Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of COVID-19: A Revaluation of Pauling’s Vitamin C Therapy

Yamasaki et al., Microorganisms, doi:10.3390/microorganisms11020397

Feb 2023

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Extensive review of vitamin C and nitric oxide focusing on the potential antiviral activity of vitamin C for SARS-CoV-2 via the production of nitric oxide. Authors note that vegetables are a major dietary source of nitrate, and that dietary vitamin C from fruits and vegetables can reduce nitrite to produce nitric oxide in the oral cavity when chewing foods.

Authors conclude that intermittent bursts of nitric oxide, for example as generated by the combination of nitrite and vitamin C, is a potential therapeutic treatment to prevent and mitigate COVID-19.

Authors also note that nitric oxide may be related to the observed lower than expected risks seen with asthma and smoking. Elevated levels of nitric oxide in the breath are used for diagnosing asthma, and smoking involves bursts of concentrated nitric oxide in cigarette smoke.

Reviews covering nitric oxide for COVID-19 include1-5.

Important missing comments or errors? Let us know.

Study covers nitric oxide and vitamin C.

1. Zhang et al., Saying No to SARS-CoV-2: the potential of nitric oxide in the treatment of COVID-19 pneumonia, Medical Gas Research, doi:10.4103/2045-9912.385414.lww.com, doi.org.

2. Zhao et al., Inhaled nitric oxide: can it serve as a savior for COVID-19 and related respiratory and cardiovascular diseases?, Frontiers in Microbiology, doi:10.3389/fmicb.2023.1277552.frontiersin.org, doi.org.

3. Yamasaki et al., Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of COVID-19: A Revaluation of Pauling’s Vitamin C Therapy, Microorganisms, doi:10.3390/microorganisms11020397.mdpi.com, doi.org.

4. Oza et al., Utility of NO and H2S donating platforms in managing COVID-19: Rationale and promise, Nitric Oxide, doi:10.1016/j.niox.2022.08.003.sciencedirect.com, doi.org.

5. Hedenstierna et al., Nitric oxide dosed in short bursts at high concentrations may protect against Covid 19, Nitric Oxide, doi:10.1016/j.niox.2020.06.005.sciencedirect.com, doi.org.

Yamasaki et al., 3 Feb 2023, Japan, peer-reviewed, 4 authors. Contact: yamasaki@sci.u-ryukyu.ac.jp (corresponding author).

This Paper Nitric Oxide All

Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of COVID-19: A Revaluation of Pauling’s Vitamin C Therapy

Hideo Yamasaki, Hideyuki Imai, Atsuko Tanaka, Joji M Otaki

Microorganisms, doi:10.3390/microorganisms11020397

Linus Pauling, who was awarded the Nobel Prize in Chemistry, suggested that a high dose of vitamin C (L-ascorbic acid) might work as a prevention or treatment for the common cold. Vitamin C therapy was tested in clinical trials, but clear evidence was not found at that time. Although Pauling's proposal has been strongly criticized for a long time, vitamin C therapy has continued to be tested as a treatment for a variety of diseases, including coronavirus infectious disease 2019 . The pathogen of COVID-19, SARS-CoV-2, belongs to the β-coronavirus lineage, which includes human coronavirus, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). This review intends to shed new light on vitamin C antiviral activity that may prevent SARS-CoV-2 infection through the chemical production of nitric oxide (NO). NO is a gaseous free radical that is largely produced by the enzyme NO synthase (NOS) in cells. NO produced by upper epidermal cells contributes to the inactivation of viruses and bacteria contained in air or aerosols. In addition to enzymatic production, NO can be generated by the chemical reduction of inorganic nitrite (NO 2 − ), an alternative mechanism for NO production in living organisms. Dietary vitamin C, largely contained in fruits and vegetables, can reduce the nitrite in saliva to produce NO in the oral cavity when chewing foods. In the stomach, salivary nitrite can also be reduced to NO by vitamin C secreted from the epidermal cells of the stomach. The strong acidic pH of gastric juice facilitates the chemical reduction of salivary nitrite to produce NO. Vitamin C contributes in multiple ways to the host innate immune system as a first-line defense mechanism against pathogens. Highlighting chemical NO production by vitamin C, we suggest that controversies on the therapeutic effects of vitamin C in previous clinical trials may partly be due to less appreciation of the pleiotropic functions of vitamin C as a universal bioreductant.

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

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{ 'indexed': {'date-parts': [[2023, 2, 17]], 'date-time': '2023-02-17T05:36:16Z', 'timestamp': 1676612176610}, 'reference-count': 222, 'publisher': 'MDPI AG', 'issue': '2', 'license': [ { 'start': { 'date-parts': [[2023, 2, 3]], 'date-time': '2023-02-03T00:00:00Z', 'timestamp': 1675382400000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'abstract': 'Linus Pauling, who was awarded the Nobel Prize in Chemistry, suggested that a high ' 'dose of vitamin C (l-ascorbic acid) might work as a prevention or treatment for the common ' 'cold. Vitamin C therapy was tested in clinical trials, but clear evidence was not found at ' 'that time. Although Pauling’s proposal has been strongly criticized for a long time, vitamin ' 'C therapy has continued to be tested as a treatment for a variety of diseases, including ' 'coronavirus infectious disease 2019 (COVID-19). The pathogen of COVID-19, SARS-CoV-2, belongs ' 'to the β-coronavirus lineage, which includes human coronavirus, severe acute respiratory ' 'syndrome (SARS), and Middle East respiratory syndrome (MERS). This review intends to shed new ' 'light on vitamin C antiviral activity that may prevent SARS-CoV-2 infection through the ' 'chemical production of nitric oxide (NO). NO is a gaseous free radical that is largely ' 'produced by the enzyme NO synthase (NOS) in cells. NO produced by upper epidermal cells ' 'contributes to the inactivation of viruses and bacteria contained in air or aerosols. In ' 'addition to enzymatic production, NO can be generated by the chemical reduction of inorganic ' 'nitrite (NO2−), an alternative mechanism for NO production in living organisms. Dietary ' 'vitamin C, largely contained in fruits and vegetables, can reduce the nitrite in saliva to ' 'produce NO in the oral cavity when chewing foods. In the stomach, salivary nitrite can also ' 'be reduced to NO by vitamin C secreted from the epidermal cells of the stomach. The strong ' 'acidic pH of gastric juice facilitates the chemical reduction of salivary nitrite to produce ' 'NO. Vitamin C contributes in multiple ways to the host innate immune system as a first-line ' 'defense mechanism against pathogens. Highlighting chemical NO production by vitamin C, we ' 'suggest that controversies on the therapeutic effects of vitamin C in previous clinical ' 'trials may partly be due to less appreciation of the pleiotropic functions of vitamin C as a ' 'universal bioreductant.', 'DOI': '10.3390/microorganisms11020397', 'type': 'journal-article', 'created': {'date-parts': [[2023, 2, 6]], 'date-time': '2023-02-06T09:08:07Z', 'timestamp': 1675674487000}, 'page': '397', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of ' 'COVID-19: A Revaluation of Pauling’s Vitamin C Therapy', 'prefix': '10.3390', 'volume': '11', 'author': [ { 'given': 'Hideo', 'family': 'Yamasaki', 'sequence': 'first', 'affiliation': [ { 'name': 'Faculty of Science, University of the Ryukyus, Nishihara ' '903-0213, Okinawa, Japan'}]}, { 'ORCID': 'http://orcid.org/0000-0002-3793-1146', 'authenticated-orcid': False, 'given': 'Hideyuki', 'family': 'Imai', 'sequence': 'additional', 'affiliation': [ { 'name': 'Faculty of Science, University of the Ryukyus, Nishihara ' '903-0213, Okinawa, Japan'}]}, { 'ORCID': 'http://orcid.org/0000-0002-8277-1188', 'authenticated-orcid': False, 'given': 'Atsuko', 'family': 'Tanaka', 'sequence': 'additional', 'affiliation': [ { 'name': 'Faculty of Science, University of the Ryukyus, Nishihara ' '903-0213, Okinawa, Japan'}]}, { 'ORCID': 'http://orcid.org/0000-0003-3425-7085', 'authenticated-orcid': False, 'given': 'Joji M.', 'family': 'Otaki', 'sequence': 'additional', 'affiliation': [ { 'name': 'Faculty of Science, University of the Ryukyus, Nishihara ' '903-0213, Okinawa, Japan'}]}], 'member': '1968', 'published-online': {'date-parts': [[2023, 2, 3]]}, 'reference': [ { 'key': 'ref_1', 'doi-asserted-by': 'crossref', 'first-page': '425', 'DOI': '10.1016/j.jmii.2020.04.015', 'article-title': 'ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, ' 'multi-organ failure, and COVID-19 disease outcome', 'volume': '53', 'author': 'Devaux', 'year': '2020', 'journal-title': 'J. 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