The Importance of Propolis in Combating COVID-19

Abstract

The Coronavirus Disease 2019 (COVID-19) pandemic has been going on since November 2019 in the World with different variants of SARS-CoV-2. Effective vaccine and drug investigations for COVID-19 are still ongoing. For decreasing the mortality rate of COVID-19 keeping social distance, using a mask, washing hands, and improving immune systems are important. Propolis is a natural bee product that contains various bioactive substrates such as polyphenolic acids, flavonoids, vitamins, minerals. Propolis via antiviral, anti-inflammatory, antioxidant, and antithrombotic activities could be used as prophylactic or adjuvant COVID-19 treatment.

Full text

Journal of Apitherapy and Nature/Apiterapi ve Doğa Dergisi, 4(1), 22-40, 2021
Review Article/Derleme Makalesi
Apiterapi ve Doğa Dergisi
Journal of Apitherapy and Nature
www.dergipark.gov.tr/jan
22
The Importance of Propolis in Combating COVID-19
COVID-19 ile Mücadelede Propolisin Önemi
Meltem UÇAR1*
1Medical Laboratory Technique, Vocational School of Health Services, European University of Lefke, Lefke,
Northern Cyprus, TR-10 Mersin, Turkey
*mucar@eul.edu.tr, ORCID: 0000-0001-5554-2622
Received/Geliş Tarihi: 03/05/2021
Accepted/ Kabul Tarihi: 24/06/2021 doi: 10.35206/jan.932050
*Corresponding author / Yazışılan yazar e-ISSN: 2667-4734
Abstract
Özet
The Coronavirus Disease 2019 (COVID-19)
pandemic has been going on since November
2019 in the World with different variants of
SARS-CoV-2. Effective vaccine and drug
investigations for COVID-19 are still ongoing.
For decreasing the mortality rate of COVID-
19 keeping social distance, using a mask,
washing hands, and improving immune
systems are important. Propolis is a natural
bee product that contains various bioactive
substrates such as polyphenolic acids,
flavonoids, vitamins, minerals. Propolis via
antiviral, anti-inflammatory, antioxidant, and
antithrombotic activities could be used as
prophylactic or adjuvant COVID-19
treatment.
Keywords: COVID-19, SARS-CoV-2,
Propolis
Koronavirüs Hastalığı 2019 (COVID-19)
salgını Dünya’da Kasım 2019’dan beri SARS-
CoV-2’nin farklı varyantlarıyla devam
etmektedir. COVID-19 için etkili aşı ve ilaç
araştırmaları devam etmektedir. COVID-
19’un ölüm oranını azaltmak için sosyal
mesafeyi korumak, maske kullanmak, elleri
yıkamak ve bağışıklık sistemlerini geliştirmek
önemlidir. Propolis, polifenolik asitler,
flavonoidler, vitaminler, mineraller gibi çeşitli
biyoaktif substratları yapısında içeren doğal
bir arı ürünüdür. Antiviral, antiinflamatuar,
antioksidan ve antitrombotik aktiviteleri
aracılığıyla propolis, profilaktik veya COVID-
19 tedavisine yardımcı olarak kullanılabilir.
Anahtar kelimeler: COVID-19, SARS-
CoV-2, Propolis
Abbreviations: COVID-19, Coronavirus disease 2019, WHO, World Health Organization, SARS-CoV, Severe
Acute Respiratory Syndrome Coronavirus-2, CoV, Coronaviruses, ACE-2, Angiotensin-Converting Enzyme 2,
TMPRSS2, Transmembrane Serine Protease 2, PAK 1, RAC/CDC42-activated kinase 1, IL, Interleukin, TNF-
α, Tumor necrosis factor-alpha, IFNγ, Interferon-gamma, G-CSF, Granulocyte colony-stimulating factor RdRp,
RNA-dependent RNA polymerase, PL-pro, Papain like protease, M-pro, Coronavirus main proteinase, CAPE,
Caffeic acid phenethyl ester, HIV, Human Immunodeficiency Virus, NF-κB, Nuclear factor kappa-light-chain-
enhancer, 3CL-pro, 3C-like proteinase, COX, Cyclooxygenase, iNOS, inducible nitric oxide synthase, NO,
Nitric oxide, PAI-1, Plasminogen activator inhibitor-1, BGP, Brazillian Green Propolis, EPP-AF®, The
Standardized Propolis Extract

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1. INTRODUCTION
As of April 26th, 2021, the world is still laboring to overcome coronavirus disease 2019
(COVID-19) in 223 countries, over 146 841 882 cases, and 3 104 743 deaths have been reported
by World Health Organization (WHO) (WHO, 2021a). COVID-19 is caused by Severe Acute
Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which was firstly identified in Wuhan,
China, in December 2019. COVID-19 may have various symptoms, such as fever, headache,
exhaustion, sputum, hypogeusia, painful throat, dyspnea, cough, diarrhea, anorexia, dizziness,
rhinorrhea, nasal congestion, hyposmia, myalgia (Kim et al., 2020; Singhal, 2020; Vipul et al.,
2020). Most infected people will develop mild to moderate illness and recover without
hospitalization. While most common symptoms are fever, dry cough, and tiredness, serious
symptoms are difficulty breathing or shortness of breath, chest pain or pressure, loss of speech
or movement. Otherwise, some patients haven’t any symptoms too during the illness. When
someone is contaminated or infected with the SARS-CoV-2 it can take 5-6 days or take up to
14 days for getting symptoms (WHO, 2021b). Polymerase Chain Reaction (PCR), Real Time-
Polymerase Chain Reaction (RT-PCR), Complete Blood Count and other laboratory tests, X-
ray, and CT scans are used to diagnose COVID-19. CT imaging is more sensitive and specific
for diagnosing COVID-19. WHO is suggested using all symptoms, RT-PCR and other
laboratory tests, and CT imaging for diagnosing infection and emphasis that only PCR test is
not enough for diagnosis COVID-19 (Feng et al., 2020; Singhal, 2020; Zitek, 2020). Infection
is transmitted human to human among asymptomatic and symptomatic patients by coughing,
sneezing, or touching contaminated surfaces (Singhal, 2020). People who are 65 or >65 years
old or who have a chronic disease such as diabetes mellitus, chronic liver disease, chronic lung
disease, chronic renal failure, chronic cardiovascular disease, hematological malignancy, and
receiving chemotherapy or immunosuppressive agents are in the high-risk groups for COVID-
19 (Kim et al., 2020). Rapid detection, treatment, and prevention of COVID-19 are very
important for saving lives in the world urgently. Social distancing, lockdown of cities, hygienic
products have been used to control the COVID-19 Pandemic (Lima et al., 2020). Scientists are
still developing more effective vaccines and drugs for COVID-19 (Al Naggar et al., 2021).
Medical plants, some compounds that are isolated from plants, and bee products such as
propolis, honey which have antiviral activity are used by people for preventing COVID-19 and
supporting immune systems and treatment (Berretta et al., 2020; Ripari et al., 2021). This
review summarizes the information on COVID-19 disease, the anti-viral activity of propolis,
and its effects on SARS-CoV-2.

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2. SARS-COV-2
Coronaviruses (CoV) are a group of positive-sense single-stranded RNA viruses. SARS-CoV-
2 uses spike glycoproteins for attaching Angiotensin-Converting Enzyme 2 (ACE 2) and
Transmembrane Serine Protease 2 (TMPRSS2) of the host cell than resulting membrane fusing
(Dalan et al., 2021; Elmahallawy et al., 2021; Harisna et al., 2021). Figure 1 shows the structure
of SARS-CoV-2 (Elmahallawy et al., 2021). SARS-CoV-2 includes 4 structural proteins
(Spike, Envelope, Membrane, and Nucleocapsid proteins), Cysteine proteinase, RNA
polymerase, and nonstructural proteins (Elmahallawy et al., 2021; Sahlan et al., 2021).
ACE-2 is a receptor not only for Angiotensin II but also SARS-CoV-2 too. ACE-2 is
expressed in the ciliated airway epithelium of the lungs, enterocytes of the small intestine,
arterial and venous endothelial cells, arterial smooth muscle cells in the heart, kidneys, adrenal
glands, pancreas, skeletal muscle, and adipose tissues (Dalan et al., 2020). Because of the wide
expression of ACE-2, using inhibitors of TMPRSS2 is more useful for preventing enter of
SARS-CoV-2 into the host cell (Hoffmann et al., 2020).
Figure 1. Structure of SARS-CoV-2.
Due to the imbalance of ACE-2 pathways patients with hypertension, type II diabetes,
or cardiovascular disease belong to high-risk groups for respiratory failure and morality in
COVID-19. As there is not enough evidence that shows the harmful or beneficial effects of
using ACE-inhibitors or Angiotensin 2 Tip 1 receptor blockers for preventing COVID-19 in
Lipid Bilayer Membrane
Spike Glycoprotein
RNA
Envelope
Protein

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high-risk group patients, all patients should continue to take their medicine as before (Dalan et
al., 2020). Figure 2 shows host cell and SARS-CoV-2 (Coronavirus (SARS-CoV-2) Viral
Proteins, Sigma-Aldrich, 2021). Besides ACE-2 and TMPRSS2, RAC/CDC42-activated kinase
1 (PAK 1) is also a target for the scientist to prevent COVID-19. After SARS-CoV-2 enters the
host cell PAK 1 upregulation has occurred which causes lung inflammation, lung fibrosis, and
other mortality factors (Dalan et al. 2020). Activation of PAK 1 that also known as pathogenic
kinase is related to various diseases/disorders such as cancers, malaria, inflammation, and viral
infection including Human Immunodeficiency Virus (HIV), influenza, and COVID-19 (Maruta
& He, 2020). Increased PAK 1 in a host cell induces replication of SARS-CoV-2 and inhibits
immune response too (Dalan et al., 2020). The other problem in COVID-19 patients is cytokine
storm that occurred after increased production of proinflammatory cytokines such as
Interleukins (IL) (IL2, IL-6, IL7, IL-10), Tumor necrosis factor-alpha (TNFα), Interferon-
gamma (IFNγ), Granulocyte colony-stimulating factor (G-CSF). Cytokine storms may cause
multi-organ system failure that is a life-threatening disorder (Elmahallawy et al., 2021). The
other mechanism for fighting against SARS-CoV-2 is suppressing its replication by different
agents. RNA-dependent RNA polymerase (RdRp) that catalyzes the synthesis of coronavirus
RNA, is so important for coronaviral replication/transcription machinery complex. Also, Papain
like protease (PL-pro) and coronavirus main proteinase (M-pro) that has a role to replicate and
generate new RNA are therapeutic targets for developing pharmacy too (Huang et al., 2020).
Figure 2. Host cell and SARS-CoV-2
ACE2
TMPRSS2
Lipid Membrane
Host Cell
Spike Protein
Nucleocapsid
Protein
Membrane Protein
Envelope Protein

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Several drugs were investigated to treatment COVID-19 such as nevilnafir, as a RdRp
inhibitor remdesivir, ribavirin, favipiravir, as a protease and proteinase inhibitor lopinavir and
darunavir, as a PAK 1 blocker melatonin, ciclesonide, ivermection, ketorolac, chloroquine, and
hydrochloroquine and propolis (Harisna et al., 2021; Huang et al., 2020; Maruta & He, 2020).
Also, several reports suggest that chloroquine and hydrochloquine caused serious arrhythmia,
kidney injuries, liver problems, blood and lymph system disorders, and failure in patients with
COVID-19 (United States Food and Drug Administration, 2020).
Some SARS-CoV-2 mutations repressive vaccine developments, affect the affinity to
ACE-2 receptor and infectiousness. and immune response (Conti et al., 2021; Huang et al.,
2020; Volz et al., 2021; Zhang et al., 2020). Different mutants form of SARS-CoV-2 found in
the United Kingdom, Brazil, and Sound Africa and recently double mutant SARS-CoV-2 found
in India. Scientists need time to be sure this variant is more deadly or more transmissible
(https://www.bbc.com/news/world-asia-india-56507988). On the other hand, various
supplements, herbal and apitherapy products such as ginseng extracts, garlic extracts,
echinacea, curcumin extracts, propolis, honey, royal jelly, bee wax, bee venom, bee pollen,
quercetin, Vitamin C, Vitamin D, Vitamin E, zinc, selenium used to support treatment of
COVID-19 by antiviral, anti-inflammatory, antioxidant and immunomodulatory activities (Ali
& Kunugi, 2021; Al Naggar et al., 2021; Jin et al., 2020; Keflie et al., 2021).
3. PROPOLIS
Propolis is a bee product that occurred by molding resinous balsam of plants and trees with bee
wax and saliva. Propolis is also known as bee glue originates from Greek and occurred Pro- (in
meaning for or defense) and -polis (in meaning city) word parts that are a defense of city or
hive. Bees use propolis as a detoxification agent and fixing material for their hives to maintain
homeostasis, to promote a beneficial microbiome, and protect from insects and animals
(Burdock, 1998; Zulhendri et al., 2021). Propolis is also used by Egyptians, Greeks, Romans,
and Incas for wound healing, corpse embalming, and antipyretic. It was used in Europe in the
17th and 20th centuries as an antibacterial agent and during the Second World War due to the
antimicrobial and anti-inflammatory activity (Santos et al., 2019). Propolis compositions and
colors can change depending on the geographic area, climate. Generally, propolis colors are
dark brown, dark green, and dark yellow. Some propolis samples were shown in Figure 3
(Çolak, 2009).

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Propolis consists of 50% resins, 30% bee wax, 10% aromatic and essential oils, 5% bee
pollen, 5% multiple organic compounds, vitamins, and minerals (Ali & Kunugi, 2021). It
includes more than 300 different compounds such as flavonoids, phenolic acids, phenolic acid
esters, terpenoids, xanthones, fatty acids, volatile fatty acids, ketones, lactones, steroids,
pollens, various minerals, vitamins. Some phenolic compounds and flavonoids found in
propolis are shown in Table 1 (Çolak, 2009; Duca et al., 2019; Santos et al., 2019;).
Figure 3. Propolis samples
Propolis can solve with ethanol, methanol, diethyl ether, acetone, toluene,
trichloroethylene, oils, water, and others with different ratios and compositions (Burdock, 1998;
Ripari et al., 2021). Commercial many kinds of extracts with different concentrations may find
in markets and pharmacies in capsule, liquid, pastilles or supplement form alone or with the
other herbals, vitamins or minerals. As for its antibacterial and antimicrobial activities, it is used
for the production of toothpaste and mouthwash solutions. (Burdock, 1998; Santoset al., 2019;
Zulhendri et al., 2021). Propolis is also used by the food industry and cosmetic industry
especially its antibacterial, antioxidant, and antiaging properties, and recently it is famous and
important in veterinary medicine too (Santos et al. 2019).

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Table 1. Some flavonoids and phenolic compounds found in propolis
Propolis has various biological activities for humans such as antioxidant, anti-
inflammatory, antibacterial, antifungal, antiviral, antimutagenic, antitumoral, anticancer,
cytotoxic, anti-proliferative, anti-angiogenic, immunomodulatory (Braakhuis, 2019; Burdock,
1998; Zulhendri et al., 2021). Figure 4 summarise the use of propolis with its properties for
bees and humans (Zulhendri et al., 2021).
Figure 4. The use of propolis by bees and humans
Flavonoids
Phenolic Compounds
Apigenin
1,1-dimethylallylcaffeate
Chrysin
2,2-dimethyl-6-carboxyethenyl-2H-1-benzopyran
Formononetin
3-(4-hydroxy-3-(oxo-butenyl)-phenylacrylic acid
Hesperetin
3,5-diphenyl-4-hydroxycinnamic acid derivate
Kaempferol
p-Coumaric acid
Medicarpin
Artepillin C
Naringenin
Caffeic acid
Neovestiol
Caffeic acid phenethyl ester (CAPE)
Pinocembrin
Resveratrol
Quercetin
Epicatechin
Vestitol
Feruric acid
Galangin
Isoliquiritigenin
Luteolin
Mono/Dicaffeoylquinic acids

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4. USE OF PROPOLIS IN WAR WITH CORONAVIRUS
As mentioned before propolis and propolis-derived compounds such as CAPE, benzoic acid,
resveratrol, p-cumaric acid, quercetin, chrysin, pinocembrin, and galangin have antiviral, anti-
inflammatory, antioxidant, and antithrombotic activity. In previous studies, it was shown that
propolis and its extracts have antiviral activity against both DNA and RNA virus such as Herpes
Simplex Virus Type 1 and Type 2, Adenovirus Type 2, Vesicular Stomatitis Virus, Poliovirus
Type 2, Varicella zoster virus, HIV, Influenza. (Burdock, 1998; Governa et al., 2019; Haris et
al., 1997; Labska et al., 2018; Yildirim et al., 2016). It was reported that various propolis
fractions affected the replication of Vaccinia Virus, Newcastle Disease Virus, and Influenza
Viruses A and B (Burdock, 1998). Debiagi et al. (1990) reported that kaempferol and chrysine
were reduced the replication of several Herpes Viruses, Adenoviruses, and a Rotavirus
concentration-dependently and quercetin was reduced infectivity and intracellular replications
of viruses in high concentrations. Also, Erdemli et al. (2015) suggested that CAPE inhibits the
HIV-1 infection, nuclear factor kappa-light-chain-enhancer (NF-κB) production, and Hepatitis
C virus replication too. Singh et al. (2020) showed that hesperidin has a higher binding activity
to RdRp of SARS-CoV-2 than remdesivir, and many polyphenols such as myricetin,
epigallocatechin gallate, theaflavin, theaflavin-3’-O-gallate, theaflavin-3’-gallate, theaflavin
3,3’-digallate, quercetagetin, and myricetin strongly bind to the active site of RdRp and other
polyphenols such as quercetin, curcumin, kaempferol, epicatechin can bind to RdRp with lower
binding energy than remdesivir. It was concluded that some natural polyphenols can be used as
an inhibitor of RdRp of SARS-CoV-2.
On the other hand, Maruta & He (2020) suggested that caffeic acids, CAPE, Artepillin
C, nymphaeols inhibit PAK1 activity, act like PAK1 inhibitors, and could be useful for
inhibiting or preventing COVID-19-induced lung fibrosis and stimulating the immune system.
Also, 3C-like proteinase (3CLpro) is an important enzyme that has a role replication of the
virus. It was shown that 2’,4’-dihydroxychalcone and 2’,4’-dihyroxy-3’-methoxychalcone that
also found in propolis have potential repressing properties against 3CLpro. As amyrin
(Triterpenes), procyanidin and proanthocyanidin influence the activity of 2’-o-ribose
methyltransferase, propolis compounds have potential restrictive properties against
methyltransferase too (Elmahallawy et al., 2021). Ali & Kunugi (2021) reviewed that rutin,
nicotiflorin, luteolin, CAPE, and Artepillin C inhibit viral replication and inflammatory
reactions by affecting 3CLpro/Mpro, PLpro, RdRp, and B56 regulatory unit of phosphatase
2A. Sahlan et al. (2021) and Kumarb et al. (2020) showed that propolis components glyasperin

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A, broussoflavonol F, and CAPE have binding affinity to SARS-CoV-2 main protease and have
therapeutic value for COVID-19.
Also, Khayrani et al. (2021) detected that propolis components glyasperin A,
broussoflavonol F, sulabiroins A, isorhamnetin, and (25)-5,7-dihydroxy-4’-methoxy-8-
prenylflavanone have the potential to inhibit the binding of ACE-2 and SARS-CoV-2. As
phenolic compounds of propolis such as galangin, p-coumaric acid, quercetin, chrysin, and
kaempferol could block or reduce the adsorption and entrance of the virus into the host cells,
propolis consumption might be useful for protecting COVID-19 and supporting adaptive
immune response (Lima et al., 2020). In previous in vitro and in vivo studies, it was shown that
flavonoids could inhibit the activity of ACE. Recently Guler et al. (2021) used ten flavonoids
(Caffeic acid, CAPE, chrysin, galangin, myricetin, rutin, hesperetin, pinocembrin, luteolin, and
quercetin) for detecting their binding ability to ACE-2 receptors and it was shown that rutin has
the best inhibition potentials for ACE-2 receptors and then followed by myricetin, CAPE,
hesperetin, and pinocembrin. It was concluded that flavonoids in ethanolic propolis extracts
have a high potential for COVID-19 treatment by inhibition of ACE-2 receptors and preventing
entry of virus to host cells (Guler et al., 2021). Also, Refaat et al. (2021) and Vijayakumar et
al. (2020) established that rutin, luteolin, and CAPE inhibit ACE 2 receptors too. Kumara et al.
(2020), showed that CAPE inhibits the TMPRSS2 and block the entry of SARS-CoV-2 into the
cell. Refaat et al. (2020) and Jain et al. (2021) detected that naringin, rutin, and quercetin have
the binding activity to S protein and inhibit viral fusion in the host cell membrane. Harisna et
al. (2021) suggested that propolis components genistin, methylophopogonone A and 3’-
methoxydaidzin inhibit main protease and spike protein and these compounds could be used as
antiviral agents.
The other mechanism of antiviral activity of propolis may be related to its zinc content.
Propolis has variable amounts of zinc such as 21 mg/kg or 9326 mg/kg (Cvek et al., 2008; Tosic
et al., 2017). Zinc ions inhibit viral enzymes that are important for the replication of the virus
in the host cells (te Velthuis et al., 2010). Kaushik et al. (2017) reported that zinc salts block
hepatitis E virus replication by inhibiting of RdRp. Also, zinc has the potential to threaten
COVID-19 by antioxidant, anti-inflammatory, and immunomodulatory properties. Zinc can
suppress the expressing of various chemokines, acute phase proteins such as fibrinogen and C-
reactive protein, proinflammatory cytokines, and some factors that have a role in inflammatory
responses such as inhibition of NFκB and modulation of T cell functions that cause cytokine
storms in COVID-19 (Keflie et al., 2021).

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Another trace element in propolis is selenium that has a role in maintaining adaptive
immune systems, inhibiting proinflammatory cytokines, chemokines, and production of free
oxygen radicals. Experimentally it was shown that a selenium-deficient diet in mice is related
to developing lung injury in post-influenza virus infections (Keflie et al., 2021; Suhupharani et
al., 2019). Suhupharani et al. (2019) biosynthesized selenium nanoparticles from ethanolic
extracts of propolis for human health due to the antimicrobial and antioxidant activity of
selenium.
Also, it was established that Vitamin A, Vitamin B12, Vitamin C, Vitamin D, Folate,
Pyridoxine, Nicotinamide, and Retinoic acid have a protective role against COVID-19 by
antioxidant, antiviral, anti-inflammatory activities and affecting the immune response (Keflie
et al., 2021). It is also known that propolis has many kinds of vitamins and micronutritions and
it could support immune systems too (Burdock, 1998; Marcucci, 1995).
Additionally, the anti-inflammatory activity of propolis is related to its components such
as phenolic acids and their esters, flavonoids, steroids, terpenoids, and amino acids. The basic
mechanisms of anti-inflammatory activity of propolis are the inhibition of cyclooxygenase
(COX) and prostaglandin biosynthesis, antioxidant activity, inhibition of nitric oxide (NO)
synthesis, reducing the level of cytokines, and immunosuppressive activity (Braakhuis, 2019).
In many studies it was reported that CAPE, quercetin, naringenin, pinocembrin, Artepillin C,
terpenoids showed anti-inflammatory activity by inhibiting COX-2, suppressing the production
of prostaglandins and leukotrienes, reducing the expression of inflammatory mediators such as
IL-10, IL-1β, inducible nitric oxide synthase (iNOS) and inhibiting the production of TNF-α,
IL-1β, IL-6, NF-κB, NO (Braakhuis, 2019; Santos et al., 2019; Zulhendri et al., 2021).
Tromboembolism, thrombosis, and microthrombosis are common in COVID-19
patients and associated with high mortality rates of COVID-19. Generally, anticoagulants use
to reduce mortality. In a previous study antithrombotic effect of propolis was also established
by decreasing platelet aggregation, other thrombosis-related parameters and suppressing
lipopolysaccharide-induced increases in plasminogen activator inhibitor-1 (PAI-1) in mice
(Berreta et al., 2020). Quercetin might use for thrombotic disease treatment as a thrombin
inhibitor. Quercetin may utilize blood clotting dysregulation conduced by viral infection
(Berreta et al., 2020; Shi et al., 2012). In an in vivo study, it was detected that CAPE inhibits
collagen-induced platelet aggregation via downregulating Tromboksane B2, COX-1, and 5-
hydroxytryptamine and increasing NO and cyclic guanosine monophosphate activity. In
addition, it was shown that CAPE, galangin, pinostropin inhibit platelet aggregation and

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propolis components including CAPE have the potential to threaten thrombotic disease (Ohkura
et al., 2020).
Duarte Silveria et al. (2021) used nan-alcoholic preparation of Brazillian Green Propolis
(BGP) The Standardized Propolis Extract (EPP-AF®) at two concentrations (400 mg and 800
mg) for 82 hospitalized adult COVID-19 patients and evaluated the patient's length of hospital
stay, dependence on oxygen therapy, development of acute kidney injury, intensive care unit
admission and use of vasoactive drugs. 400 mg BGP EPP-AF® has 21.2 total flavonoids such
as quercetin and 54 mg of total phenolics, such as gallic acid. It was shown that BPG treatment
decreased the length of hospital stay (6 days for 400 mg BGP EPP-AF®, 7 days for 800 mg
BGP EPP-AF®, and 12 days for the control group (n=42)) and renal injury significantly, but
didn’t have any effect on the need for oxygen therapy and didn’t observe any side effect of
propolis. In a case report BGP (EPP-AF®) confirmed a COVID-19 patient who was 52 years
old in a dose of 45 drops/3 times/day for 2 weeks. Patients viral clearance occurred within 12
days of treatment (Fiorini et al., 2021) Kosari et al. (2021) used a syrup that contains 1.6 mg
Hyoscyamus niger L. extract and 450 mg propolis per 10 mL, in 25 COVID-19 patients aged
between 17-85 and 25 patients also classified as placebo group in the investigation. In this
study, 10 mL syrup was administered during the 6 days three times a day. It was shown that
syrup reduced the clinical symptoms of COVID-19 such as dry cough, shortness of breath, sore
throat, chest pain, headache, dizziness, fever, abdominal pain, and diarrhea but didn’t have any
effect on nausea and vomiting. The dose of propolis at 500 mg/day is approximately equal to
30 drops of propolis extract (11% w/v of dry matter). Berretta et al. (2020) claim that 30
drops/day or one capsule might be used for preventing purposes of propolis but Soroy et al.
(2014) suggested that 1200 mg/day water extract of propolis capsule (Propoelix™) could
decrease the level of TNF-α and length of hospitalized day and increase platelet count in 31
patients with dengue hemorrhagic fever that is caused by the mosquito-borne dengue viruses.
5. CONCLUSIONS
While production and developing SARS-CoV-2 vaccines and drugs are continued individually
people should protect themselves by having potent immunity as well as using masc, antiseptics,
keeping social distance, and washing hands against COVID-19. Natural products such as
propolis could be useful for improving immune response by immunomodulatory activity,
protecting binding, entry, and colonization of SARS-CoV-2 in the host cells of people by
antiviral activity, preventing cytokine storms and thrombosis, various tissue injuries such as

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lung, kidney by the antioxidant, anti-inflammatory and antithrombotic activity in COVID-19
patients. Also, it is important to increase the number of randomized and controlled clinical trials
to assess the benefits and therapeutic potential of propolis in COVID-19. But people who
haven’t any allergies to propolis might use propolis for protecting themselves against SARS-
CoV-2 and COVID-19.
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