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ISSN: 0360-2532 (print), 1097-9883 (electronic)
Drug Metab Rev, Early Online: 111
! 2015 Taylor & Francis. DOI: 10.3109/03602532.2015.1102933

REVIEW ARTICLE

Natural polyphenols based new therapeutic avenues for advanced

biomedical applications
Megha Agrawal*
Department of Biology, University of Arkansas at Little Rock, Little Rock, AR, USA

Abstract

Keywords

Polyphenols are naturally occurring, synthetic or semisynthetic organic compounds that offer a
vast array of advanced biomedical applications. The mostly researched polyphenolic
compounds are resveratrol and flavanols, notably ()-epicatechin. The ongoing research on
clinically important resveratrol and flavanols has revealed their potentials as extremely efficient
drug agents that can be leveraged for new therapeutic designs for combating stroke related
injuries, cancer and renal failures. Here, we have highlighted recent developments in this area
with an emphasis on the biomedical applications of polyphenols. Also, a perspective on the
future research directions has been discussed. We believe that this review would facilitate
further research and development of polyphenols as a therapeutic avenue in medical science.

Antioxidant, cancer, epicatechin, resveratrol,

stroke

Introduction
Polyphenols are a structural class of naturally occurring or
synthetic/semisynthetic organic materials. They have unique
physical and chemical characteristics because of their high
molecular weights (5004000) and phenolic substructures
that consist of proteins and amino-based organics. In addition,
the formation of particular metal complexes, such as intense
blue-black iron(III) complexes, contribute to unique physical
and chemical properties of polyphenols. Polyphenols are
generally water-soluble compounds (Quideau et al., 2011).
Resveratrol (3,5,40 -trihydroxy-trans-stilbene) and flavanols, notably ()-epicatechin, are important natural polyphenolic compounds. The design and development of these
polyphenols is of immense interest for their potential health
benefits for antioxidant and anticancer activity and neuroprotective role in the vascular and nervous systems among other
applications (Athar et al., 2007; Agrawal et al., 2011, 2013;
Augustine et al., 2014; Baur & Sinclair, 2006; Clark et al.,
2012; Fernandez-Mar et al., 2012; Lee et al., 2014; Leonardo
et al., 2013; Singh et al., 2013; Smoliga et al., 2011).
Collaborative research and developmental efforts between
biotechnologists, biochemists, biologists and medical experts
are currently taking place across the globe to investigate these
clinically important polyphenolic compounds. Recent
research has indicated potential of resveratrol to impact a

*The author dedicates this paper to her father Mr. GS Agrawal for
showing the path of wisdom in her life with unconditional love, support
and encouragement.
Address for correspondence: Dr. Megha Agrawal, Department of
Biology, 2801 S University Ave, Little Rock, AR 72204, USA.
Tel:
+1
3523282802.
E-mail:
meghaagra@gmail.com
or
mxagrawal@ualr.edu

History
Received 5 August 2015
Accepted 29 September 2015
Published online 2 November 2015

variety of human diseases. The research findings on

resveratrol suggest that the prevention and treatment of
various disorders occur through multiple mechanisms of
action that may be related to its health benefits (Albani et al.,
2010).
In this review, we describe recent developments in
resveratrol and flavanol-based pathways toward therapeutic
designs and applications to prevent and treat various complex
diseases. We also present a perspective on the future research
direction in employing polyphenols and their derivatives for
new medical applications.

Occurrence, chemical synthesis, metabolism and

biochemical functions of polyphenols and their
antioxidant derivatives
Condensed tannins represent the most abundant type of
polyphenols that are found in virtually all families of plants.
Polyphenols are also concentrated in leaf tissue, the epidermis, bark layers, flowers and grape fruits. They help in
maintaining forest ecology and natural preservation by
decomposing forest litter and nutrient cycles. For example,
some woods have high levels of polyphenols that explains
their natural preservation against rot (Hart & Hillis, 1974).
Another form of natural occurrence of polyphenols is flax and
Myriophyllum spicatum (a submerged aquatic plant) that
secrete polyphenols that are involved in allelopathic interactions (Nakai, 2000; Popa et al., 2008). In addition,
polyphenols are also found in arthropods such as insects
(Wigglesworth, 1988) and crustaceans (Dennell, 1947).
As for the chemical synthesis of polyphenols, condensed
tannin, as we mentioned before, is the source for the true
polyphenols and they are usually biosynthesized from the
natural sources. However, the complex regioselectivity and

M. Agrawal

Drug Metab Rev, Early Online: 111

stereoselectivity issues pose challenge in their efficient

chemical syntheses (Krohn et al., 2010). Some early work
involved the achiral synthesis of phenolic-related components
of polyphenols (Botha et al., 1978). In another work, Nelson
and Meyers synthesis involved the permethyled derivative of
the ubiquitous diphenic acid core of ellagitannins that was
reported in 1994 (Nelson et al., 1994). There was another
report around the same time that involved stereoselective
synthesis of more complex-permethylated structures such as a
(+)-tellimagrandin II derivative (Lipshutz et al., 1994). Later,
in another report, synthesis of a permethylated pedunculagin
was done with particular focus on axial symmetry issues (Itoh
et al., 1996). It is to be noted that the total synthesis of a fully
unmasked polyphenol (ellagitannin tellimagrandin I) involved
a diastereoselective sequence that was reported by Feldman &
Ensel (1994).
The Feldman group reported in another work on the total
syntheses of unprotected polyphenols, for example, synthesis of
the ellagitannin, coriariin A and other tannin relatives (Feldman
et al., 2000). This was followed by a report by Khanbabaee and
Grosser that showed a relatively efficient total synthesis of
pedunculagin (Feldman, 2004; Khanbabaee & Gorsser, 2003).
Recently, there was much attention paid to the enantioselective total syntheses or syntheses of axially chiral biaryl
polyphenols (Bringmann et al., 2011; Pouysegu et al., 2011).
Other recent work involved controlled assembly of a variety
of polyphenols that was based on integrated strategies.
Examples include syntheses of extended series of procyanidins (oligomeric catechins) by various groups that were
reported (Kozikowski et al., 2003; Ohmori et al., 2011).
Among other therapeutic polyphenols, the clinically
important resveratrol was successfully synthesized that
included carasiphenols B and C, ampelopsins G and H, and
nepalensinol B (Snyder et al., 2011; Quideau., 2011). Other
notable synthesis routes include biomimetic synthesis, and the
first formal total synthesis involving 5-O-desgalloyl-epipunicacortein (C-glucosyl (C-glucoside subclass)) (Deffieux
et al., 2011). These advances in the synthesis of polyphenols
in the laboratories help open further avenues to refine and
optimize and tailor large-scale polyphenol chemical synthesis
for various next-generation biomedical applications.
The metabolism and biochemical functions of polyphenols
are governed by the standard regulation theory that considers
a polyphenol antioxidants ability to scavenge free radicals
and up-regulate certain metal chelation reactions. We note
that a healthy metabolic function requires that various
reactive oxygen species, such as singlet oxygen, peroxynitrite
and hydrogen peroxide, be regularly removed from cells.
Thus, reducing the concentrations of reactive oxygen species
is associated with several benefits that include ion transport
systems that may affect redox signaling.
Equation (1) shows the mechanism of how polyphenolic
antioxidants (POH) deactivate oxidant species, where (R)
denotes peroxyl radicals:
R  POH ! R  H PO

The generated phenoxyl radicals (PO) are stabilized

through resonance and/or intramolecular hydrogen bonding.
They can also combine to yield dimerization products, which

terminates the chain reaction according to the following

Equation (2) (Bors et al., 1990).
PO  PO ! PO  OP

As for the antioxidative derivatives are concerned, polyphenols usually incorporate smaller parts and building blocks
from simpler natural phenols. For example, flavonoids and
caffeic acid derivatives can be biosynthesized from phenyl
alanine and malonyl-CoA. Similarly, complex gallotannins
can be developed through the in vitro oxidation of 1,2,3,4,6pentagalloyl-glucose or dimerization processes that result in
hydrolyzable tannins. The larger, nonhydrolyzable tannins can
be generated with the precursors of the condensed tannin
biosynthesis, dihydroflavonol reductase and leucoanthocyanidin reductase (LAR) that are crucial enzymes that can
subsequently be added to catechin and epicatechin moieties
(Tanner et al., 2003). Also, we note that the solubility of
polyphenols can be increased by having the glycosylated form
that develops from glucosyltransferase activity (Krasnow &
Murphy, 2004).
One important polyphenol enzyme derivative is polyphenol oxidase (PPO) that catalyzes the oxidation of o-diphenols
to produce o-quinones. It involves rapid polymerization of oquinones to produce different color pigments, such as black,
brown or red polyphenolic pigments, which causes fruit
browning. In addition, PPO is responsible for the cuticle
hardening in insects (Malek, 1961). Laccase is another major
enzyme that is responsible for the cleavage of hydrocarbon
rings. This subsequently catalyzes the addition of a hydroxyl
group to phenolic compounds. Laccase is usualy found in
fungi like Panellus stipticus, where organisms are able to
break down lignin, which is a complex aromatic polymer in
wood. Lignin is highly resistant to degradation by conventional enzyme systems. In the next sections, we describe
various biomedical applications of important polyphenols
resveratrol and flavanol.

Biomedical applications of polyphenols

Resveratrol and flavanol are promising candidates for a
number of clinical applications such as prevention of
ischemic stroke, anticancer agents and for their various
neuroprotective roles to maintain the vascular and nervous
systems. Researches on these polyphenol compounds have
opened up various other therapeutic possibilities for various
other clinical applications. In the following sections, the
notable advances in these polyphenols for important biomedical applications are described.
Neuroprotection and prevention of ischemic cerebral
stroke
It has been shown that dietary polyphenols can control
neuronal disease pathogenesis at a molecular and symptomatic level and thus can target the pathological manifestations
of neurological disorders (Figure 1) with their ability to cross
blood-brain barrier (Khushwant et al., 2013). Figure 1
schematically illustrates the attenuation functions of polyphenols in neurological disorders.
Neuroprotective functions of resveratrol have been
researched extensively and documented. The application of

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Polyphenols and advanced biomedical applications

Figure 1. Neuroprotection by polyphenols against neurological disorders. With kind permission from Hindwai Publishing (Khushwant et al., 2013).

resveratrol can potentially be beneficial to prevent ischemic

cerebral stroke. Ischemic stroke is a serious medical condition
that occurs when there is insufficient blood flow to the brain
to meet metabolic demand. For effective cellular metabolism
and activity, oxygen availability in tissues is critically
important. Also, normal brain functions require regular
supply of glucose. Thus, the role of resveratrol in reducing
the toxic effects of inadequate supply of oxygen (hypoxia) and
glucose is of immense interest to investigate.
When oxygen-glucose deprivation OGD occurs, it can
trigger a multifaceted cellular response that leads to cerebral
injuries and cellular death. In such serious health conditions,
reactive oxygen species (ROS)-induced oxidative stress and
apoptosis are reported as key events. Further, a number of
neurodegenerative disorders occur as a result of ischemic
cerebral injuries (Burns et al., 2009).
In the events of ROS-mediated cellular injury, the human
body is capable to produce various antioxidants, such as
catalase, superoxide dismutase and uric acid to protect the
defence system (Agrawal & Biswas, 2015; Zadak et al.,
2009). However, excessive generation of ROS may cause
oxidative stress or redox imbalance that may eventually result
in disease initiation (Chan, 2001; Riley, 1994). It has been
reported that the application of resveratrol could potentially
strengthen endogenous intracellular defense systems that
could subsequently protect against cellular stress, dysfunction
and cell death (Robb & Stuart, 2010). Researchers suggested
that trans-resveratrol (tRV) has many biologic activities,
which can function as a scavenger of ROS and other free
radicals, that can oppose the toxic effects of hypoxia by its
direct or indirect effects in PC12 cells (rat pheochromocytoma cell line) (Giovannelli et al., 2011; Leonard et al., 2003;
Pandey & Rizvi, 2010; Sakata et al., 2010).

Recently, we carried out a study on protective potential of

trans-resveratrol against OGD-induced ROS-mediated apoptotic damages. These results suggested that tRV administration helped attenuate reactive oxygen free radical formation
and apoptosis. Figure 2 schematically illustrates anti-ischemic
potential of tRV by measuring the regulation of lipid
peroxidation (LPO), reactive oxygen species (ROS) production, glutathione (GSH) content and expression of apoptotic
markers viz., Bax, Bcl-2 and caspase-3 (Agrawal et al., 2011).
In another study on the applications of flavanol, we
showed that the administration of ()-epicatechin (EC) can
stimulate an endogenous cellular pathway leading to neuroprotection. Thus, polyphenols can be leveraged to develop
further understanding of cerebral ischemic stroke prevention
and transformative therapeutic designs (Leonardo et al.,
2013). We showed that EC can protect the brain against
ischemia through activation of the endogenous transcriptional
factor Nrf2. We employed both in vivo and in vitro model
systems and demonstrated the protective effects elicited by
EC. We adopted a pretreatment paradigm using primary
neuronal cultures from wild type (WT) and Nrf2 knockout
(Nrf2/) pups and subjected them to OGD (Figure 3)
(Leonardo et al., 2013).
Pretreatment with 50 or 100 mM EC protected WT neurons
from OGD, and this protection was essentially abolished in
Nrf2/ cultures. EC protected primary neurons from OGD
by increasing neuronal viability and reducing protein oxidation, effects that occurred concomitantly with increased Nrf2responsive antioxidant protein expression. It also utilized
wildtype and Nrf2 C57BL/6 knockout mice as a permanent
model of focal brain ischemia to evaluate glial cell regulation
and complex sensorimotor functioning. EC-treated wild-type
mice displayed a reduction or the absence of forelimb motor

M. Agrawal

Drug Metab Rev, Early Online: 111

Figure 2. A schematic illustrating the OGDreoxygenation induced oxidative stress pathways leading to apoptosis in PC12 cells and
protective effects of tRV. With kind permission from Elsevier (Agrawal et al., 2011).

Figure 3. EC protects primary neuronal

cultures from OGD through Nrf2 activation.
WT or Nrf2/ cells pretreated for 6 h with
EC and subjected to 4 h OGD followed by
24-h reoxygenation. With kind permission
from John Wiley & Sons Ltd (Leonardo
et al., 2013).

coordination impairments that were evident in vehicle-treated

mice. In this study, we showed that this protection was
associated with reduced anatomical injury and microglia/
macrophage activation. The protective effects elicited by EC
in both model systems were abolished in tissues and neuronal
cultures from Nrf2 knockout mice (Leonardo et al., 2013).
This research reveals that the neuroprotective mechanism of
flavanol in stroke prevention has significant clinical
relevance.

Resveratrol was investigated for its neuroprotective effect

on rats subjected to focal cerebral ischemia (FCI) injury
(Tsai et al., 2007). The study explored the possible involvement of nitric oxide (NO) in neuroprotective effect of
resveratrol on FCI. Treatment of resveratrol (0.1 and 1 mg/
kg) was found to decrease the lactate dehydrogenase (LDH) in
plasma and malondialdehyde (MDA) in FCI injury brain
tissue. However, it was found that the level of NO in plasma
was increased. It was also observed that resveratrol

DOI: 10.3109/03602532.2015.1102933

downregulated protein and mRNA expression of inducible

nitric oxide synthase (iNOS), and upregulated protein and
mRNA expression of endothelial nitric oxide synthase
(eNOS). The expression of protein and mRNA of neuronal
nitric oxide synthase (nNOS) remained unchanged. The
authors observed that pretreatment with NG-nitro-L-arginine
methyl ester (L-NAME, the nonselective NOS inhibitor) or LN5-(1-iminoethyl)-ornithine (L-NIO, the eNOS selective
inhibitor) completely blocked the effect of resveratrol in
decreasing infarction volumes (Tsai et al., 2007). This
research is of major significance as the application of
resveratrol shows potential for clinical application of pharmacology in identifying the underlying intracellular signaling
pathways to develop therapeutic strategies for treating ischemic stroke injury in patients.
It is usually considered that resveratrol preconditioning can
protect the brain from ischemiareperfusion injury. However,
to gain detailed insights into its beneficial effects after stroke,
resveratrol administration was investigated to study its
potential positive effects to the delayed phases after FCI
occurred. This study investigated the effects and possible
protective mechanism of resveratrol on the delayed phase
after focal cerebral ischemia injury in mice (Wen et al., 2008).
The authors observed that the mean neurologic scores and
infarct volumes of the ischemia and reperfusion groups were
lower than that of the control group at 7 days after middle
cerebral artery reperfusion (p50.05).
They also observed significantly less reduction of immunohistochemistry staining in a number of micro-vessels in the
cortical area of mice of the ischemia and reperfusion
groups compared with controls. Also, they found that the
ischemic hemispheres of the ischemia and reperfusion
groups had significantly (p50.05) elevated levels of protein
of matrix metalloproteinases (MMP-2) and vascular endothelial growth factor (VEGF). The authors concluded that
administration of resveratrol by gavage could be beneficial in
providing neuroprotective effect on focal cerebral ischemic
injury in the delayed phase. They further concluded the
benefits of early administration of resveratrol by gavage in the
delayed phases after focal cerebral ischemic injury. This
significant finding supports the possible use of resveratrol as a
therapeutic agent to ameliorate ischemic infarction. It can
therefore be stated that resveratrol may be considered as a
potential candidate in the development of drugs for the early
treatment in patients who sustain an ischemic stroke (Wen
et al., 2008).
Among other natural polyphenols, provinol is found in red
wine powder. Provinol was found to increase NO synthase
activity after 4 weeks of treatment in the cerebral cortex,
cerebellum and brainstem (Jendekova et al., 2006). Also,
provinols were reported to increase NO synthase activity in
the heart and aorta of NG-nitro-L-arginine methyl ester
(L-NAME)-treated rats (Kovacsova et al., 2010). These
results suggest that provinols can potently activate NO
synthase functions in both the cardiovascular and nervous
systems. However, it was also found that prolonged provinols
treatment for 7 weeks had no effect on NO synthase activity
that was decreased by L-NAME treatment (Kovacsova et al.,
2010). It was suggested that by the activation of common
receptor-binding sites that are particularly present at the

Polyphenols and advanced biomedical applications

Figure 4. Bar diagrams showing effect of increasing doses of resveratrol

in combination with lipoic acid on infarct volume. With kind permission
from public library of science (Saleh et al., 2014).

level of the cellular plasma membrane in the rat brain, the

neuroprotective function of various polyphenols and resveratrol analogs can potentially be activated (Han et al., 2006).
Researchers have hypothesized that binding polyphenols to
this receptor may be associated with increased NO synthase
activity in the brain (Kovacsova et al., 2010).
In a recent study, coadministered resveratrol and lipoic acid,
or their synthetic combinations were employed that were
shown to enhance neuroprotection in a rat model of ischemia/
reperfusion (Saleh et al., 2014). This study demonstrated the
benefits of combinatorial antioxidant therapy in the treatment
of ischemic stroke. The researchers employed male Sprague
Dawley rats that were anesthetized and the middle cerebral
artery (MCA) was occluded for 30 min followed by 5.5 h of
reperfusion. The authors observed significant, dose-dependent
decrease in infarct volume (p50.05) compared to vehicletreated animals when pretreatment with resveratrol 30 min
prior to MCA occlusion was applied. They also observed
neuroprotection when resveratrol (2  103 mg/kg; iv) was
administered within 60 min following the return of blood flow
(reperfusion). However, significant neuroprotection was
observed when pretreated with non-neuroprotective doses of
resveratrol (2  106 mg/kg) and lipoic acid (LA; 0.005 mg/kg)
in combination. When resveratrol and LA were administered
15 min following the onset of MCA occlusion, it also resulted
in neuroprotection (Saleh et al., 2014). The authors observed
that the combined pre-administration of resveratrol and LA
30 min prior to tMCAO produced a dose-dependent reduction
in infarct volume compared to vehicle-injected controls when
measured following 5.5 h of reperfusion (Figure 4). They also
observed that this effect was significant at the two highest
doses of resveratrol (2  106 and 2  105 mg/kg; p  0.05;
Figure 4) (Saleh et al., 2014). These results open up the
possibility of combining subthreshold doses of resveratrol and
LA prior to ischemia reperfusion that can provide significant
neuroprotection that is considered to result from concurrent
effects on multiple pathways (Saleh et al., 2014).

M. Agrawal

Drug Metab Rev, Early Online: 111

Figure 5. A schematic illustration of the

effect of resveratrol on intracellular signal
transduction pathways involved in carcinogenesis AP-1, activator protein-1; HIF-1a,
hypoxia-inducible factor-1a; IKK, IkB
kinase; MAPKs, mitogen-activated protein
kinases; NF-kB, nuclear factor-kB; PI3K,
phosphoinositide 3-kinase; PKC, protein
kinase C; STAT3, signal transducer and
activator of transcription 3. With kind permission from Elsevier (Kundu & Surh, 2008).

Anticancer agent
Resveratrol has also been investigated for its novel chemopreventive activity (Brents et al., 2012; Greer et al., 2014;
Sabolovic et al., 2006). The research field of polyphenolic
materials for anticancer applications is still growing. It is
anticipated that further studies could lead to new insights into
the mechanism of the anticarcinogenic actions of such organic
materials for new therapeutic designs for advanced biomedical applications. It is considered that the antitumor activities
of resveratrol are mediated through several cell-signaling
pathways that include cell cycle arrest, suppression of tumor
cell proliferation, induction of apoptosis and differentiation,
reduction of inflammation and angiogenesis, and inhibition of
adhesion, invasion and metastasis (Figure 5) (Bishayee,
2009).
Trans-resveratrol has been shown to have powerful anticarcinogenic properties that can be applied for anticancer
activity. However, the therapeutic use of tRV for such
applications is limited due to its rapid metabolism into its
conjugated forms by UDP-glucuronosyltransferases (UGTs)
that lowers the bioavailability of tRV. Dr. RadominskaPandya and her group has developed novel biomedical
pathways that can improve limited bioavailability of tRV by
modifying its structure to create analogs that can be
glucuronidated at a lower rate than tRV itself (Brents et al.,
2012; Greer et al., 2014; Sabolovic et al., 2006).
The research team led by Dr. Radominska-Pandya
designed and synthesized three synthetic stilbenoids, (E)-3(3-hydroxy-4-methoxyphenyl)-2(3,4,5trimethoxyphenyl)acrylic
acid
(NI-12a),
(E)-2,4-dimethoxy-6(4 methoxystyryl)benzaldehyde oxime (NI-ST-05) and (E)4- (3,5-dimethoxystyryl)-2,6-dinitrophenol (DNR-1) that were
based on the structure of tRV to modify the structure of tRV
(Figure 6). The group demonstrated improved glucuronidation
profiles by modifying the structure of tRV, and thus, the group
predicted that tRV analogs could have better bioavailability
in vivo than pure tRV (Greer et al., 2014). This study is
extremely important as it provides additional metabolic
pathway that could be the topic of future studies in developing
polyphenols as efficient anticarcinogenic agents.
Further, Dr. Radominska-Pandyas team carried out
screening experiments for glucuronidation activity with

human hepatic and intestinal microsomes from 10 and 13

donors, respectively. They used one pooled liver sample, and
commercially available hepatosomes (Figure 7). All hepatic
samples were shown to glucuronidate both NI-12a and NIST-05 producing two and one metabolic products, respectively. These enzymatic studies provide new insights into the
involvement of conjugative metabolism in the biotransformation of synthetic stilbenoids in humans that helps assessing
the potential utility of these molecules as novel chemotherapeutic agents.
The same group also demonstrated in a separate study that
all parts of the human gastrointestinal GI tract can be
effective in the glucuronidation of the two resveratrol isomers
and, thus, may contribute significantly to the first-pass
metabolism of this polyphenol (Sabolovic et al., 2006). The
research team led by Dr. Radominska-Pandya investigated
glucuronidation of the two resveratrol isomers in human
microsomes that were prepared from: stomach, duodenum,
four segments of the remaining small intestine (S-1 to S-4)
and colon, and from the human intestinal cell lines Caco-2
and PD-7. This study is very significant as it demonstrates for
the first time, the capacity of the human GI tract mucosa to
glucuronidate resveratrol and, therefore, it leads to the
potential therapeutic development of orally ingested resveratrol (Sabolovic et al., 2006).
There are a number of applications of resveratrol in
treating other forms of cancers. In the first animal study of the
chemopreventive effects of resveratrol on the treatment of
skin cancer, a two-stage mouse skin carcinogenesis model
was reported. It was shown that topical resveratrol significantly reduced 7,12-dimethylbenz(a)anthracene (DMBA)
initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)
promoted skin tumors in mice (Jang et al., 1997). Dietary
resveratrol significantly reduced the incidence of prostatic
adenocarcinoma in the transgenic adenocarcinoma mouse
prostate model. The application of resveratrol in treating
prostate cancer has been investigated. Researchers have
reported a biochemical basis for resveratrol-mediated suppression of prostate cancer development. In a significant
finding, a decrease in cell proliferation and increase in ER-b
was observed along with insulin-like growth factor-I and
downregulation of phospho-extracellular signal-regulated
kinase (ERK)-1 and ERK-2 (Harper et al., 2007).

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Polyphenols and advanced biomedical applications

Figure 6. Structutal modifications of tRV

leads to increased bioavailability. With kind
permission from the American chemical
society (Greer et al., 2014).

Prevention of renal failures

Figure 7. Glucuronidation activities of human hepatic (A) and human

intestinal (B) microsomes toward NI-12a and NI-ST-05. With kind
permission from the American chemical society (Greer et al., 2014).

Resveratrol has also been found to significantly reduce tumor

volume, tumor weight, and metastasis to the lung in mice
bearing highly metastatic Lewis lung carcinoma (Kimura &
Okuda, 2001).

It has been found that resveratrol can activate SIRT1, an

NAD+-dependent deacetylase that can result in many protective mechanisms against age-related health issues such as
renal failures. SIRT1 is essentially a protein and through its
molecules calorie restriction can be achieved that can help
extend the lifespan or delay age-related diseases. Through
the deacetylation of target proteins, SIRT1 regulates a number
of cellular functions that include apoptosis, mitochondrial
biogenesis, inflammation, glucose/lipid metabolism, autophagy and adaptations to cellular stress. Using animal
models, it has been shown that several types of renal injury,
such as diabetic nephropathy, drug-induced injury, aldosterone-induced injury, ischemia-reperfusion injury, sepsisrelated injury and unilateral ureteral obstruction can be
ameliorated by using resveratrol through its antioxidant effect
or SIRT1 activation (Figure 8). This opens up the possibility
for new therapeutic designs based on resveratrol that can be
employed for the prevention of renal failures (Kitada & Koya,
2013).
A number of mechanisms have been suggested for the
resveratrol-initiated activation of SIRT1. Initially, a direct
activation of SIRT1 by resveratrol was considered. However,
later, AMPK was found to be an essential requirement for the
activation of SIRT1 by resveratrol. The role of AMPK is an
important one which is essentially to regulate the metabolism
that responds the energy balance (Steinberg et al., 2009). In a
new mechanism, the activation of SIRT1 was considered
through the activation of AMPK via the inhibition of
phosphodiesterase 4 (PDE 4) along with the elevation of
cAMP in cells (Park et al., 2012;Kitada & Koya, 2013; Park
et al., 2012).
The metabolic benefits of resveratrol were shown in
another study that demonstrated a direct link between SIRT1
and resveratrol (Price et al., 2012). A mechanism was
proposed based on a moderate dose of resveratrol
(2530 mg/kg/day to mice treated with high fat diet). In this
mechanism, the activation of SIRT1 induces the deacetylation
of liver kinase B (LKB) 1 along with the activation of AMPK,
which leads to increased mitochondrial biogenesis and
function. Interestingly, it was also found that a high dose of
resveratrol (215235 mg/kg/day to mice treated with high fat

M. Agrawal

Drug Metab Rev, Early Online: 111

Figure 8. A schematic illustration showing

the actions of resveratrol through its antioxidant effects and SIRT1 activation that can
prevent renal injury, including diabetic
nephropathy, drug-induced renal injury,
aldosterone-induced renal injury, ischemiareperfusion injury, sepsis-induced kidney
injury, and obstructed kidney. With kind
permission from Hindwai Publishing (Kitada
& Koya, 2013).

diet) can directly activate AMPK, independently of SIRT1

(Price et al., 2012; Kitada & Koya, 2013).
Hubbard et al. (2013) proposed a mechanism of activating
SIRT1 based on sirtuin-activating compounds (STACs),
including resveratrol and showed that such compounds can
increase the catalytic activity of SIRT1 that uses certain
substrates following an allosteric mechanism and involving an
amino terminal domain near the catalytic core and through
direct binding to SIRT1 (Hubbard et al., 2013).
The end-stage renal disease (ESRD) occurs as a result of
diabetic nephropathy, which is one of the serious medical
conditions of diabetes. It has been suggested that oxidative
stress results in the pathogenesis of diabetic vascular
complications, including nephropathy (Kitada et al., 2010).
Resveratrol has been shown in the previous studies to improve
diabetic nephropathy in several animal models of type 1 and 2
diabetes through its antioxidative effects that resulted from
direct radical scavenging or the modulation of antioxidant
enzymes (Kitada & Koya, 2013). Resveratrol treatment was
shown to attenuate renal hypertrophy and urinary albumin
excretion in the early stage of diabetes in STZ-induced
diabetic rats without affecting the blood glucose levels (Ding
et al., 2010). Resveratrol was found to activate AMPK and
inhibit the phosphorylation of 4E-BP1 and S6 in diabetic
kidneys (Ding et al., 2010).
In another work on resveratrol, when used with 55 mg/kg,
intraperitoneal injection, it prevented the decrease in SIR2
expression and the increases in the p38MAPK and p53 levels
and the dephosphorylation of histone H3 in the kidney of
STZ-induced diabetic rats. These results suggested that SIR2
plays important roles in the beneficial effects of resveratrol in
the kidneys (Tikoo et al., 2008).
Resveratrol has been employed to treat renal ischemia. The
pretreatment of rats with resveratrol (0.23 mg/kg) was shown
to reduce the mortality rate of ischemic rats from 50% to 10%
and reduced the extent of renal damage (Giovannini et al.,
2001).

The involvement of nitric oxide in the renoprotective effect

of resveratrol in renal ischemic preconditioning in rat kidney
was studied. The researchers found that ischemic preconditioning and resveratrol treatment significantly improved the
renal dysfunction, decrease in total NO levels, and oxidative
stress induced by 45 min of ischemia followed by 24 h of
reperfusion (Chander & Chopra, 2005).
These examples demonstrate the potential of resveratrol for
applications in both acute and chronic kidney injuries due to
its antioxidant properties and ability to activate SIRT1.
However, before clinical trials on human begin, it is unclear
of the beneficial effects of resveratrol to treat human kidneys.
More studies need to be carried out to gain insights into the
detailed mechanism for the renal protective effect of
resveratrol and confirm the beneficial effects of resveratrol
in human kidney diseases.
Therapeutic agent against food allergy, pathogens
and for antibacterial effects
Food allergy occurs as a result of immune-mediated pathological reaction toward food antigens. Different T-cell events,
such as anergy, clonal deletion and the induction of regulatory
T cells cause the mucosal immune system in the intestine
responsive to innocuous food antigens (Okada et al., 2012).
To investigate the beneficial effects of resveratrol to prevent
cholera, researchers studied ingestion of resveratrol that
prevented the development of a food allergy model in mice.
The in vitro findings of resveratrol administration showed
promise in treating cholera by inhibiting DC maturation and
subsequent early T-cell activation and differentiation via
downregulation of cholera toxin CT-induced cAMP activation in mice. This suggests that resveratrol may have
potential for prophylaxis against food allergy (Okada et al.,
2012). Resveratrol has also been found to have some
inhibitions against food-borne pathogens such as E. coli,
Salmonella typhimurium, Listeria monocytogenes, and

DOI: 10.3109/03602532.2015.1102933

Polyphenols and advanced biomedical applications

bacteria Aa and Pg are considered as key components in the

etiology of periodontal disease and associated hard-tissue
destruction (OConnor et al., 2011). The authors observed a
significant decrease (p50.05) of the periodontal bacteria that
was showed in viable counts after 1 h, while no colonyforming units could be observed after 24 h. The results
suggest that resveratrol possesses significant promise for
antimicrobial applications on periodontal pathogens in vitro
(OConnor et al., 2011).
Antiaging therapeutics: antioxidant roles of
resveratrol
Figure 9. Bar charts showing western analysis on Y. pseudotuberculosis
treated with ()-hopeaphenol. With kind permission from Public library
of sciences (Zetterstrom et al., 2013).

Helicobacter pylori, without harming beneficial probiotic

bacteria.
The antimicrobial effects of wood-associated polyphenols
were investigated on food pathogens and spoilage organisms.
Researchers investigated the wood-associated polyphenolic
compounds such as pinosylvin, pinosylvin monomethyl ether,
astringin, piceatannol, isorhapontin, isorhapontigenin,
cycloXMe, dHIMP, ArX and ArXOH were assessed against
both Gram-negative (Salmonella) and Gram-positive bacteria
(Listeria monocytogenes, Staphylococcus epidermidis,
Staphylococcus aureus) and yeasts (Candida tropicalis,
Saccharomyces cerevisiae) (Plumed-Ferrer et al., 2013). The
authors concluded that the destabilization of the outer
membrane of Gram-negative microorganisms, as well as
interactions with the cell membrane, as indicated by the NPN
uptake and live/dead viability staining experiments can be
attributed to be one of the specific mechanisms behind the
antibacterial action of wood-associate polyphenols (PlumedFerrer et al., 2013).
In a separate study, researchers investigated ()-hopeaphenol that was applied to control Gram-negative pathogens
Yersinia pseudotuberculosis and Yersinia pseudomonas aeruginos. ()-Hopeaphenol was found to bind covalently to C.
trachomatis that inhibited successful infection and possibly
reduced their growth inside the eukaryotic cell. The authors
observed ()-hopeaphenol to be a selective and irreversible
T3SS inhibitor with activity in eukaryotic whole-cell infection assays with Y. pseudotuberculosis, P. aeruginosa and C.
trachomatis that signified plants as a valuable source for
natural products that blocked virulence systems in human
pathogens (Zetterstrom et al., 2013).
Dose-dependent inhibition of expression and secretion of
the translocator protein YopD was studied. The authors
conducted western blot analysis of effector proteins in total
culture and supernatant, of YPIII(pIB102) wild-type bacteria
incubated together with seven different concentrations of
()-hopeaphenol for 1 h at 26  C followed by 3 h at 37  C and
demonstrated a clear dose-dependent response for both
secretion and expression of translocator protein YopD
(Figure 9) (Zetterstrom et al., 2013).
Resveratrol was evaluated for its effect on the in vitro
growth of periodontal pathogens A. actinomycetemcomitans
(Aa) and P. gingivalis (Pg). The Gram-negative anaerobic

Antioxidant roles of resveratrol are well known. As we

mentioned before, it is believed that an excess of reactive
oxygen species (ROS) results in the aging process along with
numerous other cellular response pathways that may lead to
cellular death. An imbalance between ROS production and
antioxidant defenses result in oxidative stress. It is therefore
considered that modulating the antioxidant enzymes could
lead to reduced oxidative stress. Resveratrol is a well-known
natural antioxidant. Previous research indicated that resveratrol can effectively and directly scavenge ROS. In addition to
scavenging ROS, exogenously administered resveratrol can
modulate the expression and activity of antioxidant enzymes.
These include superoxide dismutase, glutathione peroxidase
(GPx) and catalase, and through transcriptional regulation via
nuclear factor E2-related factor 2 (Nrf2), activator proteins
(AP)-1, forkhead box O (FOXO), and SP-1 or even through
enzymatic modification (Singh et al., 2013). In a related
report, a resveratrol-based skin care formulation was proposed
with 17 times greater antioxidant activity than idebenone
(Baxter, 2008).

Conclusion and future perspectives

This review summarizes the notable biomedical applications
of polyphenols, most importantly resveratrol. The promising
attributes of polyphenols are its lack of toxicity and
availability from natural sources that make them viable for
clinically relevant therapeutics in neurodegeneration and
other applications. In this review, we described neuroprotective actions of natural polyphenolic compounds in the brain
that may be important to prevent brain damage including
ischemic stroke and neurodegenerative diseases. These
include significant reduction of neuronal death, in memory
improvement, learning and general cognitive ability.
Resveratrol holds great promise in other application areas
such as prevention of renal failures and cancer treatment.
Previous research on resveratrol and other polyphenolic
compounds to treat human kidney diseases has shown
promise and further research and development of clinically
important polyphenols are needed to optimize the experimental conditions in order to achieve best clinical results.
Resveratrol holds great potential in cancer prevention.
Resveratrol has potential to be applied for not only in the
prevention but also in a wide variety of cancer therapy.
Resveratrol can potentially suppress multiple cellular pathways that can be leveraged to develop new drugs for cancer
prevention and treatment.

10

M. Agrawal

It may be noted that the anticancer effects of resveratrol are

likely manifestations of various complementary actions that
include of a number of molecular, biochemical and physiologic pathways that are involved in carcinogenesis. A detailed
mechanism is, however, not yet understood, which is very
important to elucidate in order to design and develop new
therapeutics based on resveratrol. In this regard, further
research and development studies to address the question of
tissue-dependent functions of resveratrol need to be done.
This would help determine where resveratrol may have the
strongest preventive potential to attack the tumor cells.
The future of polyphenol research would obviously need to
be directed toward clinical practical acceptance of the health
claims that have been reported from preclinical in vitro and
animal model studies. In his regard, one promising approach
could be investigations of human clinical trials of several
employable polyphenols and their combinations with various
compatible anti-oxidant agents that would enhance their
biomedical functional properties. However, they need to be
investigated for the human risk assessment and safety
evaluation as well that will determine their pharmacological
implications and success for new drug designs.
The low bioavailability of resveratrol and some of the other
polyphenols is an issue that would require further research.
For example, the question of compatibility of resveratrol to
the bioactive levels in target organs needs to be addressed.
One possible way to enhance the bioavailability of resveratrol
could be investigating and optimizing the resveratrol metabolism, its formulation and the delivery mechanism. This can
also include the interactions of resveratrol with the environment that includes foods as well.
Another way to enhance the bioavailability of resveratrol is
to develop new derivatives by introducing unique chemical
pathways to functionalize resveratrol. One important area
includes identifying resveratrol-binding proteins and the
associated pathways that would be of clinical significance
to study. To make resveratrol and other polyphenols standard
clinical products, long-term studies are needed to be
performed.

Acknowledgements
The author is grateful to Dr A. B. Pant of Indian Institute of
Toxicology Research, Lucknow, India for providing a platform that helped shape her academic career, and also for his
unfailing support and constant encouragement.

Declaration of interest
The authors report no declarations of interest.

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