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The Role of GSH in Intracellular Iron Trafficking.
Hider, R, Aviles, MV, Chen, YL, Latunde-Dada, GO
International journal of molecular sciences. 2021;(3)
Abstract
Evidence is reviewed for the role of glutathione in providing a ligand for the cytosolic iron pool. The possibility of histidine and carnosine forming ternary complexes with iron(II)glutathione is discussed and the physiological significance of these interactions considered. The role of carnosine in muscle, brain, and kidney physiology is far from established and evidence is presented that the iron(II)-binding capability of carnosine relates to this role.
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Glutathione: An Old and Small Molecule with Great Functions and New Applications in the Brain and in Alzheimer's Disease.
Haddad, M, Hervé, V, Ben Khedher, MR, Rabanel, JM, Ramassamy, C
Antioxidants & redox signaling. 2021;(4):270-292
Abstract
Significance: Glutathione (GSH) represents the most abundant and the main antioxidant in the body with important functions in the brain related to Alzheimer's disease (AD). Recent Advances: Oxidative stress is one of the central mechanisms in AD. We and others have demonstrated the alteration of GSH levels in the AD brain, its important role in the detoxification of advanced glycation end-products and of acrolein, a by-product of lipid peroxidation. Recent in vivo studies found a decrease of GSH in several areas of the brain from control, mild cognitive impairment, and AD subjects, which are correlated with cognitive decline. Critical Issues: Several strategies were developed to restore its intracellular level with the l-cysteine prodrugs or the oral administration of γ-glutamylcysteine to prevent alterations observed in AD. To date, no benefit on GSH level or on oxidative biomarkers has been reported in clinical trials. Thus, it remains uncertain if GSH could be considered a potential preventive or therapeutic approach or a biomarker for AD. Future Directions: We address how GSH-coupled nanocarriers represent a promising approach for the functionalization of nanocarriers to overcome the blood/brain barrier (BBB) for the brain delivery of GSH while avoiding cellular toxicity. It is also important to address the presence of GSH in exosomes for its potential intercellular transfer or its shuttle across the BBB under certain conditions. Antioxid. Redox Signal. 35, 270-292.
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Roles of Glutathione in Mediating Abscisic Acid Signaling and Its Regulation of Seed Dormancy and Drought Tolerance.
Koramutla, MK, Negi, M, Ayele, BT
Genes. 2021;(10)
Abstract
Plant growth and development and interactions with the environment are regulated by phytohormones and other signaling molecules. During their evolution, plants have developed strategies for efficient signal perception and for the activation of signal transduction cascades to maintain proper growth and development, in particular under adverse environmental conditions. Abscisic acid (ABA) is one of the phytohormones known to regulate plant developmental events and tolerance to environmental stresses. The role of ABA is mediated by both its accumulated level, which is regulated by its biosynthesis and catabolism, and signaling, all of which are influenced by complex regulatory mechanisms. Under stress conditions, plants employ enzymatic and non-enzymatic antioxidant strategies to scavenge excess reactive oxygen species (ROS) and mitigate the negative effects of oxidative stress. Glutathione (GSH) is one of the main antioxidant molecules playing a critical role in plant survival under stress conditions through the detoxification of excess ROS, maintaining cellular redox homeostasis and regulating protein functions. GSH has recently emerged as an important signaling molecule regulating ABA signal transduction and associated developmental events, and response to stressors. This review highlights the current knowledge on the interplay between ABA and GSH in regulating seed dormancy, germination, stomatal closure and tolerance to drought.
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Smart nanomedicine agents for cancer, triggered by pH, glutathione, H2O2, or H2S.
Li, Y, An, L, Lin, J, Tian, Q, Yang, S
International journal of nanomedicine. 2019;:5729-5749
Abstract
Effective tumor diagnosis and therapy have always been a significant but challenging issue. Although nanomedicine has shown great potential for improving the outcomes of tumor diagnosis and therapy, the nonspecial targeted distribution of nanomedicine agents in the whole body causes a low diagnosis signal-to-noise ratio and a potential risk of systemic toxicity. Recently, the development of smart nanomedicine agents with diagnosis and therapy functions that can only be activated by the tumor microenvironment (TME) is regarded as an effective strategy to improve the theranostic sensitivity and selectivity, as well as reduce the potential side effects during treatment. This article will introduce and summarize the latest achievements in the design and fabrication of TME-responsive smart nanomedicine agents, and highlight their prospects for enhancing tumor diagnosis and therapy.
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5.
The role of thiols in antioxidant systems.
Ulrich, K, Jakob, U
Free radical biology & medicine. 2019;:14-27
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Abstract
The sulfur biochemistry of the thiol group endows cysteines with a number of highly specialized and unique features that enable them to serve a variety of different functions in the cell. Typically highly conserved in proteins, cysteines are predominantly found in functionally or structurally crucial regions, where they act as stabilizing, catalytic, metal-binding and/or redox-regulatory entities. As highly abundant low molecular weight thiols, cysteine thiols and their oxidized disulfide counterparts are carefully balanced to maintain redox homeostasis in various cellular compartments, protect organisms from oxidative and xenobiotic stressors and partake actively in redox-regulatory and signaling processes. In this review, we will discuss the role of protein thiols as scavengers of hydrogen peroxide in antioxidant enzymes, use thiol peroxidases to exemplify how protein thiols contribute to redox signaling, provide an overview over the diverse set of low molecular weight thiol-based redox systems found in biology, and illustrate how thiol-based redox systems have evolved not only to protect against but to take full advantage of a world full of molecular oxygen.
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Role of Glutathionylation in Infection and Inflammation.
Checconi, P, Limongi, D, Baldelli, S, Ciriolo, MR, Nencioni, L, Palamara, AT
Nutrients. 2019;(8)
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 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.
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Modulation of bacterial virulence and fitness by host glutathione.
Ku, JW, Gan, YH
Current opinion in microbiology. 2019;:8-13
Abstract
Glutathione is a low molecular weight thiol that is important for maintaining intracellular redox homeostasis. Some bacteria are able to import exogenous glutathione as a nutritional source and to counter oxidative stress. In cytosolic pathogens Burkholderia pseudomallei and Listeria monocytogenes, host glutathione regulates bacterial virulence. In B. pseudomallei, glutathione activates the membrane-bound histidine kinase sensor VirA that leads to activation of the Type VI Secretion System. In L. monocytogenes, host glutathione leads to the binding of bacterial glutathione to the master virulence regulator PrfA as an allosteric activator. Glutathione can also modulate virulence factors to control their activity by S-glutathionylation. Thus, host glutathione acts as a spacio-temporal cue for some pathogens to switch on their virulence programs at the right time and place.
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[Analyzing the Redox Status of Intracellular Glutathione and Its Application to an Intestinal Bowel Disease Model].
Hatori, Y
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2019;(12):1523-1530
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Abstract
Oxidative stress, including reactive oxygen species (ROS) generation and resulting glutathione oxidation, have been implicated in numerous aspects of cell physiology and human pathology such as cell senescence, cell differentiation, and inflammation. Significant effort has been made to establish methods of analyzing ROS levels and glutathione oxidation within a living cell. The recent development of redox-sensitive green fluorescent protein (GFP) variants enables a robust and accurate estimation of ROS level and glutathione oxidation at subcellular resolution. We created membrane-targeted versions of glutathione and hydrogen peroxide sensors by attaching palmitoylation signals to existing sensors (Grx1-roGFP2 and roGFP2-Orp1, respectively), and demonstrated the nonuniform distribution of these oxidative elements within cytosol. In living cells, cytosolic glutathione is highly reduced, and hydrogen peroxide is barely detected. Nevertheless, near the cytoplasmic side of intracellular vesicular membranes, significant glutathione oxidation and hydrogen peroxide were successfully probed by our sensors, clearly showing the difference between various areas within cytosol. Currently, these sensors are being applied to an intestinal inflammation model which is constituted by co-culturing intestinal epithelial cells and macrophage-like inflammatory cells derived from THP-1. This review covers the current status of studies regarding the association of oxidative stress and intestinal inflammation, with a focus on the redox regulation of intracellular glutathione.
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Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy.
Desideri, E, Ciccarone, F, Ciriolo, MR
Nutrients. 2019;(8)
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. 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.
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Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis.
Chen, Y, Han, M, Matsumoto, A, Wang, Y, Thompson, DC, Vasiliou, V
Advances in experimental medicine and biology. 2018;:37-53
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Abstract
Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize H2O2 as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.