The Influence of Flavonoid Compositions on Nrf2 Transcription Factor Expression in Case of Infections Triggered by Influenza A Virus and Transmissible Gastroenteritis Coronavirus
DOI:
https://doi.org/10.20535/ibb.2023.7.4.290103Keywords:
Nrf2, flavonoids, influenza virus, transmissible gastroenteritis coronavirusAbstract
Background. Viral infections trigger transcription factors, including Nrf2, which regulate the expression of genes related to cytokines, chemokines, and more. Nuclear factor erythroid 2-related factor 2 (Nrf2) participates in complex regulatory networks controlling the expression of cytoprotective genes and immune responses. Recently, new roles have been attributed to Nrf2, including the regulation of antiviral responses.
Objective. The aim of the study was to analyze Nrf2 activation in influenza virus infection in vivo and in transmissible gastroenteritis coronavirus (TGEV) infection in vitro, as well as the effects of the flavonoid compositions Proteflazidum® and Protoil on the Nrf2 expression in these two experimental models of viral infection.
Methods. Outbred white mice were infected with influenza A virus (A/FM/1/47/H1N1 strain). Jurkat cells were infected with TGEV, previously adapted to these cells. Flavonoid compositions Proteflazidum® and Protoil (Ecopharm, Ukraine), containing the mixture of tricin, luteolin, apigenin, quercetin, and rhamnosin, were used in corresponding dilutions. Real-Time PCR was employed to analyze Nrf2 RNA expression in the lungs of mice and in both uninfected and virus-infected cells. Additionally, ELISA was used to assess the expression of Nrf2 peptide.
Results. The Nrf2 expression in the lungs of influenza virus-infected mice showed a tendency to increase within a 100-fold range. In virus-infected mice treated with Proteflazidum® or Protoil, the level of Nrf2 expression in the lungs decreased about 10-fold compared to infected untreated mice. TGEV infection resulted in 100-fold increase in Nrf2 expression in Jurkat cells. Both Proteflazidum® and Protoil decreased Nrf2 expression in TGEV-infected cells, while their effects on Nrf2 expression in the intact cells on Day 1 were not detected.
Conclusions. Flavonoid compositions have only a slight effect on Nrf2 expression in intact cells. However, in case of virus infection, both in vivo and in vitro, they counteract the extensive up-regulation of Nrf2 expression due to viral infection.
References
Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA. 1994;91(21):9926-30. DOI: 10.1073/pnas.91.21.9926
Gao W, Guo L, Yang Y, Wang Y, Xia S, Gong H, et al. Dissecting the crosstalk between Nrf2 and NF-κB response path-ways in drug-induced toxicity. Front Cell Dev Biol. 2022;9:809952. DOI: 10.3389/fcell.2021.809952
Saha S, Buttari B, Panieri E, Profumo E, Saso L. An overview of Nrf2 signaling pathway and its role in inflammation. Molecules. 2020;25(22):5474. DOI: 10.3390/molecules25225474
Battino M, Giampieri F, Pistollato F, Sureda A, de Oliveira MR, Pittalà V, et al. Nrf2 as regulator of innate immunity: A mo-lecular Swiss army knife! Biotechnol Adv. 2018;36(2):358-70. DOI: 10.1016/j.biotechadv.2017.12.012
Gomez JC, Dang H, Martin JR, Doerschuk CM. Nrf2 modulates host defense during Streptococcus pneumoniae pneu-monia in mice. J Immunol. 2016;197(7):2864-79. DOI: 10.4049/jimmunol.1600043
Herengt A, Thyrsted J, Holm CK. NRF2 in viral infection. Antioxidants. 2021;10(9):1491. DOI: 10.3390/antiox10091491
Lee J, Koh K, Kim YE, Ahn JH, Kim S. Upregulation of Nrf2 expression by human cytomegalovirus infection protects host cells from oxidative stress. J Gen Virol. 2013;94(Pt 7):1658-68. DOI: 10.1099/vir.0.052142-0
Liu B, Fang M, He Z, Cui D, Jia S, Lin X, et al. Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation. Cell Death Dis. 2015;6(11):e1980. DOI: 10.1038/cddis.2015.322
Ramezani A, Nahad MP, Faghihloo E. The role of Nrf2 transcription factor in viral infection. J Cell Biochem. 2018;119(8):6366-82. DOI: 10.1002/jcb.26897
Olagnier D, Brandtoft AM, Gunderstofte C, Villadsen NL, Krapp C, Thielke AL, et al. Nrf2 negatively regulates STING in-dicating a link between antiviral sensing and metabolic reprogramming. Nat Commun. 2018;9(1):3506. DOI: 10.1038/s41467-018-05861-7
Gunderstofte C, Iversen MB, Peri S, Thielke A, Balachandran S, Holm CK, Olagnier D. Nrf2 negatively regulates type I in-terferon responses and increases susceptibility to herpes genital infection in mice. Front Immunol. 2019;10:2101. DOI: 10.3389/fimmu.2019.02101
Cho HY, Imani F, Miller-DeGraff L, Walters D, Melendi GA, Yamamoto M, et al. Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease. Am J Respir Crit Care Med. 2009;179(2):138-50. DOI: 10.1164/rccm.200804-535OC
Shoji M, Arakaki Y, Esumi T, Kohnomi S, Yamamoto C, Suzuki Y, et al. Bakuchiol is a phenolic isoprenoid with no¬vel enantiomer-selective anti-influenza A virus activity involving Nrf2 activation. J Biol Chem. 2015;290(46):28001-17. DOI: 10.1074/jbc.M115.669465
Lee C. Therapeutic modulation of virus-induced oxidative stress via the Nrf2-dependent antioxidative pathway. Oxid Med Cell Longev. 2018;2018:6208067. DOI: 10.1155/2018/6208067
Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and inhibitors of NRF2: a review of their potential for clinical development. Oxid Med Cell Longev. 2019;2019:1-20. DOI: 10.1155/2019/9372182
Suraweera TL, Rupasinghe HPV, Dellaire G, Xu Z. Regulation of Nrf2/ARE pathway by dietary flavonoids: a friend or foe for cancer management? Antioxidants. 2020;9(10):973. DOI: 10.3390/antiox9100973
Badshah SL, Faisal S, Muhammad A, Poulson BG, Emwas AH, Jaremko M. Antiviral activities of flavonoids. Biomed Pharmacother. 2021;140:111596. DOI: 10.1016/j.biopha.2021.111596
Atamaniuk V. EA201700340A1 - Biological active substance of polypharmacological action of plant origin - Google Pa-tents [Internet]. 2017 [cited 2023 Apr 19]. Available from: https://patents.google.com/patent/EA201700340A1/en
Trokhymchuk T, Zavelevich M, Liulchuk T, Starosyla D, Rybalko S, Rudenko A. In vitro study of anti-HIV activity of Proteflazid herbal composition. Am J Fund Appl Env Res. 2017;4:87-91.
Spivak MYa, Rybalko SL, Starosyla DB, Zavelevich MP, Oleksiienko IP, Diadiun ST, et al. Study of the effects of flavo-noid-containing composition Proteflazid on modeled papillomavirus infection in vitro. Dopov Nac Akad Nauk Ukr. 2018;(10):103-11. DOI: 10.15407/dopovidi2018.10.103
Zharkova L, Rybalko S, Panasenko G, Kovalenko E, Hetman K, Salkov S. Mechanism of adaptation of influenza viruses A/FM/1/47 (H1N1) and A/Port CHlamers/1/73 (H3N2) to the new host. Lab Diagnos. 2009;3:26-30.
Deriabin ON, Deriabina EG, Krasnobaiev EA, Bobyk VI. Effect of culture system on the genetic features of TGEV. Vestnik Selskochoz Nauk. 1991;8:138-41.
Kanzaki H, Shinohara F, Kajiya M, Kodama T. The Keap1/Nrf2 protein axis plays a role in osteoclast differentiation by regulating intracellular reactive oxygen species signaling. J Biol Chem. 2013;288(32):23009-20. DOI: 10.1074/jbc.M113.478545
Pirog T, Paliichuk O, Lutsai D, Kliuchka L, Shevchuk T. Effect of cations on the activity of NAD+P-dependent glutamate dehydrogenase in Acinetobacter calcoaceticus IMV B-7241, Rhodococcus erythropolis IMV Ac-5017 and Nocardia vac-cinii IMV B-7405 grown on industrial waste. Ukr Food J. 2021;10(1):198-208. DOI: 10.24263/2304-974X-2021-10-1-17
Galkin OY, Besarab AB, Lutsenko TN. Characteristics of enzyme-linked immunosorbent assay for detection of IgG anti-bodies specific to Сhlamydia trachomatis heat shock protein (HSP-60). Ukr Biochem J. 2017;89(1):22-30. DOI: 10.15407/ubj89.01.022
Kyryk V, Ustymenko A, Lutsenko T, Klymenko P, Tsupykov O. Regenerative effects of mouse aortic endothelial cells in a murine model of critical limb ischemia. Cell Organ Transpl. 2022;10(2):90-6. DOI: 10.22494/cot.v10i2.143
Kosmider B, Messier EM, Janssen WJ, Nahreini P, Wang J, Hartshorn KL, et al. Nrf2 protects human alveolar epithelial cells against injury induced by influenza A virus. Respir Res. 2012;13(1):43. DOI: 10.1186/1465-9921-13-43
Yageta Y, Ishii Y, Morishima Y, Masuko H, Ano S, Yamadori T, et al. Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice. J Virol. 2011;85(10):4679-90. DOI: 10.1128/JVI.02456-10
Komaravelli N, Ansar M, Garofalo RP, Casola A. Respiratory syncytial virus induces NRF2 degradation through a pro-myelocytic leukemia protein - ring finger protein 4 dependent pathway. Free Radic Biol Med. 2017;113:494-504. DOI: 10.1016/j.freeradbiomed.2017.10.380
Olagnier D, Farahani E, Thyrsted J, Blay-Cadanet J, Herengt A, Idorn M, et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. 2020 Oct 2;11(1):4938. DOI: 10.1038/s41467-020-18764-3
Wyler E, Franke V, Menegatti J, Kocks C, Boltengagen A, Praktiknjo S, et al. Single-cell RNA-sequencing of herpes simplex virus 1-infected cells connects NRF2 activation to an antiviral program. Nat Commun. 2019;10(1):4878. DOI: 10.1038/s41467-019-12894-z
Wang K, Tang Y, Wu X, Liang H, Chen D, Yu B, et al. Eugenol attenuates transmissible gastroenteritis virus-induced ox-idative stress and apoptosis via ROS-NRF2-ARE signaling. Antioxidants (Basel). 2022;11(9):1838. DOI: 10.3390/antiox11091838
Qu Y, Haas de Mello A, Morris DR, Jones-Hall YL, Ivanciuc T, Sattler RA, et al. SARS-CoV-2 inhibits NRF2-mediated an-tioxidant responses in airway epithelial cells and in the lung of a murine model of infection. Microbiol Spectr. 2023;11(3):e0037823. DOI: 10.1128/spectrum.00378-23
Hamad RS, Al-Kuraishy HM, Alexiou A, Papadakis M, Ahmed EA, Saad HM, et al. SARS-CoV-2 infection and dysregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. Cell Stress Chaperones. 2023 Oct 5. DOI: 10.1007/s12192-023-01379-0
Ninfali P, Antonelli A, Magnani M, Scarpa ES. Antiviral properties of flavonoids and delivery strategies. Nutrients. 2020;12(9):2534. DOI: 10.3390/nu12092534
Magesh S, Chen Y, Hu L. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeu-tic agents. Med Res Rev. 2012;32(4):687-726. DOI: 10.1002/med.21257
Zhang ZJ, Morris-Natschke SL, Cheng YY, Lee KH, Li RT. Development of anti-influenza agents from natural products. Med Res Rev. 2020;40(6):2290-338. DOI: 10.1002/med.21707
Yang JY, Ma YX, Liu Y, Peng XJ, Chen XZ. A Comprehensive review of natural flavonoids with anti-SARS-CoV-2 activity. Molecules. 2023;28(6):2735. DOI: 10.3390/molecules28062735
Waqas FH, Shehata M, Elgaher WAM, Lacour A, Kurmasheva N, Begnini F, et al. NRF2 activators inhibit influenza A vi-rus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner. PLoS Pathog. 2023;19(7):e1011506. DOI: 10.1371/journal.ppat.1011506
Zhang X, Chen S, Li X, Zhang L, Ren L. Flavonoids as potential antiviral agents for porcine viruses. Pharmaceutics. 2022 Aug 26;14(9):1793. DOI: 10.3390/pharmaceutics14091793
Paredes-Gonzalez X, Fuentes F, Jeffery S, Saw CL-L, Shu L, Su Z-Y, Kong A-NT. Induction of NRF2-mediated gene ex-pression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos. 2015;36(7):440-51. DOI: 10.1002/bdd.1956
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