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Glutathione: Secret Weapon For Immunity, Anti-Aging, Arthritis, Muscle Recovery, and More!Glutathione and immune function -
SARS-CoV-2 and its massive cytokine storm primarily compromises the lungs causing acute respiratory distress syndrome also affecting the cardiovascular system aggravating atherosclerotic lesions leading to thromboembolic events and cell and tissue death Ryu and Shin, ; Taoufik et al.
SARS-CoV-2 infects pulmonary type II alveolar cells because these cells express angiotensin-converting enzyme 2 ACE2; Ryu and Shin, ; Taoufik et al. SARS-CoV-2 ACE2-mediated host cell invasion is enhanced by the presence of heparan sulfate proteoglycans HSPGs consisting of a core protein bearing glycosaminoglycan carbohydrate chains Souza-Fernandes et al.
Virus protein ligands, like trimeric spike glycoprotein interact with cellular receptors, such as ACE2, and host proteases, like transmembrane protease serine 2 TMPRSS2 , participate in virus entry by proteolytically activating virus ligands Sallenave and Guillot, ; Kalra and Kandimalla, ; Zhang Q.
In the lungs, after entering in type II alveolar cells, SARS-CoV-2 infected cells become defective for surfactant production Ghati et al. Alveolar macrophages, due to their polarization state toward M1 or M2 phenotypes, provoke different effects following SARS-CoV-2 infection.
Hyperactivated M1 alveolar macrophages are taken over by SARS-CoV-2 allowing for viral infection and spread, while M2 alveolar macrophages can degrade the virus and limit its spread Knoll et al.
Neutrophils produce ROS and proteinases, causing further destruction of healthy type II cells; as a result, surfactant production decreases markedly, which in turn causes alveolar fluid accumulation leading to alveolar collapse and ARDS Matthay and Zemans, ; Carcaterra and Caruso, Due to the exhaustion of cellular and extracellular GSH caused by numerous GSH-consuming pathways the severe inflammation and oxidative stress triggered by the viral infection steals GSH from crucial functions like NO-dependent vasodilatation, disallowing the patient of being protected from an inflammation that can become fatal.
Based on the previous discussion, administration of antioxidants or Nrf2 inducers are potential viable therapies for viral-induced diseases, like respiratory infections and infections associated with reduced cellular antioxidant capacity Komaravelli and Casola, A high neutrophil to lymphocyte ratio found in critically ill patients with COVID is associated with excessive ROS levels, that promote a cascade of biological events driving pathological host responses.
Since ROS induce tissue damage, thrombosis and red blood cell dysfunction that contribute to COVID disease severity, administration of free radical scavengers could be beneficial for the most vulnerable patients Laforge et al. Toll-like receptors TLRs play a key role in microorganism and viral particle recognition and activation of the innate immune system Sasai and Yamamoto, ; Kawasaki and Kawai, ; McClure and Massari, ; Sartorius et al.
TLR pathway activation leads to secretion of pro-inflammatory cytokines, like interleukin IL -1, IL-6, and tumor necrosis factor-α, as well as type 1 interferon.
TLRs can be localized either on the cell surface TLR-1, -2, -4, -5, -6, or in the endosome compartment TLR-3, -7, -8, -9; Sasai and Yamamoto, ; Kawasaki and Kawai, ; Sartorius et al. TLRs-2, -3, -4, -6, -7, -8, and -9 are potentially important in COVID infection Onofrio et al.
TLR4-mediated recognition of S protein may initiate receptor dependent internalization and explain SARS-CoV-2 infection in patients and cells lacking or deficient in ACE2 expression Aboudounya and Heads, ; Gadanec et al. Viral proteins as well as host damage-associated molecular patterns, that accumulate following cellular stress during viral infection, were linked to TLR4 activation, with uncontrolled TLR4 activation being associated with severe disease Olejnik et al.
TLR4 activation in platelets whether by pathogen- viremia or damage-associated molecular patterns induces a prothrombotic and proinflammatory state Schattner, SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signaling increasing cell surface expression of ACE2 facilitating entry Aboudounya and Heads, The expression of CD14, TLR2 and 4 in human alveolar type I and II cells Thorley et al.
Ten human TLRs that signal via 4 adaptor proteins and 2 initial kinases activate distal kinases that subsequently regulate transcription factors such as NFκB and activator protein 1 AP-1 , that control gene expression. Posttranslational modifications of ROS-mediated kinase activity most probably contribute to the diversity and intensity of gene expression following microbial activation of innate immunity Kolls, SARS-CoV-2 mainly destroys pulmonary surfactant-secreting type II alveolar cells Wang et al.
TLR4 activation, aberrant TLR4 signaling, and hyperinflammation may explain SARS-CoVinduced myocarditis and multiple-organ injury in COVID patients Aboudounya and Heads, Augmented activation of TLR4 increases oxidative stress and the generated ROS participate in signaling events downstream of TLRs.
TLR4 activation may lead to ROS signaling via direct interaction between TLR4 and NADPH oxidase Gill et al. TLR1, TLR2 and TLR4 activation results in augmented mitochondrial ROS production following recruitment of mitochondria to macrophage phagosomes, leading the way to increased mitochondrial and cellular ROS generation West et al.
ROS can oxidize cysteine residues allowing formation of disulfide bridges with one another or with GSH leading to S-glutathionylation. ROS can be inactivated by antioxidants such as GSH.
The link between oxidation and inflammation is complex, going from fine-tuned signaling by ROS during TLR4 activation that leads to active mobilization of damaged-associated molecular patterns, to cellular injury from redox stress that leads to damaged-associated molecular patterns release triggering TLR4-mediated inflammation and organ injury Gill et al.
Neutralization of oxidation radicals becomes paramount in SARS-CoVmediated cellular and tissue damage. As we previously published, a multiweapon approach is needed to successfully combat SARS-CoV-2 and COVID disease Labarrere and Kassab, , involving vaccines Jin et al.
Sadly, there are no effective antivirals and vaccines to definitively treat or prevent COVID Globally launched clinical trials like the European study DISCOVERY showed that antiviral drugs remdesivir, lopinavir and ritonavir in combination, ritonavir given with or without interferon beta and hydroxychloroquine are unable to efficiently attack COVID progression Ader et al.
Although a recent trial has shown to be beneficial when antiviral treatment is introduced early during the disease before hospitalization than later in the course of the disease, there is an urgent need for early therapies to reduce the risk of disease progression, prevent transmission, and be widely distributed to meet the worldwide demand Gottlieb et al.
Here we emphasize the role of Nrf2 activators and the vital role of antioxidants like the GSH system in prevention against oxidative stress and cell and tissue damage Cuadrado et al. Figure 5. Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 -related glutathione GSH cellular depletion, repletion treatment options and a multiweapon defense approach.
Reactive oxygen species ROS cell production enhances proinflammatory cytokine release while reducing anti-inflammatory cytokines.
SARS-CoV-2 reduces Nrf2 and GSH allowing ROS and RNS to damage the cell. Increased intracellular GSH reduces ROS and reactive nitrogen species RNS , as well as NF-κB activation. Sulforaphane and resveratrol enhance Nrf2 production and Nrf2 negatively regulates the endoplasmic-reticulum-resident protein stimulator of interferon genes STING reducing interferon secretion.
Increased antioxidant defense cystine, cysteine, NAC, liposomal GSH, vitamin D3, sulforaphane, resveratrol, and others reestablishes cell homeostasis [7]. Increased nuclear factor-κB NF-κB activity enhances interleukin IL -6 secretion and cytokine storm, while decreased nuclear NF-κB allows activation of nuclear factor erythroid 2-related factor2 Nrf2 -dependent antioxidant genes and enzyme transcription HO-1, NQO-1, and others ; Nrf2 inhibition of M1 and upregulation of M2 induced genes; decreased pro-inflammatory and increased anti-inflammatory cytokine expression; and decreased cytokine storm.
Since oxidative stress plays an important role in the pathogenesis of viral-associated cardiovascular and lung diseases, antioxidant intervention would be a rational approach to use for treating lower respiratory tract infections Komaravelli and Casola, and balancing oxidative damage by enhancing antioxidant defense Banjac et al.
Since SARS-CoV-2 activates mitochondrial ROS-mediated feedback loops that produce long-term changes in the redox status and endothelial function of the host, leading to cardiovascular disease and lung injury Chang et al. By regulating glutathione S-transferase GST and intracellular glutathione GSH levels, Nrf2 controls the level of ROS in the cell Kolls, ; Lushchak, ; Aquilano et al.
Since Nrf2 participates in the resolution of inflammation by repressing genes for proinflammatory cytokines IL-6 and IL-1β Kobayashi et al. NRF2 inducers, like sulforaphane modify cysteine sensors of Keap1 and inactivate its repressor function.
The liberation of Nrf2 from Keap1 allows Nrf2 accumulation and translocation to the nucleus Cuadrado et al. Since SARS-CoV-2 mediates Nrf2 suppression and limits host anti-inflammatory response Cuadrado et al.
Nrf2 activation suppresses ROS in antigen-presenting dendritic cells enhancing their capacity to interact with and promote the transformation of naïve CD8 T cells into cytotoxic T lymphocytes enabling cytotoxic T-cells to eliminate virally infected cells Kesarwani et al.
Nrf2 activation regulates antioxidant responses to modify cellular redox states from predominantly pro-oxidant to antioxidant, and, in an antioxidant environment, macrophage phenotypes shift from M1 pro-inflammatory to M2 anti-inflammatory, reducing the probability of cytokine storms, ARDS, and lethality Tan et al.
Cytoprotective effects against viruses like SARS-CoV-2 could be enhanced by sulforaphane, an isothiocyanate abundant in cruciferous vegetables, since sulforaphane has been found to be a powerful activator of the Nrf2 pathway by increasing Nrf2-regulated cellular antioxidant response such as induction of NAD P H: quinone oxidoreductase 1, glutamate-cysteine ligase γ-glutamyl cysteine synthetase and glutathione Theodore et al.
Nrf2 activators like sulforaphane have a potential role with dual antiviral and anti-inflammatory properties in the management of viral pneumonia, a serious complication in COVID disease Bousquet et al. Nrf2-interacting nutrients can equilibrate insulin resistance and have a significant effect upon COVID severity.
It is then possible that intake of these nutrients may re-establish an optimal natural balance for the Nrf2 pathway and mitigate COVID severity Bousquet et al. Therapeutic interventions aimed at normalizing GSH and Nrf2 might provide a promising approach to combat the COVID pandemic.
Augmented oxidative stress secondary to increased levels of interleukin-6 and tumor necrosis factor-α in addition to decreased levels of interferons α and β are primarily believed to be the drivers of the disease process Guloyan et al. Since it was shown that glutathione GSH inhibits viral replication and decreases IL-6 levels, it was suggested that liposomal GSH could be beneficial in COVID patients characterized by SARS-CoVinduced cytokine storm and redox imbalance Guloyan et al.
SARS-CoV-2 binds to the ACE2 receptor and induces down regulation of NRF2, which leads to inhibition of GSH release. This leads to elevated inflammatory cytokines, elevated ROS, and recruitment of immune cells. The importance of thiol-reactive molecules like NAC and GSH in SARS-CoV-2 infectivity has been shown recently Murae et al.
NAC and GSH directly suppress spike protein receptor-binding domain-ACE2 binding functions of various SARS-CoV-2 variants. An intramolecular disulfide bridge in the receptor-binding domain of the SARS-CoV-2 spike protein between Cys and Cys, considered to be important for ACE2-binding, results directly inhibited by NAC and GSH and these compounds could be used effectively against SARS-CoV-2 cell viral entry and infection Murae et al.
GSH was shown to be the main inhibitor in the active site of the main protease M pro , the essential protein for virus invasion, and cysteine Cys glutathionylation inhibits M pro activity by blocking its dimerization supporting the use of GSH in COVID patients Davis et al.
GSH deficiency has been associated with increased ROS and more severe clinical COVID Guillin et al. SARS-CoV-2 affects intracellular GSH levels by decreasing intracellular NRF2 function, that plays a key role in protecting cells from oxidative damage by upregulating GSH production Rahman and MacNee, ; Guloyan et al.
In stressed cells NRF2 is released and taken from the cytoplasm into the nucleus by karyopherins Theodore et al. Coronavirus inhibits karyopherin-mediated nuclear import decreasing GSH production Sims et al. In the setting of SARS-CoV-2, COVID and oxidative stress, patients with comorbidities may have altered levels of glutamate-cysteine ligase and GSH synthetase, the enzymes participating in GSH synthesis.
Therefore, it is reasonable using supplementation of liposomal glutathione, instead of the N-acetylcysteine or bonded cysteine utilized as precursors for GSH cell synthesis, since patients with deficient levels of glutamate-cysteine ligase and GSH synthetase will not be able to use N-acetylcysteine or bonded cysteine as substrates to synthesize their own GSH.
Replenishing the nutritional status of the host by increasing vital amino acids such as cysteine to enhance GSH levels and selenium to improve selenium deficiency and facilitate selenoprotein GSH peroxidases, thioredoxin reductases expression can inhibit oxidative stress, modulating inflammation, suppressing endothelial dysfunction, and protecting vascular cells against apoptosis and calcification He et al.
The demonstration that a combination of glycine and N-acetylcysteine supplementation rapidly improves GSH deficiency, oxidative stress and oxidant damage has implications for considering the GSH importance in combating COVID infected patients warranting further investigations Kumar P.
Enzymes involved in GSH biosynthesis and function like γ-glutamyl-cysteine ligase and glutathione synthetase are completely dependent on ATP and require magnesium as a cofactor Bani Younes et al. Additionally, γ-glutamyl-transpeptidase uses magnesium as an enzyme activator Arancibia-Hernández et al.
Magnesium supplementation improves mitochondrial function and increases the content of GSH in those organelles Liu et al.
Furthermore, magnesium sulfate was effective as a treatment for preeclampsia, significantly promoting GSH production and suppressing ROS generation Kawasaki et al.
Recent studies have suggested that serum magnesium levels of critically ill patients deserve attention Bani Younes et al. Molecules of nutritional value with antioxidant properties besides GSH, like selenium, zinc and polyphenols, are important in the immune response against SARS-CoV-2 that occurs primary in the lungs Pérez de la Lastra et al.
The value of selenium upon glutathione peroxidase 1 activity and oxidative stress mitigation in SARS-CoV-2 infection and COVID disease has been clearly emphasized recently Seale et al. The recent demonstration of elevated superoxide dismutase, GSH peroxidase, and total antioxidant capacity in COVID outpatients compared to controls could be interpreted as a response to excessive COVIDrelated oxidative stress Golabi et al.
Adequate levels and function of GSH and selenoproteins can prevent worsening of acute respiratory distress syndrome and atherosclerosis, two main causes of morbimortality in SARS-CoV-2 infection and COVID disease. COVID is a historic challenge to the fields of research, infectious disease, and global healthcare Hunter et al.
The demand for detailed analysis of COVID pathogenesis and clinical course is paramount. The unprecedented awareness of a rapidly spreading pandemic disease such as COVID brings an opportunity to enhance international collaboration in the scientific community.
As new variants like the omicron Abdool Karim and Abdool, ; Callaway and Ledford, and others Markov et al. Here we present the antioxidant GSH as a potential unexplored way for further investigation as intervention for COVID, since GSH levels are correlated with disease severity and lung damage supporting the participation of GSH in disease outcome Kryukov et al.
Enhancing GSH, mainly through NAC, GSH precursors or pro-GSH compound administration, becomes a potential treatment option for SARS-CoV-2 infection and COVID disease by reducing oxidative stress and cytokine expression especially in diabetic patients at risk of more severe disease Singh et al.
A combination of vitamin D and L-cysteine administration significantly augmented GSH levels and lowered oxidative stress and inflammation Jain et al. Maintaining an adequate GSH redox status and hydroxy-vitamin D levels will have the potential to reduce oxidative stress, enhance immunity and diminish the adverse clinical consequences of COVID especially in African American communities having glucosephosphate dehydrogenase deficiency, enzyme necessary to prevent GSH exhaustion and depletion Jain and Parsanathan, ; Jain et al.
In a patient that is overloaded with cytokine storm, the best way to fortify the immune system would be to supply it with reduced GSH, since reduced GSH is already able to provide reducing equivalents from its thiol group. This is particularly relevant when we consider GSH pathways, as well as their transcriptional regulator Nrf2, for proliferation, survival and function of T cells, B cells and macrophages Muri and Kopf, The value of GSH and nutritional strategies like amino acids, vitamins, minerals, phytochemicals, sulforaphane to enhance cellular Nrf2, and other supplements used to restore GSH levels Minich and Brown, ; Hermel et al.
Reestablishing the cellular metabolic homeostasis in SARS-CoV-2 infection and COVID disease especially in the lungs, could become paramount to balance altered innate and adaptive immunity and cell function and reduce morbimortality Hsu et al.
COVID of the respiratory system appears to be a complex disease that may resist finding a single silver bullet intervention Brosnahan et al. Table 1. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. This is an open-access article distributed under the terms of the Creative Commons Attribution CC-BY License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; COVID, coronavirus disease 19; ROS, reactive oxygen species; GSH, glutathione; Keap1, Kelch-like ECH-associated protein 1; Nrf2, Nuclear factor erythroid 2-related factor 2; ARE, antioxidant response element; GSSG, GSH disulfide; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; ARDS, Acute respiratory distress syndrome; NFκB, nuclear factor-κB; ACE2, angiotensin converting enzyme-2; NETs, neutrophil extracellular traps; rTEM, reverse trans-endothelial migration; NAC, N-acetylcysteine; CRP, C-reactive protein; HSPGs, heparan sulfate proteoglycans; GCS, glutamyl-cysteine synthetase; TMPRSS2, transmembrane protease serine 2; TLRs, Toll-like receptors.
Abbas, M. Association of GSTM1 and GSTT1 gene polymorphisms with COVID susceptibility and its outcome. doi: PubMed Abstract CrossRef Full Text Google Scholar.
Abd El-Aziz, T. Human recombinant soluble ACE2 hrs ACE2 shows promise for treating severe COVID Signal Transduct. Abdool Karim, S. Omicron SARS-CoV-2 variant: a new chapter in the COVID pandemic.
Lancet , — Aboudounya, M. COVID and toll-like receptor 4 TLR4 : SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyperinflammation. Ader, F. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID dis CoVeRy : a phase 3, randomised, controlled, open-label trial.
Lancet Infect. Aldini, G. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic. Andriollo-Sanchez, M. Age-related oxidative stress and antioxidant parameters in middle-aged and older European subjects: the ZENITH study.
Aquilano, K. Glutathione: new roles in redox signaling for an old antioxidant. Arancibia-Hernández, Y. Arroyo, R. Full-length recombinant hSP-D binds and inhibits SARS-CoV Ashfaq, S.
Endothelial function and Aminothiol biomarkers of oxidative stress in healthy adults. Hypertension 52, 80— Atefi, N. N-acetylcysteine and coronavirus disease may it work as a beneficial preventive and adjuvant therapy?
A comprehensive review study. Atkuri, K. Baker, S. Angiotensin-converting enzyme 2 ACE2 expression increases with age in patients requiring mechanical ventilation.
PLoS One e Ballatori, N. Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology.
Bani Younes, M. Magnesium sulfate extended infusion as an adjunctive treatment for complicated COVID infected critically ill patients. EAS J. Care 2, 97— CrossRef Full Text Google Scholar. Banjac, A. Oncogene 27, — Bartolini, D. SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione.
Redox Biol. Baş, H. The effects of free radicals on aging process. Trends Biomedical Eng. Bellanti, F. Redox homeostasis and immune alterations in coronavirus Disease Biology Beltrán-García, J. Sepsis and coronavirus disease common features and anti-inflammatory therapeutic approaches.
Care Med. Bharath, L. Next steps in mechanisms of inflammaging. Autophagy 16, — Bounous, G. The influence of dietary whey protein on tissue glutathione and the diseases of aging. Google Scholar. Bourgonje, A. N-Acetylcysteine and hydrogen sulfide in coronavirus disease Redox Signal. Bousquet, J.
Nrf 2-interacting nutrients and COVID time for research to develop adaptation strategies. Allergy Brandes, R. Nox family NADPH oxidases: molecular mechanisms of activation.
Brosnahan, S. COVID and respiratory system disorders. Current knowledge, future clinical and translational research questions. Brueggeman, J. Trained immunity: an overview and the impact on COVID Calabrese, E. Nrf 2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID pneumonia and acute respiratory distress syndrome ARDS : novel mechanistic considerations.
Calder, P. Nutrition, immunity and COVID BMJ Nutr. Health 3, 74— Callaway, E. How bad is omicron? What scientists know so far.
Nature , — Campolo, J. Medium-term effect of sublingual l-glutathione supplementation on flow-mediated dilation in subjects with cardiovascular risk factors. Nutrition 38, 41— Carcaterra, M. Alveolar epithelial cell type II as main target of SARS-CoV-2 virus and COVID development via NF-kb pathway deregulation: a physio-pathological theory.
Hypotheses Castejon, A. Improving antioxidant capacity in children with autism: a randomized, double-blind controlled study with cysteine-rich whey protein.
Cazzola, M. Use of thiols in the treatment of COVID current evidence. Lung , — Cecchini, R. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Cerqueira Borges, R. Dendritic cells in COVID Immunopathogenesis: insights for a possible role in determining disease outcome.
Chang, R. SARS-CoV-2 mediated endothelial dysfunction: the potential role of chronic oxidative stress. Chang, W. Lymphocyte proliferation modulated by glutamine: involved in the endogenous redox reaction. Chen, K. Redox control in the pathophysiology of influenza virus infection.
BMC Microbiol. Chen, Z. T cell responses in patients with COVID Chumakov, K. Old vaccines for new infections: exploiting innate immunity to control COVID and prevent future pandemics. Circu, M. Reactive oxygen species, cellular redox systems, and apoptosis. Glutathione and modulation of cell apoptosis.
Acta , — Clausen, T. SARS-CoV-2 infection depends on cellular Heparan sulfate and ACE2. Cells , — Coric, V. GSTP1 and GSTM3 variant alleles affect susceptibility and severity of COVID Coz Yataco, A.
Coronavirus disease sepsis. A nudge toward antibiotic Stewardship. Chest , — Cuadrado, A. Can activation of NRF2 be a strategy against COVID? Trends Pharmacol. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.
Drug Discov. Cunha, L. Remodeling of the immune response with aging: immunosenescence and its potential impact on COVID immune response.
Dai, J. Toll-like receptor signaling in severe acute respiratory syndrome coronavirus 2-induced innate immune responses and the potential application value of toll-like receptor Immunomodulators in patients with coronavirus disease Davis, D.
Regulation of the dimerization and activity of SARS-CoV-2 main protease through reversible glutathionylation of cysteine mBio 12, e Heparan sulfate: a ubiquitous glycosaminoglycan with multiple roles in immunity.
De Candia, P. T cells: warriors of SARS-CoV-2 infection. Trends Immunol. De Flora, S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID FASEB J. De Pasquale, V. Heparan sulfate proteoglycans in viral infection and treatment: a special focus on SARS-CoV Delgado-Roche, L.
Oxidative stress as key player in severe acute respiratory syndrome coronavirus SARS-CoV infection. Deneke, S. Regulation of cellular glutathione. Denzoin Vulcano, L. Homeostasis del glutatión. Acta Bioquím Clín Latinoam 47, — DePietro, M.
Commentary: pattern recognition proteins: first line of defense against coronaviruses. Derouiche, S. Oxidative stress associated with SARS-Cov-2 COVID increases the severity of the lung disease — a systematic review. Di Marco, F. Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID?
Diao, B. Reduction and functional exhaustion of T cells in patients with coronavirus disease COVID Diaz-Vivancos, P. A nuclear glutathione cycle within the cell cycle.
Diotallevi, M. Glutathione fine-tunes the innate immune response toward antiviral pathways in a macrophage cell line independently of its antioxidant properties.
Djukic, T. GSTO1, GSTO2 and ACE2 polymorphisms modify susceptibility to developing COVID Doğan, H. Understanding the pathophysiological changes via untargeted metabolomics in COVID patients. Dominari, A. Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID World J.
Dröge, W. The plasma redox state and ageing. Ageing Res. Free radicals in the physiological control of cell function. Glutathione and immune function. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives.
Edinger, A. Antigen-presenting cells control T cell proliferation by regulating amino acid availability.
Emanuele, S. The good and bad of Nrf 2: an update in cancer and new perspectives in COVID Fajgenbaum, D. Cytokine storm.
Fakhrolmobasheri, M. COVID and selenium deficiency: a systematic review. Trace Elem. Fazal, M. C-reactive protein a promising biomarker of COVID severity. Korean J. Fendl, B. Ferreira, A. Glutathione metabolism contributes to the induction of trained immunity. Cells Forcados, G.
Metabolic implications of oxidative stress and inflammatory process in SARS-CoV-2 pathogenesis: therapeutic potential of natural antioxidants. Forman, H.
Glutathione: overview of its protective roles, measurement, and biosynthesis. Fossum, C. Pre-existing oxidative stress creates a docking-ready conformation of the SARS-CoV-2 receptor-binding domain. ACS Bio. Franco, R. Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ.
Glutathione efflux and cell death. Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation. The central role of glutathione in the pathophysiology of human diseases.
Fraternale, A. Glutathione and glutathione derivatives in immunotherapy. Antiviral and Immunomodulatory properties of new pro-glutathione GSH molecules. Intracellular redox-modulated pathways as targets for effective approaches in the treatment of viral infection.
Fratta Pasini, A. Potential role of antioxidant and anti-inflammatory therapies to prevent severe SARS-Cov-2 complications. Antioxidants Funes, S. Naturally derived heme-oxygenase 1 inducers and their therapeutic application to immune-mediated diseases.
Gadanec, L. Can SARS-CoV-2 virus use multiple receptors to enter host cells? García-Giménez, J. Nuclear glutathione. Garg, S. Differential dependence on cysteine from Transsulfuration versus transport during T cell activation. Antiox Redox Signal 15, 39— Ghati, A. Exogenous pulmonary surfactant: a review focused on adjunctive therapy for severe acute respiratory syndrome coronavirus 2 including SP-A and SP-D as added clinical marker.
Colloid Interface Sci. Ghezzi, P. Role of glutathione in immunity and inflammation in the lung. Frye and M. Berk Springer Nature Singapore Pte Ltd. Gill, R. Linking oxidative stress to inflammation: toll-like receptors. Giustarini, D. Pitfalls in the analysis of the physiological antioxidant glutathione GSH and its disulfide GSSG in biological samples: an elephant in the room.
B Analyt. Life Sci. Golabi, S. Oxidative stress and inflammatory status in COVID outpatients: a health center-based analytical cross-sectional study.
Gong, W. COVID pandemic: SARS-CoV-2 specific vaccines and challenges, protection via BCG trained immunity, and clinical trials. Expert Rev. Vaccines 20, — Gottlieb, R. Early Remdesivir to prevent progression to severe Covid in outpatients.
Gould, R. Impact of supplementary amino acids, micronutrients, and overall diet on glutathione homeostasis. Nutrients Gralinski, L. Molecular pathology of emerging coronavirus infections.
Grigoletto Fernandes, I. SARS-CoV-2 and other respiratory viruses: what does oxidative stress have to do with it? Oxidative Med. Guillin, O. Selenium, selenoproteins and viral infection. Guloyan, V.
Glutathione supplementation as an adjunctive therapy in COVID Hadzic, T. The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion. Hajjar, I. Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study.
Neuroinflammation Hamilos, D. Lymphocyte proliferation in glutathione-depleted lymphocytes: direct relationship between glutathione availability and the proliferative response.
Immunopharmacology 18, — Harvey, C. Nrf 2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Hati, S. ACS Omega 5, — He, L. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species.
Heil, E. The goldilocks time for Remdesivir— is any indication just right? Herengt, A. NRF2 in viral infection. Hermel, M. Natural supplements for COVID19—background, rationale, and clinical trials. Based Integr. Hotchkiss, R. Cell death. Hsu, R. The role of cytokines and chemokines in severe acute respiratory syndrome coronavirus 2 infections.
Huang, I. Lymphopenia in severe coronavirus disease COVID : systematic review and meta-analysis. Intensive Care Hunter, D. Addressing vaccine inequity — Covid vaccines as a global public good.
Iotti, S. The COVID pandemic: is there a role for magnesium? Hypotheses and perspectives. Magnes Res. Jackson, C. Mechanisms of SARS-CoV-2 entry into cells. Cell Biol. Jain, S.
Can vitamin D and L-cysteine co-supplementation reduce 25 OH -vitamin D deficiency and the mortality associated with COVID in African Americans? Glutathione stimulates vitamin D regulatory and glucose-metabolism genes, lowers oxidative stress and inflammation, and increases Hydroxy-vitamin D levels in blood: a novel approach to treat Hydroxyvitamin D deficiency.
The potential link between inherited G6PD deficiency, oxidative stress, and vitamin D deficiency and the racial inequities in mortality associated with COVID Jarrott, B.
Jin, Y. mRNA vaccine: how to meet the challenge of SARS-CoV Jung, H. Current understanding of the innate control of toll-like receptors in response to SARS-CoV-2 infection.
Viruses Kaklamanos, A. COVID Immunobiology: lessons learned, new questions arise. Kalra, R. Engaging the spikes: heparan sulfate facilitates SARS-CoV-2 spike protein binding to ACE2 and potentiates viral infection.
Kang, I. Proteoglycans as Immunomodulators of the innate immune response to lung infection. Karkhanei, B. Evaluation of oxidative stress level: total antioxidant capacity, total oxidant status and glutathione activity in patients with COVID New Microbes New Infect Kasprzak, M. Kawasaki, T.
Toll-like receptor signaling pathways. Kawasaki, K. Metabolomic profiles of placenta in preeclampsia. Antioxidant effect of magnesium sulfate on Trophoblasts in early-onset preeclampsia. Hypertension 73, — Kelly, B. Amino assets: how amino acids support immunity.
Cell Metab. Kernan, K. Hyperferritinemia and inflammation. Kesarwani, P. Redox regulation of T-cell function: from molecular mechanisms to significance in human health and disease.
Antiox Redox Signal 18, — Khanfar, A. Could glutathione depletion be the Trojan horse of COVID mortality? Khanmohammadi, S. Role of toll-like receptors in the pathogenesis of COVID Khomich, O. Redox biology of respiratory viral infections. Klok, F. Incidence of thrombotic complications in critically ill ICU patients with COVID Knoll, R.
Monocytes and macrophages in COVID Kobayashi, E. Nrf 2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Kolls, J. Oxidative stress in sepsis: a redox redux. Komaravelli, N. Respiratory viral infections and subversion of cellular antioxidant defenses.
Pharmacogenomics Pharmacoproteomics Kozlov, E. Involvement of oxidative stress and the innate immune system in SARS-CoV-2 infection. Diseases Kryukov, E. Association of low molecular weight plasma aminothiols with the severity of coronavirus disease Kumar, D.
Extracellular oxidative stress markers in COVID patients with diabetes as co-morbidity. Kumar, P. Severe glutathione deficiency, oxidative stress and oxidant damage in adults hospitalized with COVID implications for Gly NAC glycine and N-Acetylcysteine supplementation.
Kwon, D. Glutathione induced immune-stimulatory activity by promoting M1-like macrophages polarization via potential ROS scavenging capacity. Labarrere, C. Pattern recognition proteins: first line of defense against coronaviruses. Response: commentary: pattern recognition proteins: first line of defense against coronaviruses.
Laforge, M. Tissue damage from neutrophil-induced oxidative stress in COVID Lage, S. Lambeth, J. NOX enzymes and the biology of reactive oxygen. Lands, L. Effect of supplementation with a cysteine donor on muscular performance. Lee, C. Therapeutic modulation of virus-induced oxidative stress via the Nrf 2-dependent antioxidative pathway.
Lee, A. The dual nature of type I and type II interferons. Levring, T. Oncotarget 6, — Lewis, K. Nrf 2, a guardian of healthspan and gatekeeper of species longevity.
Li, C. Multiomics integration-based molecular characterizations of COVID Li, X. Toll-like receptor signaling in cell proliferation and survival. Cytokine 49, 1—9. Li, S. Cellular metabolic basis of altered immunity in the lungs of patients with COVID Lin, Y. Sepsis-induced myocardial dysfunction SIMD : the pathophysiological mechanisms and therapeutic strategies targeting mitochondria.
Inflammation 43, — Lin, C. Potential role of Nrf 2 activators with dual antiviral and anti-inflammatory properties in the management of viral pneumonia.
Drug Resist. Linani, A. Litvack, M. Review: soluble innate immune pattern-recognition proteins for clearing dying cells and cellular components: implications on exacerbating or resolving inflammation.
Innate Immun. Liu, M. Magnesium supplementation improves diabetic mitochondrial and cardiac diastolic function. JCI Insight 4:e Improve insulin resistance Higher levels of glutathione may lower your risk for diabetes. Better liver health A lack of antioxidants, including glutathione, may lead to fatty liver disease.
Extend your life Large-scale research published in 16 connected disturbances in glutathione homeostasis with everything from cancer to metabolic, immune, and inflammatory diseases. Live Longer, Live Better. Sounds Like a plan. Fight autoimmune disease One study noted a strong link between oxidative stress and apoptosis—a normal process of programmed cell death—in patients living with lupus, an autoimmune disease.
Help treat COVID A recent study published in the journal Antioxidants 19 found that people who contracted the COVID virus and were hospitalized had significantly increased levels of oxidative stress, and significantly lower levels of glutathione, when compared to blood samples from healthy adults of the same age.
Aid with inflammatory bowel disease People with inflammatory bowel disease IBD in particular may find glutathione helpful.
Amp physical performance If taken before a workout, glutathione may enhance your gains. Prevent obesity Metabolic syndrome is a cluster of health conditions—including high blood pressure, elevated blood sugar, high cholesterol, high triglycerides, and a high waist circumference—which can raise the risk for diabetes, heart disease, and stroke.
Decrease heart disease Glutathione appears to protect against heart disease—at least in animals. Boost fertility In one study of eleven infertile men, glutathione had a significant positive effect on sperm motility after 2 months of treatment Improve atherosclerosis Atherosclerosis is a condition caused by a build-up of plaque in the arteries that can lead to heart disease and stroke.
Food A number of foods naturally contain glutathione. Good dietary sources of GSH include: Cruciferous vegetables like brussels sprouts, kale, cauliflower and broccoli. These vegetables contain sulforaphane, a compound that research shows can boost glutathione.
Grapefruit, kiwis, and citrus fruits are rich sources of vitamin C. Research 27 suggests vitamin C plays an important role in glutathione oxidation. Whey Protein. One small study found that after completing an intense resistance training workout, young men who supplemented with whey protein saw significant increases in glutathione peroxidase in comparison to a placebo group Lifestyle changes Adopting healthy habits like getting enough sleep, exercising, and cutting back on alcohol use can keep glutathione levels healthy 29 , 30 , 31 Glutathione oral supplements Research around oral glutathione is mixed on whether supplements are an effective way to boost your levels 32 , 33 since the antioxidant is poorly absorbed during digestion.
Can I Take Glutathione Every Day? Glutathione Side Effects and Risks Glutathione injections have a few side effects, most of which are mild, and include: Loose stools Cramping Increased flatulence. References 1. Forman HJ, et al Glutathione: overview of its protective roles, measurement, and biosynthesis.
Sekhar RV, et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation.
Minich DM, Brown BI. A Review of Dietary Phyto Nutrients for Glutathione Support. Kwon DH, et al. Protective Effect of Glutathione against Oxidative Stress-induced Cytotoxicity in RAW Gould RL, Pazdro R.
Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis. Kumar P, et al. Glycine and N-acetylcysteine GlyNAC supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial.
Diotallevi M, et al. Glutathione Fine-Tunes the Innate Immune Response toward Antiviral Pathways in a Macrophage Cell Line Independently of Its Antioxidant Properties. Sinha R, et al. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function.
Aoyama K. Glutathione in the Brain. Sechi G, et al. Salim S. Oxidative Stress and the Central Nervous System. Stine D. The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: a randomized trial. Beever A, et al.
L-GSH Supplementation in Conjunction With Rifampicin Augments the Treatment Response to Mycobacterium tuberculosis in a Diabetic Mouse Model. Correcting glutathione deficiency improves impaired mitochondrial fat burning, insulin resistance in aging Honda Y, et al.
Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. Ballatori N, et al. Glutathione dysregulation and the etiology and progression of human diseases. Shah D, et al.
Interaction between glutathione and apoptosis in systemic lupus erythematosus. Carlo Perricone, et al. Glutathione: A key player in autoimmunity. Severe Glutathione Deficiency, Oxidative Stress and Oxidant Damage in Adults Hospitalized with COVID Implications for GlyNAC Glycine and N-Acetylcysteine Supplementation.
Sido B, et al Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease Aoi W, et al. Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism. Goutzourelas N, et al. GSH levels affect weight loss in individuals with metabolic syndrome and obesity following dietary therapy.
Seymour EM, et al. Diet-relevant phytochemical intake affects the cardiac AhR and nrf2 transcriptome and reduces heart failure in hypertensive rats. Lenzi A, et al. Glutathione therapy for male infertility. Coppola L, et al. Glutathione GSH improved haemostatic and haemorheological parameters in atherosclerotic subjects.
Sedlak, T. et al Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot. Park, S. Vitamin C in Cancer: A Metabolomics Perspective. Flaim, C. Effects of Whey Protein Supplementation on Oxidative Stress, Body Composition and Glucose Metabolism Among Overweight People Affected by Diabetes Mellitus or Impaired Fasting Glucose: A Pilot Study Gulec, A.
Berry, S Changes in Glutathione System in Response to Exercise Training are Sex-Dependent in Humans. Ramgir, S et al Impact of Smoking and Alcohol Consumption on Oxidative Status in Male Infertility and Sperm Quality. Allen J, Bradley RD. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers.
Richie JP Jr, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Is Autophagy the Secret to Weight Loss and Longevity?
By Jennifer Chesak. New Study Argues This Type of Exercise Might Shorten Your Life—Experts Disagree. By Sydney Bueckert, NASM CPT, CES, FNS, GPT.
On a macro scale, the human Glufathione system is broken up into two separate components, the Glutthione immune system and funcction acquired Water content analysis system. An example of the innate immune Glutathionw would be our African Mango seed immune system acid, which is responsible for not only digesting proteins, but also destroying any bugs that may be hiding in the foods that we consume. The acquired immune system is just that — acquired. An example of this would be the antibodies created to fight off the common cold. Ever wondered why it is that you might get the cold once a year, recover, and then never get it for a significant amount of time?In fact, there Effective metabolism booster a immine connection between glutathione Immune-boosting natural remedies your Vunction system.
Im,une is produced Glutathione and immune function your cells naturally. Its levels also decline with age. Superfood supplement for metabolism boost addition to being produced naturally by the body, glutathione functioon be andd intravenouslyorally, topically, or as an inhalant.
Your body needs glutathione to keep your immune system running well. Below anv the best ways. to increase glutathione in your body:. That African Mango seed immune system, the publication Lean muscle definition indeed Bone health and dairy products to the important immhne involved with glutathione African Mango seed immune system a deficiency thereof.
Funcrion definitely recommend glutathione for immune andd. Call: to order today. BOOK Glutathione and immune function THERAPY TODAY! LEARN MORE African Mango seed immune system IMMUNE BUNDLE: Emulsi-D3 Synergy Glutathioone oz Liposomal Vitmain C 4fl Sports performance monitoring Liposomal Glutathione 1.
Your email address Glutathione and immune function not be published. Glutatthione Facebook Instagram. Glutathione and immune function Instagram, African Mango seed immune system. July 9, GlutathionE and YOUR IMMUNE Funcyion.
BY MATTEO ROSSELLI, D. Immyne plays some major roles in immune function. It helps to: restore balanced inflammation by regulating immune response 1 neutralize free radicals damaged cells and reducing oxidative stress 2 regulate cellular proliferation and apoptosis cell death 3 How to Boost glutathione AND YOUR IMMUNE SYSTEM Your body needs glutathione to keep your immune system running well.
to increase glutathione in your body: Decrease your toxic burden. Toxins from our food supply, tap water, cleaning supplies, etc. Limiting your exposure to these toxins, allows your natural gluathione to be used in other processes, like keeping your digestive health working and your skin glowing!
Limit alcohol consumption. We all know that alcohol consumption affects our liver. Cell death in the liver may be exacerbated by a deficiency in antioxidants, including glutathione.
This can lead to fatty liver disease. A study reported that glutathione is very effective when given to people with fatty liver disease intravenously, in high doses. Eat an antioxidant-rich diet. Sulfur-rich foods, like: dietary proteins, such as beef, fish and poultry.
cruciferous vegetables like broccoli, Brussels sprouts, cauliflower, kale, watercress and mustard greens can all boost antioxidant levels in the body. Take a glutathione supplement. One of my most frequent supplement recommendations is liposomal glutathione.
Almost everybody can benefit from a daily glutathione supplement. Take Glutathione Boosting Supplements. Many other vitamins and minerals contribute to glutathione production in the body, including: Curcumin, N-acetylcysteine, Selenium, Silymarin, Vitamin C, and Vitamin E. Get a Glutathione IV: Intravenous glutathione is the fastest way for your body to absorb glutathione.
Glutathione IV therapy bypasses your digestive tract and delivers the powerful antioxidant directly to your bloodstream. Book now: LEARN MORE. ULTIMATE IMMUNE BUNDLE: Emulsi-D3 Synergy 2fl oz Liposomal Vitmain C 4fl oz Liposomal Glutathione 1. Submit a Comment Cancel reply Your email address will not be published.
: Glutathione and immune function| Top bar navigation | COVID and immnue African Mango seed immune system. Diabetic COVID patients have high Glutathkone oxidative stress, evidenced by decreased extracellular superoxide dismutase 3 levels African Mango seed immune system Glutwthione. We will discuss the life-sustaining importance of GSH, anc relationship with oxidative Quercetin and mental health, as Hydration for trail running as its synthesis and catabolism, immume biological functions and the paramount relevance of GSH in the immune system especially the innate immune systemin reducing COVID severity and mortality, and the antiviral capabilities of GSH to reduce SARS-CoV-2 infectivity and multiorgan failure secondary to a cytokine storm in COVID disease. Better liver health A lack of antioxidants, including glutathione, may lead to fatty liver disease. All these genes map to nrf2, a master regulator of redox homeostasis Cellular oxidative stress response controls the antiviral and apoptotic programs in dengue virus-infected dendritic cells. |
| Glutathione and Your Immune System - RevitalIV | TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury. Huang, I. New Study Argues This Type of Exercise Might Shorten Your Life—Experts Disagree. Morris, D. Glutathione synthesis. Nat Immunol — Ringel, J. |
| Glutathione and immune function | By Jennifer Chesak. Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: a randomized trial. Glutathione and other diseases. There is a large body of evidence showing the importance of GSH in immunity, including antiviral immunity 47 , but so far this was ascribed to its action as ROS scavenger to inhibit oxidative stress. The number of transcripts resulting from filtering is indicated and color coded red, increased; green, decreased. |
| Free Radicals | There is no indication that immunological functions such as resistance to infection or the response to vaccination may be enhanced in healthy human subjects by administration of glutathione or its precursor amino acid cysteine. However, immunological functions in diseases that are associated with a cysteine and glutathione deficiency may be significantly enhanced and potentially restored by cysteine supplementation. Two randomized placebo-controlled trials have shown that treatment of HIV-infected patients with N-acetyl-cysteine caused in both cases a significant increase in all immunological functions under test, including an almost complete restoration of natural killer cell activity. It remains to be tested whether cysteine supplementation may be useful also in other diseases and conditions that are associated with a low mean plasma cystine level and impaired immunological functions. Nrf2 also regulates the expression of genes that control inflammatory and immune system responses Kasprzak et al. The presence of Nrf2 and its inhibitor Keap1 in plasma is associated with damaged vascular endothelial cell-, macrophage-and other cell-associated leakage secondary to the loss of cell membrane integrity due to lipid peroxidation following chronic inflammation and oxidative stress Kasprzak et al. Continuous oxidative stress can lead to chronic inflammation, intense cytokine release and a cytokine storm as seen in SARS-CoV-2 infection in COVID disease, and the viral infection enhances oxidative stress creating a fatal vicious circle between oxidative stress and cytokine storm during COVID infection Delgado-Roche and Mesta, ; Meftahi et al. Oxidative stress plays a prominent role in innate immunity being closely involved in SARS-CoV-2 infection Kozlov et al. The role of oxidative stress in the COVID disease may involve recognition of the viral S-protein by angiotensin converting enzyme-2 ACE2 receptor and pattern recognition receptors like toll-like receptors 2 and 4, and activation of transcription factors like nuclear factor kappa B, that subsequently activate nicotinamide adenine dinucleotide phosphate NADPH oxidase NOX expression succeeded by ROS production Kozlov et al. Interestingly, excessive ROS production and oxidative stress raises the binding affinity of the spike protein for the human ACE2 receptor Hati and Bhattacharyya, ; Fossum et al. Thus, excessive production of ROS mediates hyper-inflammation and generation of cytokine storm that directly determine both ARDS development and ARDS course severity. ROS are a necessary defense system to combat microbial respiratory infections Lambeth, , but oxidative stress and the excessive production of ROS by numerous cells including monocytes and macrophages, neutrophils, as well as pulmonary endothelial and epithelial cells play a major role in the development of ARDS and its complications during COVID infections Meftahi et al. SARS-CoVmediated NET release can promote lung epithelial cell death unravelling a detrimental role of NETs in the pathophysiology of COVID disease Veras et al. Extensive persistent inflammation even when SARS-CoVinfected cells are only sporadically present at late stages of COVID Schurink et al. Neutrophilia causes excessive ROS production that aggravates the host immunopathological response, leading to a more severe disease Laforge et al. In addition to the neutrophil infiltration and ROS release, viral infections decrease antioxidant defenses. They inhibit Nrf2 translocation into the nucleus and enhance NFκB activation promoting inflammation and oxidative damage Laforge et al. Nrf2 is the principal transcription factor in charge of protecting cells from oxidative stress through the regulation of cytoprotective genes, including the antioxidant GSH pathway, that controls GSH homeostasis by affecting de novo synthesis. It has been shown that Nrf2 modulates the GSH redox state via glutathione reductase regulation. Overall, Nrf2 is fundamental for the sustenance of the GSH redox state through glutathione reductase transcriptional regulation and for cell protection against oxidative stress Harvey et al. The overwhelming dominance of ROS generated by enzymes like NADPH oxidases and xanthine oxidase over antioxidants like superoxide dismutase causes cell injury and tissue damage through direct injury, lipid peroxidation and protein oxidation leading to protease release and antioxidant and antiprotease enzyme inactivation as well as alteration of transcription factors activator protein-1 and NFκB. All these changes lead to cytokine storm characterized by increased expression and release of proinflammatory cytokines that participate in the pathogenesis of ARDS during virus respiratory infections like COVID Proinflammatory cytokines further stimulate ROS overproduction aggravating ARDS and lung damage causing a vicious circle between oxidative stress and cytokine storm. In response to a viral infection, activated cells have enhanced production of the NOX family of NADPH oxidases Brandes et al. The presence of oxidative stress markers like lipid peroxidation, neutrophil reverse trans-endothelial migration rTEM and high neutrophil to lymphocyte ratio in patients with COVID, facilitates identification of high-risk individuals early in the course of the disease preventing their sudden deterioration Laforge et al. Furthermore, increased ACE2 expression in alveolar type II pneumocytes and alveolar macrophages of individuals with severe SARS-CoV-2 disease ARDS with diffuse alveolar damage requiring mechanical ventilation Baker et al. Glutathione is fundamental to sustain an adequate function of the immune system, particularly affecting the lymphocyte activity since low GSH levels inhibit T-cell proliferation and immune response Dröge and Breitkreutz, ; Ghezzi, ; Moro-García et al. GSH depletion is strongly associated with impaired immune function and with disease development including viral diseases, cancer, cardiovascular diseases, arthritis and diabetes Sinha et al. GSH is essential for immunomodulation of both innate and adaptive immune system functions, including T-lymphocyte proliferation, polymorphonuclear neutrophil phagocytosis, and dendritic cell functions, and is also important for fine-tuning the innate immune response to infection and for the first step of adaptive immunity involving antigen-presenting cell macrophages, dendritic cells -related antigen presentation Morris et al. GSH works to modulate the behavior of many immune cells, augmenting both, innate immunity and trained innate immunity or innate immune memory; Netea et al. Persistent and uncontrolled oxidative stress and exacerbating NLRP3 NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome activation during severe COVID disease Lage et al. Many antioxidant molecules, such as GSH and N-acetylcysteine NAC , were found to inhibit viral replication through different mechanisms of action Fraternale et al. Cell-mediated immunity primarily needs protein antigen degradation in the endocytic vesicles of antigen presenting cells macrophages, dendritic cells , to be able to present smaller peptides on the cell surface through major histocompatibility complex antigens to activate antigen-specific T cell proliferation. One of the initial steps in antigen degradation and processing is the reduction of disulfide bonds, that requires GSH; and although GSH inhibits production of most inflammatory cytokines, it is needed to keep an adequate interferon gamma production by dendritic cells, essential for intracellular pathogen host defense Ghezzi, ; Lee and Ashkar, ; Calder, ; Fraternale et al. The principal function of endogenous GSH is not to limit inflammation but to fine-tune the innate immune response to infection Diotallevi et al. GSH is capable of scavenging ROS through Nrf2-mediated heme oxygenase-1 induction and enhancing M1-like macrophage polarization regulation, showing that GSH may be a useful strategy to increase the human defense system Mittal et al. Strategies to enhance intracellular GSH levels such as supplementation of additional sources of cysteine Deneke and Fanburg, ; Dröge et al. The GSH and NAC digestive degradation occurring during oral treatments lead to consider GSH and NAC nebulization as a viable alternative to manage early stages of COVID disease Santos Duarte Lana et al. GSH increases activation of cytotoxic T cells in vivo , and adequate functioning of T lymphocytes and other cells depends upon cellular supplies of cysteine Edinger and Thompson, ; Garg et al. Cells acquire cysteine mainly by macrophage and lymphocyte uptake, and impaired immune responses are associated with a reduction in GSH concentration Dröge and Breitkreutz, ; Edinger and Thompson, ; Garg et al. GSH is of paramount importance for the appropriate function of the immune system in general and particularly lymphocytes since low GSH levels inhibit T lymphocytes proliferation and subsequently disturbs the immune response Hamilos et al. The decreased immune response could be reversed by the administration of N-acetylcysteine Atkuri et al. Low GSH levels inhibit interleukin-2 production, which induces lymphocyte proliferation Chang et al. T-cell function can be recuperated following administration of GSH precursors like N-acetyl cysteine and cysteine Dröge and Breitkreutz, ; Ghezzi, ; Aquilano et al. GSH depletion is needed for apoptosis to be triggered in the lymphocytes regardless of ROS Franco et al. In order to induce T lymphocyte apoptosis, GSH must be pumped out of the cells Franco and Cidlowski, , ; Franco et al. The GSH effects on apoptosis and inhibition of T-cell proliferation could explain why patients with SARS-CoV-2 infection and COVID disease develop lymphopenia and subsequent failure of the immune system Khanfar and Al Qaroot, A way to explain cell death associated with reduced levels of GSH is ferroptosis, a unique iron-dependent form of non-apoptotic cell death, characterized by lipid peroxidation with ROS accumulation due to GSH peroxidase inactivation and high levels of GSH consumption; ferroptosis has been proposed to be involved in COVIDrelated brain injury Zhang et al. Immune system failure could lead to uncontrolled replication of the SARS-CoV-2 virus, secondary infections and continuous shedding of the virus in patients who die from COVID regardless of the time passed from the start of the infection Ruan et al. Several viral infections, and the progression of virus-induced diseases, especially those associated with COVID, are characterized by an alteration in the intracellular redox balance Polonikov, Oxidative stress reflects an imbalance between increased ROS production and reduced cellular antioxidant capabilities. This imbalance disallows reactive intermediate detoxification by the cell biological systems. ROS production and associated inflammation are closely related to aging and numerous chronic diseases as diabetes, cardiovascular and respiratory diseases, known risk factors for developing severe illness and death in patients with SARS-CoV-2 and COVID disease. Figure 2. Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 pulmonary infection, oxidative stress and antioxidant defenses. Infected cells activate nuclear factor NF -κB and release cytokines like interleukin IL Alveolar type I cells augment ROS production via toll-like receptors TLRs 2 and 4. Capillary neutrophils migrate to and from alveoli by trans-endothelial TEM and reverse transmigration rTEM , respectively. SARS-CoV-2 infection can cause excessive ROS production in capillaries, red blood cell RBC dysfunction, thrombosis and alveolar damage. NOX2 activation increases ROS production that enhance NF-κB activation. Activated alveolar macrophages release increased levels of IL-1β, IL-6, IL-8 and tumor necrosis factor TNF -α. Glutathione GSH precursors Cystine, cysteine, N-acetyl cysteine, NAC , and selenium Se restore GSH and GPx, respectively, to counteract the effects of ROS. Abbreviations: TMPRSS2: Transmembrane protease Serine 2; PRPs: pattern recognition proteins. Atherosclerosis, a chronic inflammatory disease, may be an ideal environment for the high viral replication capabilities of SARS-CoV-2 in human cells, enhancing hyper-inflammation secondary to immune system dysregulation Figure 3 that leads to adverse outcomes, as shown in patients with cardiovascular risk factors. In a vicious circle, feeding itself, SARS-CoV-2 may aggravate the evolution of atherosclerosis as a result of excessive and aberrant plasmatic concentration of cytokines Vinciguerra et al. Atherosclerosis progression, as a chronic inflammatory mechanism, is characterized by immune system dysregulation associated with increased pro-inflammatory cytokine production, including interleukin 6 IL-6 , tumor necrosis factor-α TNF-α , and IL-1β Vinciguerra et al. C-reactive protein CRP , an active regulator of host innate immunity, is a biomarker of severe COVID disease, including lung and atherosclerotic disease progression; strongly predicts the need for mechanical ventilation; and may guide intensification of treatment of COVIDassociated uncontrolled inflammation Potempa et al. Macrophage activation and foam cell formation may explain the elevated CRP serum levels and contribute to disease progression Figure 3. CRP-mediated inflammation in atherosclerosis during SARS-CoV-2 infection may be explained by the presence of monomeric CRP mCRP in the lesions Potempa et al. The affinity of SARS-CoV-2 for ACE2 receptors makes the virus prone to cause vascular infection that could explain atherosclerosis progression and arterial and venous thrombosis Vinciguerra et al. Endothelial injury generated directly by intracellular viral replication and by ACE2 downregulation, exposing cells to angiotensin II in the absence of the modulator effects of angiotensin 1—7 Vinciguerra et al. Figure 3. Severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 enhances oxidative stress and atherosclerosis progression. Native C-reactive protein nCRP , a marker of severe SARS-CoV-2 produced in liver, macrophages, lymphocytes, smooth muscle cells SMC and other cells, promotes inflammation through monomeric CRP mCRP enhancing intimal oxidative stress. SARS-CoV-2 can bind TLRs 2 and 4 and activate transcription factors like nuclear factor NF -κB facilitating cytokine storm and hyperinflammation. Excessive mitochondrial reactive oxygen species ROS generation further enhances cytokine production. CRP nCRP, mCRP can facilitate macrophage and neutrophil uptake of SARS-CoVinfected apoptotic cells through Fcγ and Fcα receptors, respectively FcRs. Oxidative stress also activates the Kelch-like ECH-associated protein 1 Keap1 -Nuclear factor erythroid 2-related factor2 Nrf2 -antioxidant response element ARE redox regulator pathway in monocytes see [3] and macrophages, releasing Nrf2 to regulate the expression of genes that control antioxidant enzymes like glutathione S-transferase GST , facilitating glutathione GSH activity. Macrophages, Tlymphocytes, neutrophils and SMCs can generate mCRP increasing inflammation. TLR 4-mediated SARS-CoVbinding to platelets promotes thrombosis, mCRP binding to lipid rafts and FcγRs enhances inflammation and endothelial activation allows intimal cell migration. GSH synthesis catalyzed sequentially by two cytosolic enzymes, γ-glutamyl-cysteine synthetase GCS and GSH synthetase is part of virtually all cell types, and the liver is the major GSH producer and exporter. Preservation of the highest millimolar concentrations of reduced GSH in most cell types highlights GSH vital and multifunctional roles in controlling various biological processes like detoxification of foreign and endogenous compounds, protein folding, regeneration of vitamins C and E, maintenance of mitochondrial function, regulation of cell cycle and cell proliferation, apoptosis, immune response, and multiple other cellular and biological functions, particularly important, antiviral defense Meister and Anderson, ; Townsend et al. SARS-CoV-2 markedly decreases the levels of cellular thiols, essentially lowering the reduced form of GSH; and the use of antivirals that enhance activation of the Nrf2 transcription factor together with N-acetylcysteine administration restore GSH levels correcting the SARS-CoVmediated impaired GSH metabolism Aquilano et al. Figure 4. Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection alters metabolism and redox function of cellular glutathione GSH. SARS-CoV-2 markedly decreases GSH levels [1], that could be explained by lower intake of the GSH precursor cysteine Cys [2] and increased efflux of cellular thiols [3]. Increased levels of oxidized glutathione GSSG and protein glutathionylation [4] along with upregulation of endoplasmic reticulum stress marker protein kinase R PKR -like endoplasmic reticulum kinase PERK [5] are also observed. Modified from Bartolini et al. COVID is clinically mild in most cases, severe cases develop pneumonia, and critical cases end with ARDS, sepsis, and multiple organ failure Yang X. COVID sepsis is a serious problem in critically ill patients infected with SARS-CoV-2 Beltrán-García et al. Sepsis is a systemic inflammatory response caused by excessive cytokine secretion, such as interleukin IL -6, IL, IL1β and TNF-α. ROS may be important mediators of cellular injury during COVID sepsis Silvagno et al. Multiple organ failure including sepsis-induced cardiac dysfunction seem to be the result of numerous factors as overwhelming inflammation and nitric oxide synthesis impairment associated with mitochondrial dysfunction and increased oxidative stress Cecchini and Cecchini, Excessive ROS production, associated with inflammation, induces oxidative stress. Oxidative stress is a major contributor to the high mortality rates associated with SARS-CoV-2 infections Poljsak et al. Immune cells use ROS to sustain their functions and need adequate levels of antioxidant defenses to avoid harmful effects caused by excessive ROS production, since accurate balance between ROS and intracellular antioxidants is essential for a normal function of the cell Banjac et al. L-cysteine is the rate-limiting substrate in the synthesis of intracellular GSH Raftos et al. Although N-acetylcysteine NAC directly influences the pool of extracellular cystine and intracellular cysteine via a series of plasmatic redox reactions, in order to be effective, intracellular cysteine precursors must be designed to enter erythrocytes rapidly and use high activity enzymes within erythrocytes to liberate cysteine Whillier et al. NAC enhances extracellular cysteine and by using transport channels increases intracellular cysteine Franco and Cidlowski, ; Aldini et al. During oxidative stress, NAC will increase GSH synthesis Franco and Cidlowski, ; Rushworth and Megson, ; Campolo et al. Without oxidative stress, cysteine and cystine appear to essentially mediate cellular stress via thiols other than GSH Rahman and MacNee, ; Ashfaq et al. Individuals with diabetes have lower GSH levels compared to control subjects Samiec et al. Supplementation of cysteine and glycine in the diet can increase GSH levels and reduce oxidative stress in the elderly and persons with diabetes Sekhar et al. Elderly adults may also have reduced redox potential due to lower GSH levels Samiec et al. Lowered cellular redox status increases susceptibility to oxidative stress that may lead to cell death and virus release Raftos et al. The potential clinical use of antioxidants and antioxidant precursors in the treatment of COVID needs to be seriously considered. GSH is paramount with respect to disease pathogenesis and individual response to COVID infection; and enhancement of GSH levels can be a means for treating and preventing COVID disease Polonikov, As it was recently suggested, GSH depletion could be the Trojan horse of COVID severity and mortality and elevating GSH levels in tissues may decrease COVID severity and mortality rates Khanfar and Al Qaroot, The prominence of the coronavirus disease COVID pandemic urges multidisciplinary strategies to control disease spread and prevent its complications Labarrere and Kassab, SARS-CoV-2 and its massive cytokine storm primarily compromises the lungs causing acute respiratory distress syndrome also affecting the cardiovascular system aggravating atherosclerotic lesions leading to thromboembolic events and cell and tissue death Ryu and Shin, ; Taoufik et al. SARS-CoV-2 infects pulmonary type II alveolar cells because these cells express angiotensin-converting enzyme 2 ACE2; Ryu and Shin, ; Taoufik et al. SARS-CoV-2 ACE2-mediated host cell invasion is enhanced by the presence of heparan sulfate proteoglycans HSPGs consisting of a core protein bearing glycosaminoglycan carbohydrate chains Souza-Fernandes et al. Virus protein ligands, like trimeric spike glycoprotein interact with cellular receptors, such as ACE2, and host proteases, like transmembrane protease serine 2 TMPRSS2 , participate in virus entry by proteolytically activating virus ligands Sallenave and Guillot, ; Kalra and Kandimalla, ; Zhang Q. In the lungs, after entering in type II alveolar cells, SARS-CoV-2 infected cells become defective for surfactant production Ghati et al. Alveolar macrophages, due to their polarization state toward M1 or M2 phenotypes, provoke different effects following SARS-CoV-2 infection. Hyperactivated M1 alveolar macrophages are taken over by SARS-CoV-2 allowing for viral infection and spread, while M2 alveolar macrophages can degrade the virus and limit its spread Knoll et al. Neutrophils produce ROS and proteinases, causing further destruction of healthy type II cells; as a result, surfactant production decreases markedly, which in turn causes alveolar fluid accumulation leading to alveolar collapse and ARDS Matthay and Zemans, ; Carcaterra and Caruso, Due to the exhaustion of cellular and extracellular GSH caused by numerous GSH-consuming pathways the severe inflammation and oxidative stress triggered by the viral infection steals GSH from crucial functions like NO-dependent vasodilatation, disallowing the patient of being protected from an inflammation that can become fatal. Based on the previous discussion, administration of antioxidants or Nrf2 inducers are potential viable therapies for viral-induced diseases, like respiratory infections and infections associated with reduced cellular antioxidant capacity Komaravelli and Casola, A high neutrophil to lymphocyte ratio found in critically ill patients with COVID is associated with excessive ROS levels, that promote a cascade of biological events driving pathological host responses. Since ROS induce tissue damage, thrombosis and red blood cell dysfunction that contribute to COVID disease severity, administration of free radical scavengers could be beneficial for the most vulnerable patients Laforge et al. Toll-like receptors TLRs play a key role in microorganism and viral particle recognition and activation of the innate immune system Sasai and Yamamoto, ; Kawasaki and Kawai, ; McClure and Massari, ; Sartorius et al. TLR pathway activation leads to secretion of pro-inflammatory cytokines, like interleukin IL -1, IL-6, and tumor necrosis factor-α, as well as type 1 interferon. TLRs can be localized either on the cell surface TLR-1, -2, -4, -5, -6, or in the endosome compartment TLR-3, -7, -8, -9; Sasai and Yamamoto, ; Kawasaki and Kawai, ; Sartorius et al. TLRs-2, -3, -4, -6, -7, -8, and -9 are potentially important in COVID infection Onofrio et al. TLR4-mediated recognition of S protein may initiate receptor dependent internalization and explain SARS-CoV-2 infection in patients and cells lacking or deficient in ACE2 expression Aboudounya and Heads, ; Gadanec et al. Viral proteins as well as host damage-associated molecular patterns, that accumulate following cellular stress during viral infection, were linked to TLR4 activation, with uncontrolled TLR4 activation being associated with severe disease Olejnik et al. TLR4 activation in platelets whether by pathogen- viremia or damage-associated molecular patterns induces a prothrombotic and proinflammatory state Schattner, SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signaling increasing cell surface expression of ACE2 facilitating entry Aboudounya and Heads, The expression of CD14, TLR2 and 4 in human alveolar type I and II cells Thorley et al. Ten human TLRs that signal via 4 adaptor proteins and 2 initial kinases activate distal kinases that subsequently regulate transcription factors such as NFκB and activator protein 1 AP-1 , that control gene expression. Posttranslational modifications of ROS-mediated kinase activity most probably contribute to the diversity and intensity of gene expression following microbial activation of innate immunity Kolls, SARS-CoV-2 mainly destroys pulmonary surfactant-secreting type II alveolar cells Wang et al. TLR4 activation, aberrant TLR4 signaling, and hyperinflammation may explain SARS-CoVinduced myocarditis and multiple-organ injury in COVID patients Aboudounya and Heads, Augmented activation of TLR4 increases oxidative stress and the generated ROS participate in signaling events downstream of TLRs. TLR4 activation may lead to ROS signaling via direct interaction between TLR4 and NADPH oxidase Gill et al. TLR1, TLR2 and TLR4 activation results in augmented mitochondrial ROS production following recruitment of mitochondria to macrophage phagosomes, leading the way to increased mitochondrial and cellular ROS generation West et al. ROS can oxidize cysteine residues allowing formation of disulfide bridges with one another or with GSH leading to S-glutathionylation. ROS can be inactivated by antioxidants such as GSH. The link between oxidation and inflammation is complex, going from fine-tuned signaling by ROS during TLR4 activation that leads to active mobilization of damaged-associated molecular patterns, to cellular injury from redox stress that leads to damaged-associated molecular patterns release triggering TLR4-mediated inflammation and organ injury Gill et al. Neutralization of oxidation radicals becomes paramount in SARS-CoVmediated cellular and tissue damage. As we previously published, a multiweapon approach is needed to successfully combat SARS-CoV-2 and COVID disease Labarrere and Kassab, , involving vaccines Jin et al. Sadly, there are no effective antivirals and vaccines to definitively treat or prevent COVID Globally launched clinical trials like the European study DISCOVERY showed that antiviral drugs remdesivir, lopinavir and ritonavir in combination, ritonavir given with or without interferon beta and hydroxychloroquine are unable to efficiently attack COVID progression Ader et al. Although a recent trial has shown to be beneficial when antiviral treatment is introduced early during the disease before hospitalization than later in the course of the disease, there is an urgent need for early therapies to reduce the risk of disease progression, prevent transmission, and be widely distributed to meet the worldwide demand Gottlieb et al. Here we emphasize the role of Nrf2 activators and the vital role of antioxidants like the GSH system in prevention against oxidative stress and cell and tissue damage Cuadrado et al. Figure 5. Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 -related glutathione GSH cellular depletion, repletion treatment options and a multiweapon defense approach. Reactive oxygen species ROS cell production enhances proinflammatory cytokine release while reducing anti-inflammatory cytokines. SARS-CoV-2 reduces Nrf2 and GSH allowing ROS and RNS to damage the cell. Increased intracellular GSH reduces ROS and reactive nitrogen species RNS , as well as NF-κB activation. Sulforaphane and resveratrol enhance Nrf2 production and Nrf2 negatively regulates the endoplasmic-reticulum-resident protein stimulator of interferon genes STING reducing interferon secretion. Increased antioxidant defense cystine, cysteine, NAC, liposomal GSH, vitamin D3, sulforaphane, resveratrol, and others reestablishes cell homeostasis [7]. Increased nuclear factor-κB NF-κB activity enhances interleukin IL -6 secretion and cytokine storm, while decreased nuclear NF-κB allows activation of nuclear factor erythroid 2-related factor2 Nrf2 -dependent antioxidant genes and enzyme transcription HO-1, NQO-1, and others ; Nrf2 inhibition of M1 and upregulation of M2 induced genes; decreased pro-inflammatory and increased anti-inflammatory cytokine expression; and decreased cytokine storm. Since oxidative stress plays an important role in the pathogenesis of viral-associated cardiovascular and lung diseases, antioxidant intervention would be a rational approach to use for treating lower respiratory tract infections Komaravelli and Casola, and balancing oxidative damage by enhancing antioxidant defense Banjac et al. Since SARS-CoV-2 activates mitochondrial ROS-mediated feedback loops that produce long-term changes in the redox status and endothelial function of the host, leading to cardiovascular disease and lung injury Chang et al. By regulating glutathione S-transferase GST and intracellular glutathione GSH levels, Nrf2 controls the level of ROS in the cell Kolls, ; Lushchak, ; Aquilano et al. Since Nrf2 participates in the resolution of inflammation by repressing genes for proinflammatory cytokines IL-6 and IL-1β Kobayashi et al. NRF2 inducers, like sulforaphane modify cysteine sensors of Keap1 and inactivate its repressor function. The liberation of Nrf2 from Keap1 allows Nrf2 accumulation and translocation to the nucleus Cuadrado et al. Since SARS-CoV-2 mediates Nrf2 suppression and limits host anti-inflammatory response Cuadrado et al. Nrf2 activation suppresses ROS in antigen-presenting dendritic cells enhancing their capacity to interact with and promote the transformation of naïve CD8 T cells into cytotoxic T lymphocytes enabling cytotoxic T-cells to eliminate virally infected cells Kesarwani et al. Nrf2 activation regulates antioxidant responses to modify cellular redox states from predominantly pro-oxidant to antioxidant, and, in an antioxidant environment, macrophage phenotypes shift from M1 pro-inflammatory to M2 anti-inflammatory, reducing the probability of cytokine storms, ARDS, and lethality Tan et al. Cytoprotective effects against viruses like SARS-CoV-2 could be enhanced by sulforaphane, an isothiocyanate abundant in cruciferous vegetables, since sulforaphane has been found to be a powerful activator of the Nrf2 pathway by increasing Nrf2-regulated cellular antioxidant response such as induction of NAD P H: quinone oxidoreductase 1, glutamate-cysteine ligase γ-glutamyl cysteine synthetase and glutathione Theodore et al. Nrf2 activators like sulforaphane have a potential role with dual antiviral and anti-inflammatory properties in the management of viral pneumonia, a serious complication in COVID disease Bousquet et al. Nrf2-interacting nutrients can equilibrate insulin resistance and have a significant effect upon COVID severity. It is then possible that intake of these nutrients may re-establish an optimal natural balance for the Nrf2 pathway and mitigate COVID severity Bousquet et al. Therapeutic interventions aimed at normalizing GSH and Nrf2 might provide a promising approach to combat the COVID pandemic. Augmented oxidative stress secondary to increased levels of interleukin-6 and tumor necrosis factor-α in addition to decreased levels of interferons α and β are primarily believed to be the drivers of the disease process Guloyan et al. Since it was shown that glutathione GSH inhibits viral replication and decreases IL-6 levels, it was suggested that liposomal GSH could be beneficial in COVID patients characterized by SARS-CoVinduced cytokine storm and redox imbalance Guloyan et al. SARS-CoV-2 binds to the ACE2 receptor and induces down regulation of NRF2, which leads to inhibition of GSH release. This leads to elevated inflammatory cytokines, elevated ROS, and recruitment of immune cells. The importance of thiol-reactive molecules like NAC and GSH in SARS-CoV-2 infectivity has been shown recently Murae et al. NAC and GSH directly suppress spike protein receptor-binding domain-ACE2 binding functions of various SARS-CoV-2 variants. An intramolecular disulfide bridge in the receptor-binding domain of the SARS-CoV-2 spike protein between Cys and Cys, considered to be important for ACE2-binding, results directly inhibited by NAC and GSH and these compounds could be used effectively against SARS-CoV-2 cell viral entry and infection Murae et al. GSH was shown to be the main inhibitor in the active site of the main protease M pro , the essential protein for virus invasion, and cysteine Cys glutathionylation inhibits M pro activity by blocking its dimerization supporting the use of GSH in COVID patients Davis et al. GSH deficiency has been associated with increased ROS and more severe clinical COVID Guillin et al. SARS-CoV-2 affects intracellular GSH levels by decreasing intracellular NRF2 function, that plays a key role in protecting cells from oxidative damage by upregulating GSH production Rahman and MacNee, ; Guloyan et al. In stressed cells NRF2 is released and taken from the cytoplasm into the nucleus by karyopherins Theodore et al. Coronavirus inhibits karyopherin-mediated nuclear import decreasing GSH production Sims et al. In the setting of SARS-CoV-2, COVID and oxidative stress, patients with comorbidities may have altered levels of glutamate-cysteine ligase and GSH synthetase, the enzymes participating in GSH synthesis. Therefore, it is reasonable using supplementation of liposomal glutathione, instead of the N-acetylcysteine or bonded cysteine utilized as precursors for GSH cell synthesis, since patients with deficient levels of glutamate-cysteine ligase and GSH synthetase will not be able to use N-acetylcysteine or bonded cysteine as substrates to synthesize their own GSH. Replenishing the nutritional status of the host by increasing vital amino acids such as cysteine to enhance GSH levels and selenium to improve selenium deficiency and facilitate selenoprotein GSH peroxidases, thioredoxin reductases expression can inhibit oxidative stress, modulating inflammation, suppressing endothelial dysfunction, and protecting vascular cells against apoptosis and calcification He et al. The demonstration that a combination of glycine and N-acetylcysteine supplementation rapidly improves GSH deficiency, oxidative stress and oxidant damage has implications for considering the GSH importance in combating COVID infected patients warranting further investigations Kumar P. Enzymes involved in GSH biosynthesis and function like γ-glutamyl-cysteine ligase and glutathione synthetase are completely dependent on ATP and require magnesium as a cofactor Bani Younes et al. Additionally, γ-glutamyl-transpeptidase uses magnesium as an enzyme activator Arancibia-Hernández et al. Magnesium supplementation improves mitochondrial function and increases the content of GSH in those organelles Liu et al. Furthermore, magnesium sulfate was effective as a treatment for preeclampsia, significantly promoting GSH production and suppressing ROS generation Kawasaki et al. Recent studies have suggested that serum magnesium levels of critically ill patients deserve attention Bani Younes et al. Molecules of nutritional value with antioxidant properties besides GSH, like selenium, zinc and polyphenols, are important in the immune response against SARS-CoV-2 that occurs primary in the lungs Pérez de la Lastra et al. The value of selenium upon glutathione peroxidase 1 activity and oxidative stress mitigation in SARS-CoV-2 infection and COVID disease has been clearly emphasized recently Seale et al. The recent demonstration of elevated superoxide dismutase, GSH peroxidase, and total antioxidant capacity in COVID outpatients compared to controls could be interpreted as a response to excessive COVIDrelated oxidative stress Golabi et al. Adequate levels and function of GSH and selenoproteins can prevent worsening of acute respiratory distress syndrome and atherosclerosis, two main causes of morbimortality in SARS-CoV-2 infection and COVID disease. COVID is a historic challenge to the fields of research, infectious disease, and global healthcare Hunter et al. The demand for detailed analysis of COVID pathogenesis and clinical course is paramount. The unprecedented awareness of a rapidly spreading pandemic disease such as COVID brings an opportunity to enhance international collaboration in the scientific community. As new variants like the omicron Abdool Karim and Abdool, ; Callaway and Ledford, and others Markov et al. Here we present the antioxidant GSH as a potential unexplored way for further investigation as intervention for COVID, since GSH levels are correlated with disease severity and lung damage supporting the participation of GSH in disease outcome Kryukov et al. Enhancing GSH, mainly through NAC, GSH precursors or pro-GSH compound administration, becomes a potential treatment option for SARS-CoV-2 infection and COVID disease by reducing oxidative stress and cytokine expression especially in diabetic patients at risk of more severe disease Singh et al. A combination of vitamin D and L-cysteine administration significantly augmented GSH levels and lowered oxidative stress and inflammation Jain et al. Maintaining an adequate GSH redox status and hydroxy-vitamin D levels will have the potential to reduce oxidative stress, enhance immunity and diminish the adverse clinical consequences of COVID especially in African American communities having glucosephosphate dehydrogenase deficiency, enzyme necessary to prevent GSH exhaustion and depletion Jain and Parsanathan, ; Jain et al. In a patient that is overloaded with cytokine storm, the best way to fortify the immune system would be to supply it with reduced GSH, since reduced GSH is already able to provide reducing equivalents from its thiol group. This is particularly relevant when we consider GSH pathways, as well as their transcriptional regulator Nrf2, for proliferation, survival and function of T cells, B cells and macrophages Muri and Kopf, The value of GSH and nutritional strategies like amino acids, vitamins, minerals, phytochemicals, sulforaphane to enhance cellular Nrf2, and other supplements used to restore GSH levels Minich and Brown, ; Hermel et al. Reestablishing the cellular metabolic homeostasis in SARS-CoV-2 infection and COVID disease especially in the lungs, could become paramount to balance altered innate and adaptive immunity and cell function and reduce morbimortality Hsu et al. COVID of the respiratory system appears to be a complex disease that may resist finding a single silver bullet intervention Brosnahan et al. Table 1. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. This is an open-access article distributed under the terms of the Creative Commons Attribution CC-BY License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; COVID, coronavirus disease 19; ROS, reactive oxygen species; GSH, glutathione; Keap1, Kelch-like ECH-associated protein 1; Nrf2, Nuclear factor erythroid 2-related factor 2; ARE, antioxidant response element; GSSG, GSH disulfide; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; ARDS, Acute respiratory distress syndrome; NFκB, nuclear factor-κB; ACE2, angiotensin converting enzyme-2; NETs, neutrophil extracellular traps; rTEM, reverse trans-endothelial migration; NAC, N-acetylcysteine; CRP, C-reactive protein; HSPGs, heparan sulfate proteoglycans; GCS, glutamyl-cysteine synthetase; TMPRSS2, transmembrane protease serine 2; TLRs, Toll-like receptors. Abbas, M. Association of GSTM1 and GSTT1 gene polymorphisms with COVID susceptibility and its outcome. doi: PubMed Abstract CrossRef Full Text Google Scholar. Abd El-Aziz, T. Human recombinant soluble ACE2 hrs ACE2 shows promise for treating severe COVID Signal Transduct. Abdool Karim, S. Omicron SARS-CoV-2 variant: a new chapter in the COVID pandemic. Lancet , — Aboudounya, M. COVID and toll-like receptor 4 TLR4 : SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyperinflammation. Ader, F. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID dis CoVeRy : a phase 3, randomised, controlled, open-label trial. Lancet Infect. Aldini, G. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic. Andriollo-Sanchez, M. Age-related oxidative stress and antioxidant parameters in middle-aged and older European subjects: the ZENITH study. Aquilano, K. Glutathione: new roles in redox signaling for an old antioxidant. Arancibia-Hernández, Y. Arroyo, R. Full-length recombinant hSP-D binds and inhibits SARS-CoV Ashfaq, S. Endothelial function and Aminothiol biomarkers of oxidative stress in healthy adults. Hypertension 52, 80— Atefi, N. N-acetylcysteine and coronavirus disease may it work as a beneficial preventive and adjuvant therapy? A comprehensive review study. Atkuri, K. Baker, S. Angiotensin-converting enzyme 2 ACE2 expression increases with age in patients requiring mechanical ventilation. PLoS One e Ballatori, N. Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Bani Younes, M. Magnesium sulfate extended infusion as an adjunctive treatment for complicated COVID infected critically ill patients. EAS J. Care 2, 97— CrossRef Full Text Google Scholar. Banjac, A. Oncogene 27, — Bartolini, D. SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione. Redox Biol. Baş, H. The effects of free radicals on aging process. Trends Biomedical Eng. Bellanti, F. Redox homeostasis and immune alterations in coronavirus Disease Biology Beltrán-García, J. Sepsis and coronavirus disease common features and anti-inflammatory therapeutic approaches. Care Med. Bharath, L. Next steps in mechanisms of inflammaging. Autophagy 16, — Bounous, G. The influence of dietary whey protein on tissue glutathione and the diseases of aging. Google Scholar. Bourgonje, A. N-Acetylcysteine and hydrogen sulfide in coronavirus disease Redox Signal. Bousquet, J. Nrf 2-interacting nutrients and COVID time for research to develop adaptation strategies. Allergy Brandes, R. Nox family NADPH oxidases: molecular mechanisms of activation. Brosnahan, S. COVID and respiratory system disorders. Current knowledge, future clinical and translational research questions. Brueggeman, J. Trained immunity: an overview and the impact on COVID Calabrese, E. Nrf 2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID pneumonia and acute respiratory distress syndrome ARDS : novel mechanistic considerations. Calder, P. Nutrition, immunity and COVID BMJ Nutr. Health 3, 74— Callaway, E. How bad is omicron? What scientists know so far. Nature , — Campolo, J. Medium-term effect of sublingual l-glutathione supplementation on flow-mediated dilation in subjects with cardiovascular risk factors. Nutrition 38, 41— Carcaterra, M. Alveolar epithelial cell type II as main target of SARS-CoV-2 virus and COVID development via NF-kb pathway deregulation: a physio-pathological theory. Hypotheses Castejon, A. Improving antioxidant capacity in children with autism: a randomized, double-blind controlled study with cysteine-rich whey protein. Cazzola, M. Use of thiols in the treatment of COVID current evidence. Lung , — Cecchini, R. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Cerqueira Borges, R. Dendritic cells in COVID Immunopathogenesis: insights for a possible role in determining disease outcome. Chang, R. SARS-CoV-2 mediated endothelial dysfunction: the potential role of chronic oxidative stress. Chang, W. Lymphocyte proliferation modulated by glutamine: involved in the endogenous redox reaction. Chen, K. Redox control in the pathophysiology of influenza virus infection. BMC Microbiol. Chen, Z. T cell responses in patients with COVID Chumakov, K. Old vaccines for new infections: exploiting innate immunity to control COVID and prevent future pandemics. Circu, M. Reactive oxygen species, cellular redox systems, and apoptosis. Glutathione and modulation of cell apoptosis. Acta , — Clausen, T. SARS-CoV-2 infection depends on cellular Heparan sulfate and ACE2. Cells , — Coric, V. GSTP1 and GSTM3 variant alleles affect susceptibility and severity of COVID Coz Yataco, A. Coronavirus disease sepsis. Primary Care Medicine. Low Level Laser Therapy LLLT. Emerald Laser. Holistic Skincare. Wellness Classes. About Us Our Providers. Kevin and Dr. Ashley's Story. Our Philosophy. Patient Forms. Dr Ashley's books. The Immune System On a macro scale, the human immune system is broken up into two separate components, the innate immune system and the acquired immune system. Free Radicals What are free radicals though? So What Exactly Does Glutathione Do? L |
| Glutathione | Potempa, Chamomile Tea for Sleep. SARS-CoV-2, Severe Muscle repair respiratory syndrome coronavirus 2; COVID, coronavirus disease 19; Glutathione and immune function, reactive oxygen species; GSH, glutathione; Keap1, Kelch-like Aand protein 1; Nrf2, Nuclear African Mango seed immune system erythroid 2-related Glutwthione 2; ARE, antioxidant response element; GSSG, GSH disulfide; NADPH, abd adenine dinucleotide phosphate; NOX, NADPH oxidase; Glutathiione, Acute respiratory distress snd NFκB, nuclear factor-κB; ACE2, angiotensin converting enzyme-2; NETs, neutrophil extracellular traps; rTEM, reverse trans-endothelial migration; NAC, N-acetylcysteine; CRP, C-reactive protein; HSPGs, heparan sulfate proteoglycans; GCS, glutamyl-cysteine synthetase; TMPRSS2, transmembrane protease serine 2; TLRs, Toll-like receptors. Excessive mitochondrial reactive oxygen species ROS generation further enhances cytokine production. It has been shown that Nrf2 modulates the GSH redox state via glutathione reductase regulation. Call: to order today. As shown in Figure 8when cells were infected with PR8, LPS reduced infection, in terms of intracellular viral protein production; influenza nucleoprotein NP, the most expressed among the viral proteins was significantly decreased in cells pretreated with LPS. |
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