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

Source PDF All Studies Meta AnalysisMeta

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.

Important missing comments or errors? Let us know.

This study includes nitric oxide and vitamin C.

Yamasaki et al., 3 Feb 2023, Japan, peer-reviewed, 4 authors.

Contact: yamasaki@sci.u-ryukyu.ac.jp (corresponding author).

All Studies Meta Analysis Submit Updates or Corrections

This Paper Vitamin C 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.

References

Adebayo, Varzideh, Wilson, Gambardella, Eacobacci et al., L-Arginine and COVID-19: An update, Nutrients, doi:10.3390/nu13113951

Akaberi, Krambrich, Ling, Luni, Hedenstierna et al., Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro, Redox Biol, doi:10.1016/j.redox.2020.101734

Akaike, Fujii, Kato, Yoshitake, Miyamoto et al., Viral mutation accelerated by nitric oxide production during infectionin vivo, FASEB J, doi:10.1096/fasebj.14.10.1447

Akaike, Ida, Wei, Nishida, Kumagai et al., Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics, Nat. Commun

Akaike, Maeda, Nitric oxide and virus infection, Immunology, doi:10.1046/j.1365-2567.2000.00142.x

Akaike, Noguchi, Ijiri, Setoguchi, Suga et al., Pathogenesis of influenza virus-induced pneumonia: Involvement of both nitric oxide and oxygen radicals

Akaike, Okamoto, Sawa, Yoshitake, Tamura et al., 8-nitroguanosine formation in viral pneumonia and its implication for pathogenesis, doi:10.1073/pnas.0235623100

Akerstrom, Gunalan, Keng, Tan, Mirazimi, Dual effect of nitric oxide on SARS-CoV replication: Viral RNA production and palmitoylation of the S protein are affected, Virology, doi:10.1016/j.virol.2009.09.007

Akerstrom, Mousavi-Jazi, Klingstrom, Leijon, Lundkvist et al., Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus, J. Virol, doi:10.1128/JVI.79.3.1966-1969.2005

Al Sulaiman, Korayem, Altebainawi, Al Harbi, Alissa et al., Evaluation of inhaled nitric oxide (iNO) treatment for moderate-to-severe ARDS in critically ill patients with COVID-19: A multicenter cohort study, Crit. Care, doi:10.1186/s13054-022-04158-y

Al-Sehemi, Pannipara, Parulekar, Patil, Choudhari et al., Potential of NO donor furoxan as SARS-CoV-2 main protease (M(pro)) inhibitors: In silico analysis, J. Biomol. Struct. Dyn

Albert, Ruíz, Pemán, Salavert, Domingo-Calap, Lack of evidence for infectious SARS-CoV-2 in feces and sewage, Eur. J. Clin. Microbiol, doi:10.1007/s10096-021-04304-4

Alqahtani, Aldhahir, Al Ghamdi, Albahrani, Aldraiwiesh et al., Inhaled nitric oxide for clinical management of COVID-19: A systematic review and meta-analysis, Int. J. Environ. Res. Public Health, doi:10.3390/ijerph191912803

Asada, Production and scavenging of reactive oxygen species in chloroplasts and their functions, Plant Physiol

Asada, The water-water cycle in chloroplasts: Scavenging of active oxygens and dissipation of excess photons, Annu. Rev. Plant Physiol. Plant Mol. Biol, doi:10.1146/annurev.arplant.50.1.601

Badejo, Wada, Gao, Maruta, Sawa et al., Translocation and the alternative D-galacturonate pathway contribute to increasing the ascorbate level in ripening tomato fruits together with the D-mannose/L-galactose pathway, J. Exp. Bot, doi:10.1093/jxb/err275

Bagate, Tuffet, Masi, Perier, Razazi et al., Rescue therapy with inhaled nitric oxide and almitrine in COVID-19 patients with severe acute respiratory distress syndrome, Ann. Intensive Care, doi:10.1186/s13613-020-00769-2

Bahadoran, Mirmiran, Kashfi, Ghasemi, Lost-in-translation of metabolic effects of inorganic nitrate in type 2 diabetes: Is ascorbic acid the answer?, Int. J. Mol. Sci, doi:10.3390/ijms22094735

Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of COVID-19-Final report, N. Engl. J. Med, doi:10.1056/NEJMoa2007764

Bender, Schwarz, Nitrite-dependent nitric oxide synthesis by molybdenum enzymes, FEBS Lett

Benito, Lopez, Saiz, Buxaderas, Sanchez et al., A flavonoid-rich diet increases nitric oxide production in rat aorta, Br. J. Pharmacol, doi:10.1038/sj.bjp.0704534

Benjamin, O'driscoll, Dougall, Duncan, Smith et al., Stomach NO synthesis, Nature, doi:10.1038/368502a0

Bernal, Gomes Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients, N. Engl. J. Med, doi:10.1056/NEJMoa2116044

Bhowmik, Barek, Aziz, Islam, Impact of high-dose vitamin C on the mortality, severity, and duration of hospital stay in COVID-19 patients: A meta-analysis, Health Sci. Rep, doi:10.1002/hsr2.762

Bondonno, Croft, Ward, Considine, Hodgson, Dietary flavonoids and nitrate: Effects on nitric oxide and vascular function, Nutr. Rev, doi:10.1093/nutrit/nuu014

Boretti, Banik, Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome, Pharmanutrition, doi:10.1016/j.phanu.2020.100190

Bryan, Calvert, Gundewar, Lefer, Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice, Free Radic. Biol. Med, doi:10.1016/j.freeradbiomed.2008.04.040

Capra, The Tao of Physics: An Exploration of the Parallels between Modern Physics and Eastern Mysticism

Carlsson, Wiklund, Engstrand, Weitzberg, Lundberg, Effects of pH, nitrite, and ascorbic acid on nonenzymatic nitric oxide generation and bacterial growth in urine, Nitric Oxide, doi:10.1006/niox.2001.0371

Cegolon, Mirandola, Salaris, Salvati, Mastrangelo et al., Hypothiocyanite and hypothiocyanite/lactoferrin mixture exhibit virucidal activity in vitro against SARS-CoV-2, Pathogens, doi:10.3390/pathogens10020233

Chan, Poon, Cheng, Guan, Hung et al., Detection of SARS coronavirus in patients with suspected SARS, Emerg. Infect. Dis, doi:10.3201/eid1002.030610

Chen, 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

Cheng, Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?, Med. Drug Disc

Cheung, Hung, Chan, Lung, Tso et al., Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong cohort: Systematic review and meta-analysis, Gastroenterology, doi:10.1053/j.gastro.2020.03.065

Clausen, The influence of nutrition upon resistance to infection, Physiol. Rev, doi:10.1152/physrev.1934.14.3.309

Cohen, Lamattina, Yamasaki, Nitric oxide signaling by plant-associated bacteria

Cohen, Mazzola, Yamasaki, Nitric oxide research in agriculture

Cohen, Yamasaki, Mazzola, Brassica napus seed meal soil amendment modifies microbial community structure, nitric oxide production and incidence of Rhizoctonia root rot, Soil Biol. Biochem, doi:10.1016/j.soilbio.2004.11.027

Colasanti, Persichini, Venturini, Ascenzi, S-nitrosylation of viral proteins: Molecular bases for antiviral effect of nitric oxide, IUBMB Life, doi:10.1080/713803459

Colla, Kim, Kyriacou, Rouphael, Nitrate in fruits and vegetables, Sci. Hortic-Amst, doi:10.1016/j.scienta.2018.04.016

Comly, Cyanosis in infants caused by nitrates in well water, J. Am. Med. Assoc, doi:10.1001/jama.1945.02860360014004

Corpe, Eck, Wang, Al-Hasani, Levine, Intestinal dehydroascorbic acid (DHA) transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8, J. Biol. Chem, doi:10.1074/jbc.M112.436790

Cortese-Krott, Koning, Kuhnle, Nagy, Bianco et al., The reactive rpecies Iinteractome: Evolutionary emergence, biological significance, and opportunities for redox metabolomics and personalized medicine, Antioxid. Redox Signal, doi:10.1089/ars.2017.7083

Cully, A tale of two antiviral targets-And the COVID-19 drugs that bind them, Nat. Rev. Drug Discov, doi:10.1038/d41573-021-00202-8

Dai, Tan, Ren, Shao, Tao et al., COVID-19 risk appears to vary across different alcoholic beverages, Front. Nutr, doi:10.3389/fnut.2021.772700

Dancer, Li, Hart, Tang, Jones, What is the risk of acquiring SARS-CoV-2 from the use of public toilets?, Sci. Total Environ, doi:10.1016/j.scitotenv.2021.148341

Das, Reddy, Chadchan, Patil, Biradar et al., Nickel and oxidative stress: Cell signaling mechanisms and protective role of vitamin C, Endocr. Metab. Immune, doi:10.2174/1871530319666191205122249

Daxon, Lark, Matzek, Fields, Haselton, Nebulized nitroglycerin for coronavirus disease 2019-associated acute respiratory distress syndrome: A case report, A A Pract, doi:10.1213/XAA.0000000000001376

Dedon, Tannenbaum, Reactive nitrogen species in the chemical biology of inflammation, Arch. Biochem. Biophys, doi:10.1016/j.abb.2003.12.017

Degroote, Fang, Antimicrobial properties of nitric oxide

Demartino, Kim-Shapiro, Patel, Gladwin, Nitrite and nitrate chemical biology and signalling, Br. J. Pharmacol, doi:10.1111/bph.14484

Deo, Deshmukh, Oral microbiome: Unveiling the fundamentals, J. Oral Maxillofac. Pathol, doi:10.4103/jomfp.JOMFP_304_18

Devaux, Rolain, Raoult, ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome, J. Microbiol. Immunol. Infect, doi:10.1016/j.jmii.2020.04.015

Dominguez, Cuenca, Mate-Munoz, Garcia-Fernandez, Serra-Paya et al., Effects of beetroot juice supplementation on cardiorespiratory endurance in athletes. a systematic review, Nutrients, doi:10.3390/nu9010043

Dresen, Lee, Hill, Notz, Patel et al., History of scurvy and use of vitamin C in critical illness: A narrative review, Nutr. Clin. Pract, doi:10.1002/ncp.10914

Duncan, Dougall, Johnston, Green, Brogan et al., Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate, Nat. Med, doi:10.1038/nm0695-546

Eaton, Hemoglobin S polymerization and sickle cell disease: A retrospective on the occasion of the 70th anniversary of Pauling's Science paper, Am. J. Hematol, doi:10.1002/ajh.25687

Ellis, Anderson, Chirkov, Morris-Thurgood, Jackson et al., Acute effects of vitamin c on platelet responsiveness to nitric oxide donors and endothelial function in patients with chronic heart failure, J. Cardiovasc. Pharm, doi:10.1097/00005344-200105000-00008

Elsaba, Khan, Galal, Lakshmanadoss, Bolkini, Infantile free sialic acid storage disease presenting as non-immune hydrops fetalis, J. Pediat. Neon. Individ. Med

Evans, Causation and disease: The Henle-Koch postulates revisited, Yale J. Biol. Med

Farsalinos, Barbouni, Poulas, Polosa, Caponnetto et al., Current smoking, former smoking, and adverse outcome among hospitalized COVID-19 patients: A systematic review and meta-analysis, Ther. Adv. Chronic Dis, doi:10.1177/2040622320935765

Fenech, Amaya, Valpuesta, Botella, Vitamin C content in fruits: Biosynthesis and regulation, Front. Plant Sci, doi:10.3389/fpls.2018.02006

Fernandez-Hernando, Fukata, Bernatchez, Fukata, Lin et al., Identification of Golgilocalized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase, J. Cell Biol

Filipovic, Zivanovic, Alvarez, Banerjee, Chemical biology of H 2 S signaling through persulfidation, Chem. Rev, doi:10.1021/acs.chemrev.7b00205

Fiorentino, Coppola, Izzo, Annunziata, Bernardo et al., Effects of adding L-arginine orally to standard therapy in patients with COVID-19: A randomized, double-blind, placebo-controlled, parallel-group trial. Results of the first interim analysis, Eclinicalmedicine, doi:10.1016/j.eclinm.2021.101125

Forstermann, Sessa, Nitric oxide synthases: Regulation and function, Eur. Heart J, doi:10.1093/eurheartj/ehr304

Fortenberry, Inhaled nitric oxide for pediatric acute respiratory distress syndrome: Another brick in the wall?, Crit. Care Med, doi:10.1097/CCM.0000000000003394

Foyer, Halliwell, The presence of glutathione and glutathione reductase in chloroplasts: A proposed role in ascorbic acid metabolism, Planta, doi:10.1007/BF00386001

Fukuto, Perez-Ternero, Zarenkiewicz, Lin, Hobbs et al., Hydropersulfides (RSSH) and nitric oxide (NO) signaling: Possible effects on S-nitrosothiols (RS-NO), Antioxidants, doi:10.3390/antiox11010169

Gago, Lundberg, Barbosa, Laranjinha, Red wine-dependent reduction of nitrite to nitric oxide in the stomach, Free Radic. Bio. Med, doi:10.1016/j.freeradbiomed.2007.06.007

Garcia-Diaz, Lopez-Legarrea, Quintero, Martinez, Vitamin C in the treatment and/or prevention of obesity, J. Nutr. Sci. Vitaminol, doi:10.3177/jnsv.60.367

Ginestra, Mitchell, Anesi, Christie, COVID-19 critical illness: A data-driven review, Annu. Rev. Med, doi:10.1146/annurev-med-042420-110629

Gladwin, Raat, Shiva, Dezfulian, Hogg et al., Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation, Am. J. Physiol. Circ. Physiol

Gordon, Jang, Bouhaddou, Xu, Obernier et al., A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature, doi:10.1038/s41586-020-2286-9

Green, COVID-19 accelerates endothelial dysfunction and nitric oxide deficiency, Microbes Infect, doi:10.1016/j.micinf.2020.05.006

Group, Horby, Lim, Emberson, Mafham et al., Dexamethasone in hospitalized patients with COVID-19-Preliminary report, N. Engl. J. Med

Guns, Vanherle, Hendriks, Bogie, Protein lipidation by palmitate controls macrophage function, Cells, doi:10.3390/cells11030565

Guo, Tao, Flavell, Zhu, Potential intestinal infection and faecal-oral transmission of SARS-CoV-2, Nat. Rev. Gastroenterol. Hepatol, doi:10.1038/s41575-021-00416-6

Gupta, Ghosh, Singh, Misra, Clinical considerations for patients with diabetes in times of COVID-19 epidemic, Diabetes Metab. Syndr, doi:10.1016/j.dsx.2020.03.002

Hassimotto, Genovese, Lajolo, Antioxidant activity of dietary fruits, vegetables, and commercial frozen fruit pulps, J. Agric. Food Chem, doi:10.1021/jf047894h

Hedenstierna, Chen, Hedenstierna, Lieberman, Fine, Nitric oxide dosed in short bursts at high concentrations may protect against COVID 19, Nitric Oxide, doi:10.1016/j.niox.2020.06.005

Hemilä, Bias against vitamin C in mainstream medicine: Examples from trials of vitamin C for infections, Life, doi:10.3390/life12010062

Hess, Diet, nutrition and infection, N. Engl. J. Med, doi:10.1056/NEJM193210132071501

Horie, Mcnicholas, Rezoagli, Pham, Curley et al., Emerging pharmacological therapies for ARDS: COVID-19 and beyond, Intensive Care Med

Hsu, Arcot, Alice Lee, Nitrate and nitrite quantification from cured meat and vegetables and their estimated dietary intake in Australians, Food Chem, doi:10.1016/j.foodchem.2008.11.081

Huang, Huang, Mashimo, Bloch, Moskowitz et al., Hypertension in mice lacking the gene for endothelial nitric oxide synthase, Nature, doi:10.1038/377239a0

Huizing, Hackbarth, Adams, Wasserstein, Patterson et al., Free sialic acid storage disorder: Progress and promise, Neurosci. Lett, doi:10.1016/j.neulet.2021.135896

Ichinose, Roberts, Jr, Zapol, Inhaled nitric oxide: A selective pulmonary vasodilator: Current uses and therapeutic potential, Circulation, doi:10.1161/01.CIR.0000134595.80170.62

Ignarro, Inhaled nitric oxide and COVID-19, Br. J. Pharmacol, doi:10.1111/bph.15085

Inoue, Japanese strategy to COVID-19: How does it work?, Glob. Health Med, doi:10.35772/ghm.2020.01043

Iwasaki, Grubaugh, Why does Japan have so few cases of COVID-19?, EMBO Mol. Med, doi:10.15252/emmm.202012481

Jalil, Concentrations of thiocyanate and hypothiocyanite in the saliva of young adults, J. Nihon Univ. Sch. Dent

Jendrny, Schulz, Twele, Meller, Von Kockritz-Blickwede et al., Scent dog identification of samples from COVID-19 patients-A pilot study, BMC Infect. Dis, doi:10.1186/s12879-020-05281-3

Kamenshchikov, Berra, Carroll, Therapeutic effects of inhaled nitric oxide therapy in COVID-19 patients, Biomedicines, doi:10.3390/biomedicines10020369

Kashiouris, ; L'heureux, Cable, Fisher, Leichtle et al., The emerging role of vitamin C as a treatment for sepsis, Nutrients, doi:10.3390/nu12020292

Kelly, Ohlsson, Shah, Sildenafil for pulmonary hypertension in neonates, Cochrane Database Syst. Rev, doi:10.1002/14651858.CD005494.pub4

Keyaerts, 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

Kim, Lee, Yang, Lee, Effenberger et al., Immunopathogenesis and treatment of cytokine storm in COVID-19, Theranostics, doi:10.7150/thno.49713

Kinoshita, Sato, Vellingiri, Green, Tanaka, Inverse association between hypertension treatment and COVID-19 prevalence in Japan, Int. J. Infect. Dis, doi:10.1016/j.ijid.2021.05.071

Kleinert, Art, Pautz, Regulation of the expression of inducible nitric oxide synthase

Klingstrom, Akerstrom, Hardestam, Stoltz, Simon et al., Nitric oxide and peroxynitrite have different antiviral effects against hantavirus replication and free mature virions, Eur. J. Immunol, doi:10.1002/eji.200535587

Kopic, Corradini, Sidani, Murek, Vardanyan et al., Ethanol inhibits gastric acid secretion in rats through increased AMP-kinase activity, Cell. Physiol. Biochem, doi:10.1159/000276553

Kopic, Geibel, Update on the mechanisms of gastric acid secretion, Curr. Gastro. Rep, doi:10.1007/s11894-010-0137-9

Krammer, SARS-CoV-2 vaccines in development, Nature, doi:10.1038/s41586-020-2798-3

Lee, The SARS epidemic in Hong Kong, J. Epidemiol. Commun. Health, doi:10.1136/jech.57.9.652

Li, Liu, Lu, Gao, Zhang, Palmitoylation of SARS-CoV-2 S protein is critical for S-mediated syncytia formation and virus entry, J. Med. Virol, doi:10.1002/jmv.27339

Li, Meng, Zhu, Li, Research progress of betalain in response to adverse stresses and evolutionary relationship compared with anthocyanin, Molecules, doi:10.3390/molecules24173078

Li, Yuan, Li, Wang, Spike protein mediated membrane fusion during SARS-CoV-2 infection, J. Med. Virol

Liu, Liu, Zhou, Dong, Jiang et al., Rampant C-to-U deamination accounts for the intrinsically high mutation rate in SARS-CoV-2 spike gene, RNA

Lombardi, Gani, Berti, Comberiati, Peroni et al., Asthma and COVID-19: A dangerous liaison?, Asthma Res. Pract, doi:10.1186/s40733-021-00075-z

Lorente, Gomez-Bernal, Martin, Navarro-Gonzalvez, Argueso et al., High serum nitrates levels in non-survivor COVID-19 patients, Med. Intensiv

Lorusso, Combes, Lo Coco, De Piero, Belohlavek et al., ECMO for COVID-19 patients in Europe and Israel, Intensive Care Med, doi:10.1007/s00134-020-06272-3

Lu, Glutathione synthesis, Biochim. Biophys. Acta, doi:10.1016/j.bbagen.2012.09.008

Lundberg, Carlström, Weitzberg, Metabolic effects of dietary nitrate in health and disease, Cell Metab, doi:10.1016/j.cmet.2018.06.007

Lundberg, Weitzberg, Gladwin, The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics, Nat. Rev. Drug Discov, doi:10.1038/nrd2466

Lundberg, Weitzberg, Lundberg, Alving, Intragastric nitric oxide production in humans: Measurements in expelled air, Gut, doi:10.1136/gut.35.11.1543

Ma, Hu, Feng, Wang, Nitrate and nitrite in health and disease, Aging Dis, doi:10.14336/AD.2017.1207

Magalhaes, Singh, Passos, None

Main, Fuller, Protein S-palmitoylation: Advances and challenges in studying a therapeutically important lipid modification, FEBS J, doi:10.1111/febs.15781

Mario, Roberto, Marta, Teresa, Laura, Hypothesis of COVID-19 therapy with sildenafil, Int. J. Prev. Med, doi:10.4103/ijpvm.IJPVM_258_20

Martel, Ko, Young, Ojcius, Could nasal nitric oxide help to mitigate the severity of COVID-19?, Microbes Infect, doi:10.1016/j.micinf.2020.05.002

May, How does ascorbic acid prevent endothelial dysfunction? Free Radic, Biol. Med, doi:10.1016/S0891-5849(00)00269-0

Mcfadyen, Garfield, Mancio, Ridge, Semple et al., Use of sildenafil in patients with severe COVID-19 pneumonitis, Br. J. Anaesth, doi:10.1016/j.bja.2022.04.004

Mcknight, Smith, Drummond, Duncan, Golden et al., Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans, Gut, doi:10.1136/gut.40.2.211

Miguel, Betalains in some species of the Amaranthaceae family: A review, Antioxidants, doi:10.3390/antiox7040053

Mitchell, Shonle, Grindley, The origin of the ntirate in the urine, J. Biol. Chem, doi:10.1016/S0021-9258(18)87531-7

Miyara, Tubach, Pourcher, Morelot-Panzini, Pernet et al., Low rate of daily active tobacco smoking in patients with symptomatic COVID-19, WPP19W, doi:10.32388/wpp19w.4

Morais-Almeida, Aguiar, Martin, Ansotegui, Ebisawa et al., COVID-19, asthma, and biologic therapies: What we need to know, World Allergy Organ. J

Morina, Takahama, Yamauchi, Hirota, Veljovic-Jovanovic, Quercetin 7-O-glucoside suppresses nitrite-induced formation of dinitrosocatechins and their quinones in catechin/nitrite systems under stomach simulating conditions, Food Funct, doi:10.1039/C4FO00695J

Mussa, Mohd Idris, Ahmed, Ahmad, Murtadha et al., High-Dose Vitamin C for Cancer Therapy, Pharmaceuticals, doi:10.3390/ph15060711

Nag, Kathpalia, Gorla, Wadhwa, Localization of nitro-tyrosine immunoreactivity in human retina, Ann. Anat, doi:10.1016/j.aanat.2019.01.006

Nemzer, Pietrzkowski, Hunter, Robinson, Fink, Betalain-rich dietary supplement, but not PETN, increases vasodilation and nitric oxide: A comparative, single-dose, randomized, placebo-controlled, blinded, crossover pilot study, J. Food Res, doi:10.5539/jfr.v10n1p26

Nijveldt, Van Nood, Van Hoorn, Boelens, Van Norren et al., Flavonoids: A review of probable mechanisms of action and potential applications, Am. J. Clin. Nutr, doi:10.1093/ajcn/74.4.418

Ochoa-Brust, Fernandez, Villanueva-Ruiz, Velasco, Trujillo-Hernandez et al., Daily intake of 100 mg ascorbic acid as urinary tract infection prophylactic agent during pregnancy, Acta Obstet. Gynecol. Scand

Oda, Akaike, Hamamoto, Suzuki, Hirano et al., Oxygen radicals in influenza-induced pathogenesis and treatment with pyran polymer-conjugated SOD, Science, doi:10.1126/science.2543070

Olczak-Pruc, Swieczkowski, Ladny, Pruc, Juarez-Vela et al., Vitamin C supplementation for the treatment of COVID-19: A systematic review and meta-analysis, Nutrients, doi:10.3390/nu14194217

Oldfield, Loomba, Monteith, Crowley, Medel et al., Safety and pharmacokinetics of sodium nitrite in patients with subarachnoid hemorrhage: A phase IIa study, J. Neurosurg

Ortis, Lenhart, Becker, Schwamback, Tovo et al., Drug-induced liver injury and COVID-19: A review for clinical practice, World J. Hepatol, doi:10.4254/wjh.v13.i9.1143

Otaki, Nakasone, Nakamura, Nonself mutations in the spike protein suggest an increase in the antigenicity and a decrease in the virulence of the Omicron variant of SARS-CoV-2, COVID, doi:10.3390/covid2030029

Otaki, Nakasone, Nakamura, Self and nonself short constituent sequences of amino acids in the SARS-CoV-2 proteome for vaccine development, COVID, doi:10.3390/covid1030047

Oza, Kashfi, Utility of NO and H2S donating platforms in managing COVID-19: Rationale and promise, Nitric Oxide, doi:10.1016/j.niox.2022.08.003

Padayatty, Sun, Wang, Riordan, Hewitt et al., Vitamin C pharmacokinetics: Implications for oral and intravenous use, Ann. Intern. Med, doi:10.7326/0003-4819-140-7-200404060-00010

Pannala, Mani, Spencer, Skinner, Bruckdorfer et al., The effect of dietary nitrate on salivary, plasma, and urinary nitrate metabolism in humans, Free Radic. Biol. Med, doi:10.1016/S0891-5849(02)01353-9

Patel, Mcandrew, Sellak, White, Jo et al., Biological aspects of reactive nitrogen species, Biochim. Biophys. Acta, doi:10.1016/S0005-2728(99)00028-6

Pauling, Ascorbic acid and the common cold, Am. J. Clin. Nutr, doi:10.1093/ajcn/24.11.1294

Pauling, How to Live Longer and Feel Better

Pauling, Itano, Singer, Wells, Sickle cell anemia, a molecular disease, Science, doi:10.1126/science.110.2865.543

Pauling, Orthomolecular psychiatry, Science, doi:10.1126/science.160.3825.265

Pauling, The significance of the evidence about ascorbic acid and the common cold

Pauling, Vitamin C and the Common Cold

Perkins, Ji, Connolly, Couper, Lall et al., Effect of noninvasive respiratory dtrategies on intubation or mortality among patients with acute hypoxemic respiratory failure and COVID-19: The RECOVERY-RS randomized clinical trial, JAMA, doi:10.1001/jama.2022.0028

Perrone, Belser, Wadford, Katz, Tumpey, Inducible nitric oxide contributes to viral pathogenesis following highly pathogenic influenza virus infection in mice, J. Infect. Dis, doi:10.1093/infdis/jit062

Peterson, Mackowiak, Barnett, Marling-Cason, Haley, The human gastric bactericidal barrier: Mechanisms of action, relative antibacterial activity, and dietary influences, J. Infect. Dis, doi:10.1093/infdis/159.5.979

Pignatelli, Fabietti, Ricci, Piattelli, Curia, How periodontal disease and presence of nitric oxide reducing oral bacteria can affect blood pressure, Int. J Mol. Sci, doi:10.3390/ijms21207538

Popov, Human exhaled breath analysis, Ann. Allergy Asthma Immunol, doi:10.1016/j.anai.2011.02.016

Qin, Liu, Sun, Fan, Xia et al., Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane, doi:10.1073/pnas.1116633109

Rathbone, Johnson, Wyatt, Kelleher, Heatley et al., Ascorbic acid: A factor concentrated in human gastric juice, Clin. Sci, doi:10.1042/cs0760237

Roberts, Fineman, Morin, Shaul, Rimar et al., Inhaled nitric oxide and persistent pulmonary hypertension of the newborn, N. Engl. J. Med, doi:10.1056/NEJM199702273360902

Robertson, The vitamins and resistance to infection, Medicine, doi:10.1097/00005792-193405000-00001

Rocha, Gago, Barbosa, Laranjinha, Dietary polyphenols generate nitric oxide from nitrite in the stomach and induce smooth muscle relaxation, Toxicology, doi:10.1016/j.tox.2009.09.008

Rocha, Laranjinha, Nitrate from diet might fuel gut microbiota metabolism: Minding the gap between redox signaling and inter-kingdom communication, Free Radic. Biol. Med, doi:10.1016/j.freeradbiomed.2020.02.001

Roychoudhury, Basu, Ascorbate-glutathione and plant tolerance to various abiotic stresses

Ruddell, Blendis, Walters, Nitrite and thiocyanate in the fasting and secreting stomach and in saliva, Gut, doi:10.1136/gut.18.1.73

Rusznyak, Szent-Györgyi, Vitamin, Flavonols as vitamins, Nature, doi:10.1038/138027a0

Sachs, Carlsson, Lindberg, Wallmark, Gastric, K-ATPase as therapeutic target, Annu. Rev. Pharm. Toxicol

Sakihama, Cohen, Grace, Yamasaki, Plant phenolic antioxidant and prooxidant activities: Phenolics-induced oxidative damage mediated by metals in plants, Toxicology, doi:10.1016/S0300-483X(02)00196-8

Sakihama, Mano, Sano, Asada, Yamasaki, Reduction of phenoxyl radicals mediated by monodehydroascorbate reductase, Biochem. Biophys. Res. Commun, doi:10.1006/bbrc.2000.4053

Sakihama, Tamaki, Shimoji, Ichiba, Fukushi et al., Enzymatic nitration of phytophenolics: Evidence for peroxynitrite-independent nitration of plant secondary metabolites, FEBS Lett, doi:10.1016/S0014-5793(03)01059-7

Sakihama, Yamasaki, Phytochemical antioxidants: Past, present and future

Sanchez, Ibargoyen, Mastrogiovanni, Radi, Keszenman et al., Fast and biphasic 8-nitroguanine production from guanine and peroxynitrite, Free Radic. Biol. Med, doi:10.1016/j.freeradbiomed.2022.10.317

Sandrini, Taylor, Thomas, Yates, Fractional exhaled nitric oxide in asthma: An update, Respirology

Santamarina, Beddings, Lomakin, Boisier Riscal, Gutierrez Claveria et al., Sildenafil for treating patients with COVID-19 and perfusion mismatch: A pilot randomized trial, Crit. Care, doi:10.1186/s13054-021-03885-y

Saura, Zaragoza, Mcmillan, Quick, Hohenadl et al., An antiviral mechanism of nitric oxide: Inhibition of a viral protease, Immunity, doi:10.1016/S1074-7613(00)80003-5

Shei, Baranauskas, More questions than answers for the use of inhaled nitric oxide in COVID-19, Nitric Oxide, doi:10.1016/j.niox.2022.05.001

Sobala, Schorah, Sanderson, Dixon, Tompkins et al., Ascorbic acid in the human stomach, Gastroenterology, doi:10.1016/0016-5085(89)90071-1

Sobko, Marcus, Govoni, Kamiya, Dietary nitrate in Japanese traditional foods lowers diastolic blood pressure in healthy volunteers, Nitric Oxide, doi:10.1016/j.niox.2009.10.007

Sorbo, Michaelsen, Ali, Wang, Ribeiro et al., High doses of inhaled nitric oxide as an innovative antimicrobial strategy for lung infections, Biomedicines, doi:10.3390/biomedicines10071525

Steudel, Hurford, Zapol, Inhaled nitric oxide: Basic biology and clinical applications, Anesthesiology, doi:10.1097/00000542-199910000-00030

Stuehr, Marletta, Mammalian nitrate biosynthesis: Mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide, Proc. Natl. Acad. Sci, doi:10.1073/pnas.82.22.7738

Sun, Zhang, Broderick, Fein, Measurement of nitric oxide production in biological systems by using Griess reaction assay, Sensors, doi:10.3390/s30800276

Sundqvist, Larsen, Carlstrom, Bottai, Pernow et al., A randomized clinical trial of the effects of leafy green vegetables and inorganic nitrate on blood pressure, Am. J. Clin. Nutr

Sunjaya, Allida, Di Tanna, Jenkins, Asthma and risk of infection, hospitalization, ICU admission and mortality from COVID-19: Systematic review and meta-analysis, J. Asthma, doi:10.1080/02770903.2021.1888116

Svirbely, Szent-Györgyi, The chemical nature of vitamin C, Biochem. J, doi:10.1042/bj0260865

Szabo, Multiple pathways of peroxynitrite cytotoxicity, Toxicol. Lett, doi:10.1016/S0378-4274(02)00507-6

Takahashi, Tamashiro, Sakihama, Yamamoto, Kawamitsu et al., High-susceptibility of photosynthesis to photoinhibition in the tropical plant Ficus microcarpa L. f. cv. Golden Leaves, BMC Plant Biol, doi:10.1186/1471-2229-2-2

Tan, Yip, Hans Selye, Founder of the stress theory, Singap. Med. J, doi:10.11622/smedj.2018043

Tang, Paonessa, Zhang, Ambrosone, Mccann, Total isothiocyanate yield from raw cruciferous vegetables commonly consumed in the United States, J. Funct. Foods, doi:10.1016/j.jff.2013.07.011

Tao, Tzou, Nouhin, Gupta, De Oliveira et al., The biological and clinical significance of emerging SARS-CoV-2 variants, Nat. Rev. Genet, doi:10.1038/s41576-021-00408-x

Terrett, Bell, Brown, Ellis, Sildenafil (VIAGRA(TM)), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction, Bioorg. Med. Chem. Lett, doi:10.1016/0960-894X(96)00323-X

Toda, Ayajiki, Okamura, Control of systemic and pulmonary blood pressure by nitric oxide formed through neuronal nitric oxide synthase, J. Hypertens, doi:10.1097/HJH.0b013e32832e8ddf

Torrens, Feelisch, How to beet hypertension in pregnancy: Is there more to beetroot juice than nitrate?, J. Physiol

Traber, Stevens, Vitamins, Beneficial effects from a mechanistic perspective, Free Radic. Biol. Med, doi:10.1016/j.freeradbiomed.2011.05.017

Trevejo-Nunez, Kolls, De Wit, Alcohol use as a risk factor in infections and healing: A clinician's perspective, Alcohol Res. Curr. Rev

Tun, Gleeson, Al-Joudeh, Dube, Immune-mediated hepatitis with the Moderna vaccine, no longer a coincidence but confirmed, J. Hepatol, doi:10.1016/j.jhep.2021.09.031

Tuo, Yan, Ge, Ou, Zhao, Ascorbic acid secretion in the human stomach and the effect of gastrin, World J. Gastroenterol, doi:10.3748/wjg.v6.i5.704

Usman, Siddiqi, Khan, Patel, Shahid et al., Is there a smoker's paradox in COVID-19?, BMJ Evidence-Based Med, doi:10.1136/bmjebm-2020-111492

Vabret, Britton, Gruber, Hegde, Kim et al., Immunology of COVID-19: Current state of the science, Immunity, doi:10.1016/j.immuni.2020.05.002

Valsecchi, Winterton, Safaee Fakhr, Collier, Nozari et al., High-dose inhaled nitric oxide for the treatment of spontaneously breathing pregnant patients with severe coronavirus disease 2019 (COVID-19) pneumonia, Obstet. Gynecol, doi:10.1097/AOG.0000000000004847

Villacorta, Gao, Schopfer, Freeman, Chen, Nitro-fatty acids in cardiovascular regulation and diseases: Characteristics and molecular mechanisms, Front. Biosci, doi:10.2741/4425

Vitrone, Mele, Durante-Mangoni, Zampino, Drugs and liver injury: A not to be overlooked binomial in COVID-19, J. Chemother, doi:10.1080/1120009X.2021.1988203

Wagner, Erkenbrack, Love, Stress-induced evolutionary innovation: A mechanism for the origin of cell types, Bioessays, doi:10.1002/bies.201800188

Waring, Drake, Schorah, White, Lynch et al., Ascorbic acid and total vitamin C concentrations in plasma, gastric juice, and gastrointestinal mucosa: Effects of gastritis and oral supplementation, Gut, doi:10.1136/gut.38.2.171

Watanabe, Yamasaki, Dynamics of nitrite content in fresh spinach leaves: Evidence for nitrite formation caused by microbial nitrate reductase activity, J. Nutrit. Food Sci, doi:10.4172/2155-9600.1000572

Weitzberg, Lundberg, Nonenzymatic nitric oxide production in humans, Nitric Oxide, doi:10.1006/niox.1997.0162

Weitzberg, Lundberg, Novel aspects of dietary nitrate and human health, Annu. Rev. Nutrit, doi:10.1146/annurev-nutr-071812-161159

Wong, Saier, Jr, The SARS-coronavirus infection cycle: A survey of viral membraneproteins, their functional interactions and pathogenesis, Int. J. Mol. Sci, doi:10.3390/ijms22031308

Wu, Tackle the free radicals damage in COVID-19, Nitric Oxide, doi:10.1016/j.niox.2020.06.002

Yamasaki, A function of colour, Trend. Plant Sci, doi:10.1016/S1360-1385(97)82730-6

Yamasaki, Cohen, Biological consilience of hydrogen sulfide and nitric oxide in plants: Gases of primordial earth linking plant, microbial and animal physiologies, Nitric Oxide, doi:10.1016/j.niox.2016.04.002

Yamasaki, Cohen, NO signal at the crossroads: Polyamine-induced nitric oxide synthesis in plants? Trend, Plant Sci, doi:10.1016/j.tplants.2006.09.009

Yamasaki, Grace, EPR detection of phytophenoxyl radicals stabilized by zinc ions: Evidence for the redox coupling of plant phenolics with ascorbate in the H 2 O 2 peroxidase system, FEBS Lett, doi:10.1016/S0014-5793(98)00048-9

Yamasaki, Nitric oxide research in plant biology: Its past and future, Nitric Oxide Signaling in Higher Plants

Yamasaki, Nitrite-dependent nitric oxide production pathway: Implications for involvement of active nitrogen species in photoinhibition in vivo, Philos. Trans. R. Soc. B Biol. Sci, doi:10.1098/rstb.2000.0708

Yamasaki, Sakihama, Takahashi, An alternative pathway for nitric oxide production in plants: New features of an old enzyme, Trend. Plant Sci, doi:10.1016/S1360-1385(99)01393-X

Yamasaki, The NO world for plants: Achieving balance in an open system, Plant Cell Environ, doi:10.1111/j.1365-3040.2005.01297.x

Yamasaki, Uefuji, Sakihama, Bleaching of the red anthocyanin induced by superoxide radical, Arch. Biochem. Biophys, doi:10.1006/abbi.1996.0331

Yamasaki, Watanabe, Fukuto, Cohen, Nitrite-dependent nitric oxide production pathway: Diversity of NO production systems

Yamasaki, Watanabe, Sakihama, Cohen, An overview of methods in plant nitric oxide (NO) research: Why do we always need to use multiple methods? In Plant Nitric Oxide: Methods and Protocols, Methods in Molecular Biology

Yun, Mullarky, Lu, Bosch, Kavalier et al., Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH, Science, doi:10.1126/science.aaa5004

Zhai, Li, Wang, Wu, Drug-induced liver disturbance during the treatment of COVID-19, Front. Pharmacol, doi:10.3389/fphar.2021.719308

Zhang, Dong, Cao, Yuan, Yang et al., Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China, Allergy, doi:10.1111/all.14238

Zhen, Leigh, Nitrate accumulation by wheat (Triticum aestivum) in relation to growth and tissue N concentrations, Plant Soil, doi:10.1007/BF00009253

Zhou, Li, Zhao, Chu, Wang et al., Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus, Sci. Adv, doi:10.1126/sciadv.aao4966

Download Image

Please send us corrections, updates, or comments. Vaccines and treatments are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

@CovidAnalysis

FAQ

Public domain CC0 1.0