The viral infection (SARS-CoV-2) COVID-19 has played havoc on the health of the human population globally. In late December 2019, the first case of COVID-19 was reported in Wuhan city, China. Its destructive effects like acute respiratory distress syndrome then began to be globally reported. Many treatment options such as remdesvir and dexamethasone were used to treat and reduce the hospitalization rate among COVID-19 patients. Numerous scientific studies have reported the use of nutraceuticals as a therapy for COVID-19 patients to enhance immunity. Differently formulated multivitamins that are water and fat-soluble (A, B complex, D, and C) and minerals like Mg and Zn minimize the virulence of COVID-19, oxidative stress, C-reactive protein, as well as boost the immunity.
Tyrell and Bynoe worked initially on coronaviruses in 1966 by isolating the infections from individuals with ordinary colds. COVID-19 viruses are contained, large RNA viruses with a single-stranded RNA strand that is positive in the human population 1 . In late December 2019, in Wuhan, China, a new type of coronavirus called the novel coronavirus (2019-nCoV, or COVID-19) was identified. It then spread rapidly throughout the whole of China and then worldwide 2 . SARS-CoV-2 (enclosed virus with a 32kb genomic size) also affects the respiratory tract due to infection and the alveolar epithelium tissue of the inner lungs via receptor-mediated engulfing with the help of angiotensin-converting enzyme II (ACE2) serving as a door receptor 3 ( Figure 1 ).
Chan et al. reported that the initial diagnostic symptom of SARS-CoV-2 was pneumonia linked to infection with COVID-19. The present study reveals that in infants, it causes gastrointestinal infection and asymptomatic infections 4 . SARS-CoV-2 is a beta coronavirus of the B lineage that is usually correlated to SARS-CoV 5 , 6 .
According to the innumerable amount of research, COVID-19 is propagated by an inflammatory process produced by immune system hyperactivity in an attempt to destroy the virus. Persistent inflammation can lead to lung tissue loss, pulmonary-edema fluid exudation, dyspnea, and pulmonary disease 7 .
Coronavirus causes a decrease in the alveolar lacunar sac spaces of the patients' lungs and ultimately, apoptosis (cell death) 8 . COVID-19 decreases the number of lymphocytes in the peripheral blood while elevating the inflammatory cytokine concentration in the serum. In an intense condition of COVID-19, the patientâ€™s respiratory tract inflammation cause significant pulmonary function impairment and the cytokines responsible are generated by inflammatory monocytes 9 . Scientists have discovered a cure for such patients. This quick endeavor resulted in the discovery of certain potential pharmacological medicines for hospitalized patients, including remdesivir and dexamethasone 10 , 11 .
During the pandemic, the consumption of nutraceutical products was greater and showed a double-digit percentage of growth worldwide because they provide prophylactic and therapeutically effects against disease prevention 12 , 13 , 14 , 15 . It is also considered that fat and water-soluble vitamins like vitamin B complex, C, and D along with trace minerals Zinc (Zn), Magnesium (Mg), and Iron (Fe) have a significant role in the treatment of COVID-19. They transfer a synergistic effect to the patient by promoting the antioxidant activity in the body and also competing with the energy level.
Covid-19 and Vitamin D
Martineau et al. reported that the intake of vitamin D is an efficacious supplement used for the prevention of COVID-19 infection 16 . The link between vitamin D and COVID-19 is obvious enough because vitamin D kills renin, and less so angiotensin I (the precursor to angiotensin II) is created 17 , 18 . Straight inhibition can be used in the construction of angiotensinogen II as well as ACE by vitamin D 6 , 19 . Regarding respiratory disorders, vitamin D also has an established control over the immuno-pathological inflammatory responses 16 . According to a study published in March 2020, the regular intake of vitamin D is the link between age, the prevention of comorbidities, and vulnerability. It can reduce the risk of chronic diseases such as COVID-19 infection 20 .
Murdaca et al . reported that supplements with energy boosters were more effective in patients suffering from viral infections due to COVID-19 21 . Vitamin D affected the mortality of the microbes in three respective way: it affected the corporeal barriers, sometimes affected the cellular normal immunity, and also affected the adaptive immunity 22 . COVID-19 individually affects the natural immune system response like when it is infected by other microorganisms, producing both pro-inflammatory and inflammatory cytokines at the same time 23 . Antipsychotics, antineoplastic, anti-infective, and anti-inflammatory treatments, as well as antihypertensive, antiretroviral, endocrine pharmaceuticals, and some herbal medicines can reduce the level of vitamin D in the bloodstream by activating the transmitter 24 . Vitamin D supplementation also has a significant role in antioxidation activity 25 ( Figure 2 ) .
Deficiency in vitamin D levels was also an interconnected reason for the amplified risk of COVID-19 infection in the research done in Israel 26 . Comparative studies reveal that the risk of COVID-19 was greater in the vitamin D deficient group compared to a vitamin D-rich group according to a retrospective cohort study conducted at the University of Chicago 27 . Danesh et al . observed that addressing the severe vitamin D insufficiency ultimately diminishes the probability of elevated CRP levels 28 . CRP is a surrogate marker for cytokine storm which is predicted to be increased in severe COVID-19 patients 29 . The supplementation of vitamin D is highly constructive when it comes to the reduction of circulating highly sensitive CRP 30 .
Figure 1 . Mechanism of coronavirus penetration in the cell. The Angiotensin-converting enzyme-2 aid Coronavirus penetrate the cell and then replication of its RNA and destruction of the cell along with its organelles. This figure was drawn originally by the authors using the Biorender.com platform.
One of the trace micronutrients â€” vitamin C â€” has been proven to have a critical role in the treatment of COVID-19, especially during the very first phase of infection when it was observed that the vitamin C levels in both serum and leukocytes are low 5 . COVID-19 infection leads to an increase in reactive oxygen species production and an increase in the production of proinflammatory cytokines, leading to cytokine storm, both of which cause serious lung difficulties and contribute to the formation of adult respiratory failure syndrome (ARDS) 31 , 32 . Vitamin C may have an antiviral effect according to the findings from in vitro investigations and clinical trials. A loaded dose of vitamin C is thought to have virucidal properties since it inhibited viral growth 5 .
Vitamin C may aid in the enhancement of innate immunity as well as cellular and humoral immune responses. The inadequate ingestion of micronutrients like vitamin C has been found to lower infection resistance 33 and it is the initial line of defense against foreign pathogens like viral infections 34 . Vitamin C appears to accumulate intracellularly in the neutrophils, implying that it plays a role in maintaining leukocyte activity and that it may have an anti-apoptotic effect on the neutrophils under the peripheral circulation 5 , 35 . Vitamin C vitally inhibits the cohort of proinflammatory cytokines which may help to mitigate the cytokine storm caused by COVID-19 infection, resulting in less inflammatory-induced tissue damage 36 . Abobaker et al. reported that Vitamin C may also decrease the negative immunological effects of SARS-CoV-2 contamination, allowing it to be a viable therapy option for COVID-19 (5). Vitamin C lowers the level of immune reactivity and OS, as well as immunological dysfunction, both of which are important pathophysiological processes in sepsis 37 . Gao et al . reported in their study that Vitamin C reduced the T regulatory cells' negative immunoregulatory function, promoting a T cell-mediated cellular immune response and ameliorating sepsis-induced multi-organ failure illness 38 .
COVID-19 reduces the development of cytokine storm when the late stage of COVID-19 infection is reached 39 . Severe SARS-CoV-2 virus causes endothelial destruction and malfunctioning which ultimately increases the likelihood of extensive microscale and macrovascular thrombosis and multi-organ failure 40 . Vitamin C has the capability to maintain the dysfunction of the endothelial tissues in Covid-19 and it may also contribute to reducing lung inflammation and damage 41 . Cheng et al. reported the remarkable result following a loaded dose of vitamin C in the treatment of Covid-19 pneumonia 42 . A deficiency in vitamin C can be controlled by environmental factors such as air quality and the prevalence of diseases, including type 2 diabetes 34 .
One of the respiratory disorders, ARDS pulmonary edema, is due to the prevalence of liquid and protein in the structural unit of the lung alveoli. Cell surface disruption in the lung tissue such as in the endothelium leads to an increase in the penetration of fluids, neutrophils, and erythrocytes which results in an overabundance of these components in the alveolar spaces, making the passage narrow 43 . During acute lung damage, neutrophils in the intravascular and extravascular areas are typically linked with platelets, producing a combined cause of oxidative stress due to their inflammatory thrombogenic function 44 . In patients with ARDS, a higher concentration of vitamin C is connected to a range of positive outcomes including reduced inflammatory functions, the prevention of organ damage, lower pathogenic infections and virulence, and an improved immune system 45 .
Vitamin C has potent antioxidant and anti-inflammatory capabilities, reducing the risk of oxidative cellular harm and inhibiting cytokine storm, an excessive inflammatory response. By increasing interferon generation and stimulating cell multiplication, vitamin C improves the swarm's antiviral immune response 5 .
Figure 2 . Role of major dietary supplements in COVID-19. Vit-D plays a significant role as an antioxidant agent, Fe reduces oxidative stress, Zn + increases the function of NK cells, Vitamin C with antiviral effect and reduces oxidative stress, Mg act as a vasodilator, Fe + reduces the anemic & and ROS stress. This figure was drawn originally by the authors using the Biorender.com platform.
Supplementation of B complex and COVID-19
Multi-functioned vitamin B1 overcomes the diabetic threat, prevents cardiovascular disease, improves mental health, reduces the risk of cancer, and improves immune activity 46 . Its deficiency also causes multiple malfunctions in the body such as neuronal inflammation and abnormal antibody responses 47 . Critically, T-cells are necessary to eradicate the SARS-CoV-2 virus and a thiamine deficiency can lead to a decrease in antibody levels. The use of appropriate thiamine reduces the symptoms of SARS-CoV-2 infection and the associated inflammatory processes. Additionally, the signs of coronavirus are strikingly similar to those of elevation sickness, including the high risk of pulmonary edema 48 . An increase in thiamine given to persons with COVID-19 in the early stages may help to prevent hypoxia and nosocomial infections 46 .
The combination of riboflavin and ultraviolet light damages DNA and RNA and prevents viral replication in the body. Furthermore, riboflavin-UV was fond to decrease the infectious frequency of SARS-CoV-2 in the blood plasma underneath the finding threshold 49 .
Nicotinamide is a type of cofactor that turns into a constructive block (NAD and NADP). It plays an active role in chronic general infection 50 . NAD+ is a molecule with immunomodulatory characteristics that is produced during the early stages of inflammation. IL-1, 6, & TNF-Î± are examples of pro-inflammatory mediators that can be reduced 51 . Viral nucleotides replication is compacted by nicotinamide and it provides strength to the bodyâ€™s immune system 1 , 52 . Furthermore, B3 individually lowers neutrophil infiltration and has an anti-inflammatory impact on the breathing mechanism of the lungs, as well as Niacin. Nicotinamide protects the lung tissue 46 .
B9 (Folic Acid) is a necessary cofactor in the replication of hereditary material and protein synthesis via polypeptide chain synthesis, and it also works as an inflammatory reaction. Furin is a pathogenesis-related enzyme in bacteria that can be a promising infection treatment target. Furin, which prevents the SARS-CoV-2 spike protein from sticking to the host cell, is reduced by folic acid, blocking the cell entrance and virus turnover. As a result, folic acid has been proposed as a potential treatment for COVID-19-related respiratory illness in its early stages 53 . Kumar et al. reported that the molecular modeling of folic acid with its analogs tetrahydrofolic acid and 5-methyl tetrahydrofolic acid exhibit substantial then consistent binding with SARS-CoV-2. Thus, folic acid can be used as a treatment line for COVID-19 54 .
Red blood cell creation by B12 supplies energy directly to the brain system and allows for rapid DNA production. Cobalamin is an essential nutrient for human health. The vigorous formulation of vitamin B12 involves hydroxo-adenosyl- and methyl-cobalamin 51 .
In contrast, SARS-CoV-2 may interfere with vitamin B12 metabolism, restricting microbial proliferation in the intestine. Vitamin B12 deficiency may incur similar risks to COVID-19 infection including increased OS and lactate dehydrogenase, hyperhomocysteinemia, thickening flow activation, blood vessel constriction with rising pressure, and renal and bronchial vasculopathy 46 . A B12 insufficient intake can also cause disorders in the respiratory, digestive, and neurological systems 55 . According to Dos Santos et al ., B12 can reduce COVID-19-related organ failure and its effects 56 .
Zn is a trace metal present in humans predominantly and it has efficacious roles in various aspects. Its functions involve a variety of cellular processes, especially in connection to neurotransmitted immunological health 57 . Some clinical evidence has reported that a deficiency of Zinc (Zn) causes gonadal growth retardation, the degeneration of the thymus, immune dysfunction, and lymphopenia which decreases the number of B cells. Zn+ also has a potential and significant role in antiviral immunity 57 , 58 , 59 .
An in vitro study revealed that the deficiency of Zn+ reciprocal induces a higher level of IL6 and IL1-Î˛ production 60 . Many studies support the use of Zinc as an antiviral treatment and immunity modulator 58 , 59 and it is a vital component of thymulin hormone which is intricately involved in the development and distinction of T cells, It also arouses the macrophages, causing them to yield the IL-12, causing the destruction of various pathogens 61 . Zn+ has been found to be identified as strong RNA virus inhibitor due to forming a bond with pyrithione (PT) 62 .
Furthermore, targeting RNA viruses i.e. SARS-RNA-dependent CoV-2's RNA polymerase (RdRps), is better for antiviral medication expansion since RdRp activity is entirely virus-specific. In addition, it can be stopped if there is a lack of compromising important cellular activities. Zn ions have a vital role in different kinds of cellular functions. This includes the appropriate breakdown and activation of cellular enzymes. In some disciplines, Zn metal also works in transcription factors. Furthermore, Zn 2+ is likely to be a key cofactor for a variety of viral proteins (enzymes). Overdosages of Zn 2+ can act as an intracellular second messenger that causes the apoptosis program by reducing protein synthesis 63 . Cao et al . reported that ACE-2 expression may be affected by zinc regulation inhibiting the prevalence of COVID-19 inside the cell 63 . Finzi et al . reported that treating four COVID-19 cases with a greater dosage of zinc reduced the disease symptoms within 24 hours (i) in a 63-year-old male patient given a high dose for 10 days, (ii) in a 57-year-old female patient given a high dose for 10 days, (iii) in a 41-year-old female patient given a high dose for 9 days, and (iv) in a young female patient who was 26-year-old who was given a high dose for 14 days. All four case studies showed a reduction in their COVID-19 symptoms and the patients moved toward recovery 64 .
Magnesium supplementation has a vital role including decreasing blood pressure, reducing the risk of cardiovascular disease, and stopping smooth muscle contractions 65 . Magnesium is a vasodilator and has sympatholytic properties which may help in the regulation of blood pressure 66 . Moreover, a deficiency of Mg exacerbates the inflammatory response that directly affects cytokine storms leading to the ARDs in COVID-19 Patients 67 . Pneumonia alternatively shows the form of COVID-19 infection which includes a cough, chest infection, COPD, hemoptysis, runny nose, dyspnea, and chest tightness 68 . Magnesium sulfate has been used instead of calcium to overcome smooth muscle contractions, causing bronchodilation and decreasing the inflammatory response and oxidative stress, as well as controlling pulmonary symptoms in COVID-19 66 , 69 .
Mg protects against viral infections like SARS-CoV-2. The viral protein binds to the ACE-2 receptors for the penetration of the virus inside the cell, followed by destruction 70 . The preliminary findings indicate that magnesium treatment increases the methylation of the TMPRSS2 promoter, thereby inhibiting transcription and, as a result, inhibiting the activation of the enzyme expression 71 . 72
COVID-19 patients face a severe deficiency of iron in terms of their hemoglobin levels which ultimately results in anemia (limited oxygen delivery to tissues) which seems pathological in which there is a higher ferritin level. This causes interference in terms of cell functioning in infected patients 70 , 73 . A heavy intake of ferritin in COVID-19 patients indicates a severe inflammatory response and it allows the virus to enter the human body. This situation impacts the Fe + metabolic processes 74 .
Anemia potentially leads to multi-organ failure. It's critical to understand the relationship between anemia, iron metabolism, and the evolution of COVID-19, as well as how the relationships change according to age, gender, and any current chronic conditions 73 . Fe+ chelation acts as antiviral and immunomodulatory, and it also controls the nucleotide replication and pro-inflammatory pathways in COVID-19 patients 75 , 76 . Dalamaga et al . reported that Fe+ chelation (Deferoxamine, Deferiprone, and Deferasirox) controlled different mechanisms of SARS-CoV-2 multiplication including viral replication inhibition, and B-Cell regulation, as well as the upgrading of the neutralizing anti-viral antibody, endothelial inflammation inhibition, and the anticipation of pulmonary fibrosis 76 .
The current study reported using clinical trials to reveal that nutraceutical supplementation such as water and fat-soluble vitamins along with trace minerals is the best choice as an immunity booster with management to reduce the symptoms of COVID-19.
TMPRSS2 : transmembrane protease serine 2 CRP : C-reactive Protein PT : pyrithione ARDS : Acute respiratory distress syndrome ACE2 : Angiotensin-converting enzyme II TNF-Î± : Tumor necrosis factor alpha IL : Interleukin
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