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Therapeutic Applications of Pomegranate (Punica granatum L.): A Review

July 2008
Alternative Medicine Review: a Journal of Clinical Therapeutic 13(2):128-44

Source
PubMed

Authors:

Thorne Research

The pomegranate, Punica granatum L., is an ancient, mystical, unique fruit borne on a small, long-living tree cultivated throughout the Mediterranean region, as far north as the Himalayas, in Southeast Asia, and in California and Arizona in the United States. In addition to its ancient historical uses, pomegranate is used in several systems of medicine for a variety of ailments. The synergistic action of the pomegranate constituents appears to be superior to that of single constituents. In the past decade, numerous studies on the antioxidant, anticarcinogenic, and anti-inflammatory properties of pomegranate constituents have been published, focusing on treatment and prevention of cancer, cardiovascular disease, diabetes, dental conditions, erectile dysfunction, bacterial infections and antibiotic resistance, and ultraviolet radiation-induced skin damage. Other potential applications include infant brain ischemia, male infertility, Alzheimer's disease, arthritis, and obesity.

Structure of Ellagic Acid

…

. Antioxidant Activity of Pomegranate Juice Extract in Patients with Carotid Artery Stenosis

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Atherosclerotic Lesion Size with Various Pomegranate Extracts

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Content uploaded by Julie Jurenka

Content may be subject to copyright.

Alternative Medicine Review Volume 13, Number 2 2008

Review Article

Page 128

Julie Jurenka, MT (ASCP) – Associate Editor, Alternative Medicine Review;

technical assistant, Thorne Research

Correspondence address: Thorne Research, PO Box 25, Dover, ID 83825

Email: juliej@thorne.com

Abstract

The pomegranate, Punica granatum L., is an ancient, mystical,

unique fruit borne on a small, long-living tree cultivated throughout

the Mediterranean region, as far north as the Himalayas, in

Southeast Asia, and in California and Arizona in the United

States. In addition to its ancient historical uses, pomegranate

is used in several systems of medicine for a variety of ailments.

The synergistic action of the pomegranate constituents appears

to be superior to that of single constituents. In the past decade,

numerous studies on the antioxidant, anticarcinogenic, and

anti-inﬂammatory properties of pomegranate constituents

have been published, focusing on treatment and prevention

of cancer, cardiovascular disease, diabetes, dental conditions,

erectile dysfunction, bacterial infections and antibiotic

resistance, and ultraviolet radiation-induced skin damage.

Other potential applications include infant brain ischemia,

male infertility, Alzheimer’s disease, arthritis, and obesity.

(Altern Med Rev 2008;13(2):128-144)

Introduction

e pomegranate, Punica granatum L., an an-

cient, mystical, and highly distinctive fruit, is the pre-

dominant member of two species comprising the Pu-

nicaceae family. It was lauded in ancient times in the

Old Testament of the Bible, the Jewish Torah, and the

Babylonian Talmud as a sacred fruit conferring powers

of fertility, abundance, and good luck. It also features

prominently in the ceremonies, art, and mythology of

the Egyptians and Greeks and was the personal emblem

of the Holy Roman Emperor, Maximilian. Pomegranate

is the symbol and heraldic device of the ancient city of

Granada in Spain – from which the city gets its name.

erapeutic Applications of

Pomegranate (Punica granatum L.):

A Review

Julie Jurenka, MT (ASCP)

e genus name, Punica, was the Roman name for

Carthage, where the best pomegranates were known to

grow. Pomegranate is known by the French as grenade,

the Spanish as granada, and literally translates to seeded

(“granatus”) apple (“pomum”).

e pomegranate tree typically grows 12-16

feet, has many spiny branches, and can be extremely long

lived, as evidenced by trees at Versailles, France, known

to be over 200 years old. e leaves are glossy and lance-

shaped, and the bark of the tree turns gray as the tree

ages. e ﬂowers are large, red, white, or variegated and

have a tubular calyx that eventually becomes the fruit.

e ripe pomegranate fruit can be up to ﬁve inches wide

with a deep red, leathery skin, is grenade-shaped, and

crowned by the pointed calyx. e fruit contains many

seeds (arils) separated by white, membranous pericarp,

and each is surrounded by small amounts of tart, red

juice. e pomegranate is native from the Himalayas

in northern India to Iran but has been cultivated and

naturalized since ancient times over the entire Mediter-

ranean region. It is also found in India and more arid

regions of Southeast Asia, the East Indies, and tropical

Africa. e tree is also cultivated for its fruit in the drier

regions of California and Arizona.

In addition to its ancient historical uses, pome-

granate is used in several systems of medicine for a vari-

ety of ailments. In Ayurvedic medicine the pomegranate

is considered “a pharmacy unto itself ” and is used as an

antiparasitic agent,

a “blood tonic,”

and to heal aph-

thae, diarrhea, and ulcers.

Pomegranate also serves as

Alternative Medicine Review Volume 13, Number 2 2008

Review Article

Page 129

a remedy for diabetes in the Unani system of medicine

practiced in the Middle East and India.

e current

explosion of interest in pomegranate as a medicinal and

nutritional product is evidenced by a MedLine search

from 2000 to present, revealing over 130 new scientiﬁc

papers pertaining to its health eﬀects. Between 1950 and

1999 only 25 such publications appear on MedLine.

e potential therapeutic properties of pomegranate

are wide-ranging and include treatment and prevention

of cancer, cardiovascular disease, diabetes, dental con-

ditions, erectile dysfunction, and protection from ul-

traviolet (UV) radiation. Other potential applications

include infant brain ischemia, Alzheimer’s disease, male

infertility, arthritis, and obesity.

e following abbreviations for various pome-

granate extracts will be used throughout the article:

Pomegranate juice – PJ Â

Pomegranate by-product – PBP Â

Fermented pomegranate juice – FPJ Â

Cold-pressed seed oil – CPSO Â

Pomegranate peel extract – PPE Â

Pomegranate pulp juice – PPJ Â

Pomegranate fruit extract – PFE Â

Pomegranate ﬂower extract – PFLE Â

Hydroalcoholic extract of pomegranate – HAEP Â

Gel-based pomegranate extract – GPBE Â

Biochemical Constituents

Over the past decade, signiﬁcant progress has

been made in establishing the pharmacological mecha-

nisms of pomegranate and the individual constituents

responsible for them. Extracts of all parts of the fruit

appear to have therapeutic properties,

and some stud-

ies report the bark, roots, and leaves of the tree have

medicinal beneﬁt as well.

Current research seems to

indicate the most therapeutically beneﬁcial pomegran-

ate constituents are ellagic acid ellagitannins (including

punicalagins), punicic acid, ﬂavonoids, anthocyanidins,

anthocyanins, and estrogenic ﬂavonols and ﬂavones.

Table 1 lists the principal constituents of the Punica

granatum tree and fruit. Figure 1 depicts the structure

of ellagic acid.

Table 1. Pomegranate Fruit Parts and Constituents

8-21

PLANT COMPONENT

Pomegranate juice

Pomegranate seed oil

Pomegranate pericarp

(peel, rind)

Pomegranate leaves

Pomegranate flower

Pomegranate roots and bark

CONSTITUENTS

anthocyanins;

glucose, ascorbic acid;

ellagic acid, gallic acid,

caffeic acid;

catechin, EGCG;

quercetin, rutin;

numerous

minerals, particularly iron;

amino acids

95-percent punicic acid;

other constituents, including ellagic

acid;

other fatty acids;

sterols

phenolic punicalagins; gallic acid and other fatty acids;

catechin, EGCG;

quercetin, rutin, and other flavonols;

flavones,

flavonones;

anthocyanidins

tannins (punicalin and punicafolin); and flavone glycosides,

including luteolin and apigenin

gallic acid, ursolic acid;

triterpenoids, including maslinic and

asiatic acid;

other unidentified constituents

ellagitannins, including punicalin and punicalagin;

numerous

piperidine alkaloids

Alternative Medicine Review Volume 13, Number 2 2008

Pomegranate

Page 130

Figure 1. Structure of Ellagic Acid

Constituent Standardization versus

Synergy

e goal of many pomegranate studies has

been to identify the therapeutic constituents. Common-

ly found in many plants, ellagic acid exhibits powerful

anticarcinogenic

and antioxidant

properties, propel-

ling it to the forefront of pomegranate research. Many

commercially available pomegranate extracts are being

standardized to contain 40-percent (or more) ellagic

acid; however, Lansky, a prominent researcher on the

medicinal properties of pomegranate, cautions against

focusing on ellagic acid standardization to the exclusion

of other therapeutically important pomegranate constit-

uents.

Research on ellagic acid with other ﬂavonoids

such as quercetin supports his contention.

25,26

Lan-

sky’s research conﬁrms the synergistic action of several

pomegranate constituents is superior to ellagic acid in

suppressing prostate cancer.

27,28

To quote Lansky, “e

recent profusion onto the nutraceuticals marketplace of

products standardized to 40 percent (or even higher)

ellagic acid represents a cynical, lucre-driven attempt to

replace the power of the pomegranate with the power

of ellagic acid. e pomegranate needs no such tricks

or enhancements. It is rather an extraordinary, albeit

mysterious (and messy), fruit with a complete medicinal

power contained within its juice, peel, and seeds.”

Biochemistry/Pharmacokinetics

Although little is known about the metabolism

and bioavailability of ellagitannins from food sources,

three small human trials and one case study have inves-

tigated the bioavailability, absorption, metabolism, and

in vivo antioxidant eﬀects of pomegranate. In the case

study, consumption of 180 mL pomegranate juice (PJ)

by a single subject yielded 31.9 ng/mL plasma ellagic

acid at one hour, with rapid plasma clearance by four

hours post-ingestion. is was the ﬁrst direct evidence

that ellagic acid consumed from food was absorbed in

humans.

A study of 18 healthy volunteers by the same

researchers conﬁrmed the rapid absorption and plasma

clearance of ellagitannins and also conﬁrmed urolithin

metabolites excreted in the urine can persist for 48 hours

after pomegranate juice ingestion, thereby suggesting an

explanation of the beneﬁts of long-term pomegranate

administration.

In a 13-day clinical trial involving six healthy

subjects (4 men and 2 women), one liter of PJ contain-

ing 4.37 g/L punicalagins and 0.49 g/L anthocyanins

was consumed by all six subjects for ﬁve days. ree

pomegranate juice metabolites were detected in the

plasma – urolithin A, urolithin B, and a third unidenti-

ﬁed minor metabolite; urinalysis at 24 hours revealed

six metabolites – the three found in the plasma as well

as an aglycone metabolite corresponding to each of three

plasma metabolites. Maximum excretion rates occurred

3-4 days after juice ingestion. Signiﬁcant variability of

urinary metabolite concentrations was observed among

subjects and may be attributable to diﬀerences in co-

lonic microﬂora, where the ellagitannins are believed to

be metabolized.

e persistence of urolithin A and B

in the urine may be responsible for pomegranate’s long-

term antioxidant eﬀects, rather than the polyphenols

found in the juice.

In another study, 11 healthy men and women

were placed on a polyphenol- and antioxidant-free diet

for three days prior to consuming pomegranate extract

(plant parts used were not speciﬁed). Subjects were

given 800 mg capsuled pomegranate extract daily con-

taining 330.4 mg punicalagins and 21.6 mg ellagic acid

(EA). C

max

and T

max

for plasma EA was 33.8±12.7 ng/

mL at one hour post-ingestion, similar to values ob-

served in the case study when similar amounts of pu-

nicalagins and EA were administered. is study also

demonstrated a signiﬁcant increase (31.8%) in plasma

Alternative Medicine Review Volume 13, Number 2 2008

Review Article

Page 131

antioxidant capacity 30 minutes after extract adminis-

tration; one and two hours post ingestion, values were

increased 1.62- and 1.43-fold, respectively.

Mechanisms of Action

Although pomegranate’s wide-ranging thera-

peutic beneﬁts may be attributable to several mecha-

nisms, most research has focused on its antioxidant,

anticarcinogenic, and anti-inﬂammatory properties.

Antioxidant Mechanisms

An in vitro assay using four separate testing

methods demonstrated pomegranate juice and seed

extracts have 2-3 times the antioxidant capacity of ei-

ther red wine or green tea.

Pomegranate extracts have

been shown to scavenge free radicals and decrease mac-

rophage oxidative stress and lipid peroxidation in ani-

mals

and increase plasma antioxidant capacity in el-

derly humans.

Studies in rats and mice conﬁrm the antioxi-

dant properties of a pomegranate by-product (PBP)

extract made from whole fruit minus the juice, show-

ing a 19-percent reduction in oxidative stress in mouse

peritoneal macrophages (MPM), a 42-percent decrease

in cellular lipid peroxide content, and a 53-percent in-

crease in reduced glutathione levels.

In vitro assay of a

fermented pomegranate juice (FPJ) extract and a cold-

pressed seed oil (CPSO) extract found the antioxidant

capacity of both are superior to red wine and similar to

green tea extract.

A separate study in rats with CCl

induced liver damage demonstrated pretreatment with

a pomegranate peel extract (PPE) enhanced or main-

tained the free-radical scavenging activity of the hepatic

enzymes catalase, super oxide dismutase, and peroxi-

dase, and resulted in 54-percent reduction of lipid per-

oxidation values compared to controls.

Research in humans has shown a juice made

from pomegranate pulp (PPJ) has superior antioxidant

capacity to apple juice. Using the FRAP assay (ferric

reducing/antioxidant power), Guo et al found 250 mL

PPJ daily for four weeks given to healthy elderly sub-

jects increased plasma antioxidant capacity from 1.33

mmol to 1.46 mmol, while subjects consuming apple

juice experienced no signiﬁcant increase in antioxidant

capacity. In addition, subjects consuming the PPJ exhib-

ited signiﬁcantly decreased plasma carbonyl content (a

biomarker for oxidant/antioxidant barrier impairment

in various inﬂammatory diseases) compared to subjects

taking apple juice. Plasma vitamin E, ascorbic acid, and

reduced glutathione values did not diﬀer signiﬁcantly

between groups, leading researchers to conclude pome-

granate phenolics may be responsible for the observed

results.

Anticarcinogenic Mechanisms

In vitro assays utilizing three prostate cancer

cell lines (DU-145, LNCaP, and PC-3) demonstrated

various pomegranate extracts (juice, seed oil, peel) po-

tently inhibit prostate cancer cell invasiveness and pro-

liferation, cause cell cycle disruption, induce apoptosis,

and inhibit tumor growth. ese studies also demon-

strated combinations of pomegranate extracts from

diﬀerent parts of the fruit were more eﬀective than any

single extract.

27,37

Several animal studies have elucidated pome-

granate’s potential anticancer mechanisms. Two studies

in mice implanted with the prostate cancer PC-3 cell

line demonstrated pomegranate fruit extract (PFE; ed-

ible parts of the fruit, excluding the peel) inhibits cell

growth and induces apoptosis via modulation of pro-

teins regulating apoptosis.

38,39

In an open-label, phase II clinical trial in 46

men with recurrent prostate cancer, 16 patients (35%)

showed a signiﬁcant decrease in serum prostate speciﬁc

antigen (PSA) levels (average=27%) during treatment

with eight ounces of pomegranate juice. Corresponding

in vitro assays using patient plasma and serum dem-

onstrated signiﬁcant decreases in prostate cancer cell

line proliferation and increased apoptosis. Nitric oxide

preservation via ingestion of pomegranate polyphenols

signiﬁcantly correlated with lower PSA values. ese

results indicate pomegranate may aﬀect prostate cancer

because of antiproliferative, apoptotic, antioxidant, and

possibly anti-inﬂammatory eﬀects.

Recent research also indicates pomegranate

constituents inhibit angiogenesis via downregulation of

vascular endothelial growth factor in MCF-7 breast can-

cer and human umbilical vein endothelial cell lines.

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Pomegranate

Page 132

Anti-inﬂammatory Mechanisms

Cold pressed pomegranate seed oil has been

shown to inhibit both cyclooxygenase and lipoxygenase

enzymes in vitro. Cyclooxygenase, a key enzyme in the con-

version of arachidonic acid to prostaglandins (important

inﬂammatory mediators), was inhibited by 37 percent by

a CPSO extract. Lipoxygenase, which catalyzes the con-

version of arachidonic acid to leukotrienes, also key me-

diators of inﬂammation, was inhibited by 75 percent by a

CPSO extract. By comparison, an FPJ extract resulted in

a 23.8-percent inhibition of lipoxygenase in vitro.

Another in vitro study that may have far-reaching

implications for those suﬀering from osteoarthritis (OA)

demonstrated PFE has a signiﬁcant and broad inhibitory

eﬀect on matrix metalloproteinases (MMPs), a subgroup

of collagenase enzymes expressed in high levels in arthritic

joints and involved in the turnover, degradation, and ca-

tabolism of extracellular joint matrix. In pretreated hu-

man femoral OA chondrocytes, PFE inhibited IL-1beta-

induced destruction of proteoglycan, expression of MMPs

at the cellular level, and phosphorylation and activation of

mitogen-activated protein kinases (signal transduction

molecules involved in MMP expression). e suppres-

sion of MMP expression in OA chondrocyte cultures by

PFE suggests pomegranate constituents prevent collagen

degradation and may inhibit joint destruction in OA pa-

tients.

Other Mechanisms

A pilot study in type 2 diabetic patients with hy-

perlipidemia found concentrated PJ decreased cholesterol

absorption, increased fecal excretion of cholesterol, had a

beneﬁcial eﬀect on enzymes involved in cholesterol me-

tabolism, signiﬁcantly reduced total and LDL cholesterol,

and improved total/HDL and LDL/HDL cholesterol

ratios.

PJ consumption by hypertensive patients inhib-

its serum angiotensin converting enzyme (ACE; a cata-

lyst for the conversion of angiotensin I to angiotensin II, a

potent vasoconstrictor) activity, thereby reducing systolic

blood pressure

and potentially protecting against car-

diovascular disease.

Animal studies have revealed three possible hy-

poglycemic mechanisms for Punica granatum extracts.

Pomegranate ﬂower extract (PFLE) improved insulin

sensitivity and lowered glucose levels in rats as early as 30

minutes post-glucose loading. PFLE also inhibited alpha-

glucosidase in vitro, thereby decreasing the conversion of

sucrose to glucose.

PPE demonstrates signiﬁcant hypo-

glycemic activity in diabetic rats, via enhanced insulin lev-

els and regeneration of pancreatic beta cells.

Numerous in vitro studies

3,47,48

and two human

trials

49,50

demonstrate the antimicrobial activity of pome-

granate extracts. e growth of Staphylococcus aureus,

Streptococcus pyogenes, Diplococcus pneumoniae, Escheri-

chia coli O157:H7, and Candida albicans was inhibited

via direct bacteriocidal or fungicidal activity.

Clinical Applications

Prostate Cancer

Among males in the United States and other

Western countries, prostate cancer is the second-lead-

ing cause of cancer-related death. In vitro studies show

several PFEs inhibit prostate cancer cell growth, induce

apoptosis of several prostate cancer cell lines (including

highly aggressive PC-3 prostate carcinoma cells), sup-

press invasive potential of PC-3 cells, and decrease pro-

liferation of DU-145 prostate cancer cells.

27,37,38

Lansky

et al found combining equal amounts of FPJ, PPE, and

CPSO extracts resulted in a 99-percent suppression of

DU-145 prostate cancer cell invasion across a Matrigel

matrix. CPSO extract or FPJ extract alone resulted in

60-percent suppression of invasion, and combining any

two extracts induced 90-percent suppression. Studies

in mice have also demonstrated PFE inhibits prostate

tumor growth and decreases PSA levels.

38,39

ese promising results led some of the same

researchers to conduct a two-stage phase II clinical trial

in men with recurrent prostate cancer and rising PSA

levels. All eligible patients had previous surgery or ra-

diation therapy for prostate cancer, Gleason scores (a

grading system for predicting the behavior of prostate

cancer) ≤7, rising PSA value of 0.2-5.0 ng/mL, no

prior hormonal therapy, and no evidence of metastases.

Baseline PSA doubling times were established for 22

participants who were then started on eight ounces PJ

(570 mg total polyphenol gallic acid equivalents) daily

until meeting disease progression endpoints. Endpoints

measured were: eﬀect on PSA levels, serum lipid per-

oxidation and nitric oxide levels, in vitro induction of

proliferation and apoptosis of LNCaP cells in patient

serum containing pomegranate constituents, and over-

all safety of extract administration.

Alternative Medicine Review Volume 13, Number 2 2008

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Page 133

Based on preliminary results achieved in phase

I, 24 additional patients were enrolled and 46 patients

were evaluated over 13 months in both stages of the

trial. Of these, 35 percent (n=16) demonstrated de-

creased PSA levels, the primary trial endpoint – average

decrease=27%; median decrease=18%; range 5-85%.

Four of 46 patients (8.7%) met objective response cri-

teria and exhibited >50-percent reduction in PSA val-

ues, meeting criteria for a phase III trial. In addition, an

average 40-percent reduction in serum oxidative state

was observed in patients accompanied by a signiﬁcant

reduction in serum lipid peroxidation compared to

baseline. Nitric oxide serum metabolites measured at

nine months after study initiation revealed an average

23-percent increase, which signiﬁcantly correlated with

baseline PSA levels.

An in vitro arm of the trial using patient serum

investigated whether PJ consumption had any eﬀect on

growth rates or apoptosis of LNCaP prostate cancer

cells in culture. Serum collected at nine months after

study initiation and incubated with LNCaP decreased

cell growth by an average of 12 percent in 84 percent

of patients compared to baseline. An average 17.5-per-

cent increase in apoptosis in 75 percent of patients was

also noted. is study indicates PJ or PJ constituents

may have promise as a therapy for prostate cancer, par-

ticularly recurrent type with rising PSA levels; phase III

studies are currently underway.

Other Cancer Types

Numerous in vitro studies have investigated the

therapeutic eﬀect of pomegranate extracts against sev-

eral other cancer cell lines. In HT-29 colon cancer cells,

cyclooxygenase-2 (COX-2) expression is increased via

activation of nuclear factor kappa-B (NFκB) by tumor

necrosis factor-alpha (TNF-α), an inﬂammatory cell

signaling process that may be a cause of cancer initia-

tion and progression. Treatment of HT-29 colon can-

cer cells with PJ, total pomegranate tannins, or concen-

trated pomegranate punicalagin induced a signiﬁcant

decrease in COX-2 expression. PJ treatment resulted

in the highest level of COX-2 suppression (79%) com-

pared to treatment with single constituents. e eﬀects

were attributed to synergistic activity of the bioactive

constituents thought to be necessary for pomegranate’s

anti-inﬂammatory and anticarcinogenic activity.

Another in vitro study investigated the eﬀects

of punicalagin, ellagic acid, total pomegranate tannins,

and PJ on several cell lines. Although all preparations

decreased viable cell numbers in KB and CAL-27 oral

cancer cell lines, as well as in HT-29 and HCT-116

colon cancer cell lines, a higher degree of suppression

was obtained with pure PJ, an aﬀect attributed to the

synergy of its bioactive constituents.

Research utilizing breast cancer cell lines

MCF-7 and MB-MDA-231 demonstrates pomegran-

ate constituents eﬀectively inhibit angiogenesis,

tumor

growth,

proliferation, and invasiveness,

and induce

apoptosis.

To examine the eﬀect of FPJ and CPSO

extracts, and an HPLC-isolated peak B (from the fruit

extract), Mehta and Lansky used the mouse mammary

organ culture, an animal model of breast cancer having

≥75-percent accuracy of predicting in vivo carcinogen-

esis. ey found cancerous glands treated with each

pomegranate compound exhibited decreased lesion

incidence – 37 percent for FPJ, and 75-90 percent for

both peak B and CPSO. Seed oil is comprised mainly of

punicic acid, a trienoic acid with anticarcinogenic prop-

erties and eﬀective at very low doses (1 mg/mL in organ

culture). Peak B is believed to be a phenolic compound

with potent chemopreventative properties.

Research in mice has shown PFE inhibits tum-

origenesis in lung cancer and skin cancer models. In the

lung cancer study, mice given daily oral dosages of PFE

comparable to what humans could reasonably consume

(exact dosages were not available) exhibited signiﬁcantly

less lung tumor growth than mice not receiving PFE.

In mice treated with skin-cancer-inducing 12-O-tet-

radecanoylphorbol-13-acetate (TPA), animals treated

topically with PFE had signiﬁcantly reduced incidence

of skin tumors. In the PFE-treated group, only 30 per-

cent of mice exhibited tumors compared to 100 percent

of mice treated with TPA and no PFE. is result was

attributed to suppression of inﬂammation (COX-2,

MAPKs, NFκB) and the tumor proliferation marker

ornithine decarboxylase.

Lansky and Kuwaii investigated the eﬀect of

ﬂavonoid-rich PJ and FPJ and pomegranate pericarp

extracts on HL-60 human leukemia cell diﬀerentia-

tion (the ability of cancer cells to revert to normal cells)

and proliferation. Because of the structural similarity

between plant ﬂavonoids and retinoids (the latter be-

Alternative Medicine Review Volume 13, Number 2 2008

Pomegranate

Page 134

ing

established pro-diﬀerentiating agents), it was

h y p o t h

esized that ﬂavonoid-rich pomegranate extracts

might have a similar eﬀect on diﬀerentiation. In vitro

assays conﬁrmed both the FPJ and pericarp extracts

strongly promoted cellular diﬀerentiation and inhibited

proliferation in HL-60 cell cultures; the eﬀect of PJ on

cellular diﬀerentiation was less signiﬁcant. is study

suggests another mechanism by which pomegranate

constituents impart an anticarcinogenic eﬀect.

Atherosclerosis

In vitro, animal, and human trials have exam-

ined the eﬀects of various pomegranate constituents on

prevention and attenuation of atherosclerosis. One of

the preeminent researchers in endothelial function and

nitric oxide (NO) biochemistry, Louis J. Ignarro, PhD,

investigated the eﬀects of pomegranate juice and other

fruit juices on endothelial function, comparing propen-

sities to protect NO from destruction by reactive oxy-

gen species in vitro. Results of the antioxidant portion

of the study demonstrate pomegranate juice possesses

signiﬁcantly greater antioxidant capacity at much lower

concentrations (>1000-fold dilutions) than either grape

or blueberry juice, which was attributed to the high an-

thocyanin ﬂavonoid content and higher total ﬂavonoid

content in PJ than the other juices.

Because impaired endothelial function is an

early indicator of atherosclerosis, this study examined

the eﬀect of PJ on proliferation of rat aortic smooth

muscle cells in culture. PJ proved superior to other

juices, signiﬁcantly enhancing NO’s eﬀect on cardiac

endothelium even at 2,000-fold dilutions. PJ did not

inﬂuence endothelial nitric oxide synthase (eNOS)

expression, leading Ignarro et al to conclude the anti-

oxidant properties of PJ protect NO from free radical

destruction and augment the antiproliferative action of

NO on rat aortic smooth muscle cells.

In early-stage atherosclerosis, elevated plasma

cholesterol, increased oxidative stress, and increased

cholesterol esteriﬁcation rates are factors contributing

to foam cell formation and development of athero-

sclerotic lesions.

60-62

Research in atherosclerotic apoli-

poprotein-E deﬁcient (E°) mice by Aviram et al at the

Lipid Research Laboratory in Haifa, Israel, has focused

on the ability of pomegranate extracts to inhibit athero-

genesis.

34,63

Two months of PJ to E° mice with advanced

atherosclerosis reduced MPM lipid peroxide content by

42 percent compared with placebo-treated mice; MPM

lipid peroxide content in PJ-treated mice was 20-per-

cent lower than in four-month-old control mice. In ad-

dition, MPM harvested from PJ-treated mice exhibited

80-percent lower rates of cholesterol esteriﬁcation than

placebo-treated mice. In PJ-treated mice atherosclerotic

lesion size in the aorta was 17-percent smaller than in

the age-matched placebo group. PJ and an isolated tan-

nin fraction from PJ were also given to young E° mice

prior to development of signiﬁcant atherosclerosis.

Researchers found 25- and 17-percent reductions in

plasma lipid peroxide concentrations with the isolated

tannin fraction and PJ, respectively.

Aviram et al also investigated the anti-ath-

erosclerotic eﬀects of a PBP extract after the juice was

removed. Four-month-old E° mice with signiﬁcant ath-

erosclerosis were given PBP extract (containing 51.5

µg gallic acid equiv/kg/day) with an eight-fold higher

polyphenol concentration than PJ for three months.

is resulted in a signiﬁcant reduction in MPM oxida-

tive status as evidenced by a 27-percent decrease in to-

tal macrophage peroxide levels, a 42-percent decrease in

cellular lipid peroxide levels, and a 19-percent decrease

in peritoneal macrophage uptake of oxidized LDL.

To further identify the most potent anti-athero-

genic pomegranate components, Aviram et al analyzed

several more pomegranate extracts from all parts of the

plant. Atherosclerotic E° mice were given six diﬀerent

pomegranate preparations with varying amounts of to-

tal polyphenols and gallic acid content for three months.

Antioxidant activity, atherosclerotic lesion size, MPM

oxidative status, blood sugar, and lipid proﬁles were ex-

amined. Conﬁrming earlier results, this study demon-

strated PFLE more signiﬁcantly aﬀects atherosclerotic

lesion size (Figure 2), lipid proﬁles, and blood sugar lev-

els than other extracts tested; two PPEs demonstrated

the most potent antioxidant eﬀects. Mechanisms associ-

ated with the anti-atherogenic eﬀects of pomegranate in

this study include increased MPM uptake of oxidized

LDL, decreased lipid peroxidation, and decreased cho-

lesterol levels.

e eﬀect of PJ consumption on lipid per-

oxidation in plasma and HDL- and LDL-lipoproteins

was examined in a double-armed human trial. In the

ﬁrst study, 13 healthy, nonsmoking men (ages 20-35)

were given 50 mL PJ daily (containing 1.5 mmol total

polyphenols) for two weeks. In the second study (dura-

tion ≤10 weeks), three healthy men (same age range)

Alternative Medicine Review Volume 13, Number 2 2008

Review Article

Page 135

were given increasing doses of PJ ranging from 20-80

mL daily (0.54-2.16 mmol total polyphenols). Fasting

blood samples were drawn from participants pre-study

and after one and two weeks of PJ supplementation.

No signiﬁcant eﬀect was observed in either study on

plasma lipid proﬁle or lipoprotein patterns. e results

did show, however, for the ﬁrst time in humans, that PJ

has an inhibitory eﬀect on lipid peroxidation in plasma

and in lipoproteins, with the middle dose (50 mL daily)

being the most eﬀective, yielding a 32-percent decrease

in plasma lipid peroxidation. PJ (in a dose-dependent

manner) also demonstrated up to 90-percent inhibi-

tion of collagen-induced platelet aggregation in human

platelets ex vivo.

Hyperlipidemia

Pomegranate ﬂowers have been used in both

the Unani and Ayurvedic systems of medicine as a

remedy for diabetes. Based on historical use, a study in

diabetic rats explored the eﬀects of PFLE on cardiac

lipid metabolism in 13-

to 15-week old Zucker

diabetic rats. Animals

were given 500 mg/kg

PFLE or placebo for six

weeks, and total choles-

terol, triglyceride, and

nonesteriﬁed free fatty

acids (NEFA) were de-

termined prior to treat-

ment (nonfasting), at

week 4 (nonfasting), and

week 5 (fasting) in both

rat plasma and cardiac

tissue. PFLE was shown

to activate peroxisome

proliferator-activated

receptor (PPAR-α), a

cardiac transcription fac-

tor involved in myocar-

dial energy production

via fatty acid uptake and

oxidation. PPAR-α acti-

vation decreased cardiac

uptake and circulation

of lipids. Decreases were

observed in cardiac tissue

triglyceride content at the

end of the study and in plasma total cholesterol and

NEFA after four weeks of treatment.

A pilot study involving 22 type 2 diabetic pa-

tients (8 men and 14 women) investigated the choles-

terol-lowering eﬀects of 40 g concentrated PJ for eight

weeks. Statistically signiﬁcant decreases were observed

in total cholesterol (from 202.4±27.7 mg/dL at baseline

to 191.4±21 mg/dL at study conclusion), LDL choles-

terol (124.4±31.9 mg/dL at baseline to 112.9±25.9

mg/dL at study conclusion), total/HDL cholesterol ra-

tio (5.5±1.3 at baseline to 5.1±1.1 at study conclusion),

and LDL/HDL ratio (3.4±1.2 at baseline to 3.0±0.9 at

study conclusion). e authors attributed these eﬀects

to decreased absorption and increased fecal excretion of

cholesterol, as well as possible aﬀects on HMG-CoA

reductase and sterol O-acyltransferase, two enzymes

key to cholesterol metabolism.

Figure 2. Atherosclerotic Lesion Size with Various Pomegranate Extracts

Placebo

Pomegranate Fruit

Liquid Extract

Pomegranate Polyphenol

Powder Extract

Pomegranate Juice

Pomegranate

Flower Extract

Pomegranate Ground

Arils & Seeds

Atherosclerotic Lesion Size (µm

)

2,000

1,500

1,000

500

38% decrease

70%

decrease

39% decrease

44% decrease

6% decrease

Aviram M, Volkova N, Coleman R, et al. Pomegranate phenolics from the peels, arils, and flowers are antiatherogenic: studies

in vivo in atherosclerotic apolipoprotein E-deficient (E°) mice and in vitro cultured macrophages and lipoproteins. J Agric

Food Chem 2008;56:1148-1157.

Alternative Medicine Review Volume 13, Number 2 2008

Pomegranate

Page 136

Hypertension

A small clinical trial demonstrated PJ inhib-

its serum ACE and reduces systolic blood pressure in

hypertensive patients. Ten hypertensive subjects (ages

62-77; seven men and three women) were given 50 mL/

day PJ containing 1.5 mmol total polyphenols for two

weeks. Two of seven patients were also diabetic and two

were hyperlipidemic. Seven of 10 subjects (70%) expe-

rienced a 36-percent average decrease in serum ACE ac-

tivity and a small, but signiﬁcant, ﬁve-percent decrease

in systolic blood pressure.

Carotid Artery Stenosis

In a small, long-term study, 19 subjects (ages

65-75) with severe carotid artery stenosis (70-90%

stenosis of internal carotid arteries) were randomized

to receive either 50 mL PJ daily containing 1.5 mmoles

total polyphenols (n=10) or no treatment (n=9) for

one year; ﬁve subjects continued PJ for an additional

two years. Study participants were treated with similar

hypocholesterolemic and antihypertensive medications

and no dietary or lifestyle changes occurred in either

group. Blood samples were collected and echo Doppler

analysis was performed at baseline and at 3, 6, 9, 12,

22, 28, and 36 months. Control subjects demonstrated

a mean nine-percent increase in intima-media thick-

ness (IMT) of left and right carotid arteries during the

ﬁrst year. Conversely, those consuming PJ had reduced

IMT at 3, 6, 9, and 12 months ranging from 13 percent

at three months to 35 percent at one year compared to

baseline values.

Most serum biochemistry parameters re-

mained unchanged by PJ consumption over the ﬁrst

year, with the exception of triglyceride concentrations,

which increased 16 percent but remained in the normal

range. Serum lipid peroxidation in subjects consum-

ing PJ was signiﬁcantly reduced by 59 percent after

one year, and levels of LDL-associated lipid peroxides

Table 2. Antioxidant Activity of Pomegranate Juice Extract in Patients

with Carotid Artery Stenosis

ANALYSIS

Total Antioxidant Status

(nmol/liter)

Serum Antibodies against

LDL Oxidation (EU/mL)

AAPH-induced Serum Lipid

Peroxidation (nmol/mL)

Serum Paraoxonase

1 (PON1) Arylesterase

Activity (Units/mL)

Lipid Peroxide Content of

Carotid Lesions (nmol/mg

of lesion protein)

BASELINE

0.95 ± 0.12

2670 ± 61

1670 ± 66

56 ± 5

1 MONTH

1563 ± 69

3 MONTHS

1670 ± 52

Ú61%

1 YEAR

2.20 ± 0.23

(Ò130%)

Ú19%

691 ± 43

(Ú59%)

97 ± 10

(Ò73%)

Ú44%

3 YEARS

Ú75%

107 ± 10

(Ò83%)

EU = Enzyme units

AAPH = 2.2’-azobis, 2-amidinopropane hydrochloride

Alternative Medicine Review Volume 13, Number 2 2008

Review Article

Page 137

were also decreased by as much as 90 percent after six

months of supplementation. Body mass index did not

change in treated subjects but systolic blood pressure

was reduced an average of 16 percent during the three-

year study.

In addition to previous reports of reduced

systolic blood pressure

and inhibition of lipid peroxi-

dation,

this study demonstrated that PJ consumption

(via antioxidative mechanisms) signiﬁcantly reduces

various aspects of IMT in patients with severe carotid

artery stenosis (Table 2).

Myocardial Perfusion

In a double-blind, randomized, placebo-con-

trolled trial, 39 patients were given either 240 mL PJ

(polyphenol content not speciﬁed) (n=23) or a sports

beverage of similar color, ﬂavor, and caloric content

daily for three months (n=16). Although both control

and treatment patients demonstrated similar levels of

stress-induced ischemia at baseline, at three months

stress-induced ischemia increased in the placebo group

(from 5.9±4.3 to 7.1±5.5) but decreased in the treat-

ment group (from 4.5±3.1 to 3.7±3.7). In addition, an-

gina episodes increased 38 percent in the placebo group

but decreased 50 percent in the treatment group (a net

change of 88 percent). ese results demonstrate a re-

duction in myocardial ischemia and improved myocar-

dial perfusion (as measured by stress-induced ischemia)

in patients consuming pomegranate juice.

Diabetes

In an animal model of diabetes, Huang et al dem-

onstrated the favorable eﬀect of PFLE on lipid proﬁles

and cardiac ﬁbrosis

of Zucker fatty diabetic rats. Rosen-

blat et al investigated the eﬀect of 50 mL/day PJ for three

months on oxidative stress, blood sugar, and lipid proﬁles

in 10 type 2 diabetic patients (history of diabetes for 4-10

years) and 10 healthy controls (ages 35-71).

In diabetic

patients, triglyceride levels were 2.8 times greater, HDL

cholesterol was 28-percent lower, and hemoglobin A1C

(HbA1C) values were 59-percent higher than in control

patients. Insulin was only slightly lower in patients than

controls, and C-peptide (a proinsulin metabolite marker

for endogenously secreted insulin) was slightly higher in

diabetic patients than in healthy controls at baseline (indi-

cating slight hyperinsulinemia). Consuming PJ for three

months did not signiﬁcantly aﬀect triglyceride, HDL

cholesterol, HbA1C, glucose, or insulin values, but did

lower serum C-peptide values by 23 percent compared to

baseline in diabetic patients – a sign of improved insulin

sensitivity.

PJ consumption also signiﬁcantly reduced oxi-

dative stress in the diabetic patients as evidenced by a

56-percent reduction in lipid peroxides and a 28-percent

reduction in TBARS compared to baseline serum levels.

In addition, a 39-percent decrease in uptake of oxidized

LDL by human monocyte-derived macrophages (an early

development in foam cell formation and atherogenesis)

was observed in diabetic patients after PJ consumption.

Researchers concluded that despite the sugars naturally

present in pomegranate juice, consumption did not ad-

versely aﬀect diabetic parameters but had a signiﬁcant ef-

fect on atherogenesis via reduced oxidative stress.

Dental Conditions

Topical applications of pomegranate prepara-

tions have been found to be particularly eﬀective for

controlling oral inﬂammation, as well as bacteria and

fungal counts in periodontal disease and Candida-asso-

ciated denture stomatitis.

Dental Plaque

A hydroalcoholic extract of Punica granatum

fruit (HAEP) was investigated for antibacterial eﬀect

on dental plaque microorganisms. Sixty healthy patients

(33 females/27 males; ages 9-25) with ﬁxed orthodon-

tic appliances were randomized to three groups of 20:

(1) control group who rinsed with 15 mL distilled wa-

ter; (2) a group who rinsed with 15 mL chlorhexidine,

a standard antiplaque mouth rinse; and (3) a group who

rinsed with a 15-mL HAEP solution. Rinsing duration

was one minute and dental plaque material was collected

from each patient prior to and after rinsing. Samples were

diluted and plated on Meuller-Hinton agar and incuba-

ted at 37° C for 48 hours. HAEP decreased the number

of colony forming units (CFU) of dental plaque bacteria

84 percent, comparable to chlorhexidine (79-percent in-

hibition) but signiﬁcantly better than the control rinse

(11-percent inhibition). Both HAEP and chlorhexidine

were eﬀective against Staphylococcus, Streptococcus,

Klebsiella, and Proteus species, as well as E. coli. e

ellagitannin, punicalagin, is thought to be the fraction

responsible for pomegranate’s antibacterial activity.

Alternative Medicine Review Volume 13, Number 2 2008

Pomegranate

Page 138

Periodontal Disease

A preliminary and follow-up study by a group

of ai researchers investigated the eﬀect of biodegrad-

able chips impregnated with Centella asiatica and P. gra-

natum pericarp on periodontal disease in 20 patients

with gum pocket depths of 5-8 mm. A baseline exam

was performed and followed by root planing and scal-

ing of target teeth. Subgingival placement of the medi-

cated chips (treatment group) and non-medicated chips

(placebo/control group) followed, and pocket depth,

attachment level, bleeding, and gingival and plaque in-

dexes were measured at baseline and after three and six

months. All treatment sites demonstrated a trend to-

ward decreasing plaque and signiﬁcant improvements

were noted in pocket depth and attachment level at

three months compared to placebo.

In the follow-up study, 15 patients who had

completed standard periodontal therapy but still had

pocket depths of 5-8 mm were implanted with the same

medicated chips. e same parameters were measured

again at baseline and after three and six months, but

researchers also measured inﬂammatory markers inter-

leukin-1ß (IL-1ß) and IL-6. Signiﬁcant improvement

was noted in all re-measured parameters and conﬁrmed

by signiﬁcant decreases in IL-1ß and IL-6 at three and

six months compared to baseline.

Denture Stomatitis

e primary etiologic factors for denture stom-

atitis are poor oral hygiene, inﬂammation from ill-ﬁtting

dentures, and Candida infection,

72,73

which manifest as

swelling, pain, burning in the mouth, and aphthous ul-

cers.

In a randomized, double-blind study of 60 sub-

jects (ages 19-62) with candidiasis conﬁrmed via myco-

logic examination, the eﬀect of a gel-based P. granatum

bark extract (GPBE) was evaluated for its eﬀect on heal-

ing of oral lesions and direct fungicidal eﬀect. Patients

were randomized into two groups of 30: one received

miconazole oral gel (a standard therapy) and the other

used GPBE, both three times daily for 15 days. Gels

were applied to oral surfaces, dentures were removed

and cleaned nightly, then brushed with the correspond-

ing oral gels. All subjects reported an improvement in

symptoms and general oral health. Clinical symptoms of

those using miconazole were slightly better (27/30 sat-

isfactory improvement) compared to GPBE (21/30 sat-

isfactory improvement). Clearing of Candida infection

was approximately the same in both groups (25/30 in the

miconazole group and 23/30 in the GPBE group).

Interestingly, despite randomized subject place-

ment, there were three times more subjects with good

oral hygiene scores in the miconazole group compared

to the GPBE group, possibly accounting for the superior

results observed by miconazole therapy. Also, because

the initial step in the development of Candida denture

stomatitis is adherence of organisms to dentures and the

miconazole gel was stickier than GPBE, contact dura-

tion of miconazole was longer. A stickier GPBE might

result in improved clinical response.

Bacterial Infections

e only human trials examining the antibac-

terial properties of pomegranate extracts have focused

on oral bacteria.

49,50,70,71

However, several in vitro assays

demonstrate its bacteriocidal activity against several

highly pathogenic and sometimes antibiotic-resistant

organisms. Brazilian researchers evaluated the synergis-

tic eﬀect of a P. granatum methanolic extract with ﬁve

antibiotics on 30 clinical isolates of methicillin-resistant

Staphylococcus aureus (MRSA) and methicillin-sensitive

S. aureus.

Antibiotics tested were chloramphenicol, gen-

tamicin, ampicillin, tetracycline, and oxacillin. Although

synergistic activity between the pomegranate extract

and all ﬁve antibiotics was noted in the S. aureus isolates,

synergy with ampicillin was the most pronounced. A

combination of the two increased the lag time to bacter-

ial growth by three hours (over that of ampicillin alone)

and was also bacteriocidal as evidenced by a 72.5-per-

cent reduction in methicillin-sensitive organisms and a

99.9-percent reduction in MRSA. Based on earlier re-

and the results of this study, the ellagitannin,

punicalagin, is thought to be the primary constituent

responsible for the observed antibacterial eﬀects.

Another organism that can cause signiﬁcant dis-

ease in humans is enterohemorrhagic Escherichia coli (E.

coli O157:H7), which can present with diarrhea, hem-

orrhagic colitis, thrombocytopenic purpura, and hemo-

lytic uremic syndrome. P. granatum and seven other ai

medicinal plant extracts were tested for in vitro activity

against E. coli O157:H7. An ethanolic PPE, one of the

two most eﬀective extracts against E. coli O157:H7, was

shown to be both bacteriostatic and bacteriocidal, indi-

cating PPE may be an eﬀective adjunct treatment for E.

coli O157:H7 infection.

Alternative Medicine Review Volume 13, Number 2 2008

Review Article

Page 139

Ultraviolet Radiation

In vitro studies using normal human epidermal

keratinocytes and PFE demonstrate PFE incubation

with cell cultures ameliorates ultraviolet A and B radia-

tion-induced cell damage in a dose- and time-dependent

manner, providing evidence at a cellular level that PFE

may be an eﬀective photo-chemopreventive agent.

77,78

A double-blind, placebo-controlled trial eval-

uated the protective and ameliorative properties of

pomegranate extract and its EA constituent on UV-

induced skin pigmentation. An ethanolic PPE was pre-

pared containing 89.5 percent EA, conﬁrmed by HPLC

analysis. irty-nine healthy women (ages 20-49) were

randomly assigned to one of three groups: (1) high-

dose (200 mg/day) EA tablets; (2) low-dose (100 mg/

day) EA tablets; and (3) placebo (0 mg EA) tablets for

four weeks. Prior to the ﬁrst dose, subjects received a

1.5 minimum erythema dose (MED) of UV radiation

on the inside upper right arm. Melanin, luminance, and

erythema values were measured at baseline and at the

end of each of the next four weeks. A questionnaire

was completed by subjects to evaluate PPE’s eﬀective-

ness on improvement of UV-induced slight sunburn.

Rate of change for luminance, melanin, and erythema

values was not signiﬁcantly diﬀerent for subjects receiv-

ing either EA dose compared to placebo or compared

to baseline values. However, analysis of the question-

naire results demonstrated a trend toward amelioration

of UV-induced damage in both EA groups compared

to placebo.

Erectile Dysfunction

A study using a rabbit model of arteriogenic

erectile dysfunction (ED) measured the eﬀect of PJ

concentrate on intracavernous blood ﬂow and penile

erection. Azadzoi et al found eight weeks administra-

tion of 3.87 mL PJ concentrate (112 µmol polyphenols)

daily signiﬁcantly increased intracavernous blood ﬂow

and smooth muscle relaxation, probably via its antioxi-

dant eﬀect on enhanced NO preservation and bioavail-

ability.

A randomized, double-blind, placebo-con-

trolled, 10-week crossover trial in 53 men (mean age

46) investigated PJ’s therapeutic eﬀect on mild-to-

moderate ED. Subjects with other medical conditions

that might contribute to ED were excluded, and sub-

jects were asked to refrain from taking ED medication

for the duration of the study. e trial consisted of two

four-week treatment periods separated by a two-week

washout. During the ﬁrst four weeks, subjects were

given PJ (1.5 mmol polyphenols daily) or placebo bev-

erage, followed by washout and crossover to the other

group. Although assessment via the International Index

of Erectile Function and Global Assessment Question-

naires demonstrated a trend toward improvements in

ED, statistical signiﬁcance was not achieved. is may

be attributable to small sample size, short study dura-

tion, subject compliance with beverage consumption, or

may indicate the PJ dosage did not have an appreciable

eﬀect on ED.

Male Infertility

Research in rats demonstrates PJ consumption

improves epididymal sperm concentration, spermato-

genic cell density, diameter of seminiferous tubules, and

sperm motility, and decreases the number of abnormal

sperm compared to control animals. An improvement

in antioxidant enzyme activity in both rat plasma and

sperm was also noted.

Neonatal Hypoxic-Ischemic Brain Injury

Neonatal hypoxic-ischemic (HI) brain injury

in severely preterm, very low birth-weight infants is a

major cause of infant illness and death

and has been

associated with an increase in reactive oxygen species.

Two studies in which pregnant mice were given PJ in

drinking water revealed the neonatal oﬀspring, when

subjected to experimentally-induced HI brain injury,

had signiﬁcantly less brain tissue loss (64% decrease)

and signiﬁcantly decreased hippocampal caspase-3 ac-

tivity (84% decrease) compared to neonates with ex-

perimentally-induced HI brain injury from dams who

consumed a control beverage.

85,86

ese results suggest

PJ has an antioxidant-driven neuroprotective eﬀect

conferred from mother to neonate.

Alternative Medicine Review Volume 13, Number 2 2008

Pomegranate

Page 140

Alzheimer’s Disease

e neuroprotective properties of pomegran-

ate polyphenols were evaluated in an animal model of

Alzheimer’s disease. Transgenic mice with Alzheimer’s-

like pathology treated with PJ had 50-percent less accu-

mulation of soluble amyloid-beta and less hippocampal

amyloid deposition than mice consuming sugar water,

suggesting PJ may be neuroprotective. Animals also

exhibited improved learning of water maze tasks and

swam faster than control animals.

Obesity

PFLE (400 or 800 mg/kg/day) given to obese

hyperlipidemic mice for ﬁve weeks caused signiﬁcant

decreases in body weight, percentage of adipose pad

weights, energy intake, and serum cholesterol, triglyc-

eride, glucose, and total cholesterol/HDL ratios. De-

creased appetite and intestinal fat absorption were also

observed, improvements mediated in part by inhibition

of pancreatic lipase activity.

Potential Drug Interactions

Based on pomegranate’s current popularity

and research suggesting its therapeutic beneﬁt in cancer,

cardiovascular disease, and other diseases treated with

prescription medications, it has been of interest to de-

termine whether pomegranate extracts have any eﬀect

on cytochrome P450-3A, the hepatic enzyme system

responsible for metabolism of many prescription medi-

cations. A randomized, single-dose, crossover study in

Table 3. Ongoing Pomegranate Trials

CLINTRIALS.GOV

IDENTIFIER

NCT00413530

NCT00060086

NCT00433797

NCT00381108

NCT00455416

NCT00336934

NCT00428532

NCT00655031

From: http://www.clinicaltrials.gov

STUDY FOCUS

Rising PSA levels in

men with previous

prostate cancer

Recurrent prostate

cancer

Prostate cancer

Benign prostatic

hyperplasia

Follicular lymphoma

Rising PSA levels in

men with previous

prostate cancer

Atherosclerosis in

diabetics

Prevention of

rhino-virus infection

SPONSOR

M.D. Anderson Cancer

Center; Houston, TX

Jonsson Comprehensive

Cancer Center; National

Cancer Institute

University of Oslo;

Norwegian Cancer

Society; The Research

Council of Norway

University of California,

Irvine; Jarrow

Pharmaceuticals

University of Oslo,

Norway

Jonsson Comprehensive

Cancer Center; National

Cancer Institute

HaEmek Medical Center,

Israel

Pom Wonderful LLC

ESTIMATED

ENROLLMENT

300 subjects

29-40

subjects

102 subjects

20 subjects

45 subjects

250 subjects

10 males

10 females

150 subjects

STUDY START

DATE

December

2006

March

2003

June

2007

September

2005

April

2007

November

2005

March

2007

April

2008

ESTIMATED

COMPLETION DATE

December

2008

September 2004

or longer

March

2009

March

2009

December

2009

December

2009

August

2007

June

2008

STATUS

Currently

recruiting

Ongoing

Currently

recruiting

Currently

recruiting

Currently

recruiting

Currently

recruiting

Completed;

publication

pending

Currently

recruiting

Alternative Medicine Review Volume 13, Number 2 2008

Review Article

Page 141

13 healthy human volunteers demonstrated PJ pretreat-

ment did not aﬀect elimination half-life or distribution

of intravenous midazolam (a benzodiazepine derivative

with anxiolytic, amnestic, hypnotic, anticonvulsant, and

muscle relaxant properties), nor did it aﬀect the C

max

clearance of oral midazolam.

is human study con-

tradicts a rat study showing PJ has an inhibitory eﬀect

on carbamazepine pharmacokinetics, an anticonvulsant

medication also metabolized by cytochrome P450-

3A.

Safety of Pomegranate Extracts

Pomegranate and its constituents have safely

been consumed for centuries without adverse eﬀects.

Studies of pomegranate constituents in animals at con-

centrations and levels commonly used in folk and tradi-

tional medicine note no toxic eﬀects.

Toxicity of the

polyphenol antioxidant punicalagin, abundant in pome-

granate juice, was evaluated in rats. No toxic eﬀects or

signiﬁcant diﬀerences were observed in the treatment

group compared to controls, which was conﬁrmed via

histopathological analysis of rat organs.

Research in 86 overweight human volunteers

demonstrated the safety of a tableted PFE in amounts

up to 1,420 mg/day (870 mg gallic acid equivalents)

for 28 days, with no adverse events reported or adverse

changes in blood or urine laboratory values observed.

Another study in 10 patients with carotid artery steno-

sis demonstrated PJ consumption (121 mg/L EA

equivalents) for up to three years had no toxic eﬀect

on blood chemistry analysis for kidney, liver, and heart

function.

Conclusion

An explosion of interest in the numerous

therapeutic properties of Punica granatum over the last

decade has led to numerous in vitro, animal, and clini-

cal trials. Pomegranate is a potent antioxidant, superior

to red wine and equal to or better than green tea. In

addition, anticarcinogenic and anti-inﬂammatory prop-

erties suggest its possible use as a therapy or adjunct

for prevention and treatment of several types of cancer

and cardiovascular disease. Because of pomegranate’s

antimicrobial properties, it may aid in preventing infec-

tion by dental pathogens, pathogenic E. coli O157:H7,

and antibiotic-resistant organisms such as MRSA.

Pomegranate’s eﬀect on bacterial pathogens has only

been tested in vitro, however, necessitating human trials

to refute or substantiate any clinical eﬀect. e possibil-

ity that pomegranate extracts may also have an eﬀect

on several other disease processes, such as Alzheimer’s

disease, osteoarthritis, neonatal brain injury, male infer-

tility, and obesity, underscores the need for more clinical

research. Currently, numerous clinical trials are in pro-

gress exploring the therapeutic potential of pomegran-

ate extracts (Table 3).

References

http://en.wikipedia.org/wiki/Pomegranate. 1.

[Accessed September 25, 2007]

http://www.crfg.org/pubs/ﬀ/pomegranate.html. 2.

[Accessed September 25, 2007]

Naqvi SA, Khan MS, Vohora SB. Antibacterial, 3.

antifungal, and antihelminthic investigations on

Indian medicinal plants. Fitoterapia 1991;62:221-228.

Lad V, Frawley D. 4. e Yoga of Herbs. Santa Fe, NM:

Lotus Press; 1986:135-136.

Caceres A, Giron LM, Alvarado SR, Torres MF. 5.

Screening of antimicrobial activity of plants popularly

used in Guatemala for treatment of dermatomucosal

diseases. J Ethnopharmacol 1987;20:223-237.

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The effect of extract of Punica granatum var. pleniflora for treatment of minor recurrent aphthous stomatitis

Article

Full-text available

Dec 2015

Background Herbal drugs are considered alternative agents and have been used for several years around the world. Recurrent aphthous stomatitis (RAS) is one of the most common problems recognized by dentists and skin specialists. This problem is characterized by recurring, painful, small oral mucosal ulcers with a round or oval aspect that mostly appear in keratinized mucosa, cheeks, and on the surface of the mouth under the tongue. Methods In our experiment, the alcoholic and water extracts of Punica granatum var. pleniflora, P. granatum var. Sweet Alak, and P. granatum var. Saveh Black were tested on minor RAS. The study was carried out using the double-blind method. The study population consisted of 210 participants, of whom 69 were females (32%) and 141 were males (68%). In addition to checking several factors, the pain and the degree of the participant's satisfaction had been determined based on visual analog scale. Data analysis was done in the form of a nonparametric method using Kruskal–Wallis test and SPSS version 20 software. Results The results show that the alcoholic and water extracts of P. granatum var. pleniflora have a meaningful therapeutic effect on minor RAS. Results from the antioxidant activity and its relation to total phenolics show that P. granatum var. pleniflora and P. granatum var. Sweet Alak are rich in phenols. Conclusion The water and alcoholic extracts of P. granatum varpleniflora decreased the entire time of complete treatment, and the treatment was meaningfully satisfactory for patients who participated in this experiment.

The Study of Effect of Pomegranate Juice on Type 2 Diabetes Mellietus

Article

Apr 2017

Dr. K. Jyothsna

An Interaction Network Driven Approach for Identifying Cervical, Endometrial, Vulvar Carcinomic Biomarkers and Their Multi-targeted Inhibitory Agents from Few Widely Available Medicinal Plants

Article

Full-text available

Mar 2023
APPL BIOCHEM BIOTECH

Differently expressed genes (DEGs) across cervical (CC), endometrial (EC), and vulvar carcinoma (VC) may serve as potential biomarkers for these progressive tumor conditions. In this study, DEGs of cervical (CC), endometrial (EC), and vulvar carcinoma (VC) were identified by microarray analysis. The interaction network between the identified 124 DEGs was constructed and analyzed to identify the hub genes and genes with high stress centrality. DEGs, namely, CDK1 and MMP9, were found to show highest degree and highest stress centrality respectively from the gene interaction network of 124 nodes and 1171 edges. DEG CDK1 is found to be overlapping in both cervical and endometrial carcinomic conditions while DEG MMP9 is found in vulvar carcinomic condition. Further, as it is studied that many phytochemicals play an important role as medicinal drugs, we have identified phytochemicals from few widely available medicinal plants and performed comprehensive computational study to identify a multi-targeted phytochemical against the identified DEGs, which are crucially responsible for the progression of these carcinomic conditions. Virtual screening of the phytochemicals against the target DEG protein structures with PDB IDs 4Y72 and 1GKC resulted in identifying the multi-targeted phytochemical against both the proteins. The molecular docking and dynamics simulation studies reveal that luteolin can act as a multi-targeted agent. Thus, the interactional and structural insights of luteolin toward the DEG proteins signify that it can be further explored as a multi-targeted agent against the cervical, endometrial, and vulvar carcinoma.

IN VITRO ANTIFUNGAL ACTIVITY OF THE EXTRACTS OF Punica granatum L OBTAINED BY REFLUX METHOD AGAINST Fusarium oxysoprum albedenis IN SOUTH WEST OF ALGERIA

Article

Full-text available

Jan 2022

Punica granatum (Pg), commonly known as pomegranate is a member of the monogeneric family, Punicaceae. Pg and its chemical components possess various pharmacological and toxicological properties including antioxidant, anti-inflammatory, antifungal and against vegetable and palms diseases. Bayoud is the most dangerous disease, causing significant losses of date palms in Algeria whose the responsible fungi is called Fusarium oxysporum f.sp.albednis. This study focused on the evaluation of the in vitro antifungal activity of a Punica granatum L fruit extracts obtained by the reflux method, considered as a hot method using heating with the following solvents: distilled water, methanol, ethyl acetate, and chloroform; on ten selected strains of Fusarium oxysporum f.sp. albedinis. The evaluation of antifusarial activity of Punica granatum L. was carried out by using the dilution and the direct contact method to determine the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC). The results of the extraction yield show that distilled water and methanol are the two best solvents which give a good yield compared to chloroform and ethyl acetate, 42% for methanol and 54% for distilled water, but the low yield is 0.5% for chloroform and between 1.15 for ethyl acetate. The antifungal activity results of these extracts on the solid and liquid medium, the PDA and the PDB, respectively, show that they have good inhibitory activity against all the tested fungi. According to the results obtained in the solid medium, the extracts tested have an inhibitory activity against Foa, with different MIC values ranging from 1.2 mg/ml to 4.2 mg/ml. The result of growing on liquid medium, shows that with each increase in the concentration of the extracts in the culture medium, there is a decrease in the fungal biomass, and there is a fungicide activity for all extracts used.

Surdurulebilir Gida Sistemleri Uzerine Arastirmalar -Kitap

Book

Feb 2023

Neriman Bağdatlıoğlu

Researches on Sustainable Food Systems

ANTIMICROBIAL ACTION OF PUNICA GRANATUM (POMEGRANATE) AND PASSIFLORA EDULIS (PASSION FRUIT) AGAINST ORGANISMS ISOLATED FROM INTESTINAL INFECTIONS –AN IN VITRO STUDY

Article

Feb 2023

Background and objectives: The overuse and misuse of antibiotics coupled with the intrinsic and acquired resistance of bacteria resulted in the emergence of multi-drug resistant strains. Pomegranate and Passion fruit are two fruits which have been documented to have signicant antimicrobial activity against harmful organisms which colonize the gut. The present study evaluates the antimicrobial activity of Punica granatum and Passiora edulis against organisms isolated from intestinal infections and compares the antimicrobial efcacy of the ethanolic and aqueous extracts of fruit rind of Punica granatum and leaves of Passiora edulis. Fruit ri Methods: nd of Punica granatum and the fresh leaves of Passiora edulis plants were dried, ground into powder and made into extracts. A total of 100 gastrointestinal pathogens were isolated and included in the study. The antibacterial efcacy of the aqueous and alcoholic extracts against 100 human faecal isolates was tested by employing Kirby Bauer disc diffusion technique. Sensitivity to the ethanolic and aqueous extracts of Punica Results: granatum were found to be maximum in Staphylococcus aureus. MRSA was sensitive to these extracts. Aqueous extract of Punica granatum were effective against a large number of organisms, however, better antimicrobial action was seen with the ethanolic extract of Punica granatum. No encouraging results were obtained with the extracts of Passiora edulis. Our study shows that puried forms of Pomegranate (Punica granat Interpretation and conclusions: um) can be used as an adjunct in the treatment, in conjunction with antibiotics against intestinal pathogens and can open new areas of research.

An Indonesian slimming drug with undeclared ingredients causing harm

Article

Feb 2023

This paper reports the presence of undeclared drugs in the herbal slimming supplement Sulami®. The four cases of the adverse drug reactions related to Sulami® were reported to the Dutch Pharmacovigilance Centre (Lareb) or the Dutch Poisons Information Centre (DPIC). The analysis of all four collected samples revealed adulteration with sibutramine and canrenone. Both drugs can cause serious adverse drug reactions. From a legal point of view, it is clear that Sulami® does not meet the legal requirement for safety. As defined in the European General Food Law Regulation (GFL) food business operators are responsible for food safety. This also applies to online store owners who sell herbal preparations. Thus, it is clear that it is forbidden to sell Sulami® on the European and Dutch market. Collaboration between involved national authorities make it possible to identify risky products. This allows the nationally responsible regulators to take targeted action. They can call on users to report sell points what makes it possible to arrest the sellers and confiscate the dangerous products. Beyond the national also the European enforcement organizations should take legal measures where possible, to protect public health. The Heads of Food Safety Agencies Working Group on Food Supplements “an Initiative on European level is a good example of efforts to improve consumer safety.

Recent Advances in Using Natural Antibacterial Additives in Bioactive Wound Dressings

Article

Full-text available

Feb 2023

Wound care is a global health issue with a financial burden of up to US $96.8 billion annually in the USA alone. Chronic non-healing wounds which show delayed and incomplete healing are especially problematic. Although there are more than 3000 dressing types in the wound management market, new developments in more efficient wound dressings will require innovative approaches such as embedding antibacterial additives into wound-dressing materials. The lack of novel antibacterial agents and the misuse of current antibiotics have caused an increase in antimicrobial resistance (AMR) which is estimated to cause 10 million deaths by 2050 worldwide. These ongoing challenges clearly indicate an urgent need for developing new antibacterial additives in wound dressings targeting microbial pathogens. Natural products and their derivatives have long been a significant source of pharmaceuticals against AMR. Scrutinising the data of newly approved drugs has identified plants as one of the biggest and most important sources in the development of novel antibacterial drugs. Some of the plant-based antibacterial additives, such as essential oils and plant extracts, have been previously used in wound dressings; however, there is another source of plant-derived antibacterial additives, i.e., those produced by symbiotic endophytic fungi, that show great potential in wound dressing applications. Endophytes represent a novel, natural, and sustainable source of bioactive compounds for therapeutic applications, including as efficient antibacterial additives for chronic wound dressings. This review examines and appraises recent developments in bioactive wound dressings that incorporate natural products as antibacterial agents as well as advances in endophyte research that show great potential in treating chronic wounds.

UJI ANTIOKSIDAN JAMU MADURA “EMPOT SUPER”

Article

Sep 2015

Kholifah Holil

p> The purpose of this research is to present scientific information related to madura’s herbal medicine “empot super” and herbal extract made from existing composition of the various constituent plants of empot super. Then, this research spesifically detects antioxidants activity found in herbal medicine and herbal extract expected to provide a scientific assurance either for the industry or the consumen.Samples used in this research are madura’s herbal medicine and herbal extract mixture of various simplisia those are used in the manufacture of empot super herbal medicine. To get those samples, herbal medicine is imported from madura, while the herbal extract is the production of extraction process by using ethanol. The samples are subsequently assay the antioxidants activity by using DPPH method at 571nm.The final result of this research indicates the existance of IC<sub>50</sub> proportion in herbal medicine that is 34,11mg/ml and 45,44mg/ml in herbal extract. Indeed, in the assay of herbal medicine and herbal extract classified as having a very strong antioxidants activity</em

Efficacy of a 0.5% Propolis -0.9% Pomegranate Buccal Spray Treatment Compared with 2% Miconazole Gel for Denture Stomatitis Treatment in Elderly Patients: a Randomized Clinical Trial

Article

Full-text available

Dec 2022

Statement of the problem: Natural products have attracted interest as an alternative to synthetic medi-cations for the treatment of oral diseases due to their efficacy and safety. Propolis and pomegranate extracts have both demonstrated efficacy for the treatment of denture stomatitis. However, use of the two compounds together has not been tested for this purpose. Purpose: A comparison was made of the efficacy of a commercially available propolis-pomegranate buccal spray formulation for the treatment of denture stomatitis, compared with miconazole gel, based on stomatitis lesions and Candida spp. concentrations in mouth rinses. Materials and method: This was an experimental study, characterized as an open-label, parallel two-armed, non-inferiority randomized clinical trial. Forty elderly adults aged < 60 years with denture stoma-titis were randomly allocated to two groups. The patients applied a buccal spray containing 0.5% propo-lis and 0.9% pomegranate extracts or 2% miconazole gel, a standard treatment recommended in Brazil, to the inner surface of their dentures three times a day for 14 days. They were examined at days 1, 7, 14 and stomatitis lesions were categorized according to Newton's score. Mouth rinses were made with saline solution at days 1 and 14 and then assessed for Candida spp. Results: Both treatments reduced the Newton's score, with clinical cure rates of 75 and 40% for the miconazole and propolis-pomegranate groups, respectively. The Candida concentrations in the mouth rinse decreased significantly only in the miconazole group. Conclusion: The propolis-pomegranate spray was less effective than the miconazole treatment. Howev-er, clinical improvement was also observed in patients treated with the propolis-pomegranate buccal spray.

Use of Punica granatum Linn as an antifungal agent against candidosis associated with denture stomatitis

Article

Full-text available

Jun 2003

The aim of this study was to evaluate the use of a gel containing the extract of Punica granatum as an antifungal agent against candidosis associated with denture stomatitis. Sixty patients with denture stomatitis confirmed by clinical and mycologic examination were selected. The patients were randomly allocated in two groups of 30 individuals each according to the medication prescribed: group A used miconazole (Daktarin(R) gel oral) and group B used a gel of P. granatum Linne (pomegranate). Both groups used the medicines three times per day for 15 days. Forty-eight hours after finishing the treatment the patients were re-examined and a second set of samples was collected for mycologic examination. The medicines were evaluated for their clinical response and negativity for Candida. The clinical results showed a satisfactory and regular response in 27 and 21 subjects of groups A and B, respectively. Negativity of yeasts was observed in 25 subjects of group A and 23 of group B. It can be concluded that the extract of P. granatum may be used as a topical antifungal agent for the treatment of candidosis associated with denture stomatitis.

Characterization of certain steroid hormones in Punica granatum L. seeds

Article

Jan 1998

Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer: Commentary

Article

Mar 2006

T.L. Ratliff

Crystalline chemical components of some vegetable drugs

Article

Jan 1973

Determination of phenolic compounds in pomegranate juice by using HPLC

Article

Jan 1998

Nevzat Artik

Alkaloids in the bark of Punica granatum L. (Pomegranate) from Yugoslavia

Article

Jan 1993
PHARMAZIE

The alkaloid patterns of different bark samples of Punica granatum from Yugoslavia have been studied. In addition to the known alkaloids pelletierine, N-methylpelletierine and pseudopelletierine ten further alkaloids could be detected by capillary GLC-M.S. Some of these are the 2- and 2,6-substituted alkaloids sedridine, 2-(2'-hydroxypropyl)Δ1-piperidine, 2-(2'-propenyl) Δ1-piperidine and norpseudopelletierine. The pyrrolidine alkaloids hygrine and norhygrine were only found in the root bark. The necessity for verifying the quality of the pomegranate bark as an anthelmintic drug is discussed

Article

Jan 1986

The structures of punicalin and punicalagin, isolated from the bark of Punica granatum L. (pomegranate), have been revised to 4, 6-(S, S)-gallagyl-D-glucose (1) and 2, 3-(S)-hexahydroxy-diphenoyl-4, 6-(S, S)-gallagyl-D-glucose (2), respectively, on the basis of chemical and spectroscopic evidence. In addition, a new hydrolyzable tannin, 2-O-galloyl-4, 6-(S, S)-gallagyl-D-glucose (3) was isolated from the same plant source, and characterized.

Anti-bacterial, anti-fungal and anthelmintic investigations on Indian medicinal plants

Article

Jan 1991
FITOTERAPIA

Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation

Article

Jun 2004
CLIN NUTR

Michael Aviram

Dietary supplementation with polyphenolic antioxidants to animals was shown to be associated with inhibition of LDL oxidation and macrophage foam cell formation, and attenuation of atherosclerosis development.We investigated the effects of pomegranate juice (PJ, which contains potent tannins and anthocyanins) consumption by atherosclerotic patients with carotid artery stenosis (CAS) on the progression of carotid lesions and changes in oxidative stress and blood pressure.Ten patients were supplemented with PJ for 1 year and five of them continued for up to 3 years. Blood samples were collected before treatment and during PJ consumption. In the control group that did not consume PJ, common carotid intima-media thickness (IMT) increased by 9% during 1 year, whereas, PJ consumption resulted in a significant IMT reduction, by up to 30%, after 1 year. The patients’ serum paraoxonase 1 (PON 1) activity was increased by 83%, whereas serum LDL basal oxidative state and LDL susceptibility to copper ion-induced oxidation were both significantly reduced, by 90% and 59%, respectively, after 12 months of PJ consumption, compared to values obtained before PJ consumption. Furthermore, serum levels of antibodies against oxidized LDL were decreased by 19%, and in parallel serum total antioxidant status (TAS) was increased by 130% after 1 year of PJ consumption. Systolic blood pressure was reduced after 1 year of PJ consumption by 21% and was not further reduced along 3 years of PJ consumption. For all studied parameters, the maximal effects were observed after 1 year of PJ consumption. Further consumption of PJ, for up to 3 years, had no additional beneficial effects on IMT and serum PON1 activity, whereas serum lipid peroxidation was further reduced by up to 16% after 3 years of PJ consumption.The results of the present study thus suggest that PJ consumption by patients with CAS decreases carotid IMT and systolic blood pressure and these effects could be related to the potent antioxidant characteristics of PJ polyphenols.

Antidiabetic effect of an aqueous extract of Pomegranate (Punica granatum L.) peels in normal and alloxan diabetic rats

Article

Sep 2004

Enas A. M. Khalil

Hypoglycaemic drugs are either too expensive or have undesirable side effects including hematological, coma and disturbances of liver and kidney. Limiting of diabetes without any side effects is still a challenge to the medical system. This leads to exert effort to search for effective, safer and less cost antidiabetic plants. This investigation aims to evaluate the role of Punica granatum powder peels extract in its human therapeutic dose on beta cell numbers blood glucose and plasma insulin levels in normal and alloxan diabetic rats for 4-weeks of treatment. The treatment revealed that pomegranate aqueous extract significant decreased blood glucose and increased insulin levels in normal and diabetic treated rats. Pancreas showed increased number of beta cells in normal and treated diabetic rats. In conclusion pomegranate peel aqueous extract can reduce blood sugar through regeneration of ß cells.

Therapeutic Applications of Pomegranate (Punica granatum L.): A Review

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