key: cord-0774572-xcj2k5e8
authors: Arancibia‐Hernández, Yalith Lyzet; Aranda‐Rivera, Ana Karina; Cruz‐Gregorio, Alfredo; Pedraza‐Chaverri, José
title: Antioxidant/anti‐inflammatory effect of Mg(2+) in coronavirus disease 2019 (COVID‐19)
date: 2022-03-31
journal: Rev Med Virol
DOI: 10.1002/rmv.2348
sha: 59ddb2215f95ba0edb248ee9c48416344be8eb4f
doc_id: 774572
cord_uid: xcj2k5e8

Severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) causes coronavirus disease 2019 (COVID‐19), characterised by high levels of inflammation and oxidative stress (OS). Oxidative stress induces oxidative damage to lipids, proteins, and DNA, causing tissue damage. Both inflammation and OS contribute to multi‐organ failure in severe cases. Magnesium (Mg(2+)) regulates many processes, including antioxidant and anti‐inflammatory responses, as well as the proper functioning of other micronutrients such as vitamin D. In addition, Mg(2+) participates as a second signalling messenger in the activation of T cells. Therefore, Mg(2+) deficiency can cause immunodeficiency, exaggerated acute inflammatory response, decreased antioxidant response, and OS. Supplementation with Mg(2+) has an anti‐inflammatory response by reducing the levels of nuclear factor kappa B (NF‐κB), interleukin (IL) ‐6, and tumor necrosis factor alpha. Furthermore, Mg(2+) supplementation improves mitochondrial function and increases the antioxidant glutathione (GSH) content, reducing OS. Therefore, Mg(2+) supplementation is a potential way to reduce inflammation and OS, strengthening the immune system to manage COVID‐19. This narrative review will address Mg(2+) deficiency associated with a worse disease prognosis, Mg(2+) supplementation as a potent antioxidant and anti‐inflammatory therapy during and after COVID‐19 disease, and suggest that randomised controlled trials are indicated.

SARS-CoV-2 produces coronavirus disease 2019 (COVID- 19) , which has caused more than 4.6 million deaths worldwide. 1 COVID-19 is associated with inflammation and oxidative stress (OS) conditions, inducing respiratory and cardiac complications, such as respiratory insufficiency and arrhythmias. In addition, COVID-19 patients also may submit minor complications like dry cough, fever, fatigue, sore throat, and diarrhoea. [2] [3] [4] Scientific publications have been shown that nutritional status and nutrition habits are relevant in developing different comorbidities associated with higher mortality in In this sense, magnesium (Mg 2+ ) deficiency causes low-grade chronic inflammation and OS. [8] [9] [10] It has led to the hypothesis that Mg 2+ supplementation might improve the severity of COVID-19 disease, 11,12 including a possible intervention of Mg 2+ in SARS-CoV-2 infection by inhibiting the activity of proteases required for protein S cleavage. 12 

The SARS-CoV-2 virus has been identified as a single-stranded RNAenveloped (positive sense), spherical or pleomorphic beta coronavirus of the Coronaviridae family. SARS-CoV-2 infects lung and intestinal epithelial cells via the angiotensin-converting enzyme 2 (ACE2) receptor, causing mild to moderate upper respiratory and gastrointestinal infections ( Figure 1 ). 2, 13, 14 SARS-CoV-2 can also bind to the central nervous system cells by alternative receptor CD147, expressed in high levels in the brain, producing neurological symptoms such as headaches, vision changes, dizziness, ataxia, or impaired consciousness. 15 SARS-CoV-2 virion has an outer surface with 24 to 40 spike glycoproteins (S protein; divided into S1 and S2), which fuse with different human cells such as nasal cavity cells. 16 The latter bidding is performed by the receptor-binding domain (RBD) in the protein S1 subunit, which binds specifically at ACE2 (Figure 1 ). 17 ACE2 is the predominant host cell receptor, and this is the critical protein for SARS-CoV-2 to invade susceptible cells. 14, 18, 19 Moreover, SARS-CoV-2 employs the transmembrane protease serine 2 (TMPRSS2) and the proprotein convertase furin (host cell proteases) to primes the S protein, triggering viral envelope fusion with the host cell membrane. 20, 21 Then, the virus enters basal cells by activating different endocytosis pathways, such as clathrin-dependent endocytosis, or directly releasing the SARS-CoV-2 genome into the cytosol. 22 Both routes allow the viral genome to reach the cytosol, where the SARS-CoV-2 RNA genome unwraps from its viral envelope to translate the viral polyproteins (pp). 17, 22 In the cytosol, the SARS-CoV-2 RNA genome is translated in two large open reading frames (ORF), ORF1a and ORF1b, inducing the expression of the individual non-structural proteins (nsps) and polyprotein 1a (pp1a) and 1b (pp1ab). 17, 23 The nsps comprise the viral replication and transcription complex (RTC) that includes RNAprocessing. The nsps also reorganise the host membranes, where the SARS-CoV-2 RNA will replicate and structural viral proteins will be expressed. 23 Once the viral genome has been amplified, nucleocapsid proteins (N protein) encapsulate it, where membrane proteins (M protein) and envelope proteins (E protein) ensure SARS-CoV-2 incorporation in the viral particle during the assembly process ( Figure 1 ). Finally, virions are secreted from the infected cell by exocytosis to attach to another cell surface. 17, 24 

During SARS-CoV-2 viral life cycle, SARS-CoV-2 is exposed to the innate defence system, developing pronounced inflammation and, in acute cases, severe acute respiratory syndrome (SARS) or multiorgan failure, called in general terms, COVID-19. 25, 26 During COVID-19 and its pronounced inflammation increase the secretion of interleukin (IL) -1β, IL-4, IL-10, interferon-gamma (IFN-γ), interferon-γ-inducible protein 10 (IP-10), and monocyte chemoattractant protein 1 (MCP-1). 27, 28 Furthermore, COVID-19 produces several nuclear factor kappa B (NF-κB)-mediated cytokines, including IL-6 and IL-8 ( Figure 2 ). 29 COVID-19 also induces elevated plasma levels of pro-inflammatory cytokines (tumour necrosis factor-alpha (TNF-α), IL-2, IL-6, and IL-1β). 28, 30 In addition, COVID-19 patients from the intensive care unit (ICU) show elevated levels of IL-7, IL-10, MCP1, granulocyte-colony stimulating factor (GCSF), IP-10, and macrophage inflammatory proteins (MIP-1A). 27 The latter promotes hyper-inflammation, hyperpyrexia, and organ failure. 31 Organ failure results in respiratory failure, acute cardiac complications, respiratory distress syndrome, organ dysfunction, septic shock, and in critical cases, causes death. Therefore, organ failure spreads mortality risk. 32 T cell response in developing protective immunity is essential in regulating inflammation. For example, an adequate T cell response reduces the overactivation of the inflammatory response ( Figure 2 ).

On the other hand, the suppression or deficient T cell activity increases the burden on macrophages and monocytes, exacerbating the inflammatory process, distinctive of COVID-19 ( Figure 2 ). [33] [34] [35] Laboratory results showed decreased T helper lymphocytes (CD3 + , CD4 + ) and suppressor T lymphocytes (CD3 + , CD8 + ). These cells control infections and prevent overactivity of the immune system and uncontrolled virus infection. 30 Following the latter, Zhang et al. 26 reported an impaired immune response related to deficit T cell function in patients infected with SARS-CoV-2. Since there is an impaired T cell function, the inflammatory process exacerbates inflammation with an uncontrolled increase in levels of proinflammatory cytokines and chemokines (cytokine storm), producing multi-organ failure due to tissue damage. Therefore, the cytokine storm is associated with COVID-19 severity. 35 Inflammation also produces reactive oxygen species (ROS), and if these ROS are not attenuated, OS is triggered, inducing oxidative damage to proteins, lipids, and DNA. Regarding lipids, its oxidation results in lipids radicals, such as malondialdehyde (MDA) and 4hydroxynonenal (4-HNE), 36 which are highly reactive, causing DNA damage ( Figure 2 ). The latter induces cell cycle arrest to permit DNA repair and proteostasis; however, if oxidative damage persists, apoptosis cell death is promoted. 37 A study in deceased COVID-19 patients showed elevated 4-HNE levels in the lungs, associated with lethal outcomes, suggesting that deceased COVID-19 patients have a critical failure of the antioxidant response. 38 Furthermore, the MDA levels are increased in ICU and non-intensive care unit (non-ICU) patients, compared with healthy groups. 39, 40 Therefore, these works suggest a close relationship between antioxidant response and COVID-19 severity.

ROS overproduction during SARS-CoV-2 infection has been attributed to NADPH oxidases (NOXs) activation, principally NOX2.

It has been shown that NOX2 is upregulated during COVID-19

infection. 41 Supporting the latter, SARS-CoV-2 S protein together IL-6 activate NOX2, producing high ROS levels in endothelial cells ( Figure 2 ). 42 Moreover, NOX2 is stimulated by angiotensin II (Ang II), which plasma levels are elevated in COVID-19. 43 Indeed, the upregulation of Ang II has been associated with the overstimulation of NOXs and the consequent production of ROS. 44, 45 F I G U R E 1 The viral life cycle of severe acute respiratory syndrome coronavirus type 2 (SARS-COV-2). SAR-COV-2 interacts with angiotensin-converting enzyme 2 (ACE2) receptor and then the transmembrane protease serine 2 (TMPRSS2) and proprotein convertase furin primes S protein for entry into target cells. Two endocytosis mechanisms are known that SARS-CoV-2 uses for entrance to the cell: (a) clathrin-mediated and (b) the releasing direct of its genome into the cytosol. Both mechanisms permit the viral genome to reach the cytosol, and once released, SARS-CoV-2 is translated into two open reading frames (ORF): ORF1a and ORF1b, promoting the expression of nonstructural proteins (nsps) 1-16, and the polyprotein 1a (pp1a) and pp1b. The latter allows the replication of the viral structural proteins: spike (S), envelope (e), the membrane (M), and the nucleocapsid (N). S, E, and M form the viral capsid, and N organises the nucleocapsid. Finally, the virion is packaged and released outer the infected cell. The figure was created with BioRender ARANCIBIA-HERNÁNDEZ ET AL. 

Around 600 enzymes require Mg 2+ as a cofactor, while other 200 enzymes need Mg 2+ as an activator to realise their functions ( Figure 3 ). 46 Thus, Mg 2+ is crucial for energetic metabolism, protein, and amino acid synthesis, and maintenance of the electrical potential in tissues and cell membranes. 47, 48 Mg 2+ also participates in bone mineralisation, muscle relaxation, and neurotransmission ( Figure 3 ). 49 In addition, Mg 2+ regulates lipid composition, stabilising the cellular membrane and reducing its fluidity and permeability. 50, 51 Furthermore, Mg 2+ is also involved in most reactions in which adenosine triphosphate (ATP) functions as a cofactor. For example, ATP-Mg 2+ complexes are required for the activity of glycolytic enzymes such as F I G U R E 2 Inflammation and reactive oxygen species (ROS) overproduction during coronavirus disease 2019 (COVID- 19) infection. The interaction between angiotensin convertase enzyme 2 (ACE2) receptor and severe acute respiratory syndrome coronavirus type 2 (SARS-COV-2) generates ROS through angiotensin II (Ang II) because the latter stimulates NADPH oxidase 2 (NOX2). Moreover, the antioxidant response decreases through SARS-CoV-2 infection by lessening catalase, superoxide dismutase (SOD), and glutathione (GSH). ROS overproduction oxidises lipids in the cell membranes, generating the products of lipid peroxidation malondialdehyde (MDA) and 4hydroxinonenal (4-HNE), which are increased In COVID-19 deceased patients. On the other hand, SARS-CoV-2 activates the nuclear factor kappa B (NF-κB), inducing the secretion of several cytokines and chemokines that include interferon-gamma (IFN-γ), tumoral necrosis factoralpha (TNF-α), interleukin (IL) 6 (IL-6), IL-18, and monocyte chemoattractant protein 1 (MCP-1). The latter and the deficient inactivation of T cells prompt macrophages activation, inducing the production of other cytokines, triggering cytokine storm accompanied by ROS overproduction. The figure was created with BioRender hexokinase, phosphofructokinase, aldolase, phosphoglycerate kinase, and pyruvate kinase ( Figure 3 ). 52 Mg 2+ is required for the structure and activity of DNA and RNA polymerases since it contains 2 Mg 2+ binding sites, essential for conformational changes of the enzymes during catalytic reactions. 53 Vitamin D and vitamin D, enzymes responsible for vitamin D metabolism, require Mg 2+ as a cofactor to bind to vitamin D ( Figure 3 ). Mg 2+ is also necessary for 25-hydroxylation of vitamin D in the liver and 1α-hydroxylation in the kidneys. 54 Mg 2+ participates in different cell signal pathways, functioning as a second messenger. 55, 56 Finally, Mg 2+ alters Ca 2+ flux in the sarcoplasmic reticulum, which modifies the permeability of the protons in the mitochondrial membrane, altering oxidative phosphorylation ( Figure 3 ). 57

As described above, Mg 2+ is involved in essential enzymatic reactions in the cells, including immune response. Mg 2+ has a closer relationship in adaptative immunity, related to cellular signalling and immunomodulatory pathways. 52,56,58 Mg 2+ has been described as a second signalling messenger in T cells, promoting their activation. 56, 59 In individuals with X-linked immunodeficiency with Mg 2+ deficiency, Epstein-Barr virus infection, and neoplasia (XMEN), the magnesium transporter 1 (MagT1) is downregulated in immune T cells. 56 Since MagT1 is essential for T cell receptor (TCR) stimulation and T cell activation, its downregulation is related to immunosuppression in XMEN patients. 60 The reduction of free intracellular Mg 2+ causes defective expression of the natural killer (NK) activator receptor (NKG2D) on CD8 + T and NK cells, decreasing their cytolytic responses ( Figure 4 ). 60 NK and CD8 + T cells' functions are essential for controlling viral infections because these cells induce apoptotic cellinfected death, a regulated programed cell death that does not induce inflammation, and defects in this type of cell death might cause excessive viral load. 61 Since these cells are decreased, the innate immune cells such as macrophages and neutrophils are activated to control the infection, promoting exacerbated immune response by triggering cytokine storm (Figure 4) . 60, 61 In this understanding, strengthening NKs and T cells activation through Mg 2+ supplementation could be associated with a better prognosis of COVID-19. In contrast, Mg 2+ deficiency may promote inflammation due to the deficient activation of cytolytic response in CD8 + T cells and NK cells. 56, 59, 60 Different preclinic studies have also demonstrated that Mg 2+ deficiency leads to exaggerated acute inflammatory response, such as increased circulating pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), leucocytosis, increased plasma levels of complement component C3, and the marked elevation of circulating substance P, especially after NF-κB is involved in the transcription of inflammatory genes such as cytokines (IL-1β and TNF-α). 61 showing that most of the patients are located in serious to severe cases. 72 These studies reveal that hypomagnesaemia is more frequent in patients with COVID-19, possibly associated with the severity of the disease. In this way, the severity of the COVID-19 disease might be strongly related to the pro-inflammatory state in Mg 2+ deficiency patients.

Sugimoto et al. 73 reported that Mg 2+ therapy during inflammatory states decreases NF-κB, IL-6, and TNF-α. A similar beneficial effect is observed in the inflammatory marker C reactive protein (CRP), which levels are decreased. 74 Moreover, optimal Mg 2+ status enhances vitamin D functionality that regulates inflammation by promoting an anti-inflammatory effect. 75, 76 Although the molecular mechanism of the relationship between Mg 2+ and inflammation is poorly described, even more in COVID-19, it is clear that during Mg 2 + supplementation decreases inflammation markers.

Mg 2+ could also indirectly be involved in the immune response by modulating the gut microbiome. For instance, it has been reported that diets containing Mg 2+ can change microbiome composition. [77] [78] [79] [80] [81] [82] [83] In contrast, Mg 2+ deficiency can lead to dysbiosis. 77, 79 Dysbiosis refers to quantitative or qualitative changes in the composition of the normal microbiota that causes a microbial imbalance, playing an essential role in susceptibility to infectious diseases. 84 Many studies have associated altered gut microbiome with the severity of COVID-19, producing dysbiosis 84-89 while restoring Mg 2+ levels could benefit the diversity and health of the gut microbiome. Moreover, the use of F I G U R E 4 Magnesium (Mg 2+ ), immune system, and oxidative stress (OS). (a) Mg 2+ deficiency related to the immune system produces the (1) low expression of the natural killer (NK) activator receptor (NKG2D) on the T CD8 + cells, promoting a mild or no anti-inflammatory response to viruses. Consequently, a cytokine storm is triggered. (2) Moreover, circulating inflammatory cells augment, inducing the production of interleukin (IL) 6 (IL-6), IL-1β, tumoral factor-alpha (TNF-α), and complement system C3. (3) Mg 2+ deficiency induces lipid peroxidation, which activates nuclear factor kappa B (NF-κB). Mg 2+ also induces oxidative stress by promoting (1) electron transfer system (ETS) interruption, generating reactive oxygen species (ROS) production. Furthermore, (2) the production of antioxidant enzymes is deficient, and (3) glutathione (GSH) is depleted because of anormal Mg 2+ levels. (4) Mg 2+ deficiency is also associated with metabolic syndrome and lowgrade chronic inflammation, such as obesity, diabetes, and cardiovascular diseases probiotics and prebiotics for preventing and treating COVID-19 could modulate the gut microbiome. 84, 88, 89 preeclampsia, significantly promoting GSH production and thus suppressing ROS production. 120 As described in this section, Mg 2+ deficiency represents a risk factor for maintaining an optimal oxidation-reduction state, leading to OS development. Thus, chronic

Mg 2+ deficiency has severe oxidative implications such as lipid peroxidation, causing general cellular dysfunction and even cell apoptosis associated with inflammation and OS. 94, 121 Mg 2+ deficiency is frequently associated with is a strong relationship between OS and metabolic syndrome, associated with lowgrade chronic inflammation, such as obesity, diabetes, and cardiovascular diseases (Figure 4) . 8, 58 For instance, the increase in lipid peroxidation and OS was observed in a study of obese women with Mg 2+ deficient diets, which presented low Mg 2+ concentration in erythrocytes. 122 Because Mg 2+ has multiple functions in the body, its deficiency has been related to chronic inflammatory and OS, which can compromise the immune response, inducing individuals more prone to infection such as SARS-CoV2. Thus, nutritional supplementation may strengthen the immune system to manage COVID-19.

In addition to inflammatory and OS conditions, low Mg 2+ consumption is associated with a higher incidence of diabetes and cardiovascular diseases. 96 Kopf et al. 134 reported that the correct daily intake of fruit, vegetables, and whole grains significantly decreased levels in some inflammatory markers such as the lipopolysaccharide-binding protein, TNF-α, and, IL-6. Therefore, the latter suggestion points out that Therefore, Mg 2+ may be a potential therapy in cases of COVID-19 respiratory failure due to exacerbated inflammation, preventing their development at severe.

Another aspect that may be related to respiratory failure is diaphragm dysfunction, implying a partial or complete diaphragm function loss. 147, 148 McCool and Tzelepis 149 mentioned that 'Diaphragmatic dysfunction is an underdiagnosed cause of dyspnoea.' In this sense, a possible cause of respiratory failure in COVID-19 may be diaphragm dysfunction; however, this area has been poorly explored. Interestingly, it has been reported that prolonged mechanical ventilation causes diaphragm dysfunction. 150 

During COVID-19 infection, fibrinogen and circulating D-dimer levels are elevated, inducing hypercoagulation. 159 Coagulation is a consequence of innate and adaptative immunity activation. It has been shown that inflammation-induced coagulation is featured by tissue factor (TF) activation and upregulation of coagulant pathways, promoting thrombin production. 160 COVID-19 patients. 13, 61, 165, 166 NF-κB is the common link between inflammatory and thrombotic processes by increasing cytokines (TNF-α, IL-6 and MCP-1), which activates the expression of TF, the main trigger of the coagulation cascade. 61, 71, 167 It has been shown that Mg 2+ deficiency is associated with hypercoagulability and is partly mediated by excessive inflammation related to high levels of NF-κB. 168 Interestingly, Mg 2+ supplementation reduces NF-κB expression and its activation, 73 results in a rapid increase in active PAF, inducing the NF-κB activation. 174, 175 The above indicates a strong association between the Mg 2+ deficiency and coagulopathies, where Mg 2+ supplementation may be a potential therapy in coagulopathies associated with COVID-19.

Lasting effects of illness have been reported post-COVID-19, scientific community named as 'Long-COVID' to refer to the post-COVID conditions or sequels. In a study, Kamal et al. 176 

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Assessment and characterisation of post-COVID-19 manifestations

Long-COVID': a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19

For the gemelli against COVID-19 post-acute care study group. Persistent symptoms in patients after acute COVID-19

Prevalence of potential respiratory symptoms in survivors of hospital admission after coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis

Characteristics and predictors of acute and chronic post-COVID syndrome: a systematic review and meta-analysis. EClinicalMedicine

Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a crosssectional evaluation

Could mitochondrial dysfunction Be a differentiating marker between chronic fatigue syndrome and fibromyalgia?

Chronic fatigue syndrome and mitochondrial dysfunction

Diaphragm dysfunction in severe COVID-19 as determined by neuromuscular ultrasound

Postmortem findings associated with SARS-CoV-2: systematic review and meta-analysis

Antioxidant/ anti-inflammatory effect of Mg 2+ in coronavirus disease 2019 (COVID-19)

We gratefully acknowledge to the Postdoctoral Grant's Programme from the Consejo Nacional de Ciencia y Tecnología (CONACyT) for