Dietary Polyphenols and Their Role in Oxidative Stress-Induced Human Diseases: Insights Into Protective Effects, Antioxidant Potentials and Mechanism(s) of Action

Abstract

Dietary polyphenols including phenolic acids, flavonoids, catechins, tannins, lignans, stilbenes, and anthocyanidins are widely found in grains, cereals, pulses, vegetables, spices, fruits, chocolates, and beverages like fruit juices, tea, coffee and wine. In recent years, dietary polyphenols have gained significant interest among researchers due to their potential chemopreventive/protective functions in the maintenance of human health and diseases. It is believed that dietary polyphenols/flavonoids exert powerful antioxidant action for protection against reactive oxygen species (ROS)/cellular oxidative stress (OS) towards the prevention of OS-related pathological conditions or diseases. Pre-clinical and clinical evidence strongly suggest that long term consumption of diets rich in polyphenols offer protection against the development of various chronic diseases such as neurodegenerative diseases, cardiovascular diseases (CVDs), cancer, diabetes, inflammatory disorders and infectious illness. Increased intake of foods containing polyphenols (for example, quercetin, epigallocatechin-3-gallate, resveratrol, cyanidin etc.) has been claimed to reduce the extent of a majority of chronic oxidative cellular damage, DNA damage, tissue inflammations, viral/bacterial infections, and neurodegenerative diseases. It has been suggested that the antioxidant activity of dietary polyphenols plays a pivotal role in the prevention of OS-induced human diseases. In this narrative review, the biological/pharmacological significance of dietary polyphenols in the prevention of and/or protection against OS-induced major human diseases such as cancers, neurodegenerative diseases, CVDs, diabetes mellitus, cancer, inflammatory disorders and infectious diseases have been delineated. This review specifically focuses a current understanding on the dietary sources of polyphenols and their protective effects including mechanisms of action against various major human diseases.

Full text

Dietary Polyphenols and Their Role in
Oxidative Stress-Induced Human
Diseases: Insights Into Protective
Effects, Antioxidant Potentials and
Mechanism(s) of Action
Mithun Rudrapal
1
*, Shubham J. Khairnar
2
, Johra Khan
3
,
4
, Abdulaziz Bin Dukhyil
3
,
Mohammad Azam Ansari
5
, Mohammad N. Alomary
6
, Fahad M. Alshabrmi
7
, Santwana Palai
8
,
Prashanta Kumar Deb
9
and Rajlakshmi Devi
9
1
Department of Pharmaceutical Chemistry, Rasiklal M. Dhariwal Institute of Pharmaceutical Educa tionand Research, Pune, India,
2
Department of Pharmacology, MET Institute of Pharmacy, Nashik, India,
3
Department of Medical Laboratory Sciences, College
of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia,
4
Health and Basic Sciences Research Center,
Majmaah University, Al Majmaah, Saudi Arabia,
5
Department of Epidemic Disease Research, Institute for Research and Medical
Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia,
6
National Centre for Biotechnology,
King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia,
7
Department of Medical Laboratories, College of
Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia,
8
Department of Veterinary Pharmacology and Toxicology,
College of Veterinary Science and Animal Husbandry, OUAT, Bhubaneswar, India,
9
Life Sciences Division, Institute of Advanced
Study in Science and Technology, Guwahati, India
Dietary polyphenols including phenolic acids, flavonoids, catechins, tannins, lignans,
stilbenes, and anthocyanidins are widely found in grains, cereals, pulses, vegetables,
spices, fruits, chocolates, and beverages like fruit juices, tea, coffee and wine. In recent
years, dietary polyphenols have gained significant interest among researchers due to
their potential chemopreventive/protective functions in the maintenance of human health
and diseases. It is believed that dietary polyphenols/flavonoids exert powerful antioxidant
action for protection against reactive oxygen species (ROS)/cellular oxidative stress (OS)
towards the prevention of OS-related pathological conditions or diseases. Pre-clinical
and clinical evidence strongly suggest that long term consumption of diets rich in
polyphenols offer protection against the development of various chronic diseases
such as neurodegenerative diseases, cardiovascular diseases (CVDs), cancer,
diabetes, inflammatory disorders and infectious illness. Increased intake of foods
containing polyphenols (for example, quercetin, epigallocatechin-3-gallate,
resveratrol, cyanidin etc.) has been claimed to reduce the extent of a majority of
chronic oxidative cellular damage, DNA damage, tissue inflammations, viral/bacterial
infections, and neurodegenerative diseases. It has been suggested that the antioxidant
activity of dietary polyphenols plays a pivotal role in the prevention of OS-induced human
diseases. In this narrative review, the biological/pharmacological significance of dietary
polyphenols in the prevention of and/or protection against OS-induced major human
diseases such as cancers, neurodegenerative diseases, CVDs, diabetes mellitus,
cancer, inflammatory disorders and infectious diseases have been delineated. This
review specifically focuses a current understanding on the dietary sources of
Edited by:
Keshav Raj Paudel,
University of Technology Sydney,
Australia
Reviewed by:
Tânia Rodrigues Dias,
University of Aveiro, Portugal
Vishnu Nayak Badavath,
Hebrew University of Jerusalem, Israel
*Correspondence:
Mithun Rudrapal
rsmrpal@gmail.com
Specialty section:
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 31 October 2021
Accepted: 21 January 2022
Published: 14 February 2022
Citation:
Rudrapal M, Khairnar SJ, Khan J,
Dukhyil AB, Ansari MA, Alomary MN,
Alshabrmi FM, Palai S, Deb PK and
Devi R (2022) Dietary Polyphenols and
Their Role in Oxidative Stress-Induced
Human Diseases: Insights Into
Protective Effects, Antioxidant
Potentials and Mechanism(s) of Action.
Front. Pharmacol. 13:806470.
doi: 10.3389/fphar.2022.806470
Frontiers in Pharmacology | www.frontiersin.org February 2022 | Volume 13 | Article 8064701
REVIEW
published: 14 February 2022
doi: 10.3389/fphar.2022.806470

polyphenols and their protective effects including mechanisms of action against various
major human diseases.
Keywords: dietary polyphenols, flavonoids, oxidative Stress, antioxidant, biomarkers, cellular signaling, protective
function, mechanism of action
INTRODUCTION
Dietary polyphenols comprise a significant group of naturally
occurring phytochemicals which primarily include phenolic
acids, flavonoids, catechins, tannins, lignans, stilbenes and
anthocyanidins. They possess antioxidant, chemopreventive
and a wide range of pharmacological properties (Khan et al.,
2021). Basically, our diet includes grains, cereals, pulses,
vegetables, spices, fruits, chocolates, and beverages like fruit
juices, tea, coffee and wine. They are rich in polyphenolic
compounds of medicinal importance. Over 8,000 polyphenols
have been reported from plants, out of several hundreds of
polyphenols exist in human diets (Arts and Hollman, 2005).
Research and clinical studies suggest that dietary polyphenolic
compounds are linked to the maintenance of human health and
prevention of diseases (Pandey and Rizvi, 2009). Dietary
Polyphenols can effectively lower the risk of developing a wide
range of human ailments such as cancer, cardiovascular diseases
(CVDs), diabetes, inflammatory diseases and neurodegenerative
disorders, just to name a few (Pandey and Rizvi, 2010).
Organic compounds bearing an aromatic ring with at least one
hydroxyl group are termed as “phenolics”. In case, a compound
possesses one or more aromatic rings having more than one
hydroxyl group are called polyphenols (or polyphenolic
compounds). Phenolics in plant derived foods are basically
divided into phenolic acids, flavonoids, and non-flavonoids
(Tsao, 2010). Phenolic acids are composed of hydroxyl by-
products of aromatic carboxylic acids bearing a single phenolic
ring. As per the C1-C6 or C3-C6 backbone, theyare usually referred
to as derivatives of benzoic acid or cinnamic acid. Flavonoids being
the dominant class of plant polyphenols consist of two phenolic
rings connected by a three-carbon bridge with a common C6-C3-
C6 structural skeleton (Rudrapal and Chetia, 2017).
Oxidative stress (OS) is considered either a primary or a
secondary cause for many chronic inflammatory diseases,
neurodegenerative illness, metabolic disorders, cancer and
CVDs. Dietary intake of fresh fruits and vegetables have clear
effects against a number of diseases that involve OS. However, the
role of the dietary polyphenols of their antioxidant abilities is still
unclear. Dietary polyphenols (or flavonoids) act as efficient free
radicals and reactive oxygen species (ROS) scavengers (according
to biochemical scavenger theory) owing to the presence of aromatic
structural feature, multiple hydroxyl groups, and a highly
conjugated system (Salisbury and Bronas, 2015). They have the
capability to negate ROS or to suppress cellular OS enabling them
to avert oxidative damages of biomolecules (lipids, proteins, DNA)
and thereby diminish tissue inflammation (Zhang and Tsao, 2016).
This is referred to as antioxidant effects of dietary polyphenols. The
ability of dietary polyphenols to suppress inflammation and
consequently oxidative damage to tissues is mediated through
their antioxidant effects, interference with signaling pathways of
OS and suppression of signaling transduction mechanism of pro-
inflammatory mediators and cellular inflammatory pathways at
molecular level (Apel and Hirt, 2004).
Pre-clinical and clinical evidence strongly suggest that long
term consumption of diets rich in polyphenols offer protection
against the development of various chronic diseases such as
neurodegenerative diseases, cardiovascular diseases (CVDs),
cancer, diabetes, inflammatory disorders and infectious illness
(Khan et al., 2021). Increased intake of foods containing
polyphenols (for example, quercetin, epigallocatechin-3-gallate,
resveratrol, cyanidin etc.) has been claimed to lower the incidence
of a majority of chronic oxidative cellular damage, DNA damage,
tissue inflammations, various cancers, viral/bacterial infections,
and neurodegenerative diseases (Pandey and Rizvi, 2009;Shahidi
and Ambigaipalan, 2015;Egbuna et al., 2021;Khan et al., 2021).
In this narrative review, the biological/pharmacological
significance of dietary polyphenols in the prevention of and/or
protection against OS-induced major human diseases such as
cancers, neurodegenerative diseases, CVDs, diabetes mellitus,
cancer, inflammatory disorders and infectious diseases have
been delineated. This review specifically focuses a current
understanding on the dietary sources of polyphenols and their
protective effects including mechanisms of action against various
major human diseases.
OXIDATIVE STRESS AND ITS ROLE IN
DISEASE PATHOGENESIS
The bulk of free radicals that causes damage to biological
structures (i.e., biomolecules such as proteins, lipids, DNA) are
oxygen-free radicals, also known as reactive oxygen species
(ROS). ROS include superoxide anion radical (O
2
•
–
),
perhydroxyl radical (HOO•), nitric oxide radical (NO•),
hydrogen peroxide (H
2
O
2
), singlet oxygen (
1
O
2
), hydroxyl
radical (•OH), hypochlorous acid (HOCl), hypochlorite radical
(ClO
−
), peroxynitrite (ONOO
−
), and lipid peroxides (LOPs).
ROS may be generated from various exogenous sources such
as UV light irradiation, X-rays, γrays, metal catalyzed reactions,
environmental carcinogens/toxins. Heavy/transition metals,
alcohol, tobacco, synthetic solvents, drugs (e.g., tacrolimus,
cyclosporine, bleomycin, and gentamycin), culinary sources
(e.g., waste oil, fat and smoked meat), and radiation are all
exogenous sources of ROS. Endogenous sources of ROS
include cytochrome P450 metabolism, mitochondrial reactions,
peroxisomes, and inflammatory cell activation. Whether
endogenous or exogenous, ROS when increased or excessively
produced can cause oxidative changes/damages to all cellular
macromolecules. Excessive intracellular production of ROS
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Rudrapal et al. Dietary Polyphenols Against Human Diseases

builds up cellular OS that usually cause damage to lipids, proteins,
DNA and carbohydrates. Thus, OS has been linked to the
pathogenesis of many human diseases including brain
dysfunction, cancer, inflammatory diseases, heart diseases,
diabetes and many others (Law et al., 2017).
Human body has its own in-built biological process/mechanism
to defend itself against foreign threats and pathogenic
microorganisms, including natural antioxidant defense, immunity
and/or DNA repair enzymes. Several antioxidant enzymes such as
superoxide dismutase (SOD), catalase (CAT), and reduced
glutathione (GSH) aid in the removal of free radicals (Halliwell
and Gutteridge, 2015). When not well managed, OS causes extensive
chronic and degenerative diseases, the aging process, and acute
pathologies like trauma and stroke. Most importantly, when the
production of free radicals overwhelms the antioxidant defenses, it
leads to OS, the harmful mechanism that can significantly change
cellmembranesandotherbiologicalstructuressuchaslipoproteins,
lipids, proteins, DNA etc. (Genestra, 2007). Figure 1 depicts
deleteriouseffectsofOS/ROSonbiomolecules.
Membrane lipids are vulnerable to peroxidative reactions.
Hydroxyl radical (•OH) is an essential reactive moiety and
originator of the ROS chain reaction in polyunsaturated
lipoperoxidation process. Several compounds are formed as a
result of lipid polysunsaturated fatty acids (PUFA) peroxidation,
namely isoprostanes, malondialdehyde (MDA), 4-hydroxy-2-
nonenal (4-HNE) etc. (Lobo et al., 2010;Kunwar and
Priyadarsini, 2011). These compounds are used as biomarkers
in lipid peroxidation assays and have been linked to
neurodegenerative diseases, heart disease, and diabetes
(Genestra, 2007;Lü et al., 2010;Pandey and Rizvi, 2010).
Peroxynitrite can also destroy lipoproteins and causes lipid
peroxidation of cell membranes. ROS can also affect protein
synthesis and protein functions. Protein oxidation can result in
amino acid modifications (oxidative protein modification),
accumulation of cross-linked reaction products, peptide chain
fragmentation, and augmented electrical charges (Parthasarathy
et al., 1999;Krishnamurthy and Wadhwani, 2012). Chemical
agents that generate oxygen-free radicals like ionizing radiations
and activated oxygen cause DNA damage which results in
mutations, deletion, and similar lethal genetic effects. Oxidative
DNA damage causes the development of various oxidative DNA
lesions, which may trigger mutations (Halliwell and Gutteridge,
2015). Because of DNA disruption, base moieties and sugar
become more vulnerable to oxidation, resulting in protein cross-
linking, base degradation, and single-strand breakage (Zadák et al.,
2009). Further, OS exerts deleterious effects on DNA leading to the
FIGURE 1 | Deleterious effects of OS/ROS on biomolecules. ROS generated from various sources (environmental/biological) cause oxidations of lipid, protein and
DNA molecules. Abbreviations: UV: ultraviolet rays, OH: hydroxyl, NO: nitrogen oxide, O2: oxygen, O3: Ozone, H2O2: hydrogen peroxide.
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Rudrapal et al. Dietary Polyphenols Against Human Diseases

formation of DNA lesions, which can result in genomic instability
and consequently lead to cell death. The guanine (a base of DNA) is
most susceptible to oxidation in cellular OS. In the presence of
ROS, the oxidation of guanosine to 8-oxoguanosine (8-oxoG) takes
place. The formation of 8-oxoG is the most common lesion in the
DNA molecule. When 8-oxoG is inserted during DNA replication,
it could generate double-strand breaks, which finally causes
damage to DNA molecule (Aguiar et al., 2013).
Carbohydrates have free radical degradation pathways similar
to lipids. The development of oxygen-free radicals throughout
initial glycation can lead to glycoxidative harm to biological
tissues (Benov and Beema, 2003). During the glycoxidation
process, many reactive aldehydes, including 4-HNE and MDA
are formed resulting in advanced glycation termination products
(Phaniendra et al., 2015). The pathophysiological changes that
take place during OS induced diseases are outlined in Figure 2.
DIETARY POLYPHENOLS, THEIR
CHEMISTRY AND SOURCES
Polyphenols are found naturally in fruits and vegetables such as
cereals, pulses, dried legumes, spinach, tomatoes, beans, nuts,
peppermint, cinnamon, pears, cherries, oranges, apples, red wine,
FIGURE 2 | OS induced human diseases and their pathogenesis. ROS generated from exogenous/endogenous sources induce OS which results in the
pathogenesis of various human diseases through impaired physiological functions, cellular damages and specific signaling dysfunctions. Abbreviations: ROO: alkoxyl
radical, ROO: peroxyl radical, ONOO
−
: perooxynitrite, NO
2
•
: nitrogen dioxide radical, O
2
•
−
: superoxide radical, ROS: reactive oxygen species, SOD: superoxide
dismutase, CAT: catalase, GPx: glutathione peroxidase, GSH: glutathione.
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tea, cocoa, coffee and so on (Arts and Hollman, 2005;Scalbert
et al., 2005). Polyphenols are classified into different groups
depending on the number of aromatic (phenolic) rings they
contain and the structural elements that connect these rings.
They are broadly grouped into phenolic acids, flavonoids,
stilbenes and lignans (Khan et al., 2021). Plant derived
polyphenolic compounds (for example, phenolic acids and
flavonoids) occurs in conjugated forms with one or more
sugar residues (as glycosides) bound to hydroxyl groups
through direct linkages of the polysaccharide or
monosaccharide-like sugar to an aromatic carbon (Rudrapal
and Chetia, 2017). It is naturally bound to a variety of other
molecules, including carboxylic and organic acids, lipids, amines,
and other phenolic compounds (Kondratyuk and Pezzuto, 2004).
Dietary polyphenolics can be broadly classified into flavonoids
and other polyphenols (non-flavonoids). Flavonoids are further
classified into different subgroups based on their structures such
as flavan-3-ols (examples: catechin, epicatechin,
epigallocatechin), isoflavones (examples: genistein, genistin,
daidzenin, daidzin, biochanin A, formononetin), flavones
(examples: luteolin, apigenin, chrysin), flavonones (examples:
hesperetin, naringenin), flavonols (examples: quercetin,
kaempferol, galangin, fisetin, myricetin), flavononol (example:
taxifolin), flavylium salts (examples: cyanidin, cyanin,
pelargonidin), and flavanones (examples: hesperetin,
naringenin, eriodictyol, isosakuranetin) (Pietta, 2000;Barreca
et al., 2017). Non-flavonoid polyphenols can be further
classified into phenolic acids (examples: cinnamic acid,
p-coumaric acid, caffeic acid, ferulic acid, sinapic acid, gentisic
acid, vanillic acid, gallic acid, syringic acid, protocatechuic acid),
tannins (examples: procyanidins, catechin, afzelechin,
gallocatechin, ellagic acid, gallic acid gallate, gallotannin,
ellagitannin, hexahydroxydiphenic acid), lignans (examples:
niranthin, sesamin, silymarin, rubrifloralignan A, bicyclol,
phillygenin, clemastanin B, isatindolignanoside A, diphyllin,
hinokinin, yatein, secoisolariciresinol etc.), anthocyanidins
(examples: cyanidin, delphinidin, pelargonidin, peonidin,
petunidin, and malvidin etc.), anthraquinones (examples:
physcion, chrysophanol, aloe-emodin, rhein etc.), coumarins
(examples: osthole, anthogenol, ammoresinol, phellodenol
etc.), and stilbenes (examples: resveratrol, piceatannol,
rhapontigenin, isorhapontigenin, pinosylvin, pterostilbene etc.)
FIGURE 3 | Different classes of plant polyphenols with their basic structural scaffolds. Structural scaffolds represent the chemistry behind various classesof
polyphenolic substances.
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Rudrapal et al. Dietary Polyphenols Against Human Diseases

(Serrano et al., 2009;Reinisalo et al., 2015;Abotaleb et al., 2020;
Cui et al., 2020;Luca et al., 2020). Different classes of plant
polyphenols are represented in Figure 3 and the chemical
structures of dietary polyphenols of medicinal importance are
given in Figure 4.
In plant derived polyphenolic compounds, flavonoids
comprise the largest group with an approximately 10,000
natural analogues. They are hydroxylated aromatic compounds
often exist as bright coloured (yellow to red) pigments in the
plants and microbes (Cook and Samman, 1996). The structural
framework of flavanoid compounds comprises benzo-γ-pyrone
ring system (C6-C3-C6 backbone). Structurally, they are
characterized as C15 compounds and composed of two
phenolic (C6) rings which are linked by a bridge of
heterocyclic pyrone rings. Two phenolic rings are denoted as
A and B rings, whereas, connecting heterocyclic rings is
considered as C ring in the structural skeleton (Cook and
Samman, 1996;Tresserra-Rimbau et al., 2018).
Phenolic acids are dominant category under the non-flavonoid
class of polyphenols and further subdivided into hydroxybenzoic
acids (C1-C6 backbone) and hydroxycinnamic acids (C3-C6
backbone) and structurally characterized by a carboxylic acid
group linked to the phenolic ring (Durazzo et al., 2019). They
generally exist in the plants either in free form or esterified form.
They also exist as a conjugate with sugar moiety and proteins
often and hydrolysable on acid or alkali treatment. Many foods
and beverages like wine, tea, coffee chocolate, vegetables, whole
grains and fruits contain hydroxycinnamic acid in very high
concentrations (Tsao, 2010;Panche et al., 2016).
Stilbenes are biosynthesized by plants during external
influence such as infection or injury. They contain C6-C2-C6
backbone and structurally represent 1,2-diphenylethylene
nucleus and exist either in the monomeric or oligomeric form.
Resveratrol is a naturally occurring important bioactive
compound that comes under this category (Tresserra-Rimbau
et al., 2018;Liu et al., 2019).
Like stilbenes, a coumarin type of polyphenols, also synthesize
and accumulate in the plant tissues due to the abiotic stress and
microbial attacks. They are composed of 1,2-benzopyrone
skeleton (α-chromone). They also frequently exist in the
prenylated form. Coumarin cores are often used as a template
in the synthesis of various pharmacologically important novel
compounds (Shen et al., 2009;Tresserra-Rimbau et al., 2018).
Lignans are a comparatively less abundant class of phenolic
compounds structurally characterized by a dibenzylbutane
skeleton. These types of compounds are generally found in
higher plants (gymnosperms, angiosperms, pteridophytes etc.).
Often they are found in the plant material in bound form and
make difficulty in extraction (Shen et al., 2009;Tresserra-Rimbau
et al., 2018).
Anthocyanidins are the bright coloured (blue, red, or purple
pigments) flavonoid compounds found in the flowers, fruits and
leaves etc. These are positively charged compounds containing
flavylium cations and often occur as chloride salts (Shen et al.,
FIGURE 4 | Chemical structures of some common dietary polyphenols
of medicinal importance.
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Rudrapal et al. Dietary Polyphenols Against Human Diseases

2009). Anthocyains are composed of one or more sugar moieties
in the C-3 position of the C ring. Frequently these compounds are
found in the plants as a conjugate with phenolic acids and other
organic acids. The de-glycosylated forms of anthocyanins are
called anthocyanidins. Variation in the colour of the anthocyanin
compounds is reliant to the pH acylation and methylation -OH
groups attached to the A and B ring and also pH of the
environment (Khoo et al., 2017).
Proanthocyanidins are the dimer or trimer of flavanols in
condensed form, also known as condensed tannins. Based on the
interflavanic linkages, they can be divided as type A (C2–O–C7 or
C2–O–C5 bonding), or type-B (C4–C6 or C4–C8). They often
produced from flavanol rich materials during fermentation
(Khoo et al., 2017). Open C rings containing flavanoids are
categorized as chalcones. Chalcone compounds exerts a
common chemical scaffold of 1,3- diaryl-2-propen-1-one
which is also known as chalconoid (Zhuang et al., 2017).
Dietary polyphenolics are most abundantly found in
seasonings (examples: cloves, dried peppermint, star anise,
celery seed, rosemary, spearmint, ginger, ceylan cinnamon,
parsley, marjoram, vinegar), cocoa products (examples: cocoa
powder, dark chocolate, milk chocolate), fruits (examples: black
chokeberry, black elderberry, lowbush blueberry, blackcurrant,
highbush blueberry, plum, sweet cheery, blackberry, strawberry,
red raspberry, prune, black grape, apple, peach, redcurrant,
apricot, nectarine, quince, pear, green grape), seeds (examples:
flaxseed, chestnut, hazelnut, pecan nut, soy flour, roasted
soyabean, almond, soy, black bean), vegetables (examples:
black olive, green olive, globe artichoke heads, red chicory, red
onion, green chicory, spinach, shallot, yellow onion), cereals
(examples: whole grain hard wheat flour, refined maize flour,
whole grain rye flour, whole grain wheat flour, whole grain oat
flour), alcoholic beverages (examples: red wine, white wine, rose
wine), non-alcoholic beverages (examples: coffee, black tea, green
tea, pure apple juice, pure pomegranate juice, pure blood orange
juice, pure grapefruit juice, pure lemon juice, chocolate beverage
with milk, soy milk, pure pummelo juice) and oils (examples:
extra-virgin olive oil, rapeseed oil) (Pandey and Rizvi, 2009;
Pérez-Jiménez et al., 2010;Reinisalo et al., 2015).
POLYPHENOLS AND THEIR PROTECTIVE
EFFECTS AGAINST HUMAN DISEASES
Aging and Neurodegenerative Disorders
Aging causes a variety of harmful health effects, increasing the
risk of neurodegenerative disorders, atherosclerosis,
osteophorosis, cancers and even death. The free radical theory
of aging (also known as OS theory) is well accepted as the aging
progresses. Although free radicals may be a key player in the
aging process, they do not play any central role in that. Numerous
cell-centric hypotheses has also been attributed in aging and
FIGURE 5 | Protective roles of dietary polyphenols against aging and neurodegenerative disorders. Abbreviations: Nrf 2: nuclear factor erythroid 2, HO-1: heme
oxygenase-1, NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells, P38 MAPK: protein 38 mitogen-activated protein kinase, JNK: Jun N-terminal
kinase, PGE2: prostaglandin E2.
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Rudrapal et al. Dietary Polyphenols Against Human Diseases

related disorders (Tabibzadeh, 2021). Since the potential of
antioxidative and repair pathways declines with age, oxidative
damage to biological tissues rises (Rizvi and Maurya, 2007). In
aging, the accumulation of ROS causes OS to brain biomolecules
(proteins, DNA, and lipids) leading to progression of
neurodegenerative diseases (Barnham et al., 2004). The most
common neurodegenerative disease is Alzheimer’s disease (AD),
which affects millions of people across the globe. Studies reveal
that oxidative disruption plays a critical role in several major
brain dysfunctions such as AD, Parkinson’s disease (PD),
memory loss, amyotrophic lateral sclerosis (ALS), depression
multiple sclerosis etc. (Pandey and Rizvi, 2010).
The consumption of antioxidant-rich diets decreases the
harmful consequences of aging and neurodegenerative illness.
Fruits and vegetables contain polyphenolic compounds with
antioxidants and anti-inflammatory activities have been well
reported to exhibit anti-aging properties in rats and mice
(Joseph et al., 2005). Anthocyanins found in abundance in
bright colored fruits such as berry fruits, tomatoes, oranges
etc. have strong antioxidant and anti-inflammatory properties,
inhibiting lipid peroxidation as well as cyclo-oxygenase (COX-1
and COX-2) pathways (Reis et al., 2016). Dietary supplements
containing elevated amounts of flavonoids from strawberries,
lettuce, or blueberries aid in the reversal of age-related
discrepancies in the brain and behavioral control in aged rats
(Shukitt-Hale et al., 2008). Tea catechins have antioxidant
properties that might be associated with anti-aging. The
in vitro effect of tea catechins on erythrocyte malondialdehyde
(MDA), reduced glutathione (GSH), and on membrane
sulphydryl (-SH) group in humans has been reported by
Maurya and Rizvi (2009). Polyphenols can also help to reduce
the negative effects of aging on the brain and nervous system.
EGCG reduces the progression of ALS (in a mouse model), which
is crucial for their significance in the protection of the aging of
brain (Xu et al., 2006). Resveratrol, a polyphenol found in grapes
and red wine, has anti-aging property.
Fruits and vegetables rich in polyphenols are potential
neuroprotective agents which can modulate many cellular
processes like apoptosis, redox balance signaling,
differentiation and proliferation. Polyphenols being
antioxidative agents can protect against various
neurological diseases. Resveratrol shows neuroprotective
effect against models of AD (Rahman et al., 2020).
Resveratrol hunts O
2−
•and OH
−
•free radicals and lipid
hydroperoxyl free radicals. Epigallocatechin gallate (EGCG)
protects against the neurotoxin MPTP (N-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine) which can induce Parkinson’s-
like disease, through competitively inhibition of drug
absorption or by scavenging MPTP-mediated radical
formation (Rossi et al., 2008). Figure 5 delineates the
protective roles of dietary polyphenols against aging and
neurodegenerative disorders.
FIGURE 6 | Protective effects of dietary polyphenols against CVDs. Abbreviations: Bax: BCL2 associated X apoptosis regulator, IL6: interleukin 6, CRP: C-reactive
protein, IL8: interleukin 8, Bcl-2: B-cell lymphoma 2, Caspase-3: cysteine-aspartic acid protease 3, TNF-alpha: tumour necrosis factor - alpha, P-JAK 2: protein Janus
kinase 2, STAT 3: signal transducer and activator of transcription 3
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Rudrapal et al. Dietary Polyphenols Against Human Diseases

Cardiovascular Diseases
OS can be the primary or secondary reason for various CVDs.
Preclinical evidence support that OS is linked to a variety of
CVDs, including atherosclerosis, ischemia, stroke,
cardiomyopathy, cardiac hypertrophy, and hypertension, as
well as congestive heart failure (CHF) (Vita, 2005;Bahoran
et al., 2007;Ceriello, 2008;Bonnefont-Rousselot, 2016).
Consumption of polyphenol-rich foods reduces risk of CVDs
(Khan et al., 2021). Recent studies indicate that polyphenols also
exert beneficial effects on vascular disorders by blocking platelet
aggregation as well as by preventing oxidation of low-density
lipoprotein (LDL), ameliorating endothelial dysfunction,
reducing blood pressure, improving antioxidant defenses and
alleviating inflammatory responses. Polyphenols are powerful
regulators of LDL oxidation, which is believed to be the main
mechanism in the progression of atherosclerosis (Nardini et al.,
2007). Polyphenols guard against CVDs because of their anti-
inflammatory, antioxidant, antiplatelet effects, and also by
increasing high-density lipoprotein (HDL) level. Dietary
flavonoids may reduce endothelial disorders linked with
various risk factors for atherosclerosis before plaque creation
(Khan et al., 2021). Tea catechins suppress smooth muscle cell
penetration and proliferation in the arterial wall (Bhardwaj and
Khanna, 2013). Resveratrol inhibits platelet aggregation by
selectively inhibiting cyclooxygenase 1 (COX-1), which
augments production of thromboxane A2, platelet aggregation,
and vasoconstrictor inducer (Senoner and Dichtl, 2019). It
increases nitric oxide signaling in the endothelium, resulting in
vasodilation (Harikumar and Aggarwal, 2008;Shi et al., 2019).
Figure 6 depicts the protective effects of dietary polyphenols
against CVDs.
Diabetes Mellitus
Abnormality in glucose metabolism leads to hyperglycemia and
consequently diabetes mellitus (type-1 and type-2). Apart from
co-morbidities like heart disease or stroke, chronic complications
may develop in diabetes such as diabetic retinopathy affecting
eyes cause blindness, nephropathy altered renal functions, and
neuropathy causing nerve damage and numbness/paralysis (Rizvi
and Zaid, 2001;Rizvi and Zaid 2005;Junejo et al., 2017;Junejo
et al., 2018;Junejo et al., 2020a;Junejo et al., 2020b;Hussain et al.,
2021;Junejo et al., 2021). Apigenin derivative possesses strong
antidiabetic activity extending protection against the variations
throughout OS in diabetes (Junejo et al., 2021). Quercetin
decreases lipid peroxidation and inhibits cellular oxidation in
diabetes (Pandey and Rizvi, 2009). Resveratrol prevents
cytotoxicity and OS caused by excessive glucose levels.
Resveratrol decreases diabetes-induced kidney alterations
FIGURE 7 | Protective roles of dietary polyphenols against diabetes. Abbreviations: IL-1 beta: interleukin-1β, IL-6/1B: interleukin-6, P13K-PKB: phosphoinositide-
3-kinase–protein kinase B, Akt: AK strain transforming, HMG CoA reductase: β-hydroxy-β-methylglutaryl-CoA reductase, SREBP-1: sterol regulatory element-binding
protein 1, VLDL: very low density lipoproteins, TG: Triglycerides, HB: Hemoglobin.
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Rudrapal et al. Dietary Polyphenols Against Human Diseases

(diabetic nephropathy) and thereby increases renal disorder and
OS in diabetic rats. Resveratrol reduces secretion of insulin and
deferrers insulin resistance onset which may be due to the
inhibition of K
+
ATP and K
+
V channels in βcells (Chen
et al., 2007;Oyenihi et al., 2016). The polyphenols of Hibiscus
sabdariffa weaken diabetic nephropathy in terms of serum lipid
profile and kidney oxidative markers (Lee et al., 2009). H.
sabdariffa also contains flavonoids, protocatechuic acid, and
anthocyanins. The ameliorating effects of a high antioxidant
polyphenol supplement of green tea extract, pomegranate
extract and ascorbic acid on OS due to type 2 diabetes have
been proved through decreased LDL, reduced plasma MDA, and
increased HDL indicating better antioxidant potential with
augmented total plasma GSH with preventive action against
cardiovascular complications as well (Fenercioglu et al., 2010).
The flavonoid rutin also has antidiabetic effects (Ghorbani, 2017).
FIGURE 8 | Protective effects of dietary polyphenols against cancer, infectious illness and inflammatory diseases. Abbreviations: ROS: reactive oxygen species,
RNS: reactive nitrogen species, P53: tumor protein 53, P21: tumor protein 21, CDC2: cell division control 2, CASPASE-9: cysteine-dependent aspartate-directed
protease-9, APAF-1: apoptotic protease activating factor-1, Cyt c: cytochrome c, Cytp450: cytochrome P450, G2/M arrest: cell cycle “gap2”mitotic phase arrest, ASK-
1: apoptosis signal-regulating kinase-1, PEG 2: polyethylene glycol 2, COX 2: cyclooxygenase 2, MAPK: mitogen-activated protein kinase, P38: mitogen-activated
protein kinase protein 38, ERK: extracellular signal-regulated kinase, JNK: Jun N-terminal kinase, B-cells: B lymphocytes cells, TNF-alpha: Tumor necrosis factor - alpha,
TGF-β: transforming growth factor beta, Ls: lipid hydro-peroxides, MMPs: matrix metalloproteinases, PGs: prostaglandins.
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Rudrapal et al. Dietary Polyphenols Against Human Diseases

Figure 7 outlines the protective effects of dietary polyphenols
against diabetes mellitus.
Cancer
The occurrence of cancer (or malignant diseases) is augmented
with OS along with an increase in the amount of free radicals like
ROS causing biomolecular (DNA) and tissue damages. ROS-
induced DNA damage results in induction/replication errors,
transcriptional arrest, and/or genomic instability allied with
carcinogenesis (Federico et al., 2007;Khansari et al., 2009).
Studies suggest that a diet that includes regular consumption
of fruits and vegetables (rich in polyphenols such as catechins,
resveratrol, ellagic acid, naringenin, quercetin etc.) significantly
lowers the risk of developing many cancers. The chemopreventive
action of polyphenols includes estrogenic and antiestrogenic
involvement, antiproliferation, cell cycle arrest or apoptosis
activation, oxidation resistance, induction of detoxification
enzymes, host immune system regulation, anti-inflammatory
activity, and improvements in cellular signaling (García-
Lafuente et al., 2009). Polyphenols affect pro-carcinogen
metabolism by moderating the cytochrome P450 enzymes
expression involved in carcinogen stimulation (Talalay et al.,
1988). Black tea polyphenols like EGCG, theaflavins and
thearubigins have potent anticancer properties (Shankar, 2008;
Sharma and Rao, 2009). Tea catechins with cancer prevention
efficacy inhibit the conversion of intraepithelial prostate lesions to
cancer. In prostate carcinoma cells, polyphenols from black tea
suppress proliferation of increasing apoptosis (Kim et al., 2014).
Anti-carcinogenic effects of resveratrol are due to the antioxidant
function, which inhibits hydroperoxidase, Akt (PI3K-Akt)
signaling pathway, matrix metalloprotease-9, NF-kB, protein
kinase C, cyclooxygenase, focal adhesion kinase and Bcl-2
(B cell lymphoma 2) biomarkers/enzymes (Athar et al., 2007).
Infectious Diseases
The emergence of multi-drug resistant (MDR) pathogens has
become a global threat and a cause of significant morbidity and
mortality around the world. Augmenting the OS pathway and
induction of ROS formation has emerged as potential
antimicrobial target in recent times. Flavonoids exhibit broad
spectrum of antimicrobial actions through different mechanisms
which are often observed little different than those of conventional
antibiotics and thus could be of importance in the improvement of
antimicrobial therapeutics (Dwyer et al., 2009;Rosillo et al., 2016).
During bacterial infection, the host immune response leads to
inflammation due to the generation of ROS, and consequently
leading to OS. Increased OS may lead to the vulnerability of the
infection and also triggers the malfunctioning of cellular
metabolism (Kim et al., 2019). Flavonoids are well known for
their modulatory effect against OS in the human body by
scavenging free radicals and chelating the metallic ions (Ivanov
et al., 2017;Tresserra-Rimbau et al., 2018). It is reported that many
antibacterial drugs kill bacteria by activation of ROS pathways,
whereas, a mild amount of ROS is proven to be beneficial to the
microorganism for their signaling mechanisms. The therapeutic
role of antioxidant polyphenols in mitigating OS-related tissue
damage and inflammations in bacterial and viral infections is well
defined. Black tea polyphenols have in vitro antiviral properties
(Wu et al., 2015;Górniak et al., 2019). EGCG, the main constituent
of polyphenol, has antiviral activities on a diverse range of viruses
such as human immunodeficiency virus, influenza virus and
hepatitis C virus (Steinmann et al., 2013). Polyphenolic
compounds that have been reported in very preliminary in
silico and in vitro studies to exhibit anti-SARS-CoV activity
include quercetin, acacetin, apigenin, baicalein, hesperidin,
morin, rutin, naringin, naringenin, (–)-catechin, (–)-catechin
gallate, (–)-gallocatechin gallate, diosmin, daidzein, genistein,
glycitein, kaempferol, luteolin, myricetin, silibinin, silymarin,
orientin, curcumin, and oroxylin A (Sharma and Rao, 2009;
Suzuki et al., 2016;Praditya et al., 2019;Vestergaard and
Ingmer, 2019;Jennings and Parks, 2020;Gansukh et al., 2021).
Inflammatory Diseases
Inflammation is body’s normal response to illness and infection.
When the immune system attacks the body’s own tissues, it results in
inflammation. Rheumatoid arthritis (RA) is an example of an
inflammatory disease that affects the joints (Zheng et al., 2015).
The production of ROS in injured joints promotes inflammatory
reactions. The cytokines generated play a role in the
immunoregulatory and tissue damage processes developing clinical
manifestations in RA (Direito et al., 2021). As human antioxidant
defense systems are inefficient, exogenous antioxidants must be used
to fight excess ROS (Sung et al., 2019;Direito et al., 2021).
Polyphenolshavetheabilitytoregulatetheinflammatory
pathways of common arthropathies such as gout, osteoarthritis
andRA.EGCG,quercetin,resveratrol,p-coumaric acid, luteolin,
curcumin, kaempferol and apigenin are the most effective
polyphenols against arthritis (Ahmed et al., 2006;Pragasam, 2012;
Riegsecker et al., 2013;Abba et al., 2015;Chang et al., 2015;Daily
et al., 2016;Aziz et al., 2018). Tea flavan-3-ols like EGCG are useful in
RA (Jin et al., 2020). The effects of quercetin on disease severity and
inflammation in women with RA showed considerably decreased
early morning stiffness and discomfort and after-activity pain (Javadi
et al., 2017). Kaempferol improved arthritis severity, cartilage
degradation, inflammation and bone erosion in collagen induced
arthritic (CIA) male DBA/J1 mice (Lee et al., 2018). Resveratrol
shows its anti-rheumatoid arthritis properties with reduced RA
patients’swelling, tenderness, and disease activity by lowering the
biochemical indicators of inflammation like MMP-3, IL-6, ESR,
C-reactive protein, and undercarboxylated osteocalcin (Khojah
et al., 2018;Meng et al., 2021). The protective effects of dietary
polyphenols against cancer, infectious illness and inflammatory
diseases are depicted in Figure 8.
PRO-OXIDATIVE EFFECTS OF DIETARY
POLYPHENOLS
Although much research has been focused on the antioxidant
properties of plant-derived polyphenols against chronic diseases
(neurodegenerative diseases, cardiovascular complications, cancer,
diabetes, bacterial infections, and inflammations) as described
above, they can also act as pro-oxidants in the biological systems
(in vivo). The pro-oxidative action of polyphenols depends on certain
Frontiers in Pharmacology | www.frontiersin.org February 2022 | Volume 13 | Article 80647011
Rudrapal et al. Dietary Polyphenols Against Human Diseases

factors such as their solubility characteristics, chelating behavior,
metal-reducing potential etc. and the pH at the site of action (Babich
et al., 2011). A variety of dietary polyphenols including gallic acid,
ellagic acid, quercetin, myricetin, rutin, kaempferol, resveratrol,
catechins, EGCG etc. exhibit such dual (antioxidant and pro-
oxidative) roles. However, the anticancer, antiobesity and
antimicrobial effects of green tea polyphenols (EGCG, ECG) are
primarily because of their antioxidant activity, whereas the harmful
toxic effects are due to their pro-oxidative effect (Ouyang et al., 2020).
The pro-oxidant effect of EGCG (major ingredient of tea) is observed
at considerably higher dose than that of the dose required for
antioxidant action. The pro-oxidant capacity of tea polyphenols is
such that they directly lead to the generation of ROS, and indirectly
induces apoptosis and death of cancer cells (León-González et al.,
2015). The grape seed extract exhibits in vivo pro-oxidant activity to
an appreciable extent depending on dose, duration of administration,
and other dietary components. As pro-oxidant molecules,
polyphenols can exert cytotoxic effects against cancer cells by
achieving toxic levels of ROS. Increased ROS level eventually
induces DNA degradation in the presence of metal ions such as
copper, which ultimately leads to cell death (D’Angelo et al., 2017).
The pro-oxidant effect may also be associated with a pro-apoptotic
function in various types of tumor cells (Khan et al., 2012). The pro-
oxidative effect of resveratrol may counteract the tissue damage
induced by oxidative stress (Chedea et al., 2021). Further,
polyphenols including flavonoids and anthocyanins also play a
potential pro-oxidant role and protects our body from severe
cellular oxidative stress. For instance, red wine polyphenols may
help modulate the antioxidant potential of erythrocytes, protecting
them against oxidative stress (Chedea et al., 2020).
CONCLUSION
Food phenolics are gaining importance in research as they have the
potential to improve human health. Over 8,000 polyphenols have
been reported from plants, and several hundreds of dietary
polyphenols have been found in foods. Owing to their potent
antioxidant capacity because of the presence of hydroxyl groups in
their structures, polyphenols can effectively scavenge ROS and thus
fight against OS induced pathological conditions or human
diseases. Evidence from diverse in vitro studies discussed here
supports that dietary sourced polyphenols plays a potential
protective role in the prevention of neurodegenerative diseases,
CVDs, diabetes, cancer, inflammation-related diseases, and
infectious illness. However, prospective further research with
adequate pre-clinical and clinical investigations could lead to
the development dietary polyphenolic compounds as potent
therapeutic candidates against various chronic human diseases.
AUTHOR CONTRIBUTIONS
MR conceptualized the topic, researched and analyzed the
literature, and wrote the manuscript, including interpretations.
SK and SP analyzed background literature and drafted portions of
the manuscript. AD, JK, AD, MAA, MNA and FA revised the
manuscript critically for the intellectual content. PD and RD
provided substantial scholarly support in literature review, data
curation and interpretation. All authors approved the final
version of the manuscript, ensured the accuracy and integrity
of the work, and agreed to be accountable for all aspects of
the work.
ACKNOWLEDGEMENTS
The authors would like to thank the Deanship of Scientific
Research, Abdulrahman Bin Faisal University, Dammam,
Saudi Arabia for providing Grant through project number
COVID19-2020-002-IRMC. Authors sincerely thank Sagarika
Chandra for her kind help in editing figures of the manuscript.
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