In e na ional Jou nal o
Molecula Sciences
Re iew
New Insigh s in o he Biological and Pha maceu ical
P ope ies o Royal Jelly
Saboo Ahmad 1, Ma ia G aça Campos 2,3 , Filippo F a ini 4,5, Solomon Zewdu Al aye 1and
Jianke Li 1,*
1Key Labo a o y o Pollina ing Insec Biology, Minis y o Ag icul u e, Ins i u e o Apicul u al Resea ch,
Chinese Academy o Ag icul u al Sciences, Beijing 100081, China; [email p o ec ed] (S.A.);
[email p o ec ed] (S.Z.A.)
2Coimb a Chemis y Cen e, (CQC, FCT Uni 313), Facul y o Sciences Technology, Uni e si y o Coimb a,
Rua La ga, 3004-535 Coimb a, Po ugal; mgcampos@ .uc.p
3Obse a o y o D ug-He b In e ac ions, Sciences Heal h Campus, Facul y o Pha macy, Uni e si y o
Coimb a, Azinhaga de San a Comba, 3000-548 Coimb a, Po ugal
4Depa men o Ve e ina y Sciences, Uni e si y o Pisa, Viale delle Piagge 2, 56124 Pisa, I aly;
[email p o ec ed]
5In e depa men al Resea ch Cen e “Nu aceu icals and Food o Heal h”, Uni e si y o Pisa,
Via del Bo ghe o 80, 56124 Pisa, I aly
*Co espondence: [email p o ec ed]; Fax: +86-10-8210-6448
Recei ed: 23 No embe 2019; Accep ed: 6 Janua y 2020; Published: 8 Janua y 2020
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Abs ac :
Royal jelly (RJ) is a yellowish-whi e and acidic sec e ion o hypopha yngeal and mandibula
glands o nu se bees used o eed young wo ke la ae du ing he i s h ee days and he en i e li e o
queen bees. RJ is one o he mos app ecia ed and alued na u al p oduc which has been mainly used
in adi ional medicines, heal h oods, and cosme ics o a long ime in di e en pa s o he wo ld.
I is also he mos s udied bee p oduc , aimed a un a elling i s bioac i i ies, such as an imic obial,
an ioxidan , an i-aging, immunomodula o y, and gene al onic ac ion agains labo a o y animals,
mic obial o ganisms, a m animals, and clinical ials. I is commonly used o supplemen a ious
diseases, including cance , diabe es, ca dio ascula , and Alzheime ’s disease. He e, we highligh
he ecen esea ch ad ances on he main bioac i e compounds o RJ, such as p o eins, pep ides,
a y acids, and phenolics, o a comp ehensi e unde s anding o he biochemis y, biological, and
pha maceu ical esponses o human heal h p omo ion and li e bene i s. This is po en ially impo an
o gain no el insigh in o he biological and pha maceu ical p ope ies o RJ.
Keywo ds: oyal jelly; bioac i e compounds; unc ional p ope ies; p o eins; a y acids; phenolics
1. In oduc ion
Royal jelly (RJ) is known as a “supe ood” which is p oduced by nu se bees o eed young wo ke
la ae and queen bees [
1
,
2
]. The majo componen s o RJ a e (60–70% w/w) wa e , (9–18% w/w) p o eins,
(7–18% w/w) suga s, and (3–8% w/w) lipids [
3
,
4
]. RJ also con ains mino componen s, such as mine als
(Fe, Na, Ca, K, Zn, Mg, Mn, and Cu), amino acids (eigh essen ial amino acids Val, Leu, Ile, Th , Me ,
Phe, Lys, and T p), i amins (A, B complex, C, and E), enzymes, ho mones, polyphenols, nucleo ides,
and mino he e ocyclic compounds [
3
,
5
,
6
]. RJ is an ac i e esea ch domain because i is essen ial
o la al de elopmen and queen ep oduc ion in honeybee colonies h ough he me abolism o
suga s, lipids, and p o eins [
7
,
8
]. The eby, he la ge body size, longe li espan, and e ili y o queens
compa ed o wo ke bees a e po en ially co ela ed o he special die o RJ [9].
RJ has been p oduced in la ge scale o comme cial pu poses o da e, and i s ma ke alue is
signi ican ly highe han o he bee p oduc s, such as honey o pollen, hus, i is a majo income
In . J. Mol. Sci. 2020,21, 382; doi:10.3390/ijms21020382 www.mdpi.com/jou nal/ijms
In . J. Mol. Sci. 2020,21, 382 2 o 26
sou ce o beekeepe s [
4
,
10
]. Beekeepe s ha e made g ea e o s o de elop he echnique o imp o e
RJ p oduc ion and o selec o high-p oducing s ains o honeybees. Fo ins ance, he inc ease
in he p oduc ion o RJ in China o e he las 40 yea s has been achie ed by he de elopmen o
gene ic selec ion o high RJ-p oducing bees (RJBs) om I alian bees [
11
–
13
], and he de elopmen and
implemen a ion o p oduc ion echniques o inc ease and op imize RJ p oduc ion [
14
–
16
]. A p esen
RJBs ha e he po en ial o p oduce mo e han 10 kg RJ/colony/yea , which is 10 imes mo e han o
non-selec ed I alian bees [
15
–
18
]. No ably, China is he la ges p oduce and expo e o RJ a ound he
wo ld, p oducing mo e han 4000 ons annually, wi h mo e han $2.5 billion ma ke , which is 90% o
he o al RJ p oduc ion globally and mos ly expo ed o Japan, Eu ope, and he Uni ed S a es [12,19].
The heal h-p omo ing bene i s and pha maceu ical p ope ies o RJ om animal models o
humans ha e been widely in es iga ed. RJ is a nu i ional modi ica ion o honey and bee b ead
(Figu e 1), and i is comme cially a ailable on a la ge scale as heal h ood and cosme ics in Asia,
especially in China and Japan [
9
,
10
]. Mo eo e , RJ is used o explo e u he applica ions as a d ug
and adi ional consump ion as “ emedies” o humans and animals [
20
]. To da e, he impo ance o
RJ has a ac ed a en ion a ound he wo ld, which is e idenced by he g ow h in he numbe
o publica ions and ci a ions in he co e collec ion o he Web o Science (Figu e 2). Recen ly,
he o igin and unc ion o RJ, such as majo oyal jelly p o eins (MRJPs) o he de elopmen o
he la ae [
21
], an imic obial p ope ies [
9
], medicinal alue [
20
,
22
], p o eins and pep ides [
23
],
he po en ial applica ions o cance ea men [
24
], and heal h aging and longe i y [
25
] ha e been
epo ed. To be e unde s and he biochemis y, biological, and pha maceu ical esponse o heal h and
li e bene i s o RJ, we upda e he knowledge om he esea ch ad ances o he biological ac i i ies and
pha maceu ical applica ions o RJ and i s bioac i e ing edien s ha a e associa ed wi h a m animals,
mic o-o ganisms, labo a o y animals, insec s, and clinical ials in humans. He e, ou majo ocus is on
he bioe ec s o RJ, such as an imic obial, an ioxidan , an i-in lamma o y, wound healing, an i-aging,
immunomodula o y, an i-cance , an i-diabe ic, an i-hype lipidemic, an i-hype ension, hepa o- enal
p o ec i e, neu op o ec i e, es ogenic, and e ili y e ec s. This e idence is a po en ially aluable
esou ce o u he s udies o he heal h po en ial p ope ies o RJ o bo h humans and honeybees.
In . J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 o 27
Figu e 1. Fo age bees anspo pollens in hei hind leg co biculae o which hey add nec a o o m
pollen pelle s. Fo age bees deposi and pack he pollen pelle s in o cell su ounding he b ood a ea
and o ming bee b ead. Nu se bees de elop enla ged ood glands and p oduce RJ by consuming
honey and bee b ead (Pho os aken by P o . D . Jianke Li).
Figu e 2. Numbe s o publica ions on RJ ha appea om in e na ional jou nals a e inc easing e e y
yea (da a om he co e collec ion o he Web o Science).
Figu e 1.
Fo age bees anspo pollens in hei hind leg co biculae o which hey add nec a o o m
pollen pelle s. Fo age bees deposi and pack he pollen pelle s in o cell su ounding he b ood a ea
and o ming bee b ead. Nu se bees de elop enla ged ood glands and p oduce RJ by consuming honey
and bee b ead (Pho os aken by P o . D . Jianke Li).
In . J. Mol. Sci. 2020,21, 382 3 o 26
In . J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 o 27
Figu e 1. Fo age bees anspo pollens in hei hind leg co biculae o which hey add nec a o o m
pollen pelle s. Fo age bees deposi and pack he pollen pelle s in o cell su ounding he b ood a ea
and o ming bee b ead. Nu se bees de elop enla ged ood glands and p oduce RJ by consuming
honey and bee b ead (Pho os aken by P o . D . Jianke Li).
Figu e 2. Numbe s o publica ions on RJ ha appea om in e na ional jou nals a e inc easing e e y
yea (da a om he co e collec ion o he Web o Science).
Figu e 2.
Numbe s o publica ions on RJ ha appea om in e na ional jou nals a e inc easing e e y
yea (da a om he co e collec ion o he Web o Science).
2. Bioac i e Subs ances
RJ is a ich sou ce o nu ien s and bioac i e compounds wi h he po en ial o play a i al pa in
hei biological ac i i ies and pha maceu ical applica ions [
26
]. I has been con i med ha p o eins,
pep ides, lipids, phenolics, and la onoids a e he main bioac i e compounds esponsible o he
a ious pha maceu ical p ope ies o RJ (Figu e 3). The na u al a ia ion o bioac i e compounds
depend upon he biodi e si y o lo a species p esen in he di e en ecosys em [26].
In . J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 4 o 27
2. Bioac i e Subs ances
RJ is a ich sou ce o nu ien s and bioac i e compounds wi h he po en ial o play a i al pa
in hei biological ac i i ies and pha maceu ical applica ions [26]. I has been con i med ha p o eins,
pep ides, lipids, phenolics, and la onoids a e he main bioac i e compounds esponsible o he
a ious pha maceu ical p ope ies o RJ (Figu e 3). The na u al a ia ion o bioac i e compounds
depend upon he biodi e si y o lo a species p esen in he di e en ecosys em [26].
Figu e 3. A schema ic ep esen a ion o he main biological subs ances in RJ and hei unc ional
ac i i ies. Fo de ailed in o ma ion e e o Table 1.
2.1. P o eins and Pep ides
The in es iga ion o no el p o eins in RJ has been a long- e m pe usal o biochemical expe s
and apicul u al biologis s. P o eins a e he mos abundan componen s o RJ, accoun ing o mo e
han 50% o he d y weigh and MRJPs a e he mos impo an componen s cons i u ing 80%–90% o
he o al p o ein con en [21,27]. O he s a e glucose oxidase [27], α-glucosidase, and α-amylase [28].
The MRJPs sha e a common de elopmen al genesis wi h he yellow p o ein amily [29]. The
YELLOW/MRJPs a e named acco ding o hei molecula weigh o simply numbe ed by he o de
in which hey a e disco e ed. So a , MRJPs (1–9) a e well-desc ibed wi h molecula mass 49–87 kDa,
which a e encoded by nine di e en genes [23,30]. MRJP-1 is a weak acidic glycop o ein, accoun ing
o 48% o wa e -soluble RJ p o eins and he seconda y s uc u e consis s o 9.6% α-helices, 38.3% β-
shee s, and 20% β- u ns [6,31]. Pa icula ly, MRJP-1 occu s as a monome (mono MRJP-1) o as an
oligome known as apisin by polyme iza ion wi h apisimin [31]. Apisin could be used o de e mine
he quali y o RJ [32]. MRJP-2 and MRJP-3 p oduced by Chinese bees (Apis ce ana ce ana) a e less
polymo phic compa ed o Eu opean bees (Apis melli e a ligus ica) and A icanized bees (Apis melli e a
scu ella e) [33,34], and MRJP-4 was i s ime con i med by wo-dimensional gel elec opho esis (2-
DE) analysis du ing he compa ison in he RJ o A icanized and Eu opean bees [34]. The impo an
ea u e o MRJP-5 is a wide epea ed egion loca ed be ween amino acid esidues 367 and 540 [33].
The mos signi ican pos - ansla ional modi ica ion o he MRJPs is me hyla ion which igge s
Figu e 3.
A schema ic ep esen a ion o he main biological subs ances in RJ and hei unc ional
ac i i ies. Fo de ailed in o ma ion e e o Table 1.
In . J. Mol. Sci. 2020,21, 382 4 o 26
2.1. P o eins and Pep ides
The in es iga ion o no el p o eins in RJ has been a long- e m pe usal o biochemical expe s and
apicul u al biologis s. P o eins a e he mos abundan componen s o RJ, accoun ing o mo e han 50%
o he d y weigh and MRJPs a e he mos impo an componen s cons i u ing 80%–90% o he o al
p o ein con en [
21
,
27
]. O he s a e glucose oxidase [
27
],
α
-glucosidase, and
α
-amylase [
28
]. The MRJPs
sha e a common de elopmen al genesis wi h he yellow p o ein amily [
29
]. The YELLOW/MRJPs
a e named acco ding o hei molecula weigh o simply numbe ed by he o de in which hey
a e disco e ed. So a , MRJPs (1–9) a e well-desc ibed wi h molecula mass 49–87 kDa, which a e
encoded by nine di e en genes [
23
,
30
]. MRJP-1 is a weak acidic glycop o ein, accoun ing o 48% o
wa e -soluble RJ p o eins and he seconda y s uc u e consis s o 9.6%
α
-helices, 38.3%
β
-shee s, and
20%
β
- u ns [
6
,
31
]. Pa icula ly, MRJP-1 occu s as a monome (mono MRJP-1) o as an oligome known
as apisin by polyme iza ion wi h apisimin [
31
]. Apisin could be used o de e mine he quali y o RJ [
32
].
MRJP-2 and MRJP-3 p oduced by Chinese bees (Apis ce ana ce ana) a e less polymo phic compa ed o
Eu opean bees (Apis melli e a ligus ica) and A icanized bees (Apis melli e a scu ella e) [
33
,
34
], and MRJP-4
was i s ime con i med by wo-dimensional gel elec opho esis (2-DE) analysis du ing he compa ison
in he RJ o A icanized and Eu opean bees [
34
]. The impo an ea u e o MRJP-5 is a wide epea ed
egion loca ed be ween amino acid esidues 367 and 540 [
33
]. The mos signi ican pos - ansla ional
modi ica ion o he MRJPs is me hyla ion which igge s polymo phism o MRJP 1–5 in he RJ [
35
].
MRJPs 6–9 a e ecognized in RJ h ough p o eomic analysis [
36
,
37
]. Fu he mo e, 1-pe oxi edoin and
1-glu a hione S- ans e ase a e iden i ied in RJ [
11
]. RJ also con ains a calcium-binding p o ein, known
as egucalcin, and a lipid-binding p o ein, such as apolipopho in-III [
38
]. Phospho yla ed ica apin
( enom p o ein-II) and apolipopho in-III-like p o eins a e iden i ied in RJ may p omo e he s eng h o
immuni y [
39
]. The e a e 53 N-glycosyla ion si es esiding on 25 N-glycosyla ed p o eins in RJ. Mos o
he glycosyla ed p o eins a e associa ed wi h me abolic ac i i ies and heal h bene i s [12,28].
RJ is ich in amino acids, including lysine, p oline, cys eine, aspa ic acid, aline, glu amic
acid, se ine, glycine, cys eine, h eonine, alanine, y osine, phenylalanine, hyd oxyp oline, leucine,
isoleucine, and glu amine [
22
,
40
]. These high amoun s o amino acids in he MRJPs amily is essen ial
o de eloping o bo h queen bees and la ae. Amino acids, such as a ginine, leucine, isoleucine,
his idine, lysine, h eonine, yp ophan, me hionine, aline, and phenylalanine, a e mos commonly
p esen in MRJPs, wi h MRJP-1 o 9 con ains 48%, 47%, 39.3%, 44.5%, 51.4%, 42%, 48.3%, 49.5%, and
47.3% o hese amino acids, espec i ely. The majo amino acids in MRJP-1, MRJP-2, and MRJP-4 a e
aline and leucine. MRJP-3 is ich wi h a ginine and lysine while he p ominen amino acids in MRJP-5
is me hionine and a ginine. Fu he mo e, leucine is he majo amino acid in MRJP-(6–8) and isoleucine
is he ich one in MRJP-9 [
41
,
42
]. The MRJPs p o ide nu i i e componen s such as essen ial amino
acids o RJ.
Simila o p o eins, pep ides ep esen a speci ic sequence o amino acids in RJ ha has biological
ac i i y wi h heal h e ec s and po en ial applica ions. They can be iden i ied by p o eomics, such
as jelleines-I, jelleines-II, jelleines-III, jelleines-IV, and jelleines, a e iden ical o he C- e minal o he
MRJP-1 [
43
]. Mo eo e , RJ also con ains pep ides including apidaecin, de ensin, hymenop aecin,
jelleine-II, jelleine-II (pT), and jelleine-II (pS) [
39
,
44
]. Phospho yla ed jelleine-I (pS), jelleine-II (pS), and
jelleine-IV (pS) a e ound in Apis ce ana RJ while jelleine-II (pT) and jelleine-IV (pT) in Apis melli e a
RJ [39].
2.2. Lipids and Fa y Acids
A dis inc i e ea u e o RJ is associa ed wi h i s lipids and a y acids con en . The lipids a e
80%–85% o ee a y acids wi h ew being es e i ied. This ac ion also includes 4–10% phenolic
compounds, 5–6% waxes, 3–4% s e oids, and 0.4–0.8% phospholipids. RJ con ains a medium-chain
a y acids, no mally 8–12 ca bon a oms, some hyd oxyla ed in e minal o in e nal posi ion,
as mono-hyd oxyl a y acids o dica boxylic acids, and sa u a ed o unsa u a ed a he 2-posi ion [
45
].
Abou 80–90% a y acids ha e a di e en s uc u e such as 10-hyd oxy-2-decenoic acid (10-HDA),
In . J. Mol. Sci. 2020,21, 382 5 o 26
10-hyd oxydecenoicacid(10-HDDA),andsebacicacid(SEA).This ac ionconsis so 32% ans-10-HDA,
22% 10-HDDA, 24% gluconic acid, 5% dica boxylic acids, and some o he acids [
46
]. In addi ion,
a y acids, such as 8-hyd oxy oc anoic acid (8-HOC), 3,10-dihyd oxydecanedioic acid (3,10-HDecDA),
9-hyd oxy-2-decenoic acid (9-HDA), 1,10-decanedioic acid (DecDA), 3-hyd oxydecanoic acid
(3-HHDA), and 2-decene-1,10-dioic acid (2-DecDA), can also ound in RJ [
47
]. Among all lipids
and a y acids, 10-HDA is a s able compound ep esen ing 3.5% o eeze-d ied RJ which is conside ed
an in e na ional s anda d o quali y [
5
,
46
,
48
,
49
]. In he lipid ac ion s e ols should be included, e en
i hey a e only in ace amoun s. Fo ins ance, 24-me hylene choles e ol (24-MET) con ibu e wi h
49–58% o o al s e ols in RJ. O he simila compounds include
β
-si os e ol (19–24%), iso ucos e ol
(9–16%), campes e ol (67%), and desmos e ol (0.5–4.5%) [3].
2.3. O he Cons i uen s
RJ con ains some o he bioac i e compounds, such as 23.3 (
µ
g/mg) o phenolics and 1.28 (
µ
g/mg)
o o al la onoids [
20
,
49
,
50
]. The phenolic compounds comp ise phenol and ca boxylic g oups [
51
].
F om la onoid compounds, a ious s uc u es could be dis inguished, such as la ones (apigenin and
i s glycosides, lu eolin, ch ysin, and acace in), la anones (na ingenin, hespe e in, and isosaku ane in),
la onols (kaemp e ol and iso hamne in glycosides), and iso la onoids (genis ein and o monone in).
Coumes ol is an iso la onoid phy oalexin ha can also be ound in RJ [
52
]. Fu he mo e, la onoids
a e mos ly p esen in he o m o glycosides, and he aglycones a e linked by glycosidic bonds o he
osidic g oup [
53
]. Ano he unique compound o RJ is adenosine N1-oxide, which is an oxidized p oduc
o adenosine a he N1 posi ion o adenine base moie y [
54
,
55
]. Adenosine monophospha e (AMP) and
adenosine i sel a e impo an biomolecules wi h physiological e ec s [
56
–
58
]. Ace ylcholine can also
be ound wi h a mean concen a ion o 1 mg/g d y weigh [
59
]. Ho mones, gonado opins, pan o henic
acid, es os e one, es adiol, p oges e one, and p olac in also we e iden i ied in RJ [60–64].
3. Func ional P ope ies o RJ
The biological unc ions o RJ and i s applica ion (Table 1) a e in es iga ed
in i o
and
in i o
expe imen al models, such as labo a o y animals ( abbi s, mice, a s, and hams e s), mic obial
o ganisms (bac e ia, ungi, i uses, and nema odes), a m animals (ewes and bu alos), and clinical
ials (humans disease ea men ), o p o ides he basis o u he de elopmen s o i s pha maceu ical
e ec s. The biological ac i i ies o he RJ a e a iable and ha e been co ela ed o he con en o hei
ac i e ing edien s [65].
Table 1.
The biological ac i i ies and pha maceu ical applica ions o RJ and hei bioac i e ing edien s.
Bioac i e Compounds/Expe imen al
Models E ec s Sou ces
RJ, MRJP-2, and MRJP-4
(Mic o-o ganisms) An ibac e ial, an i ungal, an i-yeas
Induce damage and dys unc ion in mic obial cell wall and memb ane
[66–68]
Royalisin and 10-HDA
(Mic o-o ganisms) An ibac e ial (G am+, G am−), an i ungal
Inhibi g ow h [9,69,70]
Jelleine I-III, jelleine-II (pS), and
jelleine-II (pT)
(Mic o-o ganisms)
An ibac e ial (G am+, G am−)
Cell deg anula ion, hemolysis, and inc ease immune de ense [39,43]
RJ, 10H∆2DA, 3,10-HDA, 11S,
10-HDA, 10-ace ooxy-2-DEA, and
Na i e jelleine-11 (Mic o-o ganisms)
An i ungal and an i-yeas
S ongly inhibi g ow h [39,43,71–73]
P e and pos adminis a ion o RJ
(Animals)
An ioxidan ac i i y
Dec ease oxida i e s ess (MDA) and inc ease an ioxidan p ope ies
(CAT, GPx, and SOD) [74]
RJ
(Humans)
An i-cance e ec
Inhibi he umo -induced angiogenesis, ac i a e immune sys em,
me abolism o 2-AF me aboli es, and s op he damage o bisphenol A
[75–77]

In . J. Mol. Sci. 2020,21, 382 6 o 26
Table 1. Con .
Bioac i e Compounds/Expe imen al
Models E ec s Sou ces
In a enously applica ion o 10-HDA
and he HuIFN-aN3
(Animals)
An i-cance e ec
Dec ease he le el o glu a hione and enhance he le el o lipid
pe oxida ion ia MDA [78]
RJ
(Animals and humans)
An i-diabe ic e ec
Imp o e he se um le el o iglyce ides, lipop o ein, and choles e ol
Dec ease glucose le el and inc ease insulin concen a ion [79–83]
MRJP-3
(Animals) Immunomodula o y e ec
Dec ease an igenici y and inhibi IL-4, IL-2, and IFN-Υp oduc ion [84]
3,10-DDA
(Humans)
Immunomodula o y e ec
Inc ease he p oduc ion o IL-12, IL-18, and s imula e he p oduc ion
o IFN-Υ
[85]
RJ (Animals and humans) Hypocholes e olemic e ec
Reduced he le el o iglyce ide, insulin, o al lipids, and choles e ol
le el by dec easing e y low-densi y lipop o ein le els [86–88]
RJ and MRJP-1
(Humans)
Hypocholes e olemic e ec
Dec eased he o al choles e ol and LDL-c le el by imp o ing he
(HDL-c) le el [89,90]
RJ, ERJ, And MRJP-1
(Animals)
An i- hype ension e ec
Reduce sys olic blood p essu e, dias olic blood p essu e, and inc ease
NO le el [62,91–93]
RJ
(Animals)
An i-in lamma o y e ec
RJ inhibi he TNF-α, IL-1β, and, IL-18 le els in he blood due o i s
an i adicals and an ioxida i e e ec [94,95]
RJ and MRJP-2
(Animals)
Hepa o- enal p o ec i e e ec
Reduce blood u ea, MDA le el, leukocy e in il a ion, c ea inine,
adhesion molecule-1 exp ession, glome ula diame e , and TNF-a
Inc eased SOD and GPx
[50,96–99]
RJ and 10-HDA
Animals
Neu o ophic e ec s
Inhibi ed p oduc ion o oligodend ocy es, as ocy es, and s imula e
neu on di e en ia ion [57,100]
RJ and RJPs
(Animals and humans)
Neu op o ec i e
Dec ease choles e ol and amyloid-be a deposi ion by down- egula ion
o β-sec e ase
Inc ease choline gic esponse, es ogen le el, and an ioxidan
capaci ies
Imp o ed blood-b ain ba ie , and au onomic ne ous sys ems
[101–103]
RJ
(Humans)
Genop o ec i e e ec
Inc ease o BCL2/BAX a io o cell su i al
Enhance in hTERT/BAX o inc easing age
Inc ease in NRF2/BAX o an ioxida i e esponse
[104]
RJ and 10-HDA
(Humans)
P o ec i e e ec
P o ec i om pho o-aging by imp o ing collagen p oduc ion ia
up- egula ion o TGF-β1 exp ession [105]
RJ
(Animals and humans) E ec on e ili y
Inc ease spe m mo ili y, lu einizing ho mones, and es os e one le els
[81,106–108]
ERJ
(Humans) An i-alle gic
Signi ican ly educing IgE-binding capaci y o blood [109]
No e: RJ ( oyal jelly); RJPs (pu i ied oyal jelly pep ides); RJPH ( oyal jelly p o ein hyd olysa e); MRJP-4 (ajo
oyal jelly p o ein 4); 10-HDA (10-hyd oxydecanoic acid); 10H
∆
2DA (10-hyd oxy-Del a-2-decenoic acid); 3,10-DDA
(3,10-dihyd oxy-decanoic acid); MDA (malondialdehyde); GPx (Glu a hione pe oxidase); SOD (supe oxide
dismu ase); IFN-
Υ
(in e e on-gamma); IL-4 (in e leukin-4); TNF-
α
( umo nec osis ac o ); BCL2: (B-cell lymphoma
2); BAX (BCL2 associa ed X p o ein); NRF2 (nuclea ac o e y h oid 2 ela ed ac o 2); 2-AF (2-amino luo ene);
BACE1 (β-si e amyloid p ecu so p o ein clea ing enzymes), and IgE (Immunoglobulin E).
3.1. Biological Ac i i y o RJ
RJ has heal h bene i s e ec s o bo h humans and honeybees. I is a na u al an ibio ic and plays
an e icien ole in de eloping he la al s ages in blood cells and main ains i s o ula o y cha ac e is ics
du ing he whole li e span. Mo eo e , RJ has an ioxidan s wi h he po en ial o educing he isk o
cance , high blood p essu e, diabe es, and ca dio ascula diseases [
94
,
110
,
111
]. RJ also a ec s he
In . J. Mol. Sci. 2020,21, 382 7 o 26
mo phological cha ac e s, g ow h, lea ning, size, and shape a ia ions in a ious c ea u es, such as
honeybees, mice, and humans [112].
3.1.1. An imic obial Ac i i y
RJ demons a es s ong an imic obial p ope ies agains di e en pa hogens [
39
,
66
,
67
,
70
], due o
he exis ence o special p o eins and pep ides [
9
,
43
], and he p esence o he 10-HDA [
9
,
113
]. Mo eo e ,
RJcould igh agains pe iodon opa hic bac e ia, suchasAgg ega ibac e ac inomyce emcomi ans,P e o ella
in e media,Fusobac e ium muclea um, and Po phy omonas gingi alis [
67
]. MRJPs (2–5 and 7) e eal
an ibac e ial ac i i y agains G am-nega i e E. coli [
114
]. Jellenie I, II, III, and IV a e impo an
an ibac e ial pep ides in RJ. Al hough he di e ence be ween jellenie (I–IV) is mino , wi h only one
esidue di e ence in he sequence, his sligh di e ence has a signi ican impac on hei an ibac e ial
ac i i ies. Jelleine I–III could inhibi bo h G am-posi i e and G am-nega i e bac e ia whe eas Jelleine-IV
doesn’ [
43
]. An ibac e ial pep ides a e posi i ely cha ged due o he exis ence o lysine, a ginine,
and his idine esidues ha allow hem o in e ac wi h anionic phospholipids o he cell memb ane
and collapse i [
115
]. Royalisin has h ee in amolecula disul ide bonds be ween cys eine esidues
and shows s ong an ibac e ial ac i i y agains di e en ypes o G am-posi i e and G am-nega i e
bac e ia [
70
]. In addi ion, na i e jelleines could inhibi G am-posi i e bac e ia (Bacillus sub ilis,
S aphylococcus au eus,Paenibacillus la ae) and G am-nega i e bac e ia (Esche ichia coli,Pseudomonas
ae uginosa). Fu he mo e, he phospho yla ed jelleines (Jelleine-II (pT) and Jelleine-II (pS) could igh
agains E. coli and B. sub ilis,P. la ae, and E. coli [
39
]. MRJPs 2 and 4 ac as an imic obial agen s and
ha e a wide ange o ac i i y agains bac e ia (G am-posi i e and G am-nega i e), ungi, and yeas s.
Recombinan MRJP-2 and MRJP-4 could kill mic oo ganisms by a aching o he cell wall o ungi,
yeas , and bac e ia ha damage he s uc u e o he cell wall [
66
,
68
]. RJ aqueous ac ion has epo ed
a s ong inhibi ion o he g ow h o Fusa ium species [
73
]. RJ has also exhibi ed an i ungal p ope ies
agains Syncephalas um acemosum,Aspe gillus umigan s, and A. nige [
72
]. Royalisin also indica es an
an i- ungal esponse agains nec o ophic ungus, such as Bo y is cine ea [
69
]. The na i e jelleine-ll
p o ein p esen s an inhibi o y e ec on Candida albicans [
39
,
43
]. Mo eo e , 10H
∆
DA has an i ungal
po en ial in inhibi ing he g ow h a e o Neu ospo a si ophila [
116
]. RJ is e ec i e agains C. albicans
and as an al e na i e agen o igh his yeas [
117
]. Fa y acids such as 3,10-HDA, 11S, 10-HDA and
10-ace ooxy-2-DEA could s ongly inhibi he g ow h o yeas s, such as C. opicalis,C. albicans, and
C. glab a a [
71
]. Mo eo e , RJ could igh agains he pes 2 i us, in luenza i us, hea i us coxsackie
B3, he pes simplex i us ype 1 (HSV-1), and ce ain habdo i uses [118,119].
3.1.2. An ioxidan Ac i i y
The an ioxidan ac i i y o RJ could be explo ed as he p e en ion and ea men o a ious ch onic
and degene a i e diseases. In he die o Sp ague–Dawley a s ed wi h con amina ed umonisin (FB)
(200 mg/kg) and RJ (150 mg/kg) o h ee weeks, RJ a enua es he ha m ul e ec o FB ia imp o ing
glu a hione pe oxidase o ma ion and educing he e ec s o lipid pe oxida ion and ee adical
gene a ion [
120
]. RJ could also eco e om cadmium-induced geno oxici y and oxida i e s ess in
mice, which imp o es he an ioxidan s a us ia glu a hione (GSH) and educes malondialdehyde
(MDA) p oduc ion [
121
]. A e a s exposed o cispla in and ca bon e achlo ide, RJ adminis a ion
could esis agains oxida i e s ess in li e and enal issues, which is achie ed by dec easing MDA
p oduc ion and inc easing he concen a ion o cellula an ioxidan enzymes, such as supe oxide
dismu ase (SOD), ca alase (CAT), glu a hione educ ase (GR), and glu a hione pe oxidase (GPx) [
122
].
In adia ion-induced lung and li e damage o Sp ague–Dawley a s, p e- and pos -adminis a ion o
RJ a e e ec i e in educing oxida i e s ess and inc easing an ioxidan p ope ies [
74
]. The an ioxidan
esponse o enzyme- ea ed RJ (ERJ) is con i med by he educ ion o ni ic oxide (NO) and in acellula
eac i e oxida i e species, and inc eased he e ec o he an ioxidan glu a hione and an ioxidan
SOD le els. Mo eo e , ERJ has he po en ial as an oxida i e agen o be used o human, as well as
animal, die s [
123
]. Simila ly, MRJP-2 has po en ial ac ion as an an ioxidan o p o ec mammalian and
In . J. Mol. Sci. 2020,21, 382 8 o 26
insec cells ia dec easing he le els o caspase-3 ac i i y and oxida i e s ess-induced cell apop osis
ollowed by inc ease cell iabili y [
68
]. Hyd oxyl adicals and hyd ogen-pe oxide sca enging ac i i y
we e e i ied wi h 29 an ioxidan pep ides isola ed om RJ hyd olysa e, in which 12 small pep ides
ha ing 2–4 esidues (Ala-Lys, Phe-A g, Ile-A g, Lys-Phe, Lys-Leu, Lys-Ty , A g-Ty , Ty -Asp, Ty -Ty ,
Leu-Asn-A g, and Lys-Asn-Ty -P o) ha ing he s onges ac i i y. Mo eo e , h ee dipep ides (Lys-Ty ,
A g-Ty , and Ty -Ty ) in RJ indica e s ong sca enging ac i i y due o a dona ion o he hyd ogen a om
om hei phenolic hyd oxyl g oup [124].
3.1.3. Wound Healing Ac i i y
Woundhealing isanimpo an heal hissueand awide ange o
in i o
and
in i o
s udiesindica e
ha RJ seems play a signi ican ole [125,126]. The de elopmen o a opic de ma i is-like skin lesions
in pic yl chlo ide ea ed NC/Nga mouse is supp essed a e ea men wi h RJ. This is achie ed by he
down- egula ing p o ein o an igen-speci ic in e e on-gamma (IFN-
Υ
) p oduc ion and up- egula ion
o NO syn hase [
127
]. The applica ion o dose-dependen RJ imp o es he healing e ec o se e e o al
mucosi is in hams e s induced by chemo he apy d ug 5- luo ou acil [
128
]. O al ea men wi h RJ
could inc ease he wound healing p ocess in diabe ic mice [
125
]. Mo eo e , RJ in 5
µ
g/mL concen a ion
p omo es he ib oblas s mig a ion in human beings by al e ing he le el o di e en lipids and enhance
he le el o sphingolipids ha p omo e wound healing [
125
]. Mo eo e , an RJ d essing is a good way
o ea ing diabe ic oo ulce pa ien s along wi h o he s anda d me hods. Fu he mo e, his me hod
c ea es asodila ion e ec s a ound he wound which could dila e blood essels o inc ease blood low
and p e en he wound om in ec ion by o he mic obial o ganisms [
129
]. In addi ion, RJ p omo es
he wound healing esponse o con ol de mal in ec ion induced by me hicillin- esis an S. au eus
(MRSA) [
126
]. Wa e -soluble p o eins o RJ and i s ac ions induce p oli e a i e and mig a o y e ec s
on a human epide mal ke a inocy e in a sc a ch wound model. A p o ein ac ion, mainly con aining
MRJP-2,3,7 ha e he po en ial o in luence wound healing bioac i i y by s imula ing ke a inocy e
g ow h and mig a ion sugges s ha hese p o eins p omo e he de elopmen o new wound healing
medica ion [
130
]. The de ensin-1 pep ide in RJ con ibu es o skin egene a ion and cu aneous wound
closu e by inc easing ma ix me allop o einase-9 sec e ion and ke a inocy e mig a ion [131].
3.1.4. Immunomodula o y Ac i i y
Immunomodula o y esponse plays a signi ican ole in alle gy, cance , and in lamma ion by
ac i a ion o an ibody o ma ion o inhibi ion o whi e blood cell ac i i ies [
132
]. The i s human
s udy in sys emic lupus e y hema osus (SLE) in child en e eals ha he e ec o RJ ea men in
SLE indica es a signi ican imp o emen a e h ee mon hs o adminis a ion [
133
]. The an i-alle gic
ac o s o RJ inhibi in e leukin-4 (IL-4) p oduc ion which is induced by an i-CD3 ac i a ed spleen
cells de i ed om o albumin (OVA)/alum-immunized mice. MRJP-3 (70 kDa) glycop o ein inhibi s
IL-4, IL-2, and IFN-
Υ
p oduc ion by T cells associa ed wi h he supp ession o cell p oli e a ion.
In a-pe i oneal MRJP-3 adminis a ion indica es inhibi ion in immune se um le el o an i-OVA IgG1
and IgE in OVA/alum-induced alle gic mice while hea - ea ed soluble MRJP-3 adminis a ion dec eases
an igenici y and main ains i s inhibi o y e ec on an ibody esponse o o albumin. Bo h
in i o
and
in i o
s udies demons a e ha MJRP-3 has s ong immunomodula o y ac i i ies [
84
]. Mo eo e , he
lowe concen a ion o wa e ex ac o RJ and 3,10-HDA ac i a e he T-cell p oli e a ion by igge ing
concana alin A (Con-A) and enhances he p oduc ion o IL-2 while a highe concen a ion o wa e
ex ac o RJ, d y powde o RJ, and ans-10-HDA inhibi T-cell p oli e a ion by dec easing IL-2
and NO p oduc ion. Wa e ex ac om RJ possesses he complexi y o biological and s onges
immunomodula o y ac i i ies [
134
]. Fa y acids, such as 10-HDA and 3,10-DDA, ha e s ong
immunomodula o y ac i i ies exhibi ed commonly by he dend i ic cell-associa ed educ ion o
allogeneicT-cellp oli e a ionandIL-2p oduc ion
in i o
, aswellas heinhibi ion o he an igen-speci ic
immune esponse
in i o
[
135
]. A a y acid 3,10-dihyd oxy-decanoic acid (3,10-DDA) o RJ s imula es
he ma u a ion o monocy e-de i ed dend i ic cells (MoDCs) by up- egula ing he exp ession o
In . J. Mol. Sci. 2020,21, 382 9 o 26
allogeneic CD1a, CD40, CD54, and CD 86, and also boos ing he allos imula o y po en ial in co-cul u e
wi h allogeneic CD4+T cells. The 3,10-DDA adminis a ions o monocy e-de i ed dend i ic cells
(MoDCs) inc ease he p oduc ion o IL-12, IL-18, and s imula e he p oduc ion o IFN-
Υ
in allogeneic
CD4+T cells in co-cul u e. The e o e, 3,10-DDA encou ages ma u a ion and Th1 pola izing po en ial o
human MoDCs
in i o
ha could ha e an an i- i al and an i- umo esponse [
85
]. 10-HDA has a ious
immunomodula o y e ec s depending on applied concen a ions. The high 10-HDA concen a ion
could s op he unc ion and ma u a ion o human MoDCs and lowe doses suppo he Th1 immune
esponse [136].
3.1.5. An i-Aging Ac i i y
RJ is associa ed wi h an inc ease in he li espan o queen honeybees as well as se e al o he
species [
9
], and imp o es he quali y o li e in old age a s [
137
]. RJ and ERJ adminis a ion ha e
he po en ial o delay aging, age- ela ed diso de , and p omo e longe i y and s ess esis ance in
Caeno habdi is elegans [
138
]. Fu he mo e, ERJ and enzyme-un ea ed RJ (NRJ) in luence in an age
ocusing mo o diso de in gene ically he e ogeneous male mice. Age- ela ed a ia ions a ec muscle
ibe size a an ad anced age, muscle sa elli e cell ma ke s, and ca abolic genes in RJ- ea ed mice, hus,
RJ may be use ul o imp o e he quali y o li e du ing aging h ough egula ing he mo o unc ions [
139
].
Royalac in, a glycop o ein om RJ, ex ends he li e span o C. elegans by p omo ing epide mal g ow h
ac o (EGF) and i s ecep o s’ signaling [
140
]. MRJPs a e longe i y-p omo ing subs ances ha inc ease
he longe i y pe iod o D osophila h ough p omo ing he an i-epide mal g ow h ac o ecep o
(EGFR)-media ed signaling pa hway [
141
]. P o ein and lipid componen s in RJ ha e he po en ial o
ex end he li e span in a ious li ing beings, including honeybees, c icke s, silkwo ms, nema odes,
mice, and inhibi senescence o human issues in cell cul u es ia down- egula ion o insulin-like
g ow h ac o s and up- egula ion o epide mal g ow h ac o signaling [
25
]. Mo eo e , 10-HDA is used
o inc ease he longe i y o C. elegans ia educed insulin-like signaling (ILS) and inc ease he li espan
by die a y es ic ion signaling and he a ge o apamycin (TOR) componen s in C. elegans [
142
].
The biological ac i i ies o RJ and hei unde lying possible mechanisms a e shown in Figu e 4.
In . J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 10 o 27
esponse [85]. 10-HDA has a ious immunomodula o y e ec s depending on applied concen a ions.
The high 10-HDA concen a ion could s op he unc ion and ma u a ion o human MoDCs and lowe
doses suppo he Th1 immune esponse [136].
3.1.5. An i-Aging Ac i i y
RJ is associa ed wi h an inc ease in he li espan o queen honeybees as well as se e al o he
species [9], and imp o es he quali y o li e in old age a s [137]. RJ and ERJ adminis a ion ha e he
po en ial o delay aging, age- ela ed diso de , and p omo e longe i y and s ess esis ance in
Caeno habdi is elegans [138]. Fu he mo e, ERJ and enzyme-un ea ed RJ (NRJ) in luence in an age
ocusing mo o diso de in gene ically he e ogeneous male mice. Age- ela ed a ia ions a ec muscle
ibe size a an ad anced age, muscle sa elli e cell ma ke s, and ca abolic genes in RJ- ea ed mice,
hus, RJ may be use ul o imp o e he quali y o li e du ing aging h ough egula ing he mo o
unc ions [139]. Royalac in, a glycop o ein om RJ, ex ends he li e span o C. elegans by p omo ing
epide mal g ow h ac o (EGF) and i s ecep o s’ signaling [140]. MRJPs a e longe i y-p omo ing
subs ances ha inc ease he longe i y pe iod o D osophila h ough p omo ing he an i-epide mal
g ow h ac o ecep o (EGFR)-media ed signaling pa hway [141]. P o ein and lipid componen s in
RJ ha e he po en ial o ex end he li e span in a ious li ing beings, including honeybees, c icke s,
silkwo ms, nema odes, mice, and inhibi senescence o human issues in cell cul u es ia down-
egula ion o insulin-like g ow h ac o s and up- egula ion o epide mal g ow h ac o signaling [25].
Mo eo e , 10-HDA is used o inc ease he longe i y o C. elegans ia educed insulin-like signaling
(ILS) and inc ease he li espan by die a y es ic ion signaling and he a ge o apamycin (TOR)
componen s in C. elegans [142]. The biological ac i i ies o RJ and hei unde lying possible
mechanisms a e shown in Figu e 4.
Figu e 4. The biological ac i i ies o RJ and hei mechanism. SOD (supe oxide dismu ase); GSH
(glu a hione); CAT (ca alase); GR (glu a hione educ ase); GPx (glu a hione pe oxidase); ROS
( eac i e oxygen species); MMP (ma ix me allopep idases); MDA (malondialdehyde); NO (ni ic
oxide); IFN-ϒ (in e e on-gamma); IL-4 (in e leukin-4); TNF-α ( umo nec osis ac o ); IFN-α
(In e e on-α); EGF (epide mal g ow h ac o ); AMPK (5′ AMP-ac i a ed p o ein kinase); MAPK
(mi ogen-ac i a ed p o ein kinase); IGF-1 (insulin-like g ow h ac o -1), and TOR ( a ge o
apamycin).
Figu e 4.
The biological ac i i ies o RJ and hei mechanism. SOD (supe oxide dismu ase);
GSH (glu a hione); CAT (ca alase); GR (glu a hione educ ase); GPx (glu a hione pe oxidase); ROS
( eac i e oxygen species); MMP (ma ix me allopep idases); MDA (malondialdehyde); NO (ni ic oxide);
IFN-
Υ
(in e e on-gamma); IL-4 (in e leukin-4); TNF-
α
( umo nec osis ac o ); IFN-
α
(In e e on-
α
);
EGF (epide mal g ow h ac o ); AMPK (5
0
AMP-ac i a ed p o ein kinase); MAPK (mi ogen-ac i a ed
p o ein kinase); IGF-1 (insulin-like g ow h ac o -1), and TOR ( a ge o apamycin).
In . J. Mol. Sci. 2020,21, 382 16 o 26
s udies and clinical ials) and alida ion a e demanded o e eal he cellula and molecula mechanisms
o RJ o heal h bene i s using cu ing-edge genomics, ansc ip omics, p o eomics, and me abolomics.
Au ho Con ibu ions:
S.A. p epa ed he o iginal d a . M.G.C., F.F., and S.Z.A. pa icipa ed in w i ing, e iew,
and edi ing. J.L. concei ed he manusc ip . All au ho s ha e ead and ag eed o he published e sion o
he manusc ip .
Funding:
The inancial suppo p o ided by he Ag icul u al Science and Technology Inno a ion P og am
(CAAS-ASTIP-2015-IAR), Mode n Ag o-Indus y Technology Resea ch Sys em (CARS-44) in China, and he
Na ional P ojec o Upg ading O e all Bee-P oduc Quali y o he Beekeeping Indus y o China.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
Abb e ia ions
ACE Angio ensin 1-con e ing enzymes
AD Alzheime ’s disease
AF Amino luo ene
AMP Adenosine monophospha e
ANO Adenosine N1-oxide
ApoA-1 Apolipop o ein A1
BACE1 β-si e amyloid p ecu so p o ein clea ing enzymes
CAT Ca alase
CCl4 Ca bon e achlo ide
cGMP Cyclic guanosine monophospha e
Con-A Concana alin A
DecDA 1,10-decanedioic acid
DOX Doxo ubicin
EGF Epide mal g ow h ac o
EGFR An i-epide mal g ow h ac o ecep o
ERJ Enzyme- ea ed RJ
FB Fumonisin
FBG Fas ing blood glucose
FY4 Food yellow 4
GPx Glu a hione pe oxidase
GR Glu a hione educ ase
GSH Glu a hione
9-HDA 9-hyd oxy-2-decenoic acid
10-HDA 10-hyd oxy-2-decenoic acid
3-HHDA 3-hyd oxydecanoic acid
10-HDDA 10-hyd oxydecenoic acid
3,10-HDecDA 3,10-dihyd oxydecanedioic acid
8-HOC 8-hyd oxy oc anoic acid
HSV-1 He pes simplex i us ype 1
HuIFN-aN3 Human in e e on-alpha
IFN-ΥIn e e on-gamma
IgE Immunoglobulin E
IkBa Inhibi o o kappa B
IkB-z IkappaBze a
IL In e leukin
ILS Insulin-like signaling
JNK-AP-1 C-Jun N- e minal kinases-ac i a ing p o ein-1
MDA Malondialdehyde
24-MET 24-me hylene choles e ol
MLKL Mixed lineage kinase domain-like p o ein
MoDCs Monocy e-de i ed dend i ic cells
MRJPs Majo oyal jelly p o eins
NAT N-ace yl ans e ase
NO Ni ic oxide
NPCs/NSs Neu al p ogeni o s o neu al s em cells
OXM Oxyme holone
PC3 P os a e cance cell line
RJ Royal jelly
RJBs Royal jelly bees

In . J. Mol. Sci. 2020,21, 382 17 o 26
SEA Sebacic acid
SHR Spon aneously hype ensi e a s
SLE Sys emic lupus e y hema osus
SOD Supe oxide dismu ase
TKIs Ty osine kinase inhibi o s
VLDL Ve y low-densi y lipop o ein le els
VSMCs Vascula smoo h muscle cells
Re e ences
1.
Knech , D.; Kaa z, H. Pa e ns o la al ood p oduc ion by hypopha yngeal glands in adul wo ke honey
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