Molecular and Biochemical Diagnosis (MBD) Vol 1, No 2, 2014 Original Article In Silico Studies on Fingolimod and Cladribine Binding to p53 Gene and Its Implication in Prediction of Their Carcinogenicity Potential Karim Mahnam1, Azadeh Hoghoughi1 1. Biology Department, Faculty of Science, Shahrekord University, Shahrekord, Iran
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Current Medicinal Chemistry, 2013, 20, 621-638 621
Honey as a Source of Dietary Antioxidants: Structures, Bioavailability and Evidence
of Protective Effects Against Human Chronic Diseases
Josè M. Alvarez-Suarez, Francesca Giampieri and Maurizio Battino* Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche, Sez. Biochimica, Universita Politecnica delle Marche, Via Ranieri 65, 60100 Ancona, Italy Abstract: In the long human tradition honey has been used not only as a nutrient but also as a medicine. Its composition is rather variable
and depends on the floral source and on external factors, such as seasonal, environmental conditions and processing. In this review, spe-
cific attention is focused on absorption, metabolism, and beneficial biological activities of honey compounds in human. Honey is a super-
saturated solution of sugars, mainly composed of fructose (38%) and glucose (31%), containing also minerals, proteins, free amino acids,
enzymes, vitamins and polyphenols. Among polyphenols, flavonoids are the most abundant and are closely related to its biological func-
tions. Honey positively affects risk factors for cardiovascular diseases by inhibiting inflammation, improving endothelial function, as
well as the plasma lipid profile, and increasing low-density lipoprotein resistance to oxidation. Honey also displays an important antitu-
moral capacity, where polyphenols again are considered responsible for its complementary and overlapping mechanisms of chemopre-
ventive activity in multistage carcinogenesis, by inhibiting mutagenesis or inducing apoptosis. Moreover, honey positively modulates the
glycemic response by reducing blood glucose, serum fructosamine or glycosylated hemoglobin concentrations and exerts antibacterial
properties caused by its consistent amount of hydrogen peroxide and non-peroxide factors as flavonoids, methylglyoxal and defensin-1
peptide. In conclusion, the evidence of the biological actions of honey can be ascribed to its polyphenolic contents which, in turn, are
usually associated to its antioxidant and anti-inflammatory actions, as well as to its cardiovascular, antiproliferative and antimicrobial
Keywords: Antioxidant capacity, antimicrobial action, bioavailability, cancer, cardiovascular disease, honey.
It is known that oxidative stress, caused by an imbalance be- The composition of honey is rather variable, depending on the tween the production of highly reactive molecules and antioxidant floral source and other external factors, such as seasonal and envi- defences, causes structural and functional damage to lipids, proteins ronmental conditions and processing. Honey contains a variety of and nucleic acids leading to many biological complications including approximately 180 compounds, such as sugars, proteins, free amino carcinogenesis, aging and atherosclerosis [1, 2]. Therefore, exoge- acids, essential minerals, vitamins and enzymes as well as a wide nous antioxidants from diet can counteract the deleterious effects of range of polyphenolic phytochemicals. This range of compounds free radicals, reducing oxidative damage . Many epidemiological will be discussed below, with specific focus on the most significant studies show in fact that a diet rich in polyphenols is often associ- components with beneficial effect on human health, essentially ated with a lower incidence of several chronic pathologies, such as flavonoids and phenolic acids. obesity, infections, cardiovascular and neurologic diseases, and 1.1. Nutrients
cancer [4-6]. In the long human tradition, honey has been used not only as a sugar but also as a medicine: it has been employed in Concerning its nutrient profile (Table 1), honey represents an
many cultures for its medicinal properties, including as a remedy interesting source of natural macro and micronutrients. First of all, for burns, cataracts, ulcers and wound healing [7, 8]. Only recently, it is an important source of calories, since 100 g of honey provide scientific research focused its attention on the therapeutic effects of approximately 300 kcal and a daily dose of 20 g covers about 3% of honey, in particular on its capacity to protect against cardiovascular the recommended daily intake of energy (RDI). Carbohydrates diseases [9, 10], cancer [11-14] and microbial infections [15, 16]. represent 95% of its dry weight: approximately a total of 26 sugars These health-protective and therapeutic impacts of honey depend (mono- and disaccharides) have been identified in honey (Table 2)
on the presence of various antioxidant components, espe-  with fructose ( 40%) and glucose ( 30%) as major sugars. It cially phenolic compounds, such as flavonoids and phenolic acids, is important to note that most of these sugars do not occur in nectar, most of which express relevant antimicrobial, antioxidant, anti- because they are the results of enzymes added by the honeybee inflammatory, antimutagenic activities capacities both during the ripening of honey or by chemical action in the concen- tro and in vivo . Besides phenolic compounds and sugars, trated form. To a lesser extent, honey contains proteins (roughly honey is a source of proteins, free amino acids, minerals, enzymes, 0.5%), mainly enzymes and free amino acids. The amount of nitro- and vitamins, representing therefore a good healthy choice. gen in honey is low, approximately 0.04%, though it may reach 0.1% with 40 to 65% as protein form and the rest as free amino This review focuses on the nutrient and phytochemical contents acids. The total of free amino acids in honey corresponds approxi- of honey and on its antioxidant capacity. An overview on the mately to 1% (w/w) of total nitrogen and ranges between 10 and bioavailability and metabolism of the most abundant honey phyto- 200 mg/100 g, according to its origin (nectar, honeydew or floral chemicals after consumption is also presented, and the currently origin), with proline as the major contributor, corresponding to hypothesized health benefits related to honey consumption is re- approximately 50% of total free amino acids . Since pollen is viewed, with particular attention given to recent evidence on its the main source of honey amino acids, their profile could be charac- impact on cardiovascular health, cancer prevention, hyperglycemias teristic and indicative of their botanical origin . In addition to regulation and antimicrobial activity. classical amino acids also b-alanine (b-Ala), a-alanine (a-Ala), g-aminobutyric acid (Gaba) and ornithine (Orn) have been found and *Address correspondence to this author at the Dipartimento di Scienze Cliniche Spe- identified in honey [19-22]. cialistiche ed Odontostomatologiche, Sez. Biochimica, Facoltà di Medicina. Universtà Politecnica delle Marche, Italy, Via Ranieri 65, 60100 Ancona, Italy; Tel: +39 071 Honey also presents a variable number of mineral elements, 2204646; Fax: +39 071 2204123; E-mail: [email protected] which varies according to geographic region, soil type and floral -;/13 $58.00+.00
2013 Bentham Science Publishers
622 Current Medicinal Chemistry, 2013, Vol. 20, No. 5
Alvarez-Suarez et al.
Chemical Composition of Honey*.
Proximates and carbohydrates
Ascorbic Acid (C) (mg) Carbohydrates (total) (g) Pantothenic acid (mg) Pyridoxine (B6) (mg) Proteins, amino acids, vitamins and minerals (g) *Amount in 100 g of honey Carbohydrates Composition in Honey.
O--D-glucopyranosyl-(1 -> 4)-D-glucopyranose O--D-glucopyranosyl-(1 -> 6)-D-glucopyranose O--D-glucopyranosyl-(1 -> 6)-D-glucopyranose O--D-glucopyranosyl-(1 -> 6)-D-frutofuranose O--D-glucopyranosyl-(1 -> 2)-D-glucopyranose O--D-glucopyranosyl-(1 -> 3)-D-glucopyranose O--D-glucopyranosyl-(1 -> 5)-D-fructofuranose O--D-glucopyranosyl-(1 -> 4)-D-glucopyranose O--D-glucopyranosyl-(1 -> 4)-D-fructose O--D-galactopyranosyl-(1 -> 6)-D-glucopyranose O--D-glucopyranosyl-(1 -> 3)-D-glucopyranose O--D-glucopyranosyl-(1 -> 6)-D-fructose O--D-glucopyranosyl-(1 -> 3)-D-fructose O--D-glucopyranosyl-(1 -> 4)-O--D-glucopyranosyl-(1 -> 2)-D-glucopyranose O--D-glucopyranosyl-(1 -> 2)--D-fructofuranosyl-(1 -> 2)--D-fructofuranoside O--D-glucopyranosyl-(1 -> 4)--D-glucopyranosyl--D-fructofuranoside O--D-glucopyranosyl-(1 -> 6)-O--D-glucopyranosyl-(1 -> 6)-D-glucopyranose O--D-glucopyranosyl-(1 -> 4)-O--D-glucopyranosyl-(1 -> 6)-D-glucopyranose O--D-glucopyranosyl-(1 -> 3)-O--D-glucopyranosyl-(1 -> 3)-D-glucopyranose O--D-glucopyranosyl-(1 -> 4)-O--D-glucopyranosyl-(1 -> 4)-D-glucopyranose O--D-glucopyranosyl-(1 -> 3)-O--D-fructofuranosyl-(2 -> 1)--D-glucopyranoside O--D-glucopyranosyl-(1 -> 6)-O--D-glucopyranosyl-(1 -> 4)-D-glucopyranose O--D-glucopyranosyl-(1 -> 6)--D-glucopyranosyl--D-fructofuranoside 1- Majority 2- Minority 3- Traces 4- not confirmed origin, representing approximately 0.2% of its dry weight. The biological functions, such as the maintenance of intracellular oxida- amount of minerals and trace elements in honey is small and their tive balance [23, 24]. Recently, the presence of Se content in Portu- contribution to the RDI is marginal (Table 1). Minerals and trace
guese unifloral honeys was reported . Se is an essential trace elements play a key role in biomedical activities associated with element, and its role in the metabolism is largely related to its in- food, since these elements have a multitude of known and unknown corporation into selenoproteins . As an essential component of Honey and Human Health
Current Medicinal Chemistry, 2013, Vol. 20, No. 5 623
antioxidant enzymes GSH-Px and thioredoxin reductase, this ele- phenolic compounds in honey is represented by flavonoids (fla- ment may promote endogenous enzymatic capacity to protect vonols, flavanols and flavones) followed by phenolic acids (benzoic against excessive generation of free radicals . Honey also con- acids, phenylacetic and hydroxycinnamic acids). The most common tains choline (0.3-25 mg/kg) and acetylcholine (0.06-5 mg/kg). phenolics acids and flavonoids identified in honey are shown in Choline is essential for cardiovascular and brain function as well as (Table 3).
for cellular membrane composition and repair, while acetylcholine acts as a neurotransmitter . Most Common Phenolic Acid and Flavonoids Identified in
Finally, the vitamin content in honey is low. Vitamins such as thiamin (B1), riboflavin (B2), pyridoxin (B6) and niacin have been reported in honey but in general their amount is small and the cor- Phenolic acid
responding contribution of honey to the RDI is very limited [7, 8]. 4- dimethylaminobenzoic acid 1.2. Enzyme and Organic Acids
p-coumaric acid One of the characteristics that distinguish honey from all other sweetening agents is the presence of enzymes. They may originate from the bee, pollen, nectar, even from yeasts or micro-organisms present in honey. Three main enzymes can be found: invertase, diastase and glucose oxidase. Invertase splits sucrose releasing its Chlorogenic acid simple constituents; during this action, other groups of more com-plex sugars have been found in small amounts, explaining in part Quercetin 3-methyl ether the complexity and variability of the minor sugars of honey. Inver- Quercetin-diglycoside tase remains in honey and retains its activity for some time, com- pleting its activity when honey is ripened. Despite this, the sucrose content of honey never becomes zero. Since invertase also synthe- Quercetin-O-rhamnoside sizes sucrose, the final low value for the sucrose content of honey probably represents an equilibrium between splitting and forming Kaempferol 8-OMe sucrose, an aspect which is often taken into account when measur-ing the maturity and quality of honey . Diastase or amylase Kaempferol 3-OMe digests starch to simpler compounds. The origin of this enzyme in honey is controversial and it is not known for sure if it comes from Kaempferol-3-O-glycosyl nectar, pollen or bee, or what its functions are because starch is not present in honey. Alpha-amylase randomly breaks the down starch Kaempferol-7-O-glycosyl chains, producing dextrins and beta-amylase which divides the reducing sugar maltose from the terminal starch chains. Diastase activity is used as an important indicator of honey quality: the higher the content of this enzyme, the higher is the quality of honey . Despite its discrete contribution to the human diet, the sup- plementation of diastase by honey can be interesting and helpful in Myricetin 3,7,4',5'-OMe increasing the metabolism of sugars, especially related with carbo-hydrate digestive disorders. Finally, glucose oxidase (GOx) is of interest because it is related to honey antibacterial properties. GOx Phenolic phytochemicals are the largest group of phytochemi- converts dextrose to a related compound, a gluconolactone, which cals ubiquitous in plants and are incorporated into the honey via in turn forms gluconic acid, the principal acid in honey, and hydro- nectar / pollen from plants visited by the honeybee. Simple phenols gen peroxide the main agent responsible for antibacterial activity in are those with a C6 carbon structure (such as phenol itself, cresol most honeys. GOx amount varies in different honeys and since it and thymol) (Fig. 1A). Phenolic acids are derived from benzoic
was found in the pharyngeal gland of the honey bee this is probably acid, phenylacetic and hydroxycinnamic acid (Fig. 1B, 1C and 1D,
the most likely source of this enzyme [28, 29]. Other enzymes re- respectively) where the hydroxyl (OH) groups can be substituted in ported in honey are catalase and acid phosphatase. It is important to the aromatic ring. Some of them have a C6-C1 structure (e.g. gallic, note that honey enzymes can be destroyed or weakened by heat vanillic and syringic acids) and aldehydes (e.g. vanillin). Others caused by careless handling during industrial processing or storage. have a C6-C2 structure, such as phenylacetic acids and acetophe-nones. Phenylpropanoid derivatives of a C6-C3 structure are mainly Finally, honey contains also a series of organic acids corre- represented by hydroxycinnamic acids such as p-coumaric, ferulic sponding to 0.17-1.17% of the total acids, representing less than and caffeic acids and their respective derivatives [37, 38]. Simple 0.5% of solids  which contribute to the flavor and in part are phenols, phenolic and phenylacetic acids can be found free and responsible for its excellent stability against microorganisms and have been identified in several floral honeys,the most frequent ones are also associated with honey antibacterial activity . Among beingp-coumaric, ferulic and caffeic acids [31-36, 39]. In honey of these acids, gluconic acid has been identified as the most important Leptospermum scoparium and Leptospermum polygalifolium from one. Other organic acids in honey are formic, acetic, butyric, lactic, New Zealand and Eucalyptus ssp. from Australia, gallic acid was oxalic, succinic, tartaric, maleic, pyruvic, pyroglutamic, a- identified as the most predominant phenolic acid [40, 41]. Other ketoglutaric, glycollic, citric, malic, 2- or 3-phosphoglyceric acid, phenolic acids havealso been reported: chlorogenic, syringic, vanil- - or -glycerophosphate, and glucose 6-phosphate. lic and p-hydroxybenzoic acids as the agents responsible for the antioxidant activity exhibited by the extracts of honey from differ- 1.3. Phenolic Phytochemicals in Honey
ent botanical origins (Leptospermum polygalifolium, Epilobium angustifolium; Nyssa aquatica; Schinus terebinthifolius; Glycine Honey phytochemicals are mainly represented by the extensive max; Melilotus spp y Robinia pseudoacacia) [39, 40]. class of phenolic compounds depending on honey origin [31-36] and, therefore, expected to have different biological activities and Flavonoids are low molecular weight compounds that share a huge biological potentialities in humans . The major class of common skeleton of diphenyl propanes, formed by two benzene 624 Current Medicinal Chemistry, 2013, Vol. 20, No. 5
Alvarez-Suarez et al.
i) R1-H,R2,R3,R4-OHo gallic ii) R1,R4-H,R3-OH,R2-OCH3o Vanillic iii) R1-H,R3-OH,R2,R4-OCH3 o Syringic R2,R3,R4-H,R1-OHo o- coumaric ii) R1,R3,R4-H,R2-OHo m- coumaric iii) R1,R2,R4-H,R3-OH o p- coumaric iv) R1,R4-H, R2,R3-OHo caffeic v) R1,R4-H,R2-OCH3,R3-OHo ferulic Fig. (1). Chemical structures of simple phenols with structure C6 (A), phenylacetic acid, C6-C2 (B), benzoic acids, C6-C1 (C), and hydroxycinnamic acids, C6-C3
(D). The different structures of benzoic acids and hydroxycinnamic acids are shown in C and D, respectively.
rings joined by a linear three-carbon chain (C6-C3-C6). Often, the absorption and metabolism of polyphenols has been elucidated carbons of the propane connecting the phenyl rings may form a through several in vitro methods, in situ animal experiments, and closed pyran ring together with one of the benzene rings thus form- some in vivo studies [17, 45]. ing a structure of 15 carbon atoms arranged in three rings, labeled Currently there are very few studies on bioavailability of honey A, B and C (Fig. 2A). These compounds generally have at least
polyphenols in humans. The most significant study, by Schramm et three phenolic OH groups and are generally combined with sugars al., , reported that after consumption of 1.5 g of honey/kg body to form glycosides, with glucose as the major sugar, but also galac- of two honey types in 40 subjects, the plasma total-phenolic content tose, rhamnose and xylose can be found, as free aglycon. At the increased (P < 0.05) similarly to antioxidant and reducing capaci- same time, flavonoids are further divided and classified according ties of plasma (P < 0.05). These data supported the concept that to the degree of oxidation of the C ring into flavones, flavonols, phenolic antioxidants from honey are bioavailable, and that they flavanones, flavanonols, flavanols or catechins, isoflavones, antho- increase plasma antioxidant activity by improving the defenses cyanins and anthocyanidins. Within these groups, flavonols (Fig. against oxidative stress. However, although the honey used in this 2B) (e.g. quercetin, myricetin and kaempferol), flavones (Fig. 2C)
investigation provided mg quantities of 4-hydroxybenzoic and 4- (apigenin, luteolin, diosmetin, chrysin) and flavanols or catechins hydroxycinnamic acids per kg of body weight, the plasma concen- (Fig. 2D) (catechin, epicatechin, epigallocatechin, epigallocatechin
tration of these acids could not be verified by HPLC analysis. Ac- gallate) are the most abundant in honey. Flavonols are characterized cording to the authors this could be due to (i) less than one-third of by an unsaturation between the C2 and C3 carbons of the C ring, a these compounds were absorbed, (ii) these compounds could have ketone group in C4 and by the presence of a hydroxyl group in posi- been distributed quickly into body compartments other than plasma, tion 3 of the ring, while flavones do not exhibit this latter group. or (iii) the monophenols underwent first pass metabolism in the Flavanols present a hydroxyl group on carbon 3 [38, 42]. These flavonoids may appear in the O-glycosylated form, in which one or more hydroxyls are linked to a sugar, thus forming a O-C bond, However, the absorption of flavonoids seems much more com- with glucose as the most common glycosidic unit, even if other plex, fundamentally due to its chemical characteristics. Fig. (3)
examples include glucorhamnose, galactose, arabinose, rutinoside illustrated the proposed mechanisms for the absorption and metabo- and rhamnose. Glycosylation can also occur froma direct link be- lism of polyphenolic compounds in the small intestine. The avail- tween the sugar and the flavonoid nucleus, forming a strong bond able literature suggests that not only the bacterial enzymes in the C-C with the formation of C-glycosides. This type of glycosylation intestine [17, 47, 48], are responsible for beta-hydrolysis of sugar occurs only at positions C moieties in the O-glycosides flavonoids. Two -endoglucosidases 6 and/or C8. The objective of glycosyla- tion seems to form a flavonoid less reactive and more soluble in capable of flavonoid glycoside hydrolysis have also been character- water; the glycosylation can be seen as an essential form of protec- ized in human small intestine, namely lactase phlorizin hydrolase tion of plants to avoid the cytoplasmic damage since flavonoids can (LPH), acting in the brush border of the small intestine epithelial accumulate in vacuoles . Most flavonols are in the shape of O- cells [48, 49] and a cytosolic -glucosidase (CBG) as an alternative glycosides and rarely of C-glycosides, while the flavones are often hydrolytic step within the epithelial cells [50, 51, 52]. LPH exhibits found in nature, both as O-glycosylated and as C- glycosylated broad substrate specificity for flavonoid-O--D-glucosides, and the released aglycone may then enter the epithelial cells as a result of its increased lipophilicity and its proximity to the cellular mem- 2. BIOAVAILABILITY AND METABOLISM OF HONEY
brane . It is has also been proposed that for CBG-catalyzed POLYPHENOLS
hydrolysis to occur, the polar glycosides must be transported into the epithelial cells, possibly with the involvement of the active so- Because evidence of the potential health-promoting and dis- dium-dependent glucose transporter 1 (SGLT1) . Published ease-preventing effects of honey continues to accumulate, it is be- studies on the bioavailability and pharmacokinetics have demon- coming more necessary to understand the nature of absorption and strated that some flavonoids can inhibit the non-Na+ -dependent metabolism of polyphenolic compounds, as these plays an impor- facilitated diffusion of monosaccharides in intestinal epithelial cells tant role in healthy beneficial effects. Current knowledge on the . Thereby, the parallel concentrative Na+ -dependent transport Honey and Human Health
Current Medicinal Chemistry, 2013, Vol. 20, No. 5 625
A) BASIC FLAVONOID STRUCTURE
i) R5-H,R3,R4-OHo quercetin ii) R3,R5-H,R4-OHo kaempferol iii) R3,R4,R5-OHo myricetin iv) R5-H,R4-OH,R3-OCH3o isorhamnetin C) FLAVONES
i) R3,R4,R5-H o galangin ii) R3,R5,R4-OHo apigenin 3,R4,R5-OHo myricetin v) R5,R4,R5-Ho crysin D) FLAVANOLS
i) R5-H,R3,R4-OHo catechins ii) R3,R4,R5-OHo gallocatechins Fig. (2). Chemical structures of the more common flavonoids in honey.
ATPase for monosaccharides is benefited . Therefore, the two diphosphate glucuronosyltransferases (UGT), and catechol- possible routes by which the glycoside conjugates are hydrolyzed O'Methyltransferase (COMTs), respectively . Besides the and the resultant aglycones cross into enterocytes are LPH/diffusion metabolic biotransformation of flavonoids, which occurs by the and transport/CBG . To these, in the case of honey, the pres- intestinal microflora and the gut-liver pathways, their bioavailabil- ence of the enzyme glycosidase in the bee salivary glands [58, 59] ity and cell/tissue accumulation have been closely associated with should also be added producing a hydrolysis of the glycosylated the multidrug-resistance-associated proteins like MRP-1 and MRP- flavonoids and releasing the aglycon form. This explains, in part, 2 (i.e. ATP-dependent efflux transporters), also named phase III the fact that unlike other phenolics present in foods or beverages, metabolism  and with their tissue distribution and substrate flavonoids in honey have been identified mostly as a form of agly- affinity in the various organs. It has been proposed that MRP-2, cons and not in their glycosylated form. Phenolic aglycons are more localized on the apical membrane of cells of the small-bowel epi- readily absorbed through the gut barrier than their corresponding thelium, transports the already intracellular flavonol back to the glycosides by passive diffusion  and, therefore, flavonoids pre- intestinal lumen, thus modulating the actual intestinal importation sent in honey may be more readily bioavailable. It has been also of these compounds. On the contrary, MRP-1, situated on the vas- proposed that after release of the glycosides from the aglycone cular pole of enterocytes, favors transport of the flavonoid from about 15% of the flavonoid aglycons are absorbed with bile mi- inside the cells into the blood [61, 62]. Moreover, it is has been celles into the epithelial cells and passed on to the lymph [47, 48]. proposed that MRP-3 and the glucose transporter GLUT2 are also Despite this, the influence of the presence, location and structure of implicated in the efflux of metabolites from the basolateral mem- the sugar moiety in the bioavailability and metabolism of glycosy- brane of the enterocytes . Once in the portal bloodstream, me- lated flavonoids has also been highlighted . tabolites rapidly reach the liver: in hepatocytes, aglycones are trans-ferred to the Golgi apparatus and possibly also to the peroxisomes, Once absorbed by the intestinal epithelium and before crossing into the bloodstream, flavonoids undergo some degree of phase II being oxidatively degraded and subjected to further phase II me-tabolism [57, 64]. These conjugate forms can retain their antioxi- metabolism with the generation of different conjugated products, dant properties, while others such as quercetin quickly enter the cell predominantly sulphates, glucuronides and methylated derivatives through the action of sulfotransferases (SULTs), uridine-5 - regaining their active, nonconjugated form [65, 66]. Finally, some flavonoid conjugates with sugar moieties resistant to the action of 626 Current Medicinal Chemistry, 2013, Vol. 20, No. 5
Alvarez-Suarez et al.
Fig. (3). Mechanisms for the absorption and metabolism of flavonoid compounds in the small intestine. CBG, cytosolic -glucosidase; COMT, catechol-O-
methyl transferase; GLUT2, glucose transporter; LPH, lactase phloridzin hydrolase; MRP1-2-3, multidrug-resistant proteins; Flav-Agly, Flavonoid aglycone;
Flav-Gly, Flavonoid glycoside, Flav-Met, Flavonoid sulfate/glucuronide/methyl metabolites; SGLT1, sodium-dependent glucose transporter; SULT, sulfotrans-
ferase; UGT, uridine-5´-diphosphate glucuronosyltransferase.
LPH/CBG are not absorbed in the small intestine and pass to the nolic acids and flavonoids. Several research groups have studied the colon and are therefore excreted with the faeces, while enterohe- AOC of honey using different methods to determine alternatively patic recirculation may result in some recycling back to the small (i) the capacity to scavenge active oxygen species (e.g. the superox- intestine through bile excretion . Others, after metabolic trans- ide anion, peroxyl and hydroxyl radicals) [81, 82] and (ii) enzy- formation, are secreted by organic acid transporters into the blood matic or non-enzymatic capacity of lipid peroxidation inhibition and subsequently excreted through the kidneys [68-70]. [78, 83]. Honey is a complex biological matrix that gives high vari-ability in measurements and makes it very difficult to obtain stan- More studies on the bioavailability and pharmacokinetics of dardized AOC indexes. Moreover, when reliable techniques are polyphenols in humans are necessary. However, recently reports are encouraging, revealing that flavonoids can be incorporated in lipo- applied, it can be demonstrated that honey has an in vitro AOC similar to those of many fruits and vegetables on a fresh weight protein domains and plasma membranes, which generally serve as basis . Honey has been shown to protect food against microbial targets for lipid peroxidation, suggesting a protective interaction of flavonoids with lipid bilayers [50, 71] and they can also accumulate growth  and deteriorative oxidation reactions, such as lipid oxidation in meat , enzymatic browning of fruits and vegetables in the nucleus  and mitochondria  affecting diverse cell , providing also an effective protection against chemically in- metabolic functions. duced lipid peroxidation in rat liver, brain and kidney homogenates [78, 83]. This particular model of lipid peroxidation just cited is 3. ANTIOXIDANT PROPERTIES
interesting because it has the advantage of including and mimicking The antioxidant properties of honey have been associated to the several of the mechanisms responsible for the generation and/or modulation of lipid peroxidation occurring in vivo: therefore, it ability and potential of reducing oxidative reactions within the food offers the possibility of identifying antioxidant compounds able to systems resulting as attractive/beneficial for human health. These oxidative reactions can cause deleterious reactions in food products mitigate lipid oxidative damage. It has been reported that honey
presents important radical scavenging capacities (Fig. 4). Several
and adverse health effects, includingchronic diseases and cancers studies demonstrated that honey is capable of scavenging hydroxyl [73, 74]. The antioxidant capacity (AOC) has been proposed as an indicator of the presence of beneficial bioactive compounds in and superoxide radicals [30, 78, 87-89]. The ability of honey to scavenge free radicals and to protect against lipid peroxidation may honey when it was identified as a dietary source of natural antioxi- contribute to preventing/reducing some inflammatory diseases in dants. The AOC varies greatly depending on the honey floral source, possibly due to the differences in the content of plant sec- which oxidative stress is involved, offering an interesting preven-tive and therapeutic option. ondary metabolites as polyphenolics and enzyme activities [75-80]. It has been found that several constituents of honey play a signifi- The AOC of honey, which depends on polyphenol contents, is cant role in AOC as glucose oxidase, catalase, ascorbic acid, or- also correlated with its color [26, 77, 80]. Frankel et al.  sug- ganic acids, Maillard reaction products, amino acids, proteins, phe- gested that the color intensity in honey is related to pigments Honey and Human Health
Current Medicinal Chemistry, 2013, Vol. 20, No. 5 627
(flavonoids, carotenoids, etc.). Actually, the dark honeys have closed C-ring itself may not be critical to the activity of flavon- shown the highest AOC, as well as, phenolic, flavonoid and caro- oids. Flavonoids with a 3-OH and 3 , 4 - catechol are reported tenoid concentrations while the light-colored honeys are character- to be 10- fold more potent than ebselen, a known RNS scavenger ized to have the lowest values, with linear positive correlations against peroxynitrite radical [91, 98]. Examples are flavonols: the between color vs phenolic and flavonoid content vs radicals scav- superiority of quercetin in inhibiting both metal and nonmetal- enging activity and protection against lipid peroxidation (P< 0.05) induced oxidative damage is partially ascribed to its free 3-OH [73, 75-78, 79, 80, 83, 88, 90]. substituent [50, 91], which is thought to increase the stability of the flavonoid radical, while the substitution of 3-OH by a methyl or glycosyl group decreases the AOC of this flavonol . A distinguishing feature among the general flavonoid structural classes is the presence or absence of an unsaturated 2-3 bond in conjugation with a 4-oxo function. It has been demonstrated that flavonoids which do not exhibit one or both features exhibit a lesser AOC than those with both elements. The conjugation between the A - and B rings permits a resonance effect of the aromatic nucleus leading stability to the flavonoid radical ; this conjugation is critical in optimizing the phenoxyl radical-stabilizing effect of the 3 ,4 -catechol . The fact that flavonols have a higher free radi- Fig. (4). Radical scavenging mechanism of phenolic compounds.
cal scavengers capacity than flavones [104, 105] may be associated to the greater number of hydroxyl groups and substituents 3-OH present in their structure. 3.1 Polyphenols as the Principal Contributors of Honey AOC
4. HONEY AND HEALTH
Since polyphenols are considered as mostly responsible for AOC in honey, the mechanisms by which these compounds con- The biological activities of honey have long been studied using tribute to its antioxidant properties are considered as the most several in vitro and animal models studies, as well as human epi- medically useful properties of honey. These positive characteristics demiologic and interventional studies (Table 4).
seem to be ascribed to their efficacy as metal chelators and as ex-cellent free-radical scavengers, as well as gene modulators able to 4.1 Honey and CVD Risk
influence enzymatic and non-enzymatic systems that regulate cellu-lar redox balance [17, 38, 91]. Studies in vitro and in vivo have shown that honey can posi- Among the phenolic acids, benzoic acid is a weak antioxidant. tively affect risk factors for CVD by inhibiting inflammation, im- This capacity is increased in the case of dihydric or trihydric deriva- proving endothelial function , improving the plasma lipid tives, where the antioxidant effect depends on the relative positions profile and increasing low-density lipoprotein (LDL) resistance to of OH groups in the aromatic ring. Thus, gallic acid (3, 4, 5- trihydroxybenzoic acid) is the most potent antioxidant within all the The oxidative modifications of lipoproteins play an important hydroxybenzoic acids. Contrary to their homologs derived from role in the pathogenesis of atherosclerosis [107, 108]. In an in vitro benzoic or phenylacetic acid, hydroxycinnamic acids exhibits model a significant correlation between AOC and inhibition of greater free radical scavenging ability. This property appears to be lipoprotein oxidisability from human serum by honey was reported related to the inclusion of the unsaturated chain bonded to the car- [73, 109], providing initial useful evidence about the protective boxyl group as a distinctive structure which provides stability by effect of honey against the oxidative damage of these molecules. resonance to phenoxyl radical, even offering additional sites for the Besides this, the improvement of endothelial function by honey has attack of free radicals . Furthermore, the existence of several also been demonstrated. Beretta et al. reported, using native electron donor groups in the benzene ring structure (as hydroxyl or honey, a significative quenching activity against lipophilic cumoxyl methoxy groups in structures) also provides a greater number of and cumoperoxyl radicals, with significant suppression/prevention resonant structures and increases the stability of the arylic radical in of cell damage, complete inhibition of cell membrane oxidation, cinnamic acids, thereby favoring their antioxidant behavior. decrease of intracellular ROS production as well as intracellular It has been widely demonstrated that flavonoids are very effec- GSH recovery in endothelial cell cultures (EA.hy926). Moreover, tive as scavengers of reactive oxygen species (ROS) peroxyl, alkyl the phenolic fraction isolated from these honeys was used to pre- peroxide, hydroxyl and superoxide radicals, as well as against reac- treat the same endothelial cells, exposed later to peroxyl radicals tive nitrogen species (RNS) likenitric oxide and peroxynitrite, pro- from AAPH and to hydrogen peroxide, and indicated as the main tecting against the oxidative damage induced by these molecules cause of the same protective effect. In another in vitro study, re- [49, 93-95]. This activity is attributed basically to three chemical ported by Ahmad et al. , the effect of honey on bovine throm- features in flavonoid structure, namely an ortho-dihydroxy structure bin-induced oxidative burst in human blood phagocytes was stud- in the B-ring [96-99], and the presence, in the C-ring, of a 2, 3 dou- ied. The results reported that phagocytes activated by bovine ble bond and/or of a 4-oxo function . thrombin and treatment with honey showed effective suppression of oxidative respiratory burst . These results suggest that, Hydroxyl groups on the B-ring donate a hydrogen and an elec- through the synergistic action of its antioxidants, the antioxidant tron to hydroxyl, peroxyl, and peroxynitrite radicals,stabilizing compounds present in honey could be beneficial in the interruption them and giving rise to relatively stable flavonoid radicals. Oxida- of the pathological progress of cardiovascular disease,could play a tion of a flavonoid occurs on the B-ring when catechol is present cardioprotective role and contribute to reducing the risks and effects , yielding a fairly stable ortho-semiquinone radical  of acute and chronic free radical induced pathologies in vivo. through facilitating electron delocalization . Other hydroxyl configurations are less clear, as the A-ring substitution, where the Although blood is not strictly part of the cardiovascular system, increasing total number of OH groups correlates little with AOC it is in any case closely related to it functionally, and its alterations . Moreover, the heterocyclic character of some flavonoids plays may be a predisposing factor for CVD. Recently, an interesting area an important role in antioxidant activity by the presence of a free 3- of research which discusses the protective effect of food polyphe- OH and allowing conjugation between the aromatic rings, the nols in red blood cells (RBC) against oxidative damage has 628 Current Medicinal Chemistry, 2013, Vol. 20, No. 5
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Effects of Honey Consumption on Health.
Effect on health
Reduction of cardiovascular risk factors Inhibition of inflammation Improvement of endothelial function Improvement of plasma lipid profile Increase of low-density lipoprotein (LDL) resistance to oxidation Cardiovascular diseases (CVD) Inhibition of Red Blood Cells (RBCs) hemolysis Improvement of eritrocytes uptake capacity Protection of RBCs against intracellular depletion of GSH and SOD activity Decrease of the susceptibility of RBCs lipid membrane against oxidative damage 71, 111, 113,118,120 Maintenance of the body weight in overweight or obese subjects (no increase) Reduction of systolic blood pressure and MDA levels Ameliorament of susceptibility of kidneys to oxidative stress Antimutagenic capacity Induction of apoptosis Antiproliferative effect 12, 149, 150, 152 Citotoxic effect on several cancer cell lines Antimetastatic effect Reduction of glycaemia 169, 172, 173, 174, 177, 178, 179, 180, 181 Reduction of serum fructosamine Reduction of glycosylated hemoglobin concentration Attenuation of post-prandial glycemic response Increase serum insulin concentration and reduce insulin resistance Microbial infection Inhibition of microorganisms of clinical relevance reported interesting results [111-117], in which flavonoids from juwaet al. evaluated the effect of honey supplementation on honey have also been studied [118-120]. elevated systolic blood pressure (SBP) in spontaneously hyperten-sive rats (SHR) as well as the capacity of honey to ameliorate oxi- Erythrocytes are the most abundant cells in the human body and dative stress in the kidney of SHR as a possible mechanism of its due to their structural and functional characteristics they are targets antihypertensive effect. Their findings demonstrated that honey for continuous oxidative stress damage. Since oxidative damage to supplementation significantly reduced SBP, and malondialdehyde the erythrocyte membrane is generally associated with an increased (MDA) levels in SHR. Recent studies indicate also that honey may lipid peroxidation process, causing malfunctioning of the mem- ameliorate susceptibility of kidney to oxidative stress in rats with branes by altering its fluidity as well as the membrane-bound en- chronic renal failure or hypertension via up-regulation of Nrf2 ac- zyme and receptor function, it has been proposed as a general tivity or expression . In another study, the protection of honey mechanism involved in cell injury and death, leading to erythrocyte on the cardiovascular system was evaluated by Rakha et al. , haemolysis [121-123]. In particular, in vitro tests have ascribed using a model of induction of hyperadrenergic activity in urethane- antioxidant and antihemolytic properties of dietary flavonoids to anesthetized rats by epinephrine. Acute administration of epineph- their localization in the membrane bilayer and to formation of se- rine for 2 hours induced several cardiac disorders and vasomotor lective bindings with RBC membrane lipids and proteins, which dysfunction. The results showed that pretreatment with natural wild may exert a significant inhibition of lipid peroxidation, and enhance honey (5 g/kg) for 1 hour prior to the injection significantly reduced membrane integrity against several chemical and physical stress the incidence of epinephrine-induced cardiac disorders and vasomo- conditions [121, 122]. This mechanism appears to partially explain tor dysfunction in anesthetized normal rats. Moreover, post- how polyphenol extracts from honey were able to inhibit RBCs treatment with natural wild honey, following the injection with oxidative hemolysis [118, 120], reduce the extracellular ferricya- epinephrine for 1 hour, showed several ameliorative outcomes to nide , protect against intracellular depletion of GSH and SOD the electrocardiographic parameters and vasomotor dysfunction of activity and to decrease the susceptibility of RBC lipid membrane anesthetized stressed rats. From the results of this study it has been to peroxidation . Another mechanism that may be involved in hypothesized that honey may exert its cardioprotective effects RBC protection by honey flavonoids seems to be erythrocyte up- against epinephrine-induced cardiac disorders and vasomotor dys- take capacity of these molecules. Previous uptake studies in human function directly, via its AOC and its great wealth of both enzy- RBC showed an excellent incorporation of honey phenolics in RBC matic and non-enzymatic antioxidants involved in cardiovascular . Flavonoid uptake by RBCs and their interactions with mem- defense mechanisms; also the contribution of substantial quantities brane were confirmed using quercetin as a reference standard model of mineral elements should be taken into account such as magne- because it has been widely identified in honey, is efficiently incor- sium, sodium, and chlorine, and/or indirectly, the enhancement of porated into erythrocytes, and finally, different studies have re- nitric oxide release, the endothelium-derived relaxing factor, ported its involvement in protecting RBCs membranes against oxi- through the influence of ascorbic acid (vitamin C) . dative damage [71, 111, 113, 118, 120]. Despite the results obtained using in vitro and animal models, Epidemiological studies suggest that hypertension is a major data from interventional studies in humans with CVD risk are few. public health concern because of its high prevalence, besides also In a study of 55 overweight or obesepatients, supplementation of 70 being an important risk factor for the development of CVD, that g of natural honey against fructose-supplemented control for 30 end-lasts in renal disease, stroke, and death [124, 125]. Research days caused a mild reduction in body weight (1.3%) and body fat has demonstrated a close relationship between oxidative stress and (1.1%), a more consistent reduction of total cholesterol (3%), LDL- hypertension, causing a vast interest in therapeutic approaches or C (5.8%), triacylglycerides (11%), and C-reactive protein (3.2%), nutritional interventions to preventively decrease oxidative stress or and an increase of HDL-C (3.3%) in subjects with normal values. to treat hypertension itself [126, 127]. As a model for humans, Ere- Meanwhile, in patients with impaired values, honey caused reduc- Honey and Human Health
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tion in total cholesterol (3.3%), LDL-C (4.3%), triacylglycerides with the most likely mechanisms being the decrease in oxidative (19%) and C-reactive protein (3.3%) . Another study evaluated stress and inflammation. These data are in accordance also with the the effects of the ingestion of 75 g of natural honey compared to the results published by Jung et al.  where quercetin reduces fat same amount of artificial honey (fructose plus glucose) or glucose accumulation in C57B1/6 the liver of mice that have undergone a in normal subjects and in both hypercholesterolemic and hyper- high-fat diet, due to its capacity to regulate the lipogenesis at tran- triglyceridemic patients. Results showed that honey consumed for scription level. 15 days decreased cholesterol (7%), LDL-C (1%), TG (2%), C- Another common flavonoid in honey with a putative important reactive protein (7%), homocysteine (6%), plasma glucose level role in the treatment of cardiovascular diseases is kaempferol. Some (6%), and increased HDL-C (2%) in normal subjects. In patients researchers have elucidated a group of mechanisms by which with hypertriglyceridemia honey decreased TG while in subjects kaempferol exhibits its beneficial properties to the cardiovascular with hyperlipidemia it decreased cholesterol (8%), LDL-C (11%), system. The protective effect of kaempferol against endothelial and C-reactive protein (75%) after 15 days of consumption . damage seems to be correlated with its ability to improve NO pro- These results support the hypothesis that honey reduces cardiovas- duction and to decrease asymmetric dimethylarginine (ADMA) cular risk factors, particularly in subjects with elevated risk factors, levels. Experiments have been performed using aorta and plasma and it does not increase body weight in overweight or obese sub- from C57BL/6J control and apolipoprotein E-deficient (ApoE/) mice treated or not with kaempferol (50 or 100 mg/kg, intragastri- The consumption of honey could affect pathways related to cally) for 4 weeks, as well as human umbilical vein endothelial cardiovascular health by several mechanisms. The actions of poly- cells (HUVECs) pretreated or not with kaempferol (1, 3 or 10 M) phenols appear to be the main relevant mechanisms. The mains for 1 h and then exposed to lysophosphatidylcholine (LPC) (10 flavonoids, quercetin and kaempferol, are reported as promising g/mL) for 24 h . Treatment with kaempferol improved endo- pharmaceutical molecules in the treatment of cardiovascular dis- thelium-dependent vasorelaxation, increased the maximal relaxa- eases, and may in some way help to understand the mechanisms by tion value, and decreased its half-maximum effective concentration which honey exerts its positive action against CVD.Quercetin is concomitantly with an increase in nitric oxide plasma concentra- rapidly conjugated with glucuronic acid and/ or sulfate during a tion, and a decrease in ADMA and MDA plasma concentrations. first metabolism step and a portion of the metabolites are also Moreover, these compounds caused an increase in the expression of methylated, reaching the blood stream as methylated, glucuroni- aortic endothelial NOS as well as of dimethylarginine dimethy- dated and sulfated products : for example, it has been recently laminohydrolase II (DDAH II) in ApoE/ mice. Finally, it was reported that glucuronidated and sulfated metabolites of quercetin found that kaempferol abolished the reduction of NO production, exhibited a protective effect on endothelial dysfunction . In the increase in ADMA concentration and the decreased expression cultured human endothelial cells quercetin has been shown to both of eNOS and DDAH II in HUVECs caused by LPC . In an in up-regulate eNOS gene expression  and stimulate the vitro study using isolated porcine coronary artery rings the vascular NO/cGMP pathway [135, 136]: these findings are of utmost interest effects of kaempferol were studied by Xu et al.. The results since currently the endothelial NOS gene is a candidate in investi- demonstrated that kaempferol enhanced the relaxation produced by gations on CVD genetics by the established role of NO in vascular bradykinin, isoproterenol and sodium nitroprusside in endothelium- homeostasis. Other studies in vitro and in animal models have also intact porcine coronary arteries. It was concluded that kaempferol in a dose dependent mode, has the ability to enhance endothelium- shown that quercetin can increase the activity of eNOS and stimu- dependent and endothelium-independent relaxations, which is not late arterial relaxation , possibly via activation of Ca2+- related with its antioxidant properties. activated K+ channels . Moreover, Shen et al. reported that quercetin and its major in vivo metabolites can protect vessels Besides its aglycon form, kaempferol has demonstrated protect- against hypochlorous acid-induced endothelial dysfunction in iso- ing effects on CVD also in its glycosylated form. It was also dem- lated arteries, presumably mediated in part, by an adenosine mono- onstrated that kaempferol-3-O-sophoroside (KPOS) inhibited LPS- phosphate-activated protein kinase (AMPK) pathway. AMPK acti- induced barrier disruption, expression of cell adhesion molecules, vation leads to subsequent eNOS activation and increased NO pro- neutrophil adhesion and trans-endothelial migration of neutrophils duction, suggesting that beneficial effects of quercetin on endothe- to human umbilical vein endothelial cells (HUVECs). Further stud- lial cell functions are in part mediated via AMPK pathway. ies revealed that KPOS suppressed the production of TNF- and the activation of NF-B by lipopolysaccharides. These results suggest In animal studies it was found that chronic treatment with die- that KPOS possesses barrier integrity activity, inhibitory activity on tary quercetin lowers blood pressure and restores endothelial dys- cell adhesion and migration to endothelial cells by blocking the function in hypertensive animal models. In a model using sponta- activation of NF-B expression and production of TNF-, thereby neously hypertensive rats (SHR) (5 weeks old), animals were endorsing its usefulness as therapy for vascular inflammatory dis- treated with quercetin (10 mg/kg) for 13 weeks. In these animals eases . Although these studies provide new insights on the quercetin reduced blood pressure and heart rate, and enhanced the potential functional benefits of honey antioxidant compounds, fur- endothelium-dependent aortic vasodilation induced by acetylcho- ther investigations in animal and human models are needed to con- line. These findings suggest that enhanced eNOS activity, and de- firm the hypothesized vascular protective effects of honey. creased NADPH oxidase-mediated superoxide anion generation associated with reduced p47 expression appear to be the essential 4.2 Honey and Cancer
mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin intake . In a re- Currently, there are few studies reporting the effect of honey in cent research Panchal et al.  reported that rats supplemented cancer, although interest in this area is growing among researchers. with quercetin presented a higher protein expression of nuclear A group of studies has been particularly focused on the efficacy of factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxy- crude honey or its components in inhibiting mutagenesis or induc- genase-1, and carnitine palmitoyltransferase 1 and lower expression ing apoptosis, and the transformation of different types cancer cell of NF-B, compared with the control group. Moreover, the sup- and proliferation in vitro; moreover, the mechanisms underlying the plemented animals showed less abdominal fat and lower systolic anti-tumorigenic effects of honey at the cellular and molecular lev- blood pressure along with attenuation of changes in structure and els are still limited. The major components of honey, i.e., sugar, function of the heart and liver compared with control rats. Thereby, particularly glucose and fructose, have been reported to display quercetin treatment attenuated most of the symptoms of metabolic both mutagenic and antimutagenic effects in different systems; syndrome, including abdominal obesity, cardiovascular remodeling, antioxidants, in their turn, often show antimutagenic activity . 630 Current Medicinal Chemistry, 2013, Vol. 20, No. 5
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As a result, since honey is a rich source of dietary sugars, little is lower S-phase fractionwas also found, as well as absence of ane- known about possible actual antimutagenic effects. In an in vitro uploidy compared with control cells. Moreover, in the in vivo stud- model Wang et al. studied the antimutagenic capacity of hon- ies, researchers observed that intralesional injection of 6 and 12% eys from seven different floral origins against the encountered food honey and oral ingestion of honey significantly inhibited tumor mutagen Trp-p-1, comparing it to that of a sugar analogue and to growth . Honey also exerted a pronounced antimetastatic ef- individually tested simple sugars. The results showed that all hon- fect in murine tumor models (mammary carcinoma (MCa) and a eys studied exhibited significant inhibition against Trp-p-1 methylcholanthrene-induced fibrosarcoma (FS)) when administered mutagenicity. Interesting was the fact that sugars selected for analy- before tumor cell inoculation (2 g/kg orally once a day for 10 con- sis, either individually or in combination demonstrated a pattern of secutive days) . The results presented by Attia et al.  inhibition similar to that of honeys, where glucose and fructose have shown other possible routes by which honey can exert its were also similar to honeys and were more antimutagenic than mal- antitumor capacity (EAT). In this study the antitumor effect of tose and sucrose. From these results it may be assumed that honey honey against EAC in mice and the possible mode of its antitumor polyphenols are not solely responsibles for honey antimutagenic action were investigated. Results evidenced that pre-oral activity. It is known that sugars can display both mutagenic and administration of mice with different honey doses before antimutagenic effects in different systems , and since honey is intraperitoneal inoculation with EAT (1 x 106 cells) increased the a rich mixture of sugars, its use as a factor able to prevent mutage- number of bone marrow cells as well as peritoneal macrophages, nesiscould result interesting. but not peripheral blood leukocytes. An increase in phagocytic functions of macrophageswas also found as well as T- and B-cell The induction of apoptosis by honey is another capacity that has functions. Moreover, in vitro studies on EAT cells demonstrated an been recently highlighted. Jaganathan et al.,  tested the apop- inhibitory effect of honey on tumor cell proliferation, on the totic effect of selected crude honey samples in colon cancer cell viability % of tumor cells as well as on the size of solid tumor. lines (HCT 15 and HT 29). Pretreatment of cells with honey pro- These results allow to hypothesize that honey antitumor activity duced a significant dose-dependent anti-proliferative effect, show- may also occur via activation of macrophages, T- and B-cells . ing the increasing accumulation of hypodiploid nuclei in the sub-G1 phase of cell cycle that indicated apoptosis. In this cell model the Honey constituents, as polyphenols, have shown complemen- same authors also reported that honey transduced the apoptotic tary and overlapping mechanisms of chemopreventive activity in signal via initial depletion of intracellular non protein thiols, conse- multistage carcinogenesis . Dietary flavonoids may be used as quently reducing the mitochondrial membrane potential and in- chemotherapeutics and preventatives against critical health condi- creasing reactive oxygen species generation. Honey induced apop- tions such as cancer. The large number of effects of flavonoids, like tosis was accompanied by up-regulating p53 and modulating the major polyphenolics in honey, on the metabolism of cancer cells is expression of pro and anti-apoptotic proteins. Further, in HT 29 difficult to summarize in a few basic and specific mechanisms. cells, honey elevated caspase-3 level and displayed typical ladder Several biochemical structures and pathways related to carcino- pattern, confirming apoptosis . Another study tested the anti- genesis can be influenced by flavonoids like: (i) cytoplas- proliferative role of acacia honey and chrysin, as a major natural mic/nuclear hormone receptors, as the most highly sensitive to flavone found in this honey in human (A375) and murine (B16-F1) flavonoids; (ii) enzymatic, by inhibition of several enzymes in- melanoma cell lines. The results showed that both compounds were volved in the oncogenesis, while the reactions of some phospha- able to induce an antiproliferative effect on melanoma cells in a tases and oxygenases are improved; (iii) growth regulation, by dose- and time-dependent manner, mediating by G(0)/G(1) cell inhibition of pathways for the transmission of environmental sig- cycle arrest and induction of hyperploid progression . Similarly, nals to the genes as the steroid path via the cytoplasmic receptor Tualang honey was investigated using human breast (MCF-7 and and the protein kinase cascades; (iv) energy metabolism, by inhibi- MDA-MB-231) and cervical (HeLa) cancer cell lines, as well as tion of glycolysis which leads to a depletion of ATP, especially in normal breast epithelial cell line (MCF-10A). After 72 h of incuba- tumor cells with mitochondrial respiratory defects. These processes tion with increasing doses of honey (1-10%) an increase in lactate lead to a rapid dephosphorylation of the BAD molecules integrative dehydrogenase (LDH) leakage from the cell membranes was evi- of glycolysis-apoptosis in SER, a relocation of BAX to mitochon- denced, indicating a cytotoxic effect of honey to all the three cancer dria and massive cell death, possibly due to removal of the inhibit- cell lines, while no cytotoxic effects was evidence in MCF-10A ing phosphate residue on the -chain of the Na+/K+ pump cell. Honey also reduced the mitochondrial membrane potential .These effects were attributed to two fundamental properties of ((m)) in cancer cell lines after 24h of treatment. Moreover, the flavonoids: the electronic and the steric characteristics. The first activation of caspase-3, -7 and -9 was observed in all honey-treated one is due to the high mobility of the electrons in the benzenoid cancer cells indicating the involvement of mitochondrial apoptotic nucleus of flavonoids which accounts for both their antioxidant and pathway . Tualang honey was also tested in oral squamous cell free-radical scavenging properties; the second one is due to the carcinomas (OSCC) and human osteosarcoma cells (HOS) . In structural similarity between the aglycone form of flavonoids and this study, the results in morphological appearance showed signifi- various compounds involved in normal cell biochemistry such as cant apoptotic cellular changes in both treated cell lines (rounded, nucleic acid bases, coenzymes, steroid hormones, neurotransmit- reduction in cell number, blebbed membrane), as well as significa- ters, cytoplasmic/nuclear hormone receptors, as well as gene induc- tive apoptotic nuclear changes (nuclear shrinkage, chromatin con- tion. Moreover, the high affinity of flavonoids for heavy metal ions densation and fragmented nucleus). Moreover, cell viability assay allows to interfere with the action of enzymes and Zn2+ fingers in showed a time and dose-dependent inhibitory effect on both cell DNA-binding proteins . lines, where signals of early apoptosis were evident, with the per- Quercetin has been the subject of several studies that have centage of early apoptotic cells which increased in a dose and time shown a significant antiproliferative activity in different tumor dependent manner . lines, and since it is one of the mostfrequentlyflavonoids identified Despite a consistentamount of results obtained using in vitro in honey, its presence could help, in part, to explain honey antipro- models, data from in vivo studies are still very limited. In bladder liferative properties. Since it is rapidly absorbed and metabolized in cancer cells, the antitumor effect of honey was examined both in circulating cells, its effects in several in vitro models of leukemia vitro and in vivo. Three human bladder cancer cell (T24, 253J and focused the attention of researchers. Kang et al.  investigated RT4) and one murine bladder cancer cell lines (MBT-2) were used. the role of quercetin in human promyelocytic leukemia cells (HL- The in vitro studies revealed significant inhibition of the prolifera- 60). Pretreatment of HL-60 cells with quercetin produced a dose- tion of T24 and MBT-2 cell lines and of RT4 and 253J cell lines. A dependent inhibition on the activities of cytosolic protein kinase C Honey and Human Health
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(PKC) and two pore K+ (TPK). Cell cycle analysis indicated that HT 29 colon cancer cells demonstrated that caffeic acid signifi- quercetin suppressed in a dose-dependent mode the number of cells cantly inhibited the cell proliferation. The cell-cycle analysis in in the G2/M phase and decreased the population of G0/G1 cells. It caffeic acid-treated cells indicated increasing accumulation of cells was also found that quercetin repressed the complete activity of at sub-G1 phase, accompanied by an increasing ROS generation phosphoinositides like phosphatidylinositol (PI), phosphatidylinosi- and reduction in the mitochondrial membrane potential, confirming tol 4-phosphate (PIP), and phosphatidylinositol 4, 5-bisphosphate a dose- and time-dependent apoptotic effect of caffeic acid [164- (PIP2): it could be concluded that the inhibitory effect of quercetin 166]. Moreover, when caffeic acid phenethyl ester (CAPE) was on the growth of HL-60 cells may be related to its inhibitory effects explored on growth, cell cycle, apoptosis and beta-catenin/T-cell on PKC and/or TPK in vitro and/or on the production of phosphoi- factor signaling in human colon cancer cell (HCT116 and SW480) nositides. More recently, it was been reported that quercetin also it completely inhibited growth, and induced G1 phase arrest and induced fast ligand-related apoptosis in these cells by promotion of apoptosis in a dose-dependent manner. In treated cells a dose- histone H3 acetylation . In other cellular models, such as dependent and time-dependent loss of total beta-Catenin proteinwas chronic myeloid leukemia (CML) cells, quercetin caused a deple- also found, associated with a decrease of nuclear beta-catenin, as tion of the activity of telomerase , a decrease of the level of well as a reduction of the expression of cyclin D1 and c-myc . Notch1 protein  and inhibition of murine leukemia WEHI-3 The studies in other tumor cell lines also confirmed the antiprolif- cells when injected into BALB/c mice, as well as a promotion of erative effect of caffeic acid. A research in human cervical cancer macrophage phagocytosis and natural killer cell activity . cells (HeLa cells) conducted by Chang et al.  showed that Studies conducted by Russo et al.  in B cells isolated from caffeic acid significantly induces apoptosis in HeLa cells in a con- chronic lymphocytic patients (B-CLL) reported that quercetin en- centration-dependent manner by inhibiting Bcl-2 activity, leading to hanced sensitivity to anti-CD95 and rTRAIL treatment with an release cytochrome c and subsequent activation of caspase-3 and increase in cell death of about 1.5- and 1.6-fold, respectively, when p53. These results indicate that caffeic acid and its esters are excel- compared with quercetin monotreatment, suggesting that quercetin lent inducers of apoptosis in tumor cell lines, allowing to hypothe- supplementation may have the capacity to strengthen the efficacy of size about the other possible mechanisms by which honey exerts its drugs widely used in the therapy of B-CLL, such as fludarabine antitumor effects. Results in vitro and in vivo are encouraging and demonstrate the The antitumor effects of quercetin are also reported in a large potential uses of honey as a possible preventive agent against the number of tumor cell models. Recent studies in breast cancer cell development of degenerative diseases. Certainly, other potential (MDA-MB-435, MCF-7) showed an inhibitory effect on cell mechanisms of honey anticancer activities, already investigated growth in a time and dose dependent manner. The analysis of cell with others polyphenolic rich-food, remain to be evaluated, such as cycle in quercetin treated cells showed significant increase in the the ability to interact/interfering with an environmental carcino- accumulation of cells at subG1 phase. Quercetin treatment also genic uptake or activation, or the capacity of inhibiting matrix met- increased Bax expression but decreased the Bcl2 levels, while alloproteinases and other enzyme families implicated in cancer cleaved caspase-3 and PARP expression were increased [159, 160]. metastasis, just to mention some of them. In human glioma cell cultures (U138MG) Braganhol et al.  reported that quercetin decreased cell proliferation and viability by 4.3 Honey and Diabetes
necrotic and apoptotic cell death, arrest the G2 checkpoint of the Honey can positively affect the glycemic response by reducing cell cycle, and decreased the mitotic index. Furthermore, it was also blood glucose , serum fructosamine  or glycosylated found that quercetin was able to protect the hippocampal organo-typic cultures from ischemic damage. Therefore, all these results hemoglobin concentration . Animal studies demonstrated that honey supplementation significantly decreases glycemic values in allowed to hypothesize that the main routes by which quercetin is both diabetic and non-diabetic rabbits , and it reduces blood capable of regulating tumor cell growth are focused on its ability to induce apoptosis by decreasing the Bcl2 levels, increasing Bax glucose concentrations in alloxan-induced  and in streptozoto-cin-induced (STZ-induced) diabetic rats in a dose-dependent mode expression, cleaved caspase-3 and PARP expression, stop cell cy- [173, 174]. The data referring to the effects of honey on fructosa- cle, and arrest the cell cycle in the G2/M phase, proving it to be an active compound with potential uses like chemotherapeutics and mine or glycosylated hemoglobin levels are still limited; however, it has been reported that chronic honey supplementation reduces preventatives supplied by diet. glycosylated hemoglobin in non-diabetic rats , while in STZ- Besides quercetin, other flavonoids identified in honey such as induced diabetic rats it decreases significantly serum concentrations kaempferol, are responsible for significant antiproliferative effects. of fructosamine . Moreover, the combination of antidiabetic Using the HL-60 cells, it was found that kaempferol caused cell drugs, such as glibenclamide or metformin, with honey results in cycle alterations, with a significant increase of cells in S-phase and further reductions in serum concentrations of both glucose and fruc- a progressive accumulation in G2/M, while cells with apoptotic tosamine in STZ-induced diabetic rats . indices confirmed a heightened caspase-3 activity and a decreasing of anti-apoptotic Bcl-2 expression . Kaempferol also showed Evidence from clinical studies showed that honey, compared with dextrose, sucrose or other sweeteners, attenuated post-prandial the capacity of reducing the risk of ovarian cancer. Recently, Luo et al. glycemic response in non-diabetic volunteers . In healthy hu-  demonstrated that kaempferol in a time-dependently way inhibited vascular endothelial growth factor (VEGF) secretion, and man subjects, it was found that natural honey consumption (1g/kg body weight) decreases glycemic post-prandial response compared suppressed in vitro angiogenesis in ovarian cancer cells. to artificial honey and D-glucose which elevated blood glucose Kaempferol also down-regulated extracellular signal-regulated kinases (ERK) phosphorylation as well as NFB and cMyc expres- levels by 47% and 52%, respectively after 60 minutes . In patients with diabetes mellitus, honey supplementation significantly sion, but promoted p21 expression, suggesting a novel ERK-NFB- reduced postprandial glycemic response causing a lower rise in cMyc-p21-VEGF pathway, which accounts for kaempferol angio-prevention effects in ovarian cancer cells. plasma glucose compared with other sugars or sweeteners . Similarly, honey decreased the concentrations of blood glucose in Among honey phytochemicals, phenolic acids like caffeic acid patients with type 2 diabetes mellitus [177,178]. Compared to su- and its esters have also been associated to the chemopreventive crose, honey lowered glycemic and peak incremental indices in effects of honey, appearing to function as an anticarcinogen at the type 1 diabetic patients , while in children with type 1 diabetes initiation and post-initiation stages of tumor development in in vitro mellitus honey reduced hyperglycemia . A glucose-lowering and in vivo experiments [164, 165]. The studies using HCT 15 and effect of honey was also reported in subjects with impaired glucose 632 Current Medicinal Chemistry, 2013, Vol. 20, No. 5
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tolerance . In this study subjects presented significantly lower levels by slowing digestion , prolonging gastric emptying and plasma glucose concentrations after consumption of honey at all- slowing down the rate of intestinal absorption . Besides fruc- time points of the honey tolerance test in comparison to the oral tose, glucose is the second major sugar constituent in honey . A glucose tolerance test. Plasma glucose levels in response to honey significant synergy has been reported between these molecules peaked at 30-60 minutes and showed a rapid decline, when com- which actively influence their absorption, indicating that intestinal pared to glucose. Significantly, the high degree of tolerance to absorption of fructose is improved in the presence of glucose . honey was recorded in subjects with diabetes, suggesting a lower Fructose and glucose have different transporters, GLUT5 (and/or glycemic index for honey. However, despite the evidence of honey GLUT2) and SGLT1, respectively ; despite this, actually the hypoglycemic effect, some studies found no beneficial effect of mechanism by which glucose enhances fructose absorption remains honey on hyperglycemia in type 2 diabetic patients and non- unclear. The recruitment of GLUT2 carrier to the brush border diabetic rats [182, 183], possibly caused by the short duration of membrane caused by increased intestinal fructose may contribute to honey supplementation or feeding . the synergistic effect of glucose on the absorption of fructose . The general schema of the absorption of glucose and fructose by From the above mentioned articles, it can be evinced that honey enterocytes in the small intestine is shown in Fig. (5). SGLT1 is
consumption or its addition to dietary carbohydrates could be bene-ficial in individuals with diabetes. However, few studies have stud- expressed in the brush border membrane of the enterocyte, where it couples the transport of two sodium ions and one glucose molecule ied fructosamine or glycosylated hemoglobin in diabetic patients across the brush border membrane. The energy produced by the after honey supplementation, making it difficult to ascertain the actual effect of honey on these parameters in diabetic patients. The sodium electrochemical potential gradient across the brush border membrane is used to facilitate the glucose accumulation inside of antidiabetic mechanisms by which honey exerts its glycemic con- enterocyte against its concentration gradient. The sodium ion that trol have also been associated with its capacity to modulate key glucose-regulating hormones, especially insulin . Studies in enters the cell along with glucose is then transported out into blood through Na/K-pump in the basolateral membrane, allowing to main- healthy subjects demonstrated that honey supplementation, com- tain the driving force for glucose transport. The accumulation of pared with glucose or the combination of glucose-fructose solution, produced significantly lower serum insulin and C-peptide concen- sugar into enterocytes generates a driving force to transport glucose from cells into the blood via GLUT2, expressed in the basolateral trations . In diabetic patients, honey supplementation in- membranes of enterocyte. A fraction of the intracellular glucose creased insulin concentrations more than sucrose , while in type 2 diabetics reduced insulin resistance . The effect of seems to be taken up into endosomes, as glucose-6-phosphate, and then released into the blood by exocytosis through the basolateral honey on glucose-regulating hormones and pancreas was also re- membrane . Otherwise, after ingestion of fructose, unlike glu- ported in animal studies using STZ-induced diabetic rats, where honey supplementation was associated with a considerable im- cose, an increase in the expression levels of GLUT5 mRNA was found . It was also suggested that there may be a disacchari- provement in pancreatic islets as well as increased serum insulin dase-related transport system which considers both fructose and glucose production from the enzymatic hydrolysis of sucrose . Fructose and glucose, the main sugars present in honey, are in- Other evidence suggests that fructose is absorbed via a saturable volved in some mechanisms related to the glycemic control. Studies carrier in the absence of glucose, while in the presence of glucose; either in diabetic rodent models or healthy and diabetic subjects fructose is absorbed via a disaccharidase-related transport system have shown that fructose reduces hyperglycemia [187-190]. Evi- . Besides this, passive diffusion across the intestinal epithe- dence suggests that fructose contributes in regulating blood sugar lium has also been proposed as a possible mechanism . Studies Fig. (5). Mechanisms for the absorption of glucose and fructose in the small intestine. F, fructose; G, glucose; GLUT2, glucose transporter; GLUT5, fructose
transporter; G6P, glucose-6-phosphate; SGLT1, sodium-dependent glucose transporter.
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have shown that glucose improves the transportation and absorption non-peroxide antibacterial activity . Its high concentration in of fructose but not vice versa, increasing the amounts of fructose manuka honey is due to the conversion of dihydroxyacetone, which that reach the liver. According to the results of the investigations is present in great amounts in the nectar ofL. scoparium flowers exposed above, the potential role of honey against diabetes mellitus , and it occurs non-enzymatically at a slow rate during storage is at an early stage, where more specific researches are needed to of honey. The study demonstrated a strong correlation between understand the mechanisms by which it can exert its hypoglycemic methylglyoxal levels and the potential of honey to inhibit the action. Even if these studies are still scarce, they have shown that growth of S. aureus. In a different research, it was suggested that honey is preferable to the most common sugars or sweeteners, be- methylglyoxal may be fully responsible also for the non-peroxide cause it is more tolerable both in healthy subjects and in patients antibacterial activity of manuka honey . with diabetes mellitus. Moreover, its consumption or its addition to other carbohydrates can be recommended in diabetic patients, be-cause of its minimal incremental effect on blood glucose compared to other sweeteners or common sugars. 4.4 Antimicrobial Action of Honey
The antimicrobial activity of honeycan be divided into two fun- damental mechanisms: (i) a non-peroxide antibacterial activity, mainly due to its high osmolarity and acidity as well as to methyl- Fig. (6). Chemical structures of the methylglyoxal.
glyoxal, bee defensing-1and flavonoid contents; (ii) a peroxide-associated antibacterial activity due to the specific hydrogen perox- The amino- and carboxy-termini are labelled N and C, respec- ide content [30, 198, 199]. The inhibition of microorganisms of clinical significance car- Another antibacterial component in honey is bee defensin-1 ried out by honey has been widely reported in many studies. Cooper peptide (Fig. 7). This peptide has been previously identified in hon-
et al. (2002) well established the antimicrobial activity of manuka eybee hemolymph , honeybee head and thoracic glands  and pasture honeys and made a comparison with an artificial honey and in royal jelly , and a potent activity was reported against solution using eighteen strains of methicillin-resistant Staphylococ- Gram-positive bacteria including B. subtilis, S. aureus, and Paeni- cus aureus, seven strains of vancomycin-sensitive enterococci, bacillus larvae . Kwakman et al.  are the authors of the isolated from infected wounds, and 20 strains of vancomycin- first report of this peptide in honey and they also investigated its resistant enterococci, isolated from hospital environmental surfaces. antibacterial capacity in their recent analysis of unprocessed Re- The authors reported that for all of the strains tested, the minimum vamil honey. Despite this interesting finding, the presence of bee inhibitory concentration of both honeys was below 10%, while the defensin-1 in honeys has not been investigated systematically, and concentrations of artificial honey necessary to achieve equivalent quantitative data on the concentration of this peptide in honey have inhibition in vitro were at least three times higher, thus confirming not yet been established. that the inhibition of bacteria by honey is not exclusively due to its osmolarity. In another study, the antimicrobial activity of five na-tive monofloral Cuban honeys against four bacterial strains, two gram-positive (Bacillus subtilis, ATCC 6633 and Staphylococcus aureus, ATCC 25923) and two gram negative species (Pseudo-monas aeruginosa, ATCC 27853 and Escherichia coli, ATCC 25922), was reported . The results indicated that S. aureus was the most sensitive microorganism, while P. aeruginosa was the most resistant. Moreover, B subtilis and E. coli were moderately sensitive to the antimicrobial activity of honey. In general, the re-sults of this study showed that Gram-positive bacteria were more sensitive to the honey antimicrobial action than Gram-negative bacteria. Other authors have also reported S. aureus as the most sensitive microorganism to honey antimicrobial action:since S. aureus has been reported as the causal agent of a range of illnesses from skin infections to life threatening diseases, such as pneumonia Fig. (7). Homology model of defensin-1 from Apis mellifera. The model of
and meningitis, this is an important achievement that suggest to the mature protein (residues 44-94) was obtained using the experimentally consider honey as a possible treatment against this agent [200-209]. resolved structure of lucifensin from Lucilia sericata (PDB ID: 2LLD) as a Honey also presents inhibitory activity against Pseudomoma aeru- template. Alignment and modelling was performed using the SwissModel ginosa, Bacillus anthracis (anthrax), Corynebacterium diphtherine server (http://swissmodel.expasy.org). Disulfide bridges are shown as sticks. (diphtheria), Klebsiella pneumoniae (pneumonia), Mycobacterim tuberculosis (tuberculosis), Salmonella typhi (typhoid fever), Vibrio Finally, the non-peroxide antibacterial activity of honey and its cholerae (cholera) . relationship with its own flavonoid composition have also been As indicated above, the antibacterial activity of honey is due to partially ascertained. Several antibacterial phenolic compounds the involvement of multiple compounds and to the contribution of have been identified in honeys [219-221], but their contribution to individual components to its total antibacterial activity. Recently the antimicrobial activity of honey remains unclear. The use of researchers have focused their attention on the presence of methyl- flavonoids against bacterial infections has two purposes: (i) to kill glyoxal, a component that contributes to honey non-peroxide anti- the bacterial cells and (ii) to counteract the spread and the effects of bacterial activity: methylglyoxal, (CH3-CO-CH=O) is the aldehyde the bacterial toxins . The bactericidal effect of flavonoids ap- form of pyruvic acid formed by two carbonyl groups (Fig. 6). This
pears to be the result of a metabolic perturbation related with ion compound is formed from sugars during heat treatment or pro- channels, which are especially sensitive points of inhibition and longed storage of carbohydrate-containing foods and beverages likely targets of flavonoids . Besides the active role that the . High levels of methylglyoxal have been found in manuka flavonoids play in the destruction of infectants, they fortify loose honey [212, 213], one of the components mainly responsible for its connective tissues by inhibiting some of the enzymes that can hy- 634 Current Medicinal Chemistry, 2013, Vol. 20, No. 5
Alvarez-Suarez et al.
drolyze their proteoglycan and protein meshwork, making the diffu- Human umbilical vein endothelial cells sion of infections through the tissue sterically difficult . The incomplete knowledge of antibacterial compounds in- volved in the antibacterial activity of honey is an obstacle for wide clinical use of honey. In recent years, the knowledge on the antibac- terial compounds in honey markedly increased. The results on Lysophosphatidylcholine honey antimicrobial properties are encouraging and demonstrate the potential uses of honey as an antibacterial agent, where its powerful Lactase phlorizin hydrolase activity against antibiotic-resistant bacteria could be an effective mode to counteract these agents. CONCLUSIONS
Honeys are a natural source of phytochemical compounds mostly represented by polyphenols. The evidence of the biological Nuclear factor kappa-light-chain-enhancer of action correlated to their polyphenolic content has been demon- activated B cell strated. Honey compounds have been associated to antioxidant and anti-inflammatory actions, reporting cardiovascular, antiprolifera- (erythroid-derived tive, and antimicrobial benefits. Although most health-promoting effects were initially observed with in vitro studies, there are in-creasing animal and clinical researches focused on translating the in vitro evidence into in vivo outcomes. A greater understanding of the Poly (ADP-ribose) polymerase mechanisms and factors governing the bioavailability of honey phytochemicals will be crucial to understanding the mechanisms by Cytosolic protein kinase C which honey exerts its beneficial effects on human health. Recommended daily intake of energy CONFLICT OF INTEREST
Reactive nitrogen species The author(s) confirm that this article content has no conflicts Reactive oxygen species Systolic blood pressure Sodium-dependent glucose transporter 1 The authors wish to thank the Università Politecnica delle Marche, Ancona, Italy for supporting this work and Ms. Monica Glebocki for extensively editing the manuscript. STZ-induced = Streptozotocin-induced Sulfotransferases Triacylglycerides Tumor necrosis factor-alpha Dimethylarginine Adenosine monophosphate-activated protein kinase Uridine-5 -diphosphate B-cell lymphoma 2 Dröge, W. Free radicals in the physiological control of cell function. Physiol Rev., 2002, 82, 47-95.
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Received: October 19, 2012
Revised: December 21, 2012
Accepted: December 27, 2012
02 21/35 55 77-20 Deutsche, Österreicher und Schweizer benötigen einen Reisepass, der bei Einreise noch sechs Monategültig sein muss. Außerdem braucht jeder Besucher eine Touristenkarte, die im Flugzeug ausgeteilt wird. DieseTouristenkarte ist kostenlos und gilt 90 Tage zur einmaligen Einreise. Die Touristenkarte mussunbedingt bis zur Ausreise aus Peru aufbewahrt und gegebenenfalls mit dem Reisepass vorgezeigtwerden.