ferulic acid) and five flavonoids (catechin, epicatechin, quercetrin,
rutin, and naringenin) were predominant and common in some desert shrubs of Tunisian
flora (Pituranthos tortuosus, Ephedra alata, Retama raetam, Ziziphus lotus, Calligonum comosum,
and Capparis spinosa) [68].

Table 3. Generic structure of major classes of flavonoids.

Flavonoids Molecular Formula

Apigenin C15 H10 O5
Flavones Luteolin C15 H10 O6
Chrysin C15 H10 O4
Kaempferol C15 H10 O6
Flavonols Quercetin C15 H10 O7
Isorhamnetin C16 H12 O7
Naringenin C15 H12 O5
Flavanones Eriodictyol C15 H12 O6
Hesperetin C16 H14 O6
Flavanols C15 H14 O2
Anthocyanidin C15 H11 O+
Taxifolin C15 H12 O7
Flavanonols
Aromadendrin C15 H12 O6
Gallocatechin C15 H14 O7
Flavan-3-ols
Catechin C15 H14 O6
Genistein C15 H10 O5
Isoflavones Daidzein C15 H10 O4
Formononetin C16 H12 O4

The main phenolic compounds in Matico (Piper angustifolium R.), Guascas (Galinsoga
parviflora), and Huacatay were chlorogenic acid and hydroxycinnamic acid derivatives [69].
High phenolic and antioxidant activity-containing medicinal plants and species such as
Chanca Piedra (Phyllanthus nirui L.), Yerba Mate (Ilex paraguariensis St-Hil), Zarzaparrilla
(Smilax officinalis), and Huacatay (Tagetes minuta) have the highest anti-hyperglycemia-
relevant in vitro α-glucosidase inhibitory activities with no effect on α-amylase [69].
Nineteen phenolic compounds from different groups are used in wound treatment, and
the compounds are tyrosol, curcumin, hydroxytyrosol, luteolin, rutin, chrysin, kaempferol,
quercetin, icariin, epigallocatechin gallate, morin, silymarin, taxifolin, hesperidin, naringin,
puerarin, isoliquiritin, genistein, and daidzein [70–73]. The most important identified
phenolics in Phlomis angustissima and Phlomis fruticosa, medicinal plants from Turkey, by
RP-HPLC-DAD were hesperidin, catechin, kaempferol, epicatechin, eupatorin, and epigal-
locatechin, and chlorogenic, syringic, vanillic, p-coumaric, ferulic, and benzoic acids [74].
Quercetin of Cordia dichotoma G. Forst. (Lashusa) is the most notable phytoconstituent
responsible for the therapeutic efficacy [75]. Vanillic acid, nepetin, verbascoside, and
hispidulin, of Clerodendrum petasites S. Moore (CP) were chosen as potential phenolic ac-
tive compounds in Thai traditional medicine for the treatment of different kinds of skin
diseases [76–78]. Bouyahya et al. [79] reported that compounds such as terpenoids, al-
kaloids, flavonoids, phenolic acids, and fatty acids of Arbutus unedo L., Thymus capitatus
managed diabetes by several mechanisms such as enzymatic inhibition, interference with
Molecules 2023, 28, 1845 5 of 43

glucose and lipid metabolism signaling pathways, and the inhibition and the activation of
gene expression involved in glucose homeostasis.
Grewia tenax, Terminalia sericea, Albizia anthelmintica, Corchorus tridens, and Lantana camara
are frequently used to treat gastroenteritis and include higher total phenolic and flavonoid
contents in Namibia [80–85]. The most important phenolics identified from pomegranate
are punicalin, gallic acid, ellagic acid, pyrogallol, salycillic acid, coumaric acid, vanillic
acid, sesamin, and caffeic [86], and phenolic compounds have been discovered to have
inhibitory effects again α-glucosidase activities [87]. Two new phenolics, leucoxenols
A and B, were obtained and identified as major secondary metabolites from the leaves of
Syzygium leucoxylon [88]. Phenolics are main phytochemicals found in Cyathea species,
and Cyathea has been considered to be a potential source of novel cancer therapeutic
compounds [89]. Purified phenolic compounds from the bark of Acacia nilotica showed
insecticidal potential against Spodoptera litura, and they could provide substitutes to syn-
thetic pesticides for controlling various pests [90]. Bellumori et al. [91] reported that the
roots of Acmella oleracea L. had about twice as many phenols as the aerial parts, and caffeic
acid derivatives were the main phenolic compounds in roots and aerial parts. Kaempferol
was found as the most abundant phenolic compound in basil leaf extract after using an
HPLC-UC method (61.4 mg.kg−1 ) [92]. Apple fruit (Annona squamosa L.) has a specific spa-
tial distribution of microbes and phenolics, its peel phenolics contain antimicrobial activity
against several Gram-positive bacteria, and its peel phenolics had a growth-promoting
effect toward autochthonous yeasts [93–96]. The phenolic contents of Cyathea dregei
(root and leaves), Felicia erigeroides (leaves and stems), Felicia erigeroides (leaves and stems),
Hypoxis colchicifolia (leaves), Hypoxis colchicifolia (leaves), and Senna petersiana (leaves) have
shown high antimicrobial and cyclooxygenase (COX) inhibitory activities [97].
The most important techniques for analysis of phenolic compounds and extracts are
nuclear magnetic resonance (NMR), high performance liquid chromatography (HPLC) with
ultraviolet-visible (UV-Vis) or photodiode array (PDA) detector or coupled to mass spec-
trometry (MS), derivatization (silylation, alkylation, etc.) as well as gas chromatography (GC)
or GC-MS analysis, phytochemical screening such as total flavonoid content (TFC),
total phenolic content (TPC), etc., and antioxidant potential tests such as 2,2-dipehnyl-
1-picrylhydrazyl (DPPH), etc. [97–107]. Solid-liquid extraction (SLE) is one of the main
methods for extraction of phenolic compounds, specially syringic acid, catechin, and
p-coumaric acid, which is simple, well established, and widely used [108]. Ultrasound-
assisted extraction (UAE) is often used for extraction of gallic acid and rutin, which is
easy to execute, uses inexpensive equipment, and consumes less solvents, and has fast
extraction, good extraction yield, and low impacts on the environment [109]. Supercriti-
cal fluid extraction (SFE) usually applies for gallic acid, anthocyanin, and protocatechuic
acid, which has high selectivity, cheaper and safer solvent, easily controlled extraction
conditions, environmental friendliness, low operating temperature, and easy separation
of solvent from solutes [110]. Microwave-assisted extraction (MAE) is used for extraction
of 3-caffeoylquinic acid, 5-caffeoylquinic acid, and ellagic acid, which has short extraction
time and low solvent consumption [111]. Pressurized liquid extraction (PLE) applies for
extraction of rutin and quercetin, which consumes fewer organic solvents, has higher
probability to avoid organic solvents by using water only, and is fast and efficient [112]. For
extraction of proanthocyanidin, naringin, and hesperidin, enzyme-assisted extraction (EAE)
is proposed, which is safe and green and does not need complex paraphernalia [113]. Key
points about phenolic acids and their derivatives are shown in Table 4. This work aims
to provide an overview of phenolic compounds and flavonoids as potential sources of
pharmaceutical and medical application from recently published studies, as well as some
interesting directions for future research.
Molecules 2023, 28, 1845 6 of 43

Table 4. Important points about phenolic acids and their derivatives.

The Derivatives of
Key Points References
Phenolic Acids
Flavonoids The largest group of natural phenolic compounds. [54,114]
Their structure is based on a 15-carbon phenyl benzopyran skeleton (C6-C3-C6, i.e.,
[54,114]
A-C-B rings).
Based on differences in the pyran ring, flavonoids can be categorized into flavones,
[54,114]
isoflavones, flavanonols, flavonols, flavanones, flavan-3-ols, and anthocyanidins.
The majority occur as glycosides, except for flavan-3-ols, which are rarely glycosylated. [54,114]
Different patterns of hydroxylation and methylation of the A and B rings consequently result
[54,114]
in a variety of compounds for each flavonoid category.
Flavones have a double bond between C-2 and C-3, a keto function in C-4, and the B ring is
[54,114]
attached at C-2.
The most common flavonoes in medicinal and aromatic plants are luteolin, apigenin,
[54,114]
and glycosides.
In isoflavones, the B ring is attached at C-3 and the main components are daidzein, genistein,
[54,114]
and glycitein.
Flavonols are flavones bearing a hydroxyl group at C-3, such as kaempferol, quercetin,
[54,114]
and myricetin.
In flavanones, the C-ring has no double bond between C2 and C3, such as in naringenin,
[54,114]
eriodictyol, and hesperetin.
Flavanonols, also called dihydroflavonols, have the same saturated C-ring as flavanones but
[54,114]
are hydroxylated at C-3.
Flavan-3-ols, also referred to as flavanols, also contain a saturated C-ring, but lack the keto
group at C-4, and are hydroxylated at C-3, such as catechin and gallocatechin, or as oligomers [54]
and polymers.
In anthocyanidins, the C-ring lacks the keto group at C-4, is hydroxylated at C-3, and,
uniquely, has two double bonds forming the flavylium cation, such as in cyanidin, petunidin, [54]
malvidin, pelargonidin, peonidin, and delphinidin.
Stilbenes They are based on 1,2-diphenylethylene, which has a C6-C2-C6 skeleton. [115]
They can be found as aglycones, monomers, oligomers, or glycosylated derivatives. [116]
Tannins Tannins are high molecular weight polyphenolic compounds. [117,118]
They can be synthesized as a defensive mechanism in response to pathogen attack and abiotic
[117,118]
stresses such as UV radiation.
Based on their structures, tannins in plants can be classified into mainly hydrolysable tannins
[117,118]
and condensed tannins, also known as proanthocyanidins.
Hydrolysable tannins are built based on gallic acid and are divided into the gallotannins and
[117,118]
ellagitannins.
Quinones They contain a di-one or di-ketone group. [119]
They are distinguished into benzoquinones and naphthoquinones and are based on their
[119]
derivative molecules.
They may occur as monomers, dimers, trimers, glycosides, or in reduced forms. [119]
Coumarins They may occur in a free or glycosylated state. [120]
They are divided into six categories, namely simple coumarins, furanocoumarins,
[120]
dihydrofuranocoumarins, pyranocoumarins, phenylcoumarins, and bicoumarins.
Curcuminoids They widely occur in Curcuma spp., especially in the rhizomes of Curcuma longa (turmeric). [121,122]
There are three major curcuminoids, namely curcumin, demethoxycurcumin,
[121,122]
and bis-demethoxycurcumin.
The structure of curcumin consists of a keto-enol tautomeric unsaturated chain linking
[121,122]
two aromatic rings bearing a hydroxyl and methoxy group.
Lignins Lignans consist of two phenylpropane units joined together by a β-β0 bond. [123]
They are divided into eight categories, namely dibenzylbutyrolactols,
dibenzocyclooctadienes, dibenzylbutanes, dibenzylbutyrolactones, arylnaphthalene, [123]
aryl-tetralins, furans, and furofurans.

2. The Important Health Benefits of Phenolic Components

Flavonoids and phenolics are commonly known as the largest phytochemical molecules
with antioxidant characteristics [124]. Traditional Chinese medicinal plants that contain phe-
nolic acids and flavonoids have shown high antioxidant activity. Nepeta italica subsp. Cad-
Molecules 2023, 28, 1845 7 of 43

mea and Teucrium sandrasicum are rich in phenolic, tannin, and flavonoids content, which
showed antioxidant and cytotoxic properties. Bauhinia variegata L. contained flavonoid
compounds and revealed antioxidant properties against oxidative damage by radical
neutralization, iron binding, and decreasing power abilities [125]. The rhizome extracts
of Polygonatum verticillatum (L.) All. exhibited antioxidant activity, which is connected
to the level of phenolic composition [126]. Singh and Yadav [127] have reported that,
among medicinal plants, oregano, clove, thyme, and rosemary contain the highest amounts
of phenolic compounds. Flavan-3-ol oligomers and monomers were potent antioxidant
compounds abundantly identified in Camellia fangchengensis [128].
Bellis perennis L. was rich in phenolic compounds, and it can be used for wounds, can-
cer, inflammation, and eye diseases [129]. A total of 27 kinds of phenolic compounds were
identified by HPLC-ESI-QTOF-MS/MS, and okra (Abelmoschus esculentus) polyphenols
exhibited great antioxidant activity in vitro [130]. The Althaea officinalis extracts showed
stronger antioxidant activity and excellent α-glucosidase, 5-lipoxygenase, and nitric oxide
inhibitory properties [131]. Dendrobium densiflorum was rich in flavonoid, alkaloid, and
antioxidant activity, Acampe papillosa was rich in total phenol, total tannin, and total saponin
content, and Coelogyne nitida exhibited higher antioxidant activity because of its higher
quercetin content [132]. Cirak et al. [133] showed that Achillea arabica Kotschy is an impor-
tant source of natural antioxidants. The antioxidant property and bioactive constituents
from the fruits of Aesculus indica (Wall. Ex Cambess.) Hook, which were quercetin and
mandelic acid, were the major bioactive molecules with notable antioxidant properties to
decrease oxidative stress caused by reactive oxygen species (ROS) [134]. The phytochemical
compounds and biological activity of Pinus cembra L. contain higher concentration of total
phenolics and flavonoids than that of needle extract, and its bark extract showed better
ability as a free radical scavenger [135]. Higher antioxidant activity in normal-tannin lentil
seed coats than low-tannin ones was reported; kaempferol tetraglycoside was dominant in
low-tannin seed coats, and procyanidins, kaempferol tetraglycoise, and catechin-3-O-glucoside
in normal-tannin has been found [136]. Zhang et al. [137] also reported that antioxidant
activity and prebiotic impacts were positively correlated for oat phenolic compounds.
3,4-dihydroxybenzoic, rutin, vanillic acid, and quercetin were detected from aqueous ex-
tracts of azendjar and taamriouth figs, and a dark peel variety consisted of more phenolics
and exerted a higher antioxidant capacity [138]. Although gallic acid was the most im-
portant compound in carob (Ceratonia siliqua L.) pulp extract, geographic origin strongly
influenced the contents of bioactive compounds and antioxidant activities [139].
Asplenium nidus L. contained gliricidin 7-O-hexoside and quercetin-7-O-rutinoside that
can fight against three pathogens, i.e., Proteus vulgaris Hauser, Proteus mirabilis Hauser, and
Pseudomonas aeruginosa (Schroeter) Migula [140]. Flavones, which were extracted from the
root of Scutellaria baicalensis Georgi, were proven as potential antibacterial agents against
Propionibacterium acnes-induced skin inflammation both in in vitro and in vivo models [141].
Kaempferol that was isolated from the Impatiens balsamina L. exhibited potential activity
to inhibit the growth of P. acnes [142]. Phenolics from kernel extract Mangifera indica L.
also showed anti-acne properties to inhibit the growth of P. acnes [143]. Medicinal plants
such as Albizia procera, Atalantia monophylla, Asclepias curassavica, Azima tetracantha,
Cassia fistula, Costus speciosus, Cinnamomum verum, Nymphaea stellata, Osbeckia chinensis,
Punica granatum, Piper argyrophyllum, Tinospora cordifolia, and Toddalia asiatica have shown
antifungal activity [144]. The strictinin isolated from the leaves of Camellia sinensis var.
assamica (J.W. Mast.) Kitam was a good substitute for antibacterial activities [145]. Phenolic
compounds, especially flavonoids, have long been reported as chemopreventive factors
in cancer therapy [146–148]. The extract of Curcuma longa L. rhizome has been suggested
as a promising source of natural active compounds to fight against malignant melanoma
due to its potential anticancer property in the B164A5 murine melanoma cell line [149].
Glircidia 7-O-hexoside and Quercetin 7-O-rutinoside, which were flavonoids isolated from
the medicine fern (Asplenium nidus), were also proposed as potential chemopreventives
against human hepatoma HepG2 and human carcinoma HeLa cells [140]. Quercetin can
Molecules 2023, 28, 1845 8 of 43

induce miR-200b-3p to regulate the mode of self-renewing divisions of the tested pancreatic
cancer [150], and a soy isoflavone genistein inhibited the activation of the nuclear factor
kappa B (NF-KB) signaling pathway that maintains the balance of cell survival and apop-
tosis; this soy isoflavone could also take its action to fight against cell growth, apoptosis,
and metastasis, including epigenetic modifications in prostate cancer [151]. Curcumin
exhibits anticancer impacts towards skin cancers, as this phenolic can influence the cell
cycle by acting as a pro-apoptotic agent [152]. Curcumin acts as a non-selective cyclic
nucleotide phosphodiesterase (PDE) inhibitor to inhibit melanoma cell proliferation, which
is associated with epigenetic integrator UHRF1 [153]. Curcumin inhibited proliferation of
the selected cell lines in prostate cancer and induced apoptosis of the cancer cells with a
dose-dependent response [154].
The cardioprotective impacts from various kinds of phenolics and flavonoids occur-
ring in medicinal plants have been investigated in many studies [155,156]. Many phenolic
and flavonoid compounds have been studied and had reported their cardioprotective
properties via different mechanisms including inhibition of ROS generation, apoptosis,
mitochondrial dysfunction, NF-KB, p53, and DNA damage both in vitro and in vivo, and
clinical studies [157]. Kaempferol, luteolin, rutin, and resveratrol showed their efficacy
against doxorubicin-induced cardiotoxicity [158,159]. Isorhamnetin provided a cardiopro-
tective effect against cardiotoxicity of doxorubicin and potentiated the anticancer efficacy
of this drug [160]. The total phenolic and flavonoid contents of the aqueous fraction
from Marrubium vulgare L. have effects on ischemia-reperfusion injury of rat hearts, which
proved that the aqueous fraction from M. vulgare had cardioprotective potential [156].
Aspalathin and phenylpyruvic acid-2-O-β-D-glucoside, two of the major compounds from
Aspalathus linearis (Burm.f.) R. Dahlgren, were demonstrated as potential protective com-
pounds to protect myocardial infarction caused by chronic hyperglycemia [155]. Puerarin is
a potential isoflavone that was reported as an interesting candidate for cardioprotection by
protecting myocardium from ischemia and reperfusion damage by means of opening the
Ca2+ -activated K+ channel and activating the protein kinase C [161]. Quercetin, hesperidin,
apigenin, and luteolin were reported as flavonoids containing potential anti-inflammatory
impacts [162]. The flavonoids and phenolic compounds of Phyllanthus acidus leaves could be
correlated with the analgesic, antioxidant, and anti-inflammatory activities [163]. Hydrox-
ytyrosol and quercetin 7-O-α-L-rhamnopyranoside exhibited anti-inflammatory activity
through lowering the levels of TNF-α, and hydroxytyrosol and caffeic acid showed signifi-
cant anti-inflammatory activity at 100 µm by reducing the release of NO in LPS-stimulated
macrophages comparable to positive control indomethacin [164].
The most important chemical compounds extracted from ethanol of Cardiospermum
halicacabum were chrysoeriol, kaempferol, apigenin, luteolin, methyl 3,4-dihydroxybenzoate,
4-hydroxybenzoic acid, quercetin, hydroquinone, protocatechuic acid, gallic acid, and
indole 3-carboxylic acid, which have shown high anti-inflammatory and antioxidant
activities [165]. The most important phenolic components with antiviral effects against COVID-19
were curcumin, Theaflavin-3,30 -digallate, EGCG, Paryriflavonol A, Resveratrol, Quercetin,
Luteolin, Scutellarein, Myricetin, and Forsythoside A [166]. In traditional Persian medicinal
science, medicinal plants such as Glycyrrhiza glabra L., Rheum palmatum L., Punica granatum L.,
and Nigella sativa L. have been introduced for treating respiratory disorders and infections
because of their phenolic compounds [167]. The anti-inflammatory activity of polypheno-
lic compounds in Gaillardia grandiflora Hort. Ex Van Houte and Gaillardia pulchella Foug
from Egypt were reported [168]. Anti-inflammatory properties of two medicinal plant
species, Bidens engleri O.E. Schulz from Asteraceae family as well as Boerhavia erecta L. from
Nyctaginaceae family, were identified and reported in various fractions [169]. Plantago
subulata has shown anti-inflammatory properties on macrophages and a protective effect
against H2 O2 injury [170]. Phenolic content changes with aromatic and medicinal plant
species and extraction method used [171]. Astilbin, a dihydroflavonol, from Smilax glabra
Roxb significantly inhibited nitric oxide production, tumor necrosis factor-α (TNF-α), and
mRNA expression of inducible nitric oxide synthase in the tested cells [172]. Apigenin is a
Molecules 2023, 28, 1845 9 of 43

main flavone with skin protective impact against UV light; this flavone can be identified
in various edible medicinal plants or plants-derived beverages, e.g., beer, red wine, and
chamomile tea [173,174]. Quercetin is a flavonol that can be discovered in apple peel,
onion skin, and Hypericum perforatum L. leaves [175]. Silymarin, a standardized extract
of flavonolignans from the milk thistle (Silybum marianum (L.) Gaernt.) fruits, consists
of silybin, a principle active component [176]. Genistein is a soybean isoflavone that
was also reported as photoprotective molecule against photocarcinogenesis by inhibiting
UV-induced DNA damage in human skin-equivalent in vitro model [177]. Equol is consid-
ered as an isoflavonoid metabolite from isoflavone daidzein or genistein produced by gut
microflora [178,179]. Genistein is an obvious example of an interesting choice of a flavonoid
phytoestrogen for improving endothelial roles in postmenopausal women with MetS [180].
A chrysin derivative was the most abundant flavone in Cytisus multiflorus, quercetin-3-O-
rutinoside was the main flavonol in Sambucus nigra, and kaempferol-3-O-rutinoside was
the main flavonol in Malva sylvestris [181]. Biological properties of phenolic compounds are
presented in Table 5.

Table 5. Biological activities of phenolic compounds.

Health Benefits Key Points References

* The stem of Dendrophthoe falcata (Loranthaceae) plant had a high content of
Antioxidant activity [182]
phenolic and flavonoid compounds and very high antioxidant activities.
* The phenolic compounds of Buchenavia tetraphylla, Buchenavia tomentosa, and
[183]
Lippia sidoides provided the main contributions to the antioxidant potential.
* The total phenolic, flavonoid, and antioxidant capacity of all blueberry cultivars
[184]
increased nonlinearly with ripening.
* Cynaroside, rosmarinic acid, cosmosiin, luteolin, apigenin, and acacetin were the
main components in ethyl acetate extracts of Salvia absconditiflora, Salvia sclarea, [185]
and Salvia palaestina with antioxidant activity.
* Phenolic compounds from Pistacia lentiscus L. black fruits exhibited potent
[186]
antioxidant properties.
* Lycium berries of different species contained a total of 186 phenolic compounds,
[187,188]
which exhibited potent antioxidant activities.
* Stachys species contained important bioactive phenolics and had promising
[189]
antioxidant impacts.
* Acacia nilotica pods and bark had potent total phenolic content, antioxidant
[190]
activity, and tyrosinase inhibitory properties.
* Bersama abyssinica (Meliathacea) was rich in phenolic compounds, flavonoids and
[191]
coumarin, and 7,8-Dimethoxycoumarin with high antioxidant activity.
* Epicatechin was the main monomeric polyphenol in the profile of longan phenolics. [192]
* Epicatechin, quercetin 3-O-rhamnoside, and kaempferol were responsible for the
[193]
high antioxidant activity of Litsea glaucescens.
* The water extract of Amsonia orientalis leaves exhibited promising antioxidant
[194]
activity when used at low concentration.
* The ethanolic extract of Amsonia orientalis leaves had the highest phenolic
[194]
substance content and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.
* A variety of phenolic compounds and stilbene derivatives in different parts of
germinated peanut suggested that the peanut sprout exerted high
Anti-inflammatory activity [195]
anti-inflammatory effects and may be related to the polyphenolic content and
antioxidant properties.
* Fermented olive cream and Lactiplantibacillus (Lpb.) plantarum IMC513 reduced
[196]
proinflammatory cytokine levels.
* Allium scorodoprasum L. subsp. rotundum extract showed high anti-inflammatory
[197]
inhibitory effects against xanthine oxidase activity.
* Helleborus purpurascens demonstrated the strongest anti-inflammatory potential,
[198]
especially because of fatty acids.
* Thalictrum minus possessed combined anti-inflammatory and antioxidant effects. [198]
* The leaf of Aurea helianthus demonstrated strong anti-inflammatory activity that
[199]
reduced NO production.
Molecules 2023, 28, 1845 10 of 43

Table 5. Cont.

Health Benefits Key Points References

* Hypericum empetrifolium aerial parts extract (HEA) exhibited antifungal activity
Antifungal activity [200]
against Candida tropicalis with 19.53 µg/mL.
* Allium sativum extract revealed strong antifungal activity effects against
[201]
Curvularia spp., Trichophyton spp., and Geotrichum spp.
* Rosa micrantha flowers extract revealed fungicide effects in Candida glabrata. [202]
* Phenolic compounds of Ulmus davidiana var. japonica showed antifungal activity
[203]
against Cryptococcus neoformans and Candida albicans.
* Zataria multiflora essential oils could act as natural fungicides; carvacrol and thymol
[204]
chemotypes of Zataria multiflora inhibited five important fungal plant pathogens.
* Aconitum heterophyllum and Polygonum bistorta exhibited significant antimicrobial
[205]
and antioxidant activity.
* The antimicrobial activities of mint and thyme were due to a wide range of diverse
Antimicrobial activity [206]
phenolics such as menthone, menthyl acetate, menthol, terpenes, and thyme.
* Phenolic compounds of Codonopsis lanceolata plants exhibited notable
[207]
antimicrobial activity.
* Phenolic compounds of cashew (Anacardium occidentale L.) compounds identified
[208]
included mainly flavanols, which showed high antimicrobial activity.
* Ixora coccinea Linn. root contained bioactive phenolic compounds including
[209]
pyrocatechol, catechin, and chlorogenic acid with potent antimicrobial effects.
* The ethyl acetate fraction of Scirpus holoschoenus showed the highest antioxidant
Antibacterial activity [210]
activity and antibacterial effect for Staphylococcus aureus and Bacillus subtilis.
* Rhanterium adpressum showed antibacterial activity. [211]
* The lignum of Rhus verniciflua contained high content of phenolic compounds
[212]
with less urushiols, which suggests efficient antibacterial activity with less toxicity.
* Phenolic compounds of Scrophularia ningpoensis Hemsl. showed antibacterial activity. [213]
* Flavonoids, saponin, alkaloids, tannins, steroids, and terpenoids of
[214]
Solanum incanum L. and Harrisonia abyssinica Oliv. exhibited antibacterial activity.
* The phenolic extracts from Cerbera manghas, Commelina diffusa, Peperomia pellucida,
Kleinhovia hospita, Mikania micrantha, Homalanthus nutans, Psychotria insularum,
[215]
Phymatosorus scolopendria, Piper graeffei, and Schizostachyum glaucifolium exhibited
antibacterial activities.
* Curcumin has been suggested as a potential treatment choice for patients with
Anti-Coronavirus Properties COVID-19 because it inhibits ACE2 and suppresses the entry of SARS-CoV-2 into [216]
the cells.
* Theaflavin, the compound responsible for the orange/black color of black tea, is
[217]
a potent inhibitor of the RNA polymerase of SARS-CoV-2.
* Catechin gallate and gallocatechin gallate also showed high inhibitory activity
against SARS-CoV-2 N protein in a concentration-dependent manner and affected [218]
virus replication.
* Myricetin could be further tested and developed as a potential SARS-CoV-2 antiviral. [219]
* The phenolic compounds Kadsurenin L. and Methysticin of Piper nigrum are
[220]
candidate ligands for inhibiting COVID-19.
* Plant-derived phenolic compounds of Isatis indigotica root were frequently used
[221]
for the prevention of SARS during the SARS outbreaks in east Asia.
* Among phenolic acid constituents, chlorogenic acid, caffeic acid, and gallic acid
of Sambucus Formosana Nakai reduced cytopathicity and virus yield in [222]
HCoV-NL63-infected cells.
* Some phenolic compounds such as diethylstilbestrol, enterodiol, enterolactone,
flavokawain A, flavokawain B, and flavokawain C showed excellent to good [223]
inhibitory activities against collagenase, elastase enzymes, and SARS-CoV-2.
* The phenolic compounds of blackcurrant (Ribes nigrum L.) had antiviral activity
[224]
in Coxsackievirus A9 and human coronavirus HCoV-OC-43.
Molecules 2023, 28, 1845 11 of 43

Table 5. Cont.

Health Benefits Key Points References

* Hydroxytyrosol obtained from olive exhibited neuroprotective impacts on
Neuroprotective potential multiple chronic neurodegenerative diseases including Alzheimer’s, Parkinson’s, [225]
and multiple sclerosis.
* The protective impacts of oil palm phenolics against neurodegenerative diseases
[226]
have been recently identified.
* Phenolic compounds of Hypericum wightianum, namely Hyperwightin E and
[227]
petiolin G, revealed noticeable neuroprotection at 10 µM.
* Inula viscosa (L.) Greuter has high total phenolics and flavonoids and
[228]
demonstrated neuroprotective properties.
* Maclura tinctoria leaf aqueous extract contained high phenolic components, and it
has been found that neuroprotective effects of it could be associated with the [229]
presence of the phenolic compounds identified.
* Phenolic compounds from Lippia microphylla and Dimorphandra gardneriana
Skin health presented a high sun protector factor because of the presence of sakuranetin [230]
flavonoids and quercetin glycosides.
* Among Moroccan medicinal plants, Allium cepa L., Chamaeleon gummifer (L.) Cass,
and Salvia rosmarinus Schleid. Mill. leaves were the most commonly used for [231]
different types of skin diseases.
* Panax ginseng C.A. Meyer and Nardostachys chinensis Bat. have been confirmed
[232]
for the treatment of skin pigmentary disorders.
* The protective effects on skin cells associated with blueberry phenolic
compounds that included inhibition of proliferation and cell cycle arrest in
[233]
malignant cells decreased oxidized macromolecules, down-regulated
inflammatory cytokine genes, and mitigated oxidative stress.
* Gel containing Ipomoea pes-caprae (Ipc) phenolic-rich leaf extract accelerated
Wound healing [234]
the wound-healing process.
* Loranthus acaciae exhibited high phenolic contents and wound healing activities. [235]
* Haworthia limifolia showed excellent wound-healing properties because of high
[236]
phenolic contents.
* Lawsonia inermis and Azadirachta indica are well known for wound healing. [237]
* Aloe vera (Aloe barbadensis) is one of the oldest medicinal plants with wound
healing activity for a variety of skin disorders including burns as well as infections [238]
and diabetic dermal wounds.
* Amphimas pterocarpoides leaves and stem bark have high phenolic and flavonoid
contents, and it has been proven that leaf and stem bark ointments increased the [239]
rate of wound healing in rats.
Anticancer activity * Sedum dendroideum showed anti-proliferative activity in breast cancer cells. [240]
* Hypericum perforatum extract exhibited a remarkable total phenol content, which
[241]
showed high anticancer activity.
* Ficus palmata Forssk. exhibited high total phenolic and flavonoids contents,
[242]
which showed its high anticancer activity.
* Euphorbia thymifolia and Euphorbia hirta showed anticancer activity against ascites
[243]
carcinoma in mice models.
* Vitis vinifera L. contained high phenolic components, which can be considered as
[244]
a promising potential for an anticancer drug.
* Phenolic compounds and alkaloid compounds of Dysphania ambrosioides might
[245]
have significantly contributed to anticancer activity.
* Sisymbrium officinale had considerable phenolic and flavonoids contents, which
[246]
was why it showed anticancer activity.

3. Hydroxybenzoic Acids (Gallic Acid and Protocatechuic Acid)

Hydroxybenzoic acids (HBAs) are antioxidant phytochemicals found in many medicinal
plants and are efficient for prevention of various human diseases [247,248]. Joshi et al. [249]
reported that 4-hydroxybenzoic acid (4HBA) is a potential antidiabetic, anticancer, antifun-
gal, antioxidant, and cardioprotective, etc. Piper garagaranum C. DC contains prenylated
hydroxybenzoic acids, and prenylated hydroxybenzoic acids indicated anti-inflammatory
characteristics, as determined in murine macrophage assays [250].
Molecules 2023, 28, 1845 12 of 43

3.1. Gallic Acid

Gallic acid is one of the most abundant polyphenols identified in nature [251,252].
Behera et al. [253] reported that gallic acid reveals antioxidant or free radical scavengers in
adipocyte proliferation. Gallic acid is found in a wide range of natural plants, it is associ-
ated with the health of human beings, and it has well-documented anticancer, antibacterial,
anti-inflammatory, and antifungal activities [254,255]. Gallic acid in Emblica officinalis medi-
ated antidiabetic potential and delineated the upregulation of pAkt, PPAR-γ, and Glut4
through gallic acid-mediated antidiabetic properties, thus providing potent therapy for
diabetes [256]. Gallic acid inhibited about 44–57% of the total CaOx crystal formations, and
it is a promising agent with antiurolithiatic properties for the treatment and prevention of
urinary or kidney stones [257]. Gallic acid supplementation adjusted serum lipid metabolism
by decreasing serum triglyceride, fat digestibility, and bacteroidetes/firmicutes ratio [258].
Gallic acid prevents the development and occurrence of gastric precancerous lesions (GPL)
by inhibiting the Wnt/β-catenin signaling pathway and then suppressing the epithelial–
mesenchymal transition (EMT) process [259]. Gallic acid is a direct thrombin inhibitor with
a platelet aggregation inhibitory effect [260]. Gallic acid shows significant binding and
disruption of protease structure, and gallic acid has a potential phytotherapeutic effect
against fungal protease, which is a notable virulence factor [261]. Gallic acid can boost
gut microbiota alterations connected with cardiovascular disease (CVD) and suggests
that males suffering from atherosclerosis may benefit from gallic acid supplementation,
as this polyphenol partially restored microbiome dysbiosis [262]. Gallic acid could de-
crease the noxious impacts of diclofenac (DIC) on the antioxidant defense system and
renal tissue [263].

3.2. Protocatechuic Acid

Protocatechuic acid (3,4-dihydroxybenzoic acid) is a natural phenolic acid, and one
of the chief metabolites of complex polyphenols [264]. It can be identified in many plants
such as bran and grain brown rice, particularly in the scales of onion, plums, grapes,
gooseberries, and nuts such as ordinary almonds [265,266]. Da-Costa-Roch et al. [267] and
Adedara et al. [268] reported that protocatechuic acid can be found in many medicinal
plants, especially Hibiscus sabdariffa L. (Hs, roselle; Malvaceae). Protocatechuic acid has
different activities such as neuroprotective activities, antiosteoporotic activities, antitumor
activities, and the protective effects against hepatotoxic and nephrotoxic activities [269,270].
It has also antibacterial, antiulcer, anti-aging, antidiabetic, anticancer, antiviral, antifibrotic,
analgesic, anti-inflammatory, anti-atherosclerotic, and cardiac activity [271,272]. Protocate-
chuic acid from bitter melon (Momordica charantia) alleviates cisplatin-induced oxidative
renal damage, which proves it has protective activity against anticancer drug-induced ox-
idative nephrotoxicity [273]. Protocatechuis acid inhibits Cd-induced neurotoxicity in rats,
increases the Nrf2 signaling pathway, and exhibits anti-apoptotic and anti-inflammatory
activities [274]. Veronica montana has protocatechuic acid as the main phenolic molecule,
and it kills bacteria by affecting its cytoplasmic membrane [275].

4. Hydroxycinnamic Acids (p-Coumaric Acid, Caffeic Acid, Ferulic Acid, Sinapic Acid)
Hydroxycinnamic acid derivatives are a notable class of polyphenols found in veg-
etables, fruits, and medicinal plants, and extensively consumed in human diet [276,277].
Hydroxycinnamic acids significantly contribute to antioxidant capacity [278]. Hydroxycin-
namic acids are widely found in plants and their products such as cereals, fruits, coffee,
vegetables, etc. [279,280].

4.1. p-Coumaric Acid

p-Coumaric acid is a plant metabolite with antioxidant and anti-inflammatory
impacts [281,282]. p-Coumaric acid boosts hepatic fatty acid oxidation and fecal lipid ex-
cretion, and it affects inflammatory and insulin resistance-related adipokines. p-Coumaric
acid stimulates electrical factors of biological and model lipid membranes [283].
Molecules 2023, 28, 1845 13 of 43

4.2. Caffeic Acid

Caffeic acid (3,4-dihydroxycinnamic acid) has been known as an important source of
natural antioxidants in different agricultural products [284,285]. It has immense use in can-
cer treatment [286,287], and it could be known as an important natural antioxidant [288].
Caffeic acid can induce apoptosis in cancer cells through increasing ROS levels and
impairing mitochondrial function, and it also benefits from reducing aggressive behav-
ior of tumors via suppressing metastasis [289]. Caffeic acid has anti-inflammatory and
antioxidant properties against 6-propyl-thiouracil (PTU)-induced hypothyroidism [290].
Meinhart et al. [291] reported that higher sums of mono-caffeoylquinic acids were found in
mulberry, quince, and bilberry, and the dicaffeoylquinic acids sum was higher in granadilla,
passion fruit, and kumquat. It is a phenolic compound extensively discovered in commonly
consumed foods such as apples, pears, and coffee [292]. The biosynthesis pathway of
caffeic acid can be categorized into two modules, (1) L-tyrosine is synthesized from carbon
sources via the glycolytic pathway, the pentose phosphate pathway, and the shikimate
pathway; (2) caffeic acid is generated by the continuous deamination and hydroxyla-
tion of L-tyrosine [293]. Trifan et al. [294] found that caffeic acid oligomers reported in
Symphytum officinale L. root may contribute to the anti-inflammatory activity for which
comfrey preparations are used in traditional medicine. Caffeic acid phenethyl ester ex-
tracted from Rhodiola sacra could provide health benefits, decreasing the magnitude of
the inflammatory process triggered by endotoxin shock and the production of inflam-
matory mediators [295]. Caffeic acid from the leaves of Annona coriacea have shown
antidepressant-like impacts, which involve important neurotransmitter systems [296].
Spagnol et al. [297] reported that caffeic acid presented antioxidant activity greater than ascorbic
acid and trolox. Caffeic acid regulates lipogenesis-related protein expression in high-fat diet
(HFD)-fed mice, alleviates endotoxemia and the proinflammatory response in HFD-fed mice,
and attenuates gut microbiota dysbiosis in HFD-fed mice [298]. Caffeic acid decreases oxidative
stress levels in the hippocampus and regulates microglial activation in the hippocampus [299].

4.3. Ferulic Acid

Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a polyphenol that is widely known
for its therapeutic potential, showing anti-aging, anti-inflammatory, and neuroprotective
impacts [300,301]. The ferulic acid molecule reveals cis-trans isomerism, with the most
abundant form in nature being the trans isomer, and both isomers have proven results in
the treatment of several pathologies such as diabetes, cancer, and neurodegenerative and
cardiac diseases [302]. Ferulic acid is important for the synthesis of significant chemical
molecules such as coniferyl alcohol, di ferulic acid, vanillin, synaptic, and curcumin, as
well as for giving the cell wall stiffness [303]. Ferulic acid can be applied as an antioxidant
to prevent damage from ultraviolet (UV) radiation and skin carcinogenesis [304]. It is
ample in numerous fruits and vegetables, including bananas, eggplant, citrus fruits, and
cabbage, as well as in seeds and leaves [305,306]. In Chinese medicinal science, ferulic is
normally joined with polysaccharides by covalent bonds in various plant cell walls such as
cereal bran and regarded as the main bioactive compound of Angelica sinensis, chuanxiong
rhizoma, and ferula [307], and it has several biological activities such as anti-apoptosis,
anticancer, antioxidant, and anti-inflammatory impacts [308]. Free ferulic acid is related to
the natural content of ferulic acid in herbs, and total ferulic acid refers to the sum of free
ferulic acid plus the amount of related hydrolyzed components [309,310]. Angelica sinensis
is a perennial herbaceous species that creates the bioactive metabolite ferulic acid [311,312].
The ferulic compounds of Salvia officinalis could be useful as a safe natural source for estro-
genic characteristics [313]. Singh et al. [314] indicated that ferulic acid is a phenol derivative
from natural sources and applied it as a potential pharmacophore that exerts multiple phar-
macological properties such as neuroprotection, Aβ aggregation modulation, antioxidant,
and anti-inflammatory. Ferulic acid increases cerebellar functional and histopathological
changes induced by diabetes, which can be attributed to its antioxidative effect and its abil-
ity to modulate nitric oxide synthase (NOS) isoforms [315]. Ramar et al. [316] showed that
Molecules 2023, 28, 1845 14 of 43

ferulic acid and resveratrol revealed antioxidant as well as antidiabetic effects, consequently
modulating liver, kidney, and pancreas damage caused by alloxan-induced diabetes, possi-
bly via inhibition of the proinflammatory factor, NF-KB. Ferulic acid treatment prevents
radiation-induced lipid peroxidation and DNA damage and restores antioxidant status
and histopathological alterations in experimental animals [317]. Hu et al. [318] found that
ferulic acid could alleviate inflammation and oxidative stress. Ferulic acid can inhibit
cancer proliferation through various mechanisms, including changing the cancer cell cycle,
inducing apoptosis, and regulating proteins involved in cell proliferation [319], and ferulic
acid could be used as a potential official adjuvant for breast cancer treatment [320].

4.4. Sinapic Acid

Sinapic acid, a widely prevalent hydroxycinnamic acid, contains numerous biological
activities related to its antioxidant property [321,322]. It protects lysosomes and prevents
lysosomal dysfunction [323]. Saeedavi et al. [324] reported that sinapic acid may be a
new therapeutic potential to treat allergic asthma through suppressing T-helper 2 immune
responses. Sinapic acid phenethyl ester boosts gene expression related to the cholesterol
metabolic process [325]. Hu et al. [326] indicated that sinapic acid can be utilized as
an effective chemo preventive agent against lung carcinogenesis. It can also alleviate
blood glucose levels by improving insulin production in pancreatic β-cells, and it can
exhibit an antioxidative impact by suppressing lipid peroxidation and increasing the
activity of antioxidant enzymes [327]. Sinapic acid significantly increases caspase-3 activity
and inhibits cell invasion, and it has anticancer impacts on prostate cancer cells [328].
Sinapic acid pretreatment mitigates renal impairment and structural injuries through
the downregulation of oxidative/nitrosative stress, inflammation, and apoptosis in the
kidney [329]. Raish et al. [330] indicated the ability of sinapic acid to restore the antioxidant
system and to suppress oxidative stress, pro-inflammatory cytokines, extracellular matrix,
and TGF-β, and showed that sinapic acid treatment (10 and 20 mg/kg) significantly
ameliorated bleomycin (BML)-induced lung injuries. Singh and Verman [331] revealed that
sinapic acid increases streptozotocin (STZ)-induced cognitive impairment by ameliorating
oxidative stress and neuro inflammation in the cortex and hippocampus. Sinapic acid can
modulate the redox state in high-fat diet (HFD) rats [332].

5. The Health Benefits of Coumarins (Umbelliferone, Esculetin, Scopoletin)

Coumarins (2H-chromen-2-one ring) with the molecular formula C9 H6 O2 are an im-
portant group of natural compounds and are used as additives in both cosmetics and
foods [333], and they constituent a notable class of heterocyclic compounds with the char-
acteristic benzo-α-pyrone moiety in its structure [334]. Coumarin has been reported to
have antibacterial, anticancer, antioxidant, anti-inflammatory, anticoagulant, and anti-
Alzheimer’s disease (AD) activities [335,336]. Coumarin derivatives are found naturally
as secondary metabolites in more than 150 species of plants and in over 30 plant fam-
ilies such as Clusiaceae, Umbelliferae, Guttiferae, Rutaceae, Oleaceae, Fabaceae, and many
more [337]. Seo et al. [338] reported that different coumarins were identified from the roots of
Angelica dahurica using NMR spectroscopy, and each coumarin revealed remarkable differ-
ences in content and inhibitory effect. Kassim et al. [339] indicated that the good antioxidant
activity of Melicope glabra (Rutaceae) is because of umbelliferone, glabranin, and scopoletin.
Coumarin-based compounds extracted from the medicinal plants are shown in Table 6.

Table 6. Coumarin-based compounds obtained from the medicinal plants used by various ancient
medical systems [340].

Compounds Molecular Formula Pharmaceutical Activity

6-hydroxy-4-methoxy-5-methylcoumarin C11 H10 O4 Microtubule stabilizing agent
(+)-Calanolide C22 H26 O5 Anti-HIV agent
Inophyllum C25 H24 O5 Anti-HIV agent
Anticancer agent
Theraphin C22 H28 O6
Antimalarial agent
Molecules 2023, 28, 1845 15 of 43

5.1. Umbelliferone
Umbelliferone is a 7-hydroxycoumarin and an isomer of caffeic acid [341], and it
has been reported for different pharmacological activities against numerous diseases
such as cancer [342]. The plant sources of umbelliferone are Acacia nilotica, Angelica
decursiva, Aegle marmelos, Artemesia tridentata, Aster praelatus, Balsamocitrus camerunensis,
Chamomilla recutita, Citrus aurantium, Cirtus natsudaidai, Citrus paradise, Coriandrum sativum,
Diospyros oocarpa, Diplostephium foliosissimum, Dystaenia takeshimana, Edgeworthia chrysantha,
Edgeworthia gardneri, Eriostemon apiculatus, Ferula communis, Ferula communis, Ferula assafoetida,
Fructus Aurantii, Glycyrrhiza glabra, Angelica archangelica, Haplophyllum villosum, Harbouria
trachypleura, Haplopappus desertzcola, Haplophyllum patavinum, Hydrangea chinensis,
Hydrangea macrophylla, Hieracium pilosella, Ipomoea mauritiana, Justicia pectoralis, Matricaria
recutita, Melicope glabra, Musa spp., Parkinsonia aculeata, Peucedanum praeruptorum, Picea
abies, Potentilla evestita, Rhododendron lepidotum, Platanus acerifolia, Selaginella stautoniana,
Saussurea eopygmaea, Stellera chamaejasme, and Typha domingensis [343]. It has been reported
to have antioxidant, anti-inflammatory, free radical scavenging, and antihyperglycemic
properties [344], and antifungal characteristics [345]. Althunibat et al. [346] reported that
umbelliferone prevented isoproterenol cardiotoxicity in rats, and it decreased isoproterenol-
induced oxidative stress and inflammation. Kutlu et al. [347] reported that umbelliferone
has a strong antioxidant and anti-inflammatory effect on sepsis, and it can be considered
as a new treatment for organ dysfunction. Umbelliferone ameliorates atopic dermatitis
(AD)-associated symptoms and inflammation via regulation of various signaling pathways,
suggesting that umbelliferone might be a potential therapeutic of AD [348]. Umbelliferone
downregulates TGF-β1 levels in kidney tissue and it may promote kidney function and
ameliorate renal oxidative stress [349]. Mohamed et al. [350] indicated that umbelliferone
ameliorated oxidative stress-related hepatotoxicity via its ability to augment cellular an-
tioxidant defenses by activating Nrf2-mediated HO-1 expression. Umbelliferone exhibits
anticancer impacts on human oral carcinoma (KB) cell lines, with the increased generation
of intracellular reactive oxygen species (ROS) triggering oxidative stress-mediated depolar-
ization of mitochondria [351]. Umbelliferone has gastric protective activity in vivo, and it
has antidiarrheal activity in vivo [352].

5.2. Esculetin
Esculetin (6,7-dihydroxycoumarin), a natural coumarin derived from herbs, has shown
different pharmacological activities [353]. Kadakol et al. [354] reported that esculetin, a
naturally occurring 6,7-dihydroxy derivative of coumarin, has revealed its potential func-
tion in various non-communicable diseases (NCDs) including obesity, diabetes, renal
failure, cardiovascular disease, cancer, and neurological disorders. Esculetin reduced both
chronic and acute topic skin inflammation, and mitigated inflammation by suppressing
infiltration of inflammatory cells [355]. It can be found in many medicinal plants such as
Artemisia capillaris, Matricaria chamomilla L., Artemisia scoparia, Citrus limonia, Cortex Fraxini,
and Ceratostigma willmottianum [356–358]. Esculetin supplementation could protect against
development of non-alcoholic fatty liver in diabetes via regulation of glucose, lipids, and
inflammation [359]. The esculetin protects human hepatoma HepG2 cells from hydrogen
peroxide-induced oxidative injury, and the production is provided via the induction of pro-
tective enzymes as part of an adaptive response mediated by Nrf2 nuclear accumulation [360].
Esculetin prevents progressive renal fibrosis under insulin resistance (IR) and type 2
diabetic nephropathy (T2D) conditions, and it decreases oxidative stress in the kidney
under IR and T2D conditions [361]. Esculetin has the ability to suppress tumor growth
and metastasis via Axin2 suppression, which can be an attractive therapeutic strategy for
the treatment of metastatic colorectal cancer (CRC) [362]. Esculetin treatment decreased
neurological defects and improved cognitive impairments in transient bilateral common
carotid artery occlusion (tBCCAO)-treated mice, and the mechanism underlying the phar-
macological impacts of esculetin involved its action on mitochondrial autophagy and the
apoptosis triggered by mitochondrial oxidative stress via mediation of mitochondrial frag-
Molecules 2023, 28, 1845 16 of 43

mentation during transient cerebral ischaemia and reperfusion injury [363]. Zhang et al. [364]
reported that esculetin could be a potential therapeutic drug for the treatment of hepatic
fibrosis by inducing stellate cell senescence. Wang et al. [365] indicated that esculetin is
safe and reliable, is easy to be absorbed by the body, and can be synthesized in a variety
of ways. Esculetin inhibits the pyroptosis of microvascular endothelial cells through the
NF-KB/NLFP3 signaling pathway and is expected to be conducive in treating pyroptosis-
related diseases [366]. Esculetin directly binds to hnRNPA1 and decreases the concentration
of hnRNPA1 in endometrial cancer cells, and it downregulates the levels of BCL-XL and
XIAP expression, resulting in apoptosis and an arrest in proliferation [367]. Esculetin
inhibits clear cell renal cell carcinoma growth in a dose- and time-dependent manner, and
it induces apoptosis and cell cycle arrest [368]. Esculetin could be used as a dietary therapy
for the prevention of alcoholic liver disease, and it can markedly prevent ethanol-induced
liver injury in mice [369].

5.3. Scopoletin
Scopoletin (6-methoxyl-7-hydroxy coumarin) has a phenolic hydroxyl structure and
is a member of the coumarin family [370]. It has a long history of use for its medicinal
characteristics in traditional Chinese medicine [371]. Scopoletin is one of the main bioactive
components of Convolvulus prostratus Forssk, known to have a role in acetylcholinesterase
inhibitor, antimicrobial, memory enhancer, and antioxidative properties [372]. It is a
major component of noni (Morinda citrifolia L.), which contributes to the anti-inflammatory,
antioxidative, immunomodulatory, and hepatoprotective properties [373]. Scopoletin could
be a potential phagocytic enhancer, and it can increase immunity through enhancing
macrophage phagocytic capabilities [374]. Scopoletin improved vancomycin-induced renal
injury via restoring the antioxidant defense system [375]. Scopoletin reduces non-alcoholic
fatty liver disease in high-fat diet-fed mice [376]. It has been reported that scopoletin could
exert a positive impact on anti-aging related to autophagy via modulation of p53 in human
lung fibroblasts [377].

6. The Health Benefits of Stilbenes (Resveratrol, Piceatannol, Pterostilbene)

Stilbenes (based on the 1,2-diphenylethylene skeleton) are a group of plant polyphe-
nols with rich structural and bioactive diversity [378]. They originate from plant families
such as Vitaceae, Gnetaceae, Leguminaceae, and Dipterocarpaceae, and, structurally, they
have a C6-C2-C6 skeleton, normally with two isomeric forms [379,380]. They have wonder-
ful potential for anti-inflammatory, antiviral, anticancer, and antioxidant activities, as well
as an application as cosmetic materials, coloring agents, and dietary supplements [381–383].
Wine and grapes are the main dietary source of stilbenes [384]. These compounds are
synthetized by plants in response to abiotic or biotic stress situations [385]. Most stil-
bene compounds reveal antimicrobial properties, acting as phytoalexins in response to
pathogen or herbivore attack [386]. Phytochemical phenols of stilbene families indicated
good stability at elevated temperatures [387].

6.1. Resveratrol
Resveratrol (3,5,40 -trihydroxy-trans-stilbene) is a plant polyphenol, extensively pop-
ularized during the last decades, owing to its promising beneficial effects on human
health [388]. It is a famous non-flavonoid polyphenol, related to the family of stilbenes
whose structure consists of two phenolic rings linked by a double bond, which promotes
two isomeric conformations: trans- and cis-resveratrol [389,390]. Resveratrol’s cis-isomer
is unstable, and its trans-isomer contains greater stability, but converts to the cis-isomer
under exposure to high pH or UV light [391,392], with heat increasing the degradation
process [391]. It exists in many traditional herbs, and in several types of fruits, especially in
the muscadine grape, red wine, cranberry, lingonberry, and redcurrant [393], and roots of
various plant species including Polygonum cuspidatum and rhubarb (Rheun rhapontiicum) [394].
It is also useful in common age-related diseases such as cancer, cardiovascular diseases,
Molecules 2023, 28, 1845 17 of 43

type 2 diabetes, and neurological conditions, and it has also positive impacts on metabolism
and can boost the lifespan of various organisms [395]. Resveratrol supplementation can
be considered as an adjuvant therapy for relieving inflammation [396]. It has great po-
tency in treating cardiovascular diseases [397]. Resveratrol attenuates kidney damage
in malignant hypertension rats, and it can increase glomerular filtration while decreases
proteinuria [398]. It inhibits the release of proinflammatory cytokines and leads to the
release of anti-inflammatory cytokines, and it scavenges free radicals and upregulates
antioxidant enzymes [399]. Chowdhury et al. [400] indicated that resveratrol treatment
indicated beneficial impacts on preventing oxidative stress and fibrosis in the kidneys
of high-fat (HF) diet-fed rats, probably by modulating the gene expression of oxidative
stress and inflammation-related parameters and enzymes. Resveratrol can downregu-
late the pro-inflammatory cytokine release decreasing lung injury [401]. Resveratrol-
containing fruits could be a promising substitute for the management of Alzheimer’s
disease [402]. It can be more effective in cardiotoxicity prevention [403]. Polygonum cuspidatum
is an important medicinal plant in China and a rich source of resveratrol compounds,
which is a secondary metabolite formed in the long-term evolution procedure of plants
to increase their response to adverse environments such as pathogens and ultraviolet
radiation [404]. As an anticancer parameter, resveratrol promotes apoptosis in hepatocel-
lular carcinoma cells [405]. Bhaskara et al. [406] reported that resveratrol is a potential
reducing factor that can prevent carcinogenesis due to its antioxidant abilities, and it acts as
an immunomodulatory agent for treating cancer. Resveratrol can exhibit anti-aging activity
through a variety of signaling pathways [407]. Resveratrol shows potent anti-rotavirus
efficacy in vitro and in vivo, and it blocks viral structural expression and genomic RNA
synthesis [408]. Resveratrol oligomers from Paeonia suffruticosa indicate neuroprotective
effects in vitro and in vivo by regulating cholinergic, antioxidant, and anti-inflammatory
pathways, and they may have promising applications in the treatment of Alzheimer’s
disease [409]. Resveratrol is also involved in neurodegenerative diseases (NDs) with mul-
tiple neuroprotective activities [410]. Antimicrobial activity of resveratrol against many
bacteria and fungi has been reported, such as antimicrobial activity against Gram-positive
bacteria such as Bacillus cereus, Bacillus megaterium, Staphylococcus aureus, Enterococcus
faecalis, Enterococcus faecium, Mycobacterium tuberculosis, Mycobacterium smegmatis, Streptococcus
pneumoniae, Streptococcus pyogenes, Propionibacterium acnes, and Listeria monocytogenes;
against Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Salmonella
enterica serovar Typhimurium, Pseudomonas aeruginosa, Helicobacter pylori, Arcobacter butzleri,
Arocobacter cryaerophilus, Haemophilus ducreyi, Neisseria gonorrhoeae, Neisseria meningitidis,
Vibrio cholerae, Fuscobacterium nucleatum, Campylobacter jejuni, and Campylobacter coli; and
against fungi such as Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton
rubrum, Epidermophyton floccosum, Microsporum gypseum, Candida albicans, Saccharomyces
cerevisiae, Botrytis cinerea, and Trichosporon beigelii [411]. Resveratrol has powerful anticancer
characteristics in different cancer cells and organs such as pancreatic cancer, colorectal
cancer, gastric cancer, esophageal cancer, hepatocellular cancer, oral cancer, and biliary tract
cancer [412]. Resveratrol decreases damage to pancreatic tissue via suppression of calcium
overload; it suppresses calcium overload and, thereby, decreases trypsinogen activation,
oxidative stress, mitochondrial dysfunction, and disorders, and it also reduces damage to
other organs such as lung and heart by decreasing microcirculatory dysfunction [413].

6.2. Piceatannol
Piceatannol (3,4,30 ,50 -tetrahydroxy-trans-stilbene), a natural polyphenolic stilbene, has
pleiotropic pharmacological potentials [414]. It can be found in different kinds of fruits and
vegetables such as blueberries, grapes, and passion fruit [415]. Piceatannol is a metabo-
lite of resveratrol found in red wine, which prevents cardiac hypertrophy in rat neonatal
cardiomyocytes [416]. It has previously been known as an antileukemic principle, which has
been shown to be an inhibitor of protein-tyrosine kinase activity [417]. It has been reported
that its low water-solubility and bioavailability could limit its application in both food and
Molecules 2023, 28, 1845 18 of 43

pharmaceutical fields [418]. Piceatannol, compared with the renowned resveratrol, is a

better anticancer factor and a superior agent with other biological properties [419]. Piceatan-
nol lightened oxidative injury and collagen synthesis in lung tissues during pulmonary
fibrosis, and it suppressed the activation and collagen synthesis of TGF-β-induced lung
fibroblasts [420]. It appears to be an appropriate nutritional or pharmacological biomolecule
that modulates effector T cell functions, namely cytokine production, differentiation,
and proliferation [421]. Piceatannol attenuates fat accumulation in steatosis-induced
HepF2 cells, it suppressed lipogenesis and fatty acid uptake in steatosis-induced HepG2
hepatocytes, and it suppressed fatty acid-induced oxidative stress [422]. It shows anti-
aggregation activity, and it increases catalase and glutathione peroxidase activity [423]. It
can also be considered as a potential chemotherapeutic factor in the treatment of leukemia,
but it may be connected with the risk of multi-drug resistance [424]. Passion fruit seed
extract and piceatannol could exert anticancer activity via human glyoxalase I (GLO I)
inhibition [425]. Piceatannol is a promising medication for preventing acute liver failure
and the mechanisms may be associated to its inhibitory impacts on ER stress, inflammation,
and oxidative stress [426]. Piceatannol has a potential inhibitory activity against human
glyoxapase I (GLO I), and it inhibits the proliferation of GLO I-dependent human lung
cancer [427]. It protects ARPE-19 cells against apoptosis induced by photo-oxidation,
and the protective effect of piceatannol is because of the activation of the Nrf2/NQO1
pathway [428]. Piceatannol is a potent enhancer of cisplatin-induced apoptosis, and it
reveals the potential for clinical development for the treatment of ovarian cancer [429].
It has been reported that piceatannol significantly decreases the degree of bovine serum
albumin (BSA) glycosylation, and this suggests its potential impact on preventing the
progression of diabetes mellitus [430].

6.3. Pterostilbene
Pterostilbene, a dimethyl ester derivative of resveratrol, may act as a cytotoxic and
anticancer factor [431]. It primarily exists in blueberries, grapevines, and heartwood
of red sandalwood [432,433]. Phenolic resveratrol, pterostilbene has been reported to
have antifungal activity against a broad range of important phytopathogenic fungi such
as Leptosphaeria maculans and Peronophythora litchii [434]. It is an anti-inflammatory and
antioxidant agent with preventive effects toward skin disorders, and its anticancer impacts
include inducing necrosis, apoptosis, and autophagy [435]. It can alleviate hepatic damage
and oxidative stress and increase hepatic antioxidant function in piglets [436]. It possesses
the abilities of antiproliferation, reversing epithelial to mesenchymal transition (EMT),
and suppression of cancer stemness, and it could suppress tumor growth and inhibit the
metastasis of tumor cells to livers and lungs with therapeutic safety in BALB/C mice [437].

7. The Important Health Benefits of Lignan (Sesamin)

Lignans are naturally occurring compounds produced and accumulated in different
edible and medicinal plants, which can be subdivided bio-synthetically into neolignan and
lignans [438,439]. Lignans, as the notable subgroup of phenylpropanoids, are involved in
the plant defense responses to numerous biotic and abiotic stresses [440]. Lignans, with
different biological activities, such as antitumor, antibacterial, antioxidant, and antiviral
activities, are generally distributed in nature and mostly exist in the xylem of plants [441,442].
The level of lignans varies between plant parts of all species [443].
Sesamin, a major lignan derived from sesame seeds, has several benefits and medicinal
characteristics [444]. It exerts various pharmacological impacts, such as prevention of
hyperlipidemia, hypertension, and carcinogenesis, as well as anticancer and chemopre-
ventive activity in vitro and in vivo [445,446], and antioxidant and anti-inflammatory char-
acteristics [447,448]. Plants reported to contain sesamin are Paulownia tomentosa Staud.,
Phyllarthron comorense, Justicia simplex, Hyptis tomentosa, Anacyclus pyrethrum, Artemisia
absinthium, Artemisia gorgonum, Chrysanthemum cinerariaefolium, C. frutescens, C. indicum,
Diotis maritima, Eupatorium ageratina, E. ritonia, E. fleischmannia, Otanthus maritimus, Aptosimum
Molecules 2023, 28, 1845 19 of 43

spinescens, Gmelina arborea Roxb., Acanthopanax senticosus, A. sessiliflorum, Eleutherococcus

divaricatus, Asarum sieboldii, Aristolochia cymbifera, Alnus glutinosa, Salicomia europaea,
Austrocedrus chilensis, Evodia micrococca, Fagara xanthoxyloides, Fagara tessmannii, Fagara
heitzii, Micromelum minutum, Melicope glabra, Spiranthera odoratissima, Flindersia pubescens,
Zanthoxylum naranjillo, Zanthoxylum tingoassuiba, Zanthoxylum piperitum, Zanthoxylum
nitidum, Zanthoxylum flavum, Zanthoxylum alatum Roxb., Zanthoxylum bungeanum, Ginkgo
biloba, Machilus glaucescens, Ocotea usambarensis, Aiouea trinervis Meisn., Talauma hodgsonii,
Magnolia spp., Picea abies, Macropiper excelsum, Piper sarmentosum, Sesamum indicum,
S. radiatum, S. mulayanum, S. malabaricum, S. alatum, S. angustifolium, S. angolense, S. calycinum,
Anemopsis californica, Quercus frainetto Ten., Vernicia fordii, Jatropha curcas, Larrea tridentata,
Morinda citrifolia, Glossostemon bruguieri, Ligustrum japonicum, and Triclisia sacleuxii [449].
Sesamin could boost the proliferation and adhesion of intestinal probiotics, leading to
modulating gut microbiota, which provided the basis for sesamin as a food-borne func-
tional parameter for improving intestinal health [450]. Sesamin suppressed breast cancer
proliferation, and it downregulated programmed death ligand 1 (PD-L1) expression, which
is mediated by NF-KB and AKT [451]. Sesamin increased osteoblast differentiation by the
increase of type I collagen (COL1A1) and alkaline phosphatase (ALP) gene expression
as well as ALP activity [452]. Sesamin ameliorated lead-induced neuroinflammation in
rats, and decreased accumulation of lead in blood and neuronal tissues of rats [453].
It ameliorated polymorphonuclear neutrophils infiltration and exudate volume [454].
Majdalawieh et al. [455] reported that sesamin can potentially be utilized as an effec-
tual adjuvant therapeutic agent in ameliorating tumor development and progression, and
it could be utilized in the prevention and treatment of different types of cancer. It has been
reported that sesamin promoted diabetes-induced neuroinflammation in rats, exhibited
neurotrophic supportive action in diabetic rats, and prevented neuronal loss in diabetic
rats [456]. Sesamin has a chondroprotective effect through inhibition of proteoglycans (PGs)
degradation induced by IL-1beta and inhibition of collagen degradation [457].

8. The Health Benefits of Condensed Tannins or Proanthocyanidins (Procyanidin B1)

Proanthocyanidins, also known as condensed tannins [458,459], belong to the oldest
of plant secondary metabolites, and these constituents are widespread in woody plants,
but are also discovered in certain forages, as well as fruits, seeds, nuts, and bark [460,461].
Yu et al. [462] reported that proanthocyanidins were prevalent in lotus seed coats. They
can be categorized into three groups according to their component units and the link-
ages between them: procyanidins, prodelphinidins, and propelargonidins [463]. The
biological activity of plant proanthocyanidins is associated with their chemical concen-
tration and structure [464]. Proanthocyanidins from Pinus thunbergii mainly included
catechin/epicatechin, and they showed significant antioxidant capacity [465]. Proantho-
cyanidins in tea, black currant, grapes, bilberry, pine bark, cranberry, and peanut skin
may lead to a decrease in the oxidative stress (ROS), induce lower iNOS and COX-2 over-
expression, then lower inflammation, and, lastly, show activities against diabetes, asthma,
neuropathologies, cardiovascular ailments, obesity, and cancer [466]. The precursors of
proanthocyanidins are produced by the phenyl propanoid pathway in the cytosol and
are converted to the vacuole, where they polymerize to create proanthocyanidins [467].
They have various bioactivities, such as anticancer, antibacterial, and antioxidant [468].
Proanthocyanidins stimulate antioxidant capacity and increase resistance against oxidative
stress-induced senescence in fruits after harvest [469].
Procyanidins are associated with the class of natural products known as proantho-
cyanidins or condensed polyphenols [470]. They have been reported to reveal broad
advantages to human health and are applied in the prevention of cancers, diabetes, cardio-
vascular diseases, etc. [471]. They are structurally diverse constituents and can be divided
into monomeric, oligomeric, or polymeric variants associated with degree of polymeriza-
tion, which plays a role in manifesting various impacts that are associated with human
health [471]. The anti-digestion and antioxidant impacts of grape seed procyanidins have
Molecules 2023, 28, 1845 20 of 43

been proven [472]. Procyanidin B1 is also a promising liver cancer antitumor drug [473]
(Na et al., 2020). Procyanidins increase the glycometabolism and decrease the secretion of
inflammatory factors of postpartum mice with gestational diabetes mellitus (GDM) [474].

9. The Health Benefits of Curcuminoids (Curcumin, Demethoxycurcumin,

Bisdemethoxycurcumin)
9.1. Curcuminoids
Curcuminoids are a group of polyphenol coloring constituents that exist in the
plant species Curcuma, such as Curcuma longa, C. Wenyujin, C. zedoaria, etc. [475,476].
They are synthesized in turmeric from cinnamic acid precursors obtained via the phenyl-
propanoid biosynthetic pathway, and there are three different precursors, namely curcuminoids
biosynthesis-cinnamic acid, ferulic acid, and coumaric acid [477]. Ramirez-Ahumada et al. [478]
reported that curcuminoid synthase activity in turmeric crude protein extracts converts
feruloyl-CoA into curcumin. Curcumins are the commercially available component in
curcuminoids, as the principle constituents, and the other two, demethoxycurcumin and
bisdemethoxycurcumin, as minor components [479,480]. Curcumin and demethoxycur-
cumin are distinctive because of the phenylmethoxy group [481]. Curcuminoids share
important pharmacological characteristics possessed by turmeric, a distinguished curry
spice, considered as an important factor in Alzheimer’s disease [482]. It has been reported
that curcuminoids of turmeric can be considered as a modern medicine for the treatment of
knee osteoarthritis [483] as well as a potential anticancer agent [484]. Zhou et al. [485] also
reported that turmeric rhizomes exhibit versatile biological activities such as a significant
anticancer property. Three curcuminoids, namely curcumin, demethoxycurcumin, and
bisdemethoxycurcumin, in turmeric were found and were shown to contain significant
synergistic anticancer activities [486]. Curcuminoids rescued neurotoxin-induced inflam-
matory gene expression and rescued neurotoxin-induced apoptotic gene expression, and
individual curcuminoids showed significant function useful for Alzheimer’s disease [482].

9.2. Curcumin
Curcumin (bis-α,β-unsaturated β-diketone), also known as diferuloylmethane, is a hy-
drophobic polyphenol obtained from the rhizome of the perennial herb genus Curcuma, which
belongs to the ginger family (Zingiberaceae) and consists of species such as Curcuma longa,
Curcuma amada, Curcuma aromatic, Curcuma zedoaria, and Curcuma raktakanta [487,488].
Curcumins contain different medicinal values such as antioxidant, anti-pulmonary fi-
brosis, anti-inflammation, antiviral, and chronic obstructive pulmonary disease impacts,
and attractively docked with multi-target molecular proteins related to diabetes [489–494].
Curcumin is insoluble in water and easily efficient in organic solvents [495]; the active
functional groups of curcumin can be oxidized by electron transfer and hydrogen
abstraction [496], and curcumin is more durable in acidic to neutral conditions than in
alkaline circumstances [495–497]. Curcumin, as an enzyme inhibitor, has proper structural
characteristics including a flexible backbone, hydrophobic nature, and different available
hydrogen bond (H-bond) donors and acceptors [498]. Curcumin is stable to heat but
is light-sensitive and produces singlet oxygen and other reactive oxygen species (ROS)
when exposed to the sun, which is also a photodynamic and photobiological property of
curcumin [499]. Curcumin decreases inflammation by inhibiting lipopolysaccharide-
induced nuclear factor-KB (NF-KB) p65 translocation and mitogen-activated protein ki-
nase activation in dendritic cells [500]. Curcumin decreases morphine dependence in
rats through an inhibitory influence on neuroinflammation and a decline in the expres-
sion of µ-opioid receptors in the prefrontal cortex [501]. Curcumin influences synaptic
plasticity genes (Arc and Fmr1) to decrease amnesia [502]. Xie et al. [503] reported that
curcumin together with photodynamic therapy have been confirmed as effective in many
kinds of cancer cells in vitro and animal models. It has been extensively applied in can-
cer treatment because of its ability to trigger cell death and suppress metastasis [504].
Mahjoob and Stochaj [505] reported that curcumin improves aging-related cellular and
Molecules 2023, 28, 1845 21 of 43

organ dysfunctions. Curcumin can be a promising antifatigue substitute for improving exer-
cise performance [506]. Its derivatives have anti-inflammatory actions for drug repurposing
in traumatic brain injury (TBI), but their molecular targets are not clear [507].

9.3. Demethoxycurcumin
Demethoxycurcumin is one of the principle active compounds of curcuminoids dis-
covered in turmeric powder, which is used as a spice in Asian cooking and traditional
medicine [508]. Recent studies reveal that demethoxycurcumin has various biological
activities including antioxidant, anti-inflammation, and anticancer activities [509–511].
Lin et al. [512] reported that demethoxycurcumin is the most active constituent against var-
ious kinds of breast cancer cell lines and induces apoptosis and autophagy. Demethoxycur-
cumin, a natural derivative of curcumin, revealed stronger inhibitory activity on nitric oxide
and tumor necrosis factor-α production in comparison with curcumin in lipopolysaccharide-
activated rat primary microglia [513]. Demethoxycurcumin remitted the inflammation of
nucleus pulposus cells without overt cytotoxic impacts [514].

9.4. Bisdemethoxycurcumin
Bisdemethoxycurcumin is a demethoxy derivative of curcumin and is much more
stable than curcumin in physiological media [514–516]. It can scavenge free radicals and
control cellular redox balance because of its antioxidant property [517,518], and it has
potential anti-allergic effects [519]. Mahattanadul et al. [520] reported that bisdemethoxy-
curcumin’s antiulcer impacts might be because of its characteristics of decreasing gas-
tric acid secretion and increasing the mucosal defensive mechanism via suppression of
inducible nitric oxide synthase (iNOS)-mediated inflammation. Bisdemethoxycurcumin
inhibits human pancreatic α-amylase (HPA) [521].

10. Conclusions
Phenolic compounds are one of the most important types of compounds with an
important role in growth and reproduction, providing protection against pathogens and
predators, and they could be the main determinant of antioxidant potential of foods. Phe-
nolics are a heterogeneous collection of compounds generated as secondary metabolites
in plants. Phenolic compounds are aromatic or aliphatic compounds with at least one
aromatic ring to which one or more OH groups are connected. They are subdivided into
different groups depending on the number of phenolic rings that they possess and the
structural elements joined to them. They are naturally occurring compounds present in
several foods such as cereals, fruits, vegetables, and beverages. Polyphenols can also be
found in dried legumes and chocolate. The distribution of phenolic compounds in plant tis-
sues and cells change considerably according to the type of chemical compound. They also
contribute towards the color and sensory characteristics of fruits and vegetables. Different
classes of phenolic compounds in plants are simple phenolics, benzoquinones, hydroxyben-
zoic acids, acetophenones, phenylacetic acids, hydroxycinnamic acids, phenylpropanoids,
naphthoquinones, xanthones, stilbenes, anthraquinones, flavonoids, isoflavonoids, lignans,
neolignans, biflavonoids, lignins, and condensed tannins. Hydroxybenzoic acids are gallic
acid and Protocatechuic acid. Hydroxycinnamic acids are p-coumaric acid, caffeic acid, fer-
ulic acid, sinapic acid, and other components such as coumarins (umbelliferone, esculetin,
scopoletin, resveratrol, piceatannol, pterostilbene), curcuminoids (curcumin, demethoxycur-
cumin, bisdemethoxycurcumin), condensed tannins or proanthocyanidins (procyanidin B1),
and lignan (sesamin). From a human physiological viewpoint, phenolic compounds are
important in defense responses such as antioxidant, anti-aging, antiproliferative, and anti-
inflammatory. High phenolic activity in many species could prove to be beneficial towards
human health if included as part of food designs for a healthy diet.
Flavonoids are the largest group of natural phenolic compounds, and, based on the
differences in the pyran ring, flavonoids can be divided into flavones, isoflavones, fla-
vanonols, flavonols, flavanones, flavan-3-ols, and anthocyanidins. They can be subdivided
Molecules 2023, 28, 1845 22 of 43

into different subgroups on the basis of the carbon of the C ring on which the B ring is
attached and the degree of unsaturation and oxidation of the C ring. Flavonoids in which
the B ring is linked in position 3 of the C ring are called isoflavones. Those in which the
B ring is linked in position 4 are called neoflavonoids, while those in which the B ring is
linked in position 2 can be further subdivided into several subgroups on the basis of the
structural characteristics of the C ring. The most prominent health benefits of phenolic
compounds are antioxidant activity, anti-inflammatory properties, antifungal activity, an-
timicrobial activity, antibacterial properties, anti-coronavirus activities, neuroprotective
potential, appropriate for skin health, suitable for wound healing, and anticancer activities.
Flavonoids, a group of natural substances with variable phenolic structure, are found in
vegetables, fruits, grains, bark, stems, roots, flowers, wine, and tea. Flavonoids are con-
sidered as an important constituent in different pharmaceutical, medicinal, nutraceutical,
and cosmetic applications. They belong to a class of low-molecular-weight phenolic com-
pounds that are extensively distributed in the plant kingdom. Future research is needed to
determine the pharmaceutical benefits of phenolic and flavonoid compounds of medicinal
plants, especially traditional Chinese medicinal plants, and to gain a better understanding
of these chemical compounds in medicinal plants and herbs. It is also important to increase
analytic techniques to allow the collection of more data on excretion and absorption.

Author Contributions: W.S., writing—original draft preparation; M.H.S., writing—original draft

preparation and editing. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Natural Science Foundation of Beijing, China (Grant
No.M21026). This research was also supported by the National Key R&D Program of China (Research
grant 2019YFA0904700).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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