Cornara Et Al.,2017 Bee Product

REVIEW

published: 28 June 2017

doi: 10.3389/fphar.2017.00412
Therapeutic Properties of Bioactive

Compounds from Different Honeybee
Products
Laura Cornara 1*, Marco Biagi 2 , Jianbo Xiao 3 and Bruno Burlando 4
1
Dipartimento di Scienze della Terra, dell’Ambiente e della Vita, Università degli Studi di Genova, Genova, Italy, 2 Unità
Operativa di Biologia Farmaceutica, Dipartimento di Scienze Fisiche, della Terra e dell’Ambiente, Università degli Studi di
Siena, Siena, Italy, 3 Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine,
University of Macau, Taipa, Macau, 4 Dipartimento di Farmacia, Università degli Studi di Genova, Genova, Italy
Honeybees produce honey, royal jelly, propolis, bee venom, bee pollen, and
beeswax, which potentially benefit to humans due to the bioactives in them. Clinical
standardization of these products is hindered by chemical variability depending
on honeybee and botanical sources, but different molecules have been isolated
and pharmacologically characterized. Major honey bioactives include phenolics,
methylglyoxal, royal jelly proteins (MRJPs), and oligosaccharides. In royal jelly there
are antimicrobial jelleins and royalisin peptides, MRJPs, and hydroxy-decenoic acid
derivatives, notably 10-hydroxy-2-decenoic acid (10-HDA), with antimicrobial, anti-
inflammatory, immunomodulatory, neuromodulatory, metabolic syndrome preventing,
Edited by:
Monique S. J. Simmonds, and anti-aging activities. Propolis contains caffeic acid phenethyl ester and artepillin
Royal Botanic Gardens, Kew, C, specific of Brazilian propolis, with antiviral, immunomodulatory, anti-inflammatory
United Kingdom
and anticancer effects. Bee venom consists of toxic peptides like pain-inducing
Reviewed by:
Parimal C. Sen,
melittin, SK channel blocking apamin, and allergenic phospholipase A2. Bee pollen
Bose Institute, India is vitaminic, contains antioxidant and anti-inflammatory plant phenolics, as well as
Letizia Angiolella,
antiatherosclerotic, antidiabetic, and hypoglycemic flavonoids, unsaturated fatty acids,
Sapienza Università di Roma, Italy
and sterols. Beeswax is widely used in cosmetics and makeup. Given the importance of
*Correspondence:
Laura Cornara drug discovery from natural sources, this review is aimed at providing an exhaustive
[email protected] screening of the bioactive compounds detected in honeybee products and of their
curative or adverse biological effects.
Specialty section:
This article was submitted to Keywords: bee pollen, bee venom, beeswax, honey, propolis, royal jelly
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
INTRODUCTION
Received: 16 February 2017
Accepted: 12 June 2017 Honeybees are social hymenopteran insects belonging to the genus Apis, characterized by the
Published: 28 June 2017
production and storage of honey and other substances potentially useful to humans. Two
Citation: domesticated species are currently known, i.e., the western A. mellifera, native to Europe, Asia
Cornara L, Biagi M, Xiao J and
and Africa, and introduced into America, and the eastern A. cerana, distributed in southern and
Burlando B (2017) Therapeutic
Properties of Bioactive Compounds
southeastern Asia.
from Different Honeybee Products. Honey is the main and most widely appreciated honeybee product. It derives from digestive
Front. Pharmacol. 8:412. processing of nectar foraged from flowers, and is stored in honeycomb cells. Honey is generally
doi: 10.3389/fphar.2017.00412 marketed for its nutritive properties, but has been also used since the antiquity as a folk remedy,
Frontiers in Pharmacology | www.frontiersin.org 1 June 2017 | Volume 8 | Article 412

Cornara et al. Properties of Compounds from Honeybee Products
while in recent times it has been introduced as a pharmaceutical originating from glucose oxidase activity, and citric acid. Small
aid and in clinical practice (Molan, 1999). Other products derive amounts of vitamins are also present, especially vitamin B
from honeybee gland secretions and different botanical materials, complex due to pollen grains, and ascorbic acid. Minerals range
either alone or variously mixed together. These substances between 0.04 and 0.2%, reflecting the mineral content of soils
include royal jelly, beeswax, propolis, bee pollen, and bee venom. where source plants grow. Potassium is the major element,
All of them have been used by humans since ancient times for accounting for about one third of total mineral content.
nutritional and curative purposes. Different plant compounds are present in honey at low
Several biological properties have been detected in honeybee concentrations and in variable amounts depending on the
products by a wide series of scientific studies, while different botanical species visited by bees and the climate of the area from
reviews have been dedicated to summarize therapeutic properties which nectar is harvested. Aroma compounds are probably the
and uses as nutraceutical, pharmaceutical and cosmetic most diversified fraction, as testified by the finding of over 500
ingredients (Viuda-Martos et al., 2008; Burlando and Cornara, volatile compounds in different types of honey. Phenolics are
2013). Various attempts at introducing some of these products the most abundant phytochemicals, usually ranging from 50 to
in clinical settings have been made, but their pharmacological 500 mg/kg (Ramanauskiene et al., 2012; da Silva et al., 2016).
and medicinal standardization is made difficult by the high
chemical variability, depending on honeybee varieties and Antioxidant Activity
botanical sources. However, different molecules or classes of It is generally accepted that phenolics are important contributors
compounds have been isolated and some of them have also been to the antioxidant capacity of honey. Given that phenolic
pharmacologically characterized, suggesting the importance of composition is greatly variable with respect to floral origin, honey
honeybee products for drug discovery from natural sources. is expected to show a wide range of antioxidant power (Gheldof
Given the importance of this latter field in the search for new et al., 2002; Petretto et al., 2015).
remedies against problematic diseases, this review is aimed to
provide an exhaustive screening of the bioactive compounds Antimicrobial Activity
detected in honeybee products and of their curative or adverse Honey is known to contrast the growth of various
biological effects. Literature data were collected in Scopus, Web microorganisms. This kind of effect has been a main attractive
of Science, PubMed, Google Scholar, https://clinicaltrials.gov, feature for honey application in clinical medicine, as testified by
and Espacenet databases. General medicinal application of the development and marketing of γ-irradiated, Manuka medical
honeybee products has been covered, while more in depth grade honey. For this honey, a scale of antibacterial activity
search on bioactivities and putative therapeutic effects has been has been defined, known as Unique Manuka Factor (UMF),
conducted on the major constituents of these products. representing equivalents of a phenol solution yielding a certain
inhibition in a radial diffusion assay on Staphylococcus aureus
(Allen et al., 1991).
HONEY The role of specific honey antibacterial factors has been
studied by sequential neutralization, showing that the
Honey is produced by foraging bees that collect flower nectar mechanisms of action are complex and variable in different
and process it through repeated digestion and regurgitation. honey types. Basic antibacterial factors are low water activity
Stomach acidic pH, together with invertase, diastase and amylase and low pH. In addition, honey generally contains glucose
enzymatic activities, give rise to a supersaturated aqueous oxidase added by bees, which by low dilution converts glucose
solution composed by 80% sugars, mainly fructose and glucose, into H2 O2 and gluconic acid. However, measurements of
with minor amounts of sucrose, maltose, and other complex minimum inhibitory concentration and DNA degradation on
sugars. Escherichia coli and Bacillus subtilis has shown that honey H2 O2
Most nitrogen is present in amino acids and peptides. Proline concentrations would not fully account for bacterial growth
is the most abundant amino acid, followed by glutamic acid, inhibition, suggesting that other honey components should be
alanine, phenylalanine, tyrosine, leucine, isoleucine, and other involved (Brudzynski et al., 2011). Two major non-peroxide
minor ones. Honey also contains low amounts of protein, antibacterial factors are methylglyoxal (MGO) in manuka
usually 0.1÷1.5% in the western honeybee A. mellifera, and honey and defensin-1 in Revamil source (RS) honey, which also
0.1÷3.0% in the Asiatic honeybee A. cerana. Most abundant contains MGO, but to a much lower extent than manuka honey.
peptides are defensin-1 and royal jelly protein (MRJP) isoforms, RS honey is the source product for Revamil medical grade
R
while major enzymes include glucose oxidase, diastase (amylase), honey (Kwakman and Zaat, 2012).
α-glucosidase, catalase, and acid phosphatase (Kubota et al., 2004; Manuka honey derives from the nectar of the manuka
Di Girolamo et al., 2012; Chua et al., 2015). Data about honey myrtle Leptospermum scoparium, growing in southeast Australia
proteome are limited, but it is arguable that each honey type has and New Zealand. In this honey, high amounts of MGO
its own peptide pattern, consisting of ubiquitous components are formed from dihydroxyacetone, present at high levels in
and a variable set of minor elements, possibly including plant manuka nectar, through a non-enzymatic process occurring
peptides. during honey storage. The very high content of MGO, up to
Honey has an average pH of 3.9, mainly due to the presence about 1,500 mg/kg, makes this honey able to kill various bacterial
of about 0.57% organic acids, predominantly gluconic acid strains, including methicillin-resistant S. aureus (Mavric et al.,

2008). However, other unidentified compounds besides MGO cladosporioides, and pathogenic Candida parapsilosis,
are likely to contribute to antibacterial activity, since it has been C. tropicalis, and Rhodotorula sp. (Kuncic et al., 2012; Moussa
experimentally shown that MGO neutralization affects honey et al., 2012). Evidence has been collected that flavonoids like
activity against S. aureus and B. subtilis, but not against E. coli quercetin, kaempferol, chrysin, galangin, and apigenin may be
and Pseudomonas aeruginosa (Kwakman et al., 2011). involved in honey activity against C. albicans (Candiracci et al.,
Defensin-1 is an immunoactive peptide secreted by the 2011).
honeybee hypopharyngeal gland and ultimately transferred to
honey. The peptide has been detected in RS honey and Antiparasitic Activity
is responsible for antibacterial activity against Gram-positive Peptides from Ziziphus sp. honey with molecular masses ranging
bacteria like Bacillus spp. Conversely, defensin-1 is not effective from 2 to 200 kDa, separated by size-exclusion chromatography,
against S. aureus if used alone, but is essential for honey have shown antiprotozoal activity against the intestinal parasite
activity against this bacterial species, suggesting a possible Giardia lamblia (Mohammed et al., 2015). In addition, three
synergistic interaction with other honey components. Peptide- different honeys from Plectranthus, Ziziphus, and acacia, have
dependent antibacterial activities have been found in other been found to possess nematicidal activity against Caenorhabditis
honey types besides RS honey, possibly depending in some cases elegans, which has been correlated to the presence of an
on the presence of defensin-1. Other evidence for synergistic unidentified glycoconjugate of about 5 kDa (Sajid and Azim,
interactions have been detected in the effect of RS honey on 2012).
E. coli and P. aeruginosa, requiring both H2 O2 and MGO, and
on vancomycin-resistant Enterococcus faecium, requiring H2 O2 Anti-inflammatory Activity
in combination with either MGO or defensin-1 (Kwakman and An extract from Italian multifloral honey, containing the
Zaat, 2012). flavonoids daidzein, apigenin, genistin, luteolin, kaempferol,
A specific study has been devoted to compare the antibacterial quercetin, and chrysin, as major components, has inhibited
mechanisms of action of Manuka and RS honey, showing the release of pro-inflammatory TNF-α and IL-1β from LPS-
defensin-1 and H2 O2 as major antibacterial factors of RS honey. stimulated N13 microglia cells (Candiracci et al., 2012). Given a
Conversely, in manuka honey these factors have not been role of neuroinflammation in neurodegenerative diseases, these
observed, while the antibacterial activity has been found to data confirm possible use of the honey flavonoid fraction in
depend on MGO and other unidentified factors (Kwakman et al., contrasting disorders like Alzheimer or Parkinson.
2011). However, another study has shown that the apparent lack Immunomodulatory effects have been reported also for honey
of defensin-1 in manuka would be due to an inactivation of the proteins. MRJP-3 has been found to suppress IL-2, IL-4, and
peptide caused by MGO-induced modifications (Majtan et al., IFN-γ production by antigen-stimulated T cells (Okamoto et al.,
2012). 2003). Glycopeptides and glycoproteins isolated from Ziziphus
Other antibacterial factors isolated from honey are honey, ranging from 2 to 450 kDa, have inhibited ROS release by
glycoproteins with high-mannose N-glycans. These proteins zymosan-activated human neutrophils and murine macrophages,
have displayed agglutinating and bactericidal activity on NO production and phagocytosis by LPS-activated murine
different clinical isolates of multi drug resistant strains, such as macrophages, and production of TNF-α by human monocytic
methicillin-resistant S. aureus MRSA, P. aeruginosa, Klebsiella cells (Mesaik et al., 2015).
pneumoniae, vancomycin-resistant enterococci (VRE), and The honey protein apalbumin-1, aka MRJP-1, has been found
extended-spectrum β-lactamase-producing (ESBL) Proteus to block the mannose receptors of human phagocytic cells,
mirabilis, and E. coli. Q-TOF-MS analysis has shown extensive thereby inhibiting phagocytic activities. Such inhibitory effect
homology of these peptides with the MRJP-1 precursor, which seems enhanced in MGO-containing honey, due to apalbumin
harbors three antimicrobial jelleins typical of royal jelly. glycation (Molan and Rhodes, 2015).
These data indicate a role for high-mannose structures in the
antibacterial activity of honey glycoproteins (Brudzynski and Antidiabetic Activity
Sjaarda, 2015; Brudzynski et al., 2015). Honey has been found to reduce blood glucose in animal models
Fractionation of an n-hexane extract of Citrus goldcrest and in patients with impaired glucose tolerance or diabetes,
honey has led to the identification of a complex fraction with though clinical studies have not provided conclusive evidence.
inhibitory activity against a clarithromycin/metronidazole- Fructose is a potential antidiabetic agent, while the presence in
resistant Helicobacter pylori strain. This fraction contains honey of a balanced mix of fructose and glucose could play
mostly acetic acid, 2,3-dihydro-3,5-dihydroxy-6-methyl-4H- an additional role in this kind of effect, since the two sugars
pyran-4-one, 2-propanone, butanal, 1,3-benzenediamine, are known to act synergistically in promoting liver glucose
propanenitrile, 2-furanmethanol, propanoic acid, 1,3-butanediol, metabolism (Erejuwa et al., 2012).
1-(1-cyclopentenyl)-1-propanol, and 5-hydroxymethylfurfural It has been shown that non-digestible, dietary
(Manyi-Loh et al., 2012). However, the specific role of each single oligosaccharides, such as fructooligosaccharides,
compound, or the presence of combinatory effects, has not been galactooligosaccharides, and lactulose, have a preventive
ascertained. role against obesity, insulin resistance, and diabetes mellitus,
Honey is also known for antimycotic effects, e.g., against by acting as prebiotics on the intestinal flora. Given that honey
non-pathogenic Aureobasidium pullulans and Cladosporium contains oligosaccharides, it has been hypothesized that these

compounds might contribute to honey prebiotic effects, and compounds or their combinations are responsible for honey
therefore, that they could be linked to honey antidiabetic, anticancer activity is lacking.
antihyperlipidemic and hepatoprotective virtues (Erejuwa et al., A unique trihydroxyketone (E-4-(1,2,4-trihydroxy-2,6,6-
2014). However, experimental evidence in support of such trimethylcyclohexyl)-but-3-en-2-one) from thyme honey,
assumption is lacking. endowed with antibacterial activity, has been shown to induce
apoptosis on PC-3 prostate cancer cells. Such an effect has
Wound Healing been put in relationship with the inhibition of p65 NF-KB
Honey has long been known for its healing capacity on wounds phosphorylation and IL-6 secretion, but these inhibitory
and burns (Molan, 2006; Vandamme et al., 2013). Revamil R
activities have been found at concentrations ranging between
medical grade honey has been specifically developed for this 1 and 100 µM, whereas apoptosis has been observed with the
purpose, while another medical-grade, wound-dressing product 100 µM dose only (Kassi et al., 2014).
is SurgihoneyTM , consisting of engineered honey with enhanced
antimicrobial power (Al-Waili et al., 2011). Adverse Effects
Antimicrobial activity is considered the most important factor Various occurrences of toxic compounds in honey have been
for honey wound healing. However, various studies indicate reported, such as polycyclic diterpene grayanotoxins in honey
that honey may also specifically act on skin cells involved from rhododendron plants like R. luteum and R. ponticum. This
in the wound healing process (Majtan et al., 2010; Ranzato kind of honey is known as “mad honey” since it may produce
et al., 2012). Various data have been collected on honey severe neural intoxication up to fatal emergency, especially in the
immunomodulatory properties, which can at least partially eastern Black Sea region of Turkey. Grayanotoxins are known
explain the ability of promoting wound healing. Even though to affect voltage-dependent Na+ channel gating. Possibly due to
some authors have argued that honey immunostimulatory effects this kind of action, and despite its toxicity, mad honey is used
may derive from bacterial lipopolysaccharide contamination, as folk medicine for hypertension, sexual dysfunction, and other
possible immunomodulatory honey constituents have been ailments (Koca and Koca, 2007; Silici and Atayoglu, 2015).
isolated. A 5.8 kDa constituent from manuka honey stimulates Plants like Boraginaceae, Asteraceae, and Fabaceae produce
TNF-α production by macrophages via toll-like receptors (Tonks pyrrolizidine alkaloids that are not toxic per se but are converted
et al., 2007), while MRJP-1 induces TNF-α and metalloproteinase into harmful pyrrolic metabolites by liver after honey ingestion.
9 (MMP-9) expression in keratinocytes (Majtan et al., 2010). The presence of these alkaloids in typical honey botanical sources,
Kanuka honey from Kunzea ericoides, a close relative of the make these compounds a potential hazard for honey consumers
manuka myrtle L. scoparium, contains type II arabinogalactans of (Edgar et al., 2002).
plant origin that have been shown to promote TNF-α production Cases of intoxication from honey consumption in New
by monocytic cell lines differentiated into macrophage by phorbol Zealand, characterized by delirium, seizures, and memory loss,
myristate acetate (Gannabathula et al., 2012). An aqueous extract have been related to honey contamination by the neurotoxic
rich in phenolics, obtained from fir honeydew honey, has been sesquiterpene lactones tutin and hyenanchin. These oxygenated
found to inhibit TNF-α-induced MMP-9 production by human sesquiterpene picrotoxanes, targeting GABAergic and glycinergic
keratinocytes, with a possible role for kaempferol and apigenin receptors, are ingested by honeybees collecting honeydew
(Majtan et al., 2013). Such a result is apparently in contrast with produced by passionvine hoppers (Scolypopa australis) feeding
another study reporting that different types of honey stimulate on sap of the poisonous shrub tutu (Coriaria spp.) (Fields et al.,
MMP-9 expression in the same cells (Ranzato et al., 2012), but in 2014; Larsen et al., 2015). Other plant secondary metabolites,
this latter case, whole honey has been used, possibly resulting in which are found in honey and could induce deleterious effects
a dominant stimulatory effect due to other components, like for to humans, include hyoscyamine and hyoscine from Solanaceae,
instance MRJPs. saponins from Sapindaceae, strychnine and gelsemine from
Gelsemiaceae, oleandrin and oleandrigenin from Apocynaceae
Anticancer Activity (Islam et al., 2014).
Inhibitory effects of honey on various kinds of cancer have Besides phytochemicals, honey can also be contaminated
been studied both in vitro and in animal models (Erejuwa by environmental pollutants, like heavy metals, pesticides, and
et al., 2014). Polyphenols are known to possess chemopreventive antibiotics. Moreover, prolonged honey storage or heating may
properties, and accordingly, it has been shown that honey give rise to Maillard reaction products, such as the furans 5-
with higher phenolic charge is more potent in inhibiting hydroxymethylfurfural from hexoses and furfural from pentoses
cancer cell proliferation (Jaganathan and Mandal, 2009). Various (Islam et al., 2014).
polyphenols occurring in honey have been studied singularly
for their mechanisms of action on cancer models, including
caffeic acid and its phenyl esters, caffeoylquinic acid derivatives, ROYAL JELLY
rosmarinic acid and derivatives, ellagic acid, as well as
the flavonoids chrysin, luteolin, acacetin, fisetin, myricetin, Royal jelly is a secretion of honeybee hypopharynx and
wogonin, apigenin, hesperidin, galangin, quercetin, kaempferol, mandibular salivary glands. It is a white-yellowish, gelatinous,
pinobanksin, and pinocembrin (Jaganathan and Mandal, 2009; acidic colloid, containing about 67% water (w/w), 16% sugar,
Abubakar et al., 2012). However, direct evidence that these 12.5% protein and amino acids, and 5% fat, with considerable

variability among different sources. Minor royal jelly constituents MRJP-1. Antimicrobial assays conducted against the gram-
include enzymes, vitamins, phenolics, and minerals (Melliou and positive S. aureus, S. saprophyticus, and B. subtilis, the gram
Chinou, 2005). negative E. coli, E. cloacae, K. pneumoniae, and P. aeruginosa, and
Proteins are the most abundant dry matter fraction, consisting the yeast C. albicans have shown that jellein-I and -II have broad-
for more than 80% of soluble glycoproteins named major royal spectrum activity, jellein-III is less active, and jellein-IV has no
jelly proteins (MRJPs), of which nine members have been antimicrobial effect (Fontana et al., 2004).
described. These proteins are encoded by a family of genes Royalisin is a 51 amino acid peptide, homologous to the
arranged in tandem array, sharing a common ancestor with the haemolymph defensin-1, with antibacterial activity against
Yellow protein family genes (Drapeau et al., 2006). MRJP-1 is the various gram-positive strains, including Staphylococcus,
most abundant one and consists of monomeric and oligomeric Streptococcus, B. subtilis, Micrococcus luteus, Sarcina lutea,
forms. The oligomer, ranging between 350 and 420 kDa, can Clostridium, Corynebacterium, Lactobacillus helveticus,
be separated into 55 and 5 kDa units, identified as MRJP-1 Paenibacillus larvae, and Leuconostoc, while no inhibition
monomers and the 5 kDa protein apisimin, which is believed has been observed against the gram negative E. coli and Serratia
to act as subunit linker. MRJP-2, MRJP-3, MRJP-4 and MRJP-5 marcescens. Antifungal activity against Botrytis cinerea has also
are glycoproteins ranging between 49 and 80 kDa (Tamura et al., been reported for royalisin (Fujiwara et al., 1990; Bachanova
2009). et al., 2002). In addition, a variant of MRJP-2, known as
The lipid fraction mostly consists of medium chain fatty apalbumin 2a, has been found to inhibit the growth of P. larvae,
acids, terminally and/or internally hydroxylated, with terminal B. subtilis, and E. coli (Bilikova et al., 2009).
mono- or dicarboxylic acid functions, either saturated or Royal jelly carboxylic acids are known to collectively exert
monounsaturated at the 2-position. Major constituents are the antimicrobial properties against gram-positive, gram-negative
10-carbon atoms fatty acids trans-10-hydroxy-2-decenoic acid bacteria, and fungi. 10-HDA has been identified as a particularly
(10-HDA), unique to royal jelly, and 10-hydroxydecanoic acid. strong antibacterial, especially against B. subtilis, S. aureus,
Sterols are also present in minor amounts (Li et al., 2013). and E. coli (Alreshoodi and Sultanbawa, 2015). Moreover, the
Royal jelly is fed until the 3rd day of life to larvae developing compound has been shown to interfere with the adherence to
into female workers and male drones, or until the end of the larval cell surfaces of the oral pathogen S. mutans, by interfering with
period to selected individuals developing into queens. Moreover, the expression of the glucosyltransferases gtfB and gtfC (Yousefi
it is an exclusive food for adult queens throughout their life et al., 2012). Strong antifungal activity against C. albicans,
(Fujita et al., 2013). The induction of larval development into C. tropicalis, and C. glabrata has been reported for sebacic acid
queen has been ascribed to major royal jelly proteins (MRJPs) and (Melliou and Chinou, 2005).
a 57-kDa protein known as royalactin (Kamakura, 2011; Buttstedt
et al., 2013), although contrary opinions have been raised against Anti-inflammatory Activity
the alleged role of this latter (Buttstedt et al., 2016). In a study on royal jelly potential for digestive trait diseases, 10-
Royal jelly has been used since ancient times in traditional HDA has been found to protect rats from experimentally induced
medicine, especially in Asiatic apitherapy, but also in the ancient gastric ulcer (Fang et al., 1994). A mechanism putatively linked
Egypt. It is currently used in the pharmaceutical and cosmetic to 10-HDA anti-inflammatory effect is the inhibition of LPS-
fields, and marketed as an over-the-counter functional food. induced NF-κB activation observed in the murine macrophage
Various studies have reported antimicrobial activities of royal cell line RAW264 (Sugiyama et al., 2012).
jelly against bacteria, fungi, and viruses, while in animal models, 10-HDA and 4-hydroperoxy-2-decenoic acid ethyl ester have
hypotensive, antitumour, antihypercholesterolemic, and anti- been shown to inhibit histone deacetylase activity, thereby
inflammatory activities have been observed (Ramadan and Al- enhancing the expression of extracellular SOD release by
Ghamdi, 2012). Moreover, antidiabetic properties, positive effects leukemia THP-1 cells, and suggesting therapeutic potential
on benign prostatic hyperplasia, and wound healing of diabetic against atherosclerosis (Makino et al., 2016). Histone deacetylase
foot ulcers have been verified in clinical trials (Siavash et al., 2015; inhibition by 10-HDA is thought to reactivate the expression
Khoshpey et al., 2016). Most studies concern crude royal jelly or of epigenetically silenced genes in mammalian cells, leading to
protein and lipid subfractions, but in several cases the activity of the hypothesis that a similar effect could be at the basis of
singular compounds has been ascertained. caste switching in bees (Spannhoff et al., 2011). Modifications of
histone acetylation have also emerged from a study showing 10-
HDA inhibition of fibroblast-like synoviocytes from rheumatoid
Antioxidant Activity
arthritis patients, suggesting potential therapeutic effects against
Small peptides consisting of 2–4 amino acid residues have been
chronic inflammation degenerative disease (Wang et al., 2015).
reported to possess strong antioxidant activity. Most active ones
have tyrosine residues at the C-terminal, allowing hydroxyl
Immunomodulatory Activity
radical and H2 O2 scavenging activities (Guo et al., 2009).
Experimental evidence has been collected arguing for royal jelly
immunomodulatory properties. A 57 kDa and 350-kDa royal jelly
Antimicrobial Activity proteins, purportedly monomeric and oligomeric MRJP-1, have
The above-mentioned jelleins are four 8–9 amino acid peptides, been reported to stimulate the proliferation of in vitro cultured
of which jellein-I, -II, and -IV are cleavage products of hepatocytes and monocytes, respectively (Kamakura et al., 2001;

Kimura et al., 2003). As a confirmation, an in vitro study has include 10-HDA, trans-2-decenoic, 10-hydroxydecanoic, 3,10-
shown that the MRJP-1 oligomer, but not MRJP-2 or MRJP-3, dihydroxydecanoic, and sebacic acids, and in addition the steroid
induces the proliferation of the human lymphoid cell line Jurkat 24-methylenecholesterol (Suzuki et al., 2008; Moutsatsou et al.,
(Moriyama et al., 2015). MRJP-1 and MRJP-2 have been found 2010). These results have been proposed as a pharmacological
to exert immunostimulatory and proinflammatory activities by basis for an anti-menopause use of royal jelly.
stimulating cytokine release, such as TNF-α, from macrophages 10-HDA has been shown to increase collagen synthesis
(Simuth et al., 2004; Majtan et al., 2006). In contrast, MRJP-3 and production of the collagen promoting factor, transforming
has been reported to suppress interleukin production by T cells growth factor β1, in human skin fibroblasts. Such an effect is
both in vitro and in vivo, reconducible to antiallergic properties thought to mediate royal jelly skin protection against UVB-
(Okamoto et al., 2003). induced photoaging (Koya-Miyata et al., 2004; Park et al.,
Various immunomodulatory activities have been reported for 2011). In addition to promoting collagen synthesis, 10-HDA has
10-HDA, including reduced T cell proliferation, inhibition of been found to inhibit the release of the MMP-1 and MMP-3
interleukin-12 production by spleen dendritic cells, and block of from rheumatoid arthritis synovial fibroblasts, possibly through
LPS- and IFN-β-induced NO production in macrophages (Gasic downregulation of the pathway involving JNK/p38 MAP kinases
et al., 2007; Sugiyama et al., 2013). In another study, a biphasic and AP-1 transcription factor (Yang et al., 2010), and of the MMP
behavior of 10-HDA on human monocyte-derived dendritic cells regulator connective tissue growth factor (Wang et al., 2012). 10-
has been found, resulting in Th1 response stimulation and Th2 HDA has also prevented UVA-induced JNK/p38 activation and
downregulation at 50 µM, and repression of both Th1 and Th2 at MMP-1 and MMP-3 upregulation in fibroblasts (Zheng et al.,
500 µM (Mihajlovic et al., 2013). 2013).
Another hydroxyl fatty acid, 3,10-dihydroxydecanoic acid, has Such a complex of effects suggest skin dermal protection
been reported to stimulate the maturation of human monocyte- and antirheumatoid activity, but in most cases concentrations
derived dendritic cells and their Th1 polarizing capability, ranging around the millimolar level have been used, apparently
suggesting a reinforcement of antitumour and antiviral immunity with low clinical feasibility. However, a registered, synthetic 10-
(Dzopalic et al., 2011). The immunomodulatory properties of HDA counterpart, known as Hydroxydecine , has been shown
R
royal jelly lipids suggest their possible use in interventions on to activate keratinocyte differentiation in vitro, to restore skin
autoimmune diseases. barrier function in skin equivalents, and to improve UV-induced
xerosis in human volunteers (Duplan et al., 2011).
Metabolic Syndrome Preventing Activity
The royal jelly proteins MRJP-1, MRJP-2, and MRJP-3 have
Neuromodulatory Activity
been shown to possess bile acid-binding properties. The most
10-HDA and 10-hydroxydecanoic acid have been shown to
active one is MRJP-1, which in rats has increased fecal bile acids
act as potent agonists of the human TRPA1 and TRPV1
and cholesterol excretion, and has powered hepatic cholesterol
receptors (Terada et al., 2011). 10-HDA has stimulated neuron
catabolism (Kashima et al., 2014). In a study aimed at disclosing
differentiation from rat embryo neural stem cells, possibly acting
royal jelly antihypertensive mechanisms, MRJP-1 has been
like the ω-3 docosahexaenoic acid, an essential diet component
transfected into vascular smooth muscle cells, leading to a
that is known to promote neurogenesis in the central nervous
reduction of contraction, migration and proliferation (Fan et al.,
system. Docosahexaenoic acid is reputed essential for brain
2016).
development and function and has shown positive effects in a
A study conducted both in vitro on L6 myotubes, and
rat Parkinson’s model, suggesting similar potentials for 10-HDA,
in vivo on mice, has demonstrated that 10-HDA enhances
which in addition could cross more easily the blood-brain barrier
insulin-independent muscle glucose uptake via AMP-activated
due to its smaller molecule (Hattori et al., 2007). Neurogenerative
protein kinase activation and GLUT4 translocation to the plasma
potentials of royal jelly fatty acids are also suggested by a study
membrane (Takikawa et al., 2013). Moreover, this fatty acid has
on synthetic, medium-chain fatty acids, in which 2-decenoic acid
been found to improve hyperlipidemic condition in a rat model
ethyl ester, a derivative of the royal jelly 2-decenoic acid, has
(Xu et al., 2002).
promoted functional recovery in a rat model of spinal cord injury
(Hirakawa et al., 2010).
Anti-aging Activity
Royal jelly is known to extend the lifespan of honeybees.
This property is at least in part due to royalactin, which has Adverse Effects
been found to induce such effect in other insect species, like Similarly to honey, environmental contaminants can also be
Drosophila melanogaster, as well as in non-insect species, like the present in royal jelly. Most common ones are pesticides belonging
nematode C. elegans (Detienne et al., 2014). Moreover, also10- to organochlorines, organophosphorus and carbamates, which
HDA has been found to increase longevity and confer thermal are generally below Minimal Risk Level. However, in some cases
and oxidative stress tolerance to C. elegans, possibly through the highly toxic, zero-tolerance chloramphenicol has been found
dietary restriction and TOR kinase signaling (Honda et al., 2015). (Bogdanov, 2006).
Royal jelly has estrogen-like effects, which in different studies Royal jelly consumption can occasionally lead to contact
have been ascribed to the ability of different lipids to act dermatitis, asthma and anaphylaxis, while MRJP-1 and MRJP-2
as weak activators of estrogen receptors. These constituents have been identified as major allergens (Rosmilah et al., 2008).

PROPOLIS activity of Brazilian propolis has been demonstrated for its

volatile fractions containing nerolidol, spatulenol, p-cimen-8-ol,
Propolis is a resinous substance that foraging bees produce ethylphenol, β-caryophyllene, acetophenone, α-pinene, β-pinene
by collecting resin from buds and other plant tissues and and limonene (Bankova et al., 2014).
then mixing it with wax and pollen to have a malleable, Propolis has been shown to act as an antifungal agent against
compact substance that they use as hive repairing material pathogenic yeasts like C. albicans, C. parapsilosis, C. tropicalis,
and sanitizer (Sun et al., 2015). The chemical composition and C. glabrata (Al-Waili et al., 2012; Mutlu Sariguzel et al.,
of propolis is dramatically dependent on its geographical and 2016). Antifungal activity has been shown for volatile compounds
floral origins. Raw propolis generally contains more than 300 from Brazilian propolis, viz. α-pinene, β-pinene and δ-cadinene,
different compounds, mostly consisting of triterpenes (50% w/w), and from Turkish propolis, viz. phenyl-, ethyl-, and benzyl
waxes (25–30%), volatile mono- and sesquiterpenes (8–12%), alcohol, and decanal (Ioshida et al., 2010). The ethanolic
giving propolis its typical resinous odor, and phenolics (5–10%) extracts of Iranian propolis have shown strong anti-C. albicans
(Huang et al., 2014). European and Asian propolis contain activity imputable to inhibition of germ tube development by
simple phenolic acids (Bankova et al., 2002), while lignans are phenolic, aromatic, and aliphatic acids (Haghdoost et al., 2016).
main compounds in tropical propolis (Petrova et al., 2010). Another ethanolic extract containing CAPE and other caffeic acid
Caffeic acid phenethyl ester (CAPE) is a major active found in derivatives has been effective against C. albicans, C. dubliniensis,
European, Asian and American propolis (Omene et al., 2013). C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis, with
Brazilian green propolis is characterized by the presence of an MFC of 125-500 mg/L, while red Brazilian propolis rich
the 3,5-diprenyl-4-hydroxycinnamic acid artepillin C, together in triterpenes and isoflavones, such as medicarpin, vestitol and
with other prenylated cinnamic acids and caffeic acid derivatives formononetin, has shown the same MFC range (Freires et al.,
(Marcucci et al., 2001). Other propolis common constituents 2016).
include organic acids, ketones, aldehydes, hydrocarbons, and
minerals (Wagh, 2013).
Antiviral Activity
Propolis is well known for its antiviral activity, which in some
Antioxidant Activity
cases can exceed that of standard drugs. For instance, an
Propolis is the bee product containing the highest amount of
ointment containing Canadian propolis has produced better
phenolics and thus it has been deeply studied for antioxidant and
results than acyclovir or placebo in the clinical treatment
radical scavenging activities (Viuda-Martos et al., 2008). Several
of genital herpes simplex (Vynograd et al., 2000). Antiviral
of these compounds possess strong antioxidant and antiradicalic
properties seem to depend mainly on the presence of CAPE
activities, including pinocembrin, chrysin, and pinobanksin (Sun
and related compounds. CAPE has been found to inhibit
et al., 2015). In DPPH and ORAC tests, pinobanksin-3-acetate
the activity of HIV-1 by acting on viral integrase (Costi
has been indicated as the strongest antioxidant constituent
et al., 2004), and to suppress hepatitis C virus replication
(Boisard et al., 2014).
in vitro (Zhang et al., 2003). Turkish Hatay propolis containing
caffeic acid derivatives has been effective on herpes simplex
Antimicrobial Activity
virus 1 and 2 (Yildirim et al., 2016). 3,4-Dicaffeoylquinic
The antimicrobial activity of propolis has been demonstrated
acid, a major constituent of Brazilian green propolis, has
in clinical, in vivo, and in vitro studies. Propolis possesses
repressed influenza A virus in mice by upregulating the TNF-
antibacterial properties against Gram positive and negative
related, apoptosis-inducing ligand (TRAIL) (Takemura et al.,
strains, also validated in clinical trials (Noronha et al., 2014).
2012).
Sensitive strains include MRSA, VRE, Streptococcus species, and
H. pylori (Kosalec et al., 2005; Coelho et al., 2007).
Propolis antibacterial effects are possibly related to the Immunomodulatory Activity
presence of such flavonoids as galangin, pinocembrin, Propolis is generally known to modulate immune responses (Orsi
rutin, quercetin, and naringenin, as well as of CAPE, since et al., 2000), and this kind of effects could explain to some extent
these compounds are known to increase bacterial membrane its antimicrobial and antiviral activities.
permeability (Stepanovic et al., 2003). Inhibition of bacterial RNA Brazilian green propolis standardized in 18.9% w/w
polymerase has been also considered for galangin, pinocembrin, polyphenols, 9.85% flavonoids and 2.3 artepillin C, administered
and CAPE (Speciale et al., 2006). The antimicrobial activity to old mice, has enhanced phagocytosis, production of antibodies
of Brazilian red propolis is thought to depend on its peculiar against sheep erythrocytes, and ear swelling (Gao et al., 2014).
content in isoflavones (Freires et al., 2016). Brazilian green propolis and artepillin C have both inhibited
Antibacterial effectiveness has been demonstrated for in vitro alloreactive CD4+ T cell responses, together with
different propolis volatile fractions, including β-eudesmol the expression of IL-2, IL-17, and IFN-γ. In healthy subjects
and δ-cadinene in Bulgarian propolis, α-pinene and trans- and asthmatic patients, CAPE has inhibited IL-5 and IFN-γ
β-terpineol in Greek propolis, β-eudesmol and benzyl benzoate production, and the proliferation of CD4+ T cells stimulated
in Hungarian propolis, nerolidol, spatulenol and ledol in Canary by soluble anti-CD3 and anti-CD28 monoclonal antibodies,
Island propolis, and farnesol, dihydroeudesmol and guaiol by targeting NF-κB and AKT/PKB pathways (Wang et al.,
in Polish propolis (Bankova et al., 2014). The antibacterial 2010).

Anti-inflammatory Activity ferulate, benzyl isoferulate, pinostrobin, 5-phenylpenta-2,4-

Many studies have reported anti-inflammatory properties of dienoic acid, and tectochrysin, have exhibited antiproliferative
propolis, possibly linked to the presence of phenolic acids. effects on DLD-1 colon cancer, HCT-116 colon carcinoma,
CAPE is considered a particularly strong anti-inflammatory KYSE-30 esophageal squamous cancer, and NCI-N87 gastric
constituent, able to specifically target NF-κB signaling (Armutcu carcinoma cells (Catchpole et al., 2015). Polish propolis rich in
et al., 2015). This compound has been also found to modulate phenolic acids and flavonoids has been shown to possess dose-
ERK MAPK signaling in T cells and mastocytes (Cho et al., dependent antiproliferative and proapoptotic activities on HCT
2014), and to regulate PI3K/Akt pathway in different human 116 colon cancer and Me45 malignant melanoma cells (Kubina
cell lines (Li et al., 2017). Possible downstream effects et al., 2015).
of these anti-inflammatory mechanisms may include the Various mechanisms of action have been disclosed for CAPE,
downregulation of key inflammatory enzymes, like xanthine including suppression of tyrosine kinase activity and induction
oxidase, cyclooxygenase, matrix metalloproteinases, and of cell cycle arrest in G1 or G2/M phase (Patel, 2016), block of
inducible nitric oxide synthase (Armutcu et al., 2015; Li et al., migration and invasiveness through Wnt inhibition and ROR2
2017). upregulation (Tseng et al., 2016), voltage-gated sodium channel
Anti-inflammatory virtues of propolis are popularly exploited block leading to reduction of breast cancer cell motility and
in mouthwash products. Antigingivitis activity has been invasiveness (Fraser et al., 2016), and selective inhibition of
ascribed to phenolics, especially CAPE (Li et al., 2017). cancerous cell viability (Kuo et al., 2015). Moreover, CAPE seems
Moreover, in randomized, double-blind, placebo-controlled synergistic with tamoxifen on MCF-7 breast cancer cells (Motawi
trials, rinse products containing Brazilian green propolis rich et al., 2016), and has induced radiosensitivity on MDA-MB-
in artepillin C have alleviated gingivitis to the same extent of a 231 (estrogen receptor negative) and T47D (estrogen receptor
NaF/cetylpyridinium chloride rinse or a chlorhexidine solution positive) breast cancer cell lines (Khoram et al., 2016).
(Bretz et al., 2014). The flavone chrysin has exerted an antiproliferative effect
Propolis is also lenitive to the skin by topical application. on human Hep-3B, TCC, A549, HeLa, and colorectal cancer
Australian and Romanian propolis have induced photo- cells (Patel, 2016), while possible mechanisms of action
protective effects on animal models, possibly due to the anti-UV include TRAIL-induced caspase activation and STAT3 inhibition
properties of polyphenols (Cole et al., 2010; Bolfa et al., 2013). (Lirdprapamongkol et al., 2013), as well as p38 and Bax
activation (Pichichero et al., 2011). Artepillin C has induced
an antiproliferative effect on prostate cancer cells by reducing
Wound Healing and Skin Protection TRAIL resistance and inhibiting NF-κB, while a proapoptotic
Animal models and clinical trials have shown the healing effect of galangin has been related to the induction of MAPK
effect of propolis on diabetic foot ulcers and other problematic phosphorylation (Zhang et al., 2013).
tissue injuries (Henshaw et al., 2014; Abu-Seida, 2015). Propolis A study on M12.C3.F6 B-cell lymphoma cancer cell line
wound healing activities are favored by the immunomodulatory, has shown that pinobanksin, pinobanksin-3-O-propanoate,
antioxidant and antiseptic effects of its rich phytocomplex pinobanksin-3-O-butyrate and pinobanksin-3-O-pentanoate
(Martinotti and Ranzato, 2015). However, other mechanisms exert an antiproliferative effect by inducing loss of mitochondrial
seem to play a role, since molecular studies have revealed membrane potential and activating caspases 3, 8 and 9 (Alday
that propolis modulates fibronectin expression and collagen et al., 2015). Similarly, the phenolic lipids cardanol and cardol
I and III deposition in burns (Olczyk et al., 2013). An from Thai propolis have shown antiproliferative effects on
Indian propolis containing flavonoids, phenolic acids and several human cancer cells (Teerasripreecha et al., 2012), while
terpenes, topically applied to rats with excision wounds, cardanol has also induced apoptosis in BT-474 breast cancer cells,
has upregulated hydroxyproline, hexosamine, uronic acid, upregulated p21, stimulated ERK, p38 and JNK phosphorylation,
nucleic acids and protein levels in wounded tissue, similar and downregulated cyclin D (Buahorm et al., 2015). Finally,
to the effect of nitrofurazone (Iyyam Pillai et al., 2010). In the polycyclic, polyisoprenylated benzophenone nemorosone
addition, in a study on Wistar rats, Brazilian green propolis from Cuban propolis has shown anticancer effects on estrogen
rich in artepillin C has revealed superior wound healing receptor-positive MCF-7 cells by blocking cell cycle in G0/G1,
activity with respect to Brazilian red propolis (Batista et al., and reducing MAPK and Akt phosphorylation (Popolo et al.,
2012). 2011).
Anticancer Activity Adverse Effects

A very large number of in vitro and pre-clinical studies on Clinical and in vivo studies on animal models have reported
propolis anticancer effects are available, while only few clinical that propolis is well tolerated and non-toxic. The No Observed
studies have been conducted and their results are controversial. Adverse Effect Level (NOAEL) on mice and rats is over
Propolis from Aydin, Turkey, rich in CAPE and flavonoids, has 1,470 mg/Kg/day at 60 days, and over 2,470 mg/Kg/day at
shown a concentration-dependent apoptotic effect on CCRF- 90 days (Burdock, 1998). In humans, toxic effects occur at dosages
SB lymphoblastic leukemic cells involving the modulation of as high as 15 g/die (Castaldo and Capasso, 2002). However,
different miRNA expressions (Yilmaz et al., 2016). New Zealand despite its favorable safety profile, propolis is a common cause
propolis and its constituents chrysin, galangin, CAPE, benzyl of allergic reactions. It has been reported that 1.2–6.6% of

patients with dermatitis are sensitive to propolis (Walgrave et al., been reported by different sources, while attempts at clarifying
2005), while major sensitizers are 3-methyl-2-butenyl caffeate, molecular mechanisms have been made by in vitro studies (Gajski
phenylethyl caffeate, benzyl salicylate, benzyl cinnamate, and 1,1- and Garaj-Vrhovac, 2013). It has been shown for instance that
dimethylallylcaffeic acid (Burdock, 1998; Walgrave et al., 2005). melittin induces apoptosis in human ovarian cancer cells, SKOV3
and PA-1, by increasing the expression levels of the DR3, DR4,
and DR6 death receptors (Jo et al., 2012).
BEE VENOM Despite many indications of possible therapeutic applications
of melittin, in vivo injection is known to entails side effects
Bee venom, also known as apitoxin, is a complex fluid like hemolysis and liver injury, which have stimulated studies
secreted by the bee venom gland located in the abdominal for the development of non-toxic hybrid derivatives. Engineered
cavity and injected into victims by a stinger, causing local melittin peptides have also been developed for different
inflammation, anticoagulant effect, and immune response. Bee biotechnological applications, e.g., to enhance antimicrobial
venom constituents include amphipathic polycationic peptides, properties or promote siRNA release from endosomes into target
of which major ones are melittin and apamin, enzymes such cells. (Moreno and Giralt, 2015).
as phospholipase A2, and low-molecular weight compounds
including active bioamines such as histamine and catecholamines Apamin
(Lee et al., 2016). Apamin is a peptide of 18 amino acids, tightly cross-linked by the
The venom has been traditionally, used in acupuncture presence of two disulphide bonds (Habermann, 1984). It exerts
and apitherapy, consisting in its injection to the patient as a highly specific toxicity mechanism, consisting in a block of
analgesic, against chronic pain and inflammation, and for other small conductance Ca2+ -dependent K+ channels (SK channels)
purposes such as immunotherapy and Parkinson’s treatment. expressed in the central nervous system and in other districts, like
A number of anticancer effects have been reported, together with the cardiovascular system and smooth muscle (Adelman et al.,
antimutagenic, antinociceptive, and radioprotective properties. 2012).
Approved pharmaceutical use has been introduced, while Due to its ability of selectively targeting SK channels, apamin
attempts at validating clinical treatment for chronic pain have has been used as a tool for the physiological characterizations
been made (Moreno and Giralt, 2015; Sobral et al., 2016). of this kind of K+ conductance (Castle et al., 1989). On a
However, different bee venom constituents are allergenic and pharmacological ground, such a property has been adopted
in hypersensitive people bee sting can arrive to produce fatal as an explanatory paradigm for accumulating evidence that
outcome (Gelder et al., 1996). apamin facilitates learning and memory. Apamin can cross
the blood-brain barrier, and its administration to animals
Melittin improves cognitive deficits, suggesting that SK channels would
Melittin is a peptide of 26 amino acid residues, with a prevalently be appropriate apamin targets in the treatment of these neural
hydrophobic N-terminus and a hydrophilic C-terminus. It has disorders (Deschaux and Bizot, 2005; Brennan et al., 2008). In
distinct biological activities and has attracted much interest from addition, the possibility of using apamin or less toxic analogs
pharmacological and biotechnological points of view. as blood-brain barrier, drug-delivery shuttles has been explored
The toxicity mechanism consists in the disruption of (Oller-Salvia et al., 2013).
phospholipid bilayers, leading to cell lysis and the release of tissue SK channels are known to be involved in the pathogenesis
injurious compounds such as lysosomal enzymes, serotonin, of Parkinson’s disease. Consistent with this premise, another
and histamine, triggering inflammation and pain (Raghuraman important perspective for neuro-therapeutic uses of apamin
and Chattopadhyay, 2007). Together with hyaluronidase and derives from its ability of protecting dopaminergic neurons from
phospholipase A2, melittin is responsible for venom allergenic degeneration in experimental models of Parkinson’s (Alvarez-
properties. It seems also a major cause of pain induction by the Fischer et al., 2013; Thomas and Justin, 2013). Among other
bee venom, through activation of TRPV receptors and release possible uses, experimental work has shown antiatherosclerotic
of algogens from injured cells (Chen et al., 2016). In contrast to effects of apamin administered to mice (Kim et al., 2012), while as
its toxicity, melittin is known as a traditional anti-inflammatory a K+ channel blocker, apamin can be useful for long-term whole
remedy for various diseases, such as dermatitis, neuritis, liver blood storage (Delgado and Pitt, 2008).
inflammation, atherosclerosis, and arthritis, but the mechanism
of action at the cellular level has not been clarified (Lee and Phospholipase A2
Bae, 2016). A possible coherent mechanism of antiatherosclerotic Phospholipase A2 (PLA2) hydrolyzes complex lipids to
effects of melittin consists in the inhibition of vascular smooth produce a fatty acid and various reaction products, including
muscle proliferation through the hindrance of platelet-derived lysophosphatidic acid, lysophosphatidylcholine, and sphingosine
growth factor beta-receptor signaling (Son et al., 2007). phosphate. These latters exert cytotoxic and immunostimulatory
The ability of interacting with biological membranes confers effects on various cell types, eventually triggering immune
strong antimicrobial properties to melittin, which have attracted responses and inflammation.
interest for fighting human pathogens, such as methicillin- Phospholipase A2 is the major allergen of bee venom,
resistant S. aureus (Choi et al., 2015), as well as plant pathogens containing three peptide and one glycopeptide T cell epitopes
(Stockwell and Duffy, 2012). Anticancer activities of melittin have recognized by allergic and non-allergic subjects (Dhillon

et al., 1992; Okano et al., 1999). However, PLA2 has also with nectar and bee salivary secretions becomes the “bee bread,”
properties translatable into therapeutic treatments. It has exerted representing a main food reserve for the hive colony (Almeida-
neuroprotective effects in a mouse model of Parkinson’s disease Muradian et al., 2005).
by activating regulatory T lymphocytes (Treg) that are known Main chemical compounds of bee pollen include
to mediate peripheral immune tolerance (Chung et al., 2015). carbohydrates, proteins and amino acids, lipids and fatty
Systemic PLA2 administration to a mouse model of neuropathic acids, phenolics, enzymes and coenzymes, vitamins and minerals
pain has alleviated cold and mechanical allodynia through (Komosinska-Vassev et al., 2015). However, the chemical
the activation of α2-adrenegic receptors (Li et al., 2015). composition of bee pollen is highly variable, depending on plant
It has also been shown that PLA2 acts cooperatively with source, geographical region, and climatic conditions, thus deeply
phosphatidylinositol-(3,4)-bisphosphate in inducing in vitro lysis affecting biological properties and therapeutic virtues (Denisow
of different tumor cell lines (Putz et al., 2006). and Denisow-Pietrzyk, 2016).
Bee pollen is an energy food used by humans as a diet
Minor Peptides and Enzymes supplement and for the conditioning of athletes. The high content
The second major allergen of honeybee venom is hyaluronidase of protein, fat, and minerals (particularly Ca, Mg, Fe, and P) gives
(Padavattan et al., 2007), while other allergenic peptides include bee pollen a nutritional value similar to, or higher than, that of
icarapin isolated from A. cerana (Wong et al., 2012), and two dried legumes. Among vitamins, the levels of pantothenic and
serine proteases named Api SI and Api SII belonging to the nicotinic acids are close to those of beef, ascorbic acid is similar to
prophenoloxidase activating factor II family (Georgieva et al., that of vegetables, such as lettuce and tomatoes, and riboflavin is
2011). Another serine protease of this family, named Bi-VSP, has comparable to that of skimmed milk power (Linskens and Jorde,
a dual behavior, since in arthropods it triggers the phenoloxidase 1997).
cascade inducing a lethal immune response, while in mammals Bee pollen is used in complementary and alternative
it acts as a toxic thrombin-like and plasmin-like fibrinolytic medicine to cure prostatitis, stomach ulcers, infectious
protease (Choo et al., 2010). diseases, and for the prevention and treatment of high-
Secapin is a serine protease inhibitor-like peptide exerting altitude-sickness syndrome (Linskens and Jorde, 1997).
anti-fibrinolytic and anti-elastolytic activities, and also displaying A wide range of therapeutic properties have been suggested,
antimicrobial properties by binding to the surfaces of fungi and including antimicrobic, antioxidant, hepatoprotective,
bacteria (Lee et al., 2016). Two peptides isolated from A. cerana chemopreventive and anticarcinogenic, antiatherosclerotic,
venom, viz. an inhibitor cysteine knot (ICK) peptide and a anti-inflammatory, antiallergenic, and immunomodulatory
Kazal-type serine protease inhibitor, have been shown to act as activities (Komosinska-Vassev et al., 2015; Denisow and
antibacterial, antifungal and insecticidal venom toxins (Kim et al., Denisow-Pietrzyk, 2016).
2013; Park et al., 2014).
Tertiapin is a 21 amino acid neurotoxin blocking inward- Antioxidant Activity
rectifier K+ channels expressed in epithelial cells, heart, The antioxidant activity of bee pollen seems to be mainly
and central nervous system. In the heart, tertiapin contrasts due to phenolic acids, like vanillic, protocatechuic, gallic, and
G-protein-gated, acetylcholine-activated K+ current that mediate p-coumaric acids, and to flavonoids like hesperidin, rutin,
parasympathetic heart rate decrease. This toxin could be allegedly kaempferol, apigenin, luteolin, quercetin, and isorhamnetin.
useful as a drug for treating disorders in atrio-ventricular These compounds are thought to inactivate electrophiles and
transmission, but at present it is used solely as a tool for K+ scavenge free radicals and reactive oxygen species (Bonvehí et al.,
channel modulation (Drici et al., 2000). 2001; Pascoal et al., 2014).
Mast cell degranulating (MCD) peptide is a 22-amino acid
peptide with two disulfide bridges, structurally similar to apamin Antimicrobial Activity
but with different mechanisms of action. At low concentrations, Antimicrobial effects of bee pollen are well known, possibly
MCD induces mast cell degranulation through histamine release, mediated by glucose oxidase activity, deriving from honeybee
while at higher concentrations it can produce anti-inflammatory secretion, while plant phenolics and flavonoids could also
effects (Buku, 1999). Moreover, MCD also acts as a neurotoxin be involved (Denisow and Denisow-Pietrzyk, 2016; Fatrcova-
by blocking fast-inactivating (A-type) and slow-inactivating Sramkova et al., 2016). Evidence about the activity of phenolic
(delayed rectifier) K+ channels, thereby increasing neuronal compounds from bee pollen extracts against Gram-positive
excitability. Long term potentiation in the hippocampus CA1 and Gram-negative pathogenic bacteria, microscopic fungi and
region has been experimentally observed, while direct brain yeasts, has been reported (Baltrušaitytė et al., 2007; Kacániová
injection leads to convulsions and neurodegeneration (Mourre et al., 2012).
et al., 1997).
Anti-inflammatory Activity
Bee pollen exerts anti-inflammatory effects that have been
BEE POLLEN compared to those of common non-steroidal anti-inflammatory
drugs, possibly depending on the activity of flavonoids,
Foraging bees bring pollen back to the hive where it is packed phenolic acids, phytosterols, and flavoring substances like
into pellets and stored. During this process, the pollen mixed anethole, an inhibitor of the NF-KB pathway (Middleton,

1998; Choi, 2007). Specific effects include the capability niacin, thiamine, biotin, and folic acid, polyphenols, carotenoids,
of removing swellings caused by cardiovascular and renal phytosterols, and minerals (Denisow and Denisow-Pietrzyk,
pathologies (Yakusheva, 2010), of protecting the liver from 2016).
carbon tetrachloride-induced damages (Yildiz et al., 2013), and
of alleviating prostate inflammation and hyperplasia (Yakusheva, Adverse Effects
2010). Positive effects on prostatic conditions have been Health risks linked to the use of bee pollen may derive
also ascribed to antiandrogen actions (Rzepecka-Stojko et al., from the occasional presence of contaminants such as heavy
2012). metals, pesticides, mycotoxins (e.g., ochratoxin A), and bacteria
(Denisow and Denisow-Pietrzyk, 2016). Moreover, bee pollen
Anticancer Activity derived from Echium vulgare, Symphytum officinale, and Senecio
Different studies have shown potential anticancer activity of bee jacobaea may contain dangerous levels of pyrrolizidine alkaloids
pollen, probably associated with antioxidant and antimutagenic with hepatotoxic properties (Kempf et al., 2010).
potentials (Denisow and Denisow-Pietrzyk, 2016). The steroid As known, pollen is highly allergenic, and consequently,
fraction of a chloroform extract from Brassica campestris bee complications or anaphylaxis due to bee pollen use have
pollen has shown strong cytotoxicity on human prostate cancer been reported, making tests for individual sensitivity highly
PC-3 cells, associated to stimulation of TNF-α secretion and recommendable before use (Jagdis and Sussman, 2012).
apoptosis induction (Wu and Lou, 2007).
Antiatherosclerotic and Antidiabetic BEESWAX

Activities Worker bees secrete beeswax by wax glands located in abdominal
Bee pollen has shown antiatherosclerotic and cardioprotective segments. This substance is generally produced in greatest
effects and has been successfully applied to patients who did not amount during colony growth phase in late spring, and is
respond to classical drugs (Polanski et al., 1998). Hypolipidemic used for making combs. Beeswax is synthesized starting from
activity, confirmed by pharmacological studies conducted on rats honey sugars, and has a crystalline structure suitable for hive
and rabbits, has been ascribed to the presence of unsaturated fatty construction.
acids, especially the ω-3, α-linolenic acid, and to phospholipids Chemical composition varies among bee species and
and phytosterols (Komosinska-Vassev et al., 2015). α-Linolenic geographical zones, and includes hydrocarbons, of which major
acid is a precursor of prostaglandin-3a that is considered a major ones are heptacosane, nonacosane, hentriacontane, pentacosane
inhibitor of platelet aggregation (Denisow and Denisow-Pietrzyk, and tricosane, free fatty acids and free fatty alcohols, linear
2016). wax monoesters, hydroxymonoesters deriving from palmitic,
Ghoshal and Saoji (2013) have found the presence of 15-hydroxypalmitic, and oleic acids, and complex wax esters
antidiabetic compounds in pollen grains, such as steroids and containing 15-hydroxypalmitic acid and diols (Münstedt and
alkaloids in the pollen of C. roseus, saponins, flavonoids, Bogdanov, 2009). A total of about 50 aroma components has
sugars, and tannins in M. charantia, sugars, flavonoids and also been reported (Ferber and Nursten, 1977). The ester/acid
sterols in B. monosperma, and alkaloids and tannins in ratio is important for beeswax characterization by different
S. cuminii, suggesting therapeutic possibilities for bee pollen as Pharmacopeias, being generally lower (3–4) in European,
a hypoglycemic agent. and higher (8–9) in Asian beeswax (Münstedt and Bogdanov,
2009).
Immunomodulatory Activity Beeswax is used as an additive in a variety of industrial
Evidence of antiallergic activity of bee pollen has been reported, products and processes, such as food industry, candles, and
including prevention of IgE binding to their high-affinity cosmetics. In pharmaceutical preparations it plays a role as a
receptor FcεRI, inhibition of histamine release from mast cells, thickener, binder, drug carrier and release retardant.
and basophil degranulation (Ishikawa et al., 2008; Moita et al.,
2014). Flavonoids, steroids, and volatile oil compounds seem to Antimicrobial Activity
be involved in immunosuppressive activities. Beeswax has been used since ancient times for its antimicrobial
properties in European and Asian traditional medicines.
Nutritional Properties Preservative effects are possibly at the basis of its use in
Bee pollen has been used as a diet supplement in recovery embalming and mummification practices by old Egyptians and
periods, in cases of malnutrition, asthenia and apathy, and Persian, or to model death masks by ancient Romans.
to increase physical and mental ability or strengthen the A beeswax crude extract has shown inhibitory effects against
immune system. Experiments on animals have shown that the S. aureus, Salmonella enterica, C. albicans and Aspergillus niger
administration of bee pollen prolongs life span, promotes weight (Ghanem, 2011), while effects against pathogenic bacteria and
gain, increases plasma hemoglobin levels, and provides tissues microscopic fungi have been reported for methanol and ethanol
with vitamin C and Mg (Khalil and El-Sheikh, 2010; Attia et al., extracts (Kacániová et al., 2012). This kind of effects could depend
2011). These virtues may be related to a complex of active at least in part on beeswax compounds of plant origin (Puleo and
substances, including amino acids, vitamins like tocopherol, Keunen, 1991).

TABLE 1 | Reported effects for major compounds from different honeybee products.
Product Compound Effect Reference
Honey H2 O2 Antimicrobial activity Brudzynski et al., 2011

MGO Antimicrobial activity Mavric et al., 2008
Defensin-1 Antimicrobial activity Kwakman and Zaat, 2012
Trihydroxyketone Apoptosis induction and p65, NF-KB and IL-6 repression in PC-3 Kassi et al., 2014
cancer cells
Royal Jelly MRJP-1 Block of mannose receptors in human phagocytic cells Molan and Rhodes, 2015
MRJP-1 Induction of TNF-α and MMP-9 in keratinocytes Majtan et al., 2010
MRJP-1 Increase of fecal bile acids and cholesterol excretion Kashima et al., 2014
MRJP-1 oligomer Promotion of Jurkat lymphoid cell proliferation Moriyama et al., 2015
MRJP-1 and MRJP-2 Stimulation of TNF-α release from macrophages Majtan et al., 2006
MRJP-3 Suppression of IL-2, IL-4, and IFN-γ production by Okamoto et al., 2003
antigen-stimulated T cells
Apalbumin 2a (MRJP-2 variant) Antimicrobial activity Bilikova et al., 2009
Jelleins Antimicrobial activity Fontana et al., 2004
Royalisin Antimicrobial activity Bachanova et al., 2002
Royalactin Increase of lifespan in honeybees and other invertebrates Detienne et al., 2014
10-HDA Antimicrobial activity Alreshoodi and Sultanbawa, 2015
10-HDA Inhibition of LPS-induced NF-κB activation in murine macrophages Sugiyama et al., 2012
10-HDA Inhibition of histone deacetylase Makino et al., 2016
10-HDA Inhibition of synoviocytes from rheumatoid arthritis Wang et al., 2015
10-HDA Inhibition of IL-12 production by dendritic cells and of NO Sugiyama et al., 2013
production by macrophages
10-HDA Modulation of dendritic cell, Th1 and Th2 activity Mihajlovic et al., 2013
10-HDA Increase of insulin-independent muscle glucose uptake Takikawa et al., 2013
10-HDA Improvement of hyperlipidemic condition in rats Xu et al., 2002
10-HDA Increase of longevity and oxidative stress tolerance in Honda et al., 2015
Caenorhabditis elegans
10-HDA Increase of TGF-β1production and collagen synthesis in fibroblasts Park et al., 2011
10-HDA Inhibition of MMP-1 and MMP-3 release from rheumatoid arthritis Yang et al., 2010
fibroblasts
10-HDA Prevention of UVA-induced JNK/p38 activation and MMP-1 and Zheng et al., 2013
MMP-3 upregulation in fibroblasts
10-HDA and 10-hydroxydecanoic Inhibition of TRPA1 and TRPV1 receptors Terada et al., 2011
10-HDA Stimulation of neuron differentiation from rat embryo stem cells Hattori et al., 2007
3,10-dihydroxydecanoic acid Stimulation of dendritic cell differentiation Dzopalic et al., 2011
Sebacic acid Antifungal activity Melliou and Chinou, 2005
Propolis CAPE Inhibition of HIV-1 integrase Costi et al., 2004
CAPE Suppression of hepatitis C virus replication in vitro Zhang et al., 2003
CAPE Antigingivitis activity Li et al., 2017
CAPE Inhibition of IL-5 and IFN-γ production Wang et al., 2010
CAPE Inhibition of CD4+ T cell proliferation by targeting NF-κB and Wang et al., 2010
AKT/PKB
CAPE Anti-inflammatory effect by targeting NF-κB Armutcu et al., 2015
CAPE Modulation of ERK in T cells and mastocytes Cho et al., 2014
CAPE Regulation of PI3K/AKT pathway in human cells Li et al., 2017
CAPE Suppression of tyr kinase activity and induction of cell cycle arrest Patel, 2016
CAPE Block of cancer cell migration and invasiveness Tseng et al., 2016
CAPE Voltage-gated sodium channel block in breast cancer cells Fraser et al., 2016
CAPE Selective inhibition of cancerous cell viability Kuo et al., 2015
Artepillin C Inhibition of CD4+ T cells, and of IL-2, IL-17, and IFN-γ release Wang et al., 2010
Artepillin C Antiproliferative effect on prostate cancer cells by targeting NF-κB Zhang et al., 2013
(Continued)

TABLE 1 | Continued
Product Compound Effect Reference
Chrysin, galangin, CAPE, benzyl Antiproliferative activity on different cancer cell lines Catchpole et al., 2015
ferulate, benzyl isoferulate, pinostrobin,
5-phenylpenta-2,4-dienoic acid, and
tectochrysin
Chrysin Antiproliferative effect on different cancer cells Patel, 2016
Chrysin TRAIL-induced caspase activation and STAT3 inhibition in Lirdprapamongkol et al., 2013
cancer cells
Chrysin p38 and Bax activation in cancer cells Pichichero et al., 2011
Galangin, pinocembrin, and CAPE Inhibition of bacterial RNA polymerase Speciale et al., 2006
Galangin Proapoptotic effect on cancer cells Zhang et al., 2013
Pinobanksin Loss of mitochondrial membrane potential and caspase Alday et al., 2015
activation in cancer cells
Pinobanksin-3-acetate Strong antioxidant effect Boisard et al., 2014
3,4-dicaffeoylquinic acid TRAIL upregulation and repression of influenza A virus in mice Takemura et al., 2012
Cardanol and cardol Antiproliferative effect on different cancer cells Teerasripreecha et al., 2012
Cardanol Induction of apoptosis in breast cancer cells with cyclin D Buahorm et al., 2015
downregulation
Nemorosone Inhibition of MCF-7 cells by cell cycle block and of MAPK and Popolo et al., 2011
AKT
Bee venom Melittin Cytotoxic effect by disruption of phospholipid bilayers Raghuraman and Chattopadhyay, 2007
Melittin Activation of TRPV receptors and release of algogens Chen et al., 2016
Melittin Anti-inflammatory effect Lee and Bae, 2016
Melittin Inhibition of PDGFR-β signaling Son et al., 2007
Melittin Antimicrobial effect Choi et al., 2015
Melittin Apoptosis induction in ovarian cancer cells by DR3, DR4, DR6 Jo et al., 2012
upregulation
Apamin Block of SK channels Castle et al., 1989
Apamin Antiatherosclerotic effect in mice Kim et al., 2012
PLA2 Allergenic effect Okano et al., 1999
PLA2 Treg activation in Parkinson’s mouse model Chung et al., 2015
PLA2 Activation of α2-adrenegic receptors in allodynia mouse model Li et al., 2015
Hyaluronidase Allergenic effect Padavattan et al., 2007
Bi-VSP serine protease Thrombin-like and plasmin-like fibrinolysis Choo et al., 2010
Secapin Serine protease inhibition and antimicrobial effect Lee et al., 2016
Inhibitor cysteine knot peptide and Antimicrobial and insecticidal effects Park et al., 2014
Kazal-type serine protease inhibitor
Tertiapin Inward-rectifier K+ channel block Drici et al., 2000
MCD Mast cell degranulation and histamine release Buku, 1999
MCD Fast- and slow-inactivating K+ channel block Mourre et al., 1997
Bee Pollen Anethole NF-KB pathway inhibition Choi, 2007
MGO, methylglyoxal; MRJP, major royal jelly protein; 10-HDA, 10-hydroxy-2-decenoic acid; CAPE, caffeic acid phenethyl ester; PLA2, phospholipase A2; MCD, mast cell
degranulating peptide.
Dermatological and Cosmetic Properties FUTURE PERSPECTIVES

Beeswax has been known as a major Ayurvedic remedy for
inflammation, bruises, burns, and cracked heels (Gokani, 2014). Pharmaceutical and clinical uses of honeybee products are
Ointments based on beeswax useful for joint pain, wounds and attracting increasing interest. Research and development in this
burns, are reported in the Ebers Papyrus (about 3500 B.P.), by the field generally concern whole materials or subfractions rather
Greek-Roman physician Galen (about 2150 B.P.), and in old texts than single compounds. Clinical trials have been conducted,
of traditional Chinese medicine, such as the “Shen Nong Book of among others, with honey for cicatrization problems and
Herbs” (about 2100–2200 B.P.) (Rit and Behrer, 1999). diabetes, with royal jelly for diabetes and rheumatoid arthritis,
Thanks to its very low irritant and comedogenic effects, with propolis for disinfection and gingivitis, and with bee
beeswax is widely used in modern cosmetics and makeup as a venom for Parkinsons’ and rheumatoid arthritis1 . However, the
thickener, emollient and emulsifier (Münstedt and Bogdanov,
2009). 1
https://clinicaltrials.gov

complexity and variability in composition of these products raise have been patented, while synthetic MGO has been added in
the need of their standardization before safe and predictable some cases to medicinal honey for strengthening wound healing
clinical uses can be achieved. properties (Wardell and Sabacinski, 2016). Methods for 10-HDA
Conversely, the use of specific compounds from honeybee purification from royal jelly, artepillin C from propolis, melittin
products as curative drugs has not been implemented yet. As and apamin from bee venom, and their uses in pharmaceutical
shown in the present review, various of these compounds have preparations have been also patented (Iinuma et al., 2014).
been in-depth characterized for their effects on biochemical Regardless whether the pharmaceutical exploitation of these
pathways, cells, and organs, suggesting a series of possible bioactives is going to take off or not, studies aimed at refining
uses as therapeutic drugs (Table 1). Moreover, preclinical the knowledge of their mechanisms of action remain of pivotal
studies indicate that some of these agents may be competitive importance for developing applications of honeybee products to
with standard drugs, possibly including MGO, MRJPs, jelleins, medicinal uses.
royalisin, 10-HDA, CAPE, artepillin C, melittin, and apamin.
However, none of them is reported at the online clinical trial
database https://clinicaltrials.gov/, with the exception of CAPE2 , AUTHOR CONTRIBUTIONS
suggesting that their medicinal use as specific drugs is not
forthcoming. LC contributed with ethnobotanical and pharmacognosy
Different reasons may explain the gap between the clinical aspects; MB contributed with pharmaceutical aspects; JX
exploitation of whole honeybee products and their single contributed with chemical aspects; BB contributed with aspects
constituents. A role may be played in some cases by the toxicity on mechanisms of actions.
of the bioactive agent, or alternatively, by an economically
inefficient scale-up of pharmaceutical manufacturing, even
though some compounds can be obtained by synthetic way ACKNOWLEDGMENT
too. Procedures for the chemical synthesis of MGO and CAPE
This work was granted by University of Genova, n. 100022-2015
2
https://clinicaltrials.gov/ct2/show/NCT02744703?term=caffeic+acid&rank=3 FRA.
REFERENCES and immunomodulatory effects (Review). Exp. Ther. Med. 9,

1582–1588. doi: 10.3892/etm.2015.2346
Abubakar, M. B., Abdullah, W. Z., Sulaiman, S. A., and Suen, A. B. (2012). A review Attia, Y. A., Al-Hanoun, A., El-Din, A. E., Bovera, F., and Shewika, Y. E. (2011).
of molecular mechanisms of the anti-leukemic effects of phenolic compounds Effect of bee pollen levels on productive, reproductive and blood traits of NZW
in honey. Int. J. Mol. Sci. 13, 15054–15073. doi: 10.3390/ijms131115054 rabbits. J. Anim. Physiol. Anim. Nutr. (Berl) 95, 294–303. doi: 10.1111/j.1439-
Abu-Seida, A. M. (2015). Effect of propolis on experimental cutaneous wound 0396.2010.01054.x
healing in dogs. Vet. Med. Int. 2015:672643. doi: 10.1155/2015/672643 Bachanova, K., Klaudiny, J., Kopernicky, J., and Simuth, J. (2002). Identification of
Adelman, J. P., Maylie, J., and Sah, P. (2012). Small-conductance Ca2+- honeybee peptide active against Paenibacillus larvae larvae through bacterial
activated K+ channels: form and function. Annu. Rev. Physiol. 74, 245–269. growth-inhibition assay on polyacrylamide gel. Apidologie 33, 259–269.
doi: 10.1146/annurev-physiol-020911-153336 doi: 10.1051/apido:2002015
Alday, E., Valencia, D., Carreno, A. L., Picerno, P., Piccinelli, A. L., Rastrelli, L., et al. Baltrušaitytė, V., Venskutonis, P. R., and Čeksterytë, V. (2007). Antibacterial
(2015). Apoptotic induction by pinobanksin and some of its ester derivatives activity of honey and beebread of different origin against S. aureus and
from Sonoran propolis in a B-cell lymphoma cell line. Chem. Biol. Interact. 242, S. epidermidis. Food Technol. Biotechnol. 45, 201–208.
35–44. doi: 10.1016/j.cbi.2015.09.013 Bankova, V., Popova, M., Bogdanov, S., and Sabatini, A. G. (2002). Chemical
Allen, K. L., Molan, P. C., and Reid, G. M. (1991). A survey of the antibacterial composition of European propolis: expected and unexpected results.
activity of some New Zealand honeys. J. Pharm. Pharmacol. 43, 817–822. Z. Naturforsch. C 57, 530–533. doi: 10.1515/znc-2002-5-622
doi: 10.1111/j.2042-7158.1991.tb03186.x Bankova, V., Popova, M., and Trusheva, B. (2014). Propolis volatile compounds:
Almeida-Muradian, L. B., Pamplona, L. C., Coimbra, S., and Barth, O. M. (2005). chemical diversity and biological activity: a review. Chem. Cent. J. 8:28.
Chemical composition and botanical evaluation of dried bee pollen pellets. doi: 10.1186/1752-153X-8-28
J. Food Compost. Anal. 18, 105–111. doi: 10.1016/j.jfca.2003.10.008 Batista, L. L., Campesatto, E. A., Assis, M. L., Barbosa, A. P., Grillo, L. A., and
Alreshoodi, F. M., and Sultanbawa, Y. (2015). Antimicrobial activity of royal jelly. Dornelas, C. B. (2012). Comparative study of topical green and red propolis
Antiinfect. Agents 13, 50–59. doi: 10.2174/2211352513666150318234430 in the repair of wounds induced in rats. Rev. Col. Bras. Cir. 39, 515–520.
Alvarez-Fischer, D., Noelker, C., Vulinovic, F., Grunewald, A., Chevarin, C., doi: 10.1590/S0100-69912012000600012
Klein, C., et al. (2013). Bee venom and its component apamin as neuroprotective Bilikova, K., Mirgorodskaya, E., Bukovska, G., Gobom, J., Lehrach, H., and
agents in a Parkinson disease mouse model. PLoS ONE 8:e61700. doi: 10.1371/ Simuth, J. (2009). Towards functional proteomics of minority component
journal.pone.0061700 of honeybee royal jelly: the effect of post-translational modifications on the
Al-Waili, N., Al-Ghamdi, A., Ansari, M. J., Al-Attal, Y., and Salom, K. antimicrobial activity of apalbumin2. Proteomics 9, 2131–2138. doi: 10.1002/
(2012). Synergistic effects of honey and propolis toward drug multi-resistant pmic.200800705
Staphylococcus aureus, Escherichia coli and Candida albicans isolates in single Bogdanov, S. (2006). Contaminants of bee products. Apidologie 37, 1–18.
and polymicrobial cultures. Int. J. Med. Sci. 9, 793–800. doi: 10.7150/ijms. doi: 10.1051/apido:2005043
4722 Boisard, S., Le Ray, A. M., Gatto, J., Aumond, M. C., Blanchard, P., Derbre, S.,
Al-Waili, N., Salom, K., and Al-Ghamdi, A. A. (2011). Honey for wound et al. (2014). Chemical composition, antioxidant and anti-AGEs activities of a
healing, ulcers, and burns; data supporting its use in clinical practice. French poplar type propolis. J. Agric. Food Chem. 62, 1344–1351. doi: 10.1021/
ScientificWorldJournal 11, 766–787. doi: 10.1100/tsw.2011.78 jf4053397
Armutcu, F., Akyol, S., Ustunsoy, S., and Turan, F. F. (2015). Therapeutic Bolfa, P., Vidrighinescu, R., Petruta, A., Dezmirean, D., Stan, L., Vlase, L., et al.
potential of caffeic acid phenethyl ester and its anti-inflammatory (2013). Photoprotective effects of Romanian propolis on skin of mice exposed

to UVB irradiation. Food Chem. Toxicol. 62, 329–342. doi: 10.1016/j.fct.2013. Choi, J. H., Jang, A. Y., Lin, S., Lim, S., Kim, D., Park, K., et al. (2015). Melittin,
08.078 a honeybee venom-derived antimicrobial peptide, may target methicillin-
Bonvehí, J. S., Torrentó, M. S., and Lorente, E. C. (2001). Evaluation resistant Staphylococcus aureus. Mol. Med. Rep. 12, 6483–6490. doi: 10.3892/
of polyphenolic and flavonoid compounds in honeybee-collected pollen mmr.2015.4275
produced in Spain. J. Agric. Food Chem. 49, 1848–1853. doi: 10.1021/jf001 Choo, Y. M., Lee, K. S., Yoon, H. J., Kim, B. Y., Sohn, M. R., Roh, J. Y., et al. (2010).
2300 Dual function of a bee venom serine protease: prophenoloxidase-activating
Brennan, A. R., Dolinsky, B., Vu, M. A., Stanley, M., Yeckel, M. F., and Arnsten, factor in arthropods and fibrin(ogen)olytic enzyme in mammals. PLoS ONE
A. F. (2008). Blockade of IP3-mediated SK channel signaling in the rat medial 5:e10393. doi: 10.1371/journal.pone.0010393
prefrontal cortex improves spatial working memory. Learn. Mem. 15, 93–96. Chua, L. S., Lee, J. Y., and Chan, G. F. (2015). Characterization of the proteins in
doi: 10.1101/lm.767408 honey. Anal. Lett. 48, 697–709. doi: 10.1080/00032719.2014.952374
Bretz, W. A., Paulino, N., Nor, J. E., and Moreira, A. (2014). The effectiveness of Chung, E. S., Lee, G., Lee, C., Ye, M., Chung, H. S., Kim, H., et al. (2015).
propolis on gingivitis: a randomized controlled trial. J. Altern. Complement. Bee venom phospholipase A2, a novel Foxp3+ regulatory T cell inducer,
Med. 20, 943–948. doi: 10.1089/acm.2013.0431 protects dopaminergic neurons by modulating neuroinflammatory responses
Brudzynski, K., Abubaker, K., St-Martin, L., and Castle, A. (2011). Re-examining in a mouse model of Parkinson’s Disease. J. Immunol. 195, 4853–4860.
the role of hydrogen peroxide in bacteriostatic and bactericidal activities of doi: 10.4049/jimmunol.1500386
honey. Front. Microbiol. 2:213. doi: 10.3389/fmicb.2011.00213 Coelho, L. G., Bastos, E. M., Resende, C. C., Paula e Silva, C. M., Sanches, B. S.,
Brudzynski, K., and Sjaarda, C. (2015). Honey glycoproteins containing de Castro, F. J., et al. (2007). Brazilian green propolis on Helicobacter pylori
antimicrobial peptides, jelleins of the major royal jelly protein 1, are responsible infection. a pilot clinical study. Helicobacter 12, 572–574. doi: 10.1111/j.1523-
for the cell wall lytic and bactericidal activities of honey. PLoS ONE 5378.2007.00525.x
10:e0120238. doi: 10.1371/journal.pone.0120238 Cole, N., Sou, P. W., Ngo, A., Tsang, K. H., Severino, J. A., Arun, S. J., et al. (2010).
Brudzynski, K., Sjaarda, C., and Lannigan, R. (2015). MRJP1-containing Topical ‘Sydney’ propolis protects against UV-radiation-induced inflammation,
glycoproteins isolated from honey, a novel antibacterial drug candidate with lipid peroxidation and immune suppression in mouse skin. Int. Arch. Allergy
broad spectrum activity against multi-drug resistant clinical isolates. Front. Immunol. 152, 87–97. doi: 10.1159/000265530
Microbiol. 6:711. doi: 10.3389/fmicb.2015.00711 Costi, R., Santo, R. D., Artico, M., Massa, S., Ragno, R., Loddo, R., et al. (2004). 2,6-
Buahorm, S., Puthong, S., Palaga, T., Lirdprapamongkol, K., Phuwapraisirisan, P., Bis(3,4,5-trihydroxybenzylydene) derivatives of cyclohexanone: novel potent
Svasti, J., et al. (2015). Cardanol isolated from Thai Apis mellifera propolis HIV-1 integrase inhibitors that prevent HIV-1 multiplication in cell-based
induces cell cycle arrest and apoptosis of BT-474 breast cancer cells via p21 assays. Bioorg. Med. Chem. 12, 199–215. doi: 10.1016/j.bmc.2003.10.005
upregulation. Daru 23, 55. doi: 10.1186/s40199-015-0138-1 da Silva, P. M., Gauche, C., Gonzaga, L. V., Costa, A. C., and Fett, R. (2016). Honey:
Buku, A. (1999). Mast cell degranulating (MCD) peptide: a prototypic peptide in chemical composition, stability and authenticity. Food Chem. 196, 309–323.
allergy and inflammation. Peptides 20, 415–420. doi: 10.1016/S0196-9781(98) doi: 10.1016/j.foodchem.2015.09.051
00167-3 Delgado, M. C., and Pitt, B. (2008). Composition and methods for preserving red
Burdock, G. A. (1998). Review of the biological properties and toxicity of bee blood cells. U.S. Patent No WO2008089337 A1. Washington, DC: U.S. Patent
propolis (propolis). Food Chem. Toxicol. 36, 347–363. doi: 10.1016/S0278- and Trademark Office.
6915(97)00145-2 Denisow, B., and Denisow-Pietrzyk, M. (2016). Biological and therapeutic
Burlando, B., and Cornara, L. (2013). Honey in dermatology and skin care: a properties of bee pollen: a review. J. Sci. Food Agric. 96, 4303–4309.
review. J. Cosmet. Dermatol. 12, 306–313. doi: 10.1111/jocd.12058 doi: 10.1002/jsfa.7729
Buttstedt, A., Ihling, C. H., Pietzsch, M., and Moritz, R. F. (2016). Royalactin is not Deschaux, O., and Bizot, J. C. (2005). Apamin produces selective improvements of
a royal making of a queen. Nature 537, E10–E12. doi: 10.1038/nature19349 learning in rats. Neurosci. Lett. 386, 5–8. doi: 10.1016/j.neulet.2005.05.050
Buttstedt, A., Moritz, R. F., and Erler, S. (2013). More than royal food - Major royal Detienne, G., De Haes, W., Ernst, U. R., Schoofs, L., and Temmerman, L. (2014).
jelly protein genes in sexuals and workers of the honeybee Apis mellifera. Front. Royalactin extends lifespan of Caenorhabditis elegans through epidermal
Zool. 10:72. doi: 10.1186/1742-9994-10-72 growth factor signaling. Exp. Gerontol. 60, 129–135. doi: 10.1016/j.exger.2014.
Candiracci, M., Citterio, B., Diamantini, G., Blasa, M., Accorsi, A., and Piatti, E. 09.021
(2011). Honey flavonoids, natural antifungal agents against Candida albicans. Dhillon, M., Roberts, C., Nunn, T., and Kuo, M. (1992). Mapping human T cell
Int. J. Food Prop. 14, 799–808. doi: 10.1080/10942910903453355 epitopes on phospholipase A2: the major bee-venom allergen. J. Allergy Clin.
Candiracci, M., Piatti, E., Dominguez-Barragan, M., Garcia-Antras, D., Immunol. 90, 42–51. doi: 10.1016/S0091-6749(06)80009-6
Morgado, B., Ruano, D., et al. (2012). Anti-inflammatory activity of a Di Girolamo, F., D’Amato, A., and Righetti, P. G. (2012). Assessment of the floral
honey flavonoid extract on lipopolysaccharide-activated N13 microglial cells. origin of honey via proteomic tools. J. Proteomics 75, 3688–3693. doi: 10.1016/
J. Agric. Food Chem. 60, 12304–12311. doi: 10.1021/jf302468h j.jprot.2012.04.029
Castaldo, S., and Capasso, F. (2002). Propolis, an old remedy used in modern Drapeau, M. D., Albert, S., Kucharski, R., Prusko, C., and Maleszka, R. (2006).
medicine. Fitoterapia 73(Suppl. 1), S1–S6. doi: 10.1016/S0367-326X(02) Evolution of the yellow/major royal jelly protein family and the emergence
00185-5 of social behavior in honey bees. Genome Res. 16, 1385–1394. doi: 10.1101/gr.
Castle, N. A., Haylett, D. G., and Jenkinson, D. H. (1989). Toxins in 5012006
the characterization of potassium channels. Trends Neurosci. 12, 59–65. Drici, M. D., Diochot, S., Terrenoire, C., Romey, G., and Lazdunski, M. (2000). The
doi: 10.1016/0166-2236(89)90137-9 bee venom peptide tertiapin underlines the role of I(KACh) in acetylcholine-
Catchpole, O., Mitchell, K., Bloor, S., Davis, P., and Suddes, A. (2015). induced atrioventricular blocks. Br. J. Pharmacol. 131, 569–577. doi: 10.1038/sj.
Antiproliferative activity of New Zealand propolis and phenolic compounds vs bjp.0703611
human colorectal adenocarcinoma cells. Fitoterapia 106, 167–174. doi: 10.1016/ Duplan, H., Questel, E., Hernandez-Pigeon, H., Galliano, M. F., Caruana, A.,
j.fitote.2015.09.004 Ceruti, I., et al. (2011). Effects of Hydroxydecine((R)) (10-hydroxy-2-decenoic
Chen, J., Guan, S. M., Sun, W., and Fu, H. (2016). Melittin, the major pain- acid) on skin barrier structure and function in vitro and clinical efficacy
producing substance of bee venom. Neurosci. Bull. 32, 265–272. doi: 10.1007/ in thetreatment of UV-induced xerosis. Eur. J. Dermatol. 21, 906–915.
s12264-016-0024-y doi: 10.1684/ejd.2011.1531
Cho, M. S., Park, W. S., Jung, W. K., Qian, Z. J., Lee, D. S., Choi, J. S., et al. (2014). Dzopalic, T., Vucevic, D., Tomic, S., Djokic, J., Chinou, I., and Colic, M.
Caffeic acid phenethyl ester promotes anti-inflammatory effects by inhibiting (2011). 3,10-Dihydroxy-decanoic acid, isolated from royal jelly, stimulates Th1
MAPK and NF-kappaB signaling in activated HMC-1 human mast cells. Pharm. polarising capability of human monocyte-derived dendritic cells. Food Chem.
Biol. 52, 926–932. doi: 10.3109/13880209.2013.865243 126, 1211–1217. doi: 10.1016/j.foodchem.2010.12.004
Choi, E. M. (2007). Antinociceptive and antiinflammatory activities of pine Edgar, J. A., Roeder, E., and Molyneux, R. J. (2002). Honey from plants containing
(Pinus densiflora) pollen extract. Phytother. Res. 21, 471–475. doi: 10.1002/ptr. pyrrolizidine alkaloids: a potential threat to health. J. Agric. Food Chem. 50,
2103 2719–2730. doi: 10.1021/jf0114482

Erejuwa, O. O., Sulaiman, S. A., and Wahab, M. S. (2012). Honey–a novel Gokani, T. (2014). Ayurveda–the science of healing. Headache 54, 1103–1106.
antidiabetic agent. Int. J. Biol. Sci. 8, 913–934. doi: 10.7150/ijbs.3697 doi: 10.1111/head.12363
Erejuwa, O. O., Sulaiman, S. A., and Wahab, M. S. (2014). Effects of honey and its Guo, H., Kouzuma, Y., and Yonekura, M. (2009). Structures and properties
mechanisms of action on the development and progression of cancer. Molecules of antioxidative peptides derived from royal jelly protein. Food Chem. 113,
19, 2497–2522. doi: 10.3390/molecules19022497 238–245. doi: 10.1016/j.foodchem.2008.06.081
Fan, P., Han, B., Feng, M., Fang, Y., Zhang, L., Hu, H., et al. (2016). Functional and Habermann, E. (1984). Apamin. Pharmacol. Ther. 25, 255–270. doi: 10.1016/0163-
proteomic investigations reveal major royal jelly protein 1 associated with anti- 7258(84)90046-9
hypertension activity in mouse vascular smooth muscle cells. Sci. Rep. 6:30230. Haghdoost, N. S., Salehi, T. Z., Khosravi, A., and Sharifzadeh, A. (2016). Antifungal
doi: 10.1038/srep30230 activity and influence of propolis against germ tube formation as a critical
Fang, E.-L., Zhou, H.-Z., Xu, H.-L., and Xing, M.-J. (1994). Antiulcer effects of virulence attribute by clinical isolates of Candida albicans. J. Mycol. Med. 26,
10-hydroxy-2-decenoic in rats. Chin. Pharmacol. Bull. 10, 139–142. 298–305. doi: 10.1016/j.mycmed.2015.11.004
Fatrcova-Sramkova, K., Nozkova, J., Mariassyova, M., and Kacaniova, M. (2016). Hattori, N., Nomoto, H., Fukumitsu, H., Mishima, S., and Furukawa, S. (2007).
Biologically active antimicrobial and antioxidant substances in the Helianthus Royal jelly and its unique fatty acid, 10-hydroxy-trans-2-decenoic acid, promote
annuus L. bee pollen. J. Environ. Sci. Health B 51, 176–181. doi: 10.1080/ neurogenesis by neural stem/progenitor cells in vitro. Biomed. Res. 28, 261–266.
03601234.2015.1108811 doi: 10.2220/biomedres.28.261
Ferber, C. E. M., and Nursten, H. E. (1977). The aroma of wax. J. Sci. Food Agric. Henshaw, F. R., Bolton, T., Nube, V., Hood, A., Veldhoen, D., Pfrunder, L., et al.
28, 511–518. doi: 10.1002/jsfa.2740280608 (2014). Topical application of the bee hive protectant propolis is well tolerated
Fields, B. A., Reeve, J., Bartholomaeus, A., and Mueller, U. (2014). Human and improves human diabetic foot ulcer healing in a prospective feasibility
pharmacokinetic study of tutin in honey; a plant-derived neurotoxin. Food study. J. Diabetes Complications 28, 850–857. doi: 10.1016/j.jdiacomp.2014.
Chem. Toxicol. 72, 234–241. doi: 10.1016/j.fct.2014.07.032 07.012
Fontana, R., Mendes, M. A., de Souza, B. M., Konno, K., Cesar, L. M., Malaspina, O., Hirakawa, A., Shimizu, K., Fukumitsu, H., Soumiya, H., Iinuma, M., and
et al. (2004). Jelleines: a family of antimicrobial peptides from the Royal Jelly of Furukawa, S. (2010). 2-Decenoic acid ethyl ester, a derivative of unsaturated
honeybees (Apis mellifera). Peptides 25, 919–928. doi: 10.1016/j.peptides.2004. medium-chain fatty acids, facilitates functional recovery of locomotor
03.016 activity after spinal cord injury. Neuroscience 171, 1377–1385. doi: 10.1016/j.
Fraser, S. P., Hemsley, F., and Djamgoz, M. B. (2016). Caffeic acid phenethyl neuroscience.2010.10.004
ester: inhibition of metastatic cell behaviours via voltage-gated sodium channel Honda, Y., Araki, Y., Hata, T., Ichihara, K., Ito, M., Tanaka, M., et al. (2015).
in human breast cancer in vitro. Int. J. Biochem. Cell Biol. 71, 111–118. 10-hydroxy-2-decenoic acid, the major lipid component of royal jelly, extends
doi: 10.1016/j.biocel.2015.12.012 the lifespan of Caenorhabditis elegans through dietary restriction and target of
Freires, I. A., Queiroz, V. C., Furletti, V. F., Ikegaki, M., de Alencar, S. M., rapamycin signaling. J. Aging Res. 2015, 7. doi: 10.1155/2015/425261
Duarte, M. C., et al. (2016). Chemical composition and antifungal potential Huang, S., Zhang, C. P., Wang, K., Li, G. Q., and Hu, F. L. (2014). Recent
of Brazilian propolis against Candida spp. J. Mycol. Med. 26, 122–132. advances in the chemical composition of propolis. Molecules 19, 19610–19632.
doi: 10.1016/j.mycmed.2016.01.003 doi: 10.3390/molecules191219610
Fujita, T., Kozuka-Hata, H., Ao-Kondo, H., Kunieda, T., Oyama, M., and Kubo, T. Iinuma, M., Furukawa, S., Naiki, M., Matsumoto, T., and Higashiura, K. (2014).
(2013). Proteomic analysis of the royal jelly and characterization of the Trans-2-decenoic acid derivative and drug containing same. U.S. Patent No
functions of its derivation glands in the honeybee. J. Proteome Res. 12, 404–411. SG11201406942S. Washington, DC: U.S. Patent and Trademark Office.
doi: 10.1021/pr300700e Ioshida, M. D. M., Young, M. C. M., and Lago, J. H. G. (2010). Chemical
Fujiwara, S., Imai, J., Fujiwara, M., Yaeshima, T., Kawashima, T., and Kobayashi, K. composition and antifungal activity of essential oil from Brazilian propolis.
(1990). A potent antibacterial protein in royal jelly. Purification and J. Essent. Oil Bearing Plants 13, 633–637. doi: 10.1080/0972060X.2010.10643873
determination of the primary structure of royalisin. J. Biol. Chem. 265, Ishikawa, Y., Tokura, T., Nakano, N., Hara, M., Niyonsaba, F., Ushio, H.,
11333–11337. et al. (2008). Inhibitory effect of honeybee-collected pollen on mast cell
Gajski, G., and Garaj-Vrhovac, V. (2013). Melittin: a lytic peptide with anticancer degranulation in vivo and in vitro. J. Med. Food 11, 14–20. doi: 10.1089/jmf.
properties. Environ. Toxicol. Pharmacol. 36, 697–705. doi: 10.1016/j.etap.2013. 2006.163
06.009 Islam, M. N., Khalil, M. I., Islam, M. A., and Gan, S. H. (2014). Toxic compounds
Gannabathula, S., Skinner, M. A., Rosendale, D., Greenwood, J. M., Mutukumira, in honey. J. Appl. Toxicol. 34, 733–742. doi: 10.1002/jat.2952
A. N., Steinhorn, G., et al. (2012). Arabinogalactan proteins contribute to the Iyyam Pillai, S., Palsamy, P., Subramanian, S., and Kandaswamy, M. (2010). Wound
immunostimulatory properties of New Zealand honeys. Immunopharmacol. healing properties of Indian propolis studied on excision wound-induced rats.
Immunotoxicol. 34, 598–607. doi: 10.3109/08923973.2011.641974 Pharm. Biol. 48, 1198–1206. doi: 10.3109/13880200903578754
Gao, W., Wu, J., Wei, J., Pu, L., Guo, C., Yang, J., et al. (2014). Brazilian green Jaganathan, S. K., and Mandal, M. (2009). Antiproliferative effects of honey and
propolis improves immune function in aged mice. J. Clin. Biochem. Nutr. 55, of its polyphenols: a review. J. Biomed. Biotechnol. 2009:830616. doi: 10.1155/
7–10. doi: 10.3164/jcbn.13-70 2009/830616
Gasic, S., Vucevic, D., Vasilijic, S., Antunovic, M., Chinou, I., and Colic, M. (2007). Jagdis, A., and Sussman, G. (2012). Anaphylaxis from bee pollen supplement.
Evaluation of the immunomodulatory activities of royal jelly components CMAJ 184, 1167–1169. doi: 10.1503/cmaj.112181
in vitro. Immunopharmacol. Immunotoxicol. 29, 521–536. doi: 10.1080/ Jo, M., Park, M. H., Kollipara, P. S., An, B. J., Song, H. S., Han, S. B., et al. (2012).
08923970701690977 Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells
Gelder, C., Harris, J., and Williams, D. (1996). Allergy to bee and wasp venom. Br. through induction of death receptors and inhibition of JAK2/STAT3 pathway.
J. Hosp. Med. 55, 349–352. Toxicol. Appl. Pharmacol. 258, 72–81. doi: 10.1016/j.taap.2011.10.009
Georgieva, D., Greunke, K., Arni, R. K., and Betzel, C. (2011). Three-dimensional Kacániová, M., Vuković, N., Chlebo, R., Haščík, P., Rovná, K., Cubon, J., et al.
modelling of honeybee venom allergenic proteases: relation to allergenicity. (2012). The antimicrobial activity of honey bee pollen, loads and bees wax from
Z. Naturforsch. C 66, 305–312. doi: 10.5560/ZNC.2011.66c0305 Slovakia. Arch. Biol. Sci. Belgrade 64, 927–934. doi: 10.2298/ABS1203927K
Ghanem, N. (2011). Study on the antimicrobial activity of honey products and Kamakura, M. (2011). Royalactin induces queen differentiation in honeybees.
some Saudi folkloric substances. Res. J. Biotechnol. 6, 38–43. Nature 473, 478–483. doi: 10.1038/nature10093
Gheldof, N., Wang, X. H., and Engeseth, N. J. (2002). Identification and Kamakura, M., Suenobu, N., and Fukushima, M. (2001). Fifty-seven-kDa protein
quantification of antioxidant components of honeys from various floral sources. in royal jelly enhances proliferation of primary cultured rat hepatocytes and
J. Agric. Food Chem. 50, 5870–5877. doi: 10.1021/jf0256135 increases albumin production in the absence of serum. Biochem. Biophys. Res.
Ghoshal, K. P., and Saoji, A. A. (2013). Phytochemical screening of the pollen of Commun. 282, 865–874. doi: 10.1006/bbrc.2001.4656
some selected plants with antidiabetic properties. Aust. J. Basic Appl. Sci. 7, Kashima, Y., Kanematsu, S., Asai, S., Kusada, M., Watanabe, S., Kawashima, T.,
105–109. et al. (2014). Identification of a novel hypocholesterolemic protein, major royal

jelly protein 1, derived from royal jelly. PLoS ONE 9:e105073. doi: 10.1371/ Lee, G., and Bae, H. (2016). Anti-inflammatory applications of melittin, a major
journal.pone.0105073 component of bee venom: detailed mechanism of action and adverse effects.
Kassi, E., Chinou, I., Spilioti, E., Tsiapara, A., Graikou, K., Karabournioti, S., et al. Molecules 21, E616. doi: 10.3390/molecules21050616
(2014). A monoterpene, unique component of thyme honeys, induces apoptosis Lee, K. S., Kim, B. Y., Yoon, H. J., Choi, Y. S., and Jin, B. R. (2016). Secapin, a bee
in prostate cancer cells via inhibition of NF-kappaB activity and IL-6 secretion. venom peptide, exhibits anti-fibrinolytic, anti-elastolytic, and anti-microbial
Phytomedicine 21, 1483–1489. doi: 10.1016/j.phymed.2014.04.032 activities. Dev. Comp. Immunol. 63, 27–35. doi: 10.1016/j.dci.2016.05.011
Kempf, M., Heil, S., Hasslauer, I., Schmidt, L., von der Ohe, K., Theuring, C., et al. Li, D., Lee, Y., Kim, W., Lee, K., Bae, H., and Kim, S. K. (2015).
(2010). Pyrrolizidine alkaloids in pollen and pollen products. Mol. Nutr. Food Analgesic effects of bee venom derived phospholipase A(2) in a mouse
Res. 54, 292–300. doi: 10.1002/mnfr.200900289 model of oxaliplatin-induced neuropathic pain. Toxins (Basel) 7, 2422–2434.
Khalil, F. A., and El-Sheikh, N. M. (2010). The effects of dietary Egyptian propolis doi: 10.3390/toxins7072422
and bee pollen supplementation against toxicity of sodium fluoride in rats. Li, L., Sun, W., Wu, T., Lu, R., and Shi, B. (2017). Caffeic acid phenethyl ester
J. Am. Sci. 11, 310–316. attenuates lipopolysaccharide-stimulated proinflammatory responses in human
Khoram, N. M., Bigdeli, B., Nikoofar, A., and Goliaei, B. (2016). Caffeic Acid gingival fibroblasts via NF-kappaB and PI3K/Akt signaling pathway. Eur. J.
Phenethyl ester increases radiosensitivity of estrogen receptor-positive and - Pharmacol. 794, 61–68. doi: 10.1016/j.ejphar.2016.11.003
negative breast cancer cells by prolonging radiation-induced DNA damage. Li, X., Huang, C., and Xue, Y. (2013). Contribution of lipids in honeybee (Apis
J. Breast. Cancer 19, 18–25. doi: 10.4048/jbc.2016.19.1.18 mellifera) royal jelly to health. J. Med. Food 16, 96–102. doi: 10.1089/jmf.2012.
Khoshpey, B., Djazayeri, S., Amiri, F., Malek, M., Hosseini, A. F., Hosseini, S., et al. 2425
(2016). Effect of royal jelly intake on serum glucose, Apolipoprotein A-I (ApoA- Linskens, H. F., and Jorde, W. (1997). Pollen as food and medicine: a review. Econ.
I), Apolipoprotein B (ApoB) and ApoB/ApoA-I ratios in patients with type 2 Bot. 51, 78–86. doi: 10.1007/BF02910407
Diabetes: a randomized, double-blind clinical trial study. Can. J. Diabetes 40, Lirdprapamongkol, K., Sakurai, H., Abdelhamed, S., Yokoyama, S.,
324–328. doi: 10.1016/j.jcjd.2016.01.003 Athikomkulchai, S., Viriyaroj, A., et al. (2013). Chrysin overcomes TRAIL
Kim, B. Y., Lee, K. S., Zou, F. M., Wan, H., Choi, Y. S., Yoon, H. J., et al. (2013). resistance of cancer cells through Mcl-1 downregulation by inhibiting STAT3
Antimicrobial activity of a honeybee (Apis cerana) venom Kazal-type serine phosphorylation. Int. J. Oncol. 43, 329–337. doi: 10.3892/ijo.2013.1926
protease inhibitor. Toxicon 76, 110–117. doi: 10.1016/j.toxicon.2013.09.017 Majtan, J., Bohova, J., Garcia-Villalba, R., Tomas-Barberan, F. A., Madakova, Z.,
Kim, S. J., Park, J. H., Kim, K. H., Lee, W. R., Pak, S. C., Han, S. M., et al. (2012). Majtan, T., et al. (2013). Fir honeydew honey flavonoids inhibit TNF-alpha-
The protective effect of apamin on LPS/fat-induced atherosclerotic mice. Evid. induced MMP-9 expression in human keratinocytes: a new action of honey in
Based Complement. Alternat. Med. 2012, 305454. doi: 10.1155/2012/305454 wound healing. Arch. Dermatol. Res. 305, 619–627. doi: 10.1007/s00403-013-
Kimura, M., Kimura, Y., Tsumura, K., Okihara, K., Sugimoto, H., Yamada, H., et al. 1385-y
(2003). 350-kDa royal jelly glycoprotein (apisin), which stimulates proliferation Majtan, J., Klaudiny, J., Bohova, J., Kohutova, L., Dzurova, M., Sediva, M.,
of human monocytes, bears the beta1-3galactosylated N-glycan: analysis of the et al. (2012). Methylglyoxal-induced modifications of significant honeybee
N-glycosylation site. Biosci. Biotechnol. Biochem. 67, 2055–2058. doi: 10.1271/ proteinous components in manuka honey: Possible therapeutic implications.
bbb.67.2055 Fitoterapia 83, 671–677. doi: 10.1016/j.fitote.2012.02.002
Koca, I., and Koca, A. F. (2007). Poisoning by mad honey: a brief review. Food Majtan, J., Kovacova, E., Bilikova, K., and Simuth, J. (2006). The
Chem. Toxicol. 45, 1315–1318. doi: 10.1016/j.fct.2007.04.006 immunostimulatory effect of the recombinant apalbumin 1-major honeybee
Komosinska-Vassev, K., Olczyk, P., Kazmierczak, J., Mencner, L., and Olczyk, K. royal jelly protein-on TNFalpha release. Int. Immunopharmacol. 6, 269–278.
(2015). Bee pollen: chemical composition and therapeutic application. Evid. doi: 10.1016/j.intimp.2005.08.014
Based Complement. Alternat. Med. 2015:297425. doi: 10.1155/2015/297425 Majtan, J., Kumar, P., Majtan, T., Walls, A. F., and Klaudiny, J. (2010). Effect
Kosalec, I., Pepeljnjak, S., Bakmaz, M., and Vladimir-Knezevic, S. (2005). of honey and its major royal jelly protein 1 on cytokine and MMP-9 mRNA
Flavonoid analysis and antimicrobial activity of commercially available propolis transcripts in human keratinocytes. Exp. Dermatol. 19, e73–e79. doi: 10.1111/j.
products. Acta Pharm. 55, 423–430. 1600-0625.2009.00994.x
Koya-Miyata, S., Okamoto, I., Ushio, S., Iwaki, K., Ikeda, M., and Kurimoto, M. Makino, J., Ogasawara, R., Kamiya, T., Hara, H., Mitsugi, Y., Yamaguchi, E.,
(2004). Identification of a collagen production-promoting factor from an et al. (2016). Royal jelly constituents increase the expression of extracellular
extract of royal jelly and its possible mechanism. Biosci. Biotechnol. Biochem. superoxide dismutase through histone acetylation in monocytic THP-1 cells.
68, 767–773. doi: 10.1271/bbb.68.767 J. Nat. Prod. 79, 1137–1143. doi: 10.1021/acs.jnatprod.6b00037
Kubina, R., Kabala-Dzik, A., Dziedzic, A., Bielec, B., Wojtyczka, R. D., Buldak, R. J., Manyi-Loh, C. E., Clarke, A. M., and Ndip, R. N. (2012). Detection of
et al. (2015). The ethanol extract of polish propolis exhibits anti-proliferative phytoconstituents in column fractions of n-hexane extract of Goldcrest honey
and/or pro-apoptotic effect on HCT 116 colon cancer and Me45 malignant exhibiting anti-Helicobacter pylori activity. Arch. Med. Res. 43, 197–204.
melanoma cells In Vitro conditions. Adv. Clin. Exp. Med. 24, 203–212. doi: 10.1016/j.arcmed.2012.04.006
doi: 10.17219/acem/31792 Marcucci, M. C., Ferreres, F., Garcia-Viguera, C., Bankova, V. S., De Castro,
Kubota, M., Tsuji, M., Nishimoto, M., Wongchawalit, J., Okuyama, M., Mori, H., S. L., Dantas, A. P., et al. (2001). Phenolic compounds from Brazilian propolis
et al. (2004). Localization of alpha-glucosidases I, II, and III in organs of with pharmacological activities. J. Ethnopharmacol. 74, 105–112. doi: 10.1016/
European honeybees, Apis mellifera L., and the origin of alpha-glucosidase S0378-8741(00)00326-3
in honey. Biosci. Biotechnol. Biochem. 68, 2346–2352. doi: 10.1271/bbb.68. Martinotti, S., and Ranzato, E. (2015). Propolis: a new frontier for wound healing?
2346 Burns Trauma 3, 9. doi: 10.1186/s41038-015-0010-z
Kuncic, M. K., Jaklic, D., Lapanje, A., and Gunde-Cimerman, N. (2012). Mavric, E., Wittmann, S., Barth, G., and Henle, T. (2008). Identification and
Antibacterial and antimycotic activities of Slovenian honeys. Br. J. Biomed. Sci. quantification of methylglyoxal as the dominant antibacterial constituent of
69, 154–158. Manuka (Leptospermum scoparium) honeys from New Zealand. Mol. Nutr.
Kuo, Y. Y., Jim, W. T., Su, L. C., Chung, C. J., Lin, C. Y., Huo, C., et al. (2015). Food Res. 52, 483–489. doi: 10.1002/mnfr.200700282
Caffeic Acid phenethyl ester is a potential therapeutic agent for oral cancer. Int. Melliou, E., and Chinou, I. (2005). Chemistry and bioactivity of royal jelly from
J. Mol. Sci. 16, 10748–10766. doi: 10.3390/ijms160510748 Greece. J. Agric. Food Chem. 53, 8987–8992. doi: 10.1021/jf051550p
Kwakman, P. H., Te Velde, A. A., de Boer, L., Vandenbroucke-Grauls, C. M., and Mesaik, M. A., Dastagir, N., Uddin, N., Rehman, K., and Azim, M. K. (2015).
Zaat, S. A. (2011). Two major medicinal honeys have different mechanisms of Characterization of immunomodulatory activities of honey glycoproteins and
bactericidal activity. PLoS ONE 6:e17709. doi: 10.1371/journal.pone.0017709 glycopeptides. J. Agric. Food Chem. 63, 177–184. doi: 10.1021/jf505131p
Kwakman, P. H., and Zaat, S. A. (2012). Antibacterial components of honey. Middleton, E. Jr. (1998). Effect of plant flavonoids on immune and inflammatory
IUBMB Life 64, 48–55. doi: 10.1002/iub.578 cell function. Adv. Exp. Med. Biol. 439, 175–182. doi: 10.1007/978-1-4615-
Larsen, L., Joyce, N. I., Sansom, C. E., Cooney, J. M., Jensen, D. J., and Perry, N. B. 5335-9_13
(2015). Sweet poisons: honeys contaminated with glycosides of the neurotoxin Mihajlovic, D., Rajkovic, I., Chinou, I., and Colic, M. (2013). Dose-
tutin. J. Nat. Prod. 78, 1363–1369. doi: 10.1021/acs.jnatprod.5b00241 dependent immunomodulatory effects of 10-hydroxy-2-decenoic acid

on human monocyte-derived dendritic cells. J. Funct. Foods 5, 838–846. Padavattan, S., Schirmer, T., Schmidt, M., Akdis, C., Valenta, R., Mittermann, I.,
doi: 10.1016/j.jff.2013.01.031 et al. (2007). Identification of a B-cell epitope of hyaluronidase, a major bee
Mohammed, S. E., Kabashi, A. S., Koko, W. S., and Azim, M. K. (2015). Antigiardial venom allergen, from its crystal structure in complex with a specific Fab. J. Mol.
activity of glycoproteins and glycopeptides from Ziziphus honey. Nat. Prod. Res. Biol. 368, 742–752. doi: 10.1016/j.jmb.2007.02.036
29, 2100–2102. doi: 10.1080/14786419.2014.986659 Park, H. G., Kyung, S. S., Lee, K. S., Kim, B. Y., Choi, Y. S., Yoon, H. J., et al. (2014).
Moita, E., Sousa, C., Andrade, P. B., Fernandes, F., Pinho, B. R., Silva, L. R., et al. Dual function of a bee (Apis cerana) inhibitor cysteine knot peptide that acts as
(2014). Effects of Echium plantagineum L. bee pollen on basophil degranulation: an antifungal peptide and insecticidal venom toxin. Dev. Comp. Immunol. 47,
relationship with metabolic profile. Molecules 19, 10635–10649. doi: 10.3390/ 247–253. doi: 10.1016/j.dci.2014.08.001
molecules190710635 Park, H. M., Hwang, E., Lee, K. G., Han, S. M., Cho, Y., and Kim, S. Y. (2011).
Molan, P., and Rhodes, T. (2015). Honey: a biologic wound dressing. Wounds 27, Royal jelly protects against ultraviolet B-induced photoaging in human skin
141–151. fibroblasts via enhancing collagen production. J. Med. Food 14, 899–906.
Molan, P. C. (1999). Why honey is effective as a medicine. I. Its use in modern doi: 10.1089/jmf.2010.1363
medicine. Bee World 80, 80–92. Pascoal, A., Rodrigues, S., Teixeira, A., Feas, X., and Estevinho, L. M. (2014).
Molan, P. C. (2006). The evidence supporting the use of honey as a wound dressing. Biological activities of commercial bee pollens: antimicrobial, antimutagenic,
Int. J. Low Extrem. Wounds 5, 40–54. doi: 10.1177/1534734605286014 antioxidant and anti-inflammatory. Food Chem. Toxicol. 63, 233–239.
Moreno, M., and Giralt, E. (2015). Three valuable peptides from bee and doi: 10.1016/j.fct.2013.11.010
wasp venoms for therapeutic and biotechnological use: melittin, apamin and Patel, S. (2016). Emerging adjuvant therapy for cancer: propolis and its
mastoparan. Toxins (Basel) 7, 1126–1150. doi: 10.3390/toxins7041126 constituents. J. Diet. Suppl. 13, 245–268. doi: 10.3109/19390211.2015.100
Moriyama, T., Ito, A., Omote, S., Miura, Y., and Tsumoto, H. (2015). Heat resistant 8614
characteristics of major royal jelly protein 1 (MRJP1) oligomer. PLoS ONE Petretto, G. L., Cossu, M., and Alamanni, M. C. (2015). Phenolic content,
10:e0119169. doi: 10.1371/journal.pone.0119169 antioxidant and physico-chemical properties of Sardinian monofloral honeys.
Motawi, T. K., Abdelazim, S. A., Darwish, H. A., Elbaz, E. M., and Shouman, Int. J. Food Sci. Technol. 50, 482–491. doi: 10.1111/ijfs.12652
S. A. (2016). Modulation of tamoxifen cytotoxicity by caffeic acid phenethyl Petrova, A., Popova, M., Kuzmanova, C., Tsvetkova, I., Naydenski, H., Muli, E.,
ester in MCF-7 breast cancer cells. Oxid. Med. Cell Longev. 2016, 3017108. et al. (2010). New biologically active compounds from Kenyan propolis.
doi: 10.1155/2016/3017108 Fitoterapia 81, 509–514. doi: 10.1016/j.fitote.2010.01.007
Mourre, C., Lazdunski, M., and Jarrard, L. E. (1997). Behaviors and Pichichero, E., Cicconi, R., Mattei, M., and Canini, A. (2011). Chrysin-induced
neurodegeneration induced by two blockers of K+ channels, the mast apoptosis is mediated through p38 and Bax activation in B16-F1 and A375
cell degranulating peptide and Dendrotoxin I. Brain Res. 762, 223–227. melanoma cells. Int. J. Oncol. 38, 473–483. doi: 10.3892/ijo.2010.876
doi: 10.1016/S0006-8993(97)00481-2 Polanski, M., Okon, K., Przybylo, R., and Frasik, W. (1998). Cardioprotective
Moussa, A., Noureddine, D., Saad, A., Abdelmelek, M., and Abdelkader, B. (2012). properties of hydrophilic pollen extract (HPE). Pol. J. Pathol. 49, 109–112.
Antifungal activity of four honeys of different types from Algeria against Popolo, A., Piccinelli, A. L., Morello, S., Sorrentino, R., Osmany, C. R., Rastrelli, L.,
pathogenic yeast: Candida albicans and Rhodotorula sp. Asian Pac. J. Trop. et al. (2011). Cytotoxic activity of nemorosone in human MCF-7 breast cancer
Biomed. 2, 554–557. doi: 10.1016/S2221-1691(12)60096-3 cells. Can. J. Physiol. Pharmacol. 89, 50–57. doi: 10.1139/y10-100
Moutsatsou, P., Papoutsi, Z., Kassi, E., Heldring, N., Zhao, C., Tsiapara, A., et al. Puleo, S. L., and Keunen, K. (1991). Beeswax minor components a new approach.
(2010). Fatty acids derived from royal jelly are modulators of estrogen receptor Cosmet. Toiletries 106, 83.
functions. PLoS ONE 5:e15594. doi: 10.1371/journal.pone.0015594 Putz, T., Ramoner, R., Gander, H., Rahm, A., Bartsch, G., and Thurnher, M.
Münstedt, K., and Bogdanov, S. (2009). Bee products and their potential use in (2006). Antitumor action and immune activation through cooperation
modern medicine. J. ApiProduct ApiMedical Sci. 1, 57–63. doi: 10.3896/IBRA.4. of bee venom secretory phospholipase A2 and phosphatidylinositol-(3,4)-
01.3.01 bisphosphate. Cancer Immunol. Immunother. 55, 1374–1383. doi: 10.1007/
Mutlu Sariguzel, F., Berk, E., Koc, A. N., Sav, H., and Demir, G. (2016). Antifungal s00262-006-0143-9
activity of propolis against yeasts isolated from blood culture: In Vitro Raghuraman, H., and Chattopadhyay, A. (2007). Melittin: a membrane-active
evaluation. J. Clin. Lab. Anal. 30, 513–516. doi: 10.1002/jcla.21889 peptide with diverse functions. Biosci. Rep. 27, 189–223. doi: 10.1007/s10540-
Noronha, V. R., Araujo, G. S., Gomes, R. T., Iwanaga, S. H., Barbosa, M. C., Abdo, 006-9030-z
E. N., et al. (2014). Mucoadhesive propolis gel for prevention of radiation- Ramadan, M. F., and Al-Ghamdi, A. (2012). Bioactive compounds and health-
induced oral mucositis. Curr. Clin. Pharmacol. 9, 359–364. doi: 10.2174/ promoting properties of royal jelly: a review. J. Funct. Foods 4, 39–52.
1574884709666140205210051 doi: 10.1016/j.jff.2011.12.007
Okamoto, I., Taniguchi, Y., Kunikata, T., Kohno, K., Iwaki, K., Ikeda, M., et al. Ramanauskiene, K., Stelmakiene, A., Briedis, V., Ivanauskas, L., and Jakstas, V.
(2003). Major royal jelly protein 3 modulates immune responses in vitro and (2012). The quantitative analysis of biologically active compounds in
in vivo. Life Sci. 73, 2029–2045. doi: 10.1016/S0024-3205(03)00562-9 Lithuanian honey. Food Chem. 132, 1544–1548. doi: 10.1016/j.foodchem.2011.
Okano, M., Nishizaki, K., Satoskar, A. R., Yoshino, T., Masuda, Y., and Harn, D. A. 12.007
Jr. (1999). Involvement of carbohydrate on phospholipase A2, a bee-venom Ranzato, E., Martinotti, S., and Burlando, B. (2012). Epithelial mesenchymal
allergen, in in vivo antigen-specific IgE synthesis in mice. Allergy 54, 811–818. transition traits in honey-driven keratinocyte wound healing: comparison
doi: 10.1034/j.1398-9995.1999.00096.x among different honeys. Wound Repair Regen. 20, 778–785. doi: 10.1111/j.
Olczyk, P., Wisowski, G., Komosinska-Vassev, K., Stojko, J., Klimek, K., Olczyk, M., 1524-475X.2012.00825.x
et al. (2013). Propolis modifies collagen types I and III accumulation in the Rit, T., and Behrer, R. (1999). Beeswax Through the Ages. Bladel: Koster Keunen
matrix of burnt tissue. Evid. Based Complement. Alternat. Med. 2013, 423809. Holland BV.
doi: 10.1155/2013/423809 Rosmilah, M., Shahnaz, M., Patel, G., Lock, J., Rahman, D., Masita, A., et al. (2008).
Oller-Salvia, B., Teixido, M., and Giralt, E. (2013). From venoms to BBB shuttles: Characterization of major allergens of royal jelly Apis mellifera. Trop. Biomed.
synthesis and blood-brain barrier transport assessment of apamin and a 25, 243–251.
nontoxic analog. Biopolymers 100, 675–686. doi: 10.1002/bip.22257 Rzepecka-Stojko, A., Pilawa, B., Ramos, P., and Stojko, J. (2012). Antioxidative
Omene, C., Kalac, M., Wu, J., Marchi, E., Frenkel, K., and O’Connor, O. A. (2013). properties of bee pollen extracts examined by EPR spectroscopy. J. Apicult. Sci.
propolis and its active component, Caffeic Acid Phenethyl Ester (CAPE), 56, 23–31. doi: 10.2478/v10289-012-0003-0
modulate breast cancer therapeutic targets via an epigenetically mediated Sajid, M., and Azim, M. K. (2012). Characterization of the nematicidal activity of
mechanism of action. J. Cancer Sci. Ther. 5, 334–342. natural honey. J. Agric. Food Chem. 60, 7428–7434. doi: 10.1021/jf301653n
Orsi, R. O., Funari, S. R. C., Soares, A. M. V. C., Calvi, S. A., Oliveira, S. L., Sforcin, Siavash, M., Shokri, S., Haghighi, S., Shahtalebi, M. A., and Farajzadehgan, Z.
J. M., et al. (2000). Immunomodulatory action of propolis on macrophage (2015). The efficacy of topical royal jelly on healing of diabetic foot ulcers:
activation. J. Venom. Anim. Toxins Incl. Trop. Dis. 6, 205–219. doi: 10.1590/ a double-blind placebo-controlled clinical trial. Int. Wound J. 12, 137–142.
S0104-79302000000200006 doi: 10.1111/iwj.12063

Silici, S., and Atayoglu, A. T. (2015). Mad honey intoxication: a systematic review Tonks, A. J., Dudley, E., Porter, N. G., Parton, J., Brazier, J., Smith, E. L., et al.
on the 1199 cases. Food Chem. Toxicol. 86, 282–290. doi: 10.1016/j.fct.2015. (2007). A 5.8-kDa component of manuka honey stimulates immune cells via
10.018 TLR4. J. Leukoc. Biol. 82, 1147–1155. doi: 10.1189/jlb.1106683
Simuth, J., Bilikova, K., Kovacova, E., Kuzmova, Z., and Schroder, W. Tseng, J. C., Lin, C. Y., Su, L. C., Fu, H. H., Yang, S. D., and Chuu, C. P. (2016).
(2004). Immunochemical approach to detection of adulteration in honey: CAPE suppresses migration and invasion of prostate cancer cells via activation
physiologically active royal jelly protein stimulating TNF-alpha release is a of non-canonical Wnt signaling. Oncotarget 7, 38010–38024. doi: 10.18632/
regular component of honey. J. Agric. Food Chem. 52, 2154–2158. doi: 10.1021/ oncotarget.9380
jf034777y Vandamme, L., Heyneman, A., Hoeksema, H., Verbelen, J., and Monstrey, S.
Sobral, F., Sampaio, A., Falcao, S., Queiroz, M. J., Calhelha, R. C., Vilas-Boas, M., (2013). Honey in modern wound care: a systematic review. Burns 39,
et al. (2016). Chemical characterization, antioxidant, anti-inflammatory and 1514–1525. doi: 10.1016/j.burns.2013.06.014
cytotoxic properties of bee venom collected in Northeast Portugal. Food Chem. Viuda-Martos, M., Ruiz-Navajas, Y., Fernandez-Lopez, J., and Perez-Alvarez, J. A.
Toxicol. 94, 172–177. doi: 10.1016/j.fct.2016.06.008 (2008). Functional properties of honey, propolis, and royal jelly. J. Food Sci. 73,
Son, D. J., Kang, J., Kim, T. J., Song, H. S., Sung, K. J., Yun, D. Y., et al. (2007). R117–R124. doi: 10.1111/j.1750-3841.2008.00966.x
Melittin, a major bioactive component of bee venom toxin, inhibits PDGF Vynograd, N., Vynograd, I., and Sosnowski, Z. (2000). A comparative multi-centre
receptor beta-tyrosine phosphorylation and downstream intracellular signal study of the efficacy of propolis, acyclovir and placebo in the treatment of genital
transduction in rat aortic vascular smooth muscle cells. J. Toxicol. Environ. herpes (HSV). Phytomedicine 7, 1–6. doi: 10.1016/S0944-7113(00)80014-8
Health A 70, 1350–1355. doi: 10.1080/15287390701428689 Wagh, V. D. (2013). Propolis: a wonder bees product and its pharmacological
Spannhoff, A., Kim, Y. K., Raynal, N. J., Gharibyan, V., Su, M. B., Zhou, Y. Y., et al. potentials. Adv. Pharmacol. Sci. 2013, 308249. doi: 10.1155/2013/308249
(2011). Histone deacetylase inhibitor activity in royal jelly might facilitate caste Walgrave, S. E., Warshaw, E. M., and Glesne, L. A. (2005). Allergic contact
switching in bees. EMBO Rep. 12, 238–243. doi: 10.1038/embor.2011.9 dermatitis from propolis. Dermatitis 16, 209–215.
Speciale, A., Costanzo, R., Puglisi, S., Musumeci, R., Catania, M. R., Caccamo, F., Wang, J., Zhang, W., Zou, H., Lin, Y., Lin, K., Zhou, Z., et al. (2015). 10-Hydroxy-
et al. (2006). Antibacterial activity of propolis and its active principles alone 2-decenoic acid inhibiting the proliferation of fibroblast-like synoviocytes by
and in combination with macrolides, beta-lactams and fluoroquinolones PI3K-AKT pathway. Int. Immunopharmacol. 28, 97–104. doi: 10.1016/j.intimp.
against microorganisms responsible for respiratory infections. J. Chemother. 18, 2015.05.036
164–171. doi: 10.1179/joc.2006.18.2.164 Wang, J. G., Ruan, J., Li, C. Y., Wang, J. M., Li, Y., Zhai, W. T., et al.
Stepanovic, S., Antic, N., Dakic, I., and Svabic-Vlahovic, M. (2003). In vitro (2012). Connective tissue growth factor, a regulator related with 10-hydroxy-
antimicrobial activity of propolis and synergism between propolis and 2-decenoic acid down-regulate MMPs in rheumatoid arthritis. Rheumatol. Int.
antimicrobial drugs. Microbiol. Res. 158, 353–357. doi: 10.1078/0944-5013- 32, 2791–2799. doi: 10.1007/s00296-011-1960-5
00215 Wang, L. C., Chu, K. H., Liang, Y. C., Lin, Y. L., and Chiang, B. L. (2010).
Stockwell, V. O., and Duffy, B. (2012). Use of antibiotics in plant agriculture. Rev. Caffeic acid phenethyl ester inhibits nuclear factor-kappaB and protein kinase B
Sci. Tech. 31, 199–210. doi: 10.20506/rst.31.1.2104 signalling pathways and induces caspase-3 expression in primary human CD4+
Sugiyama, T., Takahashi, K., Kuzumaki, A., Tokoro, S., Neri, P., and Mori, H. T cells. Clin. Exp. Immunol. 160, 223–232. doi: 10.1111/j.1365-2249.2009.
(2013). Inhibitory mechanism of 10-hydroxy-trans-2-decenoic acid (royal jelly 04067.x
acid) against lipopolysaccharide- and interferon-beta-induced nitric oxide Wardell, M., and Sabacinski, K. (2016). Wound healing compositions involving
production. Inflammation 36, 372–378. doi: 10.1007/s10753-012-9556-0 medicinal honey, mineral ions, and methylglyoxal, 1and methods of use. U.S.
Sugiyama, T., Takahashi, K., Tokoro, S., Gotou, T., Neri, P., and Mori, H. (2012). Patent No WO 2016123539 A1. Washington, DC: U.S. Patent and Trademark
Inhibitory effect of 10-hydroxy-trans-2-decenoic acid on LPS-induced IL-6 Office.
production via reducing IkappaB-zeta expression. Innate Immun. 18, 429–437. Wong, K. L., Li, H., Wong, K. K., Jiang, T., and Shaw, P. C. (2012). Location
doi: 10.1177/1753425911416022 and reduction of icarapin antigenicity by site specific coupling to polyethylene
Sun, C., Wu, Z., Wang, Z., and Zhang, H. (2015). Effect of ethanol/water solvents glycol. Protein Pept. Lett. 19, 238–243. doi: 10.2174/092986612799080211
on phenolic profiles and antioxidant properties of beijing propolis extracts. Wu, Y. D., and Lou, Y. J. (2007). A steroid fraction of chloroform extract from bee
Evid. Based Complement. Alternat. Med. 2015, 595393. doi: 10.1155/2015/ pollen of Brassica campestris induces apoptosis in human prostate cancer PC-3
595393 cells. Phytother. Res. 21, 1087–1091. doi: 10.1002/ptr.2235
Suzuki, K. M., Isohama, Y., Maruyama, H., Yamada, Y., Narita, Y., Ohta, S., et al. Xu, D., Mei, X., and Xu, S. (2002). [The research of 10-hydroxy-2-decenoic acid on
(2008). Estrogenic activities of Fatty acids and a sterol isolated from royal jelly. experiment hyperlipoidemic rat]. Zhong Yao Cai 25, 346–347.
Evid. Based Complement. Alternat. Med. 5, 295–302. doi: 10.1093/ecam/nem036 Yakusheva, E. (2010). “Pollen and bee bread: physico-chemical properties.
Takemura, T., Urushisaki, T., Fukuoka, M., Hosokawa-Muto, J., Hata, T., Biological and pharmacological effects. Use in medical practice,” in Theoretical
Okuda, Y., et al. (2012). 3,4-Dicaffeoylquinic acid, a major constituent of and Practical Basics of Apitherapy, eds D. Rakita, N. Krivtsov, and D. G.
brazilian propolis, increases TRAIL expression and extends the lifetimes of mice Uzbekova (Ryazan: Roszdrav), 84–97.
infected with the influenza A Virus. Evid. Based Complement. Alternat. Med. Yang, X. Y., Yang, D. S., Wei, Z., Wang, J. M., Li, C. Y., Hui, Y., et al. (2010).
2012, 946867. doi: 10.1155/2012/946867 10-Hydroxy-2-decenoic acid from Royal jelly: a potential medicine for RA.
Takikawa, M., Kumagai, A., Hirata, H., Soga, M., Yamashita, Y., Ueda, M., J. Ethnopharmacol. 128, 314–321. doi: 10.1016/j.jep.2010.01.055
et al. (2013). 10-Hydroxy-2-decenoic acid, a unique medium-chain fatty acid, Yildirim, A., Duran, G. G., Duran, N., Jenedi, K., Bolgul, B. S., Miraloglu, M., et al.
activates 5’-AMP-activated protein kinase in L6 myotubes and mice. Mol. Nutr. (2016). Antiviral activity of hatay propolis against replication of herpes simplex
Food Res. 57, 1794–1802. doi: 10.1002/mnfr.201300041 virus type 1 and type 2. Med. Sci. Monit. 22, 422–430. doi: 10.12659/MSM.
Tamura, S., Amano, S., Kono, T., Kondoh, J., Yamaguchi, K., Kobayashi, S., et al. 897282
(2009). Molecular characteristics and physiological functions of major royal Yildiz, O., Can, Z., Saral, O., Yulug, E., Ozturk, F., Aliyazicioglu, R., et al. (2013).
jelly protein 1 oligomer. Proteomics 9, 5534–5543. doi: 10.1002/pmic.200900541 Hepatoprotective potential of chestnut bee pollen on carbon tetrachloride-
Teerasripreecha, D., Phuwapraisirisan, P., Puthong, S., Kimura, K., Okuyama, M., induced hepatic damages in rats. Evid. Based Complement. Alternat. Med.
Mori, H., et al. (2012). In vitro antiproliferative/cytotoxic activity on cancer cell 2013:461478. doi: 10.1155/2013/461478
lines of a cardanol and a cardol enriched from Thai Apis mellifera propolis. BMC Yilmaz, U. C., Bagca, B. G., Karaca, E., Durmaz, A., Durmaz, B., Aykut, A., et al.
Complement. Altern. Med. 12:27. doi: 10.1186/1472-6882-12-27 (2016). Evaluation of the miRNA profiling and effectiveness of the propolis
Terada, Y., Narukawa, M., and Watanabe, T. (2011). Specific hydroxy fatty acids on B-cell acute lymphoblastic leukemia cell line. Biomed. Pharmacother. 84,
in royal jelly activate TRPA1. J. Agric. Food Chem. 59, 2627–2635. doi: 10.1021/ 1266–1273. doi: 10.1016/j.biopha.2016.10.056
jf1041646 Yousefi, B., Ghaderi, S., Rezapoor-Lactooyi, A., Amiri, N., Verdi, J., and Shoae-
Thomas, N. C., and Justin, D. O. L. (2013). Composition for treating parkinson’s Hassani, A. (2012). Hydroxy decenoic acid down regulates gtfB and gtfC
disease. U.S. Patent No 20070004639 A1. Washington, DC: U.S. Patent and expression and prevents Streptococcus mutans adherence to the cell surfaces.
Trademark Office. Ann. Clin. Microbiol. Antimicrob. 11:21. doi: 10.1186/1476-0711-11-21

Zhang, T., Li, Y., Lai, J. P., Douglas, S. D., Metzger, D. S., O’Brien, C. P., et al. (2003). Conflict of Interest Statement: The authors declare that the research was
Alcohol potentiates hepatitis C virus replicon expression. Hepatology 38, 57–65. conducted in the absence of any commercial or financial relationships that could
doi: 10.1053/jhep.2003.50295 be construed as a potential conflict of interest.
Zhang, W., Lan, Y., Huang, Q., and Hua, Z. (2013). Galangin induces B16F10
melanoma cell apoptosis via mitochondrial pathway and sustained activation Copyright © 2017 Cornara, Biagi, Xiao and Burlando. This is an open-access article
of p38 MAPK. Cytotechnology 65, 447–455. doi: 10.1007/s10616-012-9499-1 distributed under the terms of the Creative Commons Attribution License (CC BY).
Zheng, J., Lai, W., Zhu, G., Wan, M., Chen, J., Tai, Y., et al. (2013). The use, distribution or reproduction in other forums is permitted, provided the
10-Hydroxy-2-decenoic acid prevents ultraviolet A-induced damage and matrix original author(s) or licensor are credited and that the original publication in this
metalloproteinases expression in human dermal fibroblasts. J. Eur. Acad. journal is cited, in accordance with accepted academic practice. No use, distribution
Dermatol. Venereol. 27, 1269–1277. doi: 10.1111/j.1468-3083.2012.04707.x or reproduction is permitted which does not comply with these terms.

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REVIEW

published: 28 June 2017

Therapeutic Properties of Bioactive

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PROPOLIS activity of Brazilian propolis has been demonstrated for its

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Anti-inflammatory Activity ferulate, benzyl isoferulate, pinostrobin, 5-phenylpenta-2,4-

Anticancer Activity Adverse Effects

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Antiatherosclerotic and Antidiabetic BEESWAX

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Product Compound Effect Reference

Honey H2 O2 Antimicrobial activity Brudzynski et al., 2011

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Product Compound Effect Reference

Dermatological and Cosmetic Properties FUTURE PERSPECTIVES

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REFERENCES and immunomodulatory effects (Review). Exp. Ther. Med. 9,

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