farmaecFARMAKOEKONOMIKA. Modern Pharmacoeconomics and PharmacoepidemiologyФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология2070-49092070-4933IRBIS LLC10.17749/2070-4909/farmakoekonomika.2023.162farmaec-778Research ArticleREVIEW ARTICLESОБЗОРНЫЕ ПУБЛИКАЦИИSystematic computer analysis of the pharmacology of bioflavonoids in the context of increasing the body's antiviral defensesСистематический компьютерный анализ фармакологии биофлавоноидов в контексте повышения противовирусной защиты организмаhttps://orcid.org/0000-0002-7663-710XГромоваО. А.GromovaO. A.

Громова Ольга Алексеевна – д.м.н., профессор, научный руководитель ФИЦ «Информатика и управление» РАН

Scopus Author ID: 7003589812; ResearcherID: J-4946-2017

ул. Вавилова, д. 4, Москва 119333

Olga A. Gromova – Dr. Med. Sc., Professor, Research Supervisor

Scopus Author ID: 7003589812; ResearcherID: J-4946-2017

4 Vavilov Str., Moscow 2119333

unesco.gromova@gmail.comhttps://orcid.org/0000-0002-2659-7998ТоршинИ. Ю.TorshinI. Yu.

Торшин Иван Юрьевич – к.ф-м.н., к.х.н., старший научный сотрудник 

Scopus Author ID: 7003300274; ResearcherID: C-7683-2018

ул. Вавилова, д. 4, Москва 119333

Ivan Yu. Torshin – PhD (Phys. Math.), PhD (Chem.), Senior Researcher

Scopus Author ID: 7003300274; ResearcherID: C-7683-2018

4 Vavilov Str., Moscow 2119333

https://orcid.org/0000-0002-5070-5450ЧучалинА. Г.ChuchalinA. G.

Чучалин Александр Григорьевич – д.м.н., профессор, академик РАН, пульмонолог, заведующий кафедрой госпитальной терапии педиатрического факультета 

ул. Островитянова, д. 1, Москва 117997

Aleksandr G. Chuchalin – Dr. Med. Sc., Professor, Academician of RAS, Pulmonologist, Head of Chair of Hospital Therapy, Faculty of Pediatrics

1 Ostrovityanov Str., Moscow 117997

Федеральный исследовательский центр «Информатика и управление» Российской академии наукРоссияFederal Research Center “Informatics and Management”, Russian Academy of SciencesRussian FederationФедеральное государственное автономное образовательное учреждение высшего образования «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Министерства здравоохранения Российской ФедерацииРоссияPirogov Russian National Research Medical UniversityRussian Federation202328032023161105124Copyright © Gromova O.A., Torshin I.Y., Chuchalin A.G., 20232023Громова О.А., Торшин И.Ю., Чучалин А.Г.Gromova O.A., Torshin I.Y., Chuchalin A.G.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacoeconomics.ru/jour/article/view/778Background

Background. The rapidly developing resistance of viruses to synthetic antiviral drugs indicates the need to use substances with multitarget action (to avoid polypharmacy and to improve the safety of treatment).

Objective

Objective: systematic analysis of the scientific literature on the pharmacology of bioflavonoids with an emphasis on their antiviral action.

Material and methods

Material and methods. More than 150,000 references of primary sources were found in the PubMed/MEDLINE database of biomedical publications, including 3282 references on the antiviral effects of bioflavonoids. A systematic computerized analysis of this array of publications was carried out in order to identify the main directions in the pharmacology of bioflavonoids with an emphasis on their antiviral, antibacterial and immunomodulatory effects. The literature analysis was carried out using modern methods of topological and metric analysis of big data.

Results

Results. The molecular mechanisms of action of baicalin, hesperidin, rutin, quercetin, leukodelphinidin bioflavonoids and epigallocatechin-3-gallate, curcumin polyphenols, their anti-inflammatory, antioxidant, antiviral, bactericidal, angioprotective, regenerative effects, and their prospects in therapy, prevention and rehabilitation of patients with COVID-19 and other respiratory viral infections were described in detail.

Conclusion

Conclusion. Bioflavonoids and synergistic polyphenols exhibit not only multitarget antiviral effects by inhibiting the main protease, spike proteins, and other target proteins, but also pronounced anti-inflammatory, hepatoprotective, and immunomodulatory effects.

Актуальность

Актуальность. Быстро развивающаяся резистентность вирусов к синтетическим противовирусным препаратам указывает на необходимость использования веществ, характеризующихся мультитаргетным действием (во избежание полипрагмазии и для повышения безопасности лечения).

Цель

Цель: систематический анализ научной литературы по фармакологии биофлавоноидов c акцентом на их противовирусное действие.

Материал и методы

Материал и методы. В базе данных биомедицинских публикаций PubMed/MEDLINE найдено более 150 тыс. первоисточников, в т.ч. 3282 по противовирусным эффектам биофлавоноидов. Проведен систематический компьютерный анализ этого массива публикаций с целью выявления основных направлений фармакологии биофлавоноидов с акцентом на их противовирусные, антибактериальные и иммуномодулирующие эффекты.

Анализ литературы выполнен с использованием современных методов топологического и метрического анализа больших данных.

Результаты

Результаты. Детально описаны молекулярные механизмы действия биофлавоноидов байкалин, гесперидин, рутин, кверцитин, лейкодельфинидин и полифенолов эпигаллокатехин-3-галлат и куркумин, их противовоспалительные, антиоксидантные, противовирусные, бактерицидные, ангиопротекторные, регенеративные эффекты, а также их перспективы в терапии, профилактике и реабилитации пациентов с COVID-19 и другими респираторными вирусными инфекциями.

Заключение

Заключение. Биофлавоноиды и синергидные им полифенолы проявляют не только мультитаргетные противовирусные эффекты, ингибируя основную протеазу, спайк-белки и другие таргетные белки, но и выраженное противовоспалительное, гепатопротекторное и иммуномодулирующее действие.

иммунитетполифенолыбиофлавоноидыпротивовирусное действиеВалеониксинтеллектуальный анализ данныхimmunitypolyphenolsbioflavonoidsantiviral effectValeonixdata miningРабота выполнена при поддержке гранта Российского научного фонда (проект № 23-21-00154 «Разработка методов прогноза свойств фармакологических препаратов по их молекулярной структуре с помощью теории топологического анализа хемографов»), ФИЦ «Информатика и управление» РАН.This work was supported by the grant of the Russian Science Foundation (No. 23-21-00154 “Development of methods for predicting the properties of pharmacological preparations by their molecular structure using the theory of topological analysis of chemographs”), Federal Research Center “Informatics and Management”, RAS.ReferencesТоршин И.Ю., Громова О.А. Микронутриенты против коронавирусов. М.: ГЭОТАР-Медиа; 2020: 112 с.Torshin I.Yu., Gromova O.A. Micronutrients against coronaviruses. Moscow: GEOTAR-Media; 2020: 112 pp. (in Russ.).Торшин И.Ю., Громова О.А., Чучалин А.Г., Журавлев Ю.И. Хемореактомный скрининг воздействия фармакологических препаратов на SARS-CoV-2 и виром человека как информационная основа для принятия решений по фармакотерапии COVID-19. ФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология. 2021; 14 (2): 191–211. https://doi.org/10.17749/2070-4909/farmakoekonomika.2021.078.Torshin I.Yu., Gromova O.A., Chuchalin A.G., Zhuravlev Yu.I. Chemoreactome screening of the effects of pharmacological drugs on SARS-CoV-2 and human viromes as an information basis for making decisions on the pharmacotherapy of COVID-19. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2021; 14 (2): 191–211 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2021.078.Торшин И.Ю., Громова О.А., Стаховская Л.В. и др. Анализ 19,9 млн публикаций базы данных PubMed/MEDLINE методами искусственного интеллекта: подходы к обобщению накопленных данных и феномен “fake news”. ФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология. 2020; 13 (2): 146–63. https://doi.org/10.17749/2070-4909/farmakoekonomika.2020.021.Torshin I.Yu., Gromova O.A., Stakhovskaya L.V., et al. Analysis of 19.9 million publications of the PubMed/MEDLINE database using artificial intelligence methods: approaches to summarizing the accumulated data and the “fake news” phenomenon. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2020; 13 (2): 146–63 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2020.021.Sudre C.H., Murray B., Varsavsky T., et al. Attributes and predictors of long COVID. Nat Med. 2021; 27 (4): 626–31. https://doi.org/.1038/s41591-021-01292-y.Sudre C.H., Murray B., Varsavsky T., et al. Attributes and predictors of long COVID. Nat Med. 2021; 27 (4): 626–31. https://doi.org/.1038/s41591-021-01292-y.Bao M., Ma Y., Liang M., et al. Research progress on pharmacological effects and new dosage forms of baicalin. Vet Med Sci. 2022; 8 (6): 2773–84. https://doi.org/10.1002/vms3.960.Bao M., Ma Y., Liang M., et al. Research progress on pharmacological effects and new dosage forms of baicalin. Vet Med Sci. 2022; 8 (6): 2773–84. https://doi.org/10.1002/vms3.960.Yang J., Yang X., Li M. Baicalin, a natural compound, promotes regulatory T cell differentiation. BMC Complement Altern Med. 2012; 12: 64. https://doi.org/10.1186/1472-6882-12-64.Yang J., Yang X., Li M. Baicalin, a natural compound, promotes regulatory T cell differentiation. BMC Complement Altern Med. 2012; 12: 64. https://doi.org/10.1186/1472-6882-12-64.An H.J., Lee J.Y., Park W. Baicalin modulates inflammatory response of macrophages activated by LPS via calcium-CHOP pathway. Cells. 2022; 11 (19): 3076. https://doi.org/10.3390/cells11193076.An H.J., Lee J.Y., Park W. Baicalin modulates inflammatory response of macrophages activated by LPS via calcium-CHOP pathway. Cells. 2022; 11 (19): 3076. https://doi.org/10.3390/cells11193076.Kim S.J., Lee S.M. Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition. Toxicol Appl Pharmacol. 2012; 258 (1): 43–50. https://doi.org/10.1016/j.taap.2011.10.005.Kim S.J., Lee S.M. Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition. Toxicol Appl Pharmacol. 2012; 258 (1): 43–50. https://doi.org/10.1016/j.taap.2011.10.005.He C.X., Yu W.J., Yang M., et al. Baicalin inhibits LPS/IFN-γ-induced inflammation via TREM2/TLR4/NF-κB pathway in BV2 cells. Zhongguo Zhong Yao Za Zhi. 2022; 47 (6): 1603–10 (на кит. яз.). https://doi.org/10.19540/j.cnki.cjcmm.20211103.401.He C.X., Yu W.J., Yang M., et al. Baicalin inhibits LPS/IFN-γ-induced inflammation via TREM2/TLR4/NF-κB pathway in BV2 cells. Zhongguo Zhong Yao Za Zhi. 2022; 47 (6): 1603–10 (in Chinese). https://doi.org/10.19540/j.cnki.cjcmm.20211103.401.Yang S., Zhang J., Chen D., et al. Quercetin supplement to aspirin attenuates lipopolysaccharide-induced pre-eclampsia-like impairments in rats through the NLRP3 inflammasome. Drugs R D. 2022; 22 (4): 271–9. https://doi.org/10.1007/s40268-022-00402-6.Yang S., Zhang J., Chen D., et al. Quercetin supplement to aspirin attenuates lipopolysaccharide-induced pre-eclampsia-like impairments in rats through the NLRP3 inflammasome. Drugs R D. 2022; 22 (4): 271–9. https://doi.org/10.1007/s40268-022-00402-6.Zhang M., Lin J.M., Li X.S., Li J. Quercetin ameliorates LPS-induced inflammation in human peripheral blood mononuclear cells by inhibition of the TLR2-NF-κB pathway. Genet Mol Res. 2016; 15 (2). https://doi.org/10.4238/gmr.15028297.Zhang M., Lin J.M., Li X.S., Li J. Quercetin ameliorates LPS-induced inflammation in human peripheral blood mononuclear cells by inhibition of the TLR2-NF-κB pathway. Genet Mol Res. 2016; 15 (2). https://doi.org/10.4238/gmr.15028297.Haidari F., Heybar H., Jalali M.T., et al. Hesperidin supplementation modulates inflammatory responses following myocardial infarction. J Am Coll Nutr. 2015; 34 (3): 205–11. https://doi.org/10.1080/07315724.2014.891269.Haidari F., Heybar H., Jalali M.T., et al. Hesperidin supplementation modulates inflammatory responses following myocardial infarction. J Am Coll Nutr. 2015; 34 (3): 205–11. https://doi.org/10.1080/07315724.2014.891269.Kadasa N.M., Abdallah H., Afifi M., Gowayed S. Hepatoprotective effects of curcumin against diethyl nitrosamine induced hepatotoxicity in albino rats. Asian Pac J Cancer Prev. 2015; 16 (1): 103–8. https://doi.org/10.7314/apjcp.2015.16.1.103.Kadasa N.M., Abdallah H., Afifi M., Gowayed S. Hepatoprotective effects of curcumin against diethyl nitrosamine induced hepatotoxicity in albino rats. Asian Pac J Cancer Prev. 2015; 16 (1): 103–8. https://doi.org/10.7314/apjcp.2015.16.1.103.Tabrizi R., Vakili S., Akbari M., et al. The effects of curcumin-containing supplements on biomarkers of inflammation and oxidative stress: a systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2019; 33 (2): 253–62. https://doi.org/10.1002/ptr.6226.Tabrizi R., Vakili S., Akbari M., et al. The effects of curcumin-containing supplements on biomarkers of inflammation and oxidative stress: a systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2019; 33 (2): 253–62. https://doi.org/10.1002/ptr.6226.Bao S., Cao Y., Fan C., et al. Epigallocatechin gallate improves insulin signaling by decreasing toll-like receptor 4 (TLR4) activity in adipose tissues of high-fat diet rats. Mol Nutr Food Res. 2014; 58 (4): 677–86. https://doi.org/10.1002/mnfr.201300335.Bao S., Cao Y., Fan C., et al. Epigallocatechin gallate improves insulin signaling by decreasing toll-like receptor 4 (TLR4) activity in adipose tissues of high-fat diet rats. Mol Nutr Food Res. 2014; 58 (4): 677–86. https://doi.org/10.1002/mnfr.201300335.Dong S.J., Zhong Y.Q., Lu W.T., et al. Baicalin inhibits lipopolysaccharide-induced inflammation through signaling NF-κB pathway in HBE16 airway epithelial cells. Inflammation. 2015; 38 (4): 1493–501. https://doi.org/10.1007/s10753-015-0124-2.Dong S.J., Zhong Y.Q., Lu W.T., et al. Baicalin inhibits lipopolysaccharide-induced inflammation through signaling NF-κB pathway in HBE16 airway epithelial cells. Inflammation. 2015; 38 (4): 1493–501. https://doi.org/10.1007/s10753-015-0124-2.Hao D., Li Y., Shi J., Jiang J. Baicalin alleviates chronic obstructive pulmonary disease through regulation of HSP72-mediated JNK pathway. Mol Med. 2021; 27 (1): 53. https://doi.org/10.1186/s10020-021-00309-z.Hao D., Li Y., Shi J., Jiang J. Baicalin alleviates chronic obstructive pulmonary disease through regulation of HSP72-mediated JNK pathway. Mol Med. 2021; 27 (1): 53. https://doi.org/10.1186/s10020-021-00309-z.Chen W., Padilla M.T., Xu X., et al. Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide. Mol Carcinog. 2016; 55 (11): 1858–66. https://doi.org/10.1002/mc.22434.Chen W., Padilla M.T., Xu X., et al. Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide. Mol Carcinog. 2016; 55 (11): 1858–66. https://doi.org/10.1002/mc.22434.Huang R., Zhong T., Wu H. Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress. Arch Med Sci. 2015; 11 (2): 427–32. https://doi.org/10.5114/aoms.2015.50975.Huang R., Zhong T., Wu H. Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress. Arch Med Sci. 2015; 11 (2): 427–32. https://doi.org/10.5114/aoms.2015.50975.Sordillo P.P., Helson L. Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. In Vivo. 2015; 29 (1): 1–4.Sordillo P.P., Helson L. Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. In Vivo. 2015; 29 (1): 1–4.Avasarala S., Zhang F., Liu G., et al. Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome. PLoS One. 2013; 8 (2): e57285. https://doi.org/10.1371/journal.pone.0057285.Avasarala S., Zhang F., Liu G., et al. Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome. PLoS One. 2013; 8 (2): e57285. https://doi.org/10.1371/journal.pone.0057285.Feng H., Zhang K., Zhang K., et al. Antiviral activity and underlying mechanisms of baicalin against avian infectious bronchitis virus in vitro. Avian Pathol. 2022; 51 (6): 574–89. https://doi.org/10.1080/03079457.2022.2109453.Feng H., Zhang K., Zhang K., et al. Antiviral activity and underlying mechanisms of baicalin against avian infectious bronchitis virus in vitro. Avian Pathol. 2022; 51 (6): 574–89. https://doi.org/10.1080/03079457.2022.2109453.Li X., Liu Y., Wu T., et al. The antiviral effect of baicalin on enterovirus 71 in vitro. Viruses. 2015; 7 (8): 4756–71. https://doi.org/10.3390/v7082841.Li X., Liu Y., Wu T., et al. The antiviral effect of baicalin on enterovirus 71 in vitro. Viruses. 2015; 7 (8): 4756–71. https://doi.org/10.3390/v7082841.Rahman M.A., Shorobi F.M., Uddin M.N., et al. Quercetin attenuates viral infections by interacting with target proteins and linked genes in chemicobiological models. In Silico Pharmacol. 2022; 10 (1): 17. https://doi.org/10.1007/s40203-022-00132-2.Rahman M.A., Shorobi F.M., Uddin M.N., et al. Quercetin attenuates viral infections by interacting with target proteins and linked genes in chemicobiological models. In Silico Pharmacol. 2022; 10 (1): 17. https://doi.org/10.1007/s40203-022-00132-2.Ruansit W., Charerntantanakul W. Oral supplementation of quercetin in PRRSV-1 modified-live virus vaccinated pigs in response to HP-PRRSV-2 challenge. Vaccine. 2020; 38 (19): 3570–81. https://doi.org/10.1016/j.vaccine.2020.03.019.Ruansit W., Charerntantanakul W. Oral supplementation of quercetin in PRRSV-1 modified-live virus vaccinated pigs in response to HP-PRRSV-2 challenge. Vaccine. 2020; 38 (19): 3570–81. https://doi.org/10.1016/j.vaccine.2020.03.019.Veckenstedt A., Pusztai R. Mechanism of antiviral action of quercetin against cardiovirus infection in mice. Antiviral Res. 1981; 1 (4): 249–61. https://doi.org/10.1016/0166-3542(81)90015-2.Veckenstedt A., Pusztai R. Mechanism of antiviral action of quercetin against cardiovirus infection in mice. Antiviral Res. 1981; 1 (4): 249–61. https://doi.org/10.1016/0166-3542(81)90015-2.Suebsaard P., Charerntantanakul W. Rutin, α-tocopherol, and l-ascorbic acid up-regulate type I interferon-regulated gene and type I and II interferon expressions in monocyte-derived macrophages infected with highly pathogenic porcine virus. Vet Immunol Immunopathol. 2021; 235: 110231. https://doi.org/10.1016/j.vetimm.2021.110231.Suebsaard P., Charerntantanakul W. Rutin, α-tocopherol, and l-ascorbic acid up-regulate type I interferon-regulated gene and type I and II interferon expressions in monocyte-derived macrophages infected with highly pathogenic porcine virus. Vet Immunol Immunopathol. 2021; 235: 110231. https://doi.org/10.1016/j.vetimm.2021.110231.Šudomová M., Hassan S.T.S. Nutraceutical curcumin with promising protection against herpesvirus infections and their associated inflammation: mechanisms and pathways. Microorganisms. 2021; 9 (2): 292. https://doi.org/10.3390/microorganisms9020292.Šudomová M., Hassan S.T.S. Nutraceutical curcumin with promising protection against herpesvirus infections and their associated inflammation: mechanisms and pathways. Microorganisms. 2021; 9 (2): 292. https://doi.org/10.3390/microorganisms9020292.Li H., Li Y., Hu J., et al. Epigallocatechin-3-gallate inhibits EBV lytic replication via targeting LMP1-mediated MAPK. Oncol Res. 2021; 28 (7): 763–78. https://doi.org/10.3727/096504021X16135618512563.Li H., Li Y., Hu J., et al. Epigallocatechin-3-gallate inhibits EBV lytic replication via targeting LMP1-mediated MAPK. Oncol Res. 2021; 28 (7): 763–78. https://doi.org/10.3727/096504021X16135618512563.Isaacs C.E., Wen G.Y., Xu W., et al. Epigallocatechin gallate inactivates clinical isolates of herpes simplex virus. Antimicrob Agents Chemother. 2008; 52 (3): 962–70. https://doi.org/10.1128/AAC.00825-07.Isaacs C.E., Wen G.Y., Xu W., et al. Epigallocatechin gallate inactivates clinical isolates of herpes simplex virus. Antimicrob Agents Chemother. 2008; 52 (3): 962–70. https://doi.org/10.1128/AAC.00825-07.Ho H.Y., Cheng M.L., Weng S.F., et al. Antiviral effect of epigallocatechin gallate on enterovirus 71. J Agric Food Chem. 2009; 57 (14): 6140–7. https://doi.org/10.1021/jf901128u.Ho H.Y., Cheng M.L., Weng S.F., et al. Antiviral effect of epigallocatechin gallate on enterovirus 71. J Agric Food Chem. 2009; 57 (14): 6140–7. https://doi.org/10.1021/jf901128u.Reshamwala D., Shroff S., Sheik Amamuddy O., et al. Polyphenols epigallocatechin gallate and resveratrol, and polyphenol-functionalized nanoparticles prevent enterovirus infection. Pharmaceutics. 2021; 13 (8): 1182. https://doi.org/10.3390/pharmaceutics13081182.Reshamwala D., Shroff S., Sheik Amamuddy O., et al. Polyphenols epigallocatechin gallate and resveratrol, and polyphenol-functionalized nanoparticles prevent enterovirus infection. Pharmaceutics. 2021; 13 (8): 1182. https://doi.org/10.3390/pharmaceutics13081182.Geng P., Zhu H., Zhou W., et al. Baicalin inhibits influenza a virus infection via promotion of M1 macrophage polarization. Front Pharmacol. 2020; 11: 01298. https://doi.org/10.3389/fphar.2020.01298.Geng P., Zhu H., Zhou W., et al. Baicalin inhibits influenza a virus infection via promotion of M1 macrophage polarization. Front Pharmacol. 2020; 11: 01298. https://doi.org/10.3389/fphar.2020.01298.Shi H., Ren K., Lv B., et al. Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice. Sci Rep. 2016; 6: 35851. https://doi.org/10.1038/srep35851.Shi H., Ren K., Lv B., et al. Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice. Sci Rep. 2016; 6: 35851. https://doi.org/10.1038/srep35851.Qin S., Huang X., Qu S. Baicalin induces a potent innate immune response to inhibit RSV replication via regulating viral non-structural 1 and matrix RNA. Front Immunol. 2022; 13: 907047. https://doi.org/10.3389/fimmu.2022.907047.Qin S., Huang X., Qu S. Baicalin induces a potent innate immune response to inhibit RSV replication via regulating viral non-structural 1 and matrix RNA. Front Immunol. 2022; 13: 907047. https://doi.org/10.3389/fimmu.2022.907047.Saha R.K., Takahashi T., Suzuki T. Glucosyl hesperidin prevents influenza a virus replication in vitro by inhibition of viral sialidase. Biol Pharm Bull. 2009; 32 (7): 1188–92. https://doi.org/10.1248/bpb.32.1188.Saha R.K., Takahashi T., Suzuki T. Glucosyl hesperidin prevents influenza a virus replication in vitro by inhibition of viral sialidase. Biol Pharm Bull. 2009; 32 (7): 1188–92. https://doi.org/10.1248/bpb.32.1188.Zhao X., Tang Z., Yue C., et al. hesperidin regulates Jagged1/Notch1 pathway to promote macrophage polarization and alleviate lung injury in mice with bronchiolitis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2022; 44 (5): 777–84 (на кит. яз.). https://doi.org/10.3881/j.issn.1000-503X.14888.Zhao X., Tang Z., Yue C., et al. hesperidin regulates Jagged1/Notch1 pathway to promote macrophage polarization and alleviate lung injury in mice with bronchiolitis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2022; 44 (5): 777–84 (in Chinese). https://doi.org/10.3881/j.issn.1000-503X.14888.Ding Z., Sun G., Zhu Z. Hesperidin attenuates influenza A virus (H1N1) induced lung injury in rats through its anti-inflammatory effect. Antivir Ther. 2018; 23 (7): 611–5. https://doi.org/10.3851/IMP3235.Ding Z., Sun G., Zhu Z. Hesperidin attenuates influenza A virus (H1N1) induced lung injury in rats through its anti-inflammatory effect. Antivir Ther. 2018; 23 (7): 611–5. https://doi.org/10.3851/IMP3235.Wu W., Li R., Li X., et al. Quercetin as an antiviral agent inhibits influenza A virus (IAV) entry. Viruses. 2015; 8 (1): 6. https://doi.org/10.3390/v8010006.Wu W., Li R., Li X., et al. Quercetin as an antiviral agent inhibits influenza A virus (IAV) entry. Viruses. 2015; 8 (1): 6. https://doi.org/10.3390/v8010006.Tiboc-Schnell C.N., Filip G.A., Man S.C., et al. Quercetin attenuates naso-sinusal inflammation and inflammatory response in lungs and brain on an experimental model of acute rhinosinusitis in rats. J Physiol Pharmacol. 2020; 71 (4). https://doi.org/10.26402/jpp.2020.4.03.Tiboc-Schnell C.N., Filip G.A., Man S.C., et al. Quercetin attenuates naso-sinusal inflammation and inflammatory response in lungs and brain on an experimental model of acute rhinosinusitis in rats. J Physiol Pharmacol. 2020; 71 (4). https://doi.org/10.26402/jpp.2020.4.03.Singh A., Mishra A. Leucoefdin a potential inhibitor against SARS CoV-2 Mpro. J Biomol Struct Dyn. 2021; 39 (12): 4427–32. https://doi.org/10.1080/07391102.2020.1777903.Singh A., Mishra A. Leucoefdin a potential inhibitor against SARS CoV-2 Mpro. J Biomol Struct Dyn. 2021; 39 (12): 4427–32. https://doi.org/10.1080/07391102.2020.1777903.George T.K., Joy A., Divya K., Jisha M.S. In vitro and in silico docking studies of antibacterial compounds derived from endophytic Penicillium setosum. Microb Pathog. 2019; 131: 87–97. https://doi.org/10.1016/j.micpath.2019.03.033.George T.K., Joy A., Divya K., Jisha M.S. In vitro and in silico docking studies of antibacterial compounds derived from endophytic Penicillium setosum. Microb Pathog. 2019; 131: 87–97. https://doi.org/10.1016/j.micpath.2019.03.033.da Silva-Júnior E.F., Silva L.R. Multi-target approaches of epigallocatechin-3-O-gallate (EGCG) and its derivatives against influenza viruses. Curr Top Med Chem. 2022; 22 (18): 1485–500. https://doi.org/10.2174/1568026622666220127112056.da Silva-Júnior E.F., Silva L.R. Multi-target approaches of epigallocatechin-3-O-gallate (EGCG) and its derivatives against influenza viruses. Curr Top Med Chem. 2022; 22 (18): 1485–500. https://doi.org/10.2174/1568026622666220127112056.Matsuura R., Kawamura A., Matsumoto Y., et al. Epigallocatechin gallate stabilized by cyclodextrin inactivates influenza virus and human coronavirus 229E. Microorganisms. 2022; 10 (9): 1796. https://doi.org/10.3390/microorganisms10091796.Matsuura R., Kawamura A., Matsumoto Y., et al. Epigallocatechin gallate stabilized by cyclodextrin inactivates influenza virus and human coronavirus 229E. Microorganisms. 2022; 10 (9): 1796. https://doi.org/10.3390/microorganisms10091796.Obata K., Kojima T., Masaki T., et al. Curcumin prevents replication of respiratory syncytial virus and the epithelial responses to it in human nasal epithelial cells. PLoS One. 2013; 8 (9): e70225. https://doi.org/10.1371/journal.pone.0070225.Obata K., Kojima T., Masaki T., et al. Curcumin prevents replication of respiratory syncytial virus and the epithelial responses to it in human nasal epithelial cells. PLoS One. 2013; 8 (9): e70225. https://doi.org/10.1371/journal.pone.0070225.Han S., Xu J., Guo X., Huang M. Curcumin ameliorates severe influenza pneumonia via attenuating lung injury and regulating macrophage cytokines production. Clin Exp Pharmacol Physiol. 2018; 45 (1): 84–93. https://doi.org/10.1111/1440-1681.12848.Han S., Xu J., Guo X., Huang M. Curcumin ameliorates severe influenza pneumonia via attenuating lung injury and regulating macrophage cytokines production. Clin Exp Pharmacol Physiol. 2018; 45 (1): 84–93. https://doi.org/10.1111/1440-1681.12848.Samadizadeh S., Arabi M.S., Yasaghi M., et al. Anti-inflammatory effects of curcumin-loaded niosomes on respiratory syncytial virus infection in a mice model. J Med Microbiol. 2022; 71 (4). https://doi.org/10.1099/jmm.0.001525.Samadizadeh S., Arabi M.S., Yasaghi M., et al. Anti-inflammatory effects of curcumin-loaded niosomes on respiratory syncytial virus infection in a mice model. J Med Microbiol. 2022; 71 (4). https://doi.org/10.1099/jmm.0.001525.Gordon D.E., Jang G.M., Bouhaddou M., et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020; 583 (7816): 459–68. https://doi.org/10.1038/s41586-020-2286-9.Gordon D.E., Jang G.M., Bouhaddou M., et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020; 583 (7816): 459–68. https://doi.org/10.1038/s41586-020-2286-9.Hong S., Seo S.H., Woo S.J., et al. Epigallocatechin gallate inhibits the uridylate-specific endoribonuclease Nsp15 and efficiently neutralizes the SARS-CoV-2 strain. J Agric Food Chem. 2021; 69 (21): 5948–54. https://doi.org/10.1021/acs.jafc.1c02050.Hong S., Seo S.H., Woo S.J., et al. Epigallocatechin gallate inhibits the uridylate-specific endoribonuclease Nsp15 and efficiently neutralizes the SARS-CoV-2 strain. J Agric Food Chem. 2021; 69 (21): 5948–54. https://doi.org/10.1021/acs.jafc.1c02050.Zandi K., Musall K., Oo A., et al. Baicalein and baicalin inhibit SARS-CoV-2 RNA-dependent-RNA polymerase. Microorganisms. 2021; 9 (5): 893. https://doi.org/10.3390/microorganisms9050893.Zandi K., Musall K., Oo A., et al. Baicalein and baicalin inhibit SARS-CoV-2 RNA-dependent-RNA polymerase. Microorganisms. 2021; 9 (5): 893. https://doi.org/10.3390/microorganisms9050893.Rizzuti B., Grande F., Conforti F., et al. Rutin is a low micromolar inhibitor of SARS-CoV-2 main protease 3CLpro: implications for drug design of quercetin analogs. Biomedicines. 2021; 9 (4): 375. https://doi.org/10.3390/biomedicines9040375.Rizzuti B., Grande F., Conforti F., et al. Rutin is a low micromolar inhibitor of SARS-CoV-2 main protease 3CLpro: implications for drug design of quercetin analogs. Biomedicines. 2021; 9 (4): 375. https://doi.org/10.3390/biomedicines9040375.Manjunath S.H., Thimmulappa R.K. Antiviral, immunomodulatory, and anticoagulant effects of quercetin and its derivatives: potential role in prevention and management of COVID-19. J Pharm Anal. 2022; 12 (1): 29–34. https://doi.org/10.1016/j.jpha.2021.09.009.Manjunath S.H., Thimmulappa R.K. Antiviral, immunomodulatory, and anticoagulant effects of quercetin and its derivatives: potential role in prevention and management of COVID-19. J Pharm Anal. 2022; 12 (1): 29–34. https://doi.org/10.1016/j.jpha.2021.09.009.Gasmi A., Mujawdiya P.K., Lysiuk R., et al. Quercetin in the prevention and treatment of coronavirus infections: a focus on SARS-CoV-2. Pharmaceuticals (Basel). 2022; 15 (9): 1049. https://doi.org/10.3390/ph15091049.Gasmi A., Mujawdiya P.K., Lysiuk R., et al. Quercetin in the prevention and treatment of coronavirus infections: a focus on SARS-CoV-2. Pharmaceuticals (Basel). 2022; 15 (9): 1049. https://doi.org/10.3390/ph15091049.Di Pierro F., Iqtadar S., Khan A., et al. Potential clinical benefits of quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial. Int J Gen Med. 2021; 14: 2807–16. https://doi.org/10.2147/IJGM.S318949.Di Pierro F., Iqtadar S., Khan A., et al. Potential clinical benefits of quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial. Int J Gen Med. 2021; 14: 2807–16. https://doi.org/10.2147/IJGM.S318949.Di Pierro F., Derosa G., Maffioli P., et al. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study. Int J Gen Med. 2021; 14: 2359–66. https://doi.org/10.2147/IJGM.S318720.Di Pierro F., Derosa G., Maffioli P., et al. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study. Int J Gen Med. 2021; 14: 2359–66. https://doi.org/10.2147/IJGM.S318720.Shohan M., Nashibi R., Mahmoudian-Sani M.R., et al. The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: a randomized controlled trial. Eur J Pharmacol. 2022; 914: 174615. https://doi.org/10.1016/j.ejphar.2021.174615.Shohan M., Nashibi R., Mahmoudian-Sani M.R., et al. The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: a randomized controlled trial. Eur J Pharmacol. 2022; 914: 174615. https://doi.org/10.1016/j.ejphar.2021.174615.Dupuis J., Laurin P., Tardif J.C., et al. Fourteen-day evolution of COVID-19 symptoms during the third wave in nonvaccinated subjects and effects of hesperidin therapy: a randomized, double-blinded, placebo-controlled study. Evid Based Complement Alternat Med. 2022; 2022: 3125662. https://doi.org/10.1155/2022/3125662.Dupuis J., Laurin P., Tardif J.C., et al. Fourteen-day evolution of COVID-19 symptoms during the third wave in nonvaccinated subjects and effects of hesperidin therapy: a randomized, double-blinded, placebo-controlled study. Evid Based Complement Alternat Med. 2022; 2022: 3125662. https://doi.org/10.1155/2022/3125662.Mokra D., Adamcakova J., Mokry J. Green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG): a time for a new player in the treatment of respiratory diseases? Antioxidants (Basel). 2022; 11 (8): 1566. https://doi.org/10.3390/antiox11081566.Mokra D., Adamcakova J., Mokry J. Green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG): a time for a new player in the treatment of respiratory diseases? Antioxidants (Basel). 2022; 11 (8): 1566. https://doi.org/10.3390/antiox11081566.Park R., Jang M., Park Y.I., et al. Epigallocatechin gallate (EGCG), a green tea polyphenol, reduces coronavirus replication in a mouse model. Viruses. 2021; 13 (12): 2533. https://doi.org/10.3390/v13122533.Park R., Jang M., Park Y.I., et al. Epigallocatechin gallate (EGCG), a green tea polyphenol, reduces coronavirus replication in a mouse model. Viruses. 2021; 13 (12): 2533. https://doi.org/10.3390/v13122533.Saeedi-Boroujeni A., Mahmoudian-Sani M.R., Bahadoram M., Alghasi A. COVID-19: a case for inhibiting NLRP3 inflammasome, suppression of inflammation with curcumin? Basic Clin Pharmacol Toxicol. 2021; 128 (1): 37–45. https://doi.org/10.1111/bcpt.13503.Saeedi-Boroujeni A., Mahmoudian-Sani M.R., Bahadoram M., Alghasi A. COVID-19: a case for inhibiting NLRP3 inflammasome, suppression of inflammation with curcumin? Basic Clin Pharmacol Toxicol. 2021; 128 (1): 37–45. https://doi.org/10.1111/bcpt.13503.Marín-Palma D., Tabares-Guevara J.H., Zapata-Cardona M.I., et al. Curcumin inhibits in vitro SARS-CoV-2 infection in vero E6 cells through multiple antiviral mechanisms. Molecules. 2021; 26 (22): 6900. https://doi.org/10.3390/molecules26226900.Marín-Palma D., Tabares-Guevara J.H., Zapata-Cardona M.I., et al. Curcumin inhibits in vitro SARS-CoV-2 infection in vero E6 cells through multiple antiviral mechanisms. Molecules. 2021; 26 (22): 6900. https://doi.org/10.3390/molecules26226900.Vahedian-Azimi A., Abbasifard M., Rahimi-Bashar F., et al. Effectiveness of curcumin on outcomes of hospitalized COVID-19 patients: a systematic review of clinical trials. Nutrients. 2022; 14 (2): 256. https://doi.org/10.3390/nu14020256.Vahedian-Azimi A., Abbasifard M., Rahimi-Bashar F., et al. Effectiveness of curcumin on outcomes of hospitalized COVID-19 patients: a systematic review of clinical trials. Nutrients. 2022; 14 (2): 256. https://doi.org/10.3390/nu14020256.Громова О.А., Торшин И.Ю., Тетруашвили Н.К. Систематический обзор экспериментальных и клинических исследований по фармакологии глицирризина и его производных. Акушерство и гинекология. 2022; 4: 34–46. https://dx.doi.org/10.18565/aig.2022.4.34-46.Gromova O.A., Torshin I.Yu., Tetruashvili N.K. A systematic review of experimental and clinical studies on the pharmacology of glycyrrhizin and its derivatives. Obstetrics and Gynecology. 2022; 4: 34–46 (in Russ.). https://dx.doi.org/10.18565/aig.2022.4.34-46.Zhang N., Lv H., Shi B.H., et al. Inhibition of IL-6 and IL-8 production in LPS-stimulated human gingival fibroblasts by glycyrrhizin via activating LXRα. Microb Pathog. 2017; 110: 135–9. https://doi.org/10.1016/j.micpath.2017.06.021.Zhang N., Lv H., Shi B.H., et al. Inhibition of IL-6 and IL-8 production in LPS-stimulated human gingival fibroblasts by glycyrrhizin via activating LXRα. Microb Pathog. 2017; 110: 135–9. https://doi.org/10.1016/j.micpath.2017.06.021.van de Sand L., Bormann M., Alt M., et al. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses. 2021; 13 (4): 609. https://doi.org/10.3390/v13040609.van de Sand L., Bormann M., Alt M., et al. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses. 2021; 13 (4): 609. https://doi.org/10.3390/v13040609.Gomaa A.A., Mohamed H.S., Abd-Ellatief R.B., et al. Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: a randomized clinical trial. Inflammopharmacology. 2022; 30 (2): 477–86. https://doi.org/10.1007/s10787-022-00939-7.Gomaa A.A., Mohamed H.S., Abd-Ellatief R.B., et al. Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: a randomized clinical trial. Inflammopharmacology. 2022; 30 (2): 477–86. https://doi.org/10.1007/s10787-022-00939-7.Askari G., Sahebkar A., Soleimani D., et al. The efficacy of curcumin-piperine co-supplementation on clinical symptoms, duration, severity, and inflammatory factors in COVID-19 outpatients: a randomized double-blind, placebo-controlled trial. Trials. 2022; 23 (1): 472. https://doi.org/10.1186/s13063-022-06375-w.Askari G., Sahebkar A., Soleimani D., et al. The efficacy of curcumin-piperine co-supplementation on clinical symptoms, duration, severity, and inflammatory factors in COVID-19 outpatients: a randomized double-blind, placebo-controlled trial. Trials. 2022; 23 (1): 472. https://doi.org/10.1186/s13063-022-06375-w.Pawar K.S., Mastud R.N., Pawar S.K., Pet al. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: a randomized clinical trial. Front Pharmacol. 2021; 12: 669362. https://doi.org/10.3389/fphar.2021.669362.Pawar K.S., Mastud R.N., Pawar S.K., Pet al. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: a randomized clinical trial. Front Pharmacol. 2021; 12: 669362. https://doi.org/10.3389/fphar.2021.669362.Khan A., Iqtadar S., Mumtaz S.U., et al. Oral co-supplementation of curcumin, quercetin, and vitamin D3 as an adjuvant therapy for mild to moderate symptoms of COVID-19 – results from a pilot open-label, randomized controlled trial. Front Pharmacol. 2022; 13: 898062. https://doi.org/10.3389/fphar.2022.898062.Khan A., Iqtadar S., Mumtaz S.U., et al. Oral co-supplementation of curcumin, quercetin, and vitamin D3 as an adjuvant therapy for mild to moderate symptoms of COVID-19 – results from a pilot open-label, randomized controlled trial. Front Pharmacol. 2022; 13: 898062. https://doi.org/10.3389/fphar.2022.898062.Zhao F.Q., Wang G.F., Xu D., et al. Glycyrrhizin mediated liver-targeted alginate nanogels delivers quercetin to relieve acute liver failure. Int J Biol Macromol. 2021; 168: 93–104. https://doi.org/10.1016/j.ijbiomac.2020.11.204.Zhao F.Q., Wang G.F., Xu D., et al. Glycyrrhizin mediated liver-targeted alginate nanogels delivers quercetin to relieve acute liver failure. Int J Biol Macromol. 2021; 168: 93–104. https://doi.org/10.1016/j.ijbiomac.2020.11.204.

The authors declare that there are no conflicts of interest present.