Abstract
Abstract
COVID-19 (COronaVIrus Disease of 2019), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an ongoing global health challenge and the deadliest epidemic coronavirus outbreak to date. Early sequencing of the viral genome and knowledge from past coronavirus outbreaks (SARS-CoV-1 and Middle East Respiratory Syndrome, MERS) has led to rapid advances in knowledge of how the virus spreads and infects human hosts. Unfortunately, advancing knowledge has not yet produced a treatment that substantially lowers morbidity or mortality and only recently resulted in the development of a vaccine that prevents severe disease. Mounting evidence supports the notion that dietary supplementation of key essential nutrients may contribute to the body’s defenses against infection as well as bolster the body’s responses to infection. Evidence supporting the potential beneficial roles of vitamin C, vitamin D, zinc, and B3 vitamins is reviewed here, revealing a combination of basic research elucidating underlying mechanisms of action, preclinical studies and human intervention studies has led to the proliferation of registered clinical trials on COVID-19. Overall, the data suggest this collection of nutrients has a promising impact on reducing the risk and/or severity of COVID-19, although firm conclusions await the results of these trials.
Introduction
As of December 30, 2020, the CDC reported over 19 million cases (Centers for Disease Control and Prevention) of (COronaVIrus Disease of 2019) COVID-19 in the US, the rate of newly diagnosed cases each day exceeded 200,000, and the US death toll exceeded 330,000. Globally at this time, over 80 million COVID-19 cases had been reported (World Health Organization, “Coronavirus disease (COVID-19) situation reports”). Although staggering, these numbers may be 10-fold lower than the actual case burden world-wide (CDC 2020; Havers et al. 2020; Stringhini et al. 2020). These numbers clearly make COVID-19, the disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the deadliest epidemic coronavirus outbreak to date.
While the devastating spread of COVID-19 in the US and abroad has revealed to the medical community and lay person alike that SARS-CoV-2 is an infectious virus that readily spreads from person-to-person, in truth, only the basics of how it is spread are known at this point. Many respiratory viruses are spread by direct contact. This typically involves touching an infected person or contaminated surfaces, known as fomites, and transferring viral particles directly to the body through hand contact with the eyes, nose, and/or mouth (Morawska 2006). Early reports that SARS-CoV-2 virus can persist in an infectious state on certain materials for up to 72 h supported this as a major potential source of transmission (Van Doremalen et al. 2020). However, respiratory droplet and aerosol transmission are emerging as significant routes of person-to-person spread in indoor environments (Morawska and Cao 2020).
Respiratory droplets are created from speaking, coughing, and sneezing and can be inhaled or directly deposited on another person if they are in close proximity. These data form the basis for the World Health Organization (WHO) recommendation for frequent hand washing and maintaining a distance of 6 feet (World Health Organization, “Advice for the public on COVID-19”). Aerosol transmission, on the other hand, can occur over distances that exceed 6 feet and endure in the air for longer than respiratory droplets (Setti et al. 2020). In addition to the fact that SARS-CoV-1, the closest known viral relative of SARS-CoV-2, was known to spread via aerosol transmission (Li et al. 2005; Yu et al. 2005), recent work has shown that ordinary speech generates aerosols (Morawska et al. 2009) and the louder one speaks the more aerosol particles are produced (Asadi et al. 2019). Importantly, while numerous studies present a compelling case for aerosol transmission of COVID-19, several other studies present conflicting evidence for this type of spread (Van Doremalen et al. 2020; Guo et al. 2020; Liu et al. 2020; Ong et al. 2020).
Regardless of transmission route, the data on mortality have clearly shown some populations are more vulnerable to developing severe disease than others. As a result, the WHO has issued guidelines warning that individuals diagnosed with certain noncommunicable diseases may be more susceptible to becoming severely ill with COVID-19 (World Health Organization, “Information note on COVID-19 and NCDs”; Yang et al. 2020). Elderly patients have higher mortality rates such that some countries report 80% to 90% of deaths have occurred in patients aged ≥60 (Kang and Jung 2020). In addition to advanced age, the noncommunicable diseases that have been identified to raise risk of severe morbidity and mortality include hypertension, cardiovascular or lung disease, and diabetes mellitus (Sanyaolu et al. 2020). Obesity has also been associated with likelihood of developing more serious disease (Caussy et al. 2020; Tamara and Tahapary 2020). While there are many theories as to why age and these other factors influence disease course, no one mechanism is yet agreed upon (Cegolon et al. 2020; Dhochak et al. 2020; Yuki et al. 2020). Some work points to lung inflammation as a main contributor to a host of clinical symptoms consistent with acute respiratory distress syndrome (ARDS) (Gattinoni et al. 2020), and early research indicated this airway damage was the main cause of morbidity and mortality among SARS-CoV-2 patients (Xu et al. 2020). However, the research on this topic is still developing and the picture is complicated with multiple variables.
Like the research on transmission, prevention and treatment options have been slow in development. Prevention methods are entirely behavioral, including hand washing, social distancing, and mask wearing, and, though effective when strictly adhered to, have seen variable adoption throughout the country. To truly halt the spread of COVID-19, a vaccine that is safe and effective and can be deployed quickly on a global scale is greatly needed. Fortunately, several different vaccines have been recently developed and are now being deployed to those at highest risk for COVID-19 (front line healthcare workers). While the world awaits the implementation of various vaccines, effective treatments are the next best option to reduce morbidity and mortality associated with COVID-19.
Early treatment approaches were not effective at interrupting the process of progression of infection, although in recent months significant progress has been made on the disease management of COVID-19 (Horwitz et al. 2021). Oxygen therapy is a typical first step to addressing respiratory impairment, however some patients do not respond, and invasive mechanical ventilation is then indicated (Cascella et al. 2020). In severe cases, patient symptoms are consistent with ARDS (Gattinoni et al. 2020), and early attempts to treat patients with these symptoms did not produce expected results. More recently clinicians have reviewed these treatment strategies, suggesting that COVID-19-induced ARDS (CARDS) is not the same as “typical” ARDS (Gattinoni et al. 2020). Other therapeutic approaches have included corticosteroids (Ledford 2020), antiviral agents (Bimonte et al. 2020), immunomodulatory drugs (Gautret et al. 2020), serotherapy (Jawhara 2020), anticoagulant therapy (Kollias et al. 2020), and anti-inflammatory treatment (Buonaguro et al. 2020; Cavalli et al. 2020). Some hope for effective treatment came recently from a clinical trial of remdesivir, a nucleotide analogue drug that mimics ATP and has previously been shown to have broad-spectrum anti-viral effects against RNA viruses. The drug, when tested in more than 1000 hospitalized patients with COVID-19, was shown to modestly shorten time to recovery when compared to placebo treated patients (Beigel et al. 2020; Grein et al. 2020). Despite these promising findings, the WHO has recommended against the use of remdesivir for the treatment of COVID-19, citing a need for additional research (World Health Organization 2020). For this reason, it has received Emergency Use Authorization (EUA) from the FDA (Remdesivir (GS-5734™)).
Nutrition as a factor that influences disease course
The prevalence of comorbidities in those who become severely ill with COVID-19 has led some to suggest inflammation and altered immunity are the underlying factors that may contribute to disease course in individuals (Hotamisligil 2017; Tsoupras et al. 2018). Although the mechanisms of disease severity differ among the conditions (e.g. patients with cardiovascular disease develop more severe respiratory symptoms (Zheng et al. 2020) whereas COVID-19 patients with diabetes and high blood pressure are at increased risk of thrombotic complications (Wadman et al. 2020)), some have suggested that it is the chronic inflammation that is common among these conditions that leads to increased risk for severe COVID-19 complications (Hotamisligil 2017; Tsoupras et al. 2018). This, combined with considerable scientific support for diet and nutrition being potent immunomodulators (Chandra 1996; Hulsewé et al. 1999; Childs et al. 2019), has led many to look into nutritional status and the effects of essential nutrients as components of an effective defensive strategy against COVID-19 (Berger et al. 2020).
Particularly in light of the lack of safe and effective treatments for COVID-19 (World Health Organization, “Off-label use of medicines for COVID-19”), nutrition has emerged as a relatively safe and accessible approach to maintain a healthy immune system and therefore indirectly (or directly) gain some protection from the worst manifestations of COVID-19.
While no controlled studies have demonstrated direct links between poor nutritional status and worse COVID outcomes, considerable data support this suggestion. In particular, the increased risk of severe disease manifestations in the elderly (Wu et al. 2020) have been connected to immunosenescence, or the age-associated decline in the immune system (Meyer 2001; Pae et al. 2012), which is connected to nutritional deficiencies commonly documented in elderly populations, including calcium, vitamin C, vitamin D, folate, and zinc (Power et al. 2014). Less well-known nutrients are also implicated in health decline in the elderly, among them are B3 vitamins, which are precursors of the essential cofactor nicotinamide adenine dinucleotide (NAD+) that is central to metabolism (Massudi et al. 2012; Fang et al. 2017). Nutrient supplements have been proposed as a potential cotherapy for COVID patients (Allegra et al. 2020) Here we will highlight the potential benefits of supplementing specific nutrients, vitamin C, vitamin D, zinc, and B3 vitamins, as part of an approach to prevent and/or lessen the severity of COVID-19.
Vitamin C
While severe deficiency of vitamin C was first recognized in the 1400s to cause the “explorers’ sickness”, or scurvy, the role of vitamin C in preventing and lessening the effects of viral infections was only recently suggested in 1970 by the Nobel Laureate Linus Pauling (Pauling, 1971). Pauling’s work was based on four placebo-controlled studies showing vitamin C decreased the severity of the common cold (Pauling, 1971). Work along these lines has continued to this day (Bucher and White 2016). Rigorous analysis of this body of work (a meta-analysis of 29 studies including 11,306 participants) concluded that supplementing with 200 mg or more of vitamin C does not reduce the risk of contracting a cold but it does reduce the severity and duration of a cold (Douglas et al. 2000; Hemilä and Chalker 2013). Investigations into the effects of vitamin C on other infections has also been an active area of research. Indeed, as reviewed by Hemilä in 2017 (Hemilä 2017), at least 148 animal studies support the model that vitamin C may alleviate or prevent infections caused by bacteria, viruses, and protozoa. These studies provide important insight into the mechanism behind modulation of the immune system by vitamin C. For example, vitamin C may benefit those infected with influenza by modulating the interferon response (Kim et al. 2013). However, special considerations must be taken into account when interpreting the results from these preclinical studies. In particular, vitamin C status may impact the responsiveness to supplementation, whereby individuals who are vitamin C replete may not benefit from supplementation. In addition, supplementation may be more effective in children for unknown reasons, and patients with infections that lower vitamin C status due to infection-associated metabolic alterations (Hemilä 2017).
The safety of vitamin C, as well as the massive body of literature supporting its anti-infective properties has led many to suggest its potential as a treatment for COVID-19 (Cheng 2020). Several notable effects of SARS-CoV-2 infection indicate vitamin C could support cellular health and defenses: (1) patients with COVID-19 often have increased markers of inflammation and oxidative stress, hsCRP in particular (Chen et al. 2020); (2) the nuclear factor erythroid 2 (nfe2)-related factor 2 (nrf2) transcription factor plays an important regulatory role in respiratory diseases and is a major regulator of antioxidant responses, which vitamin C plays an essential role (Liu et al. 2019); (3) cytokine storm is observed in severe COVID-19 cases, and high-dose vitamin C has been shown to affect similar oxidative stress pathways in clinical studies of patients with sepsis (Li 2018). In addition, in a study of patients in the ICU, high-dose intravenous vitamin C shortened the time patients’ spent in this high-level care setting (Hemilä and Chalker 2019) and, when dosed with corticosteroids and thiamin, reduced mortality (Marik et al. 2017). Beneficial effects have also been documented for vitamin C in the treatment of patients receiving mechanical ventilation due to oxidative stress induced acute inflammatory lung injury (Patel et al. 2020). Notably, some direct evidence has accumulated supporting the efficacy of high-dose intravenous vitamin C for the treatment of COVID-19 patients in China. In the study, patients who received bolus doses of vitamin C (10 g to 20 g given over a period of 8–10 h, with additional boluses given to patients in critical condition) showed improvement in oxygenation, and all treated patients were eventually discharged to home (Cheng 2020). This evidence and the strong data supporting the beneficial role of vitamin C in other respiratory disease is enough to warrant controlled clinical trials of vitamin C treatment for severe hospitalized patients with COVID-19. As of December 30, 2020, 50 studies were registered on clinicaltrials.gov to investigate the effects of vitamin C alone or in combination with other treatments in patients with COVID-19.
Vitamin D
Vitamin D is another essential nutrient that plays critical roles in immune function (Prietl et al. 2013). Classically known for its role in calcium-phosphorus homeostasis and bone health (Holick 2007), the immune effects of vitamin D result from interactions between the biologically active form of vitamin D and the nuclear vitamin D receptor (VDR), which is present in immune cells, including lymphocytes, monocytes, macrophages, and dendritic cells (Stumpf et al. 1979; Bhalla et al. 1983; Di Rosa et al. 2011). vitamin D enhances the innate immune system in part by stimulating the production of antimicrobial peptides, including cathelicidins and defensins, which target a broad scope of pathogens including bacteria, fungi, and viruses (White 2010; Laaksi 2012). Although it stimulates innate immunity, vitamin D suppresses the adaptive immune system (Wei and Christakos 2015). Notably, vitamin D suppresses the production of proinflammatory cytokines, and thus may have potential to reduce cytokine storm (Di Rosa et al. 2011; Fisher et al. 2019), an excessive production of inflammatory cytokines (Tisoncik et al. 2012) associated with worse COVID-19 outcomes. As another line of defense, vitamin D helps maintain tight junctions, gap junctions, and adherens junctions as a physical cellular barrier against pathogens (Schwalfenberg 2011).
Data on vitamin D deficiency, which is a common and global public health problem (Palacios and Gonzalez 2014), suggest it may play a role in increasing COVID-19 susceptibility among the aged (Gallagher 2013), in those with increased melanin (Alzaman et al. 2016), obesity (Dhaliwal et al. 2014) and those who smoke (Kassi et al. 2014). Clinical and epidemiological data also link vitamin D deficiency to the incidence and severity of immune-related disorders, including autoimmune disorders (Charoenngam and Holick 2020). In particular, low vitamin D status is correlated with rheumatoid arthritis (Iowa Women’s Health Study, 2004; Kostoglou-Athanassiou et al. 2012; Lee and Bae 2016; Meena et al. 2018), multiple sclerosis (Duan et al. 2014), type I diabetes mellitus (Feng et al. 2015; Shen et al. 2016), and inflammatory bowel disease (Del Pinto et al. 2015; Lu et al. 2015). Living at a higher latitude, and therefore in a region with less sun exposure, is associated with a younger age of onset for multiple sclerosis (Tao et al. 2016) and higher incidence rates of type 1 diabetes (Mohr et al. 2008) and inflammatory bowel disease (Schultz and Butt 2012). In general, the impact of vitamin D supplementation on the treatment of these conditions is controversial due to varied clinical trial results (Charoenngam and Holick 2020). However, supplementation with vitamin D reduces relapse rates in patients with relapsing-remitting multiple sclerosis (Laursen et al. 2016).
Epidemiologic studies have also demonstrated associations between seasonal variations in 25(OH)D and the incidence of infectious diseases, including septic shock (Danai et al. 2007), respiratory infection (Grant 2008), and influenza (Cannell et al. 2006). Intriguingly, a strong inverse correlation was found between solar UVB irradiance and the case-fatality rate during the 1918–1919 influenza pandemic (Grant and Giovannucci 2009). Recent metanalyses of randomized trials have demonstrated that vitamin D supplementation may help prevent respiratory infections (Charan et al. 2012; Bergman et al. 2013; Autier et al. 2017; Martineau et al. 2017; Rejnmark et al. 2017), possibly through its role in the stimulation of antimicrobial peptides (Beard et al. 2011). Like vitamin C, the protective effect of vitamin D may depend on an individual’s vitamin D status at the onset of illness. Subgroup analyses of clinical data indicated vitamin D’s effects were strongest in patients with the lowest baseline serum 25(OH)D concentrations (Martineau et al. 2017). A recent study found an inverse relationship between vitamin D status and risk for positive COVID-19 diagnosis; individuals determined to have low vitamin D within the past year had a relative risk for a positive COVID-19 diagnosis that was 1.77 times higher than those with a sufficient status (Meltzer et al. 2020). Another larger cohort study found that low plasma vitamin D status, defined as below the level of 30 ng/mL, produced crude odds ratios of 1.58 and 2.09 for likelihood of COVID-19 infection and hospitalization, respectively (Merzon et al. 2020). These and other data have led many to investigate the potential of vitamin D as a preventative and/or treatment strategy for COVID-19. This work has suggested that effects of vitamin D in response to SARS-CoV-2 infection could be mediated through production of antimicrobial peptides in the respiratory epithelium and dampening the inflammatory response and cytokine storm. Vitamin D modulates expression of the gene encoding angiotensin-converting enzyme 2 (ACE2) (Mitchell 2020), which is exploited by SARS-CoV-2 as a receptor for entry (Zhang et al. 2020). Interestingly, many have postulated that higher expression of ACE2 may confer increased susceptibility to more severe clinical manifestations (Bourgonje et al. 2020). The many potential roles of vitamin D in defense against COVID-19 is summarized in Figure 1.
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17 February 2021![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/ijds20/0/ijds20.ahead-of-print/19390211.2021.1881686/20210507/images/medium/ijds_a_1881686_f0001_c.jpg"})
Figure 1. Vitamin D3 and COVID-19.
Other evidence supporting a role for vitamin D in reducing COVID-19 susceptibility includes that the initial outbreak occurred in December 2019 in Wuhan, China when vitamin D levels were likely lower overall. Additionally, during the winter and early spring the disproportional incidence, severity, and mortality rates of COVID-19 among African American, Hispanic American, Indigenous American, and other ethnic populations with darker skin may be partially attributed to lower circulating vitamin D levels than those with lighter complexions (Mitchell 2020; Yancy 2020). During the summer months, reporting by the CDC has demonstrated that these health disparities have lessened, thus further implicating vitamin D as a contributor to COVID-19 incidence and severity (Centers for Disease Control and Prevention). Additionally, there has been an increased case-fatality rate in older individuals and those with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration (Grant et al. 2020). vitamin D deficiency has also been found to contribute to the development of ARDS (Dancer et al. 2015; Gatera et al. 2018), a common complication in COVID-19 patients (Aygun 2020). Early evidence demonstrates that vitamin D insufficiency is prevalent in COVID-19 patients (D’Avolio et al. 2020; Lau et al. 2020) and that vitamin D status plays a key role in COVID-19 outcomes (Davies et al. 2020; Maghbooli et al. 2020). This evidence has led some researchers to recommend people at risk for COVID-19 take a vitamin D supplement (10,000 IU/d for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d, with the goal of raising serum 25(OH)D concentrations above 40–60 ng/mL or 100–150 nmol/L) (Grant et al. 2020). As of December 30, 2020, there are 61 registered clinical trials investigating the effects of vitamin D, alone or in combination with other approaches to treat COVID-19. As with all other interventions, well-designed randomized controlled trials and longitudinal studies will need to be completed in order to determine whether vitamin D supplementation can improve the outcomes of patients with COVID-19.
Zinc
Zinc is found in every tissue and every metalloenzyme in the body and is involved in over 300 enzymatic reactions in mammals. It is estimated that nearly 1/3 of the world has some level of zinc deficiency (World Health Organization, “WHO | Chapter 4”). This is critical, as zinc deficiency has the potential to negatively influence the function of nearly every biochemical pathway in the body. For this reason, symptoms resulting from zinc deficiency are as diverse as the enzymes that use it, and, in extremely severe cases, zinc deficiency can be fatal.
While there is no name for zinc deficiency, insufficient intake through dietary sources and/or supplementation is connected with a host of health challenges, including hypogonadism, skin disorders, cognitive dysfunction, anemia and impaired immune function (Prasad 2013). Even mild zinc deficiency has been clinically shown to negatively impact the immune system (Prasad 2013). Though some individuals may consume the recommended daily allowance of zinc, other dietary factors, such as phytate and fiber, can reduce the bioavailability of zinc, attenuating its use within the body, thus making vegans and vegetarians more susceptible to zinc deficiency (Gibson et al. 2018). Additionally, several disease states, including sickle cell anemia, chronic liver disease, kidney failure, acrodermatitis enteropathica and other chronic illnesses can result in malabsorption of dietary zinc (Prasad 2003).
Due to homeostatic mechanisms in maintaining circulating plasma and serum zinc levels, despite dietary zinc depletion, it is difficult to monitor and determine zinc status in individuals that are mild to moderately deplete (Song et al. 2009; Freitas et al. 2017). Therefore, evaluating the full extent of the impact of dietary zinc deficiency on health and the immune system has been limited and requires additional validated biomarkers of zinc status to fully elucidate zinc’s impact on health outcomes.
Among its many roles, zinc is involved in both the innate and acquired immune response, and is connected to immune cell development and function (Prasad 2008; Read et al. 2019), mucosal membrane integrity during viral infections (Wessels et al. 2017), and zinc deficiency is associated with various infections, including pneumonia (Fischer Walker and Black 2004; Hess et al. 2009). A considerable body of research has accrued around the use of zinc supplements for preventing and reducing the symptoms of the common cold and other respiratory illnesses, and has been noted as a critical factor for antiviral immunity (Mossink 2020) Systematic review/meta-analyses indicate the use of zinc lozenges can reduce the frequency of respiratory infection in children as well as reduce the duration of the common cold by about a day (Science et al. 2012). However, as with the other nutrients discussed here, the data are mixed, and more research is needed to definitively support these claims.
Due to the apparent efficacy of zinc in combatting several viral infections, it has been suggested that increasing zinc intake may be useful against COVID-19 infections. In particular, it has been suggested that 30–50 mg/d of zinc might aid in the control of RNA viruses, including influenza and coronaviruses (McCarty and DiNicolantonio 2020), however higher doses of 100–300 mg/day may result in impaired immune function, copper deficiency, anemia, and adverse effects on cholesterol (Fosmire 1990). To this end, as of December 30, 2020, 43 studies are registered in the clinical trials database to study potential benefits of supplementation for COVID-19 patients.
B3 vitamins
B3 family vitamins are essential nutrients that must be consumed at adequate levels in the diet to avoid the deficiency disease pellagra. As shown in Figure 2, there are three main B3 vitamins: nicotinamide riboside (NR), nicotinamide (NAM), and nicotinic acid (NA). In addition to preventing pellagra, B3 vitamins, especially NR, may be beneficial in promoting healthy aging and avoiding some of the physiological changes that occur with age-associated disease (Belenky et al. 2007; Bogan and Brenner 2008). These beneficial effects of NR, as well as NA and NAM, are mediated through their primary roles as precursors of NAD+.
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17 February 2021Figure 2. Nicotinamide riboside (NR, left), Nicotinamide (NAM, middle), Nicotinic acid (NA, right).
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/ijds20/0/ijds20.ahead-of-print/19390211.2021.1881686/20210507/images/medium/ijds_a_1881686_f0002_b.jpg"})
Figure 2. Nicotinamide riboside (NR, left), Nicotinamide (NAM, middle), Nicotinic acid (NA, right).
Since its discovery in 1906, NAD+ has been known as the central catalyst of metabolism. As a coenzyme, NAD+ plays two critical roles, the first as the classic electron transporter involved in cellular respiration and ATP production. The other is as a donator of adenosyl diphosphate (ADP)-ribose to poly(ADP-ribose) polymerase (PARP) and Sirtuin enzymes involved in DNA repair, gene regulation and cell signaling (Canto et al. 2013; Bian et al. 2019). These NAD-dependent enzymes have been shown to be critical in cell and tissue response to metabolic stress. Indeed, in response to various metabolic or physiologic stresses or disorders, these NAD-consuming enzymes are drastically upregulated resulting in depression of cellular NAD+, followed by cell and tissue dysfunction (Xie et al. 2020).
The NAD+ system appears to be most impacted by stress in metabolically active tissues. For example, the NAD+ metabolome is adversely affected in patients with alcohol-induced liver disease (Parker et al. 2020). This is consistent with a multitude of preclinical studies demonstrating high fat diet-induced liver disease is accompanied by disturbance of the NAD+ system (Gariani et al. 2016; Zhou et al. 2016; Han et al. 2019), and overnutrition leads to a depressed hepatic NAD+ and NAMPT (Yoshino et al. 2011). Other preclinical studies have shown that noise-induced hearing loss results in a loss of cochlear NAD+ (Brown et al. 2014), and DNA damage caused by sun and reactive oxygen species activates PARPs and dysregulates the NAD+ system (Fania et al. 2019). Other examples of metabolic stress that disturb the NAD+ system include heart failure, pregnancy and postpartum, and infection (Murray et al. 1995; Ear et al. 2019; Heer et al. 2020; Zhou et al. 2020).
While the three B3 vitamins each contribute to the generation of NAD+ via distinct metabolic pathways (Figure 3), recent data suggest these vitamins may not support healthy NAD+ levels equally. Work has expanded the identification and understanding of key enzymes that regulate the different NAD+ precursor pathways, as well as a range of NAD+-dependent enzymes. For NR, the rate limiting step for conversion to NAD+ is phosphorylation by NRK, the expression of which (NRK1) is relatively high in kidney and liver (Ratajczak et al. 2016). Multiple animal models have been developed to elucidate the conditions under which different NAD+ pathways are up or down regulated. In a genetic mouse model of dilated cardiomyopathy and heart failure the level of cardiac NAD+ is depleted and expression of nicotinamide riboside kinase 2 (NMRK2) is highly induced (Diguet et al. 2018). In contrast, expression of nicotinamide phosphoryl transferase (NAMPT) required for NAM salvage declined, suggesting that the stressed cells specifically seek out NR to replenish NAD+. The KO mice have compromised cardiac function, including reduced left ventricular ejection fraction and refraction shortening, all of which are rescued with oral NR administration. Consistent with the upregulation of NRK2 and downregulation of the salvage pathways, respectively, NAM is unable to rescue the depleted NAD+ in the failing heart (Diguet et al. 2018).
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17 February 2021Figure 3. Basic NAD Biosynthesis Pathways. Abbreviations: Tryptophan (Trp), niacin (NA), nicotinamide riboside (NR), nicotinamide (NAM), Indoleamine 2,3-dioxygenase (IDO), Tryptophan 2,3-dioxygenase (TDO), nicotinate phosphoribosyltransferase (NAPRT), nicotinamide riboside kinase (NRK), nicotinamide phosphoribosyltransferase (NAMPT), formylkynurenine (FK), nicotinate mononucleotide (NAMN), nicotinamide mononucleotide (NMN), 2-amino-3-carboxymuconate semialdehyde (ACMS), quinolinate phosphoribosyltransferases (QPRT), nicotinate adenine dinucleotide (NAAD), NAD+ synthase (NADS), nicotinamide mononucleotide adenylyltransferase (NMNAT), quinolinic acid (Qa), nicotinamide adenine dinucleotide (NAD+).
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/ijds20/0/ijds20.ahead-of-print/19390211.2021.1881686/20210507/images/medium/ijds_a_1881686_f0003_c.jpg"})
Figure 3. Basic NAD Biosynthesis Pathways. Abbreviations: Tryptophan (Trp), niacin (NA), nicotinamide riboside (NR), nicotinamide (NAM), Indoleamine 2,3-dioxygenase (IDO), Tryptophan 2,3-dioxygenase (TDO), nicotinate phosphoribosyltransferase (NAPRT), nicotinamide riboside kinase (NRK), nicotinamide phosphoribosyltransferase (NAMPT), formylkynurenine (FK), nicotinate mononucleotide (NAMN), nicotinamide mononucleotide (NMN), 2-amino-3-carboxymuconate semialdehyde (ACMS), quinolinate phosphoribosyltransferases (QPRT), nicotinate adenine dinucleotide (NAAD), NAD+ synthase (NADS), nicotinamide mononucleotide adenylyltransferase (NMNAT), quinolinic acid (Qa), nicotinamide adenine dinucleotide (NAD+).
In liver NRK1 knockout (KO) mice NAD+ synthesis from NR is impaired, whereas synthesis from tryp, NA and NAM is normal (Sambeat et al. 2019). These mice are normal through middle age when raised on a normal chow diet. However, these NRK1 KO mice fed a high-fat diet become glucose intolerant and insulin resistant, have impaired lipid oxidation and elevated markers of liver damage, fibrosis and steatosis (Sambeat et al. 2019). On a low-fat diet NAD+ levels between wild type mice and NRK1 KO mice are comparable, whereas when placed on a high-fat diet, NAD+ levels are significantly depressed in the NRK1 KO mice (Sambeat et al. 2019). These mice have high levels of DNA damage, reduced body weight, increased organ weight and in particular, increased fibrosis of liver and kidney tissues, where NRK1 expression is normally highest. Supplementing NRK1 KO mice with NAM is unable to rescue the high-fat induced functional decline (Sambeat et al. 2019). This is consistent with the notion that different precursors have different affinities for different tissues as a primary source for NAD+ synthesis, and that under metabolic stress requiring a high NAD+ demand, such as SARS-CoV-2 infection, cells and tissues specifically utilize NR to produce NAD+.
Human studies have also shown NR has superior bioavailability compared to the other dietary precursors (Trammell et al. 2016), and multiple completed and ongoing clinical trials are showing its safety and efficacy (described in depth below). In addition, while NA has been used in humans to treat dyslipidemias, it is associated with the uncomfortable side effect known as “flushing”, and at high doses (≥hundreds of mg/day) can cause hepatotoxicity (National Institutes of Health—Office of Dietary Supplements 2020). NAM has also been used nutritionally and medicinally in humans, but there are questions surrounding the concentrations at which NAM can inhibit the important signaling enzymes that consume NAD+ as a co-substrate (Bitterman et al. 2002). Finally, though some are investigating the potential of nicotinamide mononucleotide (NMN, the 5′-phosphorylated form of NR) as a precursor of NAD+, it does not fit the traditional definition of a vitamin due to its chemical form being that of a nucleotide. In addition, the preponderance of the literature shows it is unable to enter cells directly and must be converted to NR by extracellular enzymes prior to entry into most cell types (Nikiforov et al. 2011; Grozio et al. 2013; Ratajczak et al. 2016; Kim et al. 2020); the safety and human oral availability of NMN are also not yet known. Indeed, side-by-side study of NA, NAM, and NR indicate NR is the most efficient of the precursors at raising NAD+ levels in blood after oral administration in humans (Trammell et al. 2016). This, in turn, has implications on the ability of these precursors to impact the severity of COVID-19.
Several roles for NAD+ in immune function underscore the potential importance of B3 vitamin supplementation in COVID-19. (Figure 4) (Zocchi et al. 1993; Frye 1999; Imai et al. 2000; Kim et al. 2004) In host-pathogen interactions, NAD+ depletion and/or the coopting of NAD+ generating pathways have been shown to be common mechanisms of compromising host-cell defenses (Murray et al. 1995; Michos et al. 2006; Tatsuno et al. 2010; Moreira et al. 2015). One main mechanism by which cellular NAD+ abundance has been connected to viral infection is via PARP activity. Coronaviruses, togaviruses, and herpesviruses, in particular, have been reported to encode enzymatic domains that directly oppose PARP effects (Li et al. 2016; Eckei et al. 2017; Fehr et al. 2018). This represents a mechanism by which viral infections ensure the survival of the host cell and adequate support for viral replication (Grady et al. 2012).
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17 February 2021Figure 4. Role of NAD in Innate Immunity. When a corona virus enters a cell, its goal is to utilize the cells resources to replicate and disperse the virus to other cells to do the same. A single virus may produce thousands to millions of copies of itself in a single cell. The cell, however, has innate processes to reduce and prevent damage from the virus at the cellular level, serving as a first line of defense from the virus. These defense mechanisms consume NAD+, thus with NAD+ depletion, the intracellular immune defenses may be compromised. Upon viral activation, sirtuins (SIRT) are activated to control viral replication. The SIRT require NAD+, thus reducing the NAD+ pool. If there is not enough NAD+ for the cells to use, then the SIRTs will not function as needed, leading to viral replication. Viral attacks also lead to PARP activation. PARPs also utilize NAD+, and their hyperactivation may result in NAD+ depletion. If NAD+ is not present for PARP utilization, the result is viral persistence. As PARPs and SIRTs are competing for NAD+, hyperactivation of PARPs will lead to SIRT inhibition. Such inhibition leads to proinflammatory cytokine production, which contributes to hyperinflammation and the cytokine storm. Viral activation also leads to oxidative stress, further depleting NAD+ pools. Oxidative stress leads to an increase in reactive oxygen species (ROS), which in-turn reduces the ratio of NADH to NADPH, leading to oxidative damage. An increase in oxidative damage results in an increase in DNA damage, which in turn activates the PARPs needed for DNA repair. Viruses (and specifically respiratory syncytial virus) activate type-1 interferons (IFN. IFN activate CD38, which also consumes NAD+. The CD38 will then generate cADPR which increases the IFNs-induced interferon stimulated genes (ISGs) and NFκB-mediated inflammation, thus resulting in hyperinflammation. NAD+ can also decline during viral attacks due toa reduction in essential NAD+ biosynthetic pathway proteins including quinolinate phosphoribosyltransferases (QPRT) and nicotinamide phosphoribosyltransferas (NAMPT). Abbreviations: quinolinate phosphoribosyltransferases (QPRT), nicotinamide phosphoribosyltransferase (NAMPT), nicotinamide adenine dinucleotide (NAD+), interferons (IFNs), sirtuin (SIRT), poly (ADP-ribose) polymerase (PARP), cyclic ADP ribose hydrolase (CD38), reactive oxygen species (ROS), cyclic ADP ribose (cADPR), reduced nicotinamide adenine dinucleotide (NADH), reduced nicotinamide adenine dinucleotide phosphate (NADPH), interferon-stimulated genes (ISGs), Nuclear factor-κB (NFκB)
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Figure 4. Role of NAD in Innate Immunity. When a corona virus enters a cell, its goal is to utilize the cells resources to replicate and disperse the virus to other cells to do the same. A single virus may produce thousands to millions of copies of itself in a single cell. The cell, however, has innate processes to reduce and prevent damage from the virus at the cellular level, serving as a first line of defense from the virus. These defense mechanisms consume NAD+, thus with NAD+ depletion, the intracellular immune defenses may be compromised. Upon viral activation, sirtuins (SIRT) are activated to control viral replication. The SIRT require NAD+, thus reducing the NAD+ pool. If there is not enough NAD+ for the cells to use, then the SIRTs will not function as needed, leading to viral replication. Viral attacks also lead to PARP activation. PARPs also utilize NAD+, and their hyperactivation may result in NAD+ depletion. If NAD+ is not present for PARP utilization, the result is viral persistence. As PARPs and SIRTs are competing for NAD+, hyperactivation of PARPs will lead to SIRT inhibition. Such inhibition leads to proinflammatory cytokine production, which contributes to hyperinflammation and the cytokine storm. Viral activation also leads to oxidative stress, further depleting NAD+ pools. Oxidative stress leads to an increase in reactive oxygen species (ROS), which in-turn reduces the ratio of NADH to NADPH, leading to oxidative damage. An increase in oxidative damage results in an increase in DNA damage, which in turn activates the PARPs needed for DNA repair. Viruses (and specifically respiratory syncytial virus) activate type-1 interferons (IFN. IFN activate CD38, which also consumes NAD+. The CD38 will then generate cADPR which increases the IFNs-induced interferon stimulated genes (ISGs) and NFκB-mediated inflammation, thus resulting in hyperinflammation. NAD+ can also decline during viral attacks due toa reduction in essential NAD+ biosynthetic pathway proteins including quinolinate phosphoribosyltransferases (QPRT) and nicotinamide phosphoribosyltransferas (NAMPT). Abbreviations: quinolinate phosphoribosyltransferases (QPRT), nicotinamide phosphoribosyltransferase (NAMPT), nicotinamide adenine dinucleotide (NAD+), interferons (IFNs), sirtuin (SIRT), poly (ADP-ribose) polymerase (PARP), cyclic ADP ribose hydrolase (CD38), reactive oxygen species (ROS), cyclic ADP ribose (cADPR), reduced nicotinamide adenine dinucleotide (NADH), reduced nicotinamide adenine dinucleotide phosphate (NADPH), interferon-stimulated genes (ISGs), Nuclear factor-κB (NFκB)
NAD+ has been connected to several stages of defense against SARS-CoV-2 infection. NAD-consuming enzymes, particularly PARPs, are critical to early macrophage activation (Cameron et al. 2019); Sirtuins and CD38 also contribute to NAD+ consumption in later stages of inflammatory macrophage activation (Van Gool et al. 2009; Matalonga et al. 2017). NAD+ also supports epigenetic regulation of gene expression in T and B lymphocytes via sirtuin activity (Gao et al. 2001; Zhang et al. 2009; van Loosdregt et al. 2010; Kuroda et al. 2011; Kwon et al. 2012; Beier et al. 2015; Wang et al. 2017; Toubai et al. 2018; Glaría and Valledor 2020; Rahimmanesh et al. 2020; Xu et al. 2020).
While these activities are presumably at play in SARS-CoV-2 infection in humans, one way in which NAD+ supply and NAD-consuming enzymes have been specifically implicated in the immune response to SARS-CoV-2 is through the unique clinical feature of lymphocytopenia (Xu et al. 2020). This condition is simply a depletion of lymphocytes, the major players in adaptive immunity, from the blood. It is unique because typical viral infections raise the level of lymphocytes in the blood. While little direct research has been done, one promising theory points to extensive activation of PARP during innate immune responses as a critical early step that leads to depletion of cellular NAD+ and a dampening of the adaptive immune system response (Rahimmanesh et al. 2020). A recent publication involving coronavirus-infected cells and tissues examined the expression of multiple genes involved in NAD+ metabolism and confirmed the drastic upregulation of several different PARP genes along with NRK. Investigators also observed that coronavirus infection depleted cellular NAD+, NADP and ADPR as well (Heer et al. 2020). These data and the fact that the NRK pathway are transcriptionally induced by coronavirus infection suggests that replenishing NAD+ using NR as a precursor may boost the innate immune response. Indeed, subsequent experiments demonstrated that NR treatment did in fact replenish cellular NAD+ levels and reduced viral replication in coronavirus infected cells (Heer et al. 2020). NAD-dependent CD38 activity in cells of the adaptive immune system also helps with metabolic regulation of critical immune cells (Glaría and Valledor 2020).
These data and others have led many to suggest B3 vitamins may be effective in promoting innate and adaptive responses to SARS-CoV-2 infection (Badawy 2020; Miller et al. 2020; Omran and Almaliki 2020). However, while NA and NAM have been used therapeutically for many applications, NR is capable of raising intracellular NAD+ levels with superior pharmacokinetics compared to NA and NAM (Bieganowski and Brenner 2004; Trammell et al. 2016). Unlike NA and NAM, dietary NR is transported into cells via a dedicated nucleoside transporter (Belenky et al. 2008), where it is converted to NAD+ through a distinct, two-step biosynthetic pathway. NR has also been tested in several human clinical trials to show safety in multiple populations, including the aged (Trammell et al. 2016; Airhart et al. 2017; Dellinger et al. 2017; Dollerup et al. 2018; Martens et al. 2018; Conze et al. 2019; Elhassan et al. 2019; Dolopikou et al. 2020). While only two clinical studies of the effects of NR on clinical outcome of COVID-19 are listed in clinical trials.gov right now, a recently completed study suggests supplemental NR may contribute to patient recovery. The recent Phase II clinical study found that the combination of a nutritional cocktail that included NR together with the standard of care, reduced COVID-19 patient recovery time by nearly 30% compared to standard of care alone (Altay et al. 2020). The initial findings from this Phase two trial and previous preclinical studies serve as justification for future, larger studies of B3 vitamins (“Dramatic cytokine storm reversal with an over the counter NMN Cocktail”), particularly (Mateuszuk et al. 2020) if focused on NR.
The role of vitamins in immune responses to COVID-19
Sequencing of the SARS-CoV-2 genome revealed that, like other coronaviruses, SARS-CoV-2 is a positive sense single-stranded RNA genome that encodes a spike (S), envelope (E), nucleocapsid (N), membrane (M), and several accessory proteins (Fehr and Perlman 2015; Wang et al. 2020). Studies of SARS-CoV-2 have shown that, like SARS-CoV and MERS-CoV, this new coronavirus uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter cells of the airway (Li et al. 2003).
Although the exact entry and replication processes of SARS-CoV-2 are still being studied, knowledge of SARS and MERS suggest that the spike protein plays an important role in cellular entry and infection of all coronaviruses (Wit et al. 2016; Wu et al. 2020). Following entry, the viral RNA genome is released into the cytoplasm and is translated to create the main protein components of the virus (Fehr and Perlman 2015). These proteins work together with the cell’s innate machinery to facilitate viral replication (Perlman and Netland 2009). As the virus replicates, newly formed S, E, N, M, and accessory proteins assemble with the viral RNA and use the infected cell’s endoplasmic reticulum-Golgi intermediate compartment to facilitate release from the infected cell (Wit et al. 2016). During these processes, cellular damage and death from viral infection may occur due to (1) coopting of the cell's energy production machinery, (2) shutoff of necessary macromolecular synthesis within the cell, (3) competition for cellular ribosomes, and (4) competition of viral promoters and transcriptional enhancers for cellular transcriptional factors. The body detects and combats these processes through a series of immune system responses, initially involving components of the innate immune system and ultimately relying on activation of adaptive immune responses. Vitamins B3, C and D and Zinc have been shown in preclinical and some clinical studies to impact the initial innate immune response and/or modulate subsequent downstream processes related to viral infection. A list of studies providing direct evidence for vitamins in the prevention or treatment of COVID-19 and other coronaviruses is provided in Table 1.
Table 1. Published studies implicating nutrients in prevention or treatment of coronaviruses.
The widespread availability of each of the key nutrients discussed here make them easy and, for the most part, safe additions to healthy diet, lifestyle choices, and behavioral approaches to augmenting the body’s response to and avoiding infection. Whether or to what extent diet and supplementation can help prevent infection with SARS-CoV-2 or lessen its effects is currently under exploration, and the many clinical studies underway are poised to contribute greatly to knowledge in this area. In the meantime, some guidance regarding over-the-counter supplements should be observed. First, consumers should be aware that dietary supplements are regulated by the Food and Drug Administration (FDA) differently from prescription drugs. By law (the Dietary Supplement Health and Education Act of 1994) the makers of dietary supplements are not required to gain FDA approval prior to marketing a product. Instead, products that contain New Dietary Ingredients (NDI, those ingredients brought to market after October, 1994) must notify FDA at least 75 days before marketing the product that the NDI in the supplement is reasonably expected to be safe (U.S Food and Drug Administration, “Dietary supplements”). This is an important step, as it represents FDA’s only opportunity to review the safety of new ingredients in supplements and object if the agency is not satisfied. The regulatory status of vitamins C and D, zinc, and several of the B3 vitamins in supplements is clear, as these were present in the market well before 1994 and therefore have Grandfathered status in supplements. The lone exceptions include NR, which was successfully notified to FDA twice as a NDI (U.S Food and Drug Administration, “Submitted 75-day premarket notifications for new dietary ingredients”), and NMN whose regulatory status in the US is not established, as it is an NDI that has never been notified to FDA.
In the US, the primary responsibility is on the supplement maker to ensure its products are safe and any claims they make in their marketing approaches to consumers are true. So while most supplements are safe and fulfill their intended use, there are reports of quality and safety challenges (Food and Drug Administration 2011). Second, because dietary supplements are available over-the-counter, they are readily used without the supervision of a physician. While this does not present a problem for the vast majority of products in the market, it is possible to take too much of a particular supplement. Some sensitive individuals or those with certain health conditions should take great care when choosing supplements. These include pregnant or breastfeeding women; people who take certain medications, because supplements can change the effectiveness of those medications; people who are going to have surgery, because some products impact bleeding; and people who have had cancer or are receiving cancer treatments. Over-the-counter supplement use should always be discussed with a healthcare provider.
Clinical researchers have faced an unusual challenge with regards to testing various substances in mild-to-moderate COVID-19 patients. In the United States, if an individual tests positive, and has either mild symptoms that do not require hospitalization or is asymptomatic, s/he is sent home to quarantine. Quarantine includes staying at home for the designated time (averaging 14–21 days) and not allowing visitors into the home. This makes recruiting such patients for studies extremely challenging, requiring home visitations, as the patients must adhere to home quarantine. In countries such as Turkey, where there is a pharmaceutical standard of care for all that test positive, patients receive their diagnosis within 24 h, and if they are positive, they return to the hospital or clinic to receive medication. They can also be recruited for clinical studies during this visit. In the United States, it may take up to three days to receive results from a COVID-19 test, and during that time, the individuals are asked to quarantine if they believe they may have been exposed. If they are positive, they remain quarantined, and do not return to the hospital or clinic unless their symptoms become severe. This makes recruiting such patients very difficult, and thus options available to the asymptomatic, mild, and moderate/ambulatory COVID-19 patients rather limited. To address this challenge, it has been suggested that clinical studies coordinate efforts such that patients can enroll in studies from their home and receive in-home visitations from in-home health care providers. Finding home health care providers that can safely evaluate the patients in their homes is extremely difficult due the high risk of contracting COVID-19. Another challenge facing researchers is availability of funding to evaluate novel nutritional approaches to attenuate the disease and improve outcomes. Adequately powered double blind interventions can cost upwards of millions of dollars and such resources may be difficult for some researchers and companies to obtain. Funding for the nutritional interventions is not highly prioritized, however, such approaches may be just as beneficial as pharmaceutical products.
Summary and conclusions
Considering the current lack of approved therapeutics and only recent discovery and rollout of vaccines for SARS-CoV-2, there is urgent need to find alternative solutions to decrease morbidity and mortality of this virus. As more and more of the molecular mechanisms involved in SARS-CoV-2 pathogenesis are discovered, additional therapeutic approaches that target disease processes are able to be tested. Given what is known at present, data support the model that essential nutrients may aid cellular defense and repair mechanisms and thus promote recovery and/or control of symptoms in late-stage disease. However, larger multi-center trials are needed to determine the extent of these potential benefits, as well as determine the ideal time, dose, and methods of administration.
| Vitamin C | |
|---|---|
| Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? | 2020 (Cheng 2020) |
| A Novel Combination of vitamin C, Curcumin and Glycyrrhizic Acid Potentially Regulates Immune and Inflammatory Response Associated with Coronavirus Infections: A Perspective from System Biology Analysis | 2020 (Chen et al. 2020) |
| The use of IV vitamin C for patients with COVID-19: a case series | 2020 (Hiedra et al. 2020) |
| Integrative pharmacological mechanism of vitamin C combined with glycyrrhizic acid against COVID-19: findings of bioinformatics analyses | 2020 (Li et al. 2020) |
| Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome | 2020 (Chiscano-Camon et al. 2020) |
| Vitamin D | |
| vitamin D Deficiency and Outcome of COVID-19 Patients. | 2020 (Radujkovic et al. 2020) |
| Vitamin D and survival in COVID-19 patients: A quasi-experimental study. Annweiler C, | 2020 (Annweiler et al. 2020) |
| Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity. | 2020 (Panagiotou et al. 2020) |
| Vitamin D Deficiency Is Inversely Associated with COVID-19 Incidence and Disease Severity in Chinese People. | 2020 (Luo et al. 2021) |
| Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS) | 2015 (Dancer et al. 2015) |
| Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19 | 2020 (Carpagnano et al. 2020) |
| Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection | 2020 (Maghbooli et al. 2020) |
| Zinc | |
| COVID-19: Poor outcomes in patients with zinc deficiency. | 2020 (Jothimani et al. 2020) |
| Treatment with Zinc is Associated with Reduced In-Hospital Mortality Among COVID-19 Patients: A Multi-Center Cohort Study. | 2020 (Frontera et al. 2020) |
| Analysis of the predictive factors for a critical illness of COVID-19 during treatment - relationship between serum zinc level and critical illness of COVID-19. | 2020 (Yasui et al. 2020) |
| Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients | 2020 (Finzi 2020) |
| Three Cases of COVID-19 Disease With Colonic Manifestations | 2020 (Sattar et al. 2020) |
| Vitamin B3 | |
| Coronavirus and PARP expression dysregulate the NAD Metabolome: a potentially actionable component of innate immunity. | 2020 (Heer et al. 2020) |
| The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation. | 2020 (Alhammad and Fehr 2020) |
| The Coronavirus Macrodomain Is Required to Prevent PARP-Mediated Inhibition of Virus Replication and Enhancement of IFN Expression | 2019 (Grunewald et al. 2019) |
| Dramatic Cytokine Storm Reversal with an Over-the-Counter NMN Cocktail: a case study | 2020 (“Dramatic cytokine storm reversal with an over the counter NMN Cocktail”) |
| Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19 | 2020 (Altay et al. 2020) |
Disclosure statement
KB is a self-employed scientific writer; YN-E, PR, YI and AS are full-time employees of ChromaDex Corp, a global nutraceutical company.