Contribution of vitamin D3 and thiols status to the outcome of COVID-19 disease in Italian pediatric and adult patients.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), was declared a global pandemic by the World Health Organization (WHO) on March 2020, causing unprecedented disease with million deaths across the globe, mostly adults. Indeed, children accounted for only a few percent of cases. Italy was the first Western country struck by the COVID-19 epidemic. Increasing age, which is one of the principal risk factors for COVID-19 mortality, is associated with declined glutathione (GSH) levels. Over the last decade, several studies demonstrated that both vitamin D (VD) and GSH have immunomodulatory properties. To verify the association between VD, GSH and the outcome of COVID-19 disease, we conducted a multicenter retrospective study in 35 children and 128 adult patients with COVID-19. Our study demonstrated a hypovitaminosis D in COVID-19 patients, suggesting a possible role of low VD status in increasing the risk of COVID-19 infection and subsequent hospitalization. In addition, we find a thiol disturbance with a GSH depletion associated to the disease severity. In children, who fortunately survived, both VD and GSH levels at admission were higher than in adults, suggesting that lower VD and thiols levels upon admission may be a modifiable risk factor for adverse outcomes and mortality in hospitalized patients with COVID-19.

Association between Glutathione S-Transferases Gene Variants and COVID-19 Severity in Previously Vaccinated and Unvaccinated Polish Patients with Confirmed SARS-CoV-2 Infection.

As the outcome of COVID-19 is associated with oxidative stress, it is highly probable that polymorphisms of genes related to oxidative stress were associated with susceptibility and severity of COVID-19. The aim of the study was to assess the association of glutathione S-transferases (GSTs) gene polymorphisms with COVID-19 severity in previously vaccinated and unvaccinated Polish patients with confirmed SARS-CoV-2 infection. A total of 92 not vaccinated and 84 vaccinated patients hospitalized due to COVID-19 were included. The WHO COVID-19 Clinical Progression Scale was used to assess COVID-19 severity. GSTs genetic polymorphisms were assessed by appropriate PCR methods. Univariable and multivariable analyses were performed, including logistic regression analysis. GSTP1 Ile/Val genotype was found to be associated with a higher risk of developing a severe form of the disease in the population of vaccinated patients with COVID-19 (OR: 2.75; p = 0.0398). No significant association was observed for any of the assessed GST genotypes with COVID-19 disease severity in unvaccinated patients with COVID-19. In this group of patients, BMI > 25 and serum glucose level > 99 mg% statistically significantly increased the odds towards more severe COVID-19. Our results may contribute to further understanding of risk factors of severe COVID-19 and selecting patients in need of strategies focusing on oxidative stress.

Decreased plasma H2O2 levels are associated with the pathogenesis leading to COVID-19 worsening and mortality.

Oxidative Stress (OS) is involved in the pathogenesis of COVID-19 and in the mechanisms by which SARS-CoV-2 causes injuries to tissues, leading to cytopathic hypoxia and ultimately multiple organ failure. The measurement of blood glutathione (GSH), H2O2, and catalase activity may help clarify the pathophysiology pathways of this disease. We developed and standardized a sensitive and specific chemiluminescence technique for H2O2 and GSH measurement in plasma and red blood cells of COVID-19 patients admitted to the intensive care unit (ICU). Contrary to what was expected, the plasma concentration of H2O2 was substantially reduced (10-fold) in COVID-19 patients compared to the healthy control group. From the cohort of patients discharged from the hospital and those who were deceased, the former showed a 3.6-fold and the later 16-fold H2O2 reduction compared to the healthy control. There was a 4.4 reduction of H2O2 concentration in the deceased group compared to the discharged group. Interestingly, there was no variation in GSH levels between groups, and reduced catalase activity was found in discharged and deceased patients compared to control. These data represent strong evidence that H2O2 is converted into highly reactive oxygen species (ROS), leading to the worst prognosis and death outcome in COVID-19 patients admitted to ICU. Considering the difference in the levels of H2O2 between the control group and the deceased patients, it is proposed the quantification of plasma H2O2 as a marker of disease progression and the induction of the synthesis of antioxidant enzymes as a strategy to reduce the production of oxidative stress during severe COVID-19.HighlightsH2O2 plasma levels is dramatically reduced in patients who deceased compared to those discharged and to the control group.Plasmatic quantification of H2O2 can be possibly used as a predictor of disease progression.Catalase activity is reduced in COVID-19.GSH levels remain unchanged in COVID-19 compared to the control group.

Oral high-dose acetylcysteine: Effective against the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a high rate of transmission and it exhibits immune escape characteristics. N-acetyl-L-cysteine (NAC) is a precursor of reduced glutathione (GSH), which can enter cells to play an antioxidant role, so it is better than glutathione. Patients tolerate NAC well, and adverse reactions are rare and mild, so this type of drug with multiple actions is considered to be a mucolytic agent as well as a drug for the prevention/treatment of various diseases, including COVID-19. Previous studies indicated that the clinical effectiveness of NAC is dose-dependent. Low-dose NAC (0.2 g tid for adults) is a mucolytic expectorant, high-dose NAC (0.6 g bid or tid) has expectorant action as well as antioxidant action, and extreme-dose NAC (300 mg/kg.d) is used for detoxification in cases of an acetaminophen overdose. Presumably, orally administered high-dose NAC (0.6 g tid for adults and 10 mg/kg tid for children) could be used as an adjuvant to treat an Omicron infection. It should reduce the time to negative conversion and prevent severe COVID-19, reducing the duration of hospitalization and increasing the bed turnover rate.

Investigation of hemogram, oxidative stress, and some inflammatory marker levels in neonatal calves with escherichia coli and coronavirus diarrhea.

Calf diarrhea is the most common disease affecting calves in the neonatal period resulting in economic losses. Although predisposing factors play a role in the etiology of the disease, in most cases, different pathogens are involved in the development of the infection. In this study, hemogram data, glutathione and malondialdehyde levels were examined to determine lipid peroxidation and glutathione levels in E. coli- and coronavirus-infected calves. Serum amyloid A and calprotectin levels were also analyzed to determine inflammatory status. The study included a total of 45 female Montofon calves aged 0-1 week, including the E. coli group (15 calves), the coronavirus group (15 calves), and the control group (15 calves). Analysis revealed that total leukocyte, neutrophil, lymphocyte, malondialdehyde, serum amyloid A, and calprotectin levels increased in the coronavirus-infected calves compared with the E. coli group and the control group. In contrast, the levels of glutathione, one of the antioxidant markers, decreased. In conclusion, the main findings related to the determination of inflammation and oxidative status were characterized by the presence of E. coli and coronavirus diarrhea, and it is suggested that future studies may be guided by the fact that inflammatory conditions are higher in viral disease than in bacterial infection.

The Impact of Severe COVID-19 on Plasma Antioxidants.

Several studies suggested the association of COVID-19 with systemic oxidative stress, in particular with lipid peroxidation and vascular stress. Therefore, this study aimed to evaluate the antioxidant signaling in the plasma of eighty-eight patients upon admission to the Clinical Hospital Dubrava in Zagreb, of which twenty-two died within a week, while the other recovered. The differences between the deceased and the survivors were found, especially in the reduction of superoxide dismutases (SOD-1 and SOD-2) activity, which was accompanied by the alteration in glutathione-dependent system and the intensification of the thioredoxin-dependent system. Reduced levels of non-enzymatic antioxidants, especially tocopherol, were also observed, which correlated with enhanced lipid peroxidation (determined by 4-hydroxynonenal (4-HNE) and neuroprostane levels) and oxidative modifications of proteins assessed as 4-HNE-protein adducts and carbonyl groups. These findings confirm the onset of systemic oxidative stress in patients with severe SARS-CoV-2, especially those who died from COVID-19, as manifested by strongly reduced tocopherol level and SOD activity associated with lipid peroxidation. Therefore, we propose that preventive and/or supplementary use of antioxidants, especially of lipophilic nature, could be beneficial for the treatment of COVID-19 patients.

Recent Developments in the Understanding of Immunity, Pathogenesis and Management of COVID-19.

Coronaviruses represent a diverse family of enveloped positive-sense single stranded RNA viruses. COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus-2, is a highly contagious respiratory disease transmissible mainly via close contact and respiratory droplets which can result in severe, life-threatening respiratory pathologies. It is understood that glutathione, a naturally occurring antioxidant known for its role in immune response and cellular detoxification, is the target of various proinflammatory cytokines and transcription factors resulting in the infection, replication, and production of reactive oxygen species. This leads to more severe symptoms of COVID-19 and increased susceptibility to other illnesses such as tuberculosis. The emergence of vaccines against COVID-19, usage of monoclonal antibodies as treatments for infection, and implementation of pharmaceutical drugs have been effective methods for preventing and treating symptoms. However, with the mutating nature of the virus, other treatment modalities have been in research. With its role in antiviral defense and immune response, glutathione has been heavily explored in regard to COVID-19. Glutathione has demonstrated protective effects on inflammation and downregulation of reactive oxygen species, thereby resulting in less severe symptoms of COVID-19 infection and warranting the discussion of glutathione as a treatment mechanism.

Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.

N-acetylcysteine as a therapeutic approach to post-COVID-19 pulmonary fibrosis adjunctive treatment.

OBJECTIVE: Growing interest is directed to the outcomes of COVID-19 in survivors, both in the convalescent period and in the long-term, which are responsible for morbidity and quality of life deterioration. This article aims to describe the mechanisms supporting the possible use of NAC as an adjuvant treatment for post-COVID-19 pulmonary fibrosis. MATERIALS AND METHODS: A search was performed in PubMed/MEDLINE. RESULTS: Interstitial changes have been observed in the CT scan of COVID-19 pneumonia. In patients with respiratory outcomes in the post-COVID-19 stage, glutathione (GSH) deficiency was found and interpreted as a reaction to the inflammatory cascade caused by the viral infection, while the pathophysiological process of pulmonary fibrosis involves numerous cytokines, such as TGF-ß, TNF-α, IL-1, PDGF and VEGF. NAC has a good tolerability profile, is easily administered orally and inexpensively, and has antioxidant and anti-inflammatory effects that may target the pathophysiologic mechanisms involved in pulmonary fibrosis. It may revert GSH deficiency, exerts direct and indirect antioxidant activity, anti-inflammatory activity and improves immune T-cell response. CONCLUSIONS: The mechanism of action of NAC suggests a role in the treatment of pulmonary fibrosis induced by COVID-19.

How long-term metal and lead exposure among foundry workers affect COVID-19 infection outcomes in Jordan.

Foundry workers face a number of occupational health hazards, which may lead to an increased risk of respiratory disease, cancer, and anxiety level and are associated with endocrine, hematologic, renal, and neurological problems in humans. This study aims to evaluated thyroid functions, glutathione level, and the risk of infection with SARS-CoV-2 after vaccinated (two doses of the BNT162b2 mRNA COVID-19 vaccine) foundry workers in Jordan. We examined the efficacy BNT162b2 vaccine by calculating the rate of mortality and the degree of severity from mild to severe respiratory infections in 105 adult males foundry workers occupationally exposed to metals and Pb who had been received two doses, 21 days apart, of the BNT162b2 vaccine. Seventy-five male subjects not exposed to the Pb and who received two shots of the BNT162b2 vaccine (Pfizer-BioNTech) served as the control group. In foundry workers who were infected with COVID-19, the mortality rate (0%) was similar as in the control group (0%), and increased transmission of infection with SARS-CoV-2; the non-hospitalized infections increased nearly 3.4-times and hospitalized infections increased 4.29-times among people exposed to lead and metal contamination compared to the healthy persons control group. Also, among the foundry workers, the blood lead, FT3, and FT4 levels were significantly higher (p < 0.0001) and the levels of glutathione and TSH were significantly decreased (p < 0.0001) compared with the control group. In conclusion, long-term exposure to Pb is associated with a risk of infection with COVID-19 despite the 2 doses of the BNT162b2 vaccine (Pfizer-BioNTech). Also, exposure to Pb is associated with hyperthyroidism and a reduction in glutathione.

Lower levels of glutathione in the anterior cingulate cortex associate with depressive symptoms and white matter hyperintensities in COVID-19 survivors.

SARS-CoV-2 is a novel coronavirus that mainly affects the respiratory system. However, clinical manifestations such as neurological symptoms, psychopathological outcomes and brain alterations suggest brain involvement during SARS-CoV-2 infection. Depressive symptoms and cerebral white matter hypodensities/hyperintensities (WMH) have been widely reported in COVID-19 survivors and have been shown to persist after recovery from infection. At the same time viral Infections, including COVID-19, have been shown to lead to oxidative stress. Glutathione (GSH) is the main antioxidant in the brain and reduced GSH levels have been implicated both in COVID-19 and depression. We therefore hypothesise that reduced GSH levels may be associated with depressive symptoms and WMH in COVID-19 survivors. Forty-nine participants (age 18-70) surviving COVID-19 underwent magnetic resonance imaging to measure WMH and brain GSH levels in the ACC, blood sampling to measure systemic inflammation and psychopathological assessment for depressive symptoms. ACC concentrations of GSH inversely associated with both depression scores and the number and volume of WMH. The volume of WMH also positively associated with depressive symptomatology. Finally, systemic inflammation negatively predicted GSH concentration in ACC. In conclusion, we observed overlapping associations of GSH levels in ACC, WMH and severity of depression in COVID-19 survivors, and confirmed the central role of systemic inflammation, thus warranting interest for further study of oxidative stress and antioxidants in the post-acute COVID-19 syndrome.

Dynamic and Comparative Transcriptome Analyses Reveal Key Factors Contributing to Cadmium Tolerance in Broomcorn Millet.

Broomcorn millet (Panicum miliaceum L.) has great potential in Cd phytoextraction, but its mechanisms are largely unknown. Two contrasting broomcorn millet varieties, 'Ningmi6' (Cd-sensitive variety) and '4452' (Cd-tolerant variety), were investigated through morphological, physiological, and transcriptomic analyses to determine the factors responsible for their differential Cd tolerance and translocation. The Cd-tolerant variety can accumulate more Cd, and its cell wall and vacuole component Cd proportions were higher compared with the Cd-sensitive variety. Under Cd stress, the glutathione content and peroxidase activity of the Cd-tolerant variety were significantly higher than those of the Cd-sensitive variety. Additionally, weighted gene co-expression network analysis (WGCNA) revealed hub modules that were associated with Cd stress and/or variety. Notably, genes involved in these hub modules were significantly enriched for roles in glutathione metabolism, phenylpropanoid biosynthesis, ABC transport, and metal ion transport process. These results suggested that regulation of genes associated with cell wall precipitation and vacuole compartmentalization may increase Cd tolerance and reduce Cd translocation in the Cd-tolerant variety, although it can absorb more Cd. This study provides a foundation for exploring molecular mechanisms of Cd tolerance and transport in broomcorn millet and new insights into improving Cd phytoremediation with this crop through genetic engineering.

Melatonin and multiple sclerosis: antioxidant, anti-inflammatory and immunomodulator mechanism of action.

BACKGROUND: Melatonin is an indole hormone secreted primarily by the pineal gland that showing anti-oxidant, anti-inflammatory and anti-apoptotic capacity. It can play an important role in the pathophysiological mechanisms of various diseases. In this regard, different studies have shown that there is a relationship between Melatonin and Multiple Sclerosis (MS). MS is a chronic immune-mediated disease of the Central Nervous System. AIM: The objective of this review was to evaluate the mechanisms of action of melatonin on oxidative stress, inflammation and intestinal dysbiosis caused by MS, as well as its interaction with different hormones and factors that can influence the pathophysiology of the disease. RESULTS: Melatonin causes a significant increase in the levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione and can counteract and inhibit the effects of the NLRP3 inflammasome, which would also be beneficial during SARS-CoV-2 infection. In addition, melatonin increases antimicrobial peptides, especially Reg3ß, which could be useful in controlling the microbiota. CONCLUSION: Melatonin could exert a beneficial effect in people suffering from MS, running as a promising candidate for the treatment of this disease. However, more research in human is needed to help understand the possible interaction between melatonin and certain sex hormones, such as estrogens, to know the potential therapeutic efficacy in both men and women.

COVID-19 in G6PD-deficient Patients, Oxidative Stress, and Neuropathology.

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that regulates energy metabolism mainly through the pentose phosphate pathway (PPP). It is well known that this enzyme participates in the antioxidant/oxidant balance via the synthesis of energy-rich molecules: nicotinamide adenine dinucleotide phosphate reduced (NADPH), the reduced form of flavin adenine dinucleotide (FADH) and glutathione (GSH), controlling reactive oxygen species generation. Coronavirus disease 19 (COVID-19), induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a public health problem that has caused approximately 4.5 million deaths since December 2019. Concerning the role of G6PD in COVID-19 development, it is known from the existing literature that G6PD-deficient patients infected with SARS-CoV-2 are more susceptible to thrombosis and hemolysis, suggesting that G6PD deficiency facilitates infection by SARS-CoV-2. Concerning G6PD and neuropathology, it has been observed that deficiency of this enzyme is also present with an increase in oxidative markers. Concerning the role of G6PD and the neurological manifestations of COVID-19, it has been reported that the enzymatic deficiency in patients infected with SARSCoV- 2 exacerbates the disease, and, in some clinical reports, an increase in hemolysis and thrombosis was observed when patients were treated with hydroxychloroquine (OH-CQ), a drug with oxidative properties. In the present work, we summarize the evidence of the role of G6PD in COVID- 19 and its possible role in the generation of oxidative stress and glucose metabolism deficits, and inflammation present in this respiratory disease and its progression including neurological manifestations.

Hyperglycemia and Loss of Redox Homeostasis in COVID-19 Patients.

The infection with SARS-CoV-2 impairs the glucose-insulin axis and this contributes to oxidative (OS) and nitrosative (NSS) stress. Here, we evaluated changes in glucose metabolism that could promote the loss of redox homeostasis in COVID-19 patients. This was comparative cohort and analytical study that compared COVID-19 patients and healthy subjects. The study population consisted of 61 COVID-19 patients with and without comorbidities and 25 healthy subjects (HS). In all subjects the plasma glucose, insulin, 8-isoprostane, Vitamin D, H2S and 3-nitrotyrosine were determined by ELISA. The nitrites (NO2-), lipid-peroxidation (LPO), total-antioxidant-capacity (TAC), thiols, glutathione (GSH) and selenium (Se) were determined by spectrophotometry. The glucose, insulin and HOMA-IR (p < 0.001), 8-isoprostanes, 3-nitrotyrosine (p < 0.001) and LPO were increased (p = 0.02) while Vitamin D (p = 0.01), H2S, thiols, TAC, GSH and Se (p < 0.001) decreased in COVID-19 patients in comparison to HS. The SARS-CoV-2 infection resulted in alterations in the glucose-insulin axis that led to hyperglycemia, hyperinsulinemia and IR in patients with and without comorbidities. These alterations increase OS and NSS reflected in increases or decreases in some oxidative markers in plasma with major impact or fatal consequences in patients that course with metabolic syndrome. Moreover, subjects without comorbidities could have long-term alterations in the redox homeostasis after infection.

Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

Scavenging ROS to Alleviate Acute Liver Injury by ZnO-NiO@COOH.

Currently, the incidence of acute liver injury (ALI) is increasing year by year, and infection with coronavirus disease 2019 (COVID-19) can also induce ALI, but there are still no targeted therapeutic drugs. ZnO-NiO particles is mainly used to clean up reactive oxygen species (ROS) in industrial wastewater, and it is insoluble in water. Its excellent properties are discovered and improved by adding shuttle-based bonds to make it more water-soluble. ZnO-NiO@COOH particles are synthetically applied to treat ALI. The p-n junction in ZnO-NiO@COOH increases the surface area and active sites, thereby creating large numbers of oxygen vacancies, which can quickly adsorb ROS. The content in tissues and serum levels of L-glutathione (GSH) and the GSH/oxidized GSH ratio are measured to assess the capacity of ZnO-NiO@COOH particles to absorb ROS. The ZnO-NiO@COOH particles significantly reduce the expression levels of inflammatory factors (i.e., IL-1, IL-6, and TNF-α), macrophage infiltration, and granulocyte activation. ZnO-NiO@COOH rapidly adsorb ROS in a short period of time to block the generation of inflammatory storms and gain time for the follow-up treatment of ALI, which has important clinical significance.

Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID-19?

OBJECTIVE: As N-acetylcysteine (NAC) is promising as a re-purposed drug for the adjunctive or supportive treatment of serious COVID-19, this article aimed to describe current evidence. MATERIALS AND METHODS: A search was performed in PubMed/Medline for "NAC", "viral Infection", COVID-19", oxidative stress", "inflammation", retrieving preclinical and clinical studies. RESULTS: NAC is a pleiotropic molecule with a dual antioxidant mechanism; it may neutralize free radicals and acts as a donor of cysteine, restoring the physiological pool of GSH. Serious COVID-19 patients have increased levels of reactive oxygen species (ROS) and free radicals and often present with glutathione depletion, which prompts a cytokine storm. NAC, which acts as a precursor of GSH inside cells, has been currently used in many conditions to restore or protect against GSH depletion and has a wide safety margin. In addition, NAC has anti-inflammatory activity independently of its antioxidant activity. CONCLUSIONS: Clinical and experimental data suggest that NAC may act on the mechanisms leading to the prothrombotic state observed in severe COVID-19.

Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion.

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.

Plasma S-Adenosylmethionine Is Associated with Lung Injury in COVID-19.

OBJECTIVE: S-Adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are indicators of global transmethylation and may play an important role as markers of severity of COVID-19. METHODS: The levels of plasma SAM and SAH were determined in patients admitted with COVID-19 (n = 56, mean age = 61). Lung injury was identified by computed tomography (CT) in accordance with the CT0-4 classification. RESULTS: SAM was found to be a potential marker of lung damage risk in COVID-19 patients (SAM > 80 nM; CT3,4 vs. CT 0-2: relative ratio (RR) was 3.0; p = 0.0029). SAM/SAH > 6.0 was also found to be a marker of lung injury (CT2-4 vs. CT0,1: RR = 3.47, p = 0.0004). There was a negative association between SAM and glutathione level (ρ = -0.343, p = 0.011). Interleukin-6 (IL-6) levels were associated with SAM (ρ = 0.44, p = 0.01) and SAH (ρ = 0.534, p = 0.001) levels. CONCLUSIONS: A high SAM level and high methylation index are associated with the risk of lung injury in patients with COVID-19. The association of SAM with IL-6 and glutathione indicates an important role of transmethylation in the development of cytokine imbalance and oxidative stress in patients with COVID-19.