In Silico Identification of Propolis Compounds Potential as COVID-19 Drug Candidates Against SARS-CoV-2 Spike Protein

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a global health issue resulting in mortality and morbidity across the world. There is an urgent need to find treatments to inhibit virus infections and their consequences. Propolis compounds are predicted to have interactions with the SARS-CoV-2 protein since it has various phytochemicals that have been used in medicine. Here, we conducted in silico study to analyze the interaction between propolis compounds and SARS-CoV-2 spike protein by performing molecular docking. The target protein of this research is the crystal structure of the SARS-CoV-2 spike receptor-binding domain (RBD) bound with ACE2 (PDB ID: 6M0J). The ligand of this study is the bioactive compounds from Propolis of Tetragonula sapiens. The docking analysis revealed that Broussoflavonol F and Glyasperin A were the most promising propolis compounds that potentially block the binding of the SARS-CoV-2 spike protein to the host ACE2 receptor, with the binding affinity of -7.6 kcal/mol and -7.3 kcal/mol and the geometric score of 4582 and 4382, respectively. Based on this finding, those compounds are the potential to be developed as COVID-19 drug candidates. © (2023). All Rights Reserved.

Natural Ingredients to Improve Immunity.

The immune system protects the body from infectious agents such as bacteria, viruses, or fungi. Once encountered with pathogens or antigens, the innate and adaptive arms of the immune system trigger a strong immune response to eliminate them from the system and protect the body. Thus, well-balanced immunity is pivotal for maintaining human health, as an insufficient level of immune defense leads to infections and tumors. In contrast, the excessive functioning of the immune system causes the development of autoimmune diseases and allergies. Strong immunity requires adequate nutrition, dietary interventions, and sufficient intake of certain vitamins (vitamin C, vitamin D, and folic acid) and minerals (magnesium, zinc, and selenium). Therefore, nutritional and micronutrient deficiencies lead to compromised immunity. Several natural ingredients have shown potent immunomodulatory properties. The immune-enhancing properties of many plants and fungi are due to containing bioactive phytoconstituents such as polyphenols, terpenoids, ß-glucans, vitamins, etc. Probiotics and prebiotics can be used as innovative tools to reduce intestinal inflammation and downregulate hypersensitivity reactions. Plant sources of melatonin, a multifunctional molecule with proven anti-inflammatory and immunomodulatory properties, have been discovered relatively recently. The bioactive compounds augment the immune response by directly increasing the cytotoxic activity of natural killer cells, macrophages, and neutrophils. Many phytoconstituents prevent cell damage due to their powerful antimicrobial, antioxidant, and anti-inflammatory properties. The present review attempts to understand the molecular mechanisms underlying the immune-enhancing properties of some bioactive compounds from plants, fungi, animals, microorganisms, and other natural sources.

Consumption of bee products during the COVID-19 pandemic in Piaui

The aim was to investigate the use of bee products in Piaui state during the COVID-19 pandemic. To that end, data were collected remotely via an online form sent on WhatsApp and Instagram. Sampling was stratified considering the four mesoregions of Piaui and the sex of the participants using the Survey Monkey calculator. After stratification, the study contained 392 participants. A total of 85.46% of the interviewees reported regularly consuming bee products, primarily (24.78%) due to their nutritional potential. During the pandemic, 79.34% used bee products, honey being the most consumed (59.16%), followed by propolis honey (26.04%) and propolis alone (4.82%). With respect to COVID-19-related use, 23.47% and 3.21% of the subjects related consumption for disease prevention and treatment, respectively. In general, there was a 37.24% increase in the consumption of bee products during the pandemic, but most of the participants (52.05%) did not know the extent of the increase.

Exploring the potential therapeutic properties of bee products against COVID-19 (SARS CoV-2)

The new corona virus illness (COVID-19) swept around the world, quickly creating a serious international disaster. For the treatment and prevention of COVID-19, apitherapy appears to be a viable source of pharmacological and nutraceutical medicines. Honey, pollen, propolis, royal jelly, beeswax, and bee venom, for example, have been demonstrated to have significant antiviral action against infections that cause severe respiratory syndromes, including those produced by human corona viruses. Furthermore, many of these natural products are involved in the induction of antibody production, maturation of immune cells, and stimulation of innate and adaptive immunological responses and many of them are involved in the induction of antibody production, maturation of immune cells, and stimulation of innate and adaptive immunological responses.

Propolis and Their Active Constituents for Chronic Diseases.

Propolis is a mass of chemically diverse phytoconstituents with gummy textures that are naturally produced by honeybees upon collection of plant resins for utilization in various life processes in beehives. Since ancient times, propolis has been a unique traditional remedy globally utilized for several purposes, and it has secured value in pharmaceutical and nutraceutical areas in recent years. The chemical composition of propolis comprises diverse constituents and deviations in the precise composition of the honeybee species, plant source used for propolis production by bees, climate conditions and harvesting season. Over 300 molecular structures have been discovered from propolis, and important classes include phenolic acids, flavonoids, terpenoids, benzofurans, benzopyrene and chalcones. Propolis has also been reported to have diverse pharmacological activities, such as antidiabetic, anti-inflammatory, antioxidant, anticancer, immunomodulatory, antibacterial, antiviral, antifungal, and anticaries. As chronic diseases have risen as a global health threat, abundant research has been conducted to track propolis and its constituents as alternative therapies for chronic diseases. Several clinical trials have also revealed the potency of propolis and its constituents for preventing and curing some chronic diseases. This review explores the beneficial effect of propolis and its active constituents with credible mechanisms and computational studies on chronic diseases.

Antiviral Activity of Bee Products.

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 various 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.

Role and the importance of green approach in biosynthesis of nanopropolis and effectiveness of propolis in the treatment of COVID-19 pandemic

The most fascinating product of honeybee is propolis. It has an immense role in dentistry, dermatology, and otorhinolaryngology. The increased popularity of propolis as an important remedy is due to its constituents, which have anti-inflammatory, immunomodulatory, antihepatotoxic, anti-cancerous, antifungal, antioxidant, antidiabetic, and antiviral activities. The diverse biological and pharmacological activities of propolis have piqued the interest of many scientists. Many techniques like gas chromatography-mass spectrometry, chromatography, and spectroscopy are being used to identify different propolis constituents. Flavonoids, phenolic acids, and their esters are the most pharmacologically active molecules of propolis and are known to disrupt the replication machinery of the virus corroborating the anti-coronavirus activity of propolis. The main aim of this article is to provide an insight of the increasing theragnostic uses of propolis and its nanoparticles, including their chemical analysis, diverse biological activities, and the necessity for chemical standardization. In this review, we have focused at the promising effects of propolis, its optimization, and its liposomal formulation as a therapeutic intervention for COVID-19 and its accompanying comorbidities. © 2023 the author(s), published by De Gruyter.

The Effects of Propolis on Viral Respiratory Diseases.

Propolis remains an interesting source of natural chemical compounds that show, among others, antibacterial, antifungal, antiviral, antioxidative and anti-inflammatory activities. Due to the growing incidence of respiratory tract infections caused by various pathogenic viruses, complementary methods of prevention and therapy supporting pharmacotherapy are constantly being sought out. The properties of propolis may be important in the prevention and treatment of respiratory tract diseases caused by viruses such as severe acute respiratory syndrome coronavirus 2, influenza viruses, the parainfluenza virus and rhinoviruses. One of the main challenges in recent years has been severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing COVID-19. Recently, an increasing number of studies are focusing on the activity of various propolis preparations against SARS-CoV-2 as an adjuvant treatment for this infection. Propolis has shown a few key mechanisms of anti-SARS-CoV-2 action such as: the inhibition of the interaction of the S1 spike protein and ACE-2 protein; decreasing the replication of viruses by diminishing the synthesis of RNA transcripts in cells; decreasing the particles of coronaviruses. The anti-viral effect is observed not only with extracts but also with the single biologically active compounds found in propolis (e.g., apigenin, caffeic acid, chrysin, kaempferol, quercetin). Moreover, propolis is effective in the treatment of hyperglycemia, which increases the risk of SARS-CoV-2 infections. The aim of the literature review was to summarize recent studies from the PubMed database evaluating the antiviral activity of propolis extracts in terms of prevention and the therapy of respiratory tract diseases (in vitro, in vivo, clinical trials). Based upon this review, it was found that in recent years studies have focused mainly on the assessment of the effectiveness of propolis and its chemical components against COVID-19. Propolis exerts wide-spectrum antimicrobial activities; thus, propolis extracts can be an effective option in the prevention and treatment of co-infections associated with diseases of the respiratory tract.

In vitro Evaluation of Antiviral Efficacy of a Standardized Hydroalcoholic Extract of Poplar Type Propolis Against SARS-CoV-2.

Except for specific vaccines and monoclonal antibodies, effective prophylactic or post-exposure therapeutic treatments are currently limited for COVID-19. Propolis, a honeybee's product, has been suggested as a potential candidate for treatment of COVID-19 for its immunomodulatory properties and for its powerful activity against various types of viruses, including common coronaviruses. However, direct evidence regarding the antiviral activities of this product still remains poorly documented. VERO E6 and CALU3 cell lines were infected with SARS-CoV-2 and cultured in the presence of 12.5 or 25 µg/ml of a standardized Hydroalcoholic Extract acronym (sHEP) of Eurasian poplar type propolis and analyzed for viral RNA transcription, for cell damage by optical and electron microscopy, and for virus infectivity by viral titration at 2, 24, 48, and 72 h post-infection. The three main components of sHEP, caffeic acid phenethyl ester, galangin, and pinocembrin, were tested for the antiviral power, either alone or in combination. On both cell lines, sHEP showed significant effects mainly on CALU3 up to 48 h, i.e., some protection from cytopathic effects and consistent reduction of infected cell number, fewer viral particles inside cellular vesicles, reduction of viral titration in supernatants, dramatic drop of N gene negative sense RNA synthesis, and lower concentration of E gene RNA in cell extracts. Interestingly, pre-treatment of cells with sHEP before virus inoculation induced these same effects described previously and was not able to block virus entry. When used in combination, the three main constituents of sHEP showed antiviral activity at the same levels of sHEP. sHEP has a remarkable ability to hinder the replication of SARS-CoV-2, to limit new cycles of infection, and to protect host cells against the cytopathic effect, albeit with rather variable results. However, sHEP do not block the virus entry into the cells. The antiviral activity observed with the three main components of sHEP used in combination highlights that the mechanism underlying the antiviral activity of sHEP is probably the result of a synergistic effect. These data add further emphasis on the possible therapeutic role of this special honeybee's product as an adjuvant to official treatments of COVID-19 patients for its direct antiviral activity.

Phytochemicals in the Prevention and Treatment of SARS-CoV-2-Clinical Evidence.

The first case of SARS-CoV-2 infection was reported in December 2019. Due to the rapid spread of the disease and the lack of adequate therapy, the use of plants that have a long history in the treatment of viral infections has often been considered. The aim of this paper is to provide a brief review of the literature on the use of phytochemicals during the new pandemic. An extensive search of published works was performed through platforms Google Scholar, PubMed, Science Direct, Web of Science and Clinicaltrials.gov. Numerous preclinical studies on the use of phytochemicals (quercetin, curcumin, baicalin, kaempferol, resveratrol, glycyrrhizin, lycorine, colchicine) against SARS-CoV-2 have shown that these components can be effective in the prevention and treatment of this infection. Clinical research has proven that the use of black cumin and green propolis as well as quercetin has positive effects. As for other phytochemicals, in addition to preclinical testing which has already been carried out, it would be necessary to conduct clinical tests in order to assert their effectiveness. For those phytochemicals whose clinical efficacy has been proven, it would be necessary to conduct research on a larger number of patients, so that the conclusions are more representative.

Propolis: Its Role and Efficacy in Human Health and Diseases.

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 flavonoids, phenolic compounds, polyphenols, terpenes, terpenoids, coumarins, steroids, amino acids, and aromatic acids. The biologically active constituents of propolis, which include countless organic compounds such as artepillin C, caffeic acid, caffeic acid phenethyl ester, apigenin, chrysin, galangin, kaempferol, luteolin, genistein, naringin, pinocembrin, coumaric acid, and quercetin, have a broad spectrum of biological and therapeutic properties such as antidiabetic, anti-inflammatory, antioxidant, anticancer, rheumatoid arthritis, chronic obstruct pulmonary disorders, cardiovascular diseases, respiratory tract-related diseases, gastrointestinal disorders, as well as neuroprotective, immunomodulatory, and immuno-inflammatory agents. Therefore, this review aims to provide a 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.

A review: The phytochemistry, pharmacology, and pharmacokinetics of Curcumae Longae Rhizoma (Turmeric)

Curcumae Longae Rhizoma (CLR) is the rhizome of Curcuma longa L. Pharmacological studies show that CLR can be used to treat cervical cancer, lung cancer, lupus nephritis, and other conditions. In this paper, we review botany, traditional application, phytochemistry, pharmacological activity, and pharmacokinetics of CLR. The literature from 1981 to date was entirely collected from online databases, such as Web of Science, Google Scholar, China Academic Journals full-text database (CNKI), Wiley, Springer, PubMed, and ScienceDirect. The data were also obtained from ancient books, theses and dissertations, and Flora Reipublicae Popularis Sinicae. There are a total of 275 compounds that have been isolated from CLR, including phenolic compounds, volatile oils, and others. The therapeutic effect of turmeric has been expanded from breaking blood and activating qi in the traditional sense to antitumor, anti-inflammatory, antioxidation, neuroprotection, antibacterial, hypolipidemic effects, and other benefits. However, the active ingredients and mechanisms of action related to relieving disease remain ill defined, which requires more in-depth research and verification at a clinical level.

Development of propolis and essential oils containing oral/throat spray formulation against SARS-CoV-2 infection.

A broad range of evidence has confirmed that natural products and essential oils might have the potential to suppress COVID-19 infection. Therefore, this study aimed to develop an oral/throat spray formulation for prophylactic use in the oral cavity or help treatment modalities. Based on a reference survey, several essential oils, a cold-pressed oil, and propolis were selected, and cytotoxicity and antiviral activity of each component and the developed spray formulation were examined against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using Vero E6 cells. Anti-inflammatory, antimicrobial, and analgesic activities as well as mutagenicity and anti-mutagenicity of the formulation were analysed. Forty-three phenolics were identified in both propolis extract and oral/throat spray. The spray with 1:640-fold dilution provided the highest efficacy and the cytopathic effect was delayed for 54 h at this dilution, and the antiviral activity rate was 85.3%. A combination of natural products with essential oils at the right concentrations can be used as a supplement for the prevention of SARS-CoV-2 infection.

Green Synthesize and Characterization of Copper Nanoparticles Using Iranian Propolis Extracts

The propolis produced by bees is used by them to protect their hives. The cavity inside the hive’s walls is filled in during cold days to reduce entry points and mummify any intruders to ensure their survival. A current focus in nanotechnology and nanoscience is the green biosynthesis of nanoparticles (NPs) using biomaterials. Research on green methods for making metal oxide NPs is gaining momentum to safeguard the environment from the potential dangers associated with toxic chemicals. This study aimed to synthesize copper NPs (CuNPs) via propolis extraction, a novel application of nanoscience. The study was conducted under a range of pH, time conditions, and concentration ratios, and its properties were characterized by UV-Vis absorption spectra, XRD, and FTIR. An FTIR analysis revealed that compounds found in propolis extract could have an effect on the surface modification of the synthesized NPs. The propolis (Khalkhal) extract spectrum exhibited a sharp peak at 3422 cm−1, caused by free hydroxyl groups and their intra/intermolecular hydrogen bonds. There were sharp peaks at 2925, 1637, and 1515 to 1076 cm−1 associated with the C = O and C = C aromatic stretching frequencies. According to UV-Vis spectrophotometry investigation, CuO NPs exhibit a characteristic peak at 385 nm, showing significant surface plasmon resonance (SPR) with propolis (Khalkhal) extract. Furthermore, specific wavelengths of CuO NPs demonstrate peaks at 243, 292, and 350 nm for propolis (Gilan) extract. The green synthesis of CuNPs from Gilan and Khalkhal propolis can be an appropriate candidate for clinical applications such as drug delivery systems, drug formulation, and biomedical applications.

In vitro antiviral effect of Mexican and Brazilian propolis and phenolic compounds against human coronavirus 229E.

Propolis is a resinous substance collected by bees (Apis mellifera). It is used for its biological properties. This natural product is available as a safe therapeutic option. Herein, we report the antiviral effects of brown propolis extract from Mexico and green and red propolis extracts from Brazil, as well as their phenolic compounds (quercetin, caffeic acid, and rutin) in preventing infection of MRC-5 cells by HCoV-229E. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. All samples studied showed antiviral activity. Green and brown propolis extracts, and quercetin exhibited the best EC50 values with values of 19.080, 11.240, and 77.208 µg/mL against HCoV-229E, respectively, and with TC50 of 62.19, 29.192, and 298 µg/mL on MRC-5 cells, respectively. These results are the first in vitro study of the effects of propolis on HCoV-229E and provide the basis for the development of natural formulations against other coronavirus strains.

PRELIMINARY STUDY FOR COVID-19 DRUG DISCOVERY OF 30 PHYTOCHEMICAL COMPOUNDS FROM TETRAGONULA SP. PROPOLIS AS PAK1 INHIBITOR THROUGH MOLECULAR DOCKING

Objective: This study aims to evaluate 30 phytochemical compounds from Tetragonula sp. propolis as a PAK1 inhibitor using molecular docking. Methods: Thirty propolis compounds were initially confirmed before docking to comply with Lipinski rules. This simulation was performed against PAK1 using AutodockVina, while interaction profile visualization was conducted between the ligand and receptor through Ligplot+and PyMol. Results: Based on the docking score, inhibition constants, and interaction profile analyses, glyurallin B, glyasperin A, and broussoflavonol F were found to be the most potent compounds used as PAK1 inhibitors. According to several literature studies, the propolis compounds were synergistic, leading to adequate collective utilization. Conclusion: These results implicated the potentials of Tetragonula sp. propolis as a therapeutic agent against COVID-19;however, further studies are still needed.

Attitudes and approaches towards COVID-19 management among the public and pharmacists in Northern Cyprus

Purpose: To study the attitudes and approaches towards COVID-19 management among the public and pharmacists in Northern Cyprus. Method: Questionnaire were administered face-to-face and online to volunteer pharmacists and other members of the public, after receiving approval from the Near East University Ethics Boards. Responses to the questionnaire were evaluated statistically.

A review of natural foods consumed during the COVID-19 pandemic life

Coronavirus 2019 (COVID-19) is an infectious disease that has brought life to a standstill around the world. Until a vaccine was found to combat COVID-19, the world conducted research and made recommendations for nutritional natural foods. Considering the risks incurred by contracting the disease, even though the production of various vaccines and vaccination of healthy people has started in some countries, individuals need useful foods to be ready for the COVID-19 pandemic. Recently, nutrient contents such as antioxidant compounds, vitamins, minerals, and probiotics that contribute to the immune system have been investigated. This paper attempts to determine the role of these dietary supplements in reducing the risk of COVID-19 and/or changing the course of the disease in COVID-19 patients and their effects on mortality. Supplements used and recommended for the COVID-19 pandemic life were investigated. In conclusion, more research is needed to determine the effectiveness of nutrients, vitamins, minerals, probiotics, prebiotics, and antioxidants used during the COVID-19 pandemic to inhibit the effect of SARS-CoV-2. In order to overcome the new global crisis, nutritional cures and treatments should be upgraded. However, additional research on the subject is needed.

The antiviral and immunomodulatory activities of propolis: An update and future perspectives for respiratory diseases.

Propolis is a complex natural product that possesses antioxidant, anti-inflammatory, immunomodulatory, antibacterial, and antiviral properties mainly attributed to the high content in flavonoids, phenolic acids, and their derivatives. The chemical composition of propolis is multifarious, as it depends on the botanical sources from which honeybees collect resins and exudates. Nevertheless, despite this variability propolis may have a general pharmacological value, and this review systematically compiles, for the first time, the existing preclinical and clinical evidence of propolis activities as an antiviral and immunomodulatory agent, focusing on the possible application in respiratory diseases. In vitro and in vivo assays have demonstrated propolis broad-spectrum effects on viral infectivity and replication, as well as the modulatory actions on cytokine production and immune cell activation as part of both innate and adaptive immune responses. Clinical trials confirmed propolis undeniable potential as an effective therapeutic agent; however, the lack of rigorous randomized clinical trials in the context of respiratory diseases is tangible. Since propolis is available as a dietary supplement, possible use for the prevention of respiratory diseases and their deleterious inflammatory drawbacks on the respiratory tract in humans is considered and discussed. This review opens up new perspectives on the clinical investigation of neglected propolis biological properties which, now more than ever, are particularly relevant with respect to the recent outbreaks of pandemic respiratory infections.

Molecular Docking and Interaction Analysis of Propolis Compounds Against SARS-CoV-2 Receptor

Herbal medicine is a conventional medicinal option for many people, particularly in developing countries, to cure diseases, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Propolis is one of the popular herbal medicine which has various health benefits, particularly antiviral activity. In this molecular docking study, our investigation examined 25 kinds of Propolis to bind SARS-CoV-2 protein with the main targets of ACE-2 and MPro receptors. Propolis ligands were downloaded from PubChem, ACE-2, and MPro receptors from Protein Data Bank. Both ligands and targets were optimized by PyMOL. The pharmacokinetics and toxicity analysis was conducted using OSIRIS software. Molecular docking was done using PyRx 0.9, and its binding interaction was visualized by Discovery Studio. There were two compounds with the strongest interactions with ACE-2 and MPro receptors: Kaemferol and Abietic acid. Pharmacokinetic analysis revealed that these drugs have good phar-macokinetic properties. However, the findings of toxicity tests indicated that Kaempferol has the potential to be mutagenic. Kaempferol and Abietic acid compounds bind to Mpro and ACE-2 receptors and could be used to treat SARS-CoV 2 infection. However, further study on the efficacy and toxicity of this compound is required before it may be administered to humans. © 2022, Brawijaya University. All rights reserved.