Links between Vitamin K, Ferroptosis and SARS-CoV-2 Infection.

Ferroptosis is a recently discovered form of programmed cell death. It is characterized by the accumulation of iron and lipid hydroperoxides in cells. Vitamin K is known to have antioxidant properties and plays a role in reducing oxidative stress, particularly in lipid cell membranes. Vitamin K reduces the level of reactive oxygen species by modulating the expression of antioxidant enzymes. Additionally, vitamin K decreases inflammation and potentially prevents ferroptosis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to coronavirus disease 2019 (COVID-19) is associated with oxidant-antioxidant imbalance. Studies have shown that intensified ferroptosis occurs in various tissues and cells affected by COVID-19. Vitamin K supplementation during SARS-CoV-2 infection may have a positive effect on reducing the severity of the disease. Preliminary research suggests that vitamin K may reduce lipid peroxidation and inhibit ferroptosis, potentially contributing to its therapeutic effects in COVID-19 patients. The links between ferroptosis, vitamin K, and SARS-CoV-2 infection require further investigation, particularly in the context of developing potential treatment strategies for COVID-19.

SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeostasis (Fe-R-H): Role of Fe-Redox Regulators, Ferroptosis Inhibitors, Anticoagulants, and Iron-Chelators in COVID-19 Control.

Severe imbalance in iron metabolism among SARS-CoV-2 infected patients is prominent in every symptomatic (mild, moderate to severe) clinical phase of COVID-19. Phase-I - Hypoxia correlates with reduced O2 transport by erythrocytes, overexpression of HIF-1α, altered mitochondrial bioenergetics with host metabolic reprogramming (HMR). Phase-II - Hyperferritinemia results from an increased iron overload, which triggers a fulminant proinflammatory response - the acute cytokine release syndrome (CRS). Elevated cytokine levels (i.e. IL6, TNFα and CRP) strongly correlates with altered ferritin/TF ratios in COVID-19 patients. Phase-III - Thromboembolism is consequential to erythrocyte dysfunction with heme release, increased prothrombin time and elevated D-dimers, cumulatively linked to severe coagulopathies with life-threatening outcomes such as ARDS, and multi-organ failure. Taken together, Fe-R-H dysregulation is implicated in every symptomatic phase of COVID-19. Fe-R-H regulators such as lactoferrin (LF), hemoxygenase-1 (HO-1), erythropoietin (EPO) and hepcidin modulators are innate bio-replenishments that sequester iron, neutralize iron-mediated free radicals, reduce oxidative stress, and improve host defense by optimizing iron metabolism. Due to its pivotal role in 'cytokine storm', ferroptosis is a potential intervention target. Ferroptosis inhibitors such as ferrostatin-1, liproxstatin-1, quercetin, and melatonin could prevent mitochondrial lipid peroxidation, up-regulate antioxidant/GSH levels and abrogate iron overload-induced apoptosis through activation of Nrf2 and HO-1 signaling pathways. Iron chelators such as heparin, deferoxamine, caffeic acid, curcumin, α-lipoic acid, and phytic acid could protect against ferroptosis and restore mitochondrial function, iron-redox potential, and rebalance Fe-R-H status. Therefore, Fe-R-H restoration is a host biomarker-driven potential combat strategy for an effective clinical and post-recovery management of COVID-19.

Redox Status Is the Mainstay of SARS-CoV-2 and Host for Producing Therapeutic Opportunities.

Over hundreds of years, humans have faced multiple pandemics and have overcome many of them with scientific advancements. However, the recent coronavirus disease (COVID-19) has challenged the physical, mental, and socioeconomic aspects of human life, which has introduced a general sense of uncertainty among everyone. Although several risk profiles, such as the severity of the disease, infection rate, and treatment strategy, have been investigated, new variants from different parts of the world put humans at risk and require multiple strategies simultaneously to control the spread. Understanding the entire system with respect to the commonly involved or essential mechanisms may be an effective strategy for successful treatment, particularly for COVID-19. Any treatment for COVID-19 may alter the redox profile, which can be an effective complementary method for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and further replication. Indeed, redox profiles are one of the main barriers that suddenly shift the immune response in favor of COVID-19. Fortunately, several redox components exhibit antiviral and anti-inflammatory activities. However, access to these components as support elements against COVID-19 is limited. Therefore, understanding redox-derived species and their nodes as a common interactome in the system will facilitate the treatment of COVID-19. This review discusses the redox-based perspectives of the entire system during COVID-19 infection, including how redox-based molecules impact the accessibility of SARS-CoV-2 to the host and further replication. Additionally, to demonstrate its feasibility as a viable approach, we discuss the current challenges in redox-based treatment options for COVID-19.

The Possible Role of Glucose-6-Phosphate Dehydrogenase in the SARS-CoV-2 Infection.

Glucose-6-phosphate dehydrogenase (G6PD) is the second rate-limiting enzyme of the pentose phosphate pathway. This enzyme is present in the cytoplasm of all mammalian cells, and its activity is essential for an adequate functioning of the antioxidant system and for the response of innate immunity. It is responsible for the production of nicotinamide adenine dinucleotide phosphate (NADPH), the first redox equivalent, in the pentose phosphate pathway. Viral infections such as SARS-CoV-2 may induce the Warburg effect with an increase in anaerobic glycolysis and production of lactate. This condition ensures the success of viral replication and production of the virion. Therefore, the activity of G6PD may be increased in COVID-19 patients raising the level of the NADPH, which is needed for the enzymatic and non-enzymatic antioxidant systems that counteract the oxidative stress caused by the cytokine storm. G6PD deficiency affects approximately 350-400 million people worldwide; therefore, it is one of the most prevalent diseases related to enzymatic deficiency worldwide. In G6PD-deficient patients exposed to SARS-CoV-2, the amount of NADPH is reduced, increasing the susceptibility for viral infection. There is loss of the redox homeostasis in them, resulting in severe pneumonia and fatal outcomes.

Understanding Cellular Redox Homeostasis: A Challenge for Precision Medicine.

Living organisms use a large repertoire of anabolic and catabolic reactions to maintain their physiological body functions, many of which include oxidation and reduction of substrates. The scientific field of redox biology tries to understand how redox homeostasis is regulated and maintained and which mechanisms are derailed in diverse pathological developments of diseases, where oxidative or reductive stress is an issue. The term "oxidative stress" is defined as an imbalance between the generation of oxidants and the local antioxidative defense. Key mediators of oxidative stress are reactive species derived from oxygen, nitrogen, and sulfur that are signal factors at physiological concentrations but can damage cellular macromolecules when they accumulate. However, therapeutical targeting of oxidative stress in disease has proven more difficult than previously expected. Major reasons for this are the very delicate cellular redox systems that differ in the subcellular compartments with regard to their concentrations and depending on the physiological or pathological status of cells and organelles (i.e., circadian rhythm, cell cycle, metabolic need, disease stadium). As reactive species are used as signaling molecules, non-targeted broad-spectrum antioxidants in many cases will fail their therapeutic aim. Precision medicine is called to remedy the situation.

Profiling Distinctive Inflammatory and Redox Responses to Hydrogen Sulfide in Stretched and Stimulated Lung Cells.

Hydrogen sulfide (H2S) protects against stretch-induced lung injury. However, the impact of H2S on individual cells or their crosstalk upon stretch remains unclear. Therefore, we addressed this issue in vitro using relevant lung cells. We have explored (i) the anti-inflammatory properties of H2S on epithelial (A549 and BEAS-2B), macrophage (RAW264.7) and endothelial (HUVEC) cells subjected to cycling mechanical stretch; (ii) the intercellular transduction of inflammation by co-culturing epithelial cells and macrophages (A549 and RAW264.7); (iii) the effect of H2S on neutrophils (Hoxb8) in transmigration (co-culture setup with HUVECs) and chemotaxis experiments. In stretched epithelial cells (A549, BEAS-2B), the release of interleukin-8 was not prevented by H2S treatment. However, H2S reduced macrophage inflammatory protein-2 (MIP-2) release from unstretched macrophages (RAW264.7) co-cultured with stretched epithelial cells. In stretched macrophages, H2S prevented MIP-2 release by limiting nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide radicals (ROS). In endothelial cells (HUVEC), H2S inhibited interleukin-8 release and preserved endothelial integrity. In neutrophils (Hoxb8), H2S limited MIP-2-induced transmigration through endothelial monolayers, ROS formation and their chemotactic movement. H2S induces anti-inflammatory effects in a cell-type specific manner. H2S limits stretch- and/or paracrine-induced inflammatory response in endothelial, macrophage, and neutrophil cells by maintaining redox homeostasis as underlying mechanism.

Host metabolic reprogramming in response to SARS-CoV-2 infection: A systems biology approach.

Understanding the pathogenesis of SARS-CoV-2 is essential for developing effective treatment strategies. Viruses hijack the host metabolism to redirect the resources for their replication and survival. The influence of SARS-CoV-2 on host metabolism is yet to be fully understood. In this study, we analyzed the transcriptomic data obtained from different human respiratory cell lines and patient samples (nasopharyngeal swab, peripheral blood mononuclear cells, lung biopsy, bronchoalveolar lavage fluid) to understand metabolic alterations in response to SARS-CoV-2 infection. We explored the expression pattern of metabolic genes in the comprehensive genome-scale network model of human metabolism, Recon3D, to extract key metabolic genes, pathways, and reporter metabolites under each SARS-CoV-2-infected condition. A SARS-CoV-2 core metabolic interactome was constructed for network-based drug repurposing. Our analysis revealed the host-dependent dysregulation of glycolysis, mitochondrial metabolism, amino acid metabolism, nucleotide metabolism, glutathione metabolism, polyamine synthesis, and lipid metabolism. We observed different pro- and antiviral metabolic changes and generated hypotheses on how the host metabolism can be targeted for reducing viral titers and immunomodulation. These findings warrant further exploration with more samples and in vitro studies to test predictions.