New Insights into the Biological and Pharmaceutical Properties of Royal Jelly

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   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 . 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