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2 Plant Polyphenols as Nutraceuticals and Their Antioxidant Potentials
28
DPPH scavenging
activity
Hydrogen
peroxide
scavenging (H
2
O
2
)
Nitric oxide
scavenging activity
Peroxynarite
radical scavenging
Trolox equivalent
antioxidant capacity
(TEAC)
Total radical
trapping antioxident
parameter (TRAP)
Ferric reducing
antioxidant power
(FRAP)
Hydroxyl radical
Scavenging activity
Superoxide radical
scavenging activity
(SOD)
Thio
barbituric acid
(TBA)
Ferric
Thio-cyanate
(FTC)
Reducing
power
(RP)
Phospho-
molybdenum
Oxygen radical
absorbance
capacity
(ORAC)
DMPD (N, N-
dimethyl-p-
phenylene diamine
dihydrochlonde)
b-carotene linoleic
acid method/
conjugated diene
Xanthine oxidase
Cupric ion reducing
antioxidant capacity
(CUPRAC)
Metal
chelating activity
Hydroxyl Radical
Antioxidant Capacity
(HORAC)
In vitro
Assay Methods
Ferric Reducing Ability
of Plasma
Low Density Lipid
(LDL) assay
Lipid peroxidation
(LPO) assay
Reduced glutathione
(GSH) estimation
Glutathione peroxidase
(GSHPx) estimation
Glutathione-S-transferase
(GSt)
Superoxide dismutase
(SOD) method
Catalase (CAT)
c-Glutamyl transpeptidase
activity (GGT) assay
Glutathione reductase
(GR) assay
In vitro
Assay Methods
Figure 2.2 In vitro and in vivo methods for antioxidant evaluation.
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Figure 2.3 ROS-induced signaling pathways, secondary messengers, and antioxidant potential of polyphenols at specific sites in cells.
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2 Plant Polyphenols as Nutraceuticals and Their Antioxidant Potentials
30
IGF-1R hormones like PGE2 and cytokines like IL-17, IL-6, and IL-2, activate different receptors,
such as tyrosine kinases (RTKs), and dimerize Class I PI3K subunit p85 and p85 to control the AKT
pathway. The second messenger phosphatidylinositol 3, 4-bisphosphate (PIP2) is produced when
PIP2 is active, and PIP3 subsequently activates the Akt/PKB pathway to facilitate growth factor-
mediated cell survival. The PI3K pathway is inhibited, which accelerates apoptosis. Akt/PKB is
adversely regulated through the tumor suppressor protein/lipid PTEN [41, 46]. Different polyphe-
nols alter PI3K/Akt activity, prevent a variety of human illnesses, and have positive influences on
human health [41]. Kaempferol is a flavonoid that inhibits apoptosis via the Akt signaling path-
way. Myricetin therapy prevents H
2
O
2
-induced apoptosis from killing cells. Genistein promotes
the activity of endothelial nitric oxide synthase (eNOS) and increases phosphorylation of eNOS
through the PI3K/Akt pathway [47, 48].
Another enzyme, protein kinase C (PKC), is a member of the protein kinase family (lipid-depend-
ent kinases comprising11 isozymes) that participates in signal-transduction cascades by interfering
with the phosphorylation of serine/threonine. This family plays a distinct role in cell signaling via
three classified groups: conventional PKCs (cPKCs; α, β, and γ) activated through DAG, Ca
2+
, and
phospholipid, novel PKCs (nPKCs; ε, η, δ, and θ) activated only through DAG, and atypical PKCs
(λ
and ζ) activated by neither Ca
2+
nor DAG channels [49]. Curcumin inhibits PKC, which down-
stream affects NF-κB and activator protein-1 (AP-1). Downstream of PKC also inhibits UGT, the
ERK pathway, and EGFR, which modulates the transcription factors for physiologic changes. In
response to oncogenic stimuli, one more polyphenol, resveratrol, inhibits the activity of kinases
including PKC, MAPK, and IB kinase (IKK), as well as transcription factors, including hypoxia-
inducible factor-1 (HIF-1), STAT3, NF-κB, and AP-1, and acts as an anticancer drug. By activating
PKC and altering cell survival/cell cycle genes, epigallocatechin gallate (EGCG) can prevent
OS-induced cell death. At lower doses, quercetin stimulates PKC activity; however, at greater con-
centrations, it inhibits calcium- and phospholipid-dependent PKCs. Similarly, tannic acid, chloro-
genic acid, apigenin, and other polyphenol extracts from several plants and PKC activity from fruits
take part in cell signaling and transcription, regulating numerous diseases states [50].
Keap1-Nrf2-ARE has a crucial function in regulating cellular metabolism and redox equilibrium
as well as eliciting an adaptive response to OS, which can otherwise result in a variety of inflam-
matory disorders such as diabetes, AD, Parkinson’s disease, and cancer [51]. To promote the sepa-
ration of Nrf2 and Keap1, ROS either oxidizes critical reactive cysteine residues that control Keap1
activity (Cys273, Cys288, and Cys151) or activates kinases like PKC, MAPK, phosphatidylinositide
3-kinases (PI3Ks), and protein kinase-like endoplasmic reticulum kinases (PERK). When under
OS, Nrf2 is liberated from its binding to keap1, which is normally broken down by proteasomes,
and is then transported to the nucleus where it attaches to the sMaf protein and ARE to start tran-
scription. Resveratrol is downstream Keap1 proteins and modulates Nrf2 nuclear accumulation.
Similarly, polydatin from Polygonum cuspidatum’s downstream Keap1 protein promotes Nrf2
transcriptional activity and the ARE-binding capability [52]. Numerous natural polyphenols have
important roles in disease prevention by interacting with these mechanisms in both diet and
medication.
2.4.4 Antioxidant Potential of Polyphenols
Characteristic structural attributes make polyphenols a strong antagonist for oxidants. Hydroxyl
groups in the polyphenol structure can stabilize the free radicals by establishing hydrogen bonds.
Polyphenols are capable of metal chelation and thereby prevent metal-catalyzed free radical for-
mation. The hydrophobic benzoic ring, as well as hydroxyl groups in polyphenols, can beneficially
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2.4 Polyphenols and Their Antioxidant Potential 31
interact with membrane proteins via hydrogen bonds, leading to low chances of OS and associated
anomalies. Phenolic ligands can suppress the strength of binding interactions of some pro-inflam-
matory mediators. Interleukin-6 (IL-6), a major inflammatory mediator and low-density lipopro-
tein (LDL), affects dietary flavones from tea or cocoa, shows a beneficial effect on cardiovascular
health, and retards OS-induced injuries, cellular NO production, and platelet cluster formation.
Procyanidin, an active phenolic compound, contributes to anti-inflammatory activities by reduc-
ing the concentration of RONS and prostaglandin E
2
, which regulates the integrity of several
immune cells. Phenolic substances can up- or down-regulate transcriptional components engaged
in antioxidant pathways [53]. Flavone, the isoflavones daidzein and genistein, the flavonols isor-
hamnetin, kaempferol, and quercetin, the flavanone naringenin, and the anthocyanin pelargoni-
din all reduce the expression of the iNOS protein and miRNA as well as the production of NO in a
dose-dependent manner, promoting anti-inflammatory activities in the human body [54]. Dietary
polyphenols can play a pivotal role in regulating neurological disorders like AD. AD patients
observed a diminished level of the neurotransmitter acetylcholine, which in turn is responsible for
the gradual memory loss. The phenolic compounds have several hydroxyl groups that can estab-
lish hydrogen bonds, hydrophobic contacts, and π–π interactions with the amino acid residues
that make up the active site of acetylcholine. This strategy thus ensures the inhibition of acetylcho-
line hydrolysis by acetylcholinesterase (AChE). Caffeine, cinnamic acid, resveratrol, curcumin,
and quercetin are involved in AChE inhibition [55]. Citrus flavanones, such as hesperidin, hes-
peretin, and neohesperidin, as well as the polyphenols derived from the gut bacterial metabolism
of flavan-3-ols, are characterized by the smooth blood–brain barrier permeability and exhibit a
beneficial effect against OS-induced neurodegenerative injuries. Polyphenols demonstrate chemo-
preventive action in the human body. Apoptosis, metastasis, and replication are just a few of the
cellular mechanisms that might change during cancer development (the process of programmed
cell death that occurs in multicellular organisms), and inefficient activity of repair mechanisms
that proceeds through complex stages like initiation, promotion, and progression. Polyphenols can
interfere either at these stages or proceed by arresting the cell cycle, induction of apoptosis, modu-
lating signaling pathways, or influencing epigenetic alterations in cellular biomolecules [56].
Quercetin has inhibitory effects on the aryl hydrocarbon receptor that modulates the cytochrome
p450 enzyme, which is enough to activate some carcinogenic species, and a transcription factor
that can be activated by polycyclic aromatic hydrocarbons involved in lung carcinogenicity [57].
Polyphenols, including EGCG, lycopene, and curcumin, operate by the down regulation of some
signal transduction pathways to reduce the effect of OS and have beneficial effects on prostate
cancer. The risk of developing breast cancer as well as bladder cancer is minimized by the antipro-
liferative activity of polyphenols carnosol, resveratrol, EGCG, luteolin, and curcumin to a certain
extent [56]. Curcumin has some favorable impact on the healthy function of the female reproduc-
tive system because it can eliminate/retard the chances of OS by accelerating heme oxygenase-1
(HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and SOD expression levels. Because it
has the power to cause apoptosis and prevent angiogenesis, curcumin may be employed in the
treatment of cancer (the physiological process through which new blood vessels form from pre-
existing vessels, formed in the earlier stage of vasculogenesis). Curcumin can also affect insulin
levels as well as obesity, which has a direct influence on PCOS [58]. One curcumin enriched for-
mulation, Re-party
TM
, recovers alcohol-induced adverse effects developed by OS [59]. Curcumin is
also beneficial to several neurodegenerative disorders working through modulating various molec-
ular pathways, viz. NF-κB, Nrf2-ARE, PI3K/Akt, ERK1/2, MAPK, JNK, and iNOS/NO pathways
[51]. Some polyphenols, including epicatechins, can regulate OS, cellular integrity, and aging-
related pathways via mitochondrial RNA [60, 61]. Resveratrol also reduces aging-associated cogni-
tive decline [62]. Polyphenols also take an active role in ensuring renal health. The characteristic
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2 Plant Polyphenols as Nutraceuticals and Their Antioxidant Potentials
32
stilbene structure enables resveratrol to reduce elevated ROS levels in the HK-2 (human kidney 2)
renal cell line. The major flavanol EGCG can trap iron through chelation and prevents the situa-
tion of OS via RNS. Ellagic acid is also involved in renal health protection by reducing OS [63].
2.4.5 Overview of the Health Benefits of Nutraceuticals
Polyphenols, particularly flavonoids, have been named “nature’s biological response regulators”
because of extensive observations of their inherent capacity to affect the body’s reaction against
seasonal and vulnerable change [42]. The extensive distribution, diversity, and low toxicity of poly-
phenols/flavonoids compared with other bioactive/plant metabolites have led to significant human
and animal consumption. Flavonoids that are mostly found in fruits, vegetables, spices, and plant-
derived drinks, such as tea, coffee, and red wine, activate various signaling pathways, such as ERK,
PkB/Akt, PI3K, and PKC, to improve cell survival.
At doses of 100–300 nmol/L, the flavonoid (–)-epicatechin (EC), which is mostly present in green
tea, causes a fast increase in CREB phosphorylation that is ERK- and PI3K-dependent. EC also
stimulates ERK and Akt phosphorylation. The polyphenolic component (–)-epicatechin-3-gallate
(ECG), which is widely present in green tea, has been demonstrated to protect keratinocytes against
UV-B-induced photodamage and H
2
O
2
-induced OS by inhibiting p38 and ERK1/2 pathways.
Polyphenols from Curcuma longa may be potential molecules and a good option for inhibiting
oxidative-induced NLRP-3 pathways [64]. Some of the polyphenols that work against various
OS-induced signaling pathways are highlighted in Table 2.1.
2.5 Revolutionary Approaches
2.5.1 Antioxidant Prospects of Unexplored Polyphenols
Polyphenols, triterpenes, alkaloids, and other natural matrices have given rise to a range of extrac-
tion strategies for natural antioxidants. In addition to standard extraction techniques, green chem-
istry extraction methods, such as microwave- or ultrasound-assisted extraction techniques, and
nanotechnologies are in demand [92, 93]. Because of their selectivity, consistency, and productiv-
ity, these environmentally friendly technologies are widely used in industrial settings and are cur-
rently recognized as one of the most efficient energy-saving techniques. These techniques may be
used to extract polyphenols that have recently attracted attention because of their effectiveness in
a variety of non-communicable disease prevention and treatment applications. Several polyphe-
nols, including nepetin, hispidulin, patuletin, tiliroside, spinacetin, tambulin, ombuin, syringetin,
laricitrin, petunidin, peonidin, and morin, have been the focus of extensive recent research as
potential therapeutic candidates for cellular dysfunctions. These studies have not only focused on
technologies. Nepetin is an essential flavone that guards membrane protection and cell life by
preventing peptide oligomerization and aggregation. An expanding field of study has focused on
the same substance with powerful anti-inflammatory capabilities [94, 95]. Several Artemisia,
Salvia, and Scoparia plants contain the unexplored flavonoid hispidulin, which has broader
medicinal applications because of its anti-adipogenesis, antithrombotic, and antioxidant activities
[96]. Because of its fundamental quercetin-like structure, patuletin is an important flavonoid that
may be explored extensively as it is thought to have an antiproliferative function [97]. Tiliroside is
a glycoside flavonoid that is present in Amaranthaceae plants and it has antioxidant and anti-
inflammatory properties [98]. One of the spinach flavonoids, spinacetin, requires special attention
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Table 2.1 Polyphenols for inhibiting oxidative stress by various signaling pathways and second messengers.
S. No.
Polyphenol
Class &
Structure Parent Structure Food Source Signaling Pathways And Second Messenger References
1. Flavones
O
H
O
Apigenin ↓ROS, ↓MAPK/ERK, ↓PI3K/Akt, ↓H
2
O
2
-
induced apoptosis, ↓AP-1, ↓JNK, ↓PKC,
↓COX-2,
↓NF-κB, ↑Caspase-3
[65]
Chrysin ↓NF-κB, STAT3, Notch1, microRNA, ↓PI3K [66]
Luteolin ↓ROS, ↓MAPK/ERK, ↓PI3K/Akt, ↓H
2
O
2
-
induced apoptosis
2. Flavonols
O
O
OH
Kaempferol ↓ROS, ↓MAPK/ERK, ↓PI3K/↑↓Akt, ↓Nrf-2
↓SOD; ↓H
2
O
2
-induced apoptosis, ↓QR
[65, 67]
Quercetin ↓ROS, ↓MAPK/ERK, ↓PI3K/Akt, ↓Nrf-2
↑P53
[68, 69]
Rutin ↓ROS, ↓MAPK/ERK, ↓PI3K/Akt, ↓MDA [70–72]
Myricetin ↓CYP1A1, ↑QR [73, 74]
3. Flavanones
O
O
H
Eriodictyol ↓ROS, ↓MAPK (ERK/JNK/p38), ↓PI3K/Akt,
↓mTOR, ↓Nrf-2/ARE
[75, 76]
Hesperetin ↓H
2
O
2
-induced apoptosis,
↓cyclinD1, cyclinE1, cyclin-dependent kinase
2
[77]
Naringenin ↓ROS, ↓MAPK/ERK, ↓PI3K/Akt, ↓Nrf-2/
ARE
[78]
(Continued)
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Table 2.1 (Continued)
S. No.
Polyphenol
Class &
Structure Parent Structure Food Source Signaling Pathways And Second Messenger References
4. Flavanonols
O
O
OH
Dihydro-quercetin
(Taxifolin)
Downstream Nrf2/ARE [79, 80]
5. Flavanols
O
OH
(+)/(−)-Catechin
(C)
(+)/(−)-Epicatechin
(EC)
(+)/(−)-Gallocatechin
(GC)
(+)/(−)-Epigallo-catechin
(EGC)
(+)/(−)-Epicatechin-3-
gallate (EGCG)
(+)/(−)-Epigallocatechin-
3-gallate (EGCG)
↓ROS; ↑↓PI3K/Akt, ↓H
2
O
2
-induced
apoptosis; ↑GSH; ↓Nrf-2, ↓JNK
[65]
6. Iso
flavonoids
O
O
Genistein ↓ROS, ↓COX-2, ↓MAPK/ERK, ↓PI3K/Akt,
↓AP-1, ↓JNK, ↓PKC, ↓NF-κB, ↑Caspase-3,
↑P38
[81]
Daidzein ↑Caspase 3/7 activity, Interfere Bax/Bcl2 [82, 83]
Glycitein ↓JNK, ↓H
2
O
2
-induced apoptosis [84]
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S. No.
Polyphenol
Class &
Structure Parent Structure Food Source Signaling Pathways And Second Messenger References
7. Neo-
flavonoids
O
Dalbergiones Inhibited the production of NO, ↓Nrf-2/ARE [85, 86]
8. Anthocyanin
O
+
Aurantinidin
Capensinidin
Cyanidin
Delphinidin
Europinidin
Hirsutidin
Malvidin
Pelargonidin
Peonidin
Petunidin
Pulchellidin
Rosinidin
↓ROS, ↓COX-2, ↓MAPK (ERK/JNK/p38),
↓JNK, ↓Nrf-2/ARE
[87, 88]
(Continued)
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S. No.
Polyphenol
Class &
Structure Parent Structure Food Source Signaling Pathways And Second Messenger References
9. Hydrolysable
Tannins
HO
HO
HO
O
O
O
O
O
OH
HO
HO
OH
O
O
HO
HO OH
OH
Gallotannins ↓ROS, ↓MAPK/ERK, [89]
Ellagitannins ↓ROS, ↓MAPK/ERK, ↓JAK/STAT3, ↓PI3K/
Akt/mTOR
[90]
10. Condensed
Tannins
H
3
C
O
O
OH
OH
OH
O
OH
OH
OH
HO
HO
HO
Proanthocyanidins ↓ROS, ↓MAPK/ERK, ↓JAK/STAT3, ↓PI3K/
Akt/mTOR, ↓NF-κB
[91]
Table 2.1 (Continued)
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2.6 Conclusion 37
because it may have substantial antioxidant properties [99, 100]. Tambulin and ombuin are two
noble polyphenols that require extensive derivatization because of their pursuit of both antibacte-
rial and antiproliferative properties [101]. Berries have been shown to include anthocyanins, such
as petunidin and peonidin, as well as polyphenols, including syringetin and laricitrin, which
require more extensive characterization [102]. Because of its complementary effect in boosting
anticancer drugs, morin is another bioflavonoid of pharmaceutical and nutraceutical relevance
[103]. These are a few understudied polyphenols with antioxidant properties that can be researched
further to aid in the development of conventional medical practices.
2.5.2 Global Market Value and Commercial Significance
The dietary supplements segment is immense globally. The Asia–Pacific Region, USA, Canada,
Japan, China, and Europe are driving the market with a 5.6% CAGR. The Asia–Pacific Region is
the world’s largest functional food business area dominating the market with a majority of the
market share because of the rising nutritional enrichment consciousness in China. India is
expected to continue to have a beneficial influence on regional market growth [104]. Customers
choose items with added health advantages as they are now more health conscious. In the dietary
supplement industry, polyphenols are the primary option. The rising usage of polyphenols in
health foods is predicted to fuel growth in the dietary supplement industries, which is expected to
reach $2.9 billion by 2030, representing a 7.4% CAGR from the existing market of 1.67 billion USD
[104]. Analysts predict that the Asia–Pacific Region followed by Latin America is growing at a 7.3%
annual rate, especially in the polyphenol business [9]. In 2027, the polyphenols market in the USA
is expected to be worth $272.7 million USD. China, the world’s second-biggest economy, is expected
to reach a projected market size of $362.4 million USD by 2027, with a 10.9% CAGR from 2020 to
2027. From 2020 to 2027, Japan and Canada are two more important geographic markets that will
grow at rates of 3.8% and 6.4%, respectively. In Europe, Germany is predicted to grow at a CAGR
of roughly 4.5% [105]. “Polyphenols” is a popular search term in Asia and the Pacific. The keyword
“polyphenols” was frequently searched by Singaporeans on Google trends. New Zealand’s poly-
phenol search was 75% that of Singapore’s. With 67%, the United States was second, followed by
Australia (55%), Canada (54%), and China (53%). Ireland ranked fifth in the world for polyphenol
searches, with 51% of the top five zones [106]. The current Google trend also suggests that the
Asia–Pacific Region is leading the polyphenol and antioxidant business, which would provide new
opportunities for industrialists.
2.6 Conclusion
Human requirements are the beginning point for all innovations. Recently, the world of science rec-
ognized the importance and requirement of polyphenols in human life. Polyphenols are the most
abundant secondary metabolites present in the plant kingdom. Their activities on the biological func-
tions are endless. Many studies have demonstrated that polyphenols are a strong, naturally occurring
antioxidant and they can be used in many functional foods. Polyphenol consumption or a polyphenol-
rich diet can significantly slow the progression of several chronic pathological conditions, including
cancer, diabetes, cardiovascular disease, and aging etc. Our approaches should be focuses on gaining
a better understanding of the biological effects of polyphenols and their significant impact on human
health. Scientific research on polyphenols clarified epidemiological information and bioavailability
characteristics, including the rates of absorption, accumulation, and elimination, and the mechanism
of action for many biological effects. Polyphenols that control intracellular signaling pathways through
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