Royal Jelly: Biological Action and Health Benefits

Abstract

Royal jelly (RJ) is a highly nutritious natural product with great potential for use in medicine, cosmetics, and as a health-promoting food. This bee product is a mixture of important compounds, such as proteins, vitamins, lipids, minerals, hormones, neurotransmitters, flavonoids, and polyphenols, that underlie the remarkable biological and therapeutic activities of RJ. Various bioactive molecules like 10-hydroxy-2-decenoic acid (10-HDA), antibacterial protein, apisin, the major royal jelly proteins, and specific peptides such as apisimin, royalisin, royalactin, apidaecin, defensin-1, and jelleins are characteristic ingredients of RJ. RJ shows numerous physiological and pharmacological properties, including vasodilatory, hypotensive, antihypercholesterolaemic, antidiabetic, immunomodulatory, anti-inflammatory, antioxidant, anti-aging, neuroprotective, antimicrobial, estrogenic, anti-allergic, anti-osteoporotic, and anti-tumor effects. Moreover, RJ may reduce menopause symptoms and improve the health of the reproductive system, liver, and kidneys, and promote wound healing. This article provides an overview of the molecular mechanisms underlying the beneficial effects of RJ in various diseases, aging, and aging-related complications, with special emphasis on the bioactive components of RJ and their health-promoting properties. The data presented should be an incentive for future clinical studies that hopefully will advance our knowledge about the therapeutic potential of RJ and facilitate the development of novel RJ-based therapeutic opportunities for improving human health and well-being.

Keywords: aphytherapy; bioactive components; molecular and cellular activity; royal jelly.

Figure 1

Modulation of Nrf2 and NF-κB signaling pathways by royal jelly (RJ). RJ reduces reactive oxygen species (ROS)-induced tissue damage and toxicity by modulating Nrf2 and NF-κB signaling pathways. Nrf2 and NF-κB are important regulators of the body’s response to oxidative stress and inflammation. The figure shows potential molecular mechanisms of RJ action via Nrf2 and NF-κB pathways and important effects on harmful exogenous and endogenous factors, as well as interplay between Nrf2 and NF-κB signaling. NF-κB functions as a homo- or heterodimer derived from one or more of the five members of the NF-κB family (RelA/p65, RelB, cRel, NF-κB1 or p50, and NF-κB2 or p52), and is activated by stimulus-dependent inhibitor degradation, post-translational modifications, nuclear translocation, and chromatin-binding. The activated NF-κB drives the pro-inflammatory response that plays an important role in the pathogenesis of chronic inflammatory diseases. In the nucleus, p65 coordinates gene transcription by recruiting coactivators (e.g., CREB-binding proteins (CBP)) or corepressors (e.g., histone deacetylases (HDACs)). Nrf2 and NF-κB compete for the CBP-binding in the nucleus; which transcription factor will bind to CBP depends on the relative amounts of translocated Nrf2 and NF-κB. In addition, NF-κB recruits HDAC3 which deacetylates Nrf2, reduces Nrf2 levels, and inhibits expression of ARE-dependent genes.

Figure 2

Anti-senescence effect and molecular mechanisms of royal jelly (RJ) and its components on cellular senescence, healthy aging, and longevity induced by endogenous and exogenous factors. Cellular senescence is triggered by various intrinsic and extrinsic stimuli such as ROS, inflammation, mitochondrial dysfunction, genotoxic stress, irradiation and chemotherapeutic agents, telomere shortening, irreversible DNA damage, or signals such as oncogene activation or the overexpression of pluripotency factors. These stressors initiate various cellular signaling cascades, ultimately resulting in the activation of p53, p16Ink4a, or both. Their activation induces cell cycle arrest by inhibiting cyclin D–Cdk4/6 and cyclin E–Cdk2 and prevents Rb inactivation, resulting in continuous repression of E2F target genes required for S-phase. ARF can inhibit MDM2 and stabilize p53, which leads to the arrest of the cell cycle and cellular aging and the possibility of repairing minor damages. Accordingly, senescence is associated with several molecular and phenotypic alterations, such as senescence-associated secretory phenotype (SASP), cell cycle arrest, DNA damage response (DDR), senescence-associated β-galactosidase, morphogenesis, and chromatin remodeling. The anti-senesce effects of RJ and its component (MRJPs, 10-had, and RJPs) is the result of the interplay between several genes involved in downregulation of insulin/insulin-like growth factor-1 signaling (IIS) and targeting of rapamycin (mTOR), upregulation of the epidermal growth factor (EGF) signaling, dietary restriction, and enhancement of antioxidative capacity via Nrf2 activation. These signaling pathways affect cellular processes associated with longevity: DNA repair, autophagy, antioxidant activity, anti-inflammatory activity, stress resistance, and cell proliferation. In addition, RJ suppresses cellular senescence by upregulation of SOD1 and downregulation of Mtor and catenin beta like-1, and by regulating the expression levels of p53, p16, and p21. The life-expanding effect of RJ possibly originates from its antioxidant and anti-inflammatory properties, which can promote healthy aging by improving glycemic status, lipid profiles, and oxidative stress and hence can prevent the occurrence of various debilitating metabolic diseases. Furthermore, it should be noted that RJ contains epigenetically active compounds that inhibit DNMT3 or HDAC3, thus changing the epigenetic information generated in response to exogenous and endogenous factors during the aging process. Note: ATM, Ataxia telangiectasia mutated; ATR, Ataxia telangiectasia mutated and Rad3 related; BDNF, brain-derived neurotrophic factor; CDK2, Cyclin-dependent kinase 2; CDK4/6, Cyclin-dependent kinase 4 and 6; ER stress, Endoplasmic reticulum stress; NGF, nerve growth factor; Nrf2, nuclear factor-erythroid 2-related factor 2; p21 and p16, cyclin dependent kinase (CDK) inhibitors; Rb, retinoblastoma protein; ROS, Reactive oxygen species; SA-β-gal, senescence-associated β-galactosidase; SAHF, Senescence-associated heterochromatin foci; SASP, Senescence-associated secretory phenotype; TAFs, telomere-associated foci.

Figure 3

The possible protective and therapeutic mechanisms of royal jelly and its components in neuroprotection, cognitive performance, and suppression of neurodegeneration. Note: Aβ, amyloid beta; ACh, acetylcholine; AChE, acetylcholinesterase; AMPK, AMP-activated protein kinase; ARE, antioxidant responsive element; BACE1, beta-site APP cleaving enzyme 1; Bax, Bcl-2-associated X protein; BChE, butyrylcholinesterase; Bcl-2, B-cell lymphoma-2; BDNF, brain-derived neurotrophic factor; ChAT, choline acetyltransferase; CREB, cAMP-response element (CRE)-binding protein; ER β and α, estrogen receptors β and α; ERK, extracellular signal-regulated kinase; ERK1/2, extracellular signal-regulated kinase 1 or 2; eNOS, endothelial nitric oxide synthase; FOXO, forkhead box O transcription factor; GABA, gamma-aminobutyric acid; IDE, insulin-degrading enzyme; JNK, c-jun N-terminal kinase; LRP-1, low-density lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NEP, neprilysin; NF-κB, nuclear factor-kappa B; NFT, neurofibrillary tangles; NGF, nerve growth factor; NLRP3, nucleotide-binding domain and leucine-rich repeat-containing protein 3; Nrf2, nuclear factor-erythroid 2-related factor 2; OS, oxidative stress; p38, p38 protein kinases; PI3K, phosphatidylinositol 3-kinase; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator 1-a; PPAR-γ, peroxisome proliferator-activated receptor; RAGE, receptor for advanced glycation end-products; VEGF, vascular endothelial growth factor; ↑ upregulated; ↓ downregulated.

Figure 4

The effects of royal jelly (RJ) and its components on bone mineral density and strength. The key mechanisms of RJ action are based on increasing the antioxidant capacity, reducing oxidative stress, and regulating the production of inflammatory mediators, estrogenic activity, and interaction of 10-HDA with FFAR4 receptor. RJ and its components, such as 10-HDA, have an inhibitory effect on osteoclast differentiation and function by suppressing the NF-κB signaling pathway and its downstream molecules including NFATc1, CtsK, TRAP, V-ATPase D2, and MMP9, via FFAR4. Moreover, the inhibitory effect of RJ on ROS reduces RANKL, TRAP, NF-B, and caspase-3 activities in osteoclasts. RJ upregulates Runx2, Wnt, TGF-β, Osterix, Osteocalcin, and ALP by inhibiting accumulation of ROS. This contributes to the increased bone formation/mineralization and decreased bone resorption, resulting in increased bone mass, bone mineral density, and bone strength, and decreased risk of bone fractures. Note: 10-HDA, 10-hydroxy-2-decenoic acid; BMD, bone mineral density; CTX, C-terminal telopeptide; FFAR4, free fatty acid receptor 4; IL-1β, interleukin 1 beta; LPS, lpopolysaccharide; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of NF-kB ligand; RUNX2, runt-related transcription factor 2; NFAT c1, nuclear factor of activated T cell; MMP-9, matrix metalloproteinase 9; NF-κB, nuclear factor-kappa B; OPG, osteoprotegerin; Osx, Osterix, transcription factor; TGF-β, transforming growth factor;TNF-α, tumor necrosis factor alpha. ↑ upregulated; ↓ downregulated.