Review Article Emerging Roles of Propolis: Antioxidant, …downloads.hindawi.com/journals/ecam/2013/175135.pdf · 2019. 7. 31. · e antioxidant e ect of Brazilian red propolis has

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2013 Article ID 175135 8 pageshttpdxdoiorg1011552013175135

Review ArticleEmerging Roles of Propolis Antioxidant Cardioprotective andAntiangiogenic Actions

Julio Beltrame Daleprane1 and Dulcineacuteia Saes Abdalla2

1 Department of Basic and Experimental Nutrition Institute of Nutrition State University of Rio de Janeiro20559-900 Rio de Janeiro RJ Brazil

2 Department of Clinical and Toxicology Analysis Faculty of Pharmaceutical Sciences University of Sao Paulo05508-900 Sao Paulo SP Brazil

Correspondence should be addressed to Dulcineia Saes Abdalla dspabdallagmailcom

Received 15 January 2013 Revised 19 March 2013 Accepted 20 March 2013

Academic Editor Vassya Bankova

Copyright copy 2013 J B Daleprane and D S Abdalla This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Propolis has attracted attention in recent years due to its beneficial effects whichmake it a potential preventive and therapeutic agentas well as a useful additive in food and cosmetics The aim of this review is to discuss the growing evidence that propolis may viaa diverse array of biological actions assist in the prevention of some inflammation-mediated pathologies including cardiovasculardisease The active components of propolis that have been identified so far include polyphenols and flavonoids These compoundshave cardioprotective vasoprotective antioxidant antiatherosclerotic anti-inflammatory and antiangiogenic actionsMany studieshave been undertaken to elucidate themechanism(s) bywhich propolis acts which involve cellular signaling targets and interactionsat the genomic level This review will highlight the effects of propolis that may assist in the prevention of chronic degenerativediseases such as cardiovascular disease

1 Introduction

The growing market for natural products and alternativemedicines has renewed interest in bee products such ashoney royal jelly pollen and propolis [1 2] Propolis is thegeneric name for a complex resinous mixture collected byhoney bees from the buds and exudates of various plantsOnce collected this material is enriched with saliva andenzyme-containing secretions and used in the constructionadaptation and protection of hives [3 4]

In recent years many studies of the chemistry of propolishave been published which reveal that its highly variablecomposition is influenced by the local flora at the collectionsite [5ndash7] Although many biological activities of propolisare consistently observed the components responsible varybetween geographic and climatic zones [7]

There is considerable evidence on various chemical andbiological aspects of propolis but the therapeutic applica-tion and utilization by the pharmaceutical industry are stilllimited This is mainly due to the variability of its chemical

composition with geographical origin because bees utilizedifferent plants in different ecosystems Identification of themajor compounds in propolis samples is essential reports ofthe biological properties of propolis should include a detailedinvestigation of its composition and botanical sources [7 8]

The constituents of propolis include polyphenols (fla-vonoids phenolic acids and esters) terpenoids steroidsand amino acids [9] There has been extensive research intothe composition and biological activities of propolis fromvarious countries [10ndash13] Propolis samples from EuropeSouth America and Asia have different compositions andtherefore different biological activities [12 14 15] Howeverpropolis samples generally show great similarity in theiroverall composition regardless of botanical source [15]Brazilian red propolis has been found in two reports to con-tain high concentrations of phenolic compounds 232mgg[16] and 25798mgg respectively [17] Brazilian propolisalso contained higher concentrations of total phenols thansamples from other countries China 302plusmn43mgg [18] and299 plusmn 05mgg [19] Korea 2127 plusmn 74mgg [20] Argentina

2 Evidence-Based Complementary and Alternative Medicine

187mgg [21] India 15910 plusmn 026mgg [10] Portugal 151 plusmn001mgg [22] Cyprus 1004 plusmn 72mgg [23] and Thailand312 plusmn 07mgg [19]

Studies indicate that propolis from Europe and Chinacontains many flavonoids and phenolic acids tropical propo-lis generally contains low concentrations of flavonoids [21 2425]

Studies of propolis demonstrate the complexity of itscomposition and pharmacology some compounds act inde-pendently while others act synergistically The therapeuticpotential of propolis and its constituents has been the subjectof many studies which have established many pharmacolog-ical actions in preclinical testing

In particular propolis shows therapeutic potential andmay have applications in the pharmaceutical and food pro-cessing industries [25ndash27] Propolis reportedly has a rangeof biological activities including immunomodulatory [2829] antibacterial [30] fungicidal [31 32] anti-inflammatoryhealing [33] analgesicanesthetic [34 35] and anticarcino-genic effects [36]

The relationship between oxidative stress cardiovasculardisease and angiogenesis is well established Events related tothe pathophysiology of angiogenesis and associated cytokinesand growth factors can lead to a poor prognosis in manydiseases In fact chronic cardiovascular disease oxidativestress and angiogenesis are strongly associated with oneanother In this review we will present evidence that propolisextracts and their bioactive compounds have antioxidantcardioprotective and antiangiogenic activities (Figure 1)

2 Antioxidant Activity

It is well established that cellular metabolism generates re-active oxygen species (ROS) such as hydrogen peroxide(H2O2) the superoxide anion (O

2

minus) and the highly reactivehydroxyl ion (HOminus) as well as reactive nitrogen species(RNS) especially nitric oxide (NO) ROS and RNS are idealsignaling molecules because they are locally generated arehighly and rapidly diffusible and can be neutralized bycellular antioxidants [37 38] ROS are usually detoxified byintracellular enzymes such as glutathione superoxide dis-mutase and catalase [39] However unbalanced productionand degradation of ROS and RNS can result in accumulationof these reactive species commonly referred to as oxidativestress Exposure of macromolecules (lipid proteins DNAetc) to reactive species results in oxidativemodificationswithdeleterious effects [40 41]

The antioxidant capacity of propolis may be related tosome of its biological effects including chemopreventionThe flavonoids in propolis are powerful antioxidants capableof scavenging free radicals and thereby protecting the cellmembrane against lipid peroxidation [42] Moreover ROSand RNS together with other factors are involved in cellu-lar ageing and death in conditions such as cardiovasculardisease arthritis cancer diabetes Parkinsonrsquos disease andAlzheimerrsquos disease [43ndash47] Propolis can reduce cellularlevels of H

2O2and NO which may be involved in its anti-

inflammatory effects [48]

Oxidative stress

AngiogenesisCardiovasculardiseases

Propolis

Figure 1 Schematic representation of the relationship betweenoxidative stress cardiovascular disease and angiogenesis and theeffects of propolis on these integrated systems Propolis influencesmultiples biochemical signaling pathways including protectivemechanisms reducing events related to chronic inflammatory dis-eases

Diverse compounds frompropolis have been described aspotent inhibitors of oxidative stress It is well known that thecomposition of propolis is variable however one of its majorcomponents caffeic acid phenethyl ester (CAPE) blocks ROSproduction in several systems [49] CAPE has also beenidentified as one of the major cancer chemopreventive andanti-inflammatory compounds in propolis In vitro propolisinhibits peroxidation of LDL and nitration of proteins More-over in bovine aortic endothelial cells propolis was reportedto increase eNOS expression and inhibit NADPH oxidase(NOX) [50] In vivo propolis can increase antioxidant capac-ity in animals [51] and humans [52] leading to decreasedlipid peroxidation which is strongly associated with therisk of cardiovascular disease [53 54] Turkish propolisinhibited hydrogen peroxide (H

2O2-) induced damage to

DNA in cultured fibroblasts [55] The antioxidant activityof phenolic components of the Turkish propolis may reducedamage to DNA induced by H

2O2 which may be related

to its chemopreventive activity Red propolis from Cubahas shown protective effects in models of alcohol-inducedliver damage most likely due to its antioxidant properties[56] Propolis inhibited macrophage apoptosis via effects onglutathione (GSH) and the tumor necrosis factorsnuclearfactor kappa B (TNFNF-120581B) pathway [57 58] MoreoverBrazilian propolis from Baccharis dracunculifolia modulated12-dimethlyhydrazine (DMH-) induced DNA damage incolon cells [59]

Isla et al [60] described the protective effect of the Ar-gentinian propolis from different sources against copper-mediated oxidative modification of lipids in unfractionatedserum Five types of Argentinian propolis collected in dif-ferent regions inhibited lipid oxidation during the initiationand propagation phases All five types of propolis diminishedthe maximal rate and extent of diene production indicatingthat flavonoids can scavenge free radicals such as superoxide[61 62] protecting serum lipids from oxidation [60] Jasprica

Evidence-Based Complementary and Alternative Medicine 3

et al [52] showed that daily intake of powdered propolis for15 days decreased the plasmamalondialdehyde concentrationinmenThe extract (065 g) available in Croatian communitypharmacies contained 25 total flavonoids equivalent to1625mg of galangin After 30 days of treatment an increasein superoxide dismutase activity and changes in red blood cellparameters were detected including cell count hemoglobinand mean corpuscular volume and cell distribution

The antioxidant effect of Brazilian red propolis has beenattributed to chalcones and isoflavonoids (including 7-O-methylvestitol medicarpin and 342101584031015840-tetrahydrochal-cone) that act as electron donors [63] Furthermore totalflavonoid content in Brazilian red propolis is correlatedwith antioxidant activity suggesting that all the phenolicand flavonoid compounds present contribute to this activity[64] Chinese red propolis had a higher antioxidant activitythan propolis from other sources which was attributedpredominantly to CAPE [65] Chilean propolis also has anti-oxidant properties which are correlated with its chemicalcomposition [66] Additionally the antioxidant and free-radical-scavenging properties of propolis may be due to itsphenylpropanoid content [67] Thus the available data indi-cate that propolis of different origins and distinct compo-sitions consistently exhibit antioxidant actions In additionto this antioxidant effect bioactive compounds in propolisinfluence a large number of biochemical signaling pathwaysand therefore physiological and pathological processesAntioxidant capacity is one of the most important propertiesof propolis Although there are several studies corroboratingthe potential antioxidant activity of propolis there is norobust data on the safe dose in humans Thus there is needfor clinical studies using propolis and its biologically activecompounds including studies of safety and bioavailability

3 Cardioprotective Activity

Themodulation of cardiovascular disease markers by propo-lis has been shown in several studies In vitro and invivo assays have been developed to elucidate the molecularmechanisms of this beneficial effect regulation of glucoseand lipoprotein metabolism modulation of gene expressiondecrease of the activity of scavenger receptors inflammatorycytokines and oxidative stress improvement of endothelialfunction and inhibition of platelet aggregation

Atherosclerosis is a complex process involving the accu-mulation andmodification of plasma lipoproteins in the arte-rial wall as well as the recruitment and proliferation ofimmune cells This process advances through a series ofstages beginning with the appearance of a fatty streak lesioncomposed largely of foam cells which are lipid-engulfedmacrophages The fatty streak evolves into a complex athe-rosclerotic plaque consisting of a lipid core covered by afibrous cap with some areas that are rich in inflammatorycells [68ndash70] Several authors have postulated that dietarypolyphenols reduce the risk of cardiovascular disorders andprevent the development of atheromatous plaques [71ndash73]Thus as a rich source of polyphenols propolis represents

a potential alternative strategy for the prevention of cardio-vascular disorders

Propolis has been shown to modulate lipid and lipopro-tein metabolism Propolis administration diminished livercholesterol and triglyceride content and decreased the rate ofhepatic triglyceride synthesis in rats [74 75] In LDL recep-tor knockout mice (LDLrminusminus) treatment with Brazilian redpropolis (250mgkgday) decreased levels of triacylglycerol(TAG) total cholesterol (TC) and non-high-density lipopro-tein cholesterol (non-HDL-C) [76] LDLrminusminus mice treatedwith Brazilian green propolis which is rich in Artepillin Cpinocembrin kaempferol or with Chilean brown propoliswhich is rich in pinocembrin CAPE quercetin and galanginalso presented low levels of non-HDL-C Moreover micetreated with Brazilian red propolis showed significantlyreduced TAG and TC and increased HDL-C comparedto untreated mice Furthermore Turkish propolis which isrich in flavonoids (mainly galangin quercetin kaempferolapigenin pinobanksin pinocembrin and pinostrobin) pre-vented alcohol-induced acute liver damage and lipid accumu-lation and induced beneficial changes in the serum lipid pro-file HDL levels were high and LDL levels were low in micetreated with propolis and alcohol compared to alcohol only[59] Moreover propolis also positively affected HDL andLDL levels in rats Treatment of diabetic rats with propolisof poplar origin diminished levels of total cholesterol LDL-cholesterol VLDL-cholesterol and triglycerides reinforcingthe case that propolis modulates lipid metabolism and maybe helpful in syndromes caused by blood lipid abnormalities[75]

In a recent study the authors hypothesized that propolismay aid in the prevention rather than treatment of atheroscle-rosis LDLrminusminus mice were treated with distinct polyphenol-rich propolis extracts (250mg polyphenolsmLKg) [76]Brazilian green Brazilian red and Chilean brown propolisreduced the area of atherosclerotic lesionswhen administeredpreventively The strongest inhibitory effect was observedfor Brazilian red propolis which also induced regressionof atherosclerotic lesions [76] Polyphenols from propolisinhibited the progression of atherosclerosis in LDLrminusminus miceby improving the lipid profile and by downregulating proin-flammatory cytokines chemokines and angiogenic factorsPropolis downregulated the mRNA expression of key genesinvolved in the atherosclerotic process such asMCP-1 INFgIL6 CD36 and TGF120573 [76]

It is well known that the modification of the lipidprofile is strongly associated with cardiovascular disease[76 77] Propolis diminished total cholesterol and elevatedHDL-cholesterol in mice One proposed mechanism of thehypocholesterolemic action of propolis involves the ABCA1receptor Many types of propolis upregulate ABCA1 geneexpression which is associated with increased HDL levelsthus ABCA1 up-regulationmay be onemechanism by whichpropolis improves the lipid profile [76]

An ethanolic extract of Brazilian red propolis (EERP)enhanced ABCA1 promoter activity in THP-1 macrophages[77] Additionally cholesterol efflux from macrophages toApoA-I was significantly increased in a dose-dependent


manner by EERP treatment Thus EERP significantlyenhanced ApoA-I-mediated cholesterol efflux in THP-1macrophages which was accompanied by a marked up-regulation of the ABCA1 geneThe effect of EERP onABCA1-dependent cholesterol efflux may be due to the activation ofPPAR120574 and LXR120572 [77] In HepG2 and Raw 2647 cell linesEEP promoted cholesterol efflux and increased the expressionof ABCA1 and ABCG1 Accordingly C57BL6 mice treatedwith 50mgkg EEP once a day for 4 weeks by oral gavageshowed increased plasma HDL-cholesterol but unchangedLDL-cholesterol [78] Thus in vitro and in vivo data suggestthat the beneficial effects of propolis on lipid profile maybe one of the mechanisms involved in its atheroprotectiveeffects This finding suggests that polyphenols from propolismay be useful for the prevention of atherosclerosis

Platelet aggregation is a major contributor to the athero-sclerotic process Propolis components have shown impor-tant effects on platelet aggregation CAPE (15 and 25 120583M)markedly inhibited collagen-stimulated platelet aggregationAs CAPE is involved in various inhibitory pathways influenc-ing platelet aggregation it may be an important contributorto the potent antiplatelet actions of propolis [79]

NO is an important vasoactive mediator with vasodila-tory and antiaggregative actions that protect blood vesselswhen released from endothelial cells at low concentrationsHowever when NO is produced in high concentrationsby inflammatory cells it may react with other nitrogenand oxygen species inducing oxidative andor nitrosativestress Following the treatment of diabetic mice with poplarpropolis the levels of NO and nitric oxide synthase (NOS)decreased compared to nondiabetic mice [75] Propolisdecreases NO level by decreasing NOS activity thus pro-tecting blood vessel endothelial cells and reducing neuronaltoxicity Additionally propolis exerts pharmacological effectsby decreasing the actions of NO and PGE2 as well as byreducing the activation of protein kinase in diabetes [75 80]Moreover ethanolic extracts of propolis (EEP) inhibit NOproduction by decreasing iNOS expression in Raw 2647macrophages and by directly inhibiting the catalytic activityof iNOS The inhibitory effect of EEP on LPS plus IFN-g-induced NO production is mediated either by inhibition ofiNOS gene transcription via an action on NF-120581B sites inthe iNOS promoter or by direct inhibition of the catalyticactivity of iNOS [81] As excess NO production has beenimplicated in the cardiovascular inflammatory process theanti-inflammatory activities of EEP may also be mediated bymodulation of NO levels

It is well established that proliferation of vascular smoothmuscle cells (VSMCs) is involved in the onset of atheroscle-rosis Roos et al [82] evaluated the antiproliferative activity ofCAFE one of the major components of propolis and honey-derived products in primary rat aortic VSMCs stimulatedby platelet-derived growth factor (PDGF) CAFE inhibitedproliferation of VSMCs upon exposure to PDGF in a dose-dependent manner by interfering with cell cycle progressionfrom the G01- to the S-phase This study indicates that theinhibition of smooth muscle cell proliferation may also beinvolved in the atheroprotective action of propolis

4 Antiangiogenic Activity

Angiogenesis is the multistep process by which blood ves-sels are formed This tightly regulated process involves themigration proliferation and differentiation of endothelialcells [83] Regulation of angiogenesis is absent or aberrantin several diseases characterized by persistent inappropriateblood vessel development Inappropriate angiogenesis occursinmore than 80 diseases particularly inmany types of cancerand inflammatory diseases as atherosclerosis [84 85]

According to Keshavarz et al [86] green propolis extractscontaining artepillin C and CAPE significantly reduced thenumber of new vessels formed and the expression of metallo-proteinases (MMPs) and production of vascular endothelialgrowth factor (VEGF) from endothelial cells [87] Differentsteps of angiogenesis can be affected by propolis and itscomponents Brazilian propolis and its major componentartepillin C can inhibit proliferation of human umbilicalvein endothelial cells (HUVEC) as well as endothelial cellmigration and capillary tube formation in a dose-dependentmanner Moreover artepillin C can suppress angiogenesis inboth in vivo and in vitromodels while CAPE inhibits MMP-2 MMP-9 and VEGF activity [87ndash90]

The effects of Brazilian propolis on HUVEC apoptosiswere investigated by Xuan et al [91] At a low concentration(125 120583gmL) the polyphenols in ethanol extracts of Brazilianpropolis decreased the expression of integrin b4 and p53 andthe production of ROS The opposite effects were observedat high polyphenol concentrations (25 and 50120583gmL) alongwith depression of mitochondrial membrane potentialThushigh doses of polyphenols from Brazilian propolis mayinduce HUVEC apoptosis by acting on the integrin b4 andp53 signaling pathway resulting in disturbance of mitochon-drial membrane potential and increased ROS generation

Daleprane et al [92] investigated the actions of polyphe-nols from Brazilian red propolis on models of angiogen-esis Brazilian red propolis is rich in 123-trimethoxy-5-(2-propenyl)-benzene methoxyeugenol homopterocarpinmedicarpin 246-trimethylphenol 497-dimethoxy-29-iso-flavonol 749-dihydroxyisoflavone and 2H-1-benzopyran-7-ol [64] Brazilian red propolis (10mgL) reduced themigration and sprouting of endothelial cells attenuatedthe formation of new blood vessels and decreased thedifferentiation of embryonic stem cells into CD31-positivecells Moreover Brazilian red propolis inhibited hypoxia- ordimethyloxalylglycine-induced mRNA and protein expres-sion of the crucial angiogenesis promoter vascular endothe-lial growth factor (VEGF) in a time-dependent manner [92]

Hypoxia is implicated in many inflammatory diseasesThe proposal that hypoxia can induce inflammation hasgained general acceptance from studies of the hypoxia sig-naling pathway [93] Brazilian red propolis decreases accu-mulation of hypoxia-inducible factor 1 alpha (HIF1120572) underhypoxic conditions which in turn attenuates VEGF geneexpression [92] Reduced HIF1120572 protein half-life was associ-ated with increased von Hippel-Lindau (pVHL-) dependentproteasomal degradation of HIF1120572 and reduced Cdc42 pro-tein expression [92]


Brazilian green propolis extract which is rich in artepillinC was evaluated by Hattori et al for its effects on cellularresponses to hypoxia [94] Five compounds that modulatedHIF-1 activity were identified Hydroxycinnamic acid deriva-tives from Brazilian green propolis inhibited not only HIF-1transcriptional activity but also hypoxia-induced expressionof HIF-1120572 protein and downstream target genes such asGlucose transporter 1 Hexokinase 2 and vascular endothelialgrowth factor A Furthermore the HIF-1 inhibitors alsoinhibited angiogenesis Daleprane et al [76] investigated theeffect of polyphenols from Brazilian propolis on angiogenicgene expression in atherosclerotic lesions of LDLrminusminus micefinding that angiopoietin I angiopoietin II VEGF fibroblastgrowth factor metalloproteinases 2 and 9 platelet-derivedgrowth factor and platelet endothelial cell adhesionmoleculewere downregulated by polyphenols from Brazilian red andgreen propolis

It has been reported that the propolis extracts showantiproliferative activity and that both extracts induced celldeath by necrosis [95] The latter result indicates that certaincompounds contained in propolis possess cytocidal activitybased on necrosis rather than apoptosis On the otherhand polyphenols which are tumor necrosis factor-relatedapoptosis inducing ligands preferentially induce apoptosisin cancer cells and are not toxic to normal cells [96] Theseresults are therefore not consistent with each other Theinconsistency of propolis activity may be due to the pres-ence of numerous compounds in varying levels dependingon their geographical origin Generally biological activityhas been assessed by independent groups making a directcomparison of their work difficult Propolis-based medicinesare often prepared from ethanol extracts of honey hive asthe extracts are generally water insoluble Further studies arerequired to establish the quantity and safety control criteriafor propolis to allow it to be used safely and to gain themaximum benefit from its biological activities

In vitro and in vivo studies are uncovering antiangiogenicactivity in many natural health products including propolisextracts and their constituents Further preclinical researchis required to determine whether individual compoundsor complex mixtures will be optimal for clinical trials Apotential advantage of phytochemicals and other compoundsfrom propolis is that they may act through multiple cellularsignaling pathways acting in different pathophysiologicalconditions while also inhibiting angiogenesis and reducinginflammation Overall propolis constituents may be helpfulas auxiliary therapies for diseases in which angiogenesis mustbe controlled such as cancer and cardiovascular disease

5 Perspectives on Propolis Utilization

Propolis contains a broad spectrum of compounds thathave many biological activities It is considered a usefulproduct and is already used in alternativemedicine Recentlythere has been a growing interest in its utilization by thefood processing cosmetic and pharmaceutical industriesConsidering this further studies on the bioactive constituentsof propolis are necessary to identify interactions mediating

their biological effects Further studies are also required ontheir bioavailability stability in different preparations andsafe and effective doses for prevention or treatment of diseasein animals and humans

Conflict of Interests

The authors declare no conflict of interests

References

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[2] S P Myers and P A Cheras ldquoThe other side of the coin safetyof complementary and alternative medicinerdquoMedical Journal ofAustralia vol 181 no 4 pp 222ndash225 2004

[3] M C Bufalo J M G Candeias and J M Sforcin ldquoIn VitroCytotoxic Effect of Brazilian Green Propolis on Human Laryn-geal Epidermoid Carcinoma (HEp-2) Cellsrdquo Evidence-BasedComplementary and Alternative Medicine vol 6 no 4 pp 483ndash487 2009

[4] S Castaldo and F Capasso ldquoPropolis an old remedy used inmodern medicinerdquo Fitoterapia vol 73 supplement 1 pp S1ndashS62002

[5] A Russo R Longo and A Vanella ldquoAntioxidant activity ofpropolis role of caffeic acid phenethyl ester and galanginrdquoFitoterapia vol 73 supplement 1 pp S21ndashS29 2002

[6] G A Burdock ldquoReview of the biological properties and toxicityof bee propolisrdquo Food andChemical Toxicology vol 36 no 4 pp347ndash363 1998

[7] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo Journal of Ethnopharmacologyvol 133 no 2 pp 253ndash260 2011

[8] V Bankova ldquoChemical diversity of propolis and the problem ofstandardizationrdquo Journal of Ethnopharmacology vol 100 no 1-2 pp 114ndash117 2005

[9] W ZhuM Chen Q Shou Y Li and F Hu ldquoBiological activitiesof Chinese propolis and Brazilian propolis on streptozotocin-induced type 1 diabetes mellitus in ratsrdquo Evidence-Based Com-plementary and Alternative Medicine vol 2011 Article ID468529 8 pages 2011

[10] R A Laskar I Sk N Roy and N A Begum ldquoAntioxidantactivity of Indian propolis and its chemical constituentsrdquo FoodChemistry vol 122 no 1 pp 233ndash237 2010

[11] L L Chaillou and M A Nazareno ldquoBioactivity of propolisfrom Santiago del Estero Argentina related to their chemicalcompositionrdquo LWTmdashFood Science and Technology vol 42 no8 pp 1422ndash1427 2009

[12] M Hernandez O Cuesta-Rubio M C Fernandez et alldquoStudies on the constituints of yellow Cuban propolis CG-MS determination of triterpenoids and flavonoidsrdquo Journal ofAgricultural and Food Chemistry vol 58 pp 4725ndash4730 2010

[13] T L C Oldoni I C R Cabral M A B R DrsquoArcea et al ldquoIsola-tion and analysis of bioactive isoflavonoids and chalcone froma new type of Brazilian propolisrdquo Separation and PurificationTechnology vol 77 pp 208ndash213 2011

[14] M GMiguel S Nunes S A Dandlen AM Cavaco andM DAntunes ldquoPhenols and antioxidant activity of hydro-alcoholic


extracts of propolis from Algarve South of Portugalrdquo Food andChemical Toxicology vol 48 no 12 pp 3418ndash3423 2010

[15] M R Ahn S Kumazawa T Hamasaka K S Bang and TNakayama ldquoAntioxidant activity and constituents of propoliscollected in various areas of Koreardquo Journal of Agricultural andFood Chemistry vol 52 no 24 pp 7286ndash7292 2004

[16] S M Alencar T L C Oldoni M L Castro et al ldquoChemicalcomposition and biological activity of a new type of Brazilianpropolis red propolisrdquo Journal of Ethnopharmacology vol 113no 2 pp 278ndash283 2007

[17] I S R Cabral T L C Oldoni A Prado et al ldquoPhenolic com-position antibacterial and antioxidant activities of Brazilian redpropolisrdquo Quımica Nova vol 32 no 6 pp 1523ndash1527 2009

[18] M R Ahn S Kumazawa Y Usui et al ldquoAntioxidant activityand constituents of propolis collected in various areas of ChinardquoFood Chemistry vol 101 no 4 pp 1383ndash1392 2007

[19] S Kumazawa H Goto T Hamasaka S Fukumoto T Fujimotoand T Nakayama ldquoA new prenylated flavonoid from propoliscollected in Okinawa Japanrdquo Bioscience Biotechnology andBiochemistry vol 68 no 1 pp 260ndash262 2004

[20] Y M Choi D O Noh S Y Cho H J Suh K M Kim and J MKim ldquoAntioxidant and antimicrobial activities of propolis fromseveral regions of Koreardquo LWTmdashFood Science and Technologyvol 39 no 7 pp 756ndash761 2006

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[22] L Moreira L G Dias J A Pereira and L Estevinho ldquoAntiox-idant properties total phenols and pollen analysis of propolissamples from Portugalrdquo Food and Chemical Toxicology vol 46no 11 pp 3482ndash3485 2008

[23] N Kalogeropoulos S J Konteles E Troullidou I Mourtzinosand V T Karathanos ldquoChemical composition antioxidantactivity and antimicrobial properties of propolis extracts fromGreece andCyprusrdquo FoodChemistry vol 116 no 2 pp 452ndash4612009

[24] M L Castro A M D Nascimento M Ikegaki C M Costa-Neto S M Alencar and P L Rosalen ldquoIdentification of abioactive compound isolated from Brazilian propolis type 6rdquoBioorganic and Medicinal Chemistry vol 17 no 14 pp 5332ndash5335 2009

[25] K Salomao P R S Pereira L C Campos et al ldquoBrazil-ian propolis correlation between chemical composition andantimicrobial activityrdquo Evidence-Based Complementary andAlternative Medicine vol 5 no 3 pp 317ndash324 2008

[26] P L Miorin N C Levy A R Custodio W A Bretz and MC Marcucci ldquoAntibacterial activity of honey and propolis fromApismellifera andTetragonisca angustula against Staphylococcusaureusrdquo Journal of Applied Microbiology vol 95 no 5 pp 913ndash920 2003

[27] J M Murad S A Calvi A M V C Soares V Bankova andJ M Sforcin ldquoEffects of propolis from Brazil and Bulgariaon fungicidal activity of macrophages against Paracoccidioidesbrasiliensisrdquo Journal of Ethnopharmacology vol 79 no 3 pp331ndash334 2002

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[31] S Silici N A Koc D Ayangil and S Cankaya ldquoAntifungalactivities of propolis collected by different races of honeybeesagainst yeasts isolated from patients with superficial mycosesrdquoJournal of Pharmacological Sciences vol 99 no 1 pp 39ndash442005

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[44] S A Lipton Z Gu and T Nakamura ldquoInflammatorymediatorsleading to protein misfolding and uncompetitivefast off-ratedrug therapy for neurodegenerative disordersrdquo InternationalReview of Neurobiology vol 82 pp 1ndash27 2007

[45] K T Kishida and E Klann ldquoSources and targets of reactiveoxygen species in synaptic plasticity andmemoryrdquoAntioxidantsand Redox Signaling vol 9 no 2 pp 233ndash244 2007

[46] J T Keeney A M Swomley S Forster J L Harris R Sultanaand D A Butterfield ldquoApolipoprotein A-I insights from redoxproteomics for its role in neurodegenerationrdquo Proteomics Clini-cal Applications vol 7 no 1-2 pp 109ndash122 2013

[47] D A Butterfield and I Dalle-Donne ldquoRedox proteomicsrdquoAntioxidants amp Redox Signaling vol 17 no 11 pp 1487ndash14892012

[48] K Tan-No T Nakajima T Shoji et al ldquoAnti-inflammatoryeffect of propolis through inhibition of nitric oxide productionon carrageenin-induced mouse paw edemardquo Biological andPharmaceutical Bulletin vol 29 no 1 pp 96ndash99 2006

[49] M Hosnuter A Gurel O Babuccu F Armutcu E Kargi andA Isikdemir ldquoThe effect of CAPE on lipid peroxidation andnitric oxide levels in the plasmaof rats following thermal injuryrdquoBurns vol 30 no 2 pp 121ndash125 2004

[50] V Silva G Genta M N Moller et al ldquoAntioxidant activityof Uruguayan propolis In vitro and cellular assaysrdquo Journal ofAgricultural and Food Chemistry vol 59 no 12 pp 6430ndash64372011

[51] J Q Zhao Y F Wen M Bhadauria et al ldquoProtective effectsof propolis on inorganic mercury induced oxidative stress inmicerdquo Indian Journal of Experimental Biology vol 47 no 4 pp264ndash269 2009

[52] I Jasprica A Mornar Z Debeljak et al ldquoIn vivo study ofpropolis supplementation effects on antioxidative status and redblood cellsrdquo Journal of Ethnopharmacology vol 110 no 3 pp548ndash554 2007

[53] A Kart Y Cigremis H Ozen and O Dogan ldquoCaffeic acidphenethyl ester prevents ovary ischemiareperfusion injury inrabbitsrdquo Food and Chemical Toxicology vol 47 no 8 pp 1980ndash1984 2009

[54] I O Tekin E Y Sipahi M Comert S Acikgoz and GYurdakan ldquoLow-density lipoproteins oxidized after intestinalischemiareperfusion in ratsrdquo Journal of Surgical Research vol157 no 1 pp e47ndashe54 2009

[55] Y Aliyazicioglu S Demir I Turan et al ldquoPreventive andprotective effects of Turkish propolis on H

2O2induced DNA

damage in foreskin fibroblast cell linesrdquo Acta Biologica Hungar-ica vol 62 no 4 pp 388ndash396 2011

[56] D Remirez R Gonzalez S Rodriguez et al ldquoProtective effectsof propolis extract on allyl alcohol-induced liver injury inmicerdquoPhytomedicine vol 4 no 4 pp 309ndash314 1997

[57] R Claus R Kinscherf C Gehrke et al ldquoAntiapoptotic effectsof propolis extract and propol on humanmacrophages exposedto minimally modified low density lipoproteinrdquo Arzneimittel-Forschung vol 50 no 4 pp 373ndash379 2000

[58] C Pascual R Gonzalez and R G Torricella ldquoScavengingaction of propolis extract against oxygen radicalsrdquo Journal ofEthnopharmacology vol 41 no 1-2 pp 9ndash13 1994

[59] R O A de Lima A P Bazo R A Said et al ldquoModifyingeffect of propolis on dimethylhydrazine-induced DNA damagebut not colonic aberrant crypt foci in ratsrdquo Environmental andMolecular Mutagenesis vol 45 no 1 pp 8ndash16 2005

[60] M I IslaM I NMoreno A R Sampietro andMA VattuoneldquoAntioxidant activity of Argentine propolis extractsrdquo Journal ofEthnopharmacology vol 76 no 2 pp 165ndash170 2001

[61] S Scheller T Wilczok S Imielski W Krol J Gabrys and JShani ldquoFree radical scavenging by ethanol extract of propolisrdquoInternational Journal of Radiation Biology vol 57 no 3 pp 461ndash465 1990

[62] M Y Heo S J Sohn and W W Au ldquoAnti-genotoxicityof galangin as a cancer chemopreventive agent candidaterdquoMutation Research vol 488 no 2 pp 135ndash150 2001

[63] A A Righi T R Alves G Negri L M Marques H Breyerand A Salatino ldquoBrazilian red propolis unreported substancesantioxidant and antimicrobial activitiesrdquo Journal of the Scienceof Food and Agriculture vol 91 no 13 pp 2363ndash2370 2011

[64] C O Frozza C S Garcia G Gambato et al ldquoChemical charac-terization antioxidant and cytotoxic activities of Brazilian redpropolisrdquo Food and Chemical Toxicology vol 52 pp 137ndash1422013

[65] H Izuta M Shimazawa K Tsuruma Y Araki S Mishima andH Hara ldquoBee products prevent VEGF-induced angiogenesis inhuman umbilical vein endothelial cellsrdquo BMC Complementaryand Alternative Medicine vol 9 article 45 2009

[66] A Russo V Cardile F Sanchez N Troncoso A Vanella andJ A Garbarino ldquoChilean propolis antioxidant activity andantiproliferative action in human tumor cell linesrdquo Life Sciencesvol 76 no 5 pp 545ndash558 2004

[67] L G Korkina ldquoPhenylpropanoids as naturally occurringantioxidants from plant defense to human healthrdquo Cellular andMolecular Biology vol 53 no 1 pp 15ndash25 2007

[68] P Libby ldquoInflammatory mechanisms the molecular basis ofinflammation and diseaserdquoNutrition Reviews vol 65 no 12 ppS140ndashS146 2007

[69] A P Q Mello I T da Silva D S P Abdalla and N R TDamasceno ldquoElectronegative low-density lipoprotein originand impact on health and diseaserdquo Atherosclerosis vol 215 no2 pp 257ndash265 2011

[70] P Libby ldquoInflammation in atherosclerosisrdquo ArteriosclerosisThrombosis and Vascular Biology vol 32 no 9 pp 2045ndash20512012

[71] G D Norata P Marchesi S Passamonti A Pirillo F Violiand A L Catapano ldquoAnti-inflammatory and anti-atherogeniceffects of cathechin caffeic acid and trans-resveratrol inapolipoprotein E deficient micerdquo Atherosclerosis vol 191 no 2pp 265ndash271 2007

[72] D Grassi A Aggio L Onori et al ldquoTea flavonoids and nitricoxide-mediated vascular reactivityrdquo Journal of Nutrition vol138 no 8 pp 1554Sndash1560S 2008

[73] S GorinsteinH LeontowiczM Leontowicz et al ldquoInfluence oftwo cultivars of persimmonon atherosclerosis indices in rats fedcholesterol-containing diets Investigation in vitro and in vivordquoNutrition vol 27 no 7-8 pp 838ndash846 2011

[74] Y Li M Chen H Xuan and F Hu ldquoEffects of encapsulatedpropolis on blood glycemic control lipid metabolism andinsulin resistance in type 2 diabetes mellitus ratsrdquo Evidence-Based Complementary and Alternative Medicine vol 2012Article ID 981896 8 pages 2012

[75] H U Fuliang H R Hepburn H Xuan M Chen S Daya andS E Radloff ldquoEffects of propolis on blood glucose blood lipidand free radicals in rats with diabetesmellitusrdquo PharmacologicalResearch vol 51 no 2 pp 147ndash152 2005


[76] J B Daleprane V da Silva Freitas A Pacheco et al ldquoAnti-atherogenic and anti-angiogenic activities of polyphenols frompropolisrdquo Journal of Nutritional Biochemistry vol 23 no 6 pp557ndash566 2012

[77] A Iio K Ohguchi H Maruyama et al ldquoEthanolic extracts ofBrazilian red propolis increase ABCA1 expression and promotecholesterol efflux from THP-1 macrophagesrdquo Phytomedicinevol 19 no 5 pp 383ndash388 2012

[78] Y Yu Y Si G Song T Luo J Wang and S Qin ldquoEthanolicextract of propolis promotes reverse cholesterol transport andthe expression of ATP-binding cassette transporter A1 and G1in micerdquo Lipids vol 46 no 9 pp 805ndash811 2011

[79] T G Chen J J Lee K H Lin C H Shen D S Chou and JR Sheu ldquoAntiplatelet activity of caffeic acid phenethyl ester ismediated through a cyclic GMP-dependent pathway in humanplateletsrdquo Chinese Journal of Physiology vol 50 no 3 pp 121ndash126 2007

[80] N Paulino S R L Abreu Y Uto et al ldquoAnti-inflammatoryeffects of a bioavailable compound Artepillin C in Brazilianpropolisrdquo European Journal of Pharmacology vol 587 no 1ndash3pp 296ndash301 2008

[81] Y S Song C Jin K J Jung and E H Park ldquoEstrogeniceffects of ethanol and ether extracts of propolisrdquo Journal ofEthnopharmacology vol 82 no 2-3 pp 89ndash95 2002

[82] T U Roos E H Heiss A V Schwaiberger et al ldquoCaffeicacid phenethyl ester inhibits PDGF-induced proliferation ofvascular smoothmuscle cells via activation of p38MAPK HIF-1120572 and heme oxygenase-1rdquo Journal of Natural Products vol 74no 3 pp 352ndash356 2011

[83] M F Brizzi L Formato and R Bonamini ldquoThe molecularmechanisms of angiogenesis a new approach to cardiovasculardiseasesrdquo Italian Heart Journal vol 2 no 2 pp 81ndash92 2001

[84] P Carmeliet ldquoAngiogenesis in life disease and medicinerdquoNature vol 438 no 7070 pp 932ndash936 2005

[85] A A Ucuzian A A Gassman A T East and H P GreislerldquoMolecularmediators of angiogenesisrdquo Journal of BurnCare andResearch vol 31 no 1 pp 158ndash175 2010

[86] M Keshavarz A Mostafaie K Mansouri Y Shakiba and HR M Motlagh ldquoInhibition of corneal neovascularization withpropolis extractrdquo Archives of Medical Research vol 40 no 1 pp59ndash61 2009

[87] M R Ahn K Kunimasa T Ohta et al ldquoSuppression of tumor-induced angiogenesis by Brazilian propolis major componentartepillin C inhibits in vitro tube formation and endothelial cellproliferationrdquo Cancer Letters vol 252 no 2 pp 235ndash243 2007

[88] H J Hwang H J Park H J Chung et al ldquoInhibitory effects ofcaffeic acid phenethyl ester on cancer cell metastasis mediatedby the down-regulation of matrix metalloproteinase expressionin human HT1080 fibrosarcoma cellsrdquo Journal of NutritionalBiochemistry vol 17 no 5 pp 356ndash362 2006

[89] U H Jin T W Chung S K Kang et al ldquoCaffeic acidphenyl ester in propolis is a strong inhibitor of matrixmetalloproteinase-9 and invasion inhibitor isolation and iden-tificationrdquo Clinica Chimica Acta vol 362 no 1-2 pp 57ndash642005

[90] H F Liao Y Y Chen J J Liu et al ldquoInhibitory effect ofcaffeic acid phenethyl ester on angiogenesis tumor invasionandmetastasisrdquo Journal of Agricultural and Food Chemistry vol51 no 27 pp 7907ndash7912 2003

[91] H Xuan J Zhao J Miao Y Li Y Chu and F Hu ldquoEffectof Brazilian propolis on human umbilical vein endothelial cell

apoptosisrdquo Food and Chemical Toxicology vol 49 no 1 pp 78ndash85 2011

[92] J B Daleprane T Schmid N Dehne et al ldquoSuppression ofhypoxia-inducible factor-1120572 contributes to the antiangiogenicactivity of red propolis polyphenols in human endothelial cellsrdquoJournal of Nutrition vol 142 no 3 pp 441ndash447 2012

[93] H K Eltzschig and T Eckle ldquoIschemia and reperfusionmdashfrommechanism to translationrdquo Nature Medicine vol 17 no 11 pp1391ndash1401 2011

[94] H Hattori K Okuda T Murase et al ldquoIsolation identificationand biological evaluation of HIF-1-modulating compoundsfromBrazilian green propolisrdquoBioorganic andMedicinal Chem-istry vol 19 no 18 pp 5392ndash5401 2011

[95] S Umthong S Puthong and C Chanchao ldquoTrigona laevicepspropolis from Thailand antimicrobial antiproliferative andcytotoxic activitiesrdquo American Journal of Chinese Medicine vol37 no 5 pp 855ndash865 2009

[96] E Szliszka and W Krol ldquoThe role of dietary polyphe-nols in tumor necrosis factor-related apoptosis inducing lig-and (TRAIL)-induced apoptosis for cancer chemopreventionrdquoEuropean Journal of Cancer Prevention vol 20 no 1 pp 63ndash692011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


187mgg [21] India 15910 plusmn 026mgg [10] Portugal 151 plusmn001mgg [22] Cyprus 1004 plusmn 72mgg [23] and Thailand312 plusmn 07mgg [19]

Studies indicate that propolis from Europe and Chinacontains many flavonoids and phenolic acids tropical propo-lis generally contains low concentrations of flavonoids [21 2425]

Studies of propolis demonstrate the complexity of itscomposition and pharmacology some compounds act inde-pendently while others act synergistically The therapeuticpotential of propolis and its constituents has been the subjectof many studies which have established many pharmacolog-ical actions in preclinical testing

In particular propolis shows therapeutic potential andmay have applications in the pharmaceutical and food pro-cessing industries [25ndash27] Propolis reportedly has a rangeof biological activities including immunomodulatory [2829] antibacterial [30] fungicidal [31 32] anti-inflammatoryhealing [33] analgesicanesthetic [34 35] and anticarcino-genic effects [36]

The relationship between oxidative stress cardiovasculardisease and angiogenesis is well established Events related tothe pathophysiology of angiogenesis and associated cytokinesand growth factors can lead to a poor prognosis in manydiseases In fact chronic cardiovascular disease oxidativestress and angiogenesis are strongly associated with oneanother In this review we will present evidence that propolisextracts and their bioactive compounds have antioxidantcardioprotective and antiangiogenic activities (Figure 1)

2 Antioxidant Activity

It is well established that cellular metabolism generates re-active oxygen species (ROS) such as hydrogen peroxide(H2O2) the superoxide anion (O

2

minus) and the highly reactivehydroxyl ion (HOminus) as well as reactive nitrogen species(RNS) especially nitric oxide (NO) ROS and RNS are idealsignaling molecules because they are locally generated arehighly and rapidly diffusible and can be neutralized bycellular antioxidants [37 38] ROS are usually detoxified byintracellular enzymes such as glutathione superoxide dis-mutase and catalase [39] However unbalanced productionand degradation of ROS and RNS can result in accumulationof these reactive species commonly referred to as oxidativestress Exposure of macromolecules (lipid proteins DNAetc) to reactive species results in oxidativemodificationswithdeleterious effects [40 41]

The antioxidant capacity of propolis may be related tosome of its biological effects including chemopreventionThe flavonoids in propolis are powerful antioxidants capableof scavenging free radicals and thereby protecting the cellmembrane against lipid peroxidation [42] Moreover ROSand RNS together with other factors are involved in cellu-lar ageing and death in conditions such as cardiovasculardisease arthritis cancer diabetes Parkinsonrsquos disease andAlzheimerrsquos disease [43ndash47] Propolis can reduce cellularlevels of H

2O2and NO which may be involved in its anti-

inflammatory effects [48]

Oxidative stress

AngiogenesisCardiovasculardiseases

Propolis

Figure 1 Schematic representation of the relationship betweenoxidative stress cardiovascular disease and angiogenesis and theeffects of propolis on these integrated systems Propolis influencesmultiples biochemical signaling pathways including protectivemechanisms reducing events related to chronic inflammatory dis-eases

Diverse compounds frompropolis have been described aspotent inhibitors of oxidative stress It is well known that thecomposition of propolis is variable however one of its majorcomponents caffeic acid phenethyl ester (CAPE) blocks ROSproduction in several systems [49] CAPE has also beenidentified as one of the major cancer chemopreventive andanti-inflammatory compounds in propolis In vitro propolisinhibits peroxidation of LDL and nitration of proteins More-over in bovine aortic endothelial cells propolis was reportedto increase eNOS expression and inhibit NADPH oxidase(NOX) [50] In vivo propolis can increase antioxidant capac-ity in animals [51] and humans [52] leading to decreasedlipid peroxidation which is strongly associated with therisk of cardiovascular disease [53 54] Turkish propolisinhibited hydrogen peroxide (H

2O2-) induced damage to

DNA in cultured fibroblasts [55] The antioxidant activityof phenolic components of the Turkish propolis may reducedamage to DNA induced by H

2O2 which may be related

to its chemopreventive activity Red propolis from Cubahas shown protective effects in models of alcohol-inducedliver damage most likely due to its antioxidant properties[56] Propolis inhibited macrophage apoptosis via effects onglutathione (GSH) and the tumor necrosis factorsnuclearfactor kappa B (TNFNF-120581B) pathway [57 58] MoreoverBrazilian propolis from Baccharis dracunculifolia modulated12-dimethlyhydrazine (DMH-) induced DNA damage incolon cells [59]

Isla et al [60] described the protective effect of the Ar-gentinian propolis from different sources against copper-mediated oxidative modification of lipids in unfractionatedserum Five types of Argentinian propolis collected in dif-ferent regions inhibited lipid oxidation during the initiationand propagation phases All five types of propolis diminishedthe maximal rate and extent of diene production indicatingthat flavonoids can scavenge free radicals such as superoxide[61 62] protecting serum lipids from oxidation [60] Jasprica
































References




























































2O2induced DNA


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































References




























































2O2induced DNA


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































References




























































2O2induced DNA


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























References




























































2O2induced DNA


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























































2O2induced DNA


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























2O2induced DNA


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Emerging Roles of Propolis: Antioxidant, …downloads.hindawi.com/journals/ecam/2013/175135.pdf · 2019. 7. 31. · e antioxidant e ect of Brazilian red propolis has