N-Acetyl Cysteine Restores the Diminished Activity of the Antioxidant Enzymatic System Caused by SARS-CoV-2 Infection: Preliminary Findings
María Elena Soto, Linaloe Manzano-Pech, Adrían Palacios-Chavarría, Rafael Ricardo Valdez-Vázquez, Verónica Guarner-Lans, Israel Pérez-Torres
Pharmaceuticals, doi:10.3390/ph16040591
SARS-CoV-2 infects type II pneumocytes and disrupts redox homeostasis by overproducing reactive oxygen species (ROS). N-acetyl cysteine (NAC) is a precursor of the synthesis of glutathione (GSH) and it restores the loss of redox homeostasis associated to viral infections. The aim of the study is to evaluate the effect of the treatment with NAC on the enzymatic antioxidant system in serum from patients infected by SARS-CoV-2. We evaluated the enzymatic activities of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), -S-transferase (GST), and reductase (GR) by spectrophotometry and the concentrations of the glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO 2 -), and lipid peroxidation (LPO) in serum. The activity of the extracellular super oxide dismutase (ecSOD) was determined by native polyacrylamide gels, and 3-nitrotyrosine (3-NT) was measured by ELISA. A decrease in the activities of the ecSOD, TrxR, GPx, GST GR, (p = 0 ≤ 0.1), and the GSH, TAC, thiols, and NO 2 -(p ≤ 0.001) concentrations and an increase in LPO and 3-NT (p = 0.001) concentrations were found in COVID-19 patients vs. healthy subjects. The treatment with NAC as an adjuvant therapy may contribute to a reduction in the OS associated to the infection by SARS-CoV-2 through the generation of GSH. GSH promotes the metabolic pathways that depend on it, thus contributing to an increase in TAC and to restore redox homeostasis.
Institutional Review Board Statement: The studies involving human participants were reviewed and approved by ethical approval from the local ethics committee on 19 August 2020 (Control-9867/2020, register REG. CONBIOETICA-09 CEI-011-20160627). A written informed consent for enrollment or consent to use patient data was obtained from each patient or their legal surrogate. The protocol was registered (TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT 04570254).
Informed Consent Statement: The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Conflicts of Interest: The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.
References
Abbas, Verma, Verma, Siddiqui, Khan et al., Association of GSTM1 and GSTT1 gene polymorphisms with COVID-19 susceptibility and its outcome, J. Med. Virol,
doi:10.1002/jmv.27076Aisa-Alvarez, Soto, Guarner-Lans, Camarena-Alejo, Franco-Granillo et al., Usefulness of antioxidants as adjuvant therapy for septic shock: A randomized clinical trial, Medicina,
doi:10.3390/medicina56110619Aldini, Altomare, Baron, Vistoli, Carini et al., Acetylcysteine as an antioxidant and disulphide breaking agent: The reasons why, Free. Radic. Res,
doi:10.1080/10715762.2018.1468564Alsayed, Mir, Severe COVID-19 Pneumonia and genetic susceptibility: A case report and literature review, Cureus,
doi:10.7759/cureus.23636Beckman, Ischiropoulos, Zhu, Van Der Woerd, Smith et al., Kinetics of superoxide dismutase-and iron-catalyzed nitration of phenolics by peroxynitrite, Arch. Biochem. Biophys
Brower, Lanken, Macintyre, Matthay, Morris et al., National heart, lung, and blood institute ARDS clinical trials network higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome, N. Engl. J. Med
Brücksken, Palacio, Hanschmann, Thiol modifications in the extracellular space-key proteins in inflammation and viral infection, Front. Immunol,
doi:10.3389/fimmu.2022.932525Busch, Timmermans, Van Kuijk, Aendekerk, Ysermans et al., Thrombin formation via the intrinsic coagulation pathway and von Willebrand factor reflect disease severity in COVID-19, Haematologica,
doi:10.3324/haematol.2022.281693Castelli, Pelosi, Testa, Liver cancer: Molecular characterization, clonal evolution and cancer stem cells, Cancers,
doi:10.3390/cancers9090127Chavarría, Vázquez, Cherit, Bello, Suastegui et al., Antioxidants and pentoxifylline as coadjuvant measures to standard therapy to improve prognosis of patients with pneumonia by COVID-19, Comput. Struct. Biotechnol. J,
doi:10.1016/j.csbj.2021.02.009Cho, Bang, Gurung, Meng Li Clemens, Underhill et al., Retinoid regulation of antiviral innate immunity in hepatocytes, Hepatology,
doi:10.1002/hep.28380Dairou, Pluvinage, Noiran, Petit, Vinh et al., Nitration of a critical tyrosine residue in the allosteric inhibitor site of muscle glycogen phosphorylase impairs its catalytic activity, J. Mol. Biol,
doi:10.1016/j.jmb.2007.07.011De Flora, Balansky, La Maestra, Rationale for the use of N -acetylcysteine in both prevention and adjuvant therapy of COVID-19, FASEB J,
doi:10.1096/fj.202001807Engin, Engin, Engin, Can iron, zinc, copper and selenium status be a prognostic determinant in COVID-19 patients?, Environ. Toxicol. Pharmacol,
doi:10.1016/j.etap.2022.103937Erel, Neselioglu, A novel and automated assay for thiol/disulphide homeostasis, Clin. Biochem
Fitero, Bungau, Tit, Endres, Khan et al., Comorbidities, associated diseases, and risk assessment in COVID-19. A systematic review, Int. J. Clin. Pract
Goud, Bai, Abu-Soud, A Multiple-hit hypothesis involving reactive oxygen species and myeloperoxidase explains clinical deterioration and fatality in COVID-19, Int. J. Biol. Sci,
doi:10.7150/ijbs.51811Guimarães, Timerman, Rodrigues, Corrêa, Schubert et al., Position statement: Cardiopulmonary resuscitation of patients with confirmed or suspected COVID-19-2020, Arq. Bras. Cardiol
Hanumanram, Suthakaran, Mohanan, Nair, Rajendran, Extracellular oxidative stress markers in COVID-19 Patients with diabetes as co-morbidity, Clin. Pract
Heitmann, Bilich, Tandler, Nelde, Maringer et al., A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity, Nature,
doi:10.1038/s41586-021-04232-5Hiffler, Rakotoambinina, Selenium and RNA Virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19), Front. Nutr,
doi:10.3389/fnut.2020.00164Ho, Douglas, Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte/macrophages in vitro AIDS, Res. Hum. Retrovir
Izquierdo-Alonso, Pérez-Rial, Rivera, Peces-Barba, N-acetylcysteine for prevention and treatment of COVID-19: Current state of evidence and future directions, J. Infect. Public Health,
doi:10.1016/j.jiph.2022.11.009Lambden, Laterre, Levy, Francois, The SOFA score-development, utility, and challenges of accurate assessment in clinical trials, Crit. Care,
doi:10.1186/s13054-019-2663-7Manz, Bogaard, Aman, Regulation of VWF (Von Willebrand Factor) in inflammatory thrombosis, Arterioscler. Thromb. Vasc. Biol,
doi:10.1161/ATVBAHA.122.318179Maradi, Joshi, Balamurugan, Thomas, Goud, Importance of microminerals for maintaining antioxidant function after COVID-19-induced oxidative stress, Rep. Biochem. Mol. Biol,
doi:10.52547/rbmb.11.3.479Martín-Fernández, Aller, Heredia-Rodríguez, Gómez-Sánchez, Martínez-Paz et al., Lipid peroxidation as a hallmark of severity in COVID-19 patients, Redox. Biol,
doi:10.1016/j.redox.2021.102181Muhammad, Kani, Iliya, Muhammad, Binji et al., Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: A cross-sectional comparative study in Jigawa, Northwestern Nigeria, SAGE Open Med,
doi:10.1177/2050312121991246Naghashpour, Ghiassian, Mobarak, Adelipour, Piri et al., Profiling serum levels of glutathione reductase and interleukin-10 in positive and negative-PCR COVID-19 outpatients: A comparative study from southwestern Iran, Med. Virol,
doi:10.1002/jmv.27464Naveenkumar, Hemshekhar, Jagadish, Manikanta, Vishalakshi et al., Melatonin restores neutrophil functions and prevents apoptosis amid dysfunctional glutathione redox system, J. Pineal. Res
Negru, Radu, Vesa, Behl, Abdel-Daim et al., Therapeutic dilemmas in addressing SARS-CoV-2 infection: Favipiravir versus Remdesivir, Biomed. Pharmacother,
doi:10.1016/j.biopha.2022.112700Pérez-Torres, Guarner-Lans, Soria-Castro, Manzano-Pech, Palacios-Chavarría et al., Alteration in the lipid profile and the desaturases activity in patients with severe pneumonia by SARS-CoV-2, Front. Physiol,
doi:10.3389/fphys.2021.667024Pérez-Torres, Manzano-Pech, Guarner-Lans, Soto, Castrejón-Téllez et al., Deodorized garlic decreases oxidative stress caused by lipopolysaccharide in rat heart through hydrogen sulfide: Preliminary Findings, Int. J. Mol. Sci,
doi:10.3390/ijms232012529Pérez-Torres, Manzano-Pech, Rubio-Ruíz, Soto, Guarner-Lans, Nitrosative stress and its association with cardiometabolic disorders, Molecules,
doi:10.3390/molecules25112555Ranieri, Rubenfeld, Thompson, Ferguson, Caldwell et al., Acute respiratory distress syndrome: The Berlin Definition, JAMA
Raza, Dual localization of glutathione S-transferasa in the cytosol and mitochondria: Implications in oxidative stress, toxicity and disease, FEBS. Lett,
doi:10.1111/j.1742-4658.2011.08358.xRodríguez-Fierros, Guarner-Lans, Soto, Manzano-Pech, Díaz-Díaz et al., Modulation of renal function in a metabolic syndrome rat model by Antioxidants in Hibiscus sabdariffa L, Molecules,
doi:10.3390/molecules26072074Santus, Danzo, Zuffi, Pini, Saad et al., Oxidative stress and viral infections: Rationale, experiences, and perspectives on N-acetylcysteine, Eur. Rev. Med. Pharmacol. Sci
Semenova, Rychkova, Darenskaya, Kolesnikov, Nikitina et al., Superoxide dismutase activity in male and female patients of different age with moderate COVID-19, Bull. Exp. Biol. Med,
doi:10.1007/s10517-022-05491-6Sentman, Granström, Jakobson, Reaume, Basu et al., Phenotypes of mice lacking extracellular superoxide dismutase and copper-and zinc-containing superoxide dismutase, J. Biol. Chem,
doi:10.1074/jbc.M510764200Shi, Puyo, N-Acetylcysteine to combat COVID-19: An evidence review, Ther. Clin. Risk. Manag
Singh, Dhindsa, Misra, Singh, SARS-CoV2 infectivity is potentially modulated by host redox status, Comput. Struct. Biotechnol. J,
doi:10.1016/j.csbj.2020.11.016Soria-Castro, Soto, Guarner-Lans, Rojas, Perezpeña-Diazconti et al., The kidnapping of mitochondrial function associated with the SARS-CoV-2 infection, Histol. Histopathol
Soto, Guarner-Lans, Díaz-Díaz, Manzano-Pech, Palacios-Chavarría et al., Hyperglycemia and Loss of Redox Homeostasis in COVID-19 Patients, Cells
Soto, Guarner-Lans, Soria-Castro, Manzano-Pech, Pérez-Torres, Is antioxidant therapy a useful complementary measure for COVID-19 treatment? An algorithm for tts application, Medicina,
doi:10.3390/medicina56080386Tavassolifar, Aghdaei, Sadatpour, Maleknia, Fayazzadeh et al., New insights into extracellular and intracellular redox status in COVID-19 patients, Redox. Biol
Taylor, Radding, Understanding Selenium and Glutathione as Antiviral Factors in COVID-19: Does the viral M pro protease target host selenoproteins and glutathione synthesis? Front, Nutr,
doi:10.3389/fnut.2020.00143Thachil, Tang, Gando, Falanga, Cattaneo et al., ISTH interim guidance on recognition and management of coagulopathy in COVID-19, J. Thromb. Haemost,
doi:10.1111/jth.14810Yaghoubi, Youssefi, Azad, Farzad, Yavari et al., Total antioxidant capacity as a marker of severity of COVID-19 infection: Possible prognostic and therapeutic clinical application, J. Med. Virol,
doi:10.1002/jmv.27500
