How Vitamin D, Magnesium, Omega-3 and Zinc prevent and treat COVID-19 etc. – June 2021

Essential sufficiency of zinc, ω-3 polyunsaturated fatty acids, vitamin D and magnesium for prevention and treatment of COVID-19, diabetes, cardiovascular diseases, lung diseases and cancer

Biochimie. 2021 May 31;S0300-9084(21)00140-1. doi: 10.1016/j.biochi.2021.05.013
Michael J Story 1 storypharm at bigpond.com

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Despite the development of a number of vaccines for COVID-19, there remains a need for prevention and treatment of the virus SARS-CoV-2 and the ensuing disease COVID-19. This report discusses the key elements of SARS-CoV-2 and COVID-19 that can be readily treated: viral entry, the immune system and inflammation, and the cytokine storm. It is shown that the essential nutrients zinc, ω-3 polyunsaturated fatty acids (PUFAs), vitamin D and magnesium provide the ideal combination for prevention and treatment of COVID-19: prevention of SARS-CoV-2 entry to host cells, prevention of proliferation of SARS-CoV-2, inhibition of excessive inflammation, improved control of the regulation of the immune system, inhibition of the cytokine storm, and reduction in the effects of acute respiratory distress syndrome (ARDS) and associated non-communicable diseases. It is emphasized that the non-communicable diseases associated with COVID-19 are inherently more prevalent in the elderly than the young, and that the maintenance of sufficiency of zinc, ω-3 PUFAs, vitamin D and magnesium is essential for the elderly to prevent the occurrence of non-communicable diseases such as diabetes, cardiovascular diseases, lung diseases and cancer. Annual checking of levels of these essential nutrients is recommended for those over 65 years of age, together with appropriate adjustments in their intake, with these services and supplies being at government cost. The cost:benefit ratio would be huge as the cost of the nutrients and the testing of their levels would be very small compared with the cost savings of specialists and hospitalization.

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Vitamin D

Vitamin D obtained from sunlight or dietary sources is catalysed by vitamin D- 25-hydroxylase in the liver to 25-hydroxyvitamin D3 (25(OH)D), the major circulating form of vitamin D. 25(OH)D is biologically inert until it is hydroxylated by the enzyme 1a-hydroxylase (CYP27B1) in the kidney to the active form 1a,25-dihydroxyvitamin D3 (calcitriol, 1a,25(OH)2D3) [62].
Calcitriol has important immunoregulatory and anti-inflammatory effects that it exerts through interaction with the vitamin D receptor (VDR). The calcitriol/VDR complex can interact with different gene transcription factors that control inflammatory responses [63]. VDR and CYP27B1 are expressed in many types of immune cells, including lymphocytes, monocytes/macrophages, dendritic cells, T and B cells [64,65], and on pulmonary epithelial cells. These immune cells can convert 25(OH)D into biologically active calcitriol [63,66]. The calcitriol/VDR complex causes transcription of the antimicrobial peptides cathelicidins and defensins. Cathelicidins disrupt bacterial cell membranes as well as enveloped viruses such as SARS-CoV-2, while defensins promote chemotaxis of inflammatory cells through increased capillary permeability [65,67].
Synthesis of vitamin D in the skin is controlled by the season, the time of the exposure during the day and the latitude [68,69]. Vitamin D is poorly synthesized above (to the north) and below (to the south) of 35° latitude during winter months [70]. Lockdowns, implemented to minimize the spread of COVID- 19, are therefore detrimental to vitamin D synthesis as people are prevented from going out from their homes and absorbing the sunshine, which has a cumulative effect in the winter months when COVID-19 is more prevalent. The Black and Asian populations produce less vitamin D as a result of a higher skin melanin content than those with white skin [71]. Excess exposure to sunlight is the major cause of skin cancer [72]. However, there is an increased incidence of skin cancer and other cancers in countries with low levels of sunlight compared with those countries with higher levels of sunlight throughout the year [73,74], supporting the proposition that sunlight is beneficial for synthesis of vitamin D and subsequent prevention of cancers. There have been a number of reports where low sun exposure has been shown to have a negative impact on a range of health issues [75-77]. The advantage of sun exposure in providing vitamin D needs to be sensibly balanced against the potential risk of skin cancer from excessive sun exposure [78]. I
In the early stages of acute inflammation, vitamin D inhibits the proliferation of Th1 and Th17 cells and their abnormal release of IFN-y, TNF-a, IL-1, IL-2, IL12, IL-23 and IL-17, IL-21 [65]. During the resolution phase of inflammation, vitamin D-mediates differentiation of Th2 cells and release of their antiinflammatory cytokines (IL-4 and IL-10), evading the organ damage that could be caused by an excessive immune response [65]. Vitamin D has powerful antiinflammatory properties that play an important role in controlling immune function in pulmonary infection; eg, it inhibits the effects of TNF-a, it inhibits NF- kB activity in immune cells, it inhibits the activation of inflammasomes and hence release of IL-1p, and it decreases expression of IL-6, a major contributor to the so-called 'cytokine storm' [65,79].
The immune response acts in concert with the inflammatory response. The innate immune system acts as the first line of defence against invading pathogens such as viruses. Calcitriol enhances that defence by recruiting neutrophils, monocytes/macrophages and dendritic cells which kill and clear the viral pathogens, ultimately initiating the adaptive immune response. This response can be overactive resulting in the cytokine storm. Calcitriol inhibits this chronic immune response by downregulating the toll-like receptors (TLRs) that identify the viral pathogens initially, and inhibits the TNF-a/NF-KB and IFN-y signalling pathways. Calcitriol shifts the T cell profile from the pro-inflammatory Th1 and Th17 forms to the anti-inflammatory Th2 and Treg forms, respectively [80]. Tregs provide a major defence against inflammation, releasing antiinflammatory cytokines IL-10 and TGF-p. Treg levels are markedly decreased in severe COVID-19 disease, in contrast to high levels of Treg correlating with reduced levels of viral disease [81].
Natural killer cells are innate immune cells and they are known to possess strong antiviral activity as well as anticancer activity [82]. The count and activity of natural killer cells have been shown to be reduced below normal in COVID-19 patients, and vitamin D has been found to increase the activity of natural killer cells [82].
Although there is inconsistency in the data, it is apparent that vitamin D deficiency is influential in increasing risk of acute respiratory tract infections [83], particularly when considering the decrease in natural synthesis of vitamin D in winter-time when acute respiratory infections are most prevalent. Ali [84] conducted a study of COVID-19 cases and mortality in 20 European countries, finding that vitamin D status correlated negatively with COVID-19 cases but not with mortality. The effectiveness of vitamin D sufficiency in reducing risk of acute viral respiratory tract infections and pneumonia was also shown. Similar results were reported by Kara and co-workers [85], who also discussed the link between latitude, temperature and humidity and season on viral respiratory tract infections.
Allegra and co-workers [86] reported on the deficiency and supplementation of a range of vitamins including vitamin D, in particular in correlating hypovitaminosis with risk of contracting COVID-19 and associated mortality. They reported that there were positive and indeterminate results in their analysis of multiple studies. Vitamin D levels were particularly reduced in the ageing populations of Italy, Spain, and Switzerland, which were the most susceptible populations in relation to SARS-CoV-2 infection [87]. Additionally, Annweiler and co-workers [88] analysed a range of reports with the conclusion that inverse correlations were found between 25(OH)D levels in patients and COVID-19 incidence and mortality. Other reports have also covered the influence of vitamin D on outcomes of COVID-19 patients with the typical finding that vitamin D supplementation leads to an improved outcome for these patients and that vitamin D deficiency increases the risk and susceptibility for severe COVID- 19 disease and mortality [69,84,87,89-99].
In another review, Lau and co-workers [100] found that vitamin D deficiency was highly prevalent in patients with severe COVID-19, which correlated in turn with obesity, male sex, advanced age, population concentration in northern climates, coagulopathy and immune dysfunction. A further meta-analysis found that vitamin D deficiency increased risk of severe infections and mortality of the critically ill [101]. Deficiency of vitamin D has been further claimed to increase the risk of contracting osteoporosis, cancer, diabetes, multiple sclerosis, hypertension, and inflammatory and immunological diseases [102]. Although vitamin D and the benefits of supplementation in preventing cancer have been discussed previously [1], it is of note that a number of researchers have demonstrated that the risk of cancer incidence and fatality is reduced with vitamin D supplementation [eg, 103-105]. The mechanism of action of vitamin D in reducing cancer risk has also been addressed in a number of reviews [eg, 106-108].
It has been specified that a reasonable level of 25(OH)D in serum is at least 30 ng/mL (75 nmol/L) [93,109], with a preference for 40-60 ng/mL (100-150 nmol/L) to ensure good health, particularly in the elderly [69,110].
In summary, vitamin D impedes the entry and replication of SARS-CoV-2, reduces the levels of pro-inflammatory cytokines, increases the levels of antiinflammatory cytokines and increases the production of natural antimicrobial peptides [111].

Discussion

COVID-19 and its virus SARS-CoV-2 have provided an ideal opportunity to reset the approach to prevention and treatment of non-communicable diseases, particularly those that occur predominantly in the aged. COVID-19 has been shown to be linked to comorbidities such as senescence occurring in the aged, obesity/diabetes which are more severe in the aged, and cardiovascular diseases and chronic pulmonary diseases which are more prevalent in the aged, as well as cancers. It is therefore opportune to examine carefully the prevention and treatment of COVID-19 and those diseases, with particular attention to those features and characteristics that are common to these diseases. The most outstanding common features are inflammation and overactivity of the innate and adaptive immune systems. Control of inflammation and the immune system are fundamentally dependent on sufficiency of the essential nutrients zinc, q-3 PUFAs, vitamin D and magnesium.
This paper has been directed towards an appreciation of the benefits of having sufficiency of zinc,⑴-3 PUFAs, vitamin D and magnesium. These four components are essential as they are natural to the normal functioning of cells and multiple other components of the human body. They are extremely safe when supplemented in a controlled manner. Control in the aged (eg, 65 years and older) can be maintained by annual analyses of their serum levels. This canbe achieved with government support, as well as by government supplies of supplements where necessary. The cost of this service to those over 65 would be small compared with the potential savings in hospitalization and critical care costs. As an example, a German estimate of the effect of supplementing vitamin D alone on the cost savings of cancer alone in Germany showed a cost saving of approximately €254 million per year with a prevention of almost 30,000 deaths to cancer per year [351].
Zinc,⑴-3 PUFAs, vitamin D and magnesium are pleiotropic as they allow, and in fact boost, the functioning of granulocytes such as mast cells, neutrophils and eosinophils, as well as monocytes/macrophages, dendritic cells, T cells and B cells in normal conditions and when there are minor invasions of pathogens such as minor viral and bacterial infections. In contrast, zinc, q-3 PUFAs, vitamin D and magnesium all act to suppress hyperinflammation and major disruptions of the immune system that occur when there is a significant invasion by viral or bacterial pathogens such as SARS-CoV-2 or non-communicable diseases such as diabetes, cardiovascular disease or chronic pulmonary disease. In these situations, zinc,⑴-3 PUFAs, vitamin D and magnesium have the ability to suppress excessive inflammation and dysregulation of the immune system. These nutrients are therefore essential in all aspects; when present in sufficiency they are directed towards ensuring good health for humans at all times and for all ages. This is not normally the case with non-natural drugs that are prescribed for treatment of particular pathological conditions.
Vaccines are rarely 100% in their prevention of transmission and their prevention of humans contracting the particular disease; there are potential problems with mutations and diminution of their effectiveness. It is of note that vaccines perform their function through the adaptive immune system, whilst zinc,⑴-3 PUFAs, vitamin D and magnesium affect both the innate and adaptive immune systems. Supplementation of the four nutrients in treatment of COVID- 19 is therefore desirable, especially if this supplementation is beneficial in preventing or treating non-communicable diseases or reducing the adverse effects of ageing.

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