Special Issue "Glutathione Metabolism"

A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (30 June 2019).

Special Issue Editors

Guest Editor
Prof. Dr. Maria Rosa Ciriolo Website E-Mail
Department of Biology, University of Rome ‘Tor Vergata’, via della Ricerca Scientifica, 00133, Rome, Italy
Interests: De-regulated metabolism in cancer; obesity and related metabolic diseases; nutrition; stress; adipose tissue metabolism
Guest Editor
Dr. Fabio Ciccarone E-Mail
Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
Guest Editor
Prof. Sara Baldelli E-Mail
IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy

Special Issue Information

Dear Colleagues,

The phenomenal rate of expansion in the field of redox-regulated mechanisms justifies the main aim of this issue, which is to provide an overview of the biochemistry of thiol redox homeostasis centered in the glutathione and of its role in cellular metabolism. Indeed, no aspect related to this tripeptide is canonical, starting from the characteristic enzymatic synthesis, to the resistance to degradation and capability of oxidation. Moreover, its high intracellular concentration stands for an unavoidable intersection with cellular metabolic functions ranging from gene expression, DNA and protein synthesis to signal transduction, cell proliferation, detoxification and death. The incipient concept is related to the field of emerging tools in “nanotechnologies” to achieve targeted drug delivery, where glutathione has clearly penetrated fields other than biology. In this context, glutathione has emerged as a potential candidate to facilitate the receptor-mediated transcytosis of nanocarriers, especially at the blood–brain barrier. Another emerging function is related to omics, specifically referred to as exposomics, which is a proposed term and the field of study of the disease-causing effects of environmental factors. The well-established concept that redox modifications of the proteome provide a system to sense, avoid and defend against environmental toxicants is again putting glutathione at the center stage of the adaptive interface of the functional genome and the exposome. As a consequence, knowledge on the role of glutathione metabolism is never updated but is instead increasing in parallel with deeper understanding of biochemical processes and with the utilization of more sophisticated techniques.

It is, therefore, a pleasure to invite timely review papers, as well as high quality studies, on glutathione systems and their widespread implications in cellular signaling (e.g. cell death pathways and inflammation), pathophysiology (ranging from cancer to neurodegeneration), therapeutic approaches and drug delivery based on GSH or its derivatives, biomarker usage, and nutritional intersections other than antioxidant responses.

Prof. Dr. Maria Rosa Ciriolo
Dr. Fabio Ciccarone
Prof. Sara Baldelli
Guest Editors

Manuscript Submission Information

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Keywords

  • Antioxidants
  • Redox signaling
  • Redox proteome
  • Metabolic disease
  • Neurodegeneration
  • Cancer
  • Nanotechnologies

Published Papers (7 papers)

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Research

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Open AccessArticle
Parabiosis Incompletely Reverses Aging-Induced Metabolic Changes and Oxidant Stress in Mouse Red Blood Cells
Nutrients 2019, 11(6), 1337; https://doi.org/10.3390/nu11061337 - 14 Jun 2019
Abstract
Mature red blood cells (RBCs) not only account for ~83% of the total host cells in the human body, but they are also exposed to all body tissues during their circulation in the bloodstream. In addition, RBCs are devoid of de novo protein [...] Read more.
Mature red blood cells (RBCs) not only account for ~83% of the total host cells in the human body, but they are also exposed to all body tissues during their circulation in the bloodstream. In addition, RBCs are devoid of de novo protein synthesis capacity and, as such, they represent a perfect model to investigate system-wide alterations of cellular metabolism in the context of aging and age-related oxidant stress without the confounding factor of gene expression. In the present study, we employed ultra-high-pressure liquid chromatography coupled with mass spectrometry (UHPLC–MS)-based metabolomics and proteomics to investigate RBC metabolism across age in male mice (6, 15, and 25 months old). We report that RBCs from aging mice face a progressive decline in the capacity to cope with oxidant stress through the glutathione/NADPH-dependent antioxidant systems. Oxidant stress to tryptophan and purines was accompanied by declines in late glycolysis and methyl-group donors, a potential compensatory mechanism to repair oxidatively damaged proteins. Moreover, heterochronic parabiosis experiments demonstrated that the young environment only partially rescued the alterations in one-carbon metabolism in old mice, although it had minimal to no impact on glutathione homeostasis, the pentose phosphate pathway, and oxidation of purines and tryptophan, which were instead aggravated in old heterochronic parabionts. Full article
(This article belongs to the Special Issue Glutathione Metabolism)
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Review

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Open AccessReview
A Review of Dietary (Phyto)Nutrients for Glutathione Support
Nutrients 2019, 11(9), 2073; https://doi.org/10.3390/nu11092073 - 03 Sep 2019
Abstract
Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse [...] Read more.
Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse roles of glutathione in physiology are relevant to a considerable body of evidence suggesting that glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Yet, proper personalized balance in the individual is key as well as a better understanding of antioxidants and redox balance. Optimizing glutathione levels has been proposed as a strategy for health promotion and disease prevention, although clear, causal relationships between glutathione status and disease risk or treatment remain to be clarified. Nonetheless, human clinical research suggests that nutritional interventions, including amino acids, vitamins, minerals, phytochemicals, and foods can have important effects on circulating glutathione which may translate to clinical benefit. Importantly, genetic variation is a modifier of glutathione status and influences response to nutritional factors that impact glutathione levels. This narrative review explores clinical evidence for nutritional strategies that could be used to improve glutathione status. Full article
(This article belongs to the Special Issue Glutathione Metabolism)
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Open AccessReview
Role of Glutathionylation in Infection and Inflammation
Nutrients 2019, 11(8), 1952; https://doi.org/10.3390/nu11081952 - 20 Aug 2019
Abstract
Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification [...] Read more.
Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses. Full article
(This article belongs to the Special Issue Glutathione Metabolism)
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Open AccessReview
Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy
Nutrients 2019, 11(8), 1926; https://doi.org/10.3390/nu11081926 - 16 Aug 2019
Abstract
Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. [...] Read more.
Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number of chemotherapeutic agents. Targeting glutathione metabolism has been widely investigated for cancer treatment although GSH depletion as single therapeutic strategy has resulted largely ineffective if compared with combinatorial approaches. In this review, we circumstantiate the role of glutathione in tumour development and progression focusing on how interfering with different steps of glutathione metabolism can be exploited for therapeutic purposes. A dedicated section on synthetic lethal interactions with GSH modulators will highlight the promising option of harnessing glutathione metabolism for patient-directed therapy in cancer. Full article
(This article belongs to the Special Issue Glutathione Metabolism)
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Open AccessReview
Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution
Nutrients 2019, 11(8), 1741; https://doi.org/10.3390/nu11081741 - 27 Jul 2019
Abstract
Glutathione transferase P1-1 (GSTP1-1) is expressed in some human tissues and is abundant in mammalian erythrocytes (here termed e-GST). This enzyme is able to detoxify the cell from endogenous and exogenous toxic compounds by using glutathione (GSH) or by acting as a ligandin. [...] Read more.
Glutathione transferase P1-1 (GSTP1-1) is expressed in some human tissues and is abundant in mammalian erythrocytes (here termed e-GST). This enzyme is able to detoxify the cell from endogenous and exogenous toxic compounds by using glutathione (GSH) or by acting as a ligandin. This review collects studies that propose GSTP1-1 as a useful biomarker in different fields of application. The most relevant studies are focused on GSTP1-1 as a biosensor to detect blood toxicity in patients affected by kidney diseases. In fact, this detoxifying enzyme is over-expressed in erythrocytes when unusual amounts of toxins are present in the body. Here we review articles concerning the level of GST in chronic kidney disease patients, in maintenance hemodialysis patients and to assess dialysis adequacy. GST is also over-expressed in autoimmune disease like scleroderma, and in kidney transplant patients and it may be used to check the efficiency of transplanted kidneys. The involvement of GSTP in the oxidative stress and in other human pathologies like cancer, liver and neurodegenerative diseases, and psychiatric disorders is also reported. Promising applications of e-GST discussed in the present review are its use for monitoring human subjects living in polluted areas and mammals for veterinary purpose. Full article
(This article belongs to the Special Issue Glutathione Metabolism)
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Open AccessReview
Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and β-mercaptoethylamine
Nutrients 2019, 11(6), 1291; https://doi.org/10.3390/nu11061291 - 07 Jun 2019
Abstract
Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-β-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and β-mercaptoethylamine or cysteamine, MEA). [...] Read more.
Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-β-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and β-mercaptoethylamine or cysteamine, MEA). NAC is a precursor of L-cysteine, while MEA is an aminothiol able to increase GSH content; thus, I-152 represents the very first attempt to combine two pro-GSH molecules. In this review, the in-vitro and in-vivo metabolism, pro-GSH activity and antiviral and immunomodulatory properties of I-152 are discussed. Under physiological GSH conditions, low I-152 doses increase cellular GSH content; by contrast, high doses cause GSH depletion but yield a high content of NAC, MEA and I-152, which can be used to resynthesize GSH. Preliminary in-vivo studies suggest that the molecule reaches mouse organs, including the brain, where its metabolites, NAC and MEA, are detected. In cell cultures, I-152 replenishes experimentally depleted GSH levels. Moreover, administration of I-152 to C57BL/6 mice infected with the retroviral complex LP-BM5 is effective in contrasting virus-induced GSH depletion, exerting at the same time antiviral and immunomodulatory functions. I-152 acts as a pro-GSH agent; however, GSH derivatives and NAC cannot completely replicate its effects. The co-delivery of different thiol species may lead to unpredictable outcomes, which warrant further investigation. Full article
(This article belongs to the Special Issue Glutathione Metabolism)
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Open AccessReview
Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis
Nutrients 2019, 11(5), 1056; https://doi.org/10.3390/nu11051056 - 11 May 2019
Cited by 1
Abstract
Glutathione (GSH) is a critical endogenous antioxidant found in all eukaryotic cells. Higher GSH concentrations protect against cellular damage, tissue degeneration, and disease progression in various models, so there is considerable interest in developing interventions that augment GSH biosynthesis. Oral GSH supplementation is [...] Read more.
Glutathione (GSH) is a critical endogenous antioxidant found in all eukaryotic cells. Higher GSH concentrations protect against cellular damage, tissue degeneration, and disease progression in various models, so there is considerable interest in developing interventions that augment GSH biosynthesis. Oral GSH supplementation is not the most efficient option due to the enzymatic degradation of ingested GSH within the intestine by γ-glutamyltransferase, but supplementation of its component amino acids—cysteine, glycine, and glutamate—enhances tissue GSH synthesis. Furthermore, supplementation with some non-precursor amino acids and micronutrients appears to influence the redox status of GSH and related antioxidants, such as vitamins C and E, lowering systemic oxidative stress and slowing the rate of tissue deterioration. In this review, the effects of oral supplementation of amino acids and micronutrients on GSH metabolism are evaluated. And since specific dietary patterns and diets are being prescribed as first-line therapeutics for conditions such as hypertension and diabetes, the impact of overall diets on GSH homeostasis is also assessed. Full article
(This article belongs to the Special Issue Glutathione Metabolism)
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