molecules

Review
Propolis: Its Role and Efficacy in Human Health and Diseases
Nadzirah Zullkiflee 1 , Hussein Taha 2 and Anwar Usman 1, *

1 Department of Chemistry, Faculty of Science, Universiti Brunei Darussalam, Jalan Tungku Link,
Gadong BE1410, Brunei
2 Environmental and Life Science, Faculty of Science, Universiti Brunei Darussalam, Jalan Tungku Link,
Gadong BE1410, Brunei
* Correspondence: [email protected]

Abstract: With technological advancements in the medicinal and pharmaceutical industries, nu-
merous research studies have focused on the propolis produced by stingless bees (Meliponini tribe)
and Apis mellifera honeybees as alternative complementary medicines for the potential treatment
of various acute and chronic diseases. Propolis can be found in tropical and subtropical forests
throughout the world. The composition of phytochemical constituents in propolis varies depending
on the bee species, geographical location, botanical source, and environmental conditions. Typically,
propolis contains lipid, beeswax, essential oils, pollen, and organic components. The latter include
flavonoids, phenolic compounds, polyphenols, terpenes, terpenoids, coumarins, steroids, amino
acids, and aromatic acids. The biologically active constituents of propolis, which include countless
organic compounds such as artepillin C, caffeic acid, caffeic acid phenethyl ester, apigenin, chrysin,
galangin, kaempferol, luteolin, genistein, naringin, pinocembrin, coumaric acid, and quercetin, have
a broad spectrum of biological and therapeutic properties such as antidiabetic, anti-inflammatory,
antioxidant, anticancer, rheumatoid arthritis, chronic obstruct pulmonary disorders, cardiovascular
diseases, respiratory tract-related diseases, gastrointestinal disorders, as well as neuroprotective,
immunomodulatory, and immuno-inflammatory agents. Therefore, this review aims to provide a
Citation: Zullkiflee, N.; Taha, H.; summary of recent studies on the role of propolis, its constituents, its biologically active compounds,
Usman, A. Propolis: Its Role and and their efficacy in the medicinal and pharmaceutical treatment of chronic diseases.
Efficacy in Human Health and
Diseases. Molecules 2022, 27, 6120. Keywords: propolis; chronic diseases; biological activity; active compounds
https://doi.org/10.3390/
molecules27186120

Academic Editor: Vassya

Stefanova Bankova 1. Introduction
Natural products have been regarded as a rich source of bioactive compounds due
Received: 15 August 2022
to the remarkable diversity of chemicals found in nature and have great medicinal and
Accepted: 14 September 2022
Published: 19 September 2022
therapeutic potential [1]. A large number of studies have been intensively focused on
exploring chemical compounds in natural products and assessing their biological potential,
Publisher’s Note: MDPI stays neutral especially for medical treatments against a variety of acute or chronic diseases [2]. Among
with regard to jurisdictional claims in the natural products in focus, propolis has been discovered to be a promising alternative
published maps and institutional affil-
due to its numerous beneficial effects. In a number of in vivo and in vitro studies, it has
iations.
been highlighted that many symptoms of diseases could be lessened and eased upon
treated with propolis.
Bees gather the resins and beeswax from various parts of plants, such as flowers and
Copyright: © 2022 by the authors.
leaf buds, exudates, resins, gums, and mucilage, surrounding their hive and then enriched
Licensee MDPI, Basel, Switzerland.
them with their β-glucosidase enzymatic saliva [3–6]. Propolis is a valuable bee resinous
This article is an open access article
product produced by different types of bees including Apis mellifera honeybees and stingless
distributed under the terms and bees from the Meliponini tribe. The propolis of each species is very diverse and has a variety
conditions of the Creative Commons of chemical compositions. The botanical plants within a radius of up to a few kilometers
Attribution (CC BY) license (https:// surrounding beehives have a huge impact on the composition and physiochemical content
creativecommons.org/licenses/by/ of propolis.
4.0/).

Molecules 2022, 27, 6120. https://doi.org/10.3390/molecules27186120 https://www.mdpi.com/journal/molecules

Molecules 2022, 27, 6120 2 of 21

Bees use propolis as a sealant to prevent cracks and crevices and to protect their
hive against outside invaders as well as to stabilize both the temperature and moisture,
and to inhibit any bacterial and fungal build-up, inside the hive [7,8]. In many cultures,
propolis has long been recognized for its medicinal and therapeutic properties and has
been historically recorded by the ancient Egyptians, Greeks, and Romans [9]. In particular,
propolis has been used for skin beautification, mummification, preservative, and antiseptic
to wounds, abscesses, and tumors [9]. In medieval times, propolis was extensively used
as a “herbal” medicine in Eastern Europe and in the Middle East. In the early modern
era, propolis became a research subject, particularly with respect to the identification of its
chemical compositions.
Propolis has been documented to have more than 500 compounds, including flavonoids,
phenolic compounds, polyphenols, terpenes, terpenoids, coumarins, steroids, amino acids,
and aromatic acids [3,10–12]. In addition, propolis is rich in phytochemicals, including
essential oils, vitamins (A, B complexes, C, and E), and important minerals, such as alu-
minum, sodium, potassium, calcium, copper, magnesium, iron, and zinc [13,14], which also
play important roles in terms of biological activity [15]. As bees collect the raw materials
of propolis from various parts of plants, pigments and compounds produced by a variety
of plants are found in propolis, and the chemical compositions vary depending on its
geographical location, botanical sources, season, and bee species [16]. In the modern era,
research on propolis has been directly based on a deeper understanding of its biological
activity, and in numerous preclinical and clinical studies, it has been proven that a wide
range of natural compounds, including flavonoids, phenolic compounds, polyphenols,
terpenes, terpenoids, and aromatic acids in propolis are potential anticancer, antiapoptotic,
antidiabetic, anti-inflammatory, antioxidant, antibacterial, and antiviral agents [17].
Recently, with the development and improvement in technology for medicines, there
has been an emerging interest in the study of propolis and its diverse constituents. In addi-
tion to its medicinal and therapeutic properties to treat various chronic diseases, propolis
has been effectively applied in the treatment of diabetes, burns, wounds, gynecological
problems, laryngological, dermatological, and neurodegenerative diseases, gastrointestinal
disease, respiratory tract-related diseases, and cardiovascular disorders, as well as COVID-
Molecules 2022, 27, 6120 19. The potential uses of propolis in human health and diseases are schematically shown 3 of 21
in Figure 1.

Figure1.1.Biological
Figure Biologicaland
andtherapeutic
therapeuticproperties
propertiesofofpropolis.
propolis.

Most studies have focused more on A. mellifera propolis than stingless bee propolis
[3]. Recently, applications of stingless bee propolis in human health and chronic diseases
have been intensively investigated, and they have been well summarized in a small num-
ber of review articles [6–9]. This current review article summarizes recently reported stud-
ies on A. mellifera and stingless bee propolis and its role and efficacy in the treatment of
various acute and chronic diseases, its significant benefits, and its main biologically active
Molecules 2022, 27, 6120 3 of 21

Most studies have focused more on A. mellifera propolis than stingless bee propolis [3].
Recently, applications of stingless bee propolis in human health and chronic diseases have
been intensively investigated, and they have been well summarized in a small number
of review articles [6–9]. This current review article summarizes recently reported studies
on A. mellifera and stingless bee propolis and its role and efficacy in the treatment of
various acute and chronic diseases, its significant benefits, and its main biologically active
compounds and their classifications. In addition, this article focuses on the vital roles of
these biological compounds in the prevention and treatment of diseases.

2. Chemical Constituents
It is noteworthy that, typically, propolis contains mainly lipid (50%), beeswax (30%),
essential oils (10%), pollen (5%), and organic components (5%). The lipid content of stingless
bee propolis is several folds greater than that of Apis melifera honeybee hives (8–16%), so
stingless bee propolis is more water-resistant than honeybee hives [15,18]. The lipids are
collected by bees from plant resins [19–21]. In general, the organic components consist of
carboxylic acids (20%), terpenoids (15%), steroids (12%), hydrocarbons (10%), sugars (6%),
alkaloids (6%), flavonoids (4%), phenols (3%), vitamins (2%), amino acids (2%), ketones
(2%), proteins (1%), and other compounds (14%) [22,23]. The most important biological
active compounds are flavonoids, polyphenols, carboxylic acids, quercetins, fatty acids,
cinnamic acid, esters, and terpenoids, such as pinocembrin, galangin, carboxylic acids,
caffeic acid, caffeic acid phenethyl ester (CAPE), saponin, phorbol, naringenin, gallic acid,
naringin, benzoic acids, amino acids, apigenin, coumaric acid, steroids, vitamins, reducing
sugar, and essential oils [24,25], as summarized in Table 1.

Table 1. Chemical compositions of propolis and their bioactive compounds.

Chemical Compositions Bioactive Compounds Ref.

Benzoic acids, caffeic acid, cinnamic acid, coumaric
Aromatic acids
acid, ferulic acid, and gallic acid
Alcohols Glycerol, erythritol, α-cedrol, xylitol
Caffeic acid phenethyl ester, 2-propenoic acid methyl
ester, 4,3-acetyloxycaffeate,
Esters
3,4 dimethoxy-trimethylsilyl esters, and
3-methoxy-4-cinnamate
Isoferulic acid, glutamic acid, phosphoric acid, malic
Fatty and aliphatic acids acid, tartaric acid, propanoic acid, butanedoic acid,
and stearic acid
Apigenin, acacetin, chrysin, galangin, genistein, [12,15,22–25]
hesperetin, kaempferol, kaempferide, luteolin,
Flavonoids
naringenin, pinobanksin, pinocembrin, quercetin,
and tetrochrysin
Aluminium (Al), copper (Cu), magnesium (Mg), zinc
Microelements (Zn), silicon (Si), tin (Sn), manganese (Mn), nickel
(Ni), and chrome (Cr)
Sugars d-Altrose, d-glucose, maltose, and d-fructose
Vitamin A (retinol), vitamin B1 (thiamine), vitamin
B2 (riboflavin), vitamin B3 (nicotinamide), vitamin B6
Vitamins
(pyridoxine), vitamin B9 (folic acid), vitamin C
(ascorbic acid), and vitamin E (tocopherol)
Others Butane, cyclohexane, cyclopentene, and guanidine

Flavonoid and phenolic compounds are an important class of plant secondary metabo-
lites. Among flavonoids, quercetin and chrysin are mostly found and distributed in the
propolis of different bee species [4]. These flavonoids are the active compounds in plant
resin, and they have various biological activities such as anticancer, antimicrobial, and
anti-inflammatory activities [26–28]. The flavonoids are sub-categorized into several classes
including flavone, flavanone, flavan, isoflavone, flavanol, flavanonol, flavan-3-ol, and
chalcone. The classification of phenolic compounds can be seen in Figure 2. Phenolic
compounds, for instance, quinones, benzophenones, coumarins, tannins, and lignans (see
Figure 3) [29], naturally originate from fruits, vegetables, leaves, bark and roots. The
Molecules 2022, 27, 6120 4 of 21

relationship between the chemical constituents in propolis and their plant origins has
been well documented by Bankova et al. [30], and it could be anticipated that propolis
consisting of different chemical constituents has a variety of biological active compounds,
bioactivities, and pharmaceutical activities. For examples, naturally phenolic compounds
have important roles in the context of protecting plants from sunlight, herbivorous animals,
and microbial pathogens. Similar to flavonoids, phenolic compounds also exhibit biologi-
Molecules 2022, 27, 6120 5 of 21
cal activities such as antioxidant, antibacterial, anticancer, anti-inflammatory, antitumor,
plasmodicidal, and anti-HIV activities [31–33].

Figure
Figure 2.
2. Classification
Classification of
of phenolic
phenolic compounds.
compounds.
Molecules2022,
Molecules 2022,27,
27,6120
6120 65 of 21
21

Figure 3. Chemical
Figure 3. Chemical structures
structuresof
ofsub-groups
sub-groupsof offlavonoids,
flavonoids,showing
showingthat
thatthe
thevarious
varioussub-groups
sub-groupsare
related to the
are related tooxidation and substitution
the oxidation of theofheterocyclic
and substitution C ring,
the heterocyclic whilewhile
C ring, individual compounds
individual com- in a
sub-group
pounds in vary depending
a sub-group varyondepending
the substituents
on the attached to the
substituents A and B
attached torings.
the A and B rings.

Limonene, -cubebene, and

Limonene, α-cubebene, -caryophyllene are
and β-caryophyllene are aa select
select example
example of of the
the most
most preva-
preva-
lent
lent terpenes,
terpenes, while
while lupeol
lupeol and -amyrin are
and β-amyrin are triterpenes
triterpenes identified
identified in
in propolis
propolis[34].
[34]. These
These
terpenes and triterpenes are classified as volatile biosynthetic compounds
terpenes and triterpenes are classified as volatile biosynthetic compounds and originate and originate
from
fromplants.
plants.Other
Othervolatile
volatilecompounds
compounds present
presentin propolis
in propolisinclude esters
include of fatty
esters acidsacids
of fatty and
organic acids. In plants, all these volatile compounds play an important
and organic acids. In plants, all these volatile compounds play an important role in the role in the context
of attracting
context insects to
of attracting aid the
insects to pollination process,process,
aid the pollination and theyand arethey
potentially applicable
are potentially as
appli-
spices, fragrances, and flavors in perfumery, cosmetics, pharmacies, and
cable as spices, fragrances, and flavors in perfumery, cosmetics, pharmacies, and food food products. In
particular,
products. In theparticular,
broad spectrum
the broad of the biological
spectrum activities
of the of such
biological volatile
activities compounds
of such volatile have
com-
been pointed out to have analgesic, anticancer, anti-inflammatory,
pounds have been pointed out to have analgesic, anticancer, anti-inflammatory, antitumor, antifungal,
anti-
antimicrobial,
tumor, antifungal, antiviral, and antiparasitic
antimicrobial, antiviral,activities [35,36]. Itactivities
and antiparasitic has been[35,36].
demonstrated in
It has been
many studies that the biological activity and quality of propolis are directly related to its
demonstrated in many studies that the biological activity and quality of propolis are di-
chemical constituents [37]. Therefore, it is not surprising that the chemical constituents of
rectly related to its chemical constituents [37]. Therefore, it is not surprising that the chem-
propolis, in addition to its physicochemical properties, is used as a standardized parameter
ical constituents of propolis, in addition to its physicochemical properties, is used as a
for its quality [38]. Most of the common bioactive compounds responsible for the biolog-
standardized parameter for its quality [38]. Most of the common bioactive compounds
ical and pharmaceutical properties of propolis are apigenin, chrysin, galangin, luteolin,
responsible for the biological and pharmaceutical properties of propolis are apigenin,
kaempferol, pinobanksin, pinocembrin, quercetin, caffeic acid, cinnamic acid, p-coumaric
chrysin, galangin, luteolin, kaempferol, pinobanksin, pinocembrin, quercetin, caffeic acid,
acid, ferulic acid, artepillin C, CAPE, and coumarin, as summarized in Figure 4.
cinnamic acid, p-coumaric acid, ferulic acid, artepillin C, CAPE, and coumarin, as sum-
marized in Figure 4.
Molecules
Molecules2022, 27,27,
2022, 6120
6120 67ofof2121

Figure 4. Common bioactive compounds in propolis.

Figure 4. Common bioactive compounds in propolis.
3. Pharmaceutical and Therapeutic Properties of Propolis
3. Pharmaceutical
As mentioned inand
the Therapeutic Properties
previous section, severalof Propolis
studies confirmed that propolis has ther-
apeuticAs mentioned
potential in the previous
in pharmacies section,toseveral
and medicines studieschronic
treat various confirmed that particularly
diseases, propolis has
therapeutic diseases,
autoimmune potential diabetes,
in pharmacies
burns,and medicines
wounds, to treat various
gynecological chronic
problems, and diseases, par-
laryngolog-
ticularly
ical, autoimmune
dermatological, diseases, diabetes, burns,
neurodegenerative, wounds, gynecological
gastrointestinal, problems,
and respiratory and lar-
tract-related
yngological,
diseases, dermatological,
cardiovascular neurodegenerative,
disorders, gastrointestinal,
antimicrobial, anticancer and respiratory
and antioxidant tract-re-
activities, and
lated diseases,
COVID-19. Here,cardiovascular disorders,
the pharmaceutical antimicrobial,
and therapeutic anticancer
properties of and antioxidant
propolis activi-
are summa-
rized.
ties, Accordingly,
and COVID-19. the Here,
bioactive
the components
pharmaceuticalof propolis related toproperties
and therapeutic their effects
of on various
propolis are
medical conditions
summarized. and diseases
Accordingly, are gathered
the bioactive in Table 2.of propolis related to their effects on
components
various medical conditions and diseases are gathered in Table 2.
3.1. Autoimmune Diseases
3.1.1.
3.1. Diabetes
AutoimmuneMellitus (Type 2)
Diseases
Type
3.1.1. 2 diabetes
Diabetes mellitus
Mellitus (T2DM)
(Type 2) is a medical condition that arises due to an elevated
level of blood sugar (glucose) that is caused by the body not being able to produce enough
Type 2 diabetes mellitus (T2DM) is a medical condition that arises due to an elevated
insulin [39]. T2DM has attracted great interest in the research of natural compounds as a
level of blood sugar (glucose) that is caused by the body not being able to produce enough
means of prevention [39]. In this sense, a small number of studies have shown that propolis,
insulin [39]. T2DM has attracted great interest in the research of natural compounds as a
which contains flavonoids that are active ingredients as antioxidant, anti-inflammatory, and
means of prevention [39]. In this sense, a small number of studies have shown that prop-
free radical-scavenging agents, may have beneficial therapeutic values for the treatments of
olis, which contains flavonoids that are active ingredients as antioxidant, anti-inflamma-
complex diseases, including T2DM [40,41]. Indeed, apigenin, chrysin, galangin, kaempferol,
tory, and free radical-scavenging agents, may have beneficial therapeutic values for the
luteolin, genistein, and pinocembrin found in propolis have been identified to possess
treatments of complex diseases, including T2DM [40,41]. Indeed, apigenin, chrysin,
Molecules 2022, 27, 6120 7 of 21

antidiabetic effects [34]. In addition, naringin, which is a natural flavanone glycoside

found in propolis, has been reported to have insulin-like and lipid-reducing properties
that reduce both insulin resistance and hyperglycemia, and this is in addition to its anti-
inflammatory, antioxidant, anticancer, antiapoptotic, and anti-osteoporosis properties [34].
Both apigenin and naringin have been administered to increase the inhibition of enzyme
glycogen phosphorylase and glucose uptake by muscle cells. These flavonoids, including
apigenin, naringin, chrysin, galangin, kaempferol, luteolin, genistein, and quercetin help
to reduce blood glucose concentration, to detect insulin in islets or serum, and to prevent
insulin release [34].
Recently, a small number of studies have further demonstrated that the use of propolis
showed significant effects, reducing the blood glucose levels, serum insulin, and serum gly-
cosylated haemoglobin (HbA1c) levels of T2DM patients [40,42,43]. It has been suggested
that propolis could influence glucose metabolism through the suppression of intestinal
α-glucosidase activity in carbohydrate digestion and stimulate the β-cells in the islets of
Langerhans in the pancreas, resulting in an increase in insulin secretion [35]. Zakerkish et al.
pointed out that patients with T2DM who received propolis supplementation for 12 weeks
had lower insulin levels and insulin resistance [40]. Various reports have also shown that
the development and complications of T2DM are highly influenced by free radicals, oxida-
tive stress, and inflammatory cytokines [43]. Active constituents in propolis can scavenge
free radicals, lower blood glucose levels, and modulate blood lipid metabolism [36]. The
oxidative stress which results in the production of reactive oxygen species (ROS) stimulates
inflammation and inflammatory mediators [34]. T2DM associated with ROS then causes
oxidative damage to important organs, such as the heart, kidneys, nerves, and eyes [34].
Subclinical inflammation, which leads to insulin resistance, is related to the characteristics
of metabolic syndrome and hyperglycemia. High glucose levels deplete the absorption
of intestinal carbohydrates and trigger glucose uptake by peripheral tissue [35]. In this
sense, the antihyperglycemic effects of propolis inhibit the production of glucose from
dietary carbohydrates, and propolis can regulate an increase in postprandial glucose and
improve insulin resistance [35]. Propolis also improves the glycemic and lipid profiles of
T2DM patients [42], demonstrating that propolis is a promising agent in preventing and
controlling diabetes mellitus.

3.1.2. Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an immuno-inflammatory chronic disorder that leads to
severe pain and functional limitations in the joints that are triggered by the immune system
of the human body [29]. The pathogenesis and related outcomes of RA are significantly
influenced by oxidative stress and inflammation. Oxidative stress decreases the blood
antioxidants of patients with RA [29]. Inflammation is positively related to the development
of RA and has been attributed to the activation of nuclear factor kappa B (NF-κB) by
ROS [31]. There are several factors that may affect the immune response, resulting in the
release of pro-inflammatory cytokines. These cytokines can cause joint regenerative changes
that are caused by inflammation and synovial cell activation. Common cytokines include
tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6).
The treatment of RA with natural supplements with fewer side effects and cost-
effectiveness, such as propolis, has been confirmed to be beneficial due to their antioxidant
and anti-inflammatory effects [32]. In particular, the chemical compounds of propolis, such
as terpenoids, phenolics, steroids, alcohols, terpenes, and sugars, have been shown to be
responsible for treatment. Additionally, propolis has been associated with the influence
of bone, cartilage, and tooth pulp regeneration. Furthermore, propolis can also suppress
inflammatory cascades by blocking the NF-κB pathway and reducing ROS by enhancing
antioxidants [29]. This is because the affected joints of RA patients have increased oxidative
stress and inflammation, which were reduced by chemical compounds [29]. In other words,
the chemical compounds of propolis have powerful anti-inflammatory properties that
allow them to regulate the basic function of immune cells and decrease the cytokines
Molecules 2022, 27, 6120 8 of 21

mediated by the immune response in T-cells and NF-κB activation [26,27]. Ansorge et al.
highlighted that both DNA synthesis and inflammatory development in T cells can be
suppressed, while the formation of the transforming growth factor-β1 (TGF-β1) of the
cells are promoted by the caffeic acid, CAPE, hesperidin, and quercetin of propolis [28].
Zhang et al. reported that apigenin and galangin decrease the mRNA levels of TNF-α [37].
In addition, CAPE is a very significant compound of propolis that has anti-inflammatory
properties and also acts as the selective inhibitor of NF-κB activation as well as being able to
precisely inhibit NF-κB activation by extensive inflammatory stimuli including TNF-α [38].
ROS are formed during aerobic metabolism, and the antioxidant defense system
protects the cell against ROS [44]. It is conceivable that when the amount of ROS produced
is more than what the antioxidant system can handle, oxidative stress leads to metabolic
failure and significant damage to DNA, lipids, and proteins [44]. In rheumatoid arthritis,
the activation of macrophages leads to an increase in ROS, which are a very significant
mediator in arthritis [44]. In addition, antioxidants could also inhibit the production of the
cytokines that are induced by TNF-α, which is a protective mechanism against rheumatoid
arthritis. Kurek-Górecka et al. reported that the antioxidant mechanism of polyphenols
found in propolis may be attributed to their scavenging effects on ROS [39]. The production
of free radicals and their synergistic effects with antioxidants are influenced by the chelation
of metal ions and nitrogen species, which are useful in reducing RA [39].
Unfortunately, the adverse effects of propolis on the activity of RA disease are still
uncertain. A multicenter, double-blind, randomization, monitored trial has been imple-
mented in order to evaluate the effect of propolis in patients with RA [45]. The clinical
trials revealed that stingless bee propolis did not improve RA quality of life or reduce
disease activity. The lack of effect of propolis on the suppression of disease activity were
associated with medications received by participants prior to the clinical study. In contrast,
Brazilian propolis have been reported to have positive effects in reducing the activity of
RA disease in mice, demonstrating that propolis may provide novel therapy options [45].
The phosphorylation of the signal transducer and activator of the transcription pathway
was inhibited by propolis, leading to a reduction in the production of interleukin-17 that
contributes to RA disease. A case study on the effects of propolis on the activity of RA
disease has therefore been suggested, taking account of additional factors that might aid a
human trial, such as the effects of propolis on the length of recovery time, the amount of
doses, and an extension of the number of male and female participants [45].

3.1.3. Anticancer
Cancer is defined as a disease caused by the abnormal growth of cells with the potential
to spread and invade other parts of the body. Some cancer cells may be resistant to
chemotherapy and the efficacy of certain drugs may also be reduced as a result of cancer
cells developing drug resistance. According to the World Health Organization (WHO),
one of the leading causes of mortality worldwide is cancer. So far, there have been no
cures for cancer, but there are numerous treatments that can help to reduce the spread of
tumors. Thus, due to the inefficacy of currently available medicines, scientific research has
focused on the production of potential drugs from natural resources for cancer treatment.
Nowadays, one of the most popular alternative drugs used is natural products. This is due
to the wide range of natural bioactive compounds that exert beneficial effects on human
health. It was also stated that most anticancer agents are derived from natural products [46].
The study of the anticancer properties of propolis resulting from different bee species
found in various geographical locations in the treatment of breast, colon, liver, lung, and
pancreatic cancer cell lines has been extensively documented in recent years [24,47,48].
Some studies focused on the efficacy of anticancer therapy by evaluating the ability of
cancer cells to initiate apoptosis and cell cycle arrest, which are the main mechanisms of
the anticancer properties of propolis [24,47,49]. The diversity of chemical compounds of
propolis highly affects its anticancer activity. The active ingredients of propolis, such as
flavonoids, exhibit chemopreventive effects against most carcinogenesis. Other active com-
Molecules 2022, 27, 6120 9 of 21

pounds of propolis with anticancer and antiproliferative properties include apigenin, caffeic
acid, CAPE, ferulic acid, galangin, luteolin, myricetin, pinocembrin, and quercetin [50,51].
Propolis also acts as pro-apoptotic protein, activates the caspase cascade mechanisms, and
releases cytochrome C from the mitochondria into the cytosol in order to target molecules
that are important in apoptosis through the intrinsic pathway [39].
In addition, propolis has been shown to exhibit synergistic effects in radiation and
chemotherapy medications for breast cancer [50]. Overall, propolis reduces proliferation,
triggers apoptosis, prevents metastases, and inhibits the progression of the cell cycle [50].
Vatansever et al. showed that bioactive components such as caffeic acid and galangin in
Turkish propolis have antiproliferative effects on breast cancer, colon cancer, and liver
cancer cells, where compounds promote apoptosis and inhibit proliferation by reducing the
viability of cancer cells [52]. The same results were observed for propolis from Indonesia,
Greece, and Serbia [50,51], where luteolin and myricetin were exposed to breast cancer
cells, with these compounds exhibiting consistent cytotoxic activity. Meanwhile, galangin
is one of the most abundant flavonoids in propolis from Algeria and Brazil and plays an
important role in controlling cell migration and cell adhesion as well as inducing lung
cancer cells [53,54]. Caffeic acid and its derivatives found in Algerian propolis also present
anticancer and antiproliferative activities [53,55]. It was also discovered that Chinese
propolis enhances cell cycle arrest and causes apoptosis in pancreatic cancer cells [56]. In
addition, the artepillin C, CAPE, galangin, kaempferol, and quercetin found in Chinese,
Brazilian, Korean propolis exhibit strong antiangiogenic properties which help to prevent
inflammation and cancer [57,58].
Ebeid et al. described a clinical test featuring propolis on a group of 135 patients
diagnosed with breast cancer undergoing radiation therapy, where the participants were
split into three groups and subjected to different tests in order to compare their specific
reactivity on propolis supplementation based on age range, menopausal status, and ra-
diotherapy [59]. A significant decrease in radiation-induced DNA damage was reported
in concerning the group of patients who underwent radiotherapy and received propolis
supplementation due to the ionizing radiation of leukocytes from breast cancer patients.
This study therefore suggested that propolis helps to boost the efficiency of serum to neu-
tralize free radicals as well as the effect the way in which iron is absorbed by the body
and hemoglobin is produced [59]. Piredda et al. investigated the tolerability, safety, and
adherence of propolis in breast cancer patients taking medications as well as the effect of
propolis on preventing oral mucositis, and it was demonstrated that the combination of
propolis and bicarbonate prevented oral mucositis in breast cancer patients [60]. Darvishi
et al. conducted a clinical trial to compare the antioxidant and anti-inflammatory benefits
of a propolis supplement to cancer patients receiving chemotherapy [61]. Patients in the
placebo group significantly increased their levels of pro-inflammatory cytokine tumor
necrosis factor, which is a biomarker of oxidative stress, while patients with propolis sup-
plementation did not show a significant increase in their pro-inflammatory cytokines levels,
but their pro-oxidant antioxidant balance was decreased.

3.2. Cardiovascular Disease

Cardiovascular disease (CVD) is one of the leading risk factors worldwide associated
with heart and blood vessels and can cause heart attack, stroke, and angina [62]. It is
normally caused by the narrowing or blocking of blood vessels [62]. Interestingly, it
has been suggested that propolis has positive effects on the treatment of cardiovascular
diseases such as hypertension, atherosclerosis, and ischemia-reperfusion (IR) injury [63].
The chances of CVDs being affected by risk factors such as oxidative stress and obesity are
very high, but propolis supplementation, with its bioactive components, could reduce the
risks associated with CVD [63].
It has been mentioned in the literature that the cardiovascular effects of propolis are
frequently associated with its antioxidant, anti-inflammatory, immunomodulatory, antihy-
pertensive, antiangiogenic, and antiatherosclerosis properties [52]. In this sense, propolis
Molecules 2022, 27, 6120 10 of 21

has a variety of cardioprotective properties due to its active ingredients, particularly its phe-
nolic compounds, such as chrysin, luteolin, pinocembrin, and quercetin [57]. The phenolic
compounds of propolis reduce the activity of cyclooxygenase, ROS, and nitric oxide (NO)
productions, which are also related to the antioxidant properties of propolis [64]. CAPE,
another major compound of propolis, also possesses an antioxidant property and exhibits
protective effects against IR injury in different tissues, including the brain, colon, heart, and
liver [57]. Ahmed et al. suggested that Malaysian propolis showed cardioprotective activity
and antioxidant properties against isoproterenol-induced oxidative stress via cytotoxic
radical-scavenging [65]. In addition, flavonoids of propolis also have the ability to prevent
the progression of pathological cardiac hypertrophy and heart conditions [66].

3.3. Coronavirus Disease

In early 2020, as declared by the WHO, the world was affected by the global outbreak
of an infectious disease resulting from severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), also known as the coronavirus disease (COVID-19) [67]. It is a very conta-
gious disease that has resulted in widespread symptoms such as a cough, fever, body ache,
a weakened immune system, acute respiratory problems, and ultimately mortality [68]. In
addition to the recently discovered disease, the treatment for COVID-19 has been limited
until recently. Given the rapid mutation and complexity of the COVID-19 virus, there has
been an extensive effort to establish effective treatments against the disease. Since then,
many researchers have focused their research on discovering alternative treatments that
use natural resources, including bee products such as propolis [69–74]. This is because
propolis contains biological properties that are applicable to the SARS-CoV-2 infection,
such as anti-inflammatory effects, the boosting of the immune system, and reducing viral
replications [70].
Some clinical studies have shown that the presence of propolis may alleviate the
treatment and relieve the symptoms of COVID-19 patients [70,71,73]. This is because the
potential active phytochemical constituents of propolis, which include alkaloids, flavonoids,
lipids, phenols, polyphenols, saponins, and tannins, all of which are strongly associated
with the pharmacological properties of propolis. Marcucci had stated that the antiviral
activities of caffeic acids, flavonoids, aromatic acids, and their esters in propolis may prevent
the transmission as well as the propagation of the virus [7]. By inducing apoptosis or by
blocking cellular pathways, propolis and its active compounds may also reduce the viability
of endothelial cells, which promote cell migration and proliferation [70]. Active ingredients
found in propolis, such as artepillin C, baccharin, caffeic acid, drupanin, myricetin, and
quercetin, display a sufficient amount of inhibition against SARS-CoV-2 helicase in human
body [75].
Although several therapy options for COVID-19 have been investigated, and the best
course of action has not yet been determined, several patients have been assigned to the
treatment of propolis supplementation therapy, in which each patient has to consume
400 mg or 800 mg/day of propolis for a week [76]. It has been demonstrated that there
is strong evidence that propolis is not only safe for consumption but that it can also be
used to treat a number of disorders associated with severe cases of COVID-19. This is
because propolis is highly associated with its active ingredients such as apigenin, artepillin
C, quercetin, caffeic acid, CAPE, and kaempferol. In particular, quercetin possess a number
of properties that are essential in the treatment of COVID-19 including antiviral, anticancer
and senolytic activities [76]. Meanwhile, the other components mentioned above can
prevent the oncogenic kinase PAK1, which stimulates a harmful immune response.
One of the potential defense mechanisms of propolis against SARS-CoV-2 infection
is an interference with the viral entry and replication process [69,77]. An in vitro study
documented the effect of flavonoids on DNA and RNA viruses, including COVID-19 [63].
From this study, both chrysin and kaempferol were exhibited to possess a significant activ-
ity in the inhibition of viral replication [78]. Further evidence showed that the interactions
between the active constituents of propolis and SARS-CoV-2 resulted in the activity of
Molecules 2022, 27, 6120 11 of 21

RNA-dependent RNA polymerase inhibition and might also synergistically increase its
antiviral properties [69]. Sahlan et al. demonstrated that angiotensin-converting enzyme 2
(ACE2), which is a receptor in the human body, has been recognized by SARS-CoV-2 [74].
SARS-CoV-2 major protease is a potential therapeutic target for COVID-19 [74]. Further-
more, Berretta et al. also pointed out that the interactions between propolis and ACE2
result in a reduction in the invasion of the host cell by SARS-CoV-2 [71]. The inhibition of
the ACE2 enzyme is a significant target for the treatment of COVID-19. This is due to its
involvement in the binding and membrane fusion process, which may be potential targets
in the development of antiviral properties for COVID-19 treatment.

Table 2. Active components of propolis and their outcome effects on various medical conditions
and diseases.

Propolis Active
Medical Disorder Type of Diseases Outcomes Ref.
Components
◦ Reduces blood
glucose levels
Apigenin, chrysin,
◦ Decreases serum
galangin, genistein, ◦ Diabetes mellitus glycosylated
kaempferol, luteolin, (Type 2) [18,22]
haemoglobin (HbA1c)
naringin, pinocembrin,
◦ Reduces insulin levels
and quercetin
◦ Scavenges free radicals and
Auto-immune disease chelate metals

◦ Diminishes inflammation
◦ Suppresses DNA synthesis
Apigenin, caffeic acid, and the production of
CAPE, galangin, ◦ Rheumatoid arthritis inflammatory cytokines [22–24,27,28]
hesperidin, and quercetin ◦ Inhibits NF-κB activation
◦ Decreases the mRNA levels
of TNF-α

Apigenin, artepillin C, ◦ Prevents cell proliferation

◦ Breast cancer ◦ Inhibits the angiogenesis of
caffeic acid, CAPE, ◦ Colon cancer
chrysin, galangin, cancer cells
Cancer ◦ Liver cancer ◦ Stimulates apoptosis [50,53,79,80]
kaempferol, luteolin, ◦ Lung cancer
myricetin, pinocembrin, ◦ Selective toxic properties
◦ Pancreatic cancer against tumor cells
and quercetin
◦ Apoptosis effects

◦ Stroke ◦ Reduces the activity of

CAPE, chrysin, ◦ Hypertension cyclooxygenase
Cardiovascular kaempferide, luteolin, ◦ Atherosclerosis ◦ Scavenges reactive oxygen [57,63,64]
diseases pinocembrin, pinostrobin, ◦ Ischemia-reperfusion species (ROS)
and quercetin injury ◦ Stimulates nitric oxide
(NO) production

Severe acute Artepillin C, baccharin, ◦ Inhibits coronavirus in the

respiratory syndrome caffeic acid, CAPE, ◦ Coronavirus disease human body
(COVID-19) ◦ Prevents the viral [69–75]
coronavirus 2 drupanin,
(SARS-CoV-2) myricetin, and quercetin transmission and viral
propagation of the virus

◦ Protects against
gastric ulceritis
◦ Gastric ulcer ◦ Improves the
Artepillin C, CAPE, ◦ Peptic ulcer intestinal barrier
Gastrointestinal coumaric acid, galangin, ◦ Cancer ◦ Prevents pathogens, toxins,
◦ Oral mucositis [81]
disorder kaempferide, 4-methyl and bacterial dislocation
ester, and aromadendrin ◦ Gastritis colitis from gut to blood
◦ Mucositis ulcers ◦ Reduces colon damage
◦ Suppresses colonic
inflammation
Molecules 2022, 27, 6120 12 of 21

Table 2. Cont.

Propolis Active
Medical Disorder Type of Diseases Outcomes Ref.
Components

◦ Inhibits the production of

NO in microglia
◦ Neuroprotection against
Ischemia/reperfusion-
induced injury
◦ Alzheimer’s disease ◦ Prevent inflammatory stress
Apigenin, CAPE, chrysin, ◦ Parkinson’s disease
Neurological ◦ Blocks the activation of
kaempferol, pinocembrin, ◦ Epilepsy [24,82–85]
disorders NF-κB in microglia
and quercetin ◦ Ischemia ◦ Neuroprotection against
apoptosis and oxidation
◦ Enhances memory
impairment by inhibiting
oxidative damage
◦ Inhibits ROS formation

◦ Inhibits mast cell

Artepillin C, baccharin, degranulation
CAPE, chrysin, galangin, ◦ Inhibits allergen-induced
kaempferide, kaempferol, inflammation
Respiratory ◦ Asthma
naringenin, pinocembrin, ◦ Inhibits ROS production [85–87]
tract-related diseases
benzyl caffeate, geranyl ◦ Blocks NF-κB expression in
caffeate, and 3-methyl-2- macrophage cell lineage
butenyl caffeate ◦ Exhibits anti-inflammatory
and anti-allergic activities

◦ Prevents acute
Caffeic acid, CAPE, lung inflammation
cinnamic acid, ◦ Chronic obstructive ◦ Reduces stomatitis, oral
aromandendrin, pulmonary disease infections, and dental plaque [88–91]
N-acetylcysteine, (COPD) ◦ Inhibits the NF-κB pathway
p-coumaric acid, ◦ Reduces
pro-inflammatory cytokines

3.4. Gastrointestinal Disorder

Gastrointestinal (GI) disorder is a medical condition that affects the motility of gastroin-
testinal tract, which includes a range of vital digestive organs such as the mouth, esophagus,
stomach, bowels, rectum, and anus [92]. Propolis has been explored and emphasized in the
treatment of GI disorder. Nowadays, a variety of GI disorders, including those that affect
GI disorders, such as cancer, oral mucositis, peptic, gastritis, colitis, and ulcers of mucositis,
have been successfully treated with propolis due to its bioactive components with various
biological and therapeutic activities.
One of the common GI disorders is irritable bowel syndrome (IBS), which can be
detected by stomach discomfort and altered bowel function [93]. It has been documented
that the application of propolis via supplementation has improved the symptoms experi-
enced by the IBS patients [93]. This might be due to the presence of quercetin glycosides
in propolis, which reduce the visceral motor response, thus, increasing the pressure of
pain threshold. Propolis has also been reported to inhibit the transcription of the inducible
nitric oxide synthase (iNOS) gene, which can be influenced by NF-κB [93]. It has been
documented that propolis reduces colon damage, suppresses colonic inflammation, and
increases levels of mucosal and mucin secretion. Propolis can also improve the function of
the intestinal barrier from the upregulation of the intestinal protein gene [94], as propolis is
rich in prebiotics that improve the intestinal barriers, thus preventing the dislocations of
bacterial, pathogens, and toxins from the gut to the blood stream [81,94].

3.5. Neurological Disorders

Neurological disorder is a medical condition that affects the human brain, especially
the nerves that connect the spinal cord around the body. There are different types of
neurological disorders, including Alzheimer’s disease, Parkinson’s disease, epilepsy, and
Molecules 2022, 27, 6120 13 of 21

ischemia, which are accompanied by the slow immune response of the brain, elevated
oxidative stress, and induced inflammatory signaling [95]. The main mechanisms essential
in cognitive impairment, neurodegeneration, and neurological disorder in the brain have
been reported to be oxidative stress and neuroinflammations. Several studies have affirmed
that propolis can be utilized in the treatment of these disorders because of the its potential
anti-inflammatory, antioxidant, and immunomodulatory neuropharmacological effects of
its active constituents [32]. This is because the lipophilic properties of propolis allow most
of the major components of propolis to access the brain and navigate the functions of the
blood-brain barrier [10,96].
Some of the metabolite classes of propolis compounds, such as alkaloids, saponins,
sterols, tannins, and terpenoids, have positive effects on the central nervous system
(CNS) [97]. Meanwhile, polyphenolic compounds such as kaempferol, pinocembrin, and
quercetin are considered to be biomarkers in antioxidant activity that are beneficial for
oxidative stress and have anti-inflammatory effects to modulate neurological disorders.
These polyphenolic compounds have been proven to stimulate neurotransmitters, scavenge
free radicals, and inhibit specific enzymes [98].
A systematic review study to assess the potential of propolis to protect the brain and
treat neurological conditions and injuries was summarized by Zulhendri et al. [99]. It was
suggested that propolis was repeatedly shown to decrease the expression of inflammatory
and oxidative markers, such as TNF and nitric oxide, in organisms and cell cultures
exposed to chemical and radiation toxicity, while increasing and maintaining antioxidant
parameters, including superoxide dismutase. The presence of propolis prevented apoptosis
by lowering the expression of the protein-coding genes which are linked to apoptosis
signaling pathways. It is also believed that propolis helped to protect cell membranes and
prevent tissue morphology from further deteriorating due to toxicity [99].
CAPE and pinocembrin also play an essential role in the treatment of these neurologi-
cal diseases due to their neuroprotective properties [82,83]. Some of the aromatic acids of
propolis including caffeic acid, CAPE, and vanillin have the potential to enhance memory
loss due to their immunomodulatory, antioxidant, and anticancer properties. In terms of
antioxidant activity, CAPE, which acts as selective inhibitor of the NF-κB activation, also
decreases lipid peroxidation by inhibiting the cyclooxygenase-2 overproduction that is me-
diated by NF-κB transcription. Machado et al. reported that lupeol exhibits antidepressant
and anticonvulsant activities that are important in the treatment of the CNS [84]. Mean-
while, pinocembrin has been described to elicit antioxidant and anti-inflammatory effects
on the CNS by reacting on the mitogen-activated protein kinase signaling cascade and to
modulate NF-κB, thereby preventing overstimulation [85]. Furthermore, the therapeutic
potential of propolis appears to be based on its ability to reduce the expression of pro-
inflammatory mediators and the generation of ROS, with it also stimulating neuroprotective
factors and antioxidants [24].

3.6. Respiratory Tract-Related Disease

3.6.1. Asthma
Allergic disorders have become a global health burden, resulting in a number of
challenges due to the adverse factors of medicinal accessibility, high costs in terms of ther-
apy, and a lack of therapeutic potential for patients. Nevertheless, therapeutic treatments
of allergic reactions, such as asthma, atopic dermatitis, and allergic rhinitis have been
well documented and supported by many preclinical and clinical studies. Asthma is a
long-term inflammatory condition that causes narrow and swollen airways in the lungs,
resulting in chest tightness, wheezing, and difficulty breathing, especially due to allergen
inhalation. Research on asthma and its alternative medicinal treatments using natural
resources including bee products such as propolis has substantially increased. Evidently,
the active compounds of propolis have beneficial effects on asthmatic conditions due to its
anti-allergic, anti-asthmatic, and anti-inflammatory properties, which could be attributed
to the inhibitory effects on the activation of basophil and mast cells [100,101]. These two
Molecules 2022, 27, 6120 15 of 21

Molecules 2022, 27, 6120 14 of 21

its anti-allergic, anti-asthmatic, and anti-inflammatory properties, which could be at-

tributed to the inhibitory effects on the activation of basophil and mast cells [100,101].
cellstwo
These are considered to be the primary
cells are considered to be the effector cellseffector
primary in allergic
cellsinflammation reactions [101].
in allergic inflammation
Immunoglobulin E (IgE) receptors are cross-linked when an allergen
reactions [101]. Immunoglobulin E (IgE) receptors are cross-linked when an allergen binds to IgE, thus
binds
activating basophils and mast cells and resulting in the release of inflammatory
to IgE, thus activating basophils and mast cells and resulting in the release of inflamma- mediators
such
tory as histamine
mediators and
such as pro-inflammatory
histamine cytokines such
and pro-inflammatory as TNF-α
cytokines [102].
such The inhibitory
as TNF- [102].
mechanisms of propolis in allergic reactions can be seen in Figure 5.
The inhibitory mechanisms of propolis in allergic reactions can be seen in Figure 5.

Figure 5. Inhibitory
Figure mechanisms
5. Inhibitory of propolis
mechanisms in in
of propolis allergic reactions.
allergic reactions.

It has
It has been
been suggested
suggested that
that thethe aqueous
aqueous extract
extract of of Taiwanese
Taiwanese propolis
propolis consists
consists of of
T T
helper
helper cellcell response
response regulators
regulators that
that areare beneficial
beneficial in in
thethe context
context of of asthmatic
asthmatic conditions
conditions
duedue to their
to their modulatory
modulatory effects
effects on bothon both T helper
T helper cell responses
cell responses [86]. TThese
[86]. These T cells
cells can causecan
cause tissue remodeling and airway hyper responsiveness, which
tissue remodeling and airway hyper responsiveness, which are associated with asthma are associated with
asthma
[103]. [103].etKhayyal
Khayyal et al. highlighted
al. highlighted that alternative
that alternative medicines medicines
enrichedenriched with propolis
with propolis have
have resulted
resulted in a decrease
in a decrease in the frequency
in the frequency and of
and severity severity of theattacks,
the asthma asthmawhich
attacks,canwhich
be
can be correlated
correlated with the in
with the decrease decrease in inflammatory
inflammatory markers,
markers, such such as
as TNF-, TNF-α,
IL-4, IL-4,IL-
IL-5, and IL-5,
and IL-6
6 [104]. The[104].
active The active components
components of propolis,ofincluding
propolis,flavonoids
including compounds
flavonoids compounds
(chrysin,
(chrysin, galangin, kaempferide, kaempferol, and pinocembrin), have been revealed to
have substantial medicinal value, especially in in vivo studies of allergic disorders including
Molecules 2022, 27, 6120 15 of 21

asthma [86]. Nakamura et al. found that both CAPE and kaempferol have contributed to
the anti-allergic activities of Chinese and Brazilian propolis extracts [100]. According to
Tani et al., cinnamic acid derivatives such as artepillin C, baccharin, CAPE, kaempferide,
and naringenin are also present in Brazilian propolis and show anti-allergic effects, and,
in particular, the effects of artepillin C on allergen-induced allergic inflammation have
been evaluated [105]. Notably, an in vitro study showed that active compounds of propolis
including artepillin C, CAPE, benzyl caffeate, geranyl caffeate, and 3-methyl-2-butenyl
caffeate are considered to be the primary contact allergen of propolis [106]. Another in vitro
study demonstrated that artepillin C can inhibit cytokine secretions and ROS production,
blocking the expression of NF-κB in macrophage cell lineage [87,88]. CAPE also inhibits
the generation and activation of asthma by monocyte-derived dendritic cells [107]. Strong
inflammatory flavonoids, such as quercetin, relieve asthma by suppressing exotoxin and
IL-13, reducing eosinophilic mediators and type 2 helper cytokines. As a result, propolis
and its active compounds will be able to effectively control and regulate asthma.

3.6.2. Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that is caused
by an obstruction of airflow from the lungs that results in multiple problems including
breathing difficulties, wheezing, coughing, and mucus production [108]. There are several
causes of COPD, including genetic disorders, air pollution, exposure to dust, and the
most common is smoking [108]. Bronchodilators, corticosteroids, oxygen therapy, vac-
cines, and antibiotics are some of the optional treatments for COPD. The applications of
natural products in antibiotics for COPD treatment have increased [109]. Many different
types of natural products, such as ginger, thyme, curcumin, red sage, ginseng, and licorice
roots have been used in multiple respiratory treatments [110]. Recently, numerous stud-
ies have reported that bee products, such as propolis, have useful and effective benefits
in the treatment of asthma, respiratory diseases, and coughs [1,89,111]. This is because
propolis contains numerous effective components such as flavonoids, phenolic compounds,
phenolic acids, terpenes, terpenoids, not to mention its broad spectrum of therapeutic
properties, such as anti-inflammatory, antioxidant, antimicrobial, and immunomodulatory
properties [1,89,111–114]. Various clinical trials have been evaluated to validate the effi-
cacy of propolis and its bioactive components as alternative complementary therapy in
minimizing inflammatory-related conditions [104]. Inflammation was observed to have
been reduced due to the synergistic effect of active compounds present in propolis [89–91].
Various clinical trials have been studied to validate the efficacy of propolis and its bioactive
components as alternative complementary therapy in minimizing inflammatory-related
conditions [104]. Inflammation reduces due to the synergistic effect of active compounds
present in propolis [89–91].
Flavonoids, pinocembrin, polyphenols, alkaloids, coumarins, saponins, steroids, and
triterpenoids have been reported to be prominent therapeutics against respiratory inflam-
mation [115]. Patients with COPD have been reported to have reduced sputum production
after using the propolis and N-acetylcysteine formulation [104]. de Moura et al. suggested
that aqueous extract of Brazilian propolis exhibited anti-inflammatory and antiangiogenic
due to the presence of CAPE, artepillin C, and caffeoylquinic in the extract [116]. Propolis
has various biological targets and cellular effects as well as antioxidant, anti-inflammatory,
and anticancer properties. Thus, it has the ability to reduce multiple pro-inflammatory
cytokines, including TNF-α, IL-6, and IL-8.
A recent study documented that propolis successfully treated stomatitis and reduced
oral infections as well as dental plaque, which can cause ulceration [117]. The antimicrobial
properties from a mouthwash that contains propolis have helped to protect from oral
infections [118]. Furthermore, by reducing pro-inflammatory cytokines as well as inducing
apoptosis in macrophages, CAPE has the ability to inhibit the NF-κB pathway, resulting in
the upregulation of NF-κB in macrophages and epithelial cells [119]. Flavonoids such as
Molecules 2022, 27, 6120 16 of 21

kaempferol, luteolin, and naringenin have been shown to exhibit activities that might be
related to their antioxidant and anti-inflammatory properties.

4. Conclusions
In conclusion, propolis has served as a rich source in the context of drug discovery
and has shown great potential for treatment in various acute and chronic human diseases.
Research efforts on propolis have been intensively devoted in such frameworks. Propolis
has been demonstrated to have some adverse effects on the human body. The potentially
active phytochemical constituents of propolis include flavonoids, phenolic compounds,
polyphenols, terpenes, terpenoids, coumarins, steroids, amino acids, and aromatic acids.
The composition of phytochemical constituents varies according to bee species, geographi-
cal location, botanical source, and environmental conditions. Nevertheless, the biologically
active compounds of propolis are artepillin C, caffeic acid, CAPE, apigenin, chrysin, galan-
gin, kaempferol, luteolin, genistein, naringin, pinocembrin, coumaric acid, and quercetin,
which have a broad spectrum of biological and therapeutic properties such as antidiabetic,
anti-inflammatory, antioxidant, anticancer, cardioprotective, neuroprotective, immunomod-
ulatory, and immuno-inflammatory agents. Propolis has been implemented in both clinical
and physiological stages with various conditions. Most of the reported studies are based
on experimental stage and randomized clinical trials, and, hence, further studies on the
treatment of acute and chronic diseases with propolis would be of interest. It is also
necessary to expand the wide application of propolis and to further explore its isolated
bioactive components, which have multiple targets and various pharmacological activities.
An improvement of the safety of propolis products, especially for oral supplementation,
and its efficacy in long-term treatments, are also important to ensure its safe use.

Author Contributions: Conceptualization, A.U.; resources, H.T. and N.Z.; data curation, N.Z.;
writing—original draft preparation, N.Z. and A.U.; writing—review and editing, N.Z. and A.U.;
supervision, A.U. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Atanasov, A.G.; Zotchev, S.B.; Dirsch, V.M.; Supuran, C.T. Natural products in drug discovery: Advances and opportunities. Nat.
Rev. Drug Discov. 2021, 20, 200–216. [CrossRef] [PubMed]
2. Kim, J.H.; Kismali, G.; Gupta, S. Natural products for the prevention and treatment of chronic inflammatory diseases: Integrating
traditional medicine into modern chronic diseases care. Evid. Based Complement. Altern. Med. 2018, 2018, 9837863. [CrossRef]
[PubMed]
3. Wagh, V.D. Propolis: A wonder bees product and its pharmacological potentials. Adv. Pharmacol. Sci. 2013, 2013, 308249.
[CrossRef] [PubMed]
4. Salatino, A.; Salatino, M.L.F.; Negri, G. How diverse is the chemistry and plant origin of Brazilian propolis? Apidologie 2021, 52,
1075–1097. [CrossRef] [PubMed]
5. Pascoal, A.; Feás, X.; Dias, T.; Dias, L.G.; Estevinho, L.M. Chapted 13—The role of honey and propolis in the treatment of infected
wounds. In Microbiology for Surgical Infections Diagnosis, Prognosis and Treatment; Academic Press: Cambridge, MA, USA, 2014;
pp. 221–234.
6. Anjum, S.I.; Ullah, A.; Khan, K.A.; Attaullah, M.; Khan, H.; Ali, H.; Bashir, M.A.; Tahir, M.; Ansari, M.J.; Ghramh, H.A.; et al.
Composition and functional properties of propolis (bee glue): A review. Saudi J. Biol. Sci. 2019, 26, 1695–1703. [CrossRef]
[PubMed]
7. Marcucci, M.C. Propolis: Chemical composition, biological properties and therapeutic activity. Apidologie 1995, 26, 83–99.
[CrossRef]
8. Shanahan, M.; Spivak, M. Resin use by stingless bees: A review. Insects 2021, 12, 719. [CrossRef]
9. Kuropatnicki, A.K.; Szliszka, E.; Krol, W. Historical aspects of propolis research in modern times. Evid. Based Complement. Altern.
Med. 2013, 2013, 964149. [CrossRef]
10. Fokt, H.; Pereira, A.; Ferreira, A.M.; Cunha, A.; Aguiar, C. How do bees prevent hive infections? The antimicrobial properties of
propolis. Curr. Res. Technol. Educ. Top. Appl. Microbiol. Microb. Biotechnol. 2010, 2, 481–493.
11. Toreti, V.C.; Sato, H.H.; Pastore, G.M.; Park, Y.K. Recent progress of propolis for its biological and chemical compositions and its
botanical origin. Evid. Based Complement. Altern. Med. 2013, 2013, 697390. [CrossRef]
Molecules 2022, 27, 6120 17 of 21

12. Ahangari, Z.; Naseri, M.; Vatandoost, F. Propolis: Chemical composition and its applications in endodontics. Iran. Endod. J. 2018,
13, 285–292. [PubMed]
13. Pasupuleti, V.R.; Sammugam, L.; Ramesh, N.; Gan, S.H. Honey, propolis, and royal jelly: A comprehensive review of their
biological actions and health benefits. Oxid. Med. Cell. Longev. 2017, 2017, 1259510. [CrossRef] [PubMed]
14. Abdullah, N.A.; Ja’afar, F.; Yasin, H.M.; Taha, H.; Petalcorin, M.I.R.; Mamit, M.H.; Kusrini, E.; Usman, A. Physicochemical
analyses, antioxidant, antibacterial, and toxicity of propolis particles produced by stingless bee Heterotrigona itama found in
Brunei Darussalam. Heliyon 2019, 5, e02476. [CrossRef]
15. Abdullah, N.A.; Zullkiflee, N.; Zaini, S.N.Z.; Taha, H.; Hashim, F.; Usman, A. Phytochemicals, mineral contents, antioxidants, and
antimicrobial activities of propolis produced by Brunei stingless bees Geniotrigona thoracica, Heterotrigona itama, and Tetrigona
binghami. Saudi J. Biol. Sci. 2020, 27, 2902–2911. [CrossRef]
16. Bankova, V. Chemical diversity of propolis and the problem of standardization. J. Ethnopharmacol. 2005, 100, 114–117. [CrossRef]
17. Huang, S.; Zhang, C.P.; Wang, K.; Li, G.Q.; Hu, F.L. Recent advances in the chemical composition of propolis. Molecules 2014, 19,
19610–19623.
18. Devequi-Nunes, D.; Machado, B.A.S.; Barreto, G.A.; Silva, J.R.; da Silva, D.F.; da Rocha, J.L.C.; Brandão, H.N.; Borges, V.M.;
Umsza-Guez, M.A. Chemical characterization and biological activity of six different extracts of propolis through conventional
methods and supercritical extraction. PLoS ONE 2018, 13, e0207676. [CrossRef] [PubMed]
19. Bonvehi, J.S.; Coll, F.V.; Jorda, R.E. The composition, active components and bacteriostatic activity of propolis in dietetics. J. Am.
Oil Chem. Soc. 1994, 71, 529–532. [CrossRef]
20. Kalogeropoulos, N.; Konteles, S.J.; Troullidou, E.; Mourtzinos, I.; Karathanos, V.T. Chemical composition, antioxidant activity and
antimicrobial properties of propolis extracts from Greece and Cyprus. Food Chem. 2009, 116, 452–461. [CrossRef]
21. Nedjia, N.; Loucif-Ayad, W. Antimicrobial activity of Algerian propolis in foodborne pathogens and its quantitative chemical
composition. Asian Pacific J. Trop. Dis. 2014, 4, 433–437. [CrossRef]
22. Kurek-Górecka, A.; Keskin, Ş.; Bobis, O.; Felitti, R.; Górecki, M.; Otr˛eba, M.; Stojko, J.; Olczyk, P.; Kolayli, S.; Rzepecka-Stojko, A.
Comparison of the antioxidant activity of propolis samples from different geographical regions. Plants 2022, 11, 1203. [CrossRef]
[PubMed]
23. Santos, V.R. Chapter 5—Propolis: Alternative medicine for the treatment of oral microbial diseases. In Alternative Medicine;
Sakagami, H., Ed.; IntechOpen: Vienna, Austria, 2012; Volume 11, pp. 133–169.
24. Sawicka, D.; Car, H.; Borawska, M.H.; Nikliński, J. The anticancer activity of propolis. Folia Histochem. Cytobiol. 2012, 50, 25–37.
[CrossRef] [PubMed]
25. Maciejewicz, W.; Daniewski, M.; Bal, K.; Markowski, W. GC-MS identification of the flavonoid aglycones isolated from propolis.
Chromatographia 2001, 53, 343–346. [CrossRef]
26. Banskota, A.H.; Tezuka, Y.; Kadota, S. Recent progress in pharmacological research of propolis. Phyther. Res. 2001, 15, 561–571.
[CrossRef]
27. Wolska, K.; Górska, A.; Antosik, K.; Ługowska, K. Immunomodulatory effects of propolis and its components on basic immune
cell functions. Indian J. Pharm. Sci. 2019, 81, 575–588. [CrossRef]
28. Ansorge, S.; Reinhold, D.; Lendeckel, U. Propolis and some of its constituents down-regulate DNA synthesis and inflammatory
cytokine production but induce TGF-Beta1 production of human immune cells. Z. Naturforsch. 2003, 58, 580–589. [CrossRef]
29. Nattagh-Eshtivani, E.; Pahlavani, N.; Ranjbar, G.; Navashenaq, J.G.; Salehi-Sahlabadi, A.; Mahmudiono, T.; Shalaby, M.N.; Jokar,
M.; Nematy, M.; Barghchi, H.; et al. Does propolis have any effect on rheumatoid arthritis? A review study. Food Sci. Nutr. 2021,
10, 1003–1020. [CrossRef]
30. Bankova, V.S.; De Castro, S.L.; Marcucci, M.C. Propolis: Recent advances in chemistry and plant origin. Apidologie 2000, 31, 3–15.
[CrossRef]
31. Filippin, L.I.; Vercelino, R.; Marroni, N.P.; Xavier, R.M. Redox signalling and the inflammatory response in rheumatoid arthritis.
Clin. Exp. Immunol. 2008, 152, 415–422. [CrossRef]
32. Farooqui, T.; Farooqui, A.A. Beneficial effects of propolis on human health and neurological diseases. Front. Biosci. 2012, 4,
779–793. [CrossRef]
33. Zullkiflee, N.; Taha, H.; Abdullah, N.A.; Hashim, F.; Usman, A. Antibacterial and antioxidant activities of ethanolic and water
extracts of stingless bees Tetrigona binghami, Heterotrigona itama, and Geniotrigona thoracica propolis found in Brunei. Philipp. J. Sci.
2022, 151, 1455–1462.
34. Rivera-Yañez, N.; Rodriguez-Canales, M.; Nieto-Yañez, O.; Jimenez-Estrada, M.; Ibarra-Barajas, M.; Canales-Martinez, M.M.;
Rodriguez-Monroy, M.A. Hypoglycaemic and antioxidant effects of propolis of Chihuahua in a model of experimental diabetes.
Evid. Based Complement. Altern. Med. 2018, 2018, 4360356. [CrossRef] [PubMed]
35. Matsui, T.; Ebuchi, S.; Fujise, T.; Abesundara, K.J.; Doi, S.; Yamada, H.; Matsumoto, K. Strong antihyperglycemic effects of
water-soluble fraction of Brazilian propolis and its bioactive constituent, 3,4,5-tri-o-caffeoylquinic acid. Biol. Pharm. Bull. 2004, 27,
1797–1803. [CrossRef] [PubMed]
36. Fuliang, H.U.; Hepburn, H.R.; Xuan, H.; Chen, M.; Daya, S.; Radloff, S.E. Effects of propolis on blood glucose, blood lipid and
free radicals in rats with diabetes mellitus. Pharmacol. Res. 2005, 51, 147–152. [CrossRef]
37. Zhang, X.; Wang, G.; Gurley, E.C.; Zhou, H. Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response
through multiple mechanisms in macrophages. PLoS ONE 2014, 9, e107072. [CrossRef]
Molecules 2022, 27, 6120 18 of 21

38. Ramos, A.; Miranda, J. Propolis: A review of its anti-inflammatory and healing actions. J. Venom. Anim. Toxins Incl. Trop. Dis.
2007, 13, 697–710. [CrossRef]
39. Kurek-Górecka, A.; Rzepecka-Stojko, A.; Górecki, M.; Stojko, J.; Sosada, M.; Swierczek-Zieba, G. Structure and antioxidant activity
of polyphenols derived from propolis. Molecules 2014, 19, 78–101. [CrossRef]
40. Zakerkish, M.; Jenabi, M.; Zaeemzadeh, N.; Hemmati, A.A.; Neisi, N. The effect of Iranian propolis on glucose metabolism, lipid
profle, insulin resistance, renal function and inflammatory biomarkers in patients with type 2 diabetes mellitus: A randomized
double-blind clinical trial. Sci. Rep. 2019, 9, 7289. [CrossRef]
41. Daleprane, J.B.; Abdalla, D.S. Emerging roles of propolis: Antioxidant, cardioprotective, and antiangiogenic actions. Evid. Based
Complement. Altern. Med. 2013, 2013, 175135. [CrossRef]
42. Samadi, N.; Mozaffari-Khosravi, H.; Rahmanian, M.; Askarishahi, M. Effects of bee propolis supplementation on glycemic control,
lipid profile and insulin resistance indices in patients with type 2 diabetes: A randomized, double-blind clinical trial. J. Integr.
Med. 2017, 15, 124–134. [CrossRef]
43. Pahlavani, N.; Malekahmadi, M.; Firouzi, S.; Rostami, D.; Sedaghat, A.; Moghaddam, A.B.; Ferns, G.A.; Navashenaq, J.G.;
Reazvani, R.; Safarian, M.; et al. Molecular and cellular mechanisms of the effects of propolis in inflammation, oxidative stress
and glycemic control in chronic diseases. Nutr. Metab. 2020, 17, 65. [CrossRef] [PubMed]
44. Roy, J.; Galano, J.M.; Durand, T.; Le Guennec, J.Y.; Lee, J.C. Physiological role of reactive oxygen species as promoters of natural
defenses. FASEB J. 2017, 31, 3729–3745. [CrossRef] [PubMed]
45. Matsumoto, Y.; Takahashi, K.; Sugioka, Y.; Inui, K.; Okano, T.; Mandai, K.; Yamada, Y.; Shintani, A.; Koike, T. Double-blinded
randomized controlled trial to reveal the effects of Brazilian propolis intake on rheumatoid arthritis disease activity index; BeeDAI.
PLoS ONE 2021, 16, e0252357. [CrossRef]
46. Karikas, G.A. Anticancer and chemopreventing natural products: Some biochemical and therapeutic aspects. J. BUON 2010, 15,
627–638. [PubMed]
47. Elumalai, P.; Muninathan, N.; Megalatha, S.T.; Suresh, A.; Kumar, K.S.; Jhansi, N.; Kuppuswamy Kalaivani, K.; Krishnamoorthy,
G. An Insight into anticancer effect of propolis and its constituents: A review of molecular mechanisms. Evid. Based Complement.
Altern. Med. 2022, 2022, 5901191. [CrossRef]
48. Demir, S.; Aliyazicioglu, Y.; Turan, I.; Misir, S.; Mentese, A.; Yaman, S.O.; Akbulut, K.; Kilinc, K.; Deger, O. Antiproliferative and
proapoptotic activity of Turkish propolis on human lung cancer cell line. Nutr. Cancer. 2016, 68, 165–172. [CrossRef]
49. Reed, J.C. Mechanisms of apoptosis. Am. J. Pathol. 2000, 157, 1415–1430. [CrossRef]
50. Masadah, R.; Ikram, D.; Rauf, S. Effects of propolis and its bioactive components on breast cancer cell pathways and the molecular
mechanisms involved. Breast Dis. 2021, 40, S15–S25. [CrossRef]
51. Turan, I.; Demir, S.; Misir, S.; Kilinc, K.; Mentese, A.; Aliyazicioglu, Y.; Deger, O. Cytotoxic effect of Turkish propolis on liver,
colon, breast, cervix and prostate cancer cell lines. Trop. J. Pharm. Res. 2015, 14, 777. [CrossRef]
52. Vatansever, H.S.; Sorkun, K.; Gurhan, S.I.D.; Ozdal-Kurt, F.; Turkoz, E.; Gencay, O.; Salih, B. Propolis from Turkey induces
apoptosis through activating caspases in human breast carcinoma cell lines. Acta Histochem. 2010, 112, 546–556. [CrossRef]
53. Benguedouar, L.; Lahouel, M.; Gangloff, S.C.; Durlach, A.; Grange, F.; Bernard, P.; Antonicelli, F. Ethanolic extract of Algerian
propolis and galangin decreased Murine melanoma tumor progression in mice. Anticancer Agents Med. Chem. 2016, 16, 1172–1183.
[CrossRef] [PubMed]
54. Frión-Herrera, Y.; Díaz-García, A.; Ruiz-Fuentes, J.; Rodríguez-Sánchez, H.; Sforcin, J.M. Brazilian green propolis induced
apoptosis in human lung cancer A549 cells through mitochondrial-mediated pathway. J. Pharm. Pharmacol. 2015, 67, 1448–1456.
[CrossRef] [PubMed]
55. Brihoum, H.; Maiza, M.; Sahali, H.; Boulmeltout, M.; Barratt, G.; Benguedouar, L.; Lahouel, M. Dual effect of Algerian propolis on
lung cancer: Antitumor and chemopreventive effects involving antioxidant activity. Braz. J. Pharm. Sci. 2018, 54, 1–12. [CrossRef]
56. Tao, L.; Chen, X.; Zheng, Y.; Wu, Y.; Jiang, X.; You, M.; Li, S.; Hu, F. Chinese propolis suppressed pancreatic cancer Panc-1 cells
proliferation and migration via Hippo-YAP pathway. Molecules 2021, 26, 2803. [CrossRef] [PubMed]
57. Ahn, M.R.; Kunimasa, K.; Kumazawa, S.; Nakayama, T.; Kaji, K.; Uto, Y.; Hori, H.; Nagasawa, H.; Ohta, T. Correlation between
antiangiogenic activity and antioxidant activity of various components from propolis. Mol. Nutr. Food Res. 2009, 53, 643–651.
[CrossRef] [PubMed]
58. Silva, H.; Francisco, R.; Saraiva, A.; Francisco, S.; Carrascosa, C.; Raposo, A. The cardiovascular therapeutic potential of propolis-A
comprehensive review. Biology 2021, 10, 27. [CrossRef] [PubMed]
59. Ebeid, S.A.; El Moneim, N.A.A.; El-Benhawy, S.A.; Hussain, N.G.; Hussain, M.I. Assessment of the radioprotective effect of
propolis in breast cancer patients undergoing radiotherapy. New perspective for an old honey bee product. J. Radiat. Res. Appl.
Sci. 2016, 9, 431–440. [CrossRef]
60. Piredda, M.; Facchinetti, G.; Biagioli, V.; Giannarelli, D.; Armento, G.; Tonini, G.; De Marinis, M.G. Propolis in the prevention of
oral mucositis in breast cancer patients receiving adjuvant chemotherapy: A pilot randomised controlled trial. Eur. J. Cancer Care
2017, 26, e12757. [CrossRef]
61. Darvishi, N.; Yousefinejad, V.; Akbari, M.E.; Abdi, M.; Moradi, N.; Darvishi, S.; Mehrabi, Y.; Ghaderi, E.; Jamshidi-Naaeinii,
Y.; Ghaderi, B.; et al. Antioxidant and anti-inflammatory effects of oral propolis in patients with breast cancer treated with
chemotherapy: A randomized controlled trial. J. Herb. Med. 2020, 23, 100385. [CrossRef]
Molecules 2022, 27, 6120 19 of 21

62. Benjamin, E.J.; Blaha, M.J.; Chiuve, S.E.; Cushman, M.; Das, S.R.; Deo, R.; de Ferranti, S.D.; Floyd, J.; Fornage, M.; Gillespie,
C.; et al. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 2017, 135,
e146–e603. [CrossRef]
63. Hadi, A.; Rafie, N.; Arab, A. Bee products consumption and cardiovascular diseases risk factors: A systematic review of
interventional studies. Int. J. Food Prop. 2021, 24, 115–128. [CrossRef]
64. Olas, B. Bee products as interesting natural agents for the prevention and treatment of common cardiovascular diseases. Nutrients
2022, 14, 2267. [CrossRef] [PubMed]
65. Ahmed, R.; Tanvir, E.M.; Hossen, M.S.; Afroz, R.; Ahmmed, I.; Rumpa, N.E.; Paul, S.; Gan, S.H.; Sulaiman, S.A.; Khalil, M.I.
Antioxidant properties and cardioprotective mechanism of Malaysian propolis in rats. Evid. Based Complement. Altern. Med. 2017,
2017, 5370545. [CrossRef] [PubMed]
66. Vazhappilly, C.G.; Ansari, S.A.; Al-Jaleeli, R.; Al-Azawi, A.M.; Ramadan, W.S.; Menon, V.; Hodeify, R.; Siddiqui, S.S.; Merheb,
M.; Matar, R.; et al. Role of flavonoids in thrombotic, cardiovascular, and inflammatory diseases. Inflammopharmacology 2019, 27,
863–869. [CrossRef] [PubMed]
67. Cucinotta, D.; Vanelli, M. WHO declares COVID-19 a pandemic. Acta Bio-Med. 2020, 91, 157–160.
68. Shi, Y.; Wang, G.; Cai, X.P.; Deng, J.W.; Zheng, L.; Zhu, H.H.; Zheng, M.; Yang, B.; Chen, Z. An overview of COVID-19. J. Zhejiang
Univ. 2020, 21, 343–360. [CrossRef]
69. Dilokthornsakul, W.; Kosiyaporn, R.; Wuttipongwaragon, R.; Dilokthornsakul, P. Potential effects of propolis and honey in
COVID-19 prevention and treatment: A systematic review of in silico and clinical studies. J. Integr. Med. 2022, 20, 114–125.
[CrossRef]
70. Berretta, A.A.; Silveira, M.A.D.; Cóndor Capcha, J.M.; De Jong, D. Propolis and its potential against SARS-CoV-2 infection
mechanisms and COVID-19 disease. Biomed. Pharmacother. 2020, 131, 110622. [CrossRef]
71. Ripari, N.; Sartori, A.A.; da Silva Honorio, M.; Conte, F.L.; Tasca, K.I.; Santiago, K.B.; Sforcin, J.M. Propolis antiviral and
immunomodulatory activity: A review and perspectives for COVID-19 treatment. J. Pharm. Pharmacol. 2021, 73, 281–299.
[CrossRef]
72. Scorza, C.A.; Gonçalves, V.C.; Scorza, F.A.; Fiorini, A.C.; de Almeida, A.G.; Fonseca, M.; Finsterer, J. Propolis and coronavirus
disease 2019 (COVID-19): Lessons from nature. Complement. Ther. Clin. Pract. 2020, 41, 101227. [CrossRef]
73. Fiorini, A.C.; Scorza, C.A.; Almeida, A.G.; Fonseca, M.C.; Finsterer, J.; Fonseca, F.L.; Scorza, F.A. Antiviral activity of Brazilian
green propolis extract against SARS-CoV-2 (severe acute respiratory syndrome—Coronavirus 2) infection: Case report and review.
Clinics 2021, 76, e2357. [CrossRef] [PubMed]
74. Sahlan, M.; Irdiani, R.; Flamandita, D.; Aditama, R.; Alfarraj, S.; Ansari, M.J.; Khayrani, A.C.; Pratami, D.K.; Lischer, K. Molecular
interaction analysis of Sulawesi propolis compounds with SARS-CoV-2 main protease as preliminary study for COVID-19 drug
discovery. J. King Saudi Univ. 2021, 33, 101234. [CrossRef]
75. Mani, J.S.; Johnson, J.B.; Steel, J.C.; Broszczak, D.A.; Neilsen, P.M.; Walsh, K.B.; Naiker, M. Natural product-derived phytochemicals
as potential agents against coronaviruses: A review. Virus Res. 2020, 284, 197989. [CrossRef]
76. Silveira, M.A.D.; De Jong, D.; Berretta, A.A.; dos Santos Galvão, E.B.; Ribeiro, J.C.; Cerqueira-Silva, T.; Amorim, T.C.; da Conceição,
L.F.M.R.; Dantas-Gomes, M.M.; Teixeira, M.B.; et al. Efficacy of Brazilian green propolis (EPP-AF® ) as an adjunct treatment for
hospitalized COVID-19 patients: A randomized, controlled clinical trial. Biomed. Pharmacother. 2021, 138, 111526. [CrossRef]
[PubMed]
77. Yildirim, A.; Duran, G.G.; Duran, N.; Jenedi, K.; Bolgul, B.S.; Miraloglu, M.; Muz, M. Antiviral activity of Hatay propolis against
replication of herpes simplex virus type 1 and type 2. Med. Sci. Monit. 2016, 22, 422–430. [CrossRef] [PubMed]
78. Debiaggi, M.; Tateo, F.; Pagani, L.; Luini, M.; Romero, E. Effects of propolis flavonoids on virus infectivity and replication.
Microbiologica 1990, 13, 207–213.
79. Forma, E.; Bryś, M. Anticancer activity of propolis and its compounds. Nutrients 2021, 13, 2594. [CrossRef]
80. Xuan, H.; Li, Z.; Yan, H.; Sang, Q.; Wang, K.; He, Q.; Wang, Y.; Hu, F. Antitumor activity of Chinese propolis in human breast
cancer MCF-7 and MDA-MB-231 cells. Evid. Based Complement. Altern. Med. 2014, 2014, 280120. [CrossRef]
81. Ruiz-Hurtado, P.A.; Garduño-Siciliano, L.; Domínguez-Verano, P.; Balderas-Cordero, D.; Gorgua-Jiménez, G.; Canales-Álvarez, O.;
Canales-Martínez, M.M.; Rodríguez-Monroy, M.A. Propolis and its gastroprotective effects on NSAID-induced gastric ulcer
disease: A systematic review. Nutrients 2021, 13, 3169. [CrossRef]
82. Altuğ, M.E.; Serarslan, Y.; Bal, R.; Kontaş, T.; Ekici, F.; Melek, I.M.; Aslan, H.; Duman, T. Caffeic acid phenethyl ester protects
rabbit brains against permanent focal ischemia by antioxidant action: A biochemical and planimetric study. Brain Res. 2008, 1201,
135–142. [CrossRef]
83. Choi, D.; Han, J.; Lee, Y.; Choi, J.; Han, S.; Hong, S.; Jeon, H.; Kim, Y.M.; Jung, Y. Caffeic acid phenethyl ester is a potent inhibitor
of HIF prolyl hydroxylase: Structural analysis and pharmacological implication. J. Nutr. Biochem. 2010, 21, 809–817. [CrossRef]
[PubMed]
84. Machado, C.S.; Mokochinski, J.B.; de Lira, T.O.; de Oliveira, F.C.; Cardoso, M.V.; Ferreira, R.G.; Sawaya, A.C.H.F.; Ferreira, A.G.;
Pessoa, C.; Cuesta-Rubio, O.; et al. Comparative study of chemical composition and biological activity of yellow, green, brown,
and red Brazilian propolis. Evid. Based Complement. Altern. Med. 2016, 2016, 6057650. [CrossRef] [PubMed]
Molecules 2022, 27, 6120 20 of 21

85. Liu, R.; Li, J.Z.; Song, J.K.; Sun, J.L.; Li, Y.J.; Zhou, S.B.; Zhang, T.T.; Du, G.H. Pinocembrin protects human brain microvascular
endothelial cells against fibrillar amyloid-β(1-40) injury by suppressing the MAPK/NF-KB inflammatory pathways. Biomed. Res.
Int. 2014, 2014, 470393. [CrossRef] [PubMed]
86. Liew, K.Y.; Kamise, N.I.; Ong, H.M.; Aw Yong, P.Y.; Islam, F.; Tan, J.W.; Tham, C. Anti-allergic properties of propolis: Evidence
from preclinical and clinical studies. Front. Pharmacol. 2022, 12, 785371. [CrossRef] [PubMed]
87. Martins, N.S.; de Campos Fraga-Silva, T.F.; Correa, G.F.; Boko, M.M.M.; Ramalho, L.N.Z.; Rodrigues, D.M.; Hori, J.I.; Costa,
D.L.; Bastos, J.K.; Bonato, V.L.D. Artepillin C reduces allergic airway inflammation by induction of monocytic myeloid-derived
suppressor cells. Pharmaceutics 2021, 13, 1763. [CrossRef]
88. Szliszka, E.; Mertas, A.; Czuba, Z.P.; Król, W. Inhibition of inflammatory response by artepillin C in activated RAW264.7
macrophages. Evid. Based Complement. Altern. Med. 2013, 2013, 735176. [CrossRef]
89. Machado, J.L.; Assunção, A.K.; da Silva, M.C.; Dos Reis, A.S.; Costa, G.C.; Arruda Dde, S.; Rocha, B.A.; Vaz, M.M.; Paes, A.M.;
Guerra, R.N.; et al. Brazilian green propolis: Anti-inflammatory property by an immunomodulatory activity. Evid. Based
Complement. Altern. Med. 2012, 2012, 157652. [CrossRef]
90. Kolarov, V.; Kotur Stevuljević, J.; Ilić, M.; Bogdan, M.; Tušek, B.; Agic, A.; Dugajlić, M.; Tot Vereš, K.; Kutlešić Stević, S.; Zvezdin, B.
Factorial analysis of N-acetylcysteine and propolis treatment effects on symptoms, life quality and exacerbations in patients with
chronic obstructive pulmonary disease (COPD): A randomized, double-blind, placebo-controlled trial. Eur. Rev. Med. Pharmacol.
Sci. 2022, 26, 3192–3199.
91. Barroso, M.V.; Cattani-Cavalieri, I.; de Brito-Gitirana, L.; Fautrel, A.; Lagente, V.; Schmidt, M.; Porto, L.C.; Romana-Souza, B.;
Valença, S.S.; Lanzetti, M. Propolis reversed cigarette smoke-induced emphysema through macrophage alternative activation
independent of Nrf2. Bioorganic Med. Chem. 2017, 25, 5557–5568. [CrossRef]
92. Jones, S.L.; Blikslager, A.T. Disorders of the gastrointestinal system. Equine Intern. Med. 2009, 2004, 769–949.
93. Miryan, M.; Soleimani, D.; Alavinejad, P.; Abbaspour, M.; Ostadrahimi, A. Effects of propolis supplementation on irritable bowel
syndrome with constipation (IBS-C) and mixed (IBS-M) stool pattern: A randomized, double-blind clinical trial. Food Sci. Nutr.
Nutr. 2022, 10, 1899–1907. [CrossRef] [PubMed]
94. Xue, M.; Liu, Y.; Xu, H.; Zhou, Z.; Ma, Y.; Sun, T.; Liu, M.; Zhang, H.; Liang, H. Propolis modulates the gut microbiota and
improves the intestinal mucosal barrier function in diabetic rats. Biomed. Pharmacother. Pharmacother. 2019, 118, 109393. [CrossRef]
[PubMed]
95. Farooqui, A.A.; Horrocks, L.A.; Farooqui, T. Glycerophospholipids in brain: Their metabolism, incorporation into membranes,
functions, and involvement in neurological disorders. Chem. Phys. Lipids 2000, 106, 1–29. [CrossRef]
96. Walker, P.; Crane, E. Constituents of propolis. Apidologie 1987, 18, 327–334. [CrossRef]
97. Parmar, S.K.; Sharma, T.P.; Airao, V.B.; Bhatt, R.; Aghara, R.; Chavda, S.; Rabadiya, S.; Gangwal, A. Neuropharmacological effects
of triterpenoids. Phytopharmacology 2013, 4, 354–372.
98. Noelker, C.; Bacher, M.; Gocke, P.; Wei, X.; Klockgether, T.; Du, Y.; Dodel, R. The flavanoide caffeic acid phenethyl ester blocks
6-hydroxydopamine-induced neurotoxicity. Neurosci. Lett. 2005, 383, 39–43. [CrossRef]
99. Zulhendri, F.; Perera, C.O.; Tandean, S. Can propolis be a useful adjuvant in brain and neurological disorders and injuries? A
systematic scoping review of the latest experimental evidence. Biomedicines 2021, 9, 1227. [CrossRef]
100. Nakamura, R.; Nakamura, R.; Watanabe, K.; Oka, K.; Ohta, S.; Mishima, S.; Teshima, R. Effects of propolis from different areas on
mast cell degranulation and identification of the effective components in propolis. Int. Immunopharmacol. 2010, 10, 1107–1112.
[CrossRef]
101. He, S.H.; Zhang, H.Y.; Zeng, X.N.; Chen, D.; Yang, P.C. Mast cells and basophils are essential for allergies: Mechanisms of allergic
inflammation and a proposed procedure for diagnosis. Acta Pharmacol. Sin. 2013, 34, 1270–1283. [CrossRef]
102. Stone, K.D.; Prussin, C.; Metcalfe, D.D. IgE, mast cells, basophils, and eosinophils. J. Allergy Clin. Immunol. 2010, 125, S73–S80.
[CrossRef]
103. Lloyd, C.M.; Hessel, E.M. Functions of T cells in asthma: More than just T(H)2 cells. Nat. Rev. Immunol. 2013, 10, 838–848.
[CrossRef] [PubMed]
104. Khayyal, M.T.; El-Ghazaly, M.A.; El-Khatib, A.S.; Hatem, A.M.; de Vries, P.J.; El-Shafei, S.; Khattab, M.M. A clinical pharmaco-
logical study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients. Fundam. Clin.
Pharmacol. 2003, 17, 93–102. [CrossRef]
105. Tani, H.; Hasumi, K.; Tatefuji, T.; Hashimoto, K.; Koshino, H.; Takahashi, S. Inhibitory activity of Brazilian green propolis
components and their derivatives on the release of cys-leukotrienes. Bioorganic Med. Chem. 2010, 18, 151–157. [CrossRef]
[PubMed]
106. Hausen, B.M. Evaluation of the main contact allergens in propolis (1995 to 2005). Dermatitis 2005, 16, 127–129. [PubMed]
107. Wang, L.C.; Lin, Y.L.; Liang, Y.C.; Yang, Y.H.; Lee, J.H.; Yu, H.H.; Wu, W.M.; Chiang, B.L. The effect of caffeic acid phenethyl ester
on the functions of human monocyte-derived dendritic cells. BMC Immunol. 2009, 10, 39. [CrossRef] [PubMed]
108. Cukic, V.; Lovre, V.; Dragisic, D.; Ustamujic, A. Asthma and chronic obstructive pulmonary disease (COPD)—Differences and
similarities. Mater. Sociomedia 2012, 24, 100–105. [CrossRef]
109. Guo, R.; Pittler, M.H.; Ernst, E. Herbal medicines for the treatment of COPD: A systematic review. Eur. Respir. J. 2006, 28, 330–338.
[CrossRef]
110. Brierley, S.M.; Kelber, O. Use of natural products in gastrointestinal therapies. Curr. Opin. Pharmacol. 2011, 11, 604–611. [CrossRef]
Molecules 2022, 27, 6120 21 of 21

111. Zulhendri, F.; Perera, C.O.; Tandean, S.; Abdulah, R.; Herman, H.; Christoper, A.; Chandrasekaran, K.; Putra, A.; Lesmana, R. The
potential use of propolis as a primary or an adjunctive therapy in respiratory tract-related diseases and disorders: A systematic
scoping review. Biomed. Pharmacother. 2022, 146, 112595. [CrossRef]
112. Lofty, M. Biological activity of bee propolis in health and disease. Asian Pacific J. Cancer Prev. 2006, 7, 22–31.
113. Catchpole, O.; Mitchell, K.; Bloor, S.; Davis, P.; Suddes, A. Antiproliferative activity of New Zealand propolis and phenolic
compounds vs human colorectal Adenocarcinoma cells. Fitoterapia 2015, 106, 167–174. [CrossRef] [PubMed]
114. Asfaram, S.; Fakhar, M.; Keighobadi, M.; Akhtari, J. Promising anti-protozoan activities of propolis (bee glue) as natural product:
A review. Acta Parasitol. 2021, 66, 1–12. [CrossRef] [PubMed]
115. Ullah, A.; Munir, S.; Badshah, S.L.; Khan, N.; Ghani, L.; Poulson, B.G.; Emwas, A.H.; Jaremko, M. Important flavonoids and their
role as a therapeutic agent. Molecules 2020, 25, 5243. [CrossRef] [PubMed]
116. De Moura, S.A.; Ferreira, M.A.; Andrade, S.P.; Reis, M.L.; Noviello Mde, L.; Cara, D.C. Brazilian green propolis inhibits
inflammatory angiogenesis in a Murine sponge model. Evid. Based Complement. Altern. Med. 2011, 2011, 182703. [CrossRef]
117. Hwu, Y.J.; Lin, F.Y. Effectiveness of propolis on oral health: A meta-analysis. J. Nurs. Res. 2014, 22, 221–229. [CrossRef]
118. Dodwad, V.; Kukreja, B. Propolis mouthwash: A new beginning. J. Indian Soc. Periodontol. 2011, 15, 121–125.
119. Ellis, R.D.; Goodlad, J.R.; Limb, G.A.; Powell, J.J.; Thompson, R.P.H.; Punchard, N.A. Activation of nuclear factor Kappa B in
Crohn’s disease. Inflamm. Res. 1998, 47, 440–445. [CrossRef]