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Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 430
IJPSR (2016), Vol. 7, Issue 2 (Review Article)
Received on 20 August, 2015; received in revised form, 12 October, 2015; accepted, 13 November, 2015; published 01 February, 2016
POMEGRANATE SEED OIL: A COMPREHENSIVE REVIEW ON ITS THERAPEUTIC
EFFECTS
Mohammad Taher Boroushaki, Hamid Mollazadeh *and Amir Reza Afshari
Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad,
Iran.
ABSTRACT: Pomegranate, Punica granatum L. (Punicaceae), as a medicinal and
nutritional ancient fruit, has an outstanding medical history throughout the world.
Each of compartments of pomegranate has interesting pharmacological activity.
Juice, leaf, flower, and peels of pomegranate possess potent antioxidant properties,
while juice, peel and oil are all weakly estrogenic activity. Pomegranate seeds have
ethnomedical indication and high conjugated α-linolenic acids (CLn) contents.
Pomegranate seed oil (PSO) with high amount of punicic acid (PA), a conjugated
isomer of α-linolenic acid, has variety of pharmacological properties. The main
properties are as follows; antioxidant, anti-inflammatory, nephroprotective,
hepatoprotective, neuroprotective, anti-cancer, enhancing the immune system,
enhancing carbohydrate metabolism and reducing insulin resistance. Based on some
studies, effects of PSO on lipid profile are controversial and consistency of data is
rare to find yet. Therefore, this review is aimed to highlight the PSO’s composition
and beneficial effects on human health and represent the mechanisms involved in its
action.
INTRODUCTION: Natural products as an
alternative source of medicinal compounds are
interested in the researchers` viewpoint. Nowadays,
the use and investigation about medicinal plants as
curative and preventive agents against diseases are
increasing because of their popularity, low adverse
effects, easy to earn and safety. Some important
drugs such as digoxine, quinine and vinca alkaloids
are formulated from herbal medicines 1-3.
Plants produce chemical compounds with various
effects as a part of their normal metabolic
activities. About 120 active compounds currently
extracted from the medicinal plants.
QUICK RESPONSE CODE
DOI:
10.13040/IJPSR.0975-8232.7(2).430-42
Article can be accessed online on:
www.ijpsr.com
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.7 (2).430-42
All aspects of traditional plants and their close
mechanisms are not determined completely but
many beneficial effects of them have been proven.
Awareness about these characteristics of plants
leads the researchers to discover the new dosage
forms with best quality and minimum adverse
effects 2, 4, 5.
In this review, we try to evaluate and collect the
information about chemical compositions,
mechanisms, efficacy, adverse effects, benefits and
toxicity of pomegranate seed oil (PSO) as a vintage
of pomegranate.
Pomegranate:
Pomegranate (Punica granatum L.), from family
Punicaceae, has been traditionally used for
thousands of years as a medicinal fruit Fig.1.
Mediterranean regions (including Iran, India and
Pakistan) have the highest rate of pomegranate
cultivation in the world 6. Based on excavations of
the Early Bronze Age (3500–2000 BC), it is
Keywords:
PSO, Punicic Acid,
Pharmacological Properties,
Antioxidant, Anti-Inflammatory
Correspondence to Author:
Hamid Mollazadeh
Department of Pharmacology,
Faculty of Medicine, Mashhad
University of Medical Sciences,
Azadi Square, Mashhad, Iran.
E-mail: mollazadehh901@mums.ac.ir
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 431
believed that the pomegranate was one of the first
cultivated fruits for its beneficial properties.
Pomegranate was held sacred by many of the
world’s major religions and nations. In the Holy
Quran, pomegranate has been described as a
paradise fruit and a symbol of insurgence and life
everlasting in Christian art. In China, pomegranate
is widely represented in art symbolizing fertility,
posterity, abundance, numerous and virtuous
offspring, and a blessed future. It was also a
symbol of invincibility in battle by the Persians7-9.
For over 4,000 years, human beings have culti
vated pomegranate for its medicinal properties.
Juice, seeds, leaves, flowers, bark and roots of
pomegranate have various effects. Lowering fever,
treating diabetes, anthelmintic, anti-diarrhea, blood
tonic, stopping the bleeding, and healing ulcers are
the most important traditional uses of pomegranate
10-14.
FIG. 1: POMEGRANATE FRUIT
Chemical Composition and Pharmacological
Properties:
The parts of the fruits of pomegranate have
different amounts of chemical compounds
including vitamins, polysaccharides, minerals,
polyphenols, and carbohydrates that are the most
abundant ingredients in pomegranate 15, 16.
Important pharmacological components of
pomegranate are summarized in Table 1. High
antioxidant capacity of pomegranate besides its
anti-invasive, anti-proliferative and pro-apoptotic
features have been studied in many human and
animal models 15, 17-20. Moreover, phytoestrogenic
compounds isolated from seeds, juice and peels of
the fruit have many hormonal activity 21, 22.
Treatment of stomach-ache, inhibiting herpes and
influenza viruses and suppressing the reproduction
of cancer cells are the other pharmacological
characteristics of pomegranate juice and seeds
extracts. Antimicrobial, anti-inflammatory,
protective effects against liver disease,
cardiovascular protection, anti-diabetic and anti-
obesity effects of pomegranate have been
investigated and documented by many researchers
11, 23-26. The presence of different substances with
various chemical structures reveals multiple
therapeutic effects of pomegranate.
TABLE 1: MOST IMPORTANT PHARMACOLOGIC COMPOUNDS OF PUNICA GRANATUM L. 10, 11, 27-29
Chemical class
Compound(s) name
Part(s) of the plant
Simple sugars
Glucose, Fructose, Sucrose
Juice
Aliphatic organic acids
Citric acid, Malic acid, Tartaric acid
Juice
Hydroxybenzoic acids
Gallic acid, Ellagic acid, 3,3_-Di-O-
methylellagic acid
Juice, Leaf,Flower, Seed
Flavan-3-ols
Flavan-3-ol, Catechin, Epicatechin
Juice, Leaf
Flavonol glycosides
Kaempferol 3-O-glycoside, Kaempferol
3-O-rhamnoglycoside
Leaf
Anthocyanidins
Delphinidin, Cyanidin
Leaf
Ellagitannins
Punicalin, Punicalagin, Corilagin
Leaf
Amino acids
Proline, Valine, Methionine
Juice
Conjugated fatty acids
Punicic acid
Seed
Non-conjugated fattyacids
Linoleic acid, Oleic acid, Palmitic acid
Seed
Sterols
Daucosterol, Camesterol
Seed
Sex steroids
17-_-Estradiol, Testosterone
Seed
Phenyl aliphaticglycosides
Icariside D1
Seed
Pomegranate Seed Oil (PSO):
Mainly, 12–20% of total seed weight is made by
PSO. Conjugated octadecatrienoic fatty acids are
responsible for approximately 80% of seed contents
and PSO is considered to be a rich source of those
fatty acids; in particular, punicic acid(PA) (cis9,
trans11, cis13 acid)which is the main fatty acid
among them. Other isomers of conjugated linolenic
acids (CLnAs) are catalpic acid (C18:3-
9trans,11trans,13cis) and α-eleostearic acid
(C18:3-9cis, 11trans, 13trans) but the oil content of
the seed and fatty acid composition are affected by
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 432
cultivation sites, harvesting time, fruit genotypes
and climatic conditions 15, 30, 31. Total lipids in PSO
comprise mainly of triglycerides (TG) that their
composition is varied and the most important
templates are CLnA-CLnA-P and CLnA-CLnA-
CLnA32. Lipid profile of PSO is different due to its
cultivar, environmental growth conditions and
ripening stage but the common and important fatty
acids found in PSO in various types of
pomegranate have been listed in Table 2 33, 34.
Also, Table 3 shows the different fatty acid
composition of PSO in the Iranian strains of
pomegranate 35. In addition to fatty acids, minor
components of the oil including steroids, sterols,
and, cerebroside (a key component of mammalian
myelin sheaths), lignins, hydroxycinnamic acids,
and the potent antioxidant lignin derivatives are
found in PSO. PSO is abundant of phytosterols
such as β-sitosterol, campesterol, stigmasterol and
tocopherols such as α and γ-tocopherol. 32, 36, 37.
TABLE 2: COMMON AND IMPORTANT FATTY ACIDS FOUND IN PSO IN VARIOUS TYPES OF POMEGRANATE.
RESULTS ARE EXPRESSED AS AVERAGE (PERCENTAGE OF TOTAL FATTY ACIDS) ± STANDARD DEVIATION 33, 34.
Fatty Acids
India Strain
China Strain
Turkey Strain
16:0
5.7 ± 4.1
5.07 ± 1.30
2.45 ± 0.19
18:0
2.1 ± 3.1
4.20 ± 1.56
1.52 ± 0.26
18:1 (ω-9)
9.0 ± 5.6
7.86 ± 2.25
4.19 ± 0.61
18:2 (ω-6)
10.8 ± 6.9
8.36 ± 2.36
4.49 ± 0.49
18:3 (9c11t13t)
10.70 ± 4.44
6.41 ± 0.27
18:3 (9t11t13t)
8.78 ± 5.16
1.03 ± 0.16
18:3 (9t11t13c)
15.24 ± 6.17
3.48 ± 0.34
18:3 (9c11t13c)
71.5 ± 17.9
36.98 ± 10.12
74.11 ± 1.55
TABLE 3: FATTY ACID COMPOSITION OF PSO IN IRANIAN STRAINS OF POMEGRANATE 35.
Variety
Fatty acid (%)
18:3
18:2
18:1
18:0
16:0
Others
Red Seed Ardestani
79.43
6.95
6.62
2.09
3.16
1.72
Rizdavar`sDorpaye
79.22
6.87
6.30
2.50
3.36
1.73
Ashkzar`s Sour Narak
82.40
5.22
5.71
1.99
2.95
1.70
Taft`s Tokhm-e Mush
78.25
6.59
7.48
2.54
3.41
1.70
Chatrud`s Sour Shahi
78.73
7.08
6.68
2.16
3.57
1.75
Punicic acid:
PA is a conjugated α-linolenic acid (CLnA)
molecule, which is found in PSO and it may
contribute to a lot of health benefits associated with
pomegranate. PA contains a third double bond, is
known as cis9, trans11, cis13, and is referred to as
18:3 fatty acids. It is an omega-5 long chain
polyunsaturated fatty acid and a positional and
geometric isomer of α-linolenic acid (LnA; C18:3-
9c, 12c, 15c) Fig. 2 38-40.
FIG.2: CHEMICAL STRUCTURE OF PUNICIC ACID
PA features cis and trans-type double bonds with
parentage of 2:1. Numerous studies have shown
that conjugated linoleic acids (CLAs) and α-
linolenic acids (LnAs) have abundant health
benefits and PA has a very high structural
similarity with them 41, 42. Anti-inflammatory,
immunomodulatory, anti-cancer, anti-estrogen and
beneficial effects on lipid profile are examples of
beneficial effects of PA that revealed in many
studies 15, 43-45.
Pharmacological actions of PSO:
PSO has been reported to have beneficial effects
including cytotoxic and antitumor properties, body
fat-reducing and lipid metabolism-normalizing
effects, enhancing the immune system in vivo,
Showing chemo preventive activity against
hormone-related (prostate and breast) and colon
cancers, reducing the accumulation of hepatic
triglycerides and promoting epidermal tissue
regeneration 46-50. Antioxidant and anti-
inflammatory activities are the main features of
PSO which results from inhibition of lipid
peroxidation and neutrophil-activation 37, 39, 51.
Effects of PSO on body weight and serum lipid
profile are inconsistent and many studies confirmed
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 433
weight reducing effects but the effects of PSO on
reducing in serum triglyceride, phospholipid,
cholesterol, and LDL-cholesterol levels are
contradictory 40, 52. PSO reduces body weight,
leptin and insulin levels, enhances glucose
tolerance, improves peripheral insulin sensitivity,
increases carbohydrate oxidative capacity, and
inhibits the progression of type2 diabetes 31, 53.
PSO is opulent of CLnAs which consists of
octadecatrienoic fatty acid isomers with three
conjugated double bonds (C18:3). Beneficial health
effects of PSO are due to the high level of its
CLnAs 30, 54. The exact mechanisms of action of
CLnAs are not completely understood but probable
and definite mechanisms are summarized in Table
4.
TABLE 4: CLINICAL EFFECTS AND MECHANISMS OF CLnAs
Effect(s)
Mechanism(s)
Reference(s)
Antitumor and anticancer
Induce apoptosis through lipid peroxidation and protein kinase C pathway,
Act as selective estrogen receptor modulators and inhibit estrogen receptors
α and β
55
22
Anti-diabetic
Improve insulin sensitivity,
Suppress NF-κB and TNF-α activation and up regulate PPAR α and γ-
responsive genes
31
53
Reductions in hepatic and
plasma TG levels
Increase the levels of PPAR-γ and α mRNA,
Suppress the delta-9 desaturation
33
56
Antioxidant
Enhance the levels of the antioxidant enzymes,
Reduce lipid peroxidation, oxidative stress
Free radical addition to one of the conjugated double bonds of CLnAs
42, 57
Anti-inflammatory
Inhibit TNFα-induced priming of ROS production and MPO,
Up regulate colonic PPAR-δ expression,
Increase the levels of IL-17 and IFN-γ,
Modulates mucosal immune responses,
Reducing the expression of TNF-α and IL-6
39, 58
NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, TNF-α: Tumor necrosis factor-α, PPAR: Peroxisome
proliferator-activated receptor, CLnAs: conjugated linolenic acid, ROS: Reactive oxygen species, MPO: Myeloperoxidase, IL:
Interleukin, IFN: Interferon
Pharmacological studies of PSO:
Anti-inflammatory activity:
Inhibition of cyclooxygenase (COX) and
lipoxygenase (LOX) by PSO have been shown in
Schubert study 59. The results of Jiang et al. study
showed that, inflammation and its important
mediators such as prostaglandin E2 (PGE2) have a
key role in progression of diseases such as cancer
and vascular heart disease. γ- tocopherol in PSO
can inhibit PGE2 formation. They showed that,
PGE2 synthesis in both IL-1β- treated A549 human
epithelial cell and lipopolysaccharide (LPS)-
stimulated RAW264.7 macrophages was reduced
with γ-tocopherol with IC50 of 4 and 7.5μM,
respectively. γ- tocopherol and its metabolite (γ t,
2,7,8-trimethyl - 2 - (beta-carboxyethyl)-6-hydroxy
chroman) can inhibit PGE2 formation after the
explosion for 1 hr to COX-2- preinduced cells
followed by addition of arachidonic acid. Also,
suppression of inducible nitric oxide synthase
expression was reduced by γ-tocopherol 60.
Enhancing B-cell function in vivo by PA was
shown in Yamasaki et al. study. Diets containing
0%, 0.12%, or 1.2% of PSO was treated to mice for
3 weeks. After this period amounts of
immunoglobulin G and M were larger than control
group in splenocytes isolated from mice 43. Ellagic
acid is another polyphenolic compound with potent
antioxidant and anti-inflammatory activity. Ellagic
acid inhibited proliferation and migration of
platelet-derived growth factor- BBand it can inhibit
IL-1β- and tumor necrosis factor-α (TNF-α)-
induced activation of activator protein-1 (AP1) and
mitogen-activated protein kinases (MAPK).
In addition, ellagic acid inhibited proliferation and
migration of monocyte chemo attractant protein-1
production which have a key role in inflammation
61. Gallicacid is a polyphenolic compound with
anti-inflammatory properties which is found in
PSO. Madlener et al. showed that gallic acid can
inhibit COX-1 and COX-2 in humanHL-
60promyelocyticleukemiacells with IC50 values of
3.5 and 4.4nM 62. About 80% w/w of hydrophilic
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 434
fraction of PSO is PA. Costantini et al. evaluated
the anti-inflammatory effect of the aqueous
methanolic extract of PSO on some human cell
lines.
They showed that the levels of vascular endothelial
growth factor and nine pro-inflammatory cytokines
was reduced after treating with PSO, dose-
dependently 63. TNF-α is a proinflammatory
cytokine that rises in many inflammatory
conditions. The expression of NF-kB and AP-1 has
been increased in the PSO’s effect. The effects of
PSO and PA on serum TNF-α concentration is
controversial. PSO administration (800mg PSO/day
for 4 weeks) to hyperlipidemic patients had no
effect on serum TNF-α concentration but in
Hontecillas et al. study, PA can decrease TNF-α
plasma concentration in mice. Changes in serum
triglyceride, HDL–C and TNF- α are related to
each other. TNF-α promotes lipolysis and can
activate the endothelium and cause vascular
damage. TNF- α and insulin resistance are related
to each other.
It is probable that anti-TNF-α effect of PSO was
liable for its anti- diabetic and triglyceride lowering
effect 64. Decrease in TNF-α and IL-6 was
reportedby Saha and Ghosh after treatment of
diabetic rats for four weeks with CLnAs (α-ESA
and PA at 0.5 % total lipids) 65. PSO decreased
intestinal inflammation in rats with necrotizing
entrocolitis (NEC). In this model of inflammation,
rats fed with 1.5% of PSO orally and then were
exposed to asphyxia/cold stress to induce NEC.
Decrease in incidence of NEC from 61% in control
group to 28% in therapeutic group was seen. Also,
PSO normalized the serum levels of
proinflammatory cytokines such as IL-6, IL-8, IL-
12, IL-23 and TNF-α. Enterocyte proliferation was
reduced after administration of PSO 66.
All of above studies confirmed anti-inflammatory
properties of PSO. In many studies anti-
inflammatory effects of PSO were investigated
with its antioxidant and anticancer effects, but in
the present paper we mentioned the PSO’s
beneficial effects separately.
Antioxidant activity: Oxidation dependent
mechanisms are very important ways to induce
diseases such as many types of cancers and
inflammatory diseases 67. Reduction- oxidation
state may activate and deactivate certain genes that
promotes many secondary steps in disease
conditions 68. NF-κB and AP-1 are two examples of
this one. Reactive oxygen species (ROS) act as
‘signal transduction messengers to promote the
activity of the cytokines 69. Genes involved in
carcinogenesis, atherosclerotic mechanisms,
diabetic changes and HIV replication are near the
receptor sites of these cytokines 59. Thus,
antioxidant effects of PSO are effective in anti-
inflammatory and cardioprotective activities. Lipid
peroxidation and ROS production are involved in
many organs toxicity due to various factors such as
xenobiotics, drugs, environmental pollutants and
etc. 70. Nephrotoxicity, hepatotoxicity,
cardiotoxicity, and neurotoxicity are the main
examples of interference of oxidative stress and
will be discussed later.
In this section, we have an overview the
antioxidant action of PSO. Mukherjee et al. showed
that PA at concentration of 0.6% has maximum
antioxidant activity. Peroxidation of
polyunsaturated fatty acids in lipids and formation
of free radicals showed a reduction. Alternatively,
conjugated double bonds of PA and other CLnAs in
PSO entrapped free radicals 71. Membrane lipid
peroxidation was decreased by diet containing 0.25
% CLnAs compare to diet without CLnAs 72.
Lowered oxidative stress and enhanced antioxidant
enzyme serum levels were observed in Saha and
Ghosh study. They treated streptozotocin- induced
diabetic rats with α-ESA or PAwith0.5% total
lipids. After the procedure, the levels of superoxide
dismutase (SOD), gluthatione peroxidase (GPx)
and catalase (CAT) were higher in treated group
compared tocontrol group 42. This result was
confirmed by other study performed by them in
sodium arsenite- induced oxidative stress in rat
models 42.
Antioxidant activity of PSO is contributed to
tocopherols and polyphenolic compound contents
73. Oxidative stress reducing agents in PSO have
metallic chelating potential, singlet oxygen
quenchers and hydrogen donors 74. Antioxidant
effect of PSO will be discussed later.
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 435
Effects on insulin resistance:
TNF- α is one of the most important pro-
inflammatory cytokines which plays a pivotal role
in obesity, inflammation and insulin resistance.
Higher serum levels of TNF- α are accompanied
with insulin resistance. Anusree et al. showed that
TNF-α (10ng/mL for 24 hr) decreased 1.7 fold in
insulin stimulated glucose uptake with respect to
control group in 3T3-L1 adipocytes, but PA with
doses of 5, 10, 30μM restored the glucose uptake
capacity significantly and dose- dependently. PA at
dose of 30μM is comparable to rosiglitazone
(100nM) in insulin stimulated glucose uptake. The
similar condition was observed in production of
ROS with the effect of TNF- α and its restoration
with the effect of PA. TNF- α treatment caused
significant alterations in mitochondrial
transmembrane potential, reduction in ATP
production, O2 consumption, overall increase in
cellular ROS generation and a decrease in aconitase
activity. The use of PA restored these states to the
baseline 75.
Peroxisome proliferator activated receptor γ
(PPAR- γ) agonists increase mitochondrial
biogenesis and normalize the fission fusion ratio in
this organelle that be altered with inflammation and
high levels of TNF-α 76. Agonistic effects of PA on
PPAR- γ, lowering oxidative stress and serum
TNF-α levels and positive effects of PA on
mitochondrial functions are the main anti-diabetic
mechanisms of PSO 75.
Effects of PSO on obesity and insulin resistance
induced by rich fat diet in mice showed that, rich
fat diet with 1% PSO after 12 weeks induced
higher peripheral insulin sensitivity in treated group
compared to control group (164±52% vs. 92±24%
respectively), but liver insulin sensitivity showed
no significant diffrence between two groups. In this
study, obesity and fat deposition induced by this
regimen was ameliorated by PSO, significantly 31.
A similar study was performed by Miranda et al.
That used diet with 0.5% PA in rats. The results of
this study showed no changes in adipose tissue
weights and insulin resistance, but the glycemic
value in the PA group had decreased, significantly
77. Improvement in insulin sensitivity is associated
with reducing the risk of developing type 2diabetes.
Insulin sensitivity was improved with 61.79mg/day
PSO in mice which was treated with rich fat
regimen compared to control group. In addition,
final body weight, body weight accumulation,
serum adiponectin, serum leptin, and serum insulin
were reduced in treated group 78.
The use of PSO (200 and 400mg/day for 28 days)
in streptozocin-nicotinamide induced diabetic rats
showed that serum insulin levels increased but the
serum glucose level had no change. Up-regulation
of PPAR-γ responsive genes by PA may be a
mechanism of PSO-induced increase in serum
insulin 79. Anti-diabetic and insulin sensitizing
effects of α- linolenic acid were also reported in
other studies53, 78-81.
Nephroprotective activity:
Investigating nephroprotective effects of PSO was
carried out mainly by Boroushaki et al. In five
separated studies, four nephrotoxic agents,
mercuric chloride 82, diazinon 83, gentamicin 84, and
hexachlorobutadien 85 and cis-platin (under
publication) were used and protective effect of PSO
was shown. Elevated serum levels of urea and
creatinine and urinary levels of glucose and protein
as well as histopathological changes in kidney,
such as severe tubular necrosis and atrophy,
represented acute nephrotoxicity by use of these
toxic agents. Inducing oxidative stress by these
agents was shown in above mentioned studies by
elevated kidney malondialdehyde content (MDA,
as a biomarker of oxidative stress) and decreased
total thiol content in the kidney.
The use of PSO in these models of nephrotoxicity
was accompanied by its protective effects and PSO
preserved renal functions and decreased
histopathological changes in kidney. Restoration of
serum urea and creatinine and decrease in urine
glucose and protein were established after PSO
treatment. Increasing in total thiol content was seen
but was not dose dependent in all studies. Kidney
was vulnerable to oxidative stress and each factor
that induces this state can be a toxic agent on this
organ. PSO due to its high content of polyphenolic
compounds is a potent antioxidant. Moreover,
hydroxybenzoic acid derivatives and sterols in PSO
have an antioxidant effect and decrease lipid
peroxidation.
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 436
The possible nephroprotective mechanisms of PSO
mentioned in these articles includes removing
peroxy radicals and prevents Cu2+- induced lipid
peroxidation, inhibition of TNF- α- induced
priming of ROS production and myeloperoxidase,
hydroperoxide formation and biohydrogenation of
CLnAs and chelating transition metals 86.
Effects on memory:
As mentioned, polyphenols have been found to
possess antioxidant properties and recent studies
indicated that seed oil extract of pomegranate has
the highest concentration of polyphenols. Sarkaki
et al. in their in vivo study demonstrated that,
administration of PSO in permanent cerebral
ischemia causes a remarkable improvement on
memory with criterion condition responses (CCRs)
in Y-maze and step-through latency (STL) in two-
way shuttle box. The results showed that, both
active and passive avoidance memories were
meaningfully impaired in rats after cerebral
hypoxia-ischemia (CHI) (P<0.001) and PSO
treatment significantly ameliorated passive and
active memory impairments with bilateral common
carotid arteries occlusion (2CCAO) (P<0.05,
P<0.01, and P<0.001) 87. Gabizon et al. Reported
that administration of large concentrations of PSO
may postpone the manifestation of disease in young
transgenic mice (Tgs), in addition, lower doses of
Nano-PSO significantly delayed disease onset in
asymptomatic TgMHu2ME199K mice and
postponed disease aggravation in already sick mice.
Therefore, PSO formulations may be impressive on
neurodegenerative diseases 88.
Anti- cancer effects:
PSO has a potent effect on tumor cells. Hora et al.
investigated the chemo preventive effect of PSO on
skin tumor development in CD1 mice. They
concluded that, PSO (5%) significantly decreased
tumor incidence (P<0.05), multiplicity, and TPA
(12-O tetradecanoylphorbol 13-acetate) - induced
ODC (ornithine decarboxylase) activity during 20
weeks of promotion. The mechanism for this effect
can be inhibition of prostaglandin biosynthesis
(COX-1, COX-2, and LOX) by punicic acid. In this
study, in addition, topical application of 5%
pomegranate seed oil remarkably inhibited (P <0
.05) the TPA-induced epidermal ODC activity.
Overally, PSO appears to be a good natural product
with a potential chemopreventive effect against
skin cancer 89.
γ-Tocopherol is the most important constituents of
PSO that is responsible for anti-cancer activity.
Jiang et al. investigated that, γ- tocopherol, inhibits
proliferation of prostate cancer cells but appears to
have no effect on the growth of a normal prostate
epithelial cell. Their proposed mechanism for this
effect was inhibition of sphingolipid synthesis de
novo 90. In another study performed by Jiang et al.
γ-tocopherol inhibited cyclooxygenase activity in
macrophages and epithelial cells. This mechanism
is beneficial for human tumor tissues, including
human colon cancer, have been reported to contain
enhanced COX-2 expression and PGE2, because
PGE2 has been shown to promote proliferation in
certain cancer cells 60. Another similar study
showed a significant role for induction of cell death
for all cancer cell lines such as colon cancer,
prostate carcinoma cells, and osteosarcoma.
According to this study, γ-tocopherol has
chemopreventive properties by mechanisms such as
reduction levels of C- reactive protein, inhibition of
neoplastic transformation, suppression of ras p-21,
inhibition of COX-2 activity, down-regulation of
cyclins, and up-regulation of PPAR - γ 91.
As mentioned, PA as an important component of
PSO has various anti- cancer effects. In a research
performed by Lansky et al .PA was tested as a
potential inhibitor of in vitro invasion of human
PC-3 prostate cancer cells in an assay employing
Matrigel TM artificial membranes. Results showed a
considerable inhibition of PC-3 prostate cancer cell
invasion 15. In another study PSO exhibited an
enhancing B-cell function in vivo that can be
effective in some cancers 43. In a study PSO via
lipid peroxidation mechanism showed a cytotoxic
effect against leukemia cells 92.
It is known that dietary phenolic compounds can
elicit vital cellular responses such as cytotoxicity,
cell cycle arrest and apoptosis by activating a
cascade of molecular events. Hydroxybenzoic
acids, such as ellagic acid and gallic acid are other
important components of PSO. In LI et al. study,
ellagic acid had shown an anti-cancer effect with
flow cytometric assay, polymerase chain reaction
(PCR) and determination of caspase-3 activity
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 437
methods. Ellagic acid significantly Induced
p53/p21 expression, G1 arrest and apoptosis in
bladder cancer cells 93. In another study, gallic acid
showed a strong dose and time-dependent growth
inhibition and apoptotic death of human DU-145
prostate cancer cells 94. In a study provided by
Madlener et al. Gallic acid induced a dose-
dependent apoptosis in HL-60 cells and attenuated
G0/G1 to the S phase, and COX in HL-60 leukemia
cells 62.
Other constituent of PSO, ursolic acid, with
mechanisms such as apoptosis in MCF-7 via p-53
up regulation 95, apoptosis in endometrial cancer
cells via caspase-3 pathway 96, and apoptosis in
melanoma cells via the intrinsic cell death pathway
and caspase 3 activation 97 showed anti- cancer
activity.
Furthermore, sterols (daucosterol, campesterol,
stigmasterol, beta-sitosterol) have shown an anti-
cancer effect via; Inhibition of pro-inflammatory
cytokines 98, PC-3 apoptosis and cell cycle arrest
via ROS changes and prostaglandin release 99, 100,
and Reverts impaired glutathione/oxidized
glutathione ratio via estrogen/phosphatidylinositol
3-kinase pathway 101.
Effects on lipid profile:
Conjugated fatty acids are polyunsaturated fatty
acids in which at least one pair of double bonds are
separated by only one single bond, as in conjugated
linoleic acid. These fatty acids have useful
biological effects. Arao et al. investigated the
effects of PSO rich in PA (9cis, 11trans, 13cis-
conjugated linolenic acid; 9c, 11t, 13c-CLNA in
obese, hyperlipidemic Otsuka Long-Evans
Tokushima Fatty (OLETF) rats. Results showed
that, feeding with 1% pomegranate did not affect
serum lipid levels and abdominal white adipose
tissue weights.
However, 2 weeks feeding of the diet supplemented
with 5% PSO showed a significant reduction of
omental white adipose tissue weight. Also, the
accumulated hepatic triacylglycerol was
significantly decreased by PA regimen. In addition,
the activity of hepatic enzymes was not altered by
PA regimen. Also, PA contained diet could
decrease level of monounsaturated fatty acid
(MUFA) in OLETF rats. Furthermore, this in vivo
study demonstrated that PA can inhibit the delta-9
desaturation which leads to reduction in hepatic
triacylglycerol (TAG) accumulation 102. In contrast,
yang et al .reported that PSO does not alter serum
cholesterol concentration 103. Vroegrijk et al. in
their study demonstrated that PSO regimen
ameliorates rich-fat diet induced obesity and causes
a reduction in body fat mass independent of
changes in food intake or energy expenditure 31.
Anti-atherogenic effects of PA, as a type of
conjugated fatty acid and the main constituent of
PSO, has been investigated by Mirmiran et al. This
double-blind placebo-controlled clinical trial with
400 mg PSO exhibited the mean concentration of
TAG and the TAG: HDL cholesterol (HDL-C)
ratio, were significantly decreased after 4 weeks.
Also, the results showed a diminution of
cholesterol HDL-C ratio while, the serum
cholesterol, LDL cholesterol remained unchanged.
Therefore, this study could demonstrate a
beneficial effect of lipid profile including TAG and
TAG:HDL-C ratio 52. Mc Farlin et al. demonstrated
the regimen with PSO (approximately 61mg/d)
during 14 weeks can reduce the body weight with
the mechanism mediated by a leptin/adiponectin
pathway.
This study showed that weight gain was associated
with an increase in biomarkers of cholesterol
profile, adipose tissue accumulation (P<0·05). PSO
resulted in a decrease in total weight gain, leptin
and insulin, and an increase in plasma adiponect in
cocentration (P<0·05) 78. Miranda et al.
demonstrated that, dietary supplementation of 0.5%
PA did not cause to decreased fat accumulation in
adipose tissue, liver, or skeletal muscle and there
was no significant difference between the
experimental groups in serum TGs, HDL
cholesterol, or non-HDL cholesterol. An interesting
result from this research was hypoplasia induced in
the liver due to the anti-proliferative effect on
hepatocytes increased transaminase levels. Also,
this issue should be considered before proposing
PA as a functional ingredient 77. Another study
performed by Yamasaki et al. with diets containing
0%, 0.12%, or 1.2% PSO for 3 weeks, showed a
meaningful increase in serum triacylglycerol and
phospholipid levels but not in total cholesterol in
the PSO treated groups 43.
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 438
Other beneficial effects of PSO: As mentioned,
PSO has many pharmacological effects, other beneficial effects of PSO is summarized in the
Table 5.
TABLE 5: OTHER BENEFICIAL EFFECTS OF PSO.
RANK: Receptor Activator of Nuclear Factor κ B, RANKL: Receptor Activator of Nuclear Factor κ B ligand, MPO: Myeloperoxidase,
MDA: Malondialdehyde, GSR: Glutathione reductase, GSH: Glutathione, SOD: Superoxide dismutase, t-GPx: Glutathione peroxidase,
TAG: triacylglyceride, HDL: High-density lipoprotein, ROS: Reactive oxygen species
Toxicity:
In our study on PSO toxicity, only one study had
been found. In this study, in vitro toxicity was done
with Ames and Chromosomal aberration test and in
vivo toxicity was done with acute and chronic (28
days consumption) test. No mutagen city of PSO
was observed with Ames test and Chromosome
aberration test with 5000 and 333μg/ml,
respectively.2000mg/kg PSO did not show any
significant side effects in rat. Use of 0, 10,000,
50,000 and 150,000ppm of PSO per day in a 28
days period did not show any adverse effects but in
150,000ppm, that was much higher than routine
anti-diabetic and anti-inflammatory dose,
increasing in hepatic enzymes and weight was
deduced and in this study this dose was considered
as no observable adverse effect level (NOAEL) 111.
CONCLUSION: The use of pomegranate has been
increased due to its reported health benefits.
Pomegranate and its derivatives, especially PSO,
are rich source of several chemical compounds
with potential physiological activities. The
information presented in this review article has
shown some pharmacological and toxicological
mechanisms and properties of PSO. It has been
demonstrated that monotherapy or supplementation
therapy with PSO may haveprotective effects
against several diseases, including cancers,
diabetes, cardiovascular disease, inflammation,
neurotoxicity, mouth and skin disorders,
pancreatitis, and osteoporosis. These effects act
possibly due to highly antioxidant activity of PSO.
Therefore, it is recommended that, PSO can be a
very beneficial medicine for treatment and
protection of certain diseases and disorders,
although probably underlying mechanisms of this
protection need further explorations.
ACKNOWLEDGEMENTS: The authors are
grateful to the assistance of Dr. Sima Khosravi and
all scientists in Department of Pharmacology,
Faculty of Medicine, Mashhad University of
Medical Sciences, Mashhad, Iran, who helped us to
create this review with their honest cooperation.
Pharmacological effect
Mechanism(s) and clinical evidence(s)
Reference(s)
Anti- osteoporosis
Down-regulation of expression RANK-RANKL downstream signaling
targets and osteoclast differentiation markers in osteoclast-like cells,
increasing alkaline phosphatase activity,
mineralization of matrix and transcriptional levels of major osteoblast
lineage markers involving the Wnt/β-catenin signaling pathways
104
Anti- pancreatitis
Anti- inflammatory and antioxidant mechanisms of PSO caused
reduction in amylase and lipase activity in serum, pancreatic MPO
activity, edema, leukocyte infiltration and vacuolization.
105
Hepatoprotective
Decrease in MDA, DNA fragmentation, caspase- 3 and GSR activities,
elevation in levels of GSH, SOD, GST and t-GPx activities.
Consequently reduction in oxidative stress and apoptosis.
106
Improving in insulin secretion
increasing serum insulin and glutathione peroxidase activity
79
Anti-atherogenic
Decrease in TAG and the TAG:HDL cholesterol (HDL-C) ratio,
52
Neuroprotective
Neutralize ROS or enhance the expression of antioxidant gene, decrease
in lactate/pyruvate ratio, extracellular nitric oxide, and lactase
dehydrogenase generation Reduction in lipid oxidation and neuronal loss
107
108
Anti-menopausal symptoms
Reduction in the number of hot flashes per day, Reduction in sum score
of the Menopause Rating Scale II parameters in the treated group after 12
weeks but not significant in comparison to control group
109
Cosmetic
Stimulate keratinocyte proliferation, mild thickening of epidermis,
stimulating keratinocyte proliferation, stimulating type I procollagen
synthesis, inhibiting matrix metalloproteinase-1
110
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International Journal of Pharmaceutical Sciences and Research 439
REFERENCES:
1. Kashani HH, Hoseini ES, Nikzad H and Aarabi MH:
Pharmacological properties of medicinal herbs by focus on
secondary metabolites. Life science journal-acta
zhengzhou university overseas edition 2012; 9:509-520.
2. Goldman P: Herbal medicines today and the roots of
modern pharmacology. Annals of internal medicine 2001;
135:594-600.
3. Dirin MM, Mousavi S, Afshari AR, Tabrizian K and
Ashrafi MH: Potential drug-drug interactions in
prescriptions dispensed in community and hospital
pharmacies in East of Iran. Journal of research in
pharmacy practice 2014; 3:104.
4. Roodsari MR, Zamanian-Azodi M and Salimpour F:
Herbal remedies and medicine; introducing some Iranian
plants. Journal of Paramedical Sciences 2013; 4.
5. Chan K, Zhang H and Lin ZX: An overview on adverse
drug reactions to traditional Chinese medicines. British
journal of clinical pharmacology 2015.
6. Modaresi J, Nasri MF, Rashidi L, Dayani O and Kebreab
E: Short communication: Effects of supplementation with
pomegranate seed pulp on concentrations of conjugated
linoleic acid and punicic acid in goat milk. Journal of dairy
science 2011; 94:4075-4080.
7. Langley P: Why a pomegranate? BMJ: British Medical
Journal 2000; 321:1153.
8. Albanese CL: 1994 Presidential Address: Refusing the
Wild Pomegranate Seed: America, Religious History, and
the Life of the Academy. Journal of the American
Academy of Religion 1995:205-229.
9. Heber D, Schulman RN and Seeram NP: Pomegranates:
ancient roots to modern medicine: CRC press; 2006.
10. Lansky EP and Newman RA: Punica granatum
(pomegranate) and its potential for prevention and
treatment of inflammation and cancer. Journal of
ethnopharmacology 2007; 109:177-206.
11. Miguel MG, Neves MA and Antunes MD: Pomegranate
(Punica granatum L.): A medicinal plant with myriad
biological properties-A short review. Journal of Medicinal
Plants Research 2010; 4:2836-2847.
12. Kapoor R, Ronnenberg A, Puleo E, Chatterton Jr RT,
Dorgan JF, Seeram NP and Sturgeon SR: Effects of
Pomegranate Juice on Hormonal Biomarkers of Breast
Cancer Risk. Nutrition and cancer 2015:1-7.
13. Wu P-T, Fitschen PJ, Kistler BM, Jeong JH, Chung HR,
Aviram M, Phillips SA, Fernhall B and Wilund KR:
Effects of Pomegranate Extract Supplementation on
Cardiovascular Risk Factors and Physical Function in
Hemodialysis Patients. Journal of medicinal food 2015.
14. Fan L: Antimicrobial Effect of Pomegranate Juice on
Listeria innocua and Escherichia coli in Different Culture
Systems. 2015 Annual Meeting (July 25-28, 2015); 2015:
Iafp.
15. Lansky EP, Harrison G, Froom P and Jiang WG:
Pomegranate (Punica granatum) pure chemicals show
possible synergistic inhibition of human PC-3 prostate
cancer cell invasion across Matrigel™. Investigational new
drugs 2005; 23:121-122.
16. Arafat S, Basuny AM and Elsawy HA: Utilization from
leaves of olive and pomegranate as a source of bioactive
components. Journal of Advances in Biological and Basic
Research 2015; 1:28-34.
17. Syed DN, Afaq F and Mukhtar H: Pomegranate derived
products for cancer chemoprevention. Seminars in cancer
biology; 2007: Elsevier.
18. Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, Hong
J, Barnard RJ, Seeram N, Liker H, Wang H and Elashoff
R: Phase II study of pomegranate juice for men with rising
prostate-specific antigen following surgery or radiation for
prostate cancer. Clinical Cancer Research 2006; 12:4018-
4026.
19. Kim ND, Mehta R, Yu W, Neeman I, Livney T, Amichay
A, Poirier D, Nicholls P, Kirby A and Jiang W:
Chemopreventive and adjuvant therapeutic potential of
pomegranate (Punica granatum) for human breast cancer.
Breast cancer research and treatment 2002; 71:203-217.
20. Les F, Prieto JM, Arbonés-Mainar JM, Valero MS and
López V: Bioactive properties of commercialised
pomegranate (Punica granatum) juice: antioxidant,
antiproliferative and enzyme inhibiting activities. Food &
Function 2015.
21. Johanningsmeier SD and Harris GK: Pomegranate as a
functional food and nutraceutical source. Annual review of
food science and technology 2011; 2:181-201.
22. Tran HNA, Bae S-Y, Song B-H, Lee B-H, Bae Y-S, Kim
Y-H, Lansky EP and Newman RA: Pomegranate (Punica
granatum) seed linolenic acid isomers: concentration-
dependent modulation of estrogen receptor activity.
Endocrine research 2010; 35:1-16.
23. Medjakovic S and Jungbauer A: Pomegranate: a fruit that
ameliorates metabolic syndrome. Food & function 2013;
4:19-39.
24. Shiraishi T, Abe M and Miyagawa T: Cheese foods
containing conjugated polyunsaturated fatty acid
glycerides. Japanese Patent: JP 2002; 2002176913.
25. Lei F, Zhang X, Wang W, Xing D, Xie W, Su H and Du L:
Evidence of anti-obesity effects of the pomegranate leaf
extract in high-fat diet induced obese mice. International
Journal of Obesity 2007; 31:1023-1029.
26. Ahmed MM, Samir E-SA, El-Shehawi AM and Alkafafy
ME: Anti-obesity effects of taif and egyptian
pomegranates: Molecular study. Bioscience,
biotechnology, and biochemistry 2015; 79:598-609.
27. Ismail T, Sestili P and Akhtar S: Pomegranate peel and
fruit extracts: a review of potential anti-inflammatory and
anti-infective effects. Journal of Ethnopharmacology 2012;
143:397-405.
28. Shukla M, Gupta K, Rasheed Z, Khan KA and Haqqi TM:
Bioavailable constituents/metabolites of pomegranate
(Punica granatum L) preferentially inhibit COX2 activity
ex vivo and IL-1beta-induced PGE2 production in human
chondrocytes in vitro. Journal of inflammation 2008; 5:9.
29. Arun N and Singh D: Punica granatum: a review on
pharmacological and therapeutic properties. International
Journal Of Pharmaceutical Sciences And Research 2012;
3:1240-1245.
30. Kýralan M, Gölükcü M and Tokgöz H: Oil and conjugated
linolenic acid contents of seeds from important
pomegranate cultivars (Punica granatum L.) grown in
Turkey. Journal of the American Oil Chemists' Society
2009; 86:985-990.
31. Vroegrijk IO, van Diepen JA, van den Berg S, Westbroek
I, Keizer H, Gambelli L, Hontecillas R, Bassaganya-Riera
J, Zondag GC and Romijn JA: Pomegranate seed oil, a rich
source of punicic acid, prevents diet-induced obesity and
insulin resistance in mice. Food and Chemical Toxicology
2011; 49:1426-1430.
32. Elfalleh W, Ying M, Nasri N, Sheng-Hua H, Guasmi F and
Ferchichi A: Fatty acids from Tunisian and Chinese
pomegranate (Punica granatum L.) seeds. International
journal of food sciences and nutrition 2011; 62:200-206.
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 440
33. Carvalho Filho JM: Pomegranate Seed Oil (Punica
Granatum L.): A Source of Punicic Acid (Conjugated α-
Linolenic Acid). Journal of Human Nutrition & Food
Science 2014.
34. Pande G. Antioxidant capacity and lipid characterization
of Georgia-grown underutilized fruit crops: University of
Georgia; 2009.
35. Habibnia M, Ghavami M, Ansaripourc M and Vosough S:
Chemical evaluation of oils extracted from five different
varieties of Iranian pomegranate seeds. Journal of Food
Biosciences and Technology 2012; 2:35-40.
36. Tsuyuki H, Ito S and Nakatsukasa Y: Lipids in
pomegranate seeds. Nihon Daigaku No-Juigakubu
Gakujutsu Kenkyu Hokoku 1981; 38:141-148.
37. Wang R-F, Xie W-D, Zhang Z, Xing D-M, Ding Y, Wang
W, Ma C and Du L-J: Bioactive Compounds from the
Seeds of Punica granatum (Pomegranate). Journal of
Natural Products 2004; 67:2096-2098.
38. Carvalho EBTd, Melo ILPd and Mancini-Filho J:
Chemical and physiological aspects of isomers of
conjugated fatty acids. Food Science and Technology
(Campinas) 2010; 30:295-307.
39. Yuan G, Sinclair AJ, Xu C and Li D: Research Article
Incorporation and metabolism of punicic acid in healthy
young humans. Mol Nutr Food Res 2009; 53:1336-1342.
40. Yuan GF, Wahlqvist ML, Yuan JQ, Wang QM and Li D:
Effect of punicic acid naturally occurring in food on lipid
peroxidation in healthy young humans. Journal of the
Science of Food and Agriculture 2009; 89:2331-2335.
41. Grossmann ME, Mizuno NK, Schuster T and Cleary MP:
Punicic acid is an ω-5 fatty acid capable of inhibiting
breast cancer proliferation. International journal of
oncology 2010; 36:421-426.
42. Saha S and Ghosh M: Comparative study of antioxidant
activity of α-eleostearic acid and punicic acid against
oxidative stress generated by sodium arsenite. Food and
Chemical Toxicology 2009; 47:2551-2556.
43. Yamasaki M, Kitagawa T, Koyanagi N, Chujo H, Maeda
H, Kohno-Murase J, Imamura J, Tachibana H and Yamada
K: Dietary effect of pomegranate seed oil on immune
function and lipid metabolism in mice. Nutrition 2006;
22:54-59.
44. Morikawa K, Nonaka M, Narahara M, Torii I, Kawaguchi
K, Yoshikawa T, Kumazawa Y and Morikawa S:
Inhibitory effect of quercetin on carrageenan-induced
inflammation in rats. life Sciences 2003; 74:709-721.
45. Bassaganya-Riera J. Method of using punicic acid to
enhance immune response and prevent metabolic
disorders. Google Patents; 2014.
46. Caligiani A, Bonzanini F, Palla G, Cirlini M and Bruni R:
Characterization of a potential nutraceutical ingredient:
pomegranate (Punica granatum L.) seed oil unsaponifiable
fraction. Plant foods for human nutrition 2010; 65:277-
283.
47. Sassano G, Sanderson P, Franx J, Groot P, van Straalen J
and Bassaganya‐Riera J: Analysis of pomegranate seed oil
for the presence of jacaric acid. Journal of the Science of
Food and Agriculture 2009; 89:1046-1052.
48. Koba K, Imamura J, Akashoshi A, Kohno-Murase J,
Nishizono S, Iwabuchi M, Tanaka K and Sugano M:
Genetically modified rapeseed oil containing cis-9, trans-
11, cis-13-octadecatrienoic acid affects body fat mass and
lipid metabolism in mice. Journal of agricultural and food
chemistry 2007; 55:3741-3748.
49. Račková L, Ergin V, Burcu Bali E, Kuniaková M and
Karasu Ç: Pomegranate Seed Oil Modulates Functions and
Survival of BV-2 Microglial Cells in vitro. International
journal for vitamin and nutrition research Internationale
Zeitschrift für Vitamin-und Ernährungsforschung Journal
international de vitaminologie et de nutrition 2014; 84:295.
50. Topkafa M, Kara H and Sherazi STH: Evaluation of the
Triglyceride Composition of Pomegranate Seed Oil by RP-
HPLC Followed by GC-MS. Journal of the American Oil
Chemists' Society 2015; 92:791-800.
51. Boussetta T, Raad H, Lettéron P, Gougerot-Pocidalo M-A,
Marie J-C, Driss F and El-Benna J: Punicic acid a
conjugated linolenic acid inhibits TNFalpha-induced
neutrophil hyperactivation and protects from experimental
colon inflammation in rats. PloS one 2009; 4:e6458.
52. Mirmiran P, Fazeli MR, Asghari G, Shafiee A and Azizi F:
Effect of pomegranate seed oil on hyperlipidaemic
subjects: a double-blind placebo-controlled clinical trial.
British journal of nutrition 2010; 104:402-406.
53. Hontecillas R, O'Shea M, Einerhand A, Diguardo M and
Bassaganya-Riera J: Activation of PPAR γ and α by
punicic acid ameliorates glucose tolerance and suppresses
obesity-related inflammation. Journal of the American
College of Nutrition 2009; 28:184-195.
54. Nagao K and Yanagita T: Conjugated fatty acids in food
and their health benefits. Journal of bioscience and
bioengineering 2005; 100:152-157.
55. Igarashi M and Miyazawa T: Newly recognized cytotoxic
effect of conjugated trienoic fatty acids on cultured human
tumor cells. Cancer letters 2000; 148:173-179.
56. Arao K, Yotsumoto H, Han S-Y, Nagao K and Yanagita T:
The 9 cis, 11 trans, 13 cis isomer of conjugated linolenic
acid reduces apolipoprotein B100 secretion and
triacylglycerol synthesis in HepG2 cells. Bioscience,
biotechnology, and biochemistry 2004; 68:2643-2645.
57. Saha SS and Ghosh M: Antioxidant effect of vegetable oils
containing conjugated linolenic acid isomers against
induced tissue lipid peroxidation and inflammation in rat
model. Chemico-biological interactions 2011; 190:109-
120.
58. Bassaganya-Riera J, Diguardo M, Climent M, Vives C, de
Horna A, Sanchez S, Orpi M, Duran E, Einerhand AW and
O'Shea M: Punicic acid modulates mucosal immune
responses and prevents gut inflammation through PPAR
{gamma} and {delta}-dependent mechanisms. The
FASEB Journal 2010; 24:926.926.
59. Schubert SY, Lansky EP and Neeman I: Antioxidant and
eicosanoid enzyme inhibition properties of pomegranate
seed oil and fermented juice flavonoids. Journal of
ethnopharmacology 1999; 66:11-17.
60. Jiang Q, Elson-Schwab I, Courtemanche C and Ames BN:
γ-Tocopherol and its major metabolite, in contrast to α-
tocopherol, inhibit cyclooxygenase activity in
macrophages and epithelial cells. Proceedings of the
National Academy of Sciences 2000; 97:11494-11499.
61. Masamune A, Satoh M, Kikuta K, Suzuki N, Satoh K and
Shimosegawa T: Ellagic acid blocks activation of
pancreatic stellate cells. Biochemical pharmacology 2005;
70:869-878.
62. Madlener S, Illmer C, Horvath Z, Saiko P, Losert A,
Herbacek I, Grusch M, Elford HL, Krupitza G and
Bernhaus A: Gallic acid inhibits ribonucleotide reductase
and cyclooxygenases in human HL-60 promyelocytic
leukemia cells. Cancer letters 2007; 245:156-162.
63. Costantini S, Rusolo F, De Vito V, Moccia S, Picariello G,
Capone F, Guerriero E, Castello G and Volpe MG:
Potential anti-inflammatory effects of the hydrophilic
fraction of pomegranate (Punica granatum L.) seed oil on
breast cancer cell lines. Molecules 2014; 19:8644-8660.
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 441
64. Asghari G, Sheikholeslami S, Mirmiran P, Chary A,
Hedayati M, Shafiee A and Azizi F: Effect of pomegranate
seed oil on serum TNF-α level in dyslipidemic patients.
International journal of food sciences and nutrition 2012;
63:368-371.
65. Saha SS and Ghosh M: Antioxidant and anti-inflammatory
effect of conjugated linolenic acid isomers against
streptozotocin-induced diabetes. British Journal of
Nutrition 2012; 108:974-983.
66. Coursodon-Boyiddle CF, Snarrenberg CL, Adkins-Rieck
CK, Bassaganya-Riera J, Hontecillas R, Lawrence P,
Brenna JT, Jouni ZE and Dvorak B: Pomegranate seed oil
reduces intestinal damage in a rat model of necrotizing
enterocolitis. American Journal of Physiology-
Gastrointestinal and Liver Physiology 2012; 303:G744-
G751.
67. Reuter S, Gupta SC, Chaturvedi MM and Aggarwal BB:
Oxidative stress, inflammation, and cancer: how are they
linked? Free Radical Biology and Medicine 2010;
49:1603-1616.
68. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M
and Telser J: Free radicals and antioxidants in normal
physiological functions and human disease. The
international journal of biochemistry & cell biology 2007;
39:44-84.
69. Gloire G, Legrand-Poels S and Piette J: NF-κB activation
by reactive oxygen species: fifteen years later.
Biochemical pharmacology 2006; 72:1493-1505.
70. Stohs S and Bagchi D: Oxidative mechanisms in the
toxicity of metal ions. Free radical biology and medicine
1995; 18:321-336.
71. Mukherjee C, Bhattacharyya S, Ghosh S and
Bhattacharyya DK: Dietary Effects of Punicic Acid on the
Composition and Peroxidation of Rat Plasma Lipid.
Journal of Oleo Science 2002; 51:513-522.
72. Dhar P, Bhattacharyya D, Bhattacharyya D and Ghosh S:
Dietary comparison of conjugated linolenic acid (9 cis, 11
trans, 13 trans) and α-tocopherol effects on blood lipids
and lipid peroxidation in alloxan-induced diabetes mellitus
in rats. Lipids 2006; 41:49-54.
73. Elfalleh W, Tlili N, Nasri N, Yahia Y, Hannachi H, Chaira
N, Ying M and Ferchichi A: Antioxidant capacities of
phenolic compounds and tocopherols from Tunisian
pomegranate (Punica granatum) fruits. Journal of Food
Science 2011; 76:C707-C713.
74. Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y,
Nair MG and Heber D: In vitro antiproliferative, apoptotic
and antioxidant activities of punicalagin, ellagic acid and a
total pomegranate tannin extract are enhanced in
combination with other polyphenols as found in
pomegranate juice. The Journal of nutritional biochemistry
2005; 16:360-367.
75. Anusree S, Nisha V, Priyanka A and Raghu K: Insulin
resistance by TNF-α is associated with mitochondrial
dysfunction in 3T3-L1 adipocytes and is ameliorated by
punicic acid, a PPARγ agonist. Molecular and cellular
endocrinology 2015; 413:120-128.
76. Zolezzi JM, Silva-Alvarez C, Ordenes D, Godoy JA,
Carvajal FJ, Santos MJ and Inestrosa NC: Peroxisome
proliferator-activated receptor (PPAR) γ and PPARα
agonists modulate mitochondrial fusion-fission dynamics:
relevance to reactive oxygen species (ROS)-related
neurodegenerative disorders? 2013.
77. Miranda J , Aguirre L , Fernández-Quintela A, Macarulla
MT, Martínez-Castao MG, Ayo J, Bilbao E and Portillo
MP: Effects of pomegranate seed oil on glucose and lipid
metabolism-related organs in rats fed an obesogenic diet.
Journal of agricultural and food chemistry 2013; 61:5089-
5096.
78. McFarlin BK, Strohacker KA and Kueht ML:
Pomegranate seed oil consumption during a period of
high-fat feeding reduces weight gain and reduces type 2
diabetes risk in CD-1 mice. British Journal of Nutrition
2009; 102:54-59.
79. Nekooeian AA, Eftekhari MH, Adibi S and Rajaeifard A:
Effects of Pomegranate Seed Oil on Insulin Release in
Rats with Type 2 Diabetes. Iranian Journal of Medical
Sciences 2014; 39:130-135.
80. Bhandari PR: Pomegranate (Punica granatum L). Ancient
seeds for modern cure? Review of potential therapeutic
applications. International Journal of Nutrition,
Pharmacology, Neurological Diseases 2012; 2:171.
81. Banihani S, Swedan S and Alguraan Z: Pomegranate and
type 2 diabetes. Nutrition research 2013; 33:341-348.
82. Boroushaki MT, Mollazadeh H, Rajabian A, Dolati K,
Hoseini A, Paseban M and Farzadnia M: Protective effect
of pomegranate seed oil against mercuric chloride-induced
nephrotoxicity in rat. Ren Fail 2014; 36:1581-1586.
83. Boroushaki MT, Arshadi D, Jalili-Rasti H, Asadpour E
and Hosseini A: Protective effect of pomegranate seed oil
against acute toxicity of diazinon in rat kidney. Iranian
journal of pharmaceutical research: IJPR 2013; 12:821.
84. Asadpour E, Boroushaki MT and Sadeghnia H: Protective
effect of pomegranate seed oil against gentamicin induced
nephrotoxicity in rat. Toxicology Letters 2010; 196:S232.
85. Boroushaki MT, Sadeghnia HR, Banihasan M and Yavari
S: Protective effect of pomegranate seed oil on
hexachlorobutadiene-induced nephrotoxicity in rat
kidneys. Renal failure 2010; 32:612-617.
86. Boroushaki MT, Mollazadeh H, Rajabian A, Dolati K,
Hoseini A, Paseban M and Farzadnia M: Protective effect
of pomegranate seed oil against mercuric chloride-induced
nephrotoxicity in rat. Renal failure 2014; 36:1581-1586.
87. Sarkaki A and Rezaiei M: Improving active and passive
avoidance memories deficits due to permanent cerebral
ischemia by pomegranate seed extract in female rats. The
Malaysian journal of medical sciences: MJMS 2013;
20:25.
88. Gabizon R, Mizrahi M, Friedman-Levy Y, Larush L, Frid
K, Binyamin O, Feinstein N, Dori D, Ovadia H and Ben-
Hur T: Novel Pomegranate Oil Nano-Emulsions for the
Prevention and Treatment of Neurodegenerative Diseases:
The Case of Genetic CJD (P5. 236). Neurology 2014;
82:P5. 236-P235. 236.
89. Hora JJ, Maydew ER, Lansky EP and Dwivedi C:
Chemopreventive effects of pomegranate seed oil on skin
tumor development in CD1 mice. Journal of medicinal
food 2003; 6:157-161.
90. Jiang Q, Wong J, Fyrst H, Saba JD and Ames BN: γ-
Tocopherol or combinations of vitamin E forms induce
cell death in human prostate cancer cells by interrupting
sphingolipid synthesis. Proceedings of the National
Academy of Sciences of the United States of America
2004; 101:17825-17830.
91. Campbell SE, Stone WL, Lee S, Whaley S, Yang H, Qui
M, Goforth P, Sherman D, McHaffie D and Krishnan K:
Comparative effects of RRR-alpha-and RRR-gamma-
tocopherol on proliferation and apoptosis in human colon
cancer cell lines. BMC cancer 2006; 6:13.
92. Suzuki R, Noguchi R, Ota T, Abe M, Miyashita K and
Kawada T: Cytotoxic effect of conjugated trienoic fatty
acids on mouse tumor and human monocytic leukemia
cells. Lipids 2001; 36:477-482.
Boroushaki et al., IJPSR, 2016; Vol. 7(2): 430-442. SSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 442
93. Li T-M, Chen G-W, Su C-C, Lin J-G, Yeh C-C, Cheng K-
C and Chung J-G: Ellagic acid induced p53/p21
expression, G1 arrest and apoptosis in human bladder
cancer T24 cells. Anticancer Research 2005; 25:971-979.
94. Veluri R, Singh RP, Liu Z, Thompson JA, Agarwal R and
Agarwal C: Fractionation of grape seed extract and
identification of gallic acid as one of the major active
constituents causing growth inhibition and apoptotic death
of DU145 human prostate carcinoma cells. Carcinogenesis
2006; 27:1445-1453.
95. Wang X, Zhang F, Yang L, Mei Y, Long H, Zhang X,
Zhang J and Su X: Ursolic acid inhibits proliferation and
induces apoptosis of cancer cells in vitro and in vivo.
BioMed Research International 2011; 2011.
96. Achiwa Y, Hasegawa K, Komiya T and Udagawa Y:
Ursolic acid induces Bax-dependent apoptosis through the
caspase-3 pathway in endometrial cancer SNG-II cells.
Oncology reports 2005; 13:51-57.
97. Harmand PO, Duval R, Delage C and Simon A: Ursolic
acid induces apoptosis through mitochondrial intrinsic
pathway and caspase‐3 activation in M4Beu melanoma
cells. International Journal of Cancer 2005; 114:1-11.
98. Nashed B, Yeganeh B, HayGlass KT and Moghadasian
MH: Antiatherogenic effects of dietary plant sterols are
associated with inhibition of proinflammatory cytokine
production in Apo E-KO mice. The Journal of nutrition
2005; 135:2438-2444.
99. Awad AB and Fink CS: Phytosterols as anticancer dietary
components: evidence and mechanism of action. The
Journal of nutrition 2000; 130:2127-2130.
100. Awad AB, Burr AT and Fink CS: Effect of resveratrol and
β-sitosterol in combination on reactive oxygen species and
prostaglandin release by PC-3 cells. Prostaglandins,
leukotrienes and essential fatty acids 2005; 72:219-226.
101. Vivancos M and Moreno JJ: β-Sitosterol modulates
antioxidant enzyme response in RAW 264.7 macrophages.
Free Radical Biology and Medicine 2005; 39:91-97.
102. Arao K, Wang Y-M, Inoue N, Hirata J, Cha J-Y, Nagao K
and Yanagita T: Dietary effect of pomegranate seed oil
rich in 9cis, 11trans, 13cis conjugated linolenic acid on
lipid metabolism in obese, hyperlipidemic OLETF rats.
Lipids Health Dis 2004; 3:1-7.
103. Yang L, Leung KY, Cao Y, Huang Y, Ratnayake W and
Chen Z-Y: a-Linolenic acid but not conjugated linolenic
acid is hypocholesterolaemic in hamsters. British journal
of nutrition 2005; 93:433-438.
104. Spilmont M, Léotoing L, Davicco M-J, Lebecque P,
Mercier S, Miot-Noirault E, Pilet P, Rios L, Wittrant Y
and Coxam V: Pomegranate seed oil prevents bone loss in
a mice model of osteoporosis, through osteoblastic
stimulation, osteoclastic inhibition and decreased
inflammatory status. The Journal of nutritional
biochemistry 2013; 24:1840-1848.
105. Minaiyan M, Zolfaghari B, Taheri D and Gomarian M:
Preventive Effect of Three Pomegranate (Punica granatum
L.) Seeds Fractions on Cerulein-Induced Acute
Pancreatitis in Mice. International Journal of Preventive
Medicine 2014; 5:394-404.
106. Shaban NZ, El-Kersh MA, El-Rashidy FH and Habashy
NH: Protective role of Punica granatum (pomegranate)
peel and seed oil extracts on diethylnitrosamine and
phenobarbital-induced hepatic injury in male rats. Food
chemistry 2013; 141:1587-1596.
107. Al-Sabahi BN, Fatope MO, Essa MM, Subash S, Al-
Busafi SN, Al-Kusaibi FS and Manivasagam T:
Pomegranate seed oil: Effect on 3-nitropropionic acid-
induced neurotoxicity in PC12 cells and elucidation of
unsaturated fatty acids composition. Nutritional
neuroscience 2014.
108. Mizrahi M, Friedman-Levi Y, Larush L, Frid K, Binyamin
O, Dori D, Fainstein N, Ovadia H, Ben-Hur T and
Magdassi S: Pomegranate seed oil nanoemulsions for the
prevention and treatment of neurodegenerative diseases:
the case of genetic CJD. Nanomedicine: Nanotechnology,
Biology and Medicine 2014; 10:1353-1363.
109. Auerbach L, Rakus J, Bauer C, Gerner C, Ullmann R,
Wimmer H and Huber J: Pomegranate seed oil in women
with menopausal symptoms: a prospective randomized,
placebo-controlled, double-blinded trial. Menopause 2012;
19:426-432.
110. Aslam MN, Lansky EP and Varani J: Pomegranate as a
cosmeceutical source: pomegranate fractions promote
proliferation and procollagen synthesis and inhibit matrix
metalloproteinase-1 production in human skin cells.
Journal of ethnopharmacology 2006; 103:311-318.
111. Meerts I, Verspeek-Rip C, Buskens C, Keizer H,
Bassaganya-Riera J, Jouni Z, Van Huygevoort A, Van
Otterdijk F and Van de Waart E: Toxicological evaluation
of pomegranate seed oil. Food and Chemical Toxicology
2009; 47:1085-1092.
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Md. Boroushaki T, Mollazadeh H and Afshari AR: Pomegranate Seed Oil: A Comprehensive Review on Its Therapeutic Effects. Int J
Pharm Sci Res 2016; 7(2): 430-42.doi: 10.13040/IJPSR.0975-8232.7(2).430-42.
