Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2013 Article ID 656172 10 pageshttpdxdoiorg1011552013656172

Review ArticleA Review on Antihyperglycemic and AntihepatoprotectiveActivity of Eco-Friendly Punica granatum Peel Waste

Sushil Kumar Middha1 Talambedu Usha2 and Veena Pande1

1 Department of Biotechnology Bhimtal Campus Kumaun University Nainital Uttarakhand 263136 India2Department of Biotechnology amp Biochemistry Maharani Lakshmi Ammanni College for Women Bangalore 560012 India

Correspondence should be addressed to Veena Pande veena kumaunyahoocoin

Received 28 December 2012 Revised 25 March 2013 Accepted 25 April 2013

Academic Editor Edwin L Cooper

Copyright copy 2013 Sushil Kumar Middha et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Over the past decade pomegranate (Punica granatum) is entitled as a wonder fruit because of its voluminous pharmacologicalproperties In 1830 P granatum fruit was first recognized in United States Pharmacopeia the Philadelphia edition introducedthe rind of the fruit the New York edition the bark of the root and further 1890 edition the stem bark was introduced Thereare significant efforts and progress made in establishing the pharmacological mechanisms of peel (pericarp or rind) and theindividual constituents responsible for them This review provides an insight on the phytochemical components that contributetoo antihyperglycemic hepatoprotective antihyperlipidemic effect and numerous other effects of wonderful economic and eco-friendly pomegranate peel extract (PP)

1 Introduction

The family Punicaceae contains a single genus Punicaand two species the most predominant species is Punicagranatum (pomegranate) and the less predominant is Punicaprotopunica (Socotran pomegranate) atypical to the island ofSocotra

In spite of its wide prehistoric background the pome-granate has attained relatively few universally recognizednames as mentioned in Table 1 [1]

11 Scientific Classification Pomegranate (Punica granatum)has been placed under the subclass Rosidae order Myrtalesalong with other fruits such as guava and feijoa [2] It is anevergreen or deciduous and spiny plant with multiple trunksand small slender leaves with tiny stems that is believed tohave originated in Iran then moved to the Himalayas innorthern India Heterostylous funnel-shaped red flowers arecharacteristic to this plant and are found either in singles orin clusters of up to five [3] The fruit is almost round in shapewith a crown at the base created by the calyxThe skin is toughand leathery in texture yellow or deep pinkred in color andabout 2 to 5 inches in widthThe interior of the fruit containswhite spongy membranous walls that form compartments

containing sacs packed with a fleshy juicy red or whitishpulp Each sac holds an angular soft or hard seeds which areusually red or white in colour About 52 of the mass of theentire fruit is represented by these seeds [1]

Pomegranate peels or skin or rind (PP) are underesti-mated as an agricultural waste though it is part of an ancientfruit with exceptionally rich ethnomedical applications andastringent properties PP acts as ecofriendly waste because ofits numerous uses such as reducing agent in making silvernanoparticles PP also used for cattle feed and extraction ofnatural dyes [4]

12 Historical Uses of Punica granatum Many researchershave focused on the biological waste part of this wonder fruitpomegranate for the purpose of discovering many mirac-ulous effects for human health The potential therapeuticproperties of PP are wide-ranging and include treatmentand prevention for cancer [5 6] cardiovascular disease [7]diabetes [8] dental conditions [9] and erectile dysfunction[10] protection from ultraviolet (UV) radiation [10] andantimicrobial [11] Other potential applications include infantbrain ischemia Alzheimerrsquos disease [8] male infertilityarthritis [10] dermal wounds [11] and obesity [10] (Figure 1)

2 Evidence-Based Complementary and Alternative Medicine

Dental conditions

Ultraviolet (UV) radiation

Male infertility

Alzheimerrsquos disease

Obesity

Infant brainischemia

Antimicrobial

Hepatoprotective

Dermal

Anticancer

Antihyperglycemic

Cardiovasculardisease

Antineoplastic

Antiaging

Antifungal

Antilipidemic

Antiviral

Antiarthritics

Figure 1 Principal therapeutic effects of pomegranate peel

Table 1 Few commonly renowned vernacular names of Punicagranatum

Country Recognized nameRoman Carthage (Punica)

Italian Melogranato melogranogranato pomogranatoor pomopunico

Spanish Granada (the fruit) granado (the plant)Dutch GranaatappelFrench GrenadeGerman GranatapfelIndia Dadima or dalima or dalim or AnarPersian Dulim or dulimaGuatemala GranadIndonesia GangsalanSamoan LimoniBrazilian Roma romeira or romazeiraThailand Tab timMalaya Delima

In order to facilitate further investigation and utilizationwe summarized the research achievements on phyto-chemi-cal components that contribute for anti-hyperglycemic anti-lipidemic and hepato-protective effects of Punica granatumpeel waste till date

13 Proximate Physicochemical CompositionNutritional Val-ues of PP Studies have shown that PP is highly nutritiveand contains important raw materials like crude fibersprotein and carbohydrates The compositions of some of theingredients are tabulated in Table 2 [12]

Another study showed that the chemical composition ofpomegranate bagasse (the dried part of the fiber that remains

Table 2 Nutrient content of pomegranate peel per 100 g [12]

Composition ContentTotal solid 9450Moisture 540Total sugars 1770Reducing sugars 434Protein 490Crude fiber 1630Fat content 126Ash 340

once the juice is extracted) powder contains protein fat ashtotal dietary fiber insoluble dietary fiber and soluble dietaryfiber of 1094 2086 255 5029 3041 and 1988 g100 grespectively [13] However the quantification of many com-ponents such as vitamins minerals and other pharmacolog-ical properties has to be evaluated in detail

2 PhytochemicalsActive Constituents

During the ancient era significant efforts and progress weremade in establishing the pharmacological mechanisms of PPand the individual constituents responsible for them PP isknown to possess diverse phytochemicals most of which areobserved to have therapeutic properties The major chemicalconstituents along with their bioactivity are tabulated inTable 3 Figure 2 depicts the structure of all these chemicalconstituents of Table 3

Punicalin and punicalagin are the major constituentsof pericarp ranging up to 02 of the total amount Thebrilliant red colour of peel is attributed to anthocyanidinsand flavan-3-ols Flavones and flavonols constitute the majorflavonoids of peelThemethanolic extract of dried PP showed

Evidence-Based Complementary and Alternative Medicine 3

Table 3 Active constituents and their biological activity of Punica peel

Compound Bioactivity ReferenceMajor tannins of pomegranate peel

Casuarinin Antiviral antioxidant [14]Corilagin Antihypertensive antineoplastic [14ndash16]Ellagic acid [EA] Antineoplastic skin whitening [17 18]Gallic acid Antimutagenic anti-inflammatory antiviral antioxidant [17 19]Methyl gallate Antioxidant [20]Granatin A Antioxidant anti-inflammatory [21]Granatin B Antioxidant anti-inflammatory [21 22]Pedunculagin Antineoplastic antioxidant [14]Punicalagin Antioxidant antihypertensive anti-hyperglycemic [22ndash24]Punicalin Antioxidant anti HIV anti-hyperglycemic [21ndash23]

Major flavonoids of pomegranate peelCatechin Antineoplastic antioxidant [25]Cyanidin Antioxidant [26]Epicatechin Antineoplastic [25]Epigallocatechin 3-gallate Antineoplastic [25]Flavan-3-ol Antineoplastic [25]Kaempferol Antioxidant anti-inflammatory [27]Kaempferol-3-0-glucoside Antioxidant [27]Kaempferol-3-0-rhamnoglycoside Antihypertensive [27]Luteolin Antioxidant antioxidant [27]Luteolin-7-0-glucoside Antioxidant [27]Naringin Antiviral antibacterial [28]Pelargonidin Antiviral antibacterial [26]Quercetin Antiviral antioxidant antineoplastic [29]Rutin Antiviral antioxidant antihypertensive [29]

Major alkaloids of pomegranate peelPelletierine Antioxidant [30 31]Valoneic acid dilactone Antidiabetic [32]

the presence of high content of phenolic compounds (440)along with other constituents [34] Phenolic acids such ascaffeic acid fumaric acid chlorogenic acid and p-coumaricacid are present in the pericarp [17] The amount of ellagicacid in fruit peel of 12 varieties examined by Akbarpour et al[33] fluctuates considerably with a maximum of 50mg100 g(Syah-e-saveh) and a minimum of 10mg100 g (Rabbab andShishe-Kap) (Table 4) Gil et al [23] reported that the amountof total phenolics in peel was evidently higher than arils ofpomegranate fruit [33 35]

BenNasr et al [36] have described that PP has ellagic acid(EA) ellagitannins and gallic acid PP contains hydroxyben-zoic acids such as gallagic acid EA and EA glycosides [17]Anthocyanidins are principally cyanidin pelargonidin anddelphinidin [26] and flavonoids such as kaempferol luteolinand quercetin [27] Murthy et al [37] quantified methanolicextract of PP using HPLC and reported the presence of gallicacid (3403) and catechin (331)

Studies on PP were undertaken to investigate the changesin the major chemical composition during fruit maturationin two Israeli commercial varieties ldquoWonderfulrdquo and ldquoRosh-Haperedrdquo The result of the study revealed the levels of total

phenolic antioxidant activity and hydrolysable tannins werereduced during maturation while the anthocyanin levelincreased This knowledge could help establish the optimumharvest date ensuring the maximum nutritional properties ofPP [38] The results of Turkish researchers showed that thelevels of total phenolic compounds changed depending oncultivars and fruit parts In all cultivars the highest levels oftotal phenolic content were obtained from the peel extracts

3 Physical Properties

Twelve pomegranate (Punica granatum L) cultivars fromdifferent regions of Iranwere analyzed for their physical prop-erties by Akbarpour et al [33] The amount of EA ranged 10ndash50mg100 g in different varieties of PP The highest amountof EA was found in Syah-e-Saveh variety (50mg100 g)

4 Validated PharmacologicalProperties of Pomegranate Peel

41 Antioxidant Activity Superfluous generation of the freeradicals is proved to instigate and aggravate many human

4 Evidence-Based Complementary and Alternative Medicine

HO

HO

HO

HO

HO

O

OH

OHOH

OH

OHOH

OH OH

OH

OH

OH

HO

HO

HOHO

HO

HO

HO

HO

HO

HO

O

O

O

O

O

O

O

HCl

HCl

HO

O

OH

O

OO O

OO

OH

OHOH

OH

OH OHOH OH

OH OHOH

OH

OH

OH

OHOH

OH

HO

HO

HO

HO

HO

HOH3C

O+

O+

OHOH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

OH

HO HOHO

HO

O

O OO

O

O

O

HO

HO

HO

OO

OO

O

HO OH

OH

HOOCOH

OHOH

OHOH

OH

OH

OH

OH

OH

OH OH OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

CH

C C

3

CH3

O

O

O

O O

O

O

OO

O

O

OOOO

O

O

OO O

O

O

HO

HO

OO

OO

OH

OHCH2OH

O O

O O

O

O

O

O

OO

O

O

O

OO

O

O O O

O

OO

OOOO

O O

HO

HO HO

HO

HO

HOHO

HO

HO

HOHO

HO

HO

HO

HO

HO

HOHO

HO

HO

HO OH

OH

OHOH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH OH

OH

O

O O

OO

OO

O

OO

HO

HO

HO

HO

HO

HOHO

HO

HO

OHOH

OH

OH

OH

OH

OH

OOO

O

O

OO

O

O

OOO

O

HO

HO

HOHO

HO

HO

OH

OHOH

OHOH

OH

OH

OH

OH

OHOH

CH2

OHOH

OHOH

OH

OH

OH

OH

OH

OH

OH

HO

HO

O

O O

O O

O

O

O

C

Valoneic acid dilactone (VAD)

Naringin Quercetin-7-rhamnoside Methyl gallate

Epigallocatechin-3-gallate(EGCG)

Ellagic acid (EA)

PedunculaginKaempferol-3-glucoside

Flavan 3-ol

Rutin Cyanidin Catechin

Pelargonidin

Tellimagrandin IIPunicalin Corilagin

Luteolin

Gallagic acid Hexahydroxydiphenic acid Punicalagins

Epicatechin (EC) Epigallocatechin (EGC) Epicatechin-3-gallate (ECG)

Quercetin Gallic acid

Proanthocyanidin

Figure 2 Structures of polyphenolic compounds found in pomegranate peel (Punica granatum) (figures were sketched using ChemSketchsoftware alias Marvin Sketch)

Evidence-Based Complementary and Alternative Medicine 5

Table 4 Amount of EA in different varieties of peel [33]

S no Variety Thickness(mm)

Antioxidant activity(mmol100 g)

Amount of ellagic acid(mg100 g)

1 Rabbab 601 22967 10002 Malas-e-Yazd 406 23433 30003 Malas-e-Saveh 192 44050 20004 Shishe-Kap 253 30383 10005 Khazar-e-Bardeskan 210 64017 25006 Naderi 291 22517 30007 Alak 262 46350 20008 Abdandan 213 28493 37759 TabriziPoost 257 37438 325010 Syah-e-Saveh 160 31489 500011 Syah-e-Badrood 233 32763 400012 Lamsari-e-Behshahr 1727 70550 4500

ailments like arthritis cancer Alzheimerrsquos disease Parkin-sonrsquos disease AIDS and diabetic complications [51 52]Reports indicate that plants rich in anthocyanin flavonoidsand polyphenols are observed to be effective in scavengingthe free radicals [53 54] Total antioxidant activity of 12different varieties was determined by FRAP (ferric reducingantioxidant power) method described by Akbarpour etal are enlisted in Table 4 and it ranged from 22517 to70550mmolg According to Akbarpour et al [33] study thehighest antioxidant activity level was detected in ldquoLamsari-e-Behshahrrdquo and the lowest in ldquoNaderirdquo The same study hasrevealed that the antioxidant activity of peel is higher thanthat of juice and this difference is attributed to the presenceof pomegranate peel tannins [38]

The first report on antioxidant property of PP using invitro models was elucidated by Singh et al [55] The meth-anolic extract of peels showed 83 and 81 antioxidantactivity at 50 ppm using the 120573-carotene-linoleate and 22-diphenyl-2-picrylhydrazyl (DPPH) model systems respec-tively Similar group also showed 56 58 and 937 inhibitionusing the thiobarbituric acid (TBA)method hydroxyl radicalscavenging activity and serum low-density lipoprotein LDLoxidation respectively at 100 ppm [56] Owing to this prop-erty the studies can be further extended to exploit PP for theirpossible application in the preservation of food products aswell as their use as health supplements and nutraceuticals

Additional studies have also shown that PP had thehighest antioxidant activity among the peel pulp and seedfractions of 28 kinds of fruits commonly consumed in Chinaas determined by FRAP assay [57] A mixture of ethanolicmethanolic and acetone PP extract had markedly higherantioxidant capacity than the pulp extract in scavengingcapacity against superoxide anion hydroxyl and peroxylradicals as well as inhibiting CuSO

4-induced LDL oxidation

The contents of total phenolics flavonoids and Proantho-cyanidinswere also higher in peel extract than in pulp extractThe large amount of phenolics contained in peel extract maycontribute to its strong antioxidant ability [46]

Al-Mustafa and Al-Thunibat [58] have revealed the anti-oxidant activity of some Jordanian medicinal plants usedtraditionally for treatment of diabetes They were catego-rized PP under high antioxidant potential plantsThe activityinvestigated in methanolic and aqueous extract was DPPH-TEAC IC

50365 plusmn 50mggGAE 221015840-azinobis-(3-ethylben-

zothiazoline-6-sulfonic acid) (ABTS)-IC50

69 plusmn 01 120583gmLand DPPH-TEAC IC

502671 plusmn 35mggGAE and ABTS+-

IC5098 plusmn 01 120583gmL respectively Among all the plants cho-

sen by traditional healers methanolic and aqueous extractsof PP both were having potent radical scavenging activityMethanolic extract of PP exhibited the highest phenoliccontent (103GAEmgg) among all their experimental plants

In a recent study [59] the antioxidant activity of meth-anolic extract of PP on brain of normal rats demonstratedthat it reduced lipid peroxidation and nitric oxide in bothserum and brain tissue homogenate having an effect onthe scavenging capacity of superoxide anion and hydrogenperoxide

Pan et al [60] described a continuous (CUAE) and pulsedultrasound-assisted (PUAE) method for the extractions ofantioxidants from PP since there is a great demand for devel-oping efficient extraction methods in order to reduce extrac-tion time and increase the yield and activity of functionalantioxidants Cumulatively all these observations suggest thepotential antioxidant activity of PP (Table 5)

42 Antihyperglycemic Effect Over the past decade sig-nificant progress has been made in establishing the anti-hyperglycemic pharmacological mechanism of PP and theindividual compounds responsible for it Various solventextracts of PP appear to have anti-diabetic property Ontheir Jordanian medicinal plants survey native authors haverevealed 61 traditional healers recommend PP for diabetestreatment [58] Similar kind of studies done by the authorsin India also revealed the uses of PP by traditional healers(vaidya) (49) and anti-hyperglycemic effect using in vitroglucose oxidase method [61]

6 Evidence-Based Complementary and Alternative Medicine

Table 5 Overview of antioxidant pomegranate studies

Assays Effect ReferenceTrolox Equivalent AntioxidantConcentration (TEAC) Aqueous extract Prodelphinidinshowed active antioxidant activity [39]

Phospho-molybdenum complex Methanolic extract revealed lowest antioxidant activity followed by ethyl acetateacetone and water extract [40]

DPPH and ABTS radicals Remarkable free radical-scavenging power [41]DPPH and ABTS radicals Robust antioxidant activity [42]DPPH and ABTS radicals Extraordinary free radical-scavenging power [43]FRAP Peel had superior antioxidant activity than pulp and seed [44]FRAP Seed exhibited lower antioxidant activity as compared to peels [45]

DPPH and ABTS radicals Methanolic extract of PP exhibited the highest phenolic content and freeradical-scavenging power [46]

The first report on the antidiabetic properties of PP usingan in vivomodel was elucidated by Nogueira and Pereira fol-lowed by Zafar and Singh and Nozire and Serpil reproducedby several other studies [47ndash50 62ndash66]

Diabetic rats treated with 043 gkg BW of aqueous peelextract for four weeks displayed significantly lowered bloodsugar level and increased number of 120573 cells which relativelyhelp in intensification of insulin level [47] The mechanis-tic anti-diabetic activity of the extract is by stimulationregeneration and increased number of 120573 cells by protectingpancreatic tissue and subsequent release of insulin Alsoit may increase the stimulation and activation of insulinreceptor [47]

Oral administration of aqueous extract of PP at dosesof 50 and 100mgkg for 21 days brought down the fastingblood glucose total serum cholesterol (TC) triglycerides(TG) serum low density lipoprotein cholesterol (LDL-c)VLDL-C (very low-density lipoprotein cholesterol) and tissueLPO (lipid peroxidation) levels together with boost on high-density lipoprotein cholesterol (HDL-c) GSH (glutathione)content and antioxidant enzymes in contrast with diabeticcontrol groupThese authors recommended the uses of aque-ous extract of the peel as a dietary supplement in the cureand inhibition of chronic diseases categorized by aggravatedantioxidant status and diminished glucose metabolism [48]

The same group emphasized on oral administration ofthe aqueous-ethanolic extract of PP which led to signifi-cant blood glucose lowering effect in normal glucose-fedhyperglycemic in their another report on alloxan-induceddiabetic rats This report suggested that the effect can be dueto increased peripheral glucose utilization or retardation ofintestinal glucose absorption may also be partly responsiblefor inhibition of hyperglycaemia in glucose-fed rats [49]

Althunibat et al [50] had shown in their study on STZ-(streptozotocin-) induced diabetic rats that intraperitoneal(ip) administration of 10 and 20mgkg BW of PP for fourweeks significantly enhanced the activities of antioxidantenzymes in liver kidney and RBC The methanolic extractof PP (75 and 150mgkg daily) inhibits glucose level inalloxan-induced diabetic wistar rats The extract also causeda significant reduction in malondialdehyde (MDA) a lipidperoxides marker in diabetic rat tissues and elevated the total

serum antioxidant capacity in a dose-dependent mannerPhytochemical investigation demonstrates that the gallic acidin the methanolic extract of peels is mainly responsible forthis activity [8] This group suggested that the effect may bedue to the presence of terpenoids such as ursolic acid andoleanolic acid which may help to scavenge the free radicalsgenerated during diabetes (Table 6)

43 Antihyperlipidemic Effect Alterations in lipid profile areone of the most common complications in diabetes mellitusand affects 40 of all diabetic patients [51] A comparativestudy was carried out by Cheng et al (2004) [67] to elucidatethe hypolipidemic effect of crude PP and polyphenolicextract Male Sprague-Dawley (SD) rats were fed with a high-fat diet to induce hyperlipidemia and the treatment wascarried out for 28 days The results revealed decrease in thelevels of TCHDL-c ratio and serum LDL-c levels concludingPP polyphenolic extract is effective in lowering serum andhepatic lipids (Table 6)

44 Hepatoprotective Effects Recent in vivo animal studieshave evaluated the hepatoprotective effects of pomegranatehowever the exact mechanism and significant compoundshave not yet been described

The effects of continuous administration of PP on experi-mentally induced liver fibrosis in rats have been examined byToklu et al [68] The levels of serum aspartate aminotrans-ferase (AST) lactate dehydrogenase (LDH) and alanineaminotransferase (ALT) were ascertained in order to evaluateliver functions and the amount of tissue damage The ASTLDH ALT and cytokine levels in the serum which were ele-vated in liver fibrosis models were found to be considerablyreduced and brought to near-normal levels after PP treat-ment Similarly the increase in hepatic collagen levels wasalso diminished leading to an improvement in the structureand functions of the liver It was thus ascertained that PPpossesses certain hepato-protective properties making it animportant therapeutic agent in the treatment of fibrosis andoxidative damage [68 69]

Previous work showed that feeding of rats with PP pro-vided protective effect against carbon tetra chloride (CCl

4)

toxicity [55] Studies in rats with CCl4-induced liver damage

Evidence-Based Complementary and Alternative Medicine 7

Table 6 Overview of in vivo Punica peel studies for diabetes and its complications

Preclinicaltrial In vivo studies Dayweek

Nature of peelextractdosages(per kg BWday)

OutcomeStatisticallysignificantresults

Reference

Diabetes Albino Wistar rats 284 Aqueous042 gLowering of blood sugarlevel and increased numberof 120573 cells

Yes [47]

Diabetes Albino Wistar rats 1013 Methanolic200mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [48]

Diabetes Albino Wistar rats 1523 Methanolic200mg

Improvement of hepaticcardiac and renal LPO andserum T3 T4 insulin andglucose concentrations

Yes [49]

Hyperlipidemic Sprague-Dawley rats 287 Methanolic510 15

Reduction of totalcholesterolLDL-cholesteroltriglyceridesVLDL-cholesterol H

Yes [50]

Diabetes Albino Wistar rats 287 Methanolic10mg20mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [50]

Diabetes Albino Wistar rats 426 Methanolic75mgand 150mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidase and decreasedLPO level in hippocampaland cortex region of brain

Yes [8]

Diabetes Albino Wistar rats 213 Methanolic200mgand 400mg

Reduction of aldosereductase amylase PTP1Binhibition assay

Yes [32]

demonstrated pretreatment with PP enhanced or maintainedthe free radical scavenging activity of the hepatic enzymescatalase superoxide dismutase and peroxidase and resultedin 54 reduction of lipid peroxidation values compared tocontrols confirming the antioxidant property of the PP [50]

A discrete investigation in rats with CCl4-induced liver

damage demonstrated pretreatment with PP extract boostedthe free radical scavenging activity of the hepatic enzymessuperoxide dismutase and catalase and showed 54 declinein lipid peroxidation as compared to controls [69]

Hepatocellular carcinoma (HCC) a common and fatalcancer is majorly driven by oxidative stress The effect ofpomegranate emulsion (PE) on DENA-induced hepatocar-cinogenesis which mimics HCC in humans was examinedin an animal model Robust chemopreventive activities werereported owing to reduction in the incidence size volume

and multiplicity of the hepatic nodules In addition PE alsoalleviated lipid peroxidation and oxidation of proteins in theliver The report thus suggests and supports the use of pome-granate-derived agents in the treatment and prevention ofHCC in humans [70]

5 Mechanisms of Action

A recent study by Jain et al [32] has shown the probablemechanism of action of PP They have isolated and purifieda compound Valoneic acid dilactone (VAD) from the meth-anolic extract of Punica granatum (MEPG) MEPG-(400370mgkg po) and VAD-(25 50mgkg po) treated groupshave shown very minimal acinar damage and adequatenumber of pancreatic islets Their findings suggest that somepancreatic 120573-cells are still surviving to exert their insulinreleasing effect In diabetic conditionweight loss arises due to

8 Evidence-Based Complementary and Alternative Medicine

the impairment in insulin action in the conversion of glucoseinto glycogen The catabolism of fats does not occur as thereis an inhibition of lipolysis due to its unavailability whichis because of destruction in beta cells VAD and MEPGwere found to inhibit the alpha amylase activity which isa carbohydrate-hydrolysing enzyme thus decreases post-prandial hyperglycemia and improves glucose metabolismThe extracts VAD and MEPG were found to inhibit PTP1Bactivity which showed increase in insulin receptor tyrosinephosphorylation which mimicked in vivo action of insulinthereby decreased plasma glucose levels in a dose-dependentmanner The findings of their studies such as blood glucoselevels oral glucose tolerance test body weight mortalityand histopathology were in correlation with each other andindicate that MEPG and VAD could be beneficial in man-agement of diabetes and associated complications VAD wasobserved to be amore powerful inhibitor of aldose reductase120572-amylase and protein tyrosine phosphatase PTP1B whencompared to MEPG because of its polyphenolic nature

6 Toxicity StudiesSafetyAdverse Effects

There are relatively none in vivo or in vitro studies reportingthe toxic or adverse effect of the PP on any of the mammaliansystem The LD

50of the aqueous extract of PP in mice was

found to be 1321 plusmn 15mgkg ip [71]

7 Conclusion

Industries have moved towards usage of naturally derivedcompounds biologics as they are easily extractable and canbe cultured in labs Amongst these sources ecofriendly[4] Punica granatum peel has showed effectiveness due tothe array of compounds present in it These compoundshave good antioxidant activity and also serve as excellentnutritional supplements This review highlights the workthat has been done in the recent past on the PP whichincludes anti-hyperglycemic [8] hepatoprotective [56] andanti-hyperlipidemic effects [67] These experiments haveshown productive results both in in vivo and in vitro domainsHence more labs are moving towards PP as a suitabletherapeutic agent in various diseases

8 Future Direction

Despite the documented roles in nutrition there are very fewphytochemical studies The actions of mechanism of thesecompounds are still not very clearly understood however itis predicted that the mechanisms are quite complicated sincethere may be numerous factors involved in it

There is a dearth in the field of pharmacodynamics andpharmacokinetics or safety aspects of the PP There havebeen very few studies pertaining to the molecular aspects ofPP which is clearly evident by the sequence of informationavailable in the public domains Even though PP is richin healing properties due to the lacunae in many aspectsthere is an urgent requirement for further investigations todelineate its precise mechanisms and possible therapeuticvalues particularly in the field of diabetes mellitus

Conflict of Interest

The authors do not have any conflict of interest

Acknowledgments

The authors acknowledge (Dr) Dinesh Babu Ghent Uni-versity Belgium and Dr E L Cooper UCLA-CCIM LosAngeles CA USA for critically reviewing this paper Theauthors are thankful to Kumaun University Nainital and DrT L ShanthaDirectorMaharani LakshmiAmmanniCollegefor Women Bangalore India for providing the facilities tocarry out this review work

References

[1] J F Morton ldquoPomegranaterdquo in Fruits of Warm Climates pp352ndash355 ECHO Miami Fla USA 1987

[2] S K Middha Y Mittal T Usha et al ldquoPhyto-mellitus a phyto-chemical database for diabetesrdquoBioinformation vol 4 no 2 pp78ndash79 2009

[3] E Stover and E W Mercure ldquoThe pomegranate a new look atthe fruit of paradiserdquo HortScience vol 42 no 5 pp 1088ndash10922007

[4] A Shabtay H Eitam Y Tadmor et al ldquoNutritive and antiox-idative potential of fresh and stored pomegranate industrialbyproduct as a novel beef cattle feedrdquo Journal of Agricultural andFood Chemistry vol 56 no 21 pp 10063ndash10070 2008

[5] M Dikmen N Ozturk and Y Ozturk ldquoThe antioxidant poten-cy ofPunica granatum L fruit peel reduces cell proliferation andinduces apoptosis on breast cancerrdquo Journal of Medicinal Foodvol 14 no 12 pp 1638ndash1646 2011

[6] MYHongN P Seeram andDHeber ldquoPomegranate polyphe-nols down-regulate expression of androgen-synthesizing genesin human prostate cancer cells overexpressing the androgenreceptorrdquo Journal of Nutritional Biochemistry vol 19 no 12 pp848ndash855 2008

[7] J Jurenka ldquoTherapeutic applications of pomegranate (Punicagranatum L) a reviewrdquoAlternativeMedicine Review vol 13 no2 pp 128ndash144 2008

[8] S K Middha T Usha and T RaviKiran ldquoInfluence of Punicagranatum L on region specific responses in rat brain duringalloxan-induced diabetesrdquo Asian Pacific Journal of TropicalBiomedicine vol 2 no 2 pp S905ndashS909 2012

[9] M Viuda-Martos J Fernandez-Lopez and J A Perez-AlvarezldquoPomegranate and itsmany functional components as related tohuman health a reviewrdquoComprehensive Reviews in Food Scienceand Food Safety vol 9 no 2 pp 635ndash654 2010

[10] S R Kanatt R Chander and A Sharma ldquoAntioxidant andantimicrobial activity of pomegranate peel extract improves theshelf life of chicken productsrdquo International Journal of FoodScience and Technology vol 45 no 2 pp 216ndash222 2010

[11] E A Hayouni K Miled S Boubaker et al ldquoHydroalcoholicextract based-ointment from Punica granatum L peels withenhanced in vivo healing potential on dermal woundsrdquo Phy-tomedicine vol 18 no 11 pp 976ndash984 2011

[12] C N Aguilar A Aguilera-Carbo A Robledo et al ldquoProduc-tion of antioxidant nutraceutlcals by solid-state cultures ofpomegranate (Punica granatum) peel and creosote bush (Larreatridentata) leavesrdquo Food Technology and Biotechnology vol 46no 2 pp 218ndash222 2008

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 Evidence-Based Complementary and Alternative Medicine

Dental conditions

Ultraviolet (UV) radiation

Male infertility

Alzheimerrsquos disease

Obesity

Infant brainischemia

Antimicrobial

Hepatoprotective

Dermal

Anticancer

Antihyperglycemic

Cardiovasculardisease

Antineoplastic

Antiaging

Antifungal

Antilipidemic

Antiviral

Antiarthritics

Figure 1 Principal therapeutic effects of pomegranate peel

Table 1 Few commonly renowned vernacular names of Punicagranatum

Country Recognized nameRoman Carthage (Punica)

Italian Melogranato melogranogranato pomogranatoor pomopunico

Spanish Granada (the fruit) granado (the plant)Dutch GranaatappelFrench GrenadeGerman GranatapfelIndia Dadima or dalima or dalim or AnarPersian Dulim or dulimaGuatemala GranadIndonesia GangsalanSamoan LimoniBrazilian Roma romeira or romazeiraThailand Tab timMalaya Delima

In order to facilitate further investigation and utilizationwe summarized the research achievements on phyto-chemi-cal components that contribute for anti-hyperglycemic anti-lipidemic and hepato-protective effects of Punica granatumpeel waste till date

13 Proximate Physicochemical CompositionNutritional Val-ues of PP Studies have shown that PP is highly nutritiveand contains important raw materials like crude fibersprotein and carbohydrates The compositions of some of theingredients are tabulated in Table 2 [12]

Another study showed that the chemical composition ofpomegranate bagasse (the dried part of the fiber that remains

Table 2 Nutrient content of pomegranate peel per 100 g [12]

Composition ContentTotal solid 9450Moisture 540Total sugars 1770Reducing sugars 434Protein 490Crude fiber 1630Fat content 126Ash 340

once the juice is extracted) powder contains protein fat ashtotal dietary fiber insoluble dietary fiber and soluble dietaryfiber of 1094 2086 255 5029 3041 and 1988 g100 grespectively [13] However the quantification of many com-ponents such as vitamins minerals and other pharmacolog-ical properties has to be evaluated in detail

2 PhytochemicalsActive Constituents

During the ancient era significant efforts and progress weremade in establishing the pharmacological mechanisms of PPand the individual constituents responsible for them PP isknown to possess diverse phytochemicals most of which areobserved to have therapeutic properties The major chemicalconstituents along with their bioactivity are tabulated inTable 3 Figure 2 depicts the structure of all these chemicalconstituents of Table 3

Punicalin and punicalagin are the major constituentsof pericarp ranging up to 02 of the total amount Thebrilliant red colour of peel is attributed to anthocyanidinsand flavan-3-ols Flavones and flavonols constitute the majorflavonoids of peelThemethanolic extract of dried PP showed

Evidence-Based Complementary and Alternative Medicine 3

Table 3 Active constituents and their biological activity of Punica peel

Compound Bioactivity ReferenceMajor tannins of pomegranate peel

Casuarinin Antiviral antioxidant [14]Corilagin Antihypertensive antineoplastic [14ndash16]Ellagic acid [EA] Antineoplastic skin whitening [17 18]Gallic acid Antimutagenic anti-inflammatory antiviral antioxidant [17 19]Methyl gallate Antioxidant [20]Granatin A Antioxidant anti-inflammatory [21]Granatin B Antioxidant anti-inflammatory [21 22]Pedunculagin Antineoplastic antioxidant [14]Punicalagin Antioxidant antihypertensive anti-hyperglycemic [22ndash24]Punicalin Antioxidant anti HIV anti-hyperglycemic [21ndash23]

Major flavonoids of pomegranate peelCatechin Antineoplastic antioxidant [25]Cyanidin Antioxidant [26]Epicatechin Antineoplastic [25]Epigallocatechin 3-gallate Antineoplastic [25]Flavan-3-ol Antineoplastic [25]Kaempferol Antioxidant anti-inflammatory [27]Kaempferol-3-0-glucoside Antioxidant [27]Kaempferol-3-0-rhamnoglycoside Antihypertensive [27]Luteolin Antioxidant antioxidant [27]Luteolin-7-0-glucoside Antioxidant [27]Naringin Antiviral antibacterial [28]Pelargonidin Antiviral antibacterial [26]Quercetin Antiviral antioxidant antineoplastic [29]Rutin Antiviral antioxidant antihypertensive [29]

Major alkaloids of pomegranate peelPelletierine Antioxidant [30 31]Valoneic acid dilactone Antidiabetic [32]

the presence of high content of phenolic compounds (440)along with other constituents [34] Phenolic acids such ascaffeic acid fumaric acid chlorogenic acid and p-coumaricacid are present in the pericarp [17] The amount of ellagicacid in fruit peel of 12 varieties examined by Akbarpour et al[33] fluctuates considerably with a maximum of 50mg100 g(Syah-e-saveh) and a minimum of 10mg100 g (Rabbab andShishe-Kap) (Table 4) Gil et al [23] reported that the amountof total phenolics in peel was evidently higher than arils ofpomegranate fruit [33 35]

BenNasr et al [36] have described that PP has ellagic acid(EA) ellagitannins and gallic acid PP contains hydroxyben-zoic acids such as gallagic acid EA and EA glycosides [17]Anthocyanidins are principally cyanidin pelargonidin anddelphinidin [26] and flavonoids such as kaempferol luteolinand quercetin [27] Murthy et al [37] quantified methanolicextract of PP using HPLC and reported the presence of gallicacid (3403) and catechin (331)

Studies on PP were undertaken to investigate the changesin the major chemical composition during fruit maturationin two Israeli commercial varieties ldquoWonderfulrdquo and ldquoRosh-Haperedrdquo The result of the study revealed the levels of total

phenolic antioxidant activity and hydrolysable tannins werereduced during maturation while the anthocyanin levelincreased This knowledge could help establish the optimumharvest date ensuring the maximum nutritional properties ofPP [38] The results of Turkish researchers showed that thelevels of total phenolic compounds changed depending oncultivars and fruit parts In all cultivars the highest levels oftotal phenolic content were obtained from the peel extracts

3 Physical Properties

Twelve pomegranate (Punica granatum L) cultivars fromdifferent regions of Iranwere analyzed for their physical prop-erties by Akbarpour et al [33] The amount of EA ranged 10ndash50mg100 g in different varieties of PP The highest amountof EA was found in Syah-e-Saveh variety (50mg100 g)

4 Validated PharmacologicalProperties of Pomegranate Peel

41 Antioxidant Activity Superfluous generation of the freeradicals is proved to instigate and aggravate many human

4 Evidence-Based Complementary and Alternative Medicine

HO

HO

HO

HO

HO

O

OH

OHOH

OH

OHOH

OH OH

OH

OH

OH

HO

HO

HOHO

HO

HO

HO

HO

HO

HO

O

O

O

O

O

O

O

HCl

HCl

HO

O

OH

O

OO O

OO

OH

OHOH

OH

OH OHOH OH

OH OHOH

OH

OH

OH

OHOH

OH

HO

HO

HO

HO

HO

HOH3C

O+

O+

OHOH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

OH

HO HOHO

HO

O

O OO

O

O

O

HO

HO

HO

OO

OO

O

HO OH

OH

HOOCOH

OHOH

OHOH

OH

OH

OH

OH

OH

OH OH OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

CH

C C

3

CH3

O

O

O

O O

O

O

OO

O

O

OOOO

O

O

OO O

O

O

HO

HO

OO

OO

OH

OHCH2OH

O O

O O

O

O

O

O

OO

O

O

O

OO

O

O O O

O

OO

OOOO

O O

HO

HO HO

HO

HO

HOHO

HO

HO

HOHO

HO

HO

HO

HO

HO

HOHO

HO

HO

HO OH

OH

OHOH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH OH

OH

O

O O

OO

OO

O

OO

HO

HO

HO

HO

HO

HOHO

HO

HO

OHOH

OH

OH

OH

OH

OH

OOO

O

O

OO

O

O

OOO

O

HO

HO

HOHO

HO

HO

OH

OHOH

OHOH

OH

OH

OH

OH

OHOH

CH2

OHOH

OHOH

OH

OH

OH

OH

OH

OH

OH

HO

HO

O

O O

O O

O

O

O

C

Valoneic acid dilactone (VAD)

Naringin Quercetin-7-rhamnoside Methyl gallate

Epigallocatechin-3-gallate(EGCG)

Ellagic acid (EA)

PedunculaginKaempferol-3-glucoside

Flavan 3-ol

Rutin Cyanidin Catechin

Pelargonidin

Tellimagrandin IIPunicalin Corilagin

Luteolin

Gallagic acid Hexahydroxydiphenic acid Punicalagins

Epicatechin (EC) Epigallocatechin (EGC) Epicatechin-3-gallate (ECG)

Quercetin Gallic acid

Proanthocyanidin

Figure 2 Structures of polyphenolic compounds found in pomegranate peel (Punica granatum) (figures were sketched using ChemSketchsoftware alias Marvin Sketch)

Evidence-Based Complementary and Alternative Medicine 5

Table 4 Amount of EA in different varieties of peel [33]

S no Variety Thickness(mm)

Antioxidant activity(mmol100 g)

Amount of ellagic acid(mg100 g)

1 Rabbab 601 22967 10002 Malas-e-Yazd 406 23433 30003 Malas-e-Saveh 192 44050 20004 Shishe-Kap 253 30383 10005 Khazar-e-Bardeskan 210 64017 25006 Naderi 291 22517 30007 Alak 262 46350 20008 Abdandan 213 28493 37759 TabriziPoost 257 37438 325010 Syah-e-Saveh 160 31489 500011 Syah-e-Badrood 233 32763 400012 Lamsari-e-Behshahr 1727 70550 4500

ailments like arthritis cancer Alzheimerrsquos disease Parkin-sonrsquos disease AIDS and diabetic complications [51 52]Reports indicate that plants rich in anthocyanin flavonoidsand polyphenols are observed to be effective in scavengingthe free radicals [53 54] Total antioxidant activity of 12different varieties was determined by FRAP (ferric reducingantioxidant power) method described by Akbarpour etal are enlisted in Table 4 and it ranged from 22517 to70550mmolg According to Akbarpour et al [33] study thehighest antioxidant activity level was detected in ldquoLamsari-e-Behshahrrdquo and the lowest in ldquoNaderirdquo The same study hasrevealed that the antioxidant activity of peel is higher thanthat of juice and this difference is attributed to the presenceof pomegranate peel tannins [38]

The first report on antioxidant property of PP using invitro models was elucidated by Singh et al [55] The meth-anolic extract of peels showed 83 and 81 antioxidantactivity at 50 ppm using the 120573-carotene-linoleate and 22-diphenyl-2-picrylhydrazyl (DPPH) model systems respec-tively Similar group also showed 56 58 and 937 inhibitionusing the thiobarbituric acid (TBA)method hydroxyl radicalscavenging activity and serum low-density lipoprotein LDLoxidation respectively at 100 ppm [56] Owing to this prop-erty the studies can be further extended to exploit PP for theirpossible application in the preservation of food products aswell as their use as health supplements and nutraceuticals

Additional studies have also shown that PP had thehighest antioxidant activity among the peel pulp and seedfractions of 28 kinds of fruits commonly consumed in Chinaas determined by FRAP assay [57] A mixture of ethanolicmethanolic and acetone PP extract had markedly higherantioxidant capacity than the pulp extract in scavengingcapacity against superoxide anion hydroxyl and peroxylradicals as well as inhibiting CuSO

4-induced LDL oxidation

The contents of total phenolics flavonoids and Proantho-cyanidinswere also higher in peel extract than in pulp extractThe large amount of phenolics contained in peel extract maycontribute to its strong antioxidant ability [46]

Al-Mustafa and Al-Thunibat [58] have revealed the anti-oxidant activity of some Jordanian medicinal plants usedtraditionally for treatment of diabetes They were catego-rized PP under high antioxidant potential plantsThe activityinvestigated in methanolic and aqueous extract was DPPH-TEAC IC

50365 plusmn 50mggGAE 221015840-azinobis-(3-ethylben-

zothiazoline-6-sulfonic acid) (ABTS)-IC50

69 plusmn 01 120583gmLand DPPH-TEAC IC

502671 plusmn 35mggGAE and ABTS+-

IC5098 plusmn 01 120583gmL respectively Among all the plants cho-

sen by traditional healers methanolic and aqueous extractsof PP both were having potent radical scavenging activityMethanolic extract of PP exhibited the highest phenoliccontent (103GAEmgg) among all their experimental plants

In a recent study [59] the antioxidant activity of meth-anolic extract of PP on brain of normal rats demonstratedthat it reduced lipid peroxidation and nitric oxide in bothserum and brain tissue homogenate having an effect onthe scavenging capacity of superoxide anion and hydrogenperoxide

Pan et al [60] described a continuous (CUAE) and pulsedultrasound-assisted (PUAE) method for the extractions ofantioxidants from PP since there is a great demand for devel-oping efficient extraction methods in order to reduce extrac-tion time and increase the yield and activity of functionalantioxidants Cumulatively all these observations suggest thepotential antioxidant activity of PP (Table 5)

42 Antihyperglycemic Effect Over the past decade sig-nificant progress has been made in establishing the anti-hyperglycemic pharmacological mechanism of PP and theindividual compounds responsible for it Various solventextracts of PP appear to have anti-diabetic property Ontheir Jordanian medicinal plants survey native authors haverevealed 61 traditional healers recommend PP for diabetestreatment [58] Similar kind of studies done by the authorsin India also revealed the uses of PP by traditional healers(vaidya) (49) and anti-hyperglycemic effect using in vitroglucose oxidase method [61]

6 Evidence-Based Complementary and Alternative Medicine

Table 5 Overview of antioxidant pomegranate studies

Assays Effect ReferenceTrolox Equivalent AntioxidantConcentration (TEAC) Aqueous extract Prodelphinidinshowed active antioxidant activity [39]

Phospho-molybdenum complex Methanolic extract revealed lowest antioxidant activity followed by ethyl acetateacetone and water extract [40]

DPPH and ABTS radicals Remarkable free radical-scavenging power [41]DPPH and ABTS radicals Robust antioxidant activity [42]DPPH and ABTS radicals Extraordinary free radical-scavenging power [43]FRAP Peel had superior antioxidant activity than pulp and seed [44]FRAP Seed exhibited lower antioxidant activity as compared to peels [45]

DPPH and ABTS radicals Methanolic extract of PP exhibited the highest phenolic content and freeradical-scavenging power [46]

The first report on the antidiabetic properties of PP usingan in vivomodel was elucidated by Nogueira and Pereira fol-lowed by Zafar and Singh and Nozire and Serpil reproducedby several other studies [47ndash50 62ndash66]

Diabetic rats treated with 043 gkg BW of aqueous peelextract for four weeks displayed significantly lowered bloodsugar level and increased number of 120573 cells which relativelyhelp in intensification of insulin level [47] The mechanis-tic anti-diabetic activity of the extract is by stimulationregeneration and increased number of 120573 cells by protectingpancreatic tissue and subsequent release of insulin Alsoit may increase the stimulation and activation of insulinreceptor [47]

Oral administration of aqueous extract of PP at dosesof 50 and 100mgkg for 21 days brought down the fastingblood glucose total serum cholesterol (TC) triglycerides(TG) serum low density lipoprotein cholesterol (LDL-c)VLDL-C (very low-density lipoprotein cholesterol) and tissueLPO (lipid peroxidation) levels together with boost on high-density lipoprotein cholesterol (HDL-c) GSH (glutathione)content and antioxidant enzymes in contrast with diabeticcontrol groupThese authors recommended the uses of aque-ous extract of the peel as a dietary supplement in the cureand inhibition of chronic diseases categorized by aggravatedantioxidant status and diminished glucose metabolism [48]

The same group emphasized on oral administration ofthe aqueous-ethanolic extract of PP which led to signifi-cant blood glucose lowering effect in normal glucose-fedhyperglycemic in their another report on alloxan-induceddiabetic rats This report suggested that the effect can be dueto increased peripheral glucose utilization or retardation ofintestinal glucose absorption may also be partly responsiblefor inhibition of hyperglycaemia in glucose-fed rats [49]

Althunibat et al [50] had shown in their study on STZ-(streptozotocin-) induced diabetic rats that intraperitoneal(ip) administration of 10 and 20mgkg BW of PP for fourweeks significantly enhanced the activities of antioxidantenzymes in liver kidney and RBC The methanolic extractof PP (75 and 150mgkg daily) inhibits glucose level inalloxan-induced diabetic wistar rats The extract also causeda significant reduction in malondialdehyde (MDA) a lipidperoxides marker in diabetic rat tissues and elevated the total

serum antioxidant capacity in a dose-dependent mannerPhytochemical investigation demonstrates that the gallic acidin the methanolic extract of peels is mainly responsible forthis activity [8] This group suggested that the effect may bedue to the presence of terpenoids such as ursolic acid andoleanolic acid which may help to scavenge the free radicalsgenerated during diabetes (Table 6)

43 Antihyperlipidemic Effect Alterations in lipid profile areone of the most common complications in diabetes mellitusand affects 40 of all diabetic patients [51] A comparativestudy was carried out by Cheng et al (2004) [67] to elucidatethe hypolipidemic effect of crude PP and polyphenolicextract Male Sprague-Dawley (SD) rats were fed with a high-fat diet to induce hyperlipidemia and the treatment wascarried out for 28 days The results revealed decrease in thelevels of TCHDL-c ratio and serum LDL-c levels concludingPP polyphenolic extract is effective in lowering serum andhepatic lipids (Table 6)

44 Hepatoprotective Effects Recent in vivo animal studieshave evaluated the hepatoprotective effects of pomegranatehowever the exact mechanism and significant compoundshave not yet been described

The effects of continuous administration of PP on experi-mentally induced liver fibrosis in rats have been examined byToklu et al [68] The levels of serum aspartate aminotrans-ferase (AST) lactate dehydrogenase (LDH) and alanineaminotransferase (ALT) were ascertained in order to evaluateliver functions and the amount of tissue damage The ASTLDH ALT and cytokine levels in the serum which were ele-vated in liver fibrosis models were found to be considerablyreduced and brought to near-normal levels after PP treat-ment Similarly the increase in hepatic collagen levels wasalso diminished leading to an improvement in the structureand functions of the liver It was thus ascertained that PPpossesses certain hepato-protective properties making it animportant therapeutic agent in the treatment of fibrosis andoxidative damage [68 69]

Previous work showed that feeding of rats with PP pro-vided protective effect against carbon tetra chloride (CCl

4)

toxicity [55] Studies in rats with CCl4-induced liver damage

Evidence-Based Complementary and Alternative Medicine 7

Table 6 Overview of in vivo Punica peel studies for diabetes and its complications

Preclinicaltrial In vivo studies Dayweek

Nature of peelextractdosages(per kg BWday)

OutcomeStatisticallysignificantresults

Reference

Diabetes Albino Wistar rats 284 Aqueous042 gLowering of blood sugarlevel and increased numberof 120573 cells

Yes [47]

Diabetes Albino Wistar rats 1013 Methanolic200mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [48]

Diabetes Albino Wistar rats 1523 Methanolic200mg

Improvement of hepaticcardiac and renal LPO andserum T3 T4 insulin andglucose concentrations

Yes [49]

Hyperlipidemic Sprague-Dawley rats 287 Methanolic510 15

Reduction of totalcholesterolLDL-cholesteroltriglyceridesVLDL-cholesterol H

Yes [50]

Diabetes Albino Wistar rats 287 Methanolic10mg20mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [50]

Diabetes Albino Wistar rats 426 Methanolic75mgand 150mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidase and decreasedLPO level in hippocampaland cortex region of brain

Yes [8]

Diabetes Albino Wistar rats 213 Methanolic200mgand 400mg

Reduction of aldosereductase amylase PTP1Binhibition assay

Yes [32]

demonstrated pretreatment with PP enhanced or maintainedthe free radical scavenging activity of the hepatic enzymescatalase superoxide dismutase and peroxidase and resultedin 54 reduction of lipid peroxidation values compared tocontrols confirming the antioxidant property of the PP [50]

A discrete investigation in rats with CCl4-induced liver

damage demonstrated pretreatment with PP extract boostedthe free radical scavenging activity of the hepatic enzymessuperoxide dismutase and catalase and showed 54 declinein lipid peroxidation as compared to controls [69]

Hepatocellular carcinoma (HCC) a common and fatalcancer is majorly driven by oxidative stress The effect ofpomegranate emulsion (PE) on DENA-induced hepatocar-cinogenesis which mimics HCC in humans was examinedin an animal model Robust chemopreventive activities werereported owing to reduction in the incidence size volume

and multiplicity of the hepatic nodules In addition PE alsoalleviated lipid peroxidation and oxidation of proteins in theliver The report thus suggests and supports the use of pome-granate-derived agents in the treatment and prevention ofHCC in humans [70]

5 Mechanisms of Action

A recent study by Jain et al [32] has shown the probablemechanism of action of PP They have isolated and purifieda compound Valoneic acid dilactone (VAD) from the meth-anolic extract of Punica granatum (MEPG) MEPG-(400370mgkg po) and VAD-(25 50mgkg po) treated groupshave shown very minimal acinar damage and adequatenumber of pancreatic islets Their findings suggest that somepancreatic 120573-cells are still surviving to exert their insulinreleasing effect In diabetic conditionweight loss arises due to

8 Evidence-Based Complementary and Alternative Medicine

the impairment in insulin action in the conversion of glucoseinto glycogen The catabolism of fats does not occur as thereis an inhibition of lipolysis due to its unavailability whichis because of destruction in beta cells VAD and MEPGwere found to inhibit the alpha amylase activity which isa carbohydrate-hydrolysing enzyme thus decreases post-prandial hyperglycemia and improves glucose metabolismThe extracts VAD and MEPG were found to inhibit PTP1Bactivity which showed increase in insulin receptor tyrosinephosphorylation which mimicked in vivo action of insulinthereby decreased plasma glucose levels in a dose-dependentmanner The findings of their studies such as blood glucoselevels oral glucose tolerance test body weight mortalityand histopathology were in correlation with each other andindicate that MEPG and VAD could be beneficial in man-agement of diabetes and associated complications VAD wasobserved to be amore powerful inhibitor of aldose reductase120572-amylase and protein tyrosine phosphatase PTP1B whencompared to MEPG because of its polyphenolic nature

6 Toxicity StudiesSafetyAdverse Effects

There are relatively none in vivo or in vitro studies reportingthe toxic or adverse effect of the PP on any of the mammaliansystem The LD

50of the aqueous extract of PP in mice was

found to be 1321 plusmn 15mgkg ip [71]

7 Conclusion

Industries have moved towards usage of naturally derivedcompounds biologics as they are easily extractable and canbe cultured in labs Amongst these sources ecofriendly[4] Punica granatum peel has showed effectiveness due tothe array of compounds present in it These compoundshave good antioxidant activity and also serve as excellentnutritional supplements This review highlights the workthat has been done in the recent past on the PP whichincludes anti-hyperglycemic [8] hepatoprotective [56] andanti-hyperlipidemic effects [67] These experiments haveshown productive results both in in vivo and in vitro domainsHence more labs are moving towards PP as a suitabletherapeutic agent in various diseases

8 Future Direction

Despite the documented roles in nutrition there are very fewphytochemical studies The actions of mechanism of thesecompounds are still not very clearly understood however itis predicted that the mechanisms are quite complicated sincethere may be numerous factors involved in it

There is a dearth in the field of pharmacodynamics andpharmacokinetics or safety aspects of the PP There havebeen very few studies pertaining to the molecular aspects ofPP which is clearly evident by the sequence of informationavailable in the public domains Even though PP is richin healing properties due to the lacunae in many aspectsthere is an urgent requirement for further investigations todelineate its precise mechanisms and possible therapeuticvalues particularly in the field of diabetes mellitus

Conflict of Interest

The authors do not have any conflict of interest

Acknowledgments

The authors acknowledge (Dr) Dinesh Babu Ghent Uni-versity Belgium and Dr E L Cooper UCLA-CCIM LosAngeles CA USA for critically reviewing this paper Theauthors are thankful to Kumaun University Nainital and DrT L ShanthaDirectorMaharani LakshmiAmmanniCollegefor Women Bangalore India for providing the facilities tocarry out this review work

References

[1] J F Morton ldquoPomegranaterdquo in Fruits of Warm Climates pp352ndash355 ECHO Miami Fla USA 1987

[2] S K Middha Y Mittal T Usha et al ldquoPhyto-mellitus a phyto-chemical database for diabetesrdquoBioinformation vol 4 no 2 pp78ndash79 2009

[3] E Stover and E W Mercure ldquoThe pomegranate a new look atthe fruit of paradiserdquo HortScience vol 42 no 5 pp 1088ndash10922007

[4] A Shabtay H Eitam Y Tadmor et al ldquoNutritive and antiox-idative potential of fresh and stored pomegranate industrialbyproduct as a novel beef cattle feedrdquo Journal of Agricultural andFood Chemistry vol 56 no 21 pp 10063ndash10070 2008

[5] M Dikmen N Ozturk and Y Ozturk ldquoThe antioxidant poten-cy ofPunica granatum L fruit peel reduces cell proliferation andinduces apoptosis on breast cancerrdquo Journal of Medicinal Foodvol 14 no 12 pp 1638ndash1646 2011

[6] MYHongN P Seeram andDHeber ldquoPomegranate polyphe-nols down-regulate expression of androgen-synthesizing genesin human prostate cancer cells overexpressing the androgenreceptorrdquo Journal of Nutritional Biochemistry vol 19 no 12 pp848ndash855 2008

[7] J Jurenka ldquoTherapeutic applications of pomegranate (Punicagranatum L) a reviewrdquoAlternativeMedicine Review vol 13 no2 pp 128ndash144 2008

[8] S K Middha T Usha and T RaviKiran ldquoInfluence of Punicagranatum L on region specific responses in rat brain duringalloxan-induced diabetesrdquo Asian Pacific Journal of TropicalBiomedicine vol 2 no 2 pp S905ndashS909 2012

[9] M Viuda-Martos J Fernandez-Lopez and J A Perez-AlvarezldquoPomegranate and itsmany functional components as related tohuman health a reviewrdquoComprehensive Reviews in Food Scienceand Food Safety vol 9 no 2 pp 635ndash654 2010

[10] S R Kanatt R Chander and A Sharma ldquoAntioxidant andantimicrobial activity of pomegranate peel extract improves theshelf life of chicken productsrdquo International Journal of FoodScience and Technology vol 45 no 2 pp 216ndash222 2010

[11] E A Hayouni K Miled S Boubaker et al ldquoHydroalcoholicextract based-ointment from Punica granatum L peels withenhanced in vivo healing potential on dermal woundsrdquo Phy-tomedicine vol 18 no 11 pp 976ndash984 2011

[12] C N Aguilar A Aguilera-Carbo A Robledo et al ldquoProduc-tion of antioxidant nutraceutlcals by solid-state cultures ofpomegranate (Punica granatum) peel and creosote bush (Larreatridentata) leavesrdquo Food Technology and Biotechnology vol 46no 2 pp 218ndash222 2008

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Evidence-Based Complementary and Alternative Medicine 3

Table 3 Active constituents and their biological activity of Punica peel

Compound Bioactivity ReferenceMajor tannins of pomegranate peel

Casuarinin Antiviral antioxidant [14]Corilagin Antihypertensive antineoplastic [14ndash16]Ellagic acid [EA] Antineoplastic skin whitening [17 18]Gallic acid Antimutagenic anti-inflammatory antiviral antioxidant [17 19]Methyl gallate Antioxidant [20]Granatin A Antioxidant anti-inflammatory [21]Granatin B Antioxidant anti-inflammatory [21 22]Pedunculagin Antineoplastic antioxidant [14]Punicalagin Antioxidant antihypertensive anti-hyperglycemic [22ndash24]Punicalin Antioxidant anti HIV anti-hyperglycemic [21ndash23]

Major flavonoids of pomegranate peelCatechin Antineoplastic antioxidant [25]Cyanidin Antioxidant [26]Epicatechin Antineoplastic [25]Epigallocatechin 3-gallate Antineoplastic [25]Flavan-3-ol Antineoplastic [25]Kaempferol Antioxidant anti-inflammatory [27]Kaempferol-3-0-glucoside Antioxidant [27]Kaempferol-3-0-rhamnoglycoside Antihypertensive [27]Luteolin Antioxidant antioxidant [27]Luteolin-7-0-glucoside Antioxidant [27]Naringin Antiviral antibacterial [28]Pelargonidin Antiviral antibacterial [26]Quercetin Antiviral antioxidant antineoplastic [29]Rutin Antiviral antioxidant antihypertensive [29]

Major alkaloids of pomegranate peelPelletierine Antioxidant [30 31]Valoneic acid dilactone Antidiabetic [32]

the presence of high content of phenolic compounds (440)along with other constituents [34] Phenolic acids such ascaffeic acid fumaric acid chlorogenic acid and p-coumaricacid are present in the pericarp [17] The amount of ellagicacid in fruit peel of 12 varieties examined by Akbarpour et al[33] fluctuates considerably with a maximum of 50mg100 g(Syah-e-saveh) and a minimum of 10mg100 g (Rabbab andShishe-Kap) (Table 4) Gil et al [23] reported that the amountof total phenolics in peel was evidently higher than arils ofpomegranate fruit [33 35]

BenNasr et al [36] have described that PP has ellagic acid(EA) ellagitannins and gallic acid PP contains hydroxyben-zoic acids such as gallagic acid EA and EA glycosides [17]Anthocyanidins are principally cyanidin pelargonidin anddelphinidin [26] and flavonoids such as kaempferol luteolinand quercetin [27] Murthy et al [37] quantified methanolicextract of PP using HPLC and reported the presence of gallicacid (3403) and catechin (331)

Studies on PP were undertaken to investigate the changesin the major chemical composition during fruit maturationin two Israeli commercial varieties ldquoWonderfulrdquo and ldquoRosh-Haperedrdquo The result of the study revealed the levels of total

phenolic antioxidant activity and hydrolysable tannins werereduced during maturation while the anthocyanin levelincreased This knowledge could help establish the optimumharvest date ensuring the maximum nutritional properties ofPP [38] The results of Turkish researchers showed that thelevels of total phenolic compounds changed depending oncultivars and fruit parts In all cultivars the highest levels oftotal phenolic content were obtained from the peel extracts

3 Physical Properties

Twelve pomegranate (Punica granatum L) cultivars fromdifferent regions of Iranwere analyzed for their physical prop-erties by Akbarpour et al [33] The amount of EA ranged 10ndash50mg100 g in different varieties of PP The highest amountof EA was found in Syah-e-Saveh variety (50mg100 g)

4 Validated PharmacologicalProperties of Pomegranate Peel

41 Antioxidant Activity Superfluous generation of the freeradicals is proved to instigate and aggravate many human

4 Evidence-Based Complementary and Alternative Medicine

HO

HO

HO

HO

HO

O

OH

OHOH

OH

OHOH

OH OH

OH

OH

OH

HO

HO

HOHO

HO

HO

HO

HO

HO

HO

O

O

O

O

O

O

O

HCl

HCl

HO

O

OH

O

OO O

OO

OH

OHOH

OH

OH OHOH OH

OH OHOH

OH

OH

OH

OHOH

OH

HO

HO

HO

HO

HO

HOH3C

O+

O+

OHOH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

OH

HO HOHO

HO

O

O OO

O

O

O

HO

HO

HO

OO

OO

O

HO OH

OH

HOOCOH

OHOH

OHOH

OH

OH

OH

OH

OH

OH OH OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

CH

C C

3

CH3

O

O

O

O O

O

O

OO

O

O

OOOO

O

O

OO O

O

O

HO

HO

OO

OO

OH

OHCH2OH

O O

O O

O

O

O

O

OO

O

O

O

OO

O

O O O

O

OO

OOOO

O O

HO

HO HO

HO

HO

HOHO

HO

HO

HOHO

HO

HO

HO

HO

HO

HOHO

HO

HO

HO OH

OH

OHOH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH OH

OH

O

O O

OO

OO

O

OO

HO

HO

HO

HO

HO

HOHO

HO

HO

OHOH

OH

OH

OH

OH

OH

OOO

O

O

OO

O

O

OOO

O

HO

HO

HOHO

HO

HO

OH

OHOH

OHOH

OH

OH

OH

OH

OHOH

CH2

OHOH

OHOH

OH

OH

OH

OH

OH

OH

OH

HO

HO

O

O O

O O

O

O

O

C

Valoneic acid dilactone (VAD)

Naringin Quercetin-7-rhamnoside Methyl gallate

Epigallocatechin-3-gallate(EGCG)

Ellagic acid (EA)

PedunculaginKaempferol-3-glucoside

Flavan 3-ol

Rutin Cyanidin Catechin

Pelargonidin

Tellimagrandin IIPunicalin Corilagin

Luteolin

Gallagic acid Hexahydroxydiphenic acid Punicalagins

Epicatechin (EC) Epigallocatechin (EGC) Epicatechin-3-gallate (ECG)

Quercetin Gallic acid

Proanthocyanidin

Figure 2 Structures of polyphenolic compounds found in pomegranate peel (Punica granatum) (figures were sketched using ChemSketchsoftware alias Marvin Sketch)

Evidence-Based Complementary and Alternative Medicine 5

Table 4 Amount of EA in different varieties of peel [33]

S no Variety Thickness(mm)

Antioxidant activity(mmol100 g)

Amount of ellagic acid(mg100 g)

1 Rabbab 601 22967 10002 Malas-e-Yazd 406 23433 30003 Malas-e-Saveh 192 44050 20004 Shishe-Kap 253 30383 10005 Khazar-e-Bardeskan 210 64017 25006 Naderi 291 22517 30007 Alak 262 46350 20008 Abdandan 213 28493 37759 TabriziPoost 257 37438 325010 Syah-e-Saveh 160 31489 500011 Syah-e-Badrood 233 32763 400012 Lamsari-e-Behshahr 1727 70550 4500

ailments like arthritis cancer Alzheimerrsquos disease Parkin-sonrsquos disease AIDS and diabetic complications [51 52]Reports indicate that plants rich in anthocyanin flavonoidsand polyphenols are observed to be effective in scavengingthe free radicals [53 54] Total antioxidant activity of 12different varieties was determined by FRAP (ferric reducingantioxidant power) method described by Akbarpour etal are enlisted in Table 4 and it ranged from 22517 to70550mmolg According to Akbarpour et al [33] study thehighest antioxidant activity level was detected in ldquoLamsari-e-Behshahrrdquo and the lowest in ldquoNaderirdquo The same study hasrevealed that the antioxidant activity of peel is higher thanthat of juice and this difference is attributed to the presenceof pomegranate peel tannins [38]

The first report on antioxidant property of PP using invitro models was elucidated by Singh et al [55] The meth-anolic extract of peels showed 83 and 81 antioxidantactivity at 50 ppm using the 120573-carotene-linoleate and 22-diphenyl-2-picrylhydrazyl (DPPH) model systems respec-tively Similar group also showed 56 58 and 937 inhibitionusing the thiobarbituric acid (TBA)method hydroxyl radicalscavenging activity and serum low-density lipoprotein LDLoxidation respectively at 100 ppm [56] Owing to this prop-erty the studies can be further extended to exploit PP for theirpossible application in the preservation of food products aswell as their use as health supplements and nutraceuticals

Additional studies have also shown that PP had thehighest antioxidant activity among the peel pulp and seedfractions of 28 kinds of fruits commonly consumed in Chinaas determined by FRAP assay [57] A mixture of ethanolicmethanolic and acetone PP extract had markedly higherantioxidant capacity than the pulp extract in scavengingcapacity against superoxide anion hydroxyl and peroxylradicals as well as inhibiting CuSO

4-induced LDL oxidation

The contents of total phenolics flavonoids and Proantho-cyanidinswere also higher in peel extract than in pulp extractThe large amount of phenolics contained in peel extract maycontribute to its strong antioxidant ability [46]

Al-Mustafa and Al-Thunibat [58] have revealed the anti-oxidant activity of some Jordanian medicinal plants usedtraditionally for treatment of diabetes They were catego-rized PP under high antioxidant potential plantsThe activityinvestigated in methanolic and aqueous extract was DPPH-TEAC IC

50365 plusmn 50mggGAE 221015840-azinobis-(3-ethylben-

zothiazoline-6-sulfonic acid) (ABTS)-IC50

69 plusmn 01 120583gmLand DPPH-TEAC IC

502671 plusmn 35mggGAE and ABTS+-

IC5098 plusmn 01 120583gmL respectively Among all the plants cho-

sen by traditional healers methanolic and aqueous extractsof PP both were having potent radical scavenging activityMethanolic extract of PP exhibited the highest phenoliccontent (103GAEmgg) among all their experimental plants

In a recent study [59] the antioxidant activity of meth-anolic extract of PP on brain of normal rats demonstratedthat it reduced lipid peroxidation and nitric oxide in bothserum and brain tissue homogenate having an effect onthe scavenging capacity of superoxide anion and hydrogenperoxide

Pan et al [60] described a continuous (CUAE) and pulsedultrasound-assisted (PUAE) method for the extractions ofantioxidants from PP since there is a great demand for devel-oping efficient extraction methods in order to reduce extrac-tion time and increase the yield and activity of functionalantioxidants Cumulatively all these observations suggest thepotential antioxidant activity of PP (Table 5)

42 Antihyperglycemic Effect Over the past decade sig-nificant progress has been made in establishing the anti-hyperglycemic pharmacological mechanism of PP and theindividual compounds responsible for it Various solventextracts of PP appear to have anti-diabetic property Ontheir Jordanian medicinal plants survey native authors haverevealed 61 traditional healers recommend PP for diabetestreatment [58] Similar kind of studies done by the authorsin India also revealed the uses of PP by traditional healers(vaidya) (49) and anti-hyperglycemic effect using in vitroglucose oxidase method [61]

6 Evidence-Based Complementary and Alternative Medicine

Table 5 Overview of antioxidant pomegranate studies

Assays Effect ReferenceTrolox Equivalent AntioxidantConcentration (TEAC) Aqueous extract Prodelphinidinshowed active antioxidant activity [39]

Phospho-molybdenum complex Methanolic extract revealed lowest antioxidant activity followed by ethyl acetateacetone and water extract [40]

DPPH and ABTS radicals Remarkable free radical-scavenging power [41]DPPH and ABTS radicals Robust antioxidant activity [42]DPPH and ABTS radicals Extraordinary free radical-scavenging power [43]FRAP Peel had superior antioxidant activity than pulp and seed [44]FRAP Seed exhibited lower antioxidant activity as compared to peels [45]

DPPH and ABTS radicals Methanolic extract of PP exhibited the highest phenolic content and freeradical-scavenging power [46]

The first report on the antidiabetic properties of PP usingan in vivomodel was elucidated by Nogueira and Pereira fol-lowed by Zafar and Singh and Nozire and Serpil reproducedby several other studies [47ndash50 62ndash66]

Diabetic rats treated with 043 gkg BW of aqueous peelextract for four weeks displayed significantly lowered bloodsugar level and increased number of 120573 cells which relativelyhelp in intensification of insulin level [47] The mechanis-tic anti-diabetic activity of the extract is by stimulationregeneration and increased number of 120573 cells by protectingpancreatic tissue and subsequent release of insulin Alsoit may increase the stimulation and activation of insulinreceptor [47]

Oral administration of aqueous extract of PP at dosesof 50 and 100mgkg for 21 days brought down the fastingblood glucose total serum cholesterol (TC) triglycerides(TG) serum low density lipoprotein cholesterol (LDL-c)VLDL-C (very low-density lipoprotein cholesterol) and tissueLPO (lipid peroxidation) levels together with boost on high-density lipoprotein cholesterol (HDL-c) GSH (glutathione)content and antioxidant enzymes in contrast with diabeticcontrol groupThese authors recommended the uses of aque-ous extract of the peel as a dietary supplement in the cureand inhibition of chronic diseases categorized by aggravatedantioxidant status and diminished glucose metabolism [48]

The same group emphasized on oral administration ofthe aqueous-ethanolic extract of PP which led to signifi-cant blood glucose lowering effect in normal glucose-fedhyperglycemic in their another report on alloxan-induceddiabetic rats This report suggested that the effect can be dueto increased peripheral glucose utilization or retardation ofintestinal glucose absorption may also be partly responsiblefor inhibition of hyperglycaemia in glucose-fed rats [49]

Althunibat et al [50] had shown in their study on STZ-(streptozotocin-) induced diabetic rats that intraperitoneal(ip) administration of 10 and 20mgkg BW of PP for fourweeks significantly enhanced the activities of antioxidantenzymes in liver kidney and RBC The methanolic extractof PP (75 and 150mgkg daily) inhibits glucose level inalloxan-induced diabetic wistar rats The extract also causeda significant reduction in malondialdehyde (MDA) a lipidperoxides marker in diabetic rat tissues and elevated the total

serum antioxidant capacity in a dose-dependent mannerPhytochemical investigation demonstrates that the gallic acidin the methanolic extract of peels is mainly responsible forthis activity [8] This group suggested that the effect may bedue to the presence of terpenoids such as ursolic acid andoleanolic acid which may help to scavenge the free radicalsgenerated during diabetes (Table 6)

43 Antihyperlipidemic Effect Alterations in lipid profile areone of the most common complications in diabetes mellitusand affects 40 of all diabetic patients [51] A comparativestudy was carried out by Cheng et al (2004) [67] to elucidatethe hypolipidemic effect of crude PP and polyphenolicextract Male Sprague-Dawley (SD) rats were fed with a high-fat diet to induce hyperlipidemia and the treatment wascarried out for 28 days The results revealed decrease in thelevels of TCHDL-c ratio and serum LDL-c levels concludingPP polyphenolic extract is effective in lowering serum andhepatic lipids (Table 6)

44 Hepatoprotective Effects Recent in vivo animal studieshave evaluated the hepatoprotective effects of pomegranatehowever the exact mechanism and significant compoundshave not yet been described

The effects of continuous administration of PP on experi-mentally induced liver fibrosis in rats have been examined byToklu et al [68] The levels of serum aspartate aminotrans-ferase (AST) lactate dehydrogenase (LDH) and alanineaminotransferase (ALT) were ascertained in order to evaluateliver functions and the amount of tissue damage The ASTLDH ALT and cytokine levels in the serum which were ele-vated in liver fibrosis models were found to be considerablyreduced and brought to near-normal levels after PP treat-ment Similarly the increase in hepatic collagen levels wasalso diminished leading to an improvement in the structureand functions of the liver It was thus ascertained that PPpossesses certain hepato-protective properties making it animportant therapeutic agent in the treatment of fibrosis andoxidative damage [68 69]

Previous work showed that feeding of rats with PP pro-vided protective effect against carbon tetra chloride (CCl

4)

toxicity [55] Studies in rats with CCl4-induced liver damage

Evidence-Based Complementary and Alternative Medicine 7

Table 6 Overview of in vivo Punica peel studies for diabetes and its complications

Preclinicaltrial In vivo studies Dayweek

Nature of peelextractdosages(per kg BWday)

OutcomeStatisticallysignificantresults

Reference

Diabetes Albino Wistar rats 284 Aqueous042 gLowering of blood sugarlevel and increased numberof 120573 cells

Yes [47]

Diabetes Albino Wistar rats 1013 Methanolic200mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [48]

Diabetes Albino Wistar rats 1523 Methanolic200mg

Improvement of hepaticcardiac and renal LPO andserum T3 T4 insulin andglucose concentrations

Yes [49]

Hyperlipidemic Sprague-Dawley rats 287 Methanolic510 15

Reduction of totalcholesterolLDL-cholesteroltriglyceridesVLDL-cholesterol H

Yes [50]

Diabetes Albino Wistar rats 287 Methanolic10mg20mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [50]

Diabetes Albino Wistar rats 426 Methanolic75mgand 150mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidase and decreasedLPO level in hippocampaland cortex region of brain

Yes [8]

Diabetes Albino Wistar rats 213 Methanolic200mgand 400mg

Reduction of aldosereductase amylase PTP1Binhibition assay

Yes [32]

demonstrated pretreatment with PP enhanced or maintainedthe free radical scavenging activity of the hepatic enzymescatalase superoxide dismutase and peroxidase and resultedin 54 reduction of lipid peroxidation values compared tocontrols confirming the antioxidant property of the PP [50]

A discrete investigation in rats with CCl4-induced liver

damage demonstrated pretreatment with PP extract boostedthe free radical scavenging activity of the hepatic enzymessuperoxide dismutase and catalase and showed 54 declinein lipid peroxidation as compared to controls [69]

Hepatocellular carcinoma (HCC) a common and fatalcancer is majorly driven by oxidative stress The effect ofpomegranate emulsion (PE) on DENA-induced hepatocar-cinogenesis which mimics HCC in humans was examinedin an animal model Robust chemopreventive activities werereported owing to reduction in the incidence size volume

and multiplicity of the hepatic nodules In addition PE alsoalleviated lipid peroxidation and oxidation of proteins in theliver The report thus suggests and supports the use of pome-granate-derived agents in the treatment and prevention ofHCC in humans [70]

5 Mechanisms of Action

A recent study by Jain et al [32] has shown the probablemechanism of action of PP They have isolated and purifieda compound Valoneic acid dilactone (VAD) from the meth-anolic extract of Punica granatum (MEPG) MEPG-(400370mgkg po) and VAD-(25 50mgkg po) treated groupshave shown very minimal acinar damage and adequatenumber of pancreatic islets Their findings suggest that somepancreatic 120573-cells are still surviving to exert their insulinreleasing effect In diabetic conditionweight loss arises due to

8 Evidence-Based Complementary and Alternative Medicine

the impairment in insulin action in the conversion of glucoseinto glycogen The catabolism of fats does not occur as thereis an inhibition of lipolysis due to its unavailability whichis because of destruction in beta cells VAD and MEPGwere found to inhibit the alpha amylase activity which isa carbohydrate-hydrolysing enzyme thus decreases post-prandial hyperglycemia and improves glucose metabolismThe extracts VAD and MEPG were found to inhibit PTP1Bactivity which showed increase in insulin receptor tyrosinephosphorylation which mimicked in vivo action of insulinthereby decreased plasma glucose levels in a dose-dependentmanner The findings of their studies such as blood glucoselevels oral glucose tolerance test body weight mortalityand histopathology were in correlation with each other andindicate that MEPG and VAD could be beneficial in man-agement of diabetes and associated complications VAD wasobserved to be amore powerful inhibitor of aldose reductase120572-amylase and protein tyrosine phosphatase PTP1B whencompared to MEPG because of its polyphenolic nature

6 Toxicity StudiesSafetyAdverse Effects

There are relatively none in vivo or in vitro studies reportingthe toxic or adverse effect of the PP on any of the mammaliansystem The LD

50of the aqueous extract of PP in mice was

found to be 1321 plusmn 15mgkg ip [71]

7 Conclusion

Industries have moved towards usage of naturally derivedcompounds biologics as they are easily extractable and canbe cultured in labs Amongst these sources ecofriendly[4] Punica granatum peel has showed effectiveness due tothe array of compounds present in it These compoundshave good antioxidant activity and also serve as excellentnutritional supplements This review highlights the workthat has been done in the recent past on the PP whichincludes anti-hyperglycemic [8] hepatoprotective [56] andanti-hyperlipidemic effects [67] These experiments haveshown productive results both in in vivo and in vitro domainsHence more labs are moving towards PP as a suitabletherapeutic agent in various diseases

8 Future Direction

Despite the documented roles in nutrition there are very fewphytochemical studies The actions of mechanism of thesecompounds are still not very clearly understood however itis predicted that the mechanisms are quite complicated sincethere may be numerous factors involved in it

There is a dearth in the field of pharmacodynamics andpharmacokinetics or safety aspects of the PP There havebeen very few studies pertaining to the molecular aspects ofPP which is clearly evident by the sequence of informationavailable in the public domains Even though PP is richin healing properties due to the lacunae in many aspectsthere is an urgent requirement for further investigations todelineate its precise mechanisms and possible therapeuticvalues particularly in the field of diabetes mellitus

Conflict of Interest

The authors do not have any conflict of interest

Acknowledgments

The authors acknowledge (Dr) Dinesh Babu Ghent Uni-versity Belgium and Dr E L Cooper UCLA-CCIM LosAngeles CA USA for critically reviewing this paper Theauthors are thankful to Kumaun University Nainital and DrT L ShanthaDirectorMaharani LakshmiAmmanniCollegefor Women Bangalore India for providing the facilities tocarry out this review work

References

[1] J F Morton ldquoPomegranaterdquo in Fruits of Warm Climates pp352ndash355 ECHO Miami Fla USA 1987

[2] S K Middha Y Mittal T Usha et al ldquoPhyto-mellitus a phyto-chemical database for diabetesrdquoBioinformation vol 4 no 2 pp78ndash79 2009

[3] E Stover and E W Mercure ldquoThe pomegranate a new look atthe fruit of paradiserdquo HortScience vol 42 no 5 pp 1088ndash10922007

[4] A Shabtay H Eitam Y Tadmor et al ldquoNutritive and antiox-idative potential of fresh and stored pomegranate industrialbyproduct as a novel beef cattle feedrdquo Journal of Agricultural andFood Chemistry vol 56 no 21 pp 10063ndash10070 2008

[5] M Dikmen N Ozturk and Y Ozturk ldquoThe antioxidant poten-cy ofPunica granatum L fruit peel reduces cell proliferation andinduces apoptosis on breast cancerrdquo Journal of Medicinal Foodvol 14 no 12 pp 1638ndash1646 2011

[6] MYHongN P Seeram andDHeber ldquoPomegranate polyphe-nols down-regulate expression of androgen-synthesizing genesin human prostate cancer cells overexpressing the androgenreceptorrdquo Journal of Nutritional Biochemistry vol 19 no 12 pp848ndash855 2008

[7] J Jurenka ldquoTherapeutic applications of pomegranate (Punicagranatum L) a reviewrdquoAlternativeMedicine Review vol 13 no2 pp 128ndash144 2008

[8] S K Middha T Usha and T RaviKiran ldquoInfluence of Punicagranatum L on region specific responses in rat brain duringalloxan-induced diabetesrdquo Asian Pacific Journal of TropicalBiomedicine vol 2 no 2 pp S905ndashS909 2012

[9] M Viuda-Martos J Fernandez-Lopez and J A Perez-AlvarezldquoPomegranate and itsmany functional components as related tohuman health a reviewrdquoComprehensive Reviews in Food Scienceand Food Safety vol 9 no 2 pp 635ndash654 2010

[10] S R Kanatt R Chander and A Sharma ldquoAntioxidant andantimicrobial activity of pomegranate peel extract improves theshelf life of chicken productsrdquo International Journal of FoodScience and Technology vol 45 no 2 pp 216ndash222 2010

[11] E A Hayouni K Miled S Boubaker et al ldquoHydroalcoholicextract based-ointment from Punica granatum L peels withenhanced in vivo healing potential on dermal woundsrdquo Phy-tomedicine vol 18 no 11 pp 976ndash984 2011

[12] C N Aguilar A Aguilera-Carbo A Robledo et al ldquoProduc-tion of antioxidant nutraceutlcals by solid-state cultures ofpomegranate (Punica granatum) peel and creosote bush (Larreatridentata) leavesrdquo Food Technology and Biotechnology vol 46no 2 pp 218ndash222 2008

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

4 Evidence-Based Complementary and Alternative Medicine

HO

HO

HO

HO

HO

O

OH

OHOH

OH

OHOH

OH OH

OH

OH

OH

HO

HO

HOHO

HO

HO

HO

HO

HO

HO

O

O

O

O

O

O

O

HCl

HCl

HO

O

OH

O

OO O

OO

OH

OHOH

OH

OH OHOH OH

OH OHOH

OH

OH

OH

OHOH

OH

HO

HO

HO

HO

HO

HOH3C

O+

O+

OHOH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

OH

HO HOHO

HO

O

O OO

O

O

O

HO

HO

HO

OO

OO

O

HO OH

OH

HOOCOH

OHOH

OHOH

OH

OH

OH

OH

OH

OH OH OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

CH

C C

3

CH3

O

O

O

O O

O

O

OO

O

O

OOOO

O

O

OO O

O

O

HO

HO

OO

OO

OH

OHCH2OH

O O

O O

O

O

O

O

OO

O

O

O

OO

O

O O O

O

OO

OOOO

O O

HO

HO HO

HO

HO

HOHO

HO

HO

HOHO

HO

HO

HO

HO

HO

HOHO

HO

HO

HO OH

OH

OHOH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH OH

OH

O

O O

OO

OO

O

OO

HO

HO

HO

HO

HO

HOHO

HO

HO

OHOH

OH

OH

OH

OH

OH

OOO

O

O

OO

O

O

OOO

O

HO

HO

HOHO

HO

HO

OH

OHOH

OHOH

OH

OH

OH

OH

OHOH

CH2

OHOH

OHOH

OH

OH

OH

OH

OH

OH

OH

HO

HO

O

O O

O O

O

O

O

C

Valoneic acid dilactone (VAD)

Naringin Quercetin-7-rhamnoside Methyl gallate

Epigallocatechin-3-gallate(EGCG)

Ellagic acid (EA)

PedunculaginKaempferol-3-glucoside

Flavan 3-ol

Rutin Cyanidin Catechin

Pelargonidin

Tellimagrandin IIPunicalin Corilagin

Luteolin

Gallagic acid Hexahydroxydiphenic acid Punicalagins

Epicatechin (EC) Epigallocatechin (EGC) Epicatechin-3-gallate (ECG)

Quercetin Gallic acid

Proanthocyanidin

Figure 2 Structures of polyphenolic compounds found in pomegranate peel (Punica granatum) (figures were sketched using ChemSketchsoftware alias Marvin Sketch)

Evidence-Based Complementary and Alternative Medicine 5

Table 4 Amount of EA in different varieties of peel [33]

S no Variety Thickness(mm)

Antioxidant activity(mmol100 g)

Amount of ellagic acid(mg100 g)

1 Rabbab 601 22967 10002 Malas-e-Yazd 406 23433 30003 Malas-e-Saveh 192 44050 20004 Shishe-Kap 253 30383 10005 Khazar-e-Bardeskan 210 64017 25006 Naderi 291 22517 30007 Alak 262 46350 20008 Abdandan 213 28493 37759 TabriziPoost 257 37438 325010 Syah-e-Saveh 160 31489 500011 Syah-e-Badrood 233 32763 400012 Lamsari-e-Behshahr 1727 70550 4500

ailments like arthritis cancer Alzheimerrsquos disease Parkin-sonrsquos disease AIDS and diabetic complications [51 52]Reports indicate that plants rich in anthocyanin flavonoidsand polyphenols are observed to be effective in scavengingthe free radicals [53 54] Total antioxidant activity of 12different varieties was determined by FRAP (ferric reducingantioxidant power) method described by Akbarpour etal are enlisted in Table 4 and it ranged from 22517 to70550mmolg According to Akbarpour et al [33] study thehighest antioxidant activity level was detected in ldquoLamsari-e-Behshahrrdquo and the lowest in ldquoNaderirdquo The same study hasrevealed that the antioxidant activity of peel is higher thanthat of juice and this difference is attributed to the presenceof pomegranate peel tannins [38]

The first report on antioxidant property of PP using invitro models was elucidated by Singh et al [55] The meth-anolic extract of peels showed 83 and 81 antioxidantactivity at 50 ppm using the 120573-carotene-linoleate and 22-diphenyl-2-picrylhydrazyl (DPPH) model systems respec-tively Similar group also showed 56 58 and 937 inhibitionusing the thiobarbituric acid (TBA)method hydroxyl radicalscavenging activity and serum low-density lipoprotein LDLoxidation respectively at 100 ppm [56] Owing to this prop-erty the studies can be further extended to exploit PP for theirpossible application in the preservation of food products aswell as their use as health supplements and nutraceuticals

Additional studies have also shown that PP had thehighest antioxidant activity among the peel pulp and seedfractions of 28 kinds of fruits commonly consumed in Chinaas determined by FRAP assay [57] A mixture of ethanolicmethanolic and acetone PP extract had markedly higherantioxidant capacity than the pulp extract in scavengingcapacity against superoxide anion hydroxyl and peroxylradicals as well as inhibiting CuSO

4-induced LDL oxidation

The contents of total phenolics flavonoids and Proantho-cyanidinswere also higher in peel extract than in pulp extractThe large amount of phenolics contained in peel extract maycontribute to its strong antioxidant ability [46]

Al-Mustafa and Al-Thunibat [58] have revealed the anti-oxidant activity of some Jordanian medicinal plants usedtraditionally for treatment of diabetes They were catego-rized PP under high antioxidant potential plantsThe activityinvestigated in methanolic and aqueous extract was DPPH-TEAC IC

50365 plusmn 50mggGAE 221015840-azinobis-(3-ethylben-

zothiazoline-6-sulfonic acid) (ABTS)-IC50

69 plusmn 01 120583gmLand DPPH-TEAC IC

502671 plusmn 35mggGAE and ABTS+-

IC5098 plusmn 01 120583gmL respectively Among all the plants cho-

sen by traditional healers methanolic and aqueous extractsof PP both were having potent radical scavenging activityMethanolic extract of PP exhibited the highest phenoliccontent (103GAEmgg) among all their experimental plants

In a recent study [59] the antioxidant activity of meth-anolic extract of PP on brain of normal rats demonstratedthat it reduced lipid peroxidation and nitric oxide in bothserum and brain tissue homogenate having an effect onthe scavenging capacity of superoxide anion and hydrogenperoxide

Pan et al [60] described a continuous (CUAE) and pulsedultrasound-assisted (PUAE) method for the extractions ofantioxidants from PP since there is a great demand for devel-oping efficient extraction methods in order to reduce extrac-tion time and increase the yield and activity of functionalantioxidants Cumulatively all these observations suggest thepotential antioxidant activity of PP (Table 5)

42 Antihyperglycemic Effect Over the past decade sig-nificant progress has been made in establishing the anti-hyperglycemic pharmacological mechanism of PP and theindividual compounds responsible for it Various solventextracts of PP appear to have anti-diabetic property Ontheir Jordanian medicinal plants survey native authors haverevealed 61 traditional healers recommend PP for diabetestreatment [58] Similar kind of studies done by the authorsin India also revealed the uses of PP by traditional healers(vaidya) (49) and anti-hyperglycemic effect using in vitroglucose oxidase method [61]

6 Evidence-Based Complementary and Alternative Medicine

Table 5 Overview of antioxidant pomegranate studies

Assays Effect ReferenceTrolox Equivalent AntioxidantConcentration (TEAC) Aqueous extract Prodelphinidinshowed active antioxidant activity [39]

Phospho-molybdenum complex Methanolic extract revealed lowest antioxidant activity followed by ethyl acetateacetone and water extract [40]

DPPH and ABTS radicals Remarkable free radical-scavenging power [41]DPPH and ABTS radicals Robust antioxidant activity [42]DPPH and ABTS radicals Extraordinary free radical-scavenging power [43]FRAP Peel had superior antioxidant activity than pulp and seed [44]FRAP Seed exhibited lower antioxidant activity as compared to peels [45]

DPPH and ABTS radicals Methanolic extract of PP exhibited the highest phenolic content and freeradical-scavenging power [46]

The first report on the antidiabetic properties of PP usingan in vivomodel was elucidated by Nogueira and Pereira fol-lowed by Zafar and Singh and Nozire and Serpil reproducedby several other studies [47ndash50 62ndash66]

Diabetic rats treated with 043 gkg BW of aqueous peelextract for four weeks displayed significantly lowered bloodsugar level and increased number of 120573 cells which relativelyhelp in intensification of insulin level [47] The mechanis-tic anti-diabetic activity of the extract is by stimulationregeneration and increased number of 120573 cells by protectingpancreatic tissue and subsequent release of insulin Alsoit may increase the stimulation and activation of insulinreceptor [47]

Oral administration of aqueous extract of PP at dosesof 50 and 100mgkg for 21 days brought down the fastingblood glucose total serum cholesterol (TC) triglycerides(TG) serum low density lipoprotein cholesterol (LDL-c)VLDL-C (very low-density lipoprotein cholesterol) and tissueLPO (lipid peroxidation) levels together with boost on high-density lipoprotein cholesterol (HDL-c) GSH (glutathione)content and antioxidant enzymes in contrast with diabeticcontrol groupThese authors recommended the uses of aque-ous extract of the peel as a dietary supplement in the cureand inhibition of chronic diseases categorized by aggravatedantioxidant status and diminished glucose metabolism [48]

The same group emphasized on oral administration ofthe aqueous-ethanolic extract of PP which led to signifi-cant blood glucose lowering effect in normal glucose-fedhyperglycemic in their another report on alloxan-induceddiabetic rats This report suggested that the effect can be dueto increased peripheral glucose utilization or retardation ofintestinal glucose absorption may also be partly responsiblefor inhibition of hyperglycaemia in glucose-fed rats [49]

Althunibat et al [50] had shown in their study on STZ-(streptozotocin-) induced diabetic rats that intraperitoneal(ip) administration of 10 and 20mgkg BW of PP for fourweeks significantly enhanced the activities of antioxidantenzymes in liver kidney and RBC The methanolic extractof PP (75 and 150mgkg daily) inhibits glucose level inalloxan-induced diabetic wistar rats The extract also causeda significant reduction in malondialdehyde (MDA) a lipidperoxides marker in diabetic rat tissues and elevated the total

serum antioxidant capacity in a dose-dependent mannerPhytochemical investigation demonstrates that the gallic acidin the methanolic extract of peels is mainly responsible forthis activity [8] This group suggested that the effect may bedue to the presence of terpenoids such as ursolic acid andoleanolic acid which may help to scavenge the free radicalsgenerated during diabetes (Table 6)

43 Antihyperlipidemic Effect Alterations in lipid profile areone of the most common complications in diabetes mellitusand affects 40 of all diabetic patients [51] A comparativestudy was carried out by Cheng et al (2004) [67] to elucidatethe hypolipidemic effect of crude PP and polyphenolicextract Male Sprague-Dawley (SD) rats were fed with a high-fat diet to induce hyperlipidemia and the treatment wascarried out for 28 days The results revealed decrease in thelevels of TCHDL-c ratio and serum LDL-c levels concludingPP polyphenolic extract is effective in lowering serum andhepatic lipids (Table 6)

44 Hepatoprotective Effects Recent in vivo animal studieshave evaluated the hepatoprotective effects of pomegranatehowever the exact mechanism and significant compoundshave not yet been described

The effects of continuous administration of PP on experi-mentally induced liver fibrosis in rats have been examined byToklu et al [68] The levels of serum aspartate aminotrans-ferase (AST) lactate dehydrogenase (LDH) and alanineaminotransferase (ALT) were ascertained in order to evaluateliver functions and the amount of tissue damage The ASTLDH ALT and cytokine levels in the serum which were ele-vated in liver fibrosis models were found to be considerablyreduced and brought to near-normal levels after PP treat-ment Similarly the increase in hepatic collagen levels wasalso diminished leading to an improvement in the structureand functions of the liver It was thus ascertained that PPpossesses certain hepato-protective properties making it animportant therapeutic agent in the treatment of fibrosis andoxidative damage [68 69]

Previous work showed that feeding of rats with PP pro-vided protective effect against carbon tetra chloride (CCl

4)

toxicity [55] Studies in rats with CCl4-induced liver damage

Evidence-Based Complementary and Alternative Medicine 7

Table 6 Overview of in vivo Punica peel studies for diabetes and its complications

Preclinicaltrial In vivo studies Dayweek

Nature of peelextractdosages(per kg BWday)

OutcomeStatisticallysignificantresults

Reference

Diabetes Albino Wistar rats 284 Aqueous042 gLowering of blood sugarlevel and increased numberof 120573 cells

Yes [47]

Diabetes Albino Wistar rats 1013 Methanolic200mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [48]

Diabetes Albino Wistar rats 1523 Methanolic200mg

Improvement of hepaticcardiac and renal LPO andserum T3 T4 insulin andglucose concentrations

Yes [49]

Hyperlipidemic Sprague-Dawley rats 287 Methanolic510 15

Reduction of totalcholesterolLDL-cholesteroltriglyceridesVLDL-cholesterol H

Yes [50]

Diabetes Albino Wistar rats 287 Methanolic10mg20mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [50]

Diabetes Albino Wistar rats 426 Methanolic75mgand 150mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidase and decreasedLPO level in hippocampaland cortex region of brain

Yes [8]

Diabetes Albino Wistar rats 213 Methanolic200mgand 400mg

Reduction of aldosereductase amylase PTP1Binhibition assay

Yes [32]

demonstrated pretreatment with PP enhanced or maintainedthe free radical scavenging activity of the hepatic enzymescatalase superoxide dismutase and peroxidase and resultedin 54 reduction of lipid peroxidation values compared tocontrols confirming the antioxidant property of the PP [50]

A discrete investigation in rats with CCl4-induced liver

damage demonstrated pretreatment with PP extract boostedthe free radical scavenging activity of the hepatic enzymessuperoxide dismutase and catalase and showed 54 declinein lipid peroxidation as compared to controls [69]

Hepatocellular carcinoma (HCC) a common and fatalcancer is majorly driven by oxidative stress The effect ofpomegranate emulsion (PE) on DENA-induced hepatocar-cinogenesis which mimics HCC in humans was examinedin an animal model Robust chemopreventive activities werereported owing to reduction in the incidence size volume

and multiplicity of the hepatic nodules In addition PE alsoalleviated lipid peroxidation and oxidation of proteins in theliver The report thus suggests and supports the use of pome-granate-derived agents in the treatment and prevention ofHCC in humans [70]

5 Mechanisms of Action

A recent study by Jain et al [32] has shown the probablemechanism of action of PP They have isolated and purifieda compound Valoneic acid dilactone (VAD) from the meth-anolic extract of Punica granatum (MEPG) MEPG-(400370mgkg po) and VAD-(25 50mgkg po) treated groupshave shown very minimal acinar damage and adequatenumber of pancreatic islets Their findings suggest that somepancreatic 120573-cells are still surviving to exert their insulinreleasing effect In diabetic conditionweight loss arises due to

8 Evidence-Based Complementary and Alternative Medicine

the impairment in insulin action in the conversion of glucoseinto glycogen The catabolism of fats does not occur as thereis an inhibition of lipolysis due to its unavailability whichis because of destruction in beta cells VAD and MEPGwere found to inhibit the alpha amylase activity which isa carbohydrate-hydrolysing enzyme thus decreases post-prandial hyperglycemia and improves glucose metabolismThe extracts VAD and MEPG were found to inhibit PTP1Bactivity which showed increase in insulin receptor tyrosinephosphorylation which mimicked in vivo action of insulinthereby decreased plasma glucose levels in a dose-dependentmanner The findings of their studies such as blood glucoselevels oral glucose tolerance test body weight mortalityand histopathology were in correlation with each other andindicate that MEPG and VAD could be beneficial in man-agement of diabetes and associated complications VAD wasobserved to be amore powerful inhibitor of aldose reductase120572-amylase and protein tyrosine phosphatase PTP1B whencompared to MEPG because of its polyphenolic nature

6 Toxicity StudiesSafetyAdverse Effects

There are relatively none in vivo or in vitro studies reportingthe toxic or adverse effect of the PP on any of the mammaliansystem The LD

50of the aqueous extract of PP in mice was

found to be 1321 plusmn 15mgkg ip [71]

7 Conclusion

Industries have moved towards usage of naturally derivedcompounds biologics as they are easily extractable and canbe cultured in labs Amongst these sources ecofriendly[4] Punica granatum peel has showed effectiveness due tothe array of compounds present in it These compoundshave good antioxidant activity and also serve as excellentnutritional supplements This review highlights the workthat has been done in the recent past on the PP whichincludes anti-hyperglycemic [8] hepatoprotective [56] andanti-hyperlipidemic effects [67] These experiments haveshown productive results both in in vivo and in vitro domainsHence more labs are moving towards PP as a suitabletherapeutic agent in various diseases

8 Future Direction

Despite the documented roles in nutrition there are very fewphytochemical studies The actions of mechanism of thesecompounds are still not very clearly understood however itis predicted that the mechanisms are quite complicated sincethere may be numerous factors involved in it

There is a dearth in the field of pharmacodynamics andpharmacokinetics or safety aspects of the PP There havebeen very few studies pertaining to the molecular aspects ofPP which is clearly evident by the sequence of informationavailable in the public domains Even though PP is richin healing properties due to the lacunae in many aspectsthere is an urgent requirement for further investigations todelineate its precise mechanisms and possible therapeuticvalues particularly in the field of diabetes mellitus

Conflict of Interest

The authors do not have any conflict of interest

Acknowledgments

The authors acknowledge (Dr) Dinesh Babu Ghent Uni-versity Belgium and Dr E L Cooper UCLA-CCIM LosAngeles CA USA for critically reviewing this paper Theauthors are thankful to Kumaun University Nainital and DrT L ShanthaDirectorMaharani LakshmiAmmanniCollegefor Women Bangalore India for providing the facilities tocarry out this review work

References

[1] J F Morton ldquoPomegranaterdquo in Fruits of Warm Climates pp352ndash355 ECHO Miami Fla USA 1987

[2] S K Middha Y Mittal T Usha et al ldquoPhyto-mellitus a phyto-chemical database for diabetesrdquoBioinformation vol 4 no 2 pp78ndash79 2009

[3] E Stover and E W Mercure ldquoThe pomegranate a new look atthe fruit of paradiserdquo HortScience vol 42 no 5 pp 1088ndash10922007

[4] A Shabtay H Eitam Y Tadmor et al ldquoNutritive and antiox-idative potential of fresh and stored pomegranate industrialbyproduct as a novel beef cattle feedrdquo Journal of Agricultural andFood Chemistry vol 56 no 21 pp 10063ndash10070 2008

[5] M Dikmen N Ozturk and Y Ozturk ldquoThe antioxidant poten-cy ofPunica granatum L fruit peel reduces cell proliferation andinduces apoptosis on breast cancerrdquo Journal of Medicinal Foodvol 14 no 12 pp 1638ndash1646 2011

[6] MYHongN P Seeram andDHeber ldquoPomegranate polyphe-nols down-regulate expression of androgen-synthesizing genesin human prostate cancer cells overexpressing the androgenreceptorrdquo Journal of Nutritional Biochemistry vol 19 no 12 pp848ndash855 2008

[7] J Jurenka ldquoTherapeutic applications of pomegranate (Punicagranatum L) a reviewrdquoAlternativeMedicine Review vol 13 no2 pp 128ndash144 2008

[8] S K Middha T Usha and T RaviKiran ldquoInfluence of Punicagranatum L on region specific responses in rat brain duringalloxan-induced diabetesrdquo Asian Pacific Journal of TropicalBiomedicine vol 2 no 2 pp S905ndashS909 2012

[9] M Viuda-Martos J Fernandez-Lopez and J A Perez-AlvarezldquoPomegranate and itsmany functional components as related tohuman health a reviewrdquoComprehensive Reviews in Food Scienceand Food Safety vol 9 no 2 pp 635ndash654 2010

[10] S R Kanatt R Chander and A Sharma ldquoAntioxidant andantimicrobial activity of pomegranate peel extract improves theshelf life of chicken productsrdquo International Journal of FoodScience and Technology vol 45 no 2 pp 216ndash222 2010

[11] E A Hayouni K Miled S Boubaker et al ldquoHydroalcoholicextract based-ointment from Punica granatum L peels withenhanced in vivo healing potential on dermal woundsrdquo Phy-tomedicine vol 18 no 11 pp 976ndash984 2011

[12] C N Aguilar A Aguilera-Carbo A Robledo et al ldquoProduc-tion of antioxidant nutraceutlcals by solid-state cultures ofpomegranate (Punica granatum) peel and creosote bush (Larreatridentata) leavesrdquo Food Technology and Biotechnology vol 46no 2 pp 218ndash222 2008

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Evidence-Based Complementary and Alternative Medicine 5

Table 4 Amount of EA in different varieties of peel [33]

S no Variety Thickness(mm)

Antioxidant activity(mmol100 g)

Amount of ellagic acid(mg100 g)

1 Rabbab 601 22967 10002 Malas-e-Yazd 406 23433 30003 Malas-e-Saveh 192 44050 20004 Shishe-Kap 253 30383 10005 Khazar-e-Bardeskan 210 64017 25006 Naderi 291 22517 30007 Alak 262 46350 20008 Abdandan 213 28493 37759 TabriziPoost 257 37438 325010 Syah-e-Saveh 160 31489 500011 Syah-e-Badrood 233 32763 400012 Lamsari-e-Behshahr 1727 70550 4500

ailments like arthritis cancer Alzheimerrsquos disease Parkin-sonrsquos disease AIDS and diabetic complications [51 52]Reports indicate that plants rich in anthocyanin flavonoidsand polyphenols are observed to be effective in scavengingthe free radicals [53 54] Total antioxidant activity of 12different varieties was determined by FRAP (ferric reducingantioxidant power) method described by Akbarpour etal are enlisted in Table 4 and it ranged from 22517 to70550mmolg According to Akbarpour et al [33] study thehighest antioxidant activity level was detected in ldquoLamsari-e-Behshahrrdquo and the lowest in ldquoNaderirdquo The same study hasrevealed that the antioxidant activity of peel is higher thanthat of juice and this difference is attributed to the presenceof pomegranate peel tannins [38]

The first report on antioxidant property of PP using invitro models was elucidated by Singh et al [55] The meth-anolic extract of peels showed 83 and 81 antioxidantactivity at 50 ppm using the 120573-carotene-linoleate and 22-diphenyl-2-picrylhydrazyl (DPPH) model systems respec-tively Similar group also showed 56 58 and 937 inhibitionusing the thiobarbituric acid (TBA)method hydroxyl radicalscavenging activity and serum low-density lipoprotein LDLoxidation respectively at 100 ppm [56] Owing to this prop-erty the studies can be further extended to exploit PP for theirpossible application in the preservation of food products aswell as their use as health supplements and nutraceuticals

Additional studies have also shown that PP had thehighest antioxidant activity among the peel pulp and seedfractions of 28 kinds of fruits commonly consumed in Chinaas determined by FRAP assay [57] A mixture of ethanolicmethanolic and acetone PP extract had markedly higherantioxidant capacity than the pulp extract in scavengingcapacity against superoxide anion hydroxyl and peroxylradicals as well as inhibiting CuSO

4-induced LDL oxidation

The contents of total phenolics flavonoids and Proantho-cyanidinswere also higher in peel extract than in pulp extractThe large amount of phenolics contained in peel extract maycontribute to its strong antioxidant ability [46]

Al-Mustafa and Al-Thunibat [58] have revealed the anti-oxidant activity of some Jordanian medicinal plants usedtraditionally for treatment of diabetes They were catego-rized PP under high antioxidant potential plantsThe activityinvestigated in methanolic and aqueous extract was DPPH-TEAC IC

50365 plusmn 50mggGAE 221015840-azinobis-(3-ethylben-

zothiazoline-6-sulfonic acid) (ABTS)-IC50

69 plusmn 01 120583gmLand DPPH-TEAC IC

502671 plusmn 35mggGAE and ABTS+-

IC5098 plusmn 01 120583gmL respectively Among all the plants cho-

sen by traditional healers methanolic and aqueous extractsof PP both were having potent radical scavenging activityMethanolic extract of PP exhibited the highest phenoliccontent (103GAEmgg) among all their experimental plants

In a recent study [59] the antioxidant activity of meth-anolic extract of PP on brain of normal rats demonstratedthat it reduced lipid peroxidation and nitric oxide in bothserum and brain tissue homogenate having an effect onthe scavenging capacity of superoxide anion and hydrogenperoxide

Pan et al [60] described a continuous (CUAE) and pulsedultrasound-assisted (PUAE) method for the extractions ofantioxidants from PP since there is a great demand for devel-oping efficient extraction methods in order to reduce extrac-tion time and increase the yield and activity of functionalantioxidants Cumulatively all these observations suggest thepotential antioxidant activity of PP (Table 5)

42 Antihyperglycemic Effect Over the past decade sig-nificant progress has been made in establishing the anti-hyperglycemic pharmacological mechanism of PP and theindividual compounds responsible for it Various solventextracts of PP appear to have anti-diabetic property Ontheir Jordanian medicinal plants survey native authors haverevealed 61 traditional healers recommend PP for diabetestreatment [58] Similar kind of studies done by the authorsin India also revealed the uses of PP by traditional healers(vaidya) (49) and anti-hyperglycemic effect using in vitroglucose oxidase method [61]

6 Evidence-Based Complementary and Alternative Medicine

Table 5 Overview of antioxidant pomegranate studies

Assays Effect ReferenceTrolox Equivalent AntioxidantConcentration (TEAC) Aqueous extract Prodelphinidinshowed active antioxidant activity [39]

Phospho-molybdenum complex Methanolic extract revealed lowest antioxidant activity followed by ethyl acetateacetone and water extract [40]

DPPH and ABTS radicals Remarkable free radical-scavenging power [41]DPPH and ABTS radicals Robust antioxidant activity [42]DPPH and ABTS radicals Extraordinary free radical-scavenging power [43]FRAP Peel had superior antioxidant activity than pulp and seed [44]FRAP Seed exhibited lower antioxidant activity as compared to peels [45]

DPPH and ABTS radicals Methanolic extract of PP exhibited the highest phenolic content and freeradical-scavenging power [46]

The first report on the antidiabetic properties of PP usingan in vivomodel was elucidated by Nogueira and Pereira fol-lowed by Zafar and Singh and Nozire and Serpil reproducedby several other studies [47ndash50 62ndash66]

Diabetic rats treated with 043 gkg BW of aqueous peelextract for four weeks displayed significantly lowered bloodsugar level and increased number of 120573 cells which relativelyhelp in intensification of insulin level [47] The mechanis-tic anti-diabetic activity of the extract is by stimulationregeneration and increased number of 120573 cells by protectingpancreatic tissue and subsequent release of insulin Alsoit may increase the stimulation and activation of insulinreceptor [47]

Oral administration of aqueous extract of PP at dosesof 50 and 100mgkg for 21 days brought down the fastingblood glucose total serum cholesterol (TC) triglycerides(TG) serum low density lipoprotein cholesterol (LDL-c)VLDL-C (very low-density lipoprotein cholesterol) and tissueLPO (lipid peroxidation) levels together with boost on high-density lipoprotein cholesterol (HDL-c) GSH (glutathione)content and antioxidant enzymes in contrast with diabeticcontrol groupThese authors recommended the uses of aque-ous extract of the peel as a dietary supplement in the cureand inhibition of chronic diseases categorized by aggravatedantioxidant status and diminished glucose metabolism [48]

The same group emphasized on oral administration ofthe aqueous-ethanolic extract of PP which led to signifi-cant blood glucose lowering effect in normal glucose-fedhyperglycemic in their another report on alloxan-induceddiabetic rats This report suggested that the effect can be dueto increased peripheral glucose utilization or retardation ofintestinal glucose absorption may also be partly responsiblefor inhibition of hyperglycaemia in glucose-fed rats [49]

Althunibat et al [50] had shown in their study on STZ-(streptozotocin-) induced diabetic rats that intraperitoneal(ip) administration of 10 and 20mgkg BW of PP for fourweeks significantly enhanced the activities of antioxidantenzymes in liver kidney and RBC The methanolic extractof PP (75 and 150mgkg daily) inhibits glucose level inalloxan-induced diabetic wistar rats The extract also causeda significant reduction in malondialdehyde (MDA) a lipidperoxides marker in diabetic rat tissues and elevated the total

serum antioxidant capacity in a dose-dependent mannerPhytochemical investigation demonstrates that the gallic acidin the methanolic extract of peels is mainly responsible forthis activity [8] This group suggested that the effect may bedue to the presence of terpenoids such as ursolic acid andoleanolic acid which may help to scavenge the free radicalsgenerated during diabetes (Table 6)

43 Antihyperlipidemic Effect Alterations in lipid profile areone of the most common complications in diabetes mellitusand affects 40 of all diabetic patients [51] A comparativestudy was carried out by Cheng et al (2004) [67] to elucidatethe hypolipidemic effect of crude PP and polyphenolicextract Male Sprague-Dawley (SD) rats were fed with a high-fat diet to induce hyperlipidemia and the treatment wascarried out for 28 days The results revealed decrease in thelevels of TCHDL-c ratio and serum LDL-c levels concludingPP polyphenolic extract is effective in lowering serum andhepatic lipids (Table 6)

44 Hepatoprotective Effects Recent in vivo animal studieshave evaluated the hepatoprotective effects of pomegranatehowever the exact mechanism and significant compoundshave not yet been described

The effects of continuous administration of PP on experi-mentally induced liver fibrosis in rats have been examined byToklu et al [68] The levels of serum aspartate aminotrans-ferase (AST) lactate dehydrogenase (LDH) and alanineaminotransferase (ALT) were ascertained in order to evaluateliver functions and the amount of tissue damage The ASTLDH ALT and cytokine levels in the serum which were ele-vated in liver fibrosis models were found to be considerablyreduced and brought to near-normal levels after PP treat-ment Similarly the increase in hepatic collagen levels wasalso diminished leading to an improvement in the structureand functions of the liver It was thus ascertained that PPpossesses certain hepato-protective properties making it animportant therapeutic agent in the treatment of fibrosis andoxidative damage [68 69]

Previous work showed that feeding of rats with PP pro-vided protective effect against carbon tetra chloride (CCl

4)

toxicity [55] Studies in rats with CCl4-induced liver damage

Evidence-Based Complementary and Alternative Medicine 7

Table 6 Overview of in vivo Punica peel studies for diabetes and its complications

Preclinicaltrial In vivo studies Dayweek

Nature of peelextractdosages(per kg BWday)

OutcomeStatisticallysignificantresults

Reference

Diabetes Albino Wistar rats 284 Aqueous042 gLowering of blood sugarlevel and increased numberof 120573 cells

Yes [47]

Diabetes Albino Wistar rats 1013 Methanolic200mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [48]

Diabetes Albino Wistar rats 1523 Methanolic200mg

Improvement of hepaticcardiac and renal LPO andserum T3 T4 insulin andglucose concentrations

Yes [49]

Hyperlipidemic Sprague-Dawley rats 287 Methanolic510 15

Reduction of totalcholesterolLDL-cholesteroltriglyceridesVLDL-cholesterol H

Yes [50]

Diabetes Albino Wistar rats 287 Methanolic10mg20mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [50]

Diabetes Albino Wistar rats 426 Methanolic75mgand 150mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidase and decreasedLPO level in hippocampaland cortex region of brain

Yes [8]

Diabetes Albino Wistar rats 213 Methanolic200mgand 400mg

Reduction of aldosereductase amylase PTP1Binhibition assay

Yes [32]

demonstrated pretreatment with PP enhanced or maintainedthe free radical scavenging activity of the hepatic enzymescatalase superoxide dismutase and peroxidase and resultedin 54 reduction of lipid peroxidation values compared tocontrols confirming the antioxidant property of the PP [50]

A discrete investigation in rats with CCl4-induced liver

damage demonstrated pretreatment with PP extract boostedthe free radical scavenging activity of the hepatic enzymessuperoxide dismutase and catalase and showed 54 declinein lipid peroxidation as compared to controls [69]

Hepatocellular carcinoma (HCC) a common and fatalcancer is majorly driven by oxidative stress The effect ofpomegranate emulsion (PE) on DENA-induced hepatocar-cinogenesis which mimics HCC in humans was examinedin an animal model Robust chemopreventive activities werereported owing to reduction in the incidence size volume

and multiplicity of the hepatic nodules In addition PE alsoalleviated lipid peroxidation and oxidation of proteins in theliver The report thus suggests and supports the use of pome-granate-derived agents in the treatment and prevention ofHCC in humans [70]

5 Mechanisms of Action

A recent study by Jain et al [32] has shown the probablemechanism of action of PP They have isolated and purifieda compound Valoneic acid dilactone (VAD) from the meth-anolic extract of Punica granatum (MEPG) MEPG-(400370mgkg po) and VAD-(25 50mgkg po) treated groupshave shown very minimal acinar damage and adequatenumber of pancreatic islets Their findings suggest that somepancreatic 120573-cells are still surviving to exert their insulinreleasing effect In diabetic conditionweight loss arises due to

8 Evidence-Based Complementary and Alternative Medicine

the impairment in insulin action in the conversion of glucoseinto glycogen The catabolism of fats does not occur as thereis an inhibition of lipolysis due to its unavailability whichis because of destruction in beta cells VAD and MEPGwere found to inhibit the alpha amylase activity which isa carbohydrate-hydrolysing enzyme thus decreases post-prandial hyperglycemia and improves glucose metabolismThe extracts VAD and MEPG were found to inhibit PTP1Bactivity which showed increase in insulin receptor tyrosinephosphorylation which mimicked in vivo action of insulinthereby decreased plasma glucose levels in a dose-dependentmanner The findings of their studies such as blood glucoselevels oral glucose tolerance test body weight mortalityand histopathology were in correlation with each other andindicate that MEPG and VAD could be beneficial in man-agement of diabetes and associated complications VAD wasobserved to be amore powerful inhibitor of aldose reductase120572-amylase and protein tyrosine phosphatase PTP1B whencompared to MEPG because of its polyphenolic nature

6 Toxicity StudiesSafetyAdverse Effects

There are relatively none in vivo or in vitro studies reportingthe toxic or adverse effect of the PP on any of the mammaliansystem The LD

50of the aqueous extract of PP in mice was

found to be 1321 plusmn 15mgkg ip [71]

7 Conclusion

Industries have moved towards usage of naturally derivedcompounds biologics as they are easily extractable and canbe cultured in labs Amongst these sources ecofriendly[4] Punica granatum peel has showed effectiveness due tothe array of compounds present in it These compoundshave good antioxidant activity and also serve as excellentnutritional supplements This review highlights the workthat has been done in the recent past on the PP whichincludes anti-hyperglycemic [8] hepatoprotective [56] andanti-hyperlipidemic effects [67] These experiments haveshown productive results both in in vivo and in vitro domainsHence more labs are moving towards PP as a suitabletherapeutic agent in various diseases

8 Future Direction

Despite the documented roles in nutrition there are very fewphytochemical studies The actions of mechanism of thesecompounds are still not very clearly understood however itis predicted that the mechanisms are quite complicated sincethere may be numerous factors involved in it

There is a dearth in the field of pharmacodynamics andpharmacokinetics or safety aspects of the PP There havebeen very few studies pertaining to the molecular aspects ofPP which is clearly evident by the sequence of informationavailable in the public domains Even though PP is richin healing properties due to the lacunae in many aspectsthere is an urgent requirement for further investigations todelineate its precise mechanisms and possible therapeuticvalues particularly in the field of diabetes mellitus

Conflict of Interest

The authors do not have any conflict of interest

Acknowledgments

The authors acknowledge (Dr) Dinesh Babu Ghent Uni-versity Belgium and Dr E L Cooper UCLA-CCIM LosAngeles CA USA for critically reviewing this paper Theauthors are thankful to Kumaun University Nainital and DrT L ShanthaDirectorMaharani LakshmiAmmanniCollegefor Women Bangalore India for providing the facilities tocarry out this review work

References

[1] J F Morton ldquoPomegranaterdquo in Fruits of Warm Climates pp352ndash355 ECHO Miami Fla USA 1987

[2] S K Middha Y Mittal T Usha et al ldquoPhyto-mellitus a phyto-chemical database for diabetesrdquoBioinformation vol 4 no 2 pp78ndash79 2009

[3] E Stover and E W Mercure ldquoThe pomegranate a new look atthe fruit of paradiserdquo HortScience vol 42 no 5 pp 1088ndash10922007

[4] A Shabtay H Eitam Y Tadmor et al ldquoNutritive and antiox-idative potential of fresh and stored pomegranate industrialbyproduct as a novel beef cattle feedrdquo Journal of Agricultural andFood Chemistry vol 56 no 21 pp 10063ndash10070 2008

[5] M Dikmen N Ozturk and Y Ozturk ldquoThe antioxidant poten-cy ofPunica granatum L fruit peel reduces cell proliferation andinduces apoptosis on breast cancerrdquo Journal of Medicinal Foodvol 14 no 12 pp 1638ndash1646 2011

[6] MYHongN P Seeram andDHeber ldquoPomegranate polyphe-nols down-regulate expression of androgen-synthesizing genesin human prostate cancer cells overexpressing the androgenreceptorrdquo Journal of Nutritional Biochemistry vol 19 no 12 pp848ndash855 2008

[7] J Jurenka ldquoTherapeutic applications of pomegranate (Punicagranatum L) a reviewrdquoAlternativeMedicine Review vol 13 no2 pp 128ndash144 2008

[8] S K Middha T Usha and T RaviKiran ldquoInfluence of Punicagranatum L on region specific responses in rat brain duringalloxan-induced diabetesrdquo Asian Pacific Journal of TropicalBiomedicine vol 2 no 2 pp S905ndashS909 2012

[9] M Viuda-Martos J Fernandez-Lopez and J A Perez-AlvarezldquoPomegranate and itsmany functional components as related tohuman health a reviewrdquoComprehensive Reviews in Food Scienceand Food Safety vol 9 no 2 pp 635ndash654 2010

[10] S R Kanatt R Chander and A Sharma ldquoAntioxidant andantimicrobial activity of pomegranate peel extract improves theshelf life of chicken productsrdquo International Journal of FoodScience and Technology vol 45 no 2 pp 216ndash222 2010

[11] E A Hayouni K Miled S Boubaker et al ldquoHydroalcoholicextract based-ointment from Punica granatum L peels withenhanced in vivo healing potential on dermal woundsrdquo Phy-tomedicine vol 18 no 11 pp 976ndash984 2011

[12] C N Aguilar A Aguilera-Carbo A Robledo et al ldquoProduc-tion of antioxidant nutraceutlcals by solid-state cultures ofpomegranate (Punica granatum) peel and creosote bush (Larreatridentata) leavesrdquo Food Technology and Biotechnology vol 46no 2 pp 218ndash222 2008

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

6 Evidence-Based Complementary and Alternative Medicine

Table 5 Overview of antioxidant pomegranate studies

Assays Effect ReferenceTrolox Equivalent AntioxidantConcentration (TEAC) Aqueous extract Prodelphinidinshowed active antioxidant activity [39]

Phospho-molybdenum complex Methanolic extract revealed lowest antioxidant activity followed by ethyl acetateacetone and water extract [40]

DPPH and ABTS radicals Remarkable free radical-scavenging power [41]DPPH and ABTS radicals Robust antioxidant activity [42]DPPH and ABTS radicals Extraordinary free radical-scavenging power [43]FRAP Peel had superior antioxidant activity than pulp and seed [44]FRAP Seed exhibited lower antioxidant activity as compared to peels [45]

DPPH and ABTS radicals Methanolic extract of PP exhibited the highest phenolic content and freeradical-scavenging power [46]

The first report on the antidiabetic properties of PP usingan in vivomodel was elucidated by Nogueira and Pereira fol-lowed by Zafar and Singh and Nozire and Serpil reproducedby several other studies [47ndash50 62ndash66]

Diabetic rats treated with 043 gkg BW of aqueous peelextract for four weeks displayed significantly lowered bloodsugar level and increased number of 120573 cells which relativelyhelp in intensification of insulin level [47] The mechanis-tic anti-diabetic activity of the extract is by stimulationregeneration and increased number of 120573 cells by protectingpancreatic tissue and subsequent release of insulin Alsoit may increase the stimulation and activation of insulinreceptor [47]

Oral administration of aqueous extract of PP at dosesof 50 and 100mgkg for 21 days brought down the fastingblood glucose total serum cholesterol (TC) triglycerides(TG) serum low density lipoprotein cholesterol (LDL-c)VLDL-C (very low-density lipoprotein cholesterol) and tissueLPO (lipid peroxidation) levels together with boost on high-density lipoprotein cholesterol (HDL-c) GSH (glutathione)content and antioxidant enzymes in contrast with diabeticcontrol groupThese authors recommended the uses of aque-ous extract of the peel as a dietary supplement in the cureand inhibition of chronic diseases categorized by aggravatedantioxidant status and diminished glucose metabolism [48]

The same group emphasized on oral administration ofthe aqueous-ethanolic extract of PP which led to signifi-cant blood glucose lowering effect in normal glucose-fedhyperglycemic in their another report on alloxan-induceddiabetic rats This report suggested that the effect can be dueto increased peripheral glucose utilization or retardation ofintestinal glucose absorption may also be partly responsiblefor inhibition of hyperglycaemia in glucose-fed rats [49]

Althunibat et al [50] had shown in their study on STZ-(streptozotocin-) induced diabetic rats that intraperitoneal(ip) administration of 10 and 20mgkg BW of PP for fourweeks significantly enhanced the activities of antioxidantenzymes in liver kidney and RBC The methanolic extractof PP (75 and 150mgkg daily) inhibits glucose level inalloxan-induced diabetic wistar rats The extract also causeda significant reduction in malondialdehyde (MDA) a lipidperoxides marker in diabetic rat tissues and elevated the total

serum antioxidant capacity in a dose-dependent mannerPhytochemical investigation demonstrates that the gallic acidin the methanolic extract of peels is mainly responsible forthis activity [8] This group suggested that the effect may bedue to the presence of terpenoids such as ursolic acid andoleanolic acid which may help to scavenge the free radicalsgenerated during diabetes (Table 6)

43 Antihyperlipidemic Effect Alterations in lipid profile areone of the most common complications in diabetes mellitusand affects 40 of all diabetic patients [51] A comparativestudy was carried out by Cheng et al (2004) [67] to elucidatethe hypolipidemic effect of crude PP and polyphenolicextract Male Sprague-Dawley (SD) rats were fed with a high-fat diet to induce hyperlipidemia and the treatment wascarried out for 28 days The results revealed decrease in thelevels of TCHDL-c ratio and serum LDL-c levels concludingPP polyphenolic extract is effective in lowering serum andhepatic lipids (Table 6)

44 Hepatoprotective Effects Recent in vivo animal studieshave evaluated the hepatoprotective effects of pomegranatehowever the exact mechanism and significant compoundshave not yet been described

The effects of continuous administration of PP on experi-mentally induced liver fibrosis in rats have been examined byToklu et al [68] The levels of serum aspartate aminotrans-ferase (AST) lactate dehydrogenase (LDH) and alanineaminotransferase (ALT) were ascertained in order to evaluateliver functions and the amount of tissue damage The ASTLDH ALT and cytokine levels in the serum which were ele-vated in liver fibrosis models were found to be considerablyreduced and brought to near-normal levels after PP treat-ment Similarly the increase in hepatic collagen levels wasalso diminished leading to an improvement in the structureand functions of the liver It was thus ascertained that PPpossesses certain hepato-protective properties making it animportant therapeutic agent in the treatment of fibrosis andoxidative damage [68 69]

Previous work showed that feeding of rats with PP pro-vided protective effect against carbon tetra chloride (CCl

4)

toxicity [55] Studies in rats with CCl4-induced liver damage

Evidence-Based Complementary and Alternative Medicine 7

Table 6 Overview of in vivo Punica peel studies for diabetes and its complications

Preclinicaltrial In vivo studies Dayweek

Nature of peelextractdosages(per kg BWday)

OutcomeStatisticallysignificantresults

Reference

Diabetes Albino Wistar rats 284 Aqueous042 gLowering of blood sugarlevel and increased numberof 120573 cells

Yes [47]

Diabetes Albino Wistar rats 1013 Methanolic200mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [48]

Diabetes Albino Wistar rats 1523 Methanolic200mg

Improvement of hepaticcardiac and renal LPO andserum T3 T4 insulin andglucose concentrations

Yes [49]

Hyperlipidemic Sprague-Dawley rats 287 Methanolic510 15

Reduction of totalcholesterolLDL-cholesteroltriglyceridesVLDL-cholesterol H

Yes [50]

Diabetes Albino Wistar rats 287 Methanolic10mg20mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [50]

Diabetes Albino Wistar rats 426 Methanolic75mgand 150mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidase and decreasedLPO level in hippocampaland cortex region of brain

Yes [8]

Diabetes Albino Wistar rats 213 Methanolic200mgand 400mg

Reduction of aldosereductase amylase PTP1Binhibition assay

Yes [32]

demonstrated pretreatment with PP enhanced or maintainedthe free radical scavenging activity of the hepatic enzymescatalase superoxide dismutase and peroxidase and resultedin 54 reduction of lipid peroxidation values compared tocontrols confirming the antioxidant property of the PP [50]

A discrete investigation in rats with CCl4-induced liver

damage demonstrated pretreatment with PP extract boostedthe free radical scavenging activity of the hepatic enzymessuperoxide dismutase and catalase and showed 54 declinein lipid peroxidation as compared to controls [69]

Hepatocellular carcinoma (HCC) a common and fatalcancer is majorly driven by oxidative stress The effect ofpomegranate emulsion (PE) on DENA-induced hepatocar-cinogenesis which mimics HCC in humans was examinedin an animal model Robust chemopreventive activities werereported owing to reduction in the incidence size volume

and multiplicity of the hepatic nodules In addition PE alsoalleviated lipid peroxidation and oxidation of proteins in theliver The report thus suggests and supports the use of pome-granate-derived agents in the treatment and prevention ofHCC in humans [70]

5 Mechanisms of Action

A recent study by Jain et al [32] has shown the probablemechanism of action of PP They have isolated and purifieda compound Valoneic acid dilactone (VAD) from the meth-anolic extract of Punica granatum (MEPG) MEPG-(400370mgkg po) and VAD-(25 50mgkg po) treated groupshave shown very minimal acinar damage and adequatenumber of pancreatic islets Their findings suggest that somepancreatic 120573-cells are still surviving to exert their insulinreleasing effect In diabetic conditionweight loss arises due to

8 Evidence-Based Complementary and Alternative Medicine

the impairment in insulin action in the conversion of glucoseinto glycogen The catabolism of fats does not occur as thereis an inhibition of lipolysis due to its unavailability whichis because of destruction in beta cells VAD and MEPGwere found to inhibit the alpha amylase activity which isa carbohydrate-hydrolysing enzyme thus decreases post-prandial hyperglycemia and improves glucose metabolismThe extracts VAD and MEPG were found to inhibit PTP1Bactivity which showed increase in insulin receptor tyrosinephosphorylation which mimicked in vivo action of insulinthereby decreased plasma glucose levels in a dose-dependentmanner The findings of their studies such as blood glucoselevels oral glucose tolerance test body weight mortalityand histopathology were in correlation with each other andindicate that MEPG and VAD could be beneficial in man-agement of diabetes and associated complications VAD wasobserved to be amore powerful inhibitor of aldose reductase120572-amylase and protein tyrosine phosphatase PTP1B whencompared to MEPG because of its polyphenolic nature

6 Toxicity StudiesSafetyAdverse Effects

There are relatively none in vivo or in vitro studies reportingthe toxic or adverse effect of the PP on any of the mammaliansystem The LD

50of the aqueous extract of PP in mice was

found to be 1321 plusmn 15mgkg ip [71]

7 Conclusion

Industries have moved towards usage of naturally derivedcompounds biologics as they are easily extractable and canbe cultured in labs Amongst these sources ecofriendly[4] Punica granatum peel has showed effectiveness due tothe array of compounds present in it These compoundshave good antioxidant activity and also serve as excellentnutritional supplements This review highlights the workthat has been done in the recent past on the PP whichincludes anti-hyperglycemic [8] hepatoprotective [56] andanti-hyperlipidemic effects [67] These experiments haveshown productive results both in in vivo and in vitro domainsHence more labs are moving towards PP as a suitabletherapeutic agent in various diseases

8 Future Direction

Despite the documented roles in nutrition there are very fewphytochemical studies The actions of mechanism of thesecompounds are still not very clearly understood however itis predicted that the mechanisms are quite complicated sincethere may be numerous factors involved in it

There is a dearth in the field of pharmacodynamics andpharmacokinetics or safety aspects of the PP There havebeen very few studies pertaining to the molecular aspects ofPP which is clearly evident by the sequence of informationavailable in the public domains Even though PP is richin healing properties due to the lacunae in many aspectsthere is an urgent requirement for further investigations todelineate its precise mechanisms and possible therapeuticvalues particularly in the field of diabetes mellitus

Conflict of Interest

The authors do not have any conflict of interest

Acknowledgments

The authors acknowledge (Dr) Dinesh Babu Ghent Uni-versity Belgium and Dr E L Cooper UCLA-CCIM LosAngeles CA USA for critically reviewing this paper Theauthors are thankful to Kumaun University Nainital and DrT L ShanthaDirectorMaharani LakshmiAmmanniCollegefor Women Bangalore India for providing the facilities tocarry out this review work

References

[1] J F Morton ldquoPomegranaterdquo in Fruits of Warm Climates pp352ndash355 ECHO Miami Fla USA 1987

[2] S K Middha Y Mittal T Usha et al ldquoPhyto-mellitus a phyto-chemical database for diabetesrdquoBioinformation vol 4 no 2 pp78ndash79 2009

[3] E Stover and E W Mercure ldquoThe pomegranate a new look atthe fruit of paradiserdquo HortScience vol 42 no 5 pp 1088ndash10922007

[4] A Shabtay H Eitam Y Tadmor et al ldquoNutritive and antiox-idative potential of fresh and stored pomegranate industrialbyproduct as a novel beef cattle feedrdquo Journal of Agricultural andFood Chemistry vol 56 no 21 pp 10063ndash10070 2008

[5] M Dikmen N Ozturk and Y Ozturk ldquoThe antioxidant poten-cy ofPunica granatum L fruit peel reduces cell proliferation andinduces apoptosis on breast cancerrdquo Journal of Medicinal Foodvol 14 no 12 pp 1638ndash1646 2011

[6] MYHongN P Seeram andDHeber ldquoPomegranate polyphe-nols down-regulate expression of androgen-synthesizing genesin human prostate cancer cells overexpressing the androgenreceptorrdquo Journal of Nutritional Biochemistry vol 19 no 12 pp848ndash855 2008

[7] J Jurenka ldquoTherapeutic applications of pomegranate (Punicagranatum L) a reviewrdquoAlternativeMedicine Review vol 13 no2 pp 128ndash144 2008

[8] S K Middha T Usha and T RaviKiran ldquoInfluence of Punicagranatum L on region specific responses in rat brain duringalloxan-induced diabetesrdquo Asian Pacific Journal of TropicalBiomedicine vol 2 no 2 pp S905ndashS909 2012

[9] M Viuda-Martos J Fernandez-Lopez and J A Perez-AlvarezldquoPomegranate and itsmany functional components as related tohuman health a reviewrdquoComprehensive Reviews in Food Scienceand Food Safety vol 9 no 2 pp 635ndash654 2010

[10] S R Kanatt R Chander and A Sharma ldquoAntioxidant andantimicrobial activity of pomegranate peel extract improves theshelf life of chicken productsrdquo International Journal of FoodScience and Technology vol 45 no 2 pp 216ndash222 2010

[11] E A Hayouni K Miled S Boubaker et al ldquoHydroalcoholicextract based-ointment from Punica granatum L peels withenhanced in vivo healing potential on dermal woundsrdquo Phy-tomedicine vol 18 no 11 pp 976ndash984 2011

[12] C N Aguilar A Aguilera-Carbo A Robledo et al ldquoProduc-tion of antioxidant nutraceutlcals by solid-state cultures ofpomegranate (Punica granatum) peel and creosote bush (Larreatridentata) leavesrdquo Food Technology and Biotechnology vol 46no 2 pp 218ndash222 2008

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

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Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Evidence-Based Complementary and Alternative Medicine 7

Table 6 Overview of in vivo Punica peel studies for diabetes and its complications

Preclinicaltrial In vivo studies Dayweek

Nature of peelextractdosages(per kg BWday)

OutcomeStatisticallysignificantresults

Reference

Diabetes Albino Wistar rats 284 Aqueous042 gLowering of blood sugarlevel and increased numberof 120573 cells

Yes [47]

Diabetes Albino Wistar rats 1013 Methanolic200mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [48]

Diabetes Albino Wistar rats 1523 Methanolic200mg

Improvement of hepaticcardiac and renal LPO andserum T3 T4 insulin andglucose concentrations

Yes [49]

Hyperlipidemic Sprague-Dawley rats 287 Methanolic510 15

Reduction of totalcholesterolLDL-cholesteroltriglyceridesVLDL-cholesterol H

Yes [50]

Diabetes Albino Wistar rats 287 Methanolic10mg20mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidaseglutathione-S-transferaseand glutathione reductasein liver and kidney

Yes [50]

Diabetes Albino Wistar rats 426 Methanolic75mgand 150mg

Increase of the activities ofantioxidant enzymescatalase superoxidedismutase glutathioneperoxidase and decreasedLPO level in hippocampaland cortex region of brain

Yes [8]

Diabetes Albino Wistar rats 213 Methanolic200mgand 400mg

Reduction of aldosereductase amylase PTP1Binhibition assay

Yes [32]

demonstrated pretreatment with PP enhanced or maintainedthe free radical scavenging activity of the hepatic enzymescatalase superoxide dismutase and peroxidase and resultedin 54 reduction of lipid peroxidation values compared tocontrols confirming the antioxidant property of the PP [50]

A discrete investigation in rats with CCl4-induced liver

damage demonstrated pretreatment with PP extract boostedthe free radical scavenging activity of the hepatic enzymessuperoxide dismutase and catalase and showed 54 declinein lipid peroxidation as compared to controls [69]

Hepatocellular carcinoma (HCC) a common and fatalcancer is majorly driven by oxidative stress The effect ofpomegranate emulsion (PE) on DENA-induced hepatocar-cinogenesis which mimics HCC in humans was examinedin an animal model Robust chemopreventive activities werereported owing to reduction in the incidence size volume

and multiplicity of the hepatic nodules In addition PE alsoalleviated lipid peroxidation and oxidation of proteins in theliver The report thus suggests and supports the use of pome-granate-derived agents in the treatment and prevention ofHCC in humans [70]

5 Mechanisms of Action

A recent study by Jain et al [32] has shown the probablemechanism of action of PP They have isolated and purifieda compound Valoneic acid dilactone (VAD) from the meth-anolic extract of Punica granatum (MEPG) MEPG-(400370mgkg po) and VAD-(25 50mgkg po) treated groupshave shown very minimal acinar damage and adequatenumber of pancreatic islets Their findings suggest that somepancreatic 120573-cells are still surviving to exert their insulinreleasing effect In diabetic conditionweight loss arises due to

8 Evidence-Based Complementary and Alternative Medicine

the impairment in insulin action in the conversion of glucoseinto glycogen The catabolism of fats does not occur as thereis an inhibition of lipolysis due to its unavailability whichis because of destruction in beta cells VAD and MEPGwere found to inhibit the alpha amylase activity which isa carbohydrate-hydrolysing enzyme thus decreases post-prandial hyperglycemia and improves glucose metabolismThe extracts VAD and MEPG were found to inhibit PTP1Bactivity which showed increase in insulin receptor tyrosinephosphorylation which mimicked in vivo action of insulinthereby decreased plasma glucose levels in a dose-dependentmanner The findings of their studies such as blood glucoselevels oral glucose tolerance test body weight mortalityand histopathology were in correlation with each other andindicate that MEPG and VAD could be beneficial in man-agement of diabetes and associated complications VAD wasobserved to be amore powerful inhibitor of aldose reductase120572-amylase and protein tyrosine phosphatase PTP1B whencompared to MEPG because of its polyphenolic nature

6 Toxicity StudiesSafetyAdverse Effects

There are relatively none in vivo or in vitro studies reportingthe toxic or adverse effect of the PP on any of the mammaliansystem The LD

50of the aqueous extract of PP in mice was

found to be 1321 plusmn 15mgkg ip [71]

7 Conclusion

Industries have moved towards usage of naturally derivedcompounds biologics as they are easily extractable and canbe cultured in labs Amongst these sources ecofriendly[4] Punica granatum peel has showed effectiveness due tothe array of compounds present in it These compoundshave good antioxidant activity and also serve as excellentnutritional supplements This review highlights the workthat has been done in the recent past on the PP whichincludes anti-hyperglycemic [8] hepatoprotective [56] andanti-hyperlipidemic effects [67] These experiments haveshown productive results both in in vivo and in vitro domainsHence more labs are moving towards PP as a suitabletherapeutic agent in various diseases

8 Future Direction

Despite the documented roles in nutrition there are very fewphytochemical studies The actions of mechanism of thesecompounds are still not very clearly understood however itis predicted that the mechanisms are quite complicated sincethere may be numerous factors involved in it

There is a dearth in the field of pharmacodynamics andpharmacokinetics or safety aspects of the PP There havebeen very few studies pertaining to the molecular aspects ofPP which is clearly evident by the sequence of informationavailable in the public domains Even though PP is richin healing properties due to the lacunae in many aspectsthere is an urgent requirement for further investigations todelineate its precise mechanisms and possible therapeuticvalues particularly in the field of diabetes mellitus

Conflict of Interest

The authors do not have any conflict of interest

Acknowledgments

The authors acknowledge (Dr) Dinesh Babu Ghent Uni-versity Belgium and Dr E L Cooper UCLA-CCIM LosAngeles CA USA for critically reviewing this paper Theauthors are thankful to Kumaun University Nainital and DrT L ShanthaDirectorMaharani LakshmiAmmanniCollegefor Women Bangalore India for providing the facilities tocarry out this review work

References

[1] J F Morton ldquoPomegranaterdquo in Fruits of Warm Climates pp352ndash355 ECHO Miami Fla USA 1987

[2] S K Middha Y Mittal T Usha et al ldquoPhyto-mellitus a phyto-chemical database for diabetesrdquoBioinformation vol 4 no 2 pp78ndash79 2009

[3] E Stover and E W Mercure ldquoThe pomegranate a new look atthe fruit of paradiserdquo HortScience vol 42 no 5 pp 1088ndash10922007

[4] A Shabtay H Eitam Y Tadmor et al ldquoNutritive and antiox-idative potential of fresh and stored pomegranate industrialbyproduct as a novel beef cattle feedrdquo Journal of Agricultural andFood Chemistry vol 56 no 21 pp 10063ndash10070 2008

[5] M Dikmen N Ozturk and Y Ozturk ldquoThe antioxidant poten-cy ofPunica granatum L fruit peel reduces cell proliferation andinduces apoptosis on breast cancerrdquo Journal of Medicinal Foodvol 14 no 12 pp 1638ndash1646 2011

[6] MYHongN P Seeram andDHeber ldquoPomegranate polyphe-nols down-regulate expression of androgen-synthesizing genesin human prostate cancer cells overexpressing the androgenreceptorrdquo Journal of Nutritional Biochemistry vol 19 no 12 pp848ndash855 2008

[7] J Jurenka ldquoTherapeutic applications of pomegranate (Punicagranatum L) a reviewrdquoAlternativeMedicine Review vol 13 no2 pp 128ndash144 2008

[8] S K Middha T Usha and T RaviKiran ldquoInfluence of Punicagranatum L on region specific responses in rat brain duringalloxan-induced diabetesrdquo Asian Pacific Journal of TropicalBiomedicine vol 2 no 2 pp S905ndashS909 2012

[9] M Viuda-Martos J Fernandez-Lopez and J A Perez-AlvarezldquoPomegranate and itsmany functional components as related tohuman health a reviewrdquoComprehensive Reviews in Food Scienceand Food Safety vol 9 no 2 pp 635ndash654 2010

[10] S R Kanatt R Chander and A Sharma ldquoAntioxidant andantimicrobial activity of pomegranate peel extract improves theshelf life of chicken productsrdquo International Journal of FoodScience and Technology vol 45 no 2 pp 216ndash222 2010

[11] E A Hayouni K Miled S Boubaker et al ldquoHydroalcoholicextract based-ointment from Punica granatum L peels withenhanced in vivo healing potential on dermal woundsrdquo Phy-tomedicine vol 18 no 11 pp 976ndash984 2011

[12] C N Aguilar A Aguilera-Carbo A Robledo et al ldquoProduc-tion of antioxidant nutraceutlcals by solid-state cultures ofpomegranate (Punica granatum) peel and creosote bush (Larreatridentata) leavesrdquo Food Technology and Biotechnology vol 46no 2 pp 218ndash222 2008

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

8 Evidence-Based Complementary and Alternative Medicine

the impairment in insulin action in the conversion of glucoseinto glycogen The catabolism of fats does not occur as thereis an inhibition of lipolysis due to its unavailability whichis because of destruction in beta cells VAD and MEPGwere found to inhibit the alpha amylase activity which isa carbohydrate-hydrolysing enzyme thus decreases post-prandial hyperglycemia and improves glucose metabolismThe extracts VAD and MEPG were found to inhibit PTP1Bactivity which showed increase in insulin receptor tyrosinephosphorylation which mimicked in vivo action of insulinthereby decreased plasma glucose levels in a dose-dependentmanner The findings of their studies such as blood glucoselevels oral glucose tolerance test body weight mortalityand histopathology were in correlation with each other andindicate that MEPG and VAD could be beneficial in man-agement of diabetes and associated complications VAD wasobserved to be amore powerful inhibitor of aldose reductase120572-amylase and protein tyrosine phosphatase PTP1B whencompared to MEPG because of its polyphenolic nature

6 Toxicity StudiesSafetyAdverse Effects

There are relatively none in vivo or in vitro studies reportingthe toxic or adverse effect of the PP on any of the mammaliansystem The LD

50of the aqueous extract of PP in mice was

found to be 1321 plusmn 15mgkg ip [71]

7 Conclusion

Industries have moved towards usage of naturally derivedcompounds biologics as they are easily extractable and canbe cultured in labs Amongst these sources ecofriendly[4] Punica granatum peel has showed effectiveness due tothe array of compounds present in it These compoundshave good antioxidant activity and also serve as excellentnutritional supplements This review highlights the workthat has been done in the recent past on the PP whichincludes anti-hyperglycemic [8] hepatoprotective [56] andanti-hyperlipidemic effects [67] These experiments haveshown productive results both in in vivo and in vitro domainsHence more labs are moving towards PP as a suitabletherapeutic agent in various diseases

8 Future Direction

Despite the documented roles in nutrition there are very fewphytochemical studies The actions of mechanism of thesecompounds are still not very clearly understood however itis predicted that the mechanisms are quite complicated sincethere may be numerous factors involved in it

There is a dearth in the field of pharmacodynamics andpharmacokinetics or safety aspects of the PP There havebeen very few studies pertaining to the molecular aspects ofPP which is clearly evident by the sequence of informationavailable in the public domains Even though PP is richin healing properties due to the lacunae in many aspectsthere is an urgent requirement for further investigations todelineate its precise mechanisms and possible therapeuticvalues particularly in the field of diabetes mellitus

Conflict of Interest

The authors do not have any conflict of interest

Acknowledgments

The authors acknowledge (Dr) Dinesh Babu Ghent Uni-versity Belgium and Dr E L Cooper UCLA-CCIM LosAngeles CA USA for critically reviewing this paper Theauthors are thankful to Kumaun University Nainital and DrT L ShanthaDirectorMaharani LakshmiAmmanniCollegefor Women Bangalore India for providing the facilities tocarry out this review work

References

[1] J F Morton ldquoPomegranaterdquo in Fruits of Warm Climates pp352ndash355 ECHO Miami Fla USA 1987

[2] S K Middha Y Mittal T Usha et al ldquoPhyto-mellitus a phyto-chemical database for diabetesrdquoBioinformation vol 4 no 2 pp78ndash79 2009

[3] E Stover and E W Mercure ldquoThe pomegranate a new look atthe fruit of paradiserdquo HortScience vol 42 no 5 pp 1088ndash10922007

[4] A Shabtay H Eitam Y Tadmor et al ldquoNutritive and antiox-idative potential of fresh and stored pomegranate industrialbyproduct as a novel beef cattle feedrdquo Journal of Agricultural andFood Chemistry vol 56 no 21 pp 10063ndash10070 2008

[5] M Dikmen N Ozturk and Y Ozturk ldquoThe antioxidant poten-cy ofPunica granatum L fruit peel reduces cell proliferation andinduces apoptosis on breast cancerrdquo Journal of Medicinal Foodvol 14 no 12 pp 1638ndash1646 2011

[6] MYHongN P Seeram andDHeber ldquoPomegranate polyphe-nols down-regulate expression of androgen-synthesizing genesin human prostate cancer cells overexpressing the androgenreceptorrdquo Journal of Nutritional Biochemistry vol 19 no 12 pp848ndash855 2008

[7] J Jurenka ldquoTherapeutic applications of pomegranate (Punicagranatum L) a reviewrdquoAlternativeMedicine Review vol 13 no2 pp 128ndash144 2008

[8] S K Middha T Usha and T RaviKiran ldquoInfluence of Punicagranatum L on region specific responses in rat brain duringalloxan-induced diabetesrdquo Asian Pacific Journal of TropicalBiomedicine vol 2 no 2 pp S905ndashS909 2012

[9] M Viuda-Martos J Fernandez-Lopez and J A Perez-AlvarezldquoPomegranate and itsmany functional components as related tohuman health a reviewrdquoComprehensive Reviews in Food Scienceand Food Safety vol 9 no 2 pp 635ndash654 2010

[10] S R Kanatt R Chander and A Sharma ldquoAntioxidant andantimicrobial activity of pomegranate peel extract improves theshelf life of chicken productsrdquo International Journal of FoodScience and Technology vol 45 no 2 pp 216ndash222 2010

[11] E A Hayouni K Miled S Boubaker et al ldquoHydroalcoholicextract based-ointment from Punica granatum L peels withenhanced in vivo healing potential on dermal woundsrdquo Phy-tomedicine vol 18 no 11 pp 976ndash984 2011

[12] C N Aguilar A Aguilera-Carbo A Robledo et al ldquoProduc-tion of antioxidant nutraceutlcals by solid-state cultures ofpomegranate (Punica granatum) peel and creosote bush (Larreatridentata) leavesrdquo Food Technology and Biotechnology vol 46no 2 pp 218ndash222 2008

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Evidence-Based Complementary and Alternative Medicine 9

[13] M Viuda-Martos Y Ruiz-Navajas A Martin-Sanchez et alldquoChemical Physico-chemical and Functional properties ofPomegrante (Punica granatum) Bagasse powder co-productrdquoJournal of Food Engineering vol 110 no 2 pp 220ndash224 2012

[14] H Satomi K Umemura A Ueno T Hatano T Okuda and TNoro ldquoCarbonic anhydrase inhibitors from the pericarps ofPunica granatum Lrdquo Biological and Pharmaceutical Bulletinvol 16 no 8 pp 787ndash790 1993

[15] M A M Nawwar S A M Hussein and I Merfort ldquoLeaf phe-nolics of Punica granatumrdquo Phytochemistry vol 37 no 4 pp1175ndash1177 1994

[16] MAMNawwar S AMHussein and IMerfort ldquoNMR spec-tral analysis of polyphenols fromPunica granatumrdquoPhytochem-istry vol 36 no 3 pp 793ndash798 1994

[17] Y Amakura M Okada S Tsuji and Y Tonogai ldquoHigh-per-formance liquid chromatographic determination with photodi-ode array detection of ellagic acid in fresh and processed fruitsrdquoJournal of Chromatography A vol 896 no 1-2 pp 87ndash93 2000

[18] R F Wang W D Xie Z Zhang et al ldquoBioactive compoundsfrom the seeds of Punica granatum (pomegranate)rdquo Journal ofNatural Products vol 67 no 12 pp 2096ndash2098 2004

[19] T H W Huang G Peng B P Kota et al ldquoAnti-diabetic actionof Punica granatum flower extract activation of PPAR-120574 andidentification of an active componentrdquo Toxicology and AppliedPharmacology vol 207 no 2 pp 160ndash169 2005

[20] K Rena A Palida and X Y Zhang ldquoStudies on the chemicalconstituents from Xinjiang Punica granatumrdquo Journal of Chi-nese Medicinal Materials vol 32 no 3 pp 363ndash365 2009

[21] T Tanaka G I Nonaka and I Nishioka ldquoTannins and relatedcompounds C Reaction of dehydrohexahydroxydiphenic acidesters with bases and its application to the structure determina-tion of pomegranate tannins granatins A and Brdquo Chemical andPharmaceutical Bulletin vol 38 no 9 pp 2424ndash2428 1990

[22] Y Z Liu and H X Li ldquoTannins and polyphenols in pericarps ofPunica granatum Lrdquo Chinese Traditional and Herbal Drug vol38 pp 502ndash504 2007

[23] M I Gil F A Tomas-Barberan B Hess-Pierce D M Holcroftand A A Kader ldquoAntioxidant activity of pomegranate juiceand its relationship with phenolic composition and processingrdquoJournal of Agricultural and Food Chemistry vol 48 no 10 pp4581ndash4589 2000

[24] A P Kulkarni S M Aradhya and S Divakar ldquoIsolation andidentification of a radical scavenging antioxidantmdashpunicalaginfrompith and carpellarymembrane of pomegranate fruitrdquo FoodChemistry vol 87 no 4 pp 551ndash557 2004

[25] S de Pascual-Teresa C Santos-Buelga and J C Rivas-GonzaloldquoQuantitative analysis of flavan-3-ols in Spanish foodstuffs andbeveragesrdquo Journal of Agriculture and Food Chemistry vol 48no 11 pp 5331ndash5337 2000

[26] Y Noda T Kaneyuki A Mori and L Packer ldquoAntioxidantactivities of pomegranate fruit extract and its anthocyanidinsdelphinidin cyanidin andpelargonidinrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 166ndash171 2002

[27] D A van Elswijk U P Schobel E P Lansky H Irth and Jvan der Greef ldquoRapid dereplication of estrogenic compoundsin pomegranate (Punica granatum) using on-line biochemicaldetection coupled to mass spectrometryrdquo Phytochemistry vol65 no 2 pp 233ndash241 2004

[28] E P Lansky and R A Newman ldquoPunica granatum (pomegran-ate) and its potential for prevention and treatment of inflamma-tion and cancerrdquo Journal of Ethnopharmacology vol 109 no 2pp 177ndash206 2007

[29] N Artik ldquoDetermination of phenolic compounds in pome-granate juice by using HPLCrdquo Fruit Processing vol 8 no 1 pp492ndash499 1998

[30] H Neuhofer L Witte M Gorunovic and F C CzyganldquoAlkaloids in the bark of Punica granatum L (Pomegranate)from Yugoslaviardquo Pharmazie vol 48 no 5 pp 389ndash391 1993

[31] A Vidal A Fallarero B R Pena et al ldquoStudies on the toxicity ofPunica granatum L (Punicaceae) whole fruit extractsrdquo Journalof Ethnopharmacology vol 89 no 2-3 pp 295ndash300 2003

[32] V Jain G L Viswanatha D Manohar and H N ShivaprasadldquoIsolation of antidiabetic principle from fruit rinds of Punicagranatumrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 147202 11 pages 2012

[33] V Akbarpour K Hemmanti and M Sharifani ldquoPhysical andchemical properties of pomegranate (Punica granatum L) fruitin maturation stagerdquo The American-Eurasian Journal Agricul-ture and Environmental Science vol 6 no 4 pp 411ndash416 2009

[34] T Usha P Tripathi V Pande and S K Middha ldquoMoleculardocking and quantum mechanical studies on pelargonidin-3-glucoside as renoprotective ACE inhibitorrdquo ISRN Computa-tional Biology vol 2013 Article ID 428378 4 pages 2013

[35] HX Li ZWang andY Z Liu ldquoProgress in studies on chemicalconstituents and pharmacological effects of Punicaceaerdquo Chi-nese Traditional and Herbal Drugs vol 33 pp 765ndash769 2002

[36] C Ben Nasr N Ayed and M Metche ldquoQuantitative deter-mination of the polyphenolic content of pomegranate peelrdquoZeitschrift fur Lebensmittel-Untersuchung und-Forschung vol203 no 4 pp 374ndash378 1996

[37] K N C Murthy K V Reddy J M Veigas and U D MurthyldquoStudy on wound healing activity of Punica granatum peelrdquoJournal of Medicinal Food vol 7 no 2 pp 256ndash259 2004

[38] E Shwartz I Glazer I Bar-Yarsquoakov et al ldquoChanges in chemicalconstituents during the maturation and ripening of two com-mercially important pomegranate accessionsrdquo Food Chemistryvol 115 no 3 pp 965ndash973 2009

[39] GW Plumb S de Pascual-Teresa C Santos-Buelga J C Rivas-Gonzalo and G Williamson ldquoAntioxidant properties of gallo-catechin and prodelphinidins from pomegranate peelrdquo RedoxReport vol 7 no 1 pp 41ndash46 2002

[40] P S Negi andGK Jayaprakasha ldquoAntioxidant and antibacterialactivities of Punica granatum peel extractsrdquo Journal of FoodScience vol 68 no 4 pp 1473ndash1477 2003

[41] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[42] S Rout andR Banerjee ldquoFree radical scavenging anti-glycationand tyrosinase inhibition properties of a polysaccharide frac-tion isolated from the rind from Punica granatumrdquo BioresourceTechnology vol 98 no 16 pp 3159ndash3163 2007

[43] S Okonogi C Duangrat S Anuchpreeda S Tachakittirun-grod and S Chowwanapoonpohn ldquoComparison of antioxidantcapacities and cytotoxicities of certain fruit peelsrdquo Food Chem-istry vol 103 no 3 pp 839ndash846 2007

[44] M Hajimahmoodi M R Oveisi N Sadeghi et al ldquoAntioxidantproperties of peel and pulp hydro extract in ten Persianpomegranate cultivarsrdquo Pakistan Journal of Biological Sciencesvol 11 no 12 pp 1600ndash1604 2008

[45] S Surveswaran Y Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

10 Evidence-Based Complementary and Alternative Medicine

[46] Y Li C Guo J Yang J Wei J Xu and S Cheng ldquoEvaluation ofantioxidant properties of pomegranate peel extract in compar-ison with pomegranate pulp extractrdquo Food Chemistry vol 96no 2 pp 254ndash260 2006

[47] E A M Khalil ldquoAntidiabetic effect of an aqueous extract ofpomegranate (Punica granatum L) peels in normal and alloxandiabetic ratsrdquoThe Egyptian Journal of Hospital Medicine vol 16no 1 pp 92ndash99 2004

[48] H S Parmar and A Kar ldquoAntidiabetic potential of Citrussinensis and Punica granatum peel extracts in alloxan treatedmale micerdquo BioFactors vol 31 no 1 pp 17ndash24 2007

[49] H S Parmar and A Kar ldquoMedicinal values of fruit peels fromCitrus sinensis Punica granatum and Musa paradisiaca withrespect to alterations in tissue lipid peroxidation and serumconcentration of glucose insulin and thyroid hormonesrdquoJournal of Medicinal Food vol 11 no 2 pp 376ndash381 2008

[50] O Y Althunibat A H Al-Mustafa K Tarawneh K MKhleifat B H Ridzwan and H N Qaralleh ldquoProtective roleof Punica granatum L peel extract against oxidative damage inexperimental diabetic ratsrdquo Process Biochemistry vol 45 no 4pp 581ndash585 2010

[51] S K Middha B Bhattacharjee D Saini M S Baliga M BNagaveni and T Usha ldquoProtective role of Trigonella foenumgraceum extract against oxidative stress in hyperglycemic ratsrdquoEuropean Review for Medical and Pharmacological Sciences vol15 no 4 pp 427ndash435 2011

[52] R Singh M K Singh L R Chandra et al ldquoIn vitro antioxidantand free radical scavenging activity of Macrotyloma uniflorum(Gahat dal) from Kumauni regionrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[53] B Kiran V Lalitha and K A Raveesha ldquoPsoralea corylifoliaL a potent medicinal plant with broad spectrum of medicinalpropertiesrdquo International Journal of Fundamental and AppliedScience vol 2 no 1 pp 20ndash22 2013

[54] M P Prasad S Shekhar and B Amit ldquoPhytochemical analysisand antioxidant potential of Piper species and its molecularcharacterization by RAPD markersrdquo International Journal ofFundamental and Applied Science vol 1 no 1 pp 7ndash10 2012

[55] R P Singh KN CMurthy andGK Jayaprakasha ldquoStudies onthe antioxidant activity of pomegranate (Punica granatum) peeland seed extracts using in vitromodelsrdquo Journal of Agriculturaland Food Chemistry vol 50 no 1 pp 81ndash86 2002

[56] K N C Murthy G K Jayaprakasha and R P Singh ldquoStudieson antioxidant activity of pomegranate (Punica granatum) peelextract using in vivo modelsrdquo Journal of Agricultural and FoodChemistry vol 50 no 17 pp 4791ndash4795 2002

[57] L Zhang X Yang Y Zhang L Wang and R Zhang ldquoInvitro antioxidant properties of different parts of pomegranateflowersrdquo Food and Bioproducts Processing vol 89 no 3 pp 234ndash240 2011

[58] A H Al-Mustafa and O Y Al-Thunibat ldquoAntioxidant activityof some Jordanian medicinal plants used traditionally fortreatment of diabetesrdquo Pakistan Journal of Biological Sciencesvol 11 no 3 pp 351ndash358 2008

[59] E A Moneim ldquoAntioxidant activities of Punica granatum(pomegranate) peel extract on brain of ratsrdquo Journal of Medici-nal Plants Research vol 6 no 2 pp 195ndash199 2012

[60] Z Pan W Qu H Ma G G Atungulu and T H McHughldquoContinuos and pulsed ultrasound assisted extractions ofantioxidants frompomegranate peelrdquoUltrasonic Sonochemistryvol 19 no 2 pp 365ndash372 2012

[61] S K Middha T Usha P Tripathi et al ldquoAn in vitro studies onindigenous ayurvedic plants having hypoglycemic activityrdquoAsian Pacific Journal of Tropical Disease vol 2 supplement 1pp 46ndash49 2012

[62] D G Nogueira and N A Pereira ldquoEffect of an extract of Punicagranatum (pomegranate) in hyperglycemic mice treated withpropranololrdquo Revista Brasileira de Farmacia vol 65 no 1ndash3 pp46ndash51 1984

[63] D G Nogueira and N A Pereira ldquoEffect of an alcoholic extractfrom the pericarp of roma (Punica granatum L) on insulinhypoglycemia micerdquo Review Brasial Farm vol 67 p 59 1986

[64] DGNogueira andNA Pereira ldquoInhibitory action of intestinalabsorption of glucose of the pericarp of roma (Punica grantumL)rdquo Review Brasial Farm vol 67 p 129 1986

[65] R Zafar and J Singh ldquoAntidiabetic activity of Punica granatumLinnrdquo Science Culture vol 56 no 7 article 3 1990

[66] O Nozire and D Serpil ldquoValuation of the pomegranate (Punicagranatum L) peels from the stand point of pharmacyrdquo AnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 22 pp 121ndash122 1993

[67] S Cheng C Guo J Yang J Wei Y Li and J Xu ldquoExperimentalstudy on hypolipidemic effect of polyphenolic extract frompomegranate peelrdquo Journal of Preventive Medicine of ChinesePeoplersquos Liberation Army vol 3 pp 160ndash163

[68] H Z Toklu M U Dumlu O Sehirli et al ldquoPomegranate peelextract prevents liver fibrosis in biliary-obstructed ratsrdquo Journalof Pharmacy and Pharmacology vol 59 no 9 pp 1287ndash12952007

[69] Z Z Xu J H Feng H W Lu L Bao and H Kurihara ldquoEffectof pomegranate peel extracts on oxidative stress in restrainedmicerdquo Zhong Yao Cai vol 31 no 8 pp 1193ndash1196 2008

[70] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[71] E Y Qnais A S Elokda Y Y A Ghalyun and F A AbdullaldquoAntidiarrheal activity of the aqueous extract of Punica grana-tum (pomegranate) peelsrdquo Pharmaceutical Biology vol 45 no9 pp 715ndash720 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom