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REVIEW ARTICLE
ISSN: 1381-6128
eISSN: 1873-4286

no.

Composition and Potential Health Benefits of Pomegranate: A Review

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Factor:
2.412

BENTHAM
SCIENCE

Vesna Vučića,*, Milkica Grabežb, Armen Trchounianc and Aleksandra Arsića

a
Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, University of Belgrade, studentskitry 1,
Belgrade, Serbia; bFaculty of Medicine, University of Banja Luka, Bosnia and Herzegovina, Republika Srpska; cDepartment of Bio-
chemistry, Microbiology and Biotechnology, Yerevan State University, Yerevan 0025, Armenia

ARTICLE HISTORY
Received: March 30, 2019
Accepted: June 24, 2019
DOI:
10.2174/1381612825666190708183941

Keywords: Pomegranate, pomegranate juice, pomegranate peel, polyphenols, antioxidant, metabolic disease, cancer, inflammatory disease.
Current Pharmaceutical Design
Abstract: Background: Pomegranate (Punica granatum L.) fruits are widely consumed and used as preventive
and therapeutic agents since ancient times. Pomegranate is a rich source of a variety of phytochemicals, which are
responsible for its strong antioxidative and anti-inflammatory potential.
Objective: The aim of this review is to provide an up-to-date overview of the current knowledge of chemical
structure and potential health benefits of pomegranate.
Methods: A comprehensive search of available literature.
Results: The review of the literature confirms that juice and extracts obtained from different parts of this plant,
including fruit peel, seeds, and leaves exert health benefits in both in vitro and in vivo studies. The antidiabetic,
antihypertensive, antimicrobial and anti-tumour effects of pomegranate fruit are of particular scientific and clini-
cal interest.
Conclusion: Further investigations are required to clarify the mechanism of action of the bioactive ingredients
and to reveal full potential of pomegranate as both preventive and therapeutic agent.

1. INTRODUCTION
Pomegranate (Punica granatum L.) is a fruit-bearing deciduous
tree that belongs to the family Lythraceae. It most likely originated
from Iran and Afghanistan [1]. The available paleobotanical data
revealed that the pomegranate was discovered in Transcaucasia and
the North Caucasus region [2]. Now it is cultivated in Africa, South
Caucasus, South and Central Asia, North and South America and in
the Mediterranean region. Wild pomegranates grow in Armenia,
where they are considered as one of the most valuable nutritional,
medicinal and ornamental plants in the country. The pomegranate
tree is decorative and long-lived: it is known that some trees in
France are over 200 years old. The fruit is a round berry with a
thick reddish husk. The inner part of the husk is a white, thin-
walled mesocarp that forms chambers containing edible arils with
seeds inside. The arils are deep red or purple in color, due to a high
content of polyphenols, mostly anthocyanins [3]. This high amount
of polyphenols makes pomegranate a strong and unique antioxidant,
which possesses higher antioxidant activity than vitamins E, A or C
[4]. Pomegranate juice exhibits the highest antioxidant capacity
among other commonly consumed polyphenol-rich beverages and
fruit juices, including green tea, red wine and orange, grapefruit,
grape or cranberry juice [5-8].
Pomegranate peel (PoP) is the non-edible part of the pomegran-
ate fruit. Though often considered as a waste, it comprises up to
40% of the total fruit weight [9]. Previously, Singh et al. [10] found
that pomegranate peel possesses extraordinary phytochemicals that
have medicinal and nutritional significance. Nearly 48 phenolic
compounds (polyphenols, flavonoids, ellagitannins, and proantho-
cyanidins) have been identified in PoP and other parts of the fruit
[10, 11]. The content of the active phytochemicals in pomegranate
*Address correspondence to this author at the Institute for Medical Re-
search, Centre of Research Excellence in Nutrition and Metabolism, Univer-
sity of Belgrade, Tadeusa Koscuska 1, 11129 Belgrade, Serbia;
Tel: +38111303-1997; Fax: +381 11 2030-169;
E-mail: vesna.vucic.imr@gmail.com
depends on the cultivar, geographical region, the maturity and the
processing method [12]. Higher level of phenolic content has been
observed in both juice and the peels of pomegranate fruits grown in
the desert climate, compared to those in peels of fruit grown in a
Mediterranean climate [13]. Studies have shown a wide variety of
phytochemicals present in different extracts of pomegranate peels
[14-16].
2. PHYTOCHEMICALS IN POMEGRANATE JUICE
Commercial pomegranate juice (PJ), obtained by pressing the
whole pomegranate fruit, contains significant amounts of numerous
phytochemicals. Among many bioactive compounds, hydrolyzable
tannins and anthocyanins are the most investigated ones. Apart
from these polyphenols, PJ contains flavonoids, lignans, several
organic acids, fatty acids, alkaloids, triterpenoids and phytosterols
[17]. Chemical structures of the most important constituents of PJ
are presented in Fig. 1.
2.1. Hydrolyzable tannins
Hydrolyzable tannins are the main class of polyphenolics iden-
tified in PJ. They include ellagitannins, gallotannins, gallagyl es-
ters, as well as hydroxybenzoic acids and hydroxycinnamic acids.
2.1.1. Ellagitannins
Ellagitannins account for 92% of the antioxidant activity of PJ
and are concentrated in the peel, membranes, and piths of the fruit.
Ellagitannins include different numbers of galloyl and hexahy-
droxydiphenoyl (HHDP) units esterified with glucose, and can be
hydrolyzed to ellagic acid (EA) and other smaller polyphenols, such
as urolithins, by gut micribiota in mammals. Punicalagin is the
major ellagitannin in pomegranate (2,3-hexahydroxydiphenoyl-4,6-
gallagylglucoside) [18]. Besides punicalagin and its isomers, PJ
also contains punicalin A and B, and several predunculagin iso-
mers.
Among hexahydroxydiphenoyl-glycosidic derivatives, galloyl-
HHDP hexoside and galloyl-HHDP gluconate were found in PJ
[19].

1873-4286/19 $58.00+.00 © 2019 Bentham Science Publishers

1818 Current Pharmaceutical Design, 2019, Vol. 25, No. 16 Vučić et al.

Hydrolyzable tannins

Punicalagin Punicalin 1,6 digalloil-glucol

Anthocyanins

Cyanidin 3,5-diglucoside Pelargonidin 3,5-diglucoside Delphinidin-3,5-diglucoside

Phenolic acids

Catechin Ellagic acid Caffeic acid Gallic acid

Fatty acid

Punic acid
Fig. (1). Chemical structures of the main constituents of the pomegranate fruit.

2.1.2. Gallotannins 2.1.3. Hydroxybenzoic and Hydroxycinnamic Acids

Gallotannins are hydrolyzable tannins which are also detected
in different parts of pomegranate. They contain monomeric and
dimeric galloyl moieties linked to a hexose. Among gallotannins,
monogalloyl-hexoside and digalloyl-hexoside were found in the
juice so far [12].
Phenolic acids (aromatic acids, primarily derivatives of benzoic
acid and cinnamic acid) are usually found in PJ. Among hydroxy-
benzoic acids, gallic acid, ellagic acid and its glycosidic derivatives
have been detected, while among hydroxycinnamic acids, caffeic
Composition and Potential Health Benefits of Pomegranate
acid and its derivates, chlorogenic acid, p-coumaric acid, aglycone,
ferulic acid have been described [19].
2.2. Anthocyanins
Anthocyanins are the most frequently investigated polyphenols
in PJ, together with tannins, because of their well-known biological
activity. They are the phenolic compounds responsible for the red
color of pomegranate arils. The anthocyanins contain one or two
hexose sugars linked with pelargonidin (pelargonidin 3,5-
diglucoside and pelargonidin 3-glucoside), cyanidin (cyanidin 3,5-
diglucoside, cyanidin–pentoside–hexoside, cyanidin 3-glucoside,
cyanidin 3-rutinoside, and a cyanidin-pentoside) and delphinidin
(delphinidin 3,5-diglucoside and delphinidin 3-glucoside) [20].
2.3. Flavonoids
Pomegranate juice is a very rich source of flavonoids of diverse
structures, belonging to 5 subclasses: dihydrochalcones, flavan-3-
ols, flavonols, flavanones and flavones. The flavan-3-ols includes
(+)-catechin, (-)-epicatechin, and (+)-gallocatechin. Several of these
compounds were detected in PJ for the first time in the study by
Mena et al. [19].
2.4. Organic Acids
Citric acid and L-malic acid have been pointed out as the main
organic acids in PJ. In addition, ascorbic acid, fumaric acid, oxalic
acid, quinic acid, succinic acid, and tartaric acid are present, some
of which have also been identified in the leaf, fruit peel, and seed
tissues [21].
• Fatty acids (FAs) of medium (C6 - C12), long (C14 - C20),
and very long (C22 and C24) chain length have been identi-
fied in PJ [17]. Pomegranate seeds are the main source of
FAs in PJ, and they are rich in physiologically important
polyunsaturated FAs [22, 23]. A FA typical for PJ is punicic
acid, a conjugated α-linolenic acid, which has been consid-
ered beneficial in a variety of metabolic and chronic in-
flammatory diseases [24].
2.5. Alkaloids and Lignans
A pyrrolidine-type alkaloid punigratane (2,5-diheptyl-N-
methylpyrrolidine) was recently characterized in pomegranate fruit
peel [25]. Besides alkaloids, low levels of indolamines (amine de-
rivatives of indole), including tryptamine, melatonin, and serotonin,
were present in the extract of the pomegranate fruit.
Furofuran-, dibenzylbutane, and dibenzylbutyrolactone-type
lignans have been identified in different pomegranate tissues, while
isolariciresinol is the most abundant lignan present in pomegranate
fruit peel [26].
3. ANTIOXIDATIVE EFFECTS OF POMEGRANATE
Numerous studies have shown that PJ contains a wide spectrum
of compounds with strong antioxidant capacity. Among them, tan-
nins, flavonoids and phenolic acids contribute most to antioxidative
potential of the juice. These compounds exhibit their antioxidant
activity in several ways including free radical scavenging or neu-
tralizing, metal chelating, affecting the cell signaling pathways and
modulation of gene expression [27-29].
The most commonly used assay to measure antioxidant activity
of different polyphenols is DPPH (1,1-diphenyl-2-picrylhydrazyl)
radical scavenging assay [30]. The mechanism by which polyphe-
nols, above all tannins and anthocyanins, scavenge the DPPH. radi-
cal is based on the fact that they donate hydrogen atoms and reduce
the stable radical DPPH. to its non-radical form DPPH-H, thus
inhibiting the DPPH. radical activity [31]. Interestingly, plants with
higher phenolic content usually are the ones exhibiting higher radi-
cal scavenging abilities, whereas in some cases the highest antioxi-
dative properties were displayed by plants with the highest linalool
(terpene alcohol) content [32]. Many studies have shown that PJ has
Current Pharmaceutical Design, 2019, Vol. 25, No. 16 1819
a strong free radical scavenging potential, which is superior to that
of single polyphenols from the juice [33]. In biological systems,
polyphenols from PJ can donate H to lipid peroxides (LOO.) and
thus break free radical chain reactions [34]. In addition, some com-
pounds, such as punicalagin, can donate an electron from the phe-
nolic group to H2O2 and convert it to H2O, thus scavenging H2O2
[31]. Also, the electron donor capacity of PJ was confirmed by its
ability to reduce Fe3+ to Fe2+, and it depends on the number of phe-
nolic hydroxyls per molecule, rising with their increase [31].
Besides scavenging free radicals, polyphenols can inhibit their
formation through Fenton reactions, due to their metal chelating
capacity. Namely, ferrous metal (Fe2+) ions are reactive and can
induce free radical formation through the Haber-Weiss and Fenton
reaction [35], forming hydroxyl radicals. The hydroxyl radical is
strongly reactive and can induce the lipid peroxidation process. A
study showed that quercetin [36] and punicalagin chelate intracel-
lular iron in PJ, preventing free radical formation [31].
Different polyphenols effectively inhibit the activity of some
ATP-dependent enzymes, through binding to the enzyme ATP-
binding site. Due to the similarity between ATP and NADPH struc-
tures, NADPH-dependent enzymes are also affected by polyphe-
nols. Thus polyphenols from PJ inhibit the activity of xanthine oxi-
dase, which generates reactive oxygen species [37]. In addition,
flavonoids such as (+) catechin, and some procyanidins interact
with NADPH-oxidase leading to a decrease in superoxide anion
production [34]. Some authors reported that polyphenols may
modulate activities of glutathione peroxidase, catalase and glu-
tathione S-transferase [38], and recycle antioxidant and reducing
agents, such as vitamins E and C [34].
When compared to other widely available polyphenol-rich bev-
erages, such as blueberry juice, black cherry juice, açaí juice, cran-
berry juice, orange juice, red wine, green and black tea, PJ revealed
the greatest antioxidant potency [6]. Only the chokeberry juice,
which is known for its high polyphenol content [39], had similar
antioxidant properties as PJ, despite a markedly lower level of
polyphenols in PJ [40].
Furthermore, pomegranate peel and pomegranate peel extracts
(PoPx) have antioxidative and anti-inflammatory activity. PoP is a
very good source of natural antioxidants (ellagic acids, gallic acids,
ellagitannins, catechins). Punicalagin, punicalin and ellagic acids
are responsible for PoPx antioxidative activity.
The total phenolic content (TPC) in PoPx reported in the litera-
ture, varied among PoPx prepared using different solvents, cultivars
and plants from different geographical regions [14]. Methanol PoPx
of Indian pomegranate fruit contains two to three folds higher TPC
compared to 70% methanol and ethyl acetate extract, respectively
[41]. Flavonoid content (mainly anthocyanin) varied significantly in
cultivars having different skin colors. Orak et al. [42] reported that
total flavonoid content (TFC) in PoP for Turkish genotype, is ap-
proximately 12.4 fold higher than that of juice extracts. The
research by Abida and associates showed that the highest value of
phenol, flavonide, tannin and anthocyanin was found in ethyl
acetate extract of Tunisian PoP [43].
Studies have reported that PoPx has significantly higher anti-
oxidative efficacy than the pulp, seed or juice extract [42, 44] and
has scavenging capacity against hydroxyl, superoxide anion and
peroxyl radicals, thus exhibiting protective effects against
methotrexate induced oxidative stress and lipid changes in rats [45].
4. POMEGRANATE HEALTH EFFECTS
4.1. Inflammatory Diseases
Chronic inflammation is the basis of many diseases [46].
Documented antioxidative and anti-inflammatory effects of pome-
granate fruit indicate that it could be used to achieve desired effects
on inflammatory processes. Accordingly, an increasing number of
1820 Current Pharmaceutical Design, 2019, Vol. 25, No. 16
studies deal with the effects of pomegranate on chronic inflamma-
tory disorders, such as rheumatoid arthritis (RA), chronic obstruc-
tive pulmonary disease or inflammatory bowel disease (IBD), as
well as on metabolic and cardiovascular diseases and cancer.
The mechanism of the anti-inflammatory effect of pomegranate
is tightly connected to gut microbiota - a large and diverse group of
microorganisms that live in the gastrointestinal tract. They are im-
portant for body homeostasis because they participate in the diges-
tive process, energy regulation, short chain fatty acid (SCFAs) pro-
duction, vitamin synthesis and modulation of the immunologic
system [47, 48]. It has been shown that gut microbiota is involved
in the development of various diseases, such as chronic gastrointes-
tinal diseases [49], neurological diseases [50], and systemic dis-
eases [51].
In general, human studies have documented that dietary poly-
phenols may contribute to the maintenance of intestinal health.
Ellagitannins, which are one of the most important active compo-
nents of pomegranate, may interact with the gut microbiota and
influence its metabolism. It has been shown that punicalin and pu-
nicalagin are able to inhibit the growth of some pathogenic bacteria
such as Clostridia species, Staphylococcus aureus, and Pseudo-
monas aeruginosa, but also to increase the growth of commensal
bacteria as well as de novo production of SCFAs [52]. The major
SCFAs produced are acetate, propionate, and butyrate. After being
absorbed, SCFAs could be transported to different organs. Propion-
ate will mainly participate in gluconeogenesis while acetate and
butyrate will mainly participate in lipid biosynthesis. Apart from
directly serving as important energy resources, SCFAs could modu-
late the various biological response of hosts that include inflamma-
tion and oxidative stress [53, 54]. SCFAs may activate peroxisome
proliferator-activated receptors (PPARs), as shown in animal stud-
ies [55]. PPARs are the nuclear receptor proteins regulating expres-
sion of a number of genes involved in metabolic pathways, differ-
entiation and carcinogenesis, and they exist in three isoforms (
, 
or , and ) [56, 57]. SCFAs activate PPARα, thus blocking pro-
inflammatory molecules such as nuclear factor kappa-light-chain-
enhancer of activated B cells (NF-B), signal transducer and activa-
tor of transcription (STAT) and activator protein (AP)-1 in white
adipose tissue and liver cell culture. The inhibition of these mole-
cules leads to decreased transcription of inflammatory genes such
as tumor necrosis factor
(TNF-
), interleukin 6 (IL-6), IL-1,
COX-2 and resulting in anti-inflammatory effect [58].
IBD represents a group of chronic inflammatory disorders of
the digestive tract, mostly implying ulcerative colitis (UC) and
Crohn’s disease. Ellagic acid, pomegranate extract and juice have
all shown intestinal anti-inflammatory activity and attenuated
chronic colonic inflammation in murine/rat models with colitis
[59-64]. Pomegranate extract (PE) reduced oxidative stress in
plasma and colon mucosa [59]. Marin et al. [61] have reported that
ellagic acid reduced intestinal inflammation and decreased his-
tological scores in mice, thus inhibiting the progression of the UC.
They also found downregulation of COX-2 and iNOS mediators
and blockage of signaling pathways p38 MAPK, NF-κB, and
STAT3. Gene expression studies have revealed reduced mRNA
levels of NF-κB, TNF-α, IL-18, and IL-1β in experimental Spra-
gue–Dawley rats with induced colitis, treated with PJ
[64]. Further, it has been shown that PJ reduces COX-2 expression
through the inhibition of phosphatidylinositide 3-kinases (PI3K)
and protein kinase B or Akt, both necessary for NF-B activation in
murine mesangial cells [65]. The metabolites of elagic acid, such as
urolithins A, B, C and D which are produced by the gut microbiota,
also have anti-inflammatory effects. Thus, urolithin A may reduce
COX-2, enzyme that catalyzes the conversion of arachidonic acid to
prostaglandins, and decrease the level of prostaglandin E2, but also
may affect the activity of iNOS in colon cancer cells [59].
Treatment with ellagitannin and ellagic acid-enriched PoPx of
TNBS (2,4,6-trinitrobenzene sulfonic acid) induced colitis rats de-
Vučić et al.
creased TNF-α, mitogen-activated protein kinase phosphorylation
and NF-κB translocation, suggesting that PoPx has the potential to
ameliorate colonic inflammation [62]. Further, punicic acid down-
regulates inflammation in mucosal immune and epithelial cells
through a PPARγ and PPARδ dependent mechanism. Furthermore,
punicic acid robustly binds and activates PPARɤ-responsive genes
expression (CD36, Fatty Acid Binding Protein 4 (FABP4) and
GLUT4), which are involved in the regulation of immunity, lipid
and carbohydrate metabolism, respectively [52, 66]. In addition,
punicic acid can bind to PPARα as well, which activates its respon-
sive genes involved in lipid metabolism, delta 9 desaturase and
Carnitine palmitoyl transferase 1, in skeletal muscle and adipose
tissue, in obese db/db mice and a model of diet-induced obesity in
PPARγ-expressing and tissue-specific PPARγ null mice, resulting
in lipid-lowering and anti-obesity effects [67].
Beneficial effects of PoPx have also been found in human stud-
ies on patients with IBD. A study by Kamali et al. [68] conducted
on 62 adult IBD patients, demonstrated anti-inflammatory effects of
PoPx, reducing the Lighter Colitis Activity Index (LCAI) at week
4, for 41.4% vs. 18.2% reduction by placebo.
In order to evaluate the potential benefits of pomegranate in
RA, DBA/1 mice with collagen- induced arthritis, representing an
animal model of RA, were treated with pomegranate extract. The
treatment potently delayed the onset and reduced severity of arthri-
tis. The concentration of IL-6 and infiltration of the inflammatory
cells in joints were decreased. The authors also found abrogated
multiple signal transduction pathways and downstream mediators
involved in the pathogenesis of RA [69].
Several human studies have shown that anti-inflammatory food
components exerted beneficial effects on patients with RA [70-72].
A double-blind, placebo-controlled, randomized control trial in 55
patients with RA studied the effects of PE on Disease Activity
Score (DAS) 28, markers of inflammation (CRP, matrix metallo-
proteinases 3 and erythrocyte sedimentation rate (ESR)) and
markers of oxidative stress [73]. During 8 weeks the intervention
group (30 patients) received 2 capsules of 250 mg fruit extract
(PE) and the control group (25 patients) 2 capsules of 250 mg
cellulose per day. At the end of the study, the intervention group
had significantly decreased DAS 28 score compared to the pla-
cebo group, due to a reduced number of swollen and tender
joints, pain intensity and ESR, while the activity of glutathione
peroxidase was increased.
4.2. Metabolic and Cardiovascular Diseases
Pomegranate has been claimed to provide a broad spectrum of
health benefits, thus a growing body of research evaluates the influ-
ence of preparations based on different parts of this plant on diverse
ailments. In addition to juice, pomegranate peel has been tradition-
ally used in the folk medicine. Over the past decade, there has been
an increase in interest in pomegranate due to its potential health
effects [43]. A majority of the studies investigated the effect of
pomegranate on metabolic and cardiovascular health.
Several studies investigated the vasculoprotective effects of
PoPx both in vitro and in vivo. A recent in vitro study found that
active fraction of crude extract could be effective in CVD by
potently scavenging superoxide and hydroxyl radicals, protecting
LDL against oxidation and suppressing ACE activity. The most
active fraction of crude extract F5 exhibited activity against LDL
oxidation (IC50 is 16.2 µg/ml vs. 24.3 µg/ml for ascorbic acid) and
inhibited ACE activity in a dose-dependent manner (IC50 is 0.77
µg/ml vs. 0.582 µg/ml for captopril) [41].
Animal models have mostly been used to examine the pa-
thology of metabolic and cardiovascular diseases and in many stud-
ies, PJ has shown strong antioxidant effects. A study in obese
Zucker rats being fed an atherogenic diet supplemented with PJ or
pomegranate PE induced a significant decrease in several inflam-
Composition and Potential Health Benefits of Pomegranate
mation markers [74]. Both supplemented groups also had elevated
expression of arterial endothelial-nitric oxide synthase (eNOS) that
attenuates the progression of atherosclerosis [74, 75]. PJ has also
been found to protect NO against oxidative destruction (23% higher
level of NO in the supplemented group) and to enhance biological
actions of NO [76].
Treatment with PJ of streptozotocin-induced diabetes in CD-1
mice for 4 months decreased glucose and increased activity of par-
aoxogenase 1 [77], while in Sprague-Dawley rats (21 day treat-
ment) reduced markers of inflammation (IL-6, NF-κB and TNF-a),
lipid profile and elevated size and number of Langerhans islets [78].
In high-fat diet-induced obesity/metabolic syndrome in Wistar rats,
ellagic acid [79] or PE [80] alleviated the characteristic metabolic
changes and alterations in the cardiac and hepatic structure and
function. In a study on high-fat high-sugar diet-induced non-
alcoholic fatty liver disease (NAFLD) in Sprague-Dawley rats, 7
weeks administration of 60 ml PJ simultaneously with the diet
demonstrated that PJ consumption can prevent NAFLD develop-
ment by attenuating inflammation and oxidative stress [81].
Treatment of spontaneously hypertensive rats with PoPx for 30
days significantly reduced systolic blood pressure (SBP), ACE
activity, oxidative stress (55.7±4.9 AU vs. 25.96±5.0 AU) as well
as vascular remodeling [82]. PoPx has beneficial effects in an ani-
mal model for menopause, by contributing to a reduction in SBP
and to increase in endothelium-depended relaxation in coronary
arteries. It reduces oxidative stress and improves the lipid profile. In
the control group, the SBP increased after 30 days from the begin-
ning of the study (155±4 to 173±3 mmHg), but the treatment with
PoPx prevented progression of hypertension in the treated group
(150±1.5 mmHg) [83]. Treatment with PoPx in alloxan-induced
diabetes in male mice decreased the serum level of glucose and the
activity of α -amylase, with an increase in insulin level [84], and
these results are in concordance with results of a previous study
[85]. Arun et al. [9, 41] found that antidiabetic effect of fractions of
crude extracts has better activity in α -glucosidase inhibition and
higher glucose uptake in diabetic rats than those in the earlier report
using crude methanol extract.
Cardioprotective and antihypertensive effects of PJ have widely
been investigated in clinical trials, as well. Since hyperlipidemia
and atherosclerosis are among the main complications in patients
with type 2 diabetes (T2D), several studies investigated the effects
of PJ supplementation in T2D patients. In an 8-week study, 22 T2D
patients were supplemented with 40 g/day of concentrated PJ. After
the end of the study, patients had significantly lower levels of total
cholesterol and LDL-cholesterol, while triacylglycerols and HDL-
cholesterol concentrations remained unchanged [86]. Although the
patients carefully recorded their dietary intakes, the limitation of
this study was the lack of placebo/control group, which would help
in the interpretation of the results.
The other study was conducted in 10 T2D patients and 10
healthy controls consuming 50 ml of PJ/day and lasted for 3
months. The authors found no changes in lipid profile or glucose
concentrations. Nevertheless, PJ intake significantly reduced serum
lipid peroxidation (by 56%) and decreased cellular peroxide (by
71%) and the cellular uptake of oxidised LDL by monocyte-derived
macrophages, which was higher by 36% in the patient group than in
the controls before the PJ supplementation [87]. Considering that
high-glycemic index food may contribute to T2D development,
another study in 16 healthy volunteers has shown that PJ consump-
tion significantly reduced bread-derived postprandial glucose level.
Although this effect was acute, microbial metabolites from PJ ex-
hibited the potential to further modulate glucose metabolism, for a
long time after the food intake [88]. However, a polyphenol-rich PE
has shown no effect on postprandial serum glucose in the same
study. The potential glucose-lowering effects of PoP have been
reported in observation studies [89], but intervention studies in
human are missing.
Current Pharmaceutical Design, 2019, Vol. 25, No. 16 1821
Several trials investigated the effects of pomegranate on blood
pressure, as one of the major risk factors for cardiovascular dis-
eases. In 10 patients with carotid artery stenosis who consumed 50
ml of PJ for 1 year, no effects were detected in glucose and lipid
concentrations, but serum lipid peroxidation, mean intima-media
thickness and systolic blood pressure were by 20-30% lower than
the baseline [90]. This is in agreement with a previous study con-
ducted in 10 hypertensive subjects who also consumed 50 ml of PJ,
but only for 2 weeks. All patients had 5% reduced systolic blood
pressure and 36% reduced serum angiotensin converting enzyme
activity, thus the results supported the reports on anti-hypertensive
effect of PJ [91]. Blood pressure was also reduced in 30 patients
with metabolic syndrome who consumed 500 ml of PJ daily for one
week [92]. This short study with a relatively high amount of PJ
showed a significant decrease in C-reactive protein (CRP), but an
increase in triacylglycerols and very-low-density lipoprotein cho-
lesterol (VLDL-C). On the contrary, a study on 23 women with
metabolic syndrome consuming 300 ml of PJ for 6 weeks reported
decreased lipid peroxidation and level of pro-inflammatory arachi-
donic acid, but no changes in blood pressure [93]. Since the results
on antihypertensive effects of PJ are discrepant, a systematic review
and meta-analysis investigating the effects of PJ consumption on
blood pressure have recently been performed. This meta-analysis
included 8 randomized placebo-controlled trials and confirmed that
PJ consumption reduced both systolic and diastolic blood pressure
by 5 and 2 mmHg, respectively [94]. Moreover, the effect on sys-
tolic blood pressure depends neither on the duration of the study nor
on the doses of PJ. On the other hand, diastolic blood pressure was
reduced after consumption of at least 240 ml of PJ per day [94].
In spite of the documented antihypertensive effects, only a few
studies evaluated the effects of PJ consumption on cardiovascular
patients. A randomized, double-blind, placebo-controlled study was
conducted in 45 patients with incident myocardial ischemia. After 3
months supplementation with 240 ml/day of PJ, stress-induced
ischemia was significantly lower in PJ group than in the placebo
group. Other biochemical and anthropometric parameters were
unchanged at the end of the study [95]. The cardioprotective effects
of PJ have also been shown in a study on 100 patients with
ischemic heart disease (unstable angina or myocardial infarction)
who were randomly assigned to the test or control groups. During a
5-day hospitalization, the patients in the test group received 220 ml
of PJ with the conventional medical therapy, and after the 5th day
they had a significantly lower level of troponin and lipid peroxida-
tion. These results indicate the protective effects of PJ against myo-
cardial ischemia and reperfusion injury [96].
Generally, antioxidant and anti-inflammatory effects of pome-
granate have been confirmed in both in vitro and in vivo studies, as
well as in clinical trials, and results from different studies indicate
similar effects. However, long-term effects of pomegranate con-
sumption on human health need to be elucidated.
4.3. Cancer
Pomegranate has also been considered to obtain positive effects
in several cancers, including interference with tumor cell prolifera-
tion, cell cycle, invasion and angiogenesis [97]. Polyphenols from
PJ were found to inhibit at least 2 enzymes involved in breast car-
cinogenesis: aromatase, which converts androgen to estrogen, and
17-β-hydroxysteroid dehydrogenase, which is involved in estrogen
biosynthesis [98]. In vitro studies have demonstrated inhibition of
proliferation and cell growth in two breast cancer cell lines MCF-7
and MB-MDA-231 [98]. Antiproliferative and anti-aromatase ac-
tivities have also been revealed for pomegranate ellagitannin-
derived compounds (ellagic acid, gallagic acid, and urolithins A and
B) in breast cancer cells [99]. Among these compounds, urolithin B
has demonstrated the most potent aromatase inhibition activity,
followed by gallagic acid. Both compounds also inhibit testoster-
1822 Current Pharmaceutical Design, 2019, Vol. 25, No. 16 Vučić et al.

Fig. (2). Mechanism of anti-inflammatory and antitumor action of pomegranate constituents. Several compounds (ellagitannins, anthocyanins, phenols, etc.)
decrease the expression of cyclooxygenase-2 (COX-2) via NF-B and MAPK pathways, reducing the generation of proinflammatory prostaglandins as well as
cell proliferation. Inhibition of phosphatidylinositide 3-kinases (PI3K), protein kinase B or Akt, or NF-B directly, also reduces transcription of inflammatory
genes. Another transcription factor for proinflammatory molecules, activation protein 1 (AP-1), can also be inhibited by the same pomegranate components,
via MAPK-induced phosphorylation of ERK1/2, JNK1,2,3 and p38. As a result of these processes, transcription of inflammatory mediators tumour necrosis
factor (TNF-
), inducible Nitric oxide synthases (iNOS), metalloproteinases (MMP), interleukin 6 (IL-6), and IL-1 is reduced. (Reproduced from Viladomiu
M et al. Preventive and prophylactic mechanisms of action of pomegranate bioactive constituents. Evid Based Complement Alternat Med. 2013;2013:789764,
distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the origi-
nal work is properly cited).

one-induced cell proliferation [99], suggesting that pomegranate
consumption may contribute to breast cancer prevention.
Antiproliferative and cytotoxic properties of pomegranate have
also been described in prostate, lung, colon and skin cancers.
Treatment of androgen-dependent and androgen-independent pros-
tate cancer cell lines reduced the expression of genes involved in
androgen biosynthesis, such as 3β-hydroxysteroid dehydrogenase
type 2, steroid 5α reductase type 1, and androgen receptor, suggest-
ing that pomegranate intake may help against androgen-
independent prostate cancer [100]. The anti-tumor potential is not
solely confined to the edible part of the fruit. For instance, punica-
lagin and ellagic acid isolated from the PoP, as well as pomegranate
leaf extract, strongly inhibited proliferation of A549 and H1299
lung cancer cell lines [101, 102]. Moreover, pomegranate leaf ex-
tract decreased H1299 cell migration and invasion, suggesting the
potential of this extract in reducing metastasis [103].
PJ possesses higher anti-proliferative and pro-apoptotic proper-
ties than its purified polyphenols, as shown in several human colon
cancer cell lines (HT-29, HCT116, SW480, SW620). It suggests a
possible synergistic effect of different compounds present in the
juice [104]. Studies on the mechanism of action in HT-29 cancer
revealed that PJ suppressed TNFα-induced COX-2 protein expres-
sion and AKT activation, needed for NF-κB DNA binding [105].
Furthermore, treatment of Caco-2 colon cancer cells with punica-
lagin and ellagic acid from PJ reduced cyclin expression, induced
cell cycle arrest in the S phase and apoptosis, through down-
regulation of anti-apoptotic bcl-XL and activation of caspase 3 and
9 [106]. Metabolic products of ellagitannins, urolithins, have shown
to decrease oxidative stress in the same cell line [107]. Therefore,
PJ and its components have strong anticarcinogenic potential by
downregulating inflammatory signaling pathways and inducing
apoptosis in colon cancer cells. The biological effect of PJ in hu-
man cancer tissue still needs to be elucidated. Urolithins contents
found in human colon tissues from 26 patients with colorectal can-
cer after consumption of pomegranate extract were significantly
higher in the normal (1671 ± 367 ng/g) than in the malignant tissue
(42.4 ± 10.2 ng/g) [108].
Composition and Potential Health Benefits of Pomegranate
Besides PJ, anti-proliferative properties of PoPx have been
described in different human carcinoma cells (human A549 lung
non-small cell carcinoma, PC-3 human prostate cancer cells,
SKOV3 Ovarian cancer cells, and MCF-7 breast adenocarcinoma
cancer cells) and it seems that MCF-7 breast adenocarcinoma can-
cer cells are the most responsive [102]. A study by Adhami et al.
[109] has indicated that PoPx prevents the breast, prostate, colon
and lung cancer cell growth in vitro, and has a capability to inhibit
tumor growth in preclinical in vivo study. The results of the recent
study showed that exposure to PoPx inhibits breast cancer-cell line
MDA-MB-231 progression, acts by modulating matrix glycopro-
teins including MMP9 and fibronectin. Transcriptional changes in
ICAM-1, MMP9, fibronectin, and VEGF may contribute to PPE
mediated antimetastatic effects in TNBC [110]. The study investi-
gating the pomegranate mediated prevention of breast cancer sug-
gested the involvement of anti-inflammatory mechanisms which
were able to decrease two interrelated molecular pathways, such as
NF-κB and Nrf2 [111].
In vitro studies allowed exploring some of the mechanisms
underlying the beneficial effects of pomegranate constituents. The
scheme of the anti-inflammatory/anticarcinogenic effects of bioac-
tive compounds from pomegranate is presented in Fig. 2.
Animal studies evaluating the chemopreventive effect of pome-
granate against breast cancer were conducted in DMBA-induced
mammary breast cancer in female Sprague-Dawley rats [112]. The
animals that were orally administered pomegranate emulsion (PEm)
exhibited a reduction in both tumor incidence and cumulative tumor
burden in comparison to control animals by reducing cell prolifera-
tion and inducing apoptosis [112]. Tumors in PEm-treated rats ex-
hibited decreased expression of estrogen receptors ER-α and ER-β,
and β-catenin [113]. The authors concluded that PEm-induced con-
current disruption of ER and Wnt/β-catenin signaling pathways is
the molecular basis of its chemoprevention of DMBA-inflicted rat
breast tumorigenesis. Similar effects were reported in B(a)P-
induced lung cancer mouse model [101], where PJ intake has been
found to reduce acute lung injury secondary to hyperoxia in rats
[114].
Unlike in vitro studies, clinical research in patients with cancer
is still sparse. A study in prostate cancer patients has shown that
patients consuming PJ had significantly increased PSA doubling
times (14.3 ±10.8 months vs. 25.5 ± 33.5 months) [115, 116]. How-
ever, Stenner-Liewen et al. [117] have found no significant decline
in PSA levels in advanced or metastatic prostate cancer patients
consuming PJ compared to placebo.
These studies suggest that dietary agents from pomegranate are
a promising weapon against grand health challenges of today, but
identification of key dietary components and their relation to both
prevention and the treatment of diseases warrant further research.
CONCLUSION
Pomegranate is a rich source of a wide variety of compounds
with beneficial physiological activities, in particular with antioxida-
tive and anti-inflammatory properties. Although most of these
properties can be attributed to ellagic acid and ellagitannins, par-
ticularly punicalagins, punicalins, and gallagic acid, novel research
has shown that anthocyanins and specific fatty acid profile also
contribute to the reported effects. Combination of these compounds
exerts synergistic effects that are markedly higher than the effect of
single compounds. Future research should reveal the nature of these
interactions as well as the mechanisms underlying these activities.
Consumption of this fruit or its juice protects against several most
common ailments and may even improve the course of the diseases,
primarily obesity, diabetes, cardiovascular disease, inflammatory
diseases and even some types of cancer. It is worth to note that gut
microbiota plays an important role in pomegranate’s beneficial
effects since their metabolites enhance the health effects of the
pomegranate. Due to the lack of substantial scientific evidence,
Current Pharmaceutical Design, 2019, Vol. 25, No. 16 1823
further investigations are required to clarify the mechanism of ac-
tion of the bioactive ingredients and to reveal the full potential of
pomegranate as both preventive and therapeutic agent.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or other-
wise.
ACKNOWLEDGEMENTS
This review was supported by the COST Action CA 16112
Personalized Nutrition in aging society: redox control of major age-
related diseases (NutRedOx).
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