Oxidative Medicine and Cellular Longevity 2009 (Nov); 2 (5): 270–278 ~ FULL TEXT
Kanti Bhooshan Pandey and Syed Ibrahim Rizvi
Department of Biochemistry,
University of Allahabad,
Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. In the last decade, there has been much interest in the potential health benefits of dietary plant polyphenols as antioxidant. Epidemiological studies and associated meta-analyses strongly suggest that long term consumption of diets rich in plant polyphenols offer protection against development of cancers, cardiovascular diseases, diabetes, osteoporosis and neurodegenerative diseases. Here we present knowledge about the biological effects of plant polyphenols in the context of relevance to human health.
KEYWORDS: polyphenols, antioxidants, bioavailability, human diseases
From the FULL TEXT Article:
Polyphenols are naturally occurring compounds found largely in
the fruits, vegetables, cereals and beverages. Fruits like grapes,
apple, pear, cherries and berries contains up to 200–300 mg
polyphenols per 100 grams fresh weight. The products manufactured
from these fruits, also contain polyphenols in significant
amounts. Typically a glass of red wine or a cup of tea or coffee
contains about 100 mg polyphenols. Cereals, dry legumes and
chocolate also contribute to the polyphenolic intake. [1, 2]
Polyphenols are secondary metabolites of plants and are generally
involved in defense against ultraviolet radiation or aggression
by pathogens.  In food, polyphenols may contribute to the
bitterness, astringency, color, flavor, odor and oxidative stability.
Towards the end of 20th century, epidemiological studies and
associated meta-analyses strongly suggested that long term consumption
of diets rich in plant polyphenols offered some protection
against development of cancers, cardiovascular diseases,
diabetes, osteoporosis and neurodegenerative diseases [4, 5] (Figure 1).
Polyphenols and other food phenolics are the subject of increasing
scientific interest because of their possible beneficial effects on
human health. This review focuses on the present understanding
of the biological effects of dietary polyphenols and their importance
in human health and disease.
Structure and Classes of Polyphenols
More than 8,000 polyphenolic compounds have been identified
in various plant species. All plant phenolic compounds
arise from a common intermediate, phenylalanine, or a close
precursor, shikimic acid. Primarily they occur in conjugated
forms, with one or more sugar residues linked to hydroxyl
groups, although direct linkages of the sugar (polysaccharide or
monosaccharide) to an aromatic carbon also exist. Association
with other compounds, like carboxylic and organic acids,
amines, lipids and linkage with other phenol is also common. 
Polyphenols may be classified into different groups as a function
of the number of phenol rings that they contain and on the basis
of structural elements that bind these rings to one another. The
main classes include phenolic acids, flavonoids, stilbenes and
lignans.2 Figure 2 illustrates the different groups of polyphenols
and their chemical structures.
Phenolic acids are found abundantly in foods and divided into
two classes: derivatives of benzoic acid and derivatives of cinnamic
acid. The hydroxybenzoic acid content of edible plants is
generally low, with the exception of certain red fruits, black radish
and onions, which can have concentrations of several tens
of milligrams per kilogram fresh weight.  The hydroxycinnamic
acids are more common than hydroxybenzoic acids and consist
chiefly of p-coumaric, caffeic, ferulic and sinapic acids.
Favonoids comprise the most studied group of polyphenols.
This group has a common basic structure consisting of two aromatic
rings bound together by three carbon atoms that form
an oxygenated heterocycle (Fig. 2). More than 4,000 varieties
of flavonoids have been identified, many of which are responsible
for the attractive colours of the flowers, fruits and leaves.8
Based on the variation in the type of heterocycle involved, flavonoids
may be divided into six subclasses: flavonols, flavones,
flavanones, flavanols, anthocyanins
and isoflavones (Figure 3). Individual
differences within each group arise
from the variation in number and
arrangement of the hydroxyl groups
and their extent of alkylation and/or
glycosylation.  Quercetin, myricetin,
catechins etc., are some most common
Stilbenes contain two phenyl moieties
connected by a two-carbon
methylene bridge. Occurrence of
stilbenes in the human diet is quite
low. Most stilbenes in plants act as
antifungal phytoalexins, compounds
that are synthesized only in response
to infection or injury. One of the best
studied, naturally occurring polyphenol
stilbene is resveratrol (3,4',5-trihydroxystilbene),
found largely in grapes. A product of grapes, red wine
also contains significant amount of resveratrol.
Lignans are diphenolic compounds
that contain a 2,3-dibenzylbutane
structure that is formed by
the dimerization of two cinnamic
acid residues (Fig. 2). Several lignans,
such as secoisolariciresinol, are
considered to be phytoestrogens. The richest dietary source is
linseed, which contains secoisolariciresinol (up to 3.7 g/kg dry
weight) and low quantities of matairesinol. 
Occurrence and Content
Distribution of phenolics in plants at the tissue, cellular and sub
cellular levels is not uniform. Insoluble phenolics are found in
cell walls, while soluble phenolics are present within the plant
cell vacuoles.  Certain polyphenols like quercetin are found in
all plant products; fruit, vegetables, cereals, fruit juices, tea, wine,
infusions etc., whereas flavanones and isoflavones are specific to
particular foods. In most cases, foods contain complex mixtures
of polyphenols. The outer layers of plants contain higher levels of
phenolics than those located in their inner parts.  Numerous factors
affect the polyphenol content of plants, these include degree
of ripeness at the time of harvest, environmental factors, processing
and storage. Polyphenolic content of the foods are greatly
affected by environmental factors as well as edaphic factors like
soil type, sun exposure, rainfall etc. The degree of ripeness considerably
affects the concentrations and proportions of various
polyphenols.  In general, it has been
observed that phenolic acid content
decreases during ripening, whereas
anthocyanin concentrations increase.
Many polyphenols, especially phenolic
acids, are directly involved in the
response of plants to different types
of stress: they contribute to healing
by lignifications of damaged areas
possess antimicrobial properties, and
their concentrations may increase
after infection. 
Another factor that directly affects
the polyphenol content of the foods
is storage. Studies have proved that
polyphenolic content of the foods
change on storage, the reason is easy
oxidation of these polyphenols. 
Oxidation reactions result in the formation
of more or less polymerized
substances, which lead to changes in
the quality of foods, particularly in
color and organoleptic characteristics.
Such changes may be beneficial,
as is the case with black tea or harmful
as in browning of fruit. Storage
of wheat flour results in marked loss
of phenolic acids.  After six months
of storage, flour contained the same
phenolic acids in qualitative terms,
but their concentrations were 70%
lower compared with fresh. Cold
storage, in contrast, has slight effect
on the content of polyphenols in
apples, pears or onions.  Cooking
also has a major effect on concentration of polyphenols. Onions
and tomatoes lose between 75% and 80% of their initial quercetin
content after boiling for 15 min, 65% after cooking in a
microwave oven, and 30% after frying. 
Bioavailability of Polyphenols
Bioavailability is the proportion of the nutrient that is
digested, absorbed and metabolized through normal pathways.
Bioavailability of each and every polyphenol differs however
there is no relation between the quantity of polyphenols in food
and their bioavailability in human body. Generally, aglycones
can be absorbed from the small intestine; however most polyphenols
are present in food in the form of esters, glycosides or polymers
that cannot be absorbed in native form.  Before absorption,
these compounds must be hydrolyzed by intestinal enzymes or by
colonic microflora. During the course of the absorption, polyphenols
undergo extensive modification; in fact they are conjugated in
the intestinal cells and later in the liver by methylation, sulfation
and/or glucuronidation. 
As a consequence, the forms reaching the blood and tissues are different from those present in food and
it is very difficult to identify all the metabolites and to evaluate
their biological activity.  Importantly it is the chemical structure
of polyphenols and not its concentration that determines the rate
and extent of absorption and the nature of the metabolites circulating
in the plasma. The most common polyphenols in our diet
are not necessarily those showing highest concentration of active
metabolites in target tissues; consequently the biological properties
of polyphenols greatly differ from one polyphenol to another.
Evidence, although indirect, of their absorption through the gut
barrier is given by the increase in the antioxidant capacity of the
plasma after the consumption of polyphenols-rich foods. [20, 31]
Polyphenols also differs in their site of absorption in humans.
Some of the polyphenols are well absorbed in the gastro-intestinal
tract while others in intestine or other part of the digestive
tract. In foods, all flavonoids except flavanols exist in glycosylated
forms. The fate of glycosides in the stomach is not clear
yet. Most of the glycosides probably resist acid hydrolysis in the
stomach and thus arrive intact in the intestine  where only aglycones
and few glucosides can be absorbed. Experimental studies
carried out in rats  showed that the absorption at gastric level is
possible for some flavonoids, such as quercetin, but not for their
glycosides. Moreover it has been recently shown that, in rats and
mice, anthocyanins are absorbed from the stomach. [17, 24]
It was suggested that glucosides could be transported into
enterocytes by the sodium dependent glucose transporter SGLT1,
and then hydrolyzed by a cytosolic β-glucosidase. However the
effect of glucosylation on absorption is less clear for isoflavones
than for quercetin.  Proanthocyanidins differ from most of
other plant polyphenols because of their polymeric nature and
high molecular weight. This particular feature should limit their
absorption through the gut barrier, and oligomers larger than
trimers are unlikely to be absorbed in the small intestine in their
native forms. [17, 25]
It was observed that the hydroxycinnamic acids, when ingested
in the free form, are rapidly absorbed by the small intestine and
are conjugated as the flavonoids.  However these compounds are
naturally esterified in plant products and esterification impairs
their absorption because intestinal mucosa, liver and plasma do
not possess esterases capable of hydrolyzing chlorogenic acid to
release caffeic acid, and hydrolysis can be performed only by the
microflora present in colon.  Though most of the poyphenols get
absorbed in gastrointestinal tract and intestine but there are some
poyphenols which are not absorbed in these locations. These
polyphenols reach the colon, where microflora hydrolyze glycosides
into aglycones and extensively metabolize these aglycones
into various aromatic acids. 
Aglycones are split by the opening of the heterocycle at different
points depending on their chemical structure, and thus
produce different acids that are further metabolized to derivatives
of benzoic acid. After absorption, polyphenols go to several conguation
processes. These processes mainly include methylation,
sulfation and glucuronidation, representing a metabolic detoxication
process, common to many xenobiotics, that facilitates their
biliary and urinary elimination by increasing their hydrophilicity.
The methylation of poyphenols is also quite specific it generally
occurs in the C3-position of the polyphenol, but it could
occur in the C4'-position: in fact a notable amount of 4'-methylepigallocatechin
has been detected in human plasma after tea
ingestion.  Enzymes like sulfo-transferases catalyze the transfer
of a sulfate moiety during process of sulphonation. The sulfation
occurs mainly in the liver, but the position of sulfation for polyphenols
have not been clearly identified yet.  Glucuronidation
occurs in the intestine and in the liver, and the highest rate of
conjugation is observed in the C3-position.  The conjugation
mechanisms are highly efficient and free aglycones are generally
either absent, or present in low concentrations in plasma after
consumption of nutritional doses; an exception are green tea catechins,
whose aglycones can constitute a significant proportion of
the total amount in plasma. 
It is important to identify the circulating metabolites, including
the nature and the positions of the conjugating groups on the
polyphenol structure, because the positions can affect the biological
properties of the conjugates. Polyphenol metabolites circulate
in the blood bound to proteins; in particular albumin represents
the primary protein responsible for the binding. Albumin plays an
important role in bioavailability of polyphenols. The affinity of polyphenols
for albumin varies according to their chemical structure. 
Binding to albumin may have consequences for the rate of clearance
of metabolites and for their delivery to cells and tissues. It is possible
that the cellular uptake of metabolites is proportional to their
unbound concentration. Finally, it is still unclear if the polyphenols
have to be in the free form to exert their biological activity, or the
albumin-bound polyphenols can exert some biological activity. [17, 34]
Accumulation of polyphenols in the tissues is the most important
phase of polyphenol metabolism because this is the concentration
which is biologically active for exerting the effects of
polyphenols. Studies have shown that the polyphenols are able to
penetrate tissues, particularly those in which they are metabolized
such as intestine and liver. Excretion of polyphenols with their
derivatives occurs through urine and bile. It has been observed
that the extensively conjugated metabolites are more likely to be
eliminated in bile, whereas small conjugates, such as monosulfates,
are preferentially excreted in urine. Amount of metabolites
excreted in urine is roughly correlated with maximum plasma
concentrations. Urinary excretion percentage is quite high for
flavanones from citrus fruit and decreases from isoflavones to
flavonols. Thus the health beneficial effects of the polyphenols
depend upon both the intake and bioavailability. 
Polyphenols and Human Diseases
Epidemiological studies have repeatedly shown an inverse association
between the risk of chronic human diseases and the consumption
of polyphenolic rich diet. [1, 5] The phenolic groups in
polyphenols can accept an electron to form relatively stable phenoxyl
radicals, thereby disrupting chain oxidation reactions in
cellular components.  It is well established that polyphenol-rich
foods and beverages may increase plasma antioxidant capacity.
This increase in the antioxidative capacity of plasma following
the consumption of polyphenol-rich food may be explained either
by the presence of reducing polyphenols and their metabolites in
plasma, by their effects upon concentrations of other reducing
agents (sparing effects of polyphenols on other endogenous antioxidants),
or by their effect on the absorption of pro-oxidative
food components, such as iron.  Consumption of antioxidants
has been associated with reduced levels of oxidative damage to
lymphocytic DNA. Similar observations have been made with
plyphenol-rich food and beverages indicating the protective
effects of polyphenols.  There are increasing evidences that as
antioxidants, polyphenols may protect cell constituents against
oxidative damage and, therefore, limit the risk of various degenerative
diseases associated with oxidative stress. [36-38]
Number of studies has demonstrated that consumption of
polyphenols limits the incidence of coronary heart diseases. [39-41]
Atherosclerosis is a chronic inflammatory disease that develops
in lesion-prone regions of medium-sized arteries. Atherosclerotic
lesions may be present and clinically silent for decades before
becoming active and producing pathological conditions such as
acute myocardial infarction, unstable angina or sudden cardiac
death.  Polyphenols are potent inhibitors of LDL oxidation and
this type of oxidation is considered to be a key mechanism in
development of atherosclerosis.  Other mechanisms by which
polyphenols may be protective against cardiovascular diseases
are antioxidant, anti-platelet, anti-inflammatory effects as well
as increasing HDL, and improving endothelial function. 
Polyphenols may also contribute to stabilization of the atheroma
Quercetin, the abundant polyphenol in onion has been
shown to be inversely associated with mortality from coronary
heart disease by inhibiting the expression of metalloproteinase
1 (MMP1), and the disruption of atherosclerotic plaques.  Tea
catechins have been shown to inhibit the invasion and proliferation
of the smooth muscle cells in the arterial wall, a mechanism
that may contribute to slow down the formation of the atheromatous
lesion.  Polyphenols may also exert antithrombotic effects
by means of inhibiting platelet aggregation. Consumption of red
wine or non-alcoholic wine reduces bleeding time and platelet
aggregation. Thrombosis induced by stenosis of coronary artery
is inhibited when red wine or grape juice is administrated. 
Polyphenols can improve endothelial dysfunction associated with
different risk factors for atherosclerosis before the formation of
plaque; its use as a prognostic tool for coronary heart diseases
has also been proposed.  It has been observed that consumption
of black tea about 450 ml increases artery dilation 2 hours after
intake and consumption of 240 mL red wine for 30 days countered
the endothelial dysfunction induced by a high fat diet. 
Long term regular intake of black tea was found to lower blood
pressure in a cross-sectional study of 218 women above 70 years of
age. Excretion of 4-O-methylgallic acid (4OMGA, a biomarker
for tea polyphenols in body) was monitored. A higher consumption
of tea and therefore higher excretion of 4OMGA were associated
with lower blood pressure (BP). Tea polyphenols may be the
components responsible for the lowering of BP. The effect may be
due to antioxidant activity as well as improvement of endothelial
function or estrogen like activity. 
Resveratrol, the wine polyphenol prevents the platelet
aggregation via preferential inhibition of cyclooxygenase
1(COX 1) activity, which synthesizes thromboxane A2, an
inducer of the platelet aggregation and vasoconstrictor.  In
addition to this, resveratrol is capable of relaxing the isolated
arteries and rat aortic rings. The ability to stimulate Ca++-
activated K+ channels and to enhance nitric oxide signaling in
the endothelium are other pathways by which resveratrol exerts
vasorelaxant activity. [49, 50] Direct relation between cardiovascular
diseases (CVDs) and oxidation of LDL is now well established.
Oxidation of LDL particles is strongly associated with
the risk of coronary heart diseases and myocardial infarctions.
Studies have shown that resveratrol potentially inhibits the oxidation
of the LDL particles via chelating copper or by direct
scavenging of the free radicals. Resveratrol is the active compound
in red wine which is attributed for “French Paradox”, the
low incidence of CVD despite the intake of high-fat diet and
smoking among French. [51, 52] Association between polyphenol
intake or the consumption of polyphenol-rich foods and incident
of cardiovascular diseases were also examined in several
epidemiological studies and it was found that consumption of
polyphenol rich diet have been associated to a lower risk of myocardial
infarction in both case-control and cohort studies. 
Effect of polyphenols on human cancer cell lines, is most often
protective and induce a reduction of the number of tumors or
of their growth.  These effects have been observed at various
sites, including mouth, stomach, duodenum, colon, liver, lung,
mammary gland or skin. Many polyphenols, such as quercetin,
catechins, isoflavones, lignans, flavanones, ellagic acid, red wine
polyphenols, resveratrol and curcumin have been tested; all of
them showed protective effects in some models although their
mechanisms of action were found to be different. 
Development of cancer or carcinogenesis is a multistage and
microevolutionary process. Into the three major stages of carcinogenesis:
initiation, promotion and progression. Initiation is a
heritable aberration of a cell. Cells so initiated can undergo transformation
to malignancy if promotion and progression follow.
Promotion, on the other hand, is affected by factors that do not
alter DNA sequences and involves the selection and clonal expansion
of initiated cells.
Several mechanisms of action have been identified for chemoprevention
effect of polyphenols, these include estrogenic/antiestrogenic
activity, antiproliferation, induction of cell cycle arrest
or apoptosis, prevention of oxidation, induction of detoxification
enzymes, regulation of the host immune system, anti-inflammatory
activity and changes in cellular signaling. 
Polyphenols influence the metabolism of pro-carcinogens by
modulating the expression of cytochrome P450 enzymes involved
in their activation to carcinogens. They may also facilitate their
excretion by increasing the expression of phase II conjugating
enzymes. This induction of phase II enzymes may have its origin
in the toxicity of polyphenols.  Polyphenols can form potentially
toxic quinones in the body that are, themselves, substrates of these
enzymes. The intake of polyphenols could then activate these
enzymes for their own detoxication and, thus, induce a general
boosting of our defenses against toxic xenobiotics.  It has been
demonstrated that tea catechins in the form of capsules when
given to men with high-grade prostate intraepithelial neoplasia
(PIN) demonstrated cancer preventive activity by inhibiting the
conversion of high grade PIN lesions to cancer. 
Theaflavins and thearubigins, the abundant polyphenols
in black tea have also been shown to possess strong anticancer
property. Black tea polyphenols were found to inhibit proliferation
and increase apoptosis in Du 145 prostate carcinoma cells.
Higher level of insulin like growth factor-1 (IGF-1) was found to
be associated with a higher risk of development of prostate cancer.
IGF-1 binding to its receptor is a part of signal transduction
pathway which causes cell proliferation.  Black tea polyphenol
addition was found to block IGF-1 induced progression of cells
into S phase of cell cycle at a dose of 40 mg/ml in prostate carcinoma
Quercetin has also been reported to possess anticancer property
against benzo(a)pyrene induced lung carcinogenesis in
mice, an effect attrtibuted to its free radical scavenging activity. 
Resveratrol prevents all stages of development of cancer and has
been found to be effective in most types of cancer including lung,
skin, breast, prostate, gastric and colorectal cancer. It has also
been shown to suppress angiogenesis and metastasis. Extensive
data in human cell cultures indicate that resveratrol can modulate
multiple pathways involved in cell growth, apoptosis and inflammation.
The anti-carcinogenic effects of resveratrol appears to
be closely associated with its antioxidant activity, and it has been
shown to inhibit cyclooxygenase, hydroperoxidase, protein kinase
C, Bcl-2 phosphorylation, Akt, focal adhesion kinase, NFκB,
matrix metalloprotease-9 and cell cycle regulators.  These and
other in vitro and in vivo studies provide a rationale in support
of the use of dietary polyphenols in human cancer chemoprevention,
in a combinatorial approach with either chemotherapeutic
drugs or cytotoxic factors for efficient treatment of drug refractory
Impairment in glucose metabolism leads to physiological imbalance
with the onset of the hyperglycemia and subsequently diabetes
mellitus. There are two main categories of diabetes; type-1 and
type-2. Studies have shown that several physiological parameters
of the body get altered in the diabetic conditions. [61, 62] Long term
effects of diabetes include progressive development of specific
complements such as retinopathy, which affects eyes and lead to
blindness; nephropathy in which the renal functions are altered
or disturbed and neuropathy which is associated with the risks of
amputations, foot ulcers and features of autonomic disturbance
including sexual dysfunctions.
Numerous studies report the antidiabetic effects of polyphenols. Tea catechins have been investigated
for their anti-diabetic potential. [63, 64] Polyphenols may affect
glycemia through different mechanisms, including the inhibition
of glucose absorption in the gut or of its uptake by peripheral
tissues. The hypoglycemic effects of diacetylated anthocyanins
at a 10 mg/kg diet dosage were observed with maltose as a glucose
source, but not with sucrose or glucose.  This suggests that
these effects are due to an inhibition of α-glucosidase in the gut
mucosa. Inhibition of α-amylase and sucrase in rats by catechin
at a dose of about 50 mg/kg diet or higher was also observed.
The inhibition of intestinal glycosidases and glucose transporter
by polyphenols has been studied.  Individual polyphenols,
such as (+)catechin, (-)epicatechin, (-)epigallocatechin,
epicatechin gallate, isoflavones from soyabeans, tannic acid,
glycyrrhizin from licorice root, chlorogenic acid and saponins
also decrease S-Glut-1 mediated intestinal transport of glucose.
Saponins additionally delay the transfer of glucose from stomach
to the small intestine. 
Resveratrol has also been reported to act as an anti-diabetic agent. Many mechanisms have been
proposed to explain the anti-diabetic action of this stilbene,
modulation of SIRT1 is one of them which improves whole-body
glucose homeostasis and insulin sensitivity in diabetic rats. [50, 68] It
is reported that in cultured LLC-PK1 cells, high glucose induced
cytotoxicity and oxidative stress was inhibited by grape seed
polyphenols. Resveratrol inhibits diabetes-induced changes in
the kidney (diabetic nephropathy) and significantly ameliorates
renal dysfunction and oxidative stress in diabetic rats. Treatment
with resveratrol also decreased insulin secretion and delayed the
onset of insulin resistance. A possible mechanism was thought
to be related to the inhibition of K + ATP and K + V channel in
beta cells. 
Onion polyphenols, especially quercetin is known to possess
strong anti diabetic activity. A recent study shows that quercetin
has ability to protect the alterations in diabetic patients during
oxidative stress. Quercetin significantly protected the lipid peroxidation
and inhibition antioxidant system in diabetics.  Hibiscus
sabdariffa extract contains polyphenolic acids, flavonoids, protocatechuic
acid and anthocyanins. A study performed by Lee
et al.  showed that polyphenols present in the extracts from
Hibiscus sabdariffa attenuate diabetic nephropathy including
pathology, serum lipid profile and oxidative markers in kidney.
Ferulic acid (FA) is another polyphenol very abundant in vegetables
and maize bran. Several lines of evidence have shown that
FA acts as a potent anti-diabetic agent by acting at many levels.
It was demonstrated that FA lowered blood glucose followed by a
significantly increased plasma insulin and a negative correlation
between blood glucose and plasma insulin. [72, 73]
Aging is the accumulation process of diverse detrimental changes
in the cells and tissues with advancing age, resulting in an increase
in the risks of disease and death. Among many theories purposed
for the explaining the mechanism of aging, free radical/oxidative
stress theory is one of the most accepted one.  A certain amount
of oxidative damage takes place even under normal conditions;
however, the rate of this damage increases during the aging process
as the efficiency of antioxidative and repair mechanisms
decrease. [75, 76]
Antioxidant capacity of the plasma is related to
dietary intake of antioxidants; it has been found that the intake
of antioxidant rich diet is effective in reducing the deleterious
effects of aging and behavior. Several researches suggest that
the combination of antioxidant/anti-inflammatory polyphenolic
compounds found in fruits and vegetables may show efficacy
as anti-aging compounds. [77, 78] Subset of the flavonoids known
as anthocyanins, are particularly abundant in brightly colored
fruits such as berry fruits and concord grapes and grape seeds.
Anthocyanins are responsible for the colors in fruits, and they
have been shown to have potent antioxidant/anti-inflammatory
activities, as well as to inhibit lipid peroxidation and the inflammatory
mediators cyclo-oxygenase (COX)-1 and -2. 
Fruit and vegetable extracts that have high levels of flavonoids
also display high total antioxidant activity such as spinach, strawberries
and blueberries. It is reported that the dietary supplementations
(for 8 weeks) with spinach, strawberry or blueberry extracts
in a control diet were also effective in reversing age-related deficits
in brain and behavioral function in aged rats.  A recent study
demonstrates that the tea catechins carry strong anti-aging activity
and consuming green-tea rich in these catechins, may delay
the onset of aging. 
Polyphenols are also beneficial in ameliorating the adverse
effects of the aging on nervous system or brain. Paramount
importance for the relevance of food polyphenols in the protection
of the aging brain is the ability of these compounds to cross
the blood-brain barrier (BBB), which tightly controls the influx
in the brain of metabolites and nutrients as well as of drugs.
Resveratrol has been found to consistently prolong the life span;
its action is linked to an event called caloric restriction or partial
food deprivation. 
Grape polyphenol, resveratrol is very recent entry as an antiaging
agent. It has been shown that the early target of the resveratrol
is the sirtuin class of nicotinamide adenine dinucleotide
(NAD)-dependent deacetylases. Seven sirtuins have been identified
in mammals, of which SIRT-1 is believed to mediate the
beneficial effects on health and longevity of both caloric restriction
and resveratrol. 
Resveratrol increased insulin sensitivity, decreased the expression of IGF-1 and increased AMP-activated
protein kinase (AMPK) and peroxisome proliferator-activated
receptor-c coactivator 1a (PGC-1a) activity. When examined
for the mechanism, it activated forkhead box O (FOXO), which
regulates the expression of genes that contribute both to longevity
and resistance to various stresses and insulin-like growth factorbinding
protein 1 (IGFBP-1).  There are experimental evidences
that resveratrol can extend lifespan in the yeast Saccharomyces cerevisiae,
the fruit fly Drosophila melanogaster, the nematode worm
C. elegans, and seasonal fish Nothobranchius furzeri.52 Recently
quercetin has also been reported to exert preventive effect against
Oxidative stress and damage to brain macromolecules is an important
process in neurodegenerative diseases. Alzheimer’s disease is
one of the most common occurring neurodisorder affecting up
to 18 million people worldwide. Because polyphenols are highly
antioxidative in nature, their consumption may provide protection
in neurological diseases.  It was observed that the people
drinking three to four glasses of wine per day had 80% decreased
incidence of dementia and Alzheimer’s disease compared to those
who drank less or did not drink at all. 
Resveratrol, abundantly present in wine scavenges O2
- and OH•
in vitro, as well as lipid hydroperoxyl free radicals, this efficient
antioxidant activity is probably involved in the beneficial effect
of the moderate consume of red wine against dementia in the
elderly. Resveratrol inhibits nuclear factor κB signaling and thus
gives protection against microglia-dependent β-amyloid toxicity
in a model of Alzheimer’s disease and this activity is related with
the activation of the SIRT-1.82 It was found that the consumption
of fruit and vegetable juices containing high concentrations of
polyphenols, at least three times per week, may play an important
role in delaying the onset of Alzheimer’s disease.  Polyphenols
from fruits and vegetables seem to be invaluable potential agents
in neuroprotection by virtue of their ability to influence and
modulate several cellular processes such as signaling, proliferation,
apoptosis, redox balance and differentiation. 
Recently Aquilano et al.  reported that administration of
polyphenols provide protective effects against Parkinson’s disease,
a neurological disorder characterized by degeneration of
dopaminergic neurons in the substantia nigra zona compacta.
Nutritional studies have linked the consumption of green tea
to the reduced risk of developing Parkinson’s disease. In animal
models epigallocatechin gallate (EGCG) has been shown to exert
a protective role against the neurotoxin MPTP (N-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine), an inducer of a Parkinson’slike
disease, either by competitively inhibiting the uptake of
the drug, due to molecular similarity or by scavenging MPTPmediated
radical formation. EGCG may also protect neurons by
activating several signaling pathways, involving MAP kinases
which are fundamental for cell survival. 
The therapeutic role of catechins in Parkinson’s disease is also due to their ability to
chelate iron. This property contributes to their antioxidant activity
by preventing redox-active transition metal from catalyzing
free radicals formation. Moreover, the antioxidant function is
also related to the induction of the expression of antioxidant and
detoxifying enzymes particularly in the brain, which is not sufficiently
endowed of a well-organized antioxidant defense system. 
Maize bran polyphenol, ferulic acid is also reported to be beneficial
in Alzheimer’s disease. This effect is due to its antioxidant
and anti-inflammatory properties. 
Except above explained pathological events, polyphenols show
several other health beneficial effects. Dietary polyphenols
exert preventive effects in treatment of asthma. In asthma the
airways react by narrowing or obstructing when they become
irritated. This makes it difficult for the air to move in and out.
This narrowing or obstruction can cause one or a combination of
symptoms such as wheezing, coughing, shortness of breath and
chest tightness. Epidemiological evidence that polyphenols might
protect against obstructive lung disease come from studies that
have reported negative associations of apple intake with prevalence
and incidence of asthma, and a positive association with
lung function. [91, 92] Increased consumption of the soy isoflavone,
genistein, was associated with better lung function in asthmatic
patients.  Intake of polyphenols is also reported as beneficial in
osteoporosis. Supplementation of diet with genistein, daidzein or
their glycosides for several weeks prevents the loss of bone mineral
density and trabecular volume caused by the ovariectomy. 
Polyphenols also protect skin damages induced from sunlight.
Study on animals provide evidence that polyphenols present in
the tea, when applied orally or topically, ameliorate adverse skin
reactions following UV exposure, including skin damage,
erythema and lipid peroxidation. 
Black tea polyphenols are reported to be helpful in mineral
absorption in intestine as well as to possess antiviral activity.
Theaflavins present in black tea were found to have anti HIV-1
activity. These polyphenols inhibited the entry of HIV-1 cells
into the target cells. HIV-1 entry into the target cell involves
fusion of glycoprotein (GP) and envelope of the virus with the
cell membrane of the host cells. Haptad repeat units present at
N and C terminals of GP41 (membrane protein) on the viral
envelope, fuse to form the fusion active GP41 core, which is a
six-helical bundle. Theaflavins were found to block the formation
of this six-helix bundle required for entry of the virus into the
host.58 Theaflavin 3 3' digallate, and theaflavin 3' gallate were
found to inhibit Severe Acute Respiratory Syndrome (SARS)
corona virus. This antiviral activity was due to inhibition of the
chymotrypsin like protease (3CL Pro) which is involved in the
proteolytic processing during viral multiplication. 
The results of studies outlined in this review provide a current
understanding on the biological effects of polyphenols and
their relevance to human health. Polyphenols or polyphenol
rich diets provide significant protection against the development
and progression of many chronic pathological conditions
K.B.P. is a recipient of Senior Research Fellowship form Council
of Scientific & Industrial Research (CSIR), India.
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