Boosting GSH could be effective therapy against COVID-19

Glutathione (GSH) tripeptide (γ-L-glutamyl-L-cysteinyl-glycine) is the most abundant water-soluble non-protein thiol (1-10 mM) in cells, and GSH depletion may occur in Inflammatory disease and COVID-19 pathophysiology, host immune response, and disease severity and mortality.

GSH-boosting therapies could be the cornerstone of reducing the severity and lethal consequences of inflammatory diseases and COVID-19, and boosting GSH levels could prevent and suppress these diseases. The vital value of GSH makes it one of the most important areas of research in biology and medicine and may hold the key to combating systemic inflammation and SARS-CoV-2 infection and COVID-19 disease.

GSH is a unique life-essential molecule involved in key aspects of cellular homeostasis and plays a vital role in defense against oxidative damage that occurs during all different diseases, including coronavirus disease 19 (COVID-19).

GSH is a water-soluble tripeptide formed from the amino acids glutamic acid, cysteine, and glycine (Figure 1) and is present in the cytoplasm of all cells. Reduced glutathione accounts for more than 98% of the total GSH. The redox state of reduced glutathione and oxidized glutathione can be used as an important indicator of the redox environment, and changes are related to multiple cellular processes. Including cell differentiation, cell proliferation and apoptosis.

The reduced ratio of reduced glutathione to oxidized glutathione suggests that GSH deficiency manifests primarily through increased susceptibility to oxidative stress, and the resulting damage is thought to be related to SARS-CoV-2, which causes COVID-19 disease infection related. In addition, imbalances in GSH levels affect immune system function and are thought to play a role in the aging process and diseases of aging, one of the major risk factors for the development and progression of COVID-19 disease.

GSH is involved in many key processes that harness the reducing potential of thiols. According to research, several lung diseases are characterized by increased alveolar oxidant load, which may deplete the alveoli and lungs of GSH. Low glutathione is associated with abnormalities in the pulmonary surfactant system and the interaction between glutathione and antiproteases in the epithelial lining fluid of patients. Normal levels of intracellular GSH may act as a key negative control on the production of pro-inflammatory cytokines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly targets the respiratory and cardiovascular systems, and COVID-19 is mainly infected by the respiratory tract.

Many patients experience severe fatal outcomes due to overwhelming inflammation known as a "cytokine storm", which leads to ROS-mediated cell death and tissue damage typical of RNA viruses. This intense inflammation is associated with devastating systemic events such as oxidative stress, dysregulation of iron homeostasis, hypercoagulability and thrombosis, acute respiratory distress syndrome, uncontrolled inflammation, and organ failure (below).

The progression of several viral infections and virus-induced diseases, especially those associated with COVID-19, is characterized by alterations in the intracellular redox balance, an imbalance that does not allow the detoxification of reactive intermediates by cellular biological systems. ROS production and associated inflammation are strongly associated with aging and many chronic diseases, such as diabetes, cardiovascular atherosclerosis-related diseases, and respiratory diseases, which are the risk factors for severe illness and death in patients with SARS-CoV-2 and COVID-19. Known risk factor diseases.

Chronic inflammatory diseases, especially those affecting the lower respiratory system (chronic obstructive pulmonary disease, lower respiratory infection, cystic fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome), diseases affecting the cardiovascular system (arterial atherosclerosis, ischemic heart disease, stroke, etc.), many other systemic inflammatory diseases such as diabetes, COVID-19, are characterized by persistent inflammation, continuous production of reactive oxygen species/nitrogen and oxidative stress, which Antioxidant defenses (glutathione and free radical scavenging enzymes) are exceeded, leading to organ aging.

Inflammation is associated with excessive production of cellular ROS, leading to oxidation/damage of cellular components, enhanced inflammation, and activation of cell death pathways; oxidative stress and decreased antioxidant defenses contribute to the progression of nearly all diseases, and in most diseases ROS appear to be associated with inflammation and Cellular senescence is directly linked, with oxidative stress and inflammation increasing aging-associated phenotypes and inducing and exacerbating inflammatory responses, resulting in a chronic systemic inflammatory state.

As mentioned above, inflammation may also be involved in the aging process in young individuals. All chronic diseases, including COVID-19 and long-term COVID-19 syndrome, are characterized by the presence of persistent chronic inflammation and the continuous production of reactive oxygen and nitrogen, which can lead to excessive oxidative stress. The need for detailed analysis of the pathogenesis and clinical course of chronic and viral diseases, such as COVID-19, and the need to use effective therapies with minimal or no side effects is of paramount importance.

Researchers are targeting the antioxidant GSH as an intervention to counteract inflammation, premature inflammation, inflammatory disease, and long-term COVID-19 syndrome, as GSH levels correlate with tissue and organ damage, disease severity, and progression.

Enhancement of GSH, mainly administered by NAC, cysteine-rich GSH precursors (whey protein, cysteine-rich whey protein isolate) or GSH compounds, becomes effective by reducing oxidative stress and cytokine expression Potential treatment options for inflammatory diseases, especially in patients with diabetes who are also at risk for more severe COVID-19 disease. GSH dysregulation may lead to decreased autophagy in overall immune cells and increased production of pro-inflammatory cytokines during aging, further induced by mitochondrial ROS signaling.

GSH supplementation improves GSH deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, cognition and surfactant regeneration.

Enhancing the reduced form of GSH will reduce the body's oxidation and inflammation associated with chronic inflammatory disease, SARS-CoV-2 infection, and COVID-19 disease, and maintaining GSH levels with therapies that do not deplete the body's GSH will be the best option.

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