The study findings were published in the peer reviewed journal: Food Science & Nutrition.
https://onlinelibrary.wiley.com/doi/10.1002/fsn3.3034
DISCUSSION
Summary of key findings
In this systematic review of primary human studies, we investigated the role of vitamins A, C, D, and E, selenium, zinc, and α-lipoic acid in major clinical outcomes of people with COVID-19. Among the aforementioned seven antioxidants, eligible studies were found only for vitamins C and D, selenium, and zinc. The findings suggest that vitamin C may cause beneficial effects on inflammation status, Horowitz index, and mortality rate of COVID-19 patients. Moreover, vitamin D may have a positive role in the reduction of disease manifestations and severity, inflammatory biomarkers, lung involvement, ventilation requirement, hospitalization, ICU admission, and mortality in individuals with COVID-19. Also, selenium may have the potential to increase and decrease the cure rate and mortality of COVID-19 patients, respectively. Furthermore, zinc may be able to lower hospitalization, ventilation requirement, ICU admission, biomarkers of inflammation and bacterial infection, and disease complications in individuals infected with COVID-19.
Mechanisms of actions
Vitamin A
Although none of the included studies examined the role of vitamin A in subjects with COVID-19, bioinformatics findings proposed that this antioxidant may be beneficial for individuals infected with SARS-CoV-2 (Li et al., 2020). Vitamin A has an important role in enhancing the body’s immunity and regulating both cellular and humoral immune responses (Jayawardena et al., 2020). The production of antibodies, also known as immunoglobulins (Ig), is integral to the maintenance of humoral immune responses (Huang et al., 2018). An animal study showed that vitamin A can promote humoral immunity by increasing serum levels of IgG, IgM, and IgA (Ghodratizadeh et al., 2014). Vitamin A also plays a pivotal role in the development of epithelium, which is considered a frontline defense against pathogen invasion (McCullough et al., 1999). As vitamin A enhances mucin secretion in the respiratory tract and intestine, it is able to improve the antigen nonspecific immunity function of these tissues (Huang et al., 2018). Moreover, vitamin A may inhibit inflammatory processes induced by COVID-19 through the regulation of multiple key genes including mitogen-activated protein kinase 1 and 14, interleukin-10, epidermal growth factor receptor, protein kinase C beta type, intercellular adhesion molecule 1, and catalase (Li et al., 2020).
Vitamin C
The results of this systematic review indicated that vitamin C may exert favorable effects on clinical outcomes of COVID-19 patients. Vitamin C acts as a powerful antioxidant, especially for epithelial cells of the lungs (Farjana et al., 2020). It appears to scavenge reactive oxygen species (ROS) and inhibit pathways involved in neutrophil extracellular trap formation and cytokine storms (Cerullo et al., 2020). Moreover, vitamin C can suppress lactate production. This can be of great importance because serum and tissue concentrations of lactate are elevated in critically ill patients with COVID-19 (Earar et al., 2020). Lactate weakens the host immune system by decreasing the production of type I interferon and limiting viral clearance (Lottes et al., 2015; Zhang et al., 2019).
Vitamin D
The findings of this systematic review showed that vitamin D may play a positive role in improvement of COVID-19 clinical outcomes. It seems that antioxidative, antiinflammatory, and immunomodulatory properties of vitamin D can be involved in this regard (Hajhashemy et al., 2022; Musavi et al., 2020). Besides, some researchers discussed the key role of vitamin D in the RAS (Kumar et al., 2020; Malek Mahdavi, 2020; Musavi et al., 2020). As noted in the introduction, SARS-CoV-2 binds to ACE2, which is expressed on the surface of alveolar epithelial cells (Silvagno et al., 2020). Once the virus is attached, the activity of ACE2 is suppressed, which further enhances the activity of ACE1, that accordingly increases the formation of angiotensin II, leading to intensified pulmonary vasoconstriction and severe COVID-19 reactions (Malek Mahdavi, 2020). In an animal study, the expression of ACE2 in the lungs was significantly elevated by calcitriol, the bioactive form of vitamin D (Xu et al., 2017). Therefore, as a result of vitamin D supplementation, ACE2 may be expressed more, which can decrease lung injury (Imai et al., 2005). Moreover, vitamin D may reduce the production of angiotensin II and result in less pulmonary vasoconstriction through suppressing renin activity (Kumar et al., 2020).
Vitamin E
Although none of the included studies investigated the role of vitamin E in individuals with COVID-19, bioinformatics findings suggested that this micronutrient may be beneficial for patients infected with SARS-CoV-2 (Kim et al., 2020). Vitamin E is a lipid-soluble antioxidant with the ability to protect cells from damage caused by ROS, especially in respiratory infections (Lewis et al., 2019). Moreover, vitamin E is involved in various aspects of the immune response, including but not limited to the production of antibodies, phagocytosis, and T cell function (Akhtar et al., 2021). This vitamin modulates T cell function through affecting T cell membrane integrity, cell division, signal transduction, and several inflammatory mediators such as prostaglandin E2 and proinflammatory cytokines (Lewis et al., 2019). Furthermore, it seems that vitamin E can induce signals of gene expression that counteract signals associated with COVID-19 (Kim et al., 2020).
Selenium
The results of this systematic review revealed that selenium may have a promising role in amelioration of COVID-19 clinical outcomes. As mentioned earlier, COVID-19 increases the production of ROS in host cells, which can cause oxidative stress if not counteracted by the antioxidant defense system (Chernyak et al., 2020). Glutathione peroxidase-1 (GPx1), a cytosolic selenoenzyme with antiviral properties, is considered as a crucial antioxidant defense against ROS (Sajjadi et al., 2022). This selenoprotein catalyzes the detoxification of hydrogen peroxide to water molecules and is particularly involved in protection against viral respiratory infections (Guillin et al., 2019). There is evidence of an interaction between GPx1 and the main protease of SARS-CoV-2, 3-chymotrypsin-like protease, which is essential for viral replication. This interaction depends on host selenium status to combat SARS-CoV-2 virulence (Seale et al., 2020). Accordingly, selenium may improve clinical outcomes of patients with COVID-19.
Zinc
The findings of this systematic review manifested that zinc may have desirable effects on clinical outcomes of COVID-19 patients. Multiple protective mechanisms of zinc against COVID-19 infection have been proposed in the literature. It seems that SARS-CoV-2 can weaken mucociliary clearance and expose the lungs to further viral and bacterial infections (Koparal et al., 2021). In turn, zinc may enhance mucociliary clearance by improving cilia morphology and increasing cilia beat frequency (Darma et al., 2020). This mineral can also improve the integrity and barrier function of the respiratory epithelium by increasing its antioxidant activity and upregulating its tight junction proteins such as claudin-1 and zonula occludens-1 (Skalny et al., 2020). In addition, zinc may exert antiviral effects through interference with viral replication cycles (Read et al., 2019). Moreover, zinc can be beneficial for bacterial coinfection in viral pneumonia, because it may inhibit the growth of Streptococcus pneumoniae by modulating bacterial manganese homeostasis (Eijkelkamp et al., 2019). Furthermore, zinc can downregulate the production of proinflammatory cytokines through the inhibition of IκB kinase activity and nuclear factor-κB (NF-κB) signaling (Skalny et al., 2020).
Α-lipoic acid
Although none of the included studies evaluated the role of α-lipoic acid in patients with COVID-19, some researchers hypothesized that this potent antioxidant may be advantageous for subjects infected with SARS-CoV-2 (Sayıner & Serakıncı, 2021). Α-lipoic acid is able to reduce oxidative stress through the regeneration of other antioxidants and chelation of metal ions. In addition, this quasi-vitamin can inhibit the activation of NF-κB, an inflammatory transcription factor (Tibullo et al., 2017). Furthermore, α-lipoic acid may decrease the activity of a disintegrin and metalloprotease 17 (ADAM17), also known as tumor necrosis factor-α-converting enzyme (Cure & Cure, 2020). The lower activity of ADAM17 can reduce the shedding of ACE2 and severity of COVID-19 infection (Peron & Nakaya, 2020). Moreover, α-lipoic acid may increase intracellular pH by activating Na+/K+-ATPase (Cure & Cure, 2020). It seems that higher intracellular pH can inhibit SARS-CoV-2 cellular entry (Petersen et al., 2020). Also, α-lipoic acid has a potential to activate pyruvate dehydrogenase and reduce serum lactate levels (Konrad et al., 1999).
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