J. Pharm. Pharmacogn. Res., vol. 11, no. 1, pp. 63-75, January-February 2023.

DOI: https://doi.org/10.56499/jppres22.1535_11.1.63

Original Article

Oxidative stress in diverse clinical conditions of SARS-CoV-2 Cuban hospitalized patients

[Estrés oxidativo en diferentes condiciones clínicas de pacientes cubanos hospitalizados con SARS-CoV-2]

Lizette Gil-del Valle^1*, Rosario Gravier-Hernández¹, Mario M. Delgado-Guerra², Joniel A. Sánchez-Márquez², Olga E. López-Fernández², Miguel A. Acosta-Suárez¹, Teresa Rosell-Guerra¹, Rodolfo Suárez-Iznaga³, Raiza Martínez-Casanueva³, Zullyt Zamora-Rodriguez⁴, Lidia A. Fernández-García⁴, Yusimit Bermudez-Alfonso¹, María C. Hernández-Gonzalez-Abreu¹, Gabino Garrido^5**

¹Institute “Pedro Kourí” (IPK), Havana, Cuba.

²Hospital Ernesto Guevara, University of Informatics’ Science, Havana, Cuba.

³Hospital Salvador Allende, Havana, Cuba.

⁴National Center of Scientific Research, BioCubaFarma, Havana, Cuba.

⁵Departamento de Ciencias Farmacéuticas, Facultad de Ciencias, Universidad Católica del Norte, Antofagasta, Chile.

*E-mail: ^*lgil@ipk.sld.cu, ^**gabino.garrido@ucn.cl

Abstract

Context: COVID-19 related to SARS-CoV-2 infection generates inflammation with increased reactive oxygen species production. Drug treatment and others factors could influence systemic oxidative stress during pathogenic insult.

Aims: To determine the redox status in COVID-19 patients with different clinical conditions and explore the relationship between redox and hematological hemochemical variables.

Methods: In this comparative longitudinal study, blood samples were drawn from 160 individuals divided into four groups: COVID-19 asymptomatic, COVID-19 symptomatic (low and moderate symptoms), COVID-19 convalescent, and presumable healthy subjects. Demographic, redox, hematological, and hemochemical indices were assessed. Statistical analyses compared the median values of each variable and explored individual, simultaneous indices, and multivariate alteration.

Results: Relative to the healthy group, acute COVID-19, and convalescent groups had significant differences in global damage indices and antioxidant status (p<0.05). The convalescent group showed significantly higher damage (malondialdehyde, advanced oxidation protein products, nitric oxide) and lower antioxidant enzymatic activities and glutathione concentration compared to other groups (p<0.05). Global modification of redox indices showed that more than 80% of studied individuals in acute conditions had simultaneous detrimental differences compared to a healthy status. The discriminant analysis permitted obtaining two canonical functions (p< 0.05) that reflect 98% of redox variables with 95% of variances with successful case classifications.

Conclusions: These results corroborate that oxidative stress occurred in different COVID-19 and post-acute conditions with different molecular alterations of redox indices. Redox diagnosis should be considered in early diagnosis and treatment of infection, which would be worthwhile to conduct a more comprehensive study and management of disease evolution.

Keywords: antioxidant status; COVID-19; oxidative stress; oxidative damage; SARS-CoV-2.

Resumen

Contexto: El COVID-19 relacionado con la infección por SARS-CoV-2 genera inflamación con aumento de la producción de especies reactivas del oxígeno. El tratamiento farmacológico y otros factores podrían influir en el estrés oxidativo sistémico durante el insulto patogénico.

Objetivos: Determinar el estado redox en pacientes con COVID-19 con diferentes condiciones clínicas y explorar la relación entre las variables redox y hemoquímicas.

Métodos: En este estudio longitudinal comparativo, se extrajeron muestras de sangre de 160 individuos divididos en cuatro grupos: COVID-19 asintomáticos, COVID-19 sintomáticos (síntomas bajos y moderados), COVID-19 convalecientes y sujetos presuntamente sanos. Se evaluaron los índices demográficos, redox, hematológicos y hemoquímicos. Los análisis estadísticos compararon los valores medios de cada variable y exploraron las alteraciones en los índices individuales, simultáneos y multivariadas.

Resultados: En relación con el grupo sano, los grupos COVID-19 agudo y convaleciente presentaron diferencias significativas en los índices de daño global y en el estado antioxidante (p<0,05). El grupo convaleciente mostró un daño significativamente mayor (malondialdehído, productos proteicos de oxidación avanzada, óxido nítrico) y menores actividades enzimáticas antioxidantes y concentración de glutatión en comparación con los otros grupos (p<0,05). La modificación global de los índices redox mostró que más del 80% de los individuos estudiados tenían diferencias perjudiciales simultáneas en comparación con el estado saludable. El análisis discriminante permitió obtener dos funciones canónicas (p< 0,05) que reflejan el 98% de las variables redox con el 95% de las varianzas con clasificaciones de casos acertadas.

Conclusiones: Estos resultados corroboran que el estrés oxidativo se presentó en diferentes COVID-19 y condiciones post-agudas con diferentes alteraciones moleculares de los índices redox. El diagnóstico redox debe ser considerado en el diagnóstico y tratamiento precoz de la infección, lo que valdría la pena para realizar un estudio y manejo más exhaustivo de la evolución de la enfermedad.

Palabras Clave: daño oxidativo; COVID-19; estado antioxidante; estrés oxidativo; SARS-CoV-2.

Citation Format: Gil-del Valle L, Gravier-Hernández R, Delgado-Guerra MM, Sánchez-Márquez JA, López-Fernández OE, Acosta-Suárez MA, Rosell-Guerra T, Suárez-Iznaga R, Martínez-Casanueva R, Zamora-Rodriguez Z, Fernández-García LA, Bermudez-Alfonso Y, Hernández-Gonzalez-Abreu MC, Garrido G (2023) Oxidative stress in diverse clinical conditions of SARS-CoV-2 Cuban hospitalized patients. J Pharm Pharmacogn Res 11(1): 63–75. https://doi.org/10.56499/jppres22.1535_11.1.63

References

Ahmed SM, Luo L, Namani A, Wang XJ, Tang X (2017) Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis 1863(2): 585–597. https://doi.org/10.1016/j.bbadis.2016.11.005

Amatore D, Sgarbanti R, Aquilano K, Baldelli S, Limongi D, Civitelli L, Nencioni L, Garaci E, Ciriolo MR, Palamara AT (2015) Influenza virus replication in lung epithelial cells depends on redox-sensitive pathways activated by NOX4-derived ROS. Cell Microbiol 17(1): 131–45. https://doi.org/10.1111/cmi.12343

Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W, Brüggen MC, O’Mahony L, Gao Y, Nadeau K, Akdis CA (2020) Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 75(7): 1564–1581. https://doi.org/10.1111/all.14364

Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL (2009) Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem 390(3): 191–214. https://doi.org/10.1515/BC.2009.033

Bhaskar S, Sinha A, Banach M, Mittoo S, Weissert R, Kass JS, Rajagopal S, Pai AR, Kutty S (2020) Cytokine storm in COVID-19-immunopathological mechanisms, clinical considerations, and therapeutic approaches: The REPROGRAM Consortium position paper. Front Immunol 11: 1648. https://doi.org/10.3389/fimmu.2020.01648

Cecchini R, Cecchini AL (2020) SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med Hypotheses 143: 110102. https://doi.org/10.1016/j.mehy.2020.110102

Ceriello A, Testa R (2009) Antioxidant anti-inflammatory treatment in type 2 diabetes. Diabetes Care 32 Suppl 2(Suppl 2): S232–S236. https://doi.org/10.2337/dc09-S316

Channappanavar R, Perlman S (2017) Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 39(5): 529–539. https://doi.org/10.1007/s00281-017-0629-x

Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L (2020a) Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395(10223): 507–513. https://doi.org/10.1016/S0140-6736(20)30211-7

Chen R, Sang L, Jiang M, Yang Z, Jia N, Fu W, Xie J, Guan W, Liang W, Ni Z, Hu Y, Liu L, Shan H, Lei C, Peng Y, Wei L, Liu Y, Hu Y, Peng P, Wang J, Liu J, Chen Z, Li G, Zheng Z, Qiu S, Luo J, Ye C, Zhu S, Zheng J, Zhang N, Li Y, He J, Li J, Li S, Zhong N; Medical Treatment Expert Group for COVID-19 (2020b) Longitudinal hematologic and immunologic variations associated with the progression of COVID-19 patients in China. J Allergy Clin Immunol 146(1): 89–100. https://doi.org/10.1016/j.jaci.2020.05.003

Chiscano-Camón L, Ruiz-Rodriguez JC, Ruiz-Sanmartin A, Roca O, Ferrer R (2020) Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome. Crit Care 24(1): 522. https://doi.org/10.1186/s13054-020-03249-y

Clairborne A (1986) Catalase activity. In: Green-Wald R, editor. Handbook of Methods for Oxygen Radical Research. Boca Ratón: CRC Press, p. 283–284.

Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, Kritas SK (2020) Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 34(2): 327–331. https://doi.org/10.23812/CONTI-E

Dasgupta A, Kalhan A, Kalra S (2020) Long term complications and rehabilitation of COVID-19 patients. J Pak Med Assoc 70(Suppl 3)(5): S131-S135. https://doi.org/10.5455/JPMA.32

Deavall DG, Martin EA, Horner JM, Roberts R (2012) Drug-induced oxidative stress and toxicity. J Toxicol 2012: 645460. https://doi.org/10.1155/2012/645460

Delgado-Roche L, Mesta F (2020) Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res 51(5): 384–387. https://doi.org/10.1016/j.arcmed.2020.04.019

Di Meo S, Reed TT, Venditti P, Victor VM (2016) Role of ROS and RNS sources in physiological and pathological conditions. Oxid Med Cell Longev 2016: 1245049. https://doi.org/10.1155/2016/1245049

Dosch SF, Mahajan SD, Collins AR (2009) SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro. Virus Res 142(1-2): 19–27. https://doi.org/10.1016/j.virusres.2009.01.005

Dysangco A, Liu Z, Stein JH, Dubé MP, Gupta SK (2017) HIV infection, antiretroviral therapy, and measures of endothelial function, inflammation, metabolism, and oxidative stress. PLoS One 12(8): e0183511. https://doi.org/10.1371/journal.pone.0183511

Erdelmeier I, Gérard-Monnier D, Yadan JC, Chaudière J (1998) Reactions of N-methyl-2-phenylindole with malondialdehyde and 4-hydroxyalkenals. Mechanistic aspects of the colorimetric assay of lipid peroxidation. Chem Res Toxicol 11(10): 1184–1194. https://doi.org/10.1021/tx970180z

Fakhri S, Nouri Z, Moradi SZ, Farzaei MH (2020) Astaxanthin, COVID-19 and immune response: Focus on oxidative stress, apoptosis and autophagy. Phytother Res 34(11): 2790–2792. https://doi.org/10.1002/ptr.6797

Fang FC (2011) Antimicrobial actions of reactive oxygen species. mBio 2(5): e00141–11. https://doi.org/10.1128/mBio.00141-11

Gadotti AC, Lipinski AL, Vasconcellos FT, Marqueze LF, Cunha EB, Campos AC, Oliveira CF, Amaral AN, Baena CP, Telles JP, Tuon FF, Pinho RA (2021) Susceptibility of the patients infected with Sars-Cov2 to oxidative stress and possible interplay with severity of the disease. Free Radic Biol Med 165: 184–190. https://doi.org/10.1016/j.freeradbiomed.2021.01.044

Gemelli Against COVID-19 Post-Acute Care Study Group (2020) Post-COVID-19 global health strategies: the need for an interdisciplinary approach. Aging Clin Exp Res 32(8): 1613–1620. https://doi.org/10.1007/s40520-020-01616-x

Goud PT, Bai D, Abu-Soud HM (2021) A multiple-hit hypothesis involving reactive oxygen species and myeloperoxidase explains clinical deterioration and fatality in COVID-19. Int J Biol Sci 17(1): 62–72. https://doi.org/10.7150/ijbs.51811

Granger DL, Taintor RR, Boockvar KS, Hibbs JB, Jr. (1996) Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. Methods Enzymol 268: 142-151. https://doi.org/10.1016/s0076-6879(96)68016-1

Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L (2020) Management of post-acute covid-19 in primary care. BMJ 370: m3026. https://doi.org/10.1136/bmj.m3026

Ifrim DC, Quintin J, Joosten LA, Jacobs C, Jansen T, Jacobs L, Gow NA, Williams DL, van der Meer JW, Netea MG (2014) Trained immunity or tolerance: opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clin Vaccine Immunol 21(4): 534–545. https://doi.org/10.1128/CVI.00688-13

Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, Ermolaeva M, Veldhuizen R, Leung YH, Wang H, Liu H, Sun Y, Pasparakis M, Kopf M, Mech C, Bavari S, Peiris JS, Slutsky AS, Akira S, Hultqvist M, Holmdahl R, Nicholls J, Jiang C, Binder CJ, Penninger JM (2008) Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133(2): 235–249. https://doi.org/10.1016/j.cell.2008.02.043

Kalem AK, Kayaaslan B, Neselioglu S, Eser F, Hasanoglu İ, Aypak A, Akinci E, Akca HN, Erel O, Guner R (2021) A useful and sensitive marker in the prediction of COVID-19 and disease severity: Thiol. Free Radic Biol Med 166: 11–17. https://doi.org/10.1016/j.freeradbiomed.2021.02.009

Kemp HI, Corner E, Colvin LA (2020) Chronic pain after COVID-19: implications for rehabilitation. Br J Anaesth 125(4): 436–440. https://doi.org/10.1016/j.bja.2020.05.021

Khomich OA, Kochetkov SN, Bartosch B, Ivanov AV (2018) Redox biology of respiratory viral infections. Viruses 10(8): 392. https://doi.org/10.3390/v10080392

Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, Tanaka N, Moriguchi T, Motohashi H, Nakayama K, Yamamoto M (2016) Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun 7: 11624. https://doi.org/10.1038/ncomms11624

Kosanovic T, Sagic D, Djukic V, Pljesa-Ercegovac M, Savic-Radojevic A, Bukumiric Z, Lalosevic M, Djordjevic M, Coric V, Simic T (2021) Time course of redox biomarkers in COVID-19 pneumonia: Relation with inflammatory, multiorgan impairment biomarkers and CT findings. Antioxidants (Basel) 10(7): 1126. https://doi.org/10.3390/antiox10071126

Lee C (2018) Therapeutic modulation of virus-induced oxidative stress via the Nrf2-dependent antioxidative pathway. Oxid Med Cell Longev 2018: 6208067. https://doi.org/10.1155/2018/6208067

Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D, Gargiulo G, Testa G, Cacciatore F, Bonaduce D, Abete P (2018) Oxidative stress, aging, and diseases. Clin Interv Aging 13: 757–772. https://doi.org/10.2147/CIA.S158513

Liu C, Zhou Q, Li Y, Garner LV, Watkins SP, Carter LJ, Smoot J, Gregg AC, Daniels AD, Jervey S, Albaiu D (2020) Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent Sci 6(3): 315–331. https://doi.org/10.1021/acscentsci.0c00272

Majewska E, Kasielski M, Luczynski R, Bartosz G, Bialasiewicz P, Nowak D (2004) Elevated exhalation of hydrogen peroxide and thiobarbituric acid reactive substances in patients with community acquired pneumonia. Respir Med 98(7): 669–676. https://doi.org/10.1016/j.rmed.2003.08.015

Mao C, Yuan JQ, Lv YB, Gao X, Yin ZX, Kraus VB, Luo JS, Chei CL, Matchar DB, Zeng Y, Shi XM (2019) Associations between superoxide dismutase, malondialdehyde and all-cause mortality in older adults: a community-based cohort study. BMC Geriatr 19(1): 104. https://doi.org/10.1186/s12877-019-1109-z

Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47(3): 469–474. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x

Marrocco I, Altieri F, Peluso I (2017) Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev 2017: 6501046. https://doi.org/10.1155/2017/6501046

Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20(7): 1126–1167. https://doi.org/10.1089/ars.2012.5149

Muhammad Y, Kani YA, Iliya S, Muhammad JB, Binji A, El-Fulaty Ahmad A, Kabir MB, Umar Bindawa K, Ahmed A (2021) Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: A cross-sectional comparative study in Jigawa, Northwestern Nigeria. SAGE Open Med 9: 2050312121991246. https://doi.org/10.1177/2050312121991246

Muralidharan S, Mandrekar P (2013) Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J Leukoc Biol 94(6): 1167–1184. https://doi.org/10.1189/jlb.0313153

Palipoch S, Koomhin P (2015) Oxidative stress-associated pathology: A review. Sains Malays 44(10): 1441–1451.

Patlevič P, Vašková J, Švorc P, Jr., Vaško L, Švorc P (2016) Reactive oxygen species and antioxidant defense in human gastrointestinal diseases. Integr Med Res 5(4): 250–258. https://doi.org/10.1016/j.imr.2016.07.004

Phaniendra A, Jestadi DB, Periyasamy L (2015) Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem 30(1): 11–26. https://doi.org/10.1007/s12291-014-0446-0

Pickering AM, Vojtovich L, Tower J, A Davies KJ (2013) Oxidative stress adaptation with acute, chronic, and repeated stress. Free Radic Biol Med 55: 109–118. https://doi.org/10.1016/j.freeradbiomed.2012.11.001

Pincemail J, Cavalier E, Charlier C, Cheramy-Bien JP, Brevers E, Courtois A, Fadeur M, Meziane S, Goff CL, Misset B, Albert A, Defraigne JO, Rousseau AF (2021) Oxidative stress status in COVID-19 patients hospitalized in intensive care unit for severe pneumonia. A pilot study. Antioxidants (Basel) 10(2): 257. https://doi.org/10.3390/antiox10020257

Pisoschi AM, Pop A (2015) The role of antioxidants in the chemistry of oxidative stress: A review. Eur J Med Chem 97: 55–74. https://doi.org/10.1016/j.ejmech.2015.04.040

Polonikov A (2020) Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death in COVID-19 patients. ACS Infect Dis 6(7): 1558–1562. https://doi.org/10.1021/acsinfecdis.0c00288

Schaefer L (2014) Complexity of danger: the diverse nature of damage-associated molecular patterns. J Biol Chem 289(51): 35237–35245. https://doi.org/10.1074/jbc.R114.619304

Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10): R453–R462. https://doi.org/10.1016/j.cub.2014.03.034

Sebastiano M, Chastel O, de Thoisy B, Eens M, Costantini D (2016) Oxidative stress favours herpes virus infection in vertebrates: a meta-analysis. Curr Zool 62(4): 325–332. https://doi.org/10.1093/cz/zow019

Sies H, Berndt C, Jones DP (2017) Oxidative stress. Annu Rev Biochem 86: 715–748. https://doi.org/10.1146/annurev-biochem-061516-045037

Sies H, Jones DP (2020) Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 21(7): 363–383. https://doi.org/10.1038/s41580-020-0230-3

Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP (2020) The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 20(6): 363–374. https://doi.org/10.1038/s41577-020-0311-8

Vlahos R, Stambas J, Bozinovski S, Broughton BR, Drummond GR, Selemidis S (2011) Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation. PLoS Pathog 7(2): e1001271. https://doi.org/10.1371/journal.ppat.1001271

WHO (2020) Coronavirus disease (COVID-2019) situation reports 2020 [cited 13/7/2022][Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports

Witko-Sarsat V, Friedlander M, Nguyen Khoa T, Capeillère-Blandin C, Nguyen AT, Canteloup S, Dayer JM, Jungers P, Drüeke T, Descamps-Latscha B (1998) Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 161(5): 2524–2532.

Xuan Y, Gào X, Anusruti A, Holleczek B, Jansen E, Muhlack DC, Brenner H, Schöttker B (2019) Association of serum markers of oxidative stress with incident major cardiovascular events, cancer incidence, and all-cause mortality in type 2 diabetes patients: Pooled results from two cohort studies. Diabetes Care 42(8): 1436–1445. https://doi.org/10.2337/dc19-0292

Ye Q, Wang B, Mao J (2020) The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect 80(6): 607–613. https://doi.org/10.1016/j.jinf.2020.03.037

Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579(7798): 270–273. https://doi.org/10.1038/s41586-020-2012-7

© 2023 Journal of Pharmacy & Pharmacognosy Research (JPPRes)