Next Article in Journal
Revisiting the Pharmacological Value of Glucagon: An Editorial for the Special Issue “The Biology and Pharmacology of Glucagon”
Next Article in Special Issue
Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription
Previous Article in Journal
Recent Advances in Lipopolysaccharide Recognition Systems
Previous Article in Special Issue
Therapeutic Potential of Hericium erinaceus for Depressive Disorder
Review

New Insights into the Biological and Pharmaceutical Properties of Royal Jelly

1
Key Laboratory of Pollinating Insect Biology, Ministry of Agriculture, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
2
Coimbra Chemistry Centre, (CQC, FCT Unit 313), Faculty of Sciences Technology, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal
3
Observatory of Drug-Herb Interactions, Sciences Health Campus, Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
4
Department of Veterinary Sciences, University of Pisa, Viale delle Piagge 2, 56124 Pisa, Italy
5
Interdepartmental Research Center “Nutraceuticals and Food for Health”, University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(2), 382; https://doi.org/10.3390/ijms21020382
Received: 23 November 2019 / Revised: 22 December 2019 / Accepted: 6 January 2020 / Published: 8 January 2020

Abstract

Royal jelly (RJ) is a yellowish-white and acidic secretion of hypopharyngeal and mandibular glands of nurse bees used to feed young worker larvae during the first three days and the entire life of queen bees. RJ is one of the most appreciated and valued natural product which has been mainly used in traditional medicines, health foods, and cosmetics for a long time in different parts of the world. It is also the most studied bee product, aimed at unravelling its bioactivities, such as antimicrobial, antioxidant, anti-aging, immunomodulatory, and general tonic action against laboratory animals, microbial organisms, farm animals, and clinical trials. It is commonly used to supplement various diseases, including cancer, diabetes, cardiovascular, and Alzheimer’s disease. Here, we highlight the recent research advances on the main bioactive compounds of RJ, such as proteins, peptides, fatty acids, and phenolics, for a comprehensive understanding of the biochemistry, biological, and pharmaceutical responses to human health promotion and life benefits. This is potentially important to gain novel insight into the biological and pharmaceutical properties of RJ.
Keywords: royal jelly; bioactive compounds; functional properties; proteins; fatty acids; phenolics royal jelly; bioactive compounds; functional properties; proteins; fatty acids; phenolics

1. Introduction

Royal jelly (RJ) is known as a “superfood” which is produced by nurse bees to feed young worker larvae and queen bees [1,2]. The major components of RJ are (60–70% w/w) water, (9–18% w/w) proteins, (7–18% w/w) sugars, and (3–8% w/w) lipids [3,4]. RJ also contains minor components, such as minerals (Fe, Na, Ca, K, Zn, Mg, Mn, and Cu), amino acids (eight essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (A, B complex, C, and E), enzymes, hormones, polyphenols, nucleotides, and minor heterocyclic compounds [3,5,6]. RJ is an active research domain because it is essential for larval development and queen reproduction in honeybee colonies through the metabolism of sugars, lipids, and proteins [7,8]. Thereby, the larger body size, longer lifespan, and fertility of queens compared to worker bees are potentially correlated to the special diet of RJ [9].
RJ has been produced in large scale for commercial purposes to date, and its market value is significantly higher than other bee products, such as honey or pollen, thus, it is a major income source for beekeepers [4,10]. Beekeepers have made great efforts to develop the technique to improve RJ production and to select for high-producing strains of honeybees. For instance, the increase in the production of RJ in China over the last 40 years has been achieved by the development of genetic selection of high RJ-producing bees (RJBs) from Italian bees [11,12,13], and the development and implementation of production techniques to increase and optimize RJ production [14,15,16]. At present RJBs have the potential to produce more than 10 kg RJ/colony/year, which is 10 times more than for non-selected Italian bees [15,16,17,18]. Notably, China is the largest producer and exporter of RJ around the world, producing more than 4000 tons annually, with more than $2.5 billion market, which is 90% of the total RJ production globally and mostly exported to Japan, Europe, and the United States [12,19].
The health-promoting benefits and pharmaceutical properties of RJ from animal models to humans have been widely investigated. RJ is a nutritional modification of honey and bee bread (Figure 1), and it is commercially available on a large scale as health food and cosmetics in Asia, especially in China and Japan [9,10]. Moreover, RJ is used to explore further applications as a drug and traditional consumption as “remedies” for humans and animals [20]. To date, the importance of RJ has attracted attention around the world, which is evidenced by the growth in the number of publications and citations in the core collection of the Web of Science (Figure 2). Recently, the origin and function of RJ, such as major royal jelly proteins (MRJPs) for the development of the larvae [21], antimicrobial properties [9], medicinal value [20,22], proteins and peptides [23], the potential applications for cancer treatment [24], and health aging and longevity [25] have been reported. To better understand the biochemistry, biological, and pharmaceutical response to health and life benefits of RJ, we update the knowledge from the research advances of the biological activities and pharmaceutical applications of RJ and its bioactive ingredients that are associated with farm animals, micro-organisms, laboratory animals, insects, and clinical trials in humans. Here, our major focus is on the bioeffects of RJ, such as antimicrobial, antioxidant, anti-inflammatory, wound healing, anti-aging, immunomodulatory, anti-cancer, anti-diabetic, anti-hyperlipidemic, anti-hypertension, hepato-renal protective, neuroprotective, estrogenic, and fertility effects. This evidence is a potentially valuable resource for further studies of the health potential properties of RJ for both humans and honeybees.

2. Bioactive Substances

RJ is a rich source of nutrients and bioactive compounds with the potential to play a vital part in their biological activities and pharmaceutical applications [26]. It has been confirmed that proteins, peptides, lipids, phenolics, and flavonoids are the main bioactive compounds responsible for the various pharmaceutical properties of RJ (Figure 3). The natural variation of bioactive compounds depend upon the biodiversity of flora species present in the different ecosystem [26].

2.1. Proteins and Peptides

The investigation of novel proteins in RJ has been a long-term perusal for biochemical experts and apicultural biologists. Proteins are the most abundant components of RJ, accounting for more than 50% of the dry weight and MRJPs are the most important components constituting 80%–90% of the total protein content [21,27]. Others are glucose oxidase [27], α-glucosidase, and α-amylase [28]. The MRJPs share a common developmental genesis with the yellow protein family [29]. The YELLOW/MRJPs are named according to their molecular weight or simply numbered by the order in which they are discovered. So far, MRJPs (1–9) are well-described with molecular mass 49–87 kDa, which are encoded by nine different genes [23,30]. MRJP-1 is a weak acidic glycoprotein, accounting for 48% of water-soluble RJ proteins and the secondary structure consists of 9.6% α-helices, 38.3% β-sheets, and 20% β-turns [6,31]. Particularly, MRJP-1 occurs as a monomer (mono MRJP-1) or as an oligomer known as apisin by polymerization with apisimin [31]. Apisin could be used to determine the quality of RJ [32]. MRJP-2 and MRJP-3 produced by Chinese bees (Apis cerana cerana) are less polymorphic compared to European bees (Apis mellifera ligustica) and Africanized bees (Apis mellifera scutellate) [33,34], and MRJP-4 was first time confirmed by two-dimensional gel electrophoresis (2-DE) analysis during the comparison in the RJ of Africanized and European bees [34]. The important feature of MRJP-5 is a wide repeated region located between amino acid residues 367 and 540 [33]. The most significant post-translational modification of the MRJPs is methylation which triggers polymorphism of MRJP 1–5 in the RJ [35]. MRJPs 6–9 are recognized in RJ through proteomic analysis [36,37]. Furthermore, 1-peroxiredoin and 1-glutathione S-transferase are identified in RJ [11]. RJ also contains a calcium-binding protein, known as regucalcin, and a lipid-binding protein, such as apolipophorin-III [38]. Phosphorylated icarapin (venom protein-II) and apolipophorin-III-like proteins are identified in RJ may promote the strength of immunity [39]. There are 53 N-glycosylation sites residing on 25 N-glycosylated proteins in RJ. Most of the glycosylated proteins are associated with metabolic activities and health benefits [12,28].
RJ is rich in amino acids, including lysine, proline, cysteine, aspartic acid, valine, glutamic acid, serine, glycine, cysteine, threonine, alanine, tyrosine, phenylalanine, hydroxyproline, leucine, isoleucine, and glutamine [22,40]. These high amounts of amino acids in the MRJPs family is essential for developing of both queen bees and larvae. Amino acids, such as arginine, leucine, isoleucine, histidine, lysine, threonine, tryptophan, methionine, valine, and phenylalanine, are most commonly present in MRJPs, with MRJP-1 to 9 contains 48%, 47%, 39.3%, 44.5%, 51.4%, 42%, 48.3%, 49.5%, and 47.3% of these amino acids, respectively. The major amino acids in MRJP-1, MRJP-2, and MRJP-4 are valine and leucine. MRJP-3 is rich with arginine and lysine while the prominent amino acids in MRJP-5 is methionine and arginine. Furthermore, leucine is the major amino acid in MRJP-(6–8) and isoleucine is the rich one in MRJP-9 [41,42]. The MRJPs provide nutritive components such as essential amino acids to RJ.
Similar to proteins, peptides represent a specific sequence of amino acids in RJ that has biological activity with health effects and potential applications. They can be identified by proteomics, such as jelleines-I, jelleines-II, jelleines-III, jelleines-IV, and jelleines, are identical to the C-terminal of the MRJP-1 [43]. Moreover, RJ also contains peptides including apidaecin, defensin, hymenoptaecin, jelleine-II, jelleine-II (pT), and jelleine-II (pS) [39,44]. Phosphorylated jelleine-I (pS), jelleine-II (pS), and jelleine-IV (pS) are found in Apis cerana RJ while jelleine-II (pT) and jelleine-IV (pT) in Apis mellifera RJ [39].

2.2. Lipids and Fatty Acids

A distinctive feature of RJ is associated with its lipids and fatty acids content. The lipids are 80%–85% of free fatty acids with few being esterified. This fraction also includes 4–10% phenolic compounds, 5–6% waxes, 3–4% steroids, and 0.4–0.8% phospholipids. RJ contains a medium-chain fatty acids, normally 8–12 carbon atoms, some hydroxylated in terminal or internal position, as mono-hydroxyl fatty acids or dicarboxylic acids, and saturated or unsaturated at the 2-position [45]. About 80–90% fatty acids have a different structure such as 10-hydroxy-2-decenoic acid (10-HDA), 10-hydroxydecenoic acid (10-HDDA), and sebacic acid (SEA). This fraction consists of 32% trans-10-HDA, 22% 10-HDDA, 24% gluconic acid, 5% dicarboxylic acids, and some other acids [46]. In addition, fatty acids, such as 8-hydroxy octanoic acid (8-HOC), 3,10-dihydroxydecanedioic acid (3,10-HDecDA), 9-hydroxy-2-decenoic acid (9-HDA), 1,10-decanedioic acid (DecDA), 3-hydroxydecanoic acid (3-HHDA), and 2-decene-1,10-dioic acid (2-DecDA), can also found in RJ [47]. Among all lipids and fatty acids, 10-HDA is a stable compound representing 3.5% of freeze-dried RJ which is considered an international standard for quality [5,46,48,49]. In the lipid fraction sterols should be included, even if they are only in trace amounts. For instance, 24-methylene cholesterol (24-MET) contribute with 49–58% for total sterols in RJ. Other similar compounds include β-sitosterol (19–24%), isofucosterol (9–16%), campesterol (67%), and desmosterol (0.5–4.5%) [3].

2.3. Other Constituents

RJ contains some other bioactive compounds, such as 23.3 (µg/mg) of phenolics and 1.28 (µg/mg) of total flavonoids [20,49,50]. The phenolic compounds comprise phenol and carboxylic groups [51]. From flavonoid compounds, various structures could be distinguished, such as flavones (apigenin and its glycosides, luteolin, chrysin, and acacetin), flavanones (naringenin, hesperetin, and isosakuranetin), flavonols (kaempferol and isorhamnetin glycosides), and isoflavonoids (genistein and formononetin). Coumestrol is an isoflavonoid phytoalexin that can also be found in RJ [52]. Furthermore, flavonoids are mostly present in the form of glycosides, and the aglycones are linked by glycosidic bonds to the osidic group [53]. Another unique compound of RJ is adenosine N1-oxide, which is an oxidized product of adenosine at the N1 position of adenine base moiety [54,55]. Adenosine monophosphate (AMP) and adenosine itself are important biomolecules with physiological effects [56,57,58]. Acetylcholine can also be found with a mean concentration of 1 mg/g dry weight [59]. Hormones, gonadotropins, pantothenic acid, testosterone, estradiol, progesterone, and prolactin also were identified in RJ [60,61,62,63,64].

3. Functional Properties of RJ

The biological functions of RJ and its application (Table 1) are investigated in vivo and in vitro experimental models, such as laboratory animals (rabbits, mice, rats, and hamsters), microbial organisms (bacteria, fungi, viruses, and nematodes), farm animals (ewes and buffalos), and clinical trials (humans disease treatment), to provides the basis for further developments of its pharmaceutical effects. The biological activities of the RJ are variable and have been correlated to the content of their active ingredients [65].

3.1. Biological Activity of RJ

RJ has health benefits effects for both humans and honeybees. It is a natural antibiotic and plays an efficient role in developing the larval stages in blood cells and maintains its ovulatory characteristics during the whole life span. Moreover, RJ has antioxidants with the potential of reducing the risk of cancer, high blood pressure, diabetes, and cardiovascular diseases [94,110,111]. RJ also affects the morphological characters, growth, learning, size, and shape variations in various creatures, such as honeybees, mice, and humans [112].

3.1.1. Antimicrobial Activity

RJ demonstrates strong antimicrobial properties against different pathogens [39,66,67,70], due to the existence of special proteins and peptides [9,43], and the presence of the 10-HDA [9,113]. Moreover, RJ could fight against periodontopathic bacteria, such as Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Fusobacterium mucleatum, and Porphyromonas gingivalis [67]. MRJPs (2–5 and 7) reveal antibacterial activity against Gram-negative E. coli [114]. Jellenie I, II, III, and IV are important antibacterial peptides in RJ. Although the difference between jellenie (I–IV) is minor, with only one residue difference in the sequence, this slight difference has a significant impact on their antibacterial activities. Jelleine I–III could inhibit both Gram-positive and Gram-negative bacteria whereas Jelleine-IV doesn’t [43]. Antibacterial peptides are positively charged due to the existence of lysine, arginine, and histidine residues that allow them to interact with anionic phospholipids of the cell membrane and collapse it [115]. Royalisin has three intramolecular disulfide bonds between cysteine residues and shows strong antibacterial activity against different types of Gram-positive and Gram-negative bacteria [70]. In addition, native jelleines could inhibit Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, Paenibacillus larvae) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa). Furthermore, the phosphorylated jelleines (Jelleine-II (pT) and Jelleine-II (pS) could fight against E. coli and B. subtilis, P. larvae, and E. coli [39]. MRJPs 2 and 4 act as antimicrobial agents and have a wide range of activity against bacteria (Gram-positive and Gram-negative), fungi, and yeasts. Recombinant MRJP-2 and MRJP-4 could kill microorganisms by attaching to the cell wall of fungi, yeast, and bacteria that damage the structure of the cell wall [66,68]. RJ aqueous fraction has reported a strong inhibition of the growth of Fusarium species [73]. RJ has also exhibited antifungal properties against Syncephalastrum racemosum, Aspergillus fumigants, and A. niger [72]. Royalisin also indicates an anti-fungal response against necrotrophic fungus, such as Botrytis cinerea [69]. The native jelleine-ll protein presents an inhibitory effect on Candida albicans [39,43]. Moreover, 10H∆DA has antifungal potential in inhibiting the growth rate of Neurospora sitophila [116]. RJ is effective against C. albicans and as an alternative agent to fight this yeast [117]. Fatty acids such as 3,10-HDA, 11S, 10-HDA and 10-acetooxy-2-DEA could strongly inhibit the growth of yeasts, such as C. tropicalis, C. albicans, and C. glabrata [71]. Moreover, RJ could fight against herpes 2 virus, influenza virus, heart virus coxsackie B3, herpes simplex virus type 1 (HSV-1), and certain rhabdoviruses [118,119].

3.1.2. Antioxidant Activity

The antioxidant activity of RJ could be explored as the prevention and treatment of various chronic and degenerative diseases. In the diet of Sprague–Dawley rats fed with contaminated fumonisin (FB) (200 mg/kg) and RJ (150 mg/kg) for three weeks, RJ attenuates the harmful effect of FB via improving glutathione peroxidase formation and reducing the effects of lipid peroxidation and free radical generation [120]. RJ could also recover from cadmium-induced genotoxicity and oxidative stress in mice, which improves the antioxidant status via glutathione (GSH) and reduces malondialdehyde (MDA) production [121]. After rats exposed to cisplatin and carbon tetrachloride, RJ administration could resist against oxidative stress in liver and renal tissues, which is achieved by decreasing MDA production and increasing the concentration of cellular antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) [122]. In radiation-induced lung and liver damage of Sprague–Dawley rats, pre- and post-administration of RJ are effective in reducing oxidative stress and increasing antioxidant properties [74]. The antioxidant response of enzyme-treated RJ (ERJ) is confirmed by the reduction of nitric oxide (NO) and intracellular reactive oxidative species, and increased the effect of the antioxidant glutathione and antioxidant SOD levels. Moreover, ERJ has the potential as an oxidative agent to be used for human, as well as animal, diets [123]. Similarly, MRJP-2 has potential action as an antioxidant to protect mammalian and insect cells via decreasing the levels of caspase-3 activity and oxidative stress-induced cell apoptosis followed by increase cell viability [68]. Hydroxyl radicals and hydrogen-peroxide scavenging activity were verified with 29 antioxidant peptides isolated from RJ hydrolysate, in which 12 small peptides having 2–4 residues (Ala-Lys, Phe-Arg, Ile-Arg, Lys-Phe, Lys-Leu, Lys-Tyr, Arg-Tyr, Tyr-Asp, Tyr-Tyr, Leu-Asn-Arg, and Lys-Asn-Tyr-Pro) having the strongest activity. Moreover, three dipeptides (Lys-Tyr, Arg-Tyr, and Tyr-Tyr) in RJ indicate strong scavenging activity due to a donation of the hydrogen atom from their phenolic hydroxyl group [124].

3.1.3. Wound Healing Activity

Wound healing is an important health issue and a wide range of in vivo and in vitro studies indicate that RJ seems play a significant role [125,126]. The development of atopic dermatitis-like skin lesions in picryl chloride treated NC/Nga mouse is suppressed after treatment with RJ. This is achieved by the down-regulating protein of antigen-specific interferon-gamma (IFN-ϒ) production and up-regulation of NO synthase [127]. The application of dose-dependent RJ improves the healing effect of severe oral mucositis in hamsters induced by chemotherapy drug 5-fluorouracil [128]. Oral treatment with RJ could increase the wound healing process in diabetic mice [125]. Moreover, RJ in 5 µg/mL concentration promotes the fibroblasts migration in human beings by altering the level of different lipids and enhance the level of sphingolipids that promote wound healing [125]. Moreover, an RJ dressing is a good way of treating diabetic foot ulcer patients along with other standard methods. Furthermore, this method creates vasodilation effects around the wound which could dilate blood vessels to increase blood flow and prevent the wound from infection by other microbial organisms [129]. In addition, RJ promotes the wound healing response to control dermal infection induced by methicillin-resistant S. aureus (MRSA) [126]. Water-soluble proteins of RJ and its fractions induce proliferative and migratory effects on a human epidermal keratinocyte in a scratch wound model. A protein fraction, mainly containing MRJP-2,3,7 have the potential to influence wound healing bioactivity by stimulating keratinocyte growth and migration suggests that these proteins promote the development of new wound healing medication [130]. The defensin-1 peptide in RJ contributes to skin regeneration and cutaneous wound closure by increasing matrix metalloproteinase-9 secretion and keratinocyte migration [131].

3.1.4. Immunomodulatory Activity

Immunomodulatory response plays a significant role in allergy, cancer, and inflammation by activation of antibody formation or inhibition of white blood cell activities [132]. The first human study in systemic lupus erythematosus (SLE) in children reveals that the effect of RJ treatment in SLE indicates a significant improvement after three months of administration [133]. The anti-allergic factors of RJ inhibit interleukin-4 (IL-4) production which is induced by anti-CD3 activated spleen cells derived from ovalbumin (OVA)/alum-immunized mice. MRJP-3 (70 kDa) glycoprotein inhibits IL-4, IL-2, and IFN-ϒ production by T cells associated with the suppression of cell proliferation. Intra-peritoneal MRJP-3 administration indicates inhibition in immune serum level of anti-OVA IgG1 and IgE in OVA/alum-induced allergic mice while heat-treated soluble MRJP-3 administration decreases antigenicity and maintains its inhibitory effect on antibody response to ovalbumin. Both in vivo and in vitro studies demonstrate that MJRP-3 has strong immunomodulatory activities [84]. Moreover, the lower concentration of water extract of RJ and 3,10-HDA activate the T-cell proliferation by triggering concanavalin A (Con-A) and enhances the production of IL-2 while a higher concentration of water extract of RJ, dry powder of RJ, and trans-10-HDA inhibit T-cell proliferation by decreasing IL-2 and NO production. Water extract from RJ possesses the complexity of biological and strongest immunomodulatory activities [134]. Fatty acids, such as 10-HDA and 3,10-DDA, have strong immunomodulatory activities exhibited commonly by the dendritic cell-associated reduction of allogeneic T-cell proliferation and IL-2 production in vitro, as well as the inhibition of the antigen-specific immune response in vivo [135]. A fatty acid 3,10-dihydroxy-decanoic acid (3,10-DDA) of RJ stimulates the maturation of monocyte-derived dendritic cells (MoDCs) by up-regulating the expression of allogeneic CD1a, CD40, CD54, and CD 86, and also boosting the allostimulatory potential in co-culture with allogeneic CD4+ T cells. The 3,10-DDA administrations to monocyte-derived dendritic cells (MoDCs) increase the production of IL-12, IL-18, and stimulate the production of IFN-ϒ in allogeneic CD4+ T cells in co-culture. Therefore, 3,10-DDA encourages maturation and Th1 polarizing potential of human MoDCs in vitro that could have an anti-viral and anti-tumor response [85]. 10-HDA has various immunomodulatory effects depending on applied concentrations. The high 10-HDA concentration could stop the function and maturation of human MoDCs and lower doses support the Th1 immune response [136].

3.1.5. Anti-Aging Activity

RJ is associated with an increase in the lifespan of queen honeybees as well as several other species [9], and improves the quality of life in old age rats [137]. RJ and ERJ administration have the potential to delay aging, age-related disorder, and promote longevity and stress resistance in Caenorhabditis elegans [138]. Furthermore, ERJ and enzyme-untreated RJ (NRJ) influence in an age focusing motor disorder in genetically heterogeneous male mice. Age-related variations affect muscle fiber size at an advanced age, muscle satellite cell markers, and catabolic genes in RJ-treated mice, thus, RJ may be useful to improve the quality of life during aging through regulating the motor functions [139]. Royalactin, a glycoprotein from RJ, extends the life span of C. elegans by promoting epidermal growth factor (EGF) and its receptors’ signaling [140]. MRJPs are longevity-promoting substances that increase the longevity period of Drosophila through promoting the anti-epidermal growth factor receptor (EGFR)-mediated signaling pathway [141]. Protein and lipid components in RJ have the potential to extend the life span in various living beings, including honeybees, crickets, silkworms, nematodes, mice, and inhibit senescence of human tissues in cell cultures via down-regulation of insulin-like growth factors and up-regulation of epidermal growth factor signaling [25]. Moreover, 10-HDA is used to increase the longevity of C. elegans via reduced insulin-like signaling (ILS) and increase the lifespan by dietary restriction signaling and the target of rapamycin (TOR) components in C. elegans [142]. The biological activities of RJ and their underlying possible mechanisms are shown in Figure 4.

3.2. Pharmaceutical Applications

RJ is one of the oldest and as high potential bee medicines widely used to treat various diseases. Pharmaceutical studies elucidate that RJ has multiple activities that are attributable to their bioactive compounds, including proteins, peptides, lipids, phenolics, and flavonoid compounds. Recently, RJ has shown potential for use against cancer, diabetic, cardiovascular, and Alzheimer’s disease (AD) in modern pharmaceutical research [77,102,110]. The pharmaceutical effects of RJ (Figure 5) and its constituents in health-promotion through modulation of various biological activities are discussed below.

3.2.1. Anti-Cancer Effect

RJ reveals potential anti-cancer properties as the inhibition of tumor growth and/or metastasis in the liver or lung, through the inhibition of tumor-induced angiogenesis, and/or the activation of immune function [75]. The crude RJ stops the damage of bisphenol A, which causes the enlargement of human breast cancer cells [76]. The treatment for three months with RJ exhibits better effects on decreasing the prostatic-specific antigen and ameliorates the quality of life in patients with benign prostatic hyperplasia [143]. RJ has the potential to reduce the cytotoxic effects of doxorubicin (DOX) on the prostate cancer cell line (PC3) [144]. A significant, weak, and positive correlation is found between RJ and time since diagnosis of women breast cancer and used as complementary and alternative medicine [145]. The N-acetylation is the main metabolic pathway which activates arylamine carcinogens that are catalyzed by N-acetyltransferase (NAT) and require acetyl coenzyme A. RJ affects the N-acetylation and inhibits the metabolism of 2-aminofluorene (2-AF) metabolites in the human liver tumor cell line and decrease the 2-AF in J5 cells in a dose-dependent manner [77]. The 10-HDA and human interferon-alpha (HuIFN-aN3) proteins have a similar activity regarding anti-tumor response and their combination decreases the level of glutathione and enhance the level of lipid peroxidation via MDA in CaCo-2 cells [78]. All lipophilic fractions from RJ share a common anti-tumoral effect against human neuroblastoma and prevent the onset, and slow down the growth of human neuroblastoma [146].

3.2.2. Anti-Diabetic Effect

Many medicines are accessible on the market to control and decrease the difficulties of diabetes, but new techniques are essential to provide patients with the most therapeutic benefits and with the minimum adverse response. In a clinical study, serum glucose levels significantly decreased in healthy persons after RJ administration [80]. RJ supplementation showed remarkable decreases in serum glycosylated hemoglobin levels and fasting blood glucose (FBG) levels by increasing insulin concentration, which may help to control diabetes outcomes [79]. RJ administration enhances the total antioxidant capacity and reduces the homeostasis model assessment for insulin resistance in type-2 diabetic patients [147]. The administration (100 mg/kg) of RJ to diabetes mellitus rats for six weeks improves the urine parameters including uric acid, urea, albumin, creatinine, and histopathological variation of liver and kidney [81,82]. The intake of RJ possesses enviable response on serum glucose, apolipoprotein A1 (ApoA-1) concentrations, and (ApoB/ApoA-1) ratios that may decrease cardiovascular attack in people with type-2 diabetes [148]. Long-term RJ intake ameliorates hyperglycemia and partially decreases body weight in overweight/diabetic KK-Ay mice through the up-regulation of mRNA expression of adiponectic, adiponectin receptor-1, and AMP-activated protein kinase [149]. In randomized clinical trials, RJ administration (1000 mg/daily) decreases the occurrence of cardiovascular disease by attenuating the effect of fasting blood glucose level, systolic blood pressure, and interleukin-6 in patients with type-2 diabetes [150]. RJ also has the potential to reduce the irregular status of 30 mM glucose conditions in human endothelial cells under diabetic situations [151]. The splenic tissue repair in diabetic rats by RJ via increasing antioxidant enzymes and reducing glucose levels [110]. Furthermore, RJ considerably improves the serum level of triglycerides, low-density lipoprotein, very low-density lipoprotein, high-density lipoprotein, cholesterol, and ApoA-1 in diabetic patients, thereby promoting the glycemic status, oxidative stress, and lipid profile [83].

3.2.3. Anti-Hypercholesterolemic Effect

RJ reduces the total lipids and cholesterol level in serum, liver of rat, rabbits, and also decreases the total serum, lipids, and cholesterol level in humans [87]. One of the early studies reported that RJ has hypocholesterolemic response to be associated with a reduction of the gene expression of squalene epoxidase and an increase of low-density lipoprotein receptor in mice [97]. The dietary RJ administration reduces the total cholesterol and low-density lipoprotein levels by decreasing the small range of very-low-density lipoprotein levels (VLDL) [86]. The treatment with RJ in rats reduces the plasma levels of triglyceride and insulin, without affecting blood glucose, total cholesterol levels, and tends to lower systolic blood pressure [152]. Oral administration of RJ (150 mg/kg) for 12 weeks could improve the lipid profile and control menopause-associated dyslipidemia in woman [88]. RJ administration continuously for three months considerably decreases the total cholesterol and LDL-c level by improving the (HDL-c) level that mitigates the chance of cardiovascular disease [90]. The first meta-analysis was conducted to determine the efficacy of RJ consumption on blood lipid parameters. The pooled analysis indicate that the RJ ingestion may effective for the development of blood lipid parameters via decreasing total cholesterol and increasing HDL-C levels in the blood concentrations [153]. MRJP-1 has a strong hypocholesterolemic effect in rats due to the interaction with bile acid that increased fecal bile acid excretion, fecal cholesterol excretion, and hepatic cholesterol catabolism [89].

3.2.4. Anti-Hypertension Effect

Hypertension has become a cardiovascular risk factor that may cause heart failure, myocardial infarction, cerebral stroke, and metabolic syndrome in humans worldwide. Despite the various drugs recommended to lower hypertension it is important to achieve better solutions, and following that line various natural molecules are under investigation in drug discovery for this purpose. Oral administration of RJ reduces the systolic blood pressure, diastolic blood pressure, and enhances the NO level in SHR, both in an in vivo hypertension model and in an isolated rabbit thoracic aorta rings model. RJ causes vasorelaxation through inhibiting L-NAME (nitric oxide synthase inhibitor), indomethacin (cyclooxygenase inhibitor and atropine-M3 receptor blocker), and methylene blue (guanylate cyclase inhibitor) in isolated aortic rings. Additionally, RJ could inhibit high K+-induced extracellular Ca2+ influx and NE-induced intracellular Ca2+ releases in the denuded aortic ring. Furthermore, RJ could also increase NO production in cyclic guanosine monophosphate (cGMP) in isolated aortic rings. Anti-hypertensive activities of RJ are associated with NO production while muscarinic receptor agonists produced a vasodilation response by the NO/cGMP pathway and calcium channels [93]. RJ proteins have the potential to inhibit the angiotensin 1-converting enzyme’s (ACE) activity produced by the gastrointestinal enzyme hydrolysis and reduce systolic blood pressure in the spontaneously hypertensive rats (SHR) [154]. The presence of MRJP-1 protein in vascular smooth muscle cells (VSMCs) decreases cell proliferation, migration, contraction, and also reduce hypertension via influence on VSMCs [92]. However, ERJ and its peptides (Ile-Tyr, Val-Tyr, and Ile-Val-Tyr) stop ACN activities and exhibited anti-hypertensive effects after oral treatment for 28 days in the SHR. Systolic blood pressure decreases in SHR depending upon the quantity of oral administration of these peptides, which may be beneficial for improving blood pressure in people with hypertension [91].

3.2.5. Anti-Inflammatory Effect

The inflammatory process is stimulated by a wide cascade of biological and chemical aspects, including cytokines, pro-inflammatory enzymes, and low molecular weight compounds (eicosanoids) or the enzymatic breakdown of tissues [155]. RJ administration successfully inhibits the production of pro-inflammatory cytokines such as IL-1, -6, and TNF-α in a dose-dependent manner without having a cytotoxic influence on macrophage in vitro [95]. RJ could be important for the improvement of quality of life in the autoimmune diseases including rheumatoid arthritis and inflammatory bowel diseases [95]. The effect of oral RJ administration has studied on acetic acid-induced colitis in the different cell lines of rats. The proliferative reaction of CD3+ and CD45+ T-cell stimulate with colitis is significantly affected when treated with RJ and no difference is found in CD5+ T-cell and CD68+ cell. Furthermore, RJ has an anti-inflammatory action and cell regeneration response on acetic acid-induced colitis rats [156]. The anti-inflammatory response of RJ could induce renal inflammation in the rats with the use of ethylene glycol. The presence of pro-inflammatory/anti-inflammatory cytokines, such as TNF-α, IL-1β, and IL-18 levels in the blood and renal tissue of rats, reflect that anti-inflammatory response of RJ due to its anti-radicals and anti-oxidative effects [94]. The dietary RJ administration improves metabolic effect and skeletal muscle functions in aged obese rats. Furthermore, RJ ameliorates the insulin resistance and muscle lipotoxicity in the aged obese rats via suppression of TNF-1 in the serum and adipose tissues due to its anti-inflammatory response [157]. RJ administration could improve the inflammatory response in microglial cells by suppressing phosphorylation of p38, an inhibitor of kappa B (IkBa), and c-jun NH2-terminal kinases (JNK), and by stopping the nucleus translocation of nuclear factor kappa B (NF-kB) and p-65 [158]. Due to anti-inflammatory properties ERJ has the potential to be developed as food to enhancing immune activities for the prevention of inflammatory disease [159]. As a unique compound in RJ, 10-HDA significantly inhibits the activities of matrix metalloproteinases (MMP-1, MMP-3), p38, and the c-Jun N-terminal kinases-activating protein-1 (JNK-AP-1) signaling pathway, which could serve as a protective tool against the therapy of rheumatoid arthritis [160]. Moreover, 10-HDA inhibits lipopolysaccharide (LPS)-induced inhibitor of kappa-B-zeta (IkB-z) and IL-6 productions, which contribute to autoimmune and inflammatory diseases [161]. The trans-10-HDA, 10-HDA, and SEA in RJ indicates the in vitro anti-inflammatory response to the release of major inflammatory–mediators, IL-10, NO, and only SEA reduced TNF-α production. However, 10-HDA indicates a stronger anti-inflammatory effect compared to the other fatty acids [162]. For the treatment of an inflammatory disorder, the natural molecule in RJ adenosine N1-oxide (ANO) is used in intravenous and oral administration of ANO decreases the lethality to lipopolysaccharide-induced endotoxin shocks [163].

3.2.6. Organo-Protective Effect

Hepato-Renal Protective Effect

RJ is a potential alternative for the treatment of hepatic and renal dysfunctions. Dietary administration of RJ (200 mg/kg) for seven days as a hepato-protective agent could improve the severe liver damage induced by paracetamol in mice [50]. The treatment with RJ, before and after cisplatin-induced renal stress in rats, remarkably ameliorates the levels in serum of uric acid, urea nitrogen, bilirubin, and total protein, suggesting a protective response to the harmful effect of cisplatin [122]. RJ administration may be the potential preventive agent to hepatic toxicity induced by cisplatin causing histological changes in hepatic tissue through free radical scavenging, anti-oxidant properties, and anti-apoptotic stimulation [96]. RJ could be considered as beneficial to inhibit liver toxicity induced by side effects of oxymetholone (OXM) and azathioprine through reducing the activities of serum hepatic enzymes and MDA formation [164,165]. RJ has a hepato-protective effect against oxidative impairment, decreasing lipoperoxidation and corticosterone, and enhancing total antioxidant capacity in liver tissue after stress induction in rats [166]. In addition, RJ treatment ameliorates the renal ischemia/reperfusion injury in rats via reducing blood urea nitrogen, kidney MDA, leukocyte infiltration, creatinine, adhesion molecule-1 expression, glomerular diameter, the level of TNF-α, and increased the tissue ferric reducing/antioxidant power [99]. MRJP-2 could relieve hepatic necrosis against carbon tetrachloride (CCl4)-induced hepatotoxicity via inhibiting TNF-α, intercellular reactive species, and mixed lineage kinase domain-like protein (MLKL). Moreover, MRJP-2 could be a safe and reliable therapeutic approach for fighting against hepatic diseases in future human experiments [98].

Neuroprotective Effect

RJ plays a key role in brain cell differentiation like neuron from cultured neural progenitor cells/neural stems (NPCs/NSs), and also produces neurogenesis in the hippocampal dentate gyrus in an in vivo model [57,100]. RJ administration could stimulate neurite outgrowth from a cultured PC12 line [57]. Orally, RJ treatment improves the neural function due to the regeneration of hippocampal granule cells, which is critical for the cognition process [54], and also protects the brain from oxidative injury [167]. In humans, the intake of 3 g of RJ for six months upgrades glucose tolerance, erythropoiesis, and mental health [168]. Oral RJ treatment (100 mg/kg) reduces the apoptotic cell number in traumatic spinal cord injury in rabbits through decreasing the lipid peroxidation and increasing the endogenous enzymatic and non-enzymatic antioxidative protection system [169]. The potential effect on the central nervous system by RJ has been verified having once reduced the degree of damage and death of brain tissue, and 10-HDA contributes to helping in the generation of neurons [170]. RJ in treatments of neurological indications has proved to be effective on menopausal disorders in postmenopausal model rats. Memory impairment and depression-like behaviors in ovariectomized rats are recovered to the levels of sham-operated rats by RJ administration [171]. RJ administration has the potential to consolidate the learning, memory abilities, and longevity of honeybees [112], and the intake of RJ has the potential to ameliorate cognitive deficits [103]. RJ ingestion is effective on neurological disorders, such as Alzheimer’s disease in postmenopausal patients, via decreasing cholesterol and amyloid-beta deposition, increasing cholinergic response, estrogen level, and also improving the blood-brain barrier and autonomic nervous systems [102]. Moreover, RJ significantly improves the behavioral deficits and image structure of the brain of the cholesterol feed rabbits via decreasing body weight, level of lipid in blood, amyloid-beta, acetyl-cholinesterase, and MDA level while increasing choline acetyltransferase and SOD levels in brain tissues [101]. The purified RJ peptides (RJPs) are neuroprotective and could suppress beta-amyloid 40 and beta-amyloid 42 production by the down-regulation of β-secretase, β-site amyloid precursor protein cleaving enzymes (BACE1), and serving as a natural product to the treatment of neurodegenerative Alzheimer’s disease in aged people [101]. Furthermore, 10-HDA could inhibit the production of oligodendrocytes, astrocytes, and stimulates the differentiation of neurons from neural stem cells (NSCs) [100]. Active components, such as AMP and AMP N1-oxide, isolated from RJ are reported to induce neural differentiation and generate astrocytes of NPCs/NSs in pheochromocytoma (PC12) cell lines [55,58]. The AMP N1-oxide action is mediated by adenyl cyclase-couple adenosine receptor such as A2a [55], elevate the phosphorylation of extracellular signal-regulated kinase ½ (ERK ½) and cAMP-response element-binding protein (CREB) in neural progenitors or neural stem cells (NPCs/NSs) of the cultured PC12 line [54,57,100].

Other Protective Effects

RJ has the various protecting effects that could contribute to improving body functions. For instance, RJ has a protective role against radiation-induced apoptosis in human peripheral blood leukocytes through its free radical scavenging and antioxidant activities [172]. RJ indicates a genoprotective effect against DOX-induced genotoxicity in human lymphocytes and a protective mechanism probably mediated by anti-aging, anti-apoptotic, and antioxidant activities of RJ [104]. RJ administration exerted protective response against tyrosine kinase inhibitors (TKIs)-induced anorexia, fatigue, and plays a key role in sustaining the quality of life and medicine compliance in tyrosine kinase inhibitor-treated renal cell carcinoma patients [173]. RJ treatment indicates that the paclitaxel-induced histopathological and biochemical changes could be protected, and the cardioprotective effect might be correlated with the suppression of nitrosative and oxidative stress [111]. RJ exhibits a strong protective response against the cadmium exposure-induced nephrotoxicity in mice through facilitating cadmium excretion, replacing oxidant/antioxidant balance, preventing apoptosis, and inflammation [174]. 10-HDA may have the potential to protect the skin from ultraviolet (UVβ)-induced photo-aging by improving collagen production [105].

3.2.7. Effect on sexual Dysfunction and Fertility

Sexual dysfunctions and fertility deficiencies are both common clinical difficulties with limited therapeutic choices. RJ is shown to improve the fertility of male and female as discussed below.

Estrogenic Effect

RJ has an estrogenic response in in vivo and in vitro models via the interaction with estrogen receptors followed by the alteration of gene expression and cell proliferation [175]. Orally and intramuscularly, RJ administration with exogenous progesterone ameliorates the estrous effect and pregnancy rate in Awassi ewes [176]. The oral consumption of an RJ (1000 mg/daily) capsule is effective in decreasing the severity of premenstrual syndrome (PMS) and also improves the quality of life of women during their reproductive age [177]. It also effective for improving urinary and sexual problems, and ameliorates the quality of life in postmenstrual women [178]. RJ administration could improve the in vitro fertilization capacity of Nili-Ravi buffalo bull sperm and post-thaw quality [179]. RJ treatment may induce higher levels of oocyte maturation, fertilization, and blastocyst formation by enhancing the activity of glycolysis, pentose phosphate pathway, and antioxidant enzyme activity in oocyte and cumulus cell [180]. The administration of RJ endorses follicular growth and ovarian hormones in immature female rats through its estrogenic effects on the reproductive system to improve the fertility parameters [181]. Four bioactive compounds, including 10-H2DA, 2-DEA, 10-HDA, and 24-MET of RJ, indicate an estrogen receptor-β (ERβ) response and stopped the binding activity of 17-β estradiol to ERβ in an in vivo experiment [182]. 10-HDA, 10-HDDA, and SEA present strong estrogenic effects mediating estrogen signaling by modulating the recruitment of ERα, ERβ, and co-activator to target genes [183].

Effect on Fertility

RJ administration significantly increases sperm active motility, luteinizing hormones, and testosterone levels in infertile men [106]. Long-term feeding of RJ increases the testosterone levels and spermatogenesis by stopping the age-associated decline in testicular function of male hamsters [108]. Co-administration of honey and RJ could be effective in the treatment of infertility due to asthenozoospermia [184]. RJ administration improves the physiological status, such as boosted testosterone level, increased ejaculation, number of sperm, sperm motility, and improved seminal plasma fructose to heat-stress rabbits, which can restrain their summer infertility [185], and sperm parameters of ram semen in the case of liquid storage [186]. Moreover, RJ could improve summer infertility and the physiological status of heat-stressed male rabbits [187]. RJ could be protective against the negative effects of flunixin meglumine-induced sperm toxicity in the male reproductive system [188]. The co-administration of RJ and cod liver oil could improve the biochemical, hormonal, and structural aspects of testicular tissue in food yellow 4 (FY4)-induced rats [107]. The co-administration could effectively improve sperm characteristics and early embryo development as well as the sperm lipid peroxidation level by acting as a promising reproductive agent in heat-stress conditions [189].

3.3. Side Effect of RJ Consumption

RJ causes some allergic reactions, such as contact dermatitis, anaphylaxis, and asthma, due the presence of major allergens MRJP-1 and MRJP-2 [190,191,192]. Other adverse effects also cause eczemas and skin rashes [193], respiratory stress [194], bronchospasm, hemorrhagic colitis, and even death [195,196]. The oral administration of RJ may induce an allergic reaction and some minor side effects, such as light gastrointestinal problems, atopy to serious reactions like anaphylactic shock, acute asthma, intestinal bleeding, and even death [197]. RJ and honeybee venom share common allergic substances, such as immunoglobulin E (IgE), that are responsible for the onset of occupational asthma [198]. MAJR-1 and MAJR-2 are IgE-binding allergenic proteins in RJ. Therefore, protease-treated RJ efficiently ruins the allergenic protein through significantly reducing the IgE-binding capacity in in vitro assays of the blood from RJ-sensitive patients. An in vivo human skin-prick test and histamine-release test significantly decrease the allergic response of RJ in the patient through anaphylaxis. Thus, it is valuable to prepare hypoallergenic RJ through protease treatment for its safe consumption [109,192]. Additionally, the person who has other allergies or allergic problems from bee stings, honey, or asthma, pregnant and lactating women, as well as small children should avoid RJ intake [199].

4. Conclusions and Future Research Directions

RJ has been used in medical products, health nutrients, cosmetics, and commercial purposes. Different biological compounds, such as protein, peptides, peptides fraction, fatty acid, and phenolic compounds isolated from RJ, lend this product various biological activities and pharmaceutical applications. Due to this, RJ is endowed with functional properties, such as antimicrobial, antioxidant, wound healing, immunomodulatory, anti-aging, anti-cancer, anti-inflammatory, anti-hypertension, anti-hyperlipidemic, estrogenic, and neurotrophic effects. Additionally, RJ could play an important role in liver and kidney protection, and improving the reproduction system. Moreover, diabetic patients provide a hypoglycemic response through decreasing lipid peroxidation levels and improve the activities of antioxidant enzymes, such as SOD, CAT, GR, and GPx. RJ could act also as a functional food and may have a protective effect on the appearance of gastrointestinal diseases. Despite a large number of bioactive compounds that have been identified, future studies are needed in the identification, extraction, and isolation of hidden bioactive compounds and their functions. The use of bioactive compounds from RJ as alternative drugs in the clinical applications are not yet implemented, thus, more evidence would help to prove the efficacy, safety, exact amount, and quality that would be required to achieve promising health benefits. Therefore, more in vivo and in vitro experiments (animal studies and clinical trials) and validation are demanded to reveal the cellular and molecular mechanisms of RJ for health benefits using cutting-edge genomics, transcriptomics, proteomics, and metabolomics.

Author Contributions

S.A. prepared the original draft. M.G.C., F.F., and S.Z.A. participated in writing, review, and editing. J.L. conceived the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The financial support provided by the Agricultural Science and Technology Innovation Program (CAAS-ASTIP-2015-IAR), Modern Agro-Industry Technology Research System (CARS-44) in China, and the National Project for Upgrading Overall Bee-Product Quality of the Beekeeping Industry of China.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ACEAngiotensin 1-converting enzymes
ADAlzheimer’s disease
AFAminofluorene
AMPAdenosine monophosphate
ANOAdenosine N1-oxide
ApoA-1Apolipoprotein A1
BACE1β-site amyloid precursor protein cleaving enzymes
CATCatalase
CCl4Carbon tetrachloride
cGMPCyclic guanosine monophosphate
Con-AConcanavalin A
DecDA1,10-decanedioic acid
DOXDoxorubicin
EGFEpidermal growth factor
EGFRAnti-epidermal growth factor receptor
ERJEnzyme-treated RJ
FBFumonisin
FBGFasting blood glucose
FY4Food yellow 4
GPxGlutathione peroxidase
GRGlutathione reductase
GSHGlutathione
9-HDA9-hydroxy-2-decenoic acid
10-HDA10-hydroxy-2-decenoic acid
3-HHDA3-hydroxydecanoic acid
10-HDDA10-hydroxydecenoic acid
3,10-HDecDA3,10-dihydroxydecanedioic acid
8-HOC8-hydroxy octanoic acid
HSV-1Herpes simplex virus type 1
HuIFN-aN3Human interferon-alpha
IFN-ϒInterferon-gamma
IgEImmunoglobulin E
IkBaInhibitor of kappa B
IkB-zIkappaBzeta
ILInterleukin
ILSInsulin-like signaling
JNK-AP-1C-Jun N-terminal kinases-activating protein-1
MDAMalondialdehyde
24-MET24-methylene cholesterol
MLKLMixed lineage kinase domain-like protein
MoDCsMonocyte-derived dendritic cells
MRJPsMajor royal jelly proteins
NATN-acetyltransferase
NONitric oxide
NPCs/NSsNeural progenitors or neural stem cells
OXMOxymetholone
PC3Prostate cancer cell line
RJRoyal jelly
RJBsRoyal jelly bees
SEASebacic acid
SHRSpontaneously hypertensive rats
SLESystemic lupus erythematosus
SODSuperoxide dismutase
TKIsTyrosine kinase inhibitors
VLDLVery low-density lipoprotein levels
VSMCsVascular smooth muscle cells

References

  1. Knecht, D.; Kaatz, H. Patterns of larval food production by hypopharyngeal glands in adult worker honey bees. Apidologie 1990, 21, 457–468. [Google Scholar] [CrossRef]
  2. Li, J.K.; Feng, M.; Begna, D.; Fang, Y.; Zheng, A.J. Proteome Comparison of Hypopharyngeal Gland Development between Italian and Royal Jelly-Producing Worker Honeybees (Apis mellifera L). J. Proteome Res. 2010, 9, 6578–6594. [Google Scholar] [CrossRef]
  3. Melliou, E.; Chinou, I. Chemistry and bioactivities of royal jelly. In Studies in Natural Products Chemistry; Elsevier: Amsterdam, The Netherlands, 2014; Volume 43, pp. 261–290. [Google Scholar]
  4. Ramadan, M.F.; Al-Ghamdi, A. Bioactive compounds and health-promoting properties of royal jelly: A review. J. Funct. Foods 2012, 4, 39–52. [Google Scholar] [CrossRef]
  5. Sabatini, A.G.; Marcazzan, G.L.; Caboni, M.F.; Bogdanov, S.; Almeida-Muradian, L. Quality and standardisation of royal jelly. J. ApiProd. ApiMed. Sci. 2009, 1, 1–6. [Google Scholar] [CrossRef]
  6. Xue, X.; Wu, L.; Wang, K. Bee Products-Chemical and Biological Properties; Alvarez-Suarez, J.M., Ed.; Springer: Berlin/Heidelberg, Germany, 2017; pp. 181–190. [Google Scholar]
  7. Robinson, G.E.; Fahrbach, S.E.; Winston, M.L. Insect societies and the molecular biology of social behavior. Bioessays 1997, 19, 1099–1108. [Google Scholar] [CrossRef]
  8. Evans, J.D.; Wheeler, D.E. Differential gene expression between developing queens and workers in the honey bee, Apis mellifera. Proc. Natl. Acad. Sci. USA 1999, 96, 5575–5580. [Google Scholar] [CrossRef] [PubMed]
  9. Fratini, F.; Cilia, G.; Mancini, S.; Felicioli, A. Royal Jelly: An ancient remedy with remarkable antibacterial properties. Microb. Res. 2016, 192, 130–141. [Google Scholar] [CrossRef] [PubMed]
  10. Clarke, M.; McDonald, P. Australian Royal Jelly-Market Opportunity Assessment Based on Production That Uses New Labour Saving Technology; Rural Industries Research and Development Corporation: Wagga, NSW, Australia, 2017; Volume 4. [Google Scholar]
  11. Li, J.; Li, H.; Zhang, Z.; Pan, Y. Identification of the proteome complement of high royal jelly producing bees (Apis mellifera) during worker larval development. Apidologie 2007, 38, 545–557. [Google Scholar] [CrossRef]
  12. Feng, M.; Fang, Y.; Han, B.; Xu, X.; Fan, P.; Hao, Y.; Qi, Y.; Hu, H.; Huo, X.; Meng, L. In-depth N-glycosylation reveals species-specific modifications and functions of the royal jelly protein from Western (Apis mellifera) and Eastern Honeybees (Apis cerana). J. Proteome Res. 2015, 14, 5327–5340. [Google Scholar] [CrossRef] [PubMed]
  13. Altaye, S.Z.; Meng, L.; Li, J. Molecular insights into the enhanced performance of royal jelly secretion by a stock of honeybee (Apis mellifera ligustica) selected for increasing royal jelly production. Apidologie 2019, 50, 436–453. [Google Scholar] [CrossRef]
  14. Li, J.; Aiping, W. Comprehensive technology for maximizing royal jelly production. Am. Bee J. 2005, 145, 661–664. [Google Scholar]
  15. Cao, L.-F.; Zheng, H.-Q.; Pirk, C.W.; Hu, F.-L.; Xu, Z.-W. High royal jelly-producing honeybees (Apis mellifera ligustica) (Hymenoptera: Apidae) in China. J. Econ. Entomol. 2016, 109, 510–514. [Google Scholar] [CrossRef] [PubMed]
  16. Li, J.; Chen, S.; Zhong, B.; Su, S. Genetic analysis for developmental behavior of honeybee colony’s royal jelly production traits in western honeybees. Yi Chuan Xue Bao Acta Genet. Sin. 2003, 30, 547–554. [Google Scholar]
  17. Nie, H.; Liu, X.; Pan, J.; Li, W.; Li, Z.; Zhang, S.; Chen, S.; Miao, X.; Zheng, N.; Su, S. Identification of genes related to high royal jelly production in the honey bee (Apis mellifera) using microarray analysis. Genet. Mol. Biol. 2017, 40, 781–789. [Google Scholar] [CrossRef] [PubMed]
  18. Hora, Z.A.; Altaye, S.Z.; Wubie, A.J.; Li, J. Proteomics Improves the New Understanding of Honeybee Biology. J. Agric. Food Chem. 2018, 66, 3605–3615. [Google Scholar] [CrossRef] [PubMed]
  19. Altaye, S.Z.; Meng, L.F.; Lu, Y.; Li, J.K. The Emerging Proteomic Research Facilitates in-Depth Understanding of the Biology of Honeybees. Int. J. Mol. Sci. 2019, 20, 15. [Google Scholar] [CrossRef] [PubMed]
  20. Pasupuleti, V.R.; Sammugam, L.; Ramesh, N.; Gan, S.H. Honey, propolis, and royal jelly: A comprehensive review of their biological actions and health benefits. Oxid. Med. Cell. Longev. 2017, 2017, 1259510. [Google Scholar] [CrossRef]
  21. Buttstedt, A.; Moritz, R.F.; Erler, S. Origin and function of the major royal jelly proteins of the honeybee (Apis mellifera) as members of the yellow gene family. Biol. Rev. 2014, 89, 255–269. [Google Scholar] [CrossRef]
  22. Bogdanov, S. Royal Jelly, Bee Brood: Composition, Health, Medicine. J. Bee Prod. Sci. 2011, 3, 8–19. [Google Scholar]
  23. Ramanathan, A.N.K.G.; Nair, A.J.; Sugunan, V.S. A review on Royal Jelly proteins and peptides. J. Funct. Foods 2018, 44, 255–264. [Google Scholar] [CrossRef]
  24. Miyata, Y.; Sakai, H. Anti-Cancer and Protective Effects of Royal Jelly for Therapy-Induced Toxicities in Malignancies. Int. J. Mol. Sci. 2018, 19, 3270. [Google Scholar] [CrossRef] [PubMed]
  25. Kunugi, H.; Mohammed Ali, A. Royal Jelly and Its Components Promote Healthy Aging and Longevity: From Animal Models to Humans. Int. J. Mol. Sci. 2019, 20, 4662. [Google Scholar] [CrossRef]
  26. Alu’datt, M.H.; Rababah, T.; Sakandar, H.A.; Imran, M.; Mustafa, N.; Alhamad, M.N.; Mhaidat, N.; Kubow, S.; Tranchant, C.; Al-Tawaha, A.R. Fermented food-derived bioactive compounds with anticarcinogenic properties: Fermented royal jelly as a novel source for compounds with health benefits. In Anticancer Plants: Properties and Application; Springer: Berlin/Heidelberg, Germany, 2018; pp. 141–165. [Google Scholar]
  27. Furusawa, T.; Rakwal, R.; Nam, H.W.; Shibato, J.; Agrawal, G.K.; Kim, Y.S.; Ogawa, Y.; Yoshida, Y.; Kouzuma, Y.; Masuo, Y. Comprehensive royal jelly (RJ) proteomics using one-and two-dimensional proteomics platforms reveals novel RJ proteins and potential phospho/glycoproteins. J. Proteome Res. 2008, 7, 3194–3229. [Google Scholar] [CrossRef]
  28. Zhang, L.; Han, B.; Li, R.; Lu, X.; Nie, A.; Guo, L.; Fang, Y.; Feng, M.; Li, J. Comprehensive identification of novel proteins and N-glycosylation sites in royal jelly. BMC Genome 2014, 15, 135. [Google Scholar] [CrossRef] [PubMed]
  29. Drapeau, M.D.; Albert, S.; Kucharski, R.; Prusko, C.; Maleszka, R. Evolution of the Yellow/Major Royal Jelly Protein family and the emergence of social behavior in honey bees. Genome Res. 2006, 16, 1385–1394. [Google Scholar] [CrossRef] [PubMed]
  30. Albert, S.; Klaudiny, J. MRJP9, an ancient protein of the honeybee MRJP family with non-nutritional function. J. Apic. Res. 2007, 46, 99. [Google Scholar]
  31. Kimura, M.; Kimura, Y.; Tsumura, K.; Okihara, K.; Sugimoto, H.; Yamada, H.; Yonekura, M. 350-kDa royal jelly glycoprotein (apisin), which stimulates proliferation of human monocytes, bears the β1-3galactosylated N-glycan: Analysis of the N-glycosylation site. Biosci. Biotechnol. Biochem. 2003, 67, 2055–2058. [Google Scholar] [CrossRef]
  32. Furusawa, T.; Arai, Y.; Kato, K.; Ichihara, K. Quantitative analysis of Apisin, a major protein unique to royal jelly. Evid.-Based Complement. Altern. Med. 2016, 2016. [Google Scholar] [CrossRef]
  33. Qu, N.; Jiang, J.; Sun, L.; Lai, C.; Sun, L.; Wu, X. Proteomic characterization of royal jelly proteins in Chinese (Apis cerana cerana) and European (Apis mellifera) honeybees. Biochemistry 2008, 73, 676. [Google Scholar] [CrossRef]
  34. Sano, O.; Kunikata, T.; Kohno, K.; Iwaki, K.; Ikeda, M.; Kurimoto, M. Characterization of royal jelly proteins in both Africanized and European honeybees (Apis mellifera) by two-dimensional gel electrophoresis. J. Agric. Food Chem. 2004, 52, 15–20. [Google Scholar] [CrossRef]
  35. Zhang, L.; Fang, Y.; Li, R.; Feng, M.; Han, B.; Zhou, T.; Li, J. Towards posttranslational modification proteome of royal jelly. J. Proteom. 2012, 75, 5327–5341. [Google Scholar] [CrossRef] [PubMed]
  36. Santos, K.S.; dos Santos, L.D.; Mendes, M.A.; de Souza, B.M.; Malaspina, O.; Palma, M.S. Profiling the proteome complement of the secretion from hypopharyngeal gland of Africanized nurse-honeybees (Apis mellifera L.). Insect Biochem. Mol. Biol. 2005, 35, 85–91. [Google Scholar] [CrossRef] [PubMed]
  37. Liu, H.; Wang, Z.L.; Tian, L.Q.; Qin, Q.H.; Wu, X.B.; Yan, W.Y.; Zeng, Z.J. Transcriptome differences in the hypopharyngeal gland between Western Honeybees (Apis mellifera) and Eastern Honeybees (Apis cerana). BMC Genom. 2014, 15, 744. [Google Scholar] [CrossRef] [PubMed]
  38. Han, B.; Li, C.; Zhang, L.; Fang, Y.; Feng, M.; Li, J. Novel royal jelly proteins identified by gel-based and gel-free proteomics. J. Agric. Food Chem. 2011, 59, 10346–10355. [Google Scholar] [CrossRef]
  39. Han, B.; Fang, Y.; Feng, M.; Lu, X.; Huo, X.; Meng, L.; Wu, B.; Li, J. In-depth phosphoproteomic analysis of royal jelly derived from western and eastern honeybee species. J. Proteome Res. 2014, 13, 5928–5943. [Google Scholar] [CrossRef]
  40. Silici, S.; Ekmekcioglu, O.; Eraslan, G.; Demirtas, A. Antioxidative effect of royal jelly in cisplatin-induced testes damage. Urology 2009, 74, 545–551. [Google Scholar] [CrossRef]
  41. Schmitzova, J.; Klaudiny, J.; Albert, Š.; Schröder, W.; Schreckengost, W.; Hanes, J.; Judova, J.; Šimúth, J. A family of major royal jelly proteins of the honeybee Apis mellifera L. Cell. Mol. Life Sci. CMLS 1998, 54, 1020–1030. [Google Scholar] [CrossRef]
  42. Scarselli, R.; Donadio, E.; Giuffrida, M.G.; Fortunato, D.; Conti, A.; Balestreri, E.; Felicioli, R.; Pinzauti, M.; Sabatini, A.G.; Felicioli, A. Towards royal jelly proteome. Proteomics 2005, 5, 769–776. [Google Scholar] [CrossRef]
  43. Fontana, R.; Mendes, M.A.; De Souza, B.M.; Konno, K.; César, L.l.M.M.; Malaspina, O.; Palma, M.S. Jelleines: A family of antimicrobial peptides from the Royal Jelly of honeybees (Apis mellifera). Peptides 2004, 25, 919–928. [Google Scholar] [CrossRef]
  44. Bulet, P.; Stocklin, R. Insect antimicrobial peptides: Structures, properties and gene regulation. Protein Pept. Lett. 2005, 12, 3–11. [Google Scholar] [CrossRef]
  45. Li, X.a.; Huang, C.; Xue, Y. Contribution of lipids in honeybee (Apis mellifera) royal jelly to health. J. Med. Food 2013, 16, 96–102. [Google Scholar] [CrossRef] [PubMed]
  46. Terada, Y.; Narukawa, M.; Watanabe, T. Specific hydroxy fatty acids in royal jelly activate TRPA1. J. Agric. Food Chem. 2011, 59, 2627–2635. [Google Scholar] [CrossRef] [PubMed]
  47. Isidorov, V.; Bakier, S.; Grzech, I. Gas chromatographic–mass spectrometric investigation of volatile and extractable compounds of crude royal jelly. J. Chromatogr. B 2012, 885, 109–116. [Google Scholar] [CrossRef]
  48. Makino, J.; Ogasawara, R.; Kamiya, T.; Hara, H.; Mitsugi, Y.; Yamaguchi, E.; Itoh, A.; Adachi, T. Royal jelly constituents increase the expression of extracellular superoxide dismutase through histone acetylation in monocytic THP-1 cells. J. Nat. Prod. 2016, 79, 1137–1143. [Google Scholar] [CrossRef] [PubMed]
  49. Nabas, Z.; Haddadin, M.S.; Haddadin, J.; Nazer, I.K. Chemical composition of royal jelly and effects of synbiotic with two different locally isolated probiotic strains on antioxidant activities. Pol. J. Food Nutr. Sci. 2014, 64, 171–180. [Google Scholar] [CrossRef]
  50. Kanbur, M.; Eraslan, G.; Beyaz, L.; Silici, S.; Liman, B.C.; Altınordulu, Ş.; Atasever, A. The effects of royal jelly on liver damage induced by paracetamol in mice. Exp. Toxicol. Pathol. 2009, 61, 123–132. [Google Scholar] [CrossRef] [PubMed]
  51. De Paula, R.; Rabalski, I.; Messia, M.C.; Abdel-Aal, E.-S.M.; Marconi, E. Effect of processing on phenolic acids composition and radical scavenging capacity of barley pasta. Food Res. Int. 2017, 102, 136–143. [Google Scholar] [CrossRef]
  52. López-Gutiérrez, N.; del Mar Aguilera-Luiz, M.; Romero-González, R.; Vidal, J.L.M.; Frenich, A.G. Fast analysis of polyphenols in royal jelly products using automated TurboFlow™-liquid chromatography–Orbitrap high resolution mass spectrometry. J. Chromatogr. B 2014, 973, 17–28. [Google Scholar] [CrossRef]
  53. Panche, A.; Diwan, A.; Chandra, S. Flavonoids: An overview. J. Nutr. Sci. 2016, 5. [Google Scholar] [CrossRef]
  54. Hattori, N.; Nomoto, H.; Fukumitsu, H.; Mishima, S.; Furukawa, S. AMP N1-oxide, a unique compound of royal jelly, induces neurite outgrowth from pc12 vells via signaling by protein kinase A independent of that by mitogen-activated protein kinase. Evid.-Based Complement. Altern. Med. 2010, 7, 63–68. [Google Scholar] [CrossRef]
  55. Hattori, N.; Nomoto, H.; Mishima, S.; Inagaki, S.; Goto, M.; Sako, M.; Furukawa, S. Identification of AMP N1-oxide in royal jelly as a component neurotrophic toward cultured rat pheochromocytoma PC12 cells. Biosci. Biotechnol. Biochem. 2006, 70, 897–906. [Google Scholar] [CrossRef] [PubMed]
  56. Xue, X.F.; Zhou, J.H.; Wu, L.M.; Fu, L.H.; Zhao, J. HPLC determination of adenosine in royal jelly. Food Chem. 2009, 115, 715–719. [Google Scholar] [CrossRef]
  57. Hattori, N.; Nomoto, H.; Fukumitsu, H.; Mishima, S.; Furukawa, S. Royal jelly-induced neurite outgrowth from rat pheochromocytoma PC12 cells requires integrin signal independent of activation of extracellular signalregulated kinases. Biomed. Res. 2007, 28, 139–146. [Google Scholar] [CrossRef] [PubMed]
  58. Hattori, N.; Nomoto, H.; Fukumitsu, H.; Mishima, S.; Furukawa, S. AMP N1-oxide potentiates astrogenesis by cultured neural stem/progenitor cells through STAT3 activation. Biomed. Res. 2007, 28, 295–299. [Google Scholar] [CrossRef] [PubMed]
  59. Wei, W.; Wei, M.; Kang, X.; Deng, H.; Lu, Z. A novel method developed for acetylcholine detection in royal jelly by using capillary electrophoresis coupled with electrogenerated chemiluminescence based on a simple reaction. Electrophoresis 2009, 30, 1949–1952. [Google Scholar] [CrossRef]
  60. Vittek, J.; Slomiany, B. Testosterone in royal jelly. Experientia 1984, 40, 104–106. [Google Scholar] [CrossRef]
  61. Carvalho, V.D.C.; Silveira, V.Á.S.; do Prado, R.F.; Carvalho, Y.R. Effect of estrogen therapy, soy isoflavones, and the combination therapy on the submandibular gland of ovariectomized rats. Pathol.-Res. Pract. 2011, 207, 300–305. [Google Scholar] [CrossRef]
  62. Takaki-Doi, S.; Hashimoto, K.; Yamamura, M.; Kamei, C. Antihypertensive activities of royal jelly protein hydrolysate and its fractions in spontaneously hypertensive rats. Acta Med. Okayama 2009, 63, 57–64. [Google Scholar]
  63. Heyl, H.L. An Observation Suggesting the Presence of a Gonadotropic Hormone in Royal Jelly. Science 1939, 89, 540–541. [Google Scholar] [CrossRef]
  64. Gardner, T.S. The use of Drosophila melanogaster as a screening agent for longevity factors; pantothenic acid as a longevity factor in royal jelly. J. Gerontol. 1948, 3, 1–8. [Google Scholar] [CrossRef]
  65. Bărnuţiu, L.I.; Mărghitaş, L.A.; Dezmirean, D.S.; Mihai, C.M.; Bobiş, O. Chemical composition and antimicrobial activity of Royal Jelly-REVIEW. Sci. Pap. Anim. Sci. Biotechnol. 2011, 44, 67–72. [Google Scholar]
  66. Kim, B.Y.; Lee, K.S.; Jung, B.; Choi, Y.S.; Kim, H.K.; Yoon, H.J.; Gui, Z.-Z.; Lee, J.; Jin, B.R. Honeybee (Apis cerana) major royal jelly protein 4 exhibits antimicrobial activity. J. Asia-Pac. Entomol. 2019, 22, 175–182. [Google Scholar] [CrossRef]
  67. Coutinho, D.; Karibasappa, S.N.; Mehta, D.S. Royal Jelly Antimicrobial Activity against Periodontopathic Bacteria. J. Interdiscip. Dent. 2018, 8, 18. [Google Scholar]
  68. Park, M.J.; Kim, B.Y.; Park, H.G.; Deng, Y.; Yoon, H.J.; Choi, Y.S.; Lee, K.S.; Jin, B.R. Major royal jelly protein 2 acts as an antimicrobial agent and antioxidant in royal jelly. J. Asia-Pac. Entomol. 2019, 22, 684–689. [Google Scholar] [CrossRef]
  69. Bíliková, K.; Wu, G.; Šimúth, J. Isolation of a peptide fraction from honeybee royal jelly as a potential antifoulbrood factor. Apidologie 2001, 32, 275–283. [Google Scholar] [CrossRef]
  70. Bílikova, K.; Huang, S.-C.; Lin, I.-P.; Šimuth, J.; Peng, C.-C. Structure and antimicrobial activity relationship of royalisin, an antimicrobial peptide from royal jelly of Apis mellifera. Peptides 2015, 68, 190–196. [Google Scholar] [CrossRef]
  71. Melliou, E.; Chinou, I. Chemistry and bioactivity of royal jelly from Greece. J. Agric. Food Chem. 2005, 53, 8987–8992. [Google Scholar] [CrossRef] [PubMed]
  72. Moselhy, W.; Fawzy, A.; Kamel, A. An evaluation of the potent antimicrobial effects and unsaponifiable matter analysis of the royal jelly. Life Sci. J. 2013, 2, 290–296. [Google Scholar]
  73. Sauerwald, N. Combined antibacterial and antifungal properties of water-soluble fraction of royal jelly. Adv. Food Sci. 1998, 20, 46–52. [Google Scholar]
  74. Cihan, Y. Protective Role of Royal Jelly Against Radiation-Induced Oxidative Stress in Rats. Int. J. Hematol. Oncol. 2013, 28, 79–87. [Google Scholar] [CrossRef]
  75. Kimura, Y. Antitumor and antimetastatic actions of various natural products. In Studies in Natural Products Chemistry; Elsevier: Amsterdam, The Netherlands, 2008; Volume 34, pp. 35–76. [Google Scholar]
  76. Nakaya, M.; Onda, H.; Sasaki, K.; Yukiyoshi, A.; Tachibana, H.; Yamada, K. Effect of royal jelly on bisphenol A-induced proliferation of human breast cancer cells. Biosci. Biotechnol. Biochem. 2007, 71, 253–255. [Google Scholar] [CrossRef]
  77. Premratanachai, P.; Chanchao, C. Review of the anticancer activities of bee products. Asian Pac. J. Trop. Biomed. 2014, 4, 337–344. [Google Scholar] [CrossRef] [PubMed]
  78. Filipic, B.; Gradisnik, L.; Rihar, K.; Soos, E.; Pereyra, A.; Potokar, J. The influence of royal jelly and human interferon-alpha (HuIFN-alpha N3) on proliferation, glutathione level and lipid peroxidation in human colorectal adenocarcinoma cells in vitro. Arh. Hig. Rada Toksiko. 2015, 66, 269–274. [Google Scholar] [CrossRef] [PubMed]
  79. Pourmoradian, S.; Mahdavi, R.; Mobasseri, M.; Faramarzi, E.; Mobasseri, M. Effects of royal jelly supplementation on glycemic control and oxidative stress factors in type 2 diabetic female: A randomized clinical trial. Chin. J. Integr. Med. 2014, 20, 347–352. [Google Scholar] [CrossRef] [PubMed]
  80. Münstedt, K.; Bargello, M.; Hauenschild, A. Royal jelly reduces the serum glucose levels in healthy subjects. J. Med. Food 2009, 12, 1170–1172. [Google Scholar] [CrossRef]
  81. Ghanbari, E.; Nejati, V.; Azadbakht, M. Protective effect of royal jelly against renal damage in streptozotocin induced diabetic rats. Iran. J. Toxicol. 2015, 9, 1258–1263. [Google Scholar]
  82. Ghanbari, E.; Nejati, V.; Khazaei, M. Improvement in serum biochemical alterations and oxidative stress of liver and pancreas following use of royal jelly in streptozotocin-induced diabetic rats. Cell J. (Yakhteh) 2016, 18, 362. [Google Scholar]
  83. Maleki, V.; Jafari-Vayghan, H.; Saleh-Ghadimi, S.; Adibian, M.; Kheirouri, S.; Alizadeh, M. Effects of Royal jelly on metabolic variables in diabetes mellitus: A systematic review. Complement. Ther. Med. 2019, 43, 20–27. [Google Scholar] [CrossRef]
  84. Okamoto, I.; Taniguchi, Y.; Kunikata, T.; Kohno, K.; Iwaki, K.; Ikeda, M.; Kurimoto, M. Major royal jelly protein 3 modulates immune responses in vitro and in vivo. Life Sci. 2003, 73, 2029–2045. [Google Scholar] [CrossRef]
  85. Dzopalic, T.; Vucevic, D.; Tomic, S.; Djokic, J.; Chinou, I.; Colic, M. 3,10-Dihydroxy-decanoic acid, isolated from royal jelly, stimulates Th1 polarising capability of human monocyte-derived dendritic cells. Food Chem. 2011, 126, 1211–1217. [Google Scholar] [CrossRef]
  86. Guo, H.; Saiga, A.; Sato, M.; Miyazawa, I.; Shibata, M.; Takahata, Y.; Morimatsu, F. Royal jelly supplementation improves lipoprotein metabolism in humans. J. Nutr. Sci. Vitaminol. 2007, 53, 345–348. [Google Scholar] [CrossRef] [PubMed]
  87. Vittek, J. Effect of royal jelly on serum lipids in experimental animals and humans with atherosclerosis. Experientia 1995, 51, 927–935. [Google Scholar] [CrossRef] [PubMed]
  88. Lambrinoudaki, I.; Augoulea, A.; Rizos, D.; Politi, M.; Tsoltos, N.; Moros, M.; Chinou, I.; Graikou, K.; Kouskouni, E.; Kambani, S. Greek-origin royal jelly improves the lipid profile of postmenopausal women. Gynecol. Endocrinol. 2016, 32, 835–839. [Google Scholar] [CrossRef] [PubMed]
  89. Kashima, Y.; Kanematsu, S.; Asai, S.; Kusada, M.; Watanabe, S.; Kawashima, T.; Nakamura, T.; Shimada, M.; Goto, T.; Nagaoka, S. Identification of a novel hypocholesterolemic protein, major royal jelly protein 1, derived from royal jelly. PLoS ONE 2014, 9, e105073. [Google Scholar] [CrossRef] [PubMed]
  90. Chiu, H.-F.; Chen, B.-K.; Lu, Y.-Y.; Han, Y.-C.; Shen, Y.-C.; Venkatakrishnan, K.; Golovinskaia, O.; Wang, C.-K. Hypocholesterolemic efficacy of royal jelly in healthy mild hypercholesterolemic adults. Pharm. Biol. 2017, 55, 497–502. [Google Scholar] [CrossRef] [PubMed]
  91. Tokunaga, K.-H.; Yoshida, C.; Suzuki, K.-M.; Maruyama, H.; Futamura, Y.; Araki, Y.; Mishima, S. Antihypertensive effect of peptides from royal jelly in spontaneously hypertensive rats. Biol. Pharm. Bull. 2004, 27, 189–192. [Google Scholar] [CrossRef]
  92. Fan, P.; Han, B.; Feng, M.; Fang, Y.; Zhang, L.; Hu, H.; Hao, Y.; Qi, Y.; Zhang, X.; Li, J. Functional and proteomic investigations reveal major royal jelly protein 1 associated with anti-hypertension activity in mouse vascular smooth muscle cells. Sci. Rep. 2016, 6, 30230. [Google Scholar] [CrossRef]
  93. Pan, Y.; Rong, Y.; You, M.; Ma, Q.; Chen, M.; Hu, F. Royal jelly causes hypotension and vasodilation induced by increasing nitric oxide production. Food Sci. Nutr. 2019, 7, 1361–1370. [Google Scholar] [CrossRef]
  94. Aslan, Z.; Aksoy, L. Anti-inflammatory effects of royal jelly on ethylene glycol induced renal inflammation in rats. Int. Braz. J. Urol. 2015, 41, 1008–1013. [Google Scholar] [CrossRef]
  95. Kohno, K.; Okamoto, I.; Sano, O.; Arai, N.; Iwaki, K.; Ikeda, M.; Kurimoto, M. Royal jelly inhibits the production of proinflammatory cytokines by activated macrophages. Biosci. Biotechnol. Biochem. 2004, 68, 138–145. [Google Scholar] [CrossRef]
  96. Yildirim, S.; Karadeniz, A.; Karakoc, A.; Yildirim, A.; Kalkan, Y.; Şimşek, N. Effects of royal jelly on liver paraoxonase activity in rats treated with cisplatin. Turk. J. Med. Sci. 2012, 42, 367–375. [Google Scholar]
  97. Kamakura, M.; Moriyama, T.; Sakaki, T. Changes in hepatic gene expression associated with the hypocholesterolaemic activity of royal jelly. J. Pharm. Pharmacol. 2006, 58, 1683–1689. [Google Scholar] [CrossRef] [PubMed]
  98. Abu-Serie, M.M.; Habashy, N.H. Two purified proteins from royal jelly with in vitro dual anti-hepatic damage potency: Major royal jelly protein 2 and its novel isoform X1. Int. J. Biol. Macromol. 2019, 128, 782–795. [Google Scholar] [CrossRef] [PubMed]
  99. Salahshoor, M.R.; Jalili, C.; Roshankhah, S. Can royal jelly protect against renal ischemia/reperfusion injury in rats? Chin. J. Physiol. 2019, 62, 131–137. [Google Scholar] [CrossRef]
  100. Hattori, N.; Nomoto, H.; Fukumitsu, H.; Mishima, S.; Furukawa, S. Royal jelly and its unique fatty acid, 10-hydroxy-trans-2-decenoic acid, promote neurogenesis by neural stem/progenitor cells in vitro. Biomed. Res. 2007, 28, 261–266. [Google Scholar] [CrossRef]
  101. Zhang, X.; Yu, Y.; Sun, P.; Fan, Z.; Zhang, W.; Feng, C. Royal jelly peptides: Potential inhibitors of beta-secretase in N2a/APP695swe cells. Sci. Rep. 2019, 9, 168. [Google Scholar] [CrossRef]
  102. Pan, Y.; Xu, J.; Jin, P.; Yang, Q.; Zhu, K.; You, M.; Chen, M.; Hu, F. Royal Jelly Ameliorates Behavioral Deficits, Cholinergic System Deficiency, and Autonomic Nervous Dysfunction in Ovariectomized Cholesterol-Fed Rabbits. Molecules 2019, 24, 1149. [Google Scholar] [CrossRef]
  103. You, M.; Pan, Y.; Liu, Y.; Chen, Y.; Wu, Y.; Si, J.; Wang, K.; Hu, F. Royal jelly alleviates cognitive deficits and β-amyloid accumulation in APP/PS1 mouse model via activation of the cAMP/PKA/CREB/BDNF pathway and inhibition of neuronal apoptosis. Front. Aging Neurosci. 2018, 10, 428. [Google Scholar] [CrossRef]
  104. Jenkhetkan, W.; Thitiorul, S.; Jansom, C.; Ratanavalachai, T. Genoprotective effects of thai royal jelly against doxorubicin in human lymphocytes in vitro. Nat. Prod. Commun. 2018, 13, 1934578X1801300124. [Google Scholar] [CrossRef]
  105. Park, H.M.; Hwang, E.; Lee, K.G.; Han, S.-M.; Cho, Y.; Kim, S.Y. Royal Jelly Protects Against Ultraviolet B–Induced Photoaging in Human Skin Fibroblasts via Enhancing Collagen Production. J. Med. Food 2011, 14, 899–906. [Google Scholar] [CrossRef]
  106. Al-Sanafi, A.E.; Mohssin, S.A.; Abdulla, S.M. Effect of royal jelly on male infertility. Thi-Qar Med. J. 2007, 1, 1–12. [Google Scholar]
  107. Elewa, Y.H.; Mohamed, A.A.-R.; Galal, A.A.; El-naseery, N.I.; Ichii, O.; Kon, Y. Food Yellow4 reprotoxicity in relation to localization of DMC1 and apoptosis in rat testes: Roles of royal jelly and cod liver oil. Ecotoxicol. Environ. Saf. 2019, 169, 696–706. [Google Scholar] [CrossRef] [PubMed]
  108. Kohguchi, M.; Inoue, S.-I.; Ushio, S.; Iwaki, K.; Ikeda, M.; Kurimoto, M. Effect of royal jelly diet on the testicular function of hamsters. Food Sci. Technol. Res. 2007, 10, 420–423. [Google Scholar] [CrossRef]
  109. Moriyama, T.; Yanagihara, M.; Yano, E.; Kimura, G.; Seishima, M.; Tani, H.; Kanno, T.; Nakamura-Hirota, T.; Hashimoto, K.; Tatefuji, T. Hypoallergenicity and immunological characterization of enzyme-treated royal jelly from Apis mellifera. Biosci. Biotechnol. Biochem. 2013, 77, 789–795. [Google Scholar] [CrossRef] [PubMed]
  110. Al-Kushi, A.G.; Header, E.A.; ElSawy, N.A.; Moustafa, R.A.; Alfky, N.A.A. Antioxidant effect of royal jelly on immune status of hyperglycemic rats. Pharmacogn. Mag. 2018, 14, 528. [Google Scholar] [CrossRef]
  111. Malekinejad, H.; Ahsan, S.; Delkhosh-Kasmaie, F.; Cheraghi, H.; Rezaei-Golmisheh, A.; Janbaz-Acyabar, H. Cardioprotective effect of royal jelly on paclitaxel-induced cardio-toxicity in rats. Iran. J. Basic Med. Sci. 2016, 19, 221–227. [Google Scholar]
  112. Shi, J.-L.; Liao, C.-H.; Wang, Z.-L.; Wu, X.-B. Effect of royal jelly on longevity and memory-related traits of Apis mellifera workers. J. Asia-Pac. Entomol. 2018, 21, 1430–1433. [Google Scholar] [CrossRef]
  113. Šedivá, M.; Laho, M.; Kohútová, L.; Mojžišová, A.; Majtán, J.; Klaudiny, J. 10-HDA, A Major Fatty Acid of Royal Jelly, Exhibits pH Dependent Growth-Inhibitory Activity Against Different Strains of Paenibacillus larvae. Molecules 2018, 23, 3236. [Google Scholar] [CrossRef]
  114. Park, H.G.; Kim, B.Y.; Park, M.J.; Deng, Y.; Choi, Y.S.; Lee, K.S.; Jin, B.R. Antibacterial activity of major royal jelly proteins of the honeybee (Apis mellifera) royal jelly. J. Asia-Pac. Entomol. 2019, 22, 737–741. [Google Scholar] [CrossRef]
  115. Splith, K.; Neundorf, I. Antimicrobial peptides with cell-penetrating peptide properties and vice versa. Eur. Biophys. J. 2011, 40, 387–397. [Google Scholar] [CrossRef] [PubMed]
  116. Blum, M.S.; Novak, A.F.; Taber, S. 10-hydroxy-Δ2-decenoic acid, an antibiotic found in royal jelly. Science 1959, 130, 452–453. [Google Scholar] [CrossRef]
  117. Gunalp, R.; Ulusoy, M.; Celebier, I.; Keskin, N. Antifungal effect of royal jelly on Candida albicans. J. Biotechnol. 2018, 280, S70–S71. [Google Scholar] [CrossRef]
  118. Stocker, A. Isolation and Characterisation of Substances from Royal Jelly; Technische Universität München: München, Germany, 2003. [Google Scholar]
  119. Hashemipour, M.A.; Tavakolineghad, Z.; Arabzadeh, S.A.M.; Iranmanesh, Z.; Nassab, S.A.H.G. Antiviral Activities of Honey, Royal Jelly, and Acyclovir Against HSV-1. Wounds 2014, 26, 47–54. [Google Scholar] [PubMed]
  120. El-Nekeety, A.A.; El-Kholy, W.; Abbas, N.F.; Ebaid, A.; Amra, H.A.; Abdel-Wahhab, M.A. Efficacy of royal jelly against the oxidative stress of fumonisin in rats. Toxicon 2007, 50, 256–269. [Google Scholar] [CrossRef]
  121. Çavuşoğlu, K.; Yapar, K.; Yalçin, E. Royal jelly (honey bee) is a potential antioxidant against cadmium-induced genotoxicity and oxidative stress in albino mice. J. Med. Food 2009, 12, 1286–1292. [Google Scholar] [CrossRef] [PubMed]
  122. Karadeniz, A.; Simsek, N.; Karakus, E.; Yildirim, S.; Kara, A.; Can, I.; Kisa, F.; Emre, H.; Turkeli, M. Royal jelly modulates oxidative stress and apoptosis in liver and kidneys of rats treated with cisplatin. Oxid. Med. Cell. Longev. 2011, 2011. [Google Scholar] [CrossRef] [PubMed]
  123. Gu, H.; Song, I.-B.; Han, H.-J.; Lee, N.-Y.; Cha, J.-Y.; Son, Y.-K.; Kwon, J. Antioxidant Activity of Royal Jelly Hydrolysates Obtained by Enzymatic Treatment. Korean J. Food Sci. Anim. Resour. 2018, 38, 135. [Google Scholar] [PubMed]
  124. Guo, H.; Kouzuma, Y.; Yonekura, M. Structures and properties of antioxidative peptides derived from royal jelly protein. Food Chem. 2009, 113, 238–245. [Google Scholar] [CrossRef]
  125. Kim, J.; Kim, Y.; Yun, H.; Park, H.; Kim, S.Y.; Lee, K.G.; Han, S.M.; Cho, Y. Royal jelly enhances migration of human dermal fibroblasts and alters the levels of cholesterol and sphinganine in an in vitro wound healing model. Nutr. Res. Pract. 2010, 4, 362–368. [Google Scholar] [CrossRef]
  126. El-Gayar, M.H.; Aboshanab, K.M.; Aboulwafa, M.M.; Hassouna, N.A. Antivirulence and wound healing effects of royal jelly and garlic extract for the control of MRSA skin infections. Wound Med. 2016, 13, 18–27. [Google Scholar] [CrossRef]
  127. Taniguchi, Y.; Kohno, K.; Inoue, S.; Koya-Miyata, S.; Okamoto, I.; Arai, N.; Iwaki, K.; Ikeda, M.; Kurimoto, M. Oral administration of royal jelly inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice. Int. Immunopharmacol. 2003, 3, 1313–1324. [Google Scholar] [CrossRef]
  128. Suemaru, K.; Cui, R.; Li, B.; Watanabe, S.; Okihara, K.; Hashimoto, K.; Yamada, H.; Araki, H. Topical application of royal jelly has a healing effect for 5-fluorouracil-induced experimental oral mucositis in hamsters. Methods Find. Exp. Clin. Pharmacol. 2008, 30, 103–106. [Google Scholar] [CrossRef]
  129. Siavash, M.; Shokri, S.; Haghighi, S.; Mohammadi, M.; Shahtalebi, M.A.; Farajzadehgan, Z. The efficacy of topical Royal Jelly on diabetic foot ulcers healing: A case series. J. Res. Med. Sci. 2011, 16, 904. [Google Scholar]
  130. Lin, Y.; Shao, Q.; Zhang, M.; Lu, C.; Fleming, J.; Su, S. Royal jelly-derived proteins enhance proliferation and migration of human epidermal keratinocytes in an in vitro scratch wound model. BMC Complement. Altern. Med. 2019, 19, 175. [Google Scholar] [CrossRef] [PubMed]
  131. Bucekova, M.; Sojka, M.; Valachova, I.; Martinotti, S.; Ranzato, E.; Szep, Z.; Majtan, V.; Klaudiny, J.; Majtan, J. Bee-derived antibacterial peptide, defensin-1, promotes wound re-epithelialisation in vitro and in vivo. Sci. Rep. 2017, 7, 7340. [Google Scholar] [CrossRef]
  132. Labro, M.-T. Immunomodulatory effects of antimicrobial agents. Part I: Antibacterial and antiviral agents. Exp. Rev. Anti-Infect. Ther. 2012, 10, 319–340. [Google Scholar] [CrossRef] [PubMed]
  133. Zahran, A.M.; Elsayh, K.I.; Saad, K.; Eloseily, E.M.; Osman, N.S.; Alblihed, M.A.; Badr, G.; Mahmoud, M.H. Effects of royal jelly supplementation on regulatory T cells in children with SLE. Food Nutr. Res. 2016, 60, 32963. [Google Scholar] [CrossRef]
  134. Gasic, S.; Vucevic, D.; Vasilijic, S.; Antunovic, M.; Chinou, I.; Colic, M. Evaluation of the immunomodulatory activities of royal jelly components in vitro. Immunopharmacol. Immunotoxicol. 2007, 29, 521–536. [Google Scholar] [CrossRef] [PubMed]
  135. Vucevic, D.; Melliou, E.; Vasilijic, S.; Gasic, S.; Ivanovski, P.; Chinou, I.; Colic, M. Fatty acids isolated from royal jelly modulate dendritic cell-mediated immune response in vitro. Int. Immunopharmacol. 2007, 7, 1211–1220. [Google Scholar] [CrossRef]
  136. Mihajlovic, D.; Rajkovic, I.; Chinou, I.; Colic, M. Dose-dependent immunomodulatory effects of 10-hydroxy-2-decenoic acid on human monocyte-derived dendritic cells. J. Funct. Foods 2013, 5, 838–846. [Google Scholar] [CrossRef]
  137. Pyrzanowska, J.; Piechal, A.; Blecharz-Klin, K.; Joniec-Maciejak, I.; Graikou, K.; Chinou, I.; Widy-Tyszkiewicz, E. Long-term administration of Greek Royal Jelly improves spatial memory and influences the concentration of brain neurotransmitters in naturally aged Wistar male rats. J. Ethnopharmacol. 2014, 155, 343–351. [Google Scholar] [CrossRef] [PubMed]
  138. Wang, X.X.; Cook, L.F.; Grasso, L.M.; Cao, M.; Dong, Y.Q. Royal Jelly-Mediated Prolongevity and Stress Resistance in Caenorhabditis elegans Is Possibly Modulated by the Interplays of DAF-16, SIR-2.1, HCF-1, and 14-3-3 Proteins. J. Gerontol. Ser. A Biomed. Sci. Med. Sci. 2014, 70, 827–838. [Google Scholar] [CrossRef] [PubMed]
  139. Okumura, N.; Toda, T.; Ozawa, Y.; Watanabe, K.; Ikuta, T.; Tatefuji, T.; Hashimoto, K.; Shimizu, T. Royal Jelly Delays Motor Functional Impairment During Aging in Genetically Heterogeneous Male Mice. Nutrients 2018, 10, 1191. [Google Scholar] [CrossRef]
  140. Detienne, G.; De Haes, W.; Ernst, U.R.; Schoofs, L.; Temmerman, L. Royalactin extends lifespan of Caenorhabditis elegans through epidermal growth factor signaling. Exp. Gerontol. 2014, 60, 129–135. [Google Scholar] [CrossRef] [PubMed]
  141. Xin, X.X.; Chen, Y.; Chen, D.; Xiao, F.; Parnell, L.D.; Zhao, J.; Liu, L.; Ordovas, J.M.; Lai, C.Q.; Shen, L.R. Supplementation with Major Royal-Jelly Proteins Increases Lifespan, Feeding, and Fecundity in Drosophila. J. Agric. Food Chem. 2016, 64, 5803–5812. [Google Scholar] [CrossRef] [PubMed]
  142. Honda, Y.; Araki, Y.; Hata, T.; Ichihara, K.; Ito, M.; Tanaka, M.; Honda, S. 10-Hydroxy-2-decenoic acid, the major lipid component of royal jelly, extends the lifespan of Caenorhabditis elegans through dietary restriction and target of rapamycin signaling. J. Aging Res. 2015, 2015. [Google Scholar] [CrossRef]
  143. Pajovic, B.; Radojevic, N.; Dimitrovski, A.; Tomovic, S.; Vukovic, M. The therapeutic potential of royal jelly in benign prostatic hyperplasia. Comparison with contemporary literature. Aging Male 2016, 19, 192–196. [Google Scholar] [CrossRef]
  144. Abandansari, R.M.; Parsian, H.; Kazerouni, F.; Porbagher, R.; Zabihi, E.; Rahimipour, A. Effect of Simultaneous Treatment with Royal Jelly and Doxorubicin on the Survival of the Prostate Cancer Cell Line (PC3): An In Vitro Study. Int. J. Cancer Manag. 2018, 11, e13780. [Google Scholar] [CrossRef]
  145. Alsharif, F.H.; Mazanec, S.R. The use of complementary and alternative medicine among women with breast cancer in Saudi Arabia. Appl. Nurs. Res. 2019, 48, 75–80. [Google Scholar] [CrossRef]
  146. Gismondi, A.; Trionfera, E.; Canuti, L.; Di Marco, G.; Canini, A. Royal jelly lipophilic fraction induces antiproliferative effects on SH-SY5Y human neuroblastoma cells. Oncol. Rep. 2017, 38, 1833–1844. [Google Scholar] [CrossRef]
  147. Shidfar, F.; Jazayeri, S.; Mousavi, S.N.; Malek, M.; fateme HOSSEINI, A.; Khoshpey, B. Does supplementation with royal jelly improve oxidative stress and insulin resistance in type 2 diabetic patients? Iran. J. Public Health 2015, 44, 797. [Google Scholar] [PubMed]
  148. Khoshpey, B.; Djazayeri, S.; Amiri, F.; Malek, M.; Hosseini, A.F.; Hosseini, S.; Shidfar, S.; Shidfar, F. Effect of royal jelly intake on serum glucose, Apolipoprotein AI (ApoA-I), Apolipoprotein B (ApoB) and ApoB/ApoA-I ratios in patients with type 2 Diabetes: A randomized, double-blind clinical trial study. Can. J. Diabetes 2016, 40, 324–328. [Google Scholar] [CrossRef] [PubMed]
  149. Yoshida, M.; Hayashi, K.; Watadani, R.; Okano, Y.; Tanimura, K.; Kotoh, J.; Sasaki, D.; Matsumoto, K.; Maeda, A. Royal jelly improves hyperglycemia in obese/diabetic KK-Ay mice. J. Vet. Med. Sci. 2016, 16-0458. [Google Scholar] [CrossRef] [PubMed]
  150. Mousavi, S.; Jazayeri, S.; Khoshpay, B.; Malek, M.; Hosseini, A.; Hosseini, S.; Shidfar, F. Royal jelly decreases blood pressure, serum glucose, and interleukin-6 in patients with type 2 diabetes on an iso-caloric diet. J. Nutr. Food Secur. 2017, 2, 300–307. [Google Scholar]
  151. Cheraghi, O.; Abdollahpourasl, M.; Rezabakhsh, A.; Rahbarghazi, R. Distinct effects of royal jelly on human endothelial cells under high glucose condition. Iran. J. Pharm. Res. IJPR 2018, 17, 1361. [Google Scholar] [PubMed]
  152. Zamami, Y.; Takatori, S.; Goda, M.; Koyama, T.; Iwatani, Y.; Jin, X.; Takai-Doi, S.; Kawasaki, H. Royal Jelly Ameliorates Insulin Resistance in Fructose-Drinking Rats. Biol. Pharm. Bull. 2008, 31, 2103–2107. [Google Scholar] [CrossRef] [PubMed]
  153. Hadi, A.; Najafgholizadeh, A.; Aydenlu, E.S.; Shafiei, Z.; Pirivand, F.; Golpour, S.; Pourmasoumi, M. Royal jelly is an effective and relatively safe alternative approach to blood lipid modulation: A meta-analysis. J. Funct. Foods 2018, 41, 202–209. [Google Scholar] [CrossRef]
  154. Matsui, T.; Yukiyoshi, A.; Doi, S.; Sugimoto, H.; Yamada, H.; Matsumoto, K. Gastrointestinal enzyme production of bioactive peptides from royal jelly protein and their antihypertensive ability in SHR. J. Nutr. Biochem. 2002, 13, 80–86. [Google Scholar] [CrossRef]
  155. Libby, P.; Ridker, P.M.; Maseri, A. Inflammation and atherosclerosis. Circulation 2002, 105, 1135–1143. [Google Scholar] [CrossRef]
  156. Karaca, T.; Simsek, N.; Uslu, S.; Kalkan, Y.; Can, I.; Kara, A.; Yoruk, M. The effect of royal jelly on CD3(+), CD5(+), CD45(+) T-cell and CD68(+) cell distribution in the colon of rats with acetic acid-induced colitis. Allergol. Immunopathol. 2012, 40, 357–361. [Google Scholar] [CrossRef]
  157. Ibrahim, S.E.M.; Kosba, A.A. Royal jelly supplementation reduces skeletal muscle lipotoxicity and insulin resistance in aged obese rats. Pathophysiology 2018, 25, 307–315. [Google Scholar] [CrossRef] [PubMed]
  158. You, M.-M.; Chen, Y.-F.; Pan, Y.-M.; Liu, Y.-C.; Tu, J.; Wang, K.; Hu, F.-L. Royal jelly attenuates LPS-induced inflammation in BV-2 microglial cells through modulating NF-κB and p38/JNK signaling pathways. Mediat. Inflamm. 2018, 2018, 7834381. [Google Scholar] [CrossRef] [PubMed]
  159. Gu, H.; Song, I.-B.; Han, H.-J.; Lee, N.-Y.; Cha, J.-Y.; Son, Y.-K.; Kwon, J. Anti-inflammatory and immune-enhancing effects of enzyme-treated royal jelly. Appl. Biol. Chem. 2018, 61, 227–233. [Google Scholar] [CrossRef]
  160. Yang, X.Y.; Yang, D.S.; Wei, Z.; Wang, J.M.; Li, C.Y.; Hui, Y.; Lei, K.F.; Chen, X.F.; Shen, N.H.; Jin, L.Q.; et al. 10-Hydroxy-2-decenoic acid from Royal jelly: A potential medicine for RA. J. Ethnopharmacol. 2010, 128, 314–321. [Google Scholar] [CrossRef]
  161. Sugiyama, T.; Takahashi, K.; Tokoro, S.; Gotou, T.; Neri, P.; Mori, H. Inhibitory effect of 10-hydroxy-trans-2-decenoic acid on LPS-induced IL-6 production via reducing IkappaB-zeta expression. Innate Immun. 2012, 18, 429–437. [Google Scholar] [CrossRef]
  162. Chen, Y.F.; Wang, K.; Zhang, Y.Z.; Zheng, Y.F.; Hu, F.L. In Vitro Anti-Inflammatory Effects of Three Fatty Acids from Royal Jelly. Mediat. Inflamm. 2016, 2016, 3583684. [Google Scholar] [CrossRef]
  163. Kohno, K.; Ohashi, E.; Sano, O.; Kusano, H.; Kunikata, T.; Arai, N.; Hanaya, T.; Kawata, T.; Nishimoto, T.; Fukuda, S. Anti-inflammatory effects of adenosine N1-oxide. J. Inflamm. 2015, 12, 2. [Google Scholar] [CrossRef]
  164. Nejati, V.; Zahmatkesh, E.; Babaei, M. Protective effects of royal jelly on oxymetholone-induced liver injury in mice. Iran. Biomed. J. 2016, 20, 229. [Google Scholar]
  165. Ahmed, W.M.S.; Khalaf, A.A.; Moselhy, W.A.; Safwat, G.M. Royal jelly attenuates azathioprine induced toxicity in rats. Environ. Toxicol. Pharmacol. 2014, 37, 431–437. [Google Scholar] [CrossRef]
  166. Caixeta, D.C.; Teixeira, R.R.; Peixoto, L.G.; Machado, H.L.; Baptista, N.B.; de Souza, A.V.; Vilela, D.D.; Franci, C.R.; Espindola, F.S. Adaptogenic potential of royal jelly in liver of rats exposed to chronic stress. PLoS ONE 2018, 13, e0191889. [Google Scholar] [CrossRef]
  167. Cihan, Y.B.; Arsav, V.; Gocen, E. Royal Jelly in the Prevention of Radiation-Induced Brain Damages. J. Neurol. Sci. (Turk.) 2011, 28, 475–486. [Google Scholar]
  168. Morita, H.; Ikeda, T.; Kajita, K.; Fujioka, K.; Mori, I.; Okada, H.; Uno, Y.; Ishizuka, T. Effect of royal jelly ingestion for six months on healthy volunteers. Nutr. J. 2012, 11, 77. [Google Scholar] [CrossRef] [PubMed]
  169. Aslan, A.; Cemek, M.; Buyukokuroglu, M.E.; Altunbas, K.; Bas, O.; Yurumez, Y. Royal jelly can diminish secondary neuronal damage after experimental spinal cord injury in rabbits. Food Chem. Toxicol. 2012, 50, 2554–2559. [Google Scholar] [CrossRef] [PubMed]
  170. Mohamed, A.A.-R.; Galal, A.A.; Elewa, Y.H. Comparative protective effects of royal jelly and cod liver oil against neurotoxic impact of tartrazine on male rat pups brain. Acta Histochem. 2015, 117, 649–658. [Google Scholar] [CrossRef] [PubMed]
  171. Minami, A.; Matsushita, H.; Leno, D.; Matsuda, Y.; Horii, Y.; Ishii, A.; Takahashi, T.; Kanazawa, H.; Wakatsuki, A.; Suzuki, T. Improvement of neurological disorders in postmenopausal model rats by administration of royal jelly. Climacteric 2016, 19, 568–573. [Google Scholar] [CrossRef]
  172. Rafat, N.; Monfared, A.S.; Shahidi, M.; Pourfallah, T.A. The modulating effect of royal jelly consumption against radiation-induced apoptosis in human peripheral blood leukocytes. J. Med. Phys. Assoc. Med. Phys. India 2016, 41, 52. [Google Scholar]
  173. Araki, K.; Miyata, Y.; Ohba, K.; Nakamura, Y.; Matsuo, T.; Mochizuki, Y.; Sakai, H. Oral Intake of Royal Jelly Has Protective Effects Against Tyrosine Kinase Inhibitor-Induced Toxicity in Patients with Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled Trial. Medicines 2018, 6, 2. [Google Scholar] [CrossRef]
  174. Almeer, R.S.; AlBasher, G.I.; Alarifi, S.; Alkahtani, S.; Ali, D.; Abdel Moneim, A.E. Royal jelly attenuates cadmium-induced nephrotoxicity in male mice. Sci. Rep. 2019, 9, 5825. [Google Scholar] [CrossRef]
  175. Mishima, S.; Suzuki, K.-M.; Isohama, Y.; Kuratsu, N.; Araki, Y.; Inoue, M.; Miyata, T. Royal jelly has estrogenic effects in vitro and in vivo. J. Ethnopharmacol. 2005, 101, 215–220. [Google Scholar] [CrossRef]
  176. Husein, M.Q.; Kridli, R.T. Reproductive responses following royal jelly treatment administered orally or intramuscularly into progesterone-treated Awassi ewes. Anim. Reprod. Sci. 2002, 74, 45–53. [Google Scholar] [CrossRef]
  177. Shahzad, Q.; Mehmood, M.U.; Khan, H.; ul Husna, A.; Qadeer, S.; Azam, A.; Naseer, Z.; Ahmad, E.; Safdar, M.; Ahmad, M. Royal jelly supplementation in semen extender enhances post-thaw quality and fertility of Nili-Ravi buffalo bull sperm. Anim. Reprod. Sci. 2016, 167, 83–88. [Google Scholar] [CrossRef] [PubMed]
  178. Seyyedi, F.; Rafiean-Kopaei, M.; Miraj, S. Comparison of the effects of vaginal royal jelly and vaginal estrogen on quality of life, sexual and urinary function in postmenopausal women. J. Clin. Diagn. Res. JCDR 2016, 10, QC01. [Google Scholar] [CrossRef] [PubMed]
  179. Taavoni, S.; Barkhordari, F.; Goushegir, A.; Haghani, H. Effect of Royal Jelly on premenstrual syndrome among Iranian medical sciences students: A randomized, triple-blind, placebo-controlled study. Complement. Ther. Med. 2014, 22, 601–606. [Google Scholar] [CrossRef] [PubMed]
  180. Eshtiyaghi, M.; Deldar, H.; Pirsaraei, Z.A.; Shohreh, B. Royal jelly may improve the metabolism of glucose and redox state of ovine oocytes matured in vitro and embryonic development following in vitro fertilization. Theriogenology 2016, 86, 2210–2221. [Google Scholar] [CrossRef]
  181. Ghanbari, E.; Khazaei, M.R.; Khazaei, M.; Nejati, V. Royal jelly promotes ovarian follicles growth and increases steroid hormones in immature rats. Int. J. Fertil. Steril. 2018, 11, 263. [Google Scholar]
  182. Suzuki, K.-M.; Isohama, Y.; Maruyama, H.; Yamada, Y.; Narita, Y.; Ohta, S.; Araki, Y.; Miyata, T.; Mishima, S. Estrogenic activities of fatty acids and a sterol isolated from royal jelly. Evid.-Based Complement. Altern. Med. 2008, 5, 295–302. [Google Scholar] [CrossRef]
  183. Moutsatsou, P.; Papoutsi, Z.; Kassi, E.; Heldring, N.; Zhao, C.Y.; Tsiapara, A.; Melliou, E.; Chrousos, G.P.; Chinou, I.; Karshikoff, A.; et al. Fatty Acids Derived from Royal Jelly Are Modulators of Estrogen Receptor Functions. PLoS ONE 2010, 5, e15594. [Google Scholar] [CrossRef]
  184. Abdelhafiz, A.T.; Muhamad, J.A. Midcycle pericoital intravaginal bee honey and royal jelly for male factor infertility. Int. J. Gynecol. Obstet. 2008, 101, 146–149. [Google Scholar] [CrossRef]
  185. Campos, P.K.A.; Barbosa, L.P.; Neves, M.M.; Melo, B.E.S.; Morais, A.C.T.; Morais, D.B. Seminal quality and testicular morphometry of rabbits (Oryctolagus cuniculus) supplemented with royal jelly. Arq. Bras. Med. Vet. Zootec. 2012, 64, 1563–1568. [Google Scholar] [CrossRef]
  186. Moradi, A.R.; Malekinejad, H.; Farrokhi-Ardabili, F.; Bernousi, I. Royal Jelly improves the sperm parameters of ram semen during liquid storage and serves as an antioxidant source. Small Rumin. Res. 2013, 113, 346–352. [Google Scholar] [CrossRef]
  187. El-Hanoun, A.M.; Elkomy, A.E.; Fares, W.A.; Shahien, E.H. Impact of Royal Jelly to Improve Reproductive Performance of Male Rabbits under Hot Summer Conditions. World Rabbit Sci. 2014, 22, 241–248. [Google Scholar] [CrossRef]
  188. Temamoğulları, F.; Aral, F.; Yılmaz, R. Royal jelly protection on flunixin meglumine-induced spermiotoxicity and testicular degeneration in mice. Pol. J. Vet. Sci. 2018, 21, 497–506. [Google Scholar] [CrossRef] [PubMed]
  189. Mahdivand, N.; Najafi, G.; Nejati, V.; Shalizar-Jalali, A.; Rahmani, F. Royal jelly protects male rats from heat stress-induced reproductive failure. Andrologia 2019, 51, e13213. [Google Scholar] [CrossRef] [PubMed]
  190. Katayama, M.; Aoki, M.; Kawana, S. Case of anaphylaxis caused by ingestion of royal jelly. J. Dermatol. 2008, 35, 222–224. [Google Scholar] [CrossRef] [PubMed]
  191. Mizutani, Y.; Nagasawa, C.; Shibuya, Y.; Seishima, M. A case of royal jelly-induced anaphylaxis. J. Am. Acad. Dermatol. 2007, 56, Ab79. [Google Scholar]
  192. Rosmilah, M.; Shahnaz, M.; Patel, G.; Lock, J.; Rahman, D.; Masita, A.; Noormalin, A. Characterization of major allergens of royal jelly Apis mellifera. Trop. Biomed. 2008, 25, 243–251. [Google Scholar]
  193. Takahashi, M.; Matsuo, I.; Ohkido, M. Contact dermatitis due to honeybee royal jelly. Contact Dermat. 1983, 9, 452–455. [Google Scholar] [CrossRef]
  194. Peacock, S.; Murray, V.; Turton, C. Respiratory distress and royal jelly. BMJ 1995, 311, 1472. [Google Scholar]
  195. Laporte, J.R.; Ibanez, L.; Vendrell, L.; Ballarin, E. Bronchospasm induced by royal jelly. Allergy 1996, 51, 440. [Google Scholar] [CrossRef]
  196. Yonei, Y.; Shibagaki, K.; Tsukada, N.; Nagasu, N.; Inagaki, Y.; Miyamoto, K.; Suzuki, O.; Kiryu, Y. Case report: Haemorrhagic colitis associated with royal jelly intake. J. Gastroenterol. Hepatol. 1997, 12, 495–499. [Google Scholar] [CrossRef]
  197. Gómez, T.E.; Méndez, D.Y.; Borja, S.J.; Feo, B.J.; Alfaya, A.T.; Galindo, B.P.; Ledesma, F.A.; García, R.R. Occupational allergic respiratory disease due to royal jelly. Ann. Allergy Asthma Immunol. 2016, 117, 102. [Google Scholar] [CrossRef] [PubMed]
  198. Li, L.S.; Guan, K. Occupational Asthma Caused by Inhalable Royal Jelly and Its Cross-reactivity with Honeybee Venom. Chin. Med. J.-Peking 2016, 129, 2888–2889. [Google Scholar] [CrossRef] [PubMed]
  199. Thien, F.; Leung, R.; Baldo, B.; Weinbr, J.; Plomley, R.; Czarny, D. Asthma and anaphylaxis induced by royal jelly. Clin. Exp. Allergy 1996, 26, 216–222. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Forager bees transport pollens in their hind leg corbiculae to which they add nectar to form pollen pellets. Forager bees deposit and pack the pollen pellets into cell surrounding the brood area and forming bee bread. Nurse bees develop enlarged food glands and produce RJ by consuming honey and bee bread (Photos taken by Prof. Dr. Jianke Li).
Figure 1. Forager bees transport pollens in their hind leg corbiculae to which they add nectar to form pollen pellets. Forager bees deposit and pack the pollen pellets into cell surrounding the brood area and forming bee bread. Nurse bees develop enlarged food glands and produce RJ by consuming honey and bee bread (Photos taken by Prof. Dr. Jianke Li).
Ijms 21 00382 g001
Figure 2. Numbers of publications on RJ that appear from international journals are increasing every year (data from the core collection of the Web of Science).
Figure 2. Numbers of publications on RJ that appear from international journals are increasing every year (data from the core collection of the Web of Science).
Ijms 21 00382 g002
Figure 3. A schematic representation of the main biological substances in RJ and their functional activities. For detailed information refer to Table 1.
Figure 3. A schematic representation of the main biological substances in RJ and their functional activities. For detailed information refer to Table 1.
Ijms 21 00382 g003
Figure 4. The biological activities of RJ and their mechanism. SOD (superoxide dismutase); GSH (glutathione); CAT (catalase); GR (glutathione reductase); GPx (glutathione peroxidase); ROS (reactive oxygen species); MMP (matrix metallopeptidases); MDA (malondialdehyde); NO (nitric oxide); IFN-ϒ (interferon-gamma); IL-4 (interleukin-4); TNF-α (tumor necrosis factor); IFN-α (Interferon-α); EGF (epidermal growth factor); AMPK (5′ AMP-activated protein kinase); MAPK (mitogen-activated protein kinase); IGF-1 (insulin-like growth factor-1), and TOR (target of rapamycin).
Figure 4. The biological activities of RJ and their mechanism. SOD (superoxide dismutase); GSH (glutathione); CAT (catalase); GR (glutathione reductase); GPx (glutathione peroxidase); ROS (reactive oxygen species); MMP (matrix metallopeptidases); MDA (malondialdehyde); NO (nitric oxide); IFN-ϒ (interferon-gamma); IL-4 (interleukin-4); TNF-α (tumor necrosis factor); IFN-α (Interferon-α); EGF (epidermal growth factor); AMPK (5′ AMP-activated protein kinase); MAPK (mitogen-activated protein kinase); IGF-1 (insulin-like growth factor-1), and TOR (target of rapamycin).
Ijms 21 00382 g004
Figure 5. The pharmaceutical effects of RJ and their mechanism. Bax (bcl-2-like protein X); MMP-9 (matrix metallopeptidases-9); AKT (protein kinase B); MAPK (mitogen-activated protein kinase); IRS (insulin receptor substrate 1); IL-4 (interleukin-4); TNF-α (tumor necrosis factor); ROS (reactive oxygen species); AMPK (5′ AMP-activated protein kinase); SOD (superoxide dismutase); GSH (glutathione); CAT (catalase); GR(Glutathione reductase); GPx (glutathione peroxidase); MDA (malondialdehyde); NO (nitric oxide); MAKL (mixed lineage kinase domain-like); ERK (extracellular signal-regulated kinases); CREB (cAMP Response Element-Binding Protein); IGF-1 (insulin-like growth factor-1); TOR (target of rapamycin), and BACE1 (β-site amyloid precursor protein cleaving enzymes).
Figure 5. The pharmaceutical effects of RJ and their mechanism. Bax (bcl-2-like protein X); MMP-9 (matrix metallopeptidases-9); AKT (protein kinase B); MAPK (mitogen-activated protein kinase); IRS (insulin receptor substrate 1); IL-4 (interleukin-4); TNF-α (tumor necrosis factor); ROS (reactive oxygen species); AMPK (5′ AMP-activated protein kinase); SOD (superoxide dismutase); GSH (glutathione); CAT (catalase); GR(Glutathione reductase); GPx (glutathione peroxidase); MDA (malondialdehyde); NO (nitric oxide); MAKL (mixed lineage kinase domain-like); ERK (extracellular signal-regulated kinases); CREB (cAMP Response Element-Binding Protein); IGF-1 (insulin-like growth factor-1); TOR (target of rapamycin), and BACE1 (β-site amyloid precursor protein cleaving enzymes).
Ijms 21 00382 g005
Table 1. The biological activities and pharmaceutical applications of RJ and their bioactive ingredients.
Table 1. The biological activities and pharmaceutical applications of RJ and their bioactive ingredients.
Bioactive Compounds/Experimental ModelsEffectsSources
RJ, MRJP-2, and MRJP-4 (Micro-organisms)Antibacterial, antifungal, anti-yeast
Induce damage and dysfunction in microbial cell wall and membrane
[66,67,68]
Royalisin and 10-HDA
(Micro-organisms)
Antibacterial (Gram+, Gram−), antifungal
Inhibit growth
[9,69,70]
Jelleine I-III, jelleine-II (pS), and jelleine-II (pT)
(Micro-organisms)
Antibacterial (Gram+, Gram−)
Cell degranulation, hemolysis, and increase immune defense
[39,43]
RJ, 10H∆2DA, 3,10-HDA, 11S, 10-HDA, 10-acetooxy-2-DEA, and Native jelleine-11 (Micro-organisms)Antifungal and anti-yeast
Strongly inhibit growth
[39,43,71,72,73]
Pre and post administration of RJ
(Animals)
Antioxidant activity
Decrease oxidative stress (MDA) and increase antioxidant properties (CAT, GPx, and SOD)
[74]
RJ
(Humans)
Anti-cancer effect
Inhibit the tumor-induced angiogenesis, activate immune system, metabolism of 2-AF metabolites, and stop the damage of bisphenol A
[75,76,77]
Intravenously application of 10-HDA and the HuIFN-aN3
(Animals)
Anti-cancer effect
Decrease the level of glutathione and enhance the level of lipid peroxidation via MDA
[78]
RJ
(Animals and humans)
Anti-diabetic effect
Improve the serum level of triglycerides, lipoprotein, and cholesterol
Decrease glucose level and increase insulin concentration
[79,80,81,82,83]
MRJP-3
(Animals)
Immunomodulatory effect
Decrease antigenicity and inhibit IL-4, IL-2, and IFN-ϒ production
[84]
3,10-DDA
(Humans)
Immunomodulatory effect
Increase the production of IL-12, IL-18, and stimulate the production of IFN-ϒ
[85]
RJ (Animals and humans)Hypocholesterolemic effect
Reduced the level of triglyceride, insulin, total lipids, and cholesterol level by decreasing very low-density lipoprotein levels
[86,87,88]
RJ and MRJP-1
(Humans)
Hypocholesterolemic effect
Decreased the total cholesterol and LDL-c level by improving the (HDL-c) level
[89,90]
RJ, ERJ, And MRJP-1
(Animals)
Anti- hypertension effect
Reduce systolic blood pressure, diastolic blood pressure, and increase NO level
[62,91,92,93]
RJ
(Animals)
Anti-inflammatory effect
RJ inhibit the TNF-α, IL-1β, and, IL-18 levels in the blood due to its antiradicals and antioxidative effect
[94,95]
RJ and MRJP-2
(Animals)
Hepato-renal protective effect
Reduce blood urea, MDA level, leukocyte infiltration, creatinine, adhesion molecule-1 expression, glomerular diameter, and TNF-a
Increased SOD and GPx
[50,96,97,98,99]
RJ and 10-HDA
Animals
Neurotrophic effects
Inhibited production of oligodendrocytes, astrocytes, and stimulate neuron differentiation
[57,100]
RJ and RJPs
(Animals and humans)
Neuroprotective
Decrease cholesterol and amyloid-beta deposition by down-regulation of β-secretase
Increase cholinergic response, estrogen level, and antioxidant capacities
Improved blood-brain barrier, and autonomic nervous systems
[101,102,103]
RJ
(Humans)
Genoprotective effect
Increase of BCL2/BAX ratio for cell survival
Enhance in hTERT/BAX for increasing age
Increase in NRF2/BAX for antioxidative response
[104]
RJ and 10-HDA
(Humans)
Protective effect
Protect it from photo-aging by improving collagen production via up-regulation of TGF-β1 expression
[105]
RJ
(Animals and humans)
Effect on fertility
Increase sperm motility, luteinizing hormones, and testosterone levels
[81,106,107,108]
ERJ
(Humans)
Anti-allergic
Significantly reducing IgE-binding capacity of blood
[109]
Note: RJ (royal jelly); RJPs (purified royal jelly peptides); RJPH (royal jelly protein hydrolysate); MRJP-4 (ajor royal jelly protein 4); 10-HDA (10-hydroxydecanoic acid); 10H∆2DA (10-hydroxy-Delta-2-decenoic acid); 3,10-DDA (3,10-dihydroxy-decanoic acid); MDA (malondialdehyde); GPx (Glutathione peroxidase); SOD (superoxide dismutase); IFN-ϒ (interferon-gamma); IL-4 (interleukin-4); TNF-α (tumor necrosis factor); BCL2: (B-cell lymphoma 2); BAX (BCL2 associated X protein); NRF2 (nuclear factor erythroid 2 related factor 2); 2-AF (2-aminofluorene); BACE1 (β-site amyloid precursor protein cleaving enzymes), and IgE (Immunoglobulin E).
Back to TopTop