The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review

Glassman, Ira; Le, Nghia; Mirhosseini, Mercedeh; Alcantara, Cheldon Ann; Asif, Aamna; Goulding, Anabel; Muneer, Shafi; Singh, Manpreet; Robison, Jeremiah; Guilford, Frederick R.; Venketaraman, Vishwanath

doi:10.31083/j.fbl2803059

Cited by 9 publications

(7 citation statements)

References 109 publications

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“…In obese patients, OxS is associated with diminished GSH levels and decreased GSH/GSSG ratio 597 . Low GSH levels could also increase viral replication, pro-inflammatory cytokine release, endothelial damage, and immune-thrombosis, which is a hyper-coagulative clinical condition that could exacerbate morbidity and mortality in COVID-19 and PASC 598 . Since m -Dys and OxS jointly contribute to both COVID-19 and PASC pathology, nutritional to replenish optimal GSH levels could be a promising strategy to reset HMRD and support patient recovery 582 .…”

Section: Long-covid/pasc: Precision Nutrition To Reset Virus-induced ...mentioning

confidence: 99%

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

Naidu,

Wang,

Rao

et al. 2024

npj Sci Food

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SARS‐CoV‐2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is critical for the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. This single-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates a plethora of virus–host protein–protein interactions in the human body. These extensive viral protein interactions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well as altered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectious process, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2 and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases, TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL) for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectious outcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acute COVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii) hyperferritinemia (‘cytokine storm’), and (iii) thrombocytosis (coagulopathy). The mean incubation period for COVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The mean viral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients, respectively. However, about 25–70% of virus-free COVID-19 survivors continue to sustain virus-induced HMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new ‘onset’ clinical incidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patients experience several debilitating clinical condition(s) with >200 different and overlapping symptoms that may last for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-related pathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innate host responses. Based on HMRD and virus-free clinical impairments of different human organs/systems, PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%) with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxiety disorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4 (10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viral hijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage to multiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. We have also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precision nutrients to reset HMRD for health recovery of PASC patients.

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Section: Long-covid/pasc: Precision Nutrition To Reset Virus-induced ...mentioning

confidence: 99%

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

Naidu,

Wang,

Rao

et al. 2024

npj Sci Food

View full text Add to dashboard Cite

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“…Since IL-6 and TNF-alpha are inflammatory cytokines that increase ROS, their upregulation in COVID-19 leads to increasingly depleted GSH and increasingly high ROS. Previous papers have suggested that this process both damages tissues directly and also contribute to microthrombosis by dramatically increasing ROS, which in turn modifies fibrinogen [ 38 ]. Due to the central role that GSH appears to play in COVID-19, we hypothesized that supplementing endogenous glutathione with L-GSH would interrupt this cycle, which could be evidenced by decreased levels of the previously mentioned cytokines due to reduced ROS.…”

Section: Discussionmentioning

confidence: 99%

“…GSH has been suggested as a means to decrease clot formation in COVID-19 due to its ability to reduce ROS and NO species, which can cause clot formation by modifying fibrinogen, as previously mentioned [ 38 ]. Previous studies have also found that knockout mice for GXP-3, the enzyme that uses GSH to lower ROS, demonstrate increased platelet-induced microthrombosis [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation

Norris,

Chorbajian,

Dawi

et al. 2024

Antioxidants

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Thrombotic microangiopathy has been identified as a dominant mechanism for increased mortality and morbidity in coronavirus disease 2019 (COVID-19). In the context of severe COVID-19, patients may develop immunothrombosis within the microvasculature of the lungs, which contributes to the development of acute respiratory distress syndrome (ARDS), a leading cause of death in the disease. Immunothrombosis is thought to be mediated in part by increased levels of cytokines, fibrin clot formation, and oxidative stress. Glutathione (GSH), a well-known antioxidant molecule, may have therapeutic effects in countering this pathway of immunothrombosis as decreased levels of (GSH) have been associated with increased viral replication, cytokine levels, and thrombosis, suggesting that glutathione supplementation may be therapeutic for COVID-19. GSH supplementation has never been explored as a means of treating COVID-19. This study investigated the effectiveness of liposomal glutathione (GSH) as an adjunctive therapy for peripheral blood mononuclear cells (PBMC) treated with SARS CoV-2 spike protein. Upon the addition of GSH to cell cultures, cytokine levels, fibrin clot formation, oxidative stress, and intracellular GSH levels were measured. The addition of liposomal-GSH to PBMCs caused a statistically significant decrease in cytokine levels, fibrin clot formation, and oxidative stress. The addition of L-GSH to spike protein and untreated PBMCs increased total intracellular GSH, decreased IL-6, TGF-beta, and TNF-alpha levels, decreased oxidative stress, as demonstrated through MDA, and decreased fibrin clot formation, as detected by fluorescence microscopy. These findings demonstrate that L-GSH supplementation within a spike protein-treated PBMC cell culture model reduces these factors, suggesting that GSH supplementation should be explored as a means of reducing mediators of immunothrombosis in COVID-19.

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“…It is therefore possible that the concomitant use of high-dose glutathione, NAC, antioxidants, and immune support used by patient 3, along with vaccination and boosters, helped mitigate long-term side effects [101,102,202] since the patient never developed symptoms of long COVID despite exposure six times and concomitant infections with overlapping medical problems. Low glutathione levels and associated thiols, including low levels of NAC, have now been published in multiple scientific studies and reviews as being associated with the most severe complications of COVID-19 infection [206][207][208]. Dapsone has also been published as having significant benefits in a small control group of COVID-19 patients with acute respiratory distress syndrome (ARDS), decreasing mortality in COVID-19 patients admitted to the intensive care unit (ICU) [209,210].…”

Section: Discussionmentioning

confidence: 99%

Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review

Horowitz,

Fallon,

Freeman

2024

Microorganisms

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Three patients with relapsing and remitting borreliosis, babesiosis, and bartonellosis, despite extended anti-infective therapy, were prescribed double-dose dapsone combination therapy (DDDCT) for 8 weeks, followed by one or several two-week courses of pulsed high-dose dapsone combination therapy (HDDCT). We discuss these patients’ cases to illustrate three important variables required for long-term remission. First, diagnosing and treating active co-infections, including Babesia and Bartonella were important. Babesia required rotations of multiple anti-malarial drug combinations and herbal therapies, and Bartonella required one or several 6-day HDDCT pulses to achieve clinical remission. Second, all prior oral, intramuscular (IM), and/or intravenous (IV) antibiotics used for chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDS), irrespective of the length of administration, were inferior in efficacy to short-term pulsed biofilm/persister drug combination therapy i.e., dapsone, rifampin, methylene blue, and pyrazinamide, which improved resistant fatigue, pain, headaches, insomnia, and neuropsychiatric symptoms. Lastly, addressing multiple factors on the 16-point multiple systemic infectious disease syndrome (MSIDS) model was important in achieving remission. In conclusion, DDDCT with one or several 6–7-day pulses of HDDCT, while addressing abnormalities on the 16-point MSIDS map, could represent a novel effective clinical and anti-infective strategy in CLD/PTLDS and associated co-infections including Bartonella.

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The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review

Cited by 9 publications

References 109 publications

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation

Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review

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