Glutathione in Health and Disease

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 29716

Special Issue Editors

Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60100 Ancona, Italy
Interests: oxidative stress; antioxidants; oxidative biomarkers; glutathione; redox signaling; PTMs; glyoxalase system; S-glutathionylation
Special Issues, Collections and Topics in MDPI journals
Department of Life Environmental Sciencesand, Università Politecnica delle Marche, 60100 Ancona, Italy
Interests: proteins structure; Fourier Transform Infrared Spectroscopy (FT-IR); fluorescence spectroscopy; protein stability; protein aggregation; protein S-glutathionylation; glyoxalase system
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glutathione is a tripeptide with multiple properties. Not only is it the thiol buffer par excellence for the cellular environment, but it also plays the role of cofactor in many enzymatic reactions that are important for the detoxification of xenobiotics and for defense against oxidative stress. Glutathione is also the molecule utilized to perform both spontaneous and enzymatically induced S-glutathionylation. This post-translational modification is especially important in the regulation of specific metabolic pathways that can be induced/inhibited by intra- or extracellular signals. The GSH/GSSG ratio is modified in many conditions of cellular redox imbalance and has been seen to change in many human diseases, such as neurodegenerative disorders (Alzheimer’s and Parkinson’s diseases), ischemia/reperfusion injury or inflammatory diseases including fatty liver disease, diabetes mellitus type 1 and 2, inflammatory bowel disease (IBD), asthma, rheumatoid arthritis, endometriosis, metabolic syndrome, and others. In addition, glutathione is also involved in immune functions and in the antimicrobial and antiviral defense of cells. The aim of this Special Issue is to report on the current knowledge regarding the role of glutathione on metabolic pathways that are differentially regulated in specific conditions in health and disease.

Dr. Tatiana Armeni
Dr. Andrea Scirè
Guest Editors

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Keywords

  • glutathione
  • redox signaling
  • redox imbalance in human diseases
  • S-glutathionylation
  • thiols

Published Papers (9 papers)

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Research

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19 pages, 4253 KiB  
Article
Sp1-Mediated Prdx6 Upregulation Leads to Clasmatodendrosis by Increasing Its aiPLA2 Activity in the CA1 Astrocytes in Chronic Epilepsy Rats
by Ji-Eun Kim, Duk-Shin Lee and Tae-Cheon Kang
Antioxidants 2022, 11(10), 1883; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11101883 - 23 Sep 2022
Cited by 5 | Viewed by 1450
Abstract
Clasmatodendrosis is an autophagic astroglial degeneration (a non-apoptotic (type II) programmed cell death) whose underlying mechanisms are fully understood. Peroxiredoxin-6 (Prdx6), the “non-selenium glutathione peroxidase (NSGPx)”, is the only member of the 1-cysteine peroxiredoxin family. Unlike the other Prdx family, Prdx6 has multiple [...] Read more.
Clasmatodendrosis is an autophagic astroglial degeneration (a non-apoptotic (type II) programmed cell death) whose underlying mechanisms are fully understood. Peroxiredoxin-6 (Prdx6), the “non-selenium glutathione peroxidase (NSGPx)”, is the only member of the 1-cysteine peroxiredoxin family. Unlike the other Prdx family, Prdx6 has multiple functions as glutathione peroxidase (GPx) and acidic calcium-independent phospholipase (aiPLA2). The present study shows that Prdx6 was upregulated in CA1 astrocytes in chronic epilepsy rats. 2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and N-acetylcysteine (NAC, a precursor of glutathione) ameliorated clasmatodendrosis accompanied by reduced Prdx6 level in CA1 astrocytes. Specificity protein 1 (Sp1) expression was upregulated in CA1 astrocyte, which was inhibited by mithramycin A (MMA). MMA alleviated clasmatodendrosis and Prdx6 upregulation. Sp1 expression was also downregulated by CDDO-Me and NAC. Furthermore, 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) attenuated clasmatodendrosis without affecting Prdx6 expression. All chemicals shortened spontaneous seizure duration but not seizure frequency and behavioral seizure severity in chronic epilepsy rats. Therefore, our findings suggest that Sp1 activation may upregulate Prdx6, whose aiPLA2 activity would dominate over GPx activity in CA1 astrocytes and may lead to prolonged seizure activity due to autophagic astroglial degeneration. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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17 pages, 3382 KiB  
Article
Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer’s Disease Mouse Model
by Abbas Raza, Wei Xie, Kwan-Hyun Kim, Venkateshwara Rao Dronamraju, Jessica Williams, Robert Vince and Swati S. More
Antioxidants 2022, 11(6), 1075; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11061075 - 28 May 2022
Cited by 5 | Viewed by 1968
Abstract
Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical [...] Read more.
Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical translation due to poor bioavailability. We addressed this problem through the design of γ-GT-resistant GSH analogue, ψ-GSH, which successfully substituted in GSH-dependent enzymatic systems and also offered promise as a therapeutic for Alzheimer’s disease (AD). With the aim to improve its bioavailability, we studied the utility of a ψ-GSH precursor, dipeptide 2, as a potential AD therapeutic. Compound 2 retains the γ-GT stable ureide linkage and the thiol group for antioxidant property. By engaging glutathione synthetase, compound 2 was able to generate ψ-GSH in vivo. It was found to be a modest cofactor of glutathione peroxidase and prevented cytotoxicity of Aβ1–42-aggregates in vitro. Studies of compound 2 in an acute AD model generated by intracerebroventricular injection of Aβ1–42 showed cognitive benefits, which were augmented by its combination with glycine along with mitigation of oxidative stress and inflammatory pathology. Collectively, these results support further optimization and evaluation of ψ-GSH dipeptide as a potential therapeutic in transgenic AD models. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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Review

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14 pages, 774 KiB  
Review
Glutathionyl Hemoglobin and Its Emerging Role as a Clinical Biomarker of Chronic Oxidative Stress
by Andrea Scirè, Giulia Casari, Brenda Romaldi, Lidia de Bari, Cinzia Antognelli and Tatiana Armeni
Antioxidants 2023, 12(11), 1976; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12111976 - 07 Nov 2023
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Abstract
Hemoglobin is one of the proteins that are more susceptible to S-glutathionylation and the levels of its modified form, glutathionyl hemoglobin (HbSSG), increase in several human pathological conditions. The scope of the present review is to provide knowledge about how hemoglobin is subjected [...] Read more.
Hemoglobin is one of the proteins that are more susceptible to S-glutathionylation and the levels of its modified form, glutathionyl hemoglobin (HbSSG), increase in several human pathological conditions. The scope of the present review is to provide knowledge about how hemoglobin is subjected to S-glutathionylation and how this modification affects its functionality. The different diseases that showed increased levels of HbSSG and the methods used for its quantification in clinical investigations will be also outlined. Since there is a growing need for precise and reliable methods for markers of oxidative stress in human blood, this review highlights how HbSSG is emerging more and more as a good indicator of severe oxidative stress but also as a key pathogenic factor in several diseases. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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20 pages, 1066 KiB  
Review
How to Increase Cellular Glutathione
by Daniela Giustarini, Aldo Milzani, Isabella Dalle-Donne and Ranieri Rossi
Antioxidants 2023, 12(5), 1094; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12051094 - 13 May 2023
Cited by 10 | Viewed by 4426
Abstract
Glutathione (GSH) has special antioxidant properties due to its high intracellular concentration, ubiquity, and high reactivity towards electrophiles of the sulfhydryl group of its cysteine moiety. In most diseases where oxidative stress is thought to play a pathogenic role, GSH concentration is significantly [...] Read more.
Glutathione (GSH) has special antioxidant properties due to its high intracellular concentration, ubiquity, and high reactivity towards electrophiles of the sulfhydryl group of its cysteine moiety. In most diseases where oxidative stress is thought to play a pathogenic role, GSH concentration is significantly reduced, making cells more susceptible to oxidative damage. Therefore, there is a growing interest in determining the best method(s) to increase cellular glutathione for both disease prevention and treatment. This review summarizes the major strategies for successfully increasing cellular GSH stores. These include GSH itself, its derivatives, NRf-2 activators, cysteine prodrugs, foods, and special diets. The possible mechanisms by which these molecules can act as GSH boosters, their related pharmacokinetic issues, and their advantages and disadvantages are discussed. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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24 pages, 3478 KiB  
Review
Cellular Compartmentalization, Glutathione Transport and Its Relevance in Some Pathologies
by Héctor Vázquez-Meza, María Magdalena Vilchis-Landeros, Melissa Vázquez-Carrada, Daniel Uribe-Ramírez and Deyamira Matuz-Mares
Antioxidants 2023, 12(4), 834; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12040834 - 29 Mar 2023
Cited by 11 | Viewed by 3604
Abstract
Reduced glutathione (GSH) is the most abundant non-protein endogenous thiol. It is a ubiquitous molecule produced in most organs, but its synthesis is predominantly in the liver, the tissue in charge of storing and distributing it. GSH is involved in the detoxification of [...] Read more.
Reduced glutathione (GSH) is the most abundant non-protein endogenous thiol. It is a ubiquitous molecule produced in most organs, but its synthesis is predominantly in the liver, the tissue in charge of storing and distributing it. GSH is involved in the detoxification of free radicals, peroxides and xenobiotics (drugs, pollutants, carcinogens, etc.), protects biological membranes from lipid peroxidation, and is an important regulator of cell homeostasis, since it participates in signaling redox, regulation of the synthesis and degradation of proteins (S-glutathionylation), signal transduction, various apoptotic processes, gene expression, cell proliferation, DNA and RNA synthesis, etc. GSH transport is a vital step in cellular homeostasis supported by the liver through providing extrahepatic organs (such as the kidney, lung, intestine, and brain, among others) with the said antioxidant. The wide range of functions within the cell in which glutathione is involved shows that glutathione’s role in cellular homeostasis goes beyond being a simple antioxidant agent; therefore, the importance of this tripeptide needs to be reassessed from a broader metabolic perspective. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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15 pages, 4503 KiB  
Review
Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase
by Juan Segura-Aguilar, Patricia Muñoz, Jose Inzunza, Mukesh Varshney, Ivan Nalvarte and Bengt Mannervik
Antioxidants 2022, 11(2), 296; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11020296 - 31 Jan 2022
Cited by 12 | Viewed by 3079
Abstract
Glutathione is an important antioxidant that plays a crucial role in the cellular protection against oxidative stress and detoxification of electrophilic mutagens, and carcinogens. Glutathione transferases are enzymes catalyzing glutathione-dependent reactions that lead to inactivation and conjugation of toxic compounds, processes followed by [...] Read more.
Glutathione is an important antioxidant that plays a crucial role in the cellular protection against oxidative stress and detoxification of electrophilic mutagens, and carcinogens. Glutathione transferases are enzymes catalyzing glutathione-dependent reactions that lead to inactivation and conjugation of toxic compounds, processes followed by subsequent excretion of the detoxified products. Degeneration and loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal neurons generally involves oxidative stress, neuroinflammation, alpha-synuclein aggregation to neurotoxic oligomers, mitochondrial dysfunction, protein degradation dysfunction, and endoplasmic reticulum stress. However, it is still unclear what triggers these neurodegenerative processes. It has been reported that aminochrome may elicit all of these mechanisms and, interestingly, aminochrome is formed inside neuromelanin-containing dopaminergic neurons during neuromelanin synthesis. Aminochrome is a neurotoxic ortho-quinone formed in neuromelanin synthesis. However, it seems paradoxical that the neurotoxin aminochrome is generated during neuromelanin synthesis, even though healthy seniors have these neurons intact when they die. The explanation of this paradox is the existence of protective tools against aminochrome neurotoxicity composed of the enzymes DT-diaphorase, expressed in these neurons, and glutathione transferase M2-2, expressed in astrocytes. Recently, it has been reported that dopaminergic neurons can be protected by glutathione transferase M2-2 from astrocytes, which secrete exosomes containing the protective enzyme. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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19 pages, 772 KiB  
Review
Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?
by Lena Palaniyappan, Min Tae M. Park, Peter Jeon, Roberto Limongi, Kun Yang, Akira Sawa and Jean Théberge
Antioxidants 2021, 10(11), 1703; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10111703 - 27 Oct 2021
Cited by 16 | Viewed by 2959
Abstract
Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical [...] Read more.
Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical glutathione (GSH). A large body of pre-clinical data has suggested the possibility of notable GSH-deficit in a subgroup of patients with schizophrenia. Nevertheless, studies of intracortical GSH are not conclusive in this regard. In this review, we highlight the recent ultra-high field magnetic resonance spectroscopic studies linking GSH to critical outcome measures across various stages of schizophrenia. We discuss the methodological steps required to conclusively establish or refute the persistence of GSH-deficit subtype and clarify the role of the central antioxidant system in disrupting the brain structure and connectivity in the early stages of schizophrenia. We propose in-vivo GSH quantification for patient selection in forthcoming antioxidant trials in psychosis. This review offers directions for a promising non-dopaminergic early intervention approach in schizophrenia. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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27 pages, 1520 KiB  
Review
In Vivo Brain GSH: MRS Methods and Clinical Applications
by Francesca Bottino, Martina Lucignani, Antonio Napolitano, Francesco Dellepiane, Emiliano Visconti, Maria Camilla Rossi Espagnet and Luca Pasquini
Antioxidants 2021, 10(9), 1407; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10091407 - 01 Sep 2021
Cited by 24 | Viewed by 4937
Abstract
Glutathione (GSH) is an important antioxidant implicated in several physiological functions, including the oxidation−reduction reaction balance and brain antioxidant defense against endogenous and exogenous toxic agents. Altered brain GSH levels may reflect inflammatory processes associated with several neurologic disorders. An accurate and reliable [...] Read more.
Glutathione (GSH) is an important antioxidant implicated in several physiological functions, including the oxidation−reduction reaction balance and brain antioxidant defense against endogenous and exogenous toxic agents. Altered brain GSH levels may reflect inflammatory processes associated with several neurologic disorders. An accurate and reliable estimation of cerebral GSH concentrations could give a clear and thorough understanding of its metabolism within the brain, thus providing a valuable benchmark for clinical applications. In this context, we aimed to provide an overview of the different magnetic resonance spectroscopy (MRS) technologies introduced for in vivo human brain GSH quantification both in healthy control (HC) volunteers and in subjects affected by different neurological disorders (e.g., brain tumors, and psychiatric and degenerative disorders). Additionally, we aimed to provide an exhaustive list of normal GSH concentrations within different brain areas. The definition of standard reference values for different brain areas could lead to a better interpretation of the altered GSH levels recorded in subjects with neurological disorders, with insights into the possible role of GSH as a biomarker and therapeutic target. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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15 pages, 512 KiB  
Review
Glutathione in the Nervous System as a Potential Therapeutic Target to Control the Development and Progression of Amyotrophic Lateral Sclerosis
by Kiyoung Kim
Antioxidants 2021, 10(7), 1011; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071011 - 23 Jun 2021
Cited by 26 | Viewed by 4613
Abstract
Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder that affects the motor neurons responsible for regulating muscle movement. However, the molecular pathogenic mechanisms of ALS remain poorly understood. A deficiency in the antioxidant tripeptide glutathione (GSH) in the nervous system appears to [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder that affects the motor neurons responsible for regulating muscle movement. However, the molecular pathogenic mechanisms of ALS remain poorly understood. A deficiency in the antioxidant tripeptide glutathione (GSH) in the nervous system appears to be involved in several neurodegenerative diseases characterized by the loss of neuronal cells. Impaired antioxidant defense systems, and the accumulation of oxidative damage due to increased dysfunction in GSH homeostasis are known to be involved in the development and progression of ALS. Aberrant GSH metabolism and redox status following oxidative damage are also associated with various cellular organelles, including the mitochondria and nucleus, and are crucial factors in neuronal toxicity induced by ALS. In this review, we provide an overview of the implications of imbalanced GSH homeostasis and its molecular characteristics in various experimental models of ALS. Full article
(This article belongs to the Special Issue Glutathione in Health and Disease)
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