Because I am in a business where I've had to study oxidative stress as part of my job, I can tell you that fighting oxidative stress is not a difficult thing to do. The way to fight free radicals and oxidative stress is with antioxidants. There are many ways to get antioxidants. You can get them from fruits and vegetables, and supplements like Vitamin C and Glutathione. Because too much vitamin C can cause diarrhea, and Glutathione is extremely expensive, I prefer to get antioxidants from molecular hydrogen in water. A medical grade water ionizer is by far, the cheapest way I have found, to get the maximum amount of antioxidants into your body (because the cost per gallon is largely determined by how long the machine lasts, and a medical grade machine can easily last over 20 years with proper mainenance). But if you find a cheaper way, please let me know about it.
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Tackle the free radicals damage in COVID-19
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1. Text
Current therapeutic approaches to novel coronavirus SARS-CoV-2 induced severe acute respiratory syndrome (COVID-19) are in disarray. Doctors focus on the virus itself and try desperately to apply antiviral medicine such as remdesivir to COVID-19 patients. However, the benefits of antiviral drugs are not satisfactory, while severe drug-induced liver toxicities have been reported [1]. Due to the lack of specific treatment, patients have to rely on their own immune system to recover from the disease.
Free radicals such as superoxide, hydroxyl radicals, nitric oxide (NO) and peroxynitrite are highly active chemical substances that easily react with other molecules. They are exceptionally destructive, indiscriminately causing protein deterioration, cell membrane destruction, DNA damage, cell death, and organ failure. It is known that virus infection induces massive production of free radicals [2]. The pathogenic roles of free radicals in viral infection are profound, but overlooked. In all current official guidelines for COVID-19 treatment, there is no mention about the role of free radical damage in this disease.
2. The pivotal role of free radical damage in respiratory virus induced pneumonia
Dr. Takaaki Akaike and Dr. Hiroshi Maeda at the Department of Microbiology, Kumamoto University School of Medicine found that when laboratory mice were infected by the influenza virus, the replication of the virus increased rapidly and peaked on day 4, then dropped down to baseline on day 8. The lung consolidation scores (lung damage index) raised from day 2 and peaked from day 8 to day 10. Mice began to die from day 8 to day 14 [3]. Reactive oxygen species (ROS) in the infected mice began generating from day 5 and peaked on day 8. In the meantime, another important free radical NO raised at the same time, peaked on day 8 [4]. From these results, it is evident that a free radical storm occurred in the influenza virus infection. By simply applying oxygen radical scavengers superoxide dismutase (SOD) [5] or NO synthase inhibitor L-NMMA [6], the infected mice were protected and recovered. Lab mice deficient in inducible NO synthase exhibited reduced morbidity and mortality when challenged with influenza virus [7]. These results explicitly tell us that the free radicals such as ROS and NO are the culprits in the virus induced pneumonia death.
3. The interplay of cytokine storm and free radical storm
Inflammatory cytokine storm were reported in both COVID-19 [[8], [9], [10]] and SARS [11], and the cytokine storm is the most frequently mentioned pathological theory in COVID-19. These inflammatory cytokines are proteins that act as signaling molecules to recruit immune cells to the site of inflammation, induce vascular leakage and exudation, and stimulate the generation of free radicals and proteases. For example, IFNɤ, IL-1ẞ, IL-6, TNFα can all stimulate the generation of NO [6,12]. IL-2 is highly up-regulated in COVID-19 patients [10], and IL-2 is known to significantly stimulate the generation of NO in patients [13], while NO is also the key mediator of IL-2 induced hypotension and vascular leak syndrome [14]. IL-6 is another major inflammatory cytokine up-regulated in COVID-19 patients [10]. IL-6 and TNFα can provoke the generation of superoxide in neutrophils [15,16], and hydrogen peroxide can stimulate the generation of IL-6 [17]. Inhibition of NO synthesis can decrease the production of IL-6 for more than 50% [18]. The cytotoxicity effect of inflammatory cytokines can be blocked by lipid peroxidation inhibitor [19]. In summary, when discussing the cytokine storm in COVID-19, it is critical to understand that free radicals, the downstream product of cytokine storm, are the executive factors for direct damage to cells and multiple organs (See Scheme 1).
Scheme 1. The interplay of cytokine storm and free radical storm in virus infection induced overactive immune response.
4. Suppressing free radical damage as the essential strategy for COVID-19 therapy
SOD is an enzyme that can eliminate superoxide and has been shown to rescue virus infected lab animals [5,20]. Since there is no SOD available for clinical use at this time, SOD mimic compounds [21] should be considered for COVID-19 patients.
Vitamin C and vitamin E are well known as strong antioxidants and free radical scavengers. It was reported that vitamin C given orally between 3000 and 8000 mg helped reduce the duration and relieve symptoms of the common cold [22]. The common cold is largely different from SARS and COVID-19 in the severity, urgency, and the scale of free radical production. Due to the short half-life of vitamin C in plasma, large dose and continuous intravenous infusion of vitamin C should be considered. Currently, there are several on-going clinical trials of intravenous Vitamin C infusion therapy for COVID-19 patients.
Nrf2 is a transcription factor for up-regulating the expressions of many anti-oxidative factors such as SOD and catalase, therefore plays a crucial role in maintaining cellular redox homeostasis [23]. However the level and activity of Nrf2 decreases with age [24], which gives a possible explanation why elder people are particularly vulnerable to the SARS-CoV-2 infection. Therefore, Nrf2 activators might be considered for elder people suffered COVID-19.
Combination of hydroxychloroquine, azithromycin and Zinc exhibits certain therapeutic benefits on COVID-19 patients. Regardless the cardiac toxicities, hydroxychloroquine and azithromycin can suppress NO and superoxide generation [[25], [26], [27]]. Zinc is crucial antioxidant known to be cofactor of SOD [28]. Thus this combination could simply be an antioxidant combination for decreasing host oxidative stress rather than suppressing virus replication. Similarly, erythromycin may be effective for COVID-19 as it can also suppress the generation of NO and superoxide [29]. Other less toxic antioxidant medicines such as glutathione [30] and N-acetylcysteine [31] should also be considered for COVID-19 treatment.
5. Conclusions
The Koch's postulates are the dogma of infectious disease, hence people focus on targeting SARS-CoV-2 in COVID-19. However it could be a problematic strategy. The amount of SARS-Cov-2 virus is high in the first week then decreases sharply in the second week [32], just like the observation in lab animals [3]. Therefore, antiviral therapy should commence at the early stage of infection. When COVID-19 patients seek medical help and hospitalization, the disease has most likely already developed into the second or third stage, with respiratory difficulties and multiple organ failures. Thus from the second stage on, we should look beyond the virus, focusing on the cytokine storm and free radical storm as the actual pathogens. “Because pathological consequences of microbial infections are determined by the interaction of the host and the pathogen, a central theme in modern microbiology is overall understanding of the mechanism of host–pathogen interaction rather than gaining insight about a particular microbe” [33].
Declaration of competing interest
None.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266475/
COVID-19 infection and oxidative stress: an under-explored approach for prevention and treatment?
To the editors of Pan African Medical Journal
Oxidative stress is the result of an imbalance in the body between the oxidizing system, consisting mainly of free radicals, reactive oxygen species (ROS) and reactive nitrogen species (RNS) [1], and antioxidant systems that neutralize these free radicals capable of multiple deleterious effects. This oxidative stress is involved in aging [2] and is found in certain chronic pathologies such as diabetes mellitus, cancers, hypertension, coronary heart disease, etc. [3] and certain infections, particularly by the RNA viruses [4], a family to which belong corona viruses [5]. The objective of this work is to explain the role of oxidative stress in RNA virus infections and probably also in Covid 19 infection, in order to propose measures for prevention and treatment of this deadly infection which has already caused more than 118000 deaths worldwide [6]. This is an analysis of literature about oxidative stress, ways to counteract it, known links with certain RNA viruses and possible links with the new Corona virus.
Oxidative stress and reactive oxygen and nitrogen species (RONS): reactive Oxygen and Nitrogen Species (RONS) are molecules characterized by the presence of unpaired valence electrons, which cause them to react with various biological molecules [7,8]. Main ROS are hydroxyl radical (OHº), superoxide anion (O2º-), singlet oxygen (¹O2), oxygen peroxide (H2O2) and ozone (O3), a powerful oxidant formed by endothermic reaction from O2 [8]. For RNS it is nitric oxide (NO) peroxynitrite (ONOO-), the nitrosyl cation (NO+), the nitrosyl anion (NO-), nitrous acid (NH2O2) .... [1,8] These free radicals are natural byproducts of various cellular processes and the functioning of structures such as mitochondria and the endoplasmic reticulum [4]. Under physiological conditions these reactive species play an important role in cell signalling, regulation of cytokines, growth factors, as immunomodulators, etc [1] and are involved in the natural aging of the human organism [2]. But when the balance is broken between oxidizing agents and antioxidant systems, which characterizes oxidative stress, these free radicals will have deleterious effects on all biomolecules [7,8]. The most reactive, hydroxyl radical can oxidize various molecules in its proximity, including DNA, phospholipids, and proteins. The superoxide can generate other free radicals and come into contact with nitric oxide (NO) to give the peroxynitrite radical (ONOO-), a powerful oxidant with NO depletion. Hydrogen peroxide is converted to hydroxyl and can cross cell membranes. Ozone is a powerful oxidant of lipid chains, it can generate other free radicals, and interact with a large number of organic and inorganic compounds [8]. Damage caused by these free radicals will affect cell membranes through the phenomenon of lipid peroxidation, oxidation and denaturation of proteins, DNA damage which can induce inflammatory immune responses, mutations and tumorigenesis risk, apoptosis [4]. So oxidative stress is involved in the occurrence of certain pathologies such as cancers, autoimmune diseases, cataract, Alzheimer’s and neurodegenerative diseases, diabetes mellitus, cardiovascular diseases, chronic kidney disease etc [2,3,8].
What are the situations promoting oxidative stress? about our subject, it is known that oxidative stress is triggered by a wide variety of viral infections [4,7] including HIV 1, viral hepatitis B,C,D viruses, herpes viruses, respiratory viruses, most of the RNA viruses [7] probably also corona viruses belonging to this family. Let us remind that corona viruses are encapsulated RNA viruses with different types: the classic coronaviruses, responsible for moderate respiratory infections in general, the SARS-CoV and MERS-CoV involved in epidemics of more severe respiratory infections [5] and the new coronavirus (SARS-CoV2) discovered in January 2020 responsible for infectious disease called COVID-19 which is currently experiencing a worldwide outbreak [6]. Generally, viral infections lead to an increase in production of free radicals and a depletion of antioxidants [1]. The mode of action varies according to the viruses as demonstrated by the analysis of the oxidative stress induced by different viruses of the flaviviridae family [4] but we find these two phenomena increasing the oxidative stress in these RNA viruses infections and for Ivanov [7] one of the sources of production of these ROS could be the mitochondrial dysfunction caused by the penetration of the virus into the cell. A “cytokine storm” with release of Il-2, Il-6, Il-7, TNF α etc. as been described in COVID-19 [9]. These authors described a cytokine shock with hyperinflammation accompanied by cytopenia, hyperferritinemia, [1,8] which is known to generate by the Fenton reaction (Fe²+ + H2O2→ Fe³+ + HO‾ + HO‾) the production of ROS [7,8]. In addition, cytokines and endotoxins will stimulate one of the isoforms of nitric oxide synthetase (NOs), the inducible isoform iNOs, which will stimulate the production of nitric oxide NO which will react with the superoxide ion to give the powerful oxidizing peroxynitrite radical (ONOO‾) [1,8]. Other factors can promote the endogenous production of free radicals, such as intense physical activity, high blood pressure, tissue ischemia, the action of certain metals (lead, arsenic, cesium, mercury) counteracting the co-factors of antioxidant enzymes, notably superoxide dismutase, NADPH oxidase, myeloperoxidase which will lead to the production of the superoxide radical. Physical agents (ionizing radiation, UV), solvents, various pollutants, an anesthetic agent halotane and even paracetamol have also been incriminated in this genesis of free radicals [8]. Several techniques can be used to evaluate the state of oxidative stress such as electron paramagnetic resonance, direct evaluation of oxidative stress markers such as oxidized glutathione, malonyl aldehyde, quantification of total antioxidant status etc [7].
How are these free radicals neutralized? there are multiple mechanisms to neutralize these free radicals: glutathione a natural antioxydant which has also an effect on viral replication [10], certain vitamins such as vitamin E and C, carotenoids and polyphenol with scavenging effect, [8] the glutathione peroxidase| glutathione reductase system allowing reduced glutathione (GSH) to bind to free radicals giving oxidized glutathione which will be regenerated into GSH through this system, super oxide dismutase (SOD) neutralizing superoxide anion (O2o‾), catalase eliminating H2O2, the peroxyredoxin system that neutralizes the peroxidation of lipids, protecting them from oxidative damage. Some trace elements such as Zinc and Selenium have an anti-oxidant effect as co-factors of anti-oxidant enzymes [1,7,8].
What about covid-19 and oxidative stress? SARS-CoV2, probably like other RNA viruses [4] can trigger an oxidative stress. This hypothesis can easily be checked by the dosage of oxidative stress markers [7] in the blood of sick people of COVID-19. A cytokin storm with hyper inflammation had been found in these patients [9] but researchers should also chek for a possible oxidative storm with all he deleterious effects of RONS, notably lipid peroxydation and proteins oxidation of membranes which can contribute to the transformation, hyalinization of pulmonary alveolar membranes [11] with letal respiratory distress. As elders and people suffering of diabetes, hypertension and cardiovascular diseases have already a state of oxidative stress [2,3], viral infection will increasae this stress, giving us one possible explanation of the severity of COVID-19 in these categories of patients [12].
Suggestions for prevention and treatment of covid-19 infection: in frail people, we propose to reduce their level of oxidative stress by providing them with substances that increase their antioxidant system [2] such as Glutathione, some trace elements like Zinc and Selenium, vitamin E and C, carotenoids and polyphenols [1]. Glutathione has analogues and precursors such as N acetyl cysteine. Indeed, cysteine is one of the three constituent amino acids of the major natural antioxidant Glutathione which also has an immunomodulating effect and destructive action on viruses such as herpes, influenza etc. by blocking viral replication [10]. There are also many antioxidants food, and even food additives such as butylated hydroxyanisole, quercetin and curcumin [1] could also be tested. In sick people, in addition to the various used treatments, we suggest to add antioxidants mentionned above and especially, injectable N acetyl cysteine [10] which has shown its effectiveness in hemorrhagic dengue fever [13] another RNA virus infection [4]. Various antioxidant which have been experimentally used successfully as melatonin, minocycline [1], can also be tested.
Conclusion
In the fight against Covid-19 infection, all the possible treatments deserve to be taken into account. Relying on the complex pathophysiology of this viral infection, we suggest tu use also antioxydants agents in the treatment.
Authors’ contributions
Marie-Pierrette Ntyonga-Pono did the review of literature and wrote the article. The author have read and agreed to the final manuscript.
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