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Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease Running title: Propolis against SARS-CoV-2 infection and COVID-19

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Abstract

Propolis, a resinous material produced by honey bees from plant exudates, has long been used in traditional herbal medicine and is widely consumed as a health aid and immune system booster. The COVID-19 pandemic has renewed interest in propolis products worldwide; fortunately, various aspects of the SARS-CoV-2 infection mechanism are potential targets for propolis compounds. SARS-CoV-2 entry into host cells is characterized by viral spike protein interaction with cellular angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2. This mechanism involves PAK1 overexpression, which is a kinase that mediates coronavirus-induced lung inflammation, fibrosis, and immune system suppression. Propolis components have inhibitory effects on the ACE2, TMPRSS2 and PAK1 signaling pathways; in addition, antiviral activity has been proven in vitro and in vivo. In pre-clinical studies, propolis promoted immunoregulation of pro-inflammatory cytokines, including reduction in IL-6, IL-1 beta and TNF-α. This immunoregulation involves monocytes and macrophages, as well as Jak2/STAT3, NF-kB, and inflammasome pathways, reducing the risk of cytokine storm syndrome, a major mortality factor in advanced COVID-19 disease. Propolis has also shown promise as an aid in the treatment of various of the comorbidities that are particularly dangerous in COVID-19 patients, including respiratory diseases, hypertension, diabetes, and cancer. Standardized propolis products with consistent bioactive properties are now available. Given the current emergency caused by the COVID-19 pandemic and limited therapeutic options, propolis is presented as a promising and relevant therapeutic option that is safe, easy to administrate orally and is readily available as a natural supplement and functional food.
Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19
disease
Running title: Propolis against SARS-CoV-2 infection and COVID-19
Andresa Aparecida Berretta1, Marcelo Augusto Duarte Silveira2, José Manuel Cóndor Capcha3,
David De Jong4*
1 Research, Development and Innovation Department, Apis Flora Indl. Coml. Ltda, Ribeirão Preto,
São Paulo, Brazil. andresa.berretta@apisflora.com.br
2 D'Or Institute for Research and Education (IDOR), Hospital São Rafael, Salvador, Brazil.
marceloadsilveira@gmail.com
3 Interdisciplinary Stem Cell Institute at Miller School of Medicine, University of Miami, Miami,
Florida, United States. jmcondor@med.miami.edu
4 Genetics Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão
Preto, São Paulo, Brazil. ddjong@fmrp.usp.br
*author for correspondence
Abstract
Propolis, a resinous material produced by honey bees from plant exudates, has long been
used in traditional herbal medicine and is widely consumed as a health aid and immune system
booster. The COVID-19 pandemic has renewed interest in propolis products worldwide;
fortunately, various aspects of the SARS-CoV-2 infection mechanism are potential targets for
propolis compounds. SARS-CoV-2 entry into host cells is characterized by viral spike protein
interaction with cellular angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2.
This mechanism involves PAK1 overexpression, which is a kinase that mediates coronavirus-
induced lung inflammation, fibrosis, and immune system suppression. Propolis components have
inhibitory effects on the ACE2, TMPRSS2 and PAK1 signaling pathways; in addition, antiviral
activity has been proven in vitro and in vivo. In pre-clinical studies, propolis promoted
immunoregulation of pro-inflammatory cytokines, including reduction in IL-6, IL-1 beta and TNF-
α. This immunoregulation involves monocytes and macrophages, as well as Jak2/STAT3, NF-kB,
and inflammasome pathways, reducing the risk of cytokine storm syndrome, a major mortality
factor in advanced COVID-19 disease. Propolis has also shown promise as an aid in the treatment
of various of the comorbidities that are particularly dangerous in COVID-19 patients, including
respiratory diseases, hypertension, diabetes, and cancer. Standardized propolis products with
consistent bioactive properties are now available. Given the current emergency caused by the
COVID-19 pandemic and limited therapeutic options, propolis is presented as a promising and
relevant therapeutic option that is safe, easy to administrate orally and is readily available as a
natural supplement and functional food.
Keywords: Propolis, SARS-CoV-2, COVID-19, Antiviral, Anti-inflammatory, PAK1 blocker
1. Introduction
The COVID-19 pandemic is of grave concern due its impact on human health and on the
economy. It is much more deadly than influenza and other types of diseases that recently have had
worldwide impact [1], forcing countries to take unusual measures such as limiting travel, closing
schools, businesses, and other locations where many people can come into contact with each other.
Various public healthcare strategies have been adopted in an attempt to reduce the impact of the
disease, but with limited effectiveness, as the virus continues to spread, often through
asymptomatic patients [2]. Unfortunately, tests to determine if people are infectious or were
previously infected are not widely available, often are costly, and frequently do not provide timely
and accurate results. Various therapeutic alternatives have been proposed and tested; however,
most require more robust data in clinical trials before they can be widely and safely used [3].
Isolation and stay-at-home measures do not effectively protect essential workers,
especially health care personnel, who have become infected and are dying at alarming rates [4].
Economic and other necessities limit how well and how long these isolation measures can be
maintained, especially in poor countries and in poor communities such as slums and favelas [5, 6].
As populations gradually try to get back to normalcy, reducing social distancing, and people in
“non-essential professions” return to the workplace, they become more at risk for infection. In this
scenario, any options that could help ameliorate disease progression and its consequences, even
marginally, would be useful. The world needs safe alternatives to help reduce the impact of this
deadly disease.
Natural products, which have historically been widely used to help avoid and alleviate
diseases [7-9], are among the options being considered as an adjuvant treatment for SARS-CoV-2
infection [10], because they are generally inexpensive, widely available, and rarely have
undesirable side effects. Some have proven antiviral activity [11-13]. An important advantage of
using natural remedies is that people who have other health problems or who have mild flu-related
symptoms, but do not have the means or courage to visit an already overcrowded medical facility,
could take simple and inexpensive measures to help reduce the impact of infection with SARS-
CoV-2.
Considering the large number of deaths and other types of damage that the COVID-19
pandemic is causing, there is an urgent need to find treatments that have been approved as safe,
and potentially able to inhibit the new coronavirus, reduce its infectivity, and/or alleviate the
symptoms of infection [14, 15]. Along this line, propolis and its components emerge as potential
candidate materials that could help to reduce the pathophysiological consequences of SARS-CoV-
2 infection [10].
Infection by SARS-CoV-2, the virus that causes COVID-19, is characterized by binding
between viral spike proteins and angiotensin-converting enzyme 2 (ACE2) [16]. Activation of the
spike protein is mediated through proteases, such as TMPRSS2, which play important roles in the
viral infection [17]. After entry, followed by endocytosis, coronavirus infection causes PAK1
upregulation, a kinase that mediates lung inflammation, lung fibrosis and other critical mortality
factors. Increased PAK1 levels also suppress the adaptive immune response, facilitating viral
replication [10, 18]. SARS-CoV-2 infection is associated with increased levels of chemokines and
activated pro-inflammatory cytokines that lead to the development of atypical pneumonia, with
rapid respiratory impairment and pulmonary failure [19]. Immunological/inflammatory
phenomena (such as cytokine release syndrome) have been shown to be important in the spectrum
of SARS-CoV-2 infection. These mechanisms are associated with organ dysfunction more than
the viral load per se [20]. Along this line, a retrospective observational study found higher serum
levels of pro-inflammatory cytokines such as IL-6, IL-1, and TNF-α, in patients with severe
COVID-19, compared to individuals with mild disease [21].
There is considerable evidence that propolis can reduce and alleviate the symptoms of
inflammatory diseases by affecting various metabolic cycles [22-24]. Recently, several studies
have shown that propolis extract and some of its components act against several important targets
in the pathophysiological context of the disease caused by SARS-CoV-2, such as reducing
TMPRSS2 expression, and reducing ACE2 anchorage, which would otherwise facilitate entry of
the virus into the cell; this is in addition to immunomodulation of monocytes / macrophages
(reducing production of and eliminating IL-1 beta and IL-6), reduction of the transcription factors
NF-KB and JAK2 / STAT3 and blocking PAK1, which determine inflammatory activities and
fibrosis caused by COVID-19 [25-28].
Various comorbidities have been associated with severe COVID19 symptoms and a greater
chance of patients requiring intensive care; these include hypertension and diabetes. Also,
mortality rates of COVID19 patients are much higher in those with cardiovascular disease, chronic
respiratory disease, and diabetes [29, 30]. There is considerable evidence that these conditions
could be alleviated by treatment with propolis. This includes research in animal models of diabetes
[31, 32], hypertension [33, 34], and cardiovascular disease [35, 36]. Propolis has properties that
are particularly relevant to SARS-CoV-2 infection, such as immune system fortification, reduced
viral replication, and anti-inflammatory action [22, 24, 28, 37, 38].
2. Propolis and its properties
Propolis is a product derived from resins and plant exudates. Plants defend themselves from
pathogens mainly by producing phytochemicals, many of which have been extracted and used in
medicine [39]. Plant defense substances collected by bees include phenols and terpenoids [40-42].
Phytochemical compounds that show promise for the inhibition of coronavirus in humans include
quercetin, myricetin, and caffeic acid, all components of propolis [43]. Honey bees and many other
species of social bees recognize these antimicrobial properties and selectively collect and process
these plant products to make propolis, which they use to protect the colony [44]. The production
and use of propolis by honey bees evolved to the point that these social bees have considerably
fewer immune genes than solitary insect species [45]. Bees in colonies that produce more propolis
are healthier and live longer [46], and propolis consumption by the bees augments their immune
response to bacterial challenge [47].
The composition of propolis varies according to the plant species available in each region
[42, 48, 49]. As this variability can affect their medicinal properties, standardized propolis products
have been developed to help meet the need for a product that does not vary in the main bioactive
components and is safe, with minimal interaction with pharmaceutical drugs and proven efficacy
in clinical trials [50-53]. In recent decades, it has been shown to have antimicrobial (including
antiviral), anti-inflammatory, immunomodulatory, antioxidant, and anticancer properties [54].
Propolis has historically been widely used to alleviate various diseases [7-9, 55]; it also has been
considered, among other natural alternatives, as an adjuvant treatment for SARS-CoV-2 infection
[10], because it is generally inexpensive, widely available and rarely causes undesirable side
effects.
Some types of propolis that are highly valued for their medicinal properties, such as
Brazilian green propolis, are mainly produced by bees from materials they collect from specific
plants, in this case Baccharis dracunculifolia [56]. After the botanical origin of the propolis has
been identified, extracts of the plant can be made to develop useful products, such as a medicinal
mouthwash [57]. However, the medicinal properties of these plant extracts are often inferior
compared to the propolis that the bees make from these plant materials [58-60].
3. Why propolis may be a good fit for dealing with COVID-19
Among natural medicine alternatives, propolis has been widely studied and is already
extensively consumed in many countries [38, 55, 61-63]. For example, propolis products, such as
throat sprays and extracts, are produced by hundreds of companies in Brazil and are sold as a health
aid in nearly every pharmacy throughout the country, demonstrating on a practical basis that they
can be safely consumed. These propolis products, and the raw material for their manufacture, are
extensively exported by Brazilian companies, especially to Asian countries, including Japan, South
Korea, and China [50, 64]. The importance of propolis in Chinese, Japanese, Russian and Korean
medicine is reflected in the number of patents for propolis containing products registered by 2013,
including about 1200 by China and 300 400 each for Japan, Russia and Korea [42]. Since 2013,
about 1400 new propolis-related patents were applied for in the US patent office. It is a key
ingredient in traditional Chinese medicine [65]. Japanese scientists have isolated and patented
various Brazilian propolis components for cancer treatment [66], demonstrating their usefulness.
In fact, propolis has a wide spectrum of pharmacological properties and is a dietary supplement
that is commonly consumed by both healthy and sick people as a preventative precaution and for
treatment [67-69]. It is also used in veterinary medicine, due its antibacterial, antifungal, antiviral,
antiparasitic, hepatoprotective, and immunomodulatory activities [70].
In the wake of the coronavirus outbreak, South Korea has seen a boon in the use of
functional foods. According to their Ministry of Food and Drug Safety, “health functional foods”
are nutrients that have been proven to be beneficial to health [71]. In March of this year, in response
to the coronavirus pandemic, the ministry eased regulations for propolis, which is considered a
functional food, and allowed new oral formulations [72]. However, despite considerable evidence
that propolis can reduce and alleviate disease symptoms, its acceptance as a health-promoting
supplement in human medicine has been limited in many countries such as the USA because of a
relevant criticism that propolis products are not standardized and vary in their components and
biological activity. In part, this is because propolis varies with the species of plants available in
each region, from which the bees collect resins to produce it [42, 48, 49]. However, standardized
propolis products have recently become available to help fill the need for a product that does not
vary in the main bioactive components and effectiveness [50, 52]. One such option, a standardized
Brazilian propolis extract blend [54], has been tested for safety and effectiveness in clinical trials
for treating kidney disease and diabetes [51], denture stomatitis [73], and burn patients [74].
Therefore, propolis as a nutraceutical or functional food should be considered as a resource that
could help fight against the COVID-19 pandemic.
4. Some propolis compounds can potentially interact with SARS-CoV-2 MPRO
The research community has examined the genetic code of coronavirus and the
mechanisms underlying the damages caused by SARS-CoV-2, to help search for drugs and/or
potential targets in order to inactive the virus and reduce the damage that it causes. The main
protease of coronavirus SARS-CoV-2, MPRO (3-chymotrypsin-like cysteine enzyme), is essential
for coronavirus processing of polyproteins and for its life cycle, and therefore inhibition of the
active site of this enzyme is a relevant target for drug discovery [75].
Along this line, Hashem evaluated various natural compounds with an in silico approach
(molecular docking) to try to find useful options for treating SARS-CoV-2 infection. Curiously,
caffeic acid phenethyl ester (CAPE), galangin, chrysin and caffeic acid, substances found in
several different types of propolis around the world, appeared as potential drugs against this viral
target (Table 1) [76]. Specifically, CAPE was predicted to interact with SARS-CoV-2 MPRO in a
similar study [77]. Therefore, although it will be necessary to run in vitro assays to evaluate the
potential anti-SARS-CoV-2 effects of propolis and/or its constituents, these in silico results are
well boding.
5. Propolis can interact with ACE and TMPRSS2, potentially blocking or reducing SARS-
CoV-2 invasion of the host cell
SARS-CoV-2 strongly binds to angiotensin-converting enzyme 2 (ACE2), using this
enzyme as a receptor for invasion and replication in the host cell [17, 78], causing damage and
increasing interpersonal transmission [26, 79]. Consequently, ACE inhibitors have been
considered as useful drug alternatives. However, potential deleterious effects on users of
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have
emerged as a concern for treatment of COVID-19 patients. An observational study involving 8,910
patients did not confirm this suspicion, and therefore these classes of drugs remain an important
tool against potential cardiovascular events [80].
Inhibition of ACE2 enzyme is an important target for treatment against SARS-CoV-2
infection [15, 81]. Güler et al. [26] prepared an alcoholic extract of propolis and identified some
hydroxycinnamic acids (caffeic acid, p-coumaric acid, t-cinnamic acid and CAPE), the flavanons
rutin and myricetin, and the flavones hesperidin, chrysin and pinocembrin. Using molecular
docking evaluations, they found that rutin had the highest binding energy to ACE2, followed by
myricetin, caffeic acid phenethyl ester, hesperetin and pinocembrin. Rutin interacts with zinc
fingers of the active sites of ACE2, a metalloprotease that presents the same zinc finger in ACE1
[26].
In addition to the in silico evidence, Osés et al. [82] evaluated several types of propolis for
various characteristics, including inhibition of ACE. They found strong inhibition for most of the
propolis types they studied, with higher than 90% ACE inhibition. The best results were found
with the propolis components catechin and p-coumaric acid.
ACE2 and TMPRSS2 (transmembrane serine protease 2) on the surface of host cells are
used by SARS-CoV-2 via interaction with spike glycoproteins in order to proceed with invasion
and replication [15]. Vardhan & Sahoo [15] studied several molecules commonly found in
medicinal herbs using molecular docking procedures with relevant targets, such as RNA-
dependent RNA polymerase (RdRp), ACE2 and spike glycoproteins and compared the resulting
scores with those of hydroxychloroquine [15]. Limonin was the most active compound; however,
quercetin and kaempferol, also propolis compounds, gave high docking scores [15]. Kaempferol
was studied in prostate cancer models, and the expression of TMPRSS2 was reduced, showing a
potential mechanism of action for an antitumoral effect [83]. Kaempferol could be an important
propolis component for use against COVID-19, since it is involved in the inhibition of TMPRSS2
[83], potentially interacting with ACE2, RdRp and spike glycoprotein (SGp) [15], besides its
antiviral activity [84] (Table 1).
6. Propolis blocks PAK-1, potentially avoiding lung fibrosis and restoring a normal immune
response
Among the possible targets for controlling COVID-19 damage, the major “pathogenic”
kinase PAK1 is key. It is an essential component in malaria and viral infections, but it is also
involved in a wide variety of other diseases and disease conditions, including cancer,
inflammation, and immuno-suppression, when abnormally activated. Consequences of PAK1
activation include lung fibrosis [10], which is an aggravating factor in COVID-19. PAK1 is
activated by RAC. Xu et al. [18] demonstrated that caffeic acid and its ester (CAPE), components
of propolis, can inactivate RAC, consequently inhibiting PAK1. The inactivation of PAK1
directly, or up-stream, can potentially attenuate coronavirus pathogenesis [10]. B-cells and T-cells
are lymphocytes that produce specific antibodies against viruses and other intruders, and PAK1
contributes to their suppression. PAK1 inhibitors can both help combat the virus and restore a
normal immune response [10].
Propolis from Europe and temperate Asia, usually made by bees from resins collected from
Poplar trees, has predominantly flavonoid compounds, while green propolis (from Baccharis
dracunculifolia), a propolis exclusively found in Brazil, has various kinds of flavonoids and
prenylated phenylpropanoids, such as artepellin C, baccharin and drupanin. These and all other
types of propolis can inactivate PAK1 [10]. Artepillin C selectively inhibits PAK1 [85] (Table 1).
Some studies have shown that propolis can act as an immunostimulant, with the ability to
improve the immune response. Its components increase neutralizing antibody titers, activate
phagocytosis, and increase IFN-γ levels and the number of lymphocytes [86]. An increase in IFN-
γ levels was also detected by Shimizu et al. [28], who evaluated the mechanisms involved in the
effects of some types of propolis in a herpes simplex animal model.
CAPE (caffeic acid phenethyl ester) is a potent inhibitor of activation of NF-kB in myelo-
monocytic cells. Ansorge et al. [37] demonstrated that propolis, CAPE, quercetin, hesperidin and
some other propolis flavonoids can inhibit the cytokine production of Th1 and Th2 type T cells,
while increasing TGF-beta 1, an important anti-inflammatory cytokine. Moreover, CAPE can
attenuate oxidative stress and inflammation through down-regulation of JAK2/STAT3 signaling
[87] as well as having an immunomodulatory effect, in which CAPE inhibits IL-6 phosphorylation
and STAT3, which are important for pro-inflammatory Th17 development [88].
Besides the anti-inflammatory effect of CAPE and kaempferol, Paulino et al. [89]
evaluated the anti-inflammatory effect of artepellin C in rat paw edema and in cell cultures,
demonstrating that the activity was at least in part mediated by prostaglandin E2 and NO inhibition
through NF-kB modulation. Artepillin C is an important biomarker of Brazilian green propolis
(botanical source Baccharis dracunculifolia).
Immune modulation is desirable since coronavirus infection dysregulates the immune
response in the initial phases of infection, which facilitates viral replication. However, in later
stages of COVID-19, the body develops an exaggerated inflammatory response, which can greatly
damage the lungs and other organs. Propolis, different from typical immunosuppressants, can help
avoid immunosuppression during the initial phases of disease and, in later stages, reduce an
exaggerated host inflammatory response, inhibiting excess IL-6, IL-2 and JAK signaling [90].
CAPE, a propolis component, is also known as an immune-modulating agent [91] and should be
considered as an alternative to help reduce an exaggerated inflammatory response. In a mouse
model, propolis had immunomodulatory action in vivo on Toll-like receptor expression and on
pro-inflammatory cytokine production [92].
There is ample evidence for interference of propolis and/or its components with viral
replication and infectivity, potentially decreasing lung inflammation due to anti-inflammatory
properties, while promoting immune system fortification. These are useful properties that could
help minimize the symptoms and deleterious effects of COVID-19 (Figure 1).
Figure 1
7. Propolis as an antiviral substance
Propolis has been tested against various viral disease organisms; initial successes have
prompted research to determine the most useful components, which may be modified to produce
more active and specific pharmaceuticals [93]. Viruses that were controlled by propolis in animal
models with suggestion for control in humans include influenza [11, 94], herpes simplex virus type
2 [95], and HIV [93, 96]. Shimizu et al. [28] evaluated three different types of propolis in ethanol
extracts, using a murine model of herpes simplex virus type 1. Despite the chemical differences
due to the different plant origins of the resins the bees used to produce the propolis (Baccharis
dracunculifolia, Baccharis eriodata and Myrceugenia euosma), all three propolis extracts not only
had direct anti-HSV-1 effects, but also stimulated immunological activity against intradermal
HSV-1 infection in mice.
Antiviral activity of propolis has been reported for DNA and RNA viruses (poliovirus,
herpes simplex virus, and adenovirus) in an in vitro model (cultured cells). The best results were
obtained against poliovirus and herpes virus, with 99.9% inhibition of the latter, at a propolis
concentration of 30 ug/ml [97]. The propolis components chrysine and kaempferol caused a
concentration-dependent reduction of intracellular replication of herpes-virus strains when host
cell monolayers were infected and subsequently cultured in a drug-containing medium. Quercetin,
another propolis component, had the same effect, but only at the highest concentrations tested (60
ug/mL) against various human herpes simplex virus strains, with a intracellular replication
reduction of approximately 65%, while it reduced the infectivity of bovine herpes virus, human
adenovirus, human coronavirus, and bovine coronavirus about 50%. The reduction was 70% in the
case of rotavirus [84].
8. Anti-inflammatory and immunomodulatory properties of propolis
The most critical cases of COVID-19, which require ventilator-assisted intensive care and
often result in prolonged ventilator dependency and death, are a result of an exaggerated
inflammatory response to infection [98]. SARS-CoV-2 infection is associated with increased
levels of chemokines and activated pro-inflammatory cytokines that lead to the development of
atypical pneumonia, with rapid respiratory impairment and pulmonary failure [19].
Immunological/inflammatory phenomena (such as cytokine release syndrome) have been shown
to be important mortality factors in SARS-CoV-2 infection. Higher serum levels of pro-
inflammatory cytokines such as IL-6, IL-1, and TNF-α, are found in patients with severe COVID-
19 compared to those of individuals with mild disease [21]. Molecular mechanisms involved in
this immune process are the targets of various synthetic medicines being tested in patients,
including ciclesonide, hydroxy chloroquine, ivermectin, and ketorolac, which are PAK1 blockers
[10]. PAK1 (RAC/CDC42-activated kinase 1) is overexpressed in the lung in response to SARS-
CoV-2 infection and is a critical mediator of the cytokine storm that frequently results in mortality
in hospitalized patients [99]. Fortuitously, propolis components are effective PAK1 blockers
(Table 1).
There is considerable evidence that propolis can reduce and alleviate the symptoms of
inflammatory diseases [22-24] and has immunomodulatory properties [24, 37]. However, these
properties can vary according to the plant origin of the propolis, as well as the extraction
process/solvent used and the inflammatory protocol (cell culture, animal models, induction by
lipopolysaccharides) when the propolis extracts are tested [50]. Tests with animal models have
shown that propolis can reduce the levels of IL-6 and TNF-alpha, which are key pro-inflammatory
mediators, and increase the levels of the regulatory cytokine IL-10 [24]. Kaempferol, a propolis
component, reduces IL-6, TNF-alpha, and VEGF (vascular endothelial growth factor) via the
ERK-NFkB-cMyc-p21 pathway [83] (Table 1).
Tests on macrophage cell cultures also demonstrated that propolis inhibits the production
of IL-1 beta, an important component of the inflammasome inflammatory pathway, in diseases
such as rheumatoid arthritis, lupus and other autoimmune diseases [55]. Although the mechanisms
of action are not well elucidated, these propolis components have potential as complementary
supplements in the preventive treatment of chronic inflammatory diseases [100].
9. Propolis has potential as a vaccine adjuvant
Propolis is considered a safe immunostimulant and a potent vaccine adjuvant [101]. Propolis has
been widely tested as a vaccine adjuvant, because it induces an earlier immune response and
provides a longer protection period [102]. It is also included as an adjuvant ingredient in traditional
Chinese medicine [103]. Propolis flavonoids have potential as adjuvants, enhancing IgG, IL-4, and
IFN-γ in serum [104]. Fernandes et al. [86] found that propolis exerted a positive adjuvant effect
on vaccines that were developed against canine coronavirus. They assayed IFN-γ, which is an
effective way to measure the cellular response induced by a vaccine. In a mouse model, propolis,
added as an adjuvant to inactivated swine herpesvirus type 1 vaccine, stimulated increased cellular
and humoral responses, increasing IFN-γ [105, 106]. Propolis enhanced the immune response to
inactivated porcine parvovirus vaccine in guinea pigs [107]. When added to a Trichomonas
vaginalis protein vaccine, propolis increased the IgG antibody response 4-10 times in mice,
compared to the protein alone [108]. Propolis was also effective as an adjuvant in the immunization
of cattle with bovine herpesvirus [105]. It improved the humoral and cellular responses in mice
inoculated with inactivated virus vaccines [109]. Propolis as an adjuvant gave a similar immune
response (increasing IFN-γ levels), to Alum and Freund’s adjuvant in mice vaccinated with an
HIV-1 polytope vaccine candidate, with less risk of undesirable side effects [110].
10. Comorbidities and evidence of how propolis can help reduce their impact in COVID-19
patients
10.1 Cancer
Cancer is considered a relevant comorbidity factor for COVID-19. Cancer patients have a
3-4 times higher risk of progressing to severe COVID-19 disease than patients without
comorbidities. Also, the hospital environment during the coronavirus pandemic can interfere with
or delay the treatment that cancer patients should receive. Patients with symptoms may choose not
to risk a visit to a clinic or hospital to determine if they have cancer [111]. Alternative therapies
could help retard cancer or reduce the impact of cancer and cancer treatment in COVID-19
patients.
Propolis has potential as a complementary therapy for cancer. It has shown efficacy against
various types, including bladder, blood, brain, breast, colon, head and neck, kidney, liver, pancreas,
prostate, and skin cancers [112]. Propolis could help prevent cancer progression; in various parts
of the world it is considered an alternative therapy for cancer treatment [113]. Propolis extracts
have been found to inhibit tumor cell growth both in vitro and in vivo, including inhibition of
angiogenesis, demonstrating potential for the development of new anticancer drugs [114-116].
Various components of propolis have been shown to inhibit cancer cell growth, including cinnamic
acid [66], CAPE [117-119], quercetin [120], and chrysin [121]. Propolis and its components
normally have little impact on normal cells, displaying differential cytotoxicity in liver cancer,
melanoma and breast cell carcinoma cell lines [122, 123]. Propolis enhances the activity of tumor
necrosis factor related apoptosis inducing ligand (TRAIL) in cancer cells [124].
10.2 Hypertension and cardiovascular disease
Hypertension and cardiovascular disease are considered relevant comorbidities for
COVID-19 [125-127]. Propolis has demonstrated anti-hypertensive effects in rat models [33, 34,
128, 129]. In Cameroon, it is used in popular medicine to treat various ailments, including high
blood pressure [130]. Propolis has been widely used as a dietary supplement for its health benefits,
including cardiovascular protective effects [131, 132]. In a human trial, consumption of propolis
improved critical blood parameters, including HDL, GSH and TBARS levels, demonstrating that
it could contribute to a reduced risk for cardiovascular disease [132].
10.3 Obesity
Obesity is a major comorbidity and predictor of increased mortality in COVD-19 patients.
Obesity and SARS-CoV-2 both induce an inflammatory process, exacerbating SARS-CoV-2
infection in the obese [133]. Propolis reduced inflammation and prevented hyperlipidemia and
metabolic syndromes in highly caloric diet induced obesity in mice. Body weight gain, visceral
adipose tissue, liver and serum triglycerides, cholesterol, and non-esterified fatty acids were all
reduced in the propolis fed mice [78, 134]. Caffeic acid phenethyl ester, a propolis component, is
a natural anti-obesity agent [135].
10.4 Thromboembolism, thrombosis and microthrombosis
Microthrombosis, disseminated intravascular coagulation, and consequent multiorgan
failure are common in severely affected COVID19 patients, with associated high mortality rates
[136-139]. Anticoagulants are sometimes prescribed to such patients because they can reduce
mortality (Tang et al. 2020). An elevated level of plasminogen activator inhibitor-1 (PAI-1) is a
biomarker and risk factor for thrombosis and atherosclerosis [140, 141]. Various types of evidence
demonstrate that propolis can reduce platelet aggregation and other thrombosis-related parameters.
Propolis decreased thrombotic tendencies in mice by suppressing lipopolysaccharide-induced
increases in PAI-1 levels [142, 143]. Propolis downregulated platelet-derived growth factor and
platelet endothelial cell adhesion molecules in low-density lipoprotein knockout mice [144].
Platelet aggregation was reduced by propolis in tests on human blood in vitro [145] and in other
in vitro tests [146]. Caffeic acid phenethyl ester (CAPE), a well-studied bioactive propolis
component, inhibits collagen induced platelet activation [147].
10.5 Old age
The elderly are more often affected by chronic inflammation, characterized by systemically
increased levels of proinflammatory cytokines, which can contribute to development of a cytokine
storm, a major cause of COVID-19 mortality [148]. Propolis has antioxidant properties, which
could help retard or reduce aging processes [149]. CAPE, a propolis component, increased the
lifespan of Caenorhabditis elegans, a common model organism for aging studies [150]. Propolis
consumption protected against cognitive decline in elderly subjects (humans) exposed to high
altitudes [151]. Serum TGF-β1 and IL-10 levels were significantly higher in propolis-treated
elderly subjects, helping reduce inflammation, which could be the mechanism of protection against
cognitive decline. Activity of superoxide dismutase (SOD), a key antioxidant in men treated with
propolis was increased, while malondialdehyde, a marker of oxidative stress, decreased [152]. The
same tendencies were detected in a diabetic rat model [153]. Propolis has the potential to reduce
neurodegenerative damage through antioxidant activity, which helps protect against cognitive
impairment in Alzheimer’s disease as well as aging [154, 155]. In a mouse model of Alzheimer’s
disease, coniferaldehyde, an active ingredient in propolis, had neuroprotective effects. It reduced
brain β-amyloid deposits and pathological changes in the brain, helping preserve learning and
memory capacity [156]. The angiotensin system, which is key to SARS-CoV-2 invasion of host
cells, is associated with senescence. One of the reasons that SARS-CoV-2 causes significantly
higher mortality in older patients may be that they have a larger number of senescent lung cells,
which are a vulnerable target for viral infection and can help promote viral replication. That would
make senolytic drugs useful to help the elderly survive COVID-19. Quercetin, a propolis
component, which has been proposed as a therapeutic for treatment of COVID-19, has senolytic
activity [157].
10.6 Diabetes
Common comorbidities with high death rates in critically ill COVID19 patients include
diabetes [30]. Given the relation between diabetes and inflammation, and that flavonoids, major
bioactive components of propolis, protect against free radicals and other pro-oxidative compounds,
it is plausible that propolis consumption can reduce the risk of diabetes [158]. Brazilian propolis
has become popular as a healthy dietary supplement in various parts of the world because it can
help prevent inflammation and diabetes [159]. Propolis was found to reduce blood glucose, blood
lipids and free radicals in diabetic rats [31, 160]. It also reduced glycemia [32, 161] and insulin
resistance [162-164] in diabetic rats. Experimental diabetic nephropathy was also prevented [165].
Diabetes symptoms were reduced in a diabetic mouse model [166], apparently by attenuating
immune activation in adipose tissues.
Clinical trials with diabetic patients demonstrated that propolis consumption improved
antioxidant parameters [167], glycemic control [168, 169], and the lipid profile and renal function
[170]. Propolis is also an antimicrobial agent with wound healing properties [171, 172], which has
proven especially useful for diabetic patients [173, 174], who tend to develop difficult to heal
wounds.
Caffeic acid phenethyl ester (CAPE) is considered an anti-obesity agent with beneficial
effects on inflammation and diabetes [175]. CAPE reduced insulin resistance in diabetic mice and
in hepatic cell culture [176]. Chrysin, another component of propolis, also has antidiabetic
properties [177].
10.7 Kidney diseases
COVID-19 is an important threat for patients with comorbidities such as renal, or hepatic
impairment [178]. The kidney is a common target of SARS-CoV-2 [179]. COVID-19 patients are
at increased risk of kidney impairment [79], and consequently many patients with COVID-19
present renal dysfunction [180]. Increased mortality is common in COVID-19 patients with
chronic kidney disease and in those undergoing hemodialysis [181]. Propolis has shown protective
effects against kidney diseases. Nephropathy was prevented by propolis treatment in animal
models [165, 182, 183]. Brazilian red propolis attenuated hypertension and renal damage in a rat
renal ablation model [184]. Anti-diabetic activity of propolis in a rat model reduced liver damage
[160]. In a pioneering clinical trial, propolis reduced proteinuria in patients with chronic kidney
disease [51].
10.8 Bacterial infection
Bacterial infection is a common complication in COVID-19 [79]. Propolis has a long history of
use for its antibacterial properties and could help treat bacterial infections in COVID-19 patients.
The healing properties of propolis are referred to throughout the Old Testament, and propolis was
prescribed by Hippocrates in Ancient Greece for the treatment of sores and ulcers [185]. Propolis
has been popular for centuries in Russia and other countries in Eastern Europe for its antibacterial
properties [186]. The pharmacological value of propolis comes from a natural mixture of
antibacterial substances, instead of only one or a few substances as in most medicines [187].
Propolis components galangin, pinocembrin, rutin, quercetin, and naringenin, as well as CAPE
increase bacterial membrane permeability, which could explain their antimicrobial properties
[188]. De Campos et al. [189] showed that the main mechanism of action of propolis is rupture
and lysis of bacterial cells. Propolis has demonstrated antibacterial activity against Staphylococcus
aureus, Staphylococcus epidermidis, and E. coli [190], including methicillin-resistant and
methicillin-susceptible strains of Staphylococcus aureus [191]. Adding propolis extract to the
antibiotics, ampicillin, gentamycin and streptomycin, vancomycin and oxacillin increased their
antibacterial activity against Staphylococcus aureus [192, 193]. The extract also reduced cell
adhesion and consequent biofilm formation by this bacterium [193]. Propolis (sometimes known
as bee glue) has antibacterial activity against human tubercle bacillus, but often has only limited
activity against Gram-negative bacilli. These antimicrobial properties appear to be due to its high
flavonoid content [186]. Propolis can help avoid bacterial tooth decay [194]. Propolis and some of
its components inhibit bacterial motility [195]. Black poplar, Populus nigra, tree resin is the main
source of the propolis used for medicinal purposes in Europe; it contains phenols and flavonoids
that have well known antimicrobial properties [196]. Propolis can be bacteriostatic and or
bactericidal, depending on the concentration [197]. An ethanol extract of propolis inhibited
microbial growth and biofilm formation by Pseudomonas aeruginosa [198]. The antibacterial
properties of propolis make it a useful ingredient in a wound healing biofilm [199].
11. Limitations: Lack of standardization
Man has used propolis as an herbal medicine for thousands of years. Various useful
activities have been described for propolis, including, and not limited to antiviral, antibacterial,
antifungal, anti-inflammatory, immunoregulatory, antioxidant, and wound healing properties [200,
201]. However, plant geographical source, bee species, seasonality and climatic differences can
dramatically affect chemical composition [48, 202]. These details, along with variations in the
processing and solvent extraction processes (which can selectivity extract some compounds
according to their polarity) [203], can influence its biological properties. This can affect and limit
the repeatability of tests and confuse the compilation of results used to determine appropriate
dosages for human clinical trials, ultimately causing insecurity for prescribers.
Considerable work has gone into understanding the mechanisms involved in the biological
properties of propolis [54, 189, 204, 205]. Also, efforts have been made to improve technological
and analytical processes to determine adequate extraction procedures that preserve its bioactive
compounds and consistently provide the best pharmacological properties for each medical
condition [50, 200, 201, 203, 206-208]. However, although propolis is a product that can be offered
to the market in several presentations and with different classifications according to the type of
product, possibly as a health supplement, food supplement, cosmetic and/or hygiene product, the
various beneficial effects that appear in published research were not accepted by the European
Commission as acceptable "claims", based on the argument that there are qualitative and
quantitative variations in the bioactive flavonoids, which are dependent on the raw material
provided by beekeepers. Those factors, and the lack of standardized extraction and preparation
methods, are reasons that do not permit this type of approval [209], justifying the standardization
proposed by Chan [38].
Although in the bee products field “standardization” is not yet a normal procedure, this
reality already exists in the phytopharmaceutical industry. When working with herbal products, it
is normal to find differences in the raw material received, since plants suffer a strong influence of
the environment, including seasonality, soil treatment, other plant species nearby, and various
other conditions, resulting in batches of plant materials that are often chemically different,
qualitatively and/or quantitatively. It is not possible to have identical batches when working with
this type of material; however, minimal standardization is needed in order to validate safety and
efficacy studies and guarantee useful characteristics when a product is offered to the market [210].
The definition of “Standardization” by the American Herbal Product association is:
“Standardization refers to the body of information and control necessary to produce material of
reasonable consistency[211]. The mechanisms and technologies available to meet this goal are
available; however, challenges also exist. Nikam et al. [210] present useful guidelines for those
who intend to develop such standardization.
11.1 A Standardized Propolis Product
In Brazil, 12 main types of propolis have already been described [201]. Due to this great
variability and the limitations that these differences cause in the research, development and
industrial fields, Berretta et al. [54] developed a Standardized Propolis Extract, named EPP-AF®
(Patent Letter no. 0405483-0, approved by Industrial Property Magazine on July 23, 2019), which
possesses reproducibility batch-to-batch for a group of phenolic and flavonoid compounds, in
addition to a characteristic HPLC fingerprint and consistent biological effects (antimicrobial
activity) [54]. Several studies have been conducted with this extract, including analytical
development and validation [54, 212, 213], biological effects such as antimicrobial, antifungal and
wound healing properties [54, 205, 214-217], and anti-inflammatory and immunoregulatory
activities [22, 24].
12.2 Safety and Efficacy Studies
12.2.1 Non-Clinical Studies
Besides the long history of traditional use of propolis for treating diseases, various studies
in animals have demonstrated the safety of propolis [218-220]. Safety studies for EPP-AF® have
been conducted using an in vitro Ames Test, demonstrating a lack of abnormalities in the bacterial
strains that were evaluated (unpublished data) and a lack of abnormalities in a micronucleus test
(in vitro) [221]. Tavares et al. [222] also studied propolis using a micronucleus tool, with the
mutagenicity agent doxorubicin as a positive control. They found that the propolis behaved as a
“Janus” compound; it was genotoxic at higher concentrations and chemopreventive at lower ones.
This demonstrates the importance of the appropriate dosage and model for testing, which are
needed to correctly extrapolate to clinical trials. Additionally, acute and subchronic animal toxicity
tests were performed; even at very high treatment levels, EPP-AF® propolis did not reach an LD50
dose (maximum tested 3000 mg/kg) [223]. The safety data from tests with Wistar rats (1000
mg/kg) and rabbits (300 mg/kg), and the conversion factor proposed by the US Food and Drug
Agency were used to propose the dosages for human trials [50]
12.2.2 Clinical Trials
A clinical safety study was carried out at the Ribeirão Preto School of Medicine of the
University of São Paulo (FMRP/USP) with healthy volunteers in order to assess the safety of
ingesting 375 mg / day of Standardized Propolis Extract (EPP-AF®), for five days. No adverse
events were observed. The study pointed to the absence of acute toxicity after the oral use of
Standardized Propolis Extract (EPP-AF®) at a dose of 375 mg daily for five days. The significant
positive variation observed in the parameter HDL cholesterol needs further studies with a larger
number of patients to confirm this beneficial effect on the cardiovascular system (unpublished
data).
In addition, and more important in this case, a study to evaluate drug interaction was
performed using a cocktail approach to analyze the main hepatic metabolizing enzymes
(cytochrome P450 enzymes - CYPs) and the transport enzyme Pgp. The results showed that this
standardized propolis extract is safe and without risk of drug interaction, according to the criteria
established by the WHO [53]. The propolis tested in the interaction study was provided in tablets;
consequently, these results cannot necessarily be extrapolated to a propolis alcohol extract.
Using a propolis preparation, a clinical trial that was randomized, double-blind, and
placebo-controlled was conducted with 430 children (1-5 years old) in Israel with a placebo elixir
and Chizukit (a standard over-the counter drug containing Echinacea extract 50 mg/ml (Echinacea
purpurea and E. angustifolia), 50 mg/ml of propolis extract and 10 mg/ml of vitamin C, for
respiratory tract infection gave good results [224]. Another clinical study was done for asthma
treatment in adults [204]. The study, which used a propolis water extract, demonstrated reduction
in key pro-inflammatory cytokines, including tumor necrosis factor (TNF-a), ICAM-1, IL-6, IL-8
and a 3-fold increase in the “protective” cytokine IL-10; the levels of prostaglandins E2, F2a and
leukotriene D4 were reduced significantly [204].
A randomized double-blind placebo controlled clinical study of 32 patients with Chronic
Kidney Disease, demonstrated safety of the Standardized Propolis Extract (EPP-AF®) at an oral
dose of 500mg / day after administration during 12 months, with significant reduction in
proteinuria and urinary MCP1 in the propolis group compared to the placebo [51], with no side
effects. Another clinical study conducted with the Standardized Propolis Extract (EPP-AF®) in
healthy volunteers aimed to assess the antioxidant activity. There was a reduction in cell damage
induced by oxidative stress in healthy volunteers, due to an increase in the enzymatic antioxidant
capacity, especially affecting superoxide dismutase (SOD), and decreasing lipid peroxidation and
DNA oxidation (8-OHDG) (article submitted). These data indicate the important protective effect
that propolis has on cells, tissues and on the human body, reducing the effects of aging,
degenerative diseases and several other conditions that involve these oxidation processes.
Another relevant clinical trial was conducted by Soroy et al. [225] on dengue hemorrhagic
fever patients. Their double-blind, randomized and placebo-controlled trial evaluated the propolis
product PropoelixTM (two 200mg capsules, three times a day), demonstrating an improvement in
platelet counts and a decrease in TNF-alfa, promoting a reduction in the duration of hospitalization
time of the patients.
The current COVID-19 pandemic has promoted strong interest in propolis as a therapeutic
option. As a consequence, a clinical trial of Brazilian green propolis extract (EPP-AF) for
treatment of COVID-19 patients was recently initiated in Brazil
(https://clinicaltrials.gov/ct2/show/NCT04480593).
12. 3 Dosages
Clinical trials with propolis have been conducted in various regions of the world, most of
them with the limitation of a lack of standardization. Berretta et al. [50, 51, 53] evaluated many of
them; the most common dosage used was 500 mg/day for adults. Considering the case of EPP-
AF®, the clinical data until now support dosages of 375 - 500 mg of propolis/day; however, non-
clinical trials indicate that much higher dosages can be tolerated and may be useful [211]. The
dose of 500 mg/day would be equivalent to 30 drops of propolis extract (with 11% w/v of dry
matter), 3 to 4 times a day, diluted in about 100 ml of water, or 3 to 4 units/day of capsules or
tablets with the equivalent amount of extract. For preventive purposes, 30 drops/day or one
capsule, are usually taken. However, considering the dosage safely used by Soroy et al. [225] of
1200 mg/day, in more severe cases of COVID-19, dosages higher than 500 mg/day could be useful.
13. Supplements, Food and Hygiene Products made with Propolis
Propolis extracts and sprays, often combined with medicinal herb extracts and honey, are
now found in nearly every pharmacy in Brazil, attesting to their safety, popularity and usefulness
in this country, where hundreds of companies currently produce these “natural medicines”. For
each regulatory category and country, the technical rules to be followed for propolis products vary.
Some countries such as Brazil, Canada, United States of America, China, South Korea, Japan,
Australia and the European Community already possess regulation for propolis [50]; consequently,
propolis can be easily found by consumers at a low cost and potentially can be useful for preventive
and/or curative purposes in the early stages of disease.
14. Why consider using nutraceuticals or other natural alternatives instead of relying on
modern pharmaceuticals?
Propolis is extensively used in foods and beverages because of its benefits for human
health. It contains hundreds of natural compounds, including aldehydes, coumarins, polyphenols,
steroids and inorganic compounds, with a broad spectrum of biological and pharmacological
properties, including antimicrobial, antioxidant, anti-inflammatory, immunomodulatory,
antitumor, anticancer, antiulcer, hepatoprotective, cardioprotective, and neuroprotective actions
[226]. The health industry has always used natural products, including propolis, as an alternative
source of drugs [62]. The complex mix of propolis components can provide greater health benefits
than would be apparent by analyzing the individual effects of components, apparently due to
synergistic effects [97].
Modern medicine relies on powerful drugs that have specific and strong impacts on disease
organisms and on the body. This strategy and adequate sanitary measures have proven to be highly
effective, resulting in an almost constant increase in human lifespan, which has more than doubled
since 1900 to over 70 years [227]. However, the system in place for approving pharmaceuticals
also has some disadvantages, including the long lead time and considerable funding needed to
discover new options, test them for safety and effectiveness, and after 5-10 years, obtain approval
for their use. Due to the high costs involved and the possibility that this extended process will not
result in a product that will compensate the investment required, potentially useful materials may
never become available. Another problem is that modern medicine can be quite expensive, with
constantly increasing costs for individuals and countries. Consequently, adequate healthcare may
not be available to everyone who needs it. Side effects of many of these powerful medicines are
also a concern. Doctors and patients often need to weigh the risk of drug side effects against the
consequences of the disease. Also, for some diseases no effective drug is available and patient care
focuses on relieving symptoms and the consequences of infection.
Among alternatives to modern drugs, there has long been a traditional use of natural health
products. However, such products normally cannot be registered as medicines; the considerable
investment needed to qualify them as such often would not be compensated because they are
difficult to obtain a patent for and people could easily purchase or collect them. Curiously, one of
the strategies for developing modern drugs is to carefully dissect the components of natural
products, determine which ones have desirable activity, patent and synthesize them and then go
through the expensive process of getting them approved, though with some possibility that such
products could give a return on the investment because of the patents. A case in point is Brazilian
green propolis, for which there is considerable evidence of anticancer properties [228, 229]. This
propolis is not patented, but some if its components were isolated, and synthesized, and are now
patented drugs for cancer treatment [230]. Brazil continues to produce and export large quantities
of green propolis, especially to Asian countries, but various patented components are the property
of companies in other countries.
In some parts of the world, the equivalent of the US Food and Drug Administration (FDA),
officially classifies certain natural products as “Functional Foods” or some other similar category.
As such, they can be produced and marketed and used by people who believe they will be good
for their health. To be classified as functional foods, these agencies require proof that they are safe
and that they have proven health benefits [71, 231]. This option provides alternatives that are
normally inexpensive and do not require prescriptions. Specifically, propolis has been suggested
as a prophylactic treatment for high risk groups in the current COVID-19 pandemic [232].
Some investment is necessary to help qualify and register natural medicines, which may
be provided by companies or by government programs that recognize the need for this type of
investment, or both. In Brazil, the Sao Paulo state research agency (FAPESP), has a program called
PIPE (http://www.fapesp.br/pipe/) that helps small companies finance this type of research for
products that they recognize would not normally be developed without this type of support,
including natural pest control alternatives for agriculture and “natural medicine” formulations.
Various research projects on propolis products have been financed by this FAPESP PIPE program
including wound healing and antifungal products [54, 205, 214-216], and the development of a
standardized propolis formulation [54]; tests of this product were made for safety and effectiveness
in patients with chronic kidney disease and diabetes [51]; both diseases are the subjects of projects
supported by FINEP (Brazilian Study and Projects Financing Agency).
While modern medicines normally have only one or just a few active components, natural
products can have many. Propolis, for example, has hundreds of components [226], many of which
have properties that have the potential to help treat various types of disease or have various modes
of action against a specific disease and its consequences [233-235]. Another consideration is that
a strong specific effect, such as that of an anticoagulant used in an effort to prevent the
microthromboses that have become a serious consequence of advanced COVID19 [236], requires
specific dosing in order to avoid excess bleeding and other dangerous side effects [237], and such
drugs are not a safe option for patients that have some types of blood disease, or various heart and
vessel disorders. A natural anticoagulant could give some protection and at a level sufficient to
reduce the risk of thrombosis without strong side effects. Propolis has demonstrated anticoagulant
properties [147].
15. Conclusions
Considering the large number of deaths and other types of damage that the COVID-19
pandemic is causing, there is an urgent need to find therapies that can help avoid or reduce SARS-
CoV-2 infection and its consequences. Propolis has proven anti-inflammatory and
immunoregulatory effects, including PAK-1 inhibition. Also, attachment to ACE2, a major target
of the SARS-CoV-2 virus for host cell invasion, is inhibited by propolis. Propolis components,
including CAPE, rutin, quercetin, kaempferol and myricetin have demonstrated in silico a strong
interaction with ACE2. Kaempferol reduced the expression of TMPRSS2. In addition to these
activities, propolis does not interact with the main liver enzymes or with other key enzymes;
according to criteria adopted by the World Health Organization, therefore propolis can be used
concurrently with the main drugs without risk of potentiation or inactivation.
To determine if propolis specifically affects SARS-CoV-2 will require more research. But
given that propolis is a risk-free product, except for those who may develop an allergy to it, the
known biological activities of this natural bee product lead us to suggest its use for reducing the
risk and impact of infection and as an adjunct to treatment.
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgements
The present study received no funding from any source or any governing body. We thank Cristiane
Melo for preparing the drawings of the bee collecting resin and the hive opening with propolis and
Mr. Adriel Santos for kindly preparing the graphical abstract figure. Some of the research cited
involving the authors of this paper was funded by the Brazilian research funding agencies
FAPESP, CAPES, FINEP and CNPq. The development and testing of the Brazilian standardized
propolis product were partially funded by the São Paulo state research funding institution,
FAPESP, as well as the federal agencies FINEP and CNPq.
16. References
[1] O. Vardeny, M. Madjid, S.D. Solomon, Applying the Lessons of Influenza to COVID-19
During a Time of Uncertainty, Circulation 141(21) (2020) 1667-1669,
https://doi.org/10.1161/CIRCULATIONAHA.120.046837
[2] L. Setti, M. Kirienko, S.C. Dalto, M. Bonacina, E. Bombardieri, FDG-PET/CT findings
highly suspicious for COVID-19 in an Italian case series of asymptomatic patients, Eur J Nucl
Med Mol Imaging (2020), https://doi.org/10.1007/s00259-020-04819-6
[3] J.M. Sanders, M.L. Monogue, T.Z. Jodlowski, J.B. Cutrell, Pharmacologic Treatments for
Coronavirus Disease 2019 (COVID-19): A Review, JAMA (2020),
https://doi.org/doi:10.1001/jama.2020.6019
[4] P. Lapolla, A. Mingoli, R. Lee, Deaths from COVID-19 in healthcare workers in ItalyWhat
can we learn?, Infect Control Hosp Epidemiol (2020) 1-2, https://doi.org/10.1017/ice.2020.241
[5] J. Corburn, D. Vlahov, B. Mberu, L. Riley, W.T. Caiaffa, S.F. Rashid, A. Ko, S. Patel, S.
Jukur, E. Martínez-Herrera, S. Jayasinghe, S. Agarwal, B. Nguendo-Yongsi, J. Weru, S. Ouma,
K. Edmundo, T. Oni, H. Ayad, Slum Health: Arresting COVID-19 and Improving Well-Being in
Urban Informal Settlements, J Urban Health 97 (2020) 348-357, https://doi.org/10.1007/s11524-
020-00438-6
[6] R.J. Pereira, G.N.L.d. Nascimento, L.H.A. Gratão, R.S. Pimenta, The risk of COVID-19
transmission in favelas and slums in Brazil, Public Health 183 (2020) 42-43,
https://doi.org/10.1016/j.puhe.2020.04.042
[7] M.M. Cowan, Plant Products as Antimicrobial Agents, Clin Microbiol Rev 12(4) (1999) 564-
582, https://doi.org/10.1128/CMR.12.4.564
[8] F. Bakkali, S. Averbeck, D. Averbeck, M. Idaomar, Biological effects of essential oils--a
review, Food Chem Toxicol 46(2) (2008) 446-75, https://doi.org/10.1016/j.fct.2007.09.106
[9] A. Saklani, S.K. Kutty, Plant-derived compounds in clinical trials, Drug Discov Today 13(3-
4) (2008) 161-71, https://doi.org/10.1016/j.drudis.2007.10.010
[10] H. Maruta, H. He, PAK1-blockers: Potential Therapeutics against COVID-19, Med Drug
Discov (2020), https://doi.org/10.1016/j.medidd.2020.100039
[11] J. Serkedjieva, N. Manolova, V. Bankova, Anti-influenza virus effect of some propolis
constituents and their analogues (esters of substituted cinnamic acids), J Nat Prod 55(3) (1992)
294-302, https://doi.org/10.1021/np50081a003
[12] J. Calixto, Efficacy, safety, quality control, marketing and regulatory guidelines for herbal
medicines (phytotherapeutic agents), Braz J Med Biol Res 33(2) (2000) 179-189,
https://doi.org/10.1590/S0100-879X2000000200004
[13] J.B. Calixto, Twenty-five years of research on medicinal plants in Latin America: a personal
view, J Ethnopharmacol 100(1-2) (2005) 131-134, https://doi.org/10.1016/j.jep.2005.06.004
[14] M.F. Uddin M, Rizvi TA, Loney T, Suwaidi HA, Al-Marzouqi AHH, Eldin AK, Alsabeeha
N, Adrian TE, Stefanini C, Nowotny N, Alsheikh-Ali A, Senok AC., SARS-CoV-2/COVID-19:
Viral Genomics, Epidemiology, Vaccines, and Therapeutic Interventions, Viruses 12 (2020) 526,
https://doi.org/10.3390/v12050526
[15] S. Vardhan, S.K. Sahoo, Searching inhibitors for three important proteins of COVID-19
through molecular docking studies, arXiv:2004.08095 (2020).
[16] Y. Wan, J. Shang, R. Graham, R.S. Baric, F. Li, Receptor Recognition by the Novel
Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS
Coronavirus, J Virol 94(7) (2020) e00127-20, https://doi.org/10.1128/JVI.00127-20
[17] M. Hoffmann, H. Kleine-Weber, S. Schroeder, N. Kruger, T. Herrler, S. Erichsen, T.S.
Schiergens, G. Herrler, N.H. Wu, A. Nitsche, M.A. Muller, C. Drosten, S. Pohlmann, SARS-
CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven
Protease Inhibitor, Cell 181(2) (2020) 271-280 e8, https://doi.org/10.1016/j.cell.2020.02.052
[18] J.W. Xu, K. Ikeda, A. Kobayakawa, T. Ikami, Y. Kayano, T. Mitani, Y. Yamori,
Downregulation of Rac1 activation by caffeic acid in aortic smooth muscle cells, Life Sci 76(24)
(2005) 2861-72, https://doi.org/10.1016/j.lfs.2004.11.015
[19] Y. Ding, L. He, Q. Zhang, Z. Huang, X. Che, J. Hou, H. Wang, H. Shen, L. Qiu, Z. Li, J.
Geng, J. Cai, H. Han, X. Li, W. Kang, D. Weng, P. Liang, S. Jiang, Organ distribution of severe
acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients:
implications for pathogenesis and virus transmission pathways, J Pathol 203(2) (2004) 622-30,
https://doi.org/10.1002/path.1560
[20] J. Stebbing, A. Phelan, I. Griffin, C. Tucker, O. Oechsle, D. Smith, P. Richardson, COVID-
19: combining antiviral and anti-inflammatory treatments, Lancet Infect Dis 20(4) (2020) 400-
402, https://doi.org/10.1016/S1473-3099(20)30132-8
[21] C. Qin, L. Zhou, Z. Hu, S. Zhang, S. Yang, Y. Tao, C. Xie, K. Ma, K. Shang, W. Wang,
D.S. Tian, Dysregulation of immune response in patients with COVID-19 in Wuhan, China, Clin
Infect Dis 71(15) (2020) 762-768, https://doi.org/10.1093/cid/ciaa248
[22] J.I. Hori, D.S. Zamboni, D.B. Carrao, G.H. Goldman, A.A. Berretta, The Inhibition of
Inflammasome by Brazilian Propolis (EPP-AF), Evid Based Complement Alternat Med 2013
(2013) 418508, https://doi.org/10.1155/2013/418508
[23] A.R. Pineros, M.H.F. de Lima, T. Rodrigues, A.F. Gembre, T.B. Bertolini, M.D. Fonseca,
A.A. Berretta, L.N.Z. Ramalho, F.Q. Cunha, J.I. Hori, V.L.D. Bonato, Green propolis increases
myeloid suppressor cells and CD4(+)Foxp3(+) cells and reduces Th2 inflammation in the lungs
after allergen exposure, J Ethnopharmacol 252 (2020) 112496,
https://doi.org/10.1016/j.jep.2019.112496
[24] J.L. Machado, A.K. Assuncao, M.C. da Silva, A.S. Dos Reis, G.C. Costa, S. Arruda Dde,
B.A. Rocha, M.M. Vaz, A.M. Paes, R.N. Guerra, A.A. Berretta, F.R. do Nascimento, Brazilian
green propolis: anti-inflammatory property by an immunomodulatory activity, Evid Based
Complement Alternat Med 2012 (2012) 157652, https://doi.org/10.1155/2012/157652
[25] O. Sekiou, Omar, I. Bouziane, Z. Bouslama, A. Djemel, In-silico identification of potent
inhibitors of COVID-19 main protease (Mpro) and Angiotensin converting enzyme 2 (ACE2)
from natural products, ChemRxiv (2020), https://doi.org/10.26434/chemrxiv.12181404
[26] H.I. Güler, G. Tatar, O. Yildiz, A.O. Belduz, S. Kolayli, Investigation of potential inhibitor
properties of ethanolic propolis extracts against ACE-II receptors for COVID-19 treatment by
Molecular Docking Study, ScienceOpen Preprints (2020), https://doi.org/10.14293/S2199-
1006.1.SOR-.PP5BWN4.v1
[27] F. Asgharpour, A.A. Moghadamnia, M. Motallebnejad, H.R. Nouri, Propolis attenuates
lipopolysaccharide-induced inflammatory responses through intracellular ROS and NO levels
along with downregulation of IL-1beta and IL-6 expressions in murine RAW 264.7
macrophages, J Food Biochem 43(8) (2019) e12926, https://doi.org/10.1111/jfbc.12926
[28] T. Shimizu, Y. Takeshita, Y. Takamori, H. Kai, R. Sawamura, H. Yoshida, W. Watanabe,
A. Tsutsumi, Y.K. Park, K. Yasukawa, K. Matsuno, K. Shiraki, M. Kurokawa, Efficacy of
Brazilian Propolis against Herpes Simplex Virus Type 1 Infection in Mice and Their Modes of
Antiherpetic Efficacies, Evid Based Complement Alternat Med 2011 (2011) 976196,
https://doi.org/10.1155/2011/976196
[29] W.J. Guan, Z.Y. Ni, Y. Hu, W.H. Liang, C.Q. Ou, J.X. He, L. Liu, H. Shan, C.L. Lei,
D.S.C. Hui, B. Du, L.J. Li, G. Zeng, K.Y. Yuen, R.C. Chen, C.L. Tang, T. Wang, P.Y. Chen, J.
Xiang, S.Y. Li, J.L. Wang, Z.J. Liang, Y.X. Peng, L. Wei, Y. Liu, Y.H. Hu, P. Peng, J.M. Wang,
J.Y. Liu, Z. Chen, G. Li, Z.J. Zheng, S.Q. Qiu, J. Luo, C.J. Ye, S.Y. Zhu, N.S. Zhong, C. China
Medical Treatment Expert Group for, Clinical Characteristics of Coronavirus Disease 2019 in
China, N Engl J Med 382(18) (2020) 1708-1720, https://doi.org/10.1056/NEJMoa2002032
[30] R.A. Stein, COVID-19: Risk groups, mechanistic insights and challenges, Int J Clin Pract
(2020) e13512. https://doi.org/10.1111/ijcp.13512
[31] H.U. Fuliang, H.R. Hepburn, H. Xuan, M. Chen, S. Daya, S.E. Radloff, Effects of propolis
on blood glucose, blood lipid and free radicals in rats with diabetes mellitus, Pharmacol Res
51(2) (2005) 147-52, https://doi.org/10.1016/j.phrs.2004.06.011
[32] M. Al-Hariri, T.G. Eldin, B. Abu-Hozaifa, A. Elnour, Glycemic control and anti-osteopathic
effect of propolis in diabetic rats, Diabetes Metab Syndr Obes 2011(4) (2011) 377-84,
https://doi.org/10.2147/DMSO.S24159
[33] S. Mishima, C. Yoshida, S. Akino, T. Sakamoto, Antihypertensive effects of Brazilian
propolis: identification of caffeoylquinic acids as constituents involved in the hypotension in
spontaneously hypertensive rats, Biol Pharm Bull 28(10) (2005) 1909-1914,
https://doi.org/10.1248/bpb.28.1909.
[34] H. Maruyama, Y. Sumitou, T. Sakamoto, Y. Araki, H. Hara, Antihypertensive effects of
flavonoids isolated from brazilian green propolis in spontaneously hypertensive rats, Biol Pharm
Bull 32(7) (2009) 1244-50, https://doi.org/10.1248/bpb.32.1244
[35] S. Chopra, K.K. Pillai, S.Z. Husain, D.K. Giri, Propolis protects against doxorubicin-
induced myocardiopathy in rats, Exp Mol Pathol 62(3) (1995) 190-8, 10.1006/exmp.1995.1021
[36] Y. Fang, H. Sang, N. Yuan, H. Sun, S. Yao, J. Wang, S. Qin, Ethanolic extract of propolis
inhibits atherosclerosis in ApoE-knockout mice, Lipids Health Dis 12 (2013) 123,
https://doi.org/10.1186/1476-511X-12-123
[37] R.D. Ansorge S, 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 C J Biosci 58(7) (2003), https://doi.org/10.1515/znc-2003-7-823
[38] G.C.-F. Chan, K.-W. Cheung, D.M.-Y. Sze, The Immunomodulatory and Anticancer
Properties of Propolis, Clin Rev Allerg Immu 44(3) (2013) 262-273,
https://doi.org/10.1007/s12016-012-8322-2
[39] M.F. Balandrin, J.A. Klocke, E.S. Wurtele, W.H. Bollinger, Natural plant chemicals:
sources of industrial and medicinal materials, Science 228(4704) (1985) 1154-60,
https://doi.org/10.1126/science.3890182.
[40] J.H. Langenheim, Higher plant terpenoids: A phytocentric overview of their ecological
roles, J Chem Ecol 20(6) (1994) 1223-1280, https://doi.org/10.1007/BF02059809
[41] A.-X. Cheng, Y.-G. Lou, Y.-B. Mao, S. Lu, L.-J. Wang, X.-Y. Chen, Plant Terpenoids:
Biosynthesis and Ecological Functions, J Integr Plant Biol 49(2) (2007) 179-186,
https://doi.org/10.1111/j.1744-7909.2007.00395.x
[42] V.C. Toreti, H.H. Sato, G.M. Pastore, Y.K. Park, Recent progress of propolis for its
biological and chemical compositions and its botanical origin, Evid Based Complement Alternat
Med 2013 (2013) 697390, https://doi.org/10.1155/2013/697390
[43] J.S. Mani, J.B. Johnson, J.C. Steel, D.A. Broszczak, P.M. Neilsen, K.B. Walsh, M. Naiker,
Natural product-derived phytochemicals as potential agents against coronaviruses: A review,
Virus Res 284 (2020) 197989, https://doi.org/10.1016/j.virusres.2020.197989
[44] M. Simone-Finstrom, M. Spivak, Propolis and bee health: the natural history and
significance of resin use by honey bees, Apidologie 41(3) (2010) 295-311,
https://doi.org/10.1051/apido/2010016
[45] J.D. Evans, M. Spivak, Socialized medicine: individual and communal disease barriers in
honey bees, J Invertebr Pathol 103 Suppl 1 (2010) S62-S72,
https://doi.org/10.1016/j.jip.2009.06.019
[46] D. Nicodemo, E.B. Malheiros, D. De Jong, R.H.N. Couto, Increased brood viability and
longer lifespan of honeybees selected for propolis production, Apidologie 45(2) (2014) 269-275,
https://doi.org/10.1007/s13592-013-0249-y
[47] A.P. Turcatto, A.P. Lourenço, D. De Jong, Propolis consumption ramps up the immune
response in honey bees infected with bacteria, Apidologie 49(3) (2018) 287-296,
https://doi.org/10.1007/s13592-017-0553-z
[48] V. Bankova, Recent trends and important developments in propolis research, Evid Based
Complement Alternat Med 2(1) (2005) 29-32, https://doi.org/10.1093/ecam/neh059
[49] M. Miguel, S. Nunes, S.A. Dandlen, A.M. Cavaco, M.D. Antunes, Phenols, flavonoids and
antioxidant activity of aqueous and methanolic extracts of propolis (Apis mellifera L.) from
Algarve, South Portugal, Food Sci Technol 34(1) (2014), http://dx.doi.org/10.1590/S0101-
20612014000100002
[50] A.A. Berretta, C. Arruda, F. Miguel, N. Baptista, A. Nascimento, F. Marquele- Oliveira, J.
Hori, H. Barud, B. Damaso, C. Ramos, R. Ferreira, J. Bastos, Functional Properties of Brazilian
Propolis: From Chemical Composition Until the Market, in: V. Waisundara (Ed.), Superfood and
Functional Food - An Overview of Their Processing and Utilization, Intech Open, London, 2017,
pp. 55-98, http://dx.doi.org/10.5772/65932
[51] M.A.D. Silveira, F. Teles, A.A. Berretta, T.R. Sanches, C.E. Rodrigues, A.C. Seguro, L.
Andrade, Effects of Brazilian green propolis on proteinuria and renal function in patients with
chronic kidney disease: a randomized, double-blind, placebo-controlled trial, BMC Nephrol
20(1) (2019) 140, http://dx.doi.org/10.1186/s12882-019-1337-7
[52] V. Zaccaria, E.U. Garzarella, C. Di Giovanni, F. Galeotti, L. Gisone, D. Campoccia, N.
Volpi, C.R. Arciola, M. Daglia, Multi Dynamic Extraction: An Innovative Method to Obtain a
Standardized Chemically and Biologically Reproducible Polyphenol Extract from Poplar-Type
Propolis to Be Used for Its Anti-Infective Properties, Materials 12(22) (2019) 3746,
http://dx.doi.org/10.3390/ma12223746
[53] D.A.C. Cusinato, E.Z. Martinez, M.T.C. Cintra, G.C.O. Filgueira, A.A. Berretta, V.L.
Lanchote, E.B. Coelho, Evaluation of potential herbal-drug interactions of a standardized
propolis extract (EPP-AF(R)) using an in vivo cocktail approach, J Ethnopharmacol 245 (2019)
112174, http://dx.doi.org/10.1016/j.jep.2019.112174
[54] A.A. Berretta, A.P. Nascimento, P.C. Bueno, M.M. Vaz, J.M. Marchetti, Propolis
standardized extract (EPP-AF(R)), an innovative chemically and biologically reproducible
pharmaceutical compound for treating wounds, Int J Biol Sci 8(4) (2012) 512-21,
http://dx.doi.org/10.7150/ijbs.3641
[55] A. Ramos, J. Miranda, Propolis: a review of its anti-inflammatory and healing actions, J
Venom Anim Toxins Trop Dis 13(4) (2007) 697-710, https://doi.org/10.1590/S1678-
91992007000400002
[56] O. Barth, A. Freitas, A. Matsuda, L. Almeida-Muradian, Botanical origin and Artepillin-C
content of Brazilian propolis samples, Grana 52(2) (2013) 129-135,
http://dx.doi.org/10.1080/00173134.2012.747561
[57] V. Pedrazzi, M.F. Leite, R.C. Tavares, S. Sato, G.C. do Nascimento, J.P.M. Issa, Herbal
mouthwash containing extracts of Baccharis dracunculifolia as agent for the control of biofilm:
clinical evaluation in humans, ScientificWorldJournal 2015 (2015) 712683-712683,
http://dx.doi.org/10.1155/2015/712683
[58] Y.K. Park, I. Fukuda, H. Ashida, S. Nishiumi, K.-i. Yoshida, A. Daugsch, H.H. Sato, G.M.
Pastore, Suppressive Effects of Ethanolic Extracts from Propolis and Its Main Botanical Origin
on Dioxin Toxicity, J Agr Food Chem 53(26) (2005) 10306-10309,
https://doi.org/10.1021/jf058111a
[59] A.A. da Silva Filho, J.P. de Sousa, S. Soares, N.A. Furtado, M.L. Andrade e Silva, W.R.
Cunha, L.E. Gregório, N.P. Nanayakkara, J.K. Bastos, Antimicrobial activity of the extract and
isolated compounds from Baccharis dracunculifolia D. C. (Asteraceae), Z Naturforsch C J
Biosci 63(1-2) (2008) 40-6, http://dx.doi.org/10.1515/znc-2008-1-208
[60] M.C. Búfalo, A.S. Figueiredo, J.P. de Sousa, J.M. Candeias, J.K. Bastos, J.M. Sforcin, Anti-
poliovirus activity of Baccharis dracunculifolia and propolis by cell viability determination and
real-time PCR, J Appl Microbiol 107(5) (2009) 1669-80. 10.1111/j.1365-2672.2009.04354.x
[61] S. Castaldo, F. Capasso, Propolis, an old remedy used in modern medicine, Fitoterapia 73
Suppl 1 (2002) S1-6, http://dx.doi.org/10.1016/s0367-326x(02)00185-5
[62] R. Silva-Carvalho, F. Baltazar, C. Almeida-Aguiar, Propolis: A Complex Natural Product
with a Plethora of Biological Activities That Can Be Explored for Drug Development, Evid
Based Complement Alternat Med 2015 (2015) 206439, https://doi.org/10.1155/2015/206439
[63] A.K. Kuropatnicki, E. Szliszka, W. Krol, Historical Aspects of Propolis Research in Modern
Times, Evid Based Complement Alternat Med 2013 (2013) 964149,
https://doi.org/10.1155/2013/964149
[64] S. Sun, J. He, M. Liu, G. Yin, X. Zhang, A Great Concern Regarding the Authenticity
Identification and Quality Control of Chinese Propolis and Brazilian Green Propolis, J Food Nutr
Res 7(10) (2019) 725-735, http://dx.doi.org/10.12691/jfnr-7-10-6
[65] J.L. Sun, Y.L. Hu, D.Y. Wang, B.K. Zhang, J.G. Liu, Immunologic enhancement of
compound Chinese herbal medicinal ingredients and their efficacy comparison with compound
Chinese herbal medicines, Vaccine 24(13) (2006) 2343-8,
http://dx.doi.org/10.1016/j.vaccine.2005.11.053
[66] M.H. Akao Y, Matsumoto K, Ohguchi K, Nishizawa K, Sakamoto T, Araki Y, Mishima S,
Nozawa Y., Cell growth inhibitory effect of cinnamic acid derivatives from propolis on human
tumor cell lines, Biol Pharm Bull 26(7) (2003) 1057, http://dx.doi.org/10.1248/bpb.26.1057.
[67] A.H. Banskota, Y. Tezuka, S. Kadota, Recent progress in pharmacological research of
propolis, Phytother Res 15(7) (2001) 561-71, http://dx.doi.org/10.1002/ptr.1029
[68] J.H.C. Furtado Júnior, L.A.R. Valadas, S. Fonseca, P.L.D. Lobo, L.H.M. Calixto, A.G.F.
Lima, M.H.R. de Aguiar, I.S. Arruda, M.A.L. Lotif, E.M. Rodrigues Neto, M.M.F. Fonteles,
Clinical and Microbiological Evaluation of Brazilian Red Propolis Containing-Dentifrice in
Orthodontic Patients: A Randomized Clinical Trial, Evid Based Complement Alternat Med 2020
(2020) 8532701, http://dx.doi.org/10.1155/2020/8532701
[69] G. Gajek, B. Marciniak, J. Lewkowski, R. Kontek, Antagonistic Effects of CAPE (a
Component of Propolis) on the Cytotoxicity and Genotoxicity of Irinotecan and SN38 in Human
Gastrointestinal Cancer Cells In Vitro, Molecules 25(3) (2020) 658,
http://dx.doi.org/10.3390/molecules25030658
[70] L.M. Santos, M.S. Fonseca, A.R. Sokolonski, K.R. Deegan, R.P. Araújo, M.A. Umsza-
Guez, J.D. Barbosa, R.D. Portela, B.A. Machado, Propolis: types, composition, biological
activities, and veterinary product patent prospecting, J Sci Food Agric 100(4) (2020) 1369-1382,
http://dx.doi.org/10.1002/jsfa.10024
[71] J. He-rim, ‘Health functional foods’ see boom in wake of virus outbreak, The Investor, The
Korea Herald, Korea, 2020. http://www.theinvestor.co.kr/view.php?ud=20200305000843
[72] T. Koe, New rules: South Korea expands propolis oral formats, removes upper limit for
functional ingredients, 2020, https://www.nutraingredients-asia.com/Article/2020/03/09/
[73] G.d.M.S. Pina, E.N. Lia, A.A. Berretta, A.P. Nascimento, E.C. Torres, A.F.M. Buszinski,
T.A. de Campos, E.B. Coelho, V.d.P. Martins, Efficacy of Propolis on the Denture Stomatitis
Treatment in Older Adults: A Multicentric Randomized Trial, Evid Based Complement Alternat
Med 2017 (2017) 8971746, https://doi.org/10.1155/2017/8971746
[74] A.A. Berretta, Pesquisa pré-clínica e clínica de um gel termorreversível contendo extrato
padronizado de própolis (EPP-AF) para a redução do tempo de cicatrização de lesões em
pacientes queimados, Ph.D. thesis. Faculdade de Ciências Farmacêuticas de Ribeirão Preto,
Universidade de São Paulo, Ribeirão Preto, (2007), http://dx.doi.org/10.11606/T.60.2007.tde-
03122008-164750
[75] Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, The
species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and
naming it SARS-CoV-2, Nat. Microbiol. 5 (2020) 536-544, http://dx.doi.org/10.1038/s41564-
020-0695-z
[76] H. Hashem, IN Silico Approach of Some Selected Honey Constituents as SARS-CoV-2
Main Protease (COVID-19) Inhibitors, EJMO 4(3) (2020) 196-200,
http://dx.doi.org/10.26434/chemrxiv.12115359
[77] V. Kumar, J.K. Dhanjal, S.C. Kaul, R. Wadhwa, D. Sundar, Withanone and caffeic acid
phenethyl ester are predicted to interact with main protease (M(pro)) of SARS-CoV-2 and inhibit
its activity, J Biomol Struct Dyn (2020) 1-13, https://doi.org/10.1080/07391102.2020.1772108
[78] P. Zhou, X.L. Yang, X.G. Wang, B. Hu, L. Zhang, W. Zhang, H.R. Si, Y. Zhu, B. Li, C.L.
Huang, H.D. Chen, J. Chen, Y. Luo, H. Guo, R.D. Jiang, M.Q. Liu, Y. Chen, X.R. Shen, X.
Wang, X.S. Zheng, K. Zhao, Q.J. Chen, F. Deng, L.L. Liu, B. Yan, F.X. Zhan, Y.Y. Wang, G.F.
Xiao, Z.L. Shi, A pneumonia outbreak associated with a new coronavirus of probable bat origin,
Nature 579(7798) (2020) 270-273, https://doi.org/10.1038/s41586-020-2012-7
[79] D. Wang, B. Hu, C. Hu, F. Zhu, X. Liu, J. Zhang, B. Wang, H. Xiang, Z. Cheng, Y. Xiong,
Y. Zhao, Y. Li, X. Wang, Z. Peng, Clinical Characteristics of 138 Hospitalized Patients With
2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China, JAMA 323 (11) (2020) 1061-
1069, http://dx.doi.org/10.1001/jama.2020.1585
[80] M.R. Mehra, S.S. Desai, S. Kuy, T.D. Henry, A.N. Patel, Cardiovascular Disease, Drug
Therapy, and Mortality in Covid-19, N Engl J Med 382 (2020) e102,
http://dx.doi.org/10.1056/NEJMoa2007621
[81] F. Sanchis-Gomar, C.J. Lavie, C. Perez-Quilis, B.M. Henry, G. Lippi, Angiotensin-
Converting Enzyme 2 and Antihypertensives (Angiotensin Receptor Blockers and Angiotensin-
Converting Enzyme Inhibitors) in Coronavirus Disease 2019, Mayo Clin Proc 95(6) (2020)
1222-1230, https://doi.org/10.1016/j.mayocp.2020.03.026
[82] S.M. Oses, P. Marcos, P. Azofra, A. de Pablo, M.A. Fernandez-Muino, M.T. Sancho,
Phenolic Profile, Antioxidant Capacities and Enzymatic Inhibitory Activities of Propolis from
Different Geographical Areas: Needs for Analytical Harmonization, Antioxidants 9(1) (2020) 75,
http://dx.doi.org/10.3390/antiox9010075
[83] J. Da, M. Xu, Y. Wang, W. Li, M. Lu, Z. Wang, Kaempferol Promotes Apoptosis While
Inhibiting Cell Proliferation via Androgen-Dependent Pathway and Suppressing Vasculogenic
Mimicry and Invasion in Prostate Cancer, Anal Cell Pathol 2019 (2019) 1907698,
http://dx.doi.org/10.1155/2019/1907698
[84] M. Debiaggi, F. Tateo, L. Pagani, M. Luini, E. Romero, Effects of propolis flavonoids on
virus infectivity and replication, Microbiologica 13(3) (1990) 207-213.
[85] S.M. Messerli, M.-R. Ahn, K. Kunimasa, M. Yanagihara, T. Tatefuji, K. Hashimoto, V.
Mautner, Y. Uto, H. Hori, S. Kumazawa, K. Kaji, T. Ohta, H. Maruta, Artepillin C (ARC) in
Brazilian green propolis selectively blocks oncogenic PAK1 signaling and suppresses the growth
of NF tumors in mice, Phytother Res 23(3) (2009) 423-427, https://doi.org/10.1002/ptr.2658
[86] M.H.V. Fernandes, L.N. Ferreira, G.D.A. Vargas, G. Fischer, S.O. Hübner, Effect of Water
Extract from Brown Propolis on Production of IFN-ϒ After Immunization Against Canine
Parvovirus (Cpv) and Canine Coronavirus (Ccov), Ciênc Anim Bras 16(2) (2015) 235-242,
https://doi.org/10.1590/1089-6891v16i223458
[87] A.M. Mahmoud, S.M. Abd El-Twab, Caffeic acid phenethyl ester protects the brain against
hexavalent chromium toxicity by enhancing endogenous antioxidants and modulating the
JAK/STAT signaling pathway, Biomed Pharmacother 91 (2017) 303-311,
http://dx.doi.org/10.1016/j.biopha.2017.04.073
[88] Y. Okamoto, M. Tanaka, T. Fukui, T. Masuzawa, Brazilian propolis inhibits the
differentiation of Th17 cells by inhibition of interleukin-6-induced phosphorylation of signal
transducer and activator of transcription 3, Immunopharm Immunot 34(5) (2012) 803-809,
https://doi.org/10.3109/08923973.2012.657304
[89] N. Paulino, S.R. Abreu, Y. Uto, D. Koyama, H. Nagasawa, H. Hori, V.M. Dirsch, A.M.
Vollmar, A. Scremin, W.A. Bretz, Anti-inflammatory effects of a bioavailable compound,
Artepillin C, in Brazilian propolis, Eur J Pharmacol 587(1-3) (2008) 296-301,
http://dx.doi.org/10.1016/j.ejphar.2008.02.067.
[90] S.H. Nile, A. Nile, J. Qiu, L. Li, X. Jia, G. Kai, COVID-19: Pathogenesis, cytokine storm
and therapeutic potential of interferons, Cytokine Growth F R 53 (2020) 66-70,
http://dx.doi.org/10.1016/j.cytogfr.2020.05.002
[91] C.C. Li, X.J. Wang, H.R. Wang, Repurposing host-based therapeutics to control coronavirus
and influenza virus, Drug Discov Today 24(3) (2019) 726-736,
http://dx.doi.org/10.1016/j.drudis.2019.01.018
[92] C.L. Orsatti, F. Missima, A.C. Pagliarone, T.F. Bachiega, M.C. Búfalo, J.P. Araújo, Jr., J.M.
Sforcin, Propolis immunomodulatory action in vivo on Toll-like receptors 2 and 4 expression
and on pro-inflammatory cytokines production in mice, Phytother Res 24(8) (2010) 1141-6,
http://dx.doi.org/10.1002/ptr.3086
[93] J. Ito, F.R. Chang, H.K. Wang, Y.K. Park, M. Ikegaki, N. Kilgore, K.H. Lee, Anti-AIDS
agents. 48.(1) Anti-HIV activity of moronic acid derivatives and the new melliferone-related
triterpenoid isolated from Brazilian propolis, J Nat Prod 64(10) (2001) 1278-81,
http://dx.doi.org/10.1021/np010211x
[94] T. Shimizu, A. Hino, A. Tsutsumi, Y.K. Park, W. Watanabe, M. Kurokawa, Anti-influenza
virus activity of propolis in vitro and its efficacy against influenza infection in mice, Antivir
Chem Chemother 19(1) (2008) 7-13, http://dx.doi.org/10.1177/095632020801900102
[95] S. Nolkemper, J. Reichling, K.H. Sensch, P. Schnitzler, Mechanism of herpes simplex virus
type 2 suppression by propolis extracts, Phytomedicine 17(2) (2010) 132-8,
https://doi.org/10.1016/j.phymed.2009.07.006
[96] Z. Harish, A. Rubinstein, M. Golodner, M. Elmaliah, Y. Mizrachi, Suppression of HIV-1
replication by propolis and its immunoregulatory effect, Drugs Exp Clin Res 23(2) (1997) 89-96.
[97] M. Amoros, C.M. Simões, L. Girre, F. Sauvager, M. Cormier, Synergistic effect of flavones
and flavonols against herpes simplex virus type 1 in cell culture. Comparison with the antiviral
activity of propolis, J Nat Prod 55(12) (1992) 1732-40, https://doi.org/10.1021/np50090a003
[98] J.T. England, A. Abdulla, C.M. Biggs, A.Y.Y. Lee, K.A. Hay, R.L. Hoiland, C.L.
Wellington, M. Sekhon, S. Jamal, K. Shojania, L.Y.C. Chen, Weathering the COVID-19 storm:
Lessons from hematologic cytokine syndromes, Blood Rev (2020) 100707,
http://dx.doi.org/10.1016/j.blre.2020.100707
[99] H. Maruta, A. Kittaka, Chemical evolution for taming the 'pathogenic kinase' PAK1, Drug
Discov Today 25(6) (2020) 959-964, http://dx.doi.org/10.1016/j.drudis.2020.03.008
[100] J. Tozser, S. Benko, Natural Compounds as Regulators of NLRP3 Inflammasome-
Mediated IL-1beta Production, Mediators Inflamm 2016 (2016) 5460302,
https://doi.org/10.1155/2016/5460302
[101] S.H. Ashry el, T.A. Ahmad, The use of propolis as vaccine's adjuvant, Vaccine 31(1)
(2012) 31-9, http://dx.doi.org/10.1016/j.vaccine.2012.10.095
[102] Y. Fan, L. Guo, W. Hou, C. Guo, W. Zhang, X. Ma, L. Ma, X. Song, The Adjuvant
Activity of Epimedium Polysaccharide-Propolis Flavone Liposome on Enhancing Immune
Responses to Inactivated Porcine Circovirus Vaccine in Mice, Evid Based Complement Alternat
Med 2015 (2015) 972083, https://doi.org/10.1155/2015/972083
[103] L. Yang, Y. Hu, J. Xue, F. Wang, D. Wang, X. Kong, P. Li, W. Xu, Compound Chinese
herbal medicinal ingredients can enhance immune response and efficacy of RHD vaccine in
rabbit, Vaccine 26(35) (2008) 4451-5, http://dx.doi.org/10.1016/j.vaccine.2008.06.075
[104] Y. Tao, D. Wang, Y. Hu, Y. Huang, Y. Yu, D. Wang, The immunological enhancement
activity of propolis flavonoids liposome in vitro and in vivo, Evid Based Complement Alternat
Med 2014 (2014) 483513, http://dx.doi.org/10.1155/2014/483513
[105] G. Fischer, M.B. Cleff, L.A. Dummer, N. Paulino, A.S. Paulino, C. de Oliveira Vilela, F.S.
Campos, T. Storch, G. D'Avila Vargas, S. de Oliveira Hübner, T. Vidor, Adjuvant effect of green
propolis on humoral immune response of bovines immunized with bovine herpesvirus type 5,
Vet Immunol Immunopathol 116(1-2) (2007) 79-84,
http://dx.doi.org/10.1016/j.vetimm.2007.01.003
[106] G. Fischer, F.R. Conceicao, F.P. Leite, L.A. Dummer, G.D. Vargas, O. Hubner Sde, O.A.
Dellagostin, N. Paulino, A.S. Paulino, T. Vidor, Immunomodulation produced by a green
propolis extract on humoral and cellular responses of mice immunized with SuHV-1, Vaccine
25(7) (2007) 1250-1256, http://dx.doi.org/10.1016/j.vaccine.2006.10.005
[107] X. Ma, Z. Guo, Z. Shen, J. Wang, Y. Hu, D. Wang, The immune enhancement of propolis
adjuvant on inactivated porcine parvovirus vaccine in guinea pig, Cell Immunol 270(1) (2011)
13-18, http://dx.doi.org/10.1016/j.cellimm.2011.03.020
[108] Â. Sena-Lopes, F.S.B. Bezerra, R.N. das Neves, R.B. de Pinho, M.T.O. Silva, L.
Savegnago, T. Collares, F. Seixas, K. Begnini, J.A.P. Henriques, M.R. Ely, L.C. Rufatto, S.
Moura, T. Barcellos, F. Padilha, O. Dellagostin, S. Borsuk, Chemical composition,
immunostimulatory, cytotoxic and antiparasitic activities of the essential oil from Brazilian red
propolis, PLoS One 13(2) (2018) e0191797, http://dx.doi.org/10.1371/journal.pone.0191797
[109] G. Fischer, N. Paulino, M.C. Marcucci, B.S. Siedler, L.S. Munhoz, P.F. Finger, G.D.
Vargas, S.O. Hübner, T. Vidor, P.M. Roehe, Green propolis phenolic compounds act as vaccine
adjuvants, improving humoral and cellular responses in mice inoculated with inactivated
vaccines, Mem Inst Oswaldo Cruz 105(7) (2010) 908-13, https://doi.org/10.1590/S0074-
02762010000700012
[110] S. Mojarab, D. Shahbazzadeh, M. Moghbeli, Y. Eshraghi, K.P. Bagheri, R. Rahimi, M.A.
Savoji, M. Mahdavi, Immune responses to HIV-1 polytope vaccine candidate formulated in
aqueous and alcoholic extracts of Propolis: Comparable immune responses to Alum and Freund
adjuvants, Microb Pathog 140 (2020) 103932, http://dx.doi.org/10.1016/j.micpath.2019.103932
[111] E. Raymond, C. Thieblemont, S. Alran, S. Faivre, Impact of the COVID-19 Outbreak on
the Management of Patients with Cancer, Targ Oncol 15 (2020) 249-259,
http://dx.doi.org/10.1007/s11523-020-00721-1
[112] S. Patel, Emerging Adjuvant Therapy for Cancer: Propolis and its Constituents, J Diet
Suppl 13(3) (2016) 245-68, http://dx.doi.org/10.3109/19390211.2015.1008614
[113] Y. Frión-Herrera, D. Gabbia, M. Scaffidi, L. Zagni, O. Cuesta-Rubio, S. De Martin, M.
Carrara, The Cuban Propolis Component Nemorosone Inhibits Proliferation and Metastatic
Properties of Human Colorectal Cancer Cells, Int J Mol Sci 21(5) (2020) 1827,
https://doi.org/10.3390/ijms21051827
[114] Y.S. Song, E.H. Park, K.J. Jung, C. Jin, Inhibition of angiogenesis by propolis, Arch
Pharm Res 25(4) (2002) 500-4, http://dx.doi.org/10.1007/BF02976609
[115] N. Orsolić, I. Basić, Antitumor, hematostimulative and radioprotective action of water-
soluble derivative of propolis (WSDP), Biomed Pharmacother 59(10) (2005) 561-70,
http://dx.doi.org/10.1016/j.biopha.2005.03.013
[116] M.A. Watanabe, M.K. Amarante, B.J. Conti, J.M. Sforcin, Cytotoxic constituents of
propolis inducing anticancer effects: a review, J Pharm Pharmacol 63(11) (2011) 1378-86,
http://dx.doi.org/10.1111/j.2042-7158.2011.01331.x
[117] J. Wu, C. Omene, J. Karkoszka, M. Bosland, J. Eckard, C.B. Klein, K. Frenkel, Caffeic
acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of
anti-tumor effects in pre-clinical models of human breast cancer, Cancer Lett 308(1) (2011) 43-
53, http://dx.doi.org/10.1016/j.canlet.2011.04.012
[118] S. Akyol, G. Ozturk, Z. Ginis, F. Armutcu, M.R. Yigitoglu, O. Akyol, In vivo and in vitro
antıneoplastic actions of caffeic acid phenethyl ester (CAPE): therapeutic perspectives, Nutr
Cancer 65(4) (2013) 515-26, http://dx.doi.org/10.1080/01635581.2013.776693
[119] H. Chang, Y. Wang, X. Yin, X. Liu, H. Xuan, Ethanol extract of propolis and its
constituent caffeic acid phenethyl ester inhibit breast cancer cells proliferation in inflammatory
microenvironment by inhibiting TLR4 signal pathway and inducing apoptosis and autophagy,
BMC Complement Altern Med 17(1) (2017) 471, http://dx.doi.org/10.1186/s12906-017-1984-9
[120] N. Orsolić, A.H. Knezević, L. Sver, S. Terzić, I. Basić, Immunomodulatory and
antimetastatic action of propolis and related polyphenolic compounds, J Ethnopharmacol 94(2-3)
(2004) 307-15, http://dx.doi.org/10.1016/j.jep.2004.06.006
[121] D. Sawicka, H. Car, M.H. Borawska, J. Nikliński, The anticancer activity of propolis, Folia
Histochem Cytobiol 50(1) (2012) 25-37, http://dx.doi.org/10.2478/18693
[122] D. Grunberger, R. Banerjee, K. Eisinger, E.M. Oltz, L. Efros, M. Caldwell, V. Estevez, K.
Nakanishi, Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from
propolis, Experientia 44(3) (1988) 230-2, http://dx.doi.org/10.1007/BF01941717
[123] T. Nagaoka, A.H. Banskota, Y. Tezuka, I. Saiki, S. Kadota, Selective antiproliferative
activity of caffeic acid phenethyl ester analogues on highly liver-metastatic murine colon 26-L5
carcinoma cell line, Bioorg Med Chem 10(10) (2002) 3351-9, http://dx.doi.org/10.1016/s0968-
0896(02)00138-4
[124] E. Szliszka, Z.P. Czuba, M. Domino, B. Mazur, G. Zydowicz, W. Krol, Ethanolic extract
of propolis (EEP) enhances the apoptosis- inducing potential of TRAIL in cancer cells,
Molecules 14(2) (2009) 738-754, http://dx.doi.org/10.3390/molecules14020738
[125] T.M. Cook, The importance of hypertension as a risk factor for severe illness and mortality
in COVID-19, Anaesthesia 75(7) (2020) 976-977, https://doi.org/10.1111/anae.15103
[126] K. Mahajan, K. Chandra, Cardiovascular comorbidities and complications associated with
coronavirus disease 2019, Med J Armed Forces India (2020),
http://dx.doi.org/10.1016/j.mjafi.2020.05.004
[127] A. Emami, F. Javanmardi, N. Pirbonyeh, A. Akbari, Prevalence of Underlying Diseases in
Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis, Arch Acad
Emerg Med 8(1) (2020) e35, http://dx.doi.org/10.22037/aaem.v8i1.600
[128] Y. Kubota, K. Umegaki, K. Kobayashi, N. Tanaka, S. Kagota, K. Nakamura, M.
Kunitomo, K. Shinozuka, Anti-hypertensive effects of Brazilian propolis in spontaneously
hypertensive rats, Clin Exp Pharmacol Physiol 31 Suppl 2 (2004) S29-30,
http://dx.doi.org/10.1111/j.1440-1681.2004.04113.x
[129] H. Zhou, H. Wang, N. Shi, F. Wu, Potential Protective Effects of the Water-Soluble
Chinese Propolis on Hypertension Induced by High-Salt Intake, Clin Transl Sci (2020),
http://dx.doi.org/10.1111/cts.12770
[130] S. Zingue, C.B.M. Nde, T. Michel, D.T. Ndinteh, J. Tchatchou, M. Adamou, X.
Fernandez, F.T. Fohouo, C. Clyne, D. Njamen, Ethanol-extracted Cameroonian propolis exerts
estrogenic effects and alleviates hot flushes in ovariectomized Wistar rats, BMC Complement
Altern Med 17(1) (2017) 65, https://doi.org/10.1186/s12906-017-1568-8
[131] W. Yuan, H. Chang, X. Liu, S. Wang, H. Liu, H. Xuan, Brazilian Green Propolis Inhibits
Ox-LDL-Stimulated Oxidative Stress in Human Umbilical Vein Endothelial Cells Partly through
PI3K/Akt/mTOR-Mediated Nrf2/HO-1 Pathway, Evid Based Complement Alternat Med 2019
(2019) 5789574, http://dx.doi.org/10.1155/2019/5789574
[132] V. Mujica, R. Orrego, J. Pérez, P. Romero, P. Ovalle, J. Zúñiga-Hernández, M. Arredondo,
E. Leiva, The Role of Propolis in Oxidative Stress and Lipid Metabolism: A Randomized
Controlled Trial, Evid Based Complement Alternat Med 2017 (2017) 4272940,
https://doi.org/10.1155/2017/4272940
[133] K. Michalakis, I. Ilias, SARS-CoV-2 infection and obesity: Common inflammatory and
metabolic aspects, Diabetes Metab Syndr 14(4) (2020) 469-471,
https://doi.org/10.1016/j.dsx.2020.04.033
[134] S. Koya-Miyata, N. Arai, A. Mizote, Y. Taniguchi, S. Ushio, K. Iwaki, S. Fukuda, Propolis
prevents diet-induced hyperlipidemia and mitigates weight gain in diet-induced obesity in mice,
Biol Pharm Bull 32(12) (2009) 2022-8, http://dx.doi.org/10.1248/bpb.32.2022
[135] S. Rayalam, D. Mills, Y. Azhar, E. Miller, X. Wang, Caffeic Acid Phenethyl Ester and Its
Fluorinated Derivative as Natural Anti-obesity Agents (P06-089-19), Curr Dev Nutr 3
(Supplement_1) (2019), http://dx.doi.org/10.1093/cdn/nzz031.P06-089-19
[136] B.J. Barnes, J.M. Adrover, A. Baxter-Stoltzfus, A. Borczuk, J. Cools-Lartigue, J.M.
Crawford, J. Daßler-Plenker, P. Guerci, C. Huynh, J.S. Knight, M. Loda, M.R. Looney, F.
McAllister, R. Rayes, S. Renaud, S. Rousseau, S. Salvatore, R.E. Schwartz, J.D. Spicer, C.C.
Yost, A. Weber, Y. Zuo, M. Egeblad, Targeting potential drivers of COVID-19: Neutrophil
extracellular traps, J Exp Med 217(6) (2020) e20200652,
http://dx.doi.org/10.1084/jem.20200652
[137] L. Bertoletti, F. Couturaud, D. Montani, F. Parent, O. Sanchez, Venous thromboembolism
and COVID-19, Respir Med Res 78 (2020) 100759,
http://dx.doi.org/10.1016/j.resmer.2020.100759
[138] R.J. Jose, A. Manuel, COVID-19 cytokine storm: the interplay between inflammation and
coagulation, Lancet Respir Med (2020), https://doi.org/10.1016/S2213-2600(20)30216-2
[139] F.A. Klok, M.J.H.A. Kruip, N.J.M. van der Meer, M.S. Arbous, D.A.M.P.J. Gommers,
K.M. Kant, F.H.J. Kaptein, J. van Paassen, M.A.M. Stals, M.V. Huisman, H. Endeman,
Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Thromb Res
191 (2020) 145-147, http://dx.doi.org/10.1016/j.thromres.2020.04.013
[140] D.E. Vaughan, PAI-1 and atherothrombosis, J Thromb Haemost 3(8) (2005) 1879-1883,
https://doi.org/10.1111/j.1538-7836.2005.01420.x
[141] M. Cesari, M. Pahor, R.A. Incalzi, Plasminogen activator inhibitor-1 (PAI-1): a key factor
linking fibrinolysis and age-related subclinical and clinical conditions, Cardiovasc Ther 28(5)
(2010) e72-e91, http://dx.doi.org/10.1111/j.1755-5922.2010.00171.x
[142] N. Ohkura, K. Oishi, F. Kihara-Negishi, G.-I. Atsumi, T. Tatefuji, Effects of a diet
containing Brazilian propolis on lipopolysaccharide-induced increases in plasma plasminogen
activator inhibitor-1 levels in mice, J Intercult Ethnopharmacol 5(4) (2016) 439-443,
http://dx.doi.org/10.5455/jice.20160814112735
[143] H. Kitamura, Effects of Propolis Extract and Propolis-Derived Compounds on Obesity and
Diabetes: Knowledge from Cellular and Animal Models, Molecules 24(23) (2019) 4394,
http://dx.doi.org/10.3390/molecules24234394
[144] J.B. Daleprane, D.S. Abdalla, Emerging roles of propolis: antioxidant, cardioprotective,
and antiangiogenic actions, Evid Based Complement Alternat Med 2013 (2013) 175135,
https://doi.org/10.1155/2013/175135
[145] M. Bojić, A. Antolić, M. Tomičić, Ž. Debeljak, Ž. Maleš, Propolis ethanolic extracts
reduce adenosine diphosphate induced platelet aggregation determined on whole blood, Nutr J
17(1) (2018) 52, http://dx.doi.org/10.1186/s12937-018-0361-y
[146] Y.-X. Zhang, T.-T. Yang, L. Xia, W.-F. Zhang, J.-F. Wang, Y.-P. Wu, Inhibitory Effect of
Propolis on Platelet Aggregation In Vitro, J Healthc Eng 2017 (2017) 3050895,
https://doi.org/10.1155/2017/3050895
[147] G. Hsiao, J.J. Lee, K.H. Lin, C.H. Shen, T.H. Fong, D.S. Chou, J.R. Sheu, Characterization
of a novel and potent collagen antagonist, caffeic acid phenethyl ester, in human platelets: in
vitro and in vivo studies, Cardiovasc Res 75(4) (2007) 782-792,
https://doi.org/10.1016/j.cardiores.2007.05.005
[148] E.O. Gubernatorova, E.A. Gorshkova, A.I. Polinova, M.S. Drutskaya, IL-6: Relevance for
immunopathology of SARS-CoV-2, Cytokine Growth F R 53 (2020), 13-24,
http://dx.doi.org/10.1016/j.cytogfr.2020.05.009
[149] J. Kocot, M. Kiełczykowska, D. Luchowska-Kocot, J. Kurzepa, I. Musik, Antioxidant
Potential of Propolis, Bee Pollen, and Royal Jelly: Possible Medical Application, Oxid Med Cell
Longev 2018 (2018) 7074209, http://dx.doi.org/10.1155/2018/7074209
[150] S. Havermann, Y. Chovolou, H.U. Humpf, W. Wätjen, Caffeic acid phenethylester
increases stress resistance and enhances lifespan in Caenorhabditis elegans by modulation of the
insulin-like DAF-16 signalling pathway, PLoS One 9(6) (2014) e100256,
https://doi.org/10.1371/journal.pone.0100256
[151] A. Zhu, Z. Wu, X. Zhong, J. Ni, Y. Li, J. Meng, C. Du, X. Zhao, H. Nakanishi, S. Wu,
Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly
People Living at High Altitude, J Alzheimers Dis 63(2) (2018) 551-560,
http://dx.doi.org/10.3233/JAD-170630
[152] I. Jasprica, A. Mornar, Z. Debeljak, A. Smolcić-Bubalo, M. Medić-Sarić, L. Mayer, Z.
Romić, K. Bućan, T. Balog, S. Sobocanec, V. Sverko, In vivo study of propolis supplementation
effects on antioxidative status and red blood cells, J Ethnopharmacol 110(3) (2007) 548-554,
http://dx.doi.org/10.1016/j.jep.2006.10.023
[153] H.R. Sameni, P. Ramhormozi, A.R. Bandegi, A.A. Taherian, M. Mirmohammadkhani, M.
Safari, Effects of ethanol extract of propolis on histopathological changes and anti-oxidant
defense of kidney in a rat model for type 1 diabetes mellitus, J Diabetes Investig 7(4) (2016)
506-513, http://dx.doi.org/10.1111/jdi.12459
[154] J. Ni, Z. Wu, J. Meng, A. Zhu, X. Zhong, S. Wu, H. Nakanishi, The Neuroprotective
Effects of Brazilian Green Propolis on Neurodegenerative Damage in Human Neuronal SH-
SY5Y Cells, Oxid Med Cell Longev 2017 (2017) 7984327,
https://doi.org/10.1155/2017/7984327
[155] M. Ayaz, A. Sadiq, M. Junaid, F. Ullah, M. Ovais, I. Ullah, J. Ahmed, M. Shahid,
Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging
Associated Neurological Disorders, Front Aging Neurosci 11 (2019) 155,
http://dx.doi.org/10.3389/fnagi.2019.00155
[156] Y. Dong, T. Stewart, L. Bai, X. Li, T. Xu, J. Iliff, M. Shi, D. Zheng, L. Yuan, T. Wei, X.
Yang, J. Zhang, Coniferaldehyde attenuates Alzheimer's pathology via activation of Nrf2 and its
targets, Theranostics 10(1) (2020) 179-200, http://dx.doi.org/10.7150/thno.36722
[157] C. Sargiacomo, F. Sotgia, M.P. Lisanti, COVID-19 and chronological aging: senolytics
and other anti-aging drugs for the treatment or prevention of corona virus infection?, Aging
12(8) (2020) 6511-6517, http://dx.doi.org/10.18632/aging.103001
[158] R. Vinayagam, B. Xu, Antidiabetic properties of dietary flavonoids: a cellular mechanism
review, Nutr Metab 12(1) (2015) 60, https://doi.org/10.1186/s12986-015-0057-7
[159] A.P. Tiveron, P.L. Rosalen, M. Franchin, R.C. Lacerda, B. Bueno-Silva, B. Benso, C.
Denny, M. Ikegaki, S.M. Alencar, Chemical Characterization and Antioxidant, Antimicrobial,
and Anti-Inflammatory Activities of South Brazilian Organic Propolis, PLoS One 11(11) (2016)
e0165588, https://doi.org/10.1371/journal.pone.0165588
[160] R. El Adaouia Taleb, N. Djebli, H. Chenini, H. Sahin, S. Kolayli, In vivo and in vitro anti-
diabetic activity of ethanolic propolis extract, J Food Biochem 44 (2020) e13267,
https://doi.org/10.1111/jfbc.13267
[161] T. Matsui, S. Ebuchi, T. Fujise, K.J. Abesundara, S. Doi, H. Yamada, K. Matsumoto,
Strong antihyperglycemic effects of water-soluble fraction of Brazilian propolis and its bioactive
constituent, 3,4,5-tri-O-caffeoylquinic acid, Biol Pharm Bull 27(11) (2004) 1797-803,
http://dx.doi.org/10.1248/bpb.27.1797
[162] Y. Zamami, S. Takatori, T. Koyama, M. Goda, Y. Iwatani, S. Doi, H. Kawasaki, [Effect of
propolis on insulin resistance in fructose-drinking rats], Yakugaku Zasshi 127(12) (2007) 2065-
73, http://dx.doi.org/10.1248/yakushi.127.2065
[163] Y. Li, M. Chen, H. Xuan, F. Hu, Effects of Encapsulated Propolis on Blood Glycemic
Control, Lipid Metabolism, and Insulin Resistance in Type 2 Diabetes Mellitus Rats, Evid Based
Complement Alternat Med 2012 (2012) 981896, https://doi.org/10.1155/2012/981896
[164] W. Aoi, S. Hosogi, N. Niisato, N. Yokoyama, H. Hayata, H. Miyazaki, K. Kusuzaki, T.
Fukuda, M. Fukui, N. Nakamura, Y. Marunaka, Improvement of insulin resistance, blood
pressure and interstitial pH in early developmental stage of insulin resistance in OLETF rats by
intake of propolis extracts, Biochem Biophys Res Commun 432(4) (2013) 650-653,
http://dx.doi.org/10.1016/j.bbrc.2013.02.029
[165] O.M. Abo-Salem, R.H. El-Edel, G.E. Harisa, N. El-Halawany, M.M. Ghonaim,
Experimental diabetic nephropathy can be prevented by propolis: Effect on metabolic
disturbances and renal oxidative parameters, Pak J Pharm Sci 22(2) (2009) 205-210.
[166] H. Kitamura, Y. Naoe, S. Kimura, T. Miyamoto, S. Okamoto, C. Toda, Y. Shimamoto, T.
Iwanaga, I. Miyoshi, Beneficial effects of Brazilian propolis on type 2 diabetes in ob/ob mice:
Possible involvement of immune cells in mesenteric adipose tissue, Adipocyte 2(4) (2013) 227-
236, http://dx.doi.org/10.4161/adip.25608
[167] W. Gao, L. Pu, J. Wei, Z. Yao, Y. Wang, T. Shi, L. Zhao, C. Jiao, C. Guo, Serum
Antioxidant Parameters are Significantly Increased in Patients with Type 2 Diabetes Mellitus
after Consumption of Chinese Propolis: A Randomized Controlled Trial Based on Fasting Serum
Glucose Level, Diabetes Ther 9(1) (2018) 101-111, http://dx.doi.org/10.1007/s13300-017-0341-
9
[168] N. Samadi, H. Mozaffari-Khosravi, M. Rahmanian, M. Askarishahi, 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 15(2) (2017)
124-134, http://dx.doi.org/10.1016/S2095-4964(17)60315-7
[169] S. Hesami, S. Hashemipour, M.R. Shiri-Shahsavar, Y. Koushan, H. Khadem Haghighian,
Administration of Iranian Propolis attenuates oxidative stress and blood glucose in type II
diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial, Caspian J Intern
Med 10(1) (2019) 48-54, http://dx.doi.org/10.22088/cjim.10.1.48
[170] M. Zakerkish, M. Jenabi, N. Zaeemzadeh, A.A. Hemmati, N. Neisi, The Effect of Iranian
Propolis on Glucose Metabolism, Lipid Profile, Insulin Resistance, Renal Function and
Inflammatory Biomarkers in Patients with Type 2 Diabetes Mellitus: A Randomized Double-
Blind Clinical Trial, Sci Rep 9(1) (2019) 7289, http://dx.doi.org/10.1038/s41598-019-43838-8
[171] A. Oryan, E. Alemzadeh, A. Moshiri, Potential role of propolis in wound healing:
Biological properties and therapeutic activities, Biomed Pharmacother 98 (2018) 469-483,
http://dx.doi.org/10.1016/j.biopha.2017.12.069
[172] A. Picolotto, D. Pergher, G.P. Pereira, K.G. Machado, H. da Silva Barud, M. Roesch-Ely,
M.H. Gonzalez, L. Tasso, J.G. Figueiredo, S. Moura, Bacterial cellulose membrane associated
with red propolis as phytomodulator: Improved healing effects in experimental models of
diabetes mellitus, Biomed Pharmacother 112 (2019) 108640,
https://doi.org/10.1016/j.biopha.2019.108640
[173] M. Afkhamizadeh, R. Aboutorabi, H. Ravari, M. Fathi Najafi, S. Ataei Azimi, A. Javadian
Langaroodi, M.A. Yaghoubi, A. Sahebkar, Topical propolis improves wound healing in patients
with diabetic foot ulcer: a randomized controlled trial, Nat Prod Res 32(17) (2018) 2096-2099,
http://dx.doi.org/10.1080/14786419.2017.1363755
[174] F.R. Henshaw, T. Bolton, V. Nube, A. Hood, D. Veldhoen, L. Pfrunder, G.L. McKew, C.
Macleod, S.V. McLennan, S.M. Twigg, Topical application of the bee hive protectant propolis is
well tolerated and improves human diabetic foot ulcer healing in a prospective feasibility study, J
Diabetes Complicat 28(6) (2014) 850-857, http://dx.doi.org/10.1016/j.jdiacomp.2014.07.012
[175] S.H. Shin, S.G. Seo, S. Min, H. Yang, E. Lee, J.E. Son, J.Y. Kwon, S. Yue, M.Y. Chung,
K.H. Kim, J.X. Cheng, H.J. Lee, K.W. Lee, Caffeic acid phenethyl ester, a major component of
propolis, suppresses high fat diet-induced obesity through inhibiting adipogenesis at the mitotic
clonal expansion stage, J Agric Food Chem 62(19) (2014) 4306-12,
http://dx.doi.org/10.1021/jf405088f
[176] J. Nie, Y. Chang, Y. Li, Y. Zhou, J. Qin, Z. Sun, H. Li, Caffeic Acid Phenethyl Ester
(Propolis Extract) Ameliorates Insulin Resistance by Inhibiting JNK and NF-κB Inflammatory
Pathways in Diabetic Mice and HepG2 Cell Models, J Agric Food Chem 65(41) (2017) 9041-
9053, https://doi.org/10.1021/acs.jafc.7b02880
[177] J.J. Ramírez-Espinosa, J. Saldaña-Ríos, S. García-Jiménez, R. Villalobos-Molina, G.
Ávila-Villarreal, A.N. Rodríguez-Ocampo, G. Bernal-Fernández, S. Estrada-Soto, Chrysin
Induces Antidiabetic, Antidyslipidemic and Anti-Inflammatory Effects in Athymic Nude
Diabetic Mice, Molecules 23(1) (2017) 67, http://dx.doi.org/10.3390/molecules23010067
[178] L. D'Marco, M.J. Puchades, M. Romero-Parra, J.L. Gorriz, Diabetic Kidney Disease and
COVID-19: The Crash of Two Pandemics, Front Med 7 (2020) 199,
https://doi.org/10.3389/fmed.2020.00199
[179] L. Perico, A. Benigni, G. Remuzzi, Should COVID-19 Concern Nephrologists? Why and
to What Extent? The Emerging Impasse of Angiotensin Blockade, Nephron 144(5) (2020) 213-
221, http://dx.doi.org/10.1159/000507305
[180] V. Monteil, H. Kwon, P. Prado, A. Hagelkrüys, R.A. Wimmer, M. Stahl, A. Leopoldi, E.
Garreta, C. Hurtado del Pozo, F. Prosper, J.P. Romero, G. Wirnsberger, H. Zhang, A.S. Slutsky,
R. Conder, N. Montserrat, A. Mirazimi, J.M. Penninger, Inhibition of SARS-CoV-2 Infections in
Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2, Cell 181(4) (2020)
905-913.e7, http://dx.doi.org/10.1016/j.cell.2020.04.004
[181] F. Alberici, E. Delbarba, C. Manenti, L. Econimo, F. Valerio, A. Pola, C. Maffei, S.
Possenti, S. Piva, N. Latronico, E. Focà, F. Castelli, P. Gaggia, E. Movilli, S. Bove, F. Malberti,
M. Farina, M. Bracchi, E.M. Costantino, N. Bossini, M. Gaggiotti, F. Scolari, Management Of
Patients On Dialysis And With Kidney Transplant During SARS-COV-2 (COVID-19) Pandemic
In Brescia, Italy, Kidney Int Rep 5(5) (2020) 580-585,
http://dx.doi.org/10.1016/j.ekir.2020.04.001
[182] M. Bhadauria, Propolis Prevents Hepatorenal Injury Induced by Chronic Exposure to
Carbon Tetrachloride, Evid Based Complement Alternat Med 2012 (2012) 235358,
https://doi.org/10.1155/2012/235358
[183] K. Boutabet, W. Kebsa, M. Alyane, M. Lahouel, Polyphenolic fraction of Algerian
propolis protects rat kidney against acute oxidative stress induced by doxorubicin, Indian J
Nephrol 21(2) (2011) 101-116, http://dx.doi.org/10.4103/0971-4065.82131
[184] F. Teles, T.M. da Silva, F.P. da Cruz Júnior, V.H. Honorato, H. de Oliveira Costa, A.P.F.
Barbosa, S.G. de Oliveira, Z. Porfírio, A.B. Libório, R.L. Borges, C. Fanelli, Brazilian Red
Propolis Attenuates Hypertension and Renal Damage in 5/6 Renal Ablation Model, PLoS ONE
10(1) (2015) e0116535, https://doi.org/10.1371/journal.pone.0116535
[185] T.P. Cushnie, A.J. Lamb, Antimicrobial activity of flavonoids, Int J Antimicrob Agents
26(5) (2005) 343-356. http://dx.doi.org/10.1016/j.ijantimicag.2005.09.002
[186] J.M. Grange, R.W. Davey, Antibacterial properties of propolis (bee glue), J R Soc Med
83(3) (1990) 159-160.
[187] A. Kujumgiev, I. Tsvetkova, Y. Serkedjieva, V. Bankova, R. Christov, S. Popov,
Antibacterial, antifungal and antiviral activity of propolis of different geographic origin, J
Ethnopharmacol 64(3) (1999) 235-240, http://dx.doi.org/10.1016/s0378-8741(98)00131-7
[188] L. Cornara, M. Biagi, J. Xiao, B. Burlando, Therapeutic Properties of Bioactive
Compounds from Different Honeybee Products, Front Pharmacol 8 (2017) 412,
http://dx.doi.org/10.3389/fphar.2017.00412
[189] J.V.d. Campos, O.B.G. Assis, R. Bernardes-Filho, Atomic force microscopy evidences of
bacterial cell damage caused by propolis extracts on E. coli and S. aureus, Food Sci Technol 40
(2019) 55-61, https://doi.org/10.1590/fst.32018
[190] V. Bankova, R. Christov, A. Kujumgiev, M.C. Marcucci, S. Popov, Chemical composition
and antibacterial activity of Brazilian propolis, Z Naturforsch C J Biosci 50(3-4) (1995) 167-172,
http://dx.doi.org/10.1515/znc-1995-3-402
[191] S. Boisard, A.-M. Le Ray, A. Landreau, M. Kempf, V. Cassisa, C. Flurin, P. Richomme,
Antifungal and Antibacterial Metabolites from a French Poplar Type Propolis, Evid Based
Complement Alternat Med 2015 (2015) 319240, https://doi.org/10.1155/2015/319240
[192] I. Al-Ani, S. Zimmermann, J. Reichling, M. Wink, Antimicrobial Activities of European
Propolis Collected from Various Geographic Origins Alone and in Combination with
Antibiotics, Medicines 5(1) (2018) 2, http://dx.doi.org/10.3390/medicines5010002
[193] F. Scazzocchio, F.D. D'Auria, D. Alessandrini, F. Pantanella, Multifactorial aspects of
antimicrobial activity of propolis, Microbiol Res 161(4) (2006) 327-33,
http://dx.doi.org/10.1016/j.micres.2005.12.003
[194] S.A. Libério, A.L. Pereira, M.J. Araújo, R.P. Dutra, F.R. Nascimento, V. Monteiro-Neto,
M.N. Ribeiro, A.G. Gonçalves, R.N. Guerra, The potential use of propolis as a cariostatic agent
and its actions on mutans group streptococci, J Ethnopharmacol 125(1) (2009) 1-9,
http://dx.doi.org/10.1016/j.jep.2009.04.047
[195] O.K. Mirzoeva, R.N. Grishanin, P.C. Calder, Antimicrobial action of propolis and some of
its components: the effects on growth, membrane potential and motility of bacteria, Microbiol
Res 152(3) (1997) 239-246, http://dx.doi.org/10.1016/S0944-5013(97)80034-1
[196] M. Popova, S. Silici, O. Kaftanoglu, V. Bankova, Antibacterial activity of Turkish propolis
and its qualitative and quantitative chemical composition, Phytomedicine 12(3) (2005) 221-228,
http://dx.doi.org/10.1016/j.phymed.2003.09.007
[197] V. Mazzarello, M.G. Donadu, M. Ferrari, G. Piga, D. Usai, S. Zanetti, M.A. Sotgiu,
Treatment of acne with a combination of propolis, tea tree oil, and Aloe vera compared to
erythromycin cream: two double-blind investigations, Clin Pharmacol 2018(10) (2018) 175-181,
http://dx.doi.org/10.2147/CPAA.S180474
[198] A. Meto, B. Colombari, A. Meto, G. Boaretto, D. Pinetti, L. Marchetti, S. Benvenuti, F.
Pellati, E. Blasi, Propolis Affects Pseudomonas aeruginosa Growth, Biofilm Formation, eDNA
Release and Phenazine Production: Potential Involvement of Polyphenols, Microorganisms 8(2)
(2020) 243, http://dx.doi.org/10.3390/microorganisms8020243
[199] K.C. Loureiro, T.C. Barbosa, M. Nery, M.V. Chaud, C.F. da Silva, L.N. Andrade, C.B.
Corrêa, A. Jaguer, F.F. Padilha, J.C. Cardoso, E. Souto, P. Severino, Antibacterial activity of
chitosan/collagen membranes containing red propolis extract, Pharmazie 75(2) (2020) 75-81,
http://dx.doi.org/10.1691/ph.2020.9050
[200] Y.K. Park, M.H. Koo, J.A. Abreu, M. Ikegaki, J.A. Cury, P.L. Rosalen, Antimicrobial
properties of propolis on oral microorganisms, Curr Microbiol 36 (1998) 24-28,
http://dx.doi.org/10.1007/s002849900274
[201] Y.K. Park, S.M. Alencar, C.L. Aguiar, Botanical origin and chemical composition of
Brazilian propolis, J Agr Food Chem 50(9) (2002) 2502-2506, https://doi.org/10.1021/jf011432b
[202] J. Sforcin, A.J. Fernandes, C. Lopes, V. Bankova, S. Funari, Seasonal effect on Brazilian
propolis antibacterial activity, J Ethnopharmacol 73(1-2) (2000) 243-249,
http://dx.doi.org/10.1016/s0378-8741(00)00320-2
[203] F. Galeotti, F. Maccari, A. Fachini, N. Volpi, Chemical Composition and Antioxidant
Activity of Propolis Prepared in Different Forms and in Different Solvents Useful for Finished
Products, Foods 7(3) (2018) 41. http://dx.doi.org/10.3390/foods7030041
[204] M.T. Khayyal, A.S. el-Ghazaly, A.S. el-Khatib, Mechanisms involved in the
antiinflammatory effect of propolis extract, Drugs Exp Clin Res 19(5) (1993) 197-203.
[205] P.A. de Castro, M. Savoldi, D. Bonatto, M.H. Barros, M.H. Goldman, A.A. Berretta, G.H.
Goldman, Molecular characterization of propolis-induced cell death in Saccharomyces
cerevisiae, Eukaryot Cell 10(3) (2011) 398-411, http://dx.doi.org/10.1128/EC.00256-10
[206] G.C. Pietta PG, Pietta AM., Analytical methods for quality control of propolis, Fitoterapia
73 (2002), S7-S20, http://dx.doi.org/10.1016/s0367-326x(02)00186-7
[207] F.S. Marquiafável, A.P. Nascimento, H.d.S. Barud, F. Marquele-Oliveira, L.A.P. de-
Freitas, J.K. Bastos, A.A. Berretta, Development and characterization of a novel standardized
propolis dry extract obtained by factorial design with high artepillin C content, J Pharm Technol
Drug Res 4 (2015) 1, http://dx.doi.org/10.7243/2050-120X-4-1
[208] I. Cunha, A. SawayaI, F. Caetano, M.T. ShimizuI, M.C. MarcucciIII, F.T. DrezzaI, G.S.
PoviaI, P.d.O. Carvalho, Factors that influence the yield and composition of Brazilian propolis
extracts, J Braz Chem Soc 15(6) (2004) 964-970, https://doi.org/10.1590/S0103-
50532004000600026
[209] European Food Safety Authority Panel on Dietetic Products, Scientific Opinion on the
substantiation of health claims related to propolis (ID 1242, 1245, 1246, 1247, 1248, 3184) and
flavonoids in propolis (ID 1244, 1644, 1645, 3526, 3527, 3798, 3799) pursuant to Article 13(1)
of Regulation (EC) No 1924/2006, EFSA J 8(10) (2010) 1810,
http://dx.doi.org/10.2903/j.efsa.2010.1810
[210] P.H. Nikam, J. Kareparamban, J. Aruna, V. Kadam, Future Trends in Standardization of
Herbal Drugs, J Appl Pharm Sci 2(6) (2012) 38-44, http://dx.doi.org/10.7324/JAPS.2012.2631
[211] F.G. Waldesch, B. Konigswinter, H. Remagen, Herbal Medicinal Products - Scientific and
regulatory basis for development quality assurance and marketing authorisation, Medpharm CRC
Press, Boca Raton, 2003.
[212] J. Souza, L. Tacon, C. Correia, J. Bastos, L. Freitas, Spray-dried propolis extract, II:
prenylated components of green propolis, Pharmazie 62(7) (2007) 488-492.
[213] B.A. Rocha, P.C.P. Bueno, M.M.d.O.L.L. Vaz, A.P. Nascimento, N.U. Ferreira, G.d.P.
Moreno, M.R. Rodrigues, A.R.d.M. Costa-Machado, E.A. Barizon, J.C.L. Campos, P.F. de
Oliveira, N.d.O. Acésio, S.d.P.L. Martins, D.C. Tavares, A.A. Berretta, Evaluation of a Propolis
Water Extract Using a Reliable RP-HPLC Methodology and In Vitro and In Vivo Efficacy and
Safety Characterisation, Evid Based Complement Alternat Med 2013 (2013) 670451,
https://doi.org/10.1155/2013/670451
[214] P. de Castro, M. Savoldi, D. Bonatto, I. Malavazi, M. Goldman, A. Berretta, G. Goldman,
Transcriptional profiling of Saccharomyces cerevisiae exposed to propolis, BMC Complement
Altern Med 12 (2012) 194, https://doi.org/10.1186/1472-6882-12-194
[215] A.A. Berretta, P.A. de Castro, A.H. Cavalheiro, V.S. Fortes, V.P. Bom, A.P. Nascimento,
F. Marquele-Oliveira, V. Pedrazzi, L.N. Ramalho, G.H. Goldman, Evaluation of Mucoadhesive
Gels with Propolis (EPP-AF) in Preclinical Treatment of Candidiasis Vulvovaginal Infection,
Evid Based Complement Alternat Med 2013 (2013) 641480,
http://dx.doi.org/10.1155/2013/641480
[216] S. Barud Hda, A.M. de Araujo Junior, S. Saska, L.B. Mestieri, J.A. Campos, R.M. de
Freitas, N.U. Ferreira, A.P. Nascimento, F.G. Miguel, M.M. Vaz, E.A. Barizon, F. Marquele-
Oliveira, A.M. Gaspar, S.J. Ribeiro, A.A. Berretta, Antimicrobial Brazilian Propolis (EPP-AF)
Containing Biocellulose Membranes as Promising Biomaterial for Skin Wound Healing, Evid
Based Complement Alternat Med 2013 (2013) 703024, http://dx.doi.org/10.1155/2013/703024
[217] F.D. Marquele, A.R. Oliveira, P.S. Bonato, M.G. Lara, M.J. Fonseca, Propolis extract
release evaluation from topical formulations by chemiluminescence and HPLC, J Pharm Biomed
Anal 41(2) (2006) 461-468, http://dx.doi.org/10.1016/j.jpba.2005.12.022
[218] S. Mohammadzadeh, M. Shariatpanahi, M. Hamedi, R. Ahmadkhaniha, N. Samadi, S.N.
Ostad, Chemical composition, oral toxicity and antimicrobial activity of Iranian propolis, Food
Chemistry 103(4) (2007) 1097-1103, https://doi.org/10.1016/j.foodchem.2006.10.006
[219] J. Dobrowolski, S. Vohora, K. Sharma, S. Shah, S. Naqvi, P. Dandiya, Antibacterial,
Antifungal, Antiamoebic, Antiinflammatory and Antipyretic Studies on Propolis Bee Products,
Journal of Ethnopharmacology 35(1) (1991) 77-82, https://doi.org/10.1016/0378-
8741(91)90135-Z
[220] F. Mani, H.C. Damasceno, E.L. Novelli, E.A. Martins, J.M. Sforcin, Propolis: Effect of
different concentrations, extracts and intake period on seric biochemical variables, J
Ethnopharmacol 105(1-2) (2006) 95-98, http://dx.doi.org/10.1016/j.jep.2005.10.011
[221] J.M. Senedese, A.R. Rodrigues, M.A. Furtado, V.D. Faustino, A.A. Berretta, J.M.
Marchetti, D.C. Tavares, Assessment of the mutagenic activity of extracts of brazilian propolis in
topical pharmaceutical formulations on Mammalian cells in vitro and in vivo, Evid Based
Complement Alternat Med 2011 (2011) 315701, http://dx.doi.org/10.1093/ecam/nen049
[222] D.C. Tavares, G.R. Mazzaron Barcelos, L.F. Silva, C.C. Chacon Tonin, J.K. Bastos,
Propolis-induced genotoxicity and antigenotoxicity in Chinese hamster ovary cells, Toxicol In
Vitro 20(7) (2006) 1154-1158, http://dx.doi.org/10.1016/j.tiv.2006.02.009
[223] C.M.F. Reis, J.C.T. Carvalho, L.R.G. Caputo, K.C.M. Patricio, M.V.J. Barbosa, A.L.
Chieff, J.K. Bastos, Atividade antiinflamatória, antiúlcera gástrica e toxicidade subcrônica do
extrato etanólico de própolis, Rev Bras Farmacogn 9-10(1) (2000) 43-52,
https://doi.org/10.1590/S0102-695X2000000100005
[224] H.A. Cohen, I. Varsano, E. Kahan, E.M. Sarrell, Y. Uziel, Effectiveness of an herbal
preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract
infections in children: a randomized, double-blind, placebo-controlled, multicenter study, Arch
Pediatr Adolesc Med 158(3) (2004) 217-21, http://dx.doi.org/10.1001/archpedi.158.3.217.
[225] L. Soroy, S. Bagus, I.P. Yongkie, W. Djoko, The effect of a unique propolis compound
(Propoelix™) on clinical outcomes in patients with dengue hemorrhagic fever, Infect Drug
Resist 7 (2014) 323-9, http://dx.doi.org/10.2147/IDR.S71505
[226] M. Lotfy, Biological activity of bee propolis in health and disease, Asian Pac J Cancer
Prev 7(1) (2006) 22-31.
[227] C.E. Finch, Evolution in health and medicine Sackler colloquium: Evolution of the human
lifespan and diseases of aging: roles of infection, inflammation, and nutrition, Proc Natl Acad
Sci U S A 107 (Suppl 1) (2010) 1718-1724, http://dx.doi.org/10.1073/pnas.0909606106
[228] M.R. Ahn, K. Kunimasa, T. Ohta, S. Kumazawa, M. Kamihira, K. Kaji, Y. Uto, H. Hori,
H. Nagasawa, T. Nakayama, Suppression of tumor-induced angiogenesis by Brazilian propolis:
major component artepillin C inhibits in vitro tube formation and endothelial cell proliferation,
Cancer Lett 252(2) (2007) 235-243, http://dx.doi.org/10.1016/j.canlet.2006.12.039
[229] E. Szliszka, G. Zydowicz, B. Janoszka, C. Dobosz, G. Kowalczyk-Ziomek, W. Krol,
Ethanolic extract of Brazilian green propolis sensitizes prostate cancer cells to TRAIL-induced
apoptosis, Int J Oncol 38(4) (2011) 941-953, https://doi.org/10.3892/ijo.2011.930
[230] M.-h. Chuang, C.-y. Peng, C.-y. Chi, H.-y. Chung, C.-t. Liu, H.-c. Kuo, Device method of
making artepillin c in propolis for anti-cancer, in: U.-M.B. Technology (Ed.) United States,
2016, https://patents.google.com/patent/US20170226042A1/en
[231] C.K. Ferrari, Functional foods, herbs and nutraceuticals: towards biochemical mechanisms
of healthy aging, Biogerontology 5(5) (2004) 275-289, http://dx.doi.org/10.1007/s10522-004-
2566-z
[232] D. Bachevski, K. Damevska, V. Simeonovski, M. Dimova, Back to the basics: Propolis
and COVID-19, Dermatol Ther 2020 (2020) e13780, https://doi.org/10.1111/dth.13780
[233] J.M. Sforcin, Propolis and the immune system: a review, J Ethnopharmacol 113(1) (2007)
1-14, http://dx.doi.org/10.1016/j.jep.2007.05.012
[234] A. Salatino, C.C. Fernandes-Silva, A.A. Righi, M.L. Salatino, Propolis research and the
chemistry of plant products, Nat Prod Rep 28(5) (2011) 925-936,
http://dx.doi.org/10.1039/c0np00072h
[235] I.C.G. de Mendonça, I.C.C.d.M. Porto, T.G. do Nascimento, N.S. de Souza, J.M.d.S.
Oliveira, R.E.d.S. Arruda, K.C. Mousinho, A.F. dos Santos, I.D. Basílio-Júnior, A. Parolia, F.S.
Barreto, Brazilian red propolis: phytochemical screening, antioxidant activity and effect against
cancer cells, BMC Complem Altern Med 15 (2015) 357, http://dx.doi.org/10.1186/s12906-015-
0888-9
[236] C. Magro, J.J. Mulvey, D. Berlin, G. Nuovo, S. Salvatore, J. Harp, A. Baxter-Stoltzfus, J.
Laurence, Complement associated microvascular injury and thrombosis in the pathogenesis of
severe COVID-19 infection: a report of five cases, Transl Res 220 (2020) 1-13,
http://dx.doi.org/10.1016/j.trsl.2020.04.007
[237] A. Porfidia, R. Pola, Venous thromboembolism and heparin use in COVID-19 patients:
juggling between pragmatic choices, suggestions of medical societies and the lack of guidelines,
J Thromb Thrombolysis 50 (2020) 68-71, http://dx.doi.org/10.1007/s11239-020-02125-4
[238] S. Schwarz, D. Sauter, K. Wang, R. Zhang, B. Sun, A. Karioti, A.R. Bilia, T. Efferth, W.
Schwarz, Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus,
Planta Med 80(2-3) (2014) 177-182, http://dx.doi.org/10.1055/s-0033-1360277
[239] L. Yang, Y.-T. Li, J. Miao, L. Wang, H. Fu, Q. Li, W.-B. Wen, Z.-Y. Zhang, R.-W. Song,
X.-G. Liu, H.-W. Wang, H.-T. Cui, Network pharmacology studies on the effect of Chai-Ling
decoction in coronavirus disease 2019, Traditional Medicine Research 5(3) (2020) 145,
http://dx.doi.org/10.12032/TMR20200324170
[240] C.W. Lin, F.J. Tsai, C.H. Tsai, C.C. Lai, L. Wan, T.Y. Ho, C.C. Hsieh, P.D. Chao, Anti-
SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic
compounds, Antiviral Res 68(1) (2005) 36-42, http://dx.doi.org/10.1016/j.antiviral.2005.07.002
[241] Z. Wu, Y. Liu, A. Zhu, S. Wu, H. Nakanishia, Brazilian green propolis suppresses
microglia-mediated neuroinflammation by inhibiting NF-kB activation, Journal of the
Neurological Sciences 381 (2017), https://doi.org/10.1016/j.jns.2017.08.1910
[242] T. Adachi T, H. Tezuka, N.M. Tsuji, T. Ohteki T, H. Karasuyama, T. Kumazawa, Propolis
induces Ca2+ signaling in immune cells, Biosci Microbiota Food Health 38(4) (2019) 141,
http://dx.doi.org/10.12938/bmfh.19-011
[243] L.B. Sy, Y.L. Wu, B.L. Chiang, Y.H. Wang, W.M. Wu, Propolis extracts exhibit an
immunoregulatory activity in an OVA-sensitized airway inflammatory animal model, Int
Immunopharmacol 6(7) (2006) 1053-1060, http://dx.doi.org/10.1016/j.intimp.2006.01.015
[244] E. Szliszka, A.Z. Kucharska, A. Sokol-Letowska, A. Mertas, Z.P. Czuba, W. Krol,
Chemical Composition and Anti-Inflammatory Effect of Ethanolic Extract of Brazilian Green
Propolis on Activated J774A.1 Macrophages, Evid Based Complement Alternat Med 2013
(2013) 976415, http://dx.doi.org/10.1155/2013/976415
[245] J. Shvarzbeyn, M. Huleihel, Effect of propolis and caffeic acid phenethyl ester (CAPE) on
NFkappaB activation by HTLV-1 Tax, Antiviral Res 90(3) (2011) 108-115,
http://dx.doi.org/10.1016/j.antiviral.2011.03.177
[246] Z.H. Shi, N.G. Li, Y.P. Tang, L. Wei, Y. Lian, J.P. Yang, T. Hao, J.A. Duan, Metabolism-
based synthesis, biologic evaluation and SARs analysis of O-methylated analogs of quercetin as
thrombin inhibitors, Eur J Med Chem 54 (2012) 210-222,
https://doi.org/10.1016/j.ejmech.2012.04.044
[247] F.J. Tsai, C.W. Lin, C.C. Lai, Y.C. Lan, C.H. Lai, C.H. Hung, K.C. Hsueh, T.H. Lin, H.C.
Chang, L. Wan, J.J. Sheu, Y.J. Lin, Kaempferol inhibits enterovirus 71 replication and internal
ribosome entry site (IRES) activity through FUBP and HNRP proteins, Food Chem 128(2)
(2011) 312-22, http://dx.doi.org/10.1016/j.foodchem.2011.03.022
[248] B.S. Min, M. Tomiyama, C.M. Ma, N. Nakamura, M. Hattori, Kaempferol
acetylrhamnosides from the rhizome of Dryopteris crassirhizoma and their inhibitory effects on
three different activities of human immunodeficiency virus-1 reverse transcriptase, Chem Pharm
Bull (Tokyo). 49(5) (2001) 546-550, http://dx.doi.org/10.1248/cpb.49.546
[249] M. Behbahani, S. Sayedipour, A. Pourazar, M. Shanehsazzadeh, In vitro anti-HIV-1
activities of kaempferol and kaempferol-7-O-glucoside isolated from Securigera securidaca. Res
Pharm Sci 9(6) (2014) 463‐469.
[250] S. Ganesan, A.N. Faris, A.T. Comstock, Q. Wang, S. Nanua, M.B. Hershenson, U.S.
Sajjan, Quercetin inhibits rhinovirus replication in vitro and in vivo, Antiviral Res 94(3) (2012)
258-271, http://dx.doi.org/10.1016/j.antiviral.2012.03.005
[251] A. Rojas, J.A. Del Campo, S. Clement, M. Lemasson, M. Garcia-Valdecasas, A. Gil-
Gomez, I. Ranchal, B. Bartosch, J.D. Bautista, A.R. Rosenberg, F. Negro, M. Romero-Gomez,
Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets, Sci Rep 6
(2016) 31777, http://dx.doi.org/10.1038/srep31777
[252] Z. Cheng, G. Sun, W. Guo, Y. Huang, W. Sun, F. Zhao, K. Hu, Inhibition of hepatitis B
virus replication by quercetin in human hepatoma cell lines, Virol Sin 30(4) (2015) 261-268,
https://doi.org/10.1007/s12250-015-3584-5
[253] G.F. Wang, L.P. Shi, Y.D. Ren, Q.F. Liu, H.F. Liu, R.J. Zhang, Z. Li, F.H. Zhu, P.L. He,
W. Tang, P.Z. Tao, C. Li, W.M. Zhao, J.P. Zuo, Anti-hepatitis B virus activity of chlorogenic
acid, quinic acid and caffeic acid in vivo and in vitro, Antiviral Res 83(2) (2009) 186-90,
https://doi.org/10.1016/j.antiviral.2009.05.002
[254] H. Utsunomiya, M. Ichinose, K. Ikeda, M. Uozaki, J. Morishita, T. Kuwahara, A.H.
Koyama, H. Yamasaki, Inhibition by caffeic acid of the influenza A virus multiplication in vitro,
Int J Mol Med 34(4) (2014) 1020-4, https://doi.org/10.3892/ijmm.2014.1859
[255] Y. Xie, B. Huang, K. Yu, F. Shi, T. Liu, W. Xu, Caffeic acid derivatives: a new type of
influenza neuraminidase inhibitors, Bioorg Med Chem Lett 23(12) (2013) 3556-3560,
https://doi.org/10.1016/j.bmcl.2013.04.033
[256] M.R. Fesen, Y. Pommier, F. Leteurtre, S. Hiroguchi, J. Yung, K.W. Kohn, Inhibition of
HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds,
Biochem Pharmacol 48(3) (1994) 595-608, https://doi.org/10.1016/0006-2952(94)90291-7
Table 1. Potential pathways through which propolis and its components could attenuate
SARS-CoV-2 infection and its consequences
N
Targets
Propolis
Componen
ts
Effect of the components and
type of evidence
1
Viral RNA-
dependent RNA
polymerase
(RdRp) and Spike
glycoprotein
(SGp)
Limonin,
Quercetin
and
Kaempferol
Inhibitory potential with high
binding energy to viral
components from -9 to -7.1
kcal/mol (in silico) [15]
2
3a Channel
Protein
Kaempferol
Blocks the 3a channel that is
encoded by ORF 3a of SARS-
CoV (in vitro) [238]
3
ACE2
Myricetin,
Caffeic
Acid
Phenethyl
Ester,
Hesperetin
and
Pinocembri
n
Inhibitory potential with high
binding energy to ACE2 (-8.97
kcal/mol) (in silico) [26]
Kaempferol
Inhibitory potential with high
binding energy to ACE2 (-7.5
kcal/mol) (in silico) [239]
Quercetin
Inhibitory potential with high
binding energy to ACE2 (-10.4
kcal/mol) (in silico) [25]
3
TMPRSS2
Kaempferol
Downregulates androgen
receptors such as PSA and
TMPRSS2 in a prostate cancer
model (in vitro) [83]
4
PAK-1
Caffeic
Acid and
Caffeic
Acid
Phenethyl
Ester 
Downregulates PAK-1 associated
with Rac1 activation (in vitro)
[18]
Inhibits PAK-1 directly or up-
stream, blocking coronaviral
infection (Review) [10]
5
3C-like protease
Hesperetin
Inhibits cleavage activity of
3CLpro (in vitro) [240]
6
Inflammatory
response
Propolis
Extract
Inhibits NF-kB activation (in
vitro) [241]
Induces Ca2+ signaling in
dendritic cells in Peyer’s patches,
improving the immune response
(in vitro) [242]
Attenuates the inflammatory
response through intracellular
ROS and NO levels with
downregulation of IL‐1β and IL‐
6 expression (in vitro) [27]
Regulates IFN-γ, IL-6, and IL-10
cytokines in an experimental
asthma model (in vivo) [243]
Increases TGF-β and IL-10
levels, which contribute to the
regulation of the inflammatory
process in Acute Pulmonary
Inflammation (in vivo) [24]
Inhibits the production of ROS,
RNS, NO, cytokines IL-1α, IL-
1β, IL-4, IL-6, IL-12p40, IL-13,
TNF-α, G-CSF, GM-CSF, MCP-
1, MIP-1α, MIP-1β, and
RANTES in stimulated J774A.1
macrophages (in vitro) [244]
Kaempferol
Reduces TNF-α, IL-6, VEGF via
the ERK-NFkB-cMyc-p21
pathway (in vitro) [83]
Caffeic
Acid
Phenethyl
Ester
Inhibits NF-kB activation in
HTLV-1 infection (in vitro) [245]
Modulates JAK/STAT signaling
and attenuates oxidative stress
and inflammation [87].
Immunomodulati
on
Propolis
Extract
Increases humoral and cellular
response in mice immunized with
Suid herpesvirus type 1[106]
Suppresses the differentiation of
Th17 cells by inhibition of IL-6-
induced phosphorylation of
signal transducer and activator of
transcription 3 (STAT3) (in vivo)
[88]
7
Thrombosis
Quercetin
Inhibits thrombin in thrombotic
manifestations (in vitro) [246]
8
Viral replication
Kaempferol
and
Hesperetin
Inhibits internal ribosomal entry
site (IRES) activity required for
viral protein translation (in vitro)
[247]
Kaempferol
Inhibits human
immunodeficiency virus reverse
transcriptase-associated DNA
polymerase as well as RNAase H
and RNase H activities (in vitro)
[248]
Presents potent anti-HIV-1
reverse transcriptase activity (in
vitro) [249]
Quercetin
Decreases Akt phosphorylation
and viral endocytosis of
Rhinovirus (in vivo) [250]
Prevents up-regulation of
diacylglycerol acyltransferase
(DGAT) required for hepatitis C
virus replication (in vitro) [251]
Decreases heat shock proteins
and Hepatitis B virus
transcription levels (in vitro)
[252]
Caffeic
Acid
Inhibits Hepatitis B virus-DNA
replication (in vivo & in vitro)
[253]
Inhibits influenza A virus (IAV)
replication (in vitro) [254]
Inhibits influenza A virus (IAV)
activity through neuraminidases
(in vitro) [255]
Caffeic
Acid
Phenethyl
Ester
Inhibits HIV-1 integrase
(Review) [256]
Figure 1. Major pathways through which propolis can interfere with SARS-CoV-2 attachment to
the host cell, viral replication, and pathophysiological consequences. SARS-CoV-2 entry into
target cells requires spike protein binding to ACE2 and activation by TMPRSS2. After binding,
several signals are triggered, allowing viral endocytosis and PAK1 activation, which reduces the
adaptive immune response and antibody production against the virus. PAK1 also stimulates CCL2
production, which generates a fibrotic response. Viral infection induces nuclear transition factor
NF-KB activation, generating local pro-inflammatory cytokine production. Propolis-derived
compounds downregulate the expression of TMPRSS2 and the anchoring ACE2, which limits
entry of the virus. Furthermore, they promote NF-KB and monocyte/macrophage
immunomodulation, reducing pro-inflammatory cytokine overproduction, and they reduce PAK1
activation, increasing the production of antibodies against SARS-CoV-2.
... Propolis is a natural resin produced by bees from different parts of plants [8]. Propolis has numerous properties of interest in medicine, including antioxidant, antiinfammatory, and immunomodulatory properties [8][9][10][11][12][13]. In experimental models and in humans with CKD, we recently demonstrated that the use of propolis reduces renal infammatory processes and decreases proteinuria, which is considered a classic marker of renal function loss and cardiovascular risk [8][9][10][11][12][13][14]. ...
... Propolis has numerous properties of interest in medicine, including antioxidant, antiinfammatory, and immunomodulatory properties [8][9][10][11][12][13]. In experimental models and in humans with CKD, we recently demonstrated that the use of propolis reduces renal infammatory processes and decreases proteinuria, which is considered a classic marker of renal function loss and cardiovascular risk [8][9][10][11][12][13][14]. ...
... Comparison of the interleukin levels of the baseline period versus the treatment period demonstrated decreased IFN-c levels from 12 pg/ml (IQR, [11][12][13][14][15][16][17][18][19][20][21][22] to 11 pg/ml (IQR, 10-16) with EPP-AF treatment (p � 0.005 and an efect size of 0.47). IL-13 ranged from a baseline value of 14 pg/ml (IQR, 8-52) to 10 pg/ml (IQR, 6-26) with treatment (p = 0.042 and an efect size of 0.33). ...
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Background: Patients on haemodialysis (HD) present a significant inflammatory status, which has a pronounced negative impact on their outcomes. Propolis is a natural resin with anti-inflammatory and immunomodulatory properties. We assessed the safety and impact of a standardized Brazilian green propolis extract (EPP-AF®) on the inflammatory status in patients under conventional HD. Methods: Patients were assigned to receive 200 mg/day of EPP-AF® for 4 weeks followed by 4 weeks without the drug, and changes in plasma levels of interleukins (ILs), interferon gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), and high-sensitivityc-reactive protein (HsCRP) were measured. A heatmap was used to illustrate trends in data variation. Results: In total, 37 patients were included in the final analysis. Patients presented an exacerbated inflammatory state at baseline. During EPP-AF® use, there was a significant reduction in IFN-γ (p=0.005), IL-13 (p=0.04 2), IL-17 (p=0.039), IL-1ra (p=0.008), IL-8 (p=0.009), and TNF-α (p < 0.001) levels compared to baseline, and significant changes were found in Hs-CRP levels. The heatmap demonstrated a pattern of pronounced proinflammatory status at baseline, especially in patients with primary glomerulopathies, and a clear reduction in this pattern during the use of EPP-AF®. There was a tendency to maintain this reduction after suspension of EPP-AF®. No significant side effects were observed. Conclusion: Patients under haemodialysis presented a pronounced inflammatory status, and EPP-AF® was demonstrated to be safe and associated with a significant and maintained reduction in proinflammatory cytokines in this population. This trial is registered with Clinicaltrials.gov NCT04072341.
... The derivative also modulates the cellular unfolded protein response (UPR). Through the modulation of this pathway, Quercetin may have potential anti-coronavirus effects [136,137]. ...
... This experimental evidence suggests that CAPE can help inhibit fibrosis induced by the COVID-19 virus. However, hypersensitivity reactions should be considered when using it for treatment [136,138]. ...
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Infectious diseases have been a threat to human health globally. The relentless efforts and research have enabled us to overcome most of the diseases through the use of antiviral and antibiotic agents discovered and employed. Unfortunately, the microorganisms have the capability to adapt and mutate over time and antibiotic and antiviral resistance ensues. There are many challenges in treating infections such as failure of the microorganisms to respond to the therapeutic agents, which has led to more chronic infections, complications, and preventable loss of life. Thus, a multidisciplinary approach and collaboration is warranted to create more potent, effective, and versatile therapies to prevent and eradicate the old and newly emerging diseases. In the recent past, natural medicine has proven its effectiveness against various illnesses. Most of the pharmaceutical agents currently used can trace their origin to the natural products in one way, shape, or form. The full potential of natural products is yet to be realized, as numerous natural resources have not been explored and analyzed. This merits continuous support in research and analysis of ancient treatment systems to explore their full potential and employ them as an alternative or principal therapy.
... Propolis has a wide range of biological and pharmacological activities [13], Antibacterial, antifungal, anti-inammatory, antioxidant, immunomodulatory, antiviral and anticarcinogenic characteristics are only a few of them. Because of its broad-spectrum biological capabilities, propolis is becoming more popular as a reliable alternative therapy [14,15]. ...
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... Since the early phase of the pandemics, many researchers have tried to examine bioactive compounds such as propolis and others, from natural products source as leads for SARS-CoV-2 drug candidates [39][40][41][42][43][44][45][46][47]. Although these efforts are still on going up to now, the leads are still in experimental stage in general. ...
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When WHO declared that the COVID-19 pandemic was in place on March 2020, there were no standard drugs available for this new disease. One of the fastest and the most effective solution to face this problem is relying on the drug repurposing effort. Remdesivir is one of the earliest repurposed drug, as it has been originally develop for hepatitis C, and already examined for application in Ebola and Marburg virus infec-tion
... Its activity results in the suppression of MCP-1 and vascular cell adhesion molecule-1 expression, monocyte adhesion to endothelial cells and transmigration, and activation of p38 MAPK. The anti-inflammatory mechanism of propolis and flavonoids such as quercetin, luteolin, anthocyanin, hyperin and alpinetin on the TLR4/NF-κB/NLRP3 signaling pathway has been confirmed in publications [147][148][149]; it is based on the interruption of different signaling phases of the NLRP3 inflammation pathway in vitro and in vivo, by reducing the expression of NLRP3 inflammasome-related components, such as IL-1β, IL-18, NLRP3 and caspase-1 and/or blocking the inflammasome assembly, such as ASC oligomerization via signaling molecules (e.g., TLR4/NF-κB/NLRP3, PPARγ, TXNIP and Syk/Pyk2, and others). For example, EGCG reduces peritoneal inflammation by inhibiting NLRP3 expression and IL-1β release in mice treated with monosodium urate (MSU) crystals [149] through inhibition of the NLRP3 inflammasome conjugation with thioredoxin-interacting protein (TXNIP) in THP-1 cells, whereas quercetin inhibits NLRP3 and IL-1β expression and caspase-1 activity in human colonic epithelial cells. ...
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... Furthermore, in preclinical studies, propolis stimulates the immunoregulation of proinflammatory cytokines, thus reducing the risk of the cytokine storm syndrome, a major factor leading to mortality in COVID-19 patients. Propolis has been demonstrated to help treat comorbidities aggravating COVID-19 disease, such as cancer, diabetes, hypertension, etc. [61]. ...
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... A study identified anti-inflammatory compounds which targeted p38 MAPK receptor in the quest to salvage high concentrations of pro-inflammatory cytokines in COVID-19 mechanisms [103]. Quercitrin was also predicted to be a membrane permeability inhibitor (Pa = 0. Interestingly, propolis components have recently been studied as possible therapeutics for COVID-19, and it showed inhibitory effects on ACE2, TMPRSS2, and PAK1 signaling pathways [104,105]. Propolis is also used in traditional medicine worldwide due to its reported biological activities which include antibacterial, antiviral, anti-inflammatory, and anticancer [106][107][108]. ...
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