role of honey polyphenols in health

REVIEW ARTICLE Role of honey polyphenols in health

Carlos A Uthurry1*, David Hevia1, Carmen Gomez-Cordoves1

1 Instituto de Ciencia y Tecnología de Alimentos y Nutrición, ICTAN Consejo Superior de Investigaciones Científicas (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain Received 26 May 2011, accepted subject to revision 20 June 2011, accepted for publication 16 August 2011 *Corresponding author: Email: [email protected].

Summary Many bioactive phenolic compounds have been reported in hive products. This review discusses the occurrence and putative therapeutic

applications of these phenolic compounds and is intended to be read by scientists, physicians, nutritionists, and other researchers interested in

the rapidly developing science of honey and related products. In view of the information presented here, honey can be regarded as a rich

source of phenolic bioactive molecules with promising potential benefits to health.

Keywords: Honey, polyphenols, cancer, antimicrobial, antioxidant, health.

Journal of ApiProduct and ApiMedical Science 3 (4): 141 - 159 (2011) © IBRA 2011 DOI 10.3896/IBRA.4.03.4.01

Introduction Honey is a sweet substance produced as a food source mainly from

the nectar and secretions of plants by honey bees (Codex Standard

for Honey, 2001). Honey is used to feed bees during the winter

(Jaganathan and Mandal, 2009). For centuries honey has been used

as food and as natural medicine, being prescribed by physicians of

many ancient cultures for the treatment of a wide variety of ailments

(Ransome, 1937). The art of apiculture and the benefits of honey

have been known since the Egyptian first dynasty (Nicholson and

Shaw, 2000), and ancient Greeks used honey as a sweetener

(Brothwell and Brothwell, 1969). In Classical Greece, laws

concerning apiculture were suggested and Plato included honey in

his concept of a healthy diet (Skiadas and Lascaratos, 2001). The

use of honey in folk medicine is thought to be as old as civilization,

but in recent times there has been a renaissance in interest in its

use as a medicinal product. The colour of honey can vary from clear

to dark amber according to its floral source and mineral content and

it has a close relationship with its flavour and quality (Jaganathan

and Mandal, 2009). Honeys may be viscous liquids or even solid with

differing honeys identifiable by their colour, flavour, crystallization,

and the presence of pollen grains in honey sediment (Alves da Silva

et al., 2006).

Honey is mainly composed of water and sugar (about 96%)

with the remainder being substances such as amino acids, enzymes,

minerals, flavonoids, phenolic acids, ascorbic acid, carotenoid-like

substances, organic acids, and several other compounds (White and

Subers 1963; Tan et al., 1989; Alves da Silva et al., 2006). D-fructose

and D- glucose are the predominant sugars but it is the former that

occurs at higher concentrations. Sucrose occasionally exceeds 1% of

the total sugar content while maltose may be found at levels three

times higher than that of sucrose. The mineral fraction of honey is

mainly composed of potassium and smaller amounts of magnesium,

sodium, calcium, phosphorous, iron, managanese, cobalt and copper

(Alves da Silva et al., 2006). Enzymes such as invertase, amylase,

catalase and glucose oxidase are also present, and proline is the

major amino acid constituent comprising about half the content of

total free amino acids (White and Subers, 1963).

Citric and gluconic acids are also present in honey though

malic, folic, lactic, succinic, butyric, acetic and formic acids have also

be identified (Tan et al., 1989). Honey, depending on variety, is a

poor source of vitamins with only a few honeys showing evidence of

vitamins A, B2, C and B6 and carotenoid- like substances (Alves da

Silva et al., 2006). Polyphenols, especially flavonoids and phenolic

acids, are known to play an important role as antioxidants and honey

is regarded as an important source of these compounds (Schramm et

al., 2003; Viuda Martos et al., 2008b). The presence and

concentrations of these phytochemicals in honeys can vary

depending upon the floral source, the geographical and the climatic

conditions. Consequently, polyphenols have been suggested as floral

markers for the botanical authentication of unifloral honeys (Amiot

et al., 1989; Jaganathan and Mandal, 2009). Pyrzynska and Biesaga

(2009) discussed the analytical procedures for the analysis of

phenolic acids and flavonoids in honey

Polyphenols are the most important group of plant secondary

metabolites and their chemical structures range from simple

phenolic molecules to high molecular weight polymers of

approximately 30000 Da (Bravo, 1998). All polyphenols have at least

one hydroxyl group bound to an aromatic ring in the molecule and

they are biosynthesised in plants by mainly the shikimate and the

acetate pathways (Harborne, 1989). In general, apart from their

ability to provide plants with colour, polyphenols have different

functions in plants that include their ability to act as antimicrobial,

antifungal, antioxidant activities, and chelation of toxic heavy metals

(Harborne, 1993; Gould and Lister, 2005). Furthermore, much of the

colours, flavour and taste of vegetable food and beverages are

associated with the presence of polyphenols (Bravo, 1998).

According to the classification of Harborne (1989) polyphenols

can be divided into at least ten different classes depending upon

their basic chemical structure, but in honey phenolic acids and

flavonoids are the most important. The flavonoid group may be

further divided into thirteen classes (Harborne, 1988; Harborne,

1993) and more than 5000 flavonoids have been described since the

late 1980s. Generally, polyphenols are divided into two major

groups, the low- molecular- weight polyphenols comprising simple

phenols and flavonoids, and the higher-molecular- weight

polyphenols represented by tannins.

Simple phenols (Fig.1 A) are those with a C6 carbon structure

(such as phenol itself, cresol and thymol). Some have a C6-C1

structure, such as phenolic acids (for example, gallic, vanillic and

syringic acids) and aldehydes (for example, vanillin). Those with a C6

-C2 structure such as phenylacetic acids and acetophenones and the

phenylpropanoid group with a C6-C3 structure are mainly

represented by the hydroxycinnamic acids such as p-coumaric, ferulic

and caffeic acids and their respective derivatives. Simple phenols,

phenolic and phenylacetic acids can be found free in a large variety

of plant species but their methyl and ethyl esthers and glycosides can

also occur in the free form and/or bound forms (Harborne, 1989;

Bravo, 1998).

Flavonoids with a C6-C3-C6 structure represent the most widely

distributed phenolic compounds in plants, and their carbon skeleton

consists of an aromatic ring (A) fused to a heterocyclic ring (C)

carrying an oxygen atom, and the other ring (B) is generally linked to

number two carbon atom of the ring C (Fig. 1 B). In nature, they can

be found as free aglycones although they usually occur as glycosides

and their derivatives. At the same time, flavonoids are further divided

and classified with respect to the degree of oxidation of the ring C

into flavones (such as apigenin, luteolin and diosmetin), flavonols,

(such as quercetin, myricetin and kaempferol), flavanones (such as

naringenin and hesperidin), flavan-3-ols, (such as catechin and

epicatechin), anthocyanidins and their glycosides (such as malvidin,

cyaniding and pelargonidin). It is important to mention that flavones,

flavonols and their glycosides are the most common flavonoids found

in the plant kingdom (Bravo, 1998).

On the other hand tannins are molecules of intermediate to

high molecular weight and have an important degree of

hydroxylation. They are typically found in plants and can be classified

in two large groups: hydolysable tannins and condensed tannins;

although there is a third group, the phlorotannins, which occurs in

brown algae but are not consumed by humans (Ragan and

142 Uthurry, Hevia, Gomez-Cordoves

Fig. 1. Basic structures of a simple phenol (A), a flavonoid showing the identification of its rings (B), and a condensed tannin or proanthocya-

nidin (C). NOTE: Fig. 1 (C) is based on one illustration appearing in: BRAVO, L (1998) Polyphenols: chemistry, dietary sources, metabolism and

nutritional significance. Nutrition Reviews 56 (11): 317-333.(Permission granted by: Blackwell Publishing Ltd., John Wiley & Sons Ltd.).

Glombitza, 1986). Hydrolysable tannins consist of molecules of

either gallic acid or ellagic acid esterified to a polyol molecule such

as glucose (Porter, 1989). These tannins can increase their

molecular weight by consecutive esterification with other galloyl or

ellagic molecules forming large polymers (Bravo, 1998). Further

esterification with more gallic acid molecules is also plausible. This

kind of tannin can be easily hydrolysed using diluted acids, alkalis,

water and enzymes. Condensed tannins or proanthocyanidins are

high-molecular-weight polymers, and the monomeric unit is a flavan

-3-ol molecule such as catechin or epicatechin (Fig. 1 C). Oligomers

such as dimers, trimers and tetramers of proanthocyanidins are well

described but there are molecules with a degree of polymerization

greater than 50. Molecular weights can reach values higher than

30000 Da (Würsch et al., 1984).

Since honey is a food product derived from plant nectar or

plant exudate, it is an excellent source of various polyphenols. This

review aims to clearly define the current state of knowledge of the

phenolic composition of honey and evaluate its relevance to human

health.

Benefits and therapeutic properties of polyphenols in honey

Preliminary scope

Studies into the biochemistry of polyphenols and their properties of

pharmacological and therapeutic interest have been extensive. For

example, flavonoids have important benefits in cardiovascular

health, mainly on blood pressure and in the prevention of the

damage due to lipid peroxidation of the low density proteins (Raj

Narayana et al., 2001). Other therapeutic aspects of polyphenols are

the protection of gastric mucus, liver mucus, anti-inflammatory and

anti-neoplasic behaviour, antimicrobial activity (including the

selective inhibition of some immunodeficiency viruses such as HIV-1

and HIV-2), and the biochemical effects on enzymes and hormones

(Raj Narayana et al., 2001). Flavonoids, the most typical plant

phenolics, have been the subject of many scientific researches.

Havsteen (2002) produced a valuable contribution towards

understanding the biochemistry and pharmacological potential of

flavonoids, highlighting their interesting antiviral properties. He also

remarked on current medical interest for the use of chemically pure

flavonoids in the treatment of certain diseases, based on their

effectiveness for inhibiting some enzymes, scavenging free radicals,

and simulating the behaviour of hormones and neurotransmitters.

Figure 2 shows some benefitial properties of the phenolic

compounds.

Polyphenols can behave as antioxidants in vivo and in vitro

because they function as terminators of free radicals and chelators of

metal ions which could catalyse the lipid peroxidation (Bravo, 1998).

The antioxidant activity of these molecules is due to a rapid donation

of hydrogen atoms to stabilise the free radicals and the remaining

phenoxy radicals can also react with any other radical to terminate

the propagation route (Shahidi and Wanasundara, 1992). The

chemical structure of polyphenols greatly influences their antioxidant

activity (Bravo, 1998). Flavonoids, have one or more of some

Honey and health 143

Fig. 2. Properties of polyphenols in health.

Fig. 3. The structure of some flavonoids found in honey and their features related to the antioxidant activity.

Flavonoid R3’ R4’ R3 R5 R7

Apigenin H OH H OH OH

Chrysin H H H OH OH

Galangin H H OH OH OH

Kaempferol H OH OH OH OH

Luteolin OH OH H OH OH

Quercetin OH OH OH OH OH

structural features involved in antioxidant activity such as: an o-

diphenolic group in the B ring, a 2-3 double bond conjugated with

the 4-oxo function (in ring C), hydroxyl groups in positions 5 and 7

(in ring A) (Ratty and Das, 1988; Bors et al., 1990; Manach et al.,

1996). Some flavonoids present in honey are shown in Figure 3.

Table 1 summarises some of the phenolic compounds identified in

different types of honey using either high-perfoemance liquid

chromatography (HPLC) or capillary electrophoresis (CE) techniques

with diode array detection (DAD) (Pyrzynska and Biesaga, 2009)

Generally, the antioxidant activity also correlates directly with

the degree of hydroxylation (Ratty and Das, 1988). In nature,

flavonoids usually occur as 3-O-glycosides and the presence of the

sugar moiety dramatically decreases the antioxidant activity of the

compound. Yet, free flavonoids, best known as aglycones, have

known antioxidant activity (Ratty and Das, 1988).

The role of polyphenols as antioxidant agents against radical

reactive species such as those belonging to the reactive oxygen

species (ROS) and reactive nitrogen species (RNS) groups is of

remarkable interest. Radicals belonging to ROS such as OH.

(hydroxyl), RCOO. (peroxyl) and RO. (alcohoxyl) are of major

concern in the study of the oxidative stress of living tissues (Ames et

al., 1993) since they can be scavenged by flavonoids (Shahidi and

Wanasundara, 1992). On the other hand, the highly reactive

nitrogen species peroxynitrite (ONOO-) has been investigated

regarding the ability of flavonoids, such as anthocyanins, to act as

scavengers (Haenen et al., 1997; Tsuda et al., 2000). Investigation

of the relationship between the chemical structure and the

antioxidant power (in terms of radical scavenging activity) of several

flavonoids demonstrated that this activity strongly depends on the

substitution pattern of the free hydroxyl groups in its base structure

(Ratty and Das, 1988; Bors et al., 1990; Manach et al., 1996; Bravo,

1998; Amic et al., 2003).

Kroon and Williamson (2005) discussed the benefits for health

connected to the intake of food rich in polyphenols and proposed

that the presence of polyphenolic substances in a balanced diet is

specially valuable. They further proposed that, just as recommended

daily intake values (RDI) exist for most micronutrients such as

vitamins and oligoelements, the evaluation of RDIs for various

polyphenols in food will also be possible in the not too distant future.

Functional foods, known as nutraceuticals, designed foods,

therapeutic foods and medicinal foods, fit the concept of optimal

nutrition (Berner and O’Donnell, 1998; Nagai and Inoue, 2004). In

fact, honey, propolis and royal jelly are considered among the foods

that possess the property of functionality, due to their naturally high

antioxidant potential and their anti-inflammatory properties (Ali et al.,

1991; Ali, 1995), associated with the presence of galangin (Raso et

al., 2001; Rosi et al., 2002a, 2002b), caffeic acid, phenethyl esters

(Ali, 1995), and chrysin (Mirzoeva and Calder, 1996; Martos et al.,


Type of honey Analytical technique Identified phenolic compounds References

Acacia, eucalyptus, lime, chestnut, heather, lavender, rosemary, orange, sunflower and rapeseed honeys.

HPLC-DAD 4-hydroxybenzoic acid, protocatechuic acid, gallic acid, syringic acid, vanillic acid, p-coumaric acid, caffeic acid, ferulic acid.

Dimitrova et al. (2007).

Australian Eucalyptus honey. HPLC-DAD Gallic acid, chlorogenic acid, caffeic acid,

p-coumaric acid, ferulic acid, ellagic acid. Yao et al. (2004 a).

Citrus, thyme, rosemary, lavender honeys. CE-DAD

Syringic acid, p-coumaric acid, caffeic acid, cinnamic acid, chlorogenic acid, ferulic acid, gallic acid.

Aljadi and Kamaruddin (2004).

Eucalyptus honey. HPLC-DAD

Myricetin, tricetin, quercetin, luteolin, quercetin-3-methyl ether, kaempferol, pinocembrin, chrysin, pinobanksin, isorhamnetin, genkwanin.

Yao et al. (2004 b).

New Zealand and Australian Leptospermum honeys.

HPLC-DAD

Myricetin, tricetin, quercetin, luteolin, kaempferol, kaempferol-8-methyl ether, pinocembrin, chrysin, gallic acid, ellagic acid, chlorogenic acid, caffeic acid, p-coumaric acid, ferulic acid, syringic acid.

Yao et al. (2003).

Rosemary honey. CE-DAD Kaempferol, ferulic acid, chrysin, pinocembrin, p-coumaric acid.

Dimitrova et al. (2007).

Table 1. Some identified phenolic compounds occurring in honeys (Pyrzynska and Biesaga, 2009).

2000; Bruschi et al., 2003). Hive products have demonstrated

antiviral properties (Amoros et al., 1992), including the inhibition of

viral activation including HIV-1. This viral inactivation is thought to

be due to the chrysin, acacetin and apigenin components

(Critchfield et al., 1996). Other therapeutic properties of bee-

products that have been reported included their anti-ulcer and

antibacterial properties derived from the occurrence of flavonoids

such as galangin and quercetin (Mirzoeva et al., 1997; Cushnie and

Lamb, 2005). However, in honey there are other antimicrobial

factors apart from polyphenols, such as the recently discovered

methylglyoxal in manuka honey (Mavric et al., 2008; Adams et al.,

2008), sugar content, hydrogen peroxide and bee defensin-1

(Kwakman et al., 2010). Indeed, it is important to note that not all

antimicrobial properties can be attributed to polyphenols.

Paradoxically honeys with the same phenolic profiles can either

possess antibacterial activity or be totally devoid of any (Weston et

al., 2000). Henriques et al. (2006) also studied the antibacterial

activity of honeys that produce hydrogen peroxide. There is a

substantial body of research on the antiproliferative effect of honey

and its components on some cancers (Ghosh et al., 2005;

Jaganathan et al., 2010a; Pichichero et al., 2010; Jaganathan et al.,

2010b) .

Finally, it is important to be aware that the bioavailability of

dietary polyphenols is critical to realising their health benefits.

Manach et al. (2004, 2005) reported that polyphenol bioavailability is

dependant upon many variables including gut absorption,

glucuronide excretion to the intestinal lumen, microbiota

metabolism, liver and gut metabolism, plasma kinetics, a variety of

metabolites in the bloodstream, bonding to albumin, cell assimilation

and metabolism, accumulation in tissues and bile, and urinary

excretion. Proanthocyanidins are abundant in the human diet but

they are not well absorbed in the gut and the intake of flavonols,

flavones and flavanols remains relatively small. In addition to their

limited absorption and rapid elimination, final plasma concentrations

of procanthocyandins hardly ever exceed 1 µmol / L. Flavonoids with

the highest bioavailability are flavanones and isoflavones reaching

plasma concentrations in the vicinity of 5 µmol / L. Hydroxycinnamic

acids are widely distributed in the diet at substantial levels but their

bioavailability is poor due to estherification.

On account of these observations, honey has valuable

properties which make it considered as an irreplaceable source of

compounds with interesting therapeutic activities suitable to being

part of a healthy diet.

The radical scavenging and antioxidant activities of honeys Honey is regarded as a functional food largely due to the presence

of phenolic compounds that are able to act as free radical

scavengers, thus protecting cells and living tissues against oxidative

stress. This oxidative stress has been associated with enhanced

cellular ageing that is itself a feature of degenerative diseases such

as cancer, cardiovascular disease and related diseases (Kinsella et

al., 1993). Polyphenols in honey can scavenge hydroxyl, peroxyl and

alcohoxyl radicals through their ability to act as a hydrogen donor

and thus displaying their antioxidant properties.

Sánchez Moreno (2002) described diverse methods for the

assessment of the free radical scavenging activity in food and

biological systems. These reactive chemical species and free radicals

include superoxide (O2.), hydrogen peroxide (H2O2), hypochlorous

acid (HOCl), hydroxyl radical (HO.), peroxyl radical (ROO.) as

determined by the TRAP (Total Radical Trapping Antioxidant

Parameter), the ORAC (Oxygen Radical Absorbance Capacity)

methods, the ABTS [2,2-azinobis-(3-ethylbenzothiazoline-6-

sulphonate)], TEAC (Trolox Equivalent Antioxidant Capacity) method,

the DPPH (2, 2-dyphenyl-1-picrylhydrazyl) radical scavenging

capacity assay, and the DMPD (N-N-dimethyl-p-phenylendiamine)

method. Studies reporting the antioxidant power of honeys usually

depend on the use of the DPPH method, although the ORAC method

is increasing at a steady rate, together with those involving free

radical scavenging mechanisms.

Beretta et al. (2005) proposed a standard analytical platform for

the reliable assessment of the antioxidant activity of honey.

Significant correlations were recorded among the results of the

different methods used by the researchers. Principal component

analysis grouped the analysed samples according to their antioxidant

power and phenolic content. The authors emphasized the use of

combined methods to either foresee or confirm the health benefits of

honey in relation to their antioxidants´ concentration.

When the chemical composition and bioactivity of chestnut tree,

rhododendron and multifloral honeys from Anatolia (Turkey) was

investigated it was observed that chestnut-tree honey exhibited the

highest polyphenolic content, the highest radical scavenging activity

for superoxide, and the highest reducing power. Multifloral honey

exhibited the highest scavenging activity for the reactive nitrogen

species peroxynitrite (Küçük et al., 2007).

Baltrušaityté et al. (2007a) studied the radical scavenging

activity of Lithuanian honeys of different floral origin. Antioxidant

power of these samples was remarkably widespread. The beneficial

effects of bee products for health depend upon their source due to

the strong variability in the antioxidant power. Further investigations

have been recommended in order to elucidate connections between

floral origin, phenolic composition and antioxidant activity as

measures of the benefits of hive products on health.

The antioxidant activity of honey as phenolic content has been

extensively studied. Research on the antioxidant activity of honeys

from Yemen found that some Yemeni honeys contained significantly

higher phenolic contents than other honeys, and the percentage

antioxidant activities were higher than in the investigated non-

Yemeni honeys (Al-Mamary et al., 2002). Based on these results,

Yemeni honeys were found to be rich in antioxidant phenols with


antioxidant therapeutic potential (Al-Mamary et al., 2002).

Malaysian honeys were studied in relation to their polyphenolic

content and antioxidant properties (Aljadi and Kamaruddin, 2004).

Two of the most common Malaysian Apis mellifera honeys, namely

Gelam and Coconut honeys, were studied regarding their phenolic

content, radical scavenging activity (using the DPPH method), and

total antioxidant power (using the Ferric Reducing Ability Plasma

(FRAP) method). The data showed a significant correlation between

the antioxidant activity of the honeys and their total phenolic

contents. Gelam honey had a higher total phenolic content (21.4 μg/

g) than Coconut honey (15.6 μg/g), as well as greater radical

scavenging activity, water content and total antioxidant potential.

These observations supported those of Frankel and colleagues

(1998) that water content of honey and antioxidant activity were

correlated (Aljadi and Kamaruddin, 2004).

In a study of crude Italian honeys, Millefiori honeys showed a

higher flavonoid content than Acacia honeys in accordance with their

greater antioxidant power (Blasa et al., 2006). In another study, the

seven most common types of Slovenian honeys were studied in

terms of their total phenolic content, antioxidant activity and colour

(Bertoncelj et al., 2007). Honey samples were from acacia, lime,

chestnut, fir, spruce, multifloral and forest (honeydew honey from

coniferous trees). Analytical results showed that the total phenolic

content and the antioxidant activity varied greatly among the

different types of honey. Darker honeys (fir, spruce, forest) showed

higher total phenolic content and higher antioxidant capacity than

lightest honeys (acacia and lime). Total phenolic content ranged

from 44.8 mg. gallic acid/Kg in acacia honey to 241.1 mg. gallic

acid/Kg in fir honey. A significant correlation between the

antioxidant activity and the phenolic content was also found. In

accordance to these results, the polyphenolic composition and the

antioxidant activity of Czech honeys, Lachman et al. (2010)

suggested similarities between lime, rape and raspberry honeys,

followed by floral honeys, while multifloral and honeydew honeys

were remarkably different.

Oddo et al. (2008) studied the antioxidant activity of Australian

honeys from Trigona carbonaria, a stingless bee from Australia and

found that, when compared with honeys from different countries of

the world, the flavonoid content was high (about 10.0 mg quercetin

equivalents/100 g of honey). However, their phenolic content was

lower (about 55.74 mg gallic acid equivalents/100 g of honey) than

that recorded by Vit et al. (2008) for Czech A. mellifera honey. The

Australian honey also displayed a higher total antioxidant activity

than the Czech A. mellifera sample, while the radical scavenging

activity was similar to that reported for floral and honeydews blends

of Spanish honey (Oddo et al., 2008).

Honeys from the Czech Republic (Lachman et al., 2010)

evaluated for their antioxidant activity and total phenolic

composition. Forty honey samples of different types such as

multifloral, lime, rape, raspberry, mixture and honeydew were

studied. Total phenolics content ranged from 82.5 to 242.5 mg / Kg

honey, those with the lowest content were lime honeys, whereas

honeydew honeys exhibited the highest concentrations. The

antioxidant activity values recorded using the FRAP, DPPH. and ABTS.

methods demonstrated that floral honeys were the least active while

honeydew honeys had the highest activity. The authors noted that

the observed low activity of floral honeys was in accordance with the

results of Al-Mamary et al. (2002), and was indicative of the

presence of different phenolic compounds with different antioxidant

activity. Raspberry honeys showed marked antioxidant activity which

had also been reported by the results of Buřičová and Reblová

(2008).

Gheldof and Engeseth (2002) and Gheldof et al. (2002)

compared the scavenging activity of honey for oxygen radicals (3-17

Imol TE/g) to that of fruits and legumes (0.5-19 Imol TE/g).

The possible changes in the antioxidant power and the

polyphenolic composition of honey when fermented into mead were

another subject of research. It was found that pasteurisation of the

starting musts did not induce any significant change in the

antioxidant power of the resulting meads, although phenolic profiles

had changed due to temperature (Wintersteen et al., 2005).

Free-radical scavenging activities of bee hive products and

extracts, were examined from samples of multifloral honeys,

monofloral honeys and honeydews. A high variability of the phenolic

content was reported. Honeydew samples were the richest in

phenolic compounds and showed a significant radical scavenging

activity. However, it was observed that not all the activity of the

samples accounted for the phenolic content. In fact, correlation

between proline content and the radical scavenging capacity was

found to be greater than that indicated by their total phenolic

content. In this case scientists suggested giving more importance to

the amino acid composition of honeys when evaluating their

antioxidant power (Meda et al., 2005).

Kishore et al., (2011) evaluated the total phenolic content, the

antioxidant and the radical scavenging activity of Asian honeys. They

found a higher phenolic content in tualang honey (83.96 mg gallic

acid equivalent /100 g of honey) than in Gelam, Indian forest and

pineapple honeys, and observed strong correlations of the phenol

content with the antioxidant and radical scavenging activities. They

also observed a significant peroxynitrite and superoxide anion

scavenging ability from this honey.

Regarding research with cells, Blasa et al. (2007) studied the

role of Italian honey flavonoids as agents against the oxidative

damage to human red blood cells. This study investigated water and

ether phenolic fractions from honeys to assess their phenolic and

flavonoid contents and their antioxidant activities. Differences in their

FRAP values were noted and it was concluded that hydrophillic

polyphenols were mostly glycosides and water soluble high

molecular weight polymers, whereas the lipophillic polyphenols were

low-molecular weight flavonoids. The aqueous fractions showed the


highest antioxidant activity and the organic fraction showed activity

against haemolytic agents and radicals involved in the lipid

peroxidation of the cell membrane and this activity could in part be

explained due to the higher liposolubility of these compounds.

Beretta et al. (2007) studied the protective effect of honey

against hydrogen peroxide and peroxyl radicals able to damage

endothelial cells and highlighted the synergistic action of honey

antioxidants (mainly phenolic acids and flavonoids). This antioxidant

activity had the ability to remove ROS that lead to oxidative stress

of endothelial cells and thus lowering the risk of develpoing acute

and chronic free-radical mediated pathologies such as

atherosclerosis and cancer in vivo.

In the search of healing products based on honey, Van den

Berg et al. (2008) studied the antioxidant and anti-inflammatory

properties of honey in vitro, and found that buckwheat honey was

the most effective in reducing ROS such as hydroxyl radicals

(formed from superoxide anion produced by the polimorphonuclear

neutrophils) and reactive nitrogen species such as peroxynitrite

anion (formed from the nitric oxide released by macrophages)

frequently found in wounds. Thus, this honey can help to reduce

the inflammatory effects in a wound and the surrounding tissue, and

help to improve wound healing due to its antibacterial and

antioxidant properties.

The cytotoxic activity of Indian honey has recently been

studied (Jaganathan et al., 2010b). Apart from flavonoids, phenolic

acids such as di-hydroxybenzoic and cinnamic acids were found.

This study observed that honey with the highest phenolic content

and antioxidant activity increased numbers of 3T3 cells viability in a

dose-dependant manner when cells were oxidative-induced to

death. Moreover, it was found that this honey could induce

apoptosis in cultured breast cancer cells (MCF-7) by arresting the

cells at the sub-G1 phase (Jaganathan et al., 2010b).

It has also been demonstrated that an increase in the

concentration of human plasma antioxidants was verified after the

intake of food rich in them, such as buckwheat honey. Therefore,

the antioxidant and reducing power of plasma increased significantly

and it was advised to have a higher honey intake in order to

increase the antioxidant defences in healthy adults (Schramm et al.,

2003).

Gheldof and Engeseth (2002) found that honeys from different

floral sources can protect against the oxidation of lipoproteins in

human plasma. Their results suggested that darker honeys such as

buckwheat honey displayed more protection than lighter ones such

as clover and acacia honeys.

The maintenance of the redox status of human plasma by

flavonoids in Italian multifloral honeys was studied by Fiorani et al.

(2006). Hydrophillic flavonoids were found to be remarkably more

effective than lipophillic flavonoids in promoting the chemical

reduction of the anion ferricyanide. However, the content of

hydrophillic flavonoids was lower than that of lipophillic flavonoids,

suggesting the presence of water-soluble phenolic polymers and

sugars. HPLC-MS (liquid chromatography with mass detection)

analyses of lipophillic flavonoids revealed the presence of high

concentrations of the aglycones of quercetin, luteolin, kaempferol,

fisetin, isorhamnetin, acacetin, chrysin, apigenin, galangin and

tamarixetin. Cell-based assays demonstrated that lipophillic

flavonoids developed greater protection for erythrocytes than

hydrophllic ones, by passing through the cell membrane,

accumulating in the cell and readily binding to haemoglobin. The

antioxidant role of intracellular flavonoids was explained by a donor-

electron mechanism to a trans-plasma membrane oxidoreductase

(PMOR) which may consequently promote the reduction of

extracellular oxidants.

Gheldof et al. (2003) investigated whether the intake of honey

could improve the human serum antioxidant status. After volunteers

had consumed beverages of water, water with buckwheat honey,

black tea, black tea with buckwheat honey and black tea with a sugar

analogue of honey, it was found that those who had consumed water

with buckwheat honey, significantly increased their plasma

antioxidant capacity, when compared with subjects receiving the

other beverages. Nevertheless, further studies on the bioavailability

of honey phenolics and more long-term studies are required to better

assess in vivo honey inhibition of plasma lipid peroxidation.

The antimicrobial and antiviral activity of honeys

The antimicrobial properties of honey have been known for millennia.

Aristotle (384-322 BC) discussed the properties of different honeys

and indicated pale honey for the treatment of sore eyes and wounds,

while Dioscorides (ca. 50 AD) referred to a pale yellow honey form

Attica as being the best for treating rotten and hollow ulcers. Honey

has inhibitory effects against several types of bacteria such as Gram

positive, Gram negative, aerobic and anaerobic bacteria (Molan,

1992).

There are several studies investigating the antimicrobial activity

of honey. The antibacterial activity of honey is usually associated

with the release of hydrogen peroxide, from the oxidation of glucose

to glucolactone and then to gluconic acid in presence of the enzyme

glucose oxidase (Adock, 1962; White and Subers, 1963). This activity

is called peroxide-activity and constitutes, at variable extent, the

mode of action of some honeys (Henriques et al., 2006). However,

another antibacterial non--peroxide activity in honey is mainly due to

their polyphenol content, sugar and other recently discovered factors.

Firstly, non-peroxide antimicrobial activity of honey from stingless

honeybees (Meliponinae) has been demonstrated as being important

because antibacterial activity due to hydrogen peroxide might be

reduced by the action of catalase present in human serum. (Temaru

et al., 2007). Secondly, New Zealand manuka honey (Leptospermun

scoparium (Myrtaceae)) have been studied regarding their

antibacterial activity and its relationship with their phenolic


composition (Weston and Brocklebank, 2000), but in recent years

Mavric et al. (2008) and Adams et al. (2008) described

methylglyoxal as the dominant antibacterial compound of manuka

honey. Atrott and Henle (2009) proved the close relationship

between methylglyoxal content and the antibacterial activity in

manuka honey. Moreover, Kwakman et al. (2010) characterized

other antibacterial non-peroxide factors of honey such as bee

defensin-1 along with methylglyoxal and sugar. Therefore, the

antimicrobial activity of honey can have several explanations and not

all the honeys behave similarly.

Regarding polyphenols, Burdock (1998) attributed the

antibacterial properties of honey to the presence of aromatic acids

and esters, whereas Takaisi and Schilcher (1994) said that

pinocembrin, galangin and caffeic acid phenethyl ester can inhibit

bacterial RNA polymerase. Moreover, Cushnie and Lamb (2005)

suggested an antibacterial mechanism of action started by galangin;

this involves degradation of the cytoplasmic membrane causing loss

of potassium ions and the subsequent cell autolysis. Furthermore,

Mirzoeva et al. (1997) proposed another mechanism of action for

quercetin, a flavonoid that may occur in honeys. They suggested

that quercetin may increase bacterium membrane permeability

leading to electric potential dissipation and decrease in the synthesis

of ATP. Kirnpal-Kaur et al. (2011) fractionated tualang honey into

polar, acidic and basic fractions using the solid phase extraction

technique (SPE) in order to evaluate their antibacterial properties

against wound and enteric bacteria, and found that the acidic

fraction enhanced the antibacterial properties of this honey. In an

effort to identify the main phytochemicals with antibacterial activity

present in the acidic fraction, the need for further investigations was

acknowledged, although preliminary evidence indicted that these

compounds could be polyphenols.

The inhibition of microorganisms of clinical significance

The recorded antimicrobial properties of honeys against some of the

most important microorganisms from a clinical standpoint will now

be described. Antimicrobial activity derived from the occurrence of

polyphenols will be emphassised, although any other activity whose

cause is not clearly defined will also be included.

Gram positive bacteria such as Staphylococcus aureus, the

causal agent of a range of illnesses from skin infections to life-

threatening diseases such as pneumonia and meningitis, did not

grow in the presence of honeys produced by A. mellifera and

Tetragonisca angustula bees in the Brazilian states of Paraná and

Minas Gerais. In order to study this effect, honeys were analysed by

high performance liquid chormatography (HPLC) and the anti-

microbial activity was connected to phenolic compounds, such as 4-

hydroxybenzoic acid (HBEN). These compounds occur in higher

concentrations in propolis than in honey, and propolis was more

effective against S. aureus than honey (Miorin et al., 2003). This

bacterium has proved to be variable in susceptibility to different

honeys. Turkish honeys from Anatolia showed a moderate inhibition

towards some strains of S. aureus (Küçük et al., 2007), while Turkish

rhododendron honeys partially inhibited the growth of this bacterium

(Silici et al., 2010). Honey from stingless bees had powerful activity

against S. aureus when compared to that exhibited by manuka honey

produced by honeybees belonging to Apidae family (A. mellifera, A.

cerana) (Temaru et al., 2007). Argentinean honeys from the province

of Córdoba evidenced high activity against S. aureus, which was

considered to be of remarkable clinical importance, since an increase

in difficult-to-treat skin infections had been reported in the last

decade and resistance against several antibiotics had developed

(Basualdo et al., 2007). A study of the properties of several Cuban

honeys demonstrated that Gram positive bacteria are more sensitive

than Gram negative bacteria (Alvarez Suárez et al., 2010), with S.

aureus the most sensitive bacterium (Alvarez Suárez et al., 2010).

Honeys from A. mellifera produced in Thailand also showed inhibitory

effects (Srisayam and Chantawannakul, 2010). Strains of S. aureus

were found to be very sensitive to Spanish honeydew honeys (Pérez

Martín et al., 2008) whereas in other studies using honeys from

Galicia (northwest of Spain) two strains of the bacterium, including a

difficult-to-treat strain in humans such as the methicillin-resistant

Staphylococcus aureus (MRSA), exhibited different sensitivities

(Gallardo-Chacón et al., 2008). South African honeys from

indigenous Leucospermum cordifolium and Erica species showed

poor antibacterial activity against this Gram positive bacterium

(Basson and Grobler, 2008). Baltrušaityté et al. (2007b) observed

that Lithuanian honeys exhibited antibacterial effects on S. aureus

and concluded that this was mainly due to the presence of hydrogen

peroxide. Honeys produced in the Czech Republic are also

antimicrobially effective with some honeydew honeys possessing the

greatest effects (Vorlova et al., 2005). In a study with unifloral and

multifloral Portuguese honeys, Henriques et al. (2005) analysed their

antibacterial activity against a strain of S. aureus, and observed that

all of the samples tested possessed peroxide activity except some

honeys derived from Lavandula stoechas which revealed non-

peroxide antibacterial activity. Recently, Isla et al. (2011) observed

that algarrobo honey (Prosopis nigra) and a multifloral honey from

the northwestern provinces of Argentina had activity against S.

aureus. They identified at least five antibacterial compounds in the

algarrobo honey and four compounds in the multifloral honey and

found that most of them corresponded to flavonoids. One of these

flavonoids was identified as pinocembrin. The authors also pointed

out that the antibacterial activity of the analysed honeys might be

mainly due to their phenol content because of the significant

correlation observed between the phenolic content and the

antibacterial activity.

Among the Gram negative bacteria, Escherichia coli is of great

concern from a health point of view. It may cause life threatening

gastric infections and diarrhoea, following consumption of


contaminated food, as well as other infections such as cystitis,

meningitis, peritonitis and pneumonia. There are several studies on

the antibiotic effect of honey towards E. coli. E. coli exhibited

sensitivity to stingless honeybee honey (Temaru et al., 2007),

Spanish honeys (Gallardo-Chacón et al., 2008), Cuban honeys

(Alvarez-Suárez et al., 2010), and Thailand honeys (Srisayam and

Chantawanakul, 2010). Basualdo et al. (2007) demonstrated that E.

coli can be inhibited by some Argentinean honeys while, Fangio et

al. (2010) demonstrated the effectiveness of honeys produced in the

province of Buenos Aires (Argentina) against this enterobacterium.

The antimicrobial activity of these honeys was mainly non-peroxide

and the presence of phytochemicals such as phenolic compounds

was considered in the most active honeys (Fangio et al., 2010).

Nevertheless, rhododendron Turkish honeys showed no inhibitory

effect (Silici et al., 2010), and Basson and Grobler (2008) found poor

antibiotic activity of South African honeys from indigenous L.

cordifolium and Erica species. Some Czech Republican honeys were

also tested for their antibacterial activity against E. coli and

researchers concluded that honeydew honeys are the most effective

(Vorlova et al., 2005). Recently, Brudzynski and Miotto (2011), in an

investigation with twenty Canadian unheated honeys, quantified

Maillard reaction- like products (MRLPs) and total phenol contents,

apart from assessing the antioxidant activity using the ORAC

method. One of their results indicated that both the recorded

antioxidant activity and the content of MRLPs of these honeys

mainly contributed to the antibacterial activity against E. coli. This

antibacterial activity confirms the work of Rufian-Henares and de la

Cueva (2009) who suggested that the antibacterial activity of coffee

melanoidins against E. coli is due to their behavior as metal-

chelators

Pseudomoma aeruginosa, an important pathogenic bacterium

which can cause several health disorders in humans including lung,

urinary, tissue, blood and wound infections was studied in many

published reports. Silici et al. (2010) showed that rhododendron

honeys from Turkey have antimicrobial activity against P. aeruginosa

when diluted at 50% and 75% in water. A. mellifera honeys

produced in Thailand also inhibited the growth of this bacterium

(Srisayam and Chantawannakul, 2010). Honey from stingless

honeybees showed significant inhibitory effects on the growth of P.

aeruginosa (Temaru et al., 2007). The bactericidal potency of

Saharan honey against this pathogen was studied by Boukraa and

Niar (2007) who reported that Saharan honey showed higher

potency than Algerian honeys, probably due to antibacterial

substances from the botanic flora ocurring in the Sahara. This Gram

negative and aerobic micro-organism was sensitive to some honeys

produced in the province of Córdoba (Argentina) (Basualdo et al.,

2007), but was the least sensitive in comparison with other bacteria

Alvarez-Suárez et al., 2010), while not sensitive to honey samples

evaluated by Gallardo-Chacón et al. (2008).

Helicobacter pylori, can occur in the stomach, and is linked to

the development of ulcers and many types of gastritis. There is

evidence that honey can have inhibitory effects against this

bacterium. Küçük et al. (2007) reported a moderate inhibitory effect

by honeys harvested in Anatolia (Turkey), and studies conducted

with manuka (L. scoparium) honey showed interesting antibacterial

activity. We must remember that, as previously described,

antibacterial activity of manuka honey is now mainly attributed to the

occurrence of methylglyoxal (Mavric et al., 2008, Adams et al., 2008;

Attrot and Henle, 2009). It has been suggested that this honey can

also act by healing the gastric mucosa and stimulating epithelial cells

growth.

Bacillus cereus, a Gram positive, aerobic and beta-haemolytic

bacterium, is a food-borne pathogen for humans, whose growth

results in the production of enterotoxins causing nausea, vomiting,

abdominal cramps and diarrhoea. There are reports of the sensitivity

of the bacterium towards some honeys. For example, some Thai

honeys can inhibit growth of the bacillus (Srisayam and

Chantawannakul, 2010), and similar activity was observed in studies

using different honeys which included honey from Galicia (Spain)

(Gallardo-Chacón et al., 2008). In contrast, Bacillus cereus was

found to be resistant when rhododendron Turkish honeys were

tested for their antibacterial activity (Silici et al., 2010).

Honeys produced in Anatolia (Turkey), in Cuba and in the

Turkish Black Sea Region showed inhibition effects on strains of

Bacillus subtilis (Küçük et al., 2007; Silici et al., 2010; Alvarez-Suárez

et al., 2010), a Gram positive sporing bacterium occurring in soil

which can contaminate food but rarely causes infections in humans.

Some other honey sensitive-pathogens described in the

literature are Bacillus anthracis (anthrax), Corynebacterium

diphtherine (diphtheria), Klebsiella pneumoniae (pneumonia),

Mycobacterim tuberculosis (tuberculosis), Salmonella typhi (typhoid

fever), Vibrio cholerae (cholera) and different streptococci, among

others. For example, Klebsiella pneumoniae was found to be sensitive

to Argentinean (Basualdo et al., 2007), and Thai honeys (Srisayam

and Chantawannakul, 2010). The growth of Enterococcus faecalis

was inhibited by stingless honeybee honey (Temaru et al., 2007),

and this bacterium also showed sensitivity to honey according to the

research performed by Gallardo-Chacón et al. (2008).

In addition, other bacteria sensitive to different types of honey

are Staphylococcus epidermidis (Basualdo et al., 2007; Baltrušaityté,

2007b), S. uberis (Basualdo et al., 2007), Pediococcus mirabilis (Silici

et al., 2010), Aeromonas hydrophila (Silici et al., 2010), Micrococcus

luteus (Srisayam and Chantawannakul, 2010), Streptococcus oralis

(Basson and Grobler, 2008), Streptococcus anginosus (Basson and

Grobler, 2008), Salmonella enterica ser. Typhimurium (Vorlova et

al., 2005; Gallardo-Chacón et al., 2008), Shigella sonnei (Gallardo-

Chacón et al., 2008), Listeria monocytogenes (Vorlova et al., 2005;

Gallardo-Chacón et al., 2008) and Streptococcus mutans (Basson

and Grobler, 2008). Among yeasts, some Candida species were

inhibited by Turkish honeys (Küçük et al., 2007).


The initial event in the development of bacterial infections of

the gastrointestinal gut is the attachment of bacteria to the mucosal

epithelial cells (Raupach et al., 1999) and the blocking of this event

represents an interesting strategy for the prevention of diseases

(Sherman et al., 1983; Leung and Finlay, 1991; O´Farrelly et al.,

1992; Peralta et al., 1994). Alnaqdy et al. (2005) studied the

antimicrobial activity of Omani honeys against Salmonella interitidis

and the ability of these honeys to prevent the bacterium from

adhering to intestinal epithelial cells in vitro.

However, in spite of the antimicrobial activity, there are yeasts

like Candida albicans and Saccharomyces cereviseae which showed

resistance towards some honeys (Silici et al., 2010; Srisayam and

Chantawannakul, 2010), while rhododendron honeys were not

effective against strains of B. cereus, E. coli and Yersinia

enterocolítica (Silici et al., 2010).

The bactericidal properties of honey led researchers to

investigate its applications on cutaneous wound healing and the

treatment of burns. Mohd Nasir et al. (2010) and Kirnpal-Kaur et al.,

(2011) found that tualang honey (Koompassia excelsa) had

important bactericidal and bacteriostatic effects in the treatment of

burns by using dressings soaked with this honey. Also, non-toxicity

of honey against tissue cell cultures of human keratinocyte and

fibroblasts has recently been found in vitro. This kind of evidence

may positively influence the choice of wound dressings in clinical

prescriptions (Du Toit and Page, 2009).

Inhibition of viruses

Antiviral properties of honeys are also of great concern from a

therapeutic point of view. Chritchfield et al. (1995) showed that

some important flavonoids of honey such as chrysin, acacetin and

apigenin can inhibit the human immunodeficiency virus (HIV-1)

activation, via a probable mechanism involving the inhibition of viral

transcription. Other researchers have demonstrated the inhibitory

effects of chrysin against herpes simplex virus type 1 (HSV-1) (Lyu

et al., 2005). Hu et al. (1994) observed that chrysin and apigenin

have a significant antiviral activity against HIV-1 in acutely infected

H9 lymphocytes. Apigenin also exhibited antiviral activity against

influenza virus (H3N2) in vitro (Liu et al., 2008).

Molecular biological processes at DNA level are responsible for

cell events that lead to the development of some phenomena such

as carcinogenesis, and, in this line, binding studies of different

flavonoids were undertaken. Apigenin, a cancer chemopreventive

agent, has the highest affinity of ligand-DNA binding when

compared to those of morine and naringin (Nafisi et al., 2008).

Chiang et al. (2005) observed that apigenin behaves as a

potent antiviral substance against herpes virus type-2 (HSV-2),

adenovirus (ADV-3), hepatitis B surface antigen (HBsA) and hepatitis

B e antigen (HBeA).

Al-Waili (2004) studied the activity of honey on two types of

herpes: labial and genital herpes. His results demonstrated that the

topic application of honey on recurrent attacks of this viral disease

was effective. This study reported that in the labial herpes the mean

time of healing was 43% better than with the conventional treatment

with acyclovir, while for genital herpes the mean healing time was

improved around 59%. The authors remarked that some cases

remitted completely after treatment with honey, although none of

the attack remitted when using acyclovir. Honey has also

demonstrated anti-Rubella activity in experiments performed on

monkey kidney cell cultures infected with the Rubella virus (Zeina et

al., 1996).

Finally, further investigations are required to study the

relationship between the phenolic composition of honeys and their

therapeutic properties, now that it is has been proposed that honey

from stingless bees may be used to manufacture pharmaceuticals, as

well as nutritional supplements and cosmetics (Temaru et al., 2007).

Antitumour properties

Honey and its components have several applications in cancer

therapy. There are a number of reports focusing on honey and some

individual components undertaken in cell cultures, animal models and

humans (Fig. 4) as described later in the text. So, for instance, the

use of honey has revealed a significant inhibition of the proliferation

in three human bladder cancer cell lines (T24, 253J and RT4) and

one murine bladder cancer cell line (MBT-2). When researchers used

between 1 and 25% of honey BrdU labelling index was significantly

lower and the same was observed for the S-phase fraction when

compared with control cells. In the in vivo studies, cancer cells were

implanted subcutaneously in the abdomens of mice and tumour

growth was significantly inhibited after intralesional injection of 6 and

12% of honey as well as after oral ingestion of honey (Swellam et

al., 2003). In other research, honey was used in solution as

treatment in W256 mammary carcinoma implants in Wistar rats, and

a decrease in relative tumour weight was observed suggesting that

honey modulated tumour growth (Tomasin and Cintra Gomes-

Marcondes, 2011). Honey not only has antitumour properties, but

has protective effects on the oxidative stress and carcinogenesis

induced by carcinogenic compounds as methylnitrosourea (MNU). In

fact, one week after Sprague Dawely rats were injected with

methylnitrosourea one group of rats were given orally 5 g honey

(containing 0.2 g of ground Nigella sativa seeds) per rat, per day.

After six months the methylnitrosourea injected in the control group

produced a variety of oxidative stresses ranging from severe

inflammatory reaction in lung and skin to colon adenocarcinoma,

whereas honey and Nigella sativa together protected 100% (12/12)

against effects of methylnitrosourea (Mabrouk et al., 2002).

The antitumour effects of eugenol, chrysin and galangin have

demonstrated antitumoural activity (Jaganathan et al., 2011)

Eugenol, a natural compound available in honey, has antiproliferative


effects in colon cancer cells (HT29, HT15) and increased the

accumulation of cells at sub-G1 phase. Eugenol increased levels of

ROS, DNA fragmentation and decreases mitochondrial membrane

potential (MMP). Eugenol was found to be a potential

chemopreventive agent against colon cancer cells (Jaganathan et

al., 2011). Eugenol has not only antitumoural properties in this cell

type, but also it has antiproliferative effects in other cells such as

prostate or melanoma cancer cells (Ghosh et al., 2005, 2009). In

animal models, this compound has demonstrated interesting

results. So, when Ehrlich ascites carcinoma (EAC) cells were injected

in female mice and then, either 0,2 ml (25% v/v) of honey or

eugenol (from 80 to 120 mg/Kg) were administered

intraperitoneally, an inhibitory effect in tumour growth was reported

of 30% with eugenol and close to 40% with honey. Another

important compound with antitumoural properties is chrysin. This

compound and honey (acacia honey) have antiproliferative effects in

human (A375) and murine (B16-F1) melanoma cell lines. In this

case honey and chrysin induced G 0/G 1 cell cycle arrest, and hence,

chrysin has been considered as a potential candidate for cancer

prevention and treatment (Pichichero et al., 2010). In other

research, cell viability assay and flow cytometric analysis suggested

that chrysin exhibited a dose-dependent and time-dependent ability

to block, in G1 phase, rat C6 glioma cell line. It was demonstrated

that expression of cyclin-dependent kinase inhibitor, p21, was

significantly increased, and both cyclin-dependent kinase 2 and 4

(CDK2, CDK4) kinase activities were reduced by chrysin in a dose-

dependent manner (Weng et al., 2005). Several individual

compounds of honey have shown apoptotic effects. For instance,

galangin is effective as an anti-proliferative and apoptotic agent in

human myeloid cell lines (K562 and KCL22) and in imatinib mesylate-

resistant myeloid cells (K562-R and KCL22-R). Galangin induced a

decrease in Bcl-2 levels and markedly increased the apoptotic activity

of imatinib in both imatinib sensitive and imatinib-resistant Bcr-Abl+

cell lines. These observations suggest that galangin is an interesting

candidate for a combination therapy in the treatment of imatinib-

resistant leukemias (Tolomeo et al., 2008). The honey components

quercetin (Murakami et al., 2008), caffeic acid (Nagaoka et al.,

2003), acacetin (Shen et al., 2010), kaempferol (Luo et al., 2010),

and apigenin (Shukla and Gupta, 2010) have all been studied in

relation to cancer.

Not all studies have been conducted on cell and animal models;

in fact honey has also been evaluated in clinical cancer cases and

with beneficial effects. Honey has been evaluated as a treatment for

radiotherapy or chemotherapy, induced mucositis in humans

(Motallebnejad et al., 2008; Rashad et al., 2009). Mucositis is a

frequently encountered oral complication of both radiation and


Fig. 4. The benefits of honey against cancer at cell, animal and human levels.

chemotherapy of head and neck cancers. In the case of the research

to assess the effect of honey against radiation-induced mucositis,

Motallebnejad et al. (2008) performed a single blind clinical trial with

forty patients with head and neck cancer and under radiotherapy

treatment. Twenty of them were administered honey before, during

and after radiation and the rest saline before and after radiation.

Then, patients were evaluated weekly for mucositis and an

important reduction in mucositis among honey-treated patients was

found. In view of this result, it can be concluded that honey is an

effective treatment in mucositis derived from cancer treatments.

Another possible clinical use of honey is in the management of

radiation-induced burns in women treated for breast cancer. In this

case, women were treated with honey and pentoxifylline and so the

area of burned skin was reduced by more than 25% with honey, so

that patients underwent shorter radiotherapy treatments (Shoma et

al, 2010).

Life Mel honey is a natural honey produced by bees that are fed

a blend of different therapeutic herbs such as Calendula, Avena

sativa, Echinacea, nettles, ginseng, red clover, Melissa and

dandelion, among others. Their flavonoids, vitamins and minerals

enrich Life Mel honey and each herb has a specific function to offset

the adverse effect of drugs used in cancer patients undergoing

chemotherapy. Neutropenia is a common side effect affecting cancer

patients under chemotherapy treatments, consisting in a decrease of

neutrophils in blood. The low levels of these blood cells put these

patients at risk of infections. In fact, Zidan et al. (2006) observed

that intake of Life Mel honey helped to prevent neutropenia induced

by chemotheraphy, and haemoglobine levels were high in 64% of

the cases.

If we gather all of these results it is possible to believe that

honey is an important source of interesting compounds for the

treatment of cancer, and that it can be regarded as a functional food

in the cancer field.

Antiulcer and cardioprotective properties

Of great interest are the antiulcer properties of honey and, also of

propolis, described by Viuda Martos et al. (2008a, 2008b). These

authors cited several sources regarding the relationship between the

antiulcer action of honeys and their flavonoid content. The antiulcer

capacity of honeys has been attributed to their many flavonoids

(Gracioso et al., 2002, Batista et al., 2004, Hiruma-Lima et al, 2006).

Flavonoids in beehive products may inhibit the formation of gastric

ulcers via various suggested mechanisms. For example, Speroni and

Ferri (1993) deduced that these compounds increased the level of

mucosal prostaglandins; Vilegas et al. (1999) added that apart from

the formation of these prostaglandins, honey flavonoids can also

inhibit acid secretions thus preventing ulceration. Another proposed

theory to explain the development of gastric ulcers argues that the

lesions are provoked by reactive oxygen species, and that the

flavonoids in honey scavenge them and thus inhibit lipid peroxidation

and so prevent tissue damage (Martin et al., 1998, Young et al.,

1999, Duarte et al., 2001). Some studies confirmed the antiulcer

activity of some flavonoids found in honey, such as kaempherol and

quercetin (Leite et al., 2001, Yao et al., 2004 b, Orsolic and Basic,

2005, Fiorani et al., 2006), also hesperitin and naringin which were

both found in orange honey (Ferreres et al., 1993, 1994; Kanaze et

al., 2003).

The cardioprotective role of natural honey was studied by

Rakha et al. (2008) in relation with the decrease of the vulnerability

of the heart to several kinds of cardiac disorders and vasomotor

dysfunction associated with hyperadrenergic activity.

Hyperadrenergic activity may be caused by stress, emotion, and

among physiological causes, there is evidence of a close association

between palpitation, tachycardia, arrythmia, and the

pheochromocytoma (an adrenaline-secreting tumour of adrenal

medullary tissue). Adrenaline (epinephrine), a well-known drug

widely used to maintain blood pressure, may cause side effects such

as tachycardia, arrythmias, hypertension and oxidative stress. Natural

wild honey can ameliorate the cardiac disorders induced by

adrenaline injected in urethane-anestethised rats probably thanks to

its total antioxidant capacity and its great pool of enzymatic and non-

enzymatic antioxidants involved in cardiovascular defense

mechanisms.

The cardiovascular benefits of various flavonoids, their effects

on blood pressure and the role played by some molecules such as

quercetin and its glycosides in the prevention of the oxidative

damage of low density lipoproteins (LDL) are fully described in the

literature (Raj Narayana et al., 2001). Some honeys can protect LDL

from oxidative damages (Gheldof and Engeseth, 2002; Gheldof et al.,

2003), and it is important from a clinical aspect , since oxidative

modifications of LDL are considered critical in the onset of

atherosclerosis (Esterbauer et al., 1992 ).

Conclusions

The phenolic composition of honey appears to have an important role

in the health giving properties of bee hive products. Honey, together

with other natural foods, seems to be an important component of the

human diet.

Increasingly the amount of honey consumed in a well-balanced

diet could help to improve the prevention of free radical related-

diseases, as well as contributing to the management of more

common infective disorders. Honey can also be considered as a

natural alternative in the treatment of some herpes, and increasing

interest amongst clinicians of the effects of flavonoids such as

chrysin, acacetin and apigenin on HIV-1 virus is important.

In the cancer field, honey and some of its compounds, such as

eugenol, chrysin and galangin have demonstrated prevention and

treatment potential.


On account of its historical background of healthy properties

and the increasing experimental knowledge, honey can be regarded,

as a functional food which might be reasonably consumed

throughout life. Nevertheless, further studies are required to

determine and explore the mechanisms of flavonoid/polyphenol

derived benefits and to possibly discover new and as yet unreported

benefits of this natural product.

References ADAMS, C J; BOULT, C H; DEADMAN, B J; FARR, J M; GRAINGER, M

N; MANLEY-HARRIS, M; SNOW, M J (2008). Isolation by HPLC

and characterisation of the bioactive fraction of New Zealand

Manuka (Leptospermum scoparium) honey. Carbohydrate

Research 343 (4): 651-659. DOI: 10.1016/j.carres.2007.12.011

ADOCK, D (1962) The effect of catalase on inhibine and peroxide

values of variuos honeys. Journal of Apicultural Research 1:

38-40.

ALI, A T; CHOWDHURY, M N; AL-HUMAYYD, M S (1991) Inhibitory

effect of natural honey on Helicobacter pylory. Tropical

Gastroenterology 12: 73-77.

ALI, A T (1995) Natural honey exerts its protective effects against

ethanol-induced gastric lesions in rats by preventing deplerion

of glandular nonprotein sulfhydryls. Tropical Gastroenterology

16: 18-26.

ALJADI, A M; KAMARUDDIN, M Y (2004) Evaluation of the phenolic

contents and antioxidant capacities of two Malaysian floral

honeys. Food Chemistry 85: 513-518.

AL-MAMARY, M; AL-MEERI, A; AL-HABORI, M (2002) Antioxidant

activities and total phenolics of different types of honey.

Nutrition Research 22: 1041-1047.

ALNAQDY, A; AL-JABRI, A; AL MAHROOQI, Z; NZEAKO, B; NSANZE,

H (2005) Inhibition effect of honey on the adherence of

Salmonella to intestinal epithelial cells in vitro. International

Journal of Food Microbiology 103: 347-351.

ALVAREZ-SUÁREZ, J M; TULIPANI, S; DÍAZ, D; ESTÉVEZ, Y;

ROMANDINI, S; GIAMPIERI, F; DAMIANI, E; ASTOLFI, P;

BOMPADRE, S; BATTINO, M. (2010) Antioxidant and

antimicrobial capacity of several monofloral Cuban honeys and

their correlation with color, polyphenol content and other

chemical compounds. Food and Chemical Toxicology 48: 2490-

2499.

ALVES DA SILVA, R; ARRAES MAIA, G; MACHADO DE SOUZA, P H;

CORREIA DA COSTA, J M (2006). Composição e propriedades

terapêuticas do mel de abelha. Alimentos e Nutrição 17 (1):

113-120.

AL-WAILI, N S (2004) Topical honey application vs. acyclovir for the

treatment of recurrent herpes simplex lesions. Medical Science

Monitoring 10 (8): MT 94-8.

AMES, B N; SHIGENAGA, M K; HAGEN, T M (1993) Oxidants,

antioxidants, and the degenerative diseases of aging.

Proceedings of the National Academy of Science of the United

States 90 (17): 7915-7922.

AMIC, D; DAVIDOVIC-AMIC, D; BEŠLO, D; TRINAJSTIC, N (2003)

Structure-radical scavenging activity relationships of flavonoids.

Croatica Chemica Acta 76 (1): 55-61.

AMIOT, M J ; AUBERT, S; GONNET, M; TACCHINI, M (1989) Les

composés phénoliques des miels : étude préliminaire sur

l´identification et la quantification par familles. Apidologie 20:

115-125.

AMOROS, M; SAUVAGER, F; GIRRE, L; CORMIER, M (1992) In vitro

antiviral activity of propolis. Apidologie 23 (3): 231-240.

ATTROT, J; HENLE, T (2009) Methylglyoxal in Manuka honey-

Correlation with antibacterial properties. Czech Journal of Food

Science 27, Special Issue: S163-S165

BALTRUŠAITYTÉ, V; VENSKUTONIS, P R; ČEKSTERYTÉ, V (2007a)

Radical scavenging activity of different floral origin honey and

beebread phenolic extracts. Food Chemistry 101: 502-514.

BALTRUŠAITYTÉ, V; VENSKUTONIS, P R; ČEKSTERYTÉ, V (2007b)

Antibacterial activity of honey and beebread of different origin

against S. aureus and S. epidermis. Food Technology and

Biotechnology 45 (2): 201-208.

BASSON, N J; GROBLER, S R (2008) Antimicrobial activity of two

South African honeys produced from indigenous Leucospermum

cordifolium and Erica species on selected micro-organisms. In

BMC Complementary and Alternative Medicine 15 (8) July. p41.

Available at: http://www.biomedcentral.com/1472-6882/8/41.

BASUALDO, C; SGROY, V; FINOLA, M S; MARIOLI, J M (2007)

Comparison of the antibacterial activity of honey from different

provenance against bacteria usually isolated from skin wounds.

Veterinary Microbiology 124: 375-381.

BATISTA, L M; de ALMEIDA, A B; de PIETRO MAGRI, L; TOMA, W;

CALVO, T R; VILEGAS, W; SOUZA-BRITO, A R (2004) Gastric

antiulcer activity of Syngonanthus arthrotrichus SILVEIRA.

Biological & Pharmaceutical Bulletin 27 (3): 328-332

BERETTA, G; GRANATA, P; FERRERO, M; ORIOLI, M; MAFFEI

FACINO, R (2005) Standardization of antioxidant properties of

honey by a combination of spectrophotometric/fluorimetric

assays and chemometrics. Analytica Chimica Acta 533: 185-191.

BERETTA, G; ORIOLI, M; FACINO, R M (2007) Antioxidant and

radical scavenging activity of honey in endothelial cell cultures

(EA.hy926). Planta Medica 73 (11): 1182-1189.

BERNER, L A; O´DONNELL, J A (1998) Functional Foods and Health

Claims Legislation: Applications to Dairy Foods. International

Dairy Journal 8: 355-362.


http://www.sciencedirect.com/science/article/pii/S0008621507005447

BERTONCELJ, J; DOBERŠEK, U; JAMNIK, M; GOLOB, T (2007)

Evaluation of the phenolic content, antioxidant activity and

colour of Slovenian honey. Food Chemistry 105: 822-828.

BLASA, M; CANDIRACCI, M; ACCORSI, A; PIACENTINI, M P;

ALBERTINI, M C; PIATTI, E (2006) Raw Millefiori honey is

packed full of antioxidants. Food Chemistry 97: 217-222.

BLASA, M; CANDIRACCI, M; ACCORSI, A; PIACENTINI, M P; PIATTI,

E (2007) Honey flavonoids as protection agents against

oxidative damage to human red blood cells. Food Chemistry

104: 1635-1640.

BORS, W; HELLER, W; MICHEL, C; SARAN, M (1990). Flavonoids as

antioxidants: determination of radical-scavenging efficiencies.

Methods in Enzymology 186: 343-355.

BOUKRAÂ, L; NIAR, A (2007) Sahara honeys shows higher potency

against Pseudomonas aeruginosa compared to north Algerian

types of honey. Journal of Medicinal Food 10 (4): 712-714.

BRAVO, L (1998) Polyphenols: chemistry, dietary sources,

metabolism and nutritional significance. Nutrition Reviews 56

(11): 317-333.

BROTHWELL, D; BROTHWELL, P (1969) Food in Antiquity: a Survey

of the Diet of Early Peoples. Thames & Hudson; London, UK.

BRUDZYNSKI, K; MIOTTO, D (2011) The relationship between the

content of Maillard reaction-like products and bioactivity of

Canadian honeys. Food Chemistry 124: 869 -874

BRUSCHI, M L; FRANCO, S L; GREMIĂO, M P D (2003) Application of

an HPLC Method for Analysis of Propolis Extract. Journal of

Liquid Chromatography and Related Technologies 26 (14):

2399-2409.

BURDOCK, G A (1998) Review of the biological properties and

toxicity of bee propolis. Food Chemistry and Toxicology 36:

347--363.

BUŘIČOVÁ, L; RÉBLOVÁ, Z (2008) Czech medicinal plants as

possible sources of antioxidants. Czech Journal of Food Science

26: 132-138.

CHIANG, L-CH; NG, L-T; CHENG, P-W; CHIANG, W; LIN, CHCH

(2005) Antiviral activities of extracts and selected pure

constituents of Ocimum Basilicum. Clinical and Experimental

Pharmacology and Physiology 32: 811-816.

CODEX STANDARD FOR HONEY, CODEX STAN 12-1981 (reviewed in

1987 and 2001). In Codex Alimentarius.

CRITCHFIELD, J W; BUTERA, S T; FOLKS, T M (1995) Inhibition of

HIV-1 activation in chronically infected cells by flavonoid

compounds. National Conference on Human Retroviruses and

Related Infections, Washington DC, Retrovirus Diseases

Branch, Centers for Disease Control and Prevention, Atlanta,

GA.

CRITCHFIELD, J W; BUTERA, S T; FOLKS, T M (1996) Inhibition of

HIV-1 activation in latenly infected cells by flavonoid

compounds. AIDS Research and Human Retroviruses 12:

39-46.

CUSHNIE, T P T; LAMB, A J (2005) Detection of galangin-induced

cytoplasmic membrane damage in Staphylococcus aureus by

measuring potassium loss. Journal of Ethnopharmacology 101:

243-248.

DIMITROVA, B; GEVRENOVA, R; ANKLAM, E; (2007) Analysis of

phenolic acids in honeys of different floral origin by solid-phase

extraction and high-performance liquid chromatography.

Phytochemical Analysis 18: 24-32.

DUARTE, J; GALISTEO, M; ANGELES-OCETE, M; PEREZ-VIZCAINO, F;

ZARZUELO, A; TAMARGO, J (2001) Effects of chronic quercetin

treatment on hepatic oxidative status of spontaneously

hypertensive rats. Molecular and Cellular Biochemistry 221

(1/2): 155-160

DU TOIT, D F ; PAGE, B J (2009) An in vitro evaluation of the cell

toxicity of honey and silver dressings. Journal of Wound Care

18 (9): 383-9.

ESTERBAUER, H; GEBICKI, J; PUHL, H; JURGENS G (1992) The role

of lipid peroxidation and antioxidants in oxidative modification

of LDL. Free Radical Biology and Medicine 13: 341-390.

FANGIO, M F; IURLINA, M O; FRITZ, R (2010) Characterisation of

Argentinean honeys and evaluation of its inhibitory action on

Escherichia coli growth. International Journal of Food Science

and Technology 45: 520-529.

FERRERES, F; GARCIA-VIGUERA, C; TOMAS-LORENTE, F; TOMAS-

BARBERAN, F A (1993) Hesperetin C a marker of the floral

origin of citrus honey. Journal of the Science of Food and

Agriculture 61: 121-123.

FERRERES, F; GINER, J M; TOMAS-BARBERAN, F A (1994) A

comparative study of hesperetin and methyl anthranilate as

markers of the floral origin of citrus honey. Journal of the

Science of Food and Agriculture 65 (3): 371-372.

FIORANI, M; ACCORSI, A; BLASA, M; DIAMANTINI, G; PIATTI, E

(2006) Flavonoids from Italian multifloral honeys reduce the

extracellular ferricyanide in human red blood cells. Journal of

Agricultural and Food Chemistry 54: 8328-8334.

FRANKEL, S; ROBINSON, G E; BERENBAUM, M R (1998) Antioxidant

capacity and correlated characteristics of 14 unifloral honeys.

Journal of Apicultural Research 37 (1): 27-31.

GALLARDO-CHACON, J J; CASELLES, M; IZQUIERDO-PULIDO, M;

RIUS, N (2008) Inhibitory activity of monofloral and multifloral

honeys against bacterial pathogens. Journal of Apicultural

Research 47 (2): 131-136.

GHELDOF, N; ENGESETH, N J (2002) Antioxidant capacity of honeys

from various floral sources based on the determination of

oxygen radical absorbance capacity and inhibition of in vitro

lipoprotein oxidation in human serum sample. Journal of

Agricultural and Food Chemistry 50 (10): 3050-3055.

GHELDOF, N; WANG, X; ENGESETH, N J (2002) Identification and

quantification of antioxidants compounds of honeys form

various floral sources. Journal of Agricultural and Food

Chemistry 50 (10): 5870-5877.


GHELDOF, N; WANG, X H; ENGESETH, N J (2003) Buckwheat honey

increases serum antioxidant capacity in humans. Journal of

Agricultural and Food Chemistry 51 (5): 1500-5.

GHOSH, R; NADIMINTY, N; FITZPATRICK, J E; ALWORTH, W L;

SLAGA, T J; KUMAR, A P (2005) Eugenol causes melanoma

growth suppression through inhibition of E2F1 transcriptional

activity. Journal of Biological Chemistry 280: 5812-5819

GHOSH, R; GANAPATHY, M; ALWORTH, W L; CHAN, D C; KUMAR, A

P (2009) Combination of 2-methoxyestradiol (2-ME2) and

eugenol for apoptosis induction synergistically in androgen

independent prostate cancer cells. Journal of Steroid

Biochemistry and Molecular Biology 113: 25-35.

GOULD, K S; LISTER, C (2005) Flavonoid functions in plants. In

Andersen ØM, Markham KR editors. Flavonoids: chemistry,

biochemistry, and applications. CRC Press; Boca Raton, FL. pp

397-441.

GRACIOSO, J S; VILEGAS, W; HIRUMA-LIMA, C A; BRITO, A R M S

(2002) Effects of tea from Turnera ulmifolia L. on mouse

gastric mucosa support the turneraceae as a new source of

antiulcerogenic drugs. Biological & Pharmaceutical Bulletin 25

(4): 487-491

HAENEN, G R M M; PAQUAY, J B G; KORTHOUWER, R E M; BAST, A

(1997) Peroxynitrite scavenging by flavonoids. Biochemical and

Biophysical Research Communications 236: 591-593.

HARBORNE, J B (1988) The Flavonoids: advances in research since

1980. Chapman and Hall; London, UK.

HARBORNE, J B (1989) Methods in Plant Biochemistry, I: plant

phenolics. Academic Press; London, UK.

HARBORNE, J B (1993) The Flavonoids: advances in research since

1986. Chapman and Hall; London, UK.

HAVSTEEN, B H (2002). The biochemistry and medical significance

of the flavonoids. Pharmacology and Therapeutics 96: 67-202.

HENRIQUES, A; BURTON, N F; COOPER, R A (2005) Antibacterial

activity of selected Portuguese honeys. Journal of Apicultural

Research 44 (3): 119-123.

HENRIQUES, A; JACKSON, S; COOPER, R; BURTON, N (2006). Free

radical production and quenching in honeys with wound

healing potential. Journal of Antimicrobial Chemotherapy 58:

773-777.

HIRUMA-LIMA, C A; CALVO, T R; RODRIGUES, C M; ANDRADE, F D;

VILEGAS, W; BRITO, A R (2006) Antiulcerogenic activity of

Alchornea castaneaefolia: effects on somatostatin, gastrin and

prostaglandin. Journal of Ethnopharmacology 104 (1-2): 215-

224

HU, CH-Q; CHEN, K; SHI, Q; KILKUSKIE, R E; CHENG, Y C; LEE, K H

(1994) Anti-AIDS agents, 10. Acacetin-7-O-β-D-galactopyrano-

side, an anti-HIV principle from Chrysanthemum Morifolium

and a structure-activity correlation with some related

flavonoïds. Journal of Natural Products 57 (1): 42-51.

ISLA, MI; CRAIG,A; ORDOÑEZ, R; ZAMPINI, C; SAYAGO, J;

BEDASCARRASBURE, E; ALVAREZ, A; SALOMON, V;

MALDONADO, L (2011) Physicochemical and bioactive

properties of honeys from Northwestern Argentina. LWT Food

Science and Technology 44: 1922-1930.

JAGANATHAN, S K; MANDAL, M (2009) Antiproliferative effects of

honey and of its polyphenols: A review. Journal of Biomedicine

and Biotechnology: 1-13.

JAGANATHAN, S K; MONDHE, D; WANI, Z A; PAL, H C; MANDAL, M

(2010a). Effect of honey and eugenol on Ehrlich ascites and

solid carcinoma. Journal of Biomedicine and Biotechnology

2010: 989163.

JAGANATHAN, S K; MANDAL, S M; JANA, S K; DAS, S; MANDAL, M

(2010b) Studies on the phenolic profiling, anti-oxidant and

cytotoxic activity of Indian honey: in vitro evaluation. Natural

Products Research 24 (14):1295-306.

JAGANATHAN, S K; MAZUMDAR, A; MONDHE, D; MANDAL, M (2011).

Apoptotic effect of eugenol in human colon cancer cell lines.

Cell Biology International Jun. 1 35 (6): 607-615

KANAZE, F I; GABRIELI, C; KOKKALOU, E; GEORGARAKIS, M;

NIOPAS, I (2003) Simultaneous reversed-phase high-

performance liquid chromatography method for the

determination of diosmin, hesperidin and naringin in different

citrus fruit juices and pharmaceutical formulations. Journal of

Pharmaceutical and Biomedical Analysis 33 (2): 243-249.

KINSELLA, J F ; FRANKEL, E ; GERMAN, B ; KANNER, J (1993)

Possible mechanisms for the protective role of antioxidants in

wine and plant foods. Food Technology 47 (4): 85-89.

KIRNPAL-KAUR, B S; TAN, H-T; BOUKRAA, L; GAN, S-H (2011)

Different solid phase extraction fractions of Tualang

(Koompassia excelsa) honey demonstrated diverse antibacterial

properties against wound and enteric bacteria. Journal of

Apiproduct and Apimedical Science 3 (1): 59-65. DOI 10.3896/

IBRA.4.03.1.10.

KISHORE, R K; HALIM, A S; SYAZANA, M S N; SIRAJUDEEN, K N S

(2011) Tualang honey has higher phenolic content and greater

radical scavenging activity compared with other honey sources.

Nutrition Research 31: 322-325.

KROON, P; WILLIAMSON, G (2005) Polyphenols: dietary components

with established benefits to health? (Perspective). Journal of

the Science of Food and Agriculture 85: 1239-1240.

KÜÇÜK, M; KOLAYLI, S; KARAOGLU, S; ULUSOY, E; BALTACI, C;

CANDAN, F (2007) Biological activities and chemical

composition of three honeys of different types from Anatolia.

Food Chemistry 100: 526-534.

KWAKMAN, P H; TE VELDE, A A; DE BOER, L; SPEIJER, D;

VANDENBROUCKE-GRAULS, C M; ZAAT, S A (2010) How honey

kills bacteria. FASEB Journal 24 (7): 2576-2582.

LACHMAN, J; ORSÁK, M; HEJTMÁNKOVÁ, A; KOVÁŘOVÁ, E (2010)


http://www.jaas.org.uk/articles/tualang-honey-fractions-and-their-antibacterial-properties

Evaluation of antioxidant activity and total phenolics of

selected Czech honeys. LWT Food Science and Technology 43

(1): 52-58.

LEITE, J P; RASTRELLI, L; ROMUSSI, G; OLIVEIRA, A B; VILEGAS, J

H; VILEGAS, W; PIZZA, C (2001) Isolation and HPLC

quantitative analysis of flavonoid glycosides from Brazilian

beverages (Maytenus ilicifolia and M. aquifolium). Journal of

Agricultural and Food Chemistry 49 (8): 3796-3801

LEUNG, K Y; FINLAY, B B (1991) Intracellular replication is essential

for the virulence of Salmonella typhimurium. Proceedings of

the National Academy of Science of the United States 88:

11470-11474.

LIU, AI-LIN; LIU, B; QIN, H-L; LEE, S M; WANG, Y-T; DU, G-H

(2008) Anti-influenza virus activities of flavonoids from the

medicinal plant Elsholtzia rugulosa. Planta Medica 74 (8):

847-851.

LUO, H; DADDYSMAN, M K; RANKIN, G O; JIANG, B H; CHEN, Y C

(2010). Kaempferol enhances cisplatin's effect on ovarian

cancer cells through promoting apoptosis caused by down

regulation of cMyc. Cancer Cell International 10: 16.

LYU, S-Y; RHIM, J-Y; PARK, W-B (2005) Antiherpetic activities of

flavonoids against Herpex Simplex Virus Type 1 (HSV-1) and

Type 2 (HSV-2) in vitro. Archives of Pharmacal Research 28

(11): 1293-1301.

MABROUK, G M; MOSELHY, S S; ZOHNY, S F; ALI, E M; HELAL, T E;

AMIN, A A; KHALIFA, A A (2002) Inhibition of

methylnitrosourea (MNU) induced oxidative stress and

carcinogenesis by orally administered bee honey and Nigella

grains in Sprague Dawely rats. Journal of Experimental and

Clinical Cancer Research 21: 341-346.

MANACH, C; REGERAT, F; TEXIER, O; AGULLO, G; DEMIGNE, C;

REMESY, C (1996) Bioavailability, metabolism, and

physiological impact of 4-oxo.flavonoids. Nutrition Research

16: 517-544.

MANACH, C; SCALBERT, A; MORAND, C H; RÉMESY, C H; JIMENEZ,

L (2004) Polyphenols: food sources and bioavailability.

American Journal of Clinical Nutrition 79: 727-747.

MANACH, C; WILLIAMSOM, G; MORAND, CH; SCALBERT, A;

RÉMESY, C H (2005) Bioavailability and bioefficacy of

polyphenols in humans. I. Review of 97 bioavailability studies.

American Journal of Clinical Nutrition 81: 230S-242S.

MARTIN, M J; CASA, C; ALARCON-DE-LA-LASTRA, C; CABEZA, J;

VILLEGAS, I; MOTILVA, V (1998) Antioxidant mechanisms

involved in gastroprotective effects of quercetin. Zeitsfritch für

Naturforschung C. Journal of Biosciences 53 (1/2): 82-88.

MARTOS, I; FERRERES, F; TOMÁS-BARBERÁN, F A (2000)

Identification of Flavonoid Markers for the Botanical Origin of

Eucalyptus Honey. Journal of Agricultural and Food Chemistry

48: 1498-1502.

MAVRIC, E; WITTMANN, S; BARTH, G; HENLE, T. (2008).

Identification and quantification of methylglyoxal as the

dominant antibacterial constituent of Manuka (Leptospermum

scoparium) honeys from New Zealand. Molecular Nutrition and

Food Research 52 (4): 483-489

MEDA, A; LAMIEN, C H E; ROMITO, M; MILLOGO, J; NACOULMA, O

G (2005) Determination of the total phenolic, flavonoid and

proline contents in Burkina Fasan honey, as well as their radical

scavenging activity. Food Chemistry 91: 571-577.

MEDICINAL HONEY COMPANY. Honey Research. Available at: http://

www.medicinalhoney.com.au/research.htm

MIORIN, P L; LEVY JUNIOR, N C; CUSTODIO, A R; BRETZ, W A;

MARCUCCI MC (2003) Antibacterial activity of honey and

propolis from Apis mellifera and Tetragonisca angustula against

Staphylococcus aureus. Journal of Applied Microbiology 95:

913-920.

MIRZOEVA, O K; CALDER, P C (1996) The effect of propolis and its

components on eicosanoid production during the inflammatory

response. Prostaglandins, Leukotrienes and Essential Fatty

Acids 55: 441-449.

MIRZOEVA, O K; GRISJANIN, R N; CALDER, P C (1997) Antimicrobial

action of propolis and some of its components: the effects on

growth, membrane potential and motility of bacteria.

Microbiological Research 152: 239-246.

MOHD NASIR, N-A; SUKARI HALIM, A; BANGA SINGH, K-K.;

ARAVAZHI DORAI, A; MUHAMMAD HANEEF, M-N (2010)

Antibacterial properties of tualang honey and its effect in burn

wound management: a comparative study. BMC

Complementary and Alternative Medicine 10: 31.

MOLAN, P C (1992) The antibacterial activity of honey. 1. The nature

of the antibacterial activity. Bee World 73 (1): 5-28.

MOTALLEBNEJAD, M; AKRAM, S; MOGHADAMNIA, A; MOULANA, Z;

OMIDI, S (2008) The effect of topical application of pure honey

on radiation-induced mucositis: a randomized clinical trial. The

Journal of Contemporary Dental Practice 9: 40-47.

MURAKAMI, A; ASHIDA, H; TERAO, J (2008) Multitargeted cancer

prevention by quercetin. Cancer Letters 269 (2): 315-325.

NAFISI, S; HASHEMI, M; RAJABI, M; TAJMIR-RIAHI, H A (2008) DNA

adducts with antioxidant flavonoids: morin, apigenin, and

naringin. DNA Cell Biology 27 (8): 433-442.

NAGAI, T; INOUE, R (2004) Preparation and functional properties of

water extract and alkaline extract of royal jelly. Food Chemistry

84: 181-186.

NAGAOKA, T; BANSKOTA, A H; TEZUKA, Y; HARIMAYA, Y; KOIZUMI,

K; SAIKI, I; KADOTA, S (2003) Inhibitory effects of caffeic acid

phenethyl ester analogues on experimental lung metastasis of

murine colon 26-L5 carcinoma cells. Biological and

Pharmaceutical Buletin 26: 638-641.


NICHOLSON, P T; SHAW, I (2000) Ancient Egyptian materials and

technology. Cambridge University Press; Cambridge, UK.

ODDO, L P; HEARD, T A; RODRÍGUEZ-MALAVER, A; ANA PÉREZ, R;

FERNÁNDEZ-MUIÑO, M; SANCHO, M T; SESTA, G; LUSCO, L;

VIT, P (2008) Composition and antioxidant activity of Trigona

Carbonaria honey from Australia. Journal of Medicinal Food 11

(4): 789-794.

O´FARRELLY, C; BRANTON, D; WANKE, C A (1992) Oral ingestion of

egg yolk immunoglobulin from hens immunized with an

enterotoxigenic Escherichia coli strain prevents diarrhea in

rabbits challenged with the same strain. Infection and

Immunity 60 (7): 2593-2597.

ORSOLIC, N; BASIC, I (2005) Water-soluble derivative of propolis

and its polyphenolic compounds enhance tumoricidal activity of

macrophages. Journal of Ethnopharmacology 102 (1): 37–45

PERALTA, R C; YOKOYAMA, H; IKEMORI, Y; KUROKI, M; KODAMA,

Y (1994) Passive immunization against experimental

salmonellosis in mice by orally administered hen egg-yolk

antibodies specific for 14-kDa fimbriae of Salmonella interitidis.

Journal of Medical Microbiology 41: 29-35

PÉREZ-MARTÍN, R A; VELA HORTIGUELA, L; LORENZO LOZANO, P;

ROJO CORTINA, M D; DE LORENZO CARRETERO, C (2008) In

vitro antioxidant and antimicrobial activities of Spanish honeys.

International Journal of Food Properties 11 (4): 727-737.

PICHICHERO, E; CICCONI, R; MATTEI, M; MUZI, M G; CANINI, A

(2010) Acacia honey and chrysin reduce proliferation of

melanoma cells through alterations in cell cycle progression.

International Journal of Oncology 37: 973-981.

PORTER, L W (1989) Tannins. In Harborne, J B. Methods in Plant

Biochemistry, I: plant phenolics. Academic Press; London, UK.

pp. 389-419.

PYRZYNSKA, K; BIESAGA, M (2009) Analysis of phenolic acids and

flavonoids in honey. Trends in Analytical Chemistry 28 (7): 893

-902.

RAGAN, M A; GLOMBITZA, K (1986) Phlorotannins, brown algal

polyphenols. Progress in Phycological Research 4: 129-241.

RAJ NARAYANA, K; SRIPAL REDDY, M; CHALUVADI, M R; KRISHNA,

D R (2001) Bioflavonoids classification, pharmacological,

biochemical effects and therapeutic potential. Indian Journal of

Pharmacology 33: 2-16.

RAKHA, M K; NABIL, Z I; HUSSEIN, A A (2008) Cardioactive and

vasoactive effects of natural wild honey against cardiac

malperformance induced by hyperadrenergic activity. Journal

of Medicinal Food 11 (1): 91-98.

RANSOME, H M (1937) The sacred bee in ancient times and folklore.

Courier Dover 2004.

RASHAD, U M; AL-GEZAWY, S M; EL-GEZAWY, E; AZZAZ, A N (2009)

Honey as topical prophylaxis against radiochemotherapy-

induced mucositis in head and neck cancer. The Journal of

Laryngology and Otology 123 (2): 223-228.

RASO, G M; MELI, R; CARLO, G; PACILIO, M; CARLO, R (2001)

Inhibition of inducible nitric oxide synthase and cyclooxygenase-

2 expression by flavonoids in macrophage J77A.1. Life Sciences

68 (8): 921-931

RATTY, A K; DAS, N P (1988) Effects of flavonoids on nonenzymic

lipid peroxidation: structure-activity relationship. Biochem ical

Medicine and Metabolic Biology 39: 69-79.

RAUPACH, B; MECSAS, J; HECZKO, U; FALKOW, S; FINLAY, B B

(1999) Bacterial epithelial cell cross talk. Current Topics in

Microbiology and Immunology236: 137-161.

ROSSI, A; LONGO, R; RUSSO, A; BORRELLI, F; SAUTEBIN, L (2002a)

The role of the phenethyl ester of caffeic acid (CAPE) in the

inhibition of rat lung cyclooxygenase activity by propolis.

Fitoterapia 73 (1): 30-37.

ROSSI, A; LIGRESTI, A; LONGO, R; RUSSO, A; BORRELLI, F;

SAUTEBIN, L (2002b) The inhibitory effect of propolis and

caffeic acid phenethyl ester on cyclooxygenase activity in J774

macrophages. Phytomedicine 9 (6): 530-535.

RUFIAN-HENARES, J A; DE LA CUEVA, S P (2009) Antimicrobial

activity of coffee melanoidins- A study on their metal-chelating

properties. Journal of Agricultural and Food Chemistry 57: 432-

438

SÁNCHEZ-MORENO, C; LARRAURI, J A; SAURA-CALIXTO, F (1998) A

procedure to measure the antirradical efficiency of polyphenols.

Journal of the Science of Food and Agriculture 76: 270–276.

SANCHEZ-MORENO, C (2002) Review: Methods Used to Evaluate the

Free Radical Scavenging Activity in Foods and Biological

Systems. Food Science and Technology International 8: 121-

137.

SCHRAMM, D D; KARIM, M; SCHRADER, H R; HOLT, R R; CARDETTI,

M; KEEN, C L (2003) Honey with high levels of antioxidants can

provide protection to healthy human subjects. Journal of

Agricltural and Food Chemistry 51: 1732-1735

SHAHIDI, F; WANASUNDARA, P K J P D (1992) Phenolic antioxidants.

Critical Reviews in Food Science and Nutrition 32: 67-103.

SHEN, K H; HUNG, S H; YIN, L T; HUANG, C S; CHAO, C H; LIU, C L;

SHIH, Y W (2010) Acacetin, a flavonoid, inhibits the invasion

and migration of human prostate cancer DU145 cells via

inactivation of the p38 MAPK signaling pathway. Molecular and

Cellular Biochemistry 333: 279-291.

SHERMAN, D M; ACRES, S D; SADOWSKI, P L; SPRINGER, J A; BRAY,

B; RAYBOULD, T J; MUSCOPLAT, C C (1983) Protection of

calves against fatal enteric colibacillosis by orally administered

Eschericha coli K99-specific monoclonal antibody. Infection and

Immunity 42: 653-658.

SHOMA, A; ELDARS, W; NOMAN, N; SAAD, M; ELZAHAF, E;

ABDALLA, M; ELDIN, D S; ZAYED, D; SHALABY, A; MALEK, H A

(2010) Pentoxifylline and local honey for radiation-induced burn

following breast conservative surgery. Current Clinical

Pharmacology 5 (4): 251-256.


SHUKLA, S; GUPTA, S (2010) Apigenin: a promising molecule for

cancer prevention. Pharmaceutical Research 27: 962-978.

SILICI, S; SAGDIC, O; EKICI, L (2010) Total phenolic content,

antiradical, antioxidant and antimicrobial activities of

Rhododendron honeys. Food Chemistry 121: 238-243.

SKIADAS, P K; LASCARATOS, J G (2001) Dietetics in ancient Greek

philosophy: Plato´s concepts of healthy diet. European Journal

of Clinical Nutrition 55: 532-537.

SPERONI, E; FERRI, S (1993) Gastroprotective effects in the rat of a

new flavonoid derivative. Acta Horticulturae 322: 249-252.

SRISAYAM, M; CHANTAWANNAKUL, P (2010) Antimicrobial and

antioxidant properties of honeys produced by Apis Mellifera in

Thailand. Journal of Apiproduct and Apimedical Science 2 (2):

77-83. DOI: 10.3896/IBRA.4.02.2.03

SWELLAM, T; MIYANAGA, N; ONOZAWA, M; HATTORI, K; KAWAI,

K; SHIMAZUI, T; AKAZA, H (2003) Antineoplasic activity of

honey in an experimental bladder cancer implantation model:

in vivo and in vitro studies. International Journal of Urology 10:

213-219.

TAKAISI, N B; SCHILCHER, H (1994) Electron microscopy and

microcalorimetric investigations of the possible mechanism of

the antibacterial action of a defined propole provenance.

Planta Medica 60: 222-227

TAN, S T; WILKINS, A L; HOLLAND, P T; MCGHIE, T K (1989)

Extractives from New Zealand Unifloral Honeys. 2. Degraded

Carotenoids and Other Substances from Heather Honey.

Journal of Agricutural and Food Chemistry 37: 1217-1221.

TEMARU, E; SHIMURA, S; AMANO, K; KARASAWA, T (2007)

Antibacterial activity of honey from stingless honeybees

(Hymenoptera; Apidae; Meliponinae). Polish Journal of

Microbiology 56 (4): 281-285.

TOLOMEO, M; GRIMAUDO, S; DI CRISTINA, A; PIPITONE, R M;

DUSONCHET, L; MELI, M; CROSTA, L; GEBBIA, N; INVIDIATA,

F P; TITONE, L; SIMONI, D (2008) Galangin increases the

cytotoxic activity of imatinib mesylate in imatinib-sensitive and

imatinib-resistant Bcr-Abl expressing leukemia cells. Cancer

Letters 265: 289-297.

TOMASIN, R; CINTRA GOMES-MARCONDES, M C (2011) Oral

administration of Aloe vera and honey reduces walker tumour

growth by decreasing cell proliferation and increasing

apoptosis in tumour tissue. Phytotherapy Research 25 (4): 619

-623.

TSUDA, T; KATO, Y; OSAWA T (2000) Mechanism for the

peroxynitrite scavenging activity by anthocyanins. FEBS Letters

484: 207-210.

VAN DEN BERG, A J; VAN DEN WORM, E; VAN UFFORD, H C;

HALKES, S B; HOEKSTRA, M J; BEUKELMAN, C J (2008) An in

vitro examination of the antioxidant and anti-inflammatory

properties of buckwheat honey. Journal of Wound Care 17 (4):

172-4, 176-8.

VILEGAS, W; SANOMMIYA, M; RASTRELLI, L; PIZZA, C (1999)

Isolation and structure elucidation of two new flavonoid

glycosides from the infusion of Maytenus aquifolium leaves.

Journal of Agricultural and Food Chemistry 47 (2): 403-406.

VIT, P; GUTIÉRREZ, M G; TITĔRA, D; BEDNÁŘ, M; RODRÍGUEZ-

MALAVER, A J (2008) Mieles checas categorizadas según su

actividad antioxidante. Acta Bioquimica Clínica Latinoamericana

42: 237-244.

VIUDA MARTOS, M; RUIZ NAVAJAS, Y; FERNÁNDEZ LÓPEZ, J; PÉREZ

ALVAREZ, J A (2008a) Honey and its benefits as a functional

food. Alimentación, Equipos y Tecnología 233: 36-39.

VIUDA MARTOS, M; RUIZ NAVAJAS, Y; FERNÁNDEZ LÓPEZ, J; PÉREZ

ALVAREZ, J A (2008 b) Functional properties of honey, propolis

and royal jelly. Journal of Food Science R: Concise Reviews and

Hypotheses in Food Science 73 (9): R117--R124.

VORLOVA, L; KARPISKOVA, R; CHABINIOKOVA, I; KALABOVA, K;

BRAZDOVA, Z (2005) The antimicrobial activity of honeys

produced in the Czech Republic. Czech Journal of Animal

Science 50 (8): 376-384.

WENG, M S; HO, Y S; LIN, J K (2005) Chrysin induces G1 phase cell

cycle arrest in C6 glioma cells through inducing p21Waf1/Cip1

expression: involvement of p38 mitogen-activated protein

kinase. Biochemical Pharmacology 69: 1815-1827.

WESTON, R J; BROCKLEBANK, L K; LU, Y (2000) Identification and

quantitative levels of antibacterial components of some New

Zealand honeys. Food Chemistry 70: 427-435.

WHITE, J W; SUBERS, M H (1963) Studies on honey inhibine, a

chemical assay. Journal of Apicultural Research 15: 23-28.

WINTERSTEEN, C L; ANDRAE, L M; ENGESETH, N J (2005) Effect of

heat treatment on antioxidant capacity and flavour volatiles of

mead. Journal of Food Science 70 (2): C119-C126.

WÜRSCH, P; DEL VEDOVO, S; ROSSET, J; SMILEY, M (1984) The

tannin granules from ripe carob pod. Lebensmittel-Wissenschaft

und Technologie 17: 351-354.

YAO, L; DATTA, N; TOMÁS- BARBERÁN, F A; FERRERES, F; MARTOS,

I; SINGANOSUNG, R; (2003) Flavonoids, phenolic acids and

abscicic acid in Australian and New Zealand Leptospermum

honeys. Food Chemistry 81: 159-168.

YAO, L; JIANG, Y M; SINGANOSUNG, R; DATTA, N; RAYMONT, K

(2004 a) Phenolic acids and abscicic acid in Australian

Eucalyptus honeys and their potential for floral authentication.

Food Chemistry 86: 169-177.

YAO, L; JIANG, Y M; D´ARCY, B; SINGANOSUNG, R; DATTA, N;

CAFFIN, N; RAYMONT, K (2004 b) Quantitative high-

performance liquid chromatography analyses of flavonoids in

Australian Eucalyptus honeys. Journal of Agricultural and Food

Chemistry 52 (2): 210-214.

YOUNG, J F; NIELSEN, S E; HARALDSDOTTIR, J; DANESHVAR, B;

LAURIDSEN, S T; KNUTHSEN, P; CROZIER, A; SANDSTROM, B;

DRAGSTED, L O (1999) Effect of fruit juice intake on urinary


http://www.jaas.org.uk/articles/20100401_2

quercetin excretion and biomarkers of antioxidative status.

American Journal of Clinical Nutrition 69 (1): 87-94.

ZEINA, B; OTHMAN, O; AL-ASSAD, S (1996) Effect of honey versus

thyme on Rubella virus survival in vitro. Journal of Alternative

and Complementary Medicine 2 (3): 345-348. DOI:10.1089/

acm.1996.2.345.

ZIDAN, J; SHETVER, L; GERSHUNY, A; ABZAH, A; TAMAM, S;

STEIN, M; FRIEDMAN, E (2006) Prevention of chemotherapy-

induced neutropenia by special honey intake. Medical Oncology

23 (4): 549-552.


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role of honey polyphenols in health

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