Biomedicine & Pharmacotherapy

Biomedicine & Pharmacotherapy 131 (2020) 110622
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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Propolis and its potential against SARS-CoV-2 infection mechanisms and

COVID-19 disease
Running title: Propolis against SARS-CoV-2 infection and COVID-19
Andresa Aparecida Berretta a, Marcelo Augusto Duarte Silveira b, José Manuel Cóndor Capcha c,
David De Jong d, *
a
Research, Development and Innovation Department, Apis Flora Indl. Coml. Ltda, Ribeirão Preto, São Paulo, Brazil
b
D’Or Institute for Research and Education (IDOR), Hospital São Rafael, Salvador, Brazil
c
Interdisciplinary Stem Cell Institute at Miller School of Medicine, University of Miami, Miami, Florida, United States
d
Genetics Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
A R T I C L E I N F O A B S T R A C T
Keywords: Propolis, a resinous material produced by honey bees from plant exudates, has long been used in traditional
Propolis herbal medicine and is widely consumed as a health aid and immune system booster. The COVID-19 pandemic
SARS-CoV-2 has renewed interest in propolis products worldwide; fortunately, various aspects of the SARS-CoV-2 infection
COVID-19
mechanism are potential targets for propolis compounds. SARS-CoV-2 entry into host cells is characterized by
Antiviral
Anti-inflammatory
viral spike protein interaction with cellular angiotensin-converting enzyme 2 (ACE2) and serine protease
PAK1 blocker 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, hyper
tension, 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.
1. Introduction often through asymptomatic patients [2]. Unfortunately, tests to deter

mine if people are infectious or were previously infected are not widely
The COVID-19 pandemic is of grave concern due its impact on available, often are costly, and frequently do not provide timely and
human health and on the economy. It is much more deadly than influ accurate results. Various therapeutic alternatives have been proposed
enza and other types of diseases that recently have had worldwide and tested; however, most require more robust data in clinical trials
impact [1], forcing countries to take unusual measures such as limiting before they can be widely and safely used [3].
travel, closing schools, businesses, and other locations where many Isolation and stay-at-home measures do not effectively protect
people can come into contact with each other. Various public healthcare essential workers, especially health care personnel, who have become
strategies have been adopted in an attempt to reduce the impact of the infected and are dying at alarming rates [4]. Economic and other ne
disease, but with limited effectiveness, as the virus continues to spread, cessities limit how well and how long these isolation measures can be
* Corresponding author.
E-mail addresses: [email protected] (A.A. Berretta), [email protected] (M.A.D. Silveira), [email protected] (J.M. Cóndor
Capcha), [email protected] (D. De Jong).
https://doi.org/10.1016/j.biopha.2020.110622
Received 10 June 2020; Received in revised form 4 August 2020; Accepted 5 August 2020
Available online 17 August 2020
0753-3322/© 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Téléchargé pour Manal El goubi ([email protected]) à ClinicalKey France Guest Users à partir de ClinicalKey.fr par Elsevier sur septembre 21, 2020.
Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée. Copyright ©2020. Elsevier Inc. Tous droits réservés.
A.A. Berretta et al. Biomedicine & Pharmacotherapy 131 (2020) 110622
maintained, especially in poor countries and in poor communities such as immune system fortification, reduced viral replication, and
as slums and favelas [5,6]. As populations gradually try to get back to anti-inflammatory action [22,24,28,37,38].
normalcy, reducing social distancing, and people in “non-essential
professions” return to the workplace, they become more at risk for 2. Propolis and its properties
infection. In this scenario, any options that could help ameliorate dis
ease progression and its consequences, even marginally, would be use Propolis is a product derived from resins and plant exudates. Plants
ful. The world needs safe alternatives to help reduce the impact of this defend themselves from pathogens mainly by producing phytochemi
deadly disease. cals, many of which have been extracted and used in medicine [39].
Natural products, which have historically been widely used to help Plant defense substances collected by bees include phenols and terpe
avoid and alleviate diseases [7–9], are among the options being noids [40–42]. Phytochemical compounds that show promise for the
considered as an adjuvant treatment for SARS-CoV-2 infection [10], inhibition of coronavirus in humans include quercetin, myricetin, and
because they are generally inexpensive, widely available, and rarely caffeic acid, all components of propolis [43]. Honey bees and many
have undesirable side effects. Some have proven antiviral activity other species of social bees recognize these antimicrobial properties and
[11–13]. An important advantage of using natural remedies is that selectively collect and process these plant products to make propolis,
people who have other health problems or who have mild flu-related which they use to protect the colony [44]. The production and use of
symptoms, but do not have the means or courage to visit an already propolis by honey bees evolved to the point that these social bees have
overcrowded medical facility, could take simple and inexpensive mea considerably fewer immune genes than solitary insect species [45]. Bees
sures to help reduce the impact of infection with SARS-CoV-2. in colonies that produce more propolis are healthier and live longer
Considering the large number of deaths and other types of damage [46], and propolis consumption by the bees augments their immune
that the COVID-19 pandemic is causing, there is an urgent need to find response to bacterial challenge [47].
treatments that have been approved as safe, and potentially able to The composition of propolis varies according to the plant species
inhibit the new coronavirus, reduce its infectivity, and/or alleviate the available in each region [42,48,49]. As this variability can affect their
symptoms of infection [14,15]. Along this line, propolis and its com medicinal properties, standardized propolis products have been devel
ponents emerge as potential candidate materials that could help to oped to help meet the need for a product that does not vary in the main
reduce the pathophysiological consequences of SARS-CoV-2 infection bioactive components and is safe, with minimal interaction with phar
[10]. maceutical drugs and proven efficacy in clinical trials [50–53]. In recent
Infection by SARS-CoV-2, the virus that causes COVID-19, is char decades, it has been shown to have antimicrobial (including antiviral),
acterized by binding between viral spike proteins and angiotensin- anti-inflammatory, immunomodulatory, antioxidant, and anticancer
converting enzyme 2 (ACE2) [16]. Activation of the spike protein is properties [54]. Propolis has historically been widely used to alleviate
mediated through proteases, such as TMPRSS2, which play important various diseases [7–9,55]; it also has been considered, among other
roles in the viral infection [17]. After entry, followed by endocytosis, natural alternatives, as an adjuvant treatment for SARS-CoV-2 infection
coronavirus infection causes PAK1 upregulation, a kinase that mediates [10], because it is generally inexpensive, widely available and rarely
lung inflammation, lung fibrosis and other critical mortality factors. causes undesirable side effects.
Increased PAK1 levels also suppress the adaptive immune response, Some types of propolis that are highly valued for their medicinal
facilitating viral replication [10,18]. SARS-CoV-2 infection is associated properties, such as Brazilian green propolis, are mainly produced by
with increased levels of chemokines and activated pro-inflammatory bees from materials they collect from specific plants, in this case Bac
cytokines that lead to the development of atypical pneumonia, with charis dracunculifolia [56]. After the botanical origin of the propolis has
rapid respiratory impairment and pulmonary failure [19]. Immunolo been identified, extracts of the plant can be made to develop useful
gical/inflammatory phenomena (such as cytokine release syndrome) products, such as a medicinal mouthwash [57]. However, the medicinal
have been shown to be important in the spectrum of SARS-CoV-2 properties of these plant extracts are often inferior compared to the
infection. These mechanisms are associated with organ dysfunction propolis that the bees make from these plant materials [58–60].
more than the viral load per se [20]. Along this line, a retrospective
observational study found higher serum levels of pro-inflammatory cy 3. Why propolis may be a good fit for dealing with COVID-19
tokines such as IL-6, IL-1, and TNF-α, in patients with severe COVID-19,
compared to individuals with mild disease [21]. Among natural medicine alternatives, propolis has been widely
There is considerable evidence that propolis can reduce and alleviate studied and is already extensively consumed in many countries [38,55,
the symptoms of inflammatory diseases by affecting various metabolic 61–63]. For example, propolis products, such as throat sprays and ex
cycles [22–24]. Recently, several studies have shown that propolis tracts, are produced by hundreds of companies in Brazil and are sold as a
extract and some of its components act against several important targets health aid in nearly every pharmacy throughout the country, demon
in the pathophysiological context of the disease caused by SARS-CoV-2, strating on a practical basis that they can be safely consumed. These
such as reducing TMPRSS2 expression, and reducing ACE2 anchorage, propolis products, and the raw material for their manufacture, are
which would otherwise facilitate entry of the virus into the cell; this is in extensively exported by Brazilian companies, especially to Asian coun
addition to immunomodulation of monocytes / macrophages (reducing tries, including Japan, South Korea, and China [50,64]. The importance
production of and eliminating IL-1 beta and IL-6), reduction of the of propolis in Chinese, Japanese, Russian and Korean medicine is re
transcription factors NF-KB and JAK2 / STAT3 and blocking PAK1, flected in the number of patents for propolis containing products
which determine inflammatory activities and fibrosis caused by registered by 2013, including about 1200 by China and 300 – 400 each
COVID-19 [25–28]. for Japan, Russia and Korea [42]. Since 2013, about 1400 new
Various comorbidities have been associated with severe COVID19 propolis-related patents were applied for in the US patent office. It is a
symptoms and a greater chance of patients requiring intensive care; key ingredient in traditional Chinese medicine [65]. Japanese scientists
these include hypertension and diabetes. Also, mortality rates of have isolated and patented various Brazilian propolis components for
COVID19 patients are much higher in those with cardiovascular disease, cancer treatment [66], demonstrating their usefulness. In fact, propolis
chronic respiratory disease, and diabetes [29,30]. There is considerable has a wide spectrum of pharmacological properties and is a dietary
evidence that these conditions could be alleviated by treatment with supplement that is commonly consumed by both healthy and sick people
propolis. This includes research in animal models of diabetes [31,32], as a preventative precaution and for treatment [67–69]. It is also used in
hypertension [33,34], and cardiovascular disease [35,36]. Propolis has veterinary medicine, due its antibacterial, antifungal, antiviral, anti
properties that are particularly relevant to SARS-CoV-2 infection, such parasitic, hepatoprotective, and immunomodulatory activities [70].
Table 1
Potential pathways through which propolis and its components could attenuate SARS-CoV-2 infection and its consequences.
N Targets Aspect of SARS-CoV-2 infection Propolis Components Effect of the components and type of evidence
1 Viral RNA-dependent RNA Viral component that attaches to host cell Limonin, Quercetin and Inhibitory potential with high binding energy to viral
polymerase (RdRp) and Spike Kaempferol components from -9 to -7.1 kcal/mol (in silico) [15]
glycoprotein (SGp)
2 3a Channel Protein Viral component that attaches to host cell Kaempferol Blocks the 3a channel that is encoded by ORF 3a of SARS-
CoV (in vitro) [238]
Myricetin, Caffeic Acid
Phenethyl Ester, Inhibitory potential with high binding energy to ACE2
Hesperetin and (-8.97 kcal/mol) (in silico) [26]
Pinocembrin
3 ACE2 Main receptor for viral entry
Inhibitory potential with high binding energy to ACE2 (-7.5
Kaempferol
kcal/mol) (in silico) [239]
Inhibitory potential with high binding energy to ACE2
Quercetin
(-10.4 kcal/mol) (in silico) [25]
Serine protease that mediates spike Downregulates androgen receptors such as PSA and
3 TMPRSS2 Kaempferol
protein priming for viral entry TMPRSS2 in a prostate cancer model (in vitro) [83]
Downregulates PAK-1 associated with Rac1 activation (in
PAK-1 (RAC/CDC42-activated kinases) -
Caffeic Acid and Caffeic vitro) [18]
4 PAK-1 Responsible for suppression of immune
Acid Phenethyl Ester Inhibits PAK-1 directly or up-stream, blocking coronaviral
system in hosts
infection (Review) [10]
Mediates the proteolytic processing of
replicase polypeptides 1a and 1ab into
5 3C-like protease Hesperetin Inhibits cleavage activity of 3CLpro (in vitro) [240]
functional proteins in SARS-CoV-2
infection
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
Propolis Extract 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
Response to viral infection that leads to
6 Inflammatory response Inflammation (in vivo) [24]
organ injury
Inhibits the production of ROS, RNS, NO, cytokines IL-1α,
IL-1β, IL-4, IL-6, IL-12p40, IL-13, TNF-α, G-CSF, GM-CSF,
MCP-1, MIP-1α, MIP-1β, and RANTES in stimulated
J774A.1 macrophages (in vitro) [244]
Reduces TNF-α, IL-6, VEGF via the ERK-NFkB-cMyc-p21
Kaempferol
pathway (in vitro) [83]
Inhibits NF-kB activation in HTLV-1 infection (in vitro)
Caffeic Acid Phenethyl [245]
Ester 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]
Adaptive immune response against viral
Immunomodulation Propolis Extract Suppresses the differentiation of Th17 cells by inhibition of
infection
IL-6-induced phosphorylation of signal transducer and
activator of transcription 3 (STAT3) (in vivo) [88]
Blood clotting dysregulation caused by Inhibits thrombin in thrombotic manifestations (in vitro)
7 Thrombosis Quercetin
viral infection [246]
Kaempferol and Inhibits internal ribosomal entry site (IRES) activity
Viral translation
Hesperetin required for viral protein translation (in vitro) [247]
Inhibits human immunodeficiency virus reverse
transcriptase-associated DNA polymerase as well as
Transcription Kaempferol RNAase H and RNase H activities (in vitro) [248]
Presents potent anti-HIV-1 reverse transcriptase activity (in
vitro) [249]
Decreases Akt phosphorylation and viral endocytosis of
Endocytosis
Rhinovirus (in vivo) [250]
Prevents up-regulation of diacylglycerol acyltransferase
8 Viral replication Replication and virion integrity Quercetin (DGAT) required for hepatitis C virus replication (in vitro)
[251]
Decreases heat shock proteins and Hepatitis B virus
Replication
transcription levels (in vitro) [252]
Inhibits Hepatitis B virus-DNA replication (in vivo & in
Endocytosis
vitro) [253]
Endocytosis Caffeic Acid Inhibits influenza A virus (IAV) replication (in vitro) [254]
Inhibits influenza A virus (IAV) activity through
Endocytosis
neuraminidases (in vitro) [255]
Caffeic Acid Phenethyl
Transcription Inhibits HIV-1 integrase (Review) [256]
Ester
In the wake of the coronavirus outbreak, South Korea has seen a boon zinc fingers of the active sites of ACE2, a metalloprotease that presents
in the use of functional foods. According to their Ministry of Food and the same zinc finger in ACE [26].
Drug Safety, “health functional foods” are nutrients that have been In addition to the in silico evidence, Osés et al. [82] evaluated several
proven to be beneficial to health [71]. In March of this year, in response types of propolis for various characteristics, including inhibition of ACE.
to the coronavirus pandemic, the ministry eased regulations for propolis, They found strong inhibition for most of the propolis types they studied,
which is considered a functional food, and allowed new oral formula with higher than 90% ACE inhibition. The best results were found with
tions [72]. However, despite considerable evidence that propolis can the propolis components catechin and p-coumaric acid.
reduce and alleviate disease symptoms, its acceptance as a ACE2 and TMPRSS2 (transmembrane serine protease 2) on the sur
health-promoting supplement in human medicine has been limited in face of host cells are used by SARS-CoV-2 via interaction with spike
many countries such as the USA because of a relevant criticism that glycoproteins in order to proceed with invasion and replication [15].
propolis products are not standardized and vary in their components and Vardhan & Sahoo [15] studied several molecules commonly found in
biological activity. In part, this is because propolis varies with the spe medicinal herbs using molecular docking procedures with relevant tar
cies of plants available in each region, from which the bees collect resins gets, such as RNA-dependent RNA polymerase (RdRp), ACE2 and spike
to produce it [42,48,49]. However, standardized propolis products have glycoproteins and compared the resulting scores with those of hydrox
recently become available to help fill the need for a product that does ychloroquine [15]. Limonin was the most active compound; however,
not vary in the main bioactive components and effectiveness [50,52]. quercetin and kaempferol, also propolis compounds, gave high docking
One such option, a standardized Brazilian propolis extract blend [54], scores [15]. Kaempferol was studied in prostate cancer models, and the
has been tested for safety and effectiveness in clinical trials for treating expression of TMPRSS2 was reduced, showing a potential mechanism of
kidney disease and diabetes [51], denture stomatitis [73], and burn action for an antitumoral effect [83]. Kaempferol could be an important
patients [74]. Therefore, propolis as a nutraceutical or functional food propolis component for use against COVID-19, since it is involved in the
should be considered as a resource that could help fight against the inhibition of TMPRSS2 [83], potentially interacting with ACE2, RdRp
COVID-19 pandemic. and spike glycoprotein (SGp) [15], besides its antiviral activity [84]
(Table 1).
4. Some propolis compounds can potentially interact with SARS-
CoV-2 MPRO 6. Propolis blocks PAK-1, potentially avoiding lung fibrosis and
restoring a normal immune response
The research community has examined the genetic code of corona
virus and the mechanisms underlying the damages caused by SARS-CoV- Among the possible targets for controlling COVID-19 damage, the
2, to help search for drugs and/or potential targets in order to inactive major “pathogenic” kinase PAK1 is key. It is an essential component in
the virus and reduce the damage that it causes. The main protease of malaria and viral infections, but it is also involved in a wide variety of
coronavirus SARS-CoV-2, MPRO (3-chymotrypsin-like cysteine enzyme), other diseases and disease conditions, including cancer, inflammation,
is essential for coronavirus processing of polyproteins and for its life and immuno-suppression, when abnormally activated. Consequences of
cycle, and therefore inhibition of the active site of this enzyme is a PAK1 activation include lung fibrosis [10], which is an aggravating
relevant target for drug discovery [75]. factor in COVID-19. PAK1 is activated by RAC. Xu et al. [18] demon
Along this line, Hashem evaluated various natural compounds with strated that caffeic acid and its ester (CAPE), components of propolis,
an in silico approach (molecular docking) to try to find useful options for can inactivate RAC, consequently inhibiting PAK1. The inactivation of
treating SARS-CoV-2 infection. Curiously, caffeic acid phenethyl ester PAK1 directly, or up-stream, can potentially attenuate coronavirus
(CAPE), galangin, chrysin and caffeic acid, substances found in several pathogenesis [10]. B-cells and T-cells are lymphocytes that produce
different types of propolis around the world, appeared as potential drugs specific antibodies against viruses and other intruders, and PAK1 con
against this viral target (Table 1) [76]. Specifically, CAPE was predicted tributes to their suppression. PAK1 inhibitors can both help combat the
to interact with SARS-CoV-2 MPRO in a similar study [77]. Therefore, virus and restore a normal immune response [10].
although it will be necessary to run in vitro assays to evaluate the po Propolis from Europe and temperate Asia, usually made by bees from
tential anti-SARS-CoV-2 effects of propolis and/or its constituents, these resins collected from Poplar trees, has predominantly flavonoid com
in silico results are well boding. pounds, while green propolis (from Baccharis dracunculifolia), a propolis
exclusively found in Brazil, has various kinds of flavonoids and preny
5. Propolis can interact with ACE2 and TMPRSS2, potentially lated phenylpropanoids, such as artepellin C, baccharin and drupanin.
blocking or reducing SARS-CoV-2 invasion of the host cell These and all other types of propolis can inactivate PAK1 [10]. Artepillin
C selectively inhibits PAK1 [85] (Table 1).
SARS-CoV-2 strongly binds to angiotensin-converting enzyme 2 Some studies have shown that propolis can act as an immunosti
(ACE2), using this enzyme as a receptor for invasion and replication in mulant, with the ability to improve the immune response. Its compo
the host cell [17,78], causing damage and increasing interpersonal nents increase neutralizing antibody titers, activate phagocytosis, and
transmission [26,79]. Consequently, ACE inhibitors have been consid increase IFN-γ levels and the number of lymphocytes [86]. An increase
ered as useful drug alternatives. However, potential deleterious effects in IFN-γ levels was also detected by Shimizu et al. [28], who evaluated
on users of angiotensin-converting enzyme (ACE) inhibitors and angio the mechanisms involved in the effects of some types of propolis in a
tensin receptor blockers (ARBs) have emerged as a concern for treatment herpes simplex animal model.
of COVID-19 patients. An observational study involving 8,910 patients CAPE (caffeic acid phenethyl ester) is a potent inhibitor of activation
did not confirm this suspicion, and therefore these classes of drugs of NF-kB in myelo-monocytic cells. Ansorge et al. [37] demonstrated
remain an important tool against potential cardiovascular events [80]. that propolis, CAPE, quercetin, hesperidin and some other propolis fla
Inhibition of ACE2 enzyme is an important target for treatment vonoids can inhibit the cytokine production of Th1 and Th2 type T cells,
against SARS-CoV-2 infection [15,81]. Güler et al. [26] prepared an while increasing TGF-beta 1, an important anti-inflammatory cytokine.
alcoholic extract of propolis and identified some hydroxycinnamic acids Moreover, CAPE can attenuate oxidative stress and inflammation
(caffeic acid, p-coumaric acid, t-cinnamic acid and CAPE), the flavanons through down-regulation of JAK2/STAT3 signaling [87] as well as
rutin and myricetin, and the flavones hesperidin, chrysin and pino having an immunomodulatory effect, in which CAPE inhibits IL-6
cembrin. Using molecular docking evaluations, they found that rutin phosphorylation and STAT3, which are important for
had the highest binding energy to ACE2, followed by myricetin, caffeic pro-inflammatory Th17 development [88].
acid phenethyl ester, hesperetin and pinocembrin. Rutin interacts with Besides the anti-inflammatory effect of CAPE and kaempferol,
Paulino et al. [89] evaluated the anti-inflammatory effect of artepellin C been shown to be important mortality factors in SARS-CoV-2 infection.
in rat paw edema and in cell cultures, demonstrating that the activity Higher serum levels of pro-inflammatory cytokines such as IL-6, IL-1,
was at least in part mediated by prostaglandin E2 and NO inhibition and TNF-α, are found in patients with severe COVID-19 compared to
through NF-kB modulation. Artepillin C is an important biomarker of those of individuals with mild disease [21]. Molecular mechanisms
Brazilian green propolis (botanical source Baccharis dracunculifolia). involved in this immune process are the targets of various synthetic
Immune modulation is desirable since coronavirus infection dysre medicines being tested in patients, including ciclesonide, hydroxy
gulates the immune response in the initial phases of infection, which chloroquine, ivermectin, and ketorolac, which are PAK1 blockers [10].
facilitates viral replication. However, in later stages of COVID-19, the PAK1 (RAC/CDC42-activated kinase 1) is overexpressed in the lung in
body develops an exaggerated inflammatory response, which can response to SARS-CoV-2 infection and is a critical mediator of the
greatly damage the lungs and other organs. Propolis, different from cytokine storm that frequently results in mortality in hospitalized pa
typical immunosuppressants, can help avoid immunosuppression during tients [99]. Fortuitously, propolis components are effective PAK1
the initial phases of disease and, in later stages, reduce an exaggerated blockers (Table 1).
host inflammatory response, inhibiting excess IL-6, IL-2 and JAK There is considerable evidence that propolis can reduce and alleviate
signaling [90]. CAPE, a propolis component, is also known as an the symptoms of inflammatory diseases [22–24] and has immunomod
immune-modulating agent [91] and should be considered as an alter ulatory properties [24,37]. However, these properties can vary accord
native to help reduce an exaggerated inflammatory response. In a mouse ing to the plant origin of the propolis, as well as the extraction
model, propolis had immunomodulatory action in vivo on Toll-like re process/solvent used and the inflammatory protocol (cell culture, ani
ceptor expression and on pro-inflammatory cytokine production [92]. mal models, induction by lipopolysaccharides) when the propolis ex
There is ample evidence for interference of propolis and/or its tracts are tested [50]. Tests with animal models have shown that
components with viral replication and infectivity, potentially decreasing propolis can reduce the levels of IL-6 and TNF-alpha, which are key
lung inflammation due to anti-inflammatory properties, while promot pro-inflammatory mediators, and increase the levels of the regulatory
ing immune system fortification. These are useful properties that could cytokine IL-10 [24]. Kaempferol, a propolis component, reduces IL-6,
help minimize the symptoms and deleterious effects of COVID-19 TNF-alpha, and VEGF (vascular endothelial growth factor) via the
(Fig. 1). ERK-NFkB-cMyc-p21 pathway [83] (Table 1).
Tests on macrophage cell cultures also demonstrated that propolis
7. Propolis as an antiviral substance inhibits the production of IL-1 beta, an important component of the
inflammasome inflammatory pathway, in diseases such as rheumatoid
Propolis has been tested against various viral disease organisms; arthritis, lupus and other autoimmune diseases [55]. Although the
initial successes have prompted research to determine the most useful mechanisms of action are not well elucidated, these propolis compo
components, which may be modified to produce more active and spe nents have potential as complementary supplements in the preventive
cific pharmaceuticals [93]. Viruses that were controlled by propolis in treatment of chronic inflammatory diseases [100].
animal models with suggestion for control in humans include influenza
[11,94], herpes simplex virus type 2 [95], and HIV [93,96]. Shimizu 9. Propolis has potential as a vaccine adjuvant
et al. [28] evaluated three different types of propolis in ethanol extracts,
using a murine model of herpes simplex virus type 1. Despite the Propolis is considered a safe immunostimulant and a potent vaccine
chemical differences due to the different plant origins of the resins the adjuvant [101]. Propolis has been widely tested as a vaccine adjuvant,
bees used to produce the propolis (Baccharis dracunculifolia, Baccharis because it induces an earlier immune response and provides a longer
eriodata and Myrceugenia euosma), all three propolis extracts not only protection period [102]. It is also included as an adjuvant ingredient in
had direct anti-HSV-1 effects, but also stimulated immunological ac traditional Chinese medicine [103]. Propolis flavonoids have potential
tivity against intradermal HSV-1 infection in mice. as adjuvants, enhancing IgG, IL-4, and IFN-γ in serum [104]. Fernandes
Antiviral activity of propolis has been reported for DNA and RNA et al. [86] found that propolis exerted a positive adjuvant effect on
viruses (poliovirus, herpes simplex virus, and adenovirus) in an in vitro vaccines that were developed against canine coronavirus. They assayed
model (cultured cells). The best results were obtained against poliovirus IFN-γ, which is an effective way to measure the cellular response
and herpes virus, with 99.9% inhibition of the latter, at a propolis induced by a vaccine. In a mouse model, propolis, added as an adjuvant
concentration of 30 ug/ml [97]. The propolis components chrysine and to inactivated swine herpesvirus type 1 vaccine, stimulated increased
kaempferol caused a concentration-dependent reduction of intracellular cellular and humoral responses, increasing IFN-γ [105,106]. Propolis
replication of herpes-virus strains when host cell monolayers were enhanced the immune response to inactivated porcine parvovirus vac
infected and subsequently cultured in a drug-containing medium. cine in guinea pigs [107]. When added to a Trichomonas vaginalis
Quercetin, another propolis component, had the same effect, but only at protein vaccine, propolis increased the IgG antibody response 4-10 times
the highest concentrations tested (60 ug/mL) against various human in mice, compared to the protein alone [108]. Propolis was also effective
herpes simplex virus strains, with a intracellular replication reduction of as an adjuvant in the immunization of cattle with bovine herpesvirus
approximately 65%, while it reduced the infectivity of bovine herpes [105]. It improved the humoral and cellular responses in mice inocu
virus, human adenovirus, human coronavirus, and bovine coronavirus lated with inactivated virus vaccines [109]. Propolis as an adjuvant gave
about 50%. The reduction was 70% in the case of rotavirus [84]. a similar immune response (increasing IFN-γ levels), to Alum and
Freund’s adjuvant in mice vaccinated with an HIV-1 polytope vaccine
8. Anti-inflammatory and immunomodulatory properties of candidate, with less risk of undesirable side effects [110].
propolis
10. Comorbidities and evidence of how propolis can help reduce
The most critical cases of COVID-19, which require ventilator- their impact in COVID-19 patients
assisted intensive care and often result in prolonged ventilator de
pendency and death, are a result of an exaggerated inflammatory 10.1. Cancer
response to infection [98]. SARS-CoV-2 infection is associated with
increased levels of chemokines and activated pro-inflammatory cyto Cancer is considered a relevant comorbidity factor for COVID-19.
kines that lead to the development of atypical pneumonia, with rapid Cancer patients have a 3-4 times higher risk of progressing to severe
respiratory impairment and pulmonary failure [19]. Immunologica COVID-19 disease than patients without comorbidities. Also, the hos
l/inflammatory phenomena (such as cytokine release syndrome) have pital environment during the coronavirus pandemic can interfere with
Fig. 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.
or delay the treatment that cancer patients should receive. Patients with is used in popular medicine to treat various ailments, including high
symptoms may choose not to risk a visit to a clinic or hospital to blood pressure [130]. Propolis has been widely used as a dietary sup
determine if they have cancer [111]. Alternative therapies could help plement for its health benefits, including cardiovascular protective ef
retard cancer or reduce the impact of cancer and cancer treatment in fects [131,132]. In a human trial, consumption of propolis improved
COVID-19 patients. critical blood parameters, including HDL, GSH and TBARS levels,
Propolis has potential as a complementary therapy for cancer. It has demonstrating that it could contribute to a reduced risk for cardiovas
shown efficacy against various types, including bladder, blood, brain, cular disease [132].
breast, colon, head and neck, kidney, liver, pancreas, prostate, and skin
cancers [112]. Propolis could help prevent cancer progression; in
10.3. Obesity
various parts of the world it is considered an alternative therapy for
cancer treatment [113]. Propolis extracts have been found to inhibit
Obesity is a major comorbidity and predictor of increased mortality
tumor cell growth both in vitro and in vivo, including inhibition of
in COVD-19 patients. Obesity and SARS-CoV-2 both induce an inflam
angiogenesis, demonstrating potential for the development of new
matory process, exacerbating SARS-CoV-2 infection in the obese [133].
anticancer drugs [114–116]. Various components of propolis have been
Propolis reduced inflammation and prevented hyperlipidemia and
shown to inhibit cancer cell growth, including cinnamic acid [66], CAPE
metabolic syndromes in highly caloric diet induced obesity in mice.
[117–119], quercetin [120], and chrysin [121]. Propolis and its com
Body weight gain, visceral adipose tissue, liver and serum triglycerides,
ponents normally have little impact on normal cells, displaying differ
cholesterol, and non-esterified fatty acids were all reduced in the
ential cytotoxicity in liver cancer, melanoma and breast cell carcinoma
propolis fed mice [78,134]. Caffeic acid phenethyl ester, a propolis
cell lines [122,123]. Propolis enhances the activity of tumor necrosis
component, is a natural anti-obesity agent [135].
factor related apoptosis inducing ligand (TRAIL) in cancer cells [124].
10.4. Thromboembolism, thrombosis and microthrombosis

10.2. Hypertension and cardiovascular disease
Microthrombosis, disseminated intravascular coagulation, and
Hypertension and cardiovascular disease are considered relevant consequent multiorgan failure are common in severely affected
comorbidities for COVID-19 [125–127]. Propolis has demonstrated COVID19 patients, with associated high mortality rates [136–139].
anti-hypertensive effects in rat models [33,34,128,129]. In Cameroon, it Anticoagulants are sometimes prescribed to such patients because they
can reduce mortality (Tang et al. 2020). An elevated level of plasmin Caffeic acid phenethyl ester (CAPE) is considered an anti-obesity
ogen activator inhibitor-1 (PAI-1) is a biomarker and risk factor for agent with beneficial effects on inflammation and diabetes [175].
thrombosis and atherosclerosis [140,141]. Various types of evidence CAPE reduced insulin resistance in diabetic mice and in hepatic cell
demonstrate that propolis can reduce platelet aggregation and other culture [176]. Chrysin, another component of propolis, also has anti
thrombosis-related parameters. Propolis decreased thrombotic ten diabetic properties [177].
dencies in mice by suppressing lipopolysaccharide-induced increases in
PAI-1 levels [142,143]. Propolis downregulated platelet-derived growth 10.7. Kidney diseases
factor and platelet endothelial cell adhesion molecules in low-density
lipoprotein knockout mice [144]. Platelet aggregation was reduced by COVID-19 is an important threat for patients with comorbidities such
propolis in tests on human blood in vitro [145] and in other in vitro tests as renal or hepatic impairment [178]. The kidney is a common target of
[146]. Caffeic acid phenethyl ester (CAPE), a well-studied bioactive SARS-CoV-2 [179]. COVID-19 patients are at increased risk of kidney
propolis component, inhibits collagen induced platelet activation [147]. impairment [79], and consequently many patients with COVID-19 pre
sent renal dysfunction [180]. Increased mortality is common in
10.5. Old age COVID-19 patients with chronic kidney disease and in those undergoing
hemodialysis [181]. Propolis has shown protective effects against kid
The elderly are more often affected by chronic inflammation, char ney diseases. Nephropathy was prevented by propolis treatment in an
acterized by systemically increased levels of proinflammatory cytokines, imal models [165,182,183]. Brazilian red propolis attenuated
which can contribute to development of a cytokine storm, a major cause hypertension and renal damage in a rat renal ablation model [184].
of COVID-19 mortality [148]. Propolis has antioxidant properties, which Anti-diabetic activity of propolis in a rat model reduced liver damage
could help retard or reduce aging processes [149]. CAPE, a propolis [160]. In a pioneering clinical trial, propolis reduced proteinuria in
component, increased the lifespan of Caenorhabditis elegans, a common patients with chronic kidney disease [51].
model organism for aging studies [150]. Propolis consumption pro
tected against cognitive decline in elderly subjects (humans) exposed to 10.8. Bacterial infection
high altitudes [151]. Serum TGF-β1 and IL-10 levels were significantly
higher in propolis-treated elderly subjects, helping reduce inflamma Bacterial infection is a common complication in COVID-19 [79].
tion, which could be the mechanism of protection against cognitive Propolis has a long history of use for its antibacterial properties and
decline. Activity of superoxide dismutase (SOD), a key antioxidant in could help treat bacterial infections in COVID-19 patients. The healing
men treated with propolis was increased, while malondialdehyde, a properties of propolis are referred to throughout the Old Testament, and
marker of oxidative stress, decreased [152]. The same tendencies were propolis was prescribed by Hippocrates in Ancient Greece for the
detected in a diabetic rat model [153]. Propolis has the potential to treatment of sores and ulcers [185]. Propolis has been popular for
reduce neurodegenerative damage through antioxidant activity, which centuries in Russia and other countries in Eastern Europe for its anti
helps protect against cognitive impairment in Alzheimer’s disease as bacterial properties [186]. The pharmacological value of propolis comes
well as aging [154,155]. In a mouse model of Alzheimer’s disease, from a natural mixture of antibacterial substances, instead of only one or
coniferaldehyde, an active ingredient in propolis, had neuroprotective a few substances as in most medicines [187]. Propolis components
effects. It reduced brain β-amyloid deposits and pathological changes in galangin, pinocembrin, rutin, quercetin, and naringenin, as well as
the brain, helping preserve learning and memory capacity [156]. The CAPE increase bacterial membrane permeability, which could explain
angiotensin system, which is key to SARS-CoV-2 invasion of host cells, is their antimicrobial properties [188]. De Campos et al. [189] showed
associated with senescence. One of the reasons that SARS-CoV-2 causes that the main mechanism of action of propolis is rupture and lysis of
significantly higher mortality in older patients may be that they have a bacterial cells. Propolis has demonstrated antibacterial activity against
larger number of senescent lung cells, which are a vulnerable target for Staphylococcus aureus, Staphylococcus epidermidis, and E. coli [190],
viral infection and can help promote viral replication. That would make including methicillin-resistant and methicillin-susceptible strains of
senolytic drugs useful to help the elderly survive COVID-19. Quercetin, a Staphylococcus aureus [191]. Adding propolis extract to the antibiotics,
propolis component, which has been proposed as a therapeutic for ampicillin, gentamycin and streptomycin, vancomycin and oxacillin
treatment of COVID-19, has senolytic activity [157]. increased their antibacterial activity against Staphylococcus aureus [192,
193]. The extract also reduced cell adhesion and consequent biofilm
10.6. Diabetes formation by this bacterium [193]. Propolis (sometimes known as bee
glue) has antibacterial activity against human tubercle bacillus, but
Common comorbidities with high death rates in critically ill often has only limited activity against Gram-negative bacilli. These
COVID19 patients include diabetes [30]. Given the relation between antimicrobial properties appear to be due to its high flavonoid content
diabetes and inflammation, and that flavonoids, major bioactive com [186]. Propolis can help avoid bacterial tooth decay [194]. Propolis and
ponents of propolis, protect against free radicals and other pro-oxidative some of its components inhibit bacterial motility [195]. Black poplar,
compounds, it is plausible that propolis consumption can reduce the risk Populus nigra, tree resin is the main source of the propolis used for me
of diabetes [158]. Brazilian propolis has become popular as a healthy dicinal purposes in Europe; it contains phenols and flavonoids that have
dietary supplement in various parts of the world because it can help well known antimicrobial properties [196]. Propolis can be bacterio
prevent inflammation and diabetes [159]. Propolis was found to reduce static and or bactericidal, depending on the concentration [197]. An
blood glucose, blood lipids and free radicals in diabetic rats [31,160]. It ethanol extract of propolis inhibited microbial growth and biofilm for
also reduced glycemia [32,161] and insulin resistance [162–164] in mation by Pseudomonasaeruginosa [198]. The antibacterial properties of
diabetic rats. Experimental diabetic nephropathy was also prevented propolis make it a useful ingredient in a wound healing biofilm [199].
[165]. Diabetes symptoms were reduced in a diabetic mouse model
[166], apparently by attenuating immune activation in adipose tissues. 11. Limitations: Lack of standardization
Clinical trials with diabetic patients demonstrated that propolis
consumption improved antioxidant parameters [167], glycemic control Man has used propolis as an herbal medicine for thousands of years.
[168,169], and the lipid profile and renal function [170]. Propolis is also Various useful activities have been described for propolis, including, and
an antimicrobial agent with wound healing properties [171,172], which not limited to antiviral, antibacterial, antifungal, anti-inflammatory,
has proven especially useful for diabetic patients [173,174], who tend to immunoregulatory, antioxidant, and wound healing properties [200,
develop difficult to heal wounds. 201]. However, plant geographical source, bee species, seasonality and
climatic differences can dramatically affect chemical composition [48, bacterial strains that were evaluated (unpublished data) and a lack of
202]. These details, along with variations in the processing and solvent abnormalities in a micronucleus test (in vitro) [221]. Tavares et al. [222]
extraction processes (which can selectivity extract some compounds also studied propolis using a micronucleus tool, with the mutagenicity
according to their polarity) [203], can influence its biological proper agent doxorubicin as a positive control. They found that the propolis
ties. This can affect and limit the repeatability of tests and confuse the behaved as a “Janus” compound; it was genotoxic at higher concentra
compilation of results used to determine appropriate dosages for human tions and chemopreventive at lower ones. This demonstrates the
clinical trials, ultimately causing insecurity for prescribers. importance of the appropriate dosage and model for testing, which are
Considerable work has gone into understanding the mechanisms needed to correctly extrapolate to clinical trials. Additionally, acute and
involved in the biological properties of propolis [54,189,204,205]. Also, subchronic animal toxicity tests were performed; even at very high
efforts have been made to improve technological and analytical pro treatment levels, EPP-AF® propolis did not reach an LD50 dose
cesses to determine adequate extraction procedures that preserve its (maximum tested 3000 mg/kg) [223]. The safety data from tests with
bioactive compounds and consistently provide the best pharmacological Wistar rats (1000 mg/kg) and rabbits (300 mg/kg), and the conversion
properties for each medical condition [50,200,201,203,206–208]. factor proposed by the US Food and Drug Agency were used to propose
However, although propolis is a product that can be offered to the the dosages for human trials [50]
market in several presentations and with different classifications ac
cording to the type of product, possibly as a health supplement, food 12.2. Clinical Trials
supplement, cosmetic and/or hygiene product, the various beneficial
effects that appear in published research were not accepted by the Eu A clinical safety study was carried out at the Ribeirão Preto School of
ropean Commission as acceptable "claims", based on the argument that Medicine of the University of São Paulo (FMRP/USP) with healthy
there are qualitative and quantitative variations in the bioactive flavo volunteers in order to assess the safety of ingesting 375 mg / day of
noids, which are dependent on the raw material provided by beekeepers. Standardized Propolis Extract (EPP-AF®), for five days. No adverse
Those factors, and the lack of standardized extraction and preparation events were observed. The study pointed to the absence of acute toxicity
methods, are reasons that do not permit this type of approval [209], after the oral use of Standardized Propolis Extract (EPP-AF®) at a dose of
justifying the standardization proposed by Chan [38]. 375 mg daily for five days. The significant positive variation observed in
Although in the bee products field “standardization” is not yet a the parameter HDL cholesterol needs further studies with a larger
normal procedure, this reality already exists in the phytopharmaceutical number of patients to confirm this beneficial effect on the cardiovascular
industry. When working with herbal products, it is normal to find dif system (unpublished data).
ferences in the raw material received, since plants suffer a strong in In addition, and more important in this case, a study to evaluate drug
fluence of the environment, including seasonality, soil treatment, other interaction was performed using a cocktail approach to analyze the main
plant species nearby, and various other conditions, resulting in batches hepatic metabolizing enzymes (cytochrome P450 enzymes - CYPs) and
of plant materials that are often chemically different, qualitatively and/ the transport enzyme Pgp. The results showed that this standardized
or quantitatively. It is not possible to have identical batches when propolis extract is safe and without risk of drug interaction, according to
working with this type of material; however, minimal standardization is the criteria established by the WHO [53]. The propolis tested in the
needed in order to validate safety and efficacy studies and guarantee interaction study was provided in tablets; consequently, these results
useful characteristics when a product is offered to the market [210]. cannot necessarily be extrapolated to a propolis alcohol extract.
The definition of “Standardization” by the American Herbal Product Using a propolis preparation, a clinical trial that was randomized,
association is: “Standardization refers to the body of information and double-blind, and placebo-controlled was conducted with 430 children
control necessary to produce material of reasonable consistency” [211]. The (1-5 years old) in Israel with a placebo elixir and Chizukit (a standard
mechanisms and technologies available to meet this goal are available; over-the counter drug containing Echinacea extract 50 mg/ml (Echi
however, challenges also exist. Nikam et al. [210] present useful nacea purpurea and E. angustifolia), 50 mg/ml of propolis extract and 10
guidelines for those who intend to develop such standardization. mg/ml of vitamin C, for respiratory tract infection gave good results
[224]. Another clinical study was done for asthma treatment in adults
11.1. A Standardized Propolis Product [204]. The study, which used a propolis water extract, demonstrated
reduction in key pro-inflammatory cytokines, including tumor necrosis
In Brazil, 12 main types of propolis have already been described factor (TNF-a), ICAM-1, IL-6, IL-8 and a 3-fold increase in the “protec
[201]. Due to this great variability and the limitations that these dif tive” cytokine IL-10; the levels of prostaglandins E2, F2a and leukotriene
ferences cause in the research, development and industrial fields, Ber D4 were reduced significantly [204].
retta et al. [54] developed a Standardized Propolis Extract, named A randomized double-blind placebo controlled clinical study of 32
EPP-AF® (Patent Letter no. 0405483-0, approved by Industrial Property patients with Chronic Kidney Disease, demonstrated safety of the
Magazine on July 23, 2019), which possesses reproducibility Standardized Propolis Extract (EPP-AF®) at an oral dose of 500 mg / day
batch-to-batch for a group of phenolic and flavonoid compounds, in after administration during 12 months, with significant reduction in
addition to a characteristic HPLC fingerprint and consistent biological proteinuria and urinary MCP1 in the propolis group compared to the
effects (antimicrobial activity) [54]. Several studies have been con placebo [51], with no side effects. Another clinical study conducted with
ducted with this extract, including analytical development and valida the Standardized Propolis Extract (EPP-AF®) in healthy volunteers
tion [54,212,213], biological effects such as antimicrobial, antifungal aimed to assess the antioxidant activity. There was a reduction in cell
and wound healing properties [54,205,214–217], and damage induced by oxidative stress in healthy volunteers, due to an
anti-inflammatory and immunoregulatory activities [22,24]. increase in the enzymatic antioxidant capacity, especially affecting su
peroxide dismutase (SOD), and decreasing lipid peroxidation and DNA
12. Safety and Efficacy Studies oxidation (8-OHDG) (article submitted). These data indicate the
important protective effect that propolis has on cells, tissues and on the
12.1. Non-Clinical Studies human body, reducing the effects of aging, degenerative diseases and
several other conditions that involve these oxidation processes.
Besides the long history of traditional use of propolis for treating Another relevant clinical trial was conducted by Soroy et al. [225] on
diseases, various studies in animals have demonstrated the safety of dengue hemorrhagic fever patients. Their double-blind, randomized and
propolis [218–220]. Safety studies for EPP-AF® have been conducted placebo-controlled trial evaluated the propolis product PropoelixTM
using an in vitro Ames Test, demonstrating a lack of abnormalities in the (two 200 mg capsules, three times a day), demonstrating an
improvement in platelet counts and a decrease in TNF-alfa, promoting a never become available. Another problem is that modern medicine can
reduction in the duration of hospitalization time of the patients. be quite expensive, with constantly increasing costs for individuals and
The current COVID-19 pandemic has promoted strong interest in countries. Consequently, adequate healthcare may not be available to
propolis as a therapeutic option. As a consequence, a clinical trial of everyone who needs it. Side effects of many of these powerful medicines
Brazilian green propolis extract (EPP-AF) for treatment of COVID-19 are also a concern. Doctors and patients often need to weigh the risk of
patients was recently initiated in Brazil (https://clinicaltrials.gov/ct2/ drug side effects against the consequences of the disease. Also, for some
show/NCT04480593). diseases no effective drug is available and patient care focuses on
relieving symptoms and the consequences of infection.
12.3. Dosages Among alternatives to modern drugs, there has long been a tradi
tional use of natural health products. However, such products normally
Clinical trials with propolis have been conducted in various regions cannot be registered as medicines; the considerable investment needed
of the world, most of them with the limitation of a lack of standardi to qualify them as such often would not be compensated because they
zation. Berretta et al. [50,51,53] evaluated many of them; the most are difficult to obtain a patent for and people could easily purchase or
common dosage used was 500 mg/day for adults. Considering the case collect them. Curiously, one of the strategies for developing modern
of EPP-AF®, the clinical data until now support dosages of 375 - 500 mg drugs is to carefully dissect the components of natural products, deter
of propolis/day; however, non-clinical trials indicate that much higher mine which ones have desirable activity, patent and synthesize them and
dosages can be tolerated and may be useful [211]. The dose of 500 then go through the expensive process of getting them approved, though
mg/day would be equivalent to 30 drops of propolis extract (with 11% with some possibility that such products could give a return on the in
w/v of dry matter), 3 to 4 times a day, diluted in about 100 ml of water, vestment because of the patents. A case in point is Brazilian green
or 3 to 4 units/day of capsules or tablets with the equivalent amount of propolis, for which there is considerable evidence of anticancer prop
extract. For preventive purposes, 30 drops/day or one capsule, are erties [228,229]. This propolis is not patented, but some if its compo
usually taken. However, considering the dosage safely used by Soroy nents were isolated, and synthesized, and are now patented drugs for
et al. [225] of 1200 mg/day, in more severe cases of COVID-19, dosages cancer treatment [230]. Brazil continues to produce and export large
higher than 500 mg/day could be useful. quantities of green propolis, especially to Asian countries, but various
patented components are the property of companies in other countries.
13. Supplements, Food and Hygiene Products made with In some parts of the world, the equivalent of the US Food and Drug
Propolis Administration (FDA), officially classifies certain natural products as
“Functional Foods” or some other similar category. As such, they can be
Propolis extracts and sprays, often combined with medicinal herb produced and marketed and used by people who believe they will be
extracts and honey, are now found in nearly every pharmacy in Brazil, good for their health. To be classified as functional foods, these agencies
attesting to their safety, popularity and usefulness in this country, where require proof that they are safe and that they have proven health ben
hundreds of companies currently produce these “natural medicines”. For efits [71,231]. This option provides alternatives that are normally
each regulatory category and country, the technical rules to be followed inexpensive and do not require prescriptions. Specifically, propolis has
for propolis products vary. Some countries such as Brazil, Canada, been suggested as a prophylactic treatment for high risk groups in the
United States of America, China, South Korea, Japan, Australia and the current COVID-19 pandemic [232].
European Community already possess regulation for propolis [50]; Some investment is necessary to help qualify and register natural
consequently, propolis can be easily found by consumers at a low cost medicines, which may be provided by companies or by government
and potentially can be useful for preventive and/or curative purposes in programs that recognize the need for this type of investment, or both. In
the early stages of disease. Brazil, the Sao Paulo state research agency (FAPESP), has a program
called PIPE (http://www.fapesp.br/pipe/) that helps small companies
14. Why consider using nutraceuticals or other natural finance this type of research for products that they recognize would not
alternatives instead of relying on modern pharmaceuticals? normally be developed without this type of support, including natural
pest control alternatives for agriculture and “natural medicine” formu
Propolis is extensively used in foods and beverages because of its lations. Various research projects on propolis products have been
benefits for human health. It contains hundreds of natural compounds, financed by this FAPESP PIPE program including wound healing and
including aldehydes, coumarins, polyphenols, steroids and inorganic antifungal products [54,205,214–216], and the development of a stan
compounds, with a broad spectrum of biological and pharmacological dardized propolis formulation [54]; tests of this product were made for
properties, including antimicrobial, antioxidant, anti-inflammatory, safety and effectiveness in patients with chronic kidney disease and
immunomodulatory, antitumor, anticancer, antiulcer, hep diabetes [51]; both diseases are the subjects of projects supported by
atoprotective, cardioprotective, and neuroprotective actions [226]. The FINEP (Brazilian Study and Projects Financing Agency).
health industry has always used natural products, including propolis, as While modern medicines normally have only one or just a few active
an alternative source of drugs [62]. The complex mix of propolis com components, natural products can have many. Propolis, for example, has
ponents can provide greater health benefits than would be apparent by hundreds of components [226], many of which have properties that
analyzing the individual effects of components, apparently due to syn have the potential to help treat various types of disease or have various
ergistic effects [97]. modes of action against a specific disease and its consequences
Modern medicine relies on powerful drugs that have specific and [233–235]. Another consideration is that a strong specific effect, such as
strong impacts on disease organisms and on the body. This strategy and that of an anticoagulant used in an effort to prevent the micro
adequate sanitary measures have proven to be highly effective, resulting thromboses that have become a serious consequence of advanced
in an almost constant increase in human lifespan, which has more than COVID19 [236], requires specific dosing in order to avoid excess
doubled since 1900 to over 70 years [227]. However, the system in place bleeding and other dangerous side effects [237], and such drugs are not
for approving pharmaceuticals also has some disadvantages, including a safe option for patients that have some types of blood disease, or
the long lead time and considerable funding needed to discover new various heart and vessel disorders. A natural anticoagulant could give
options, test them for safety and effectiveness, and after 5-10 years, some protection and at a level sufficient to reduce the risk of thrombosis
obtain approval for their use. Due to the high costs involved and the without strong side effects. Propolis has demonstrated anticoagulant
possibility that this extended process will not result in a product that will properties [147].
compensate the investment required, potentially useful materials may
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