Iberoamerican Journal of Medicine
https://iberoamjmed.com/article/doi/10.53986/ibjm.2024.0001
Iberoamerican Journal of Medicine
Original article

Nuclear Factor Erythroid 2-Related Factor (NRF2), Heme Oxygenase 1 (HO-1) and Total Oxidant-Antioxidant Status in Patients with COVID-19

Factor nuclear relacionado con el eritroide 2 (NRF2), hemo oxigenasa 1 (HO-1) y estado oxidante-antoxidante total en pacientes con COVID-19

Mehmet Çelik, Mehmet Reşat Ceylan, İsmail Koyuncu, Nevin Güler Dinçer, Sevil Alkan

Downloads: 1
Views: 709

Abstract

Introduction: Studies on nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels in COVID-19 patients are limited. This study aimed to investigate the relationship between some biomarkers of oxidant-antioxidant status with COVID-19 disease.
Material and methods: The patients older than 18 years of age who tested positive for SARS CoV-2 PCR (polymerase chain reaction) with clinical symptoms and signs were included in this study. Total antioxidant status (TAS), total antioxidant status (TOS), oxidative stress index (OSI) and HO-1 and Nrf2 levels were analyzed from serum samples taken before and after treatment.
Results: In this study, 16 patients followed up with the diagnosis of COVID-19 were included. 9 (56.3%) of the patients were female and 7 (43.8%) were male. The mean age was 33.75 ± 17.03 years. All patients were symptomatic and were hospitalized to be followed up. It was determined that Nrf2 and HO-1 values increased significantly after treatment. Moreover, there was a significant positive correlation between Nrf2 and TAS values and TAS increases significantly in parallel to an increase in Nrf2, and there was a significant but negative correlation between Nrf2 and TOS and OSI values, and thus an increase in Nrf2 led to a decrease in TOS and OSI values. There was a significant positive correlation between HO-1 and TAS, and TAS increased significantly, as HO-1 increased.
Conclusions: The decrease in TOS and OSI and the increase in Nrf2 and HO-1 during the follow-up period in COVID-19 patients suggest that the body tries to prevent ROS-related oxidative stress via Nrf2 and HO-1 and that oxidative stress may have a key role in the pathophysiology of COVID-19.

Keywords

COVID-19; Heme oxygenase-1; Nuclear factor erythroid 2-related factor 2; Oxidative stress index; Total antioxidant status; Total oxidant status

Resumen

Introducción: Los estudios sobre los niveles del factor 2 relacionado con el factor nuclear eritroide 2 (Nrf2) y la hemo oxigenasa-1 (HO-1) en pacientes con COVID-19 son limitados. Este estudio tuvo como objetivo investigar la relación entre algunos biomarcadores del estado oxidante-antioxidante con la enfermedad COVID-19.
Material y métodos: Se incluyeron en este estudio los pacientes mayores de 18 años que dieron positivo a PCR (reacción en cadena de la polimerasa) de SARS CoV-2 con síntomas y signos clínicos. Se analizaron el estado antioxidante total (TAS), el estado antioxidante total (TOS), el índice de estrés oxidativo (OSI) y los niveles de HO-1 y Nrf2 a partir de muestras de suero tomadas antes y después del tratamiento.
Resultados: En este estudio se incluyeron 16 pacientes seguidos con diagnóstico de COVID-19. 9 (56,3%) de los pacientes eran mujeres y 7 (43,8%) eran hombres. La edad media fue 33,75 ± 17,03 años. Todos los pacientes presentaban síntomas y fueron hospitalizados para seguimiento. Se determinó que los valores de Nrf2 y HO-1 aumentaron significativamente después del tratamiento. Además, hubo una correlación positiva significativa entre los valores de Nrf2 y TAS y TAS aumenta significativamente en paralelo a un aumento en Nrf2, y también hubo una correlación significativa pero negativa entre Nrf2 y los valores de TOS y OSI y, por lo tanto, un aumento en Nrf2 condujo a una disminución en los valores TOS y OSI. Hubo una correlación positiva significativa entre HO-1 y TAS, y TAS aumentó significativamente a medida que aumentaba HO-1.
Conclusiones: La disminución de TOS y OSI y el aumento de Nrf2 y HO-1 durante el período de seguimiento en pacientes con COVID-19 sugieren que el cuerpo intenta prevenir el estrés oxidativo relacionado con ROS a través de Nrf2 y HO-1 y que el estrés oxidativo puede tener un papel clave en la fisiopatología de COVID-19.

Palabras clave

COVID-19; Hemo oxigenasa-1; Factor nuclear eritroide 2; Índide de estrés oxidativo; Estado antioxidante total; Estado oxidante total

References

1. Msemburi W, Karlinsky A, Knutson V, Aleshin-Guendel S, Chatterji S, Wakefield J. The WHO estimates of excess mortality associated with the COVID-19 pandemic. Nature. 2023;613(7942):130-7. doi: 10.1038/s41586-022-05522-2.
2. COVID-19 Excess Mortality Collaborators. Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020-21. Lancet. 2022;399(10334):1513-36. doi: 10.1016/S0140-6736(21)02796-3.
3. Rabi FA, Al Zoubi MS, Kasasbeh GA, Salameh DM, Al-Nasser AD. SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far. Pathogens. 2020;9(3):231. doi: 10.3390/pathogens9030231.
4. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5.
5. Pincemail J, Cavalier E, Charlier C, Cheramy-Bien JP, Brevers E, Courtois A, et al. Oxidative Stress Status in COVID-19 Patients Hospitalized in Intensive Care Unit for Severe Pneumonia. A Pilot Study. Antioxidants (Basel). 2021;10(2):257. doi: 10.3390/antiox10020257.
6. Robert L, Labat-Robert J. Stress in biology and medicine, role in aging. Pathol Biol (Paris). 2015;63(4-5):230-4. doi: 10.1016/j.patbio.2015.07.008.
7. Zinovkin RA, Grebenchikov OA. Transcription Factor Nrf2 as a Potential Therapeutic Target for Prevention of Cytokine Storm in COVID-19 Patients. Biochemistry (Mosc). 2020;85(7):833-7. doi: 10.1134/S0006297920070111.
8. Alcaraz MJ, Fernández P, Guillén MI. Anti-inflammatory actions of the heme oxygenase-1 pathway. Curr Pharm Des. 2003;9(30):2541-51. doi: 10.2174/1381612033453749.
9. General Directorate of Public Health Republic of Turkey Ministry of Health [Internet]. COVID-19 (SARS-CoV-2 Infection) Guide. Scientific Committee Study. Available from: https://covid19bilgi.saglik.gov.tr/depo/rehberler/COVID-19_Rehberi.pdf (accessed 10 May 2022).
10. Sies H. Oxidative stress: a concept in redox biology and medicine. Redox Biol. 2015;4:180-3. doi: 10.1016/j.redox.2015.01.002.
11. Suhail S, Zajac J, Fossum C, Lowater H, McCracken C, Severson N, et al. Role of Oxidative Stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) Infection: A Review. Protein J. 2020;39(6):644-56. doi: 10.1007/s10930-020-09935-8.
12. Tarpey MM, Wink DA, Grisham MB. Methods for detection of reactive metabolites of oxygen and nitrogen: in vitro and in vivo considerations. Am J Physiol Regul Integr Comp Physiol. 2004;286(3):R431-44. doi: 10.1152/ajpregu.00361.2003.
13. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38(12):1103-11. doi: 10.1016/j.clinbiochem.2005.08.008.
14. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 2004;37(4):277-85. doi: 10.1016/j.clinbiochem.2003.11.015.
15. Harma M, Harma M, Erel O. Increased oxidative stress in patients with hydatidiform mole. Swiss Med Wkly. 2003;133(41-42):563-6. doi: 10.4414/smw.2003.10397.
16. Sánchez-Rodríguez MA, Mendoza-Núñez VM. Oxidative Stress Indexes for Diagnosis of Health or Disease in Humans. Oxid Med Cell Longev. 2019;2019:4128152. doi: 10.1155/2019/4128152.
17. Karkhanei B, Talebi Ghane E, Mehri F. Evaluation of oxidative stress level: total antioxidant capacity, total oxidant status and glutathione activity in patients with COVID-19. New Microbes New Infect. 2021;42:100897. doi: 10.1016/j.nmni.2021.100897.
18. Mehri F, Rahbar AH, Ghane ET, Souri B, Esfahani M. Changes in oxidative markers in COVID-19 patients. Arch Med Res. 2021;52(8):843-9. doi: 10.1016/j.arcmed.2021.06.004.
19. Aykac K, Ozsurekci Y, Yayla BCC, Gurlevik SL, Oygar PD, Bolu NB, et al. Oxidant and antioxidant balance in patients with COVID-19. Pediatr Pulmonol. 2021;56(9):2803-10. doi: 10.1002/ppul.25549.
20. Gümüş H, Erat T, Öztürk İ, Demir A, Koyuncu I. Oxidative stress and decreased Nrf2 level in pediatric patients with COVID-19. J Med Virol. 2022;94(5):2259-64. doi: 10.1002/jmv.27640.
21. Su WL, Lin CP, Hang HC, Wu PS, Cheng CF, Chao YC. Desaturation and heme elevation during COVID-19 infection: A potential prognostic factor of heme oxygenase-1. J Microbiol Immunol Infect. 2021;54(1):113-6. doi: 10.1016/j.jmii.2020.10.001.
22. Ma LL, Zhang P, Wang HQ, Li YF, Hu J, Jiang JD, et al. heme oxygenase-1 agonist CoPP suppresses influenza virus replication through IRF3-mediated generation of IFN-α/β. Virology. 2019;528:80-8. doi: 10.1016/j.virol.2018.11.016.
23. Espinoza JA, León MA, Céspedes PF, Gómez RS, Canedo-Marroquín G, Riquelme SA, et al. Heme Oxygenase-1 Modulates Human Respiratory Syncytial Virus Replication and Lung Pathogenesis during Infection. J Immunol. 2017;199(1):212-23. doi: 10.4049/jimmunol.1601414.
24. Rossi M, Piagnerelli M, Van Meerhaeghe A, Zouaoui Boudjeltia K. Heme oxygenase-1 (HO-1) cytoprotective pathway: A potential treatment strategy against coronavirus disease 2019 (COVID-19)-induced cytokine storm syndrome. Med Hypotheses. 2020;144:110242. doi: 10.1016/j.mehy.2020.110242.
25. McCord JM, Hybertson BM, Cota-Gomez A, Gao B. Nrf2 activator PB125® as a carnosic acid-based therapeutic agent against respiratory viral
diseases, including COVID-19. Free Radic Biol Med. 2021;175:56-64. doi: 10.1016/j.freeradbiomed.2021.05.033.
26. Cuadrado A, Pajares M, Benito C, Jiménez-Villegas J, Escoll M, Fernández-Ginés R, et al. Can Activation of NRF2 Be a Strategy against COVID-19? Trends Pharmacol Sci. 2020;41(9):598-610. doi: 10.1016/j.tips.2020.07.003.
27. Wu YH, Tseng CP, Cheng ML, Ho HY, Shih SR, Chiu DT. Glucose-6-phosphate dehydrogenase deficiency enhances human coronavirus 229E infection. J Infect Dis. 2008;197(6):812-6. doi: 10.1086/528377.
28. 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;11(1):4938. doi: 10.1038/s41467-020-18764-3.
29. Gorse GJ, O'Connor TZ, Hall SL, Vitale JN, Nichol KL. Human coronavirus and acute respiratory illness in older adults with chronic obstructive pulmonary disease. J Infect Dis. 2009;199(6):847-57. doi: 10.1086/597122.
30. Turgunova L, Mekhantseva I, Bacheva I, Amirkhanova D, Butyugina M, Samoilova N. Prognostic factors for the severe course of COVID-19 in the different COVID-19 peak periods in Central Kazakhstan. J Clin Med Kaz. 2022;19(4):53-8. doi: 10.23950/jcmk/12293.
31. Binici İ, Alp HH, Huyut Z, Gürbüz E, Günbatar H, Akmeşe Ş, et al. The Status of Antioxidants and Oxidative Damage in Patients with COVID-19. Ahi Evran Medical Journal. 2023;7(1):114-23. doi: 10.46332/aemj.1152479.
32. Küçük U, Alkan Çeviker S, Şener A. Relationship between in-hospital mortality and inflammation markers in COVID-19 patients with the diagnosis of coronary artery disease. J Contemp Med. 2021;11(3):267-71. doi: 10.16899/jcm.869095.


Submitted date:
05/25/2023

Reviewed date:
09/09/2023

Accepted date:
10/04/2023

Publication date:
10/18/2023

653006d9a9539574cb67ccb2 iberoamericanjm Articles
Links & Downloads

Iberoam J Med

Share this page
Page Sections