Jelleine, a Family of Peptides Isolated from the Royal Jelly of the Honey Bees (Apis mellifera), as a Promising Prototype for New Medicines: A Narrative Review

Abstract

The jelleine family is a group of four peptides (jelleines I–IV) originally isolated from the royal jelly of honey bee (Apis mellifera), but later detected in some honey samples. These oligopeptides are composed of 8–9 amino acid residues, positively charged (+2 to +3 at pH 7.2), including 38–50% of hydrophobic residues and a carboxamide C-terminus. Jelleines, generated by processing of the C-terminal region of major royal jelly proteins 1 (MRJP-1), play an important biological role in royal jelly conservation as well as in protecting bee larvae from potential pathogens. Therefore, these molecules present numerous benefits for human health, including therapeutic purposes as shown in preclinical studies. In this review, we aimed to evaluate the biological effects of jelleines in addition to characterising their toxicities and stabilities. Jelleines I–III have promising antimicrobial activity and low toxicity (LD50 > 1000 mg/Kg). However, jelleine-IV has not shown relevant biological potential. Jelleine-I, but not the other analogues, also has antiparasitic, healing, and pro-coagulant activities in addition to indirectly modulating tumor cell growth and controlling the inflammatory process. Although it is sensitive to hydrolysis by proteases, the addition of halogens increases the chemical stability of these molecules. Thus, these results suggest that jelleines, especially jelleine-I, are a potential target for the development of new, effective and safe therapeutic molecules for clinical use.

Royal Jelly: Biological Action and Health Benefits

“…An overview of the molecular and cellular mechanisms of RJ is shown in Table 5, while the doses of RJ used in some clinical trials are shown in Table 6. [307] RJ − reduces oxidative stress and levels of IL-6, IL-8, and TNF-α [292,298,299,[327][328][329][330][331] Note: Aβ, amyloid beta; ACE, angiotensin-converting enzyme; Ach, acetylcholine; Akt, protein kinase B; ALP, alkaline phosphatase; ALT, alanin-aminotransferase; AMPK, AMP-activated protein kinase; anti-OVA, antibodies that detect ovalbumin; AP-1, Activator protein 1; ApoA-I, apolipoprotein A-I; Apo-B, apolipoprotein B; APP, amyloid precursor protein; ARE, antioxidant response element; AST, aspartate aminotransferase; ATF4, activating transcription factor-4; ATM, ataxia telangiectasia-mutated; ATR, ataxia telangiectasia-mutated and Rad3-related; BACE1, beta-site APP cleaving enzyme 1; BAT, brown adipose tissue; Bax, Bcl-2associated X protein; BBB, blood-brain barrier; Bcl-2, B-cell lymphoma- mTOR, mammalian target of rapamycin; MUC2, mucin; NaMN, nicotinic acid mononucleotide; NEP, neprilysin; NFAT c1, nuclear factor of activated T cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NGF, nerve growth factor; NLRP1, NOD-like receptor (NLR) family pyrin domain-containing 1; NO, nitric oxide; Nrf2, nuclear factor E2-related factor 2; OPG, osteoprotegerin; Osx, Osterix; OVX, ovariectomy; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1 alpha; PI3K, phosphatidylinositol 3-kinase; PPAR-γ, peroxisome proliferator-activated receptor gamma; PTEN, phosphatase and tensin homolog; RAGE, receptor for advanced glycation end products; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of NF-κB ligand; RB, retinoblastoma gene; RCC, renal cell carcinoma; ROS, reactive oxygen species; RUNX2, runt-related transcription factor 2; S6K1, S6 kinase 1; SASP, senescenceassociated secretory phenotype; SCFAs, short-chain fatty acids; SOD, superoxide dismutase; T, Testosterone; T3, triiodothyronine; T4, thyroxine; TC, total cholesterol; TGF-β, transforming growth factor-beta; TNF-α, Tumor Necrosis Factor alpha; TNBS, 2, 4,6-trinitrobenzene sulfonic acid; TRP-1, tyrosinase-related protein 1; TRP-2, tyrosinase-related protein 2; TSH, thyroid stimulating hormone; UCP1, uncoupling protein 1; VLDL-C, very-low-density lipoprotein cholesterol; VSMCs, vascular smooth muscle cells. For premature babies 50 mg to 1 g per day − growth and development − strengthen immunity and nervous system [6] Children:…”

“…Insects only recently became interesting to scientists as fat tissue and other insect cells produce numerous antimicrobial peptides that can be found in their hemolymph. Antimicrobial peptides (AMPs) are also present in RJ [ 48 , 63 , 68 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 ]. In addition to antibacterial activity, these peptides show antiviral, antitumoral, immunoregulatory, and hepatoprotective effects as well.…”

“…10-HDA showed prominent bactericidal activity towards animal- and human-specific pathogens, including several strains of Staphylococcus ( S. aureus , S. alactolyticus , S. intermedius B , S. xylosus , and S. cholearasuis ), Vibrio parahaemolyticus , and hemolytic Escherichia coli [ 68 ]. The antibacterial activity of royalisin and 10-HDA have been reported in both Gram-positive and Gram-negative species of bacteria [ 48 , 63 , 68 , 292 , 293 , 294 , 295 ]. These two antibacterial components are important for bees themselves.…”

“…The proteolytic stability was also improved by 10- to 100-fold. The halogenation of chlorine-, bromine-, and iodine-jelleine-I was more effective than fluorine-jelleine-I [ 292 , 298 , 299 ]. The antibacterial activity of halogenated derivatives of jelleine-1 (applied at 1 μM to 256 μM) was confirmed against Staphylococcus aureus , Bacilus subtilis , Staphylococcus epidermidis , Escherichia coli , Pseudomonas aeruginosa , Klebsiella influenza , and Cronobacter sakazakii at 10 5 to 10 6 CFU/mL.…”

“…Multiple small doses of royal jelly increase resistance to stress in laboratory animals while high doses are lethal. Antibacterial and bactericidal properties have been proven against the species Bacillus alvei , Streptococcus haem , Staphylococcus aureus , Proteus vulgaris , Micrococus , and Listeria monocytogene [ 101 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 , 306 ].…”