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Review ArticleHoney as a Potential Natural Antioxidant
Medicine:An Insight into Its Molecular Mechanisms of Action
Sarfraz Ahmed,1,2 Siti Amrah Sulaiman,3 Atif Amin Baig,4
Muhammad Ibrahim,2
Sana Liaqat,2 Saira Fatima,2 Sadia Jabeen,2 Nighat Shamim,2 and
Nor Hayati Othman 1
1Department of Pathology, School of Medical Sciences, Universiti
Sains Malaysia, Kubang Kerian, 16150 Kelantan, Malaysia2Department
of Biochemistry, Bahauddin Zakariya University, Multan 60800,
Pakistan3Department of Pharmacology, School of Medical Sciences,
Universiti Sains Malaysia, Kubang Kerian, 16150 Kelantan,
Malaysia4Faculty of Medicine, Universiti Sultan Zainal Abidin,
Darul Iman, Kuala Terengganu, 20400 Terengganu, Malaysia
Correspondence should be addressed to Nor Hayati Othman;
[email protected]
Received 28 September 2017; Accepted 19 November 2017; Published
18 January 2018
Academic Editor: Sharad S. Singhal
Copyright © 2018 Sarfraz Ahmed et al. This is an open access
article distributed under the Creative Commons Attribution
License,which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly
cited.
Honey clasps several medicinal and health effects as a natural
food supplement. It has been established as a potentialtherapeutic
antioxidant agent for various biodiverse ailments. Data report that
it exhibits strong wound healing, antibacterial,anti-inflammatory,
antifungal, antiviral, and antidiabetic effects. It also retains
immunomodulatory, estrogenic regulatory,antimutagenic, anticancer,
and numerous other vigor effects. Data also show that honey, as a
conventional therapy, might be anovel antioxidant to abate many of
the diseases directly or indirectly associated with oxidative
stress. In this review, thesewholesome effects have been thoroughly
reviewed to underscore the mode of action of honey exploring
various possiblemechanisms. Evidence-based research intends that
honey acts through a modulatory road of multiple signaling pathways
andmolecular targets. This road contemplates through various
pathways such as induction of caspases in apoptosis; stimulation
ofTNF-α, IL-1β, IFN-γ, IFNGR1, and p53; inhibition of cell
proliferation and cell cycle arrest; inhibition of lipoprotein
oxidation,IL-1, IL-10, COX-2, and LOXs; and modulation of other
diverse targets. The review highlights the research done as well as
theapertures to be investigated. The literature suggests that honey
administered alone or as adjuvant therapy might be a
potentialnatural antioxidant medicinal agent warranting further
experimental and clinical research.
1. Introduction
Current stream treatment modalities utilizing chemo
drugsdissimulate multidrug resistance and several other sideeffects
[1]. This urges to quest for alternate options. Naturalproducts are
pondered as a practical alternative approach toabate the ever
increasing scold of diseases and some of theirunavoidable side
effects [2, 3]. Recently, honey as a naturalproduct has clinched
the attention of researchers as a com-plementary and alternative
medicine [4–6].
Honey as a folk medicine is referred in the utmostancient
written archives [7, 8]. Demarcation of its usesin current
professional medicine as a potential therapy isentirely
underutilized. However, there is an affinity for some
researchers to fire out a coherent proposition that usage
ofhoney as a natural product supplement is well intentionedfor
reflection as a therapy or adjuvant antioxidant therapyin current
medicine [9, 10]. The composition of honey variesfrom floral source
to origin. A general average compositionof honey has been presented
in Table 1. It is composed ofat least 181 substances and primarily
fabricates the fructose(38%) and glucose (31%) as major sugars.
Besides fructoseand glucose, other identified disaccharides include
maltose,sucrose, maltulose, turanose, isomaltose,
laminaribiose,nigerose, kojibiose, gentiobiose, and B-trehalose.
Trisaccha-rides include maltotriose, erlose, melezitose, centose
3-a5,isomaltosylglucose, l-kestose, isomaltotriose, panose,
isopa-nose, and theanderose [11]. It also comprises enzymes,
HindawiOxidative Medicine and Cellular LongevityVolume 2018,
Article ID 8367846, 19
pageshttps://doi.org/10.1155/2018/8367846
http://orcid.org/0000-0002-8640-5740https://doi.org/10.1155/2018/8367846
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amino acids, proteins, flavonoids, phenolic acids, and a
mis-cellaneous group. There are 26 amino acids reported inhoney;
among them, proline is the major contributor thatconstitutes 50–85%
of the total amino acids [12]. The minorvolume of vitamins includes
riboflavin, niacin, folic acid,pantothenic acid, vitamin B6, and
ascorbic acid. Differenttrace elements cover calcium, iron, zinc,
potassium, phos-phorus, magnesium, selenium, chromium, and
manganese.Organic acids are other important group of compounds
inhoney, for instance, acetic, butyric, citric, succinic,
lactic,malic, and gluconic acid and a number of other aromaticacids
[13]. The various enzymes present in honey are glucoseoxidase,
sucrose diastase, catalase, and acid phosphatase[14–16]. Some of
the flavonoids and phenolic compoundsthat have been identified in
honey include kaempferol, quer-cetin, chrysin, pinobanksin,
luteolin, apigenin, pinocembrin,genistein, hesperetin, p-coumaric
acid, naringenin, gallicacid, ferulic acid, ellagic acid, syringic
acid, vanillic acid,and caffeic acid [17, 18]. Flavonoids and
phenolic acid con-stituents have been reported to be solely
responsible for theantioxidant and other medicinal effects of honey
[6, 18–24].The chemical structures of major flavonoids and
phenolicacids in honey have been demonstrated in Figures 1 and
2.
Honey has been studied against various ailments in ani-mal and
human models. Published research denotes it as anovel antioxidant
agent [24, 25]. It exhibits a broad spectrum
therapeutic properties such as anti-inflammatory [26],
anti-bacterial [27], antimutagenic [28], expedite wound
healings[29], antidiabetic [30], antiviral [31], antifungal [32],
andantitumoural [5, 33, 34] effects. It could be purported as
anatural cancer “vaccine” as it reduces chronic
inflammation,improves healing of chronic ulcers and wounds,
andimproves immune status; the opposite of these are risk fac-tors
to cancer formation [5]. Its anticancer activity has beenproved
against various types of cancer: breast [35–39], colo-rectal [40],
renal [41], prostate [36], endometrial [36], cervi-cal [39], and
oral [42]. Honey has the potential to reducecardiovascular risk
factors in normal healthy individuals[43]. It causes to reduce
systolic blood pressure and level oftriglycerides and VLDL
(low-density lipoprotein) in experi-mental animals [44]. In a
randomized clinical trial, lowerincidence of acute respiratory
symptoms was observed inindividuals who took honey on a daily basis
[45]. It improvesfemale hormones [46], increases the percentage of
spermsand motility, and reduces the toxic effects on
spermatogene-sis and testosterone level [47, 48]. Postmenopausal
womenwho received honey therapy showed improvement in
theirimmediate memory compared with the improvement seenin women
receiving estrogen plus progestin therapy [49].
Understanding the mode of action of honey is substantialand
under phase area. The review presents a role of honey inmodulation
of different types of diseases and the possiblemechanisms involved.
It also highlights a synopsis of findingsthrough which it makes a
road from different signaling path-ways to different molecular
targets. The review also shows therational explanations for the
therapeutic effects of honey andthe apertures to be
investigated.
2. Medicinal Effects of Honey andMechanisms of Action
2.1. Antioxidant Effects of Honey. Antioxidants are agents
tocounteract deterioration caused by oxidants such as such asO2,
OH
−, superoxide, and/or lipid peroxyl radicals. Cancer,synthesis
of mutagens, aging, atherosclerosis, and manychronic and
degenerative lingering diseases are susceptibleto oxidative stress
[52]. Cells exhibit defense system againstoxidative damage. This
defense system consists of free radi-cals and other oxidative
protective agents such as, catalase,superoxide dismutase,
peroxidase, ascorbic acid, tocopherol,and polyphenols [53]. These
antioxidant agents stimulatebiomolecules such as carbohydrates,
proteins, lipids, andnucleic acids. Cells are altered by this
stimulation and ulti-mately provoking antioxidant response [54].
Honey exhibitsstrong antioxidant activity [6]. This antioxidant
capacity ofhoney contributes to the prevention of several acute
andchronic disorders such as inflammatory, allergic,
thrombotic,diabetic, cardiovascular, cancer, and others. The
antioxidantproperties of honey can be measured in the form of
antirad-ical activity using, oxygen radical absorbance
capacity(ORAC) assay, 1,1-diphenyl-2-picrylhydrazyl (DPPH)
scav-enging assay, and ferric reducing antioxidant power
(FRAP)assay [24]. Honey from various floral origin and
differentcountries has been shown to exhibit high antioxidant
proper-ties [24]. The phenolic acids and flavonoids are
responsible
Table 1: General composition of honey [50, 51].
Component Value/100 g
Total carbohydrates 82.4 g
Fructose 38.5 g
Glucose 31.28 g
Sucrose 1.31 g
Maltose 7.31 g
Total acid as gluconic 0.57 g
Moisture content 17.1 g
Ash 0.169 g
Fibre 0.2 g
Amino acids/proteins 0.3 g
N 0.041 g
Fe 0.42mg
K 52mg
Ca 6.00mg
P 4.00mg
Mg 2.00mg
Cu 1–100 μg/g
Zn 0.22mg
Vitamin B2 0.038mg
Vitamin B3 0.21mg
Vitamin B5 0.068mg
Vitamin B6 0.024mg
Vitamin B9 2μg
Vitamin C 0.5mg
Miscellaneous groups —
2 Oxidative Medicine and Cellular Longevity
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for the well-established antioxidant activity of honey.
Apartfrom these, sugars, proteins, amino acids, carotenes,
organicacids, Maillard reaction products, production of
reactiveoxygen species (ROS), and other minor components
alsocontribute to antioxidant effect [53, 55]. Researchers also
showed that honey (1.2 g/kg) elevated the amount andactivity of
antioxidant agents such as beta-carotene, vita-min C, glutathione
reductase, and uric acid in healthyhuman subjects [56]. The exact
antioxidant mechanism isunknown, but the proposed mechanisms
include free
Chrysin Kaempferol Quercetin
Pinobanksin Pinocembrin Luteolin
Apigenin Hesperetin Naringenin
Genistein
OHOH
HO
O
O
OH
OH
HO
O
O
OH
O
OHHO
O
O
OH
HO
O
O
OH
OH
HO
O
O
OH
HO
O
O
OH
OHOH
HO
O
O
OH
HO
O
O
OHOH
OH
HO
O
O
OHOH
OHOH
HO
O
O
OH
Figure 1: Chemical structures of flavonoids in honey [17].
p-coumaric acid Gallic acid Ellagic acid
Ferulic acid Syringic acid Caffeic acid
OH
OH
OH
HO
OO
H3CO
H3CO OCH3
COOH
HO
O
OH
OHOH
HO
HO
HO
HO
O
OH
HO OO
OH
OHOO
Figure 2: Chemical structures of phenolic acids in honey
[17].
3Oxidative Medicine and Cellular Longevity
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radical sequestration, hydrogen donation, metallic ion
che-lation, flavonoids substrate action for hydroxyl, and
super-oxide radical actions [25, 57]. Figure 3 is presenting all
thepossible mechanisms involved in the antioxidant effects ofhoney.
The antioxidant effect of honey is well established,but urges to
explore the exact mechanisms involved andextrapolation to clinical
trials.
2.2. Antibacterial and Wound Healing Effects of Honey.
Dif-ferent clinical trials and in vitro studies have
reportedbroad-spectrum antimicrobial properties of honey [58].
Itwas reported that honey constrains the growth of
pathogenicstrains such as Streptococcus pyogenes, Streptococcus
typhi,Staphylococcus aureus, coagulase-negative Streptococcus
andE.coli, and species [59]. It also diminishes the growth
ofinfecting strains such as Pseudomonas aeruginosa, Acineto-bacter
baumannii, and Klebsiella pneumonia in full thicknessburn wound in
rats [60].
Antibacterial effect of honey is attributed to presence ofinert
antibiotic factors in it. These factors include its acidicpH,
osmotic effect of sugars, and production of H2O2 byperoxidase. Some
nonperoxidase substances also supportantibacterial activity which
include flavonoids, phenolicacids, and lysozyme [61]. In its
mechanism of action, a signif-icant role is played by bee
defensin-1(antimicrobial peptide),methylglyoxal (phytochemical),
and hydrogen peroxide pro-duction by enzyme glucose oxidase [62].
Furthermore, highsugar contents of honey can also be helpful in
eliminatingbacteria through osmosis [63]. Methylglyoxal (MGO)
inhoney and its precursor dihydroxyacetone (DHA) have
beenrecognized as inhibitors of bacterial growth through
ureaseinhibition. Urease enzyme facilitates bacteria to
acclimateand grow rapidly by producing ammonia in acidic
environ-ment [64]. A very recent study reveals that honey
combatsbacterial infections by two different mechanisms:
inhibitionof bacterial quorum sensing (QS) system to retard the
expres-sion of las, MvfR, and rhl regulons, as well as its
associatedvirulence factors, and bactericidal components
whichactively kill bacterial cells [65].
Biofilms have emerged as a key factor in antibioticresistance.
Biofilms protect bacteria from antibiotics result-ing in relentless
infection. Honey acts as a bactericidalnegotiator, penetrates in
biofilms, recovers aggressiveinfection, and eradicates colonies
[66, 67]. It has shownbactericidal effect against biofilms of
pathogenic referencestrains such as Methicillin-resistant
Staphylococcus epider-midis (MRSE), Extended-spectrum
beta-lactamases (ESBL),
Klebsiella pneumonia, Pseudomonas aeruginosa, Staphylo-coccus
aureus (SA), Proteus mirabilis, Pseudomonas aerugi-nosa (PA),
Clostridium difficile, and enterohemorrhagic E.coli. It improves
wounds healing, prevents invasive infec-tions, eliminates biofilm
colonization, interrupts outbreaks,and thus preserves current
antibiotic stocks [66, 68–70]. Itinhibits biofilm growth by
preventing the binding of bacterialstrains with tissue fibronectin
at infection site. It also reducesexpression of fibronectin binding
surface proteins such asSfb1 and Sof, which are crucial for
bacteria to bind withfibronectin [71]. It also significantly
suppresses the expres-sion of quorum sensing genes (AI-2 importer
and indolebiosynthesis), curli genes (csgBAC), and virulence
genes(LEE genes) in virulent E. coli. Glucose and fructose
contentin the honey were considered to be key components
inrepressing biofilm formation [72].
Normal wound healing is a multipart process in whichcoinciding
series of events occur which include coagulation,inflammation, cell
proliferation, tissue remodeling, andreplacement of damaged tissue
[73]. Honey has been usedwidely for the treatment of various types
of chronic, burn,necrotic, diabetic foot and postoperative split
skin wounds[61, 74–76]. In inflammatory phase of wound healing,
honeyassists in the elimination of necrotic tissues [63],
improvesthe remodeling phase [63], and inhibits bacterial
growth[59], resulting in improved healing. Recent study indicatesan
increased production of IL-6 and TNF-α by honey at thewound site in
the healing process in IL-6-deficient mice[77]. Honey facilitates
an increased stimulation and produc-tion of lymphocytes,
phagocytes, monocytes, and/or macro-phages to release cytokines and
interleukins such as TNF-α,IL-1β, and IL-6, expediting the healing
process [78]. Highsugar contents and osmolarity of honey also
contributetowards healing. Water is drawn out from the wound bedby
the osmotic effect of honey through a simple outflow oflymph if the
blood circulation at the wound site is sufficientto carry out this
process [79]. Research has shown that honeyimproves wound healing
through antioxidant response byactivating AMPK (5′adenosine
monophosphate-activatedprotein kinase) and antioxidant enzymes
which ameliorateoxidative stress. The antioxidant system comprises
exoge-nous and endogenous antioxidants. The endogenous
anti-oxidants are classified as enzymatic and
nonenzymaticantioxidants. The enzymatic antioxidants include
superoxidedismutase (SOD), catalase (CAT), and glutathione
perox-idase (GPx). The nonenzymatic antioxidants comprisevitamins E
and C, glutathione (GSH), and some small
Free radical confiscation Hydrogen donation Metallic ion
chelation oract as substrate for radicals
Stimulation of cells through carbohydrates, proteins, &
nucleic acids to produce ROS-reducing oxidative stress
Antioxidant effects of honey
Elevation of beta-carotene, vitaminC, glutathione reductase,
& uric acid
Figure 3: Mechanisms of antioxidant effects of honey.
4 Oxidative Medicine and Cellular Longevity
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molecules, while exogenous antioxidants include
somemicronutrients [24, 80]. These antioxidants also
supportproliferation and migration of human dermal fibroblastsand
mitochondrial function to assist healing [81].
Another mechanism explains that wound sites haveusually two
types of protein-digesting enzymes: serine pro-teases and matrix
metalloproteases. These protease enzymesare generally inactive due
the presence of some inhibitors.The proteases become active when
the inhibitors becomeinactive by H2O2. Thus, H2O2 plays a role as
physiologicalswitching stimuli for activation and inactivation of
theseenzymes through oxidation. It has been reported that
honeystimulates and enhances H2O2 production. The wounddebris and
bacteria are digested by active proteases. Theactive effect of
honey sweeps off this debris easily due tothe osmotic outflow [7,
82]. During inflammation, H2O2also stimulates the growth of
fibroblasts and epithelial cellsto repair the damage. Similarly,
H2O2 stimulates nucleartranscription factors (NTFs) for cell
multiplication andwound healing [7].
Some additional mechanisms elaborate that H2O2 stimu-lates
insulin receptor complexes to trigger a chain of molecu-lar events
in the cell. This results in facilitating the uptake ofamino acids
and glucose for cell growth. Honey itself mayprovide vitamins,
minerals, sugars, and amino acids to thegrowing cells. This
supports phagocytes to engulf infectingbacteria through glucose
consumption. Honey also stimu-lates cytokines release from monocyte
and lymphocyte pro-liferation to repair tissues. Monocyte
activation by mitogenor honey leads to the production of reactive
oxygen speciesto initiate a greater inflammatory response. It
causes oedemain surrounding tissue restricting circulation in
capillaries.This results in reduction of oxygen supply and
nutrients tocells. It ultimately restricts the cell growth to
replace tissuesto repair wounds [7, 83]. All the possible
mechanisms
involved in antibacterial and wound healing effects of honeyhave
been demonstrated in Figure 4.
2.3. Antifungal Effects of Honey. Honey exhibits
antifungalactivity. Research has shown that it has antifungal
activityagainst Aspergillus niger, Aspergillus flavus,
Penicilliumchrysogenum, Microsporum gypseum, Candida
albicans,Saccharomyces, and Malassezia species [84]. The
potentialantimicrobial effect of honey is attributed to the
presence ofglucose oxidase, methylglyoxal, and high sugar
contents[85–88]. The mechanism is not completely understood;
how-ever, some potential pathways have been suggested.
Honey inhibits fungal growth through prevention of theirbiofilm
formation, disruption of established biofilms, andinstigating
changes to exopolysaccharide structure. It distortsthe cell
membrane integrity which results in shrinkage of cellsurface in
biofilm, leading to death or growth retardation[89]. Atomic force
microscopic studies have revealed thatwhen biofilm is treated with
honey (40% w/v) exopolysac-charide layer thickness is reduced to
half and roughnessincreases followed by its complete removal [90].
Researchershave shown that flavonoid part of honey decelerates
thegrowth of fungi, affects the external morphology and mem-brane
integrity, and inhibits some cellular processes that areinvolved in
germ-tube growth. The inhibition of germ-tubeemergence correlates
with poor growth of membrane. Honeyflavonoid extract has also been
found to affect hyphal transi-tion by reducing the percentage of
cells in the G0/G1 phaseand/or G2/M phase [91]. Figure 5 is showing
the possiblemechanisms involved in antifungal effects of honey.
Thedetailed description of antifungal effects of honey and
molec-ular targets involved is a key gap to be probed yet.
2.4. Antiviral Effects of Honey. The viral activity is
usuallyelicited by native or universal stimuli which lead to
infections
Inhibition of QS systemthrough retardation of las,MvfR, rhl
regulons, curli,& virulence genes
Methylglyoxal
Production of ROS species& osmosis
Honey Bee-defencin 1 & other componentsActivation of AMPK,
CAT, SOD & GPx
H2O2
Glucose oxidase stimulation& glucose absorption
Antibacterial and wound healing effects
Inhibits bacterial urease enzyme
Cell stimulation
Release of cytokinesand interleukins (e.g.TNF-𝛼, IL-1𝛽, and
IL-6)
Stimulation of serineproteases, metalloproteases,insulin
receptor complexes,fibroblasts, epithelial cells, &NTFs
Figure 4: Mechanisms of antibacterial and wound healing effects
of honey. AMPK= 5′adenosine monophosphate-activated protein
kinase;QS = quorum sensing; SOD= superoxide dismutase; GPx =
glutathione peroxidase; NTFs = nuclear transcription factors;
TNF-α= tumournecrosis factor alpha; IL = interleukins.
5Oxidative Medicine and Cellular Longevity
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and lesions [92]. Current studies have manifested that
honeyholds potential antiviral effects. Antiviral effect of honey
isattributed to its various ingredients which have been foundto be
operative in controlling of lesions, for instance,
copperinactivates virus that is a trace element part of honey.
Simi-larly, presence of ascorbic acid, flavonoids, and H2O2
pro-duction by honey also leads to viral growth inhibition
byinterrupting viral transcription and translation [93, 94]. Dataof
in vitro studies has shown antiviral activity of honeyagainst
different types of viruses such as Rubella, herpessimplex, and
varicella zoster viruses [31, 95, 96]. Honeycomprises secretion
from the salivary and pharyngealglands of the honeybee’s head.
Recently, nitric oxide (NO)metabolites, nitrite, and nitrate have
been identified in sal-ivary gland’s section [56]. It is well
established that NO isan energetic molecule that produces host
defense againstviruses, both DNA and RNA viruses. NO acts by
slowingdown the development of viral lesions as well as
arrestingtheir replication [56, 97]. In its mode of action,
NOrepresses replication by interfering with viral
polymerase,nucleic acid, and/or viral capsid proteins. The
flavonoidcontent of honey has also been reported to inhibit the
viraltranscription and replication [98, 99]. Figure 6 is
presentingthe possible mechanisms involved in antiviral activity
ofhoney. To understand the actual influence of honey onviruses and
mechanisms intends to do more research tomap the road.
2.5. Anti-Inflammatory Effects of Honey. Inflammation is
theintricate biological response of vascular tissues to
detrimentalstimuli. It is a defensive way of response shown by the
tissuesand organism to remove the pathogens or stimuli whichare the
cause of injury. Inflammation is classified into two
classes: acute and chronic inflammation. Acute inflammationis an
early retort of the body towards stimuli. The indica-tion of acute
inflammation is redness, pain, itching, andloss of ability to
perform function [100]. If the acuteinflammation is not treated
well and prolonged, then itis converted into chronic inflammation.
It is consideredas a major cause of several chronic diseases or
disorders.Thus, anti-inflammatory action is supposed to
counteractunceasing diseases such as liver diseases [101], kidney
dis-eases [102], and cancer [103]. Several factors can beinvolved
in proinflammatory response such as cytokines,cyclooxygenases
(COXs), lipoxygenases (LOXs), mitogens,macrophages, TNF factors,
and many other factors ofinflammatory pathways.
The anti-inflammatory action of honey is well docu-mented [104].
It has shown anti-inflammatory responsefrom cell cultures [40],
animal models, to clinical trials[104, 105]. The exact mechanism of
action of honey towardsinflammation is not well understood yet. In
inflammatorypathway, two of its components activated in ailments
aremitogen-activated protein kinase (MAPK) and nuclear factorkappa
B (NF-κB) pathways [120]. Activation of MAPKand NF-κB ultimately
results in induction of several otherinflammatory mediators,
enzymes, cytokines, proteins, andgenes such as cyclooxygenase-2
(COX-2), lipoxygenase 2(LOX-2), C-reactive protein (CRP),
interleukins (IL-1, IL-6,and IL-10), and TNF-α. All these markers
of proinflamma-tory action are known to play a major role in
inflammationand angiogenesis-related etiology of disease [30, 119].
Recentevidence of in vivo studies has shown the
anti-inflammatorymechanisms of honey. These studies showed that
honeydecreases edema and plasma levels of proinflammatory
cyto-kines such as IL-6, TNF-α, PGE2, NO, iNOS, and COX-2. It
Honey
Deterioration of membraneintegrity and inhibition ofcellular
processes of germ-tube emergence
Arrest of percentage of cells in G0/G1and/or G2/M phase
Instigation of changes toexopolysaccharides ofmembranes of
fungal cells/biofilms
Effect on biofilms and external morphology resulting in growth
retardation or death of fungal cells
Figure 5: Mechanisms of antifungal effects of honey.
Honey
Cu, H2O2, flavonoids, andascorbic acid
NO Inhibition of viral polymerase, nucleicacids, and/or capsid
proteins
Inhibition of transcription & translation
Inactivation of viruses
Figure 6: Mechanisms of antiviral effects of honey. Cu = copper;
NO=nitric oxide.
6 Oxidative Medicine and Cellular Longevity
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was also demonstrated that honey attenuates NF-κB translo-cation
to the nucleus and suppresses IκBα (inhibitor of kappaB)
degradation [106, 107]. It has been reported that phenolicacids and
flavonoids such as chrysin, quercetin, and galanginare able to
suppress the activity of proinflammatory enzymes,for example,
cyclooxygenase-2 (COX-2), prostaglandins[108], and inducible nitric
oxide synthase (iNOs) [109].Research has shown that flavonoid
content of honey slowsdown the expression of MMP-9 (matrix
metallopeptidase9), an inflammatory mediator that causes chronic
inflamma-tion. Honey has the ability to significantly inhibit the
expres-sion of anti-inflammatory cytokines such as IL-1 and
IL-10and growth factors PDGF (platelet-derived growth factor)and
TGF-β (transforming growth factor-β). In vitro modelof MM6 cell
lines using 1% solution of honey was con-cluded [110]. Another
possible mechanism shows thatreactive oxygen species are produced
by macrophages,monocytes, and neutrophils that enhance
inflammation.Honey ceases the release of such types of cells to
promoteanti-inflammatory effect. It also inhibits the production
ofkeratinocytes and leukocytes to reduce inflammation. Ithas been
demonstrated that in inflammatory responseH2O2 production by honey
stimulates the growth of fibro-blasts and epithelial cells to
repair the inflammatory damage.This anti-inflammatory action of
honey makes it a novelagent to modulate a disease [111–113].
Anomalous arachidonic acid metabolism is involved
ininflammation. LOXs metabolize arachidonic acid to leukotri-enes
(LTs). There are three types of lipoxygenase (LOX) iso-zymes:
12-LOX, 15-LOX, and 5-LOX. 12-LOX provokesinflammatory/allergic
disorders, 15-LOX synthesizes anti-inflammatory 15-HETE
(15-hydroxyeicosatetraenoic acid),and 5-LOX generates 5-HETE
(5-hydroxyeicosatetraenoicacid) and LTs [114]. Many polyphenols in
honey have beenreported to suppress LOXs [114]. The
anti-inflammatoryeffect of honey can be attributed to its phenolic
compoundsand flavonoids [15, 128, 129]. Figure 7 is depicting
thepossible mechanisms of anti-inflammatory effect of honey.
To understand the actual influence of honey on LOXs, COXs,and
TNF signaling pathways and mechanisms involvedintends to do more
research to map the road.
2.6. Honey and Its Antidiabetic Properties. Diabetes melli-tus
is a complex metabolic syndrome. Insulin deficiencyor nonfunctional
insulin is responsible for it [115]. In thissyndrome, many
anomalies in lipoprotein and carbohydratemetabolism are involved
with an elevated glucose level[116, 117]. Acute complications in
this disorder may includehyperosmolar, diabetic ketoacidosis and
hyperglycemic state,which may lead to death [118].
Honey has shown antidiabetic effects from animalmodels to
clinical trials [30, 119]. Researchers have invokedit as a
potential antidiabetic agent [120]. Its concentrationstested such
as 0.2, 1.2, and 2.4 g/kg/day showed an improvedantioxidant effect
exerting a hypoglycemic in streptozotocin-induced diabetic rats
[30]. Similarly, glucose level in type-2diabetes mellitus was found
to be reduced when honey wasadministered by inhalation as 60% (W/V)
[119]. This antidi-abetic or hypoglycemic effect of honey is
attributed to thepresence of fructose in it [122]. Fructose assists
to regulatethe insulin-response system, resulting in controlled
bloodglucose level. Another hypothesis suggests that glucose
levelis reduced by the postponement of digestion and
absorptionwhich are brought about by oligosaccharide palatinose,
asucrose. It results in modulation of diabetes in diabeticpatients
[123]. It has also been reported that captivationof glucose in
cells can be increased in collaboration withfructose [124, 125],
leading to a decreased food-intake orabsorption to direct a
hypoglycemic effect. Monosaccha-rides such as glucose, fructose,
and galactose are formedby the hydrolysis of carbohydrates prior to
their absorp-tion [126]. It has been suggested that fructose is
takenup by the two receptors GLUT5 and/or GLUT2 via pro-tein- and
energy-mediated diffusion [127]. The expressionof GLUT2 mRNA is
generally increased by glucose andfructose. However, an increased
expression of GLUT5
Anti-inflammatory effects
Inhibition of expression of markers of inflammatory pathways
Honey
Suppression of the expression of ROSthrough inhibition of
release of cells suchas macrophages, monocytes,
neutrophils,keratinocytes, and leukocytes
Inhibition of the expression of MMP9
such as IL-1, IL-10, IL-6, COX-2, TNF-𝛼, NF-𝜅B, I𝜅B𝛼,PDGF,
TGF-𝛽, LOXs, NO, iNOS, and prostaglandins.
Increased production of H2O2
Figure 7: Mechanisms of anti-inflammatory effects of honey.
MMP-9 =matrix metallopeptidase 9; IL = interleukin; COX-2 =
cyclooxygenase2; LOXs = lipoxygenases; TNF-α= tumour necrosis
factor alpha; PGE2 = prostaglandin E2; NO=nitric oxide; iNOS=
inducible nitric oxidesynthase; NF-κB=nuclear factor kappa B; IκBα=
inhibitor of kappa B; PDGF= platelet-derived growth factor; TGF-β=
transforminggrowth factor-β.
7Oxidative Medicine and Cellular Longevity
-
mRNA is caused solely by fructose, resulting in its
fastabsorption [128–130]. Research has shown that a hypogly-cemic
effect was observed when mice induced with diabe-tes were fed with
fructose [131]. Glucose level can also beregulated by a specific
hypoglycemic role of the fructose inthe liver. In this mode of
action, fructose stimulates thephosphorylation enzymes, for
instance, glucokinase, trigger-ing hepatic glucose phosphorylation
[132]. The inhibitionof these enzymes results in inhibition of
glycogenolysis.Thus, whole metabolism of glycogen and glucose is
regu-lated by fructose, showing its vital regulatory role to
controlhyperglycemia [133, 134].
Another proposed mechanism explains that hypoglyce-mic effect of
honey may be through the role of honey inmodulating the insulin
signaling pathway [120, 135]. Akey component of insulin signaling
is the PI3K/Akt [136].It is known for its role in modulatory
functions of severalsubstrates which regulate cell cycle
progression, cell survival,and cellular growth. The effect of honey
extracts on Akt-activated insulin signaling pathway in pancreatic
cells wasrecently investigated under hyperglycemic condition. It
wasobserved that the development of insulin resistance was
char-acterized by increased levels of NF-κB, MAPK, and
insulinreceptor substrate 1 (IRS-1) serine phosphorylation.
Aktexpression and insulin contents were found to be
markedlyreduced. This study showed that pretreatment with honeyand
quercetin extract improves insulin resistance and insulincontents.
Honey treatment increased the expression of Aktand reduced the
expression of IRS-1 serine phosphorylation,NF-κB, and MAPK [120,
135–137].
Honey supplementation shows its modulatory effects onoxidative
stress and hyperglycemia. Its antioxidant activityto ameliorate
diabetes is well established [24]. Besides this,it also ameliorates
several other metabolic derangementsobserved in diabetes such as
reduced levels of triglycerides,hepatic transaminases, glycosylated
hemoglobin (HbA1c),and increased HDL cholesterol [138]. Figure 8 is
showing
the possible mechanisms of antidiabetic effects of honey.
Fur-ther studies are warranted to explore the exact
mechanismsinvolved in antidiabetic activity of honey.
2.7. Antimutagenic Effects of Honey.Mutagenicity, the abilityto
induce genetic mutation, is interlinked with carcinogenic-ity
[139]. Honey exhibits strong antimutagenic activity [140].The
effect of honey on radiation (UV or γ)-exposed Escheri-chia coli
cells was investigated to observe SOS response,which is an
error-prone repair pathway contributing tomutagenicity [140]. Some
important genes such as umuC,recA, and umuD involved in
SOS-mediated mutagenesiswere knocked out to elaborate the results.
Honey reducedmutation frequency significantly in treatment groups
thanin controls. The suppression of error-prone mutagenic
repairpathways (for instance SOS response in E. coli) was the
pos-sible mechanism contributing to the antimutagenic effect.The
antimutagenic activity of honey from seven different flo-ral
sources (acacia, buckwheat, fireweed, soybean, tupelo, andChristmas
berry) and honey sugar analogue against Trp-p-1was tested by the
Ames assay [28]. All honeys showed a sig-nificant inhibition of
mutagenicity caused by Trp-p-1. About30% honey in the infusion
formulation was most effective ininhibiting HAA (heterocyclic
aromatic amines) formationand overall mutagenicity beef steak and
chicken breast[141]. Figure 9 is showing the possible mechanisms of
anti-mutagenic effects of honey. A broad spectrum research isneeded
to conduct to understand the mechanisms of antimu-tagenic effects
of honey.
2.8. Anticancer Effects of Honey. Cancer cells possess
twodistinct characteristics: unrestrained cell multiplicationand
inadequate apoptotic turnover [142]. Drugs whichare commonly used
for cancer treatment are apoptosisinducers [143]. Programmed cell
death or apoptosis is cat-egorized into three phases: (a) an
induction phase, (b) aneffector phase, and (c) a degradation phase.
The induction
Modulation of insulin response system/reduced blood glucose
level
Honey
Fructose
Regulation & modulation of insulin signaling pathway
throughincreased expression of Akt and reduced expression of
IRS-1serine phosphorylation, NF-𝜅B, and MAPK
Regulation of expression ofGLUT5 & GLUT2 receptors
Regulation & modulation of phosphorylationenzymes such as
glucokinase in liverglycogenolysis
Figure 8: Mechanisms of antidiabetic effects of honey.
MAPK=mitogen-activated protein kinase; NF-κB=nuclear factor kappa
B;Akt = altered PI3 kinase; IRS-1 = insulin receptor substrate
1.
8 Oxidative Medicine and Cellular Longevity
-
phase stimulates proapoptotic signal transduction
cascadesthrough death-inducing signals (ceramide signaling,
reactiveoxygen species, Bcl-2 family proteins such as Bad, Bax,and
Bid, and over activation of Ca2+ signalling pathway).Effector phase
is committed to bring cell death via a keyregulator, mitochondrion.
The last degradation phase com-prises nuclear and cytoplasmic
events. Nuclear changeincludes chromatin and nuclear condensation,
cell shrinkage,DNA fragmentation, and membrane blebbing. In the
cyto-plasm, a complex cascade of protein-cleaving enzymes
calledcaspases is activated. The cell is finally destined into
frag-mented apoptotic bodies, which are phagocytosed by
mac-rophages or other surrounding cells [143, 144].
The apoptosis usually follows two pathways: thecaspase-8 or
death-receptor pathway and caspase-9 ormitochondrial pathway.
Literature established that honey induces apoptosis invarious
types of cancer cells [22, 39, 40, 145, 146]. This apo-ptotic
temper of honey is vital because many drugs used forcancer
treatment are apoptosis inducers [147]. Thus, thehoney and its
active components can regulate apoptosis byoperating at various
points of these two signaling pathways.
Honey induces apoptosis in human breast, colon, andcervical
cancer cell lines model via depolarization of themitochondrial
membrane by reducing the mitochondrialmembrane potential [22, 39].
These studies proved thecaspase-9 pathway apoptotic induction by
honey. Anotherresearch investigated that crude honey was sole
responsibleto induce apoptosis in human colon cancer and glioma
C6cell lines by elevating caspase-3 activation level and PARP(Poly
(ADP-ribose) polymerase) cleavage. This characteristicwas
attributed to higher tryptophan and phenolic contentsof honey [40,
145, 148]. Researchers showed that it inducesapoptosis by
upregulating and modulating the expression ofpro- and antiapoptotic
proteins in colon cancer cell linesHCT-15 and HT-29. It was found
to elevate the expressionof caspase-3, p53, and proapoptotic
protein Bax. It downreg-ulated the expression of antiapoptotic
protein Bcl-2. Thewhole mechanism explained that ROS generation by
honeyresults in the activation of p53, which in turn modulates
theexpression of pro or antiapoptotic proteins like Bax andBcl-2
[22]. Honey administered with Aloe vera was foundto boost the
expression of proapoptotic protein Bax anddecrease antiapoptotic
protein Bcl-2 expression in Wistarrats with W256 mammary carcinoma
implants [147, 148].Furthermore, two different studies demonstrated
that honey
exerts its cancer therapeutic and cancer preventive effects
inmultiple ways such as modulation of immune response
byameliorating haematological parameters and stimulation ofthe
intrinsic/mitochondrial apoptotic pathway at serologicaland cancer
tissue level. In these studies, honey was given byoral feeding to
Sprague-Dawley rat model using differentconcentrations such as 0.2,
1.0, and 2.0 g/kg body weight. Itameliorated the intrinsic
apoptotic pathway through upregu-lation of the expression of
proapoptotic proteins such ascaspase-9, APAF-1 (apoptotic protease
activating factor 1),p53, IFN-γ (interferon gamma), and IFNGR1
(interferongamma receptor 1). Concomitantly, honey was found
todownregulate the expression of antiapoptotic proteins suchas
Bcl-xL (B-cell lymphoma extra large), TNF-α, COX-2,E2 (estrogen),
and ESR1 (estrogen receptor 1) [149, 150]. Itwas also demonstrated
that honey alone induces intrinsic orcaspase-9 apoptotic pathway
with no evidence of theinvolvement of extrinsic or caspase-8
pathway [149, 150].Flavonoids and phenolic contents of honey have
beenencountered to occlude the cell cycle of glioma [145],
mel-anoma [146], colon [40], and cancer cell lines in G0/G1phase.
This inhibitory effect on tumor cell proliferationfollows the
downregulation of many cellular pathways viatyrosine
cyclooxygenase, ornithine decarboxylase, and kinase[40, 145, 146,
151]. The mechanisms of action of honeyinclude mainly its
interference with multiple molecular tar-gets and cell signaling
pathways such as apoptotic, antipro-liferative or cell cycle
arrest, anti-inflammatory, estrogenicmodulatory, antimutagenic,
insulin modulatory, angiogene-sis modulatory, and immunomodulatory
pathways [6, 17].Reviews by Ahmed et al. [6] and Erejuwa et al.
[17] havewell explained the possible mechanisms of
anticancereffects of honey. Figures 10, 11, and 12 are showing a
sum-marized presentation of mechanisms of anticancer effectsof
honey. Further studies are necessary to understand theexact
influence of honey on the apoptotic pathways in can-cer cells like
the activation of caspase-8, p21, p38 MAPK(mitogen-associated
protein kinase and p38 pathways), p-38 JNK (c-Jun N-terminal
kinase), release of cytochromec, and the suppression of
antiapoptotic proteins such asIAP (inhibitor of apoptosis
proteins), c-FLIP (cellular Fliceinhibitory protein), and Akt
(altered PI3 kinase), and theinitiation of extrinsic pathway of
apoptosis by inductionof TRAIL (TNF-related apoptosis-inducing
ligand) andFas (fatty acid synthase-associated protein) receptor
stimu-lation in cancer cells.
Inhibition of Trp-p-1 and HAA
Honey
Suppression of SOS error-prone repair pathway
Antimutagenic effect
Figure 9: Mechanisms of antimutagenic effects of honey. Trp =
tryptophan; HAA=heterocyclic aromatic amines; SOS = response of
anerror-prone repair pathway contributing to mutagenicity.
9Oxidative Medicine and Cellular Longevity
-
= stimulate or upregulate
= inhibit or downregulate
Akt
PARP
Caspase, cascadeCaspase-3, caspase-8,and caspase-9
1kBaprogression
Il-1𝛽, IL-6,TNF-𝛼
Bax
iNOS
gelatinaseProtease
MAPK
apoptosisCyt. C
Bcl-2ROS oxidative stress
p53
NF-𝜅B
initiation
proliferation cell cycle
IRS-1
Honey
COX-2
Figure 11: Molecular target modulation—the anticancer effects of
honey (adopted from [17]). Bcl-2 = B cell lymphoma 2; Bcl-xL = B
celllymphoma extra large; Cyt. C = cytochrome C;
MAPK=mitogen-activated protein kinase; NF-κB=nuclear factor kappa
B; Akt = alteredPI3 kinase; IRS-1 = insulin receptor substrate; IL
= interleukin; COX-2 = cyclooxygenase 2; TNF-α= tumour necrosis
factor alpha;iNOS= inducible nitric oxide synthase; IκBα= inhibitor
of kappa B; PARP= poly ADP-ribose polymerase.
Honey
Bcl-2, Bcl-xL p53Bax
Caspase-9
Mitochondrio
APAF Cyt. C +
Caspase-3
Apoptosis
Caspase-8
TNF
TRAIL
TRADD
Honey
ExtrinsicIntrinsic
Inhibition
Stimulation
Supposed stimulation
Caspase-7
Figure 10: Effect of honey on apoptotic pathways (adopted from
[6]). Bcl-2 = B cell lymphoma 2; Bcl-xL = B cell lymphoma extra
large;Cyt. C = cytochrome C; APAF-1 = apoptotic protease activating
factor 1; TNF = tumor necrosis factor; TRAIL = TNF-related
apoptosis-inducing ligand; TRADD = TNFR-associated death domain
protein.
10 Oxidative Medicine and Cellular Longevity
-
2.9. Antiproliferative Effects of Honey. Cell divides into
twothrough cell cycle to replace cell death. The cell cycle
com-prises of three distinguished phases known as G0, G1, S,and
G2/M. Cells remain still in G0 phase and not partic-ipating in the
cell division. Cell gears up in G1 phase tomove through cell
division, and S phase involves synthesisof DNA. G2 and M phases are
just ready to mitosis with4n DNA. All the events in the cell cycle
are regulatedand monitored by several different proteins. The
controlpanel of cell cycle comprises cyclins and
cyclin-dependentkinases. G1/S phase transition is a vital
regulatory point,where cell’s fate is destined for quiescence,
proliferation, dif-ferentiation, and apoptosis. Overexpression and
dysregula-tion of cell cycle growth factors such as cyclin D1
andcyclin-dependent kinases (CDK) are linked with pathogene-sis.
The loss of this regulation is the hallmark of cancer as well[152].
The nuclear protein Ki-67 is a novel marker to probethe growth
fraction of cell proliferation. It is absent in theresting phase
(G0), but expressed during the cell cycle in allthe proliferation
phases (G1, S, G2, and mitosis) during cellcycle [153].
Administration of honey and Aloe vera solution showed amarked
decrease in expression of Ki67-LI in tumor cells inWistar rats
having 256 carcinomas [147]. Honey and its sev-eral components like
flavonoids and phenolics are reportedto block the cell cycle of
colon cancer cell lines in G0/G1phase [40]. This inhibitory effect
on tumor cell proliferationfollows the downregulation of many
cellular pathways viaproteins such as tyrosine cyclooxygenase,
ornithine decar-boxylase, and kinase. Thus, it can be hypothesized
that hon-ey—or its components—mediates inhibition of cell growthand
is due to perturbation in the cell cycle which may possi-bly lead
to apoptosis [40, 145, 146, 154]. The cell cycle is a
process regulated also by p53 protein, which as a result ofDNA
damage increases the levels of cyclin-dependent kinase(Cdk)
inhibitors such as p21, p16, and p27 proteins [22].Honey is
reported to be involved in modulation of p53 reg-ulation in colon
cancer cell lines [22]. Figure 13 is depict-ing the possible
mechanisms of antiproliferative effects ofhoney. Honey can suppress
and or block the abnormaldivision of cells by working at various
points of cell cycle.This is still urging to investigate the effect
of honey onthe levels of cyclin-dependent kinases, complexes of
cyclins,cyclin-dependent protein kinases, and
cyclin-dependentkinase inhibitors such as p16, p21, and p27
proteins in cellcycle proliferation.
2.10. Immunomodulatory Effects of Honey. Immunomodula-tion is
progression of altering an immune system in a con-structive or else
damaging style. Many biological andchemical blends have the ability
to modify immune system[155]. Immunomodulatory cytokines such as
TNF-α, IL-1,IL-6, and IL-10 boost activation and proliferation of
bloodcells to induce phagocytic and lymphocytic activity,
trigger-ing an immunomodulatory response [156]. Honey was foundto
provoke stimulation to the immune system of the body tocombat
infections in rats. It stimulates T-lymphocytes, B-lymphocytes, and
neutrophils in cell culture. B-lymphocytesultimately stimulate the
production of antibodies in primaryand secondary immune responses
against thymus-dependentand thymus-independent antigens [157]. It
stimulates mono-cytes to release the cytokines such as TNF-α, IL-1,
and IL-6,activating numerous aspects of immune response.
Stimula-tory action of honey towards leucocytes illustrates
anotheraction called “respiratory burst.” In this action, glucose
ofhoney is absorbed to produce H2O2, which is considered
Anticancer effect
Honey
Estrogen modulation
Antimutagenic activity
Antioxidant activity
Antiproliferative activity
Immunomodulatory activity
Anti-inflammatory activity
Apoptotic activity
Insulin and agniogenesis modulation
Figure 12: Schematic summary of anticancer effects of honey
(adopted from [6]).
Arrest of cell cycle at G0/G1 phase
Honey
Inhibitory effect on Ki-67 & modulatory effect on p53
Antiproliferative effects
Figure 13: Mechanisms of antiproliferative effects of honey.
11Oxidative Medicine and Cellular Longevity
-
as a leading constituent to stimulate the immune system.It also
delivers substrate to glycolysis to produce energyin macrophages to
allow them to perform immune modu-latory function [4, 158].
Research has manifested that sugars which are slowlyabsorbed
result in the formation of short chain fatty acid(SCFA)
fermentation products. It is a probable mechanismthat the ingestion
of honey may result in SCFA formation.It has been established that
either directly or indirectly, SCFAhas immune modulatory actions.
Thus, honey may stimulatethe immune system via these fermentable
sugars [159]. Asugar, nigerose, present in honey has been found to
beimmune protective [160]. Nonsugar components of honeymay also be
responsible for immunomodulation. Antioxi-dant content of the honey
contributes to immunomodulatoryaction as well. Though antioxidant
compounds have beenreported to stimulate immune function in vitro,
but thereare no direct studies manifesting the effects of honey
antiox-idants on immune system [159, 160]. Different studies
pre-sented that Manuka, Pasture, Nigerian Jungle, and royaljelly
honeys used in variant concentrations were found toincrease IL-1β,
IL-6, and TNF-α, apalbumin 1, productionin cell line models [35,
78, 161]. The active component inManuka was 5.8 kDa, which
increased the production ofthese cytokines and TNF-α via TLR4
(toll-like receptor-4)in cell line culture. These authors settled
that the compoundwas not an amino acid, lipopolysaccharide,
mineral, or vita-min urging probe to elucidate the nature of this
immuneregulatory compound [78]. Treatment with honey (0.2, 1.0,and
2.0 kg/kg) showed a potentiating effect on haematolog-ical
parameters such as Hb, RBC, PCV, lymphocytes, andeosinophils. It
also showed an increasing effect on IFN-γand IFNGR1 at serum and
cancer tissue level in rats inducedwith breast cancer [149, 150].
Honey, when tested usingconcentration 1.2 g/kg body weight, was
found to increasethe antioxidant agents (vitamin C and β-carotene),
mono-cytes, lymphocytes, eosinophils, serum iron and copper,
glutathione reductase, and trace elements (Zn and Mg) inhealthy
human subjects. It caused to decrease immuno-globulin E, ferritin,
and liver and muscle enzymes, aspartatetransaminase, alanine
transaminase, lactate dehydrogenase,creatinine kinase, and fasting
blood sugars [56].
The results of clinical trials showed that Life Mel honey(LMH)
reduced the incidence of anaemia in 64% of patientsby decreasing
thrombocytopenia and neutropenia [162]. Astudy demonstrated that
probiotic bacteria in honey havemultiple actions in immunity: (a)
protect the damagedimmune system; (b) enhance the levels of
circulating immu-noglobulins, frequency of interferon and
immunophagocyticactivity; and (c) shift the events of the
chemically inducedreactions [163]. Synthetic medicines and natural
productssuch as honey are supposed to inhibit PG production[164].
Immune function can be restored by the treatmentwith prostaglandin
inhibitors or by reducing systemicPGE2 levels. The use of honey as
a PG inhibitor to preventa disease is emerging. Honey has shown
inhibitory effectson PGE2 in carrageenan-induced acute paw edema in
rats[107]. Figure 14 is showing the possible mechanisms ofaction of
honey for its immune regulatory effects. Furtherprobes are
recommended to elucidate the effects and mecha-nisms of immune
modulatory effects, perhaps using artificialimmune challenges.
2.11. Cardiovascular Effects of Honey. Honey has the abilityto
regulate some cardiovascular risk factors which includeblood
glucose, cholesterol, CRP (C-reactive proteins), andbody weight
[43]. Honey contains glucose, fructose, andsome trace elements such
as copper and zinc, which may playa vital role to ameliorate the
cardiac risks. It causes todecrease LDL (low-density lipoprotein),
high-density lipo-protein cholesterol (HDL-C), triacylglycerole,
body fat, glu-cose, and cholesterol levels in cardiac patients and
healthyhuman subjects who took honey 70 g for 30 days. It
retardsthe level of CRP, which stimulates nitric oxide
production
T-lymphocytes, neutrophils &eosinophils, & other blood
cells
Stimulation of macrophagesCytokines TNF-𝛼, IL-1, and IL-6
production
Respiratory burstby sugar content
H2O2 production
Production ofantibodies
B-lymphocytes Monocytes Provides substrateto glycolysis
Honey Sugars absorbedfrom honey
SCFA
Modulation of IFN-𝛾, IFGR1, & PGE2
Immunomodulatory effect
Elevation of antioxidantagents, minerals, liver,and muscles
enzymes
Figure 14: Mechanisms of immunomodulatory effects of honey.
IFN-γ= interferon gamma; IFNGR1= interferon gamma receptor 1;IL =
interleukin; TNF-α= tumour necrosis factor alpha; PGE2=
prostaglandin E2; SCFA= short chain fatty acid.
12 Oxidative Medicine and Cellular Longevity
-
[43]. Nitric oxide has many cardioprotective effects
whichinclude regulation of blood pressure, vascular tone,
inhibi-tion of platelet aggregation, leukocyte adhesion, and
pre-vention of smooth muscle cell proliferation [165]. NOacts as a
critical mediator for vasodilation in blood vessels.It is induced
by many factors such as acetylcholine, shearstress, and cytokines
via eNOS synthesis. NO causes phos-phorylation of several proteins
that causes smooth musclerelaxation. The vasodilatory effect of NO
plays a majorrole in renal regulation of extracellular fluid
homeostasisand is also critical for the regulation of blood
pressureand blood flow [165, 166]. Some flavonoids in honey
havebeen reported to modulate cardiovascular risks by
decreasingoxidative stress and increasing nitric oxide (NO)
bioavail-ability. Similarly, rutin promotes NO production
byenhancing eNOS gene expression and its activity. Naringininhibits
hypercholesterolemia-induced intercellular adhe-sion molecule-1
(ICAM-1) expression on endothelial cells.Recent studies have shown
that catechin and quercetin asmajor honey flavonoids have
inhibitory effects on thedevelopment of aortic atherosclerotic
lesions and athero-genic modification of LDL [167].
Honey pretreatment was found to restore the decreasedlevels of
enzymes such as superoxide dismutase, glutathioneperoxidase, and
glutathione reductase including creatinekinase-MB, lactate
dehydrogenase, aspartate transaminase,and alanine transaminase
against isoproterenol-inducedmyocardial infarction in Wistar rats
[168]. It shows thathoney gives defense from harmful effects
prompted by freelethal radicals [169]. Another study has shown that
honeycauses to increase antioxidant markers in rat
myocardialinfraction model ameliorating cardiac troponin I (cTnI),
tri-glycerides (TG), total cholesterol (TC), and lipid
peroxida-tion (LPO) products [169]. All the possible mechanisms
ofcardiovascular effects of honey have been demonstrated inFigure
15. However, the exact mechanisms of action of honeystill remain
obscure for its cardiovascular effects. This urgesfor further
investigation.
3. Pharmacokinetics of Honey
Literature lacks reports for the pharmacokinetics of
honey.However, research has shown that honey may affect
thepharmacokinetics of some drugs [170]. In vivo humanstudies
reported that honey interferes with the activity ofcytochrome p450
(CYP450) isozymes [170]. Preliminaryclinical investigations for the
effect of honey on CYP450activity suggest that honey might increase
CYP3A4 activity;however, it does not affect the activity of CYP2D6
and/orCYP2C19. It was also observed that increased CYP3A4 activ-ity
requires regular ingestion of honey, while occasionalingestion is
unlikely to significantly affect drug plasma con-centrations. Thus,
honey may cause altered response to drugsmetabolized by CYP3A4
[170]. CYP3A4 is the major phase Idrug-metabolizing enzyme, and
P-glycoprotein is an ATP-dependent drug efflux pump that regulates
the intestinalabsorption of orally administered drugs. In contrast,
anotherhuman study reported that daily consumption of honey doesnot
affect hepatic and intestinal CYP3A and P-glycoproteinactivities
[171, 172].
4. Limitations of Honey
Honey should be evaluated for its toxicological effects basedon
plants and or nectar source. Though not all, but intoxica-tion by
honey may be expected, for instance, mad honey iscontaminated with
grayanotoxin. Grayanotoxin is found inrhododendron plants in
countries such as China, Tibet,Turkey, Nepal, Myanmar, Japan, New
Guinea, Philippines,Indonesia, and North America. Mad honey
collected inspring is more toxic containing more grayanotoxin
[173].Grayanotoxin causes intoxication which may includeweakness,
dizziness, excessive perspiration, hypersalivation,nausea,
vomiting, and paresthesias. It may even lead to life-threatening
cardiac complications such as complete atrioven-tricular block
[173]. Honey may become contaminated withgerms from plants, bees,
and dust during production,
HoneyDecreased LDL, HDL-C,triglycerol, cholesterol, troponinΙ,
body fat, and glucose
Catechin and quercetin in honey
Rutin in honey Decreased CRP
Increased release of NOeNOS gene
Inhibitory effect ondevelopment of aorticatherosclerotic
lesionsand atherogenicmodification of LDLs
NO production
Reduced risk of cardiovascular diseases
Figure 15: Mechanisms of cardiovascular protective effects of
honey. eNOS= endothelial nitric oxide synthase; NO=nitric oxide;
LDL= low-density lipoprotein; HDL-C= high-density lipoprotein
cholesterol; CRP=C-reactive proteins.
13Oxidative Medicine and Cellular Longevity
-
collection, and/or processing. Fortunately,
antimicrobialactivity of honey ensures that most contaminating
germscannot survive or reproduce. However, bacteria that
canreproduce using spores, including those that cause botulism,may
survive. This is the reason that botulism has beenreported in
infants given honey orally. To solve this issue,honey or
medical-grade honey should be irradiated to inac-tivate the
bacterial spores [174]. Sometimes, food allergydue to honey is
frequently accompanying with pollenallergy due to the presence of
pollens during its collection.Thus, honey may have the possibility
of sensitivity in anypatient with suspected but unresolved food
allergy [175].A typical consumption of sugar and high fructose
cornsyrup (HFCS) totals the nearly ¾ pound per day for
everyindividual above age 2. However, an amount, which
simplyoverwhelms, results in elevated blood sugar levels,
excessiveinsulin release, and resultant fat production and storage
inthe liver [176].
5. Conclusion
Honey can be considered a serine potential natural antioxi-dant
medicine. Evidence-based research shows that honeyacts through a
modulatory road of multiple signaling path-ways and molecular
targets. It may interfere with multipletargets in cell signaling
pathways such as induction of cas-pases in apoptosis, stimulation
of TNF-α, IL-1β, IFN-γ,IFNGR1, p53, and immune cells, inhibition of
cell prolifer-ation, cell cycle arrest, inhibition of lipoprotein
oxidation,IL-1, IL-10, COX-2, LOXs, and PGE2, and modulation
ofother diverse targets. This results in triggering the
ameliora-tion of antioxidant, antimutagenic,
anti-inflammatory,immune regulatory, and estrogenic responses to
abate differ-ent types of diseases. Effect of honey on
pharmacokinetics ofdrug leads to dissimilar progressions of the
body. Furtherresearch is needed to establish the possible
mechanismsinvolved. More clinical and experimental trials are
alsointended to validate the authenticity of honey either aloneor
as an adjuvant therapy.
Conflicts of Interest
The authors declare no conflict of interest.
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