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The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis

Briassoulis et al., Antioxidants, doi:10.3390/antiox12111942

Oct 2023

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Zinc for COVID-19

2nd treatment shown to reduce risk in July 2020, now with p = 0.00000032 from 46 studies, recognized in 17 countries.

Lower risk for mortality, ventilation, hospitalization, progression, recovery, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 112 treatments. c19early.org

Review of the anti-oxidative, anti-inflammatory, anti-apoptotic, and anti-necroptotic role of zinc in COVID-19 and sepsis. Authors discuss how zinc functions as a structural component in proteins, a catalytic co-factor in enzymes, and plays a regulatory role in processes like DNA synthesis and protein-DNA interactions. Authors examine how zinc acts as an antioxidant, affects inflammation through pathways like NF-κB, regulates immune function, and modulates programmed cell death mechanisms like apoptosis and necroptosis. They summarize clinical data showing declines in zinc levels are associated with worse outcomes in sepsis and COVID-19. Authors review only a small subset of the clinical evidence, for more complete coverage see1.

Reviews covering zinc for COVID-19 include2-16.

Important missing comments or errors? Let us know.

1. c19early.org, c19early.org/zmeta.html.c19early.org/zmeta.html.

2. Fazli et al., Possible Link between Gut Microbiota, Diet, and COVID-19 Infection, Journal of Medical Bacteriology, 12:4, jmb.tums.ac.ir/index.php/jmb/article/view/525.ac.ir.

3. Mu et al., Anti-inflammatory and Nutritional Interventions Against SARS-CoV-2: A Comprehensive Review, Journal of Agriculture and Food Research, doi:10.1016/j.jafr.2024.101422.sciencedirect.com, doi.org.

4. Jin et al., The nutritional roles of zinc for immune system and COVID-19 patients, Frontiers in Nutrition, doi:10.3389/fnut.2024.1385591.frontiersin.org, doi.org.

5. Briassoulis et al., The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis, Antioxidants, doi:10.3390/antiox12111942.mdpi.com, doi.org.

6. Winn et al., Effect of any form of steroids in comparison with that of other medications on the duration of olfactory dysfunction in patients with COVID-19: A systematic review of randomized trials and quasi-experimental studies, PLOS ONE, doi:10.1371/journal.pone.0288285.plos.org, doi.org.

7. Schloss et al., Nutritional deficiencies that may predispose to long COVID, Inflammopharmacology, doi:10.1007/s10787-023-01183-3.springer.com, doi.org.

8. Arora et al., Global Dietary and Herbal Supplement Use during COVID-19—A Scoping Review, Nutrients, doi:10.3390/nu15030771.mdpi.com, doi.org.

9. Wang et al., Zinc and COVID-19: Immunity, Susceptibility, Severity and Intervention, Critical Reviews in Food Science and Nutrition, doi:10.1080/10408398.2022.2119932.tandfonline.com, doi.org.

10. Foshati et al., Antioxidants and clinical outcomes of patients with coronavirus disease 2019: A systematic review of observational and interventional studies, Food Science & Nutrition, doi:10.1002/fsn3.3034.wiley.com, doi.org.

11. DiGuilio et al., Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy, International Journal of Molecular Sciences, doi:10.3390/ijms23062995.mdpi.com, doi.org.

12. Wessels et al., Zinc deficiency as a possible risk factor for increased susceptibility and severe progression of Corona Virus Disease 19, British Journal of Nutrition, doi:10.1017/S0007114521000738.cambridge.org, doi.org.

13. Sethuram et al., Potential Role of Zinc in the COVID-19 Disease Process and its Probable Impact on Reproduction, Reproductive Sciences, doi:10.1007/s43032-020-00400-6.springer.com, doi.org.

14. Joachimiak et al., Zinc against COVID-19? Symptom surveillance and deficiency risk groups, PLOS Neglected Tropical Diseases, doi:10.1371/journal.pntd.0008895.plos.org, doi.org.

15. Alexander et al., Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19, Nutrients, doi:10.3390/nu12082358.mdpi.com, doi.org.

16. Derwand et al., Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win today's battle against COVID-19?, Medical Hypotheses, doi:10.1016/j.mehy.2020.109815.sciencedirect.com, doi.org.

Briassoulis et al., 31 Oct 2023, peer-reviewed, 5 authors. Contact: briasoug@uoc.gr (corresponding author), stavroula.ilia@uoc.gr, briaspan@med.uoa.gr, med1p1130027@med.uoc.gr, ggbriass@med.uoc.gr.

This Paper Zinc All

The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis

George Briassoulis, Panagiotis Briassoulis, Stavroula Ilia, Marianna Miliaraki, Efrossini Briassouli

Antioxidants, doi:10.3390/antiox12111942

Zinc is a structural component of proteins, functions as a catalytic co-factor in DNA synthesis and transcription of hundreds of enzymes, and has a regulatory role in protein-DNA interactions of zinc-finger proteins. For many years, zinc has been acknowledged for its anti-oxidative and anti-inflammatory functions. Furthermore, zinc is a potent inhibitor of caspases-3, -7, and -8, modulating the caspase-controlled apoptosis and necroptosis. In recent years, the immunomodulatory role of zinc in sepsis and COVID-19 has been investigated. Both sepsis and COVID-19 are related to various regulated cell death (RCD) pathways, including apoptosis and necroptosis. Lack of zinc may have a negative effect on many immune functions, such as oxidative burst, cytokine production, chemotaxis, degranulation, phagocytosis, and RCD. While plasma zinc concentrations decline swiftly during both sepsis and COVID-19, this reduction is primarily attributed to a redistribution process associated with the inflammatory response. In this response, hepatic metallothionein production increases in reaction to cytokine release, which is linked to inflammation, and this protein effectively captures and stores zinc in the liver. Multiple regulatory mechanisms come into play, influencing the uptake of zinc, the binding of zinc to blood albumin and red blood cells, as well as the buffering and modulation of cytosolic zinc levels. Decreased zinc levels are associated with increasing severity of organ dysfunction, prolonged hospital stay and increased mortality in septic and COVID-19 patients. Results of recent studies focusing on these topics are summarized and discussed in this narrative review. Existing evidence currently does not support pharmacological zinc supplementation in patients with sepsis or COVID-19. Complementation and repletion should follow current guidelines for micronutrients in critically ill patients. Further research investigating the pharmacological mechanism of zinc in programmed cell death caused by invasive infections and its therapeutic potential in sepsis and COVID-19 could be worthwhile.

Conflicts of Interest: The authors declare no conflict of interest.

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{ 'indexed': {'date-parts': [[2023, 11, 1]], 'date-time': '2023-11-01T07:24:22Z', 'timestamp': 1698823462343}, 'reference-count': 252, 'publisher': 'MDPI AG', 'issue': '11', 'license': [ { 'start': { 'date-parts': [[2023, 10, 31]], 'date-time': '2023-10-31T00:00:00Z', 'timestamp': 1698710400000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'abstract': 'Zinc is a structural component of proteins, functions as a catalytic co-factor in DNA ' 'synthesis and transcription of hundreds of enzymes, and has a regulatory role in protein–DNA ' 'interactions of zinc-finger proteins. For many years, zinc has been acknowledged for its ' 'anti-oxidative and anti-inflammatory functions. Furthermore, zinc is a potent inhibitor of ' 'caspases-3, -7, and -8, modulating the caspase-controlled apoptosis and necroptosis. In ' 'recent years, the immunomodulatory role of zinc in sepsis and COVID-19 has been investigated. ' 'Both sepsis and COVID-19 are related to various regulated cell death (RCD) pathways, ' 'including apoptosis and necroptosis. Lack of zinc may have a negative effect on many immune ' 'functions, such as oxidative burst, cytokine production, chemotaxis, degranulation, ' 'phagocytosis, and RCD. While plasma zinc concentrations decline swiftly during both sepsis ' 'and COVID-19, this reduction is primarily attributed to a redistribution process associated ' 'with the inflammatory response. In this response, hepatic metallothionein production ' 'increases in reaction to cytokine release, which is linked to inflammation, and this protein ' 'effectively captures and stores zinc in the liver. Multiple regulatory mechanisms come into ' 'play, influencing the uptake of zinc, the binding of zinc to blood albumin and red blood ' 'cells, as well as the buffering and modulation of cytosolic zinc levels. Decreased zinc ' 'levels are associated with increasing severity of organ dysfunction, prolonged hospital stay ' 'and increased mortality in septic and COVID-19 patients. Results of recent studies focusing ' 'on these topics are summarized and discussed in this narrative review. Existing evidence ' 'currently does not support pharmacological zinc supplementation in patients with sepsis or ' 'COVID-19. Complementation and repletion should follow current guidelines for micronutrients ' 'in critically ill patients. Further research investigating the pharmacological mechanism of ' 'zinc in programmed cell death caused by invasive infections and its therapeutic potential in ' 'sepsis and COVID-19 could be worthwhile.', 'DOI': '10.3390/antiox12111942', 'type': 'journal-article', 'created': { 'date-parts': [[2023, 10, 31]], 'date-time': '2023-10-31T16:44:03Z', 'timestamp': 1698770643000}, 'page': '1942', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in ' 'COVID-19 and Sepsis', 'prefix': '10.3390', 'volume': '12', 'author': [ { 'ORCID': 'http://orcid.org/0000-0003-0928-6183', 'authenticated-orcid': False, 'given': 'George', 'family': 'Briassoulis', 'sequence': 'first', 'affiliation': [ { 'name': 'Postgraduate Program “Emergency and Intensive Care in Children, ' 'Adolescents, and Young Adults”, School of Medicine, University ' 'of Crete, 71003 Heraklion, Greece'}]}, { 'ORCID': 'http://orcid.org/0000-0002-9789-9002', 'authenticated-orcid': False, 'given': 'Panagiotis', 'family': 'Briassoulis', 'sequence': 'additional', 'affiliation': [ { 'name': 'Second Department of Anesthesiology, Attikon University ' 'Hospital, School of Medicine, National and Kapodistrian ' 'University of Athens, 12462 Athens, Greece'}]}, { 'ORCID': 'http://orcid.org/0000-0002-0936-368X', 'authenticated-orcid': False, 'given': 'Stavroula', 'family': 'Ilia', 'sequence': 'additional', 'affiliation': [ { 'name': 'Postgraduate Program “Emergency and Intensive Care in Children, ' 'Adolescents, and Young Adults”, School of Medicine, University ' 'of Crete, 71003 Heraklion, Greece'}, { 'name': 'Paediatric Intensive Care Unit, University Hospital, School of ' 'Medicine, University of Crete, 71110 Heraklion, Greece'}]}, { 'ORCID': 'http://orcid.org/0000-0001-7622-202X', 'authenticated-orcid': False, 'given': 'Marianna', 'family': 'Miliaraki', 'sequence': 'additional', 'affiliation': [ { 'name': 'Paediatric Intensive Care Unit, University Hospital, School of ' 'Medicine, University of Crete, 71110 Heraklion, Greece'}]}, { 'given': 'Efrossini', 'family': 'Briassouli', 'sequence': 'additional', 'affiliation': [ { 'name': 'Infectious Diseases Department “MAKKA”, First Department of ' 'Paediatrics, “Aghia Sophia” Children’s Hospital, School of ' 'Medicine, National and Kapodistrian University of Athens, 11527 ' 'Athens, Greece'}]}], 'member': '1968', 'published-online': {'date-parts': [[2023, 10, 31]]}, 'reference': [ { 'key': 'ref_1', 'doi-asserted-by': 'crossref', 'first-page': '1552', 'DOI': '10.1007/s00134-020-06151-x', 'article-title': 'Incidence and Mortality of Hospital- and ICU-Treated Sepsis: Results ' 'from an Updated and Expanded Systematic Review and Meta-Analysis', 'volume': '46', 'author': 'Mellhammar', 'year': '2020', 'journal-title': 'Intensive Care Med.'}, { 'key': 'ref_2', 'doi-asserted-by': 'crossref', 'first-page': '801', 'DOI': '10.1001/jama.2016.0287', 'article-title': 'The Third International Consensus Definitions for Sepsis and Septic ' 'Shock (Sepsis-3)', 'volume': '315', 'author': 'Singer', 'year': '2016', 'journal-title': 'JAMA'}, { 'key': 'ref_3', 'doi-asserted-by': 'crossref', 'first-page': '2042', 'DOI': '10.1097/CCM.0000000000005195', 'article-title': 'Coronavirus Disease 2019 as Cause of Viral Sepsis: A Systematic Review ' 'and Meta-Analysis', 'volume': '49', 'author': 'Karakike', 'year': '2021', 'journal-title': 'Crit. 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