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Reset of Oxidative Stress (OxS)

Serum levels of SOD, CAT, GSH, and GPx are significantly altered in viral-induced HMR/D. Reduced total antioxidant capacity (in blood) of SARS-CoV-2 infected individuals serves as a predictive marker for COVID-19 severity. Both OxS and hyper-inflammatory state during the acute phase of COVID-19, could also predict severity of chronic fatigue, depression, and anxiety symptoms even after 3 to 4 months in the virus-free PASC patients. Based on cluster analysis, a majority of PASC patients show severe abnormalities in SpO₂ , increased OxS and reduced antioxidant indices. Severe OxS with elevated blood levels of high sensitivity-C-reactive protein (hs-CRP) is a hallmark of hyper-inflammatory state in COVID-19 and PASC; therefore, antioxidant enzymes could be considered an effective nutritional strategy to resolve OxS and reset viral-induced HMR/D.

Superoxide dismutase(s): Superoxide dismutases (SODs) are metallo-enzymes that trigger endogenous antioxidant machinery, the first-line defense against cytotoxic ROS in the body. SOD catalyzes the conversion of superoxide (O₂˙⁻) into O₂ and H₂O₂ . The H₂O₂  is further hydrolyzed to water via CAT and GPX enzymes. Three isoforms of SOD exist in human body: the cytosolic Cu-, Zn-SOD (SOD1), the mitochondrial Mn-SOD (SOD2) and the extracellular Cu-, Zn-SOD (SOD3). OxS plays a critical role in COVID-19 and PASC; therefore, the therapeutic use of SOD and SOD-mimetics may prove beneficial in metabolic reset of viral-induced HMR/D.

Catalase: Catalase (CAT), a heme enzyme that catalyzes the decomposition of H₂O₂ to water + molecular O₂, provides a vital cellular antioxidant defense. Excessive production of H₂O₂ in mitochondria could damage lipids, proteins, mDNA, resulting in necrosis or apoptosis; where then CAT could protect such cells from H₂O₂-induced oxidative injury and help regulate the cellular redox-oxidative status. CAT-mediated decomposition of H₂O₂ to water minimizes the downstream flow of excessive ROS, which otherwise could trigger OxS and m-Dys during viral-induced HMR/D. CAT plays a crucial intermediary role in viral spike (S)-protein binding to hACE2 receptors, thereby affects the host susceptibility to SARS-CoV-2 infection. CAT could also regulate cytokine production in leukocytes, protect alveolar cells from oxidative injury, and block SARS-CoV-2 replication.

Glutathione: Glutathione (GSH) (γ-L-glutamyl-L-cysteinyl-glycine) is a tripeptide synthesized in the cytosol by two ATP-consuming enzymatic reactions. GSH reaches millimolar levels (1–10 mM) within cells, micromolar levels (10–30 μM) in plasma, and its low redox potential (E'₀ = −240 mV) makes GSH an ideal cellular redox buffer. GSH is commonly found in reduced GSSG form in cytosol, nucleus, mitochondria, and endoplasmic reticulum. The GSSG/GSH redox couple interacts with other antioxidant enzymes to maintain mitochondrial function and cellular redox homeostasis. GSH plays the role of ‘master antioxidant’ in tissues; where the high millimolar levels of GSSG in reduced form emphasizes its regulatory role in processes such as detoxification, protein folding, antiviral defense and immune response. Mitochondria are the main source of ROS, generated from the ETC/OXPHOS and any excess release of toxic free radicals could trigger OxS and m-Dys. GSH is the main cellular antioxidant to reduce H₂O₂ and lipid hydroperoxides (LOOH) catalyzed by GPXs.

The SARS-CoV-2-induced FeRD, its ensuing OxS could deplete cellular antioxidant reserves and increase severity of viral-induced HMR/D. Decreased expression of GSH synthesis leads to low free GSH levels, resulting in elevated ROS, immune dysfunction, and increased disease severity. Furthermore, comorbidities such as hypertension (56.6%), obesity (41.7%), and diabetes (33.8%) are frequently linked to OxS and chronic inflammation in hospitalized COVID-19 patients. In obese patients, OxS is associated with diminished GSH levels and decreased GSH/GSSG ratio. Low GSH levels could also increase viral replication, pro-inflammatory cytokine release, endothelial damage, and immune-thrombosis, which is a hyper-coagulative clinical condition that could exacerbate morbidity and mortality in viral-induced HMR/D. Since m-Dys and OxS jointly contribute to patho-physiology, nutritional to replenish optimal GSH levels could be a promising strategy to reset viral-induced HMR/D and support patient recovery.

N-Acetyl-L-Cysteine: N-Acetyl-L-Cysteine (NAC) is a sulfur-containing amino acid that breaks disulfide bonds, increases viscosity of mucoproteins and serves as an antioxidant in pulmonary mucous secretions of the respiratory tract. NAC is widely used as a mucolytic agent to improve airway clearance in chronic respiratory diseases. As a precursor for GSH synthesis, adjuvant therapy with NAC could resolve viral-induced OxS via GSH release and help restore cellular redox homeostasis in HMR/D. NAC, as a precursor for reduced GSH, demonstrates antioxidant, anti-inflammatory and immunomodulatory effects, which may prove beneficial in modulating any excess inflammatory activation during COVID-19. Therefore, nutritional supplementation with NAC could effectively resolve OxS and target pathophysiological pathways and persistent pulmonary fibrotic sequelae in viral-induced HMR/D.

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