antioxidants

antioxidants

Review
Synergic Effect of Honey with Other Natural Agents in
Developing Efficient Wound Dressings
Angela Spoială 1,2, * , Cornelia-Ioana Ilie 1,2 , Denisa Ficai 2,3 , Anton Ficai 1,2,4
and Ecaterina Andronescu 1,2,4
1 Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Chemical
Engineering and Biotechnologies, University Politehnica of Bucharest, 1-7 Gh. Polizu Street,
011061 Bucharest, Romania
2 National Centre for Micro and Nanomaterials & National Centre for Food Safety, Faculty of Chemical
Engineering and Biotechnologies, University Politehnica of Bucharest, 313 Splaiul Independentei,
3 Department of Inorganic Chemistry, Physical Chemistry and Electrochemistry, Faculty of Chemical
Engineering and Biotechnologies, University Politehnica of Bucharest, 1-7 Gh. Polizu Street,
4 Academy of Romanian Scientists, 3 Ilfov Street, 050045 Bucharest, Romania
* Correspondence: [email protected]
Abstract: Honey has been used for therapeutic and nutritional purposes since ancient times. It was
considered one of the essential medical assets in wound healing. According to research, honeybees
have significant antibacterial, antioxidant, anti-inflammatory, antitumor, and wound-healing prop-
erties. Lately, scientific researchers have focused on apitherapy, using bee products to protect and
strengthen the immune system. Since honey is the most important natural product rich in minerals,
proteins, and vitamins, it has been intensively used in such therapies. Honey has gained significant
consideration because of the beneficial role of its antioxidant compounds, such as enzymes, proteins,
amino and organic acids, polyphenols, and carotenoids, but mainly due to flavonoids and phenolic
acids. It has been proven that phenolic compounds are responsible for honey’s biological activity
and that its physicochemical properties, antioxidants, and antimicrobial potential are significant for
human health. The review also presents some mechanisms of action and the medical applications of
Citation: Spoială, A.; Ilie, C.-I.; Ficai, honey, such as wound healing dressings, skin grafts, honey-based nanofibers, and cochlear implants,
D.; Ficai, A.; Andronescu, E. Synergic as the most promising wound healing tools. This extensive review has been written to highlight
Effect of Honey with Other Natural honey’s applications in medicine; its composition with the most important bioactive compounds also
Agents in Developing Efficient illustrates its synergistic effect with other natural products having remarkable therapeutic properties
Wound Dressings. Antioxidants 2023, in wound healing.
12, 34. https://doi.org/10.3390/
antiox12010034
Keywords: honey; bioactive compounds; biological activity; mechanisms of action; synergic effect;
Academic Editor: Stanley Omaye wound healing
Received: 9 November 2022

Revised: 18 December 2022
Accepted: 21 December 2022
1. Background
Published: 24 December 2022
The word “honey” comes from the Latin word “melem” and Greek “µελιττα”, which
means “bee,” and is a product obtained through processing and manufacturing the nectar
produced by bees and stored in honeycomb cells to feed the beehive population. Since
Copyright: © 2022 by the authors. ancient times, honey procurement has been the primary purpose of apiculture, and its
Licensee MDPI, Basel, Switzerland.
origin appears untraceable. A Mesolithic rock was found in a cave in Valencia, Spain,
This article is an open access article
dating back at least 8000 years, with illustrations of two honey hunters collecting honey
distributed under the terms and
and a honeycomb from a wild bee’s nest. The pictures describe the hunters carrying baskets
conditions of the Creative Commons
and using a ladder or series of ropes to reach the nest [1].
Attribution (CC BY) license (https://
In Georgia, archaeologists discovered honey remains inside an ancient tomb dating
creativecommons.org/licenses/by/
4.0/).
back between 4700 and 5500 years [2,3]. In Georgia, there is a custom that the buried person
Antioxidants 2023, 12, 34. https://doi.org/10.3390/antiox12010034 https://www.mdpi.com/journal/antioxidants

Antioxidants 2023, 12, 34 2 of 30
has a jar of honey nearby to take with them on their journey to the afterlife [4]. Documents
belonging to India’s Vedic and Ayurvedic systems dating back 4000 years were found, in
which the therapeutic use of honey in multiple medical applications is presented [5].
In ancient Egypt, honey had various uses, from cooking to embalming the dead.
In addition, as far back as the Hellenistic period, Greek beekeepers have chosen to do
pastoral beekeeping to increase their production of bee products. In other words, they
move part or all of their hive to different areas depending on the species of flowering
plants [6]. Furthermore, honey was used as a drug to treat various diseases dating back to
2100–2000 BC. For instance, in 384–322 BC, Aristotle described pale honey as being “good
for sore eyes and wounds” [7–9].
Humans have used honey as food and medicine from ancient times until today due to
its nutritional and health benefits [10,11]. The composition of honey varies and is connected
to factors that directly affect its composition and quality, such as the bee species, floral
origins, and environmental and humidity conditions [12]. The primary compound in honey
is a carbohydrate, with a sugar intake of about 70–85%, especially fructose and glucose,
and other components present in minor quantities, which can vary depending on the type
of honey [8,13].
A significant number of studies have reported that honey has been used in traditional
medicine. In addition, the role of honey as an antioxidant is essential as a hepatoprotective and
cardioprotective agent [14–18]. Furthermore, honey has a protective effect against gastroin-
testinal diseases [14,19]. As mentioned above, honey is among the best natural wound healers
available. The ancient Chinese, Egyptians, Greeks, Assyrians, and Romans used different
types of honey to treat wounds and gut pathologies. A number of gram-negative bacteria,
like Escherichia coli, Salmonella sp., Shigella sp., Helicobacter pylori, etc., display a significant or
great sensitivity to the action of honey’s biologically active compounds [20,21].
Additionally, honey has anti-inflammatory [18,22–24] and anticancer activities on
breast, cervical [25], and prostate cancers [26], as well as osteosarcoma [27]. Furthermore,
honey is traditionally used as an antidiabetic [24,28], antioxidant [28], hypolipidemic
agent [29] and also improves thyroid disturbances [14,30].
The review was documented using EndNote X9.3 distributed by Clarivate Analytics
(Philadelphia, PA, USA) LLC as the search engine, using the following keywords: “honey”
and “wound healing” with Title/Keywords/Abstract type restrictions. Based on these
restrictions, 805 papers were found; thus, the findings were mainly focused on articles about
synergism. Furthermore, additional searches were done to extend these data, highlight
certain biological activities, explain results and mechanisms, correlate composition and
activities, etc. As a consequence of this methodology, a complimentary review paper was
derived, with 56 papers from the last 5 years. The first section of the review provides
context for honey’s use and composition in bioactive compounds, as well as associated
properties for developing wound healing. In addition, the synergic effect of honey with
various products, such as cinnamon, basil, ginger, and garlic, is illustrated. Furthermore,
the honey’s mechanism of action and biological activity were considered important to the
research. In the end, after the mechanisms of action, attention was shifted to preclinical
and clinical trials, using honey and honey-based products. Following the above structure,
we consider that the main interest after showing honey’s composition and properties was
to illustrate the synergic effect with natural products and the mechanism of action and
biological activity of honey.
2. The Composition-Related Activity of Honey

The most important content of all the honey components is the bioactive compounds,
including phenolic compounds. The polyphenols found in honey are correlated to botanical
sources, such as pollens, nectars, resins, and different oils available to the bees. Therefore,
different floral species will have distinct influences on their bioactive properties [31]. In
addition, the bioactive properties of honeybees might be defined by the cerumen, a resin
that stingless bees collect, combining it with saliva and beeswax to seal their hives [32].

In addition, the bioactive properties of honeybees might be defined by the cerumen, a
resin that stingless bees collect, combining it with saliva and beeswax to seal their hives
[32]. The process is followed first by a physical transformation within the nectar in the
The process
cerumen. is followed
Afterwards, first by a change
a biological physical istransformation
created during within
the the nectar in the
fermentation process,
cerumen. Afterwards, a biological change is created during the fermentation
helped by yeasts and bacteria. Lastly, the process is followed by a chemical transformation process,
helped by yeastswhen
that happens and bacteria.
the beesLastly, theenzymes
secrete process isfrom
followed
theirby a chemical
cephalic transformation
glands during induced
that happens when the bees secrete enzymes from their cephalic glands during induced
hydrolysis. Consequently, the physicochemical composition of the honey is influenced by
hydrolysis. Consequently, the physicochemical composition of the honey is influenced by
the presence of phytochemicals in the cerumen [33–35].
the presence of phytochemicals in the cerumen [33–35].
Further, honey contains small quantities of organic acids, amino acids, proteins, en-
Further, honey contains small quantities of organic acids, amino acids, proteins, en-
zymes, lipids, flavonoids, and vitamins; these compounds are responsible for its biological
zymes, lipids, flavonoids, and vitamins; these compounds are responsible for its biological
properties (Figure 1), such as wound healing, antibacterial effects against a wide range of
properties (Figure 1), such as wound healing, antibacterial effects against a wide range of
pathogenicbacteria
pathogenic bacteria [36,37],
[36,37], antifungal
antifungal [38,39],
[38,39], antiviral
antiviral [36,37],
[36,37], antioxidant
antioxidant [28,40,41],
[28,40,41], and and
antitumor [42] activities, and other skin disorders [10,36,43,44]. For example,
antitumor [42] activities, and other skin disorders [10,36,43,44]. For example, antioxidants antioxidants
suchasaspolyphenols
such polyphenols efficiently
efficiently reduce
reduce theof
the risk risk of several
several pathologies,
pathologies, like cardiovascu-
like cardiovascular,
lar, pulmonary (asthma), infected or chronic wounds and
pulmonary (asthma), infected or chronic wounds and skin ulcers, ophthalmologic skin ulcers, ophthalmologic
(cata-
(cataracts),
racts), etc. [24,36–43,45].
etc. [24,36–43,45].
Figure
Figure1.1.Interdependence of of
Interdependence honey composition
honey and and
composition biological activity
biological by different
activity factors.
by different The The
factors.
figure was designed with ConceptDraw Diagram 16.
figure was designed with ConceptDraw Diagram 16.
The
Theabove-mentioned
above-mentioned explanation
explanation gives reasons
gives for the
reasons forwidespread
the widespreaduse ofuse
honey ob- ob-
of honey
tained from commercial, artificial, and natural beehives. However, the composition of
tained from commercial, artificial, and natural beehives. However, the composition of honey
honey and its antioxidant capacity depend on flowering plants [10]. Also, its natural in-
and its antioxidant capacity depend on flowering plants [10]. Also, its natural ingredients
gredients have shown different activities against multiple microorganisms. Its action must
have shown different activities against multiple microorganisms. Its action must likely depend
likely depend on the grazing grounds, the weather conditions where the bees were raised,
on the grazing grounds, the weather conditions where the bees were raised, and the natural
and the natural structure of the blossom nectar [46]. It is worth mentioning that honey has
structure of the blossom nectar [46]. It is worth mentioning that honey has an increasing effect
an increasing effect on the levels of antioxidants, iron, and rare elements in the blood [47].
on the levels
It has been of reported
antioxidants, iron, and
that honey rarelower
could elements in the blood
cardiovascular [47].
risk in healthy patients
It has been reported that honey could lower cardiovascular
and those with risk problems. The various parameters, such as plasma risk in healthy
glucose, patients
insulin,
and those with
cholesterol, risk problems.
triacylglycerides, bloodThe various
lipids, parameters,
C-reactive such
proteins, andashomocysteine,
plasma glucose, insulin,
were
cholesterol,intriacylglycerides,
investigated vivo with naturalblood lipids, C-reactive
and artificial proteins,
honey; however, raw and
honeyhomocysteine,
was used to were
investigated
have significantin vivo with natural
ameliorative andonartificial
effects honey; however,
the parameters mentioned rawabove
honey[48].
was In
used to
have significant ameliorative effects on the parameters mentioned above [48]. In particular,
Tualang (Koompassia excelsa) honey has been reported to have protective effects on mem-
ory, including enhanced morphology of memory-related brain areas, increased levels of
brain-derived neurotrophic factor, reduced brain oxidative stress, increased acetylcholine
concentration, and reduced acetylcholinesterase activity in brain homogenates [49–52].
Based on its chemical composition, honey can contain approximately 200 bioactive
compounds (carbohydrates, proteins, enzymes, amino acids, minerals, vitamins, polyphe-
nols, carotenoids, etc.). These substances are well known for their antioxidant, antibacterial,
antithrombotic, antiallergic, anti-inflammatory, antimutagenic, anti-cytostatic, and immune-
suppressive effects [44,52–55].
There is approximately 95–99% contains dry matter for all the sugar intakes. Further-
more, fructose is the most abundant, making up roughly 32–38% of its total sugar intake.
In addition to fructose and glucose, there are other disaccharides and oligosaccharides,
including sucrose, maltose, maltotriose, and panose. In addition, apart from sugars of all
types, there are other components, such as organic acids, minerals, and trace elements,
such as calcium, potassium, sodium, magnesium, phosphorus, sulphur, iron, zinc, copper,
and manganese. The factors above are considered essential to various life forms having
important functions in biochemical processes, as constituents of bioactive compounds,
while in high concentrations, might become toxic [54,56].
There are essential vitamins, such as ascorbic acid (Vitamin C), thiamine (Vitamin B1),
pantothenic acid (Vitamin B5), riboflavin (Vitamin B2), nicotinic acid (Vitamin B3), pyridoxine
(Vitamin B6), biotin (Vitamin B8), folic acid (Vitamin B9), and cyanocobalamin (Vitamin B12)
that are present in honey [57,58]. There are enzymes and protein constituents that play
vital roles in various activities, including antimicrobial activity and calcium absorption [59].
Additionally, honey composition and biological activity depend on geographical origin, floral
source, seasonal and climate factors, and production processes (see Figure 1) [54,60,61].
Antioxidant compounds, such as amino acids, enzymes, proteins, carotenoids, and
polyphenols, are well credited for the beneficial properties of honey [33,62]. The flavour
of honey depends on the geographical area, type of environment and storage conditions,
aroma, and phenolic compounds, which depend on its botanical sources, and the bee
species (Melipona sp. and Scaptotrigona sp.) involved [63,64].
A well-known fact is that phenolic compounds are responsible for honey’s antimicro-
bial activity, while it has been considered that its physicochemical properties and its antiox-
idant and antimicrobial potential are significant for human health. Several studies have
revealed that the antioxidant capacity of honey also depends on the presence of flavonoids,
which play a vital role in reducing oxidative stress. For instance, various flavonoids and
terpenoids have been reported in multiple types of honey. In Manuka honey, pinocembrin,
chrysin, pinobanksin, 8-methoxy kaempferol, luteolin, isorhamnetin, galanin, kaempferol,
sakuranetin, quercetin, mangiferolic acid, and 3β-hydroxy-24-methylenecycloartan-26-oic
acid have been identified [14,54,65]. Accordingly, the International Honey Commission will
summarise some of the physicochemical properties of Tualang and Manuka honey, such as
appearance (could be dark brown, light-dark brown, amber-brown, or colourless), mois-
ture content (varying from 20–25%), pH (3–6), total reducing sugars (55–86%), electrical
conductivity (0.49–8.77 mS/cm), and ash content (0.01–0.19 g/100 g) [14].
There is mining, as well as other industrial activities, releases many toxic metals ab-
sorbed into plants’ soil, atmosphere, and water. The honey harvested near heavy industrial
sites or highways may contain high levels of harmful elements such as arsenic, cadmium,
mercury, and lead, which have unknown biological functions in organisms [56,66,67]. On
the other hand, a lack or reduced levels of elements in the soil, rocks, or water influence the
mineral composition of different plants bees use to collect nectar. In other words, honey
can serve as an excellent bioindicator of environmental pollution with heavy metals. Also,
the elemental composition can indicate honey’s geographical origin and the isotopic ratio
of the biologically active compounds [56,67–69].
Regarding composition, some minor components, such as proteins, minerals, vitamins,
and phenolic compounds, play a vital role in bee activities. The study, which involves
phenolic composition, includes their isolation and comprehensive characterization, which
could play an essential role in elucidating their input into antimicrobial properties. Ad-
ditionally, commercial standards or natural honey were used to establish antimicrobial
activity [35]. The complexity of the honey matrix and phenolic compounds requires replac-
ing the conventional, non-specific methods with other, more adequate ones. For instance,
HPLC coupled with mass spectrometry offers a viable analytical alternative. The use of
mass spectrometry was able to detect phenolic compounds through a high-sensitivity
method and provide precise structural information [70].
Phenolic compounds are among the most chemically heterogeneous compounds pro-
duced in plants. Currently, honeybees and their products have a significant role as natural
antioxidants. This is because phenolic compounds and their antioxidant properties have be-
come the most critical features in evaluating the quality and functionality of honey [70,71].
High-performance liquid chromatography combined with a photodiode array detector
or diode array detector (HPLC-PDA/DAD) is the conventional method used to determine
phenolic compounds in honey [72]. Even though this technique is precise, simple, rapid,
and inexpensive, additional procedures are still required. Spectroscopic technologies are
the most popular for analysing the quality of honey. For example, near-infrared (NIR)
spectroscopy can successfully determine the total content of honey’s phenolic, flavonoid,
and antioxidant content. Additionally, Fourier transform infrared (FT-IR) and Raman
spectroscopy have been used to evaluate honey quality, mainly determining sugar, moisture,
and acidity. Lately, FT-IR and Raman have been effectively applied to determine the
antioxidant capacity of different foods [73].
A study from Australia on extracts of stingless bee (Tetragonula carbonaria) cerumen
determined the presence of gallic acid and pimaric acid. Moreover, cerumen is known for
preventing linoleic acid oxidation, thus exhibiting antioxidant activity [74,75].
In another paper regarding M. subnitida honey from Brazil, gallic, vanillic,
3,3-dihydroxybenzoic, coumaric acids, and some isomers of abscisic acid (trans-trans and
cis-trans) were identified [76]. Alvarez-Suarez et al. have shown the presence of fer-
ulic acid, 2,4-dihydroxybenzoic acid, syringic acid, 3,4-hydroxybenzoic acid, ellagic acid,
p-coumaric acid, trans-cinnamic acid, and the flavonoids, catechin, myricetin, kaempferol,
quercetin, rutin, naringenin, hesperetin, and chrysin were all found in M. subnitida and
M. scutellaris Latrelle honey. The HPLC-DAD-ESI-MS/ MS analysis identified 19 com-
pounds in M. beecheii honey [12].
In the study [33], three bee species (M. flavolineata, M. Mexicana, and A. mellifera) from
different Amazon regions were used. The honeybee presented 14 phenolic compounds; the
significant compounds were gallic acid and quercetin. Another study [44] reported that
gallic acid was the most plentiful phenolic compound in Brazilian A. mellifera honey. Still,
p-coumaric, protocatechuic, cinnamic acid, quercetin, and myricetin were also detected in
small amounts. Further, other studies show gallic acid’s effectiveness on apoptosis, prostate
carcinoma, and cervical cancer cells [77].
A similar study conducted by researchers from Brazil found in honey 19 types of
pollen samples, while M. caesalpiniifolia was found in 9 [78]. In addition, eastern Ecuadorian
honey has different types of pollen (more than 14 botanical families) [79].
The study [33] reported that 16 pollen types were in honey, and the Fabaceae family
was the most present. The samples with a predominantly single pollen type showed the
highest total phenolic content [33].
The melissopalynological technique allows the evaluation of honey’s botanical and
geographical origins. Due to floral resources, climatic fluctuations, and other native bee
species, stingless bees can change their trophic position [33,76].
Accordingly, the floral source, geographic origins, storage conditions, and composition
of honey’s phenolic compounds may affect the antioxidant activity of honey. Additionally,
the botanical sources of nectar influence the physicochemical properties of honey. Fur-
thermore, information regarding chemical composition confirms the variances in honey
phenols’ qualitative and quantitative composition. The total polyphenols in Portugal’s
rosemary, viper’s bugloss, and heather honey revealed variations from 226 µg/g for honey
extract and up to 728 µg/g for natural honey. The total content of phenolic compounds in
herbal honey from Romania was 20–450 µg/g [80,81].
Table 1 illustrates various countries revealing their polyphenol composition based on

plant-based products. According to these data, the polyphenol content varies widely, from
~7 to over 11,000 µg/g, depending on the species and the country.
Table 1. Polyphenol composition in various countries.
No. Polyphenols [µg/g] Plant-Based Food Species Name Country Reference

1 226.00 Rosemary plant Rosmarinus officinalis Portugal [80]
2 406.00 Viper’s Bugloss Plant Echium vulgare Portugal [80]
3 728.00 Heather plant Calluna vulgaris Portugal [80]
4 20.00 Acacia plant Robinia pseudoacacia Romania [81]
5 128.00 Lime plant Tipia sp. Romania [81]
6 450.00 Honeydew Mountain multi-flora Romania [81]
7 131.00 Apiaceae fruit Lagoecia cuminoides Greece [82]
8 716.00 Asteraceae herb Artemisia arborescens Greece [82]
9 54.00 Asteraceae leaves Taraxacum officinale Greece [82]
10 802.00 Caprifoliaceae flower Sambucus nigra Greece [82]
11 158.00 Lamiaceae herb Hyssopus officinalis Greece [82]
12 71.00 Lamiaceae flower Lavandula vera Greece [82]
13 1018.00 Lamiaceae leaves Mentha pulegium Greece [82]
14 1349.00 Araceae rhizome Acorus calamus Poland [83]
15 7693.00 Asteraceae herbal Achillea millefolium Poland [83]
16 7985.00 Asteraceae leaves Echinacea purpurea Poland [83]
17 11,020.00 Lamiaceae herbal Rosmarinus officinalis Poland [83]
18 2893.50 Papaveraceae herbal Chelidonium majus Poland [83]
19 50.82 Raspberry herb Rubus sp. Australia [84]
20 16.56 Thyme herb Thymus vulgaris Australia [84]
21 6.76 Camomile herb Matricaria chamomilla Australia [84]
22 2560.60 Oleaceae leaves Olea europaea Bulgaria [85]
23 826.10 Oleaceae leaves Olea europaea Bulgaria [85]
24 186.70 Vitaceae berries Vitis vinifera Czech Republic [86]
25 1243.10 Vitaceae stem Vitis vinifera Czech Republic [86]
26 659.40 Vitaceae leaves Vitis vinifera Czech Republic [86]
27 50.12 Amaranthaceae leaves Achyranthes aspera India [87]
28 196.39 Brassicaceae leaves Brassica juncea India [88]
29 179.57 Brassicaceae seedlings Brassica juncea India [88]
30 92.20 Tamaricaceace stem Tamarix aphylla Tunisia [89]
31 668.00 Tamaricaceace leaves Tamarix aphylla Tunisia [89]
32 594.45 Primulaceae leaves Labisia pumila Malaysia [90]
33 1192.12 Primulaceae leaves Labisia pumila Malaysia [90]
34 307.64 Asteraceae leaves Artemisia absinthium South Korea [91]
Another example of phenolic acids was presented in a study from Australia, which
was relatively low and ranged from 2.13 mg/100 g in sunflower honey to 12.11 mg/100 g
in tea tree honey [84]. Polish researchers have discovered phenolic acid and flavonoids in
buckwheat, acacia, and honeydew honey while developing liquid chromatography and
tandem mass spectroscopy analytical methods [92]. Some studies revealed that phenolic
acids and phenylpropanoids showed significant antibacterial activity. The contribution of
natural phenolic compounds to the nutritional quality of fruits and fruit products might
play a vital role in the daily diet. Therefore, phenolic acids and phenylpropanoids could be
proposed as reliable indicators of honey’s quality and authenticity [93,94].
3. Synergic Effect of Honey with Other Natural Products

Traditional medicine practitioner has used natural products isolated from plants and
animals to treat human diseases since ancient times. As time passed, natural treatment
decreased in interest in the synthetic drug industry, which provides an alternative; still,
some countries rely on traditional medicine for their health care [95]. Chronic wounds
and especially burns are significant to treat immediately due to the appearance of the
risk of microbial infections [96]. Many healing drugs are less affordable and have partial
effectiveness and toxic effects. The search for new healing agents in traditional medicine
has great potential for developing effective alternative therapies [97].
Abderrahim et al. [98] reported the synergism and therapeutic properties (antimicro-
bial, antioxidant, and wound healing) of Euphorbia honey and Allium sativum L. (garlic).
Regarding the antimicrobial activity, A. sativum exhibited better sensitivity to S. aureus,
E. coli, and C. albicans than Euphorbia honey. Another study [90] indicated that the an-
timicrobial activity of A. sativum extracts is due to allicin, which acts by damaging DNA
and RNA synthesis. Contrary to the above statement, other compounds such as diallyl
disulphides, S-allyl cysteine, and diallyl trisulphide also exhibited good antimicrobial
effects [99]. Moreover, due to its antioxidant and antimicrobial effects, the use of garlic
to treat infectious diseases dates back centuries [100]. Furthermore, garlic contains car-
bohydrates, dietary fibres, enzymes, vitamins, minerals (K+ , Ca2+ , Na+ , Zn2+ , Cu2+ , Fe3+ ,
Se2+ , Ge4+ , Mg2+ , Mn2+ ), polyphenols, carotenoids and at least 33 sulphur-based com-
pounds (ajoene, allicin, alliin, allyl sulphides, allyl disulphides, allyl trisulphides, cysteine,
cyclophilin, cysteine sulfoxides, cystine, diallyl sulfides, dimethyl sulphides, glutathione,
disulphides, methionine, methyl sulphides, sulphates, pseudoscordinine, thiosulfinates,
scordinine, trisulphides, and tetrathiol) that are responsible for poignant garlic odour and
its antioxidant, therapeutic, antibacterial and anti-carcinogen effect. The bee species used
in the study was T. iridipennis [98,101,102]. Also, Euphorbia honey presents antimicrobial,
anti-inflammatory, antioxidant, and immuno-modulatory activity and stimulates wound
regeneration, contributing to wound healing processes [103]. The biological properties
of honey are due to its chemical composition. Honey contains mainly sugars, water, and
other substances such as proteins (enzymes), organic acids, vitamins (B1 , B2 , B3 , B5 and
B6 ), minerals (K+ , Ca2+ , Na+ , Mg2+ , P3+ , Cu2+ , Fe3+ , Zn2+ and Mn2+ ), pigments, phe-
nolic compounds, and large particles of volatile and solid particles derived from honey
harvesting [38,98,104–110].
Figure 2 presents the synergic effect of honey with some medicinal plants used in the
studies presented in the manuscript.
In the medicinal context, synergism is the result of combining two or more components
to obtain a better product with the best properties. For example, Andualem [102] presented
that the mixture of Tengen honey and garlic induced a significant sensitivity of Gram-
positive and Gram-negative bacteria (E. coli, S. typhi, S. aureus, and Streptococcus pneumonia).
In another study, the mixture of honey and garlic extract demonstrated better antimicrobial
activity than the individual components. In contrast, it has been found that garlic extract
presents better antioxidant activity than honey and their mixture [111]. Similarly, another
research concluded that Euphorbia honey had a significantly higher amount of flavonoids,
which led to better antioxidant activity [112].
Antioxidants 2023, 12,
Antioxidants2023, 12, 34
34 8 of 32 8 of 30
Figure
Figure2.2.The
Thesynergic
synergiceffect
effectofofhoney
honeywith
withmedicinal
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InThetheresearch
medicinal hascontext,
compared synergism
the burnis the resultcapacity
healing of combining two or more
(epithelisation, compo- and
contraction,
nents
histological recovery) of Euphorbia honey and a mixture of honey with A. sativum[102]
to obtain a better product with the best properties. For example, Andualem with silver
presented
sulfadiazine thatand
the mixture
betadineofsolution.
Tengen honey The dataandsuggests
garlic induced
that aamixture
significant
withsensitivity
sulfadiazineof has
Gram-positive and Gram-negative bacteria (E. coli, S. typhi, S. aureus, and Streptococcus
a shorter epithelisation and contraction time compared to betadine solution and Euphorbia
pneumonia). In another study, the mixture of honey and garlic extract demonstrated better
honey [98]. In addition, another species from the Euphorbiaceae family, Euphorbia hirta linn, is
antimicrobial activity than the individual components. In contrast, it has been found that
an important medicinal plant, and its entire plant is used to heal wounds [113,114].
garlic extract presents better antioxidant activity than honey and their mixture [111]. Sim-
In another study, the antibacterial and synergic properties of O. basilicum with honey
ilarly, another research concluded that Euphorbia honey had a significantly higher
were evaluated by an agar diffusion assay. Due to honey’s significant input to wound healing,
amount of flavonoids, which led to better antioxidant activity [112].
acceleration and control of wound infection were demonstrated [115]. The purpose of the
The research has compared the burn healing capacity (epithelisation, contraction,
study was
and histological to exhibit the sensibility
recovery) of Euphorbia of several
honeypathogenic
and a mixturebacteria isolated
of honey from
with A. the clinic, like
sativum
with silver sulfadiazine and betadine solution. The data suggests that a mixture with sul-faecalis,
gram-positive strains (Bacillus subtilis, Clostridium perfringens, C. chauvoei, Enterococcus
S. aureus)has
fadiazine anda gram-negative (E. coli,and
shorter epithelisation Klebsiella pneumonia,
contraction P. aeroginosa,
time compared S. typhi, S.
to betadine typhimirium,
solution
Xanthomonas campestris) on the action of the O. basilicum with
and Euphorbia honey [98]. In addition, another species from the Euphorbiaceae family, honey [115].
A member
Euphorbia hirta linn,of the
is anLamiaceae
importantfamily,
medicinalO. basilicum,
plant, and has
itsbeen
entireextensively
plant is used grown and used
to heal
in worldwide
wounds [113,114]. cuisine for its aromatic taste and flavour [115]. Originally, O. basilicum has
beenIngrown
anotherinstudy,tropical and subtropical
the antibacterial regions,properties
and synergic encompassing almost 150
of O. basilicum withspecies.
honey The
Ayurvedic
were evaluated system
by an fromagarIndia is considered
diffusion assay. Due representative of its healing
to honey’s significant inputproperties.
to wound From
a sales and
healing, businessand
acceleration point of view,
control the O.infection
of wound basilicumwereplant’s sales have[115].
demonstrated naturally increased
The pur-
due of
pose tothe
thestudy
highwas demand, which
to exhibit is attributed
the sensibility to its pathogenic
of several ornamental natureisolated
bacteria [116]. fromAs a plant
the
thatclinic,
is usedlikeingram-positive strains (Bacillus
various treatments, subtilis,
O. basilicum can Clostridium
help in casesperfringens, C. chauvoei,
of cerebral strokes, hy-
Enterococcus
pertension, faecalis,
diabetes, S. lipid
aureus)disorders,
and gram-negative (E. coli, Klebsiella
alcohol intoxication pneumonia,
[117], anxiety, P. aer-
cardiovascular
oginosa,
diseases, S. typhi, S. typhimirium,
headaches, nerve pains,Xanthomonas campestris)and
anti-convulsing on anti-inflammatory
the action of the O. basilicum
coughs, colds,
with honey [115].
migraines, menstrual cramps, and sinusitis [118]. O. basilicum also has carminative, galacta-
A member
gogue, of the Lamiaceae
anti-plasmonic [119], andfamily,
hemolytic O. basilicum, has been extensively
activity. Additionally, it is also grown
used inand anorexia,
used in worldwide cuisine for its aromatic taste and flavour
earache, colic, kidney problems, dysentery, dizziness, gonorrhoea, insomnia, [115]. Originally, O. basilicum
gum ulcers,
has been
piles, grown inand
paralysis, tropical
nauseaand [117].
subtropical regions,
A number ofencompassing
infections caused almost by150 species.
various The are
bacteria
Ayurvedic system from India is considered representative of its healing
complicated to treat because most antibiotics are ineffective due to drug resistance. In properties. From
aunderdeveloped
sales and businesscountries,
point of view, the O. basilicum
antibiotics are costly, plant’s sales
and the havetonaturally
need establishincreased
new, cheaper
due to the high demand, which is attributed to its ornamental nature [116]. As a plant that
medications is imperious. Natural products come in handy, being recognised as safe
products in numerous countries. Developing natural-based pharmaceutical products has
become of great interest to researchers [117].
The studies [115] revealed that the combined effect of honey with plants, in this case,
O. basilicum, showed synergism. It was observed that by increasing the honey concentra-
tion, the antibacterial effect was substantially enhanced. Salmah et al. [120] reported the
synergism between O. basilicum and honey against cutaneous wound healing in rats. The
results of the study showed that adding plant extracts improved the healing process. In
a similar study, it was discovered that honey has superior antimicrobial activity against
Clerodendrum myricoides when compared to C. albicans [115].
This synergic antibacterial effect can be highly efficient in treating infested injuries and
can be utilized as a prospective antimicrobial. Furthermore, by knowing the mechanisms
and identifying the components within the honey or basil oils, additional studies must
be done to find the response for the synergic effects. The method of assigning the exact
mechanism of synergism between honey and O. basilicum can be carried out to treat infected
wounds and other bacterial infections [115].
Rezvani et al. [121] also investigated the synergic effect by evaluating the antibacterial
activity of honey and cinnamon against S. mutans. In addition, studies have shown that
S. mutans is the primary bacteria causing dental caries. The study aimed to develop
antibacterial agents that affect S. mutans and could inhibit plaque development on tooth
surfaces. The interest of researchers in alternative medicine, strictly in using herbal extracts,
has increased recently. Further, numerous studies have reported substantial antibacterial
activity for plants and natural antibiotics against S. mutans [122–124]. In addition, the
antimicrobial capacity of honey has been intensively studied. Still, no data are available
regarding the effects of the mixture of cinnamon and honey against cariogenic bacteria [121].
The combination of different plant extracts against the target bacteria would ensure
the exposure of the pathogens to chemicals, which could lead to totally intensified activ-
ity [125,126]. Therefore, it was discussed that the combined treatment with honey and
some plants displayed a significant synergism against bacteria compared to their natural
extracts [127]. For example, honey and cinnamon extracts are powerfully effective against
S. mutans, and it can be implied that their combination would be more productive [121].
Furthermore, mixing another plant like ginger has proven honey’s synergistic an-
tibacterial properties. Ahmed et al. [128] discussed this aspect, including the synergism of
honey and ginger against bacterial strains like E. coli and S aureus. Similarly, the study also
demonstrated that the extracts of honey and ginger have the potential to serve as antibacte-
rial agents for drug-resistant bacterial strains. In conclusion, it can be stated that neither
honey nor ginger hurts human tissues. They could be safely integrated into oral products
to prevent caries formation. Additionally, the synergism of both agents would have a
considerable therapeutic effect against S. mutans [129]. Table 2 presents some information
regarding the synergic effect of honey on other compounds.
Table 2. Synergic effect of honey with other natural products.
No. Natural Products Key Features References

It has been shown that there is synergic antimicrobial
activity between raw garlic extract and honey, but the
antioxidant activity of the mixture is lower than that of
1 garlic raw extract [98]
A. sativum. Moreover, the mix of honey–A. sativum
extract presented increased wound healing capacity
compared to Euphorbia honey.
The mixture of garlic extracts and Tengen honey has
significant sensitivity against Gram-positive and
2 garlic [102]
Gram-negative bacteria, which leads to their potential
to treat infectious diseases.
Table 2. Cont.
No. Natural Products Key Features References

Mixing Medihoney and rifampicin against laboratory
and clinical strains of S. aureus, including MRSA
strains, demonstrated a good synergism effect.
3 rifampicin [105]
Also, results support the potential of combining
Manuka honey and antibiotics in treating S.
aureus-related skin infections.
The combined effect of honey and plants showed
synergism. This fact is explained by the antibacterial
4 basil effect that can be extremely useful in treating infested [115]
lesions and can also be used as a potential
antimicrobial.
The synergic effects of honey combined with the
alcoholic extract of O. basilicum appeared to have
5 sweet basil [120]
essential properties that made it useful as a wound
dressing.
The study reveals that cinnamon could improve
6 cinnamon [121]
honey’s antibacterial effect against S. mutans.
In vitro data from this study shows antimicrobial
activity has a synergic effect by combining ginger and
honey against bacterial cells isolated from carious teeth.
This investigation suggests that a paste made by
7 ginger [127]
blending ginger and honey could be used as a
mouthwash in treating dental caries, mouth sores, and
sore throats and could be incorporated into toothpaste
to prevent dental caries.
Results confirmed that ginger strongly improves the
MIC of honey, thus letting hope for a honey benefit and
8 ginger [128]
would constitute an alternative way against the
resistance to bacteria.
4. Mechanisms of Action and Biological Activity of Honey

The present section refers to the biological activity of honey and its mechanisms of action
due to its bioactive constituents [130]. This product can be an immunomodulatory agent
due to its anti-inflammatory and antioxidant activity [131,132], and it stimulates the prolif-
eration of T and B lymphocytes and phagocytosis. Also, honey regulates the production of
proinflammatory cytokines (tumour necrosis factor α ~ TNF-α, interleukins 1β and 6 ~ IL-1β,
IL-6) [133,134]. The immunomodulatory activity of honey is due not just to polyphenols but
also to the sugar held [135,136]. Moreover, this apitherapeutic product contains prebiotic
compounds (such as non-digestible carbohydrates and polyphenols) that improve the gut
microbiota. Furthermore, honey contains probiotics, which play an essential role in gut health.
As seen in Figure 3, honey develops an interdependence and synergic effect between all
biological activities and boosts the immune system and health [130,137–139].
Kowalska et al. [140] demonstrated for the first time that using bee products encap-
sulated with arabinoxylans isolated from the rye bran could significantly ameliorate the
inflammatory response in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages, de-
creasing the secretion of IL-6, TNF-α and nitric oxide (NO). For the encapsulated core, it
has been made with honey and royal jelly. Moreover, the honeydew honey microcapsules
exhibited significantly more antioxidant activity than native honeydew honey. In the case
of the royal jelly, it was quite the opposite. The antioxidant activity was not different from
the native royal jelly. Therefore, the authors showed that using bioactive heteropolysac-
charide carriers to encapsulate honey and royal jelly to develop innovative platforms with
controlled release of bioactive compounds with potential immunomodulatory properties.
Antioxidants 2023,
Antioxidants 2023,12,
12,34
34 11 of 32 11 of 30
Figure 3. Graphic representation of the immunomodulatory mechanism of honey. The figure was
designed
Figure with ConceptDraw
3. Graphic representationDiagram 16.
of the immunomodulatory mechanism of honey. The figure was
designed with ConceptDraw Diagram 16.
5. Antimicrobial Activity
Kowalska
Kwakman et al. [140]
et al. [141]demonstrated
suggested that for the antibacterial
first time thatactivity
using bee products
of honey encap-
against B. subtilis,
sulated with
S. aureus arabinoxylans
MRSA, isolated from the rye
E. coli, ciprofloxacin-resistant bran couldand
P. aeruginosa, significantly ameliorate the
vancomycin-resistant E. faecium
inflammatory response in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages,
depends on H2 O2 , sugar, methylglyoxal, and bee defensin-1. The mechanisms of action de- de-
creasing
pendingtheonsecretion
the type of of honey
IL-6, TNF-α and nitric
and strains. oxide (NO).
For example, For the encapsulated
in another study, Kwakman core,etital. [142]
has been made with honey and royal jelly. Moreover, the honeydew honey microcapsules
showed that the antibacterial activity of manuka honey against S. aureus and B. subtilis de-
exhibited
pends on significantly
methylglyoxal moreand antioxidant activity than
several unknown native
factors or honeydew
compounds honey.
(suchInasthe case
polyphenols).
ofIn
the royal jelly, it was quite the opposite. The antioxidant activity was not different
addition, the antimicrobial activity is due to the low pH, osmotic stress (high sugar content), from
the
andnative royal jelly.
the presence of Therefore,
enzymes that the produce
authors showed
hydrogen that using bioactive
peroxide [143]. heteropolysac-
charideHenriques
carriers to encapsulate honey and royal jelly to develop innovative
et al. [144] reported the bactericidal activity of manuka platforms
honeywithagainst
controlled release of bioactive compounds with potential immunomodulatory properties.
S. aureus strains. According to TEM analysis, structural changes were observed in honey-
treated cells. Honey determined an inhibition in cell growth, altered the cell cycle, and
5. Antimicrobial Activity
accumulated with fully developed septa at cell division without separating. In another
studyKwakman et al. [141]
[145], enlarged suggested
cells that septa
containing the antibacterial activity of honey
in methicillin-resistant against
S. aureus B. sub-
were observed
tilis, S. aureus MRSA, E. coli, ciprofloxacin-resistant P. aeruginosa, and vancomycin-re-
when treated with manuka honey, which suggested the interruption of cell division. More-
sistant E. faecium depends on H2O2, sugar, methylglyoxal, and bee defensin-1. The mech-
over, this study shows that these changes were due to other antibacterial compounds, not
anisms of action depending on the type of honey and strains. For example, in another
sugars or methylglyoxal.
study, Kwakman et al. [142] showed that the antibacterial activity of manuka honey
In particular, manuka honey inhibits P. aeruginosa by destabilizing the cell membrane
against S. aureus and B. subtilis depends on methylglyoxal and several unknown factors
and downregulating a structural protein (OprF), which maintains the cell shape and stabil-
or compounds (such as polyphenols). In addition, the antimicrobial activity is due to the
ity [146,147]. The
low pH, osmotic stress (highSEM andsugar
TEMcontent),
images indicate the presence
and the presence of artefacts
of enzymes and abnormal
that produce
cells in P. aeruginosa,
hydrogen peroxide [143]. which suggests cell disruption and lysis. The honey has a mod-
erate on P. aeruginosa,
Henriques et al. [144] reported the bactericidal activity of manuka honey against S. as for
antibacterial activity doesn’t act with a similar mechanism
S. aureus,
aureus strains. andAccording
produces to different structural
TEM analysis, changeschanges
structural [146]. Awere
recent study [148]
observed shows that
in honey-
antibacterial activity against P. aeruginosa
treated cells. Honey determined an inhibition in cell growth, altered the cell cycle, and Thus,
manuka honey’s has multiple pathways.
Bouzo et al.with
accumulated [148]fully
demonstrate
developed that the antimicrobial
septa at cell divisionactivity
without of separating.
Manuka honey cannot be ex-
In another
plained
study only
[145], by the methylglyoxal
enlarged cells containingpresence.
septa in Manuka honey induces
methicillin-resistant severalwere
S. aureus transcriptional
ob-
changes
served when and affectswith
treated many biological
manuka honey, processes (plasmid,the
which suggested antibiotic resistance,
interruption adaptation,
of cell divi-
andMoreover,
sion. protectionthis arestudy
upregulated).
shows that Furthermore,
these changes other
werefunctions are overexpressed
due to other antibacterial com- by honey,
such asnot
pounds, thesugars
transport of molecules, RNA processing and degradation, nucleotide biosynthe-
or methylglyoxal.
sis, membrane proteins, metabolism, DNA replication, cell wall degradation, biosynthesis
of cofactors, etc. Protein secretion, fatty acid metabolism, amino acid biosynthesis, and
metabolism are downregulated by manuka honey’s action.
al. [148] demonstrate that the antimicrobial activity of Manuka honey cannot be explained
only by the methylglyoxal presence. Manuka honey induces several transcriptional
changes and affects many biological processes (plasmid, antibiotic resistance, adaptation,
and protection are upregulated). Furthermore, other functions are overexpressed by
honey, such as the transport of molecules, RNA processing and degradation, nucleotide
biosynthesis, membrane proteins, metabolism, DNA replication, cell wall degradation, bi-
osynthesis of cofactors, etc. Protein secretion, fatty acid metabolism, amino acid biosyn-
thesis, and metabolism are downregulated by manuka honey's action.
TheThe manuka
manuka honey
honey damages
damages thethe cytoplasmatic
cytoplasmatic membrane
membrane bybydepolarisation.
depolarisation. AsAs such,
such,
the the collapse
collapse of the
of the proton
proton motive
motive force
force andand membrane
membrane permeabilizationcan
permeabilization canbebeanother
an- key
other keyantibacterial
to the to the antibacterial
activityactivity of manuka
of manuka honeyhoney
[148].[148]. The physiological
The physiological changes
changes associated
associated with membrane
with membrane polarization
polarization and integrity
and integrity are presented
are presented in a in a recent
recent study
study [149].
[149]. Similarly,
Similarly,
avocado, avocado, chestnut,
chestnut, and polyfloral
and polyfloral honeyhoney
induce induce the same
the same effects
effects on S.onaureus
S. aureus
and E. coli,
and E. coli, especially
especially membrane membrane
damage. damage.
The relationship between mechanisms
The relationship between mechanisms of action and activity
of action is correlated
and activity with honey
is correlated with honey
type, chemical composition, concentration, physical properties (pH, water
type, chemical composition, concentration, physical properties (pH, water content, content, etc.), etc.),
andandstorage
storageconditions [149,150],
conditions as highlighted
[149,150], in Figure
as highlighted 4.
in Figure 4.
Figure
Figure 4. Antimicrobial
4. Antimicrobial mechanisms
mechanisms of of honey.The
honey. Thefigure
figurewas
wasdesigned
designedwith
withConceptDraw
ConceptDrawDia-
Diagram 16.
gram 16.
Maeda et al. [129] have conducted a study regarding the antibacterial activity of
honey against
Maeda et al.community-associated
[129] have conducted methicillin-resistant
a study regarding the S. aureus (CA-MRSA),
antibacterial activitydescribing
of
the therapeutic
honey effect of honey onmethicillin-resistant
against community-associated skin and soft tissue infections.
S. aureus Lately, describ-
(CA-MRSA), it has been ob-
ingserved that methicillin-resistant
the therapeutic S. aureus
effect of honey on skin and (MRSA) has appeared
soft tissue infections.within
Lately,healthcare
it has beenfacilities,
observed that methicillin-resistant
particularly S. aureus
hospitals. Additionally, it (MRSA)
has beenhas appearedthat
reported within healthcare
S. aureus MRSA facil-
occurred
ities, particularly
among hospitals. Additionally,
healthy individuals it has been They
without hospitalisation. reported thatdifferent
are very S. aureusfrom
MRSAhealthcare-
associated MRSA (HA-MRSA). This community-associated methicillin-resistant S. aureus
(CA-MRSA) is usually associated with severe skin and soft tissue infections, particularly in
young, healthy individuals and those with no risk factors for the acquisition of S. aureus
HA-MRSA. Further research still needs to be conducted to indicate that this antimicrobial
activity has clinical application [151].
In other research, Ghramh et al. [152] also considered the antibacterial potential of three
honey samples collected from the Saudi region against pathologic bacteria. The purpose of
the study was to evaluate the antibacterial activity of Sider (Ziziphus spina-christi), Dharm
(Lavandula dentata), and Majra (Hypoestes forskaolii) honey samples collected from the Asir
region of Saudi Arabia and investigate in vitro the antibacterial activity of these honey samples
against E. coli, Proteus mirabilis, S. aureus, S. flexneri, and S. epidermidis. Results confirmed
that Dharm and Sider honey samples showed better antibacterial activity than majra honey.
Further, Saudi honey can be considered a promising future antimicrobial agent. It should be
investigated as an alternative for managing resistant bacterial pathogens [153,154].
The increasing resistance to antifungal drugs has prompted the need to evaluate new
antifungal compounds with fewer side effects. Drug resistance and honey have attracted
attention mainly for their potential antifungal effects. This study presents the antifungal
activity of four types of honey from Algeria, which were tested against pathogenic yeasts such
as C. albicans and Rhodotorula sp. Among commensal organisms, C. albicans, a polymorphic
fungus, was investigated due to the significant damage caused by inhabiting the oral, vaginal,
and gastrointestinal mucosa. The results of in vitro studies confirmed that it could inhibit the
growth of many species of Rhodotorula sp., but no effect was reported on C. albicans [39]. Similar
studies have reported the behaviour of C. albicans at a microscale level after treatment with
Euphorbia hirta L. leaf extract. Results found multiple irregularities concerning morphology,
lysis, and yeast cell disintegration. The control cultures showed normal morphology for
Candida sp., with uniform density, a structured nucleus, and an endomembrane cytoplasm
with a regular, intact cell wall. In conclusion, the study suggested innovative approaches
to developing appropriate anticandidal agents for human infections [155,156]. Additionally,
C. albicans and Rhodotorula sp. were investigated due to venous catheter-associated illness
and fungemia. The results show that using a specific antifungal therapy may increase the
survival chances of hospitalized patients and, most importantly, reduce the cost of health
care, morbidity, and mortality [157,158]. Regarding the in vitro antifungal activity of lavender
honey, Estevinho et al. [38] observed that honey stops the growth of C. albicans, C. krusei, and
Cryptococcus neoformans. The authors reported that the biological activity of lavender honey
was typically credited to the phenolic compounds. The phenolic antimicrobial mechanism is
related to their potential to denature proteins [38].
In recent times, one of the most crucial challenges in medicine is fighting antibiotic
resistance against a broad spectrum of infections caused by different pathogenic agents. Due
to intensive progress and scientific advances, research has given birth to nanotechnology,
an intelligent and innovative alternative that could solve problems related to microbial
resistance. Consequently, nanomaterials and nanoparticles are successfully used in various
applications in medicine and pharmaceuticals [159]. Silver nanoparticles synthesised using
plant extracts have been chosen because they have promising applications in fields like drug
and gene delivery, biological sensors, catalysts, electronics, energy storage, antimicrobial
protection, and biomedical treatments [160]. Therefore, it is used as a cytotoxic agent against
cancer cells [161]. In recent years, honey has attracted attention as a mediator in silver
nanoparticles’ green synthesis to treat various health disorders. Honey is a natural product
with an active function in the inhibition process for many pathogenic organisms because it is
described as having essential active compounds such as flavonoids, glycosides, and phenolic
acids. As in many studies that confirmed the efficacy of silver nanoparticles against many
perturbing factors, silver nanoparticles were produced by using Tualang honey in Malaysia as
a stabilizing agent [162]. This study reveals the potential of honey from two different floral
sources (Ziziphus spina-christi and Acacia gerrardii) as biogenic mediators for silver nanoparticle
synthesis to evaluate their antioxidant, cytotoxic, and antibacterial properties. This ultimately
indicates that synthesizing silver nanoparticles using bee’s honey is an effective agent in
some biomedical applications. Moreover, Ag has proven to suppress microbially and cell
growth; biogenic AgNPs were cytotoxic against HepG2 cells and antibacterial against S. aureus,
P. aeruginosa, and E. coli. AgNPs showed a high antioxidant capacity with repercussions on
suppressing microbial and HepG2 cell growth [163].
The high sugar content of honey influences the growth of most microorganisms, but
even diluted honey solutions still have important antimicrobial properties that are often
higher than those of sugar solutions. Since the 1960s, H2 O2 production has been an essential
aspect of the biological activity in honey [164]. H2 O2 is produced when glucose oxidase,
secreted from the pharyngeal glands of the bee and presented in honey, reacts with water.
While glucose oxidase may vary in different kinds of honey, many types of honey are
generated. H2 O2 is at the proper level to kill microorganisms. A specific Leptospermum
honey from Australia and New Zealand exhibits “extra” antimicrobial properties due
to the volatile parts of the floral compounds [165]. This mystery regarding the “extra”
antimicrobial activity of Leptospermum honey has not been identified yet [166,167]. The
research on the honey samples revealed unique, unusual antibacterial activity due to newly
identified compounds. The study on broad-spectrum bacteria showed that antibacterial
activity has the same effectiveness against antibiotic-resistant pathogens. Results also
confirmed that honey positively affects tissue growth and stimulates wound healing [168].
6. Antioxidant Activity
An antioxidant is a substance that, at low concentrations, interrupts or prevents
substrate oxidation and acts through mechanisms such as single electron transfer, hydrogen
atom transfer, or chelating transition metals [169].
In the organism, oxidative stress is a complex process represented by the imbalance
between the production of free radicals and the capacity to eliminate them with endoge-
nous (enzymes, bilirubin, albumin) and exogenous antioxidants (phenolic compounds,
carotenoids, vitamins, etc.). The reactive oxygen species (ROS), such as superoxide radical
anion, hydrogen peroxide, etc., are the promoters in the metabolic processes. Any excess
ROS can determine several pathologies [170]. Honey can be considered an exogenous
antioxidant due to its chemical composition, especially for phenolic compounds [171].
The honey’s mechanisms of antioxidant activity could involve glutathione reductase
(GR), vitamin C (Vit. C), beta-carotene, uric acid, hydrogen donation, metallic ion chelation
(MIC), or free radical removal (FRR). Additionally, honey reduces ROS and stimulates
biomolecules (nucleic acids, proteins, carbohydrates, lipids, etc.) [28,41]. Furthermore, the
antioxidant activity of honey depends on the botanical source, and darker honey has more
antioxidants than lighter honey [172–174]. In Table 3, the effects of honey administration
can be seen.
Table 3. Honey mechanism of action.
No. Type of Bee Product Mode of Administration Effects of Honey References
honey (from the lime tree, ↑ (high) β-carotene

Oral administration of 1.2 g ↑ GSH (glutathione)
1 chestnut, rapeseed, [175]
honey/kg body ↑ vitamin C
eucalyptus, and heather) ↑ uric acid
↑ serum vitamin C, iron, and copper levels
↑ β-carotene
↑ uric acid
↑ GSH
↑lymphocyte and eosinophil %
Oral administration of 1.2 g
↓ (low) liver enzymes (AST—aspartate
2 honey honey/kg body weight (7 men [176]
aminotransferase, ALT-alanine
and 3 women) for 2 weeks aminotransferase)
↓ serum Ig E (imunoglobulin E)
↓ lactic acid dehydrogenase
↓ creatinine kinase
↓ monocytes up to 50%
in vivo induced liver injury
3 honey-pollen mix through oral administration of ↑ TBARS (thiobarbituric acid reactive substance) [177]
↓ GSH in liver
acetaminophen on mice
↑ CAT (catalase), GR (glutathione reductase),
Oral administration of honey
4 honey TAS (total antioxidant status) and GSH for [178]
combined with metformin or honey combined with metformin or
glibenclamide on rats
glibenclamide
0.2, 1.2 and 2.4 g honey/kg ↑SOD (superoxide dismutase)
5 honey body weight/day -oral ↓ TAS, CAT, GPx (glutathione peroxidase), GR [179]
administration on rats and GST (glutathione S-transferase)
Intravenous administration (2 g
6 honey honey/kg body weight of ↑ NO (nitric oxide) levels [176]
sheep)
Oral administration of 1.5 g/kg
or 0.75 g honey/kg body ↑ ROS levels in athletes that consumed 1.5 g
7 Tualang honey [180]
weight on two groups of honey/ kg body
woman athletes
↓ body weight, total cholesterol, low-density
Oral consumption: 1, 1.5 and 2 lipoprotein cholesterol, and triglyceride
8 honey [181]
g/kg/day for every 2 weeks ↑ high-density lipoprotein-cholesterol,
haemoglobin A1c
“↑”-high and “↓”-low quantity.
Quantifying honey’s quality, composition, and antioxidant capacity must be consid-

ered, which depends entirely on the floral source from which the nectar was collected,
season, processing, and environmental factors [182]. These factors may also influence the
composition of the honey and its antioxidant capability. It is well known that free radicals
cause oxidative stress, which might lead to many disorders such as cancer formation,
inflammation, ageing, the progression of diabetes, cardiovascular diseases, weakening of
the immune system, degenerative diseases of the nervous system, heart and lung diseases
and cataracts also [60]. Living in the age of technology has encouraged humans to consume
healthier foods, especially those rich in natural antioxidants, which may prevent and treat
chronic disorders. These natural antioxidants can fight against free radicals, and honey is
the most appropriate natural food rich in antioxidants [76,183].
Honey has antimicrobial, antiviral, antiparasitic, anti-inflammatory, antimutagenic,
anticancer, and immuno-suppressive actions [184]. The therapeutic techniques using
bee products to protect and strengthen the immune system are called apitherapy. Since
honey is the most important natural product rich in minerals, proteins, vitamins, phenolic
compounds, and other essential acids, it has been intensively used in these techniques [185].
The main goal of this study was achieved, and the antioxidant capacity of several mono-
floral honeys from Turkey has been proven [60].
7. Anti-Inflammatory Activity
Inflammation is the immune system’s response triggered by dangerous factors, such
as pathogens, tissue injury, toxic compounds, irradiation, etc., which can induce acute
or chronic inflammatory processes [186]. In response to tissue damage, the organism
initiates a chemical signalling cascade, which activates leukocyte chemotaxis and cytokine
production [187]. Otherwise, inflammation is a defence mechanism for the organism. It
is a critical element in the pathological progression of many diseases [186,188]. Also, the
human body’s oxidative stress and inflammation processes are associated with multiple
signalling pathways [189]. Moreover, ROS production leads to inflammation and the release
of cytokines in the damaged tissue [190].
The anti-inflammatory activity of honey is due to the phenolic compounds [191]. The
bioactive compounds of the honey act by downregulating the inflammatory transcrip-
tion factors or by controlling the production of cytokines and inflammatory mediators:
prostaglandin E2 , cyclooxygenase-2 (COX-2), tyrosine kinase, and ornithine decarboxylase
(ODC) [131,132,136]. Similarly, honey stimulates the antioxidant capacity of cells. It inhibits
the inflammatory response by downregulating nuclear factor-kB (NF-kB), NLR3 inflamma-
some, and mitogen-activated protein kinases (MAPK) signalling and upregulating AMPK,
nuclear factor erythroid 2 (Nrf2), antioxidant response element (ARE), heme oxygenase-1
(HO-1), and interleukin-10 (IL-10) [192].
A recent study identified a new bioactive compound in honey: vesicle-like nanoparti-
cles (H-VLNs), which contain proteins, lipids, and small-sized RNAs [193]. The adminis-
tration of H-VLNs inhibited the activation of NLRP 3 inflammasome and ameliorated the
mice’s inflammation and liver damage. Additionally, the H-VLNs suppressed the forma-
tion and activation of NLRP 3 inflammasome, all downstream processes like generation of
Casp1, and secretion of cytokine IL-1β and IL-18 [193].
8. Antitumor Activity
The biological properties of honey also include antitumor activity. Honey can in-
hibit the growth and proliferation of tumoral cells by regulating the cell cycle, activating
mitochondrial pathways, inducing apoptosis, permeabilizing the outer membrane, regu-
lating ROS production, reducing inflammation, and modulating angiogenesis and insulin
signalling [194,195]. Honey can be an antitumor agent due to the polyphenols and carbo-
hydrates it contains [136,194,195].
Cell death involves three phases: the induction phase, the effector phase, and the
degradation phase [196]. Additionally, cell death can be classified into three types: type I,
or apoptosis, which shows cytoplasmatic shrinkage, nuclear disintegration, chromatin

condensation, plasma membrane bleeding, and the formation of apoptotic bodies that are
degraded by lysosomes; type II, or autophagy (cytoplasmatic vacuolisation and lysosomal
degradation), and type III, or necrosis, which is characterized by the absence of phagocytosis
and lysosomes [197,198]. In general, apoptosis can be initiated by an extrinsic pathway
(death receptor) that acts within caspase 8 or by an intrinsic (mitochondrial) way through
Antioxidants 2023, 12, 34 caspase 9. Specifically, caspases 8 and 9 are converged in caspase 3, which performs 17 of 32 death
substrates. Moreover, cell death is characterized by overexpression of B-cell lymphoma
protein 2 (BCL2 ) and by an inhibitor of apoptosis (IAP) protein [199].
Honey induces apoptosis by upregulating or stimulating caspases 3, 8, and 9, Bax, p53,
Honey induces apoptosis by upregulating or stimulating caspases 3, 8, and 9, Bax,
p53, apoptoticprotease
apoptotic proteaseactivating factor11(APAF-1),
activating factor (APAF-1),γ-interferon
γ-interferon (γ-IFN),
(γ-IFN), γ-interferon
γ-interferon re- recep-
tor 1 (γ-IFNGR1), altered P13 kinase (Akt), fatty acid synthetase ligand
ceptor 1 (γ-IFNGR1), altered P13 kinase (Akt), fatty acid synthetase ligand (FasL), extra- (FasL), extracellular
signal-regulated
cellular signal-regulated protein kinase
protein (P-ERK1/2)
kinase (P-ERK1/2) expression,
expression, E-cadherin
E-cadherinexpression,
expression,antioxidant
an-
response
tioxidant element
response 6 (ATF6),
element X-box
6 (ATF6), binding
X-box binding proteins
proteins 1 1(XBP1)
(XBP1)andand cytochrome
cytochrome C. C. Addi-
tionally, honey
Additionally, honey acts
actsby
bydownregulating/ inhibiting
downregulating/ inhibiting nuclear
nuclear protein
protein Ki67Ki67 labelling
labelling in- index
dex(Ki67-LI),
(Ki67-LI),BCL
BCL 2 ,2,iNOS,
iNOS,COX-2,
COX-2, estrogen (E2), estrogen
estrogen (E2), estrogenreceptor
receptor11(ESR1),
(ESR1),insulin
insulin re-receptor
substrate
ceptor (IRS-1),
substrate (IRS-1), poly(ADP-ribose)
poly(ADP-ribose)polymerase (PARP),α-TNF,
polymerase (PARP), IL-1β,
α-TNF,IL-1β, IL-6,
IL-6, gelatinase,
gelati-
protease,
nase, MAPK,
protease, MAPK, NF-kB,
NF-kB,anan
inhibitor
inhibitorofofkappa
kappaB B(1(1kBa),
kBa),cyclin-dependent
cyclin-dependent kinasekinase (CDK2
and 4),
(CDK2 andhuman
4), humanepidermal
epidermal factor
factorreceptors
receptors(EGFR,
(EGFR,HER2), p-retinoblastoma(p-RB),
HER2), p-retinoblastoma (p-RB), Kras
gene
Kras expression,
gene expression, mammalian
mammalian target of rapamycin
target of rapamycin(mTOR) gene expression,
(mTOR) malondialde-
gene expression,
malondialdehyde
hyde (MMP 2 and (MMP 9),2glutathione
and 9), glutathione S-transferase
S-transferase (GST),(GST), superoxide
superoxide dismutase
dismutase (SOD) and
(SOD) and catalase (CAT) [28,194,200–206]. A summary of the mode
catalase (CAT) [28,194,200–206]. A summary of the mode of action of honey’s bioactiveof action of honey’s
bioactive compounds
compounds as antitumor
as antitumor agentsagents is represented
is represented in Figure
in Figure 5. 5.
Figure
Figure 5. Antitumor
5. Antitumor effects
effects of honey’s
of honey’s bioactive
bioactive compounds.
compounds. The The figure
figure was was designed
designed withwith
Con-Concept-
ceptDraw Diagram16.
Draw Diagram 16.
9. Wound
9. Wound Healing
Healing Activity
Activity
The
The wound-healing
wound-healing process
process is complex,
is complex, and theandmechanisms
the mechanisms
involvedinvolved have multiple
have multiple
pathways.
pathways. As explained
As explained aboveabove and represented
and represented in 6,
in Figure Figure
honey6,inhibits
honey the
inhibits
growththe
ofgrowth
of pathogens,
pathogens, stimulates
stimulates the immune
the immune cells, regulates
cells, regulates cytokines
cytokines and ROS andproduction,
ROS production,
and and
stimulates thethe
stimulates wound
woundrepair processes
repair by accelerating
processes re-epithelization.
by accelerating Furthermore,
re-epithelization. Furthermore,
honey’s bioactive
honey’s compounds
bioactive compounds accelerate collagen
accelerate matrix
collagen production
matrix [207]. [207].
production
023, 12, 34
Figure 6. Potential of honey as a wound healing agent. The figure was designed with ConceptDraw
Figure 6. Potential of honey as a wound healing agent. The figure was designed with ConceptDraw Diagram 16.
Diagram 16. “↑”-high and “↓”-low quantity.
Figure 6 describes the effects of honey on the stages of wound repair and their im-
portant cellular mechanisms. Wound healing is usually divided into 4 steps: haemostasis,
inflammation, proliferation, and remodelling. During the first step, in the haemostasis
phase, activated platelets are blockers to impede bleeding and help fibrin matrix formation.
The two most crucial roles of platelets are to inhibit bacterial infection and to recruit immune
cells [208,209]. The inflammation happens as a defence mechanism against pathogenic
wound invasion. After the injury, neutrophils are engaged in removing necrotic tissue from
the wound, releasing ROS and other enzymes. Like neutrophils, macrophages also elimi-
nate necrotic cellular remains and promote inflammation by releasing ROS, cytokines, and
growth factors [210,211]. During the proliferation phase of wound healing, keratinocytes
migrate onto the wound to restore the epidermal layer. Fibroblasts replace the previous
fibrin matrix with granulation tissue. Still, most significant new blood vessels are devel-
oped during angiogenesis and proliferative wound healing. Macrophages and regulatory
T cells are essential and vital for wound healing [212–215]. The remodelling process is
characterized by anti-inflammatory macrophages, myofibroblasts, fibroblasts, collagen
fibrils, and keratinocytes, which restore wound healing [215,216].
The bodies of children are more vulnerable to injuries and wounds, so they are sus-
ceptible to nasty infections. Therefore, there should be consideration of proper antiseptic
modalities to prevent and treat diseases and disorders. New antibiotics must be developed,
but resistance can be generated quite quickly, so many researchers have become reticent
about their development [168,217,218]. As we all know, honey is used for its antimicrobial
and wound-healing properties. Still, medical-grade Manuka honey (MGH) was developed
to provide insurance and efficacy for clinical applications. Additionally, MGH must fulfil
some requirements, such as killing endospores, being pollutant-free (pesticides, heavy

metals, etc.), and having rigorous quality processing and storage standards and regula-
tions. Further, MGH acts as an antimicrobial agent and decreases the risk of developing
antimicrobial resistance. It must be noted that all of the honey’s constituents play essential
roles in antimicrobial activity. Still, significant antimicrobial activity is shown where the
higher concentration of polyphenols is presented. Flavonoids, acting as antimicrobials,
induce diverse mechanisms such as DNA inhibition, cytoplasmic membrane, and energy
metabolism [219]. The most important feature of the MGH is preventing pathogens from
invading the infection. Finally, MGH is also confirmed to be successful in its application to
wounds such as traumatic injuries, burns, hematomas, pressure ulcers, diabetic foot ulcers,
lacerations, and skin tears [220–223].
Next, another example of honey’s biological and therapeutic properties in wound healing
will be presented. After many years of studying honey for its medical applications, its
essential role in wound healing has been clarified. Additionally, after reviewing honey’s
mechanisms of action and therapeutic properties in wound healing, clinical trials are the
next step in recovery. Laboratory studies have compared honey with hydrofiber silver or
silver sulfadiazine; still, honey was more effective in eliminating microbial contaminants and
promoting re-epithelialization [37]. For example, a study explored the systemic pathology of
diabetic wounds with the beneficial help of using honey during the regeneration process [224].
Further, animals are also crucial for wound healing; as a result, the first study was reported in
Algeria regarding the use of honey for cutaneous wound healing in horses [225].
The presence of the organic compound 5-hydroxymethylfurfural (HMF) may con-
tribute to honey’s toxicity or not; therefore, its presence in honey or other foods must be
thoroughly investigated [226]. However, HMF is not naturally formed in honey or other
food products [227]. While honey contains water, sugars, and other compounds, due to
inadequate storage conditions (high temperature, metallic containers, etc.), HMF could be
formed. The honey sugar degradation at high temperatures through the Maillard reaction
led to HMF production [228]. Therefore, to ensure honey’s freshness and safety parameters,
there have been standards and regulations that set the maximum limit for HMF in honey
at 40 mg/kg [229,230]. Nevertheless, HMF presence in honey due to heat treatment or
extended storage may enhance HMF production, which might have negative effects on
human health, such as mutagenicity, hepato- and renal toxicity, chromosomal aberrations,
and irritation of the mucous membranes of the skin, eye, and respiratory tract [231,232].
Although there is new research on HMF’s widely positive effects on humans, such
as anti-inflammatory [233], antioxidant [234], and antiallergic [235] are some effects that
highlight the negative and positive nature of HMF on human health. Another important
aspect that has to be investigated is the HMF effect on the honeybee. Among the studies
presented in the literature, authors established that using HMF-food supplements has
caused dysentery, intestinal ulceration, and even bee death [236]. Therefore, in addition to
the presented information on the negative effects of HMF on humans and honey and the
further use of honey in wound healing applications, extensive research must be considered
to establish an adequate formation and usage of HMF in honey [226].
10. Preclinical and Clinical Trials Using Honey and Honey-Based Products
As already stated in this review, honeybees are effective agents in wound healing. Thus,
it is used in the development of wound-healing dressings. It has started to be intensively
harvested in developing countries, mainly used in wound dressings. The Faculty of
Medicine from Egypt has conducted a clinical test [237] that implied the utilisation of
honey dressings on patients with infected diabetic foot wounds. The treatment involves the
application of honey to the patient’s wounds for three months until healing occurs when
the grafting treatment fails. There were significant changes noted within the foot wounds.
The bacterial load was reduced after the first week of treatment, and complete healing was
observed in 43.3% of ulcers. Still, it has to be mentioned that failure was observed in 6.7%
of cases of ulcers. After finishing the trials, studies demonstrated that honey dressings are a
good candidate for the treatment of patients with diabetic foot wounds. Most importantly,
it has proven safe, cost-effective, and clinically effective.
Another experiment [238] also proved honey’s medicinal purpose. The study uses
honey for split-thickness skin graft fixation, primarily due to its adhesive effects. There
were eleven patients with diverse skin graft diagnoses included in the study. Based on the
results, it has been shown that honey is a very effective agent used for split-thickness skin
graft fixation, and no infection or graft rejection was observed. Since honey is a natural
agent, it can be successfully used in all skin grafts to fix split-thickness skin grafts.
Lately, honey has dramatically impacted all medical fields, especially in apitherapy, which
treats disorders with the help of bee products, including honey. The healing properties of
honey have been known since antiquity. Additionally, its various phytochemical compounds,
rich in phenols, contributed to its biological properties. A number of studies presented the
idea that antibacterial properties are due to the levels of hydrogen peroxide, glucose oxidase,
and catalase [21]. Despite that, some studies have shown that the antibacterial activity of
Manuka honey is attributed to methylglyoxal and not hydrogen peroxide [239].
Moreover, in addition to the antibacterial and antioxidant action, honey displays
extensive therapeutic properties, for example, antiulcer, anti-atherogenic, antiviral, and
anti-inflammatory [240]. Based on the evidence that somatic mutation promotes cancer
formation and is responsible for superoxide anion radicals and inflammation, the anticancer
effect of honey has recently been investigated. The studies made in this direction on animal
models and clinical trials have demonstrated that honey has anticancer activities. Cancer
is deadly, and treatments depend on the cancer stage and, unfortunately, are not 100%
successful or effective. It has been studied that the right approach against cancer should be
via chemoprevention. This new concept involves a balanced diet and a healthy life with
daily controlled consumption of honey, reducing cancer risk. Additionally, honey as a
chemo-preventive agent is defined as using natural or synthetic compounds to eliminate
the risk of developing or reoccurring cancer [241]. H2 O2 has a double feature in cancer
development. First, the higher amounts of H2 O2 are responsible for the alterations of
tumour cells. On the other hand, H2 O2 can induce apoptosis of tumour cells, which
modulates the activity of the anticancer drug [242]. Furthermore, in vitro and in vivo
studies have shown that honey’s antiproliferation activity is due to cell cycle arrest, which
includes a synergy with antitumour drugs [243].
Another promising application was the fabrication of pomegranate or honey nanofibers
for antibacterial wound dressings. The tests consisted of honey, pomegranate peel extract,
and bee venom samples used with polyvinyl alcohol to develop a novel nanofibrous wound
dressing [244]. The nanofibrous scaffolds present better properties than conventional dress-
ings due to their larger surface-to-volume ratio, higher porosity, and tiny pore size. These
advantages include better wound permeation and prevention from further infection [244].
Additionally, the use of honey in wound healing was due to its antimicrobial and anti-
inflammatory properties [245]. It has been stated that the combination of honey and PVA, a
biocompatible polymer, seems promising, and honey/PVA-based gels have better biocom-
patibility for creating burn-care dressings [246]. It has been demonstrated that pomegranate
and its peel have great potential due to their anti-inflammatory and anti-infective effects.
Pomegranate juice and its peel have significant amounts of polyphenolic compounds
such as ellagic and gallic acids, flavanols, anthocyanins, catechins, and procyanidins. The
peel possesses more polyphenolic compounds than pomegranate juice, thereby having
promising wound-healing potential. Therefore, after displaying the essential properties
of pomegranate and peel extract, it can be concluded that it could be used in designing
wound dressings [247].
Furthermore, all honey-based products derived from beekeeping, pollen and propolis
are being used for their nutritional and medicinal purposes. Still, propolis has special
interest due to its antimicrobial and antioxidant properties, which are beneficial in de-
veloping honey-based healing dressings [126,191]. Another interesting natural product
included in many wound dressings was bee venom. Venom has been the focus of many
research groups for its potent therapeutic effect in various pathological conditions ranging
from pain, rheumatic arthritis, skin diseases, and tumours. Similarly, bee venom is a
promising candidate for wound healing due to its powerful antibacterial effect and po-
tent anti-inflammatory properties [248,249]. In a study [250], pomegranate peel powder
extract and bee venom were loaded within honey/PVA nanofiber scaffolds to test their
wound healing activity in an animal model using two types of honey: manuka honey
and lyophilised multiflora honey powder. The pomegranate peel powder extract shows
significant antioxidant and antibacterial effects. The results demonstrated that it also pro-
moted wound healing, collagen regeneration, fibroblast infiltration, vascularisation, and
epithelialisation. In addition, it was reported that honey-based nanofibers presented strong
antibacterial activity against gram-positive and Gram-negative organisms. It was noted
that manuka honey was more effective than lyophilised honey against E. coli. However,
excellent antibacterial activity was also observed in lyophilised honey, suggesting a possible
synergic effect between honey and pomegranate peel powder that led to strong antibacterial
activity against E. coli. Cytotoxicity tests have shown that all scaffolds had ~100% cell
viability, indicating that the nanofibrous dressings have no significant cytotoxicity against
skin cells. In conclusion, results indicated that Manuka honey/pomegranate/bee venom
nanofibers are promising instruments for wound healing [250].
The use of honey in wound care has become more and more critical due to its proven
beneficial properties in wound healing and its antibacterial and antibiofilm properties.
Costeloe et al. [251] presented the experience of medical-grade honey with successful
outcomes in treating a cochlear implant. The results demonstrated that the patients had
complete wound closure without surgical reconstruction.
11. Conclusions
Over time, biomedical sciences have shifted attention toward honey due to its therapeutic
effects and biological properties. Recent findings confirmed that honey has antimicrobial,
antioxidant, and anti-inflammatory activities and fights against diseases from wounds to
cancer. Additionally, it has been proven that honey’s beneficial use in medical applications
is responsible for the presence of flavonoids and vitamins within it. The review highlights
how the most important content of honey is attributed to the bioactive compounds, which
include constituents such as phenolic compounds, amino acids, proteins, enzymes, lipids,
flavonoids, and vitamins and are responsible for its biological properties such as wound
healing, antibacterial, antifungal, antioxidant, and antiviral activities. The antioxidant efficacy
of honey is credited to its content of amino and organic acids, proteins, enzymes, carotenoids,
polyphenols, and especially its flavonoids and phenolic acids. Special attention was paid to the
synergic effects of the interaction of honey with other natural products containing bioactive
compounds that possess therapeutic properties and can assure a synergic result. Furthermore,
the other natural products described in this review that can be synergic with honey are garlic,
cinnamon, and basil, which have antibacterial, antioxidant, and antimicrobial activities. For
example, basil and garlic have good wound-healing properties, while cinnamon fights against
bacterial infections. On the other hand, garlic’s antioxidant and antibacterial properties
have proven their usefulness in treating infectious diseases. Another natural compound
described in this review was basil, which showed significant synergism with honey against
cutaneous wound healing in animals. The review also presented the synergic effect of honey
with cinnamon against S. mutans bacteria. Several studies in this direction have reported a
strong antibacterial effect against S. mutans that could prevent plaque formation on tooth
surfaces. As a result, research on natural products considers synergism between the plant
ingredients to benefit the maximum therapeutic efficiency. Additionally, the review focused
on the most critical applications of honey in the medical field, especially in wound care. In
conclusion, it can be stated that honey could be considered a promising instrument with
significant beneficial applications in wound healing dressings. Therefore, understanding the
therapeutic effects of honey and its essential bioactive compounds and molecular mechanisms
may provide significant insights for conducting novel approaches with applications in future
clinical trials.
Author Contributions: Conceptualization, A.S. and A.F.; methodology, A.S., C.-I.I. and, A.F.; soft-
ware, C.-I.I. and A.S., validation, A.F. and D.F.; writing—original draft preparation, A.S., C.-I.I. and
D.F.; writing—review and editing, A.S., C.-I.I., A.F. and E.A.; visualization, A.F., D.F. and E.A.; super-
vision, A.F. and E.A.; project administration, E.A.; funding acquisition, E.A. All authors have read
and agreed to the published version of the manuscript.
Funding: The APC was funded by the University Politehnica of Bucharest.
Acknowledgments: Financial contribution was provided by the Proof-of-Concept Project, funded by
the University POLITEHNICA of Bucharest.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Crane, E. The Archaeology of Beekeeping; Cornell University Press: Ithaca, NY, USA, 1983.
2. Kvavadze, E.; Gambashidze, I.; Mindiashvili, G.; Gogochuri, G. The first find in southern Georgia of fossil honey from the Bronze
Age, based on palynological data. Veg. Hist. Archaeobotany 2007, 16, 399–404. [CrossRef]
3. Lomsadze, G. Georgia, Unearths the World’s Oldest Honey. Available online: https://eurasianet.org/report-georgia-unearths-
the-worlds-oldest-honey (accessed on 6 June 2022).
4. The World’s First Winemakers Were the World’s First Beekeepers. Available online: https://guildofscientifictroubadours.com/
(accessed on 6 June 2022).
5. Pećanac, M.; Janjić, Z.; Komarcević, A.; Pajić, M.; Dobanovacki, D.; Misković, S.S. Burns treatment in ancient times. Med. Pregl.
2013, 66, 263–270. [PubMed]
6. Bresson, A. The Making of the Ancient Greek Economy; Princeton University Press: Princeton, NJ, USA, 2015.
7. Mandal, M.D.; Mandal, S. Honey: Its medicinal property and antibacterial activity. Asian Pac. J. Trop. Biomed. 2011, 1, 154–160.
[CrossRef]
8. Vallianou, N. Honey and its Anti-Inflammatory, Anti-Bacterial and Anti-Oxidant Properties. Gen. Med. Open Access 2014, 2.
[CrossRef]
9. Almasaudi, S.B.; Al-Nahari, A.A.M.; Abd El-Ghany, E.S.M.; Barbour, E.; Al Muhayawi, S.M.; Al-Jaouni, S.; Azhar, E.; Qari,
M.; Qari, Y.A.; Harakeh, S. Antimicrobial effect of different types of honey on Staphylococcus aureus. Saudi J. Biol. Sci. 2017,
24, 1255–1261. [CrossRef]
10. Yousuf, F.A.; Mehmood, M.H.; Malik, A.; Siddiqui, R.; Khan, N.A. Antiacanthamoebic properties of natural and marketed honey
in Pakistan. Asian Pac. J. Trop. Biomed. 2016, 6, 967–972. [CrossRef]
11. Alvarez-Suarez, J.M.; Tulipani, S.; Romandini, S.; Bertoli, E.; Battino, M. Contribution of honey in nutrition and human health: A
review. Mediterr. J. Nutr. Metab. 2009, 3, 15–23. [CrossRef]
12. Alvarez-Suarez, J.M.; Giampieri, F.; Brenciani, A.; Mazzoni, L.; Gasparrini, M.; González-Paramás, A.M.; Santos-Buelga, C.;
Morroni, G.; Simoni, S.; Forbes-Hernández, T.Y.; et al. Apis mellifera vs. Melipona beecheii Cuban polifloral honeys: A
comparison based on their physicochemical parameters, chemical composition and biological properties. LWT 2018, 87, 272–279.
[CrossRef]
13. Khan, F.R.; Ul Abadin, Z.; Rauf, N. Honey: Nutritional and medicinal value. Int. J. Clin. Pract. 2007, 61, 1705–1707. [CrossRef]
14. Rao, P.V.; Krishnan, K.T.; Salleh, N.; Gan, S.H. Biological and therapeutic effects of honey produced by honey bees and stingless
bees: A comparative review. Rev. Bras. Farmacogn. 2016, 26, 657–664. [CrossRef]
15. Vit, P.; Medina, M.; Eunice Enríquez, M. Quality standards for medicinal uses of Meliponinae honey in Guatemala, Mexico and
Venezuela. Bee World 2004, 85, 2–5. [CrossRef]
16. El-Kholy, W.M.; Hassan, H.A.; Nour, S.E.; Elmageed, A.Z.E.; Matrougui, K. Hepatoprotective effects of Nigella sativa and bees’
honey on hepatotoxicity induced by administration of sodium nitrite and sunset yellow. FASEB J. 2009, 23, 733.2. [CrossRef]
17. Erejuwa, O.O.; Sulaiman, S.A.; Wahab, M.S.; Sirajudeen, K.N.S.; Salleh, M.S.; Gurtu, S. Hepatoprotective effect of tualang honey
supplementation in streptozotocin-induced diabetic rats. Int. J. Appl. Res. Nat. Prod. 2012, 4, 37–41.
18. Biluca, F.C.; da Silva, B.; Caon, T.; Mohr, E.T.B.; Vieira, G.N.; Gonzaga, L.V.; Vitali, L.; Micke, G.; Fett, R.; Dalmarco, E.M.; et al.
Investigation of phenolic compounds, antioxidant and anti-inflammatory activities in stingless bee honey (Meliponinae). Food
Res. Int. 2020, 129, 108756. [CrossRef]
19. Ezz El-Arab, A.M.; Girgis, S.M.; Hegazy, E.M.; Abd El-Khalek, A.B. Effect of dietary honey on intestinal microflora and toxicity of
mycotoxins in mice. BMC Complement. Altern. Med. 2006, 6, 6. [CrossRef]
20. McGovern, D.P.B.; Abbas, S.Z.; Vivian, G.; Dalton, H.R. Manuka Honey against Helicobacter Pylori; Gastrointestinal Department,
Royal Cornwall Hospital: Cornwall, UK, 1999.
21. Somall, N.A.I.; Coley, K.E.; Molan, P.C.; Hancock, B.M. Susceptibility of Helicobacter pylori to the antibacterial activity of manuka
honey. J. R. Soc. Med. 1994, 87, 9–12. [CrossRef]
22. Kassim, M.; Achoui, M.; Mustafa, M.R.; Mohd, M.A.; Yusoff, K.M. Ellagic acid, phenolic acids, and flavonoids in Malaysian honey
extracts demonstrate in vitro anti-inflammatory activity. Nutr. Res. 2010, 30, 650–659. [CrossRef]
23. Nasuti, C.; Gabbianelli, R.; Falcioni, G.; Cantalamessa, F. Antioxidative and gastroprotective activities of anti-inflammatory
formulations derived from chestnut honey in rats. Nutr. Res. 2006, 26, 130–137. [CrossRef]
24. El-Seedi, H.R.; Eid, N.; Abd El-Wahed, A.A.; Rateb, M.E.; Afifi, H.S.; Algethami, A.F.; Zhao, C.; Al Naggar, Y.; Alsharif, S.M.; Tahir,
H.E.; et al. Honey Bee Products: Preclinical and Clinical Studies of Their Anti-inflammatory and Immunomodulatory Properties.
Front. Nutr. 2022, 8, 761267. [CrossRef]
25. Fauzi, A.N.; Norazmi, M.N.; Yaacob, N.S. Tualang honey induces apoptosis and disrupts the mitochondrial membrane potential
of human breast and cervical cancer cell lines. Food Chem. Toxicol. 2011, 49, 871–878. [CrossRef]
26. Samarghandian, S.; Afshari, J.T.; Davoodi, S. Chrysin reduces proliferation and induces apoptosis in the human prostate cancer
cell line pc-3. Clinics 2011, 66, 1073–1079. [CrossRef] [PubMed]
27. Ghashm, A.A.; Othman, N.H.; Khattak, M.N.; Ismail, N.M.; Saini, R. Antiproliferative effect of Tualang honey on oral squamous
cell carcinoma and osteosarcoma cell lines. BMC Complement. Altern. Med. 2010, 10, 49. [CrossRef] [PubMed]
28. Ahmed, S.; Sulaiman, S.A.; Baig, A.A.; Ibrahim, M.; Liaqat, S.; Fatima, S.; Jabeen, S.; Shamim, N.; Othman, N.H. Honey as a
Potential Natural Antioxidant Medicine: An Insight into Its Molecular Mechanisms of Action. Oxid. Med. Cell. Longev. 2018,
2018, 8367846. [CrossRef] [PubMed]
29. Adnan, F.; Sadiq, M.; Jehangir, A. Anti-hyperlipidemic effect of Acacia Honey (Desi Kikar) in cholesterol-diet induced hyperlipi-
demia in rats. Biomedica 2011, 27, 62–67.
30. Adewoye, E.O.; Omolekulo, T. Effect of Honey on Altered Thyroid State in Female Wistar Rats. Arch. Basic Appl. Med. 2014,
2, 63–68.
31. Roubik, D.; Vit, P.; Pedro, S. Pot-Honey: A Legacy of Stingless Bees; Springer Science and Business Media: New York, NY, USA, 2013.
[CrossRef]
32. Simone-Finstrom, M.; Spivak, M. Propolis and bee health: The natural history and significance of resin use by honey bees.
Apidologie 2010, 41, 295–311. [CrossRef]
33. Ávila, S.; Beux, M.R.; Ribani, R.H.; Zambiazi, R.C. Stingless bee honey: Quality parameters, bioactive compounds, health-
promotion properties and modification detection strategies. Trends Food Sci. Technol. 2018, 81, 37–50. [CrossRef]
34. Jalil, A.M.A.; Kasmuri, A.R.; Hadi, H. Stingless Bee Honey, the Natural Wound Healer: A Review. Skin Pharm. Physiol. 2017,
30, 66–75. [CrossRef]
35. De Queiroz Pimentel, R.B.; da Costa, C.A.; Albuquerque, P.M.; Junior, S.D. Antimicrobial activity and rutin identification ofhoney
produced by the stingless bee Melipona compressipes manaosensis and commercial honey. Complement. Altern. Med. 2013, 13, 151.
[CrossRef]
36. Vandamme, L.; Heyneman, A.; Hoeksema, H.; Verbelen, J.; Monstrey, S. Honey in modern wound care: A systematic review.
Burns 2013, 39, 1514–1525. [CrossRef]
37. Oryan, A.; Alemzadeh, E.; Moshiri, A. Biological properties and therapeutic activities of honey in wound healing: A narrative
review and meta-analysis. J Tissue Viability 2016, 25, 98–118. [CrossRef]
38. Estevinho, M.L.; Afonso, S.E.; Feas, X. Antifungal effect of lavender honey against Candida albicans, Candida krusei and
Cryptococcus neoformans. J. Food Sci. Technol. 2011, 48, 640–643. [CrossRef]
39. Moussa, A.; Noureddine, D.; Saad, A.; Abdelmelek, M.; Abdelkader, B. Antifungal activity of four honeys of different types from
Algeria against pathogenic yeast: Candida albicans and Rhodotorula sp. Asian Pac. J. Trop. Biomed. 2012, 2, 554–557. [CrossRef]
40. Alvarez-Suarez, J.M.; Tulipani, S.; Diaz, D.; Estevez, Y.; Romandini, S.; Giampieri, F.; Damiani, E.; Astolfi, P.; Bompadre, S.; Battino,
M. Antioxidant and antimicrobial capacity of several monofloral Cuban honeys and their correlation with color, polyphenol
content and other chemical compounds. Food Chem. Toxicol 2010, 48, 2490–2499. [CrossRef]
41. Erejuwa, O.O.; Sulaiman, S.A.; Wahab, A.M.S. Honey: A novel antioxidant. Molecules 2012, 17, 4400–4423. [CrossRef]
42. Man, N.N.M.; Hassan, R.; Ang, C.Y.; Abdullah, A.D.; Radzi, M.M.A.; Sulaiman, S.A. Antileukemic Effect of Tualang Honey on
Acute and Chronic Leukemia Cell Lines. Biomed Res. Int. 2015, 2015, 307094. [CrossRef]
43. Alvarez-Suarez, J.M.; Giampieri, F.; Battino, M. Honey as a Source of Dietary Antioxidants Structures, Bioavailability and
Evidence of Protective Effects Against Human Chronic Diseases. Curr. Med. Chem. 2013, 20, 621–638. [CrossRef]
44. Nascimento, K.S.; Sattler, G.J.A.; Macedo, L.L.F.; González, S.C.V.; Pereira de Melo, I.L.; da Silva Araújo, E.; Granato, D.; Sattler,
A.; de Almeida-Muradian, L.B. Phenolic compounds, antioxidant capacity and physicochemical properties of Brazilian Apis
mellifera honeys. LWT 2018, 91, 85–94. [CrossRef]
45. Kozłowska, A.; Szostak-W˛egierek, D. Flavonoids-food sources and health benefits. Rocz. Państwowego Zakładu Hig. 2014, 65, 79–85.
46. Aal, A.M.; El-Hadidy, M.R.; El Mashad, N.; El-Sebaie, A. Antimicrobial Effect of Bee Honey in Comparison to Antibiotics on
Organisms Isolated From Infected Burns. Ann. Burn Fire Disasters 2007, 20, 83–88.
47. Theunissen, F.; Grobler, S.; Gedalia, I. The antifungal action of three South African honeys on Candida albicans. Apidologie 2001,
32, 371–379. [CrossRef]
48. Al-Waili, N.S. Natural Honey Lowers Plasma Glucose, C-Reactive Protein, Homocysteine, and Blood Lipids in Healthy, Diabetic,
and Hyperlipidemic Subjects: Comparison with Dextrose and Sucrose. J. Med. Food 2004, 7, 100–107. [CrossRef] [PubMed]
49. Al-Himyari, F.A. The use of honey as a natural preventive therapy of cognitive decline and dementia in the middle east.
Alzheimer’s Dement. 2009, 5, P247. [CrossRef]
50. Othman, Z.; Zakaria, R.; Hussain, N.H.N.; Hassan, A.; Shafin, N.; Al-Rahbi, B.; Ahmad, A.H. Potential Role of Honey in Learning
and Memory. Med. Sci. 2015, 3, 3–15. [CrossRef] [PubMed]
51. Chepulis, L.M.; Starkey, N.J.; Waas, J.R.; Molan, P.C. The effects of long-term honey, sucrose or sugar-free diets on memory and
anxiety in rats. Physiol. Behav. 2009, 97, 359–368. [CrossRef]
52. Chew, C.Y.; Chua, L.S.; Soontorngun, N.; Lee, C.T. Discovering potential bioactive compounds from Tualang honey. Agric. Nat.
Resour. 2018, 52, 361–365. [CrossRef]
53. Liu, J.-R.; Ye, Y.-L.; Lin, T.-Y.; Wang, Y.-W.; Peng, C.-C. Effect of floral sources on the antioxidant, antimicrobial, and anti-
inflammatory activities of honeys in Taiwan. Food Chem. 2013, 139, 938–943. [CrossRef]
54. Mračević, Ð.S.; Krstić, M.; Lolić, A.; Ražić, S. Comparative study of the chemical composition and biological potential of honey
from different regions of Serbia. Microchem. J. 2020, 152, 104420. [CrossRef]
55. Zaidi, H.; Ouchemoukh, S.; Amessis-Ouchemoukh, N.; Debbache, N.; Pacheco, R.; Serralheiro, M.L.; Araujo, M.E. Biological
properties of phenolic compound extracts in selected Algerian honeys—The inhibition of acetylcholinesterase and α-glucosidase
activities. Eur. J. Integr. Med. 2019, 25, 77–84. [CrossRef]
56. Bilandzic, N.; Gajger, T.I.; Kosanovic, M.; Calopek, B.; Sedak, M.; Kolanovic, S.B.; Varenina, I.; Luburic, D.B.; Varga, I.; Dokic, M.
Essential and toxic element concentrations in monofloral honeys from southern Croatia. Food Chem. 2017, 234, 245–253. [CrossRef]
57. Ciulu, M.; Solinas, S.; Floris, I.; Panzanelli, A.; Pilo, M.I.; Piu, P.C.; Spano, N.; Sanna, G. RP-HPLC determination of water-soluble
vitamins in honey. Talanta 2011, 83, 924–929. [CrossRef]
58. Meo, S.A.; Al-Asiri, S.A.; Mahesar, A.L.; Ansari, M.J. Role of honey in modern medicine. Saudi J. Biol. Sci. 2017, 24, 975–978.
[CrossRef]
59. Ariefdjohan, M.W.; Martin, B.R.; Lachcik, P.J.; Weaver, C.M. Acute and Chronic Effects of Honey and Its Carbohydrate Constituents
on Calcium Absorption in Rats. J. Agric. Food Chem. 2008, 56, 2649–2654. [CrossRef]
60. Gul, A.; Pehlivan, T. Antioxidant activities of some monofloral honey types produced across Turkey. Saudi J. Biol. Sci. 2018,
25, 1056–1065. [CrossRef]
61. Osés, S.M.; Pascual-Maté, A.; de la Fuente, D.; de Pablo, A.; Fernández-Muiño, M.A.; Sancho, M.T. Comparison of methods to
determine antibacterial activity of honeys against Staphylococcus aureus. NJAS-Wagening. J. Life Sci. 2016, 78, 29–33. [CrossRef]
62. Chuttong, B.; Chanbang, Y.; Sringarm, K.; Burgett, M. Physicochemical profiles of stingless bee (Apidae: Meliponini) honey from
South East Asia (Thailand). Food Chem. 2016, 192, 149–155. [CrossRef]
63. Da Costa, A.C.V.; Sousa, J.M.B.; da Silva, M.A.A.P.; Garruti, D.d.S.; Madruga, M.S. Sensory and volatile profiles of monofloral
honeys produced by native stingless bees of the brazilian semiarid region. Food Res. Int. 2018, 105, 110–120. [CrossRef]
64. Ávila, S.; Hornung, P.S.; Teixeira, G.L.; Malunga, L.N.; Apea-Bah, F.B.; Beux, M.R.; Beta, T.; Ribani, R.H. Bioactive compounds and
biological properties of Brazilian stingless bee honey have a strong relationship with the pollen floral origin. Food Res. Int. 2019,
123, 1–10. [CrossRef]
65. Ahmed, S.; Othman, N.H. Review of the Medicinal Effects of Tualang Honey and a Comparison with Manuka Honey. Malays. J.
Med. Sci. 2013, 20, 6–13.
66. Yarsan, E.; Karacal, F.; Ibrahim, I.G.; Dikmen, B.; Koksal, A.; Das, Y.K. Contents of Some Metals in Honeys from Different Regions
in Turkey. Bull. Environ. Contam. Toxicol. 2007, 79, 255–258. [CrossRef]
67. Bilandžić, N.; Gačić, M.; Ðokić, M.; Sedak, M.; Šipušić, Ð.I.; Končurat, A.; Gajger, I.T. Major and trace elements levels in multifloral
and unifloral honeys in Croatia. J. Food Compos. Anal. 2014, 33, 132–138. [CrossRef]
68. Pisani, A.; Protano, G.; Riccobono, F. Minor and trace elements in different honey types produced in Siena County (Italy). Food
Chem. 2008, 107, 1553–1560. [CrossRef]
69. Pellerano, R.G.; Uñates, M.A.; Cantarelli, M.A.; Camiña, J.M.; Marchevsky, E.J. Analysis of trace elements in multifloral Argentine
honeys and their classification according to provenance. Food Chem. 2012, 134, 578–582. [CrossRef]
70. Leyva-Jimenez, F.J.; Lozano-Sanchez, J.; Borras-Linares, I.; Cadiz-Gurrea, M.d.l.L.; Mahmoodi-Khaledi, E. Potential antimicrobial
activity of honey phenolic compounds against Gram positive and Gram negative bacteria. LWT 2019, 101, 236–245. [CrossRef]
71. Lianda, R.L.P.; D’Oliveira Sant’Ana, L.; Echevarriaa, A.; Castro, R.N. Antioxidant Activity and Phenolic Composition of Brazilian
Honeys and their Extracts. J. Braz. Chem. Soc. 2012, 23, 618–627. [CrossRef]
72. Cigic, I.K.; Prosen, H. An overview of conventional and emerging analytical methods for the determination of mycotoxins. Int. J.
Mol. Sci. 2009, 10, 62–115. [CrossRef]
73. Tahir, H.E.; Xiaobo, Z.; Zhihua, L.; Jiyong, S.; Zhai, X.; Wang, S.; Mariod, A.A. Rapid prediction of phenolic compounds and
antioxidant activity of Sudanese honey using Raman and Fourier transform infrared (FT-IR) spectroscopy. Food Chem. 2017,
226, 202–211. [CrossRef]
74. Massaro, C.F.; Shelley, D.; Heard, T.A.; Brooks, P. In Vitro Antibacterial Phenolic Extracts from “Sugarbag” Pot-Honeys of
Australian Stingless Bees (Tetragonula carbonaria). J. Agric. Food Chem. 2014, 62, 12209–12217. [CrossRef]
75. Massaro, F.C.; Brooks, P.R.; Wallace, H.M.; Russell, F. Cerumen of Australian stingless bees (Tetragonula carbonaria): Gas
chromatography-mass spectrometry fingerprints and potential anti-inflammatory properties. Naturwissenschaften 2011, 98, 329–337.
[CrossRef]
76. Da Silva, I.A.; da Silva, T.M.; Camara, C.A.; Queiroz, N.; Magnani, M.; de Novais, J.S.; Soledade, L.E.; Lima Ede, O.; de Souza,
A.L.; de Souza, A.G. Phenolic profile, antioxidant activity and palynological analysis of stingless bee honey from Amazonas,
Northern Brazil. Food Chem. 2013, 141, 3552–3558. [CrossRef]
77. Heleno, S.A.; Martins, A.; Queiroz, M.J.; Ferreira, I.C. Bioactivity of phenolic acids: Metabolites versus parent compounds: A
review. Food Chem. 2015, 173, 501–513. [CrossRef]
78. Silva, T.M.S.; dos Santos, F.P.; Evangelista-Rodrigues, A.; da Silva, E.M.; da Silva, G.S.; de Novais, J.S.; dos Santos, F.; de Assis,
R.; Camara, C.A. Phenolic compounds, melissopalynological, physicochemical analysis and antioxidant activity of jandaíra
(Melipona subnitida) honey. J. Food Compos. Anal. 2013, 29, 10–18. [CrossRef]
79. Guerrini, A.; Bruni, R.; Maietti, S.; Poli, F.; Damiano, R.; Paganetto, G.; Muzzoli, M.; Scalvenzi, L.; Sacchetti, G. Ecuadorian stingless
bee (Meliponinae) honey: A chemical and functional profile of an ancient health product. Food Chem. 2009, 114, 1413–1420.
[CrossRef]
80. Ferreira, I.C.F.R.; Aires, E.; Barreira, J.C.M.; Estevinho, L.M. Antioxidant activity of Portuguese honey samples Different
contributions of the entire honey and phenolic extract. Food Chem. 2009, 114, 1438–1443. [CrossRef]
81. Mărghitaş, L.A.; Dezmirean, D.; Moise, A.; Bobis, O.; Laslo, L.; Bogdanov, S. Physico-chemical and bioactive properties of different
floral origin honeys from Romania. Food Chem. 2009, 112, 863–867. [CrossRef]
82. Proestos, C.; Chorianopoulos, N.; Nychas, G.J.E.; Komaitis, M. RP-HPLC Analysis of the Phenolic Compounds of Plant Extracts.
Investigation of Their Antioxidant Capacity and Antimicrobial Activity. J. Agric. Food Chem. 2005, 53, 1190–1195. [CrossRef]
83. Wojdylo, A.; Oszmianski, J.; Czemerys, R. Antioxidant activity and phenolic compounds in 32 selected herbs. Food Chem. 2007,
105, 940–949. [CrossRef]
84. Socha, R.; Juszczak, L.; Pietrzyk, S.; Fortuna, T. Antioxidant activity and phenolic composition of herbhoneys. Food Chem. 2009,
113, 568–574. [CrossRef]
85. Yancheva, S.; Mavromatis, P.; Georgieva, L. Polyphenol profile and antioxidant activity of extracts from olive leaves. J. Cent. Eur.
Agric. 2016, 17, 154–163. [CrossRef]
86. Balík, J.; Kyseláková, M.; Vrchotová, N.; Tříska, J.; Kumšta, M.; Veverka, J.; Híc, P.; Totušek, J.; Lefnerová, D. Relations between
polyphenols content and antioxidant activity in vine grapes and leaves. Czech J. Food Sci. 2008, 26, S25–S32. [CrossRef]
87. Kumar, V.; Sharma, A.; Bhardwaj, R.; Thukral, A.K. Polyphenol profiling in the leaves of plant from the carchment area of river
Beas, India. Int. J. Pharma Bio Sci. 2015, 6, 1005–1012.
88. Sharma, A.; Kumar, V.; Thukral, A.K.; Bhardwaj, R. Epibrassinolide-imidacloprid interaction enhances non-enzymatic antioxidants
in Brassica juncea L. Indian J. Plant Physiol. 2016, 21, 70–75. [CrossRef]
89. Mahfoudhi, A.; Prencipe, F.P.; Mighri, Z.; Pellati, F. Metabolite profiling of polyphenols in the Tunisian plant Tamarix aphylla (L.)
Karst. J. Pharm. Biomed. Anal. 2014, 99, 97–105. [CrossRef] [PubMed]
90. Karimi, E.; Jaafar, H.Z. HPLC and GC-MS determination of bioactive compounds in microwave obtained extracts of three varieties
of Labisia pumila Benth. Molecules 2011, 16, 6791–6805. [CrossRef] [PubMed]
91. Lee, Y.-J.; Thiruvengadam, M.; Chung, I.-M.; Nagella, P. Polyphenol composition and antioxidant activity from the vegetable
plant Artemisia absinthium L. Aust. J. Crop Sci. 2013, 12, 1921–1926.
92. Biesaga, M. Analysis of phenolic acids and flavonoids in honey. Trac. Trends Anal. Chem. 2009, 28, 893–902. [CrossRef]
93. Kamaruddin, M.Y.; Aljadi, A. Isolation and Identification of Phenolic Acids in Malaysian Honey with Antibacterial Activities.
Turk. J. Med. Sci. 2003, 33, 229–236.
94. Ramanauskiene, K.; Stelmakiene, A.; Briedis, V.; Ivanauskas, L.; Jakstas, V. The quantitative analysis of biologically active
compounds in Lithuanian honey. Food Chem. 2012, 132, 1544–1548. [CrossRef]
95. Dorai, A.A. Wound care with traditional, complementary and alternative medicine. Indian J. Plast. Surg. 2012, 45, 418–424.
[CrossRef]
96. Church, D.; Elsayed, S.; Reid, O.; Winston, B.; Lindsay, R. Burn wound infections. Clin. Microbiol. Rev. 2006, 19, 403–434.
[CrossRef]
97. Barku, V.Y.A.; Boye, A.; Quansah, N. Antioxidant and wound healing studies on the extracts of Corchorus olitorius leaf. Sci. Res.
Rev. J. 2013, 1, 67–73.
98. Abderrahim, L.A.; Taibi, K.; Ait Abderrahim, N.; Boussaid, M.; Rios-Navarro, C.; Ruiz-Sauri, A. Euphorbia honey and garlic:
Biological activity and burn wound recovery. Burns 2019, 45, 1695–1706. [CrossRef]
99. Mikaili, P.; Maadirad, S.; Moloudizargari, M.; Aghajanshakeri, S.; Sarahroodi, S. Therapeutic Uses and Pharmacological Properties
of Garlic, Shallot, and Their Biologically Active Compounds. Iran. J. Basic Med. Sci. 2013, 16, 1031–1048.
100. Khashan, A.A. Antibacterial activity of garlic extract (Allium sativum) against Staphylococcus aureus in vitro. J. Bio-Sci. Biotechnol.
2014, 3, 346–348.
101. Khan, M.S.; Quershi, N.A.; Jabeen, F.; Asghar, M.S.; Shakeel, S. Analysis of minerals profile, phenolic compounds and potential of
Garlic (Allium sativum) as antioxidant scavenging the free radicals. Int. J. Biosci. (IJB) 2016, 8, 72–82. [CrossRef]
102. Andualem, B. Synergistic Antimicrobial Effect of Tenegn Honey (Trigona iridipennis) and Garlic Against Standard and Clinical
Pathogenic Bacterial Isolates. Int. J. Microbiol. Res. 2013, 4, 16–22. [CrossRef]
103. Bettar, I.; González-Miret, M.L.; Hernanz, D.; Marconi, A.; Heredia, F.J.; Terrab, A. Characterisation of Moroccan Spurge
(Euphorbia) honeys by their physicochemical characteristics, mineral contents and colour. Arab. J. Chem. 2019, 12, 2052–2060.
[CrossRef]
104. Escuredo, O.; Miguez, M.; Fernandez-Gonzalez, M.; Seijo, M.C. Nutritional value and antioxidant activity of honeys produced in
a European Atlantic area. Food Chem. 2013, 138, 851–856. [CrossRef]
105. Muller, P.; Alber, D.G.; Turnbull, L.; Schlothauer, R.C.; Carter, D.A.; Whitchurch, C.B.; Harry, E.J. Synergism between Medihoney
and rifampicin against methicillin-resistant Staphylococcus aureus (MRSA). PLoS ONE 2013, 8, e57679. [CrossRef]
106. Irish, J.; Carter, D.A.; Shokohi, T.; Blair, S.E. Honey has an antifungal effect against Candida species. Med. Mycol. 2006, 44, 289–291.
[CrossRef]
107. Wasihun, A.G.; Kasa, B.G. Evaluation of antibacterial activity of honey against multidrug resistant bacteria in Ayder Referral and
Teaching Hospital, Northern Ethiopia. Springerplus 2016, 5, 842. [CrossRef] [PubMed]
108. Anyanwu, C. Investigation of in vitro antifungal activity of honey. J. Med. Plants Res. 2012, 6, 3512–3516. [CrossRef]
109. Alves, A.; Ramos, A.; Gonçalves, M.M.; Bernardo, M.; Mendes, B. Antioxidant activity, quality parameters and mineral content of
Portuguese monofloral honeys. J. Food Compos. Anal. 2013, 30, 130–138. [CrossRef]
110. Fernández-Torres, R.; Pérez-Bernal, J.L.; Bello-López, M.Á.; Callejón-Mochón, M.; Jiménez-Sánchez, J.C.; Guiraúm-Pérez, A.
Mineral content and botanical origin of Spanish honeys. Talanta 2005, 65, 686–691. [CrossRef] [PubMed]
111. Guo, S.; Bai, L.; Ho, C.-T.; Bai, N. Characteristic Components, Biological Activities and Future Prospective of Fructus Mori: A
Review. Curr. Pharmacol. Rep. 2018, 4, 210–219. [CrossRef]
112. Čeksteryte, V. Evaluation of antioxidant activity and flavonoid composition in differently preserved bee products. Czech J. Food
Sci. 2016, 34, 133–142. [CrossRef]
113. Angioi, R.; Morrin, A.; White, B. The Rediscovery of Honey for Skin Repair: Recent Advances in Mechanisms for Honey-Mediated
Wound Healing and Scaffolded Application Techniques. Appl. Sci. 2021, 11, 15192. [CrossRef]
114. Tuhin, R.H.; Begum, M.M.; Rahman, M.S.; Karim, R.; Begum, T.; Ahmed, S.U.; Mostofa, R.; Hossain, A.; Abdel-Daim, M.; Begum,
R. Wound healing effect of Euphorbia hirta linn. (Euphorbiaceae) in alloxan induced diabetic rats. BMC Complement. Altern. Med.
2017, 17, 423. [CrossRef]
115. Khalil, A.T.; Khan, I.; Ahmad, K.; Khan, Y.A.; Khan, M.; Khan, M.J. Synergistic antibacterial effect of honey and Herba Ocimi
Basilici against some bacterial pathogens. J. Tradit Chin. Med. 2013, 33, 810–814. [CrossRef]
116. Svecova, E.; Neugebauerova, J. A study of 34 cultivars of basil (Ocimum L.) and their morphological, economic and biochemical
characteristics, using standardized descriptors. Acta Univ. Sapientiae Aliment. 2010, 3, 118–135.
117. Namias, N. Honey in the Management of Infections. Surg. Infect. 2003, 4, 219–226. [CrossRef]
118. Özcan, M. Mineral contents of some plants used as condiments in Turkey. Food Chem. 2004, 84, 437–440. [CrossRef]
119. Sajjadi, S.E. Analysis of the essential oils of two cultivated basil (Ocimum basilicum L.) from Iran. DARU J. Pharm. Sci. 2006,
14, 128–130.
120. Salmah, I.; Mahmood, A.A.; Sidik, K. Synergistic effects of alcoholic extract of sweet basil (Ocimum basilicum L) leaves and honey
on cutaneous wound healing in rats. Int. J. Mol. Med. Adv. Sci. 2005, 1, 220–224.
121. Rezvani, M.B.; Niakan, M.; Kamalinejad, M.; Ahmadi, F.S.; Hamze, F. The synergistic effect of honey and cinnamon against
Streptococcus mutans bacteria. Asian Pac. J. Trop. Biomed. 2017, 7, 314–320. [CrossRef]
122. Palombo, E.A. Traditional Medicinal Plant Extracts and Natural Products with Activity against Oral Bacteria: Potential Application
in the Prevention and Treatment of Oral Diseases. Evid. Based Complement. Altern. Med. 2011, 2011, 680354. [CrossRef]
123. Fani, M.; Kohanteb, J. Inhibitory activity of aloe vera gel on some clinically isolated cariogenic and periodontopathic bacteria.
J. Oral Sci. 2012, 54, 15–21. [CrossRef]
124. Ferrazzano, G.F.; Roberto, L.; Amato, I.; Cantile, T.; Sangianantoni, G.; Ingenito, A. Antimicrobial properties of green tea extract
against cariogenic microflora: An in vivo study. J. Med. Food 2011, 14, 907–911. [CrossRef]
125. Al-Bayati, F.A. Synergistic antibacterial activity between Thymus vulgaris and Pimpinella anisum essential oils and methanol
extracts. J. Ethnopharmacol. 2008, 116, 403–406. [CrossRef]
126. Probst, I.S.; Sforcin, J.M.; Rall, V.L.M.; Fernandes, A.A.H.; Fernandes Júnior, A. Antimicrobial activity of propolis and essential
oils and synergism between these natural products. J. Venom. Anim. Toxins Incl. Trop. Dis. 2011, 17, 159–167. [CrossRef]
127. Patel, R.V.; Thaker, V.T.; Patel, V.K. Antimicrobial activity of ginger and honey on isolates of extracted carious teeth during
orthodontic treatment. Asian Pac. J. Trop. Biomed. 2011, 1, S58–S61. [CrossRef]
128. Ahmed, M.; Aissat, S.; Djebli, N.; Boulkaboul, A.; Abdelmalek, M.; Khiati, B. The Influence of Starch of Ginger on the Antibacterial
Activity of Honey of Different Types from Algeria against Escherichia coli and Staphylococcus aureus. Int. J. Microbiol. Res. 2011,
2, 258–262.
129. Maeda, Y.; Loughrey, A.; Earle, J.A.; Millar, B.C.; Rao, J.R.; Kearns, A.; McConville, O.; Goldsmith, C.E.; Rooney, P.J.; Dooley, J.S.;
et al. Antibacterial activity of honey against community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).
Complement Ther. Clin. Pract. 2008, 14, 77–82. [CrossRef] [PubMed]
130. Masad, R.J.; Haneefa, S.M.; Mohamed, Y.A.; Al-Sbiei, A.; Bashir, G.; Fernandez-Cabezudo, M.J.; Al-Ramadi, B.K. The Immunomod-
ulatory Effects of Honey and Associated Flavonoids in Cancer. Nutrients 2021, 13, 1269. [CrossRef] [PubMed]
131. Schieber, M.; Chandel, N.S. ROS function in redox signaling and oxidative stress. Curr. Biol. 2014, 24, R453–R462. [CrossRef]
[PubMed]
132. Ranneh, Y.; Akim, A.M.; Hamid, H.A.; Khazaai, H.; Fadel, A.; Zakaria, Z.A.; Albujja, M.; Bakar, M.F.A. Honey and its nutritional
and anti-inflammatory value. BMC Complement. Med. Ther. 2021, 21, 30. [CrossRef]
133. Tonks, A. Honey stimulates inflammatory cytokine production from monocytes. Cytokine 2003, 21, 242–247. [CrossRef]
134. Al-Hatamleh, M.A.I.; Hatmal, M.M.; Sattar, K.; Ahmad, S.; Mustafa, M.Z.; Bittencourt, M.C.; Mohamud, R. Antiviral and
Immunomodulatory Effects of Phytochemicals from Honey against COVID-19: Potential Mechanisms of Action and Future
Directions. Molecules 2020, 25, 5017. [CrossRef]
135. Chepulis, L.M. The effect of honey compared to sucrose, mixed sugars, and a sugar-free diet on weight gain in young rats. J. Food
Sci. 2007, 72, S224–S229. [CrossRef]
136. Ahmed, S.; Othman, N.H. Honey as a potential natural anticancer agent: A review of its mechanisms. Evid. Based Complement.
Altern. Med. 2013, 2013, 829070. [CrossRef]
137. Schell, K.R.; Fernandes, K.E.; Shanahan, E.; Wilson, I.; Blair, S.E.; Carter, D.A.; Cokcetin, N.N. The Potential of Honey as a Prebiotic
Food to Re-engineer the Gut Microbiome Toward a Healthy State. Front. Nutr. 2022, 9, 957932. [CrossRef]
138. De Melo, F.H.C.; Menezes, F.; de Sousa, J.M.B.; Dos Santos Lima, M.; da Silva Campelo Borges, G.; de Souza, E.L.; Magnani, M.
Prebiotic activity of monofloral honeys produced by stingless bees in the semi-arid region of Brazilian Northeastern toward
Lactobacillus acidophilus LA-05 and Bifidobacterium lactis BB-12. Food Res. Int. 2020, 128, 108809. [CrossRef]
139. Mustar, S.; Ibrahim, N. A Sweeter Pill to Swallow: A Review of Honey Bees and Honey as a Source of Probiotic and Prebiotic
Products. Foods 2022, 11, 2102. [CrossRef]
140. Kowalska, G.; Rosicka-Kaczmarek, J.; Miskiewicz, K.; Zaklos-Szyda, M.; Rohn, S.; Kanzler, C.; Wiktorska, M.; Niewiarowska, J.
Arabinoxylan-Based Microcapsules Being Loaded with Bee Products as Bioactive Food Components Are Able to Modulate the
Cell Migration and Inflammatory Response-In Vitro Study. Nutrients 2022, 14, 2529. [CrossRef]
141. Kwakman, P.H.; te Velde, A.A.; de Boer, L.; Speijer, D.; Vandenbroucke-Grauls, C.M.; Zaat, S.A. How honey kills bacteria. FASEB
J. 2010, 24, 2576–2582. [CrossRef]
142. Kwakman, P.H.; Te Velde, A.A.; de Boer, L.; Vandenbroucke-Grauls, C.M.; Zaat, S.A. Two major medicinal honeys have different
mechanisms of bactericidal activity. PLoS ONE 2011, 6, e17709. [CrossRef]
143. Da Silva, P.M.; Gauche, C.; Gonzaga, L.V.; Costa, A.C.; Fett, R. Honey: Chemical composition, stability and authenticity. Food
Chem. 2016, 196, 309–323. [CrossRef]
144. Henriques, A.F.; Jenkins, R.E.; Burton, N.F.; Cooper, R.A. The intracellular effects of manuka honey on Staphylococcus aureus.
Eur. J. Clin. Microbiol. Infect. Dis. 2010, 29, 45–50. [CrossRef]
145. Jenkins, R.; Burton, N.; Cooper, R. Manuka honey inhibits cell division in methicillin-resistant Staphylococcus aureus. J. Antimicrob.
Chemother. 2011, 66, 2536–2542. [CrossRef]
146. Henriques, A.F.; Jenkins, R.E.; Burton, N.F.; Cooper, R.A. The effect of manuka honey on the structure of Pseudomonas aeruginosa.
Eur. J. Clin. Microbiol. Infect. Dis. 2011, 30, 167–171. [CrossRef]
147. Jenkins, R.; Roberts, A.; Brown, H.L. On the antibacterial effects of manuka honey: Mechanistic insights. Res. Rep. Biol. 2015,
6, 215–224. [CrossRef]
148. Bouzo, D.; Cokcetin, N.N.; Li, L.; Ballerin, G.; Bottomley, A.L.; Lazenby, J.; Whitchurch, C.B.; Paulsen, I.T.; Hassan, K.A.; Harry,
E.J. Characterizing the Mechanism of Action of an Ancient Antimicrobial, Manuka Honey, against Pseudomonas aeruginosa
Using Modern Transcriptomics. mSystems 2020, 5, e00106-20. [CrossRef] [PubMed]
149. Combarros-Fuertes, P.; Estevinho, L.M.; Teixeira-Santos, R.; G. Rodrigues, A.; Pina-Vaz, C.; Fresno, J.M.; Tornadijo, M.E. Antibac-
terial Action Mechanisms of Honey: Physiological Effects of Avocado, Chestnut, and Polyfloral Honey upon Staphylococcus
aureus and Escherichia coli. Molecules 2020, 25, 1252. [CrossRef] [PubMed]
150. Zaheen, Z.; Yatoo, A.; Ali, S.; Niamat, A.; Majid, S.; Rasool, S.; Mudasir Rashid, S.; Ahmad, S.B.; Mir, M.; Zehra, U. Honey: Types,
Composition and Antimicrobial Mechanisms. In Therapeutic Applications of Honey and Its Phytochemicals; Muneeb, U., Rehman,
S.M., Eds.; Springer Nature Sibgapore Pte Ltd.: Singapore, 2020; pp. 193–214. [CrossRef]
151. Elston, D.M. Community-acquired methicillin-resistant Staphylococcus aureus. J. Am. Acad Derm. 2007, 56, 1–16. [CrossRef]
[PubMed]
152. Ghramh, H.A.; Khan, K.A.; Alshehri, A.M.A. Antibacterial potential of some Saudi honeys from Asir region against selected
pathogenic bacteria. Saudi J. Biol. Sci. 2019, 26, 1278–1284. [CrossRef] [PubMed]
153. Deng, J.; Liu, R.; Lu, Q.; Hao, P.; Xu, A.; Zhang, J.; Tan, J. Biochemical properties, antibacterial and cellular antioxidant activities of
buckwheat honey in comparison to manuka honey. Food Chem. 2018, 252, 243–249. [CrossRef]
154. Hegazi, A.G.; Guthami, F.M.; Gethami, A.F.; Allah, F.M.; Saleh, A.A.; Fouad, E.A. Potential antibacterial activity of some Saudi
Arabia honey. Vet. World 2017, 10, 233–237. [CrossRef]
155. Basma, A.A.; Zuraini, Z.; Sasidharan, S. A transmission electron microscopy study of the diversity of Candida albicans cells induced
by Euphorbia hirta L. leaf extract in vitro. Asian Pac. J. Trop. Biomed. 2011, 1, 20–22. [CrossRef]
156. Molero, G.; Díez-Orejas, R.; Navarro-García, F.; Monteoliva, L.; Pla, J.; Gil, C.; Sánchez-Pérez, M.; Nombela, C. Candida albicans:
Genetics, dimorphism and pathogenicity. Int. Microbiol. 1998, 2, 95–106.
157. Fesharaki, S.H.; Aghili, S.R.; Shokohi, T.; Boroumand, M.A. Catheter-related candidemia and identification of causative Candida
species in patients with cardiovascular disorder. Curr. Med. Mycol. 2018, 4, 7–13. [CrossRef]
158. Tuon, F.F.; de Almeida, G.M.F.; Costa, S.F. Central venous catheter-associated fungemia due to Rhodotorula spp.—A systematic
review. Med. Mycol. 2007, 45, 441–448. [CrossRef]
159. Ghaffari-Moghaddam, M.; Hadi-Dabanlou, R.; Khajeh, M.; Rakhshanipour, M.; Shameli, K. Green synthesis of silver nanoparticles
using plant extracts. Korean J. Chem. Eng. 2014, 31, 548–557. [CrossRef]
160. Vidhu, V.K.; Aromal, S.A.; Philip, D. Green synthesis of silver nanoparticles using Macrotyloma uniflorum. Spectrochim. Acta.
Part A Mol. Biomol. Spectrosc. 2011, 83, 392–397. [CrossRef]
161. Mohammed, A.E.; Al-Qahtani, A.; Al-Mutairi, A.; Al-Shamri, B.; Aabed, K.F. Antibacterial and Cytotoxic Potential of Biosynthe-
sized Silver Nanoparticles by Some Plant Extracts. Nanomaterials 2018, 8, 382. [CrossRef]
162. Haiza, H.; Azizan, A.; Mohidin, A.H.; Halin, D.S.C. Green Synthesis of Silver Nanoparticles Using Local Honey. Nano Hybrids
2013, 4, 87–98. [CrossRef]
163. Al-Brahim, J.S.; Mohammed, A.E. Antioxidant, cytotoxic and antibacterial potential of biosynthesized nanoparticles using bee
honey from two different floral sources in Saudi Arabia. Saudi J. Biol. Sci. 2020, 27, 363–373. [CrossRef]
164. White, J.W.; Subers, J.M.H.; Schepartz, A.I. The identification of inhibine, the antibacterial factor in honey, as hydrogen peroxide
and its origin in a honey glucose-oxidase system. Biochim. Biophys. Acta 1963, 73, 57–70. [CrossRef]
165. Allen, K.L.; Molan, P.C.; Reid, G.M. A survey of the antibacterial activity of some New Zealand honeys. J. Pharm. Pharmacol. 1991,
43, 817–822. [CrossRef]
166. Russell, K.M.; Molan, P.C.; Wilkins, A.L.; Holland, P.T. Identification of some antibacterial constituents of New Zealand manuka
honey. J. Agric. Food Chem. 1990, 38, 10–13. [CrossRef]
167. Wilkins, A.L.; Lu, Y.; Molan, P.C. Extractable organic substances from New Zealand unifloral manuka (Leptospermum scoparium)
honeys. J. Apic. Res. 2015, 32, 3–9. [CrossRef]
168. Blair, S.E.; Carte, D.A. The potential for honey in the management of wounds and infection. Aust. Infect. Control 2005, 10, 24–31.
[CrossRef]
169. Santos-Sánchez, N.F.; Salas-Coronado, R.; Villanueva-Cañongo, C.; Hernández-Carlos, B. Antioxidant Compounds and Their
Antioxidant Mechanism. Antioxidants 2019, 10, 1–28.
170. MacDonald-Wicks, L.K.; Wood, L.G.; Garg, M.L. Methodology for the determination of biological antioxidant capacityin vitro: A
review. J. Sci. Food Agric. 2006, 86, 2046–2056. [CrossRef]
171. Mushtaq, S.; Imtiyaz, Z.; Wali, A.F.; Khan, A.; Rashid, S.M.; Amin, I.; Ali, A.; Rehman, M.U.; Arafah, A. Honey: A Powerful
Natural Antioxidant and Its Possible Mechanism of Action. In Therapeutic Applications of Honey and Its Phoitochemicals; Rehman,
M.U., Majid, S., Eds.; Springer: Singapore, 2020; pp. 11–31. [CrossRef]
172. Nweze, J.A.; Olovo, C.V.; Nweze, E.I.; John, O.O.; Paul, C. Therapeutic Properties of Honey. In Honey Analysis; de Toledo, V.A.A.,
Chambó, E.D., Eds.; IntechOpen: London, UK, 2019; p. 21.
173. Khalil, M.I.; Sulaiman, S.A.; Boukraa, L. Antioxidant Properties of Honey and Its Role in Preventing Health Disorder. Open
Nutraceuticals J. 2010, 3, 6–16. [CrossRef]
174. Chaikham, P.; Prangthip, P. Alteration of antioxidative properties of longan flower-honey after high pressure, ultra-sonic and
thermal processing. Food Biosci. 2015, 10, 1–7. [CrossRef]
175. Tomás-Barberán, F.A.; Martos, I.; Ferreres, F.; Radovic, B.S.; Anklam, E. HPLC flavonoid profiles as markers for the botanical
origin of European unifloral honeys. J. Sci. Food Agric. 2001, 81, 485–496. [CrossRef]
176. Al-Waili, N.S. Effects of daily consumption of honey solution on hematological indices and blood levels of minerals and enzymes
in normal individuals. J. Med. Food 2003, 6, 135–140. [CrossRef]
177. Kupeli Akkol, E.; Orhan, D.D.; Gurbuz, I.; Yesilada, E. In vivo activity assessment of a “honey-bee pollen mix” formulation.
Pharm. Biol. 2010, 48, 253–259. [CrossRef]
178. Erejuwa, O.O.; Sulaiman, S.A.; Wahab, M.S.; Salam, S.K.; Salleh, M.S.; Gurtu, S. Comparison of antioxidant effects of honey,
glibenclamide, metformin, and their combinations in the kidneys of streptozotocin-induced diabetic rats. Int. J. Mol. Sci. 2011,
12, 829–843. [CrossRef]
179. Erejuwa, O.O.; Gurtu, S.; Sulaiman, S.A.; Ab Wahab, M.S.; Sirajudeen, K.N.; Salleh, M.S. Hypoglycemic and antioxidant effects of
honey supplementation in streptozotocin-induced diabetic rats. Int. J. Vitam. Nutr. Res. 2010, 80, 74–82. [CrossRef]
180. Ahmad, N.S.; Abdul Aziz, A.; Kong, K.W.; Hamid, M.S.A.; Cheong, J.P.G.; Hamzah, S.H. Dose-Response Effect of Tualang Honey
on Postprandial Antioxidant Activity and Oxidative Stress in Female Athletes: A Pilot Study. J. Altern. Complement. Med. 2017,
23, 989–995. [CrossRef]
181. Bahrami, M.; Ataie-Jafari, A.; Hosseini, S.; Foruzanfar, M.H.; Rahmani, M.; Pajouhi, M. Effects of natural honey consumption in
diabetic patients: An 8-week randomized clinical trial. Int. J. Food Sci. Nutr. 2009, 60, 618–626. [CrossRef]
182. Kıvrak, Ş.; Kıvrak, I. Assessment of phenolic profile of Turkish honeys. Int. J. Food Prop. 2017, 20, 864–876. [CrossRef]
183. Konuskan, B.D.; Mungan, B. Effects of Variety, Maturation and Growing Region on Chemical Properties, Fatty Acid and Sterol
Compositions of Virgin Olive Oils. J. Am. Oil Chem. Soc. 2016, 93, 1499–1508. [CrossRef]
184. Bogdanov, S.; Jurendic, T.; Sieber, R.; Gallmann, P. Honey for Nutrition and Health: A Review. J. Am. Coll. Nutr. 2009, 27, 677–689.
[CrossRef]
185. Can, Z.; Yildiz, O.; Sahin, H.; Turumtay, A.E.; Silici, S.; Kolayli, S. An investigation of Turkish honeys: Their physico-chemical
properties, antioxidant capacities and phenolic profiles. Food Chem. 2015, 180, 133–141. [CrossRef]
186. Chen, L.; Deng, H.; Cui, H.; Fang, J.; Zuo, Z.; Deng, J.; Li, Y.; Wang, X.; Zhao, L. Inflammatory responses and inflammation
associated diseases in organs. Oncotarget 2018, 9, 7204–7218. [CrossRef]
187. Jabbour, H.N.; Sales, K.J.; Catalano, R.D.; Norman, J.E. Inflammatory pathways in female reproductive health and disease.
Reproduction 2009, 138, 903–919. [CrossRef]
188. Nathan, C.; Ding, A. Nonresolving inflammation. Cell 2010, 140, 871–882. [CrossRef]
189. Ranneh, Y.; Ali, F.; Akim, A.M.; Hamid, H.A.; Khazaai, H.; Fadel, A. Crosstalk between reactive oxygen species and pro-
inflammatory markers in developing various chronic diseases: A review. Appl. Biol. Chem. 2017, 60, 327–338. [CrossRef]
190. Farkhondeh, T.; Samarghandian, S. Antidotal Effects of Curcumin Against Agents-Induced Cardiovascular Toxicity. Cardiovasc.
Haematol. Disord.-Drug Targets 2016, 16, 30–36. [CrossRef] [PubMed]
191. Viuda-Martos, M.; Ruiz-Navajas, Y.; Fernandez-Lopez, J.; Perez-Alvarez, J.A. Functional properties of honey, propolis, and royal
jelly. J. Food Sci. 2008, 73, R117–R124. [CrossRef] [PubMed]
192. Talebi, M.; Talebi, M.; Farkhondeh, T.; Samarghandian, S. Molecular mechanism-based therapeutic properties of honey. Biomed.
Pharm. 2020, 130, 110590. [CrossRef] [PubMed]
193. Chen, X.; Liu, B.; Li, X.; An, T.T.; Zhou, Y.; Li, G.; Wu-Smart, J.; Alvarez, S.; Naldrett, M.J.; Eudy, J.; et al. Identification of
anti-inflammatory vesicle-like nanoparticles in honey. J. Extracell. Vesicles 2021, 10, e12069. [CrossRef] [PubMed]
194. Erejuwa, O.O.; Sulaiman, S.A.; Wahab, M.S. Effects of honey and its mechanisms of action on the development and progression of
cancer. Molecules 2014, 19, 2497–2522. [CrossRef]
195. Waheed, M.; Hussain, M.B.; Javed, A.; Mushtaq, Z.; Hassan, S.; Shariati, M.A.; Khan, M.U.; Majeed, M.; Nigam, M.; Mishra, A.P.;
et al. Honey and cancer: A mechanistic review. Clin. Nutr. 2019, 38, 2499–2503. [CrossRef]
196. Susin, S.A.; Zamzami, N.; Kroemer, G. Mitochondria as regulators of apoptosis: Doubt no more. Biochim. Biophys. Acta 1998,
1366, 151–165. [CrossRef]
197. Galluzzi, L.; Maiuri, M.C.; Vitale, I.; Zischka, H.; Castedo, M.; Zitvogel, L.; Kroemer, G. Cell death modalities: Classification and
pathophysiological implications. Cell Death Diffe.r 2007, 14, 1237–1243. [CrossRef]
198. Galluzzi, L.; Vitale, I.; Aaronson, S.A.; Abrams, J.M.; Adam, D.; Agostinis, P.; Alnemri, E.S.; Altucci, L.; Amelio, I.; Andrews, D.W.;
et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death
Differ. 2018, 25, 486–541. [CrossRef]
199. Andersen, M.H.; Becker, J.C.; Straten, P. Regulators of apoptosis: Suitable targets for immune therapy of cancer. Nat. Rev. Drug
Discov. 2005, 4, 399–409. [CrossRef]
200. Jaganathan, S.K. Honey Constituents and their apoptotic effect in colon cancer cells. J. Apiproduct Apimedical Sci. 2009, 1, 29–36.
[CrossRef]
201. Jaganathan, S.K.; Mandal, M. Involvement of non-protein thiols, mitochondrial dysfunction, reactive oxygen species and p53 in
honey-induced apoptosis. Investig. New Drugs 2010, 28, 624–633. [CrossRef]
202. Tomasin, R.; Gomes-Marcondes, M.C. Oral administration of Aloe vera and honey reduces Walker tumour growth by decreasing
cell proliferation and increasing apoptosis in tumour tissue. Phytother. Res. 2011, 25, 619–623. [CrossRef]
203. Afrin, S.; Giampieri, F.; Gasparrini, M.; Forbes-Hernandez, T.Y.; Cianciosi, D.; Reboredo-Rodriguez, P.; Amici, A.; Quiles, J.L.;
Battino, M. The inhibitory effect of Manuka honey on human colon cancer HCT-116 and LoVo cell growth. Part 1: The suppression
of cell proliferation, promotion of apoptosis and arrest of the cell cycle. Food Funct. 2018, 9, 2145–2157. [CrossRef]
204. Afrin, S.; Haneefa, S.M.; Fernandez-Cabezudo, M.J.; Giampieri, F.; Al-Ramadi, B.K.; Battino, M. Therapeutic and preventive
properties of honey and its bioactive compounds in cancer: An evidence-based review. Nutr. Res. Rev. 2020, 33, 50–76. [CrossRef]
205. Wee, L.H.; Morad, N.A.; Aan, G.J.; Makpol, S.; Wan Ngah, W.Z.; Mohd Yusof, Y.A. Mechanism of Chemoprevention against Colon
Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/beta-catenin Pathways. Asian Pac. J. Cancer
Prev. 2015, 16, 6549–6556. [CrossRef]
206. Tahir, A.A.; Sani, N.F.; Murad, N.A.; Makpol, S.; Ngah, W.Z.; Yusof, Y.A. Combined ginger extract & Gelam honey modulate
Ras/ERK and PI3K/AKT pathway genes in colon cancer HT29 cells. Nutr. J. 2015, 14, 31. [CrossRef]
207. Majtan, J. Honey: An immunomodulator in wound healing. Wound Repair Regen 2014, 22, 187–192. [CrossRef]
208. Golebiewska, E.M.; Poole, A.W. Platelet secretion: From haemostasis to wound healing and beyond. Blood Rev. 2015, 29, 153–162.
[CrossRef]
209. Cognasse, F.; Hamzeh, H.; Chavarin, P.; Acquart, S.; Genin, C.; Garraud, O. Evidence of Toll-like receptor molecules on human
platelets. Immunol. Cell Biol. 2005, 83, 196–198. [CrossRef]
210. Segel, G.B.; Halterman, M.W.; Lichtman, M.A. The paradox of the neutrophil’s role in tissue injury. J. Leukoc. Biol. 2011, 89, 359–372.
[CrossRef] [PubMed]
211. Boniakowski, A.E.; Kimball, A.S.; Jacobs, B.N.; Kunkel, S.L.; Gallagher, K.A. Macrophage-Mediated Inflammation in Normal and
Diabetic Wound Healing. J. Immunol. 2017, 199, 17–24. [CrossRef] [PubMed]
212. Baum, C.L.; Arpey, C.J. Normal Cutaneous Wound Healing: Clinical Correlation with Cellular and Molecular Events. Dermatol.
Surg. 2005, 31, 674–686. [CrossRef] [PubMed]
213. Gurevich, D.B.; Severn, C.E.; Twomey, C.; Greenhough, A.; Cash, J.; Toye, A.M.; Mellor, H.; Martin, P. Live imaging of wound
angiogenesis reveals macrophage orchestrated vessel sprouting and regression. EMBO J. 2018, 37, e97786. [CrossRef] [PubMed]
214. Liu, Z.; Xu, Y.; Chen, L.; Xie, J.; Tang, J.; Zhao, J.; Shu, B.; Qi, S.; Chen, J.; Liang, G.; et al. Dendritic epidermal T cells facilitate
wound healing in diabetic mice. Am. J. Transl. Res. 2016, 8, 2375–2384.
215. Li, J.; Chen, J.; Kirsner, R. Pathophysiology of acute wound healing. Clin. Dermatol. 2007, 25, 9–18. [CrossRef]
216. Darby, I.A.; Laverdet, B.; Bonte, F.; Desmouliere, A. Fibroblasts and myofibroblasts in wound healing. Clin. Cosmet. Investig.
Dermatol. 2014, 7, 301–311. [CrossRef]
217. Sandseter, E.B.H.; Kennair, L.E.O. Children’s Risky Play from an Evolutionary Perspective: The Anti-Phobic Effects of Thrilling
Experiences. Evol. Psychol. J. 2011, 9, 257–284. [CrossRef]
218. Gupta, P.D.; Birdi, T.J. Development of botanicals to combat antibiotic resistance. J. Ayurveda Integr. Med. 2017, 8, 266–275.
[CrossRef]
219. Maddocks, S.; Jenkins, R. Honey: A sweet solution to the growing problem of antimicrobial resistance? Future Microbiol. 2013,
8, 1419–1429. [CrossRef]
220. Molan, P.; Rhodes, T. Honey: A Biologic Wound Dressing. Wounds 2015, 27, 141–151.
221. Kateel, R.; Adhikari, P.; Augustine, A.J.; Ullal, S. Topical honey for the treatment of diabetic foot ulcer: A systematic review.
Complement. Ther. Clin. Pract. 2016, 24, 130–133. [CrossRef]
222. Yang, Z.; Guan, Y.; Li, J.; Li, L.; Li, Z. Chrysin attenuates carrageenan-induced pleurisy and lung injury via activation of
SIRT1/NRF2 pathway in rats. Eur. J. Pharmacol. 2018, 836, 83–88. [CrossRef]
223. Holland, L.C.; Norris, J.M. Medical grade honey in the management of chronic venous leg ulcers. Int. J. Surg. 2015, 20, 17–20.
[CrossRef]
224. Sarkar, S.; Mukhopadhyay, A.; Chaudhary, A.; Rajput, M.; Pawar, H.S.; Mukherjee, R.; Das, A.K.; Banerjee, P.; Chatterjee, J.
Therapeutic interfaces of honey in diabetic wound pathology. Wound Med. 2017, 18, 21–32. [CrossRef]
225. Khiati, B.; Bacha, S.; Aissat, S.; Ahmed, M. The use of Algerian honey on cutaneous wound healing: A case report and review of
the literature. Asian Pac. J. Trop. Dis. 2014, 4, S867–S869. [CrossRef]
226. Shapla, U.M.; Solayman, M.; Alam, N.; Khalil, M.I.; Gan, S.H. 5-Hydroxymethylfurfural (HMF) levels in honey and other food
products: Effects on bees and human health. Chem. Cent. J. 2018, 12, 35. [CrossRef]
227. Doner, L.W. The sugars of honey—A review. J. Sci. Food Agric. 1977, 28, 443–456. [CrossRef]
228. Markowicz, D.B.; Monaro, E.; Siguemoto, E.; Séfora, M. Maillard reaction products in processed foods: Pros and cons. In Food
Industrial Processes-Methods And Equipment, 1st ed.; Valdez, B., Ed.; InTech: Rijeka, Croatia, 2012; pp. 281–300.
229. Alimentarius, C. Revised codex standard for honey. Codex Stan 2001, 12, 1982.
230. Official Journal of the European Union. Regulation (EU) No 1151/2012 of the European Parliament and of the Council on Quality
Schemes for Agricultural Products and Foodstuffs; 2012; Volume L 343, pp. 1–29.
231. Glatt, H.; Schneider, H.; Liu, Y. V79-hCYP2E1-hSULT1A1, a cell line for the sensitive detection of genotoxic effects induced by
carbohydrate pyrolysis products and other food-borne chemicals. Mutat. Res. 2005, 580, 41–52. [CrossRef]
232. Monien, B.H.; Engst, W.; Barknowitz, G.; Seidel, A.; Glatt, H. Mutagenicity of 5-hydroxymethylfurfural in V79 cells expressing human
SULT1A1: Identification and mass spectrometric quantification of DNA adducts formed. Chem. Res. Toxicol. 2012, 25, 1484–1492.
[CrossRef]
233. Kitts, D.D.; Chen, X.-M.; Jing, H. Demonstration of Antioxidant and Anti-inflammatory Bioactivities from Sugar–Amino Acid
Maillard Reaction Products. J. Agric. Food Chem. 2012, 60, 6718–6727. [CrossRef] [PubMed]
234. Zhao, L.; Chen, J.; Su, J.; Li, L.; Hu, S.; Li, B.; Zhang, X.; Xu, Z.; Chen, T. In vitro antioxidant and antiproliferative activities of
5-hydroxymethylfurfural. J. Agric. Food Chem. 2013, 61, 10604–10611. [CrossRef] [PubMed]
235. Yamada, P.; Nemoto, M.; Shigemori, H.; Yokota, S.; Isoda, H. Isolation of 5-(hydroxymethyl)furfural from Lycium chinense and its
inhibitory effect on the chemical mediator release by basophilic cells. Planta Med. 2011, 77, 434–440. [CrossRef] [PubMed]
236. Bailey, L. The Effect of Acid-Hydrolysed Sucrose on Honeybees. J. Apic. Res. 1966, 5, 127–136. [CrossRef]
237. Moghazy, A.M.; Shams, M.E.; Adly, O.A.; Abbas, A.H.; El-Badawy, M.A.; Elsakka, D.M.; Hassan, S.A.; Abdelmohsen, W.S.; Ali,
O.S.; Mohamed, B.A. The clinical and cost effectiveness of bee honey dressing in the treatment of diabetic foot ulcers. Diabetes Res.
Clin. Pract. 2010, 89, 276–281. [CrossRef]
238. Emsen, I.M. A different and safe method of split thickness skin graft fixation: Medical honey application. Burns 2007, 33, 782–787.
[CrossRef]
239. Adams, C.J.; Boult, C.H.; Deadman, B.J.; Farr, J.M.; Grainger, M.N.; Manley-Harris, M.; Snow, M.J. Isolation by HPLC and
characterisation of the bioactive fraction of New Zealand manuka (Leptospermum scoparium) honey. Carbohydr. Res. 2008,
343, 651–659. [CrossRef]
240. Hussein, S.Z.; Yusoff, M.K.; Makpol, S.; Yusof, M.Y.A. Gelam Honey Attenuates Carrageenan-Induced Rat Paw Inflammation via
NF-κB Pathway. PLoS ONE 2013, 8, e72365. [CrossRef]
241. Kuppusamy, P.; Yusoff, M.M.; Maniam, G.P.; Ichwan, S.J.; Soundharrajan, I.; Govindan, N. Nutraceuticals as potential therapeutic
agents for colon cancer: A review. Acta Pharm. Sin. B 2014, 4, 173–181. [CrossRef]
242. Lopez-Lazaro, M. Dual role of hydrogen peroxide in cancer: Possible relevance to cancer chemoprevention and therapy. Cancer
Lett. 2007, 252, 1–8. [CrossRef]
243. Badolato, M.; Carullo, G.; Cione, E.; Aiello, F.; Caroleo, M.C. From the hive: Honey, a novel weapon against cancer. Eur. J. Med.
Chem. 2017, 142, 290–299. [CrossRef]
244. Miguel, S.P.; Figueira, D.R.; Simões, D.; Ribeiro, M.P.; Coutinho, P.; Ferreira, P.; Correia, I.J. Electrospun polymeric nanofibres as
wound dressings: A review. Colloids Surf. B: Biointerfaces 2018, 169, 60–71. [CrossRef]
245. Puppi, D.; Piras, A.M.; Detta, N.; Ylikauppila, H.; Nikkola, L.; Ashammakhi, N.; Chiellini, F.; Chiellini, E. Poly(vinyl alcohol)-
based electrospun meshes as potential candidate scaffolds in regenerative medicine. J. Bioact. Compat. Polym. 2010, 26, 20–34.
[CrossRef]
246. Neres Santos, A.M.; Duarte Moreira, A.P.; Piler Carvalho, C.W.; Luchese, R.; Ribeiro, E.; McGuinness, G.B.; Fernandes Mendes,
M.; Nunes Oliveira, R. Physically Cross-Linked Gels of PVA with Natural Polymers as Matrices for Manuka Honey Release in
Wound-Care Applications. Materials 2019, 12, 559. [CrossRef]
247. Ismail, T.; Sestili, P.; Akhtar, S. Pomegranate peel and fruit extracts: A review of potential anti-inflammatory and anti-infective
effects. J. Ethnopharmacol. 2012, 143, 397–405. [CrossRef]
248. Lee, J.Y.; Kang, S.S.; Kim, J.-H.; Bae, C.S.; Choi, S.H. Inhibitory effect of whole bee venom in adjuvant-induced arthritis. In Vivo
2005, 19, 801–805.
249. Lee, W.R.; Kim, S.J.; Park, J.H.; Kim, K.H.; Chang, Y.C.; Park, Y.Y.; Lee, K.G.; Han, S.M.; Yeo, J.H.; Pak, S.C.; et al. Bee venom
reduces atherosclerotic lesion formation via anti-inflammatory mechanism. Am. J. Chin. Med. 2010, 38, 1077–1092. [CrossRef]
250. Abou, Z.S.S.; Abdellatif, A.; Azzazy, H.M.E. Fabrication of pomegranate/honey nanofibers for use as antibacterial wound
dressings. Wound Med. 2020, 28, 100181. [CrossRef]
251. Costeloe, A.; Vandjelovic, N.D.; Evans, M.A.; Saraiya, S.S. The use of honey in cochlear implant associated wounds in pediatric
patients. Int. J. Pediatr. Otorhinolaryngol. 2018, 111, 80–83. [CrossRef]
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antioxidants

Received: 9 November 2022

Antioxidants 2023, 12, 34. https://doi.org/10.3390/antiox12010034 https://www.mdpi.com/journal/antioxidants

2. The Composition-Related Activity of Honey

Antioxidants 2023, 12, 34 3 of 30

Table 1 illustrates various countries revealing their polyphenol composition based on

Table 1. Polyphenol composition in various countries.

No. Polyphenols [µg/g] Plant-Based Food Species Name Country Reference

3. Synergic Effect of Honey with Other Natural Products

Table 2. Synergic effect of honey with other natural products.

No. Natural Products Key Features References

No. Natural Products Key Features References

4. Mechanisms of Action and Biological Activity of Honey

Table 3. Honey mechanism of action.

No. Type of Bee Product Mode of Administration Effects of Honey References

honey (from the lime tree, ↑ (high) β-carotene

Quantifying honey’s quality, composition, and antioxidant capacity must be consid-

or apoptosis, which shows cytoplasmatic shrinkage, nuclear disintegration, chromatin

some requirements, such as killing endospores, being pollutant-free (pesticides, heavy

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