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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: [email protected] (M. Paredes-Barquero), [email protected] (J.M. Fuentes), [email protected] (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).
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