Uploaded by User14157

ANA ARI

advertisement
Journal of Functional Foods 94 (2022) 105143
Contents lists available at ScienceDirect
Journal of Functional Foods
journal homepage: www.elsevier.com/locate/jff
In vitro and in vivo models to study the biological and pharmacological
properties of queen bee acid (QBA, 10-hydroxy-2-decenoic acid): A
systematic review
Marta Paredes-Barquero a, c, *, Mireia Niso-Santano a, b, c, José M. Fuentes a, b, c,
Guadalupe Martínez-Chacón a, b, c, *
a
Departamento de. Bioquímica y Biología Molecular y Genética, Facultad de Enfermería y Terapia Ocupacional, Universidad de Extremadura Avda de la Universidad s/
n, 10003 Cáceres Spain
b
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) Madrid, Spain
c
Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Cáceres Spain
A R T I C L E I N F O
A B S T R A C T
Keywords:
10-Hydroxy-2-Decenoic Acid
QBA
In vivo model
In vitro model
PRISMA
Systematic review
Royal jelly (RJ) is one of the most valued natural products and is considered beneficial to human health, mainly
due to its many biological and pharmacological properties. 10-Hydroxy-2-decenoic acid (10H2DA), also known
as queen bee acid (QBA), is exclusive to RJ and represents the main lipid component of this food. Most in vitro
studies using QBA have reported its beneficial health properties but only a few in vivo studies have focused on
these benefits. Therefore, the focus of the present systematic review (SR) according to the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was to analyze the properties of QBA in
different diseases such as cardiovascular, age-related or neurodegenerative diseases and cancer, employing in
vivo and in vitro models and summarize the beneficial and protective effect of QBA that were observed in most of
the studies.
1. Introduction
Natural bee products, including honey, propolis and royal jelly (RJ),
have been considered beneficial due to their many biological and
pharmacological properties that improve human health and enhance
longevity in different cell types and tissues from animal models (NisoSantano, M., González-Polo, R. A., Paredes-Barquero, M., Fuentes, J. M.,
& Aschner, M., 2019).
In recent years, there has been special interest in studying how diet
influences the development of certain disorders. RJ is one of the most
widely used health-promoting foods. RJ is a bee product that is a source
of nutrition for queen honey bees and is used in medical products, health
foods and cosmetics.
RJ exhibits a variety of biological and pharmacological activities,
such as antitumor (Bincoletto, C., Eberlin, S., Figueiredo, C. A. V,
Luengo, M. B., & Queiroz, M. L. S., 2005), antimicrobial (Brudzynski &
Abbreviations: 10-HAD, 10-hydroxydecanoic acid; 10-H2DA, 10-Hydroxy-2-Decenoic Acid; ACC, acetyl-CoA carboxylase; AMP, adenine monophosphate; ATP,
adenosine triphosphate; AMPK, AMP-activated protein kinase; Ang II, Angiotensin II; ATG, autophagy-related; CR, Caloric restriction; CRM, CR mimetics; DC,
dendritic cell; DMSO, dimethyl sulfoxide; EB, Evan’s blue; EGCG, epigallocatechin-3-gallate; ELISA, enzyme-linked immunosorbent; ERK, Extracellular signal
regulated Kinase; FLG, filaggrin; FoxO1a, Forkhead box O1; FoxO3a, Forkhead box O3; JNK, c-Jun N-terminal kinase; LKB1, Sirtuin-1 deacetylates liver kinase B1;
LTA, lipoteichoic acid; MITF, Melanocyte Inducing Transcription Factor; MoDCs, monocyte-derived dendritic cells; mTOR, mammalian target of rapamycin; NF-κB,
Nuclear factor kappa B; Nrf2, Nuclear factor-erythroid 2 related factor 2; PI3K, phosphatidylinositol 3-kinase; pRJ, protease-treated royal jelly; PRISMA, Preferred
Reporting Items for Systematic Reviews and Meta-Analyses; PROSPERO, International Prospective Register of Systematic Reviews; QBA, queen bee acid; RAS, reninangiotensin system, RJ, Royal Jelly; ROS, reactive oxygen species; SC, stratum corneum; SIRT1, silent mating type information regulation two homolog one; SR,
systematic review; SYRCLE, Systematic Review Centre for Laboratory Animal Experimentation; TA, tibial anterior; TEWL, transepidermal water loss; TGF-β1,
transforming growth factor-β1; TLR, Tolerogenic Receptors; TNF-α, Tumor necrosis factor; TolDC, tolerogenic DCs; ULK1, UNC-51-like kinase; VSMC, rat vascular
smooth muscle cells.
* Corresponding authors at: Universidad de Extremadura, Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Enfermería y Terapia
Ocupacional, Cáceres, Spain.
E-mail addresses: martapb@unex.es (M. Paredes-Barquero), jfuentes@unex.es (J.M. Fuentes), guadalupemc@unex.es (G. Martínez-Chacón).
https://doi.org/10.1016/j.jff.2022.105143
Received 15 March 2022; Received in revised form 30 May 2022; Accepted 31 May 2022
Available online 7 June 2022
1756-4646/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Sjaarda, 2015), hypotensive (Matsui et al., 2002), anti­
hypercholesterolemic (Vittek, 1995), anti-inflammatory (Kohno et al.,
2004; Yang et al., 2010), antioxidant (Casamenti et al., 2015), antiaging
(Ahmad, S., Campos, M. G., Fratini, F., Altaye, S. Z., & Li, J., 2020), and
immunomodulatory (Kohno et al., 2004; Okamoto et al., 2003) activ­
ities, and promotes cell proliferation (Kamakura, M., Suenobu, N., &
Fukushima, M. 2001; Kawano et al., 2019; Lin et al., 2019).
RJ is naturally rich in fatty acids. It has been reported that the lipid
fraction of RJ, including 10-hydroxy-2-decenoic acid (10-H2DA, namely,
queen bee acid (QBA)), is the main fatty acid in RJ, representing
approximately 40% of the total fatty acids present in RJ, and is exclusive
to this food (Takikawa et al., 2013). This makes QBA the major indicator
of Royal Jelly quality (Sabatini, 2009). In addition to the lipid fraction,
RJ is composed of a complex of proteins that represents 9 to 18% of its
content (of which 90% are proteins called mayor royal jelly proteins,
whose main functions are antibacterial and immunomodulatory). The
water content of RJ is 60–70%, the carbohydrate content is 7–18%, and
the lipid content is 3–8% (10-H2DA is the only fatty acid present
exclusively in RJ, and 10-hydroxydecanoic acid (10-HDA) is the second
major fatty acid), and the rest includes amino acids and traces of mineral
salts and vitamins: this food constitutes the main food of queen bees
(Chamova, 2020; Sugiyama, T., Takahashi, K., & Mori, H., 2012).
Most studies have reported beneficial effects of 10-H2DA in vitro,
although a clear mechanism of action has not yet been elucidated.
Several studies have reported that QBA also exhibits physiological and
pharmacological properties, such as antitumor (Townsend, G. F., Mor­
gan, J. F., & Hazlett, B., 1959, 1960, Townsend, G. F., Brown, W. H.,
Felauer, E. E., & Hazlett, B., 1961) and anti-inflammatory activity;
antibiotic (Blum, M. S., Novak, A. F., & Taber, S., 1959) and anti­
hypercholesterolemic (Xu, D., Mei, X., & Xu, S., 2002) functions; inhi­
bition of angiogenesis (antiangiogenic activities) (Izuta, H., Chikaraishi,
Y., Shimazawa, M., Mishima, S., & Hara, H., 2009), facilitation of
collagen production (Koya-Miyata et al., 2004); and immunomodulatory
activities, since it inhibits the innate immune response and modulates
the adaptive immune response (Gasic et al., 2007; Vucevic et al., 2007).
However, a few studies exploring 10-H2DA in vivo have focused on its
benefits. In vivo studies reduced anxiety-like behavior; promoted neu­
rogenesis and neuronal health; facilitated the generation of all cell types
in the brain, including neurons, astrocytes and oligodendrocytes;
increased neuronal production, but not glial production (Hattori, N.,
Nomoto, H., Fukumitsu, H., Mishima, S., & Furukawa, S., 2007);
improved body composition (Weiser, M. J., Grimshaw, V., Wynalda, K.
M., Mohajeri, M. H., & Butt, C. M., 2018); and extended lifespan via
dietary restriction and mammalian target of rapamycin (mTOR)
signaling (Honda et al., 2015).
QBA could activate autophagy, as occurs with other fatty acids, both
in vivo and in vitro (Niso-Santano et al., 2015). This autophagy modu­
lation could contribute to processes such as lipid metabolism, lip­
otoxicity, life extension, and antitumor activity (O’Rourke, E. J.,
Kuballa, P., Xavier, R., & Ruvkun, G., 2013; Singh et al., 2009; Yao et al.,
2014). To summarize this evidence with precision and certainty (Lib­
erati et al., 2009), we conducted an SR following the guidelines of the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA). The main objective of this review was to collect informa­
tion from in vivo and in vitro studies in which QBA was investigated at
baseline or against stress, with respect to administration, doses and
routes, and in terms of relationships with beneficial effects.
International Prospective Register of Systematic Reviews (PROSPERO),
and a registration number is not necessary.
2.2. Eligibility criteria
The population, intervention, comparator, outcome and study design
(PICOS) model was implemented in this systematic review (SR) as rec­
ommended by the PRISMA guidelines (Liberati et al., 2009).
(1) Population: in vivo and in vitro models for different diseases were
included; (2) Interventions: several studies using diverse treatments to
induce stress in order to subsequently evaluate the beneficial effect of
QBA were compared; (3) Comparator: we incorporated studies with a
non-treated group use as a control; (4) Outcome: studies with measur­
able conclusions using different techniques were accepted and (5) Study
design: we included in vivo and in vitro studies evaluating QBA and its
beneficial effect in certain pharmacologically-induced diseases.
Book chapters, meeting abstracts, editorials or reviews were not
included. Studies that used bacteria or yeast as a model or those whose
main topic was the production or mode of obtaining QBA were excluded.
2.3. Information source and search
The studies were extracted from the following three electronic da­
tabases: Web of Science, Scopus, and PubMed. The search criteria
included English language and original articles that were identified
using this structured search strategy (TS = 10-hydroxy-2-decenoic acid)
originating from 2017 to March 2021.
2.4. Study selection
Titles and abstracts were evaluated for inclusion (English language,
original articles, date of publication (from 2017 to March 2021), use of
QBA, animal or cell models, etc.) or exclusion (reviews, production or
method of obtaining QBA, studies published before 2017). Those eligible
for inclusion and full-text articles were read for evaluation. Fig. 1 pre­
sents a flow diagram describing the inclusion/exclusion process fol­
lowed by reasoning.
2.5. Data collection process
The following data were extracted from the articles: first author, year
of publication, title, journal, animal model (number and species) and
cell culture (type) used, concentration, route of administration, solvent,
mode of acquisition and treatment period of QBA, in vitro or in vivo
model, form of analysis to estimate the beneficial effect of QBA (RNA
and protein levels, histology, immunohistochemistry, immunofluores­
cence, colorimetric test, biochemical parameters, liquid chromatogra­
phy–mass spectrometry (LC-MS/MS), cytokine analysis, mitochondrial
membrane potential analysis, Reactive oxygen species (ROS) generation
analysis, enzyme-linked immunosorbent (ELISA) assay, activity of en­
zymes, concentration of metabolites, antimicrobial assay, cell viability,
proliferation, migration and apoptosis, chromatin immunoprecipitation,
assessment of Evan’s blue (EB) dye, amount of amino acids, glucose
tolerance, cadmium tolerance, body composition or behavioral testing
and a concise conclusion. This information was evaluated, classified,
and categorized to elucidate the beneficial effect of QBA with respect to
different diseases (data not shown).
2. Materials and methods
2.6. Risk of bias in individual studies
2.1. Protocol and registration
The risk of bias tool created by the Systematic Review Centre for
Laboratory Animal Experimentation (SYRCLE) was used to determine
six types of potential biases: selection, performance, detection, attrition,
reporting and other biases. Three possible judgments are available for
each domain: low risk, high risk or unclear (Table 3).
The creation of this review was established following the PRISMA
statement (Liberati et al., 2009). Approval from an ethics committee was
not needed. There were no direct human health correlations; therefore,
the results acquired in this review do not need to be included in the
2
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Fig. 1. Flow diagram of study selection.
2.7. Statistical analysis
and 2021 (1) (Eslami-kaliji, F., Sarafbidabad, M., Kiani-Esfahani, A.,
Mirahmadi-Zare, S. Z., & Dormiani, K., 2021).
No statistical analysis were performed.
3.2.2. In vivo and in vitro models
The number of studies that used in vivo models, 63.63% (14/22)
(Almeer et al., 2018; Chen et al., 2018; Fan et al., 2020; Hong, S. H.,
Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020; Legaki, N., Narita,
Y., Hattori, N., Hirata, Y., & Ichihara, K., 2020; Peng, C. C., Sun, H. T.,
Lin, I. P., Kuo, P. C., & Li, J. C., 2017; Shirakawa, T., Miyawaki, A., &
Matsubara, T., 2020; Takahashi et al., 2018; Tsuchiya et al., 2020;
Watadani et al., 2017; Weiser, M. J., Grimshaw, V., Wynalda, K. M.,
Mohajeri, M. H., & Butt, C. M., 2018; You, M., Miao, Z., Pan, Y., & Hu, F.,
2019, You, M., Miao, Z., Tian, J., & Hu, F., 2020; Zhang et al., 2017), was
very similar compared to the number that used in vitro models, 72.72%
(16/22) (Cai et al., 2018; Chen et al., 2018; Eslami-kaliji, F., Sar­
afbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare, S. Z., & Dormiani,
K., 2021; Gu, L., Zeng, H., & Maeda, K., 2017; Hong, S. H., Hwang, S. W.,
Son, Y. K., Lee, N. Y., & Kim, O., 2020; Kawahata et al., 2018; Lin et al.,
2020; Pandeya et al., 2019; Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., &
Li, J. C., 2017; Shirakawa, T., Miyawaki, A., & Matsubara, T., 2020;
Tsuchiya et al., 2020; Usui et al., 2019; Weiser, M. J., Grimshaw, V.,
Wynalda, K. M., Mohajeri, M. H., & Butt, C. M., 2018; Yang, Y. C., Chou,
W. M., Widowati, D. A., Lin, I. P., & Peng, C. C., 2018; You, M., Miao, Z.,
Pan, Y., & Hu, F., 2019, You, M., Miao, Z., Tian, J., & Hu, F., 2020). Most
of the in vivo studies used a murine model, representing 85.71% (12/14)
(Almeer et al., 2018; Chen et al., 2018; Fan et al., 2020; Legaki, N.,
Narita, Y., Hattori, N., Hirata, Y., & Ichihara, K., 2020; Peng, C. C., Sun,
H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017; Shirakawa, T., Miyawaki, A.,
& Matsubara, T., 2020; Takahashi et al., 2018; Tsuchiya et al., 2020;
Watadani et al., 2017; You, M., Miao, Z., Pan, Y., & Hu, F., 2019, You,
M., Miao, Z., Tian, J., & Hu, F., 2020; (Zhang et al., 2017); 7.14% were
carried out in rats (1/14) (Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N.
3. Results
3.1. Study selection
The final number of relevant original articles identified was 163 from
the Web of Science (73), PubMed (41), and Scopus (49) (databases
mentioned in Fig. 1). Duplicate articles (74) were removed. Of the
remaining 89 studies, 61 were excluded based on title and abstract
eligibility criteria. From the final 28 full-text articles selected, 6 more
were excluded after further assessment of eligibility, resulting in a total
of 22 articles.
3.2. Study characteristics
3.2.1. Number of studies
Twenty-two original articles were selected in this review. The
selected articles represent the years 2017 to 2021: 2017 (4) (Gu, L.,
Zeng, H., & Maeda, K., 2017; Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C.,
& Li, J. C., 2017; Watadani et al., 2017; Zhang et al., 2017), 2018 (7)
(Almeer et al., 2018; Cai et al., 2018; Chen et al., 2018; Kawahata et al.,
2018; Takahashi et al., 2018; Weiser, M. J., Grimshaw, V., Wynalda, K.
M., Mohajeri, M. H., & Butt, C. M., 2018; Yang, Y. C., Chou, W. M.,
Widowati, D. A., Lin, I. P., & Peng, C. C., 2018), 2019 (3) (Pandeya et al.,
2019; Usui et al., 2019; You, M., Miao, Z., Pan, Y., & Hu, F., 2019), 2020
(7) (Fan et al., 2020; Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., &
Kim, O., 2020; Legaki, N., Narita, Y., Hattori, N., Hirata, Y., & Ichihara,
K., 2020; Lin et al., 2020; Shirakawa, T., Miyawaki, A., & Matsubara, T.,
2020; Tsuchiya et al., 2020; You, M., Miao, Z., Tian, J., & Hu, F., 2020)
3
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Y., & Kim, O., 2020), while the remaining 7.14% (1/14) (Weiser, M. J.,
Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C. M., 2018)
used both models. Among the cell lines used in vitro, their origin was
human in 37.5% (6/16) of the studies (Eslami-kaliji, F., Sarafbidabad,
M., Kiani-Esfahani, A., Mirahmadi-Zare, S. Z., & Dormiani, K., 2021; Gu,
L., Zeng, H., & Maeda, K. 2017; X. M. Lin et al., 2020; Usui et al., 2019;
Yang, Y. C., Chou, W. M., Widowati, D. A., Lin, I. P., & Peng, C. C., 2018;
You, M., Miao, Z., Pan, Y., & Hu, F., 2019) rat in 12.5% (2/16)
(Kawahata et al., 2018; Weiser, M. J., Grimshaw, V., Wynalda, K. M.,
Mohajeri, M. H., & Butt, C. M., 2018), and mouse in 37.5% (6/16) (Chen
et al., 2018; Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O.,
2020; Pandeya et al., 2019; Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., &
Li, J. C., 2017; Shirakawa, T., Miyawaki, A., & Matsubara, T., 2020;
Tsuchiya et al., 2020); 12.5% (2/16) of the studies (Cai et al., 2018; You,
M., Miao, Z., Tian, J., & Hu, F., 2020) used a combination of different
cell lines.
The different animal and cell models used are described in Table 1
and Table 2.
S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020; You, M., Miao, Z., Tian, J.,
& Hu, F., 2020).
Most of the articles used QBA (Cai et al., 2018; Chen et al., 2018;
Eslami-kaliji, F., Sarafbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare,
S. Z., & Dormiani, K., 2021; Fan et al., 2020; Gu, L., Zeng, H., & Maeda,
K., 2017; Lin et al., 2020; Pandeya et al., 2019; Peng, C. C., Sun, H. T.,
Lin, I. P., Kuo, P. C., & Li, J. C., 2017; Tsuchiya et al., 2020; Usui et al.,
2019; Watadani et al., 2017; Weiser, M. J., Grimshaw, V., Wynalda, K.
M., Mohajeri, M. H., & Butt, C. M., 2018; Yang, Y. C., Chou, W. M.,
Widowati, D. A., Lin, I. P., & Peng, C. C., 2018; You, M., Miao, Z., Pan, Y.,
& Hu, F., 2019, You, M., Miao, Z., Tian, J., & Hu, F., 2020) as the main
treatment, but there were a few that used RJ itself (Almeer et al., 2018;
Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020; Legaki,
N., Narita, Y., Hattori, N., Hirata, Y., & Ichihara, K., 2020; Pandeya et al.,
2019; Shirakawa, T., Miyawaki, A., & Matsubara, T., 2020; Takahashi
et al., 2018; Tsuchiya et al., 2020; Usui et al., 2019; Zhang et al., 2017)
or different fractions/extracts derived from the RJ (Kawahata et al.,
2018; Legaki, N., Narita, Y., Hattori, N., Hirata, Y., & Ichihara, K., 2020;
Pandeya et al., 2019).
The method of administration was mostly oral, mixed with food or
water or introduced by oral gavage (Almeer et al., 2018; Chen et al.,
2018; Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020;
Legaki, N., Narita, Y., Hattori, N., Hirata, Y., & Ichihara, K., 2020;
Shirakawa, T., Miyawaki, A., & Matsubara, T., 2020; Takahashi et al.,
2018; Tsuchiya et al., 2020; Watadani et al., 2017; Weiser, M. J.,
Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C. M., 2018;
You, M., Miao, Z., Pan, Y., & Hu, F., 2019, You, M., Miao, Z., Tian, J., &
Hu, F., 2020). Only two studies used an intragastric method (Fan et al.,
2020; Zhang et al., 2017), and the application in another study was by
smear (Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017).
The solvents used to dissolve QBA or RJ in the animal experiments
were diverse, from distilled or purified water (Hong, S. H., Hwang, S. W.,
Son, Y. K., Lee, N. Y., & Kim, O., 2020; Takahashi et al., 2018; S. Zhang
et al., 2017) to physiological saline (Almeer et al., 2018; Tsuchiya et al.,
2020; You, M., Miao, Z., Pan, Y., & Hu, F., 2019), ethanol (Watadani
et al., 2017), food (Legaki, N., Narita, Y., Hattori, N., Hirata, Y., &
Ichihara, K., 2020; Shirakawa, T., Miyawaki, A., & Matsubara, T., 2020;
Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C.
M., 2018), dimethyl sulfoxide (DMSO) (Chen et al., 2018) or even
vaseline (Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017). In
the case of cell experiments, the majority of the studies dissolved QBA in
DMSO (Cai et al., 2018; Chen et al., 2018; Eslami-kaliji, F., Sar­
afbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare, S. Z., & Dormiani,
K., 2021; Gu, L., Zeng, H., & Maeda, K., 2017; X. M. Lin et al., 2020;
Pandeya et al., 2019; Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J.
C., 2017; Tsuchiya et al., 2020; Weiser, M. J., Grimshaw, V., Wynalda, K.
M., Mohajeri, M. H., & Butt, C. M., 2018; You, M., Miao, Z., Pan, Y., &
Hu, F., 2019), two in different types of alcohols (Gu, L., Zeng, H., &
Maeda, K., 2017; Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri,
M. H., & Butt, C. M., 2018), one in purified water (Hong, S. H., Hwang, S.
W., Son, Y. K., Lee, N. Y., & Kim, O., 2020), one in PBS (Kawahata et al.,
2018) and one in NaOH (Usui et al., 2019).
Procedure times varied greatly between animal and cell experiments.
The first category ranged from 1 to 4 weeks (Almeer et al., 2018; Chen
et al., 2018; Fan et al., 2020; Hong, S. H., Hwang, S. W., Son, Y. K., Lee,
N. Y., & Kim, O., 2020; Legaki, N., Narita, Y., Hattori, N., Hirata, Y., &
Ichihara, K., 2020; Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C.,
2017; Shirakawa, T., Miyawaki, A., & Matsubara, T., 2020; Takahashi
et al., 2018; Tsuchiya et al., 2020; Watadani et al., 2017; You, M., Miao,
Z., Pan, Y., & Hu, F., 2019, 2020; Zhang et al., 2017) or even months
(Weiser, M.J., Grimshaw, V., Wynalda, K.M., Mohajeri, M.H., & Butt, C.
M., 2018). The latter category contained experiments with a duration as
short as minutes (Usui et al., 2019) or up to hours (Cai et al., 2018; Chen
et al., 2018; Eslami-kaliji, F., Sarafbidabad, M., Kiani-Esfahani, A.,
Mirahmadi-Zare, S. Z., & Dormiani, K., 2021; Hong, S. H., Hwang, S. W.,
Son, Y. K., Lee, N. Y., & Kim, O., 2020; Kawahata et al., 2018; Lin et al.,
3.2.3. Interventions
In the 22 articles selected for this review, animal or cell models that
presented different diseases naturally or pharmacologically were used.
As a result, we divided the reviewed studies into the following 2 groups:
A total of 63.63% of the studies (14/22) employed in vivo models,
and experimental induction was used to create animal models of disease:
neuroinflammation (You, M., Miao, Z., Pan, Y., & Hu, F., 2019, You, M.,
Miao, Z., Tian, J., & Hu, F., 2020), immunosuppression (Fan et al.,
2020), lung injury (Chen et al., 2018), cancer (Peng, C. C., Sun, H. T.,
Lin, I. P., Kuo, P. C., & Li, J. C., 2017; Zhang et al., 2017), osteoarthritis
(Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020),
osteoporosis (Tsuchiya et al., 2020), hepatotoxicity (Almeer et al.,
2018), chronic mild stress (Legaki, N., Narita, Y., Hattori, N., Hirata, Y.,
& Ichihara, K., 2020), sarcopenia (Shirakawa, T., Miyawaki, A., &
Matsubara, T., 2020; Takahashi et al., 2018), metabolic disorder
(Watadani et al., 2017) and impaired brain health and body composition
(Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt,
C. M., 2018).
A total of 72.72% of the studies (16/22) employed in vitro models.
These cellular models of different diseases were classified into three
groups according to cell origin:
Human: Human brain microvascular endothelial cells (HBMECs)
(neuroinflammation) (You, M., Miao, Z., Pan, Y., & Hu, F., 2019), WiDR
human adenocarcinoma cells (colon cancer) (Yang, Y. C., Chou, W. M.,
Widowati, D. A., Lin, I. P., & Peng, C. C., 2018), human lung cancer cell
lines (A549, NCI-H460, and NCI-H23), human normal lung fibroblasts
(IMR90), normal liver cells (L-02) and normal gastric cells (GES-1) (lung
cancer) (Lin et al., 2020), human epidermis model (epidermis) (Gu, L.,
Zeng, H., & Maeda, K. 2017), HEK-293 (cardiovascular disease) (Cai
et al., 2018), dendritic cells (DCs) and HEK-TLR4 (immunomodulation)
(Eslami-kaliji, F., Sarafbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare,
S. Z., & Dormiani, K., 2021), HepG2 (metabolic disorder) (Usui et al.,
2019) and SH-SY5Y (neuroinflammation) (You, M., Miao, Z., Tian, J., &
Hu, F., 2020).
Rat: Primary rat hippocampal cells (brain health and body compo­
sition and Alzheimer’s disease) (Kawahata et al., 2018; Weiser, M. J.,
Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C. M., 2018) and
rat vascular smooth muscle cells (VSMCs) (cardiovascular disease) (Cai
et al., 2018).
Mouse: Mouse embryonic fibroblasts, adipose-like cell line (3 T3-L1)
(metabolic disorder) (Pandeya et al., 2019), B16F10 melanoma cells
(cancer) (Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017),
primary bone marrow cells (osteoporosis) (Tsuchiya et al., 2020), C2C12
and C3H10T1/2 cells (sarcopenia) (Shirakawa, T., Miyawaki, A., &
Matsubara, T., 2020), BV-2 cells (neuroinflammation) (You, M., Miao,
Z., Tian, J., & Hu, F., 2020) and RAW 264.7 cells (lung injury, neuro­
inflammation and osteoarthritis) (Chen et al., 2018; Hong, S. H., Hwang,
4
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Table 1
Results of animal models included in this SR. In this table, we describe the different diseases analyzed, the type of animal model, whether the treatment used was with
QBA or its derivative, solvent use and the method of acquisition, the type of administration (topical, intragastric, and oral), QBA concentration, follow-up period/end
time point of the experiment and the main conclusion of each study.
Disease
In vivo
model
What has
been used?
Solvent
Mode of
acquisition
Concentration/
dose
Administration
Time of
procedure
Main conclusion
Study ID
Neuroinflammation
C57BL6/
J mice
QBA
–
Purchase
100 mg/kg/d
Oral gavage
4 weeks
QBA exerts antineuroinflammatory
effects through
autophagy and
regulating
mitochondrial
function
QBA improve
immunity in the
thymus and spleen
and has a potential
role in the therapy
for hypoimmunity
QBA delays
inflammatory
process and alleviate
inflammation
reaction
RJ improves stressinduced depression
like behavior
(You, M.,
Miao, Z.,
Tian, J., &
Hu, F.,
2020)
(You, M.,
Miao, Z.,
Pan, Y., &
Hu, F.,
2019)
(Fan et al.,
2020)
Physiological
saline
Oral
Immunosuppression
BALB/c
mice
QBA
–
Purchase
100 mg/kg/d
Intragastric
1 week
Lung injury
C57BL/6
mice
QBA
DMSO
Purchase
100 mg/kg/d
Oral
1 week
Chronic mild stress
BALB/c
mice
Lyophilized
royal jelly
(RJ)
Ethanolic
extract of RJ
(EERJ)
RJ
Food
Purchase
4.5 g/kg/
d (RJ)
Oral
3 weeks
2.4 g/kg/
d (EEJR)
Hepatotoxicity
Swiss
mice
Physiological
saline
Purchase
85 mg/kg/d
Oral gavage
1 week
Brain health and
body composition
SpragueDawley
rats
BALB/c
mice
QBA
Food
Purchase
12 or 24 mg/
kg/d
Oral
3.5–6
months
Tumor
BALB/c
mice
RJ
Distilled
water
Purchase
1.5 g/kg/d
Intragastric
6 weeks
Osteoarthritis
SpragueDawley
Rats
Enzymatic
RJ
Purified
water
Purchase
50, 100 or 200
mg/kg/d
Oral
3 weeks
Osteoporosis
C57BL6/
J mice
RJ
Physiological
saline
5% ethanol in
corn oil
Gift
1 g/kg/d
Oral gavage
4 weeks
Purchase
40 mg/kg/d
Melanoma
C57BL/6
J
QBA
Vaseline
Natural
obtaining of
RJ and
further
purification
of QBA
0.5%, 1% or
2%
Smear
3 weeks
Sarcopenia
C57BL/
6J mice
Lyophilized
proteasetreated RJ
(pRJ)
Food
Purchase
1%
Oral
4 weeks
30 or 60 mg/
kg/d
QBA
4 months
RJ improves
hepatotoxicity
induced by CdCl2
exposure
QBA improves
neuron growth,
protects neuron from
damage and
decreases anxietylike behavior
RJ can influence
tumor growth and
QBA may slow
breast cancer
development
ERJ improves
osteoarthritis
inhibiting articular
cartilage
degeneration
QBA suppresses
osteoclastogenesis
by inhibiting NF-κB
signaling through its
receptor
QBA could be a
melanogenesis
inhibitor by
downregulating of
MITF protein,
tyrosinase and
melanin production
pRJ and QBA
stimulate both
proliferation and
differentiation of
skeletal muscles
fibers
(Chen et al.,
2018)
(Legaki, N.,
Narita, Y.,
Hattori, N.,
Hirata, Y., &
Ichihara, K.,
2020)
(Almeer
et al., 2018)
(Weiser, M.
J.,
Grimshaw,
V.,
Wynalda, K.
M.,
Mohajeri,
M. H., &
Butt, C. M.,
2018)
(Zhang
et al., 2017)
(Hong, S.
H., Hwang,
S. W., Son,
Y. K., Lee,
N. Y., &
Kim, O.,
2020)
(Tsuchiya
et al., 2020)
(Peng, C. C.,
Sun, H. T.,
Lin, I. P.,
Kuo, P. C., &
Li, J. C.,
2017)
(Shirakawa,
T.,
Miyawaki,
A., &
Matsubara,
T., 2020)
(continued on next page)
5
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Table 1 (continued )
Disease
Metabolic disorders
In vivo
model
What has
been used?
Solvent
Mode of
acquisition
Concentration/
dose
Administration
Time of
procedure
Main conclusion
Study ID
ICR mice
RJ
Distilled
water
Purchase
1 mg/kg/d
Oral
3 weeks
(Takahashi
et al., 2018)
KK-Ay
mice
QBA
Ethanol
Purchase
3 mg/kg/d
Oral
4 weeks
RJ increases the
phosphorylation of
AMPK and acetylCoA carboxylase
(ACC) in the soleus
muscle
QBA improves
hyperglycemia and
insulin resistance
2020; Pandeya et al., 2019; Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., &
Li, J. C., 2017; Shirakawa, T., Miyawaki, A., & Matsubara, T., 2020;
Yang, Y. C., Chou, W. M., Widowati, D. A., Lin, I. P., & Peng, C. C., 2018;
You, M., Miao, Z., Pan, Y., & Hu, F., 2019, You, M., Miao, Z., Tian, J., &
Hu, F., 2020) or days (Gu, L., Zeng, H., & Maeda, K., 2017; Tsuchiya
et al., 2020; Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M.
H., & Butt, C. M., 2018).
The ranges of doses used in the animal experiments varied from 1 to
200 mg/kg/day (Almeer et al., 2018; Chen et al., 2018; Fan et al., 2020;
Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020;
Takahashi et al., 2018; Tsuchiya et al., 2020; Watadani et al., 2017;
Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C.
M., 2018; You, M., Miao, Z., Pan, Y., & Hu, F., 2019, You, M., Miao, Z.,
Tian, J., & Hu, F., 2020), with 100 mg/kg/day being the most commonly
used dose (Chen et al., 2018; Fan et al., 2020; You, M., Miao, Z., Pan, Y.,
& Hu, F., 2019, You, M., Miao, Z., Tian, J., & Hu, F., 2020). The highest
doses used are between 1 and 4.5 g/kg/day (Legaki, N., Narita, Y.,
Hattori, N., Hirata, Y., & Ichihara, K., 2020; Tsuchiya et al., 2020; Zhang
et al., 2017). Two studies used QBA/RJ between 0.5 and 2% (Peng, C. C.,
Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017; Shirakawa, T., Miya­
waki, A., & Matsubara, T., 2020).
The concentrations of QBA used in cell experiments ranged from 1 to
100 µM (Gu, L., Zeng, H., & Maeda, K., 2017; Lin et al., 2020; Weiser, M.
J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C. M., 2018;
You, M., Miao, Z., Tian, J., & Hu, F., 2020) and 1–6 mM (Cai et al., 2018;
Chen et al., 2018; Eslami-kaliji F., Sarafbidabad M., Kiani-Esfahani A.,
Mirahmadi-Zare S.Z., Dormiani K., 2021; Pandeya et al., 2019; Peng, C.
C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017; Shirakawa, T.,
Miyawaki, A., & Matsubara, T., 2020; Tsuchiya et al., 2020; Usui et al.,
2019; Yang, Y. C., Chou, W. M., Widowati, D. A., Lin, I. P., & Peng, C. C.,
2018; You, M., Miao, Z., Pan, Y., & Hu, F., 2019). Some of the studies
used ranges of 50–300 µg/mL (Hong, S. H., Hwang, S. W., Son, Y. K., Lee,
N. Y., & Kim, O., 2020; Kawahata et al., 2018; Pandeya et al., 2019) or
ranges of 0.25–10 mg/mL (Pandeya et al., 2019; Shirakawa, T., Miya­
waki, A., & Matsubara, T., 2020; Usui et al., 2019). Broadly speaking,
none of the studies used a single concentration of QBA/RJ: this is the
reason why we cannot discuss the most commonly used concentration.
The administration routes, doses and concentrations used, times of
procedures and other information about QBA are summarized in Ta­
bles 1 and 2.
(Watadani
et al., 2017)
different proteins (Cai et al., 2018; Chen et al., 2018; Fan et al., 2020;
Kawahata et al., 2018; Lin et al., 2020; Pandeya et al., 2019; Peng, C. C.,
Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017; Shirakawa, T., Miya­
waki, A., & Matsubara, T., 2020; Takahashi et al., 2018; Usui et al.,
2019; Watadani et al., 2017; Yang, Y. C., Chou, W. M., Widowati, D. A.,
Lin, I. P., & Peng, C. C., 2018; You, M., Miao, Z., Pan, Y., & Hu, F., 2019,
You, M., Miao, Z., Tian, J., & Hu, F., 2020), fluorescence detection (12)
(immunofluorescence, histopathology, immunocytochemistry, EB and
ORO staining) (Almeer et al., 2018; Cai et al., 2018; Chen et al., 2018;
Gu, L., Zeng, H., & Maeda, K., 2017; Hong, S. H., Hwang, S. W., Son, Y.
K., Lee, N. Y., & Kim, O., 2020; Kawahata et al., 2018; Lin et al., 2020;
Pandeya et al., 2019; Shirakawa, T., Miyawaki, A., & Matsubara, T.,
2020; Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., &
Butt, C. M., 2018; You, M., Miao, Z., Pan, Y., & Hu, F., 2019, You, M.,
Miao, Z., Tian, J., & Hu, F., 2020), ELISA (7) (assays for enzyme activity,
concentrations of metabolites, cytokines analysis, antimicrobial assay,
tolerance test and enzyme immunoassay (EIA)) (Almeer et al., 2018;
Chen et al., 2018; Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., &
Kim, O., 2020; Legaki, N., Narita, Y., Hattori, N., Hirata, Y., & Ichihara,
K., 2020; Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017;
Yang, Y. C., Chou, W. M., Widowati, D. A., Lin, I. P., & Peng, C. C., 2018;
You, M., Miao, Z., Tian, J., & Hu, F., 2020), flow cytometry (4) (to
evaluate apoptosis, cell cycle, ROS generation, mitochondrial mem­
brane potential and inflammatory cytokines) (Chen et al., 2018; Lin
et al., 2020; You, M., Miao, Z., Pan, Y., & Hu, F., 2019, You, M., Miao, Z.,
Tian, J., & Hu, F., 2020), cell viability (6) (Eslami-kaliji, F., Sar­
afbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare, S. Z., & Dormiani,
K., 2021; Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O.,
2020; Shirakawa, T., Miyawaki, A., & Matsubara, T., 2020; Yang, Y. C.,
Chou, W. M., Widowati, D. A., Lin, I. P., & Peng, C. C., 2018; You, M.,
Miao, Z., Pan, Y., & Hu, F., 2019, You, M., Miao, Z., Tian, J., & Hu, F.,
2020), body composition (6) (weight, muscle, tomography and histo­
morphometric analysis) (Almeer et al., 2018; Fan et al., 2020; Hong, S.
H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020; Takahashi
et al., 2018; Tsuchiya et al., 2020; Weiser, M. J., Grimshaw, V., Wynalda,
K. M., Mohajeri, M. H., & Butt, C. M., 2018), animal behavioral testing
(2) (Legaki, N., Narita, Y., Hattori, N., Hirata, Y., & Ichihara, K., 2020;
Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C.
M., 2018), proteome (1) [48], RNA-Seq (2) (You, M., Miao, Z., Tian, J.,
& Hu, F., 2020; Zhang et al., 2017), Chip-qPCR (2) (Kawahata et al.,
2018; Makino et al., 2016), LC-MS/MS (2) (Hong, S. H., Hwang, S. W.,
Son, Y. K., Lee, N. Y., & Kim, O., 2020; You, M., Miao, Z., Pan, Y., & Hu,
F., 2019), Ultra High Performance Liquid Chromatography (UPLC) (1)
(Pandeya et al., 2019), absorbance (2) (Hong, S. H., Hwang, S. W., Son,
Y. K., Lee, N. Y., & Kim, O., 2020; Takahashi et al., 2018), luminometry
(1) (Cai et al., 2018), microarrays (1) (Legaki, N., Narita, Y., Hattori, N.,
Hirata, Y., & Ichihara, K., 2020) and biochemical parameters (2)
(Almeer et al., 2018; Takahashi et al., 2018).
3.2.4. Outcomes
Follow-up evaluations for each study were classified according to the
type of examination, including quantitative polymerase chain reaction
(qPCR) (14) to evaluate gene expression (Almeer et al., 2018; Cai et al.,
2018; Chen et al., 2018; Eslami-kaliji, F., Sarafbidabad, M., KianiEsfahani, A., Mirahmadi-Zare, S. Z., & Dormiani, K., 2021; Gu, L.,
Zeng, H., & Maeda, K., 2017; Kawahata et al., 2018; Legaki, N., Narita,
Y., Hattori, N., Hirata, Y., & Ichihara, K., 2020; Pandeya et al., 2019;
Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017; Shirakawa,
T., Miyawaki, A., & Matsubara, T., 2020; Usui et al., 2019; Watadani
et al., 2017; You, M., Miao, Z., Pan, Y., & Hu, F., 2019, You, M., Miao, Z.,
Tian, J., & Hu, F., 2020), Western blotting (14) to evaluate expression of
4. Discussion
The aim of this SR was to highlight the beneficial effects related to RJ
and, more specifically, QBA, both in vitro and in vivo to alleviate or
6
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Table 2
Results of in vitro models included in this SR. In this table, we described the different diseases analyzed, cell models used, whether the treatment used was with QBA or
its derivative, the solvent and the method of acquisition, QBA concentration, follow-up period/end time point of experiment and the main conclusion of each study.
Disease
In vitro model
What has
been used?
Solvent
Mode of
obtaining
Concentration/
dose
Time of
procedure
Main conclusion
Study ID
Lung injury
RAW 264.7 cells
QBA
DMSO
Purchase
1, 2′ 5 y 5 mM
1h
(Chen et al.,
2018)
Neuroinflammation
Human brain
microvessel
endothelial cells
(HBMECs)
BV-2 cells
RAW 264.7 cells
SH-SY5Y cells
Primary rat
hippocampal
neurons
QBA
DMSO
Purchase
1, 2, 4 and 6 mM
or 1 M
1h
QBA
–
Purchase
1, 2, 4 or 6 µM
24 h
QBA delays
inflammatory process
and alleviate
inflammation reaction
QBA exerts antineuroinflammatory
effects through
autophagy and
regulating
mitochondrial function
QBA
Methanol
Purchase
0–30 µM
48 h-7
days
QBA improves neuron
growth, protects neuron
from damage and
decreases anxiety-like
behavior
Osteoarthritis
RAW 264.7 cells
Enzymatic
Royal Jelly
Purified
water
Purchase
50, 100, 200 μg/
mL
24 h
ERJ improves
osteoarthritis inhibiting
articular cartilage
degeneration
Osteoporosis
Primary bone
marrow cells
QBA
DMSO
Purchase
0′ 5 mM
3 days
Alzheimer disease
Primary rat
hippocampal
neurons
PBS
(-)-soluble
fractions of
RJ
DMSOsoluble
fractions of
RJ
QBA
PBS(-)
Purchase of RJ
and subsequent
fractionation
100 μg/mL
18 or 48 h
QBA suppresses
osteoclastogenesis by
inhibiting NF-κB
signaling through its
receptor
QBA improves growth,
reduces mortality and
enhances mitochondrial
health
0′ 1, 0′ 5, 1 mM
24 h
Lyophilized
proteasetreated RJ
(pRJ) and
QBA
QBA
–
Natural
obtaining of RJ
and further
purification of
QBA
Purchase
0′ 25, 0′ 5, or 1
mg/mL (pRJ) or
0′ 5 mM (QBA)
0–72 h
DMSO
Purchase
0′ 25, 0′ 5 and 1
mM
1h
Brain health and
body composition
DMSO
Melanoma
B16F10 melanoma
cells
Sarcopenia
C2C12 cells
C3H10T1/2 cells
Cardiovascular
disease
Rat vascular
smooth muscle
cells (VSMCs)
HEK 293 cells
Immunomodulation
Dendritic cells
(DCs)
HEK-TLR4 cells
QBA
DMSO
Purchase
0′ 1, 0′ 3, 0′ 5,
0′ 7, 0′ 9 y 1′ 1
mM
24 h
Lung Cancer
Human lung
cancer cell lines
(A549, NCI-H460,
and NCI-H23)
IMR90 human
normal lung
fibroblasts
L-02 normal liver
cells
GES-1 normal
gastric cells
Human threedimensional
epidermis model
QBA
DMSO
Purchase
1, 3, 10, 30 or
100 µM
3, 6, 12, 24
or 36 h
QBA
Ethanol
Purchase
10, 20, and 40
µM
24 h or 5
days
Epidermis
DMSO
(You, M., Miao,
Z., Pan, Y., & Hu,
F., 2019)
(You, M., Miao,
Z., Tian, J., & Hu,
F., 2020)
(Weiser, M. J.,
Grimshaw, V.,
Wynalda, K. M.,
Mohajeri, M. H.,
& Butt, C. M.,
2018)
(Hong, S. H.,
Hwang, S. W.,
Son, Y. K., Lee, N.
Y., & Kim, O.,
2020)
(Tsuchiya et al.,
2020)
(Kawahata et al.,
2018)
QBA could be a
melanogenesis inhibitor
by downregulating of
MITF protein, tyrosinase
and melanin production
pRJ and QBA stimulate
both proliferation and
differentiation of
skeletal muscles fibers
(Peng, C. C., Sun,
H. T., Lin, I. P.,
Kuo, P. C., & Li, J.
C., 2017)
QBA is effective against
vascular inflammation
attenuating Ang IIinduced inflammatory
responses
QBA can be use in
immunotherapies in
autoimmune diseases
and prevent the
rejection in
transplantation and
biomaterials
implantation
QBA induces ROSmediated apoptosis and
cell cycle arrest
(Cai et al., 2018)
QBA improves the
moisturizing function of
the stratum corneum
(Gu, L., Zeng, H.,
& Maeda, K.,
2017)
(Shirakawa, T.,
Miyawaki, A., &
Matsubara, T.,
2020)
(Eslami-kaliji, F.,
Sarafbidabad, M.,
Kiani-Esfahani,
A., MirahmadiZare, S. Z., &
Dormiani, K.,
2021)
(Lin et al., 2020)
(continued on next page)
7
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Table 2 (continued )
Disease
In vitro model
What has
been used?
Solvent
Mode of
obtaining
Concentration/
dose
Time of
procedure
Main conclusion
Study ID
Colon Cancer
WiDR human
adenocarcinoma
cell
QBA
–
Royal Jelly was
purchase and
QBA purified
0′ 1-5 mM
24 h
QBA is a potential antiinflammatory agent and
bactericide
Metabolic disorders
HepG2 cells
QBA
NaOH
0′ 1 M
Purchased
0′ 5, 1, 2 and 4
mM
0,10, 30,
60, 120
and 240
min
0, 4, 8, 12,
24, 36 and
48 h
48 h
QBA plays a role in
energy metabolism with
a similar effect of insulin
(Yang, Y. C.,
Chou, W. M.,
Widowati, D. A.,
Lin, I. P., & Peng,
C. C., 2018)
(Usui et al., 2019)
Royal Jelly
Mouse embryonic
fibroblasts,
adipose like cell
line (3 T3-L1)
Royal Jelly
1′ 25, 2′ 5, 5 and
10 mg/mL
DMSO
Royal Jelly and
QBA were
purchase and
the Ethyl
acetate was
isolated from
RJ
reduce the effects of various diseases as important as metabolic disor­
ders, cancer, neurodegenerative diseases or age-related diseases, among
others.
RJ is increasingly used as a dietary supplement for its healthpromoting effects; therefore, the number of published studies
analyzing whether the beneficial effects are promoted by QBA, its main
fatty acid, has increased in 2021. QBA, like other unsaturated fatty acids,
is not only an essential nutrient but also exerts beneficial effects in the
context of obesity, metabolic syndrome, atherosclerosis and neuro­
degeneration. The same occurs with other natural substances, such as
anacardic acid, curcumin, resveratrol, spermidine and epigallocatechin3-gallate (EGCG) (Mariño, G., Pietrocola, F., Madeo, F., & Kroemer, G.,
2014).
RJ itself may produce allergic reactions due to its protein content.
Protease treatment can reduce RJ-associated allergenicity, resulting in
protease-treated royal jelly (pRJ). This proteolysis process had no effect
on the QBA content of RJ (Moriyama et al., 2013).
Characterization of the molecular mechanisms by which this healthy
food exerts its beneficial effects is needed. This would help us to study
the possible pathways and their ability to reduce aging and agingassociated pathologies, such as neurodegeneration or neuro­
inflammation, some metabolic disorders or cancer.
Some of the studies selected in this SR used different cell types, but
most of the studies were performed in murine models. The main benefit
of using rodents is their accessibility for genetic manipulations and their
ease of handling and treatments that require less volume and doses.
Furthermore, the beneficial effects can be measured in an accessible way
and in an objective fashion (Lee & Longo, 2011; Mariño, G., Pietrocola,
F., Madeo, F., & Kroemer, G., 2014). In this sense, the identification of
animal models that mimic the different human pathologies is essential to
determine the evolution of certain diseases, to identify new therapies
and to study the limitations and benefits of these drugs (Colle, D., Farina,
M., Ceccatelli, S., & Raciti, M., 2018, 2020; Cristóvão et al., 2020).
1 mg/mL
(Pandeya et al.,
2019)
maximal activity of mitochondrial enzymes by endurance training in the
soleus muscle, even though no significant effect of RJ treatment on
mitochondrial adaptation was observed in the plantaris or tibial anterior
(TA) muscles. Acute RJ treatment and endurance exercise additively
increased the phosphorylation of AMPK and acetyl-CoA carboxylase
(ACC) in the soleus muscle, while no effect was noted in the plantaris or
TA muscles. Neither endurance training nor RJ treatment had a signif­
icant effect on final body weight at the end of the experiment (Takahashi
et al., 2018). Daily oral administration of pRJ in mice prevents a
decrease in the size of skeletal muscle fibers (Niu et al., 2013; Shirakawa,
T., Miyawaki, A., & Matsubara, T., 2020). It also increased the expres­
sion of proliferation- and differentiation-related genes but did not alter
the expression of catabolic genes.
Free fatty acid receptor 4 (FFAR4) could be a therapeutic target for
the treatment of obesity-related metabolic disorders (Brenner, C., Gal­
luzzi, L., Kepp, O., & Kroemer, G., 2013), as well as inflammation and
cancer (Lin et al., 2020; Yang, Chou, Widowati, Lin, & Peng, 2018).
However, in osteoporosis, another age-related disease, QBA interacts
directly with FFAR4 on osteoclasts, suppressing osteoclast genesis by
inhibiting the Nuclear factor kappa B (NF-κB) signaling pathway (Tsu­
chiya et al., 2020). QBA improves rheumatoid arthritis by blocking the
p38 kinase and c-Jun N-terminal kinase (JNK)-AP-1 signaling pathways
(Yang et al., 2010); moreover, Tumor necrosis factor (TNF)-α and IL-6
levels are decreased and inhibit articular cartilage degeneration by
preventing extracellular matrix degradation and cartilage cell damage
(Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020). This
receptor might also be involved in the regulation of adipogenesis
(Horrocks and Farooqui, 2004), inflammation, insulin resistance (Honda
et al., 2015; Takikawa et al., 2013) and bone resorption (Tsuchiya et al.,
2020; Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., &
Butt, C. M., 2018).
QBA decreases muscle mass in female mice but increases bone den­
sity (Fan et al., 2020; Weiser, M. J., Grimshaw, V., Wynalda, K. M.,
Mohajeri, M. H., & Butt, C. M., 2018) in a sex-dependent manner. It has
also been reported that QBA protects against bone loss induced by es­
trogen deficiency in menopause-related issues (Fan et al., 2020), further
implying that estrogen receptors are important sites of QBA activity.
Together, these findings indicate that QBA is a modulator of estradiol
receptors (Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017;
Sugiyama, T., Takahashi, K., & Mori, H., 2012; Weiser, M. J., Grimshaw,
V., Wynalda, K. M., Mohajeri, M. H., & Butt, C. M., 2018) and allows us
to explain the sex differences in body composition by QBA-estrogen
receptor interactions (Welle, 2002).
A phytoestrogen-rich diet can have estrogenic effects in the absence
of estradiol or at lower levels observed in adult male Sprague–Dawley
4.1. Age-related diseases
In most mammalian species, including humans, aging is associated
with a decline in skeletal muscle mass and function, termed sarcopenia
(Delmonico et al., 2007; Ibebunjo et al., 2013; Welle, 2002). Sarcopenia
is associated with the downregulation of genes that regulate mito­
chondrial biogenesis, fission and fusion, which indicates that sarcopenia
is characterized by depressed mitochondrial energy metabolism and
dynamics (Ibebunjo et al., 2013).
The oral administration of RJ in mice familiarized with treadmill
exercise had a significant positive effect on inducing the increase in
8
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Table 3
Summary of SYRCLÉ s risk of bias. In this table, we describe all types of bias for each in vivo study reviewed. Selection bias (sequence generation, baseline characteristics
and allocation concealment), performance bias (random housing and blinding), detection bias (random outcome assessment and blinding), attrition bias (incomplete
outcome data) and reporting bias (selective outcome reporting).
Study ID
Random
sequence
analysis
(Selection
bias)
Baseline
characteristics
(Selection bias)
Allocation
concealment
(Selection
bias)
Random
housing
(Performance
bias)
Blinding
(Performance
bias)
Random
outcome
assessment
(Detection
bias)
Binding of
outcome
assessment
(Detection
bias)
Incomplete
outcome data
(attrition
bias)
Selective
reporting
(Reporting
bias)
(Weiser, M. J.,
Grimshaw,
V., Wynalda,
K. M.,
Mohajeri, M.
H., & Butt, C.
M., 2018)
(Chen et al.,
2018)
(Fan et al.,
2020)
(Zhang et al.,
2017)
(Legaki, N.,
Narita, Y.,
Hattori, N.,
Hirata, Y., &
Ichihara, K.,
2020)
(Almeer et al.,
2018)
(Peng, C. C.,
Sun, H. T.,
Lin, I. P., Kuo,
P. C., & Li, J.
C., 2017)
(Tsuchiya et al.,
2020)
(You, M., Miao,
Z., Pan, Y., &
Hu, F., 2019)
(You, M., Miao,
Z., Tian, J., &
Hu, F., 2020)
(Hong, S. H.,
Hwang, S. W.,
Son, Y. K.,
Lee, N. Y., &
Kim, O.,
2020)
(Takahashi
et al., 2018)
(Watadani
et al., 2017)
(Shirakawa, T.,
Miyawaki, A.,
& Matsubara,
T., 2020)
Low
Low
High
Low
Low
High
Unclear
Low
Low
Low
Low
Low
Low
High
High
High
Low
Low
Low
Low
High
Low
High
High
High
Low
Low
Low
Low
Low
Low
High
High
High
Low
Low
Low
High
Low
Low
High
High
High
Low
Low
Low
Low
Low
Low
High
High
High
Low
Low
Low
Low
High
Low
High
High
High
Low
Low
Unclear
Unclear
High
High
High
High
High
Low
Low
Low
Low
Low
Low
High
High
High
Low
Low
Low
Low
Low
Low
High
High
High
Low
Low
Low
Low
Low
Low
High
High
High
Low
Low
Low
Low
Low
Low
High
High
High
Low
Low
Low
High
High
Low
High
High
High
Low
Low
High
High
High
High
High
High
High
Low
Low
rats (Weber, K. S., Setchell, K. D. R., Stocco, D. M., & Lephart, E. D.,
2001). This increases Extracellular signal regulated Kinase (ERK)
(Makino et al., 2016) and AMPK signaling (Watadani et al., 2017).
Sirtuin-1 deacetylates liver kinase B1 (LKB1), increasing its capacity to
phosphorylate and activate AMPK (Ghosh, H. S., McBurney, M., &
Robbins, P. D., 2010; Lau, A. W., Liu, P., Inuzuka, H., & Gao, D., 2014).
induce the proliferation of VSCMs (Wang et al., 2008). QBA attenuated
Ang II-induced inflammatory responses in rat VSCMs, making QBA an
effective component against vascular inflammation (Cai et al., 2018).
Mitochondria play an important role in metabolic health, and their
disruption is implicated in different diseases, such as obesity (a major
public health problem (Kopelman, 2000) caused by excess white adipose
tissue (Park, 2009)) and insulin resistance (Montgomery & Turner,
2015).
The administration of RJ in vivo induced weight loss and improved
hyperglycemia in obese/diabetic mice but did not improve insulin
resistance (Yoshida et al., 2017). However, long-term administration of
QBA markedly improves hyperglycemia and insulin resistance, even
though it does not prevent obesity (Usui et al., 2019; Watadani et al.,
2017). Interestingly, QBA plays a role in energy metabolism and can
affects body composition. Aged male rats and young mice that consumed
QBA exhibited increased weight gain and adipose mass and better
4.2. Metabolic disorders
The primary risk factor for cardiovascular disease is aging. The
structural and molecular changes associated with age accelerate these
processes (Monk & George, 2015). Atherosclerosis, the major cause of
death associated with cardiovascular diseases, is produced by the
accumulation of VSMCs, secreted products, inflammatory cells, lipids
and debris (Wang & Bennett, 2012). Angiotensin II (Ang II), the active
component of the renin-angiotensin system (RAS), has been shown to
9
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
degeneration. It is clear that QBA promotes neurogenesis from neural
stem/progenitor cells and neuroprotection through autophagy activa­
tion in in vitro studies (Hattori, N., Nomoto, H., Fukumitsu, H., Mishima,
S., & Furukawa, S., 2007; Martínez-Chacón et al., 2021).
weight maintenance during behavioral stress whereas QBA decreased
adipose tissue in females (Weiser, M. J., Grimshaw, V., Wynalda, K. M.,
Mohajeri, M. H., & Butt, C. M., 2018).
In vitro, a study performed in the 3 T3-L1 cell line, one of the most
reliable models to study adipogenesis (Zhang et al., 2015), showed that
RJ inhibited lipid accumulation and that QBA inhibited the initiation of
adipogenesis, indicating potential anti-adipogenic activity. QBA also
inhibits ROS production, which means that it could be useful against
obesity-linked oxidative stress (Pandeya et al., 2019).
QBA plays a role in energy metabolism, inhibiting lipolysis and
promoting glycolysis and lipogenesis via an insulin-like effect by sup­
pressing aquaporin 9 (AQP9) gene expression (Calamita et al., 2012;
Usui et al., 2019). It also prevented hepatic injury, oxidative stress, and
inflammation by upregulating Nuclear factor-erythroid 2 related factor
2 (Nrf2) and the antiapoptotic protein Bcl-2 in a murine model (Almeer
et al., 2018). Honey exhibited this effect in rats by inducing antioxidant
enzymes and reducing the levels of serum transaminases, alkaline
phosphatase and bilirubin (Mahesh, A., Shaheetha, J., Thangadurai, D.,
& Rao, D. M., 2009). Similar results were observed with EGCG, further
extending lifespan in healthy rats by activating the longevity factors
Forkhead box O3 (FoxO3a) and silent mating type information regula­
tion two homolog one (SIRT1) (Niu et al., 2013). In other studies, un­
saturated fatty acids promoted the formation of triglyceride-enriched
lipid droplets and induced autophagy in hepatocytes, affecting lip­
oapoptosis. This induction of autophagy protects against lipotoxicity
and may have therapeutic benefits for obesity-induced steatosis and
liver injury (Mei et al., 2011).
Caloric restriction (CR) and CR mimetics (CRMs) reduce body weight
and activate AMPK by changing the AMP/ATP ratios and depleting
intracellular acetyl coenzyme A (as a result of changing NADH/NADC
ratios and increasing SIRT1 expression). This is accompanied by a
reduction in the acetylation of most autophagy proteins, including
autophagy-related (ATG): ATG5, ATG7, ATG12, and ATG8 (Calamita
et al., 2012; Makino et al., 2016), and activation of the autophagic
process in all the studied organs in mice together with weight loss
(Calamita et al., 2012; Makino et al., 2016). Several CRMs reduce the
advancement of neurodegenerative diseases (as shown for spermidine,
nicotinamide and resveratrol), likely through their capacity to induce
autophagy in rodents (Makino et al., 2016). In contrast, other substances
used to increase body weight have inhibited the autophagic process
(Calamita et al., 2012).
Given that QBA activates the same signaling pathways as some
known CR, this fatty acid may be a new potential CRM (MartínezChacón et al., 2021).
4.4. Immunomodulation and cancer
QBA could be applied in different dendritic cell (DC)-based immu­
notherapies in autoimmune diseases and prevent rejection in trans­
plantation and biomaterial implantation (Eslami-kaliji, F.,
Sarafbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare, S. Z., & Dor­
miani, K., 2021) through an increase in the levels of IL-10, an important
anti-inflammatory mediator, accompanied by a reduction in proin­
flammatory mediators and decreased production of IL-6 (You, M., Miao,
Z., Tian, J., & Hu, F., 2020).
While saturated fatty acids activate the immune system, unsaturated
fatty acids, such as QBA, inhibit agonist-induced activation of Tolero­
genic Receptors (TLRs) (Lancaster et al., 2018) and lead to decreased
adhesion to expressed receptors (Sanderson, P., Yaqoob, P., & Calder, P.
c., 1995). QBA has an inhibitory effect on the maturation of DCs when
they are cultured at the surface of different biomaterial films. These cells
not only possess similar morphology to iDCs but also exhibit tolerogenic
DCs (tolDC), characterized through the low-level expression of markers,
particularly CD86 and CD80 (Zheng, X., Zhou, F., Gu, Y., Duan, X., &
Mo, A., 2017) immunophenotyping in the presence of QBA (Eslamikaliji, F., Sarafbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare, S. Z., &
Dormiani, K., 2021).
Many different compounds are widely used to generate tolDCs in
tissue engineering, autoimmune disease, and transplantation. The
tolDCs generated through rapamycin possess a weak ability to secrete
cytokines while being powerful stimulators for T cells (Boks et al.,
2012), but those generated through IL-10 have considerable potential in
tolerance induction, a high ability to secrete IL-10 and a low ability to
activate T cells (Keselowsky, B. G., & Lewis, J. S., 2017).
The tolDCs generated through QBA have similar immunophenotyp­
ing characteristics to those generated by IL-10, and because the in vivo
consumption of IL-10 leads to systemic suppression of the immune
system, QBA could be a potent candidate for clinical tests (Eslami-kaliji,
F., Sarafbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare, S. Z., & Dor­
miani, K., 2021).
QBA recovers dysfunction of the thymus, and the spleen restores
immunity after immunosuppressive treatment in mice. In this case, QBA
could promote immunological capabilities to improve human health.
Low doses of QBA stimulated the proliferation of T-cells in human
monocyte-derived dendritic cells (MoDCs) in culture and in vitro cell
proliferation of splenocytes (Fan et al., 2020; Gasic et al., 2007;
Mihajlovic, D., Rajkovic, I., Chinou, I., & Colic, M., 2013).
QBA exerts an anti-inflammatory response in vitro (Chen, Y. F.,
Wang, K., Zhang, Y. Z., Zheng, Y. F., & Hu, F. L., 2016; 2018; Yang, Y. C.,
Chou, W. M., Widowati, D. A., Lin, I. P., & Peng, C. C., 2018). In vivo,
QBA delayed the inflammatory process and decreased inflammatoryrelated cell cytokine production in pneumonia caused by lipoteichoic
acid (LTA) from Staphylococcus aureus (Chen et al., 2018; Kuo et al.,
2003).
QBA also induced apoptosis and cell cycle arrest, which indicates
possible therapeutic potential against other inflammatory diseases, such
as lung cancer (Lin et al., 2020), the most common cause of cancer death
(Nasim, F., Sabath, B. F., & Eapen, G. A., 2019), or colon cancer (Yang,
Y. C., Chou, W. M., Widowati, D. A., Lin, I. P., & Peng, C. C., 2018). QBA
also inhibits melanogenesis by downregulating Melanocyte Inducing
Transcription Factor (MITF) protein, tyrosinase and melanin production
(Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C., 2017). In
contrast, other melanogenesis inhibitors, such as kojic acid, arbutin, and
ascorbic acid, did not have this effect (Choi et al., 2010; Kim et al.,
2004).
Unsaturated fatty acids such as oleate and linoleate stimulate
4.3. Neurodegenerative diseases
RJ and QBA improved health and extended the lifespans of nema­
todes, flies and mice (Honda et al., 2015). Studies have shown that fatty
acids in the diet are related to the fatty acid composition of the brain
(Horwitt, M. K., Harvey, C. C., & Century, B., 1959), neuronal devel­
opment (Farquharson, J., Cockburn, F., Patrick, W. A., Jamieson, E. C.,
& Logan, R. W., 1992) and neuroprotection, making QBA a potential
treatment for a multitude of neurological disorders (Horrocks, L. A., &
Farooqui, A. A., 2004).
QBA increased growth, reduced mortality and enhanced mitochon­
drial health in primary hippocampal neurons (Kawahata et al., 2018;
Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C.
M., 2018). It also confers improvements in mood- or cognition-related
behaviors, ameliorates brain pathology and restores cognitive func­
tions in vivo. Similar results were obtained in a mouse model of amyloid
deposition with dietary hydroxytyrosol (Nardiello, P., Pantano, D.,
Lapucci, A., Stefani, M., & Casamenti, F., 2018). Fatty acids contained in
RJ reduced depression-like behavior (Weiser, M. J., Grimshaw, V.,
Wynalda, K. M., Mohajeri, M. H., & Butt, C. M., 2018) by acting on
corticosterone synthesis in the adrenal gland and hippocampal neuronal
10
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
autophagic flow in epithelial mammary cells (Pauloin et al., 2010). A
study performed in a mouse model of breast cancer revealed that RJ
affected the expression of diverse genes, especially genes related to
immunity, highlighting the importance of the immunomodulatory effect
of RJ (Zhang et al., 2017; Zhang et al., 2017). Moreover, QBA may be
implicated in slowing breast cancer development (Zhang et al., 2017).
The regulation of innate immune signaling and tumor development can
occur through the modulation of autophagy. In this sense, the down­
regulation of UNC-51-like kinase (ULK1) has been found in most breast
cancer tissues (Zhang et al., 2017).
QBA could also play an important role in the development of auto­
phagy through an anti-neuroinflammatory effect. QBA activated the NFκB pathway, similar to EGCG (Niu et al., 2013). QBA also increased the
transcriptional activity of Forkhead box O1 (FoxO1a), which addition­
ally increased the upstream protein expression of SIRT1 and FoxO3a. On
the other hand, it promotes the activation of the AMPK pathway and can
regulate autophagy by either phosphorylating ULK1, which then acti­
vates the phosphatidylinositol 3-kinase (PI3K) complex (You, M., Miao,
Z., Pan, Y., & Hu, F., 2019), and can also upregulate SIRT1 in an NADdependent manner (Qiu et al., 2015). In this sense, SIRT1 can mediate
autophagy through the deacetylation of FoxO1a or FoxO3a and has a
potential protective role in gastric cancer (Qiu et al., 2015). EGCG ex­
tends lifespan in healthy rats by reducing liver and kidney damage and
improving age-associated inflammation and oxidative stress through the
inhibition of NF-κB signaling by activating longevity (Niu et al., 2013).
5. Conclusion
The present SR integrated data across studies with the goal of pro­
vides a new pharmacological basis for the beneficial potential of RJ, and
more specifically QBA, as a functional and health-promoting food item
that enables the prevention of various diseases. QBA exerts its protective
effects both in vitro and in vivo. In this SR, we have found beneficial
effects respect to age-related diseases, metabolic disorders, immuno­
modulation and cancer, but further in vivo studies are needed to eluci­
date the mechanism of action by which QBA exerts its protective effects,
as well as to clarify its role in the modulation of cardiovascular and
neurodegenerative diseases through the prevention of inflammation,
oxidative stress and apoptosis.
CRediT authorship contribution statement
Marta Paredes-Barquero: Conceptualization, Data curation, Formal
analysis, Investigation, Methodology. Mireia Niso-Santano: Supervi­
sion, Writing – review & editing. José M. Fuentes: Supervision, Writing
– review & editing. Guadalupe Martínez-Chacón: Conceptualization,
Data curation, Formal analysis, Investigation, Methodology,
Supervision.
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.
4.5. Other diseases
It has been proven that the topical application of QBA increases the
amount of filaggrin (FLG), the main protein involved in the formation of
the stratum corneum (SC), the outermost layer of the skin, and the
protein in charge of maintaining hydration of the epidermis (Kezic et al.,
2008) and the levels of amino acids (Gu, L., Zeng, H., & Maeda, K.,
2017). Although QBA poorly penetrates into skin, a study demonstrated
that the use of RJ incorporated liposomes greatly increased QBA pene­
tration (Perminaite, K., Maria Fadda, A., Sinico, C., & Ramanauskiene,
K., 2021). This barrier does not shrink with age, but the loss of water and
reduction of lipids and ceramides can lead to dry skin, which is
frequently accompanied by other effects, such as pruritus (Gu, L., Zeng,
H., & Maeda, K., 2017; Tagami, 2008). QBA also promotes collagen
production in fibroblast cell lines through transforming growth factor-β1
(TGF-β1), which is an important factor for collagen production (KoyaMiyata et al., 2004).
It has been proved that autophagy activators such as rapamycin,
lithium, LYN-1604 or cysteamine among others exert a protective effect
for dry eye disease, keratitis and other corneal diseases (MartínezChacón et al., 2020). QBA, as an autophagy activator itself (MartínezChacón et al., 2021), could have a positive impact over corneal diseases
when used topically.
In situ gels containing RJ or QBA are promising ocular drug delivery
systems compared to conventional topical eye drops (Perminaite et al.,
2021).
Acknowledgements
This work was supported by a grant (IB18048) from Junta de
Extremadura, Spain and a grant (RTI2018-099259-A-I00) from Minis­
terio de Ciencia e Innovación, Spain and from the Instituto de Salud
Carlos III, CIBERNED (CB06/05/004). This work was also partially
supported by “Fondo Europeo de Desarrollo Regional” (FEDER) from the
European Union.
M.P-B is a recipient of a fellowship from the “Plan Propio de
Iniciación a la Investigación, Desarrollo Tecnológico e Innovación,
(University of Extremadura)”. G.M-C is supported by University of
Extremadura (ONCE Foundation). M.N-S was funded by the “Ramon y
Cajal” Program (RYC-2016-20883) Spain. J.M.F. received research
support from the Instituto de Salud Carlos III, CIBERNED (CB06/05/
004).
References
Ahmad, S., Campos, M. G., Fratini, F., Altaye, S. Z., & Li, J. (2020). New Insights into the
Biological and Pharmaceutical Properties of Royal Jelly. International Journal of
Molecular Sciences, 21(2), 382. https://doi.org/10.3390/ijms21020382
Almeer, R. S., Alarifi, S., Alkahtani, S., Ibrahim, S. R., Ali, D., & Moneim, A. (2018). 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. Biomedicine and Pharmacotherapy, 106(May),
1490–1498. https://doi.org/10.1016/j.biopha.2018.07.089
Bincoletto, C., Eberlin, S., Figueiredo, C. A. V., Luengo, M. B., & Queiroz, M. L. S. (2005).
Effects produced by Royal Jelly on haematopoiesis: Relation with host resistance
against Ehrlich ascites tumour challenge. International Immunopharmacology, 5(4),
679–688. https://doi.org/10.1016/j.intimp.2004.11.015
Blum, M. S., Novak, A. F., & Taber, S. (1959). 10-Hydroxy-delta 2-decenoic acid, an
antibiotic found in royal jelly. Science (New York, N.Y.), 130(3373), 452–453.
https://doi.org/10.1126/science.130.3373.452
Boks, M. A., Kager-Groenland, J. R., Haasjes, M. S. P., Zwaginga, J. J., van Ham, S. M., &
ten Brinke, A. (2012). IL-10-generated tolerogenic dendritic cells are optimal for
functional regulatory T cell induction - A comparative study of human clinicalapplicable DC. Clinical Immunology, 142(3), 332–342. https://doi.org/10.1016/j.
clim.2011.11.011
Brenner, C., Galluzzi, L., Kepp, O., & Kroemer, G. (2013). Decoding cell death signals in
liver inflammation. Journal of Hepatology, 59(3), 583–594. https://doi.org/10.1016/
j.jhep.2013.03.033
Brudzynski, K., & Sjaarda, C. (2015). Honey glycoproteins containing antimicrobial
peptides, Jelleins of the Major Royal Jelly Protein 1, are responsible for the cell wall
4.6. Human clinical studies
Positive results have been found in different human clinical studies
with RJ supplementation. Oral intake of RJ may improve erythropoiesis,
glucose tolerance and mental health (Morita et al., 2012), prevent the
decline in femoral bone mass and strength in postmenopausal women
(Matsushita, H., Shimizu, S., Morita, N., Watanabe, K., & Wakatsuki, A.,
2021), increased hydration of the stratum corneum without affecting
transepidermal water loss (TEWL) (Yoshimoto et al., 2018) and act as a
good hypocholesterolemic agent and thus attenuating the risk of car­
diovascular diseases (Chiu et al., 2017). But, there is a need of further
research to confirm these results.
11
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
lytic and bactericidal activities of honey. PloS One, 10(4), Article e0120238. https://
doi.org/10.1371/journal.pone.0120238
Cai, Q., Ji, S., Sun, Y., Yu, L., Wu, X., & Xie, Z. (2018). 10-Hydroxy-trans-2-decenoic acid
attenuates angiotensin II-induced inflammatory responses in rat vascular smooth
muscle cells. Journal of Functional Foods, 45(January), 298–305. https://doi.org/
10.1016/j.jff.2018.04.034
Calamita, G., Gena, P., Ferri, D., Rosito, A., Rojek, A., Nielsen, S., Marinelli, R. A.,
Frühbeck, G., & Svelto, M. (2012). Biophysical assessment of aquaporin-9 as
principal facilitative pathway in mouse liver import of glucogenetic glycerol. Biology
of the Cell, 104(6), 342–351. https://doi.org/10.1111/boc.201100061
Casamenti, F., Grossi, C., Rigacci, S., Pantano, D., Luccarini, I., & Stefani, M. (2015).
Oleuropein Aglycone: A Possible Drug against Degenerative Conditions. In Vivo
Evidence of its Effectiveness against Alzheimer’s Disease. Journal of Alzheimer’s
Disease, 45(3), 679–688. https://doi.org/10.3233/JAD-142850
Chamova, R. (2020). The Role Of Royal Jelly To Human Health. December, 23–25.
Chen, Y. F., Wang, K., Zhang, Y. Z., Zheng, Y. F., & Hu, F. L. (2016). In Vitro AntiInflammatory Effects of Three Fatty Acids from Royal Jelly. Mediators of
Inflammation, 2016. https://doi.org/10.1155/2016/3583684
Chen, Y. F., You, M. M., Liu, Y. C., Shi, Y. Z., Wang, K., Lu, Y. Y., & Hu, F. L. (2018).
Potential protective effect of Trans-10-hydroxy-2-decenoic acid on the inflammation
induced by Lipoteichoic acid. Journal of Functional Foods, 45(January), 491–498.
https://doi.org/10.1016/j.jff.2018.03.029
Chiu, H. F., Chen, B. K., Lu, Y. Y., Han, Y. C., Shen, Y. C., Venkatakrishnan, K.,
Golovinskaia, O., & Wang, C. K. (2017). Hypocholesterolemic efficacy of royal jelly
in healthy mild hypercholesterolemic adults. In Pharmaceutical Biology (Vol., 55(1),
497–502. https://doi.org/10.1080/13880209.2016.1253110
Choi, Y. K., Rho, Y. K., Yoo, K. H., Lim, Y. Y., Li, K., Kim, B. J., Seo, S. J., Kim, M. N.,
Hong, C. K., & Kim, D.-S. (2010). Effects of vitamin C vs. multivitamin on
melanogenesis: Comparative study in vitro and in vivo. International Journal of
Dermatology, 49(2), 218–226. https://doi.org/10.1111/j.1365-4632.2009.04336.x
Colle, D., Farina, M., Ceccatelli, S., & Raciti, M. (2018). Paraquat and Maneb Exposure
Alters Rat Neural Stem Cell Proliferation by Inducing Oxidative Stress: New Insights
on Pesticide-Induced Neurodevelopmental Toxicity. Neurotoxicity Research, 34(4),
820–833. https://doi.org/10.1007/s12640-018-9916-0
Colle, D., Santos, D. B., Naime, A. A., Gonçalves, C. L., Ghizoni, H., Hort, M. A., &
Farina, M. (2020). Early Postnatal Exposure to Paraquat and Maneb in Mice
Increases Nigrostriatal Dopaminergic Susceptibility to a Re-challenge with the Same
Pesticides at Adulthood: Implications for Parkinson’s Disease. Neurotoxicity Research,
37(1), 210–226. https://doi.org/10.1007/s12640-019-00097-9
Cristóvão, A. C., Campos, F. L., Je, G., Esteves, M., Guhathakurta, S., Yang, L., Beal, M. F.,
Fonseca, B. M., Salgado, A. J., Queiroz, J., Sousa, N., Bernardino, L., Alves, G.,
Yoon, K. S., & Kim, Y. S. (2020). Characterization of a Parkinson’s disease rat model
using an upgraded paraquat exposure paradigm. European Journal of Neuroscience, 52
(4), 3242–3255. https://doi.org/10.1111/ejn.14683
Delmonico, M. J., Harris, T. B., Lee, J. S., Visser, M., Nevitt, M., Kritchevsky, S. B.,
Tylavsky, F. A., & Newman, A. B. (2007). Alternative definitions of sarcopenia, lower
extremity performance, and functional impairment with aging in older men and
women. Journal of the American Geriatrics Society, 55(5), 769–774. https://doi.org/
10.1111/j.1532-5415.2007.01140.x
Eslami-kaliji, F., Sarafbidabad, M., Kiani-Esfahani, A., Mirahmadi-Zare, S. Z., &
Dormiani, K. (2021). 10-Hydroxy-2-Decenoic Acid a Bio-Immunomodulator in
Tissue Engineering; Generates Tolerogenic Dendritic Cells By Blocking the Toll-Like
Receptor4. Journal of Biomedical Materials Research - Part A. https://doi.org/
10.1002/jbm.a.37152
Fan, P., Han, B., Hu, H., Wei, Q., Zhang, X., Meng, L., Nie, J., Tang, X., Tian, X., Zhang, L.,
Wang, L., & Li, J. (2020). Proteome of thymus and spleen reveals that 10-hydroxy­
dec-2-enoic acid could enhance immunity in mice. Expert Opinion on Therapeutic
Targets, 24(3), 267–279. https://doi.org/10.1080/14728222.2020.1733529
Farquharson, J., Cockburn, F., Patrick, W. A., Jamieson, E. C., & Logan, R. W. (1992).
Infant cerebral cortex phospholipid fatty-acid composition and diet. Lancet (London,
England), 340(8823), 810–813. https://doi.org/10.1016/0140-6736(92)92684-8
Gasic, S., Vucevic, D., Vasilijic, S., Antunovic, M., Chinou, I., & Colic, M. (2007).
Evaluation of the immunomodulatory activities of royal jelly components in vitro.
Immunopharmacology and Immunotoxicology, 29(3–4), 521–536. https://doi.org/
10.1080/08923970701690977
Ghosh, H. S., McBurney, M., & Robbins, P. D. (2010). SIRT1 negatively regulates the
mammalian target of rapamycin. PLoS ONE, 5(2), 1–8. https://doi.org/10.1371/
journal.pone.0009199
Gu, L., Zeng, H., & Maeda, K. (2017). 10-Hydroxy-2-Decenoic Acid in Royal Jelly Extract
Induced Both Filaggrin and Amino Acid in a Cultured Human Three-Dimensional
Epidermis Model. Cosmetics, 4(4). https://doi.org/10.3390/cosmetics4040048
Hattori, N., Nomoto, H., Fukumitsu, H., Mishima, S., & Furukawa, S. (2007). Royal jelly
and its unique fatty acid, 10-hydroxy-trans-2-decenoic acid, promote neurogenesis
by neural stem/progenitor cells in vitro. Biomedical Research, 28(5), 261–266.
https://doi.org/10.2220/biomedres.28.261
Honda, Y., Araki, Y., Hata, T., Ichihara, K., Ito, M., Tanaka, M., & Honda, S. (2015). 10Hydroxy-2-Decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the
Lifespan of Caenorhabditis Elegans Through Dietary Restriction and Target of
Rapamycin Signaling. Journal of Aging Research, 2015. https://doi.org/10.1155/
2015/425261
Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O. (2020). Prevention or
treatment of enzyme treated royal jelly on monosodium-iodoacetate-induced
osteoarthritis. Journal of Biomedical Translational Research, 21(1), 1–10. https://doi.
org/10.12729/jbtr.2020.21.1.1
Horrocks, L. A., & Farooqui, A. A. (2004). Docosahexaenoic acid in the diet: Its
importance in maintenance and restoration of neural membrane function.
Prostaglandins, Leukotrienes, and Essential Fatty Acids, 70(4), 361–372. https://doi.
org/10.1016/j.plefa.2003.12.011
Horwitt, M. K., Harvey, C. C., & Century, B. (1959). Effect of dietary fats on fatty acid
composition of human erythrocytes and chick cerebella. Science (New York, N.Y.),
130(3380), 917–918. https://doi.org/10.1126/science.130.3380.917
Ibebunjo, C., Chick, J. M., Kendall, T., Eash, J. K., Li, C., Zhang, Y., … Glass, D. J. (2013).
Genomic and Proteomic Profiling Reveals Reduced Mitochondrial Function and
Disruption of the Neuromuscular Junction Driving Rat Sarcopenia. Molecular and
Cellular Biology, 33(2), 194–212. https://doi.org/10.1128/mcb.01036-12
Izuta, H., Chikaraishi, Y., Shimazawa, M., Mishima, S., & Hara, H. (2009). 10-Hydroxy-2decenoic acid, a major fatty acid from royal jelly, inhibits VEGF-induced
angiogenesis in human umbilical vein endothelial cells. Evidence-Based
Complementary and Alternative Medicine : ECAM, 6(4), 489–494. https://doi.org/
10.1093/ecam/nem152
Kamakura, M., Suenobu, N., & Fukushima, M. (2001). Fifty-seven-kDa protein in royal
jelly enhances proliferation of primary cultured rat hepatocytes and increases
albumin production in the absence of serum. Biochemical and Biophysical Research
Communications, 282(4), 865–874. https://doi.org/10.1006/bbrc.2001.4656
Kawahata, I., Xu, H., Takahashi, M., Murata, K., Han, W., Yamaguchi, Y., Fujii, A.,
Yamaguchi, K., & Yamakuni, T. (2018). Royal jelly coordinately enhances
hippocampal neuronal expression of somatostatin and neprilysin genes conferring
neuronal protection against toxic soluble amyloid-β oligomers implicated in
Alzheimer’s disease pathogenesis. Journal of Functional Foods, 51(May), 28–38.
https://doi.org/10.1016/j.jff.2018.10.006
Kawano, Y., Makino, K., Jinnin, M., Sawamura, S., Shimada, S., Fukushima, S., & Ihn, H.
(2019). Royal jelly regulates the proliferation of human dermal microvascular
endothelial cells through the down-regulation of a photoaging-related microRNA.
Drug Discoveries & Therapeutics, 13(5), 268–273. https://doi.org/10.5582/
ddt.2019.01070
Keselowsky, B. G., & Lewis, J. S. (2017). Dendritic cells in the host response to implanted
materials. Seminars in Immunology, 29, 33–40. https://doi.org/10.1016/j.
smim.2017.04.002
Kezic, S., Kemperman, P. M. J. H., Koster, E. S., De Jongh, C. M., Thio, H. B.,
Campbell, L. E., Irvine, A. D., McLean, I. W. H., Puppels, G. J., & Caspers, P. J.
(2008). Loss-of-function mutations in the filaggrin gene lead to reduced level of
natural moisturizing factor in the stratum corneum. Journal of Investigative
Dermatology, 128(8), 2117–2119. https://doi.org/10.1038/jid.2008.29
Kim, D.-S., Park, S.-H., Kwon, S.-B., Li, K., Youn, S.-W., & Park, K.-C. (2004).
(-)-Epigallocatechin-3-gallate and hinokitiol reduce melanin synthesis via decreased
MITF production. Archives of Pharmacal Research, 27(3), 334–339. https://doi.org/
10.1007/BF02980069
Kohno, K., Okamoto, I., Sano, O., Arai, N., Iwaki, K., Ikeda, M., & Kurimoto, M. (2004).
Royal jelly inhibits the production of proinflammatory cytokines by activated
macrophages. Bioscience, Biotechnology, and Biochemistry, 68(1), 138–145. https://
doi.org/10.1271/bbb.68.138
Kopelman, P. G. (2000). Obesity as a medical problem. Nature, 404(6778), 635–643.
https://doi.org/10.1038/35007508
Koya-Miyata, S., Okamoto, I., Ushio, S., Iwaki, K., Ikeda, M., & Kurimoto, M. (2004).
Identification of a collagen production-promoting factor from an extract of royal
jelly and its possible mechanism. Bioscience, Biotechnology, and Biochemistry, 68(4),
767–773. https://doi.org/10.1271/bbb.68.767
Kuo, C. T., Chiang, L. L., Lee, C. N., Yu, M. C., Bai, K. J., Lee, H. M., Lee, W. S., Sheu, J. R.,
& Lin, C. H. (2003). Induction of nitric oxide synthase in RAW 264.7 macrophages by
lipoteichoic acid from Staphylococcus aureus: Involvement of protein kinase C- and
nuclear factor-κB-dependent mechanisms. Journal of Biomedical Science, 10(1),
136–145. https://doi.org/10.1159/000068076
Lancaster, G. I., Langley, K. G., Berglund, N. A., Kammoun, H. L., Reibe, S., Estevez, E., …
Febbraio, M. A. (2018). Evidence that TLR4 Is Not a Receptor for Saturated Fatty
Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage
Metabolism. Cell Metabolism, 27(5), 1096–1110.e5. https://doi.org/10.1016/j.
cmet.2018.03.014
Lau, A. W., Liu, P., Inuzuka, H., & Gao, D. (2014). SIRT1 phosphorylation by AMPactivated protein kinase regulates p53 acetylation. American Journal of Cancer
Research, 4(3), 245–255. http://www.ncbi.nlm.nih.gov/pubmed/24959379%
0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4065405.
Lee, C., & Longo, V. D. (2011). Fasting vs dietary restriction in cellular protection and
cancer treatment: From model organisms to patients. Oncogene, 30(30), 3305–3316.
https://doi.org/10.1038/onc.2011.91
Legaki, N., Narita, Y., Hattori, N., Hirata, Y., & Ichihara, K. (2020). Royal jelly reduces
depression-like behavior through possible effects on adrenal steroidogenesis in a
murine model of unpredictable chronic mild stress. Bioscience, Biotechnology and
Biochemistry, 84(3), 606–612. https://doi.org/10.1080/09168451.2019.1691496
Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P. A.,
Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009). The PRISMA statement
for reporting systematic reviews and meta-analyses of studies that evaluate health
care interventions: Explanation and elaboration. PLoS Medicine, 6(7). https://doi.
org/10.1371/journal.pmed.1000100
Lin, X. M., Liu, S. B., Luo, Y. H., Xu, W. T., Zhang, Y., Zhang, T., Xue, H., Zuo, W. B.,
Li, Y. N., Lu, B. X., & Jin, C. H. (2020). 10-HDA Induces ROS-Mediated Apoptosis in
A549 Human Lung Cancer Cells by Regulating the MAPK, STAT3, NF-κB, and TGF-β1
Signaling Pathways. BioMed Research International, 2020. https://doi.org/10.1155/
2020/3042636
Lin, Y., Shao, Q., Zhang, M., Lu, C., Fleming, J., & Su, S. (2019). Royal jelly-derived
proteins enhance proliferation and migration of human epidermal keratinocytes in
an in vitro scratch wound model. BMC Complementary and Alternative Medicine, 19
(1), 1–16. https://doi.org/10.1186/s12906-019-2592-7
12
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Mahesh, A., Shaheetha, J., Thangadurai, D., & Rao, D. M. (2009). Protective effect of
Indian honey on acetaminophen induced oxidative stress and liver toxicity in rat.
Biologia, 64(6), 1225–1231. https://doi.org/10.2478/s11756-009-0205-5
Makino, J., Ogasawara, R., Kamiya, T., Hara, H., Mitsugi, Y., Yamaguchi, E., Itoh, A., &
Adachi, T. (2016). Royal Jelly Constituents Increase the Expression of Extracellular
Superoxide Dismutase through Histone Acetylation in Monocytic THP-1 Cells.
Journal of Natural Products, 79(4), 1137–1143. https://doi.org/10.1021/acs.
jnatprod.6b00037
Mariño, G., Pietrocola, F., Madeo, F., & Kroemer, G. (2014). Caloric restriction mimetics:
Natural/physiological pharmacological autophagy inducers. Autophagy, 10(11),
1879–1882. https://doi.org/10.4161/auto.36413
Martínez-Chacón, G., Paredes-Barquero, M., Yakhine-Diop, S. M., Uribe-Carretero, E.,
Bargiela, A., Sabater-Arcis, M., Morales-García, J., Alarcón-Gil, J., Alegre-Cortés, E.,
Canales-Cortés, S., Rodríguez-Arribas, M., Camello, P. J., Pedro, J.-M.-B.-S., PerezCastillo, A., Artero, R., Gonzalez-Polo, R. A., Fuentes, J. M., & Niso-Santano, M.
(2021). Neuroprotective properties of queen bee acid by autophagy induction. Cell
Biology and Toxicology. https://doi.org/10.1007/s10565-021-09625-w
Martínez-Chacón, G., Vela, F. J., Campos, J. L., Abellán, E., Yakhine-Diop, S. M. S., &
Ballestín, A. (2020). Autophagy modulation in animal models of corneal diseases: A
systematic review. Molecular and Cellular Biochemistry, 474(1–2), 41–55. https://doi.
org/10.1007/s11010-020-03832-5
Matsui, T., Yukiyoshi, A., Doi, S., Sugimoto, H., Yamada, H., & Matsumoto, K. (2002).
Gastrointestinal enzyme production of bioactive peptides from royal jelly protein
and their antihypertensive ability in SHR. The Journal of Nutritional Biochemistry, 13
(2), 80–86. https://doi.org/10.1016/s0955-2863(01)00198-x
Matsushita, H., Shimizu, S., Morita, N., Watanabe, K., & Wakatsuki, A. (2021). Effects of
royal jelly on bone metabolism in postmenopausal women: A randomized, controlled
study. In Climacteric (Vol., 24(2), 164–170. https://doi.org/10.1080/
13697137.2020.1806815
Mei, S., Ni, H. M., Manley, S., Bockus, A., Kassel, K. M., Luyendyk, J. P., Copple, B. L., &
Ding, W. X. (2011). Differential roles of unsaturated and saturated fatty acids on
autophagy and apoptosis in hepatocytes. Journal of Pharmacology and Experimental
Therapeutics, 339(2), 487–498. https://doi.org/10.1124/jpet.111.184341
Mihajlovic, D., Rajkovic, I., Chinou, I., & Colic, M. (2013). Dose-dependent
immunomodulatory effects of 10-hydroxy-2-decenoic acid on human monocytederived dendritic cells. Journal of Functional Foods, 5(2), 838–846. https://doi.org/
10.1016/j.jff.2013.01.031
Monk, B. A., & George, S. J. (2015). The Effect of Ageing on Vascular Smooth Muscle Cell
Behaviour - A Mini-Review. Gerontology, 61(5), 416–426. https://doi.org/10.1159/
000368576
Montgomery, M. K., & Turner, N. (2015). Mitochondrial dysfunction and insulin
resistance: An update. Endocrine Connections, 4(1). https://doi.org/10.1530/EC-140092
Morita, H., Ikeda, T., Kajita, K., Fujioka, K., Mori, I., Okada, H., Uno, Y., & Ishizuka, T.
(2012). Effect of royal jelly ingestion for six months on healthy volunteers. Nutrition
Journal, 11(1), 1. https://doi.org/10.1186/1475-2891-11-77
Moriyama, T., Yanagihara, M., Yano, E., Kimura, G., Seishima, M., Tani, H., Kanno, T.,
Nakamura-Hirota, T., Hashimoto, K., Tatefuji, T., Ogawa, T., & Kawamura, Y.
(2013). Hypoallergenicity and immunological characterization of enzyme-treated
royal jelly from apis mellifera. Bioscience, Biotechnology and Biochemistry, 77(4),
789–795. https://doi.org/10.1271/bbb.120924
Nardiello, P., Pantano, D., Lapucci, A., Stefani, M., & Casamenti, F. (2018). Diet
Supplementation with Hydroxytyrosol Ameliorates Brain Pathology and Restores
Cognitive Functions in a Mouse Model of Amyloid-β Deposition. Journal of
Alzheimer’s Disease, 63(3), 1161–1172. https://doi.org/10.3233/JAD-171124
Nasim, F., Sabath, B. F., & Eapen, G. A. (2019). Lung Cancer. Medical Clinics of North
America, 103(3), 463–473. https://doi.org/10.1016/j.mcna.2018.12.006
Niso-Santano, M., González-Polo, R. A., Paredes-Barquero, M., Fuentes, J. M., &
Aschner, M. (2019). Natural Products in the Promotion of Healthspan and Longevity.
Clinical Pharmacology and Translational Medicine, 3(1), 149–151. https://doi.org/
10.31700/2572-7656.000123
Niso-Santano, M., Malik, S. A., Pietrocola, F., Bravo-San Pedro, J. M., Mariño, G.,
Cianfanelli, V., … Kroemer, G. (2015). Unsaturated fatty acids induce non-canonical
autophagy. The EMBO Journal, 34(8), 1025–1041. https://doi.org/10.15252/
embj.201489363
Niu, K., Guo, H., Guo, Y., Ebihara, S., Asada, M., Ohrui, T., Furukawa, K., Ichinose, M.,
Yanai, K., Kudo, Y., Arai, H., Okazaki, T., & Nagatomi, R. (2013). Royal jelly
prevents the progression of sarcopenia in aged mice in vivo and in vitro. Journals of
Gerontology - Series A Biological Sciences and Medical Sciences, 68(12 A), 1482–1492.
https://doi.org/10.1093/gerona/glt041
Niu, Y., Na, L., Feng, R., Gong, L., Zhao, Y., Li, Q., Li, Y., & Sun, C. (2013). The
phytochemical, EGCG, extends lifespan by reducing liver and kidney function
damage and improving age-associated inflammation and oxidative stress in healthy
rats. Aging Cell, 12(6), 1041–1049. https://doi.org/10.1111/acel.12133
O’Rourke, E. J., Kuballa, P., Xavier, R., & Ruvkun, G. (2013). ω-6 Polyunsaturated fatty
acids extend life span through the activation of autophagy. Genes and Development,
27(4), 429–440. https://doi.org/10.1101/gad.205294.112
Okamoto, I., Taniguchi, Y., Kunikata, T., Kohno, K., Iwaki, K., Ikeda, M., & Kurimoto, M.
(2003). Major royal jelly protein 3 modulates immune responses in vitro and in vivo.
Life Sciences, 73(16), 2029–2045. https://doi.org/10.1016/s0024-3205(03)00562-9
Pandeya, P. R., Lamichhane, R., Lee, K. H., Kim, S. G., Lee, D. H., Lee, H. K., & Jung, H. J.
(2019). Bioassay-guided isolation of active anti-adipogenic compound from royal
jelly and the study of possible mechanisms. BMC Complementary and Alternative
Medicine, 19(1), 1–14. https://doi.org/10.1186/s12906-018-2423-2
Park. (2009). Silibinin attenuates adipogenesis in 3T3-L1 preadipocytes through a
potential upregulation of the insig pathway. International Journal of Molecular
Medicine, 23(5), 521–527. Doi: 10.3892/ijmm_00000174.
Pauloin, A., Chat, S., Péchoux, C., Hue-Beauvais, C., Droineau, S., Galio, L., Devinoy, E.,
& Chanat, E. (2010). Oleate and linoleate stimulate degradation of β-casein in
prolactin-treated HC11 mouse mammary epithelial cells. Cell and Tissue Research,
340(1), 91–102. https://doi.org/10.1007/s00441-009-0926-3
Peng, C. C., Sun, H. T., Lin, I. P., Kuo, P. C., & Li, J. C. (2017). The functional property of
royal jelly 10-hydroxy-2-decenoic acid as a melanogenesis inhibitor. BMC
Complementary and Alternative Medicine, 17(1), 1–9. https://doi.org/10.1186/
s12906-017-1888-8
Perminaite, K., Maria Fadda, A., Sinico, C., & Ramanauskiene, K. (2021). Formulation of
Liposomes Containing Royal Jelly and Their Quality Assessment. Journal of
Nanoscience and Nanotechnology, 21(5), 2841–2846. https://doi.org/10.1166/
jnn.2021.19053
Perminaite, K., Marksa, M., Stančiauskaitė, M., Juknius, T., Grigonis, A., &
Ramanauskiene, K. (2021). Formulation of ocular in situ gels with lithuanian royal
jelly and their biopharmaceutical evaluation in vitro. Molecules, 26(12), 1–20.
https://doi.org/10.3390/molecules26123552
Qiu, G., Li, X., Che, X., Wei, C., He, S., Lu, J., Jia, Z., Pang, K., & Fan, L. (2015). SIRT1 is a
regulator of autophagy: Implications in gastric cancer progression and treatment.
FEBS Letters, 589(16), 2034–2042. https://doi.org/10.1016/j.febslet.2015.05.042
Sabatini, A. G. (2009). Quality and standardisation of Royal Jelly. Journal of ApiProduct
and ApiMedical Science, 1(1), 16–21. https://doi.org/10.3896/ibra.4.01.1.04
Sanderson, P., Yaqoob, P., & Calder, P. c. (1995). Effects of Dietary Lipid Manipulation
upon Rat Spleen Lymphocyte Functions and the Expression of Lymphocyte Surface
Molecules. Journal of Nutritional & Environmental Medicine, 5(2), 119–132. Doi:
10.3109/13590849509000211.
Shirakawa, T., Miyawaki, A., & Matsubara, T. (2020). Daily Oral Administration of
Protease-Treated Royal Jelly Protects Against Denervation-Induced Skeletal Muscle
Atrophy. Nutrients, 12(3089), 1–13.
Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K.,
Cuervo, A. M., & Czaja, M. J. (2009). Autophagy regulates lipid metabolism. Nature,
458(7242), 1131–1135. https://doi.org/10.1038/nature07976
Sugiyama, T., Takahashi, K., & Mori, H. (2012). Royal Jelly Acid, 10-Hydroxy-trans-2Decenoic Acid, as a Modulator of the Innate Immune Responses. Endocrine, Metabolic
& Immune Disorders-Drug Targets, 12(4), 368–376. https://doi.org/10.2174/
187153012803832530
Tagami, H. (2008). Functional characteristics of the stratum corneum in photoaged skin
in comparison with those found in intrinsic aging. Archives of Dermatological
Research, 300(SUPPL. 1), 1–6. https://doi.org/10.1007/s00403-007-0799-9
Takahashi, Y., Hijikata, K., Seike, K., Nakano, S., Banjo, M., Sato, Y., Takahashi, K., &
Hatta, H. (2018). Effects of royal jelly administration on endurance training-induced
mitochondrial adaptations in skeletal muscle. In. Nutrients (Vol. 10, Issue 11).
https://doi.org/10.3390/nu10111735
Takikawa, M., Kumagai, A., Hirata, H., Soga, M., Yamashita, Y., Ueda, M., Ashida, H., &
Tsuda, T. (2013). 10-Hydroxy-2-decenoic acid, a unique medium-chain fatty acid,
activates 5’-AMP-activated protein kinase in L6 myotubes and mice. Molecular
Nutrition & Food Research, 57(10), 1794–1802. https://doi.org/10.1002/
mnfr.201300041
Townsend, G. F., Brown, W. H., Felauer, E. E., & Hazlett, B. (1961). Studies on the in
vitro antitumor activity of fatty acids. IV. The esters of acids closely related to 10hydroxy-2-decenoic acids from royal jelly against transplantable mouse leukemia.
Canadian Journal of Biochemistry and Physiology, 39, 1765–1770. https://doi.org/
10.1139/o61-195
Townsend, G. F., Morgan, J. F., & Hazlett, B. (1959). Activity of 10-hydroxydecenoic acid
from royal jelly against experimental leukaemia and ascitic tumours. Nature, 183
(4670), 1270–1271. https://doi.org/10.1038/1831270a0
Townsend, G. F., Morgan, J. F., Tolnai, S., Hazlett, B., Morton, H. J., & Shuel, R. W.
(1960). Studies on the in vitro antitumor activity of fatty acids. I. 10-Hydroxy-2decenoic acid from royal jelly. Cancer Research, 20, 503–510. http://www.ncbi.nlm.
nih.gov/pubmed/13839101.
Tsuchiya, Y., Hayashi, M., Nagamatsu, K., Ono, T., Kamakura, M., Iwata, T., &
Nakashima, T. (2020). The key royal jelly component 10-hydroxy-2-decenoic acid
protects against bone loss by inhibiting NF-kB signaling downstream of FFAR4.
Journal of Biological Chemistry, 295(34), 12224–12232. https://doi.org/10.1074/jbc.
ra120.013821
Usui, S., Soda, M., Iguchi, K., Abe, N., Oyama, M., Nakayama, T., & Kitaichi, K. (2019).
Down-regulation of aquaporin 9 gene transcription by 10-hydroxy-2-decenoic acid:
A major fatty acid in royal jelly. Food Science and Nutrition, 7(11), 3819–3826.
https://doi.org/10.1002/fsn3.1246
Vittek, J. (1995). Effect of royal jelly on serum lipids in experimental animals and
humans with atherosclerosis. Experientia, 51(9–10), 927–935. https://doi.org/
10.1007/BF01921742
Vucevic, D., Melliou, E., Vasilijic, S., Gasic, S., Ivanovski, P., Chinou, I., & Colic, M.
(2007). Fatty acids isolated from royal jelly modulate dendritic cell-mediated
immune response in vitro. International Immunopharmacology, 7(9), 1211–1220.
https://doi.org/10.1016/j.intimp.2007.05.005
Wang, J. C., & Bennett, M. (2012). Aging and atherosclerosis: Mechanisms, functional
consequences, and potential therapeutics for cellular senescence. Circulation
Research, 111(2), 245–259. https://doi.org/10.1161/CIRCRESAHA.111.261388
Wang, Y., Yan, T., Wang, Q., Wang, W., Xu, J., Wu, X., & Ji, H. (2008). PKC-dependent
extracellular signal-regulated kinase 1/2 pathway is involved in the inhibition of Ib
on AngiotensinII-induced proliferation of vascular smooth muscle cells. Biochemical
and Biophysical Research Communications, 375(1), 151–155. https://doi.org/
10.1016/j.bbrc.2008.07.137
13
M. Paredes-Barquero et al.
Journal of Functional Foods 94 (2022) 105143
Watadani, R., Kotoh, J., Sasaki, D., Someya, A., Matsumoto, K., & Maeda, A. (2017). 10Hydroxy-2-decenoic acid, a natural product, improves hyperglycemia and insulin
resistance in obese/diabetic KK-Ay mice, but does not prevent obesity. Journal of
Veterinary Medical Science, 79(9), 1596–1602. https://doi.org/10.1292/jvms.170348
Weber, K. S., Setchell, K. D. R., Stocco, D. M., & Lephart, E. D. (2001). Dietary soyphytoestrogens decrease testosterone levels and prostate weight without altering LH,
prostate 5α-reductase or testicular steroidogenic acute regulatory peptide levels in
adult male Sprague-Dawley rats. Journal of Endocrinology, 170(3), 591–599. https://
doi.org/10.1677/joe.0.1700591
Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C. M. (2018).
Long-term administration of queen bee acid (QBA) to rodents reduces anxiety-like
behavior, promotes neuronal health and improves body composition. Nutrients, 10
(1). https://doi.org/10.3390/nu10010013
Welle, S. (2002). Cellular and Molecular Basis of Age-Related Sarcopenia. Canadian
Journal of Applied Physiology, 27(1), 19–41. https://doi.org/10.1139/h02-002
Xu, D., Mei, X., & Xu, S. (2002). The research of 10-hydroxy-2-decenoic acid on
experiment hyperlipoidemic rat. Zhong Yao Cai = Zhongyaocai = Journal of Chinese
Medicinal Materials, 25(5), 346–347. http://www.ncbi.nlm.nih.gov/pubmed
/12583195.
Yang, X.-Y., Yang, D., Wei-Zhang, Wang, J.-M., Li, C.-Y., Hui-Ye, Lei, K.-F., Chen, X.-F.,
Shen, N.-H., Jin, L.-Q., & Wang, J.-G. (2010). 10-Hydroxy-2-decenoic acid from
Royal jelly: a potential medicine for RA. Journal of Ethnopharmacology, 128(2),
314–321. Doi: 10.1016/j.jep.2010.01.055.
Yang, Y. C., Chou, W. M., Widowati, D. A., Lin, I. P., & Peng, C. C. (2018). 10-Hydroxy-2Decenoic Acid of Royal Jelly Exhibits Bactericide and Anti-Inflammatory Activity in
Human Colon Cancer Cells. BMC Complementary and Alternative Medicine, 18(1), 1–7.
https://doi.org/10.1186/s12906-018-2267-9
Yao, Q. H., Zhang, X. C., Fu, T., Gu, J. Z., Wang, L., Wang, Y., Lai, Y. B., Wang, Y. Q., &
Guo, Y. (2014). ω-3 polyunsaturated fatty acids inhibit the proliferation of the lung
adenocarcinoma cell line A549 in vitro. Molecular Medicine Reports, 9(2), 401–406.
https://doi.org/10.3892/mmr.2013.1829
Yoshida, M., Hayashi, K., Watadani, R., Okano, Y., Tanimura, K., Kotoh, J., Sasaki, D.,
Matsumoto, K., & Maeda, A. (2017). Royal jelly improves hyperglycemia in obese/
diabetic KK-Ay mice. Journal of Veterinary Medical Science, 79(2), 299–307. https://
doi.org/10.1292/jvms.16-0458
Yoshimoto, N., Iwata, Y., Numata, S., Saito, K., Iwata, T., Arima, M., Shima, H.,
Tahara, S., Kuroda, M., & Sugiura, K. (2018). Recurrent cutaneous Rosai-Dorfman
disease. European Journal of Dermatology, 28(4), 562–563. https://doi.org/10.1684/
ejd.2018.3348
You, M., Miao, Z., Pan, Y., & Hu, F. (2019). Trans-10-hydroxy-2-decenoic acid alleviates
LPS-induced blood-brain barrier dysfunction by activating the AMPK/PI3K/AKT
pathway. European Journal of Pharmacology, 865(January). https://doi.org/10.1016/
j.ejphar.2019.172736
You, M., Miao, Z., Tian, J., & Hu, F. (2020). Trans-10-hydroxy-2-decenoic acid protects
against LPS-induced neuroinflammation through FOXO1-mediated activation of
autophagy. European Journal of Nutrition, 59(7), 2875–2892. https://doi.org/
10.1007/s00394-019-02128-9
Zhang, J., Tang, H., Deng, R., Wang, N., Zhang, Y., Wang, Y., Liu, Y., Li, F., Wang, X., &
Zhou, L. (2015). Berberine suppresses adipocyte differentiation via decreasing CREB
transcriptional activity. PLoS ONE, 10(4), 1–16. https://doi.org/10.1371/journal.
pone.0125667
Zhang, L., Fu, L., Zhang, S., Zhang, J., Zhao, Y., Zheng, Y., He, G., Yang, S., Ouyang, L., &
Liu, B. (2017). Discovery of a small molecule targeting ULK1-modulated cell death of
triple negative breast cancer in vitro and in vivo. Chemical Science, 8(4), 2687–2701.
https://doi.org/10.1039/C6SC05368H
Zhang, S., Nie, H., Shao, Q., Hassanyar, A. kalan, & Su, S. (2017). RNA-Seq analysis on
effects of royal jelly on tumour growth in 4T1-bearing mice. Journal of Functional
Foods, 36, 459–466. Doi: 10.1016/j.jff.2017.07.010.
Zheng, X., Zhou, F., Gu, Y., Duan, X., & Mo, A. (2017). Effect of Different Titanium
Surfaces on Maturation of Murine Bone Marrow-Derived Dendritic Cells. Scientific
Reports, 7(February), 1–9. https://doi.org/10.1038/srep41945
14
Related documents
Download