PreprintPDF Available

High-dose intravenous vitamin C treatment for COVID-19

  • Independent researcher. Not affiliated to any institution
Preprints and early-stage research may not have been peer reviewed yet.
ResearchGate Logo

This preprint is featured on the COVID-19 research community page

View COVID-19 community


COVID-19 pneumonia seems to be a lung injury caused by the hyperactivation immune effector cells. High-dose vitamin C may result in immunosuppression at the level of these effectors. Therefore, intravenous high-dose vitamin C could be safe and beneficial choice of treatment in the early stages of COVID-19.
High-dose intravenous
vitamin C treatment for
(a mechanistic approach)
Adnan EROL, MD.
Erol Project Development House for the disorders of energy metabolism
Silivri-Istanbul, Turkey
Key words: Sars-CoV-2; Covid-19; Vitamin-C; GAPDH; Macrophage
COVID-19 pneumonia seems to be a lung injury caused by the hyperactivation immune
effector cells. High-dose vitamin C may result in immunosuppression at the level of these
effectors. Therefore, intravenous high-dose vitamin C could be safe and beneficial choice
of treatment in the early stages of COVID-19.
The two-time Nobel Prize-winning chemist Linus Pauling regarded vitamin C almost
as a panacea; therefore, he claimed that high doses vitamin C could combat a host of illnesses,
including cancer. He further believed that vitamin C would make the flu disappear completely
off the face of the earth.
Coronaviruses (CoVs) are large, enveloped, and positive sense RNA viruses that
infect a broad range of vertebrates and cause disease of medical and veterinary significance.
Human respiratory corona viruses have been known since the 1960s to circulate worldwide
and to cause respiratory infection with rather mild symptoms, suggesting that they are well-
adapted to the human host. However, zoonotic coronaviruses, such as severe acute respiratory
syndrome (SARS) and Middle East respiratory syndrome coronavirus (MERS-CoV), can
cause severe respiratory tract infection with high mortality [1].
Pulmonary pathology during severe coronavirus infection
Primary cell types found in the lower respiratory tract are alveolar epithelial cells and
alveolar macrophages (AMs). AMs are not only susceptible to infections, but also release a
significant amount infectious virus. Pathological examinations of samples obtained from
patients who died of SARS revealed diffuse alveolar damage, accompanied by prominent
hyperplasia of pulmonary epithelial cells and presentation of activated alveolar and interstitial
macrophages. Strikingly, these pulmonary manifestations were usually found after clearance
of viremia and in the absence of other opportunistic infections. Therefore, local inflammatory
responses due to excessive host immune response could result in alveolar damage [2].
In a murine model of SARS infection, fast and robust virus replication accompanied
by a delayed type I IFN (interferon) response. Accordingly, type I IFN expression was barely
detectable in most cell types. Plasmacytoid dendritic cells are a notable exception. They
utilize TLR7 (toll-like receptor-7) to sense viral nucleic acids and can induce robust type I
IFN expression following coronavirus infection. The extremely rapid replication of SARS-
CoV together with the upcoming, but delayed, type I IFN response caused extensive lung
inflammation. This was accompanied by influx of inflammatory monocyte-macrophages,
which are attracted by inflammatory mediators. Furthermore, macrophages themselves
additionally produced high levels of inflammatory mediators through type I IFN stimulation,
resulting in further macrophage influx in a pathological feedback loop. Altogether, massive
accumulation of pathogenic inflammatory macrophages increased the severity of SARS.
Moreover, type I IFN-induced immune dysregulation enforce apoptosis of T cells, which
would normally promote virus clearance, resulting in reduced numbers of virus-specific CD8
and CD4 T cells [1, 3].
Activation of effector immune cells
The rapid kinetics of SARS-CoV replication and relative delay in type I IFN
signaling may promote inflammatory M1 macrophage accumulation suggesting that targeted
antagonism of this pathway would improve outcomes in patients with severe coronavirus
infections [2]. Notably, the 2019 novel coronavirus (COVID-19) behaves more like SARS-
CoV; accordingly it was named as SARS-CoV-2, progressing rapidly with acute respiratory
distress syndrome (ARDS) and septic shock, which were eventually followed by multiple
organ failure due to virus-induced cytokine storm in the body [4].
In response to infection macrophages must react rapidly with a substantial pro-
inflammatory burst to kill microorganisms and to recruit additional immune cells to infection
site. A sharp increase in the rate of glycolysis is closely associated with inflammatory
phenotype in macrophages. Activated macrophages and effector T lymphocytes are shifted to
the high glycolytic rate and high glucose uptake, even under oxygen-rich conditions, which is
called as “Warburg effect”, upon immune activation, similar to cancer cells. Warburg effect is
associated with diverse cellular processes, such as angiogenesis, hypoxia, polarization of
macrophages, and activation of T cells. This phenomenon is intimately linked to several
disorders, including sepsis, autoimmune diseases and cancer [5].
Another interesting aspect of glycolysis induction in activated immune cells is the
role of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). It has
been shown that GAPDH binds to the IFNγ coding mRNA, repressing its translation.
However, GAPDH dissociates from IFNγ mRNA, allowing to its translation, upon glycolysis
activation [6]. In addition, due to the glycolytic pathway stimulation in activated immune
cells, their TCA becomes disrupted. Therefore, an accumulation of certain metabolites,
including succinate, occurs. Succinate, in turn, may increase hypoxia-inducible factor-
dependent activation of target genes, such as IL-1β and GLUT1 [7]. Glucose transporter,
GLUT1, is required for the metabolic reprogramming, activation, and expansion of effector
lymphocytes and M1 macrophages [7, 8].
Interaction between macrophages and alveolar epithelial type II (ATII) cells
Type I IFNs (type I interferons) produced by almost all type of cells play a vital role
in host defense against viral infection and cancer immunosurveillance. In response to viral
products pattern recognition receptors, such as retinoic-acid-inducible gene I (RIG-I)-like
receptors (RLRs) transmit downstream signaling pathway to trigger type I IFN production in
alveolar epithelial cells. Upon sensing cytosolic viral RNAs RLRs undergo conformational
changes, oligomerization, and exposure of the CARD domains to recruit a signaling adaptor
called mitochondrial antiviral-signaling (MAVS) protein. The transmembrane (TM) domain
of MAVS is necessary for its mitochondrial outer membrane localization. Once activated,
MAVS develop a functional prion-like structure at mitochondria, leading to the
phosphorylation of IRF3 and subsequent transcription and type I IFNs [9].
Activated macrophages produce large amounts of lactate, which are exported by
MCT4 [5]. Alveolar epithelial cells import lactate, creating a lactate shuttle between
macrophages and ATII cells, and use it as substrate for mitochondrial oxidative energy (ATP)
production [10]. In ATII cells, Lactate inhibits MAVS mitochondrial localization, RLR-
MAVS association, and MAVS aggregation and downstream signaling activation by binding
to the TM domain of MAVS. Thus, macrophage released lactate may attenuate host innate
immune response through decreasing type I IFN production for viral clearance [9].
Proposed mechanism of action of high-dose vitamin C in immune effector cells
Vitamin C is known as an essential anti-oxidant and enzymatic co-factor for
physiological reactions, such as hormone production, collagen synthesis, and immune
potentiation. Humans are unable to synthesize vitamin C; therefore, they must acquire vitamin
C from dietary sources [11]. Vitamin C is transported across cellular membranes by sodium
vitamin C co-transporter (SVCT). In addition, vitamin C spontaneously oxidizes both
intracellularly and extracellularly to its biologically inactive form, dehydroascorbate (DHA)
[11, 12]. DHA is unstable at physiological pH and, unless it is reduced back to vitamin C by
glutathione (GSH), it may irreversibly be hydrolyzed. Therefore, DHA is reduced to vitamin
C after import at the expense of GSH, thioredoxin, and NADPH (reduced nicotinamide
adenine dinucleotide phosphate). Consequently, reactive oxygen species (ROS) production
increases inside the activated immune cells (similar to cancer cells) due to the reduction of
ROS scavenging systems involving redox couples, such as NADPH/NADP+ and GSH/GSSG
(glutathione disulfide). Therefore, high-dose vitamin C, unlike the general assumption, acts as
a pro-oxidant in a cell type-dependent manner [12].
Sepsis is characterized by systemic inflammation, increased oxidative stress, insulin
resistance, and peripheral hypoxia. Remarkably, severe sepsis resulted in a ~43-fold increase
in GAPDH expression [13]. GAPDH is a redox-sensitive enzyme that can become rate-
limiting when glycolysis upregulated in the setting of Warburg effect, as it is in both cancer
cells [12] and activated immune cells. In addition to oxidizing and inhibiting GAPDH, the
elevated ROS may also lead to the DNA damage and the activation of poly(ADP-ribose)
polymerase (PARP). PARP activation leads to the NAD+ (nicotinamide adenine dinucleotide)
consumption following vitamin C treatment. Significantly, NAD+ is required for the
enzymatic activity of GAPDH as a co-factor; therefore, the decrease in NAD+ further
diminishes GAPDH enzymatic activity. Altogether, high-dose vitamin C-induced GAPDH
inhibition decreases the generation of ATP and pyruvate that induces an energetic crisis
(Figure), ultimately leading to cell death [11, 12]. In other words, GAPDH inhibition may
lead to the loss of activity of immune effector cells and related immunosuppression. These
results provide a mechanistic rationale for exploring the therapeutic use of vitamin C to
prevent inflammatory hyperactivation in myeloid and lymphoid cells.
Intravenous high-dose vitamin C treatment for 2019-nCoV disease
The results of meta-analyses have been demonstrated that intravenous (IV) high-dose
vitamin C treatment has significant benefits in the treatment of sepsis and septic shock. Sepsis
is a life-threatening organ dysfunction syndrome triggered by a disrupting host systemic
inflammatory reaction to the pathogenetic microorganisms and their products. ARDS,
devastating and mostly lethal condition, is also easily developed in patients with systemic
inflammatory response, such as sepsis [14].
Rolipram, a typical phosphodiesterase-4 inhibitor, can inhibit TNFα production in
activated macrophages and restrain acute inflammatory response. Rolipram was suggested as
a novel drug treatment for sepsis and septic shock due to its potent immunosuppressive effects
[15]. By analogy, the beneficial effects of intravenous high-dose vitamin C in sepsis and
septic shock are most likely due to its immunosuppressive effects.
While immune effector cells are dependent on glycolysis for their bioenergetic
functions, lung epithelial cells use mitochondrial oxidative phosphorylation to produce ATP.
Therefore, high-dose vitamin C treatment acts as a prooxidant for immune cells, but as an
antioxidant for lung epithelial cells. Furthermore, vitamin c treatment may protect innate
immunity of ATII through the inhibition of the lactate secretion, produced by the activated
immune cells.
In connection with the prooxidant role of vitamin C, which requires
pharmacological (millimolar) rather than physiological (micromolar) concentrations,
reevaluating the high-dose infusion of vitamin C would be a timely choice for the COVID-19-
related ARDS. Altogether, patients diagnosed with COVID-19 and hospitalized with the
breathing difficulty and abnormal biomarkers seem to be candidate for a short period of high
dose intravenous vitamin C treatment in the early periods of the disease. However, the
concern that may arise with high-dose vitamin c treatment is osmotic cell death of immune
cells, but not apoptosis, which could generate a local inflammation in alveolar medium.
Therefore, IV glucocorticoid treatment must be added to attenuate the possible inflammatory
complications of high-dose vitamin c treatment. Previously experienced and comparably well-
tolerated treatment regimen for high-dose intravenous vitamin C could be the administration
of 50 mg/ per kilogram body weight every 6 hours for 4 days [14] with a glucose restriction.
In addition, hydrocortisone 50 mg IV every 6 hours for 7 days must be added to fight against
therapy-induced inflammation. Vitamin C when used as a parenteral agent in high doses may
act pleiotropically as a prooxidant to attenuate pro-inflammatory mediator expression,
improving alveolar fluid clearance, and to act as an antioxidant to improve epithelial cell
[1] E. Kindler, V. Thiel
SARS-CoV and IFN: Too Little, Too Late
Cell Host Microbe, 19 (2016), pp.139-141
[2] T. Yoshikawa, T. Hill, K. Li, J. Peters, C.T. Tseng
Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial
cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of
monocyte-derived macrophages and dendritic cells
J Virol, 83 (2009), pp. 3039-3048
[3] R. Channappanavar, A.R. Fehr, R. Vijay, M. Mack, J. Zhao, D.K. Meyerholz, S.
Perlman Dysregulated Type I interferon and inflammatory monocyte-
macrophage responses cause lethal pneumonia in SARS-CoV-infected mice
Cell Host Microbe, 19 (2016), pp. 181-193
[4] N. Chen, M. Zhou, X. Dong, J. Qu, F. Y. Gong, Han, et al.
Epidemiological and clinical characteristics of 99 cases of 2019 novel
coronavirus pneumonia in Wuhan, China: a descriptive study
Lancet, Jan 30 (2020), pii: S0140-6736(20)30211-7. doi: 10.1016/S0140-
[5] D. Zhang, Z. Tang, H. Huang, G. Zhou, C. Cui, Y. Weng, et al.
Metabolic regulation of gene expression by histone lactylation
Nature, 574 (2019), pp. 75-580
[6] L.A. O’Neill, R.J. Kishton, J. Rathmell
A guide to immunometabolism for immunologists
Nat Rev Immunol, 16 (2016), pp. 55365
[7] G.M. Tannahill, A.M. Curtis, J. Adamik, E.M. Palsson-McDermott, A.F.
McGettrick, G. Goel, et al.
Succinate is an inflammatory signal that induces IL-through HIF-
Nature, 496 (2013), 238-242
[8] A.N. Macintyre, V.A. Gerriets, A.G. Nichols, R.D. Michalek, M.C. Rudolph, D.
Deoliveira, et al.
The glucose transporter Glut1 is selectively essential for CD4 T cell activation
and effector function
Cell Metab, 20 (2014), pp. 61-72
[9] W. Zheng, G. Wang, Z-G. Xu, et al.
Lactate is a natural suppressor of RLR signaling by targeting MAVS
Cell, 178 (2019), pp. 176-189
[10] R.G. Lottes, D.A. Newton, D.D. Syropoulos, J.E. Baetz
Lactate as substrate for mitochondrial respiration in alveolar epithelial type II cells
Am J Physiol Lung Cell Mol Phys, 309 (2015), pp. L953-L961
[11] B. Ngo, J.M. Van Ripper, L.C. Cantley, J. Yun
Targeting cancer vulnerabilities with high-dose vitamin C
Nat Rev Cancer, 19 (2019), pp. 271-282
[12] J. Yun, E. Mullarky, C. Lu, K.N. Bosch, A. Kavalier, K. Rivera, et al.
Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by
targeting GAPDH
Science, 350 (2015), pp. 1391-1396
[13] M. Cummings, J. Sarveswaran, S. Homer-Vanniasinkam, D. Burke, N.M. Orsi
Glyceraldehyde-3-phosphate dehydrogenase is an inappropriate housekeeping
gene for normalising gene expression in sepsis
Inflammation, 37 (2014), pp. 1889-94
[14] M.G. Kashiouris, M. L'Heureux, C.A. Cable, B.J. Fisher, S.W. Leichtle, A.A.F. Iii
The Emerging Role of Vitamin C as a Treatment for Sepsis
Nutrients, Jan 22 (2020). pii: E292. doi: 10.3390/nu12020292
[15] J.X. Yang, K.C. Hsieh, Y.L. Chen, C.K. Lee, M. Conti, T.H. Chuang, et al.
Phosphodiesterase 4B negatively regulates endotoxin-activated interleukin-1
receptor antagonist responses in macrophages
Sci Rep, 7 (2017), p. 46165
Vitamin C
Vitamin C
Activated effector Immune cell
Glucose versus DHA
competitive transport from
Vitamin C
Alveolar epithelial cell
... 52 At high serum concentrations, only attainable by intravenous administration (millimolar [mM] range), vitamin C seems to elicit a dual response with both antioxidant and pro-oxidant properties depending on cell type. 51,53 Activated immune cells with high turnover rates rely on accelerated glycolysis (the "Warburg effect") 54 while others such as lung epithelial cells rely on oxidative phosphorylation for energy production. High doses of vitamin C can overwhelm the redox pathways in highly glycolytic cells leading to elevated endogenous ROS. Increased oxidative stress, together with inhibition of ATP production from high levels of ROS, leads to a cellular energy crisis and cell death. ...
... 51 This may provide a mechanism of immunosuppression by preventing myeloid and lymphoid cells' hyperactivation, yet still providing antioxidant protection to lung epithelial cells. 53 Prior trials utilizing high-dose vitamin C for conditions such as sepsis demonstrate mixed results. 55,56 More recent studies show a potential mortality benefit with high-dose vitamin C given intravenously combined with steroids for patients with sepsis complicated by acute respiratory distress syndrome (ARDS). ...
Full-text available
Worldwide, the turmoil of the SARS-CoV-2 (COVID-19) pandemic has generated a burst of research efforts in search of effective prevention and treatment modalities. Current recommendations on natural supplements arise from mostly anecdotal evidence in other viral infections and expert opinion, and many clinical trials are ongoing. Here the authors review the evidence and rationale for the use of natural supplements for prevention and treatment of COVID-19, including those with potential benefit and those with potential harms. Specifically, the authors review probiotics, dietary patterns, micronutrients, antioxidants, polyphenols, melatonin, and cannabinoids. Authors critically evaluated and summarized the biomedical literature published in peer-reviewed journals, preprint servers, and current guidelines recommended by expert scientific governing bodies. Ongoing and future trials registered on were also recorded, appraised, and considered in conjunction with the literature findings. In light of the controversial issues surrounding the manufacturing and marketing of natural supplements and limited scientific evidence available, the authors assessed the available data and present this review to equip clinicians with the necessary information regarding the evidence for and potential harms of usage to promote open discussions with patients who are considering dietary supplements to prevent and treat COVID-19.
... Considering glycolysis is also thought to be the main energy source for the immune effector cells [166], HD-IVC administration might also have a prooxidant effect on the immune effector cells, thus downregulating proinflammatory mediator expression and improving alveolar fluid clearance during SARS-CoV-2 infection [172]. Moreover, lung ECs, just like any other normal cell type, mostly depend on mitochondrial oxidative phosphorylation for ATP production, which is why HD-IVC should act as an antioxidant in the lung ECs, enhancing their function [74]. ...
... Moreover, lung ECs, just like any other normal cell type, mostly depend on mitochondrial oxidative phosphorylation for ATP production, which is why HD-IVC should act as an antioxidant in the lung ECs, enhancing their function [74]. Still, intravenous glucocorticoid treatment is proposed to be taken together with HD-IVC to reduce possible inflammation caused by osmotic death of the immune effector cells [172]. Nevertheless, there is currently no evidence pointing to the cytotoxic effect of vitamin C pharmacological concentrations in the treatment of COVID-19 infection. ...
Full-text available
The story of vitamin C (L-ascorbic acid) as an antioxidant and a cofactor in numerous biochemical reactions is a part of its long history and it is well known today. However, many questions of its mechanism of action and the benefits that it has on human health are still emerging. This applies not only to the recommended doses but also to the route of its administration. Besides, there are numerous questions about the therapeutic efficacy of vitamin C in various human (infectious) diseases, as well as its immune system function and antiviral potential. The fact that vitamin C can act as a reductant (antioxidant) and a prooxidant further emphasizes its oxidation-reduction (redox) potential in real physiological conditions. Today, the question of the intravenous administration of vitamin C effect in patients with SARS-CoV-2 requires special attention. This review aims to showcase known facts about vitamin C and its mechanisms of action to better understand the current new challenges related to vitamin C.
... In fact, intravenous (IV) administration only has been able to restore high-level ascorbic acid plasma concentration [36]. Even if always being a matter of controversy [37,38], high doses (several grams) of IV vitamin C could help reducing the "cytokines storm" [39] and could have immunosuppressive effects [40]. When compared to a placebo group, Zhang et al. [41] recently demonstrated in a preprint paper without peer-reviewing that high-doses of IV vitamin C (12 g every 12 h) for 7 days improved oxygenation in COVID-19 critically ill patients. ...
... The meta-analysis reported that administration of high doses of vitamin C was associated with a reduction in-hospital mortality among patients with severe sepsis [68]. The hepatoprotective property of water soluble vitamin C is attributed to its antioxidant action, Animal models have lent strong evidence that vitamin C supplementation significantly decreases hepatic markers of oxidative stress, hepatocellular ballooning, and inflammation [69]. The prooxidant potential of vitamin C is enhanced with the presence of iron and copper catalysts in vitro. ...
Varying degrees of liver injuries have been reported in patients infected with the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). In general, oxidative stress is actively involved in initiation and progression of liver damage. The liver metabolizes various compounds that produce free radicals. Maintaining the oxidative/antioxidative balance is important in coronavirus disease 2019 (COVID-19) patients. Antioxidant vitamins, essential trace elements and food compounds, such as polyphenols, appear to be promising agents, with effects in oxidative burst. Deficiency of these nutrients suppresses immune function and increases susceptibility to COVID-19. Daily micronutrient intake is necessary to support anti-inflammatory and antioxidative effects but for immune function may be higher than current recommended dietary intake. Antioxidant supplements (β-carotene, vitamin A, vitamin C, vitamin E, and selenium) could have a potential role in patients with liver damage. Available evidence suggests that supplementing the diet with a combination of micronutrients may help to optimize immune function and reduce the risk of infection. Clinical trials based on the associations of diet and SARS-CoV-2 infection are lacking. Unfortunately, it is not possible to definitively determine the dose, route of administration and best timing to intervene with antioxidants in COVID-19 patients because clinical trials are still ongoing. Until then, hopefully, this review will enable clinicians to understand the impact of micronutrient dietary intake and liver status assessment in COVID-19 patients.
... Consumption of fermented dairy products like yoghurt or kefir on a daily basis also supports and enhances gut immunity. One should try to avoid excessive consumption of foods high in saturated fats, oils salt and processed food products containing trans-fat, which decreases the body's ability to fight infection [27,[52][53][54][55]. ...
The second outbreak of severe acute respiratory syndrome coronavirus (SARS-CoV-2) is of great concern due to its awful mortality and morbidity rate with decreasing nutritional status and poor lifestyle as well as noteworthy food crisis and affected economy of the world. Increasing food prices, food crisis, global hunger and decreasing availability and feasibility of food are the foremost causes of decreasing nutritional status, which increases the risk of susceptibility to infection and, in turn, leads to unfavorable outcomes of the diseases. Although, in times of the Covid-19 pandemic, nutrition is of potential attention, and there is a requirement for more exploration in the field of nutrition for the prevention of diseases arising from coronavirus infection. Elderly and individuals with co-morbidity, such as respiratory diseases, cardiovascular diseases, diabetes mellitus and metabolic diseases, are more prone towards getting infected with the coronavirus. Good nutrition is mandatory for healthy immune responses, which can be improved by the inclusion of vitamin A, B6, B12, C, D, E, zinc, selenium, iron, copper and an antioxidant-rich diet.
... Cai et al. showed that vitamin C can improve the outcome in pneumonia due to influenza virus by its effect on inhibition of CORT synthesis which reduces the susceptibility to influenza viral infection [21]. Regarding critically ill COVID-19 patients with pneumonia with a high mortality rate, it seems that timely administration of high-dose intravenous vitamin C has been particularly effective by inhibiting the production of cytokine storm due to COVID-19 [22]. Results of this study showed that administration of intravenous vitamin C can increase the concentration of vitamin C in critically ill patients after 72 h. ...
Full-text available
Background: Critically ill patients frequently suffer from vitamin C deficiency. Previous studies showed that high doses of vitamin C administration had conflicting results on clinical outcomes in patients with severe sepsis, burns, and trauma. Because of the high incidence and morbidity/mortality with severe pneumonia, we aimed to investigate the effect of administration of high dose vitamin C in critically ill patients with severe pneumonia. Methods: Eighty critically ill patients with pneumonia were enrolled in this randomized double-blinded clinical trial. Patients with a CURB-65 score > 3, one major criterion, or ≥ 3 minor criteria were considered as severe pneumonia. Patients were randomly assigned to intervention or placebo groups receiving standard treatment plus 60 mg/kg/day vitamin C as a continuous infusion or normal saline in the same volume correspondingly for 96 h. Serum levels of vitamin C were noted at baseline and 48 h after vitamin C administration. Duration of mechanical ventilation, ICU length of stay, PaO2/FiO2, and mortality rate were noted for all patients till the 28th day. Any complications related to the vitamin C administration were recorded. Results: Duration of mechanical ventilation and vasopressor use were significantly lower in the intervention group (p: < 0.001 and 0.003, respectively). Baseline levels of vitamin C in both groups did not have a significant difference but its levels increased in the intervention group and decreased in the control group during the study period. Mortality rate insignificantly decreased in the intervention group (p = 0.17). Three patients showed hypotension and tachycardia during the administration of vitamin C which was self-limited with decreasing the dose of vitamin C. Our results showed that the intravenous administration of a relatively high dose of vitamin C to critically ill patients with severe pneumonia was safe and could decrease the inflammation, duration of mechanical ventilation, and vasopressor use without any significant effect on mortality. Trial registration: IRCT registration number: IRCT20190312043030N1, Registration date: 2019-08-26, Seied Hadi Saghaleini.
... In high doses, vitamin C act as prooxidant which reduces the release of pro-inflammatory mediators, enhance alveolar fluid clearance and also act as an antioxidant in strengthening epithelial barrier. Furthermore, the meta-analysis has transparently provided evidence that high dose IV Vitamin C is quite beneficial in the management of sepsis and septic shock during COVID-19 [52]. Despite all these claims, the Australian Government, after detailed review of previously conducted randomized controlled trials, has suggested lack of solid evidence for the effectiveness against SARS-CoV-2 induced pneumonia and acute respiratory distress syndrome [53]. ...
Full-text available
Recently, the outbreak of severe acute respiratory syndrome cornoavirus-2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has become a great perturbation all around the globe and has many devastating effects on every aspect of life. Apart from the oxygen therapy and extracorporeal membrane oxygenation, Remdesivir and Dexamethasone have been proven to be efficacious against COVID-19, along with various vaccine candidates and monoclonal antibody cocktail therapy for Regeneron. All of these are currently at different stages of clinical trials. People with weak immunity are more prone to a severe infection of SARS-CoV-2. Therefore, early and judicious nutritional supplementation along with pharmacological treatment and clinician collaborations are critical in restituting the current situation. Nutritional supplements help in acquiring strong immunity to prevent the progression of disease any further. Vitamin C, vitamin D, selenium, zinc and many other nutritional and dietary supplements inhibit the production of inflammatory cytokines during a viral infection and prevents several unwanted symptoms of infection. Many dietary components like citrus fruits, black elderberry, ginger, and probiotics have the ability to attack viral replication. These supplements can also tame the overriding immune system during coronavirus infection. Keeping in view these facts, nutritional and dietary supplements can be used along with other management modalities. These nutritional and dietary supplements are potential candidates to curb the convulsive unfolding of novel COVID-19, in combination with other standard treatment protocols. In this review, various search engines were used to exploit available literature in order to provide a comprehensive review on nutritional and dietary supplements with respect to the viral infections. It will also provide a brief overview on some of the clinical trials that are in progress to assess the role of nutritional supplements, either alone or in combination with other pharmacological drugs, in fight against COVID-19.
Full-text available
The end of the year 2019 was marked by the introduction of a third highly pathogenic coronavirus, after SARS-CoV (2003) and MERS-CoV (2012), in the human population which was officially declared a global pandemic by the World Health Organization (WHO) on March 11, 2020. Indeed, the pandemic of COVID-19 (Coronavirus Disease 19) has evolved at an unprecedented rate: after its emergence in Wuhan, the capital of the province of Hubei of the People's Republic of China, in December 2019, the total number of confirmed cases did not cease growing very quickly in the world. In this manuscript, we have provided an overview of the impact of COVID-19 on health, and we have proposed different nutrients suitable for infected patients to boost their immune systems. On the other hand, we have described the advantages and disadvantages of COVID-19 on the environment including the quality of water, air, waste management, and energy consumption, as well as the impact of this pandemic on human psychology, the educational system, and the global economy. In addition, we have tried to come up with some solutions to counter the negative repercussions of the pandemic.
Full-text available
Purpose of Review The SARS-CoV-2 (COVID-19) outbreak has manifested into a major public health concern across the globe, affecting particularly the most vulnerable population groups. Currently, there are various clinical trials being conducted to develop effective treatments. It is estimated that it could take one or more years before these drugs pass all safety tests and concrete results with regard to their effectiveness become available. In addition, despite the recent development of vaccines (licensed for use under conditional licenses) and the commencement of COVID-19 vaccination programs in several countries, there is still a need for safe and novel strategies that may reduce the symptomatology and/or prevent the severe complications associated with COVID-19. Natural compounds previously shown to have antiviral potential should be thoroughly considered and investigated for use in prophylactic treatment of COVID-19 due to their availability and safety. Recent Findings The current narrative review investigates whether there is evidence in the literature that supplementation with dietary minerals and vitamins may have a role in preventing infection with SARS-CoV-2 or in reducing COVID-19 symptomatology and disease progression. The current evidence from the literature supports that zinc and vitamin C have a potential in reducing the inflammatory response associated with SARS-CoV-2 while folate and vitamin D may have a role in antagonizing the entry of SARs-CoV-2 virus in host calls. Summary Thus, further research should be conducted that could lead to the development of nutritional supplements involving natural and widely available compounds such as zinc, folate, vitamin C, and vitamin D. The latter could be an effective, safe, and inexpensive way to either prevent infection with SARS-CoV-2 and/or lessen the burden of COVID-19 disease.
The prevailing global health crisis, posed by the pandemic COVID-19, has threatened the livelihood of the public around the world. The dramatic coronavirus surge (2019-nCoV) is denoted as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Initially, this deadly ailment was identified to have originated from bats and thereafter, passed on to human beings, in December 2019 via unknown modes of biological transmission in Wuhan, China. One of the leading causes of COVID-19 mortality could be attributed to respiratory failure (hypoxemic or hypercapnic) due to acute respiratory distress. From an immunological perspective, the virus triggers secondary haemophagocytic lymphohistiocytosis, which results in fulminant, followed by fatal hypercytokinaemia alongside multiple organ failure, which happens in adults, in most of the predominant cases. As several scientific communities and researchers, tirelessly strive to find a suitable cure since there is a need for finding a registered medication/vaccine against COVID-19, it becomes quite pertinent for boosting our immune system. As the immune system, supports the body’s ability, as a fortress, to defend against pathogenic microbes, comprising of viruses, fungi, bacteria and protozoan species, thereby restricting infection. This review emphasizes the utilization of naturally-derived or otherwise plant-based supplements/foods that facilitate in enhancing or boosting the immunity against COVID-19, irrespective of one’s age. For a healthy lifestyle, the use of micro and macronutrients, such as: magnesium, zinc, vitamin-rich foods, especially vitamins C, D and E, since health could be enhanced and an individual could be further aided to overcome the infection. This report, majorly investigates the significance of antioxidants and their roles as immune boosters, through determining the various vitamins C and D-rich compounds, alongside the various secondary metabolites-endowed foods from various sources, which could most likely facilitate in improving immunity and thereby, controlling COVID-19.
Full-text available
Sepsis, a life-threatening organ dysfunction due to a dysregulated host response to infection, is a leading cause of morbidity and mortality worldwide. Decades of research have failed to identify any specific therapeutic targets outside of antibiotics, infectious source elimination, and supportive care. More recently, vitamin C has emerged as a potential therapeutic agent to treat sepsis. Vitamin C has been shown to be deficient in septic patients and the administration of high dose intravenous as opposed to oral vitamin C leads to markedly improved and elevated serum levels. Its physiologic role in sepsis includes attenuating oxidative stress and inflammation, improving vasopressor synthesis, enhancing immune cell function, improving endovascular function, and epigenetic immunologic modifications. Multiple clinical trials have demonstrated the safety of vitamin C and two recent studies have shown promising data on mortality improvement. Currently, larger randomized controlled studies are underway to validate these findings. With further study, vitamin C may become standard of care for the treatment of sepsis, but given its safety profile, current treatment can be justified with compassionate use.
Full-text available
The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases1,2. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous ‘lactate clock’ in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer. The lactylation of lysine residues on histones in mammalian cells is stimulated by hypoxia and bacterial challenges, and increased histone lactylation induces genes involved in wound healing.
Full-text available
Over the past century, the notion that vitamin C can be used to treat cancer has generated much controversy. However, new knowledge regarding the pharmacokinetic properties of vitamin C and recent high-profile preclinical studies have revived interest in the utilization of high-dose vitamin C for cancer treatment. Studies have shown that pharmacological vitamin C targets many of the mechanisms that cancer cells utilize for their survival and growth. In this Opinion article, we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation. Although the mechanisms and predictive biomarkers that we discuss need to be validated in well-controlled clinical trials, these new discoveries regarding the anticancer properties of vitamin C are promising to help identify patient populations that may benefit the most from high-dose vitamin C therapy, developing effective combination strategies and improving the overall design of future vitamin C clinical trials for various types of cancer.
Full-text available
CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival.
Full-text available
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has long been used as a default reference gene in quantitative mRNA profiling experiments. However, its expression reportedly varies in response to a range of pathophysiological variables (inflammation, oxidative stress, hyperinsulinaemia, hypoxia) which feature prominently in sepsis. We therefore assessed the applicability of using GAPDH as a reference gene for expression studies in sepsis compared to other housekeeping genes (succinate dehydrogenase complex subunit A (SDHA), hypoxanthine phosphoribosyltransferase (HPRT)-1). Severe sepsis resulted in a 42.4-fold increase in median GAPDH expression (P < 0.001), whereas median HPRT expression was raised more modestly (2.9-fold; P < 0.001), and there was no significant difference in SDHA expression between sepsis and control patients. HPRT was identified by NormFinder to be the most stably expressed single gene. In order to assess the impact of this variability on data interpretation, interleukin (IL)-10 expression was normalised separately to GAPDH and to the geometric mean of HPRT and SDHA. In the former case, there was no significant difference in IL-10 expression between controls and septic patients, whilst in the latter, a significant 8.5-fold increase in median IL-10 expression was noted (P < 0.001). GAPDH is thus an unreliable housekeeping gene for normalising gene expression in sepsis which should be replaced by alternative, validated reference genes.
Full-text available
Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.
Full-text available
Severe acute respiratory syndrome (SARS), which is caused by a novel coronavirus (CoV), is a highly communicable disease with the lungs as the major pathological target. Although SARS likely stems from overexuberant host inflammatory responses, the exact mechanism leading to the detrimental outcome in patients remains unknown. Pulmonary macrophages (Mphi), airway epithelium, and dendritic cells (DC) are key cellular elements of the host innate defenses against respiratory infections. While pulmonary Mphi are situated at the luminal epithelial surface, DC reside abundantly underneath the epithelium. Such strategic locations of these cells within the airways make it relevant to investigate their likely impact on SARS pathogenesis subsequent to their interaction with infected lung epithelial cells. To study this, we established highly polarized human lung epithelial Calu-3 cells by using the Transwell culture system. Here we report that supernatants harvested from the apical and basolateral domains of infected Calu-3 cells are potent in modulating the intrinsic functions of Mphi and DC, respectively. They prompted the production of cytokines by both Mphi and DC and selectively induced CD40 and CD86 expression only on DC. However, they compromised the abilities of the DC and Mphi in priming naïve T cells and phagocytosis, respectively. We also identified interleukin-6 (IL-6) and IL-8 as key SARS-CoV-induced epithelial cytokines capable of inhibiting the T-cell-priming ability of DC. Taken together, our results provide insights into the molecular and cellular bases of the host antiviral innate immunity within the lungs that eventually lead to an exacerbated inflammatory cascades and severe tissue damage in SARS patients.
In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
Highly pathogenic human respiratory coronaviruses cause acute lethal disease characterized by exuberant inflammatory responses and lung damage. However, the factors leading to lung pathology are not well understood. Using mice infected with SARS (severe acute respiratory syndrome)-CoV, we show that robust virus replication accompanied by delayed type I interferon (IFN-I) signaling orchestrates inflammatory responses and lung immunopathology with diminished survival. IFN-I remains detectable until after virus titers peak, but early IFN-I administration ameliorates immunopathology. This delayed IFN-I signaling promotes the accumulation of pathogenic inflammatory monocyte-macrophages (IMMs), resulting in elevated lung cytokine/chemokine levels, vascular leakage, and impaired virus-specific T cell responses. Genetic ablation of the IFN-αβ receptor (IFNAR) or IMM depletion protects mice from lethal infection, without affecting viral load. These results demonstrate that IFN-I and IMM promote lethal SARS-CoV infection and identify IFN-I and IMMs as potential therapeutic targets in patients infected with pathogenic coronavirus and perhaps other respiratory viruses.
More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impairs tumor growth in Apc/KrasG12D mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.