Immune-Boosting and Antiviral Effects of Antioxidants in COVID-19 Pneumonia: A Therapeutic Perspective
Stefano Sanduzzi Zamparelli, Alessandro Sanduzzi Zamparelli, Marialuisa Bocchino
Life, doi:10.3390/life15010113
The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with pneumonia emerging as a major complication in severe cases. The pathogenesis of COVID-19 is marked by the overproduction of reactive oxygen species (ROS) and an excessive inflammatory response, resulting in oxidative stress and significant tissue damage, particularly in the respiratory system. Antioxidants have garnered considerable attention for their potential role in managing COVID-19 pneumonia by mitigating oxidative stress and modulating immune responses. This review provides a comprehensive overview of the literature on the use of antioxidants in hospitalized patients with mild-to-moderate COVID-19. Studies exploring antioxidants, including vitamins, trace elements, nitric oxide (NO), ozone (O3), glutathione (GSH), L-carnitine, melatonin, bromelain, N-acetylcysteine (NAC), and numerous polyphenols, have yielded promising outcomes. Through their ROS-scavenging properties, these molecules support endothelial function, reduce the thrombosis risk, and may help mitigate the effects of the cytokine storm, a key contributor to COVID-19 morbidity and mortality. Clinical evidence suggests that antioxidant supplementation may improve patient outcomes by decreasing inflammation, supporting immune cell function, and potentially shortening recovery times. Furthermore, these molecules may mitigate the symptoms of COVID-19 by exerting direct antiviral effects that inhibit the infection process and genomic replication of SARS-CoV-2 in host cells. Moreover, antioxidants may work synergistically with standard antiviral treatments to reduce viral-induced oxidative damage. By integrating findings from the literature with real-world data from our clinical experience, we gain a more profound understanding of the role of antioxidants in managing COVID-19 pneumonia. Further research combining comprehensive literature reviews with real-world data analysis is crucial to validate the efficacy of antioxidants and establish evidence-based guidelines for their use in clinical practice.
Conflicts of Interest: The authors declare no conflicts of interest.
References
Ahmadi, Mehrabi, Zare, Ghadir, Masoumi, Efficacy of Nanocurcumin as an Add-On Treatment for Patients Hospitalized with COVID-19: A Double-Blind, Randomized Clinical Trial, Int. J. Clin. Pract,
doi:10.1155/2023/5734675.100Alshammari, Fatima, Alraya, Khuzaim Alzahrani, Kamal et al., Selenium and COVID-19: A Spotlight on the Clinical Trials, Inventive Compositions, and Patent Literature, J. Infect. Public Health,
doi:10.1016/J.JIPH.2022.09.011.123Ambrosino, Sanduzzi Zamparelli, Mosella, Formisano, Molino et al., Clinical Assessment of Endothelial Function in Convalescent COVID-19 Patients: A Meta-Analysis with Meta-Regressions, Ann. Med,
doi:10.1080/07853890.2022.2136403Arabi, Hadi, Gholambareshi, Bahrami, Hazrati et al., The Effect of L-Carnitine Supplementation on Mortality and Clinical Outcomes in Ventilator-Dependent Critically Ill Patients with Obesity and COVID-19: Protocol for a Randomized Double-Blind Placebo-Controlled Trial, Contemp. Clin. Trials Commun,
doi:10.1016/J.CONCTC.2023.101082Batista, Cintra, Lucena, Manhães-De-Castro, Toscano et al., The Role of Vitamin B12 in Viral Infections: A Comprehensive Review of Its Relationship with the Muscle-Gut-Brain Axis and Implications for SARS-CoV-2 Infection, Nutr. Rev,
doi:10.1093/NUTRIT/NUAB092Bellamine, Pham, Jain, Wilson, Sahin et al., L-Carnitine Tartrate Downregulates the Ace2 Receptor and Limits SARS-Cov-2 Infection, Nutrients,
doi:10.3390/NU13041297Bertoncini-Silva, Vlad, Ricciarelli, Giacomo Fassini, Suen et al., Enhancing the Bioavailability and Bioactivity of Curcumin for Disease Prevention and Treatment, Antioxidants,
doi:10.3390/AN-TIOX13030331Biancatelli, Berrill, Catravas, Marik, Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19), Front. Immunol,
doi:10.3389/FIMMU.2020.01451.103Bohn, Hall, Sepiashvili, Jung, Steele et al., Pathophysiology of COVID-19: Mechanisms Underlying Disease Severity and Progression, Physiology,
doi:10.1152/PHYSIOL.00019.2020Bouillon, Leboff, Neale, Health Effects of Vitamin D Supplementation: Lessons Learned From Randomized Controlled Trials and Mendelian Randomization Studies, J. Bone Miner. Res,
doi:10.1002/JBMR.4888Camini, Da Silva Caetano, Almeida, De Brito Magalhães, Implications of Oxidative Stress on Viral Pathogenesis, Arch. Virol,
doi:10.1007/S00705-016-3187-YCarvajal, García-Castillo, Cuellar, Campillay-Véliz, Salazar-Ardiles et al., New Insights into the Pathogenesis of SARS-CoV-2 during and after the COVID-19 Pandemic, Front. Immunol,
doi:10.3389/FIMMU.2024.1363572Carvalho, Araujo, Da Silva, Da Silva, De Araújo et al., Retinol Levels and Severity of Patients with COVID-19, Nutrients,
doi:10.3390/NU15214642Castillo, Entrenas Costa, Vaquero Barrios, Alcalá Díaz, López Miranda et al., Effect of Calcifediol Treatment and Best Available Therapy versus Best Available Therapy on Intensive Care Unit Admission and Mortality among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical Study, J. Steroid Biochem. Mol. Biol,
doi:10.1016/J.JSBMB.2020.105751Cerullo, Negro, Parimbelli, Pecoraro, Perna et al., The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19, Front. Immunol,
doi:10.3389/FIMMU.2020.574029Chalmers, Crichton, Goeminne, Cao, Humbert et al., Management of Hospitalised Adults with Coronavirus Disease 2019 (COVID-19): A European Respiratory Society Living Guideline, Eur. Respir. J,
doi:10.1183/13993003.00048-2021Charoenngam, Holick, Immunologic Effects of Vitamin D on Human Health and Disease, Nutrients,
doi:10.3390/NU12072097Chen, Liu, Gao, Sun, Chao et al., Inhalation of Nitric Oxide in the Treatment of Severe Acute Respiratory Syndrome: A Rescue Trial in Beijing, Clin. Infect. Dis,
doi:10.1086/425357.128D'agnano, Scialò, Perna, Atripaldi, Sanduzzi et al., Exploring the Role of Krebs von Den Lungen-6 in Severe to Critical COVID-19 Patients, Life,
doi:10.3390/LIFE12081141De Wit, Van Doremalen, Falzarano, Munster, SARS and MERS: Recent Insights into Emerging Coronaviruses, Nat. Rev. Microbiol,
doi:10.1038/nrmicro.2016.81Desaki, Takizawa, Kasama, Kobayashi, Morita et al., Nuclear Factor-Kappa b Activation in Silica-Induced Interleukin 8 Production by Human Bronchial Epithelial Cells, Cytokine,
doi:10.1006/CYTO.2000.0704Dewan, Shinde, Glutathione an Effective Adjuvant Therapy for Acute Respiratory Distress Syndrome Associated with COVID-19 Infection, J. Adv. Med. Med. Res,
doi:10.9734/JAMMR/2022/V34I2231583Dhar, Bhattacharjee, Promising Role of Curcumin against Viral Diseases Emphasizing COVID-19 Management: A Review on the Mechanistic Insights with Reference to Host-Pathogen Interaction and Immunomodulation, J. Funct. Foods,
doi:10.1016/J.JFF.2021.104503Do, Kwon, Park, Lee, Effects of Vitamin D on Expression of Toll-like Receptors of Monocytes from Patients with Behçet's Disease, Rheumatology,
doi:10.1093/RHEUMATOLOGY/KEN109Dussault, George, Trullinger, Peroxides as Oxidative Enzyme Inhibitors: Mechanism-Based Inhibition of a Cysteine Protease by an Amino Acid Ozonide, Bioorg. Med. Chem. Lett,
doi:10.1016/S0960-894X(99)00563-6.138Erfani, Alizadeh, Faraji, Teymouri, Vitamin B12 Effectiveness in the Management of Hospitalized COVID-19 and Its Clinical Outcomes and Complications: A Randomized Clinical Trial, Health Sci. Rep,
doi:10.1002/HSR2.1509Essalmani, Jain, Susan-Resiga, Andréo, Evagelidis et al., Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity, J. Virol,
doi:10.1128/JVI.00128-22.107Fan, Zhu, Zheng, Zhang, Seidner et al., Magnesium Treatment on Methylation Changes of Transmembrane Serine Protease 2 (TMPRSS2), Nutrition,
doi:10.1016/J.NUT.2021.111340.120Farnoosh, Akbariqomi, Badri, Bagheri, Izadi et al., Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-Blind Clinical Trial, Arch. Med. Res,
doi:10.1016/J.ARC-MED.2021.06.006Florescu, Stanciu, Zaharia, Kosa, Codreanu et al., Intravenous Vitamin C for Patients Hospitalized with COVID-19: Two Harmonized Randomized Clinical Trials, JAMA,
doi:10.1001/JAMA.2023.21407Fowler, Truwit, Hite, Morris, Dewilde et al., Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial, JAMA,
doi:10.1001/JAMA.2019.11825Frontera, Rahimian, Yaghi, Liu, Lewis et al., Treatment with Zinc Is Associated with Reduced In-Hospital Mortality Among COVID-19 Patients: A Multi-Center Cohort Study, Res. Sq,
doi:10.21203/RS.3.RS-94509/V1.117Gain, Song, Angtuaco, Satta, Kelesidis, The Role of Oxidative Stress in the Pathogenesis of Infections with Coronaviruses, Front. Microbiol,
doi:10.3389/FMICB.2022.1111930Giovinazzo, Gerardi, Uberti-Foppa, Lopalco, Portillo, Potential Usefulness of Mediterranean Diet Polyphenols against COVID-19-Induced Inflammation: A Review of the Current Knowledge, J. Physiol. Biochem,
doi:10.3390/MOLECULES25245888Granada-Flor, Sousa, Filipe, Santos, De Almeida, Quercetin Dual Interaction at the Membrane Level, Chem. Commun,
doi:10.1039/C8CC09656B.108Grant, Lahore, Mcdonnell, Baggerly, French et al., Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths, Nutrients,
doi:10.3390/NU12040988Gruber-Bzura, High-Dose Vitamin C Supplementation as a Legitimate Anti-SARS-CoV-2 Prophylaxis in Healthy Subjects-Yes or No?, Nutrients,
doi:10.3390/NU14050979Guerrero-Romero, Micke, Simental-Mendía, Rodríguez-Morán, Vormann et al., Importance of Magnesium Status in COVID-19, Biology,
doi:10.3390/BIOLOGY12050735.121Guloyan, Oganesian, Baghdasaryan, Yeh, Singh et al., Glutathione Supplementation as an Adjunctive Therapy in COVID-19, Antioxidants,
doi:10.3390/ANTIOX9100914Hafizi, Kalanaky, Fakharzadeh, Karimi, Fakharian et al., Beneficial Effects of the Combination of BCc1 and Hep-S Nanochelating-Based Medicines on IL-6 in Hospitalized Moderate COVID-19 Adult Patients: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial, Trials,
doi:10.1186/S13063-023-07624-2.125Hakamifard, Soltani, Maghsoudi, Rismanbaf, Aalinezhad et al., The Effect of Vitamin E and Vitamin C in Patients with COVID-19 Pneumonia; a Randomized Controlled Clinical Trial, Immunopathol. Persa,
doi:10.34172/ipp.2022.08Hernández, Viñals, Pablos, Vilás, Papadakos et al., Ozone Therapy for Patients with COVID-19 Pneumonia: Preliminary Report of a Prospective Case-Control Study, Int. Immunopharmacol,
doi:10.1016/J.INTIMP.2020.107261Herold, Becker, Ridge, Budinger, Influenza Virus-Induced Lung Injury: Pathogenesis and Implications for Treatment, Eur. Respir. J,
doi:10.1183/09031936.00186214Huo, Tang, Li, Han, Gu et al., Melatonin Alleviates Lung Injury in H1N1-Infected Mice by Mast Cell Inactivation and Cytokine Storm Suppression, PLoS Pathog,
doi:10.1371/JOURNAL.PPAT.1011406Jahangirifard, Omidi, Sharifzadeh, Mirtajani, Peyravian et al., The Effect of Bromelain (Anaheal) on Clinical and Para-Clinical Parameters in Hospitalized COVID-19 Patients, Acta Med. Iran,
doi:10.18502/ACTA.V59I12.8066Jakovac, COVID-19 and Vitamin D-Is There a Link and an Opportunity for Intervention?, Am. J. Physiol.-Endocrinol. Metab,
doi:10.1152/AJPENDO.00138.2020Jeeva, Sunitha, Ananthalakshmi, Rajkumari, Ramesh et al., Enzymatic Antioxidants and Its Role in Oral Diseases, J. Pharm. Bioallied Sci,
doi:10.4103/0975-7406.163438Jnk, Kinase, ROS, reactive oxygen species; O2 -, anion superoxide; OH -, hydroxyl radicals; H2O2, hydrogen peroxide; NQO1, NADPH quinone oxidoreductase 1; PLpro, papain-like protease; RdRp, RNA-dependent RNA polymerase; GGH, glutathione; IFN-γ, interferon-γ; GSSG, oxidized glutathione; LTB4, leukotriene B4; NOX, NADPH oxidase; CPT-1, carnitine palmitoyltransferase; MDA, malondialdehyde; SOD, superoxide dismutase, G6PD, glucose 6-phosphate dehydrogenase; MIF-1, macrophage inhibitory factor-1; HNF4-α, hepatocyte nuclear factor 4-α; Mg, magnesium; TLR, Toll-like receptor; PAF, platelet-aggregating factor; RNS, reactive nitrogen species; NLRP3, NOD-like receptors family pyrin group containing 3; SIRT-1, sirtuin-1; O3, ozone; CAT, catalase; HO-1, hemeoxygenase; NAC, n-acetylcysteine; VCAM-1, vascular cell adhesion molecule-1; NO, nitric oxide; INF-1, infermeron-1; H2S, hydrogen sulfide; MAVS, mitochondrial antiviral signaling; γ-GCS, γ-glutamylcysteine synthetase; IRF-1, and interferon regulatory factor 1; Th1, helper T cells; 3CLpro, 3-chymotrypsin-like protease; ICAM-1, intercellular adhesion molecule-1; IP-10, interferon-γ-induced protein-10; RANTES, regulated upon activation normal T cell expressed and secreted; GM-CSF, granulocyte macrophage colony-stimulating factor; G-CSF, granulocyte colonystimulating factor; XO, xanthine oxidase; PDI, protein disulfide isomerase; RHA, RNA helicase; FGF-2, fibroblastic growth factor; eNOS, endothelial nitric oxide synthase; PPAR-γ, peroxisome proliferator-activated receptor-γ; N, nucleocapsid; Se, selenium; CRP, C-reactive protein; GPx, GSH peroxidase; TrxR, thioredoxin reductase; RAR, retinoic acid receptor; RXR, retinoid receptor X; EGFR, epidermal growth factor receptor; PRKCB, protein kinase C-β; dsRNA, double-stranded RNA; RIG-I, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein 5; DPP-4, dipeptidyl peptidase-4; hAPN, human aminopeptidase N; NAPDH, nicotinamide adenine dinucleotide phosphate; JAK/STAT, janus kinase/signal transducers and activators
Kabir, Uddin, Hossain, Abdulhakim, Alam et al., NCOVID-19 Pandemic: From Molecular Pathogenesis to Potential Investigational Therapeutics, Front. Cell Dev. Biol,
doi:10.3389/FCELL.2020.00616Kansakar, Trimarco, Manzi, Cervi, Mone et al., Exploring the Therapeutic Potential of Bromelain: Applications, Benefits, and Mechanisms, Nutrients,
doi:10.3390/NU16132060Keyaerts, Vijgen, Chen, Maes, Hedenstierna et al., Inhibition of SARS-Coronavirus Infection in Vitro by S-Nitroso-N-Acetylpenicillamine, a Nitric Oxide Donor Compound, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2004.04.012.127Kornberg, Bhargava, Kim, Putluri, Snowman et al., Dimethyl Fumarate Targets GAPDH and Aerobic Glycolysis to Modulate Immunity, Science,
doi:10.1126/SCIENCE.AAN4665Labarrere, Kassab, Glutathione Deficiency in the Pathogenesis of SARS-CoV-2 Infection and Its Effects upon the Host Immune Response in Severe COVID-19 Disease, Front. Microbiol,
doi:10.3389/FMICB.2022.979719Lahaye, Parant, Haesebaert, Goldet, Bendim'red et al., Minerals and Antioxidant Micronutrients Levels and Clinical Outcome in Older Patients Hospitalized for COVID-19 during the First Wave of the Pandemic, Nutrients,
doi:10.3390/NU15061516Levy, Delvin, Marcil, Spahis, Can Phytotherapy with Polyphenols Serve as a Powerful Approach for the Prevention and Therapy Tool of Novel Coronavirus Disease 2019 (COVID-19)?, Am. J. Physiol. Endocrinol. Metab,
doi:10.1152/AJPENDO.00298.2020Li, Wu, Li, Liang, Fai Tse et al., Revealing the Targets and Mechanisms of Vitamin A in the Treatment of COVID-19, Aging,
doi:10.18632/AGING.103888Malek Mahdavi, A Brief Review of Interplay between Vitamin D and Angiotensin-Converting Enzyme 2: Implications for a Potential Treatment for COVID-19, Rev. Med. Virol,
doi:10.1002/RMV.2119Marín-Corral, Rodríguez-Morató, Gomez-Gomez, Pascual-Guardia, Muñoz-Bermúdez et al., Metabolic Signatures Associated with Severity in Hospitalized Covid-19 Patients, Int. J. Mol. Sci,
doi:10.3390/IJMS22094794.104Mata, Morcillo, Gimeno, Cortijo, N-Acetyl-l-Cysteine (NAC) Inhibit Mucin Synthesis and pro-Inflammatory Mediators in Alveolar Type II Epithelial Cells Infected with Influenza Virus A and B and with Respiratory Syncytial Virus (RSV), Biochem. Pharmacol,
doi:10.1016/J.BCP.2011.05.014Mccreary, Schnell, Rhoda, Randomized Double-Blind Placebo-Controlled Proof-of-Concept Trial of Resveratrol for Outpatient Treatment of Mild Coronavirus Disease (COVID-19), Sci. Rep,
doi:10.1038/s41598-022-13920-9.113Midha, Kumar, Kumar, Madan, Mega Doses of Retinol: A Possible Immunomodulation in Covid-19 Illness in Resource-Limited Settings, Rev. Med. Virol,
doi:10.1002/RMV.2204Minakshi, Padhan, Rani, Khan, Ahmad et al., The SARS Coronavirus 3a Protein Causes Endoplasmic Reticulum Stress and Induces Ligand-Independent Downregulation of the Type 1 Interferon Receptor, PLoS ONE,
doi:10.1371/JOURNAL.PONE.0008342Moatasim, Kutkat, Osman, Gomaa, Okda et al., Potent Antiviral Activity of Vitamin B12 against Severe Acute Respiratory Syndrome Coronavirus 2, Middle East Respiratory Syndrome Coronavirus, and Human Coronavirus 229E, Microorganisms,
doi:10.3390/MICROOR-GANISMS11112777Munshi, Hussein, Toraih, Elshazli, Jardak et al., Vitamin D Insufficiency as a Potential Culprit in Critical COVID-19 Patients, J. Med. Virol,
doi:10.1002/JMV.26360Musavi, Abazari, Barartabar, Kalaki-Jouybari, Hemmati-Dinarvand et al., The Benefits of Vitamin D in the COVID-19 Pandemic: Biochemical and Immunological Mechanisms, Arch. Physiol. Biochem,
doi:10.1080/13813455.2020.1826530Nascimento Marreiro, Cruz, Oliveira, Morais, Freitas et al., Antiviral and Immunological Activity of Zinc and Possible Role in COVID-19, Br. J. Nutr,
doi:10.1017/S0007114521002099.116Nicoliche, Bartolomeo, Lemes, Pereira, Nunes et al., Anti-Inflammatory and Antioxidant Effects of Curcumin and Curcuminoids in SH-SY5Y Cells Infected by SARS-CoV-2, Sci. Rep,
doi:10.1038/s41598-024-61662-7Nioi, Mcmahon, Itoh, Yamamoto, Hayes, Identification of a Novel Nrf2-Regulated Antioxidant Response Element (ARE) in the Mouse NAD(P)H:Quinone Oxidoreductase 1 Gene: Reassessment of the ARE Consensus Sequence, Biochem. J,
doi:10.1042/BJ20030754Olczak-Pruc, Szarpak, Navolokina, Chmielewski, Panasiuk et al., The Effect of Zinc Supplementation on the Course of COVID-19-A Systematic Review and Meta-Analysis, Ann. Agric. Environ. Med,
doi:10.26444/aaem/155846.115Pallath, Ahirwar, Tripathi, Asia, Sakarde et al., COVID-19 and Nutritional Deficiency: A Review of Existing Knowledge, Horm. Mol. Biol. Clin. Investig,
doi:10.1515/HMBCI-2020-0074Pan, Fang, Zhang, Pan, Liu et al., Chinese Herbal Compounds against SARS-CoV-2: Puerarin and Quercetin Impair the Binding of Viral S-Protein to ACE2 Receptor, Comput. Struct. Biotechnol. J,
doi:10.1016/J.CSBJ.2020.11.010.105Pecoraro, Martini, Salvottini, Carbonare, Piacentini et al., The Potential Role of Zinc, Magnesium and Selenium against COVID-19: A Pragmatic Review, Child Adolesc. Obes,
doi:10.1080/2574254X.2021.1941706.119Pecorelli, Bocci, Acquaviva, Belmonte, Gardi et al., NRF2 Activation Is Involved in Ozonated Human Serum Upregulation of HO-1 in Endothelial Cells, Toxicol. Appl. Pharmacol,
doi:10.1016/J.TAAP.2012.12.001.137Prakash, Kaur, Kaur, Prabha, Bhatacharya et al., Efficacy and Safety of Inhaled Nitric Oxide in the Treatment of Severe/Critical COVID-19 Patients: A Systematic Review, Indian J. Pharmacol,
doi:10.4103/IJP.IJP_382_21.131Rahban, Habibi-Rezaei, Mazaheri, Saso, Moosavi-Movahedi, Anti-Viral Potential and Modulation of Nrf2 by Curcumin: Pharmacological Implications, Antioxidants,
doi:10.3390/ANTIOX9121228Rajendran, Chathambath, Al-Sehemi, Pannipara, Unnikrishnan et al., Critical Role of Nitric Oxide in Impeding COVID-19 Transmission and Prevention: A Promising Possibility, Environ. Sci. Pollut. Res,
doi:10.1007/S11356-022-19148-4.130Rederstorff, Krol, Lescure, Understanding the Importance of Selenium and Selenoproteins in Muscle Function, Cell. Mol. Life Sci,
doi:10.1007/S00018-005-5313-YRocksén, Lilliehöök, Larsson, Johansson, Bucht, Differential Anti-Inflammatory and Anti-Oxidative Effects of Dexamethasone and N-Acetylcysteine in Endotoxin-Induced Lung Inflammation, Clin. Exp. Immunol,
doi:10.1046/J.1365-2249.2000.01373.XRostami, Alavi, Daghagheleh, Maraghi, Hosseini, A Randomized Clinical Trial Investigating the Impact of Magnesium Supplementation on Clinical and Biochemical Measures in COVID-19 Patients, Virol. J,
doi:10.1186/S12985-024-02362-6.122Rudenko, Vetoshkina, Marenkova, Borisova-Mubarakshina, Antioxidants of Non-Enzymatic Nature: Their Function in Higher Plant Cells and the Ways of Boosting Their Biosynthesis, Antioxidants,
doi:10.3390/ANTIOX12112014Sabico, Enani, Sheshah, Aljohani, Aldisi et al., Effects of a 2-Week 5000 Iu versus 1000 Iu Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial, Nutrients,
doi:10.3390/NU13072170Sadeghi, Dehnavi, Asadirad, Xu, Majeed et al., Curcumin and Chemokines: Mechanism of Action and Therapeutic Potential in Inflammatory Diseases, Inflammopharmacology,
doi:10.1007/S10787-023-01136-WSafaee Fakhr, Di Fenza, Gianni, Wiegand, Miyazaki et al., Inhaled High Dose Nitric Oxide Is a Safe and Effective Respiratory Treatment in Spontaneous Breathing Hospitalized Patients with COVID-19 Pneumonia, Nitric Oxide,
doi:10.1016/J.NIOX.2021.08.003.132Sahebkar, Serban, Ursoniu, Banach, Effect of Curcuminoids on Oxidative Stress: A Systematic Review and Meta-Analysis of Randomized Controlled Trials, J. Funct. Foods,
doi:10.1016/J.JFF.2015.01.005Samad, Dutta, Sodunke, Fairuz, Sapkota et al., Fat-Soluble Vitamins and the Current Global Pandemic of COVID-19: Evidence-Based Efficacy from Literature Review, J. Inflamm. Res,
doi:10.2147/JIR.S307333Sanduzzi Zamparelli, Fucci, Rea, Perna, Bocchino et al., The Role of SARS-CoV-2 Nucleocapsidic Antigen and Krebs von Den Lungen 6 Serum Levels in Predicting COVID-19 Pneumonia Outcome, Diagnostics,
doi:10.3390/DIAGNOSTICS14060642Sanduzzi, Zamparelli, Nasopharyngeal and Oropharyngeal Swabs, And/Or Serology for SARS COVID-19: What Are We Looking For?, Int. J. Environ. Res. Public Health,
doi:10.3390/IJERPH17093289Saptarini, Rahayu, Herawati, Antioxidant Activity of Crude Bromelain of Pineapple (Ananas comosus (L.) Merr) Crown from Subang District, Indonesia, J. Pharm. Bioallied Sci,
doi:10.4103/JPBS.JPBS_200_19Shohan, Nashibi, Mahmoudian-Sani, Abolnezhadian, Ghafourian et al., The Therapeutic Efficacy of Quercetin in Combination with Antiviral Drugs in Hospitalized COVID-19 Patients: A Randomized Controlled Trial, Eur. J. Pharmacol,
doi:10.1016/J.EJPHAR.2021.174615.110Shrivastava, Sahu, Cecchi, Shrestha, Shah et al., An Emerging Natural Antioxidant Therapy for COVID-19 Infection Patients: Current and Future Directions, Food Front,
doi:10.1002/FFT2.207Silvestri, Rossi, Melatonin: Its Possible Role in the Management of Viral Infections-a Brief Review, Ital. J. Pediatr,
doi:10.1186/1824-7288-39-61Singh, Gautam, Chandel, Ghosh, Dey et al., Protease Inhibitory Effect of Natural Polyphenolic Compounds on SARS-CoV-2: An In Silico Study, Molecules,
doi:10.3390/MOLE-CULES25204604.102Sinopoli, Caminada, Isonne, Santoro, Baccolini, What Are the Effects of Vitamin A Oral Supplementation in the Prevention and Management of Viral Infections? A Systematic Review of Randomized Clinical Trials, Nutrients,
doi:10.3390/NU14194081Skalny, Rink, Ajsuvakova, Aschner, Gritsenko et al., Zinc and Respiratory Tract Infections: Perspectives for COVID-19 (Review), Int. J. Mol. Med,
doi:10.3892/IJMM.2020.4575Smith, Wilson, Gandhi, Vatsia, Khan, Ozone Therapy: An Overview of Pharmacodynamics, Current Research, and Clinical Utility, Med. Gas Res,
doi:10.4103/2045-9912.215752.136Soltan-Sharifi, Mojtahedzadeh, Najafi, Khajavi, Rouini et al., Improvement by N-Acetylcysteine of Acute Respiratory Distress Syndrome through Increasing Intracellular Glutathione, and Extracellular Thiol Molecules and Anti-Oxidant Power: Evidence for Underlying Toxicological Mechanisms, Hum. Exp. Toxicol,
doi:10.1177/0960327107083452Somi, Faghih Dinevari, Taghizadieh, Varshochi, Sadeghi Majd et al., Effect of Vitamin A Supplementation on the Outcome Severity of COVID-19 in Hospitalized Patients: A Pilot Randomized Clinical Trial, Nutr. Health,
doi:10.1177/02601060221129144Taher, Lashgari, Sedighi, Rahimi-Bashar, Poorolajal et al., A Pilot Study on Intravenous N-Acetylcysteine Treatment in Patients with Mild-to-Moderate COVID19-Associated Acute Respiratory Distress Syndrome, Pharmacol. Rep,
doi:10.1007/S43440-021-00296-2Talebi, Ghasemi, Etminani-Esfahani, Mohammadi, Haddadi, Effects of L-Carnitine Supplementation in Patients with Mild-to-Moderate COVID-19 Disease: A Pilot Study, Pharmacol. Rep,
doi:10.1007/S43440-022-00402-YTan, Manchester, Esteban-Zubero, Zhou, Reiter, Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism, Molecules,
doi:10.3390/MOLECULES201018886Tavassolifar, Aghdaei, Sadatpour, Maleknia, Fayazzadeh et al., New Insights into Extracellular and Intracellular Redox Status in COVID-19 Patients, Redox Biol,
doi:10.1016/J.REDOX.2022.102563Tehrani, Yadegarynia, Abrishami, Moradi, Gharaei et al., An Investigation into the Effects of Intravenous Vitamin C on Pulmonary CT Findings and Clinical Outcomes of Patients with COVID 19 Pneumonia A Randomized Clinical Trial, Urol. J,
doi:10.22037/UJ.V18I.6863Tepasse, Vollenberg, Fobker, Kabar, Schmidt et al., Vitamin a Plasma Levels in Covid-19 Patients: A Prospective Multicenter Study and Hypothesis, Nutrients,
doi:10.3390/NU13072173Tomaszewska, Rustecka, Lipińska-Opałka, Piprek, Kloc et al., The Role of Vitamin D in COVID-19 and the Impact of Pandemic Restrictions on Vitamin D Blood Content, Front. Pharmacol,
doi:10.3389/FPHAR.2022.836738Vahedian-Azimi, Abbasifard, Rahimi-Bashar, Guest, Majeed et al., Effectiveness of Curcumin on Outcomes of Hospitalized COVID-19 Patients: A Systematic Review of Clinical Trials, Nutrients,
doi:10.3390/NU14020256Wong, Rinaldi, Ho, Zinc Deficiency Enhanced Inflammatory Response by Increasing Immune Cell Activation and Inducing IL6 Promoter Demethylation, Mol. Nutr. Food Res,
doi:10.1002/MNFR.201400761Wu, Yin, Jiang, Xu, Structure Genomics of SARS-CoV-2 and Its Omicron Variant: Drug Design Templates for COVID-19, Acta Pharmacol. Sin,
doi:10.1038/s41401-021-00851-wXie, Choi, Al-Aly, Mortality in Patients Hospitalized for COVID-19 vs Influenza in Fall-Winter 2023-2024, JAMA,
doi:10.1001/JAMA.2024.7395Xu, Baylink, Chen, Reeves, Xiao et al., The Importance of Vitamin D Metabolism as a Potential Prophylactic, Immunoregulatory and Neuroprotective Treatment for COVID-19, J. Transl. Med,
doi:10.1186/S12967-020-02488-5Yang, Wang, Long, Li, Quercetin: Its Main Pharmacological Activity and Potential Application in Clinical Medicine, Oxid. Med. Cell Longev,
doi:10.1155/2020/8825387.109Yao, Paguio, Dee, Tan, Moulick et al., The Minimal Effect of Zinc on the Survival of Hospitalized Patients with COVID-19: An Observational Study, Chest,
doi:10.1016/j.chest.2020.06.082.118Zafarullah, Li, Sylvester, Ahmad, Molecular Mechanisms of N-Acetylcysteine Actions, Cell. Mol. Life Sci,
doi:10.1007/S000180300001Zamparelli, Capitelli, Coppola, Venditto, Santoro et al., A Phase II Study on the Effect of Taurisolo ® Administered via AEROsol in Hospitalized Patients with Mild to Moderate COVID-19 Pneumonia: The TAEROVID-19 Study, Cells,
doi:10.3390/CELLS11091499.114Zeng, Ma, Zhou, Liu, Huang et al., Spectrum and Clinical Characteristics of Symptomatic and Asymptomatic Coronavirus Disease 2019 (COVID-19) with and Without Pneumonia, Front. Med,
doi:10.3389/FMED.2021.645651Zhang, Wu, Li, Zhao, Wang, Cytokine Release Syndrome in Severe COVID-19: Interleukin-6 Receptor Antagonist Tocilizumab May Be the Key to Reduce Mortality, Int. J. Antimicrob. Agents,
doi:10.1016/J.IJANTIMICAG.2020.105954Zhu, Zhang, Wang, Li, Yang et al., A Novel Coronavirus from Patients with Pneumonia in China, N. Engl. J. Med,
doi:10.1056/NEJMOA2001017DOI record:
{
"DOI": "10.3390/life15010113",
"ISSN": [
"2075-1729"
],
"URL": "http://dx.doi.org/10.3390/life15010113",
"abstract": "<jats:p>The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with pneumonia emerging as a major complication in severe cases. The pathogenesis of COVID-19 is marked by the overproduction of reactive oxygen species (ROS) and an excessive inflammatory response, resulting in oxidative stress and significant tissue damage, particularly in the respiratory system. Antioxidants have garnered considerable attention for their potential role in managing COVID-19 pneumonia by mitigating oxidative stress and modulating immune responses. This review provides a comprehensive overview of the literature on the use of antioxidants in hospitalized patients with mild-to-moderate COVID-19. Studies exploring antioxidants, including vitamins, trace elements, nitric oxide (NO), ozone (O3), glutathione (GSH), L-carnitine, melatonin, bromelain, N-acetylcysteine (NAC), and numerous polyphenols, have yielded promising outcomes. Through their ROS-scavenging properties, these molecules support endothelial function, reduce the thrombosis risk, and may help mitigate the effects of the cytokine storm, a key contributor to COVID-19 morbidity and mortality. Clinical evidence suggests that antioxidant supplementation may improve patient outcomes by decreasing inflammation, supporting immune cell function, and potentially shortening recovery times. Furthermore, these molecules may mitigate the symptoms of COVID-19 by exerting direct antiviral effects that inhibit the infection process and genomic replication of SARS-CoV-2 in host cells. Moreover, antioxidants may work synergistically with standard antiviral treatments to reduce viral-induced oxidative damage. By integrating findings from the literature with real-world data from our clinical experience, we gain a more profound understanding of the role of antioxidants in managing COVID-19 pneumonia. Further research combining comprehensive literature reviews with real-world data analysis is crucial to validate the efficacy of antioxidants and establish evidence-based guidelines for their use in clinical practice.</jats:p>",
"alternative-id": [
"life15010113"
],
"author": [
{
"ORCID": "https://orcid.org/0000-0003-3336-7290",
"affiliation": [
{
"name": "Division of Pneumology and Semi-intensive Respiratory Therapy, A. Cardarelli Hospital, 80131 Naples, Italy"
}
],
"authenticated-orcid": false,
"family": "Sanduzzi Zamparelli",
"given": "Stefano",
"sequence": "first"
},
{
"ORCID": "https://orcid.org/0000-0002-0977-2643",
"affiliation": [
{
"name": "Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy"
},
{
"name": "UNESCO Chair for Health Education and Sustainable Development, University of Naples “Federico II”, 80131 Naples, Italy"
},
{
"name": "ERN Lung, 60596 Frankfurt am Main, Germany"
}
],
"authenticated-orcid": false,
"family": "Sanduzzi Zamparelli",
"given": "Alessandro",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy"
}
],
"family": "Bocchino",
"given": "Marialuisa",
"sequence": "additional"
}
],
"container-title": "Life",
"container-title-short": "Life",
"content-domain": {
"crossmark-restriction": false,
"domain": []
},
"created": {
"date-parts": [
[
2025,
1,
16
]
],
"date-time": "2025-01-16T15:44:23Z",
"timestamp": 1737042263000
},
"deposited": {
"date-parts": [
[
2025,
1,
16
]
],
"date-time": "2025-01-16T16:03:24Z",
"timestamp": 1737043404000
},
"indexed": {
"date-parts": [
[
2025,
1,
16
]
],
"date-time": "2025-01-16T16:40:31Z",
"timestamp": 1737045631787,
"version": "3.33.0"
},
"is-referenced-by-count": 0,
"issue": "1",
"issued": {
"date-parts": [
[
2025,
1,
16
]
]
},
"journal-issue": {
"issue": "1",
"published-online": {
"date-parts": [
[
2025,
1
]
]
}
},
"language": "en",
"license": [
{
"URL": "https://creativecommons.org/licenses/by/4.0/",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2025,
1,
16
]
],
"date-time": "2025-01-16T00:00:00Z",
"timestamp": 1736985600000
}
}
],
"link": [
{
"URL": "https://www.mdpi.com/2075-1729/15/1/113/pdf",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "1968",
"original-title": [],
"page": "113",
"prefix": "10.3390",
"published": {
"date-parts": [
[
2025,
1,
16
]
]
},
"published-online": {
"date-parts": [
[
2025,
1,
16
]
]
},
"publisher": "MDPI AG",
"reference-count": 0,
"references-count": 0,
"relation": {},
"resource": {
"primary": {
"URL": "https://www.mdpi.com/2075-1729/15/1/113"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"title": "Immune-Boosting and Antiviral Effects of Antioxidants in COVID-19 Pneumonia: A Therapeutic Perspective",
"type": "journal-article",
"volume": "15"
}
