Covid-19 and Vitamin D

Martineau reported that the intake of vitamin D is an efficacious supplement used for the prevention of COVID-19 infection16. 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 created17, 18. Straight inhibition can be used in the construction of angiotensinogen II as well as ACE by vitamin D6, 19. Regarding respiratory disorders, vitamin D also has an established control over the immuno-pathological inflammatory responses16. 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 infection20.

Murdaca . reported that supplements with energy boosters were more effective in patients suffering from viral infections due to COVID-1921. 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 immunity22. 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 time23. 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 transmitter24. Vitamin D supplementation also has a significant role in antioxidation activity25 (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 Israel26. 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 Chicago27. Danesh . observed that addressing the severe vitamin D insufficiency ultimately diminishes the probability of elevated CRP levels28. CRP is a surrogate marker for cytokine storm which is predicted to be increased in severe COVID-19 patients29. The supplementation of vitamin D is highly constructive when it comes to the reduction of circulating highly sensitive CRP30.

Water-Soluble Vitamins

Vitamin C

One of the trace micronutrients — vitamin C — 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 low5. 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 growth5.

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 resistance33 and it is the initial line of defense against foreign pathogens like viral infections34. 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 circulation5, 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 damage36. Abobaker 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 sepsis37. Gao . 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 illness38.

COVID-19 reduces the development of cytokine storm when the late stage of COVID-19 infection is reached39. Severe SARS-CoV-2 virus causes endothelial destruction and malfunctioning which ultimately increases the likelihood of extensive microscale and macrovascular thrombosis and multi-organ failure40. 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 damage41. Cheng reported the remarkable result following a loaded dose of vitamin C in the treatment of Covid-19 pneumonia42. A deficiency in vitamin C can be controlled by environmental factors such as air quality and the prevalence of diseases, including type 2 diabetes34.

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 narrow43. 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 function44. 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 system45.

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 response5.

Supplementation of B complex and COVID-19

B1

Multi-functioned vitamin B1 overcomes the diabetic threat, prevents cardiovascular disease, improves mental health, reduces the risk of cancer, and improves immune activity46. Its deficiency also causes multiple malfunctions in the body such as neuronal inflammation and abnormal antibody responses47. 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 edema48. An increase in thiamine given to persons with COVID-19 in the early stages may help to prevent hypoxia and nosocomial infections46.

B2

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 threshold49.

B3

Nicotinamide is a type of cofactor that turns into a constructive block (NAD and NADP). It plays an active role in chronic general infection50. NAD+ is a molecule with immunomodulatory characteristics that is produced during the early stages of inflammation. IL-1, 6, & TNF-α are examples of pro-inflammatory mediators that can be reduced51. Viral nucleotides replication is compacted by nicotinamide and it provides strength to the body’s immune system1, 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 tissue46.

B9

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 stages53. Kumar 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-1954.

B12

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-cobalamin51.

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 vasculopathy46. A B12 insufficient intake can also cause disorders in the respiratory, digestive, and neurological systems55. According to Dos Santos ., B12 can reduce COVID-19-related organ failure and its effects56.

Trace Minerals

Zinc (Zn)

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 health57. 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 immunity57, 58, 59.

An in vitro study revealed that the deficiency of Zn+ reciprocal induces a higher level of IL6 and IL1-β production60. Many studies support the use of Zinc as an antiviral treatment and immunity modulator58, 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 pathogens61. 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 is likely to be a key cofactor for a variety of viral proteins (enzymes). Overdosages of Zn can act as an intracellular second messenger that causes the apoptosis program by reducing protein synthesis63. Cao . reported that ACE-2 expression may be affected by zinc regulation inhibiting the prevalence of COVID-19 inside the cell63. Finzi . 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 recovery64.

Magnesium (Mg)

Magnesium supplementation has a vital role including decreasing blood pressure, reducing the risk of cardiovascular disease, and stopping smooth muscle contractions65. Magnesium is a vasodilator and has sympatholytic properties which may help in the regulation of blood pressure66. Moreover, a deficiency of Mg exacerbates the inflammatory response that directly affects cytokine storms leading to the ARDs in COVID-19 Patients67. Pneumonia alternatively shows the form of COVID-19 infection which includes a cough, chest infection, COPD, hemoptysis, runny nose, dyspnea, and chest tightness68. 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-1966, 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 destruction70. 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 expression71. 72

Iron (Fe)

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 patients70, 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 processes74.

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 conditions73. Fe+ chelation acts as antiviral and immunomodulatory, and it also controls the nucleotide replication and pro-inflammatory pathways in COVID-19 patients75, 76. Dalamaga . 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 fibrosis76.