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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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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
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.
2 D'Or Institute for Research and Education (IDOR), Hospital São Rafael, Salvador, Brazil.
3 Interdisciplinary Stem Cell Institute at Miller School of Medicine, University of Miami, Miami,
Florida, United States.
4 Genetics Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão
Preto, São Paulo, Brazil.
*author for correspondence
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-
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
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
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
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
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
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
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
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
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 ( 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.
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.
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Table 1. Potential pathways through which propolis and its components could attenuate
SARS-CoV-2 infection and its consequences
Effect of the components and
type of evidence
Viral RNA-
dependent RNA
(RdRp) and Spike
Inhibitory potential with high
binding energy to viral
components from -9 to -7.1
kcal/mol (in silico) [15]
3a Channel
Blocks the 3a channel that is
encoded by ORF 3a of SARS-
CoV (in vitro) [238]
Inhibitory potential with high
binding energy to ACE2 (-8.97
kcal/mol) (in silico) [26]
Inhibitory potential with high
binding energy to ACE2 (-7.5
kcal/mol) (in silico) [239]
Inhibitory potential with high
binding energy to ACE2 (-10.4
kcal/mol) (in silico) [25]
Downregulates androgen
receptors such as PSA and
TMPRSS2 in a prostate cancer
model (in vitro) [83]
Acid and
Downregulates PAK-1 associated
with Rac1 activation (in vitro)
Inhibits PAK-1 directly or up-
stream, blocking coronaviral
infection (Review) [10]
3C-like protease
Inhibits cleavage activity of
3CLpro (in vitro) [240]
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,
1, MIP-1α, MIP-1β, and
RANTES in stimulated J774A.1
macrophages (in vitro) [244]
Reduces TNF-α, IL-6, VEGF via
the ERK-NFkB-cMyc-p21
pathway (in vitro) [83]
Inhibits NF-kB activation in
HTLV-1 infection (in vitro) [245]
Modulates JAK/STAT signaling
and attenuates oxidative stress
and inflammation [87].
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)
Inhibits thrombin in thrombotic
manifestations (in vitro) [246]
Viral replication
Inhibits internal ribosomal entry
site (IRES) activity required for
viral protein translation (in vitro)
Inhibits human
immunodeficiency virus reverse
transcriptase-associated DNA
polymerase as well as RNAase H
and RNase H activities (in vitro)
Presents potent anti-HIV-1
reverse transcriptase activity (in
vitro) [249]
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)
Inhibits Hepatitis B virus-DNA
replication (in vivo & in vitro)
Inhibits influenza A virus (IAV)
replication (in vitro) [254]
Inhibits influenza A virus (IAV)
activity through neuraminidases
(in vitro) [255]
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). ...
Full-text available
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 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]. ...
Full-text available
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]. ...
The appearance of cognitive decline as a major hallmark of neurological and neurodegenerative disorders make it an intriguing pathophysiological state for which there is an urgent need for the development of effective pharmacotherapy. Decades of research have uncovered a multitude of promising factors that can serve as the starting point for research and development in this domain of research. Depleted cholinergic neurotransmission and oxidative damage are two such causative factors for cognitive impairment associated with neurodegeneration. Approved treatments for neurodegenerative disorders like Alzheimer's Disease (AD) provide only symptomatic relief and are known to cause unwanted side effects. Honeybee products are made up of bioactive substances, which have long been known for their medicinal and health-promoting effects. The purpose of the present study was to explore the neuroprotective potential of bee venom and bee propolis separately and in combination with the standard drug rivastigmine as a novel treatment regimen against scopolamine-induced cognitive decits. Intraperitoneal administration of bee venom (0.5 mg/Kg), propolis (250 mg/Kg, oral) and rivastigmine (0.5 mg/Kg) or their combinations showed improved cognitive functions in scopolamine exposed mice as assessed by passive avoidance test. Administration of honeybee products (venom and propolis) alone and in combination signicantly decreased the activity of acetylcholinesterase in the brain of scopolamine treated animals. Bee products either alone or in combination further decreased the lipid peroxidation with a concomitant increase in the activity of antioxidant enzymes (SOD, catalase, GPx, GR, and GST) in the brains of the animals treated with scopolamine. The data obtained suggests that the treatment with combination of bee venom and propolis could be developed into a novel and effective therapy against cognitive dementia associated with neurological and neurodegenerative disorders including Alzheimer's disease.
... 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. ...
Full-text available
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. ...
Full-text available
The incidence of allergic diseases and their complications are increasing worldwide. Today, people increasingly use natural products, which has been termed a “return to nature”. Natural products with healing properties, especially those obtained from plants and bees, have been used in the prevention and treatment of numerous chronic diseases, including allergy and/or inflammation. Propolis is a multi-component resin rich in flavonoids, collected and transformed by honeybees from buds and plant wounds for the construction and adaptation of their nests. This article describes the current views regarding the possible mechanisms and multiple benefits of flavonoids in combating allergy and allergy-related complications. These benefits arise from flavonoid anti-allergic, anti-inflammatory, antioxidative, and wound healing activities and their effects on microbe-immune system interactions in developing host responses to different allergens. Finally, this article presents various aspects of allergy pathobiology and possible molecular approaches in their treatment. Possible mechanisms regarding the antiallergic action of propolis on the microbiota of the digestive and respiratory tracts and skin diseases as a method to selectively remove allergenic molecules by the process of bacterial biotransformation are also reported.
... 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]. ...
Honey bees provide many products exerting a wide range of benefits to humans. Honey, propolis, royal jelly, beeswax, bee venom, bee pollen and bee bread have been used as natural medicines since ancient times because of their therapeutic effects. These products have demonstrated healing properties against wounds, diabetes, gastrointestinal diseases, cancer, asthma, neurological diseases, bacterial and viral infections. The antibacterial and antibiofilm activity of honey bee products is widely studied and a huge body of evidence supports it. On the other hand, their antiviral effect has not been extensively studied. However, recent research has demonstrated their potential against diverse viral infections including SARS-CoV-2. Hence, honey bee products could be alternatives to treat viral diseases, especially when there is no effective treatment available. This narrative review aims to present up to date data (including ongoing clinical trials) regarding the antiviral activity of honey bee products, aiming to elucidate how honey bee product supplementation contributes to antiviral treatment.
... 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]. ...
Full-text available
The coronavirus disease 2019 (COVID-19) is a pandemic that has severely posed substantial health challenges and claimed millions of lives. Though vaccines have been produced to stem the spread of this disease, the death rate remains high since drugs used for treatment have therapeutic challenges. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the disease, has a slew of potential therapeutic targets. Among them is the furin protease, which has a cleavage site on the virus's spike protein. The cleavage site facilitates the entry of the virus into human cells via cell-cell fusion. This critical involvement of furin in the disease pathogenicity has made it a viable therapeutic strategy against the virus. This study employs the consensus docking approach using HYBRID and AutoDock Vina to virtually screen a pre-filtered library of 3942 natural product compounds of African origin against the human furin protease (PDB: 4RYD). Twenty of these compounds were selected as hits after meeting molecular docking cut-off of - 7 kcal.mol-1, pose alignment inspection, and having favorable furin-ligand interactions. An area under the curve (AUC) value of 0.72 was computed from the receiver operator characteristic (ROC) curve, and Boltzmann-enhanced discrimination of the ROC curve (BEDROC) value of 0.65 showed that AutoDock Vina was a reasonable tool for selecting actives for this target. Seven of these hits were proposed as potential leads having had bonding interactions with catalytic triad residues Ser368, His194, and Asp153, and other essential residues in the active site with plausible binding free energies between - 189 and - 95 kJ/mol from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations as well as favorable ADME/Tox properties. The molecules were also predicted as antiviral, anti-inflammatory, membrane permeability inhibitors, RNA synthesis inhibitors, cytoprotective, and hepatoprotective with probable activity (Pa) above 0.5 and probable inactivity values below 0.1. Some of them also have anti-influenza activity. Influenza virus has many similarities with SARS-CoV-2 in their mode of entry into human cells as both are facilitated by the furin protease. Pinobanksin 3-(E)-caffeate, one of the potential leads is a propolis compound. Propolis compounds have shown inhibitory effects against ACE2, TMPRSS2, and PAK1 signaling pathways of SARS-CoV-2 in previous studies. Likewise, quercitrin is structurally similar to isoquercetin, which is currently in clinical trials as possible medication for COVID-19. Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-02056-1.
Full-text available
Propolis is a bee-produced substance rich in bioactive compounds, which has been utilized widely in folk medicine, in food supplement and cosmetology areas because of its biological properties, (antibacterial, antiviral, antioxidant, anti-inflammatory, etc.). The subject of this study is associated with the chemical analysis and the biological evaluation of 16 propolis samples from the northeast Aegean region Greek islands, a well-recognized geographic area and the homeland of rich flora as a crossroads between Europe and Asia. Our study resulted in the detection of a significant percentage of diterpenes by gas chromatography–mass spectrometry (GC-MS), while flavonoids were identified in low percentages among studied samples. Furthermore, the DPPH assay highlighted that eight of the samples (Lesvos and Lemnos origin) demonstrated a promising antioxidant profile, further verified by their total phenolic content (TPC). Additionally, the propolis samples most rich in diterpenes showed significant antibacterial and fungicidal properties against human pathogenic microorganisms, proving them to be a very interesting and promising crude material for further applications, concluding that floral diversity is the most responsible for the bioactivity of the propolis samples.
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Propolis samples from a geographical part of northwest Greece (Prespa National Park, PNP), which is characterized as a plant endemism center and biodiversity hotspot, were characterized through pollen analysis, chemically analyzed, and biologically evaluated. The majority of the studied propolis showed typical chemical constituents (phenolic acids, flavonoids, and chalcones) of European type, while a sample of Mediterranean-type propolis (rich in diterpenes) was also identified. The palynological characterization was implemented to determine the botanical origin and to explain the chemical composition. The total phenolic content and the DPPH assay showed that the European-type propolis samples possessed strong antioxidant activity (86–91% inhibition at 200 μg/mL). Moreover, promising antibacterial activity of the extracts (MIC values 0.56–1.95 mg/mL) and moderate antifungal activity (MIC values 1.13–2.40 mg/mL) were noticed, while the sample with the highest activity had a significant content in terpenes (Mediterranean type). Propolis samples from the PNP area represent a rich source of antibacterial and antioxidant compounds and confirm the fact that propolis is a significant natural product with potential use for improving human health and stimulating the body’s defense. Finally, it is noteworthy that a significant chemical diversity was demonstrated, even in samples from a limited geographical area as this of PNP.
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With technological advancements in the medicinal and pharmaceutical industries, numerous research studies have focused on the propolis produced by stingless bees (Meliponini tribe) and Apis mellifera honeybees as alternative complementary medicines for the potential treatment of various acute and chronic diseases. Propolis can be found in tropical and subtropical forests throughout the world. The composition of phytochemical constituents in propolis varies depending on the bee species, geographical location, botanical source, and environmental conditions. Typically, propolis contains lipid, beeswax, essential oils, pollen, and organic components. The latter include flavo-noids, phenolic compounds, polyphenols, terpenes, terpenoids, coumarins, steroids, amino acids, and aromatic acids. The biologically active constituents of propolis, which include countless organic compounds such as artepillin C, caffeic acid, caffeic acid phenethyl ester, apigenin, chrysin, galangin, kaempferol, luteolin, genistein, naringin, pinocembrin, coumaric acid, and quercetin, have a broad spectrum of biological and therapeutic properties such as antidiabetic, anti-inflammatory, antioxidant, anticancer, rheumatoid arthritis, chronic obstruct pulmonary disorders, cardiovascular diseases, respiratory tract-related diseases, gastrointestinal disorders, as well as neuroprotective, immunomodulatory, and immuno-inflammatory agents. Therefore, this review aims to provide a summary of recent studies on the role of propolis, its constituents, its biologically active compounds , and their efficacy in the medicinal and pharmaceutical treatment of chronic diseases.
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The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE-II, is a type I integral membrane protein of 805 amino acids that contains 1 HEXXH-E zinc binding consensus sequence. ACE-II has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). In this study, the potential of some flavonoids presents in propolis to bind to ACE-II receptors was calculated with in silico. Binding constants of ten flavonoids, caffeic acid, caffeic acid phenethyl ester, chrysin, galangin, myricetin, rutin, hesperetin, pinocembrin, luteolin and quercetin were measured using the AutoDock 4.2 molecular docking program. And also, these binding constants were compared to reference ligand of MLN-4760. The results are shown that rutin has the best inhibition potentials among the studied molecules with high binding energy − 8.04 kcal/mol, and it is followed by myricetin, quercetin, caffeic acid phenethyl ester and hesperetin. However, the reference molecule has binding energy of – 7.24 kcal/mol. In conclusion, the high potential of flavonoids in ethanolic propolis extracts to bind to ACE-II receptors indicates that this natural bee product has high potential for COVID-19 treatment, but this needs to be supported by experimental studies.
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Introduction Underlying disease have a critical role in vulnerability of populations for a greater morbidity and mortality when they suffer from COVID-19. The aim of current study is evaluating the prevalence of underlying disease in died people with COVID-19. Methods The current study have been conducted according to PRISMA guideline. International database including PubMed, Scopus, Web of Science, Cochrane and google scholar were searched for relevant studies up to 1 June. All relevant articles that reported underlying disease in died cases of COVID-19 were included in the analysis. Results After screening and excluding duplicated and irrelevant studies, 32 articles included in the analysis. The most prevalent comorbidities were hypertension, diabetes, cardiovascular disease, liver disease, lung disease, malignancy, cerebrovascular disease, COPD and asthma. Among all reported underlying disease, highest and lowest prevalence was related to hypertension and asthma which were estimated 46% (37% - 55%) and 3% (2%- 6%), respectively. Conclusion In summary, underlying disease have a critical role in poor outcomes, severity of disease and high mortality rate of COVID-19 cases. Patients with hypertension, cardiovascular disease and diabetes should be carefully monitored and be aware of health protocols.
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The epidemiological burden of COVID-19 is a healthcare challenge throughout the world, not only in terms of testing the limits of medical capacities, but also as an enigma considering preventive strategies and methods. The upper respiratory tract mucosa is the first line of defense, as a physical barrier, as well as through multiple innate and adaptive immune mechanisms which are crucial for efficient antiviral responses. Identifying methods able to reduce or prevent colonization, viral adhesion, and promote virus shedding on mucous membranes or have the ability to inactivate pathogens and thus reduce virus dose and/or increase immune response would be essential in the management of COVID-19 outbreak and help in flattening the curve. We review the effects of propolis, an old remedy with proven antiviral properties, as a possible low-cost inhibitor of SARS-CoV-2 in the oropharyngeal niche, prophylaxis, or adjuvant therapy.
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Coronavirus disease 2019 (COVID-19) has caused a devastating global pandemic and continues to overwhelm the health-care facilities and shatter the economies of countries worldwide. Although it primarily affects the lungs, it shares a strong interplay with the cardiovascular system. The presence of underlying cardiovascular disease and its risk factors (diabetes, hypertension) predispose the patients to increased severity and mortality associated with COVID-19. On the other hand, COVID-19 itself leads to various cardiovascular complications, which increase its associated morbidity and mortality in affected patients. It is, therefore, prudent to review the rapidly evolving data in this field and understand the mechanisms behind the cardiovascular involvement of this lethal disease.
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The recent novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV) has caused a large number of deaths around the globe. There is an urgent need to understand this new virus and develop prophylactic and therapeutic drugs. Since drug development is an expensive, intense and time-consuming path, timely repurposing of the existing drugs is often explored wherein the research avenues including genomics, bioinformatics, molecular modeling approaches offer valuable strengths. Here, we have examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) (active withanolides of Ashwagandha) and Caffeic Acid Phenethyl Ester (CAPE, bioactive ingredient of propolis) to a highly conserved protein, Mpro of SARS-CoV-2. We found that Wi-N and CAPE, but not Wi-A, bind to the substrate-binding pocket of SARS-CoV-2 Mpro with efficacy and binding energies equivalent to an already claimed N3 protease inhibitor. Similar to N3 inhibitor, Wi-N and CAPE were interacting with the highly conserved residues of the proteases of coronaviruses. The binding stability of these molecules was further analyzed using molecular dynamics simulations. The binding free energies calculated using MM/GBSA for N3 inhibitor, CAPE and Wi-N were also comparable. Data presented here predicted that these natural compounds may possess the potential to inhibit the functional activity of SARS-CoV-2 protease (an essential protein for virus survival), and hence (i) may connect to save time and cost required for designing/development, and initial screening for anti-COVID drugs, (ii) may offer some therapeutic value for the management of novel fatal coronavirus disease, (iii) warrants prioritized further validation in the laboratory and clinical tests.
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The coronavirus SARS-CoV-2 (COVID-19) outbreak is having a profound impact on the management of patients with cancer. In this review, we comprehensively investigate the various aspects of cancer care during the pandemic, taking advantage of data generated in Asia and Europe at the frontline of the COVID-19 pandemic spread. Cancer wards have been subjected to several modifications to protect patients and healthcare professionals from COVID-19 infection, while attempting to maintain cancer diagnosis, therapy, and research. In this setting, the management of COVID-19 infected patients with cancer is particularly challenging. We also discuss the direct and potential remote impacts of the global pandemic on the mortality of patients with cancer. As such, the indirect impact of the pandemic on the global economy and the potential consequences in terms of cancer mortality are discussed. As the infection is spreading worldwide, we are obtaining more knowledge on the COVID-19 pandemic consequences that are currently impacting and may continue to further challenge cancer care in several countries.
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COVID-19 mortality is strongly associated with the development of severe pneumonia and acute respiratory distress syndrome with the worst outcome resulting in cytokine release syndrome and multiorgan failure. It is becoming critically important to identify at the early stage of the infection those patients who are prone to develop the most adverse effects. Elevated systemic interleukin-6 levels in patients with COVID-19 are considered as a relevant parameter in predicting most severe course of disease and the need for intensive care. This review discusses the mechanisms by which IL-6 may possibly contribute to disease exacerbation and the potential of therapeutic approaches based on anti-IL-6 biologics.
A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a “Cytokine Storm Syndrome” (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.