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22 pages, 4428 KiB

Open AccessArticle

Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation

by Inês Santos, Cristiano Ramos, Cindy Mendes, Catarina O. Sequeira, Catarina S. Tomé, Dalila G.H. Fernandes, Pedro Mota, Rita F. Pires, Donato Urso, Ana Hipólito, Alexandra M.M. Antunes, João B. Vicente, Sofia A. Pereira, Vasco D. B. Bonifácio, Sofia C. Nunes and Jacinta Serpa

Nutrients 2019, 11(10), 2523; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11102523 - 19 Oct 2019

Cited by 33 | Viewed by 6075

Abstract

Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine [...] Read more.

Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine and glutathione (GSH) impacts the mechanisms of resistance to carboplatin in ovarian cancer. Different players in cysteine metabolism can be crucial in chemoresistance, such as the cystine/glutamate antiporter system Xc (xCT) and the H₂S-synthesizing enzyme cystathionine β-synthase (CBS) in the pathway of cysteine catabolism. We hypothesized that, by disrupting cysteine metabolic flux, chemoresistance would be reverted. Since the xCT transporter is also able to take up selenium, we used selenium-containing chrysin (SeChry) as a plausible competitive inhibitor of xCT. For that, we tested the effects of SeChry on three different ovarian cancer cell lines (ES2, OVCAR3, and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2). Results showed that, in addition to being highly cytotoxic, SeChry does not affect the uptake of cysteine, although it increases GSH depletion, indicating that SeChry might induce oxidative stress. However, enzymatic assays revealed an inhibitory effect of SeChry toward CBS, thus preventing production of the antioxidant H₂S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PURE_G4-FA) nanoparticles increased the specificity for SeChry delivery to ovarian cancer cells, reducing significantly the toxicity against non-malignant cells. Collectively, our data support SeChry@PURE_G4-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity. Full article

(This article belongs to the Special Issue Glutathione Metabolism)

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20 pages, 5735 KiB

Open AccessArticle

Parabiosis Incompletely Reverses Aging-Induced Metabolic Changes and Oxidant Stress in Mouse Red Blood Cells

by Evan J. Morrison, Devin P. Champagne, Monika Dzieciatkowska, Travis Nemkov, James C. Zimring, Kirk C. Hansen, Fangxia Guan, Derek M. Huffman, Laura Santambrogio and Angelo D’Alessandro

Nutrients 2019, 11(6), 1337; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11061337 - 14 Jun 2019

Cited by 19 | Viewed by 6291

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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18 pages, 1716 KiB

Open AccessReview

Glutathione and Nitric Oxide: Key Team Players in Use and Disuse of Skeletal Muscle

by Sara Baldelli, Fabio Ciccarone, Dolores Limongi, Paola Checconi, Anna Teresa Palamara and Maria Rosa Ciriolo

Nutrients 2019, 11(10), 2318; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11102318 - 30 Sep 2019

Cited by 37 | Viewed by 6535

Abstract

Glutathione (GSH) is the main non-enzymatic antioxidant playing an important role in detoxification, signal transduction by modulation of protein thiols redox status and direct scavenging of radicals. The latter function is not only performed against reactive oxygen species (ROS) but GSH also has [...] Read more.

Glutathione (GSH) is the main non-enzymatic antioxidant playing an important role in detoxification, signal transduction by modulation of protein thiols redox status and direct scavenging of radicals. The latter function is not only performed against reactive oxygen species (ROS) but GSH also has a fundamental role in buffering nitric oxide (NO), a physiologically-produced molecule having-multifaceted functions. The efficient rate of GSH synthesis and high levels of GSH-dependent enzymes are characteristic features of healthy skeletal muscle where, besides the canonical functions, it is also involved in muscle contraction regulation. Moreover, NO production in skeletal muscle is a direct consequence of contractile activity and influences several metabolic myocyte pathways under both physiological and pathological conditions. In this review, we will consider the homeostasis and intersection of GSH with NO and then we will restrict the discussion on their role in processes related to skeletal muscle function and degeneration. Full article

(This article belongs to the Special Issue Glutathione Metabolism)

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20 pages, 586 KiB

Open AccessReview

A Review of Dietary (Phyto)Nutrients for Glutathione Support

by Deanna M. Minich and Benjamin I. Brown

Nutrients 2019, 11(9), 2073; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11092073 - 03 Sep 2019

Cited by 116 | Viewed by 35632

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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12 pages, 1138 KiB

Open AccessReview

Role of Glutathionylation in Infection and Inflammation

by Paola Checconi, Dolores Limongi, Sara Baldelli, Maria Rosa Ciriolo, Lucia Nencioni and Anna Teresa Palamara

Nutrients 2019, 11(8), 1952; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11081952 - 20 Aug 2019

Cited by 35 | Viewed by 5602

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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12 pages, 743 KiB

Open AccessReview

Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy

by Enrico Desideri, Fabio Ciccarone and Maria Rosa Ciriolo

Nutrients 2019, 11(8), 1926; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11081926 - 16 Aug 2019

Cited by 89 | Viewed by 10626

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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34 pages, 3598 KiB

Open AccessReview

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution

by Alessio Bocedi, Annalisa Noce, Giulia Marrone, Gianluca Noce, Giada Cattani, Giorgia Gambardella, Manuela Di Lauro, Nicola Di Daniele and Giorgio Ricci

Nutrients 2019, 11(8), 1741; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11081741 - 27 Jul 2019

Cited by 48 | Viewed by 7912

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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11 pages, 770 KiB

Open AccessReview

Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and β-mercaptoethylamine

by Rita Crinelli, Carolina Zara, Michaël Smietana, Michele Retini, Mauro Magnani and Alessandra Fraternale

Nutrients 2019, 11(6), 1291; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11061291 - 07 Jun 2019

Cited by 15 | Viewed by 4291

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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21 pages, 307 KiB

Open AccessReview

Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis

by Rebecca L. Gould and Robert Pazdro

Nutrients 2019, 11(5), 1056; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11051056 - 11 May 2019

Cited by 79 | Viewed by 9676

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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