
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)13169-6
10.1016/j.heliyon.2024.e37138
e37138
Review Article
Royal jelly a promising therapeutic intervention and functional food supplement: A systematic review
Kumar Rajesh drkumar81@rediffmail.com
a
Thakur Ankita Ankitathakur2305@gmail.com
a
Kumar Suresh sureshk8971@gmail.com
a
Hajam Younis Ahmad younismajeed64@gmail.com
b⁎
a Department Biosciences, Himachal University, Shimla, Himachal Pradesh-171005, India
b Department of Life Sciences and Allied Health Sciences, Sant Baba Bhag Singh University, Jalandhar, Punjab -144030, India
⁎ Corresponding author. younismajeed64@gmail.com
30 8 2024
15 9 2024
30 8 2024
10 17 e371389 6 2024
27 8 2024
28 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Royal jelly (RJ), a secretion produced by honeybees, has garnered significant interest for its potential as a therapeutic intervention and functional food supplement. This systematic review aims to synthesize current research on the health benefits, bioactive components, and mechanisms of action of RJ. Comprehensive literature searches were conducted across multiple databases, including PubMed, Scopus, and Web of Science, focusing on studies published from 2000 to 2024 (April). Findings indicate that RJ exhibits a wide range of pharmacological activities, including anti-inflammatory, antioxidant, antimicrobial, and anti-aging effects. Beneficial biological properties of RJ might be due to the presence of flavonoids proteins, peptides, fatty acids. Both preclinical and clinical studies have reported that RJ improves the immune function such as wound healing, and also decreases the severity of chronic diseases including diabetes and cardiovascular disorders. The molecular mechanisms underlying these effects involve modulation of signalling pathways such as NF-κB, MAPK, and AMPK. Despite promising results, the review identifies several gaps in the current knowledge, including the need for standardized dosing regimens and long-term safety assessments. Furthermore, variations in RJ composition due to geographic and botanical factors necessitate more rigorous quality control measures. This review underscores the potential of RJ as a multifunctional therapeutic agent and highlights the necessity for further well designed studies to fully elucidate its health benefits and optimize its use as a functional food supplement.

Graphical abstract

Image 1

Highlights

• Royal jelly is rich in proteins, vitamins, minerals, and bioactive compounds.

• Royal jelly has nutritional value and protects against cellular damage.

• Royal jelly has anti-inflammatory properties, antimicrobial, and metabolic regulator.

• Royal jelly boosts the functional ability of the immune system.

• Royal jelly is used for anticancer, wound healing, antiaging, and neuroprotection.

Keywords

Apitherapy
Functional food
Pharmacological activities
Complementary medicine
==== Body
pmc1 Introduction

Honey bees are eusocial insects, holding special status in nature by providing various ecosystem services such as pollination, environmental indicators, production of honey, and other valuable products such as propolis, wax, RJ, etc. Among these products, honey is perhaps the most widely known and most widely used product. RJ, a milky secretion produced by worker bees 1–3 days old larvae of all the honeybee castes (queen, worker, and drone) are fed with RJ. Well known for its purported health benefits, RJ has garnered considerable attention in scientific research and traditional medicine alike. Bee pollen, another product collected by honey bees, is a nutrient rich substance gathered from flowers and used as a food source for the hive. Rich in vitamins, minerals, proteins, and antioxidants, bee pollen has been hailed for its potential health-promoting properties and is consumed by humans in various forms, including supplements and health foods (Table 1). Propolis, often referred to as “bee glue," is a resinous substance collected by bees from tree buds and sap. Utilized by bees to seal cracks in the hive and defend against pathogens, propolis exhibits antimicrobial, anti-inflammatory, and antioxidant properties, making it a subject of interest in both traditional and modern medicine. Bee venom, produced by specialized glands in the abdomen of worker bees, contains a complex mixture of peptides and enzymes with diverse biological activities. While bee stings can elicit painful reactions in humans, controlled exposure to bee venom has been explored for its potential therapeutic effects in conditions ranging from arthritis to certain types of cancer [1,2]. In this scientific exploration of RJ has been uncovered in order to explore its potential benefits for human health and well-being, underscoring the profound interconnectedness between humans and the natural world.Table 1 Summarizes the composition, bioactive compounds, and health benefits associated with various bee products, providing a concise overview of their medicinal properties.

Table 1Bee Product	Composition	Bioactive Compounds	Health Benefits	
Honey	Carbohydrates (glucose, fructose), di- and oligosaccharides, organic acids, enzymes, vitamins, amino acids, peptides	Polyphenols, flavonoids	Anti-inflammatory, antioxidant, potential prevention of diseases like cancer, diabetes, obesity	
Propolis	Resin, wax, essential oils, pollen, esters, diterpenes, lignans, alcohols, vitamins, flavonoids, amino acids, fatty acids, minerals	Caffeic acid phenethyl ester (CAPE), flavonoids, phenolic acids	Neuroprotective effects, antioxidative, anti-cancer properties	
Bee Pollen/Bee Bread	Carbohydrates, proteins, vitamins, amino acids, lipids, fatty acids	Phenolic compounds	Health-promoting activities, antimicrobial, anti-inflammatory	
Bee Venom	Carbohydrates, lipids, proteins, enzymes (hyaluronidase, phospholipase A2), peptides (melittin, apamin, MCD), pheromones, minerals	Phospholipase A2, hyaluronidase, peptides	Anti-inflammatory, immune system modulation, potential neuroprotective and anti-cancer properties	
Royal Jelly	Sugars, lipids, proteins, amino acids, vitamins, minerals	Royalactin, hydroxy-decenoic acid (10-HDA), proteins	Potential health maintenance, pharmaceutical applications	

2 Urgency and need of this review

The urgency of this review arises from the growing interest in the therapeutic effects of RJ, a natural substance produced by worker honeybees. Despite its traditional use and anecdotal health benefits, scientific understanding of its mechanisms and clinical applications remains limited. Given the increasing demand for alternative therapies and potential healthcare innovations, a comprehensive critical appraisal is essential. This review aims to analyze existing evidence, elucidate the pharmacological effects of RJ, and offer insights into its therapeutic potential. Through rigorous analysis, it seeks to fill research gaps, to guide future research, and potentially unlock new therapeutic interventions. This appraisal will help distinguish evidence-based therapeutic potential from conjecture, thereby enriching our understanding of natural remedies and potentially paving the way for novel healthcare innovations.

3 Royal jelly

RJ, produced by worker bees from the hypopharyngeal and mandibular glands through partial digestion of honeydew, is crucial for the development and caste differentiation of honeybee larvae [3,4]. 1-3 days-old larvae of all the honeybee castes (queen, worker, and drone) are fed with RJ. RJ is a yellowish-white gelatinous substance made from proteins, carbohydrates, lipids, and vitamins produced by secretory cells in the glandular acini [5,6]. It is transported to the mouthparts of worker bees and consumed by the queen and larvae, supporting colony growth.

Historically significant in ancient Greek and Egyptian cultures, RJ was linked to immortality and beauty, notably used by Cleopatra. Since the 1960s, research in apitherapy has explored its health benefits, including antimicrobial, anti-aging, anti-tumor, antioxidative, anti-diabetic, immunomodulatory, and neuroprotective effects [[6], [7], [8], [9]]. These properties suggest potential applications for conditions like infertility, digestive disorders, Alzheimer's, and depression [10,11].

In Chinese culture, RJ is widely used as a dietary supplement and cosmetic ingredient, offering benefits such as maintaining reproductive health, enhancing memory, preventing dementia, and reducing anxiety. Its anti-inflammatory action helps intestinal health by modulating cytokine levels (Fig. 1). The impact of RJ on fertility may be due to its ability to increase hormone production, and its anti-aging properties position it as a promising ingredient in medicinal and cosmetic formulations (Table 2). The longevity-promoting effects in queen bees, attributed to Major RJ Proteins (MRJPs), suggest potential implications for human lifespan extension (Table 2). Proper handling and cold storage are essential due to its perishable nature. RJ regulates different physiological functions in bees and indicates potential regulatory roles in humans, making it relevant for commercial, cosmetic, and medicinal applications (Table 3). Furthermore, its rich nutritional composition, comprising proteins, vitamins, minerals, and unique bioactive compounds, underscores its therapeutic potential. The enduring fascination with RJ in traditional medicine underscores its enduring legacy as a natural remedy with profound implications for human health and wellness (Table 3).Fig. 1 Showing the role of royal jelly (RJ) in the management of different disease.

Fig. 1

Table 2 Shows the physical characteristics of royal jelly (RJ), health benefits, major proteins, lipid, carbohydrate, Other Components, Storage Recommendations, Importance for Bees and Pharmacological Focus content.

Table 2Component	Description	
Appearance	White or yellowish gelatinous substance	
Taste	Sweet-sour	
pH	3.4–4.5	
Main Health Benefits	Antioxidant, Anti-inflammatory, Neurotrophic, Hypotensive	
Antidiabetic, Antihypercholesterolemic, Antirheumatic Antitumor	
Antifatigue, Antimicrobial, Nematocidal, Anti-aging	
Component	Description	Pharmacological Importance	
Major Proteins	- Major royal jelly proteins (MRJPs) (constitute 50 % of dry matter weight) Royalisin Jelleines

	MRJPs: Active ingredients<br>− Antioxidative peptides (up to 29 identified)	
Aspimin<br>− Newly discovered proteins	
Lipid Fraction	- 3–6% of wet weight

	- Trans-10-hydroxy-2-decenoic acid (10-HDA): Exhibits various biological properties (anti-aging, neurogenic, anticancer, antiobesity, antibacterial)

	
7–18 % of dry weight	
Mainly short hydroxyl fatty acids (constitute 80–85 %)	
Also contains phenols (4–10 %), waxes (5–6%), steroids (3–4%), phospholipids (0.4–0.8 %)	
Carbohydrates	− 90 % fructose and glucose 7.5–16 % of RJ

	
Other Components	Vitamins, Minerals, Phenols, Esters, Aldehydes, Ketones	
Alcohol, Bioactive substances” like ACh and nucleotides	
Storage Recommendations	- Should be stored frozen to retain biological properties

	
Storage above 5 °C reduces soluble nitrogen and free amino acids	
Importance for Bees	- Sole food for bee queens throughout their lifespan Associated with bee queen's “long lifespan, high fertility, and excellent learning and memory ability”

	
Pharmacological Focus	Investigation of anti-aging properties with focus on cognitive function in advanced aging and Alzheimer's disease (AD)	
Reviewing studies on RJ's effects “on cognitive aging and AD pathology in cell cultures, animal models, and” humans when possible	
Elaborating on molecular changes underlying these effects	

Table 3 This table provides a summary of the various therapeutic implications of royal jelly, highlighting its potential benefits for overall health and well-being.

Table 3Therapeutic Implication	Description	
Antioxidant Properties	Flavonoids, phenolic compounds, and vitamins help to neutralize free radicals and reduce oxidative stress.	
Anti-inflammatory Effects	Components such as “10-Hydroxy-2-decenoic acid (10-HDA)” exhibit anti-inflammatory properties, and reduce inflammation in arthritis and skin irritations.	
Immune System Support	Boosts the immune system by stimulating the production of immune cells such as lymphocytes and macrophages, thus improving overall immune function and response to infections.	
Wound Healing	The presence of proteins, vitamins, and amino acids in royal jelly can accelerate wound healing by promoting tissue repair and regeneration, making it beneficial for treating cuts, burns, and other skin injuries.	
Cardiovascular Health	Royal jelly contains compounds like fatty acids and peptides that may have cardio-protective effects by lowering cholesterol, improving blood vessel function, and reducing the risk of cardiovascular diseases.	
Neuroprotective Effects	Compounds like 10-HDA and royalisin have neuroprotective properties, potentially enhancing the survival of nerve cells in conditions like Alzheimer's, Parkinson's, and cognitive reduction.	
Anti-diabetic Properties	Royal jelly may be a potential adjunctive therapy for managing diabetes by regulating blood sugar levels and improving insulin sensitivity.	
Anti-cancer Potential	Royal jelly has been found to have anti-cancer properties through mechanisms like inhibiting tumor cell growth, inducing apoptosis, and enhancing the body's immune response against cancer cells.	
Hormonal Balance	Royal jelly contains hormone-like substances such as royalactin, which may help regulate hormonal balance, particularly in reproductive health, by supporting fertility, and menstrual regularity, and relieving symptoms of hormonal imbalances such as PMS and menopause.	
Skin Health and Beauty	The vitamins, minerals, and amino acids present in royal jelly contribute to skin nourishment and rejuvenation, promoting a healthy complexion, reducing signs of aging like wrinkles and fine lines, and alleviating skin conditions such as eczema and acne.	

4 Methods

The systematic review of randomized controlled trails (RCTs) was carried out following the rules and procedure mentioned in the Cochrane Handbook for systemic review analysis [12].

4.1 Search strategy

A comprehensive computerized search was conducted across different databases such as PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Web of Science (https://mjl.clarivate.com/search results), Science Direct (https://www.sciencedirect.com/), and Google Scholar (https://scholar.google.com/) 2000 to 2024. Moreover, we carefully reviewed the reference lists of all significant studies and reviews. The following terms were used either singly or in combination as inclusion criteria: “anti-inflammatory," “antibacterial," “anti diabetic," “apoptotic," “respiratory," “gastrointestinal," “cardiovascular," and “nervous system," neurodegenerative diseases (e.g., Alzheimer's, Parkinson's), hepatotoxicity, renal toxicity, metabolic disorders (e.g., diabetes, obesity, hyperlipidaemia), reproductive disorders (e.g., PCOS, infertility and oligospermia), and viral diseases (e.g., COVID-19). After about 200 results were found, their abstracts were examined to determine their applicability. About 110 research and review publications were carefully scrutinized in order to compile the current article, with additional exclusion criteria such non-English language and lack of full-text manuscript availability being applied.

4.2 Study selection

Two authors independently screened titles and abstracts having relevance with trials, followed by retrieval and examination of the full length text of the paper to screen out the relevant trial studies having relevance with our review article. Relevant data were extracted from all these articles and summarized by applying the standardized format to evaluate the quality of study and to synthesis evidence. The extracted data encompassed information like the title, name of authors, year of publication, and name of country, parameters of the studied trail including biological, pharmacological and food supplement roles of RJ. The systematic review and meta-analysis did not include any studies that used RJ as a medicinal solution for a variety of disorders with treatment durations shorter than one week. Every stage of the study selection procedure was carried out separately by at least two authors to assure accuracy, and disagreements were settled by consensus (Fig. 2).Fig. 2 Flow chart of the process of the study selection.

Fig. 2

4.3 Data extraction

Data abstraction form was used to individually and twice extract pertinent data from each included article. Dispute resolution was accomplished through consultation. The following details were recorded: the type and dosage of RJ, the type of placebo or control group, the duration of the treatment, the formulation used, the minimal active concentration tested, the duration of the study, the model used (in vitro or in vivo study), and other basic pharmacological data; the level of interest outcomes (pharmacological properties such as antidiabetic, anticancer, cardiovascular, antihypertensive, anti-inflammatory, immunomodulatory and reproductive related studies).

5 Chemical composition of RJ

RJ is an acidic secretion with a pH of 3.5–4.2. It mostly consists of water 60–70 %, sugars 7–18 %, proteins 9–18 %, lipids 3–8%, minerals, and trace amounts of vitamins. Major lipids in it consist of 10-hydroxy-2-decanoic acid and sebacic acid [13]. 10H2DA is known for its anti-cancerous and anti-angiogenic activity whereas sebacic acid has anti-aging effects. Major RJ Proteins (MRJPs) present in the RJ increases the lifespan of Queenbee (Table 4). It consists of peptides like royalisin, jelleines and royalactina. The various pharmacological aspects of RJ are attributed to its unique and rich composition of proteins, carbohydrates, vitamins, lipids, minerals, flavonoids, and polyphenols along with various biologically active substances (Table 5).Table 4 Gross chemical composition of royal jelly [14].

Table 4Chemical Component	Percentage (%)	
Water	60–70	
Proteins	10–18	
Carbohydrates	11–23	
Lipids (Fats)	3–8	
Ash	1–2	
Vitamins	Trace amounts	
Minerals	Trace amounts	
Enzymes	Trace amounts	
Hormones	Trace amounts	
Other Bioactive Compounds	Trace amounts	

Table 5 Phytochemical profile of royal jelly.

Table 5Bioactive Compound	Percentage (%)	
Royalactin	1–3	
10-Hydroxy-2-decenoic acid (10-HDA)	1–3	
Acetylcholine	0.5–1	
Adenosine	0.2-0.5	
Nucleotides (AMP, ADP, ATP)	0.1-0.3	
Gamma-aminobutyric acid (GABA)	0.1-0.2	
Polyphenols	0.1-0.2	
Flavonoids	Trace amounts	
Phospholipids	Trace amounts	
Sterols	Trace amounts	
Growth factors (EGF and TGF)	Trace amounts	

5.1 Carbohydrates

RJ contains approximately 7.5–15 % sugars, with fructose and glucose comprising the majority, making up around 90 % of the sugar content. Additionally, maltose, trehalose, melibiose, ribose, and erlose constitute about 0.8–3.6 % of the sugar composition in RJ [15] (Fig. 3). These sugars present in RJ act as aphago stimulants, operating through insulin signalling cascades and nutrient sensing pathways, thereby enhancing nutrient intake crucial for larval and queen development [16].Fig. 3 Showing 2D chemical structures of different carbohydrates present in the royal jelly.

Fig. 3

5.2 Lipids

Lipids constitute about 7–18 % of RJ, significantly contributing to its biological activities. Predominantly composed of short hydroxy fatty acids with 8–12 carbon atoms and dicarboxylic groups, key components include 10-hydroxy-2-decenoic acid (10H2DA), and sebacic acid (SA) [17] (Fig. 4).Fig. 4 Showing the 2D structures of important lipids and flavonoids present in the royal jelly.

Fig. 4

10H2DA plays a crucial role in caste differentiation by regulating epigenesis through the inhibition of histone deacetylases, enzymes that break down ε-acetyl-lysine residues of histones [16,18]. It has bactericidal effects against harmful bacteria like Paenibacillus larvae, protecting bee hives [19], and shows antibacterial effects against lipoteichoic acid from Staphylococcus aureus and other pathogenic bacteria linked to human colon cancer [20,21].

10H2DA also exhibits neurogenic activities by stimulating progenitor cell differentiation, mimicking neurotrophic factors [22]. It is used in cosmetics and anti-cancer drugs for its skin-whitening properties and anti-proliferative effects by suppressing transcription factors and proteins such as tyrosinase-related protein 1 (TRP-1) and TRP-2 [23]. Additionally, 10H2DA inhibits the activity of matrix metalloproteinases (MMPs), preventing tissue aging and diseases like rheumatoid arthritis [24,25].

SA and 10H2DA have anti-inflammatory properties by regulating proteins in the kappa-B signalling and mitogen-activated protein kinase (MAPK) pathways [21,26]. These acids also increase the activity of estrogen receptors ERα and ERβ, benefiting the skeletal and muscular systems [27,28].

5.3 Proteins

Proteins make up about 50 % of RJ, with approximately 80 % consisting of nine Major RJ Proteins (MRJPs), which have molecular weights between 49 and 87 kDa. These proteins are nutritionally valuable and play a crucial role in the development of young female larvae through cell proliferation [29]. Among MRJPs, MRJP 1 is significant; existing in heat-resistant oligomer and less resistant monomer forms [30]. The glycoprotein royalactin mimics epidermal growth factor (EGF) effects in rat hepatocytes and regulates developmental processes in bee larvae [31].

Other RJ proteins include jelleines, royalisin, and aspimin, with royalisin and jelleines being antimicrobial peptides that enhance immune responses in bee larvae. Royalisin, rich in cysteine residues, remains stable at extreme temperatures and low pH, while its antimicrobial properties are due to hydrophobic residues that disrupt bacterial membranes. Apolipophorin-3 and glucose oxidase contribute to RJ's antimicrobial properties by forming lipid-protein complexes and catalyzing glucose oxidation into hydrogen peroxide, respectively [7].

5.4 Phenols, flavonoids, and free amino acids

The antioxidant properties of RJ are due to polyphenolic compounds and flavonoids [32]. Key phenolic compounds include pinobanksin, dodecanoic acid, octanoic acid, and 1,2-benzenedicarboxylic acid. Flavonoids of RJ are categorized into flavanones (hesperetin, naringenin, isoakuranetin), flavonols (kaempferol, isorhamnetin), flavones (apigenin, glucoside of luteolin, chrysin, acacetin), and isoflavonoids (formononetin, genistein, coumestrol) (Fig. 4). These compounds provide anti-inflammatory and antiapoptotic properties [17]. RJ from younger larvae contains higher levels of proteins and phenolic compounds, enhancing free radical scavenging activity [32].

RJ also contains trace amino acids like valine, glutamic acid, serine, glycine, cysteine, alanine, tyrosine, phenylalanine, leucine, isoleucine, and threonine, contributing to its nutritional and biological activity [17,33]. In addition to this, RJ includes vitamins B complex, C, A, and E, with a high concentration of vitamin B5 (Pantothenic acid), linked to lifespan extension. It also contains elements like P, S, W, V, Ni, Na, Mg, Ca, Cu, Zn, Fe, Al, Sr, Pb, Hg, Ba, Bi, Cd, Sn, Cr, Mn, and Mo, with mineral salts making up about 1.5 % of its composition [34]. RJ is rich in acetylcholine, crucial for cognitive function and memory, regulated by choline acetyltransferase activity influenced by glucose and insulin metabolism, potentially preventing cognitive dysfunction [35,36]. RJ also contains nucleotides, free bases, phosphates, ADP, ATP, and AMP, which are essential for energy production and enzymatic actions [37]. AMP N1-oxide, unique to RJ, promotes neurite outgrowth and PC12 cell differentiation into neurons, mimicking nerve growth factor activity through MAPK/ERK1/2 and PI3K/Akt pathways [17,38].

6 Pharmacological importance of RJ

RJ exhibits numerous properties which are known to have beneficial effects on humans like cardiovascular disease [39], antihypertensive activity [40], hypo-cholesterolemic activity [41], anti-aging [42], anti-cancerous [43], memory enhancer [44], hepatoprotective [45], anti-obesity [46], anti-diabetic [47], wound healing [48], anti-inflammatory and antioxidative [49]. Each constituent of RJ has shown its advantages regarding human welfare and acted as an excellent therapeutic agent against various diseases (Fig. 5 and Table 6).Fig. 5 Depicts the different pharmacological and biologically defensive properties of royal jelly.

Fig. 5

Table 6 This table summarizes the diseases, their causes and symptoms, the properties of royal jelly relevant to each condition, effective bioactive compounds found in royal jelly, and the biological properties of royal jelly relevant to each condition.

Table 6Disease	Causes	Symptoms	Property of Royal Jelly	Effective Bioactive Compound	Biological Property	
Ulcerative Colitis	Chronic, inflammatory bowel disease	Abdominal pain, diarrhea, rectal bleeding	Inhibition of pro-inflammatory cytokines TNF-α and IL-1β, elevation of anti-inflammatory cytokine IL-10	Royalactin, Royalisin	Anti-inflammatory, boosts activity of IL-10, decreases T-cell proliferation, inhibits TNF-α and IL-1β	
Crohn's Disease	Chronic, inflammatory bowel disease	Abdominal pain, diarrhea, weight loss	Inhibition of pro-inflammatory cytokines TNF-α and IL-1β, elevation of anti-inflammatory cytokine IL-10	Royalactin, Royalisin	Anti-inflammatory, boosts activity of IL-10, decreases T-cell proliferation, inhibits TNF-α and IL-1β	
Lactose Intolerance	Lack of β-galactosidase, maldigestion of lactose from milk and milk products	Abdominal pain, diarrhea, flatulence	Synergism with probiotic yogurt, boosting probiotics in fermented milk products	Lactobacillus helveticus	Enhances probiotic activity, aids in lactose digestion	
Chronic Diarrhea	Various causes including infections, dietary issues, and intestinal disorders	Frequent, loose stools, abdominal pain	Anti-diarrheal potency due to antimicrobial activity of royalisin and royalactin	Royalisin, Royalactin	Antimicrobial, anti-diarrheal	
Chronic Constipation	Lack of fiber, dehydration, sedentary lifestyle, medications	Straining during bowel movements, infrequent bowel movements	Acetylcholine in RJ induces smooth muscle contractions, antimicrobial activity of royalisin and royalactin	Acetylcholine, Royalisin, Royalactin	Induces smooth muscle contractions, antimicrobial, potentially aids in bowel movements	
Gastric Ulcers	NSAID use, H. pylori infection, excessive alcohol consumption	Abdominal pain, bloating, heartburn, nausea	Normalization of gastric tissues via increase of PGE-2 and COX-2, reduction of MPO and iNOS	Not specified	Normalizes gastric tissues, reduces inflammation	
Intestinal Ulcers	NSAID use, H. pylori infection, excessive alcohol consumption	Abdominal pain, bloating, heartburn, nausea	Attenuation of pro-inflammatory cytokines TNF-α and IL-1β, reduction of lipid peroxidation, augmentation of endogenous antioxidant enzymes SOD and CAT	Not specified	Reduces inflammation, increases antioxidant activity	
Peptic Ulcers	NSAID use, H. pylori infection, excessive alcohol consumption	Abdominal pain, bloating, heartburn, nausea	Reduction of gastric ulcers via anti-inflammatory action, attenuation of pro-inflammatory cytokines TNF-α and IL-1β, augmentation of antioxidant enzyme activity	Not specified	Reduces inflammation, increases antioxidant activity	
Nicotine-Induced Gastric Mucosal Changes	Ingestion of nicotine, leading to mucosal damage	Abdominal discomfort, changes in mucosal integrity	Amelioration of mucosal changes via unknown mechanisms	Not specified	Unknown, possibly anti-inflammatory	

6.1 Neuroprotective action of RJ

RJ has demonstrated numerous beneficial effects on the nervous system, including memory enhancement, increased energy levels, prevention of senility, anxiety reduction, and calming effects on hyperactivity. Its neuropharmacological actions involve modulating gamma-aminobutyric acid (GABA) neurotransmission, a crucial regulator of brain activity. RJ influences GABA-transaminase (GABA-T), the enzyme metabolizing GABA, which is synthesized from glutamate by glutamate decarboxylase (GAD) [50]. Studies indicate RJ administration elevates GABA levels in rats with tartrazine-induced cortical injury, suggesting neuroprotective effects, but decreases GABA levels in the striatum and hypothalamus of aging rats, showing complex regulation of GABAergic neurotransmission (Fig. 6).Fig. 6 Showing the neuroprotective effect of propolis, royal jelly modulates the neurotransmission by stimulating the gamma amino butyric acid (GABA) in the brain which in turn stimulates the synthesis of serotonin and dopamine, increases the levels neurotransmitters, and hence acts as neuroprotective natural agent. In addition to this administration of royal jelly increases the synthesis and secretion of other neurotransmitters and also some neuroprotective molecules.

Fig. 6

RJ also contains tryptophan and tyrosine, precursors for serotonin and dopamine, crucial for mood and cognitive function [51,52]. Treatment with RJ and tyrosine in experimental models increased brain dopamine levels and its metabolites [53,54], enhancing cognition through improved neurotransmission. RJ mitigates age-related cognitive decline induced by d-galactose in mice, restoring brain noradrenaline and dopamine levels [55], indicating its neuroprotective potential (Fig. 6).

RJ reduces cortical neuron death from toxins like tartrazine and cadmium and restores levels of neurotransmitters such as noradrenaline, dopamine, and serotonin, supporting neuronal integrity. It also stimulates neuroprotective molecule synthesis, evidenced by increased cysteic acid levels in aged rats [56,57], suggesting involvement in the cysteine-taurine metabolic pathway [58]. The beneficial effects of RJ on the nervous system likely stem from neurotransmission modulation, neuroprotection against age-related cognitive decline, and stimulation of neuroprotective pathways, underscoring its potential as a supplement and therapeutic agent for cognitive enhancement and neuroprotection (Fig. 6).

6.2 RJ as an anti-aging remedy

According to Halloran et al. (2012), aging is a major risk factor for neurodegenerative diseases [59], notably Alzheimer's disease (AD), which is characterized by progressive loss of working and situational memory [60]. Previous studies reported that RJ can protect spatial memory in rats modeled with sporadic AD through an intracerebroventricular injection of streptozotocin (icv-STZ) by enhancing hippocampal neurogenesis and reducing oxidative stress and neurodegeneration [36,61] (Fig. 7).Fig. 7 Royal jelly (RJ) is used as anti-aging by preventing the neurodegeneration through the reduction in oxidative stress, because RJ increases the GSH content and accelerating the activities of antioxidative enzymes such as SOD, CAT, G6PDH, GR, GPX and GST. Moreover, RJ decreases the secretion of inflammatory cytokines by down-regulating the inflammatory pathways and hence protects the neurons from damages and prevents the aging. Royal jelly suppresses the progression and development of tumors by inhibiting te angiogenesis, activation of immune system and prevents the metastasis and tumorgenesis.

Fig. 7

In AD models, such as 10-month-old APP/PS1 mice, RJ improves memory by preventing neuronal death and modulating the cAMP/PKA/CREB/BDNF pathway [62]. Furthermore, RJ ameliorates memory deficiencies in ovariectomized (OVX) rats and improves memory in OVX cholesterol-fed rabbits by regulating oxidative stress and cholinergic neurotransmitter levels [63,64].

RJ also affects neurotransmitter levels in the prefrontal cortex, influencing cognitive processes related to working memory (WM) [65]. Long-term RJ administration reduces striatal GABAergic transmission and GABA concentration in aged Wistar male rats, enhancing dopamine transmission activity and spatial memory [56]. MRJPs specifically enhance spatial memory by modulating cysteine, taurine, and energy metabolism [66]. Thus, RJ shows significant potential in improving memory function through multiple mechanisms.

6.3 Effect of RJ on fertility

Male infertility is influenced by factors such as smoking, alcohol consumption, sexual behavior, and diet. Primary infertility prevalence among couples ranges from 13.2 % to 17.3 %, with ovulatory problems accounting for 39.7 % and male factors 29.1 % [67]. Male factors alone are responsible for at least half of all infertility cases [68], with estimates suggesting a prevalence of 40.9 % [69]. Male factors contribute to infertility in 20–70 % of cases, with infertile men comprising 2.5 %–12 % of the population [70].

RJ has shown benefits for human fertility, including improvements in hormone balance, sperm, and ovule quality [71]. [72] RJ supplementation elevates testosterone levels, ejaculate volume, seminal fructose, sperm motility, and sperm count in male animals [10]. Cryopreservation of sperm reduces viability, but RJ treatment at specific concentrations can enhance sperm viability over time.

RJ significantly improves total sperm motility in chilled and frozen-thawed ram sperm due to its high calcium ion concentration. RJ administration at doses of 50, 100, and 150 mg/kg increases sperm motility in animal models like rabbit bucks and mice [73]. Thus, RJ is a promising natural supplement for enhancing male fertility, but optimal dosage and administration methods need further research to maximize its efficacy.

6.4 Anti-tumor action

RJ, a bee secretion, contains compounds like 10-hydroxy-2-decanoic acid (10H2DA) and proteins such as apalbumin-1 and apalbumin-2, which inhibit cancer progression (Fig. 7). 10H2DA can inhibit VEGF, reducing angiogenesis, cell proliferation, and migration, thus hindering tumor vascularisation [74]. RJ also has antioxidative properties, enhancing the production of antioxidants like GSH, GSH-Px, SOD, and GST in the kidneys and liver of rats [75] (Fig. 7). This antioxidative effect is synergistic with Cisplatin, an anti-cancer agent, helping combat oxidative stress-induced cancer. RJ inhibits tumor growth, prevents angiogenesis, activates immune functions, and alleviates cancer-related fatigue when supplemented in cancer patients. It shows promise as an adjunctive treatment during menopause for breast cancer by suppressing cancer cell proliferation, metastasis, and tumorigenesis through inhibition of angiogenesis and immune system stimulation [76,77].

6.5 Antibiotic effect

Royalisin, a protein in RJ, exhibits strong antibacterial properties against various Gram-positive bacteria but not Gram-negative bacteria [78]. Direct ingestion of RJ can degrade its active components due to pH changes [19,49]. Jelleines, also in RJ, show antimicrobial actions: Types I, II, and III act against Gram-positive bacteria, Gram-negative bacteria, and yeast, respectively, while Type IV does not [79]. Some MRJPs (2–5) have antibacterial activity against E. coli, a Gram-negative bacterium.

Bilikova et al. (2015) found that royalisin and royalisin-D significantly reduced survival rates of S. intermedius and P. aeruginosa, Gram-negative and Gram-positive bacteria, respectively, with royalisin showing higher efficacy [80]. Conversely, Hasan et al. (2020) found RJ had antimicrobial activity against E. coli, unlike gentamicin and its combination with doxycycline, which were ineffective [81]. MRJPs (2–5) and 7 produced recombinantly demonstrated consistent antibacterial activity [82]. RJ also showed antibacterial activity against S. aureus when infused into milk, enhancing the properties of milk [83]. Furthermore, RJ was more effective against anaerobic periodontopathic bacteria than aerobic ones in a study comparing RJ and chlorhexidine [84]. Hence, RJ and its components exhibit significant antimicrobial properties, particularly against Gram-positive bacteria and certain Gram-negative strains, with varying efficacy depending on the specific proteins and conditions used.

6.6 Wound healing effect and anti-inflammatory action

The cosmetic industry often incorporates RJ due to its antioxidative, antibacterial, anti-inflammatory, and wound-healing properties. RJ has been shown to prevent the release of pro-inflammatory cytokines like TNF-α, IL-6, and IL-1 in mouse macrophage cultures without harming the cells (Fig. 8) [85]. Components of RJ, such as MRJP3, regulate cytokine release. It also contains ascorbic acid-2-O-α-glucoside (AA-2G), which stimulates collagen production, and 10H2DA, which enhances TGF-β1 release, further promoting collagen production and wound healing [86] (Fig. 8).Fig. 8 Royal jelly (RJ) inhibits the inflammatory pathways by declining the synthesis and secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1) by suppressing the activation of macrophages. In addition to this RJ regulates the inflammatory secretion and promotes the production of collagen. Royal jelly (RJ) helps in the healing of wounds by promoting the production of collagen because royal jelly contains various enzymes which accelerate the healing of wounds. Moreover, reduction in the secretion of proinflammatory cytokines (TNF-α, IL-6 and IL-1) by suppresses the activation of macrophages.

Fig. 8

A study on enzyme-treated RJ (ERJ) showed it supports macrophage growth and protects against lipopolysaccharide (10.13039/501100012274 LPS )-induced stress. ERJ reduced inflammatory markers (TNF-α, IL-1, IL-6, IL-10, IL-12, IFN-γ) and boosted B and T lymphocyte proliferation and natural killer cell activity in mice (Fig. 8). Previous studies have investigated RJ's fatty acids (10-HDA, 10-HDAA, Sebacic acid) and found they inhibit key inflammatory mediators like nitric oxide and IL-10 in a dose-dependent manner, with Sebacic acid also reducing tumor necrosis factor alpha (TNF-α) secretion [20]. These fatty acids modulate inflammatory genes and pathways, including MAPK and NF-κB. It has been reported that 10-HDA's anti-inflammatory effects by reducing the expression of genes such as IL-1, IL-6, COX-2, and MCP-1 in vitro. In mice, a 100 mg/kg dose of 10-HDA reduced lung damage and inflammatory cytokines (IL-10, MCP-1, TNF-α) caused by lipoteichoic acid (LTA) [62]. Therefore, RJ and its components show significant potential for treating inflammatory conditions and enhancing skin health (Fig. 8).

6.7 Effect on gastrointestinal diseases

Gastrointestinal disorders, including irritable bowel syndrome, peptic ulcers, liver diseases, pancreatitis, gallstones, and Crohn's disease, are prevalent, especially in tropical regions [87]. It has been studied that functional gastrointestinal issues affect about 40 % of people globally [88]. Dietary patterns significantly influence these conditions, with a Westernized diet high in carbohydrates and animal proteins linked to chronic inflammatory bowel diseases [89]. The transition from urban to rural settings impacts gut microbiota composition [90].

The gastrointestinal tract's role in nutrient absorption and immune response increases the risk of inflammatory, autoimmune, and chronic conditions [91]. RJ is noted for its therapeutic potential against inflammation, liver disease, hypercholesterolemia, oxidative stress, and immune diseases [92]. RJ contains bioactive compounds, including proteins, vitamins, phenolics, and flavonoids, with its major protein constituents (MRJPs) highlighted as significant therapeutic agents [93,94].

6.8 Immunomodulatory effects

RJ exhibits diverse pharmacological activities, particularly immunomodulatory effects. Oka et al. (2001) found that RJ inhibits mast cells in DNP-KLH mice, reducing antigen-specific IgE and histamine production while restoring macrophage function and enhancing Th1/Th2 response [95]. In β-lactoglobulin allergic mice, RJ reduces serum anti-β-Lg IgE, IgG, and histamine, mitigating allergic symptoms [96].

RJ also suppresses atopic dermatitis-like lesions in NC/Nga mice by modulating IFN-γ production and iNOS expression [97]. In SLE-prone mice, RJ lowers serum IL-10, anti-ssDNA, dsDNA, erythrocyte autoantibody levels, and splenic autoreactive B cells [98]. In children with SLE, RJ increases CD4+ and CD8+ regulatory T cells while decreasing CD4+ T cells, reducing disease severity [99].

In Graves' disease, RJ decreases TNF-α in lymphocytes and increases IFN-γ and Th1/Th2 cytokine ratios [100]. Protease-treated RJ enhances mucosal IgA responses by promoting antigen uptake by M cells [101]. MRJP3 and apolipoprotein III-like protein in RJ exhibit immunoregulatory activity; MRJP3 suppresses T-cell IL-4, IL-2, IFN-γ production and reduces anti-OVA IgE and IgG1 levels [102]. Apolipoprotein III-like protein enhances immune response post-phosphorylation [103].

10-HDA, a component of RJ, shows mixed immune effects: it reduces IL-6 production and NF-κB activation but inhibits T cell proliferation and antigen-specific responses [[104], [105], [106]]. However, it can restore body, thymus, and spleen weights in cyclophosphamide-induced mice, improving the thymus/spleen index and enhancing T and B cell activity [107] (Fig. 9).Fig. 9 Royal jelly (RJ) shows immunomodulatory effect against the various immune compromising diseases by decreasing the secretion and synthesis of different immune biomolecules. Moreover, major royal jelly proteins (MRJPs) suppresses the production of IL-4, IL-2 and IFN-γ thereby drives the immunomodulatory effects.

Fig. 9

6.9 Reduce liver damage

RJ demonstrates significant hepatoprotective properties. It regulates 267 liver genes in mice, decreasing squalene epoxidase (SQLE) and increasing low-density lipoprotein receptor (LDLR), thus reducing cholesterol levels [108]. RJ also upregulates genes encoding GST and GSH-Px [108].

Liver function, crucial for metabolism, is often impaired by toxic chemicals and drugs, marked by elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels [109]. Toxicants like cadmium and CCl4 lower glutathione (GSH) and increase malondialdehyde (MDA). RJ restores antioxidants (SOD, CAT and GSH) and reduces AST and ALT, mitigating liver damage [110,111]. RJ also alleviates liver injury from azathioprine and paracetamol [112,113].

RJ counteracts cisplatin (CDDP) and taxol (TXL)-induced liver injury by restoring GST and GSH-Px levels and reducing hepatocyte apoptosis [114]. It lowers ALP and LDH levels elevated by TXL and modulates liver growth regulatory factors [115]. RJ diminishes iNOS and IL-1β expression while upregulating Nrf2 and Bcl-2, and down regulating caspases-3 and Bax, protecting against cadmium toxicity [116]. RJ components like MRJP2 protect against CCl4-induced liver injury by mitigating the oxidative in liver by enhancing antioxidant capacity [117]. Thus, RJ safeguards the liver from various injuries by enhancing its antioxidant defenses.

6.10 Diabetes

Diabetes, particularly Type 2 Diabetes (T2DM), results from insulin secretion and resistance issues, affecting adipose tissue, liver, and skeletal muscle [118,119]. T2DM is linked to liver diseases like hepatic cirrhosis, hepatocellular carcinoma, and nonalcoholic fatty liver disease, emphasizing the liver's role in glucose and lipid homeostasis [120,121].

RJ has demonstrated beneficial effects in managing diabetes. In women with T2DM, RJ reduces serum fasting blood glucose and glycosylated hemoglobin levels while increasing insulin concentration, thereby reducing the risk of complications [122,123]. RJ also raises serum apolipoprotein A-I (ApoA-I) levels and improves the ApoB/ApoA-I ratio in T2DM patients (Khoshpey et al., 2016).

In STZ-induced diabetic rats, RJ lowers fasting blood glucose, AST, ALT, and ALP levels, while increasing insulin, albumin, and total protein levels [124]. Additionally, RJ enhances total antioxidant capacity and reduces insulin resistance in diabetic patients [125]. Long-term RJ administration inhibits glucose-6-phosphatase, improving hyperglycemia by increasing adiponectin and adiponectin receptor 1 mRNA expression, and activating AMP-activated protein kinase in abdominal fat [119].

6.11 Restrain obesity

Obesity, a chronic condition influenced by various factors, is marked by heightened oxidative stress and prolonged activation of macrophages in peripheral tissues. Addressing inflammation and oxidative stress is key to effective treatment. RJ supplementation in overweight adults has shown promising results, reducing total cholesterol, C-reactive protein, and increasing adiponectin, serum total antioxidant capacity, bilirubin, and leptin, thus benefiting overweight individuals [126]. Studies in mice fed a high-fat diet and supplemented with RJ observed reduced inflammation and elevated levels of Irisin, promoting metabolic thermogenesis in brown adipose tissue [127,128]. Despite 10-HDA being a significant component of RJ, it was found ineffective in preventing obesity [129].

6.12 Anticancer

RJ shows promising potential in cancer treatment. RJ improves myelosuppression in mice with Ehrlich ascites tumors by inhibiting spleen hematopoietic function and enhancing survival rates, likely through reducing prostaglandin E2 [130]. Prostaglandin E2 regulates lymphocyte proliferation, inhibits macrophage tumoricidal activity, and modulates immune responses [130]. RJ inhibits the proliferation of human breast cancer MCF-7 cells induced by bisphenol A [131] and reduces glutathione levels while increasing lipid peroxidation in human Caco-2 cells when combined with interferon α [132]. In a 4T1 breast cancer mouse model, RJ treatment reduces tumor weight and enhances antioxidant activity in the liver, kidney, and serum [133]. RJ extracts also show strong cytotoxicity against human glioblastoma multiforme [134] and HeLa cells [135].

Lipophilic extract of RJ inhibits human neuroblastoma cell proliferation [136]. Components such as AMP-N1 oxide promote axonal growth and activate the MAPK signaling pathway [23]. MRJP2 promotes caspase-dependent apoptosis in HepG2 cells [137], while 10-HDA inhibits melanin production in B16F1 melanoma cells [23]. The derivative HPO-DAEE induces apoptosis in human lung cancer cells via the ROS-ERK-p38 and CHOP pathways [138].

7 Importance of RJ in health of animals

Numerous studies have investigated the effects of RJ on animal health. RJ enhances cartilage development due to its high collagen content and strengthens bone and tooth structures due to calcium and selenium. It protects blood cells, heart, liver tissues, muscles, and the nervous system due to its potassium content. RJ improves wound healing; a study on mice showed daily RJ application significantly increased wound healing compared to controls, suggesting RJ showed significantly higher effect as compared to Nitrofurazone [139]. RJ also enhanced the healing of tympanic membrane perforations in guinea pigs [140]. In reproductive health, RJ increased sperm motility, reduced abnormal sperm rates, and improved sperm quality in animals [141]. It inhibited age-related testosterone decline in old hamsters [142] and mitigated the negative effects of stress on male rabbit fertility during hot conditions, improving various sperm parameters and plasma biochemical markers [143]. RJ has nephroprotective effects, preventing cisplatin-induced kidney damage [144]. In diabetic rats, RJ alleviated oxidative stress and improved liver and pancreas biochemical markers [145]. It also protects against cadmium-induced genotoxicity and oxidative stress in rats [146]. RJ mitigated the adverse effects of aluminum chloride on reproductive and hormonal health in poisoned rats [147]. It improved sperm parameters and reduced oxidative stress in male rats exposed to hydrogen peroxide [148]. RJ increased ovulation rates and estrus onset in animals [147,149].

Supplementation with bee products improved immunity and performance in quail [150,151]. RJ reduced hyperglycemia and body weight in obese/diabetic mice [119], prevented hyperlipidemia, and improved blood clotting levels [152]. It also reduced epidural fibrosis after laminectomy in rats [153] and delayed atheroma formation in hyperlipidemic rabbits. RJ exhibited osteo inductive and anti-inflammatory effects in treating periodontal diseases [154] and reduced osteoporosis-related bone loss in oophorectomized rats [155]. It restored immune function and improved premature mortality in mice with low micronutrient intake [156]. RJ enhanced spatial memory and inhibited cognitive impairment in older rats [65,66].

RJ showed immunomodulatory effects in the 4T1 breast cancer model in mice, enhancing TNF-a and IgG levels and improving kidney cell size [133]. It reduced breast tumor development and enhanced antioxidant capacity [157]. RJ also reduced the size of WEHI-164 fibrosarcoma tumors in mice [158]. RJ protected cardiac muscle from ischemia, enhancing contraction activity and coronary blood flow. It alleviated physical fatigue in mice [159] and modulated disorders in a Parkinson's disease model in rats [160] RJ protected the colonic mucosa from acetic acid-induced damage in rats, reducing mast cell numbers and colonic erosion [161]. It decreased oral mucositis in rats subjected to radiotherapy [162]. RJ reduced corticosterone levels and improved the antioxidant defense system in stressed rats [163]. RJ, propolis, and bee pollen showed significant antibacterial effects against Aeromonas hydrophila and Vibrio cholerae, suggesting potential in controlling pathogenic bacteria [164].

7.1 RJ: A natural boost health for human

RJ is known for its benefits in cell regeneration, metabolism, and vitality. Rich in natural hormones, vitamins, essential fatty acids, amino acids, sterols, phosphorous compounds, and acetylcholine, RJ aids nerve message transmission and endocrine function. Its nucleic acids and collagen components provide anti-aging effects (Table 7). Gammaglobulin in RJ strengthens the immune system, while 10-HDA has strong antibiotic properties [165,[166], [167], [168], [169], [170]].Table 7 Dosage of royal jelly for human use.

Table 7Condition	Dose	Effect of Royal Jelly	References	
Elderly Physical Performance and Memory	Not specified	Slows muscle strength deterioration and helps preserve memory	[65,171]	
Skin Protection	Not specified	Increases collagen production, protects against UVB-induced photoaging	[165]	
Infection and Inflammation	Not specified	Inhibits Pseudomonas aeruginosa adhesion, protects from inflammatory responses, and offers protection against Fumonisin toxicity	[113,172]	
MRSA Infections	Not specified	Potential alternative treatment	[173]	
Dry Eye Syndrome	Not specified	Increases tear secretion, preserves lacrimal gland function	[174,175]	
Upper Respiratory Tract Infections	Not specified	Suggested as supplements for treatment	[176]	
Cardiovascular Health	350 mg per capsule	Reduces serum total cholesterol and LDL levels	[177]	
6 g per day for 4 weeks	Lowers small VLDL levels	[178]	
Glucose Metabolism	20 g	Improves glucose tolerance	[179]	
Autoimmune Diseases	Not specified	Improves clinical severity scores and laboratory markers in systemic lupus erythematosus	[99]	
Dental Health	0.2 % RJ	Antibacterial effects	[180,181]	
Allergies	Not specified	Reduces intestinal anaphylactic responses and histological lesions caused by β-Lg sensitivity	[96]	
Thyroid Health	Not specified	May have anti-thyroid effects, beneficial for Graves' disease	[85]	
Skin Pigmentation	Not specified	Inhibits melanogenesis, suggesting use in skincare products	[23]	
Liver Health	Not specified	Protects against alcohol-induced hepatomegaly, restores transaminase levels	[182]	
Not specified	Offers hepatoprotection against paclitaxel-induced toxicity	[115]	
Skin Hydration	520 mg per day for 10 weeks	Improves epidermal hydration and ceramide levels	[183]	
Diabetic Foot Ulcers	Not specified	Aids in healing diabetic foot ulcers	[184]	
Kidney Health	Not specified	Antioxidants positively impact renal damage caused by oxidative stress and inflammation	[185]	
Athletic Performance	Not specified	Improves body height, muscle mass, reduces fat components	[186]	
Pain Relief	200 mg/kg	Analgesic effects comparable to aspirin for acute pain, more effective than aspirin for chronic pain	[187]	
Breast Cancer	Not specified	Inhibits growth-promoting effect of Bisphenol A on MCF-7 breast cancer cells	[131]	

RJ mitigates damage from 5-fluorouracil and exhibits antitumor, antibiotic, immunomodulatory, estrogenic, and neurogenic activities [188,189]. A six-month intake of RJ improves erythropoiesis, glucose tolerance, and mental health in humans [190]. It significantly improves sperm count and motility, aiding infertility treatment [170] and is effective in treating early menopause and ovarian damage caused by Adriamycin [191]. For chronic conditions like menopausal osteoporosis and cardiovascular disorders, 150 mg of RJ for three months improves lipid profiles and may control menopause-related dyslipidemia [192]. RJ also improves the quality of life for postmenopausal women, treating sexual and urinary dysfunctions [193]. A 1000 mg capsule of RJ for two months can reduce pre-menstrual syndrome (PMS) [194].

RJ, combined with Indian honey, positively affects fetal membranes in cases of early rupture [195]. RJ contains major fatty acids like 10-H2DA, 10-HDAA, and SEA, which have anti-inflammatory effects and modulate key inflammatory pathways [26]. RJ stimulates the central nervous system, enhancing muscle tone and activity, and promotes neurotrophic effects via Glial Cell-Derived Neurotrophic Factor (GDNF) production, aiding brain cell differentiation and function [196]. RJ improves serum antioxidant capacity and insulin resistance in diabetes [122,125,197] and significantly impacts glycemic control in Type 2 diabetics [198]. It may aid in weight management in diabetic women [199]. RJ supports fatigue recovery in cancer patients [199] and improves oral mucosa symptoms during radiotherapy and chemotherapy, shortening healing times [200]. RJ may protect against radiation-induced apoptosis in human blood leukocytes [201]. RJ and honey exhibit antioxidant effects, reducing Cisplatin-induced nephrotoxicity in cancer patients [202].

7.1.1 Dosage of RJ for human use

Preparation and formulation of dosage of RJ varies from individual to individual as well as from one age group to another age group. In table, 8 dosage of RJ has been summarized (Table 8).Table 8 Dosage of royal jelly for human use.

Table 8Group	Condition/Need	Dosage	Supplement Constituents	Reference (s)	
Infants	Growth and development, strengthen immunity and nervous system	0.5 g/day for 2–12 months	Raw royal jelly	[[203], [204], [205], [206], [207]]	
Premature Infants	Complications of prematurity	50 mg to 1 g/day	
Complications of prematurity	Medium dose of 0.25 g/day	
Children (1–5 yrs)	Low immune system, nervous system impairment, weakness, loss of appetite, anorexia, anaemia	0.5 g/day	Royal jelly	
Children (5–12 yrs)	Low immune system, nervous system impairment, weakness, loss of appetite, anorexia, anaemia	0.5–1 g/day	
Children (1–5 yrs)	Acute infection and colds	2.5 g/day for 1–3 days	
Children (5–12 yrs)	Acute infection and colds	5 g/day for 1–3 days	
Adults	Immunity, insomnia, skin disorders, anaemia, low libido, hormonal imbalance, wounds, premenstrual syndrome, menopause, osteoporosis	1–2 g/day	
Diabetes, depression, Hashimoto's disease, arthritis	3–5 g/day	
Recent depression	Up to 10 g/day for 10 days/month for 3 months	
Immunity, convalescence, preparation for surgery, autoimmune diseases, cancer, hormonal imbalances, infertility, ovarian cyst, uterine fibroma, thyroid problems	1 g/day, up to 10 g/day for 1–3 days in beginning of colds or acute infections, up to 3–5 days post-op healing	Royal jelly, bee products, plants	
Heavy working conditions	10 g/day	Royal jelly	
Early onset of colds	10 g/day for 1–3 days	
Post-operative healing	5–10 g/day for 3–5 days	
Side effects of chemotherapy	3 g/day for 6–8 weeks	
Neurodegenerative diseases, multiple sclerosis, Parkinson's disease	10–15 g/day	
Adults	Severe acne	Topical application with Boswellia essential oil; oral treatment with propolis	Royal jelly, Boswellia essential oil, propolis	[85,[208], [209], [210]]	

7.2 Role of RJ in diet formulation

Bee products like RJ, offer essential nutrients crucial for health, especially amid rising environmental pollution and inadequate diets. RJ is rich in 10-HDA, B vitamins, and folate, provides significant nutrition (Lab Reference: CS20133271). While natural folate in RJ is vital, synthetic folic acid supplements may pose risks during pregnancy [211]. Preventive and cell-regenerative actions of RJ are supported by apinutrition (incorporation of bee products to promote overall health and vitality). These functional foods, prominent due to their ease of assimilation and pharmacological benefits are widely consumed [132,188,210,211].

RJ has demonstrated efficacy in alleviating allergic symptoms, managing cholesterol, and supporting conditions like muscular dystrophy, MS, and Parkinson's disease. It aids immune function during radiotherapy and chemotherapy, replenishing cells destroyed by treatment. With its rich amino acid and gamma globulin content, RJ strengthens the immune system against viral infections. It also contains essential nutrients supporting various health aspects, including energy, immunity, cardiovascular health, and mental well-being [180,[212], [213], [214], [215]]. Additionally, RJ acts as an adaptogen enhancing fertility and potentially extending lifespan without disease [214].

8 Significance

This review article provides a comprehensive critical appraisal of the pleiotropic therapeutic effects of RJ, underscoring its potential as a multifaceted natural remedy and food supplements. Following the systematic evaluation of the current scientific literature, it was elucidated that RJ has diverse biological activities anti-diabetic, anti-inflammatory, antioxidant, antimicrobial, and anti-cancer properties. It highlights the molecular mechanisms underlying these effects, thereby advancing our understanding of how RJ can contribute to health and disease management. This critical assessment and summarization of the published findings could play a significant support for both clinical and research communities to identify the gaps in existing literature, propose directions for future research, and support the development of RJ-based therapeutic strategies. The findings of this review emphasize the importance of integrating RJ into complementary and alternative medicine, potentially leading to innovative approaches in treating various ailments as well as food supplements.

9 Novelty

This systematic review uniquely synthesizes recent evidence on the multifaceted therapeutic potential of royal jelly, highlighting its emerging role not only as a functional food supplement but also as a promising intervention in various health conditions. Moreover, this review underscores the novel bioactive components of royal jelly and their biological activities such as anti-inflammatory, antimicrobial (antibacterial, antifungal and antiviral) and antibiotic. In addition this RJ and its metabolites having various health benefits such as gastrointestinal protection, cardiovascular, anti-tumor, anti-ageing, neuroprotective (e.g., Alzheimer's, Parkinson's), hepatotoxicity, metabolic disorders (e.g., diabetes, obesity, hyperlipidaemia), reproductive disorders (e.g., PCOS, infertility and oligospermia) and wound-healing activities. Mechanisms of action of RJ and its therapeutic efficacy offer comprehensive perspective that could guide future research and clinical applications.

10 Conclusion

This review critically appraises the pleiotropic therapeutic effects of RJ, demonstrating its vast potential as a natural therapeutic agent. The comprehensive analysis reveals that RJ exhibits significant anti-inflammatory, antioxidant, antimicrobial, and anti-cancer properties, supported by various molecular mechanisms. Therefore, RJ holds promise for incorporation into complementary and alternative medicine, offering a multifaceted approach to health and disease management.

Limitations

This review, while comprehensive, faces several limitations. First, the heterogeneity of study designs and methodologies in the existing literature complicates the synthesis of findings and may introduce bias. Second, many studies on the therapeutic effects are preclinical trial on RJ, necessitating cautious extrapolation to human applications. Moreover, the variability in the composition of RJ due to differences in bee species, diet, and environmental factors poses challenges in standardizing dosages and formulations. Lastly, the limited number of large-scale, well-controlled clinical trials restricts the ability to draw definitive conclusions about its efficacy and safety. Addressing these limitations in future research is crucial for advancing our understanding and application of RJ in medicine.

Future research and perspectives

RJ holds promise as a natural substance with potential health benefits. As a natural material with possible health advantages, RJ holds promise. Several sectors are interested in it because of its high nutrient profile, which includes proteins, vitamins, and minerals. In the future, RJ research may aim to fully exploit its potential in a range of areas, including medical, nutrition, and cosmetics. In order to understand more about its bioactive components and their effects on human health and perhaps develop new supplements or treatments, researchers may investigate them in greater depth. RJ components may be synthesized via biotechnology for a variety of uses. Furthermore, ethical beekeeping practices and sustainable production methods may grow more popular as environmental conservation gains momentum. As scientific understanding grows, there could be a broader range of products incorporating RJ, catering to diverse consumer needs.

Data availability

Data will be made available on request.

CRediT authorship contribution statement

Rajesh Kumar: Writing – review & editing, Conceptualization. Ankita Thakur: Writing – original draft. Suresh Kumar: Supervision. Younis Ahmad Hajam: Writing – review & editing, Visualization, Supervision, Resources, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Authors would like to appreciate the Department Biosciences, Himachal University, Shimla, Himachal Pradesh and Department of Life Sciences and Allied Health Sciences, Sant Baba Bhag Singh University, Jalandhar, Punjab, India for providing academic and administrative support.
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References

1 Ullah A. Aldakheel F.M. Anjum S.I. Raza G. Khan S.A. Gajger I.T. Pharmacological properties and therapeutic potential of honey bee venom Saudi Pharmaceut. J. 31 1 2023 96 109 10.1016/j.jsps.2022.11.008
2 Khalil A. Elesawy B.H. Ali T.M. Ahmed O.M. Bee venom: from venom to drug Molecules 26 16 2021 4941 10.3390/molecules26164941 34443529
3 Maghsoudlou A. Mahoonak A.S. Mohebodini H. Toldra F. Royal jelly: chemistry, storage and bioactivities J. Apicult. Sci. 63 1 2019 17 40 10.2478/jas-2019-0007
4 Moselhy W.A. Fawzy A.M. Kamel A.A. An evaluation of the potent antimicrobial effects and unsaponifiable matter analysis of the royal jelly Life Sci. J. 10 2 2013 290 296
5 Park G.H. Kim Y.B. Park Ji M. Deng Y. Soo Y. Sik K. Rae B. Antibacterial activity of major royal jelly proteins of the honeybee (Apis mellifera) royal jelly J. Asia Pac. Entomol. 22 2019 737 741 10.1016/j.aspen.2019.06.005
6 Zhang X. Yu Y. Sun P. Fan Z. Zhang W. Feng C. Royal jelly peptides: potential inhibitors of β-secretase in N2a/APP695swe cells Sci. Rep. 9 1 2019 168 10.1038/s41598-018-35801-w 30655564
7 Fratini F. Cilia G. Mancini S. Felicioli A. Royal Jelly: an ancient remedy with remarkable antibacterial properties Microbiol. Res. 192 2016 130 141 10.1016/j.micres.2016.06.007 27664731
8 Ibrahim S.E.M. Kosba A.A. Royal jelly supplementation reduces skeletal muscle lipotoxicity and insulin resistance in aged obese rats Pathophysiology 4 2018 307 315 10.1016/j.pathophys.2018.05.001
9 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. 113 2013 346 352 10.1016/j.smallrumres.2013.03.003
10 Elnagar S.A. Royal jelly counteracts bucks' “summer infertility” Anim. Reprod. Sci. 121 1–2 2010 174 180 10.1016/j.anireprosci.2010.05.008 20538419
11 Mahdivand N. Najafi G. Nejati V. Shalizar-Jalali A. Rahmani F. Royal jelly protects male rats from heat stress-induced reproductive failure Andrologia 51 3 2019 e13213 10.1111/and.13213
12 Van Tulder M. Furlan A. Bombardier C. Bouter L. Updated method guidelines for systematic reviews in the cochrane collaboration back review group Spine 28 12 2003 1290 1299 10.1097/00007632-200306150-00014 12811274
13 Yu X. Tu X. Tao L. Daddam J. Li S. Hu F. Royal Jelly fatty acids: chemical composition, extraction, biological activity, and prospect J. Funct.Foods 111 2023 105868 10.1016/j.jff.2023.105868
14 Guo J. Wang Z. Chen Y. Cao J. Tian W. Ma B. Dong Y. Active components and biological functions of royal jelly J. Funct.Foods 82 2021 104514 10.1016/j.jff.2021.104514
15 Xue X. Wu L. Wang K. Chemical composition of royal jelly Bee Products—Chemical and Biological Properties 2017 181 190 10.1007/978-3-319-59689-1_8
16 Buttstedt A. Ihling C.H. Pietzsch M. Moritz R.F.A. Royalactin is not a royal making of a queen Nature 10 2016 537 10.1038/nature19349
17 Kocot J. Kielczykowska M. Luchowska-Kocot D. Kurzepa J. Musik I. Antioxidant potential of propolis, bee pollen, and royal jelly: possible medical application Oxid. Med. Cell. Longev. 2018 7074209 10.1155/2018/7074209
18 Polsinelli G.A. Yu H.D. Regulation of histone deacetylase 3 by metal cations and 10-hydroxy-2E-decenoic acid: possible epigenetic mechanisms of queen-worker bee differentiation PLoS One 13 2018 e0204538 10.1371/journal.pone.0204538
19 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 Paenibacilluslarva Molecules 23 12 2018 3236 10.3390/molecules23123236 30544571
20 Chen Y.F. You M.M. Liu Y.C. Shi Y.Z. Wang K. Lu Y.Y. Hu F.L. Potential protective effect of Trans-10-hydroxy-2-decenoic acid on the inflammation induced by Lipoteichoic acid J. Funct.Foods 45 2018 491 498 10.1016/j.jff.2018.03.029
21 Yang Y.C. Chou W.M. Widowati D.A. Lin I.P. Peng C.C. 10-hydroxy-2-decenoic acid of royal jelly exhibits bactericide and anti-inflammatory activity in human colon cancer cells BMC Compl. Alternative Med. 18 2018 202 10.1186/s12906-018-2267-9
22 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 signal-regulated kinases Biomed. Res. 28 3 2007 139 146 10.2220/biomedres.28.139 17625346
23 Peng C.C. Sun H.T. Lin I.P. Li J.C. Kuo P.C. The functional property of royal jelly 10-hydroxy-2-decenoic acid as a melanogenesis inhibitor BMC Compl. Alternative Med. 17 1 2017 392 10.1186/s12906-017-1888-8
24 Zheng J. Lai W. Zhu G. Wan M. Chen J. Tai Y. Lu C. 10-Hydroxy-2-decenoic acid prevents ultraviolet A-induced damage and matrix metalloproteinases expression in human dermal fibroblasts J. Eur. Acad. Dermatol. Venereol. 27 2013 1269 1277 10.1111/j.1468-3083.2012.04707.x 23030720
25 Wang J.G. Ruan J. Li C.Y. Wang J.M. Li Y. Zhai W.T. Zhang W. Ye H. Shen N.H. Lei K.F. Connective tissue growth factor, a regulator related with 10-hydroxy-2-decenoic acid down-regulate MMPs in rheumatoid arthritis Rheumatol. Int. 32 2012 2791 2799 10.1007/s00296-011-1960-5 21850473
26 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. 1 2016 3583684 10.1155/2016/3583684
27 Moutsatsou P. Papoutsi Z. Kassi E. Heldring N. Zhao C. Tsiapara A. Melliou E. Chrousos G.P. Chinou I. Karshikoff A. Fatty acids derived from royal jelly are modulators of estrogen receptor functions PLoS One 5 2010 e15594 10.1371/journal.pone.0015594
28 Weiser M.J. Grimshaw V. Wynalda K.M. Mohajeri M.H. Butt C.M. Long-term administration of queen bee acid (QBA) to rodents reduces anxiety-like behaviour, promotes neuronal health and improves body composition Nutrients 10 2017 13 10.3390/nu10010013 29295499
29 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. 64 2016 5803 5812 10.1021/acs.jafc.6b00514 27388939
30 Moriyama T. Ito A. Omote S. Miura Y. Tsumoto H. Heat resistant characteristics of major royal jelly protein 1 (MRJP1) oligomer PLoS One 10 2015 e0119169 10.1371/journal.pone.0119169
31 Kamakura M. Royalactin induces queen differentiation in honeybees Nature 473 2011 478 483 10.1038/nature10093 21516106
32 Liu J.R. Yang Y.C. Shi L.S. Peng C.C. Antioxidant properties of royal jelly associated with larval age and time of harvest J. Agric. Food Chem. 56 2008 11447 11452 10.1021/jf802494e 19007163
33 Pina A. Begou O. Kanelis D. Gika H. Kalogiannis S. Tananaki C. Theodoridis G. Zotou A. Targeted profiling of hydrophilic constituents of royal jelly by hydrophilic interaction liquid chromatography-tandem mass spectrometry J. Chromatogr. A 1531 2018 53 63 10.1016/j.chroma.2017.11.019 29198446
34 Stocker A. Schramel P. Kettrup A. Bengsch E. Trace and mineral elements in royal jelly and homeostatic effects J. Trace Elem. Med. Biol. 19 2005 183 189 10.1016/j.jtemb.2005.08.004 16325534
35 Wessler I. Gartner H.A. Michel-Schmidt R. Brochhausen C. Schmitz L. Anspach L. Grunewald B. Kirkpatrick C.J. Honeybees produce millimolar concentrations of non-neuronal acetylcholine for breeding: possible adverse effects of neonicotinoids PLoS One 11 2016 e0156886 10.1371/journal.pone.0156886
36 Zamani Z. Reisi P. Alaei H. Pilehvarian A.A. Effect of Royal Jelly on spatial learning and memory in rat model of streptozotocin-induced sporadic Alzheimer's disease Adv. Biomed. Res. 1 2012 26 23210085
37 Wu L. Chen L. Selvaraj J.N. Wei Y. Wang Y. Li Y. Zhao J. Xue X. Identification of the distribution of adenosine phosphates, nucleosides and nucleobases in royal jelly Food Chem. 173 2015 1111 1118 10.1016/j.foodchem.2014.10.137 25466132
38 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. base Compl. Alternative Med. 7 2010 63 68 10.1093/ecam/nem146
39 Fujisue K. Yamamoto E. Sueta D. Arima Y. Hirakawa K. Tabata N. Tsujita K. A randomized, double-blind comparison study of royal jelly to augment vascular endothelial function in healthy volunteers J. Atherosclerosis Thromb. 29 9 2022 1285 1294
40 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. 7 4 2019 1361 1370 10.1002/fsn3.970 31024709
41 Mohamed H.K. Mobasher M.A. Ebiya R.A. Hassen M.T. Hagag H.M. El-Sayed R. Awad N.S. Anti-inflammatory, anti-apoptotic, and antioxidant roles of honey, royal jelly, and propolis in suppressing nephrotoxicity induced by doxorubicin in male albino rats Antioxidants11 5 2022 1029 10.3390/antiox11051029
42 Ali A.M. Kunugi H. Royal jelly as an intelligent anti-aging agent—a focus on cognitive aging and Alzheimer's disease A review 10 2020 Antioxidants9 10.3390/antiox9100937 937
43 Kul Köprülü T. Erkal B. Kara A. Tekin S. Investigation of the effects of the royal jelly on genomic demethylation and tumor suppressor genes in human cancer cells Med. Oncol. 40 1 2022 59 10.1007/s12032-022-01927-1 36564533
44 Raoufi S. Salavati Z. Komaki A. Shahidi S. Zarei M. Royal jelly improves learning and memory deficits in an amyloid β-induced model of Alzheimer's disease in male rats: involvement of oxidative stress Metab. Brain Dis. 4 2023 1239 1248 10.1007/s11011-023-01168-9 36809522
45 Jalili C. Roshankhah S. Jalali A. Salahshoor M.R. Hepatoprotective activity of royal jelly on mercuric chloride–induced damage model in rats Journal of Reports in Pharmaceutical Sciences 8 2 2019 181 187 10.4103/jrptps.JRPTPS_27_19
46 Pandeya P.R. Lamichhane R. Lee K.H. Kim S.G. Lee D.H. Lee H.K. Jung H.J. Bioassay-guided isolation of active anti-adipogenic compound from royal jelly and the study of possible mechanism BMC Compl. Alternative Med. 19 2019 1 14 10.1186/s12906-018-2423-2
47 Fallah M. Najafi F. Kavoosi G. Proximate analysis, nutritional quality and anti‐amylase activity of bee propolis, bee bread and royal jelly IJFST (Int. J. Food Sci. Technol.) 5 2022 2944 2953 10.1111/ijfs.15605
48 Lin Y. Zhang M. Lin T. Wang L. Wang G. Chen T. Su S. Royal jelly from different floral sources possesses distinct wound-healing mechanisms and ingredient profiles Food Funct. 12 23 2021 12059 12076 10.1039/D1FO00586C 34783324
49 Botezan S. Baci G.M. Bagameri L. Pașca C. Dezmirean D.S. Current status of the bioactive properties of royal jelly: a comprehensive review with a focus on its anticancer, anti-inflammatory and antioxidant effects Molecules 28 3 2023 1510 10.3390/molecules28031510 36771175
50 Yakoot M. Salem A. Helmy S. Effect of Memo®, a natural formula combination, on mini-mental state examination scores in patients with mild cognitive impairment Clin. Interv. Aging 8 2013 975 981 10.2147/CIA.S44777 23950642
51 Zhang M. Wang L.M. Chen Z.H. Zhao Z.P. Li Y.C. Deng Q. Huang Z.J. Zhang X. Li C. Zhou M.G. Multilevel logistic regression analysis on hypercholesterolemia related risk factors among adults in China Zhonghua Yufang Yixue Zazhi 52 2018 151 157 10.3760/cma.j.issn.0253-9624.2018.02.007 29429269
52 Inoue Y. Hara H. Mitsugi Y. Yamaguchi E. Kamiya T. Itoh A. Adachi T. 4-hydroperoxy-2-decenoic acid ethyl ester protects against 6-hydroxydopamine-induced cell death via activation of Nrf2-ARE and eIF2α-ATF4 pathways Neurochem. Int. 112 2018 288 296 10.1016/j.neuint.2017.08.011 28823537
53 Gil-Iturbe E. Solas M. Cuadrado-Tejedo M. García-Osta A. Escoté X. Ramírez M.J. Lostao M.P. GLUT12 expression in brain of mouse models of Alzheimer's disease Molecular Neurobiology57 2020 798 805 10.1007/s12035-019-01743-1
54 Smiljanic K. Todorovic S. Mladenovic Djordjevic A. Vanmierlo T. Lütjohann D. Ivkovic S. Kanazir S. Limited daily feeding and intermittent feeding have different effects on regional brain energy homeostasis during aging Biogerontology 19 2018 121 132 10.1007/s10522-018-9743-y 29340834
55 Yakoot M. Salem A. Omar A.M. Effectiveness ofaHerbal formula in women with menopausal syndrome Res. Complementary Med. 18 2011 264 268 10.1159/000333430
56 Pyrzanowska J. Wawer A. Joniec-Maciejak I. Piechal A. Blecharz-Klin K. Graikou K. Widy-Tyszkiewicz E. Long-term administration of Greek Royal Jelly decreases GABA concentration in the striatum and hypothalamus of naturally aged Wistar male rats Neurosci. Lett. 675 2018 17 22 10.1016/j.neulet.2018.03.034 29578001
57 Ji W.Z. Zhang C.P. Wei W.T. Hu F.L. The in vivo antiaging effect of enzymatic hydrolysate from royal jelly in d-galactose induced aging mouse J. Chin. Inst. Food Sci. Technol. 2016 18 25 10.16429/j.1009-7848.2016.01.003
58 Hattori N. Ohta S. Sakamoto T. Mishima S. Furukawa S. Royal jelly facilitates restoration of the cognitive ability in trimethyltin-intoxicated mice Evid. base Compl. Alternative Med. 2011 165968 10.1093/ecam/nep029
59 Halloran J. Hussong S.A. Burbank R. Podlutskaya N. Fischer K.E. Sloane L.B. Galvan V. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behaviourthroughout lifespan in mice Neuroscience 223 2012 102 113 10.1016/j.neuroscience.2012.06.054 22750207
60 Kirova A.M. Bays R.B. Lagalwar S. Working memory and executive function decline across normal aging, mild cognitive impairment, and Alzheimer's disease BioMed Res. Int. 2015 748212 10.1155/2015/748212
61 Guardia de Souza E Silva T. do Val de Paulo M.E.F. da Silva J.R.M. da Silva Alves A. Britto L.R.G. Xavier G.F. Lopes Sandoval M.R. Oral treatment with royal jelly improves memory and presents neuroprotective effects on icv-STZ rat model of sporadic Alzheimer's disease Heliyon 6 2 2020 e03281 10.1016/j.heliyon.2020.e03281
62 You M. Pan Y. Liu Y. Chen Y. Wu Y. Si J. 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. 10 2018 428 10.3389/fnagi.2018.00428 30687079
63 Minami A. Matsushita H. Ieno D. Matsuda Y. Horii Y. Ishii A. Suzuki T. Improvement of neurological disorders in postmenopausal model rats by administration of royal jelly Climacteric: The Journal of the International Menopause Society 19 6 2016 568 573 10.1080/13697137.2016.1238452 27736245
64 Pan Y. Xu J. Jin P. Yang Q. Zhu K. You M. Hu F. Royal jelly ameliorates behavioural deficits, cholinergic system deficiency, and autonomic nervous dysfunction in ovariectomized cholesterol-fed Rabbits Molecules 24 6 2019 1149 10.3390/molecules24061149 30909491
65 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. 155 1 2014 343 351 10.1016/j.jep.2014.05.032 24882731
66 Chen D. Liu F. Wan J.B. Lai C.Q. Shen L.R. Effect of major royal jelly proteins on spatial memory in aged rats: metabolomics analysis in urine J. Agric. Food Chem. 65 15 2017 3151 3159 10.1021/acs.jafc.7b00202 28362493
67 Kazemijaliseh H. Tehrani F.R. Behboudi-Gandevani S. Hosseinpanah F. Khalili D. Azizi F. The prevalence and causes of primary infertility in Iran: a population-based study Global J. Health Sci. 7 2015 226 232
68 Schuppe H.C. Pilatz A. Hossain H. Diemer T. Wagenlehner F. Weidner W. Urogenital infection as a risk factor for male infertility DeutschesArzteblatt International 114 2017 339 346
69 Jafari H. Latifnejad Roudsari R. Taghipour A. Khadem Ghaebi N. Ebrahim Zadeh S. Comparison of knowledge and attitude towards reproductive donation procedures between recipient and non-recipient infertile couples at Mashhad Infertility Center Journal of TorbatHeydariyeh University of Medical Sciences 3 2015 16 25 http://jms.thums.ac.ir/article-1-82-en.html
70 Agarwal A. Mulgund A. Hamada A. Chyatte M.R. A unique view on male infertility around the globe Reprod. Biol. Endocrinol. 13 2015 1 9 10.1186/s12958-015-0032-1 25567742
71 Lewis R. The Infertility Cure: the Ancient Chinese Wellness Program for Getting Pregnant and Having Healthybabies 2008 Hachette UK
72 Stangaciu S. Mărghitaş L.A. Dezmirean D. Bonta V. Mărgăoan R. Bobiş O. Quality parameters needed for bee products used in apitherapy Bulletin UASVM Animal Science and Biotechnologies 72 1 2015 67 71 10.15835/buasvmcn-asb:10561
73 Kodai T. Umebayashi K. Nakatani T. Ishiyama K. Noda N. Compositions of royal jelly II. Organic acid glycosides and sterols of the royal jelly of honeybees (Apis mellifera) Chem. Pharmaceut. Bull. 55 10 2007 1528 1531 10.1248/cpb.55.1528
74 Townsend G.F. Morgan J.F. Hazlett B. Activity of 10-hydroxydecenoic acid from royal jelly against experimental leukaemia and ascitic tumours Nature 183 1959 1270 1271 10.1038/1831270a0 13657083
75 Schmidt H.H. Stocker R. Vollbracht C. Paulsen G. Riley D. Daiber A. Cuadrado A. Antioxidants in translational medicine Antioxidants & RedoxSignalling 23 2015 1130 1143 10.1089/ars.2015.6393
76 Bălan A. Moga M.A. Dima L. Toma S. Neculau E.A. Anastasiu C.V. Royal jelly—a traditional and natural remedy for postmenopausal symptoms and aging-related pathologies Molecules 25 2020 3291 10.3390/molecules25143291 32698461
77 Salama S. Shou Q. Abd El-Wahed A.A. Elias N. Xiao J. Swillam A. Umair M. Guo Z. Daglia M. Wanget K. Royal jelly: beneficial properties and synergistic effects with chemotherapeutic drugs with particular emphasis in anticancer strategies Nutrients 14 2022 4166 10.3390/nu14194166 36235818
78 Fujiwara S. Imai J. Fujiwara M. Yaeshima T. Kawashima T. Kobayashi K. A potent antibacterial protein in royal jelly. Purification and determination of the primary structure of royalisin Peptides25 2004 919 928 10.1016/S0021-9258(19)38596-5
79 Fontana R. Mendes M.A. de Souza B.M. Konno K. César L.M. Malaspina O. Palma M.S. Jelleines: a family of antimicrobial peptides from the royal jelly of honeybees (Apis mellifera) Peptides 25 6 2004 919 928 10.1016/j.peptides.2004.03.016 15203237
80 Bílikova K. Huang S.C. Linb I.P. Simuth J. Peng C.C. Peptides structure and antimicrobial activity relationship of royalisin, an antimicrobial peptide from royal jelly of Apis mellifera Peptides 68 2015 190 196 10.1016/j.peptides.2015.03.001 25784287
81 Hasan A.A. Sahib S. Hillawi H. Khudhur H.R. Techniques M. Antimicrobial activity of royal jelly against E. Coli in comparison with three selective antibiotics Ann. Trop. Med. Publ. Health 23 2020 231 414 10.36295/ASRO.2020.231414
82 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. 22 3 2019 737 741 10.1016/j.aspen.2019.06.005
83 Hassan A.A. Essam Y. Nassrallah A. Cheng W. El-maksoud A.A.A. Royal jelly improves the physicochemical properties and biological activities of fermented milk with enhanced probiotic viability Lwt 155 2022 112912 10.1016/j.lwt.2021.112912
84 Khosla A. Gupta S.J. Jain A. Shetty D.C. Sharma N. Evaluation and comparison of the antimicrobial activity of royal jelly-A holistic healer against periodontopathic bacteria J. Indian Soc. Periodontol. 24 2020 221 226 32773971
85 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 Biosc. Biotech. Biochem. 68 1 2004 138 145 10.1271/bbb.68.138
86 Satomi K.M. Okamoto I. Ushio S. Iwaki K. Ikeda M. Kurimoto M. Identification of a collagen production-promoting factor from an extract of royal jelly and its possible mechanism Biosci., Biotechnol., Biochem. 68 4 2004 767 773 10.1271/bbb.68.767 15118301
87 Ananthakrishnan A.N. Xavier R.J. Gastrointestinal Diseases Hunter's Tropical Medicine and Emerging Infectious Diseases 2020 16 26
88 Sperber A.D. Bangdiwala S.I. Drossman D.A. Ghoshal U.C. Simren M. Tack J. Whitehead W.E. Dumitrascu D.L. Fang X. Fukudoetet al S. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome foundation global study Gastroenterology 160 2021 99 114 10.1053/j.gastro.2020.04.014 32294476
89 Rizzello F. Spisni E. Giovanardi E. Imbesi V. Salice M. Alvisi P. Valerii M.C. Gionchetti P. Implications of the WesternizedDiet in the onset and progression of IBD Nutrients 11 2019 1033 31072001
90 De Filippo C. Di Paola M. Ramazzotti M. Albanese D. Pieraccini G. Banci E. Miglietta F. Cavalieri D. Lionetti P. Diet,Environments, and gut microbiota. A preliminary investigation in children living in rural and urban Burkina Faso and Italy Frontiersin Microbiology 8 2017 1979 1983 10.3389/fmicb.2017.01979
91 Vona R. Pallotta L. Cappelletti M. Severi C. Matarrese P. The impact of oxidative stress in human pathology: focus on gastrointestinal disorders Antioxidants 10 2021 201 33573222
92 Mostafa R.E. El-Marasy S.A. Abdel Jaleel G.A. Bakeer R.M. Protective effect of royal jelly against diclofenac-InducedHepato-renal damage and gastrointestinal ulcerations in rats Heliyon 6 2020 e03330 10.1016/j.heliyon.2020.e03330
93 Li S. Tao L. Yu X. Zheng H. Wu J.H.F. Royal jelly proteins and their derived peptides: preparation, properties, and BiologicalActivities J. Agric. Food Chem. 69 2021 14415 14427 10.1021/acs.jafc.1c05942 34807598
94 Ahmad S. Campos M.G. Fratini F. Altaye S.Z. Li J. New insights into the biological and pharmaceutical properties of RoyalJelly Int. J. Mol. Sci. 2020 382
95 Oka H. Emori Y. Kobayashi N. Hayashi Y. Nomoto K. Suppression of allergic reactions by royal jelly in association with the restoration of macrophage function and the improvement of Th1/Th2 Cell responses Int. Immunopharm. 1 3 2001 521 532 10.1016/s1567-5769(00)00007-2
96 Guendouz M. Haddi A. Grar H. Kheroua O. Saidi D. Kaddouri H. Preventive effects of royal jelly against anaphylactic response in a murine model of cow's milk allergy Pharmaceut. Biol. 55 1 2017 2145 2152
97 Taniguchi Y. Kohno K. Inoue S.I. Koya-Miyata S. Okamoto I. Arai N. Kurimoto M. Oral administration of royal jelly inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice Int. Immunopharm. 3 9 2003 1313 1324 10.1016/s1567-5769(03)00132-2
98 Mannoor M.K. Shimabukuro I. Tsukamotoa M. Watanabe H. Yamaguchi K. Sato Y. Honeybee royal jelly inhibits autoimmunity in SLE-prone NZB x NZW F1 mice Lupus 18 1 2009 44 52 10.1177/0961203308094765 19074168
99 Zahran A.M. Elsayh K.I. Saad K. Eloseily E.M. Osman N.S. Alblihed M.A. Mahmoud M.H. Effects of royal jelly supplementation on regulatory T cells in children with SLE Food Nutr. Res. 60 1 2016 32963 10.3402/fnr.v60.32963
100 Erem C. Deger O. Ovali E. Barlak Y. The Effects of royal jelly on autoimmunity in Graves' Disease Endocrine 30 2 2006 175 183 10.1385/endo:30:2:175 17322576
101 Kai H. Motomura Y. Saito S. Hashimoto K. Tatefuji T. Takamune N. Misumi S. Royal jelly enhances antigen-specific mucosal IgA response Food Sci. Nutr. 1 3 2013 222 227 10.1002/fsn3.29 29387350
102 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. 16 2003 2029 2045 10.1016/s0024-3205(03)00562-9
103 Han B. Fang Y. Feng M. Lu X. Huo X. Meng L. Li J. In-depth phosphoproteomic analysis of royal jelly derived from western and eastern honeybee species J. Proteome Res. 13 12 2014 5928 5943 10.1021/pr500843j 25265229
104 Sugiyama T. Takahashi K. Kuzumaki A. Tokoro S. Neri P. Mori H. Inhibitory mechanism of 10-hydroxy-trans-2-decenoic acid (royal jelly acid) against lipopolysaccharide- and interferon-β-induced nitric oxide production Inflammation 36 2 2013 372 378 10.1007/s10753-012-9556-0 23079939
105 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. 29 3–4 2007 521 536 10.1080/08923970701690977 18075862
106 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. Immunopharm. 7 9 2007 1211 1220 10.1016/j.intimp.2007.05.005
107 Fan P. Han B. Hu H. Wei Q. Zhang X. Meng L. Li J. Proteome of thymus and spleen reveals that 10-hydroxydec-2-enoic acid could enhance immunity in mice Expert Opin. Ther. Targets 24 3 2020 267 279 10.1080/14728222.2020.1733529 32077781
108 Kamakura M. Maebuchi M. Ozasa S. Komori M. Ogawa T. Sakaki T. Moriyama T. Influence of royal jelly on mouse hepatic gene expression and safety assessment with a DNA microarray J. Nutr. Sci. Vitaminol. 51 3 2005 148 155 10.3177/jnsv.51.148 16161764
109 Kanbur M. Eraslan G. Beyaz L. Silici S. Liman B.C. Altinordulu S. Atasever A. The effects of royal jelly on liver damage induced by paracetamol in mice Exp. Toxicol. Pathol. 61 2 2009 123 132 10.1016/j.etp.2008.06.003 18693095
110 Çavuşoğlu K. Yapar K. Oruç E. Yalçın E. The protective effect of royal jelly on chronic lambda-cyhalothrin toxicity: serum biochemical parameters, lipid peroxidation, and genotoxic and histopathological alterations in Swiss albino mice J. Med. Food 10 2011 1229 1237 10.1089/jmf.2010.0219 21663479
111 Cemek M. Aymelek F. Büyükokurŏglu M.E. Karaca T. Büyükben A. Yilmaz F. Protective potential of royal jelly against carbon tetrachloride induced-toxicity and changes in the serum sialic acid levels Food Chem. Toxicol. 48 10 2010 2827 2832 10.1016/j.fct.2010.07.013 20637822
112 Ahmed W.M.S. Khalaf A.A. Moselhy W.A. Safwat G.M. Royal jelly attenuates azathioprine induced toxicity in rats Environ. Toxicol. Pharmacol. 1 2014 431 437 10.1016/j.etap.2013.12.010 24444696
113 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 Toxicon50 2 2007 256 269 10.1016/j.toxicon.2007.03.017
114 Karadeniz A. Simsek N. Karakus E. Yildirim S. Kara A. Can I. Turkeli M. Royal jelly modulates oxidative stress and apoptosis in liver and kidneys of rats treated with cisplatin Oxid. Med. Cell. Longev. 1 2011 981793 10.1155/2011/981793
115 Malekinejad H. Fani M. Shafiee-Roodbari S.K.H. Delkhosh-Kasmaie F. Rezaei-Golmisheh A. Crosstalk between E2f1 and c-Myc mediates hepato-protective effect of royal jelly on taxol-induced damages Hum. Exp. Toxicol. 36 6 2017 626 637 10.1177/0960327116660752 27496854
116 Almeer R.S. Alarifi S. Alkahtani S. Ibrahim S.R. Ali D. Moneim A. The potential hepatoprotective effect of royal jelly against cadmium chloride-induced hepatotoxicity in mice is mediated by suppression of oxidative stress and upregulation of Nrf2 expression Biomed. Pharmacother. 106 2018 1490 1498 10.1016/j.biopha.2018.07.089 30119224
117 Caixeta D.C. Teixeira R.R. Peixoto L.G. Machado H.L. Baptista N.B. de Souza A.V. Salmen Espindola F. Adaptogenic potential of royal jelly in liver of rats exposed to chronic stress PloS One13 1 2018 e0191889 10.1371/journal.pone.0191889
118 DeFronzo R.A. Ferrannini E. Groop L. Henry R.R. Herman W.H. Holst J.J. Weiss R. Type 2 diabetes mellitus Nat. Rev. Dis. Prim. 2015 15019 10.1038/nrdp.2015.19
119 Yoshida M. Hayashi K. Watadani R. Okano Y. Tanimura K. Kotoh J. Maeda A. Royal jelly improves hyperglycemia in obese/diabetic KK-Ay mice J. Vet. Med. Sci. 79 2 2017 299 307 10.1292/jvms.16-0458 27890887
120 Guven A. Yavuz O. Cam M. Ercan F. Bukan N. Comunoglu C. Gokce F. Effects of melatonin on streptozotocin-induced diabetic liver injury in rats Acta Histochem. 108 2 2006 85 93 10.1016/j.acthis.2006.03.005 16714049
121 Sivajothi V. Dey A. Jayakar B. Rajkapoor B. Antihyperglycemic property of Tragia cannabina in streptozotocin-induced diabetic rats J. Med. Food 10 2 2007 361 365 10.1089/jmf.2006.030 17651075
122 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 Chinese Journal of Integrated Medicine 20 5 2014 347 352 10.1007/s11655-014-1804-8
123 Woerle H.J. Neumann C. Zschau S. Tenner S. Irsigler A. Schirra J. Göke B. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes Importance of postprandial glycemia to achieve target HbA1c levels Diabetes Res. Clin. Pract. 77 2 2007 280 285 10.1016/j.diabres.2006.11.011 17240473
124 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 Journal (Yakhteh) 18 3 2016 362
125 Shidfar F. Jazayeri S. Mousavi S.N. Malek M. Hosseini A.F. Khoshpey B. Does supplementation with royal jelly improve oxidative stress and insulin resistance in type 2 diabetic patients? Iran. J. Public Health 44 6 2015 797 803 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524304/ 26258092
126 Petelin A. Kenig S. Kopiňc R. Dězelak M. Černelic Bizjak M. Jenko Praznikar Z. Effects of royal jelly administration on lipid profile, satiety, inflammation, and antioxidant capacity in asymptomatic overweight adults Evid. base Compl. Alternative Med. 2019 1 2019 4969720 10.1155/2019/4969720
127 Irandoost P. MesriAlamdari N. Saidpour A. Shidfar F. Roshanravan N. Asghari Jafarabadi M. Vafa M. The effects of royal jelly and tocotrienol-rich fraction on impaired glycemic control and inflammation through irisin in obese rats J. Food Biochem. 12 2020 e13493 10.1111/jfbc.13493
128 Yoneshiro T. Kaede R. Nagaya K. Aoyama J. Saito M. Okamatsu-Ogura Y. Terao A. Royal jelly ameliorates diet-induced obesity and glucose intolerance by promoting brown adipose tissue thermogenesis in mice Obes. Res. Clin. Pract. 12 2 2018 127 137 10.1016/j.orcp.2016.12.006 28089395
129 Watadani R. Kotoh J. Sasaki D. Someya A. Matsumoto K. Maeda A. 10- Hydroxy-2-decenoic acid, a natural product, improves hyperglycemia and insulin resistance in obese/diabetic KK-Ay mice, but does not prevent obesity J. Vet. Med. Sci. 79 9 2017 1596 1602 10.1292/jvms.17-0348 28740028
130 Bincoletto C. Eberlin S. Figueiredo C.A.V. Luengo M.B. Queiroz M.L.S. Effects produced by royal jelly on haematopoiesis: relation with host resistance against Ehrlich ascites tumour challenge Int. Immunopharm. 5 4 2005 679 688 10.1016/j.intimp.2004.11.015
131 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 Biosc. Biotech. Biochem. 71 1 2007 253 255 10.1271/bbb.60453
132 Filipic B. Potokar J. Effect of royal jelly (RJ) on human interferon-alpha (HuIFN-α) inhibition of human colon cancer cells (CaCo-2) proliferation in vitro Biomedicina Slovenica 20 2014 1 7
133 Zhang S. Shao Q. Geng H. Su S. The effect of royal jelly on the growth of breast cancer in mice Oncology Letters14 6 2017 7615 7621 10.3892/ol.2017.7078
134 Borawska M.H. Markiewicz-˙ Zukowska R. Naliwajko S.K. Moskwa J. Bartosiuk E. Socha K. Mariak Z. The interaction of bee products with temozolomide in human diffuse astrocytoma, glioblastoma multiforme and astroglia cell lines Nutr. Cancer 66 7 2014 1247 1256 10.1080/01635581.2014.951735 25256634
135 Salazar-Olivo L.A. Paz-Gonz′alez V. Screening of biological activities present in honeybee (Apis mellifera) royal jelly Toxicol. Vitro 5 2005 645 651 10.1016/j.tiv.2005.03.001
136 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. 38 3 2017 1833 1844 10.3892/or.2017.5851 28737831
137 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. 128 2019 782 795 10.1016/j.ijbiomac.2019.01.210 30711561
138 Kamiya T. Watanabe M. Hara H. Mitsugi Y. Yamaguchi E. Itoh A. Adachi T. Induction of human-lung-cancer-a549-cell apoptosis by 4-Hydroperoxy-2-decenoic acid ethyl ester through intracellular ROS accumulation and the induction of proapoptotic CHOP expression J. Agric. Food Chem. 66 41 2018 10741 10747 10.1021/acs.jafc.8b04424 30296076
139 Shirzad M. Yousofi M. Zamanzad B. Sedaghat A. Hosseini M. Shahinfard N. Shirzad H. Effects of royal jelly on sterile skin cut repair Journal of HerbMed Pharmacology 3 2 2014 97 100 https://herbmedpharmacol.com/Article/JHP_20150527163601
140 Çallı C. Tuğyan K. Öncel S. Pınar E. Demirtaşoğlu F. Tolon B. Yılmaz O. Kıray A. The effectiveness of royal jelly on tympanic membranes perforations (An Experimental Study) The Journal of Otolaryngology- Head & Neck Surgery37 2 2008 179 184 10.2310/7070.2008.0034
141 Temamoğulları F. Aral F. Demirkol R. Erkek farelerdearısütününuzun surely uygulanmasınınbazıspermatolojiközelliklerüzerineetkisi F.Ü. Sağ. Bil. Derg 20 5 2006 341 344
142 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 science and Technology Research10 4 2007 420 423 10.3136/fstr.10.420
143 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. 22 3 2014 241 248 10.4995/wrs.2014.1677
144 Ibrahim A. Eldaim M.A.A. Abdel-Daim M.M. Nephroprotective effect of bee honey and royal jelly against subchronic cisplatin toxicity in rats Cytotechnology 68 4 2016 1039 1048 25720368
145 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 Journal18 3 2016 362 370 10.22074/cellj.2016.4564
146 Çavusoglu 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 6 2009 1286 1292 10.1089/jmf.2008.0203 20041783
147 Al-Eisa R.A. Al-Nahari H.A. The attenuating effect of royal jelly on hormonal parameters in aluminum chloride (AlCl3) intoxicated rats Int. J. Pharmaceut. Res. Allied Sci. 6 2 2017 70 85
148 Hassan A.A. Effect of royal jelly on sexual efficiency in adult male rats Iraqi J. Vet. Sci. 23 2009 155 160 https://www.cabidigitallibrary.org/doi/pdf/10.5555/20103085498
149 Sosa-Pérez G. Pérez-Ruiz E. Pérez-Hernández P. Cortez-Romero C. Gallegos-Sánchez J. Intravenous administration of royal jelly in ovarian activity and ovulatory rate of Pelibuey sheep Agroproductividad10 2 2017 42 46 http://www.colpos.mx/wb_pdf/Agroproductividad/2017/AGROPRODUCTIVIDAD_II-2017.pdf
150 Babaei S. Rahimi S. Torshizi M.A.K. Tahmasebi G. Miran S.N.K. Effects of propolis, royal jelly, honey and bee pollen on growth performance and immune system of Japanese quails Vet. Res. Forum 7 1 2016 13 20 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867032/ 27226882
151 Seven I. Şimşek U.G. Gökçe Z. Seven P.T. Arslan A. Yilmaz O. The effects of royal jelly on performance and fatty acid profiles of different tissues in quail (Coturnix coturnix japonica) reared under high stocking density Turk. J. Vet. Anim. Sci. 38 3 2014 271 277 10.3906/vet-1303-62
152 Premratanachai P. Chanchao C. Review of the anticancer activities of bee products Asian Pac. J. Trop. Biomed. 4 5 2014 337 344 25182716
153 Günaldi O. Güçlü G. Postalci L. Eseoğlu M. Yilmaz I. Ofluoğlu E. Erdoğan S. Can royal jelly prevent epidural fibrosis development after laminectomy? An experimental study J. Neurol. Sci. 31 2 2014 257 265 2014
154 Yanagita M. Kojima Y. Mori K. Yamada S. Murakami S. Osteoinductive and anti-inflammatory effect of royal jelly on periodontal ligament cells Biomed. Res. 32 4 2011 285 291 10.2220/biomedres.32.285 21878736
155 Kafadar I.H. Güney A. Türk C.Y. Öner M. Silici S. Royal jelly and bee pollen decrease bone loss due to osteoporosis in an oophorectomized rat model Eklem Hastalik Cerrahisi 23 2 2012 100 105 https://pubmed.ncbi.nlm.nih.gov/22765489/ 22765489
156 Kwon H.O. Lee M. Cho Y.H. Jun W. Lee J. Royal jelly supplementation ameliorated immune impairment via inhibition of oxidative stress in low micronutrient-induced immunodeficient mice J. Food Nutr. Res. 5 2 2017 74 79 10.12691/JFNR-5-2-1
157 Zhang S. Shao Q. Shen Z. Su S. Immunomodulatory response of 4T1 murine breast cancer model to camellia royal jelly Biomed. Res. 28 3 2017 1223 1230
158 Shirzad M. Kordyazdi R. Shahinfard N. Nikokar M. Does Royal jelly affect tumor cells Journal of HerbMed Pharmacology 2 2 2013 45 48
159 Kamakura M. Mitani N. Fukuda T. Fukushima M. Antifatigue effect of fresh royal jelly in mice J. Nutr. Sci. Vitaminol. 47 6 2001 394 401 10.3177/jnsv.47.394 11922114
160 Taherianfard M. Ahmadi Jokani S. Khaksar Z. Royal jelly can modulate behavioural and histo-morphometrical disorders caused by Parkinson's disease in rats Physiology and Pharmacology 21 2 2017 120 128 http://ppj.phypha.ir/article-1-1242-en.html
161 Karaca T. Bayıroğlu F. Yoruk M. Kaya M.S. Uslu S. Comba B. Mis L. Effect of royal jelly on experimental colitis induced by acetic acid and alteration of mast cell distribution in the colon of rats Eur. J. Histochem. 54 4 2010 193 196
162 Cihan Y.B. Deniz K. The effects of royal jelly against radiation-induced acute oral mucositis International Journal of Hematology and Oncology 27 1 2014 36 44 10.4999/uhod.11059
163 Teixeira R.R. De Souza A.V. Peixoto L.G. Machado H.L. Caixeta D.C. Vilela D.D. Espindola F.S. Royal jelly decreases corticosterone levels and improves the brain antioxidant system in restraint and cold stressed rats Neurosci. Lett. 655 2017 179 185 10.1016/j.neulet.2017.07.010 28709905
164 Salimi S. Naghavi N.S. Karbasizadeh V. Propolis, royal jelly and pollen from beehive have antibacterial effect on aquatic pathogenic bacterial isolates International Journal of Molecular and Clinical Microbiology 1 2013 218 224
165 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 14 9 2011 899 906 10.1089/jmf.2010.1363 21812645
166 Pavel C.I. Mărghitaş L.A. Bobiş O. Dezmirean D.S. Şapcaliu A. Radoi I. Mădaş M.N. Biological activities of royal jelly-review Scientific Papers Animal Science and Biotechnologies 44 2 2011 108 118 https://spasb.ro/index.php/public_html/article/view/1878/1790
167 Ramadan M.F. Al-Ghamdi A. Bioactive compounds and health-promoting properties of royal jelly: a review J. Funct.Foods 4 2012 39 52 10.1016/j.jff.2011.12.007
168 Yang X. Li J. Wang R. Antibacterial mechanism of 10-HDA against Bacillus subtilis Advances in Applied Biotechnology 332 2015 317 324 10.1007/978-3-662-45657-6_34
169 Siavash M. Shokri S. Haghighi S. Shahtalebi M.A. Farajzadehgan Z. The efficacy of topical royal jelly on healing of diabetic foot ulcers: a double-blind placebo-controlled clinical trial Int. Wound J. 12 2015 137 142 10.1111/iwj.12063 23566071
170 Ahmadnia H. Sharifi N. Alizadeh S. Roohani Z. Kamalati A. Marjan S.S. Wonderful effects of royal jelly on treatment of male-factor related infertility Austin J. Reproductive Med. Infertil. 2 6 2015 1031 https://austinpublishinggroup.com/reproductive-medicine/fulltext/ajrm-v2-id1031.php
171 Meng G. Wang H. Pei Y. Li Y. Wu H. Song Y. Wang J. Effects of protease-treated royal jelly on muscle strength in elderly nursing home residents: a randomized, double-blind, placebo-controlled, dose-response study Sci. Rep. 7 1 2017 11416 10.1038/s41598-017-11415-6
172 Susilowati H. Murakami K. Yumoto H. Amoh T. Hirao K. Miyake Y. Royal jelly inhibits Pseudomonas aeruginosa adherence and reduces excessive inflammatory responses in human epithelial cells BioMed Res. Int. 2017 3191752 10.1155/2017/3191752
173 Dinkov D. Stratev D. Balkanska R. Sergelidis D. Anti-bacterial activity of royal jelly and rape honey against methicillin-resistant staphylococcusaureus strains Journal of Food and Health Science 2 2 2016 67 73 10.3153/JFHS16007
174 Imada T. Nakamura S. Kitamura N. Shibuya I. Tsubota K. Oral administration of royal jelly restores tear secretion capacity in rat blink-suppressed dry eye model by modulating lacrimal gland function PLoS One 9 9 2014 e106338 10.1371/journal.pone.0106338
175 Inoue S. Kawashima M. Hisamura R. Imada T. Izuta Y. Nakamura S. Tsubota K. Clinical evaluation of a royal jelly supplementation for the restoration of dry eye: a prospective randomized double-blind placebo-controlled study and an experimental mouse model PLoS One 12 1 2017 e0169069 10.1371/journal.pone.0169069
176 Yüksel S. Akyol S. The consumption of propolis and royal jelly in preventing upper respiratory tract infections and as dietary supplementation in children Journal of Intercultural Ethnopharmacology 5 3 2016 308 311 27366357
177 Chiu H.F. Chen B.K. Lu Y.Y. Han Y.C. Shen Y.C. Venkatakrishnan K. Wang C.K. Hypocholesterolemic efficacy of royal jelly in healthy mild hypercholesterolemic adults Pharmaceut. Biol. 55 1 2017 497 502 10.1080/13880209.2016.1253110
178 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. 53 4 2007 345 348 10.3177/jnsv.53.345 17934240
179 Münstedt K. Bargello M. Hauenschild A. Royal jelly reduces the serum glucose levels in healthy subjects J. Med. Food 12 5 2009 1170 1172 10.1089/jmf.2008.0289 19857086
180 Meto A. Meto A. Pastes based on royal jelly, an alternative for the minimally invasive treatment of pulpitis (histopathological experimental data) AJBS 2017 1 7
181 Dhanesuan N. Srisuparbh D. Tiranathanagul S. Rungsiyanant S. The in vitro effect of royal jelly Apis mellifera on proliferation of human gingival periodontal ligament fibroblasts and human bone cells Thai Pharm Health Sci 6 3 2011 182 187
182 Li C. Mannoor M.K. Toma N. Taniguchi T. Inafuku M. Yamaguchi K.K. Watanabe H. The efficacy of Royal Jelly in the restoration of alcoholic liver injury in mouse model Biomed. Res. 22 1 2011 1 8
183 Cho Y. Kim J. Shin J. Bae M. Shin M.K. Dietary royal jelly improves epidermal hydration with increased levels of ceramides in the epidermis of mid-aged healthy human subjects J. Dermatol. Sci. 84 1 2016 e35 10.1016/j.jdermsci.2016.08.115
184 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. 16 7 2011 904 909 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263103/ 22279458
185 Aslan Z. Aksoy L. Anti-inflammatory effects of royal jelly on ethylene glycol induced renal inflammation in rats Int. Braz J. Urol. 41 5 2015 1008 1013 10.1590/s1677-5538.ibju.2014.0470 26689528
186 Joksimovič A. Stanković D. Joksimović I. Molnar S. Joksimović S. Royal jelly as a supplement for young football players Sport Sci. 2 1 2009 62 67
187 Arzi A. Houshmand G. Goudarzi M. Khadem Haghighian H. Rashidi Nooshabadi M.R. Comparison of the analgesic effects of royal jelly with morphine and aspirin in rats using the formalin Journal of Babol University of Medical Sciences 17 2 2015 50 56 http://jbums.org/article-1-5285-en.html
188 Sugiyama T. Takahashi K. Mori H. Royal jelly acid, 10-hydroxy-trans-2-decenoic acid, as a modulator of the innate immune responses, endocrine, metabolic & immune disorders-drug targets (formerly current drug targets-immune Endocrine & Metabolic Disorders) 12 4 2012 368 376 10.2174/187153012803832530
189 Stratev D. Vashin I. Balkanska R. Dinkov D. Antibacterial activity of Royal jelly and rape honey against Aeromonas hydrophila (ATCC 7965) Journal of Food and Health Science 1 2 2015 67 74 10.3153/JFHS15006
190 Morita H. Ikeda T. Kajita K. Fujioka K. Mori I. Okada H. Ishizuka T. Effect of royal jelly ingestion for six months on healthy volunteers Nutr. J. 11 1 2012 77 http://www.nutritionj.com/content/11/1/77 22995464
191 Mahmoud K. Anas T. The role of honey with royal jelly in protecting the graafian follicles from the toxicity of the Adriamycin Drug Int. J. Pharm. Pharmaceut. Sci. 7 4 2015 376 385 https://journals.innovareacademics.in/index.php/ijpps/article/view/4364
192 Lambrinoudaki I. Augoulea A. Rizos D. Politi M. Tsoltos N. Moros M. Panoulis K. Greek-origin royal jelly improves the lipid profile of postmenopausal women Gynecol. Endocrinol. 32 10 2016 835 839 10.1080/09513590.2016.1188281 27227757
193 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. 10 5 2016 QC01
194 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 Compl. Ther. Med. 22 4 2014 601 606 10.1016/j.ctim.2014.05.004
195 Abdelhafiz A.T. Abdelmonaem J. Abdlerahman M. Omar M. Aly D. FV44 Egyptian bee honey and royal jelly as prophylaxis against premature tearing of the fetal membranes: an in vitro testing model (Note) Zeitschrift fur Wundheilung 16 2011 91
196 Bogdanov S. Royal jelly, bee brood: composition, health, medicine: a review Bee Product Science 2015 35
197 Khoshpey B. Djazayeri S. Amiri F. Malek M. Hosseini A.F. Hosseini 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 40 4 2016 324 328 10.1016/j.jcjd.2016.01.003 27026221
198 Mobasseri M. Ghiyasvand S. Ostadrahimi A. Ghojazadeh M. Noshad H. Pourmoradian S. Effect of fresh royal jelly ingestion on glycemic response in patients with type 2 diabetes Iran. Red Crescent Med. J. 17 9 2015 e20074 5
199 a Pourmoradian S. Mahdavi R. Mobasseri M. Faramarzi E. Mobasseri M. Effects of royal jelly supplementation on body weight and dietary intake in type 2 diabetic females Health Promot. Perspect. 2 2 2012 231 235 24688939
b Mofid B. Rezaeizadeh H. Termos A. Rakhsha A. Mafi A.R. Taheripanah T. Kashi A.S.Y. Effect of processed honey and royal jelly on cancer-related fatigue: a double-blind randomized clinical trial Electron. Physician 8 6 2016 2475 27504161
200 Erdem O. Güngörmüş Z. The effect of royal jelly on oral mucositis in patients undergoing radiotherapy and chemotherapy Holist. Nurs. Pract. 2014 242 246 10.1097/hnp.0000000000000033 24919094
201 a 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. 41 1 2016 52 57 10.4103/0971-6203.177281 27051171
b Osama H. Abdullah A. Gamal B. Emad D. Sayed D. Hussein E E. Bahaa T. Effect of honey and royal jelly against cisplatin-induced nephrotoxicity in patients with cancer J. Am. Coll. Nutr. 2017 1 5 10.1080/07315724.2017.1292157
202 Bărnutiu L.I. Mărghitaş L.A. Dezmirean D. Bobiş O. Bonta V. Pavel C. Preliminary study on chemical composition of fresh royal jelly from transylvania Bulletin UASVM Animal Science and Biotechnologies 69 2012 1 2 10.15835/buasvmcn-asb:69:1-2:8385
203 Magdalena M. Effect of royal jelly on breast infant with distrophy and maldevelopment ApimondiaInternational Beekeeping Congress in Bukarest, Romania 2010 583 585
204 Strant M. Grosu R. Apitherapy in daily practice The Apiquality&Apimedica International Symposium 2016 22 25
205 M. Strant, A. Varadi, Royal Jelly, Studies, Clinical Cases, Api-Therapy Symposium and Workshop, Cluj-Napoca, Romania(2016) 18-19 February.
206 Strant M.M. Yücel B. Topal E. Puscasu A.M. Margaoan R. Varadi A. Use of Royal Jelly as Functional Food on Human and Animal Health Hayvansal Üretim 60 2 2019 131 144 Personal experience and practices for royal jelly, Cluj Napoca
207 Strant M. A treasure in apiterapy ‘’Royal jelly’’- myths and realities. II Marmaris Apitherapy and Apicultural Products Symposium 2017 41 42
208 Tatsuhiko T. Naoko K. Yuko H. Application of the material of honeybee origin. Application of the consmetic material of the honeybee origin (Japanese) Frag J. 30 2011 17 24
209 Calzavara‐Pinton P. Zane C. Facchinetti E. Capezzera R. Pedretti A. Topical Boswellic acids for treatment of photoaged skin Dermatol. Ther. 23 1 2010 10.1111/j.1529-8019.2009.01284.x
210 Hamidpour R. Hamidpour S. Hamidpour M. Shahları M. Frankincense (RǔXiāng; Boswellia Species): from the selection of traditional applications to the novel phytotherapy for the prevention and treatment of serious diseases Journal of Traditional and Complementary Medicine 3 4 2013 221 226 10.4103/2225-4110.119723 24716181
211 Desoto M.C. Hitlan R.T. Synthetic folic acid supplementation during pregnancy may increase the risk of developing autism J. Pediatr. Biochem. 2 4 2012 251 261 10.3233/JPB-120066
212 Sarıtaş N. Yıldız K. Büyükipekci S. Coşkun B. Effect of different levels of royal jelly on biochemical parameters of swimmers Afr. J. Biotechnol. 10 52 2011 10718 10723 10.5897/AJB11.1862
213 Min J. Lee Y. Han S.M. Choi Y. Dietary effect of royal jelly supplementation on epidermal levels of hydration, filaggrins, free amino acids and the related enzyme expression in UV irradiated hairless mice Korean J. Nutr. 46 2 2013 109 118 10.4163/kjn.2013.46.2.109
214 Menkovska M. The newest experience with effervescent tablets containing royal jelly as functional food on packing, dosage and synergistic action in prevention, prophylaxis and healing J. Food Process. Technol. 4 10 2013 1 8 10.4172/2157-7110.1000272
215 Raja R.R. Nutraceuticals and cosmeceuticals for human beings–an overview American Journal of Food Science and Health 2 2 2016 7 17 http://www.aiscience.org/journal/ajfsh
