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Abstract In recent years, the therapeutic use of non-drug substances such as herbal and medicinal foods is increasing progressively. Of these substances, Punica granatum L., which is an ancient and highly distinctive fruit, has been proposed for treatment of several different illnesses. Ellagic acid (EA) is one of those biological molecules found in pomegranate and may have therapeutic potential in many diseases. EA has been detected not only in pomegranate but also in a wide variety of fruits and nuts such as raspberries, strawberries, walnuts, grapes and black currants, and is becoming an increasingly popular dietary supplement over recent years. Similar to other ellagitannins (ETs), EA is quite stable under physiological conditions in the stomach. EA and ETs as active agents induce vasorelaxation, oxygen free radical scavenging, hypolipidemic, anti-inflammatory and anti-carcinogenic activities in various animal preparations call an attention to the need for designing adequate tests in humans to assess these potentially useful properties in diseased states.
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ISSN: 0963-7486 (print), 1465-3478 (electronic)
Int J Food Sci Nutr, 2013; 64(7): 907–913
!2013 Informa UK Ltd. DOI: 10.3109/09637486.2013.798268
The pharmacological use of ellagic acid-rich pomegranate fruit
Coskun Usta
, Semir Ozdemir
, Michele Schiariti
, and Paolo Emilio Puddu
Department of Pharmacology,
Department of Biophysics, Faculty of Medicine, Akdeniz University, Antalya, Turkey, and
Department of
Cardiovascular, Respiratory, Nephrological and Geriatrical Sciences, Laboratory of Biotechnologies Applied to Cardiovascular Medicine, Sapienza,
University of Rome, Rome, Italy
In recent years, the therapeutic use of non-drug substances such as herbal and medicinal foods
is increasing progressively. Of these substances, Punica granatum L., which is an ancient and
highly distinctive fruit, has been proposed for treatment of several different illnesses. Ellagic
acid (EA) is one of those biological molecules found in pomegranate and may have therapeutic
potential in many diseases. EA has been detected not only in pomegranate but also in a wide
variety of fruits and nuts such as raspberries, strawberries, walnuts, grapes and black currants,
and is becoming an increasingly popular dietary supplement over recent years. Similar to other
ellagitannins (ETs), EA is quite stable under physiological conditions in the stomach. EA and ETs
as active agents induce vasorelaxation, oxygen free radical scavenging, hypolipidemic, anti-
inflammatory and anti-carcinogenic activities in various animal preparations call an attention to
the need for designing adequate tests in humans to assess these potentially useful properties in
diseased states.
Ellagic acid, ellagitannins, polyphenols, Punica
granatum L
Received 24 January 2013
Revised 8 April 2013
Accepted 15 April 2013
Published online 23 May 2013
Throughout the past decades, there has been a significantly
increased use of dietary supplements such as vitamins, herbals
and medicinal foods in the general population. From 1990 to
1997, more than 15 million adults in the United States reported
using herbal supplements in conjunction with prescribed medica-
tions (Eisenberg et al., 1998). In addition, from 1997 to 2002,
there was a further increase of more than 50% in the consumption
of dietary supplements (Tindle et al., 2005).
The pomegranate, Punica granatum L., is an ancient, mystical
and highly distinctive fruit. In addition to its historical uses,
pomegranate is found in several medicinal systems for a variety of
ailments. Over the past decade, significant progress has been
made in establishing the pharmacological mechanisms of pom-
egranate and its individual responsible constituents.
Current research seems to indicate that the most therapeutic-
ally beneficial pomegranate constituents are ellagitannins (ETs;
including ellagic acid (EA)), punicic acid, f lavonoids, anthocya-
nidins, anthocyanins and estrogenic flavonols and flavones (Espı
et al., 2007; Quideau & Feldman, 1996). Pomegranate’s con-
sumption has been associated with cardiovascular health benefits,
since it contains relevant amounts of phenolic anti-oxidants, and
particularly ETs, considered responsible, at least in part, for these
physiological properties (Larrosa et al., 2010). These polyphenols
contained in pomegranate and different fruits and nuts are
described in the category of hydrolysable tannins, phytochemicals
of the non-flavonoid polyphenol group, including ETs, which
release EA upon hydrolysis and under the physiological
conditions of the gastrointestinal tract (Falsaperla et al., 2005).
EA content of several food products can be quite high.
EA, a polyphenol compound found in a wide variety of fruits
and nuts, such as raspberries, strawberries, walnuts, grapes, and
black currants, is becoming an increasingly popular dietary
supplement over the recent years because it can be easily
extracted and used (Devipriya et al., 2007b). There is a relatively
high content of EA in raspberries (1500 mg/g dry weight),
strawberries (630 mg/g dr y weight), cranber ries (120 mg/g dry
weight), walnuts (590 mg/g dry weight), pecans (330 mg/g dry
weight) and other plant foods (Figure 1; Bala et al., 2006).
Although several functions of EA are described, the mechanism
of its biological functionality is not very well-understood.
Commonly found in many plants, EA exhibits powerful anti-
carcinogenic and anti-oxidant properties, propelling it to the
forefront of pomegranate research (Hassoun et al., 2004;
Priyadarsini et al., 2002; Rukkumani et al., 2004).
There are promising results showing that phytochemicals may
exert their benefits in the prevention and therapy of many diseases
including cancer, atherosclerosis and alcoholism, partially based
on their ability to quench reactive oxygen species and thereby
protecting critical cellular targets (i.e. DNA, proteins and lipids)
from oxidative insult (Mertens-Talcott & Percival, 2005;
Murakami et al., 2002). Recently, ETs and EA appear among
the topics of interest in medicine and food science. This review
will concentrate on the EA and aims at pointing to the important
potential characteristics of EA and ETs in pomegranate
(P. granatum L.) and other fruits and nuts, from a large body of
evidence in animal preparations and clinical investigations, to
foster interest in pharmacological and nutritional properties that
may have indeed application to human disease states. To
accomplish this, Medline English literature was searched, without
restrictions, for EA both in animal and human investigations.
Correspondence: Coskun Usta, MD, Department of Pharmacology,
Faculty of Medicine, Akdeniz University, Antalya, Turkey. Tel: +90
242-2496921. E-mail:
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Bioavailability and metabolism
ETs have been claimed to possess stable structural properties
under physiological conditions in the stomach. EA, however,
following its absorption in digestive tract, is methyl conjugated by
the action of catechol O-methyltransferase quickly (Larrosa et al.,
2010, 2012). The pharmacokinetic profile of this absorption has
poor characteristics, and only a part of this absorption takes place
in the stomach (Lei et al., 2003). The metabolism of EA proceeds
by conversion of EA to dimethyl-EA-glucuronide, which is the
most abundant metabolite detected up to date via a two-step
reaction (Whitley et al., 2003).
Bioavailability and metabolism of EA and ET have also been
assessed extensively in animal studies. In these studies, Urolithin
A (Uro-A) and Urolithin B (Uro-B) were detected as the
predominant metabolites of EA in urine and feces (Doyle &
Griffiths, 1980).
In humans, 1 h after 180 ml of pomegranate juice consumption,
the maximum EA blood concentration was 31.9 ng/ml, which was
rapidly metabolized in the next 4 h (Seeram et al., 2004). In
another study, the concentration time profile of EA was evaluated,
and the maximum concentration of EA in plasma was 213 ng/ml,
approximately 1 h after oral administration of 0.8 g/kg of pom-
egranate leaf extract (Lei et al., 2003).
In conclusion, ETs are generally not absorbed. Released EA at
gut level is also poorly absorbed in the stomach and small
intestine and largely metabolized by unidentified bacteria in the
intestinal lumen to produce urolithins. Microbial metabolism
primarily starts in the small intestine, and the first metabolites
produced retain four phenolic hydroxyls. The latters are further
metabolized along the intestinal tract to remove hydroxyl units
leading to Uro-A and Uro-B in the distal parts of the colon
(Devipriya et al., 2007b).
Anti-oxidative effects of EA
The phenolic phytochemicals such as EA can aid in the cellular
anti-oxidant defense response by activating the expression of
enzymes involved in anti-oxidant defense and repressing the
expression of oxidative stress producing pathways, such as
nicotinamide adenine dinucleotide phosphate-oxidase, and CYP
dependent phase-I enzymes (Mazumder et al., 1997). Devipriya
et al. have shown in an animal model that EA, at the concentration
of 60 mg/kg of body weight, decreases the intensity of alcohol-
induced toxicity and could be developed as a potential drug for
alcohol abuse (Devipriya et al., 2007a). They also showed the
anti-oxidant and cytoprotective properties of EA against oxidative
stress induced by alcohol (Cozzi et al., 1995). EA protected from
damage induced by mitomycin-C and hydrogen peroxide in
Chinese hamster ovary cells, probably by a scavenger mechanism
of oxygen species produced by H
treatment, and protected
DNA double helix from alkylating agent injury (Iino et al., 2001).
Iino et al. suggested that whisky is less irritating to the rat gastric
mucosa, as compared with pure ethanol, and this property of
whisky may be explained by EA contained in whisky and the
radical scavenging action of EA (Iino et al., 2002). In addition,
Figure 1. Plant ellagitannins and transformation to ellagic acid.
908 C. Usta et al. Int J Food Sci Nutr, 2013; 64(7): 907–913
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EA was shown to exhibit gastric protective action against gastric
lesions induced by ammonium hydroxide or reperfusion in the
ischemic stomach, probably due to its anti-oxidative activity.
Finally, it was found that oral administration of EA can
circumvent the carbon tetrachloride toxicity and subsequent
liver fibrosis (Thresiamma & Kuttan, 1996).
Anti-inflammatory effects of EA
Although the anti-inflammatory and anti-nociceptive effects of
EA were present in several animal models, little information
exists on the exact mechanism related to EA (Corbett et al., 2010;
Gainok et al., 2011; Rogerio et al., 2006). Rogerio et al.
demonstrated that EA significantly decreases paw edema as
measured by calipers after an injection of 1% carrageenan and
decreases the number of acid-induced writhing periods in mice
(Rogerio et al., 2006). A possible involvement in the inflamma-
tory cascade was observed through inhibition of cyclooxygenase
(COX) protein expression, resulting in anti-inflammatory effects.
If EA was a COX inhibitor, then it might be a potent anti-
inflammatory and anti-nociceptive agent. Accordingly, this
reduction in writhing periods may stem from COX inhibition or
another anti-nociceptive pathway (Afaq et al., 2005). These latter
findings were congruent with those of Rogerio et al. (2006). There
are several additional studies suggesting that different plants
containing EA may significantly reduce paw edema in rats
(Corbett et al., 2010; Feresin et al., 2002; Ojewole, 2006).
EA was shown to inhibit Interleukin (IL)-1beta- and tumor
necrosis factor (TNF)-alpha induced activation of activator
protein-1 and mitogen-activated protein kinases in activated
pancreatic stellate cells in vitro (Masamune et al., 2005). EA
exhibits anti-inflammatory properties by inducible nitric oxide
synthase (iNOS), COX-2, TNF-alpha and IL-6 down-regulation
due to nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-kB) repression and exerts its chemopreventive effect on
colon carcinogenesis in rats (Umesalma & Sudhandiran, 2010).
Similarly, pomegranate extract and EA drastically decreased COX-
2 and iNOS overexpression, reduced mitogen-activated protein
kinases phosphorylation and prevented the nuclear NF-kB trans-
location in a murine chronic model of Chron’s disease (Rosillo
et al., 2012). Recently, Gime
´nez-Bastida et al. (2012b) have tested
several metabolites of ET and observed that anti-inflammatory
effects of Uro-A is predominant in colon fibroblasts, which
implicates potential beneficial effects of ET-containing foods on
gut inflammatory diseases. Inhibition of monocyte adhesion and
endothelial cell migration in human aortic endothelial cells were
also detected after exposure to ET metabolites including Uro-A
glucuronide, Uro-B glucuronide or their corresponding aglycones,
which may underlie the beneficial effects against cardiovascular
diseases (Gime
´nez-Bastida et al., 2012a).
Anti-carcinogenic activities
EA was shown as a potent anti-carcinogenic agent in human
studies and animal models, and one of the main mechanisms is by
modulating the metabolism of environmental toxins and therefore
preventing the initiation of carcinogenesis induced by these
chemicals (Zhang et al., 1993). EA is reported to possess
significant anti-mutagenic activity. Teel (1986) suggested that one
of the mechanisms by which EA inhibits mutagenesis and
carcinogenesis is by forming adducts with DNA, thus masking
binding sites to be occupied by the mutagen or carcinogen.
However, this assumption has never been proved directly and still
remains to be elucidated. Soni et al. (1997) showed that EA may
inhibit the mutagenesis induced by aflatoxin B1 in Salmonella
tester strains TA98 and TA100. Another set of experiments
suggested that EA may lead to G
phase arrest within 48 h, able to
inhibit overall cell growth and to induce apoptosis in CaSki cells
after 72 h of treatment. Fur thermore, EA was suggested to have a
role in cell cycle regulation of cancer cells via activation of the
cyclin-dependent kinase (CDK) inhibitory protein p21
(Narayanan et al., 1999) and to prevent the cancer progression
by down-regulation of protein kinase C signaling pathway leading
to cell proliferation in lymphoma (Mishra & Vinayak, 2013).
EA was also found to significantly reduce the number of bone
marrow cells with chromosomal aberrations and chromosomal
fragments (Thresiamma et al., 1998). Chen et al. suggested that the
anti-tumor-promoting action of EA and of other related phenolics
may be mediated, in part, by inducing a redox modification of
protein kinase C, which serves as a receptor for tumor promoters
(Chen et al., 2000). Other studies have shown that EA is a potent
inhibitor of DNA topoisomerases, which are involved in carcino-
genesis. By using specific in vitro assays, structure–function
activity studies identified the 3,3-hydroxyl groups and the lactone
groups as the most essential elements for the topoisomerase
inhibitory actions of plant phenolics (Constantinou et al., 1995).
Furthermore, EA and polyhydroxylated urolithins were suggested
to act as adenosine triphosphate (ATP)-competitive inhibitors of
human topoisomerase II (Furlanetto et al., 2012).
Khanduja et al. looked into the anti-carcinogenic potential of
plant polyphenols such as EA and quercetin against N-
nitrosodiethylamine-induced lung tumorigenesis in mice. EA
was effective in decreasing the lipid peroxidation and increasing
the glutathione levels. This impact was suggested as one of the
factors responsible for higher anti-carcinogenic properties as
compared to quercetin in mice (Khanduja et al., 1999). However,
combined quercetin and EA treatment increased the activation of
p53 and p21cip1/waf1 and the MAP kinases, JNK1,2 and p38, in a
more than additive manner, suggesting a mechanism by which
quercetin and EA synergistically induce apoptosis in cancer cells
(Mertens-Talcott et al., 2005).
Losso et al. suggested that EA exhibit a selective cytotoxicity
and anti-proliferative activity and induced apoptosis in Caco-2,
MCF-7, Hs 578T and DU 145 cancer cells without any toxic
effect on the viability of normal human lung fibroblast cells. It
was also observed that the mechanism of apoptosis induction in
EA-treated cancer cells was associated with decreased
ATP production, which is crucial for the viability of cancer
cells (Losso et al., 2004). EA significantly reduced the viable
cells, induced G
-phase arrest of the cell cycle and apoptosis.
It also increased p53 and p21 and decreased CDK2 gene
expression that may lead to the G
arrest of T24 cells and
promoted caspase-3 activity after exposure for 1, 3, 6, 12 and 24 h,
which led to induction of apoptosis. Furthermore, the EA-induced
apoptosis on T24 cells was blocked by the broad-spectrum
caspase inhibitor (carbobenzoxy-valyl-alanyl-aspartyl-[O-
methyl]-fluoromethylketone; Li et al., 2005). In a study,
EA application resulted in remarkable stimulation of apoptosis
through inhibition of the prosurvival transcription factor NF-kB
(Edderkaoui et al., 2008). Additionally, Malik et al. evaluated
a crude pomegranate fruit extract containing EA for its
anti-proliferative and pro-apoptotic properties and found that it
can cause both cell growth inhibition and apoptosis in a
dose-dependent manner in androgen-insensitive PC3 cells
via modulation of the cyclin kinase inhibitor–cyclin–CDK
machinery (Malik et al., 2005). It was also shown that the potential
of EA to down-regulate the 17b-estradiol-induced human
telomerase reverse transcriptase aþbþmRNA expression may
be a mechanism via which, at least in part, chemopreventive
effects in breast cancer are obtained (Strati et al., 2009).
In a recent study, the involvement of phosphatidylinositol
30-kinase(PI3K)-Akt signaling was also suggested as molecular
pathway by which EA may induce apoptosis and subsequently
DOI: 10.3109/09637486.2013.798268 Ellagic acid pharmacology 909
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suppress colon cancer during 1,2-dimethylhydrazine-induced rat
colon carcinogenesis (Umesalma & Sudhandiran, 2011). Taken
all these evidences together, interest in EA has increased so much
that the American Cancer Society maintains an information link
on its Web site (
However, despite these clinical and experimental studies that
ascribed beneficial effects of pomegranate to EA, anti-carcino-
genic effect of pomegranate juice consumption can not only be
due only to EA but also other phytochemicals (Mena, 2011). A
clinical trial in patients with rising PSA values after surgery or
radiotherapy begun in January, 2003. During this study, patients
were treated with 8 oz of pomegranate juice daily for 2 years.
Interestingly, mean PSA doubling time following treatment, from
15 months at baseline to 54 months post-treatment increased
significantly (Pantuck et al., 2006). In an ex vivo mitogenic
bioassay, serum obtained from these pomegranate juice-treated
patients inhibited proliferation and stimulated apoptosis of
prostate cancer cell line prostate cancer cells in vitro (Pantuck
et al., 2006; Schubert et al., 1999). Moreover, pomegranate juice
components may also be effective in the treatment of metastasis of
other cancers, since the mechanisms of metastasis are similar for
most cancers (Wang et al., 2012). Accordingly, Rocha et al.
showed that pomegranate juice exert inhibitory effect on meta-
static processes in breast cancer cells in addition to prostate
cancer cells (Rocha et al., 2012). Another randomized, double
blind, controlled clinical trial investigated the effects of pom-
egranate tablets on symptoms of benign prostatic hyperplasia is
now being conducted and was not completed yet (Table 1). In a
phase II ongoing study, pomegranate juice is evaluated in patients
with recurrent adenocarcinoma of the prostate. Table 1 condenses
all the information that may be obtained at present on running
clinical trials with pomegranate juice.
Anti-hyperlipidemic effects of EA
Consumption of pomegranate juice has been suggested to reduce
oxidation of low-density lipoprotein (LDL) cholesterol (LDL-c)
and leading to the elimination of arterial plaques both in human
and animal studies (Aviram, 2012; Aviram & Rosenblat, 2012).
However, despite the findings showing striking reduction in blood
pressure, LDL oxidation and carotid intimal-media thickness,
serum glucose and lipid profiles have not been altered by
pomegranate juice consumption (Aviram et al., 2004; Sumner
et al., 2005). Similarly, pomegranate seed oil was also unable to
change serum cholesterol and LDL levels in Obese Zucker rats
(de Nigris et al., 2007). This beneficial effect of pomegranate
juice in atherosclerotic disease in animal models was ascribed to
the presence of EA (Yu et al., 2005). Pomegranate juice and
extracts, rich in EA and ETs, have been shown to exert multiple
anti-atherogenic effects. Pomegranate juice protected lipoproteins
from oxidation by up-regulating the expression and activity of
paraoxonase (PON)1 and PON2 in hepatic cells and in macro-
phages and inducing the association of PON1 to high-density
lipoprotein (HDL) (Fuhrman et al., 2010; Khateeb et al., 2010;
Shiner et al., 2007). On the other hand, anti-oxidative properties
of pomegranate juice on mouse macrophages have been sug-
gested to act via pomegranate juice-induced stimulation of
macrophage PON2 expression, while serum PON1 stimulation
by pomegranate juice consumption were not implicated in this
effect (Rosenblat et al., 2010). PONs are lactonases that prevent
Table 1. Clinical trials with pomegranate juice.
Clinical trials
GOV identifier Study focus Sponsor Study start date Status
NCT00413530 Rising PSA levels in men with previous
prostate cancer
M.D. Anderson Cancer
December 2006 Currently recruiting
NCT00719030 A study of the effectiveness of pomegranate
pills in men with prostate cancer before
University of California,
Los Angeles
October 2009 Currently recruiting
NCT00668954 Antioxidant effects of pomegranate juice
versus placebo in adults with type 2
diabetes mellitus
University of Colorado,
April 25, 2008 Unknown
NCT00727519 The Effect of pomegranate juice on oxidative
stress in hemodialysis patients
Western Galilee Hospital-
July 27, 2008 Completed but unknown
NCT00060086 Pomegranate juice in treating patients with
recurrent prostate cancer
University of California,
Los Angeles
May 6, 2003 This study is ongoing, but
not recruiting
NCT00428532 The effect of licorice root extract and pom-
egranate juice on atherosclerotic param-
eters in diabetic patients
HaEmek Medical Center,
January 2007 Unknown
NCT01220206 POMx in the treatment of erectile
POM Wonderful LLC June 2011 Ongoing
NCT01220817 Safety and efficacy of POMx capsules in men
with recurrent prostate cancer: an 18-
month study
POM Wonderful LLC October 8, 2010 Completed
NCT00682149 Effects of polyphenol containing antioxidants
on oxidative stress in diabetic patients
Yeditepe University
May 2008 Unknown
NCT00455416 Dietary intervention in follicular lymphoma
Oslo University Hospital April 2007 Ongoing
NCT01100866 Study of POMELLAÔextract to treat pros-
tate cancer
Vancouver Coastal Health December 2009 Currently recruiting
NCT00470808 The effect of a natural polyphenolic extract
From pomegranate (POMX) on the
development of atherosclerosis in diabetic
HaEmek Medical Center,
April 2007 Unknown
NCT00728299 The effects of consumption of pomegranate
juice on carotid intima-media thickness
Radiant Research July 31, 2008 Completed
NCT00381108 Study of the effects of pomegranate tablets on
enlarged prostates
University of California,
September 26, 2006 Ongoing
910 C. Usta et al. Int J Food Sci Nutr, 2013; 64(7): 907–913
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LDL-c from peroxidation, thereby preventing atherosclerosis.
Pomegranate extracts also reduced the levels of cholesterol in
macrophages by inhibiting the uptake of native and oxidized LDL
(ox-LDL) and stimulating HDL efflux and protected monocytes
and endothelial cells from peroxide and ox-LDL damage (Aviram
et al., 2008; Sestili et al., 2007).
In addition to the prevention of lipoproteins oxidation, the anti-
atherogenic properties of pomegranate also include its capacity to
induce the expression of endothelial nitric oxide synthase in
human and rat artery endothelial cells and to inhibit activated
platelets aggregation as well as to reduce the production of the
circulating platelet activating agent thromboxane A2 (de Nigris
et al., 2007; Mattiello et al., 2009). Other extracts rich in EA and
ETs, such as walnut extracts, were also able to delay LDL
oxidation and to decrease the levels of intercellular adhesion
molecule 1 (ICAM-1) and vascular cell adhesion molecule 1
(VCAM 1) in human endothelial cells (Anderson et al., 2001;
Karlsson et al., 2010; Papoutsi et al., 2008).
EA has been reported to have anti-inflammatory effects by
reducing the levels of prostaglandin synthases and by decreasing
the expression levels of adhesion molecules such as ICAM-1,
VCAM-1 and E-selectin (Huang et al., 2011; Yu et al., 2007).
In addition, EA also induces anti-angiogenic responses by
decreasing the levels of the metalloproteinase matrix metallopro-
teinase-12 and inhibiting vascular endothelial growth
factor-induced endothelial and vascular smooth muscle cells
migration (Labrecque et al., 2005; Takahashi et al., 2010).
Recently (Kannan & Quine, 2013) showed that oral pre-
treatment with EA was safe and effective in cardioprotection
against isoproterenol-induced arrhythmias, hypertrophy and myo-
cardial necrosis. Anti-lipid peroxidation property and anti hyper-
lipidemic activity through 3-hydroxy-3 methyl glutaryl CoA
reductase inhibition by EA may be the reasons for the beneficial
action of EA against experimentally induced myocardial
Other effects
Pomegranate extracts have been reported to exhibit hypotensive
and anti-diabetic effects in Wistar rats (Mohan et al., 2010). The
administration of 100–300 mg/kg/d for 4 weeks of pomegranate
juice extract to animals treated with angiotensin II decreased
mean arterial blood pressure and the biochemical changes induced
by diabetes and angiotensin II (Huang et al., 2005b). The
consumption of pomegranate flower extract and punicic acid
increases oral glucose tolerance and decreases the fasting glucose
plasma levels in experimental diabetes (Bagri et al., 2009;
Hontecillas et al., 2009). The mechanisms that may be involved in
these anti-diabetic effects include an increase in peroxisome
proliferator-activated receptor-gamma expression in cardiac,
skeletal muscle and adipose tissue (Huang et al., 2005a;
Yoshimura et al., 2005). Yoshimura et al. (2005) demonstrated
that an oral administration of EA-rich pomegranate extract
effectively whitened the pigmented skin of guinea pigs. This
effect was probably due to inhibition of the proliferation of
melanocytes and melanin synthesis by tyrosinase in melanocytes.
We have a preliminary experience showing that in rat thoracic
aorta, EA administration causes vasorelaxation, which is, in part,
modulated via endothelium-dependent mechanisms and through
inhibition of calcium influx (Yilmaz & Usta, 2013).
In an era where supplementations to ailments became so popular to
see a tremendous growth over the past 20 years, it may be timing to
make studies using pomegranate, a fruit used as a medicinal food
for centuries. It is, however, important to stress that data obtained
until now from humans are limited, thus indicating that EA, the
main active compound of pomegranate juice, and its potential
health protective effects are mostly derived from animal or in vitro
studies. In addition, it is not clearly established whether all
protective effects are attributed to EA per se, or to other food
components as well included in the same foods like quercetin,
which is reported to act synergistically with EA, or to the presence
in pomegranate juice of a high amount of anthocyanins, already
found to exert anti-carcinogenic properties. Moreover, the bene-
ficial effects of EA have been mostly attributed to its active
metabolites such as Uro-A and Uro-B. Therefore, further investi-
gations are needed to clarify these issues unequivocally.
Poor absorption from the gut may limit the bioavailability and
clinical usefulness of EA. Therefore more pharmacokinetic
research, especially in humans, is required before the real
usefulness of EA is determined. Nevertheless, the evidence
pointing to two main constituents of pomegranate, EA and ETs,
as active agents to induce in various animal preparations, both
in vitro and in vivo, vasorelaxation, oxygen scavenging, hypolipi-
demic, anti-inflammatory and anti-carcinogenic activities, call
attention to the need for designing adequate tests in humans to
assess these potentially useful properties in diseased states. It will
be essential to assess whether health protective effects of EA and/or
ETs are seen at plasma concentrations (around 50 nM) obtained
after ordinary quantity of pomegranate juice (5200 ml).
Unfortunately, the large majority of current clinical trials in man
are ongoing and for those completed, yet, little information exists.
This study was supported by Akdeniz University Scientific Research Unit
grant (No: 2010.01.0103.003).
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
Afaq F, Saleem M, Krueger CG, Reed JD, Mukhtar H. 2005.
Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract
modulates MAPK and NF-kappaB pathways and inhibits skin tumori-
genesis in CD-1 mice. Int J Cancer 113:423–433.
Anderson KJ, Teuber SS, Gobeille A, Cremin P, Waterhouse AL,
Steinberg FM. 2001. Walnut polyphenolics inhibit in vitro human
plasma and LDL oxidation. J Nutr 131:2837–2842.
Aviram M. 2012. Atherosclerosis: cell biology and lipoproteins –
paraoxonases protect against atherosclerosis and diabetes development.
Curr Opin Lipidol 23:169–171.
Aviram M, Rosenblat M. 2012. Pomegranate protection against cardio-
vascular diseases. Evid Based Complement Alternat Med 2012:
Aviram M, Rosenblat M, Gaitini D, Nitecki S, Hoffman A, Dornfeld L,
Volkova N, et al. 2004. Pomegranate juice consumption for 3 years by
patients with carotid artery stenosis reduces common carotid intima-
media thickness, blood pressure and LDL oxidation. Clin Nutr 23:
Aviram M, Volkova N, Coleman R, Dreher M, Reddy MK, Ferreira D,
Rosenblat M. 2008. Pomegranate phenolics from the peels, arils, and
flowers are antiatherogenic: studies in vivo in atherosclerotic
apolipoprotein e-deficient (E 0) mice and in vitro in cultured
macrophages and lipoproteins. J Agric Food Chem 56:1148–1157.
Bagri P, Ali M, Aeri V, Bhowmik M, Sultana S. 2009. Antidiabetic effect
of Punica granatum flowers: effect on hyperlipidemia, pancreatic cells
lipid peroxidation and antioxidant enzymes in experimental diabetes.
Food Chem Toxicol 47:50–54.
Bala I, Bhardwaj V, Hariharan S, Kumar MN. 2006. Analytical methods
for assay of ellagic acid and its solubility studies. J Pharm Biomed Anal
Chen C, Yu R, Owuor ED, Kong AN. 2000. Activation of antioxidant-
response element (ARE), mitogen-activated protein kinases (MAPKs)
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and caspases by major green tea polyphenol components during cell
survival and death. Arch Pharm Res 23:605–612.
Constantinou A, Stoner GD, Mehta R, Rao K, Runyan C, Moon R. 1995.
The dietary anticancer agent ellagic acid is a potent inhibitor of DNA
topoisomerases in vitro. Nutr Cancer 23:121–130.
Corbett S, Daniel J, Drayton R, Field M, Steinhardt R, Garrett N. 2010.
Evaluation of the anti-inflammatory effects of ellagic acid. J Perianesth
Nurs 25:214–220.
Cozzi R, Ricordy R, Bartolini F, Ramadori L, Perticone P, De Salvia R.
1995. Taurine and ellagic acid: two differently-acting natural antioxi-
dants. Environ Mol Mutagen 26:248–254.
de Nigris F, Balestrieri ML, Williams-Ignarro S, D’Armiento FP, Fiorito
C, Ignarro LJ, Napoli C. 2007. The influence of pomegranate fruit
extract in comparison to regular pomegranate juice and seed oil on
nitric oxide and arterial function in obese Zucker rats. Nitric Oxide 17:
Devipriya N, Srinivasan M, Sudheer AR, Menon VP. 2007a. Effect of
ellagic acid, a natural polyphenol, on alcohol-induced prooxidant and
antioxidant imbalance: a drug dose dependent study. Singapore Med J
Devipriya N, Sudheer AR, Menon VP. 2007b. Dose-response effect of
ellagic acid on circulatory antioxidants and lipids during alcohol-
induced toxicity in experimental rats. Fundam Clin Pharmacol 21:
Doyle B, Griffiths LA. 1980. The metabolism of ellagic acid in the rat.
Xenobiotica 10:247–256.
Edderkaoui M, Odinokova I, Ohno I, Gukovsky I, Go VL, Pandol SJ,
Gukovskaya AS. 2008. Ellagic acid induces apoptosis through
inhibition of nuclear factor kappa B in pancreatic cancer cells.
World J Gastroenterol 14:3672–3680.
Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M,
Kessler RC. 1998. Trends in alternative medicine use in the United
States, 1990–1997: results of a follow-up national survey. JAMA 280:
´n JC, Garcı
´a-Conesa MT, Toma
´n FA. 2007. Nutraceuticals:
facts and fiction. Phytochemistry 68:2986–3008.
Falsaperla M, Morgia G, Tartarone A, Ardito R, Romano G. 2005.
Support ellagic acid therapy in patients with hormone refractory
prostate cancer (HRPC) on standard chemotherapy using vinorelbine
and estramustine phosphate. Eur Urol 47:449–454; discussion 454–
Feresin GE, Tapia A, Gutierrez RA, Delporte C, Backhouse Erazo N,
Schmeda-Hirschmann G. 2002. Free radical scavengers, anti-inflam-
matory and analgesic activity of Acaena magellanica. J Pharm
Pharmacol 54:835–844.
Fuhrman B, Volkova N, Aviram M. 2010. Pomegranate juice polyphenols
increase recombinant paraoxonase-1 binding to high-density lipopro-
tein: studies in vitro and in diabetic patients. Nutrition 26:359–366.
Furlanetto V, Zagotto G, Pasquale R, Moro S, Gatto B. 2012. Ellagic acid
and polyhydroxylated urolithins are potent catalytic inhibitors of
human topoisomerase II: an in vitro study. J Agric Food Chem 60:
Gainok J, Daniels R, Golembiowski D, Kindred P, Post L, Strickland R,
Garrett N. 2011. Investigation of the anti-inflammatory, antinocicep-
tive effect of ellagic acid as measured by digital paw pressure via the
Randall-Selitto meter in male Sprague-Dawley rats. AANA J 79:
´nez-Bastida JA, Gonza
´as A, Larrosa M, Toma
´n JC, Garcı
´a-Conesa MT. 2012a. Ellagitannin metabolites,
urolithin A glucuronide and its aglycone urolithin A, ameliorate
TNF-a-induced inflammation and associated molecular markers in
human aortic endothelial cells. Mol Nutr Food Res 56:784–796.
´nez-Bastida JA, Larrosa M, Gonza
´as A, Toma
´n JC, Garcı
´a-Conesa MT. 2012b. Intestinal ellagitannin metabol-
ites ameliorate cytokine-induced inflammation and associated molecu-
lar markers in human colon fibroblasts. J Agric Food Chem 60:
Hassoun EA, Vodhanel J, Abushaban A. 2004. The modulatory effects of
ellagic acid and vitamin E succinate on TCDD-induced oxidative stress
in different brain regions of rats after subchronic exposure. J Biochem
Mol Toxicol 18:196–203.
Hontecillas R, O’Shea M, Einerhand A, Diguardo M, Bassaganya-Riera J.
2009. Activation of PPAR gamma and alpha by punicic acid
ameliorates glucose tolerance and suppresses obesity-related inflam-
mation. J Am Coll Nutr 28:184–195.
Huang ST, Wang CY, Yang RC, Wu HT, Yang SH, Cheng YC, Pang JH.
2011. Ellagic acid, the active compound of Phyllanthus urinaria,exerts
in vivo anti-angiogenic effect and inhibits MMP-2 activity. Evid Based
Complement Alternat Med 2011:215035.
Huang TH, Peng G, Kota BP, Li GQ, Yamahara J, Roufogalis BD, Li Y.
2005a. Anti-diabetic action of Punica granatum flower extract:
activation of PPAR-gamma and identification of an active component.
Toxicol Appl Pharmacol 207:160–169.
Huang TH, Yang Q, Harada M, Li GQ, Yamahara J, Roufogalis BD, Li Y.
2005b. Pomegranate flower extract diminishes cardiac fibrosis in
Zucker diabetic fatty rats: modulation of cardiac endothelin-1 and
nuclear factor-kappaB pathways. J Cardiovasc Pharmacol 46:856–862.
Iino T, Nakahara K, Miki W, Kiso Y, Ogawa Y, Kato S, Takeuchi K. 2001.
Less damaging effect of whisky in rat stomachs in comparison with
pure ethanol. Role of ellagic acid, the nonalcoholic component.
Digestion 64:214–221.
Iino T, Tashima K, Umeda M, Ogawa Y, Takeeda M, Takata K, Takeuchi
K. 2002. Effect of ellagic acid on gastric damage induced in ischemic
rat stomachs following ammonia or reperfusion. Life Sci 70:
Kannan MM, Quine SD. 2013. Ellagic acid inhibits cardiac arrhythmias,
hypertrophy and hyperlipidaemia during myocardial infarction in rats.
Metabolism 62:52–61.
Karlsson S, Na
˚nberg E, Fjaeraa C, Wijkander J. 2010. Ellagic acid
inhibits lipopolysaccharide-induced expression of enzymes involved in
the synthesis of prostaglandin E2 in human monocytes. Br J Nutr 103:
Khanduja KL, Gandhi RK, Pathania V, Syal N. 1999. Prevention of
N-nitrosodiethylamine-induced lung tumorigenesis by ellagic acid and
quercetin in mice. Food Chem Toxicol 37:313–318.
Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B. 2010.
Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by
pomegranate polyphenols: a role for PPAR-gamma pathway.
Atherosclerosis 208:119–125.
Labrecque L, Lamy S, Chapus A, Mihoubi S, Durocher Y, Cass B,
Bojanowski MW, et al. 2005. Combined inhibition of PDGF and VEGF
receptors by ellagic acid, a dietary-derived phenolic compound.
Carcinogenesis 26:821–826.
Larrosa M, Garcı
´a-Conesa MT, Espı
´n JC, Toma
´n FA. 2010.
Ellagitannins, ellagic acid and vascular health. Mol Aspects Med 31:
Flavonoids and related compounds bioavailability and function. In:
Spencer JPE, Crozier A, editors. Chapter 9. Bioavailability and
metabolism of ellagic acid and ellagitannins. FL: CRC Press Taylor &
Francis Group. p 183–196.
Lei F, Xing DM, Xiang L, Zhao YN, Wang W, Zhang LJ, Du LJ. 2003.
Pharmacokinetic study of ellagic acid in rat after oral administration of
pomegranate leaf extract. J Chromatogr B Analyt Technol Biomed Life
Sci 796:189–194.
Li TM, Chen GW, Su CC, Lin JG, Yeh CC, Cheng KC, Chung JG. 2005.
Ellagic acid induced p53/p21 expression, G1 arrest and apoptosis in
human bladder cancer T24 cells. Anticancer Res 25:971–979.
Losso JN, Bansode RR, Trappey A, Bawadi HA, Truax R. 2004. In vitro
anti-proliferative activities of ellagic acid. J Nutr Biochem 15:672–678.
Malik A, Afaq F, Sarfaraz S, Adhami VM, Syed DN, Mukhtar H. 2005.
Pomegranate fruit juice for chemoprevention and chemotherapy of
prostate cancer. Proc Natl Acad Sci USA 102:14813–14818.
Masamune A, Satoh M, Kikuta K, Suzuki N, Satoh K, Shimosegawa T.
2005. Ellagic acid blocks activation of pancreatic stellate cells.
Biochem Pharmacol 70:869–878.
Mattiello T, Trifiro
`E, Jotti GS, Pulcinelli FM. 2009. Effects of
pomegranate juice and extract polyphenols on platelet function.
J Med Food 12:334–339.
Mazumder A, Neamati N, Sunder S, Schulz J, Pertz H, Eich E, Pommier
Y. 1997. Curcumin analogs with altered potencies against HIV-1
integrase as probes for biochemical mechanisms of drug action. J Med
Chem 40:3057–3063.
Mena P, Girone
´s-Vilaplana A, Moreno DA, Garcı
´a-Viguera C. 2011.
Pomegranate fruit for health promotion: myths and realities. Funct
Plant Sci Biotechnol 5:33–42.
Mertens-Talcott SU, Bomser JA, Romero C, Talcott ST, Percival SS.
2005. Ellagic acid potentiates the effect of quercetin on p21waf1/cip1,
p53, and MAP-kinases without affecting intracellular generation of
reactive oxygen species in vitro. J Nutr 135:609–614.
Mertens-Talcott SU, Percival SS. 2005. Ellagic acid and quercetin interact
synergistically with resveratrol in the induction of apoptosis and cause
912 C. Usta et al. Int J Food Sci Nutr, 2013; 64(7): 907–913
Int J Food Sci Nutr Downloaded from by AMS on 01/27/14
For personal use only.
transient cell cycle arrest in human leukemia cells. Cancer Lett 218:
Mishra S, Vinayak M. 2013. Ellagic acid checks lymphoma promotion via
regulation of PKC signaling pathway. Mol Biol Rep 40:1417–1428.
Mohan M, Waghulde H, Kasture S. 2010. Effect of pomegranate juice on
Angiotensin II-induced hypertension in diabetic Wistar rats. Phytother
Res 24:S196–S203.
Murakami A, Nakamura Y, Koshimizu K, Takahashi D, Matsumoto K,
Hagihara K, Taniguchi H, et al. 2002. FA15, a hydrophobic derivative
of ferulic acid, suppresses inflammatory responses and skin tumor
promotion: comparison with ferulic acid. Cancer Lett 180:121–129.
Narayanan BA, Geoffroy O, Willingham MC, Re GG, Nixon DW. 1999.
p53/p21(WAF1/CIP1) expression and its possible role in G1 arrest and
apoptosis in ellagic acid treated cancer cells. Cancer Lett 136:215–221.
Ojewole JA. 2006. Antiinflammatory and analgesic effects of Psidium
guajava Linn. (Myrtaceae) leaf aqueous extract in rats and mice.
Methods Find Exp Clin Pharmacol 28:441–446.
Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, Hong J, Barnard RJ,
Seeram N, et al. 2006. Phase II study of pomegranate juice for men
with rising prostate-specific antigen following surgery or radiation for
prostate cancer. Clin Cancer Res 12:4018–4026.
Papoutsi Z, Kassi E, Chinou I, Halabalaki M, Skaltsounis LA, Moutsatsou
P. 2008. Walnut extract (Juglans regia L.) and its component ellagic
acid exhibit anti-inflammatory activity in human aorta endothelial cells
and osteoblastic activity in the cell line KS483. Br J Nutr 99:715–722.
Priyadarsini KI, Khopde SM, Kumar SS, Mohan H. 2002. Free radical
studies of ellagic acid, a natural phenolic antioxidant. J Agric Food
Chem 50:2200–2206.
Quideau S, Feldman KS. 1996. Ellagitannin chemistry. Chem Rev 96:
Rocha A, Wang L, Penichet M, Martins-Green M. 2012. Pomegranate
juice and specific components inhibit cell and molecular processes
critical for metastasis of breast cancer. Breast Cancer Res Treat 136:
Rogerio AP, Fontanari C, Melo MC, Ambrosio SR, de Souza GE, Pereira
PS, Franc¸a SC, et al. 2006. Anti-inflammatory, analgesic and anti-
oedematous effects of Lafoensia pacari extract and ellagic acid.
J Pharm Pharmacol 58:1265–1273.
Rosenblat M, Volkova N, Aviram M. 2010. Pomegranate juice (PJ)
consumption antioxidative properties on mouse macrophages, but not
PJ beneficial effects on macrophage cholesterol and triglyceride
metabolism, are mediated via PJ-induced stimulation of macrophage
PON2. Atherosclerosis 212:86–92.
Rosillo MA, Sa
´nchez-Hidalgo M, Ca
´rdeno A, Aparicio-Soto M, Sa
Fidalgo S, Villegas I, de la Lastra CA. 2012. Dietary supplementation
of an ellagic acid-enriched pomegranate extract attenuates chronic
colonic inflammation in rats. Pharmacol Res 66:235–242.
Rukkumani R, Aruna K, Varma PS, Rajasekaran KN, Menon VP. 2004.
Comparative effects of curcumin and an analog of curcumin on alcohol
and PUFA induced oxidative stress. J Pharm Pharm Sci 7:274–283.
Schubert SY, Lansky EP, Neeman I. 1999. Antioxidant and eicosanoid
enzyme inhibition properties of pomegranate seed oil and fermented
juice flavonoids. J Ethnopharmacol 66:11–17.
Seeram NP, Lee R, Heber D. 2004. Bioavailability of ellagic acid in
human plasma after consumption of ellagitannins from pomegranate
(Punica granatum L.) juice. Clin Chim Acta 348:63–68.
Sestili P, Martinelli C, Ricci D, Fraternale D, Bucchini A, Giamperi L,
Curcio R, et al. 2007. Cytoprotective effect of preparations from
various parts of Punica granatum L. fruits in oxidatively injured
mammalian cells in comparison with their antioxidant capacity in cell
free systems. Pharmacol Res 56:18–26.
Shiner M, Fuhrman B, Aviram M. 2007. Macrophage paraoxonase 2
(PON2) expression is up-regulated by pomegranate juice phenolic anti-
oxidants via PPAR gamma and AP-1 pathway activation.
Atherosclerosis 195:313–321.
Soni KB, Lahiri M, Chackradeo P, Bhide SV, Kuttan R. 1997. Protective
effect of food additives on aflatoxin-induced mutagenicity and
hepatocarcinogenicity. Cancer Lett 115:129–133.
Strati A, Papoutsi Z, Lianidou E, Moutsatsou P. 2009. Effect of ellagic
acid on the expression of human telomerase reverse transcriptase
(hTERT) alphaþbetaþtranscript in estrogen receptor-positive MCF-7
breast cancer cells. Clin Biochem 42:1358–1362.
Sumner MD, Elliott-Eller M, Weidner G, Daubenmier JJ, Chew MH,
Marlin R, Raisin CJ, Ornish D. 2005. Effects of pomegranate juice
consumption on myocardial perfusion in patients with coronary heart
disease. Am J Cardiol 96:810–814.
Takahashi M, Yamashita A, Moriguchi-Goto S, Sugita C, Matsumoto T,
Matsuda S, Sato Y, et al. 2010. Inhibition of factor XI reduces
thrombus formation in rabbit jugular vein under endothelial denudation
and/or blood stasis. Thromb Res 125:464–470.
Teel RW. 1986. Ellagic acid binding to DNA as a possible mechanism for
its antimutagenic and anticarcinogenic action. Cancer Lett 30:329–336.
Thresiamma KC, George J, Kuttan R. 1998. Protective effect of curcumin,
ellagic acid and bixin on radiation induced genotoxicity. J Exp Clin
Cancer Res 17:431–434.
Thresiamma KC, Kuttan R. 1996. Inhibition of liver fibrosis by ellagic
acid. Indian J Physiol Pharmacol 40:363–366.
Tindle HA, Davis RB, Phillips RS, Eisenberg DM. 2005. Trends in use of
complementary and alternative medicine by US adults: 1997–2002.
Altern Ther Health Med 11:42–49.
Umesalma S, Sudhandiran G. 2010. Differential inhibitory effects of the
polyphenol ellagic acid on inflammatory mediators NF-kappaB, iNOS,
COX-2, TNF-alpha, and IL-6 in 1,2-dimethylhydrazine-induced rat
colon carcinogenesis. Basic Clin Pharmacol Toxicol 107:650–655.
Umesalma S, Sudhandiran G. 2011. Ellagic acid prevents rat colon
carcinogenesis induced by 1, 2 dimethyl hydrazine through inhibition
of AKT-phosphoinositide-3 kinase pathway. Eur J Pharmacol 660:
Wang L, Ho J, Glackin C, Martins-Green M. 2012. Specific pomegranate
juice components as potential inhibitors of prostate cancer metastasis.
Transl Oncol 5:344–355.
Whitley AC, Stoner GD, Darby MV, Walle T. 2003. Intestinal epithelial
cell accumulation of the cancer preventive polyphenol ellagic acid –
extensive binding to protein and DNA. Biochem Pharmacol 66:
Yılmaz B, Usta C. 2013. Ellagic acid-induced endothelium-dependent
and endothelium-independent vasorelaxation in rat thoracic aortic rings
and the underlying mechanism. Phytother Res 27:285–289.
Yoshimura M, Watanabe Y, Kasai K, Yamakoshi J, Koga T. 2005.
Inhibitory effect of an ellagic acid-rich pomegranate extract on
tyrosinase activity and ultraviolet-induced pigmentation. Biosci
Biotechnol Biochem 69:2368–2373.
Yu YM, Chang WC, Wu CH, Chiang SY. 2005. Reduction of oxidative
stress and apoptosis in hyperlipidemic rabbits by ellagic acid. J Nutr
Biochem 16:675–681.
Yu YM, Wang ZH, Liu CH, Chen CS. 2007. Ellagic acid inhibits IL-
1beta-induced cell adhesion molecule expression in human umbilical
vein endothelial cells. Br J Nutr 97:692–698.
Zhang Z, Hamilton SM, Stewart C, Strother A, Teel RW. 1993. Inhibition
of liver microsomal cytochrome P450 activity and metabolism of the
tobacco-specific nitrosamine NNK by capsaicin and ellagic acid.
Anticancer Res 13:2341–2346.
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... The promising outcomes of the radical-quenching capacity of the cookies fortified with CS extract were probably due to their phytochemical composition, particularly their richness in phenolic acids (mainly gallic acid and caffeoylquinic acids derivatives), flavonoids (mainly catechin), and hydrolysable tannins (namely ellagic acid), whose scavenging potential has already been proven in previous studies [30][31][32]. Notably, the cookies enriched with CS extract disclosed, in general, a markedly higher counteracting power when compared to the control cookies (without extract), emphasizing the exceptional contribution of the CS extract to the radical-scavenging capacity of the functional cookies. ...
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Chestnut (Castanea sativa) shells (CSs), an undervalued agro-industrial biowaste, have arisen as a source of bioactive compounds with promising health-promoting effects. This study attempted, for the first time, to develop a functional food, namely cookies, using a CS extract obtained by an eco-friendly technology (subcritical water extraction). The cookies were characterized regarding their nutritional composition, total phenolic and flavonoid contents (TPC and TFC, respectively), antioxidant/antiradical activities, phenolic profile, and sensory evaluation. The results demonstrated that the CS-extract-enriched cookies were mainly composed of carbohydrates (53.92% on dry weight (dw)), fat (32.62% dw), and fiber (5.15% dw). The phenolic profile outlined by HPLC-PDA revealed the presence of phenolic acids, flavonoids, and hydrolysable tannins, attesting to the high TPC and TFC. The in vitro antioxidant/antiradical effects proved the bioactivity of the functional cookies, while the sensory evaluation unveiled excellent scores on all attributes (≥6.25). The heatmap diagram corroborated strong correlations between the TPC and antioxidant/antiradical properties, predicting that the appreciated sensory attributes were closely correlated with high carbohydrates and phenolic compounds. This study encourages the sustainable recovery of antioxidants from CSs and their further employment as an active nutraceutical ingredient in functional cookies.
... Moreover, catechins were reported to be safe when applied to human (Bae et al., 2020). Ellagic acid can perform as oxygen free radical scavenger, anti-inflammatory and anti-carcinogen (Usta et al., 2013). It's also known for its antimicrobial activity (Evtyugin et al., 2020). ...
Formulating plant extracts as nanoemulsions would maximize their use in different applications. This work aimed at formulating henna (Lawsonia inermis) extract as nanoemulsion (HENE) and studying its antimicrobial activity on some food-borne pathogens in comparison to the bulk henna extract (HE). The active compounds in henna leaves were extracted by cold solvent extraction method using ethanol and was analyzed using high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR) and UV–visible spectrophotometry (UV–Vis). It was found that the extract is rich in phenolic compounds, mainly, catechin, methyl gallat, elagic acid and coumaric acid. The ultrasonic emulsification was used to prepare HENE with average droplet size of 90 nm as measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The antimicrobial activities of HENE on seven pathogenic bacteria (Bacillus cereus, Staphylococcus aureus, Listeria monocytogenes, Salmonella typhimurium, Escherichia coli, Pseudomonas aeruginosa and Yersinia enterocolitica) and seven fungi (Trichoderma reesei, Aspergillus terreus, Penicillium digitatum, Aspergillus niger, Candida albicans, Aspergillus flavus and Saccharomyces cerevisiae) were compared with HE and penicillin. The preservative efficacy of HENE at 0.03% and 0.05% v/v on yoghurt as a model system over a cold storage period of 15 days was studied. HENE showed higher antibacterial efficacy (P < 0.05) against B. cereus, E. coli and P. aeruginosa. The antifungal effect of HENE exceeded that of both penicillin and HE (P < 0.05), in particular, against P. digitatum, S. cerevisiae and A. terreus (P < 0.001). During storage period of yoghurt, no mold or yeast were detected.
... From the antioxidative tests, we have found that SC extract is enriched in antioxidant components, and we also observed good analgesic, anti-inflammatory, and antipyretic responses from the in vivo tests. As it is already mentioned that antioxidants have significant roles in treating inflammation and associated diseases, so it is supposed that antioxidant molecules reported in this plant such as vanillic acid (a phenolic compound) [50], oleanolic acid (a triterpenoid) [51], maslinic acid (a triterpenoid) [52], luteolin (a flavonoid) [53], myricetin (a polyphenolic compound) [54], and ellagic acid (a polyphenolic compound) [55] might be responsible for the mentioned pharmacological effects (Figure 7). Therefore, we aimed to conduct the in silico study of these antioxidant compounds to determine the better binding affinities with related receptors. ...
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Sonneratia caseolaris is a widely distributed mangrove plant having much therapeutic importance in traditional medicine. This plant is reported for possessing numerous compounds that are already used for many therapeutic purposes. After finding the presence of antioxidant components in the qualitative antioxidative assay, we went to conduct quantitative tests where the total contents of phenolics, flavonoids, and tannins were estimated as 122 mg GAE/gm, 613 mg QE/gm, and 30 mg GAE/gm, respectively. In DPPH free radical, H 2 O 2 , and superoxide radical scavenging assay, the SC 50 values were found to be 87, 66, and 192 μg/ml, respectively. In FeCl 3 reducing power assay, the RC 50 of SC extract and ascorbic acid were 80 and 28 μg/ml, respectively. This extract revealed a significant peripheral analgesic effect in the acetic acid-induced writhing model in mice by reducing the writhing impulse by about 21% and 39% at 250 and 500 mg/kg doses, respectively, and a central analgesic effect in the tail immersion method by elongating the time up to about 22% and 37% at the same doses. In the anti-inflammatory test in mice, this extract reduced the paw edema size over the observed period in a dose-dependent manner. It also showed a significant reduction in the elevated rectal temperature of mice in the observing period in Brewer's yeast-induced pyrexia model. In silico analysis revealed better binding characteristics of ellagic acid and luteolin among other compounds with various receptors that might be responsible for antioxidative and anti-inflammatory properties. From our observation, we suppose that SC fruits might be a potential source of drug leads for various inflammatory disorders.
... It was first discovered by chemist Henri Braconnot in 1831 ( Grasser and Enna, 1922). The highest levels of ellagic acid are found in raw chestnuts, walnuts, pecans, cranberries, raspberries, strawberries, and grapes, distilled beverages, peaches and pomegranates (Infante et al., 2011;Usta et al., 2013). It is found either in free form or as a part of complex compounds called ellagitannins, which can be metabolized to ellagic acid and many of its metabolites, including urolithins (Larrosa et al., 2006). ...
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Serious infections, and rising resistant infections, by pathogenic bacteria, have become developing threats worldwide. There is an increasing need to develop and discover a new treatment options that can act effectively to cure infections, with lesser resistance, side effects and toxicity. Identification of new treatment options against pathogens is an important issue nowadays. Ellagic acid is a non-drug compound that has been shown to possess many biological activities and is presented in many red fruits and berries. This study aims to evaluate and measure the antimicrobial activity and the minimum bactericidal concentration (MBC) of ellagic acid on Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Escherichia coli. The antibacterial activity of ellagic acid was evaluated against ten purified bacterial isolates via agar disc diffusion assay, and minimum bactericidal concentration assay (MBC). The results show that ellagic acid was an effective antimicrobial compound against all the tested pathogens. The MBC range was shown to be between (1-2) mg/ml for MRSA, and E.coli, and between(1-1.5) mg/ml for P. aeruginosa. This current study has detected and proved the antimicrobial activity of ellagic acid against important and widely resistant pathogenic bacteria like MRSA, P. aeruginosa, and E.coli.
... P. granatum extract beneficial roles are attributed to its compounds such as hydrolyzable tannins, anthocyanins, gallotannins, and ellagic acid (Madrigal-Carballo et al. 2009) which contains approximately 539.2 mg/L of hydrolyzable tannins, 306.0 mg/L of anthocyanins, and 33.2 mg/L of ellagic acid derivatives (Gil et al. 2000). Ellagic acid has shown improved growth performance in humans and has protective effects on peptic ulcer and brain health (Del Rio et al. 2013;Farzaei et al. 2015;Keservani et al. 2016;Rosillo et al. 2012;Usta et al. 2013). ...
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In the present study, we determined the potential effects of ellagic acid and mesocarp extract of Punica granatum on the productive and reproduction performance of laying hens. Five treatment groups were setup: (1) control group (without ellagic acid), (2) 50 mg of ellagic acid, (3) 100 mg of ellagic acid, (4) 200 mg of ellagic acid, and (5) mesocarp extract of P. granatum. All the groups were investigated for feed intake, body weight, egg production, egg quality, fertility, hatchability, antioxidant status of serum and liver, lipid peroxidation, and antibacterial activities. Egg production, feed intake, and bodyweight were significantly increased (p < 0.05) with 100 mg of ellagic acid and P. granatum extract while no significant effect was observed on albumen and yolk weight, yolk index, yolk color, egg-shape index, and Haugh unit. Both ellagic acid and P. granatum extract significantly improved hatchability while 100 and 200 mg/kg of ellagic acid numerically decreased fertility. Besides, ellagic acid (100 mg/kg) and P. granatum extract significantly decreased malondialdehyde concentration and increased total antioxidant capacity, glutathione peroxidase, and total superoxide dismutase in serum and liver samples of laying hens (p < 0.05). The lipid peroxidation was decreased among the treatment groups, with 100 mg of ellagic acid and P. granatum extract showed the best activity. Moreover, ellagic acid demonstrated strong killing activity against Escherichia coli and Staphylococcus aureus while it was ineffective against methicillin-resistant S. aureus. Our results conclude that ellagic acid and P. granatum promoted egg production, hatchability, and antioxidant enzyme activities of the laying hens.
... Ellagic acid (EA), a polyphenol presents in fruits, nuts, and herbs, owns some salient pharmacological properties (Usta et al., 2013;Gupta et al., 2021). EA is also commercially available as nutraceuticals and used to protect against chronic diseases such as diabetes (Altindag et al., 2021) and cardiovascular (Mansouri et al., 2020) and neurodegenerative diseases . ...
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Ellagic acid (EA), a naturally occurring polyphenolic compound, is detected in free form or linked to polyols or sugars, constituting hydrolyzable tannins or ellagitannins in distinct fruits, nuts, and herbs. Today, a considerable number of botanicals and enriched foods containing EA are commercially available as nutraceuticals and used to prevent mild cognitive impairment (MCI) due to the excellent neuroprotective capacity of EA. Here, this study aims to provide an overview of the physicochemical properties, source, and pharmacokinetics of EA and to emphasize the importance and mechanisms of EA in the prevention and management of MCI. To date, preclinical studies of EA and its derivatives in various cell lines and animal models have advanced the idea of dietary EA as a feasible agent capable of specifically targeting and improving MCI. The molecular mechanisms of EA and its derivatives to prevent or reduce MCI are mainly through reducing neuroinflammation, oxidative stress, neuronal apoptosis, synaptic dysfunction and loss, and defective mitochondrial functions. Nevertheless, well-designed and correctly large randomized controlled trials in the human population need to be performed to reinforce the scientific facticity of the beneficial effects of EA against MCI. Synchronously, the mechanism of EA against MCI is least provided cynosure and expects more attention from the emerging research community.
... Ellagic acid showed the anti-inflammatory activity, free radical scavenging (Mari Kannan and Darlin Quine, 2011), anti-oxidative stress and anti-apoptotic (Mari Kannan and Darlin Quine, 2012). Other potential, it also showed that the ellagic acid, is considered to have osteo-inductive capability and have anti-inflammatory properties (Usta et al., 2013). The antiinflammatory properties works by inhibit the pro-inflammatory cytokines that affected on inhibition of bone formation or osteogenesis (Al-obaidi et al., 2014). ...
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The objective of this study was to determine the intervention mechanism of Ellagic Acid (ES) against inflammatory proteins NFKB1 and HSP70. Target Protein Analysis using SeaTarget ( The compound is then analyzed for its target protein in the human body using the STITCH database ( Then analyzed the interactions between proteins using the STRINGdb database ( In the analysis results with SEA, Ellagic Acid can target HSP70. Based on the results of interactions using STITCH, ellagic acid can target the Alpha Protein Kinase Catalytic Sub-unit (PRKCA). Protein Kinase Catalytic Sub-unit Alpha facilitates ellagic acid interactions with Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and Heat Shock 60kDa Protein 1 (HSPD1). Where NFKB1 is a pleiotropic transcription factor in various processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis, and apoptosis. Ellagic acid can help reduce inflammation. It is predicted that the active compound in ellagic acid acts as an anti-inflammatory. The NFKB1 and HSP70 pathways play a role in inflammation and have activity for inflammation regulation. Keywords: Ellagic acid, HSP70, Human & Health; Inflammation, NFKB1, STITCH
... Used as antioxidant and anti-proliferative agent. Medicinally used as dietary additive, anti-cancer agent and in curing heart diseases [61,62,63,64,65,66]. ...
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Bio-enhancers are the compounds that enhance the bioavailability of active pharmaceutical ingredients without itself having any pharmacological action. Most of them are of natural origin and do not have any side effects. They enhance the bioavailability by influencing variety of mechanisms involved in the drug action like penetration enhancement, improving metabolism, enzyme inhibition, drug targeting etc. Use of these compounds help to reduce the dose frequency which in turn reduces drug retention in turn causing the toxicity and it also helps in developing cost-effective products. Present days these are widely used to enhance the bioavailability of anti-bacterial, anti-viral, antibiotic, anticancer, anti-inflammatory, cardiovascular drugs etc and effective drug targeting. The present review is designed to emphasize the importance of certain phytoconstituents working as bio-enhancers, their classification and different mechanisms of their activity.
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Background: Malaria is one of the leading causes of death worldwide caused by parasites of the genus Plasmodium. The reduced efficacy of the mainstay antimalarial drugs due to the widespread of drug-resistant Plasmodium falciparum (P. falciparum) necessitates an effort to develop novel antimalarial drugs with new targets. The effects of a phenolic compound, ellagic acid, against the malaria parasite have previously been reported. This present study aimed to evaluate the effect of ellagic acid on pH of the P. falciparum digestive vacuole. Methods: The antimalarial potential of ellagic acid against the chloroquine-sensitive strain (3D7) of P. falciparum was assessed by using a malarial SYBR Green 1 fluorescence-based (MSF) assay. The effect of different concentrations of ellagic acid on the pH of the parasite's digestive vacuole at mid-trophozoite stage was examined by using a ratiometric pH indicator, fluorescein isothiocyanate (FITC)-dextran on the flow cytometry. Results: The result of the MSF assay showed that ellagic acid has an antimalarial activity (half-maximal inhibitory concentration [IC50] = 1.85 ± 4.57 nM) at par with a standard drug, artemisinin (IC50 = 1.91 ± 5.41 nM). The pH of the digestive vacuole of ellagic acid-treated parasites was significantly changed (pH values ranged from 6.11 to 6.74) in a concentration-dependent manner as compared to untreated parasites (P < 0.001). A similar effect was shown by the parasites treated with a standard proton pump inhibitor, concanamycin A. Conclusion: These findings suggest that ellagic acid might have altered the digestive vacuole pH through the inhibition of proton pumps that regulate the acidification of this organelle. Overall, this study provides a valuable insight into the potential of ellagic acid as a promising antimalarial candidate with a novel mechanism of action.
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A prior national survey documented the high prevalence and costs of alternative medicine use in the United States in 1990. To document trends in alternative medicine use in the United States between 1990 and 1997. Nationally representative random household telephone surveys using comparable key questions were conducted in 1991 and 1997 measuring utilization in 1990 and 1997, respectively. A total of 1539 adults in 1991 and 2055 in 1997. Prevalence, estimated costs, and disclosure of alternative therapies to physicians. Use of at least 1 of 16 alternative therapies during the previous year increased from 33.8% in 1990 to 42.1% in 1997 (P < or = .001). The therapies increasing the most included herbal medicine, massage, megavitamins, self-help groups, folk remedies, energy healing, and homeopathy. The probability of users visiting an alternative medicine practitioner increased from 36.3% to 46.3% (P = .002). In both surveys alternative therapies were used most frequently for chronic conditions, including back problems, anxiety, depression, and headaches. There was no significant change in disclosure rates between the 2 survey years; 39.8% of alternative therapies were disclosed to physicians in 1990 vs 38.5% in 1997. The percentage of users paying entirely out-of-pocket for services provided by alternative medicine practitioners did not change significantly between 1990 (64.0%) and 1997 (58.3%) (P=.36). Extrapolations to the US population suggest a 47.3% increase in total visits to alternative medicine practitioners, from 427 million in 1990 to 629 million in 1997, thereby exceeding total visits to all US primary care physicians. An estimated 15 million adults in 1997 took prescription medications concurrently with herbal remedies and/or high-dose vitamins (18.4% of all prescription users). Estimated expenditures for alternative medicine professional services increased 45.2% between 1990 and 1997 and were conservatively estimated at $21.2 billion in 1997, with at least $12.2 billion paid out-of-pocket. This exceeds the 1997 out-of-pocket expenditures for all US hospitalizations. Total 1997 out-of-pocket expenditures relating to alternative therapies were conservatively estimated at $27.0 billion, which is comparable with the projected 1997 out-of-pocket expenditures for all US physician services. Alternative medicine use and expenditures increased substantially between 1990 and 1997, attributable primarily to an increase in the proportion of the population seeking alternative therapies, rather than increased visits per patient.
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The current paper summarizes the antioxidative and antiatherogenic effects of pomegranate polyphenols on serum lipoproteins and on arterial macrophages (two major components of the atherosclerotic lesion), using both in vitro and in vivo humans and mice models. Pomegranate juice and its by-products substantially reduced macrophage cholesterol and oxidized lipids accumulation, and foam cell formation (the hallmark of early atherogenesis), leading to attenuation of atherosclerosis development, and its consequent cardiovascular events.
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Pomegranate juice (PJ) is a natural product that inhibits prostate cancer progression. A clinical trial on patients with recurrent prostate cancer resulted in none of the patients progressing to a metastatic stage during the period of the trial. We have previously found that, in addition to causing cell death of hormone-refractory prostate cancer cells, PJ also markedly increases adhesion and decreases migration of the cells that do not die. However, because PJ is a very complex mixture of components and is found in many different formulations, it is important to identify specific components that are effective in inhibiting growth and metastasis. Here, we show that the PJ components luteolin, ellagic acid, and punicic acid together inhibit growth of hormone-dependent and hormone-refractory prostate cancer cells and inhibit their migration and their chemotaxis toward stromal cell-derived factor 1α (SDF1α), a chemokine that is important in prostate cancer metastasis to the bone. These components also increase the expression of cell adhesion genes and decrease expression of genes involved in cell cycle control and cell migration. Furthermore, they increase several well-known tumor-suppression microRNAs (miRNAs), decrease several oncogenic miRNAs, and inhibit the chemokines receptor type 4 (CXCR4)/SDF1α chemotaxis axis. Our results suggest that these components may be more effective in inhibiting prostate cancer growth and metastasis than simply drinking the juice. Chemical modification of these components could further enhance their bioavailability and efficacy of treatment. Moreover, because the mechanisms of metastasis are similar for most cancers, these PJ components may also be effective in the treatment of metastasis of other cancers.
PURPOSE: Alcoholic liver disease is a major medical complication of alcohol abuse and a common liver disease in western countries. Increasing evidence demonstrates that oxidative stress plays an important etiologic role in the development of alcoholic liver disease. Alcohol alone or in combination with high fat is known to cause oxidative injury. The present study therefore aims at evaluating the protective role of curcumin, an active principle of turmeric and a synthetic analog of curcumin (CA) on alcohol and thermally oxidised sunflower oil (Delta PUFA) induced oxidative stress. METHODS: Male albino Wistar rats were used for the experimental study. The liver marker enzymes: gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), the lipid peroxidative indices: thiobarbituric acid reactive substances (TBARS) and hydroperoxides (HP) and antioxidants such as vitamin C, vitamin E, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were used as biomarkers for testing the antioxidant potential of the drugs. RESULTS: The liver marker enzymes and lipid peroxidative indices were increased significantly in alcohol, Delta PUFA and alcohol + Delta PUFA groups. Administration of curcumin and CA abrograted this effect. The antioxidant status which was decreased in alcohol, A PUFA and alcohol + A PUFA groups was effectively modulated by both curcumin and CA treatment. However, the reduction in oxidative stress was more pronounced in CA treatment groups compared to curcumin. CONCLUSION: In conclusion, these observations show that CA exerts its protective effect by decreasing the lipid peroxidation and improving antioxidant status, thus proving itself as an effective antioxidant.
The role of pomegranate on folk medicine has been largely established and in recent years a notable increase of scientific support has occurred. However, what is real? Evidence suggests that phenolic phytochemicals of pomegranate fruit, mainly anthocyanins and ellagitannins, could exert multiple therapeutic properties on health management as playing an essential role in oxidative stress balance, preventing important cardiovascular diseases, and fighting as chemoprotective agent against several kinds of cancer. In addition, pomegranate antioxidant bioactives also could possess a role as neuroprotectors in some neurological disorders just as broad antimicrobial activities among other beneficial implications. Regarding promising prospects of pomegranate phenolics, this review summarizes the available scientific information related to health promotion features of pomegranate-derived products and underlines the influence of multiple constituents on the observed biological actions, pointing out pomegranate juice as interesting source to obtain the pomegranate attributed health benefits.
Dietary supplementation with polyphenolic antioxidants to animals was shown to be associated with inhibition of LDL oxidation and macrophage foam cell formation, and attenuation of atherosclerosis development.We investigated the effects of pomegranate juice (PJ, which contains potent tannins and anthocyanins) consumption by atherosclerotic patients with carotid artery stenosis (CAS) on the progression of carotid lesions and changes in oxidative stress and blood pressure.Ten patients were supplemented with PJ for 1 year and five of them continued for up to 3 years. Blood samples were collected before treatment and during PJ consumption. In the control group that did not consume PJ, common carotid intima-media thickness (IMT) increased by 9% during 1 year, whereas, PJ consumption resulted in a significant IMT reduction, by up to 30%, after 1 year. The patients’ serum paraoxonase 1 (PON 1) activity was increased by 83%, whereas serum LDL basal oxidative state and LDL susceptibility to copper ion-induced oxidation were both significantly reduced, by 90% and 59%, respectively, after 12 months of PJ consumption, compared to values obtained before PJ consumption. Furthermore, serum levels of antibodies against oxidized LDL were decreased by 19%, and in parallel serum total antioxidant status (TAS) was increased by 130% after 1 year of PJ consumption. Systolic blood pressure was reduced after 1 year of PJ consumption by 21% and was not further reduced along 3 years of PJ consumption. For all studied parameters, the maximal effects were observed after 1 year of PJ consumption. Further consumption of PJ, for up to 3 years, had no additional beneficial effects on IMT and serum PON1 activity, whereas serum lipid peroxidation was further reduced by up to 16% after 3 years of PJ consumption.The results of the present study thus suggest that PJ consumption by patients with CAS decreases carotid IMT and systolic blood pressure and these effects could be related to the potent antioxidant characteristics of PJ polyphenols.
Peroxisome proliferator-activated receptor (PPAR)-{gamma} activators are widely used in the treatment of type 2 diabetes because they improve the sensitivity of insulin receptors. Punica granatum flower (PGF) has been used as an anti-diabetic medicine in Unani medicinal literature. The mechanism of actions is, however, unknown. In the current study, we demonstrated that 6-week oral administration of methanol extract from PGF (500 mg/kg, daily) inhibited glucose loading-induced increase of plasma glucose levels in Zucker diabetic fatty rats (ZDF), a genetic animal model for type 2 diabetes, whereas it did not inhibit the increase in Zucker lean rats (ZL). The treatment did not lower the plasma glucose levels in fasted ZDF and ZL rats. Furthermore, RT-PCR results demonstrated that the PGF extract treatment in ZDF rats enhanced cardiac PPAR-{gamma} mRNA expression and restored the down-regulated cardiac glucose transporter (GLUT)-4 (the insulin-dependent isoform of GLUTs) mRNA. These results suggest that the anti-diabetic activity of PGF extract may result from improved sensitivity of the insulin receptor. From the in vitro studies, we demonstrated that the PGF extract enhanced PPAR-{gamma} mRNA and protein expression and increased PPAR-{gamma}-dependent mRNA expression and activity of lipoprotein lipase in human THP-1-differentiated macrophage cells. Phytochemical investigation demonstrated that gallic acid in PGF extract is mostly responsible for this activity. Thus, our findings indicate that PPAR-{gamma} is a molecular target for PGF extract and its prominent component gallic acid, and provide a better understanding of the potential mechanism of the anti-diabetic action of PGF.
Protein Kinase C (PKC) isozymes are key components involved in cell proliferation and their over activation leads to abnormal tumor growth. PKC follows signalling pathway by activation of downstream gene NF-kB and early transcription factor c-Myc. Over activation of NF-kB and c-Myc gene are also linked with unregulated proliferation of cancer cells. Therefore any agent which can inhibit the activation of Protein kinase C, NF-kB and c-Myc may be useful in reducing cancer progression. To investigate this hypothesis we have tested the effect of ellagic acid on these genes in Dalton's lymphoma bearing (DL). The role of ellagic acid was also tested in regulation of tumor suppressor gene Transforming growth factor-β1 (TGF-β1). DL mice were treated with three different doses (40, 60 and 80 mg/kg body weight) of ellagic acid. Ascites cells of mice were used for the experiments. Ellagic acid administration to DL mice decreased oxidative stress by reducing lipid peroxidation. Ellagic acid also down regulates the expression of classical isozymes of PKC i.e. PKCα, PKCβ, and PKCγ as well as activity of total PKC and NF-kB, indicating its antitumor action. The anticarcinogenic action of ellagic acid was also confirmed by up regulation of TGF-β1 and down regulation of c-Myc. Lymphoma prevention by ellagic acid is further supported by decrease in cell proliferation, cell viability, ascites fluid accumulation and increase in life span of DL mice. All these findings suggest that ellagic acid prevents the cancer progression by down regulation of PKC signaling pathway leading to cell proliferation.
Breast cancer is the most common cancer and the second leading cause of cancer death and morbidity among women in the western world. Pomegranate juice (PJ) and three of its specific components have been shown to inhibit processes involved in prostate cancer metastasis. If this also proves to be true for breast cancer, these natural treatments will be promising agents against breast cancer that can serve as potentially effective and nontoxic alternatives or adjuncts to the use of conventional selective estrogen receptor modulators for breast cancer prevention and treatment. To test this possibility, we have used two breast cancer cell lines, MDA-MB-231 cells (ER(-)) and MCF7 (ER(+)), and the non-neoplastic cell line MCF10A. We show that, in addition to inhibiting growth of the breast cancer cells, PJ or a combination of its components luteolin (L) + ellagic acid (E) + punicic acid (P) increase cancer cell adhesion and decrease cancer cell migration but do not affect normal cells. These treatments also inhibit chemotaxis of the cancer cells to SDF1α, a chemokine that attracts breast cancer cells to the bone. We hypothesized that PJ and L + E + P stimulate expression of genes that increase adhesion and inhibit genes that stimulate cell migration and inhibit chemotaxis to SDF1α. Using qPCR, we confirmed these proposed effects on gene expression and in addition we found that a gene important in epithelial-to-meshenchymal transitions is decreased. We also found that pro-inflammatory cytokines/chemokines are significantly reduced by these treatments, thereby having the potential to decrease inflammation and its impact on cancer progression. Discovery that PJ and L + E + P are inhibitory of metastatic processes in breast cancer cells in addition to prostate cancer cells indicate that they are potentially a very effective treatment to prevent cancer progression in general.