Nutrients 2010, 2, 1106-1131; doi:10.3390/nu2111106
Polyphenols and Human Health: Prevention of Disease and
Mechanisms of Action
David Vauzour, Ana Rodriguez-Mateos, Giulia Corona, Maria Jose Oruna-Concha and
Jeremy P. E. Spencer *
Molecular Nutrition Group, Department of Food and Nutritional Sciences, School of Chemistry,
Food and Pharmacy, The University of Reading, PO Box 226, Reading RG6 6AP, UK;
E-Mails: firstname.lastname@example.org (D.V.); email@example.com (A.R.-M.);
firstname.lastname@example.org (G.C.); email@example.com (M.J.O.-C.)
* Author to whom correspondence should be addressed; E-Mail: firstname.lastname@example.org;
Tel.: +44-0-118-378-8724; Fax: +44-0-118-931-0080.
Received: 25 September 2010; in revised form: 25 October 2010 / Accepted: 1 November 2010 /
Published: 8 November 2010
Abstract: Polyphenols are found ubiquitously in plants and their regular consumption has
been associated with a reduced risk of a number of chronic diseases, including cancer,
cardiovascular disease (CVD) and neurodegenerative disorders. Rather than exerting direct
antioxidant effects, the mechanisms by which polyphenols express these beneficial
properties appear to involve their interaction with cellular signaling pathways and related
machinery that mediate cell function under both normal and pathological conditions. We
illustrate that their interactions with two such pathways, the MAP kinase (ERK, JNK, p38)
and PI3 kinase/Akt signaling cascades, allow them to impact upon normal and abnormal
cell function, thus influencing the cellular processes involved in the initiation and
progression of cancer, CVD and neurodegeneration. For example, their ability to activate
ERK in neurons leads to a promotion of neuronal survival and cognitive enhancements,
both of which influence the progression of Alzheimer’s disease, whilst ERK activation by
polyphenols in vascular endothelial cells influences nitric oxide production, blood pressure
and ultimately CVD risk. The main focus of this review is to provide an overview of the
role that polyphenols play in the prevention of cancer, cardiovascular disease and
neurodegeneration. We present epidemiological data, human intervention study findings, as
well as animal and in vitro studies in support of these actions and in each case we consider
how their actions at the cellular level may underpin their physiological effects.
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Keywords: polyphenols; cancer; cardiovascular disease; neurodegeneration; advanced
glycation end products; signaling pathways
Epidemiological studies suggest that high dietary intake of polyphenols is associated with decreased
risk of a range of diseases including cardiovascular disease (CVD), specific forms of cancer  and
neurodegenerative diseases . In particular, a group of polyphenols known as flavonoids have been
strongly linked with beneficial effects in many human, animal and in vitro studies . With respect to
cardiovascular health, flavonoids may alter lipid metabolism , inhibit low-density lipoprotein (LDL)
oxidation , reduce atherosclerotic lesion formation  inhibit platelet aggregation , decrease
vascular cell adhesion molecule expression , improve endothelial function  and reduce blood
pressure . However, flavonoids have also been shown to exert beneficial cognitive effects and to
reverse specific age-related neurodegeneration  and to exert a variety of anti-carcinogenic effects,
including an ability to induce apoptosis in tumor cells [12-14], inhibit cancer cell proliferation [15,16]
and prevent angiogenesis and tumor cells invasion . This review will detail the evidence for the
role of polyphenols in the context of these three chronic diseases and where relevant, the probable
modes by which they exert their activity in vivo.
2. Polyphenols and Cancer
Cancer refers to a group of diseases that are associated with a disturbance in the control of cell
growth and metabolism . Indeed, the unbalanced control of cellular proliferation is a primary
characteristic of cancer cells and, as such, any molecule capable of inhibiting cancer cell proliferation
may also be useful as a potential chemo-preventive agent [19-22]. There are many different types of
cancer, although breast (predominately women), lung, colorectal and prostate cancer accounts for over
half of all new cases. It is widely believed that a high daily intake of fruit and vegetables helps to
prevent the onset of, and progression of, cancer. Over the past 20 years, case-control studies have
indicated an inverse correlation between regular fruit and vegetable consumption and the development
of various types of cancer [23,24]. More recently, data from large cohort investigations have gone
some way to confirm these epidemiological associations [25-29]. However, there is a degree of
controversy, in that some studies have reported no reduction in bladder, pancreatic and stomach cancer
incidence due to fruit and vegetables intake [30-32] and a recent epidemiological study has provided
evidence for no, or little, association between fruit and vegetable intake and overall cancer risk [25,33].
Despite this, it remains a possibility that specific fruits or vegetables, or specific polyphenols found
within these, may exert protective effects against cancer development, particularly in the
gastrointestinal tract where they will be at highest concentration. In fact, many studies have shown that
various polyphenol-rich fruits and vegetables are particularly effective in protecting against colon
cancer development [34,35].
At the cellular level, there is good evidence that polyphenols present in tea, red wine, cocoa, fruit
juices, and olive oil influence carcinogenesis and tumor development . For example, they may
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interact with reactive intermediates  and activated carcinogens and mutagens , may modulate
the activity of key proteins involved in controlling cell cycle progression  and influence the
expression of many cancer-associated genes . Perhaps most notably, the anticancer properties of
green tea flavanols have been reported in animal models , human cell lines , as well as in
human intervention studies . Furthermore, green tea consumption has been proposed to
significantly reduce the risk of cancer of the biliary tract , bladder , breast  and colon .
Many of the anti-cancer properties associated with green tea are believed to be mediated by the
flavanol, epigallocatechin gallate (EGCG), which has been shown to induce apoptosis and inhibit
cancer cell growth by altering the expression of cell cycle regulatory proteins and the activity of
signaling proteins involved in cell proliferation, transformation and metastasis . In addition to
flavonoids, phenolic alcohols, lignans and secoiridoids (all found at high concentration in olive oil) are
also thought to induce anti-carcinogenic effects  and have been reported in large intestinal cancer
cell models , in animals [51,52] and in humans . These effects may be mediated by the ability
of olive oil phenolics to inhibit the initiation, promotion and metastasis in human colon
adenocarcinoma cells [53,54] and to down-regulate the expression of COX-2 and Bcl-2 proteins that
have a crucial role in colorectal carcinogenesis  (Figure 1).
Polyphenols may exert these anticancer effects via a variety of mechanisms, including removal of
carcinogenic agents [37,49], modulation of cancer cell signaling [48,55] and cell cycle progression
[15,16], promotion of apoptosis [12-14] and modulation of enzymatic activities . For example, the
enhancement of glutathione peroxidase, catalase, NADPH-quinone oxidoreductase, glutathione
S-transferase and/or cytochrome P450 enzyme activity by polyphenols may aid in the detoxification of
carcinogenic agents . Furthermore, they may modulate the activity of signaling pathways [58-60]
(i.e., MAPK kinase and PI3 Kinase), which are involved in cancer cell proliferation [61-63]. The
MAPK signaling pathway has long been viewed as an attractive pathway for anticancer therapies,
based on its central role in regulating the growth and survival of cells from a broad spectrum of human
cancers , and its role in the transcriptional and post-transcriptional activation of COX-2 
(Figure 1). In this context, certain polyphenols have been shown to exert a strong inhibitory effect on
the growth of colon adenocarcinoma cells through the inhibition of p38/CREB signaling, a decrease in
COX-2 expression and the stimulation of a G2/M phase cell cycle block . In addition,
hydroxytyrosol , epicatechin and dimer B2  have been shown to strongly inhibit ERK1/2
phosphorylation and downstream cyclin D1 expression leading to a block in cell cycle progression
(Figure 1). Alternatively, polyphenols such as hydroxytyrosol and tea flavanols such as EGCG have
been shown to reduce COX-2 over-expression, which is associated with colorectal neoplasia in
colorectal cancer [68-71].
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Figure 1. The interaction of polyphenols with cellular signaling pathways involved in
chronic disease. Flavonoid-induced activation and/or inhibition of MAP kinase and PI3
kinase signaling leads to the activation of transcription factors which drive gene
expression. For example, activation of ERK/Akt and the downstream transcription factor
CREB by flavonoids may promote changes in neuronal viability and synaptic plasticity,
which ultimately influence neurodegenerative processes. Polyphenol-induced inhibition of
the JNK, ASK1 and p38 pathways leads to inhibition of both apoptosis in neurons and a
reduction of neuroinflammatory reactions in microglia (reduced iNOS expression and NO•
release). Alternatively, their interaction with signaling may lead to direct activation of
proteins such as eNOS, which controls nitric oxide release in the vasculature and thus
influences CVD risk.
Tumors are also characterized by an increase in glucose uptake and a high rate of glycolysis, which
can led to the non-enzymatic glycation of proteins and the generation of so called advanced glycation
end products (AGEs). Indeed, the measurement of the AGEs, NЄ-carboxymethyllysine (CML) and
argpyrimidine in several human tumors has been linked to their involvement in cancer progression
. Certain polyphenols have been proposed to counteract AGE formation both in vivo and in vitro
and thus may limit their impact on the carcinogenesis process [73-76]. Furthermore, receptors for
AGEs, such as RAGE, have also been recognized to play an important role in regulating cancer cell
invasion and metastasis [77,78] (Figure 2) and flavanols such as EGCG may inhibit the cancer cell
proliferation by blocking RAGE related signaling .
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Figure 2. Formation of Advanced Glycation Endproducts (AGEs) and the sites where
flavonoids may inhibit their formation (*). These include monosaccharide autoxidation,
glycation, glycoxidation, as well as AGE receptor binding, which results in the activation
and release of inflammation mediators.
3. Polyphenols and Cardiovascular Disease
Cardiovascular disease (CVD), in particular coronary heart disease and stroke, is a major cause of
mortality in developed nations . CVD is a chronic, multi-factorial disease in which a range of
genetic and environmental factors plays a role in its initiation, progression and development. For
example, smoking, high saturated fat diets and physical inactivity are well known environmental
factors that are known to increase the risk of CVD [81-84]. This array and variety of factors makes it
difficult to explore the impact that an individual factor, for example a specific dietary nutrient, has on
the progression of CVD. Despite this, numerous epidemiological and human intervention studies have
suggested that regular consumption of polyphenol-rich foods, such as fruits, vegetables, cocoa, tea and
wine, may exert cardio-protective effects in humans [85-94]. Prospective studies have indicated a
correlation between the intake of flavonols, flavones and flavanols and a reduced risk of coronary
artery disease  and anthocyanin and flavanone intake and reduced CVD related mortality .
Furthermore, meta-analyses have indicated that the consumption of three cups of tea per day reduces
CVD risk by 11%  and regular, moderate red wine consumption is associated with a 32% reduced
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risk of CVD . However, there remains significant debate over which polyphenols are active, or
most active, in the context of CVD. Indeed, a recent systematic review has concluded that soy and
cocoa flavonoids have the most beneficial effect on reducing cardiovascular risk , whilst other
polyphenols are ineffective [87,99-101]. The reasons for these inconsistencies may relate to a number
of factors, including the use of different dietary intake questionnaires and food composition tables,
differences in the levels and types of polyphenols studied and differences in the populations
investigated, such as well-nourished populations and populations with high polyphenol intake showing
no effect .
Various human, animal and cell studies have suggested that polyphenols may exert beneficial
effects on the vascular system via an induction of antioxidant defenses [103-105], by lowering blood
pressure [98,106-111], by improving endothelial function [108,112-121], by inhibiting platelet
aggregation [107,122-124] and low density lipoprotein oxidation [105,125] and by reducing
inflammatory responses [126,127]. A daily intake of flavanol containing cocoa was found to be the
causal factor in determining the relatively low incidence of hypertension and CVD incidence in the
Kuna Amerinds of the San Blas Island in Panama . In support of these findings, three recent
meta-analyses have confirmed the blood pressure lowering capacity of flavanol-rich cocoa
[98,106,110]. Whilst a correlation between high black tea consumption and decreased blood pressure
has been reported [129,130], the effects of tea polyphenols have proved less consistent, with reports
indicating they both reduce blood pressure  or have no effect in animal models .
Furthermore, unlike those studies with cocoa, human intervention studies investigating the short-term
effect of tea consumption on blood pressure have failed to show positive effects [133-136] and there are
inconsistent data with regards to the effect of red wine or grapes on blood pressure [88,89,111,137-140].
However, in general there is a growing body of evidence to support the short-term and long-term
benefits of cocoa, purple grape juice, tea and red wine consumption with regards to endothelial
function and CVD risk [104,108,112-115,133,135,141-145].
One suggested mechanism for the action of polyphenols on vascular function involves their ability
to modulate the levels of and activity of nitric oxide synthase (eNOS) and therefore nitric oxide (NO)
bioavailability to the endothelium [112,146-150] (Figure 1). In support of this, aortic ring experiments
using physiological concentrations of polyphenols have shown that polyphenols induce
endothelium-dependent relaxation [148,151-156]. This regulation of vascular nitric oxide is thought to
involve the ability of polyphenols to interact with kinase signaling pathways such as the
PI3-kinase/Akt pathway and intracellular Ca+2 on eNOS phosphorylation and subsequent NO
production [157,158] (Figure 1). As well as activating eNOS, many polyphenols have also been shown
to increase eNOS expression, to induce prostacyclin production, to inhibit endothelin-1 and endothelial
NADPH oxidase [149,159-162] and to inhibit angiogenesis and the migration and proliferation of
vascular cells and matrix metalloproteinase (MMP) activation . They have also been proposed to
inhibit platelet aggregation [163,164] with cocoa, purple grape juice, red wine, black tea, coffee and
berry interventions all effective in acutely and chronically inhibiting platelet activation and
aggregation [107,122,123,164-169]. Lastly, flavanols and flavonols may act to prevent AGE-related
vascular injury [170,171] via their regulation of MAPK signaling through RAGE  and the
down-regulation of transcription factors such as NF-kB leading to the suppression of NADPH
oxidase  (Figure 1).
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4. Polyphenols and Neurodegeneration
Neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases represent an increasing
problem in our aging societies, primarily as there is an increased prevalence of both Alzheimer’s
disease [174,175] and Parkinson’s disease [175-177] with age. These and other neurodegenerative
disorders appear to be triggered by multi-factorial events including neuroinflammation, glutamatergic
excitotoxicity, increases in oxidative stress, iron and/or depletion of endogenous antioxidants [178-180].
In terms of dietary modulation of these diseases, epidemiological studies have suggested that moderate
wine consumption may reduce the incidence of certain age-related neurological disorders including
Alzheimer’s disease [181-183]. Furthermore, regular dietary intake of flavonoid-rich foods and/or
beverages has been associated with 50% reduction in the risk of dementia , a preservation of
cognitive performance with ageing [185,186], a delay in the onset of Alzheimer’s disease  and a
reduction in the risk of developing Parkinson’s disease .
Many studies have reported the bioavailability of polyphenols in the systemic circulation [188-191].
Whilst less is known regarding their degree of brain bioavailability, flavanones such as hesperetin,
naringenin and their in vivo metabolites, have been shown to traverse the BBB in relevant in vitro and
in situ models . Moreover, several anthocyanins have also been identified in the cortex and
cerebellum of rat  and pig [194,195] following feeding with blueberries. Together, these results
suggest that polyphenols are able to transverse the BBB, albeit to varying degrees depending on their
structure. Thus, such compounds are likely to be candidates for direct neuroprotective and
Flavonoids may act to protect the brain in a number of ways, including by protection of vulnerable
neurons, the enhancement of existing neuronal function or by stimulating neuronal regeneration .
For example, polyphenols have been shown to protect neurons against oxidative stress  and
Aβ-induced-induced neuronal injury  and polyphenol-rich Ginkgo biloba extracts have been
shown to be neuroprotective  by protecting hippocampal neurons from nitric oxide- and
beta-amyloid-induced neurotoxicity . Furthermore, anthocyanins and isoflavones [201,202] may
be capable of reducing the neurodegeneration associated with the accumulation AGEs during normal
 and abnormal brain ageing . In the context of Parkinson’s disease, the citrus flavanone
tangeretin has been observed to maintain nigro-striatal integrity and functionality following lesioning
with 6-hydroxydopamine, suggesting that it may serve as a potential neuroprotective agent against the
underlying pathology associated with Parkinson’s disease . In addition to the neuroprotection
elicited by flavonoids, phenolic compounds such as caffeic acid and tyrosol has also been shown to
protect against 5-S-cysteinyl-dopamine  and peroxynitrite neurotoxicity  in vitro.
There is also a growing interest in the potential of polyphenols to improve memory, learning and
general cognitive ability [208-211]. Human investigations have suggested that fruits and vegetables
may have an impact on memory [212-214] and depression  and there is a large body of animal
behavioral evidence to suggest that berries, in particular blueberries and strawberries, are effective at
reversing age-related deficits in spatial working memory [216-221], in improving object recognition
memory  and in modulating inhibitory fear conditioning [220,221]. The beneficial effects of
flavonoid-rich foods and beverages on psychomotor activity in older animals have also been reported
[217,223]. In addition to berries, tea [35,224], pomegranate , Ginkgo biloba [226-235] and pure
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flavonols such as quercetin, rutin  and fisetin  have also been shown to be beneficial in
reversing neuronal and behavioral aging. Furthermore, Ginkgo biloba has been shown to promote
inhibitory avoidance conditioning in rats with high-dose intake leading to short-term, but not
long-term, passive avoidance learning in senescent mice [238,239].
The effects of polyphenols on cognition and against neurodegenerative processes appear to be
mediated via their interactions with neuronal and glial signaling pathways that affect gene expression
and interfere with the cell death mechanisms [233,234]. For example, flavonoids may exert direct
modulation of protein and lipid kinase signaling pathways [209,232,234], via the inhibition of MAPK
signaling cascades, such as p38 or ERK1/2 [226,240] (Figure 1). The effects of flavonoids on these
kinases may influence downstream transcription factors , including nuclear factor-Kappa B
(NF-κB) [202,241], which responds to p38 signaling and is involved in iNOS induction . This
suggests that there may be interplay between signaling pathways, transcription factors and cytokine
production in determining the neuroinflammatory response in the CNS (Figure 1). In addition, the
actions of flavonoids on neuronal signaling may mediate their ability to protect against neurotoxicity
induced by AGEs .
Polyphenols are found ubiquitously in plants and are therefore consumed in relatively high
quantities in the human diet. Over the last 20 years, a significant amount of data has emerged with
regards to the potential health effects of several classes of polyphenolic compounds, in particular
flavonoids. Along with this, reasonable understandings of the bioavailability of polyphenols and the
mechanisms by which they exert such benefits in vivo have been determined. These mechanisms are
now believed to involve interactions with a number of cellular signaling pathways, which are
important in the normal functioning of cells. Such interactions appear to modulate these pathways in a
way that acts to control various pathogenic processes relevant to chronic disease progression. In this
respect, polyphenols, in particular flavonoids structurally resemble inhibitors of cell signaling
cascades, such as the PD98059, a MAPK inhibitor and the LY294002, a phosphatidylinositol-3 kinase
(PI3) inhibitor. Indeed, the latter inhibitor was modeled on the structure of quercetin . LY294002
and quercetin fit into the ATP binding pocket of the enzyme and it appears that the number and
substitution of hydroxyl groups on the B ring and the degree of un-saturation of the C2-C3 bond are
important determinants of this particular bioactivity. In this regard, quercetin and some of its in vivo
metabolites have been suggested to inhibit Akt/protein kinase B (PKB) signaling pathways , a
mechanism of action consistent with quercetin and its metabolites acting at and inhibiting PI3-kinase
activity. Although we have gained a better understanding of how polyphenols interact with cells, there
is still a long way to go before the precise cellular targets and mechanisms of action can be established.
While various lines of evidence via biomarker assessments and the use of pharmacological tools
in vivo (i.e., specific enzyme inhibitors, receptor agonists or antagonist) have indicated several
potential mechanisms of action, a comprehensive proof and conclusive understanding has yet to be
established. This relates mainly to significant limitations with regard to current data from in vitro
investigations that aimed at elucidating the mechanisms of action by which polyphenols exert their
bioactivities in vivo. It is notable that in most cases, in vitro data with regards to polyphenol bioactivity
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have been derived via the direct use of plant/food extracts or isolated native compounds, a practice that
does not take into account the processes of absorption and metabolism that polyphenols undergo in
humans. As such, one should express caution when interpreting the wealth of in vitro data linking
numerous polyphenols to actions in the body and effects against various disease processes, especially
if no data has been collected regarding the action of physiological metabolites of polyphenols in the
same cell systems. For example, if there is no evidence for the absorption of a particular polyphenol in
humans, can one really gain meaningful insight into its biological effects by exposing it to cultured
cells of the cardiovascular system and/or brain? There are specific exceptions, for example the
gastrointestinal tract, where polyphenols may come into direct contact with the cells without having
undergone absorption and metabolism. Therefore, it is perhaps relevant to investigate the effects of
polyphenols and polyphenol extracts on colon cancer cells, although as the gut microbiota also
extensively metabolizes them one must take account of these effects prior to concluding on a
mechanism of action in vivo. These and other limitations significantly hamper the translation of
in vitro data on the biological effects of flavanols and procyanidins into meaningful insight and
mechanistic understanding of the in vivo effects in humans.
Whilst the case for the biological functions of polyphenols in humans is accumulating, there
remains insufficient evidence to claim clear and undisputed positive health effects relating to their
consumption, particularly with regards to long-term dietary ingestion and human health.
Epidemiological studies have failed to show conclusive results, in some cases due to the lack of
appropriate nutrient databases and/or the use of an inappropriately controlled study population. Much
of the strongest data, particularly with regards to CVD, is based on short-term human studies, in many
cases lacking appropriate controls and a defined polyphenol content of the foods assessed. In addition
to better-defined human intervention studies aimed at assessing physiological endpoints linked to
disease, further research is also required regarding the bioavailability of polyphenols, particularly with
regards to the effects of food matrices on absorption and the influence on age, gender and genotype on
both absorption and metabolism These studies are required in order to help determine the physiological
metabolic forms responsible for activity in vivo, as well as to help define adequate biomarkers of
polyphenol intake. Therefore, at present, while the vast literature regarding the potential of
polyphenols to improve in human health is encouraging, more long-term, randomized, controlled,
dietary intervention trials with appropriate controls are warranted in order to assess the full and
unequivocal role that polyphenols play in preventing chronic human disease. The outcomes of these
studies may ultimately be used to make specific dietary recommendations regarding the efficacy of
polyphenols in preventing chronic disease risk and to fully validate polyphenols as the new agents
against various chronic human diseases.
The authors are funded by the Biotechnology and Biological Sciences Research Council
(BB/F008953/1; BB/E023185/1; BB/G005702/1), the FSA (FLAVURS) and the European Union
(FP7 FLAVIOLA). There is no conflict of interest to disclose, having read the Journals guidelines. All
authors contributed to the preparation of the manuscript and agreed the final version.
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