SARS-CoV-2 Infections Lead To Increased Levels Of Oxidative Stress, Oxidant Damage And Glutathione Deficiency

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A new study by researchers from Baylor College of Medicine, Houston-USA has found that COVID-19 patients especially those that have been hospitalized, typically exhibit increased levels of oxidative stress, oxidant damage and glutathione deficiency. The study findings have implications for the inclusion of Glycine and N-Acetylcysteine (GlyNAC) supplementation into standard treatment protocols.

Oxidative stress (OxS) is a harmful condition caused by excess reactive-oxygen species (ROS) and is normally neutralized by antioxidants among which Glutathione (GSH) is the most abundant. GSH deficiency results in amplified OxS due to compromised antioxidant defenses.
 
As a result of little being known about GSH or OxS in COVID-19 infection, the study team measured GSH, TBARS (a marker of OxS) and F2-isoprostane (marker of oxidant damage) concentrations in 60 adult patients hospitalized with COVID-19.
 
Shockingly compared to uninfected controls, COVID-19 patients of all age groups had severe GSH deficiency, increased OxS and elevated oxidant damage which worsened with advancing age.
 
Surprisingly these defects were also present in younger age groups, where they do not normally occur.
 
As a result of GlyNAC (combination of glycine and N-acetylcysteine) supplementation beeing shown in clinical trials to rapidly improve GSH deficiency, OxS and oxidant damage, GlyNAC supplementation has implications for combating these defects in COVID-19 infected patients and warrants urgent investigation.
 
The study findings were published in the peer reviewed journal: Antioxidants.
https://www.mdpi.com/2076-3921/11/1/50

Since 2019, the world has been in the grip of a pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes an inflammatory viral pneumonia called coronavirus disease 2019 (COVID-19) [1,2].

Patients infected with COVID-19 can develop fever and respiratory symptoms and are often admitted to the hospital due to progressive dyspnea and systemic complications necessitating support measures ranging from supplemental oxygen to the need for mechanical ventilation and intensive care [3,4].

The COVID-19 pandemic is associated with episodic global surges (‘waves’) associated with large numbers of patients seeking hospitalization which places huge strains on healthcare staff, overruns hospitals and severely challenges healthcare systems as was witnessed globally with the recent delta variant.

The discovery and rollout of COVID-19 vaccines were expected to boost herd immunity to rein in the raging pandemic, but viral mutations, vaccine hesitancy and vaccine non-availability have led to the rise of new strains of SARS-Cov-2 sequentially named β, δ, κ, μ, and the recent South African Omicron strain which has led to much global fear and concern due to its rapid international spread and has been designated by the World Health Organization as a variant of concern [5].

These newer strains appear to have variable vaccine resistance resulting in breakthrough infections even in vaccinated patients, and COVID-19 waves continue to surge even in heavily vaccinated countries as is currently occurring in the United Kingdom and the European Union.

As a result, the global scientific and medical communities are urgently trying to prepare for and manage newer COVID-19 waves, as this cycle tends to repeat at periodic intervals.

In a new development, a recent study reports new data from an analysis of 13638 patients (with and without COVID-19) which suggests that these patients have an increased risk of death in the following 12-months [6]. While older adults (OA) > 65 years of age have a higher risk of hospitalization and death due to acute COVID-19 infection [7], this new study reports that post-COVID mortality in adults < 65 year of age is higher than those > 65 year of age [6].

The underlying reasons for this increase in post-COVID mortality are currently unclear but unrelated to cardio-respiratory etiology and attributed to COVID-19 related biological and physiological stresses [6]. Because COVID-19 is a highly dynamic and unpredictable disease it is urgently necessary to identify and target all mechanistic defects which may be associated with poor health in patients with acute COVID-19, and also in the post-COVID aftermath.

Oxidative stress (OxS) is a harmful condition caused by excess accumulation of reactive oxygen species and is linked to lung disease [8,9], heart disease [10,11], neurological disorders [12], diabetic complications [13], liver [14] and kidney diseases [15], and to the biology of the aging process [16,17]. Under physiological conditions, OxS is neutralized by antioxidants among which glutathione (GSH) is the most abundant endogenous intracellular antioxidant [18,19,20].

Conditions with the highest risk of complications (including mortality) as a result of COVID-19 infection include older age, diabetes and immunocompromised status [21,22,23,24,25], and all three conditions have in common a high risk of elevated OxS and GSH deficiency [18,19,20].

We have studied GSH deficiency and OxS in older humans, immunocompromised HIV patients and diabetic patients and have reported that correcting these defects with GlyNAC (combination of GSH precursor amino acids glycine, and cysteine provided as N-acetylcysteine) significantly improves multiple additional defects and boosts health [26,27,28,29,30,31,32].

Although GSH deficiency is proposed as the most likely cause for serious manifestations and death in COVID-19 [33], little is known of GSH adequacy, OxS, or oxidant damage in adults hospitalized with COVID-19. Therefore, we measured intracellular GSH concentrations and plasma OxS in hospitalized COVID-19 patients and report our findings here.

Conclusions

COVID-19 infection is associated with severe intracellular GSH deficiency, elevated oxidative stress and oxidant damage. These defects are present in all age groups including young and middle-aged humans where they are not normally expected. The magnitude of these defects progressively increases with age and is most severe in older humans > 60 year of age. Because GlyNAC supplementation has been shown to be highly effective in correcting GSH deficiency, lowering OxS and oxidant damage in diverse populations including older humans, HIV patients and diabetic patients, it could also improve these defects in patients with COVID-19, and needs to be evaluated in future trials.


Current State of the Evidence

The acute respiratory disease COVID-19 caused by the novel coronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has spawned a global pandemic with untold morbidity and mortality, accompanied by devastating disruption to all facets of society, economy, and health care system.1,2 SARS-CoV-2 is a single-stranded, positive-sense RNA virus that was initially identified in Wuhan city in China in December 2019 from an outbreak of pneumonia cases in connection with Huanan Seafood Wholesale Market.3 

It is closely related to other tremendously pathogenic beta-coronaviruses that have emanated in this century, namely severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV).4 Unlike SARS-CoV-1 and MERS-CoV that exhibit only limited human-to-human transmissions,5 a person being infected with SARS-CoV-2 who is just mildly ill or even asymptomatic can spread the disease to an average of two or three others, resulting in an exponential rate of increase in infection cases. SARS-CoV-2 virus has engendered 10-fold higher in the number of cases than the 2003 SARS epidemic in a quarter of the time.6 The rapid transmission of this highly pathogenic virus has warranted a pressing global need for the instantaneous development and deployment of therapeutic approaches and preventive measures against the disease.7

Common hematological manifestations of COVID-19 infection include lymphocytopenia associated with intensification of the inflammatory process and direct infection of lymphocytes and destruction of lymphoid organs, increased ferritin levels owing to inflammation, and a higher rate of erythrocyte sedimentation in severe disease. Blood group A and males are more likely to become infected. Male sex, older age, and the presence of comorbidities are correlated with increased risk of COVID-19-related mortality.8,9 The development of thrombocytopenia may occur in severe disease due to reduced platelet production and increased destruction or consumption of platelets. Elevated D-dimer levels concomitant with high levels of fibrin degradation products and low antithrombin activity render COVID-19 patients to be at risk of hypercoagulability and thrombotic complications. Neutrophil-to-lymphocyte ratio and plasma D-dimer concentrations are relatively easy to quantify and possess clinical value for disease prognosis.10 

High levels of proinflammatory cytokines and chemokines, including interleukin (IL)-6, IL-2, IL-2 receptor, IL-10, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) may cause multiorgan damage as well as cardiovascular complications.11 Cardiac arrhythmia has also been reported and is associated with a cytokine storm-triggered systemic hyperinflammatory state and immune response that may cause injury to cardiac monocytes, resulting in myocardial dysfunction and the ensuing development of arrhythmia.

Similarly, infection of alveolar pneumocytes cells by SARS-CoV-2 virus triggers the initiation of systemic inflammation and elevated immunoreactivity that potentiate T-cell and macrophage activation infiltrating infected myocardial tissues, leading to cardiovascular damage and myocarditis. Additionally, atherosclerotic plaques can be destabilized by systemic inflammatory response which happens simultaneously with pro-inflammatory and pro-oxidative effects of SARS-CoV-2, thereby giving rise to acute coronary syndrome and ischemic heart disease among COVID-19 patients.12

Previous research with coronaviruses using both in vitro and in vivo experimental designs has contributed to a valuable guiding foundation for elucidating therapeutic strategies for the treatment of COVID-19. On top of understanding the microbial pathogenesis and the molecular and cellular mechanisms of disease biology, activity of a therapeutic agent in a translational research, be it either in vitro or in vivo, is critical to proffer advancement to first-in-human clinical trials based on laboratory findings of pharmacology, toxicology, and immunology.13 

For COVID-19 repurposing of an existing clinically approved drug, it is pivotal to demonstrate its antiviral, anti-inflammatory, and related effects against SARS-CoV-2 in cell-based systems in vitro. The assessment of drug potency may be impacted by the type of the virus (eg, full-length wildtype, reporter viruses, or sub-genomic replicons, etc.) and the cell culture utilized (eg, Vero E6, Huh7, FRhK, or human airway epithelial cells), thus, necessitating high quality and standardized cellular assays, or at least with robust and universally accepted control groups.14

Recent randomized controlled trials depict that repurposed antiviral drugs such as remdesivir, lopinavir, and interferon beta-1α regimens have small or null effect on hospitalized patients with COVID-19, as determined by outcomes such as overall mortality, initiation of mechanical ventilation, and duration of hospitalization.15,16 Combination treatment of remdesivir with anti-inflammatory drug baricitinib is associated with shorter time to recovery and accelerated improvement in clinical status, notably among those receiving high-flow oxygen or non-invasive ventilation.17 

Treatment with dexamethasone reduces 28-day mortality in patients who are receiving invasive mechanical ventilation or oxygen without invasive mechanical ventilation, however, no discernible benefit and the possibility of causing harm have been found among those who are not receiving respiratory support.18 Neutralizing antibody bamlanivimab results in fewer hospitalizations and a lower symptom burden.19 Safe and effective vaccines that can confer significant protection against COVID-19 infection in real-world settings encompass BNT162b2 [Pfizer-BioNTech],20 mRNA-1273 [Moderna],21 NVX-CoV2373 [Novavax],22 CoV2 preS dTM-AS03 [Sanofi Pasteur-GlaxoSmithKline],23 Ad26.COV2.S [Johnson & Johnson/Janssen],24 and ChAdOx1 nCoV-19 (AZD1222) [Oxford-AstraZeneca].25

The overwhelming impact of the COVID-19 crisis has driven the push for reimagining and repositioning of previously approved medical treatments for other indications to speed up the discovery and development of safe and efficacious agents to enlarge the alternatives for adjunctive treatment or prevention of progression into severe COVID-19 illness.14 From the clinical front, it is presently worrisome to have no effective antimicrobial agents to treat the infected individuals and, optimally, eliminate viral shedding and the ensuing transmission cascades.

N-acetylcysteine is a mucolytic drug which exhibits antioxidant and anti-inflammatory effects.26 The compound has been available in clinical practice for several decades to treat various medical conditions, including bronchitis, acute respiratory distress syndrome, paracetamol intoxication, chemotherapy-related toxicity, doxorubicin cardiotoxicity, heavy metal intoxication, ischemia-reperfusion cardiac injury, human immunodeficiency virus infection or acquired immunodeficiency syndrome, and neuropsychiatric disorders. N-acetylcysteine is also marketed as a dietary supplement that is suggested to possess antioxidant and hepatic-protecting effects. The antioxidant characteristic of N-acetylcysteine has been ascribable to its reactivity with •OH, CO3, •NO2, and thiyl radicals, the ability to repair oxidative damaged key cellular molecules, and activity as a precursor for biosynthesis of glutathione.27 There is a growing body of evidence that highlights the intrinsic antimicrobial and antibiofilm activities in many respiratory pathogens, including Escherichia, Pseudomonas, Staphylococcus, Acinetobacter, Haemophilus, and Klebsiella.26,28–30 High concentrations of N-acetylcysteine do not carry the risk of adverse interactions with most commonly used antibiotics and can exert intrinsic antimicrobial activity against Haemophilus influenza.26 Being a precursor for glutathione biosynthesis which is a crucial determinant of antimicrobial activity against bacteria, N-acetylcysteine is often prescribed as a mucolytic agent in conjunction with antibiotic treatment in respiratory tract infections to improve the outcomes of the course of therapy.31

N-acetylcysteine has recently been suggested as an adjunctive therapy to the standard care for SARS-CoV-2 infection considering the favorable risk and benefit ratio and its effects on synthesizing glutathione, improving immune function, and modulating inflammatory response.32–34 It achieves the therapeutic effects through two main activities: 1) mucolytic action conferred by the free sulfhydryl group which reduces disulfide bonds in the cross-linked mucus glycoproteins matrix, thus decreasing the viscosity of mucus; 2) antioxidative action attributable to a direct interaction with free radicals, an indirect effect as a precursor to cysteine which is required for glutathione biosynthesis, and a replenishment of thiol pools that is central to redox regulation and control.35 In light of these properties, we hypothesize that N-acetylcysteine plays a role in the treatment of COVID-19 infection by the following postulated mechanisms of action (Figure 1):

  1. Envelope (E) and spike (S) proteins have a triple cysteine structural motif located directly after the E protein’s transmembrane domain (NH2– … L-Cys-A-Y-Cys-Cys-N … -COOH) and a similar motif located in the carboxy terminus of the S protein (NH2– … S-Cys-G-S-Cys-Cys-K … -COOH). The position, orientation, and composition of these two motifs may serve as a center for the structural link between the E and S proteins which is mediated by the formation of disulfide bonds between the corresponding cysteine residues.36 Previous studies have indicated that the entry of viral glycoprotein is affected by thiol-disulfide balance within the viral surface and the cell-surface of the host.37,38 Any perturbations in the thiol-disulfide interchange equilibrium would deter the entry of the virus into host cells.39,40 Cleavage of disulfide bridges by N-acetylcysteine disrupts the structural components of the interacting proteins, thereby impairing receptor binding affinity and infectivity.
  2. N-acetylcysteine is a chemical reducer of disulfide bonds via its free sulfhydryl groups may interact with the extracellular disulfide bridges of angiotensin II receptor, alter its tertiary structure, and inhibit the binding of angiotensin II to its surface receptors (AT1a receptors) with subsequent attenuation of signal transduction and cell action. The AT1a receptors possess two sets of disulfide bridges at the extracellular domain of the receptors: C18-C274 and C101-C180. N-acetylcysteine can reduce the disulfide bonds in a dose-dependent manner,41,42 decreasing angiotensin II and increasing angiotensin 1–7 (a biologically active peptide exerting many opposing actions to angiotensin II), thus protecting against lung inflammation and fibrosis.43
  3. The sulfhydryl group of N-acetylcysteine inhibits angiotensin converting enzyme, reducing production of angiotensin II.44 In human lungs, angiotensin converting enzyme is expressed in lower lungs on type I and II alveolar epithelial cells. Following infection, viral entry begins with the attachment of spike (S) protein expressed on the viral envelope to angiotensin converting enzyme on the alveolar surface. Hence, N-acetylcysteine may prevent viral entry by limiting viral protein angiotensin converting enzyme interaction and internalization of the receptor-ligand complex.45 It also protects against oxidative stress and prevents glycosylation of proteins which may confer protection against respiratory disease syndrome and lung failure.
  4. The antioxidant effect of N-acetylcysteine ameliorates oxidative stress and inflammatory response in COVID-19.46 It amplifies the signaling functions of toll-like receptor 7 protein and mitochondrial antiviral-signaling protein for boosting type 1 interferon production.47 Type I interferon functions to induce expression of various interferon-stimulated genes that exert antiviral activities to host cells.48
  5. The receptor for advanced glycation end products (RAGE) and its ligands have a crucial role in the pathogenesis of COVID-19 pneumonia and acute respiratory distress syndrome as well as lung inflammation. Circulating levels of soluble RAGE (sRAGE, a decoy receptor) are positively associated with acute respiratory distress syndrome severity and mortality risk, whereas reduction in circulating levels of sRAGE drop results in disease resolution.49 Advanced glycation end products are formed by a reaction of the dicarbonyl compounds methylglyoxal and glyoxal with amino acids in proteins during glycolysis. Methylglyoxal and methylglyoxal-derived AGE can further activate inflammatory cells by binding to RAGE.50 N-acetylcysteine induces endogenous glutathione and hydrogen sulfide synthesis, thus attenuating methylglyoxal-induced protein glycation and additional glycosylation events in SARS-CoV-2 which may then inhibit the virus’s infectivity and associated pathologies.51
  6. N-acetylcysteine inhibits NF-κB activation by suppressing TNF-induced IκB kinases, followed by impediment of proteasome-dependent degradation.52 This prevents translocation of NF-κB from cytoplasm to the nucleus and block expression of pro-inflammatory cytokines and chemokines which have been correlated with severity and lethality in various acute respiratory viral infections, including Influenza A H5N1, highly pathogenic H1N1, SARS-CoV, MERS-CoV, and SARS-CoV-2.53

Figure 1 Schematic representation of the possible effects of N-acetylcysteine on SARS-CoV-2 infection. N-acetylcysteine may inhibit envelope (E) protein and spike (S) protein of the virus, decrease angiotensin II receptor binding (AT2R), inhibit angiotensin converting enzyme (ACE), induce endogenous glutathione (GSH) synthesis which is associated with increased antioxidant effect and decreased glycation of intracellular proteins, and prevent nuclear translocation of NF-κB which suppresses the production of pro-inflammatory mediators and cytokines.

reference link :https://www.dovepress.com/n-acetylcysteine-as-adjuvant-therapy-for-covid-19–a-perspective-on-th-peer-reviewed-fulltext-article-JIR

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