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

Immunothrombosis has emerged as a dominant pathological process exacerbating morbidity and mortality in acute- and long-COVID-19 infections. The hypercoagulable state is due in part to immune system dysregulation, inflammation and endothelial cell damage, as well as a reduction in defense systems. One defense mechanism in particular is glutathione (GSH), a ubiquitously found antioxidant. Evidence suggests that reduction in GSH increases viral replication, pro-inflammatory cytokine release, and thrombosis, as well as decreases macrophage-mediated fibrin removal. The collection of adverse effects as a result of GSH depletion in states like COVID-19 suggest that GSH depletion is a dominant mechanism of immunothrombosis cascade. We aim to review the current literature on the influence of GSH on COVID-19 immunothrombosis pathogenesis, as well as the beneficial effects of GSH as a novel therapeutic for acute- and long-COVID-19.

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

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

Glutathione Supplementation as an Adjunctive Therapy in COVID-19.

Morbidity and mortality of coronavirus disease 2019 (COVID-19) are due in large part to severe cytokine storm and hypercoagulable state brought on by dysregulated host-inflammatory immune response, ultimately leading to multi-organ failure. Exacerbated oxidative stress caused by increased levels of interleukin (IL)-6 and tumor necrosis factor α (TNF-α) along with decreased levels of interferon α and interferon ß (IFN-α, IFN-ß) are mainly believed to drive the disease process. Based on the evidence attesting to the ability of glutathione (GSH) to inhibit viral replication and decrease levels of IL-6 in human immunodeficiency virus (HIV) and tuberculosis (TB) patients, as well as beneficial effects of GSH on other pulmonary diseases processes, we believe the use of liposomal GSH could be beneficial in COVID-19 patients. This review discusses the epidemiology, transmission, and clinical presentation of COVID-19 with a focus on its pathogenesis and the possible use of liposomal GSH as an adjunctive treatment to the current treatment modalities in COVID-19 patients.

Antiparasitic and Antifungal Medications for Targeting Cancer Cells Literature Review and Case Studies.

CONTEXT: Chronic inflammation is a new catch phrase for the explanation of all chronic degenerative diseases, from asthma, arthritis, heart disease, auto-immune disease, and irritable bowel disease to cancer. Occult infections from oncovirus, bacterial, and fungal infections as well as from lesser known parasitic infections are driving forces in the cellular evolution and degeneration of cancer cells. An approach using currently available medications that target both fungal and parasitic metabolism appears to interfere with the metabolic synergy that is associated with tumor growth and aggressiveness. OBJECTIVE: The review examined whether antiparasitic and antifungal medications that interfere with the metabolism of cancers, can be useful in cancer therapy by treating cancer as an infectious disease and as a metabolic parasite. DESIGN: The research team searched the National Center for Biotechnology Information (NCBI) PubMed database databases, using different keyword combinations, including repurposed drug, antifungal, antiparasitic, cancer, parasite, anti-cancer repurposed. SETTING: Prevention and Healing, St Louis, Mo, USA. RESULTS: The literature search identified a number of studies, including in vitro, in vivo and clinical, which support the use of antifungal and antiparasitic medication in the treatment of cancer. In the clinical area, the authors observed benefit from the use of antifungal and antiparasitic medication in the treatment of a variety of cancer cases. CONCLUSIONS: Due to the complexity of the behavior and biology of cells, scientists' primary focus should be on detection and elimination of sources of inflammation. Antiparasitic medications, and also antiviral, antibiotic, and antifungal medications should be thought of as underrecognized, underappreciated, and forgotten medications that can be part of cancer therapy. The information offered in this review suggests scientists should think of cancer not only as a metabolic disease but also as a metabolic parasite and should consider using antiparasitic medications under a new understanding of the role of inflammation, infection, and mitochondrial dysfunction in the development of cancer cells.

Oxidative Stress and Low Glutathione in Common Ear, Nose, and Throat Conditions: A Systematic Review.

Context • Oxidative stress and tissue-damaging, oxygen (O2)-related, free-radical formation is inherent in human metabolism, and the tissues of the ear, nose, and throat (ENT) have an increased exposure to injury from those substances. Because glutathione (GSH) is a major component in an antioxidant defense against oxidative damage in ENT tissues, a review of the impact of lowered GSH and oxidative stress in conditions associated with the upper respiratory tract is warranted. Objective • The review intended to summarize the role that oxidative stress and GSH play. Design • The research team performed a literature review from 1980 to the present that was based on the following keywords: oxidative stress, oxidation, antioxidant, and GSH in common ENT conditions. The review found the following conditions: (1) rhinitis, (2) allergic rhinitis, (3) chronic rhinosinusitis (CRS), (4) CRS with polyps, (5) otitis media with effusion, (6) chronic otitis media (COM), (7) COM and cholesteatoma, (8) tympanic membrane sclerosis, (9) tonsillitis, (10) Meniere's disease, (11) laryngeal conditions, and (12) chronic cough. Results • ENT conditions have been found to be associated with oxidative stress and with low GSH. A limited number of the reviewed studies discussed antioxidant use or repletion of GSH. Although only a few reports support the use of GSH or antioxidants as adjuncts in the management of ENT conditions, no reports of side effects were found related to their use. Conclusions • Many ENT conditions are associated with oxidative stress and decreased GSH, both locally in the affected tissues and systemically. The oxidative stress of those conditions may be related to depletion of GSH, which is increased by the higher levels of O2 in the upper respiratory tract. A small number of studies have reported clinical benefits from the use of an antioxidant or GSH support. The findings of benefits and the lack of reports of side effects suggest that the clinical use of antioxidants and support with GSH in ENT conditions may be considered as adjuncts to conventional management and that more research is warranted.

Analysis of glutathione levels in the brain tissue samples from HIV-1-positive individuals and subject with Alzheimer's disease and its implication in the pathophysiology of the disease process.

HIV-1 positive individuals are at high risk for susceptibility to both pulmonary tuberculosis (TB) and extra-pulmonary TB, including TB meningitis (TBM) which is an extreme form of TB. The goals of this study are to determine the mechanisms responsible for compromised levels of glutathione (GSH) in the brain tissue samples derived from HIV-1-infected individuals and individuals with Alzheimer's disease (AD), investigate the possible underlying mechanisms responsible for GSH deficiency in these pathological conditions, and establish a link between GSH levels and pathophysiology of the disease processes. We demonstrated in the autopsied human brain tissues that the levels of total and reduced forms of GSH were significantly compromised in HIV-1 infected individuals compared to in healthy subjects and individuals with AD. Brain tissue samples derived from HIV-1-positive individuals had substantially higher levels of free radicals than that derived from healthy and AD individuals. Enzymes that are responsible for the de novo synthesis of GSH such as γ-glutamate cysteine-ligase catalytic subunit (GCLC-rate limiting step enzyme) and glutathione synthetase (GSS-enzyme involved in the second step reaction) were significantly decreased in the brain tissue samples derived from HIV-1-positive individuals with low CD4 + T-cells (< 200 cells/mm(3)) compared to healthy and AD individuals. Levels of glutathione reductase (GSR) were also decreased in the brain tissue samples derived from HIV-1 infected individuals. Overall, our findings demonstrate causes for GSH deficiency in the brain tissue from HIV-1 infected individuals explaining the possible reasons for increased susceptibility to the most severe form of extra-pulmonary TB, TBM.

Deficient glutathione in the pathophysiology of mycotoxin-related illness.

Evidence for the role of oxidative stress in the pathophysiology of mycotoxin-related illness is increasing. The glutathione antioxidant and detoxification systems play a major role in the antioxidant function of cells. Exposure to mycotoxins in humans requires the production of glutathione on an "as needed" basis. Research suggests that mycotoxins can decrease the formation of glutathione due to decreased gene expression of the enzymes needed to form glutathione. Mycotoxin-related compromise of glutathione production can result in an excess of oxidative stress that leads to tissue damage and systemic illness. The review discusses the mechanisms by which mycotoxin-related deficiency of glutathione may lead to both acute and chronic illnesses.

Glutathione supplementation improves macrophage functions in HIV.

In this study, we determined the effects of glutathione (GSH)-enhancing agents in restoring the levels of GSH in isolated macrophages from individuals with HIV infection thereby resulting in improved control of Mycobacterium tuberculosis. Our results indicate that treatment with N-acetyl cysteine or a liposomal formulation of glutathione (lGSH) resulted in replenishment of reduced also known as free GSH (rGSH), and correlated with a decrease in the intracellular growth of M. tuberculosis. Finally, we observed differences in the amount of the catalytic subunit of glutamine-cysteine ligase (GCLC), glutathione synthase, and glutathione reductase present in macrophages derived from healthy and HIV-infected individuals. These changes correlated with changes in free radicals as well as rGSH levels. Our results indicate that HIV infection leads to increased production of free radicals and decreased production of GCLC resulting in depletion of rGSH and this may lead, in part, to the loss of innate immune function observed in HIV patients. These findings represent a novel mechanism for control of M. tuberculosis infection, and a possible supplement to current HIV treatments.

Glutathione and infection.

BACKGROUND: The tripeptide γ-glutamylcysteinylglycine or glutathione (GSH) has demonstrated protective abilities against the detrimental effects of oxidative stress within the human body, as well as protection against infection by exogenous microbial organisms. SCOPE OF REVIEW: In this review we describe how GSH works to modulate the behavior of many cells including the cells of the immune system, augmenting the innate and the adaptive immunity as well as conferring protection against microbial, viral and parasitic infections. This article unveils the direct antimicrobial effects of GSH in controlling Mycobacterium tuberculosis (M. tb) infection within macrophages. In addition, we summarize the effects of GSH in enhancing the functional activity of various immune cells such as natural killer (NK) cells and T cells resulting in inhibition in the growth of M. tb inside monocytes and macrophages. Most importantly we correlate the decreased GSH levels previously observed in individuals with pulmonary tuberculosis (TB) with an increase in the levels of pro-inflammatory cytokines which aid in the growth of M. tb. MAJOR CONCLUSIONS: In conclusion, this review provides detailed information on the protective integral effects of GSH along with its therapeutic effects as they relate to the human immune system and health. GENERAL SIGNIFICANCE: It is important to note that the increases in the levels of pro-inflammatory cytokines are not only detrimental to the host due to the sequel that follow such as fever and cachexia, but also due to the alteration in the functions of immune cells. The additional protective effects of GSH are evident after sequel that follows the depletion of this antioxidant. This is evident in a condition such as Cystic Fibrosis (CF) where an increased oxidant burden inhibits the clearance of the affecting organism and results in oxidant-induced anti-protease inhibition. GSH has a similar protective effect in protozoans as it does in human cells. Thus GSH is integral to the survival of some of the protozoans because some protozoans utilize the compound trypanothione [T(SH)2] as their main antioxidant. T(SH)2 in turn requires GSH for its production. Hence a decrease in the levels of GSH (by a known inhibitor such as buthionine sulfoximine [BSO] can have adverse effects of the protozoan parasites. This article is part of a Special Issue entitled Cellular functions of glutathione.

Glutathione and adaptive immune responses against Mycobacterium tuberculosis infection in healthy and HIV infected individuals.

Glutathione (GSH), a tripeptide antioxidant, is essential for cellular homeostasis and plays a vital role in diverse cellular functions. Individuals who are infected with Human immuno deficiency virus (HIV) are known to be susceptible to Mycobacterium tuberculosis (M. tb) infection. We report that by enhancing GSH levels, T-cells are able to inhibit the growth of M. tb inside macrophages. In addition, those GSH-replenished T cell cultures produced increased levels of Interleukin-2 (IL-2), Interleukin-12 (IL-12), and Interferon-gamma (IFN-γ), cytokines, which are known to be crucial for the control of intracellular pathogens. Our study reveals that T lymphocytes that are derived from HIV infected individuals are deficient in GSH, and that this deficiency correlates with decreased levels of Th1 cytokines and enhanced growth of M. tb inside human macrophages.