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1.
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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GSH Levels Serve As a Biological Redox Switch Regulating Sulforaphane-Induced Cell Fate in Human Lens Cells.
Huynh, TPN, Bowater, RP, Bernuzzi, F, Saha, S, Wormstone, IM
Investigative ophthalmology & visual science. 2021;(15):2
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Abstract
PURPOSE Sulforaphane (SFN) is a therapeutic phytochemical agent for many health conditions. SFN-induced cytotoxicity is shown to have promise in preventing posterior capsule opacification (PCO). In the current study, we aimed to elucidate key processes and mechanisms linking SFN treatment to lens cell death. METHODS The human lens epithelial cell line FHL124 and central anterior epithelium were used as experimental models. Cell death was assessed by microscopic observation and cell damage/viability assays. Gene or protein levels were assessed by TaqMan RT-PCR or immunoblotting. Mitochondrial networks and DNA damage were assessed by immunofluorescence. Mitochondrial membrane potential, activating transcription factor 6 (ATF6) activity, ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and glutathione reductase (GR) activity were measured using different light reporter assays. SFN metabolites were analyzed by LC-MS/MS. RESULTS Treatment with N-acetylcysteine (NAC), a reactive oxygen species scavenger, prevented SFN-induced cell death in both models. NAC also significantly protected FHL124 cells from SFN-induced mitochondrial dysfunctions, endoplasmic reticulum stress (ERS), DNA damage and autophagy. SFN significantly depleted GSH, the major antioxidant in the eye, and reduced GR activity, despite doubling its protein levels. The most abundant SFN conjugate detected in lens cells following SFN application was SFN-GSH. The addition of GSH protected lens cells from all SFN-induced cellular events. CONCLUSIONS SFN depletes GSH levels in lens cells through conjugation and inhibition of GR activity. This leads to increased reactive oxygen species and oxidative stress that trigger mitochondrial dysfunction, ERS, autophagy, and DNA damage, leading to cell death. In summary, the work presented provides a mechanistic understanding to support the therapeutic application of SFN for PCO and other disorders.
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The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering the Immune Responses against Mycobacterium bovis BCG Strain in Individuals with Type 2 Diabetes.
To, K, Cao, R, Yegiazaryan, A, Owens, J, Sasaninia, K, Vaughn, C, Singh, M, Truong, E, Sathananthan, A, Venketaraman, V
Biomolecular concepts. 2021;(1):16-26
Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains a devastating infectious disease in the world. There has been a daunting increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. T2DM patients are three times more vulnerable to M. tb infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research, M. tb still has unexplored characteristics in successfully evading host defenses. The lengthy duration of treatment, the emergence of multi-drug-resistant strains and extensive-drug-resistant strains of M. tb have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within in vitro granulomas generated from immune cells derived from peripheral blood of healthy subjects. However, the effectiveness of everolimus treatment against mycobacterial infection in individuals with T2DM is unknown. Furthermore, the effectiveness of the combination of in vivo glutathione (GSH) supplementation in individuals with T2DM along with in vitro treatment of isolated immune cells with everolimus against mycobacterial infection has never been tested. Therefore, we postulated that liposomal glutathione (L-GSH) and everolimus would offer great hope for developing adjunctive therapy for mycobacterial infection. L-GSH or placebo was administered to T2DM individuals orally for three months. Study subjects' blood was drawn pre- and post-L-GSH/or placebo supplementation, where Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood to conduct in vitro studies with everolimus. We found that in vitro treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular M. bovis BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with in vitro everolimus treatment produced a greater effect in inhibiting the growth of intracellular Mycobacterium bovis BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with in vitro everolimus treatment in modulating the levels of cytokines such as IFN-γ, TNF-α, and IL-2 and IL-6, in favor of improving control of the mycobacterial infection. In summary, in vitro everolimus-treatment alone and in combination with oral L-GSH supplementation for three months in individuals with T2DM, was able to increase the levels of T-helper type 1 (Th1) cytokines IFN-γ, TNF-α, and IL-2 as well as enhance the abilities of granulomas from individuals with T2DM to improve control of a mycobacterial infection.
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Vitamin C decreases reduced glutathione in chronic haemodialysis patients: a pilot, randomised, double-blind trial.
Martins, ML, da Silva, AT, Machado, RP, Ramos, HP, Martinelli, C, Silveira, TT, da Silva, EL, Wazlawik, E
International urology and nephrology. 2021;(8):1695-1704
Abstract
PURPOSE Whey protein has antioxidant properties through its amino acid cysteine, which enhances the biosynthesis of glutathione, the most abundant antioxidant non-protein in mammalians. Glutathione influences vitamin C recycling and increases its protective effect on oxidative stress (OS). The aim of this study was to analyse the effect of whey protein and vitamin C supplementation on OS biomarkers in chronic haemodialysis (HD) patients. METHODS This pioneer trial was a randomised, double-blind, pilot study in patients from a dialysis clinic. Patients were randomised into three groups (1:1:1) and stratified by HD frequency (2 or 3 times/week). Sachets containing protein powder (20.0 g) with/without vitamin C (0.25 g) or placebo (20.0 g of white rice flour) with vitamin C (0.25 g) were supplemented after each HD session, 3 times/week for 8 weeks. Blood samples were collected at the baseline period and after 8 weeks for the measurement of reduced glutathione (GSH), oxidised glutathione (GSSG), the GSH:GSSG ratio, malondialdehyde, vitamin C, and glutathione peroxidase-1. RESULTS Twenty-two patients were enrolled, of which 18 concluded the trial, 6 per group (18.2%, n = 4 losses during follow-up). The vitamin C group presented decreased GSH levels after supplementation (p = 0.053) and a decreasing tendency in the GSH:GSSG ratio (non-statistically significant), while MDA levels significantly decreased only in the whey protein-supplemented groups (p ≤ 0.05). CONCLUSION The results suggest a pro-oxidant effect of 0.25 g of vitamin C alone in chronic HD patients. CLINICAL TRIAL REGISTRATION https://ensaiosclinicos.gov.br/ , RBR-65b8f4.
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A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker.
Kelley, KC, Grossman, KF, Brittain-Blankenship, M, Thorne, KM, Akerley, WL, Terrazas, MC, Kosak, KM, Boucher, KM, Buys, SS, McGregor, KA, et al
BMC cancer. 2021;(1):510
Abstract
BACKGROUND Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. METHODS Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. RESULTS Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28-124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. CONCLUSION Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. TRIAL REGISTRATION NCT00742911 , first posted 28/08/2008.
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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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Shoot base responds to root-applied glutathione and functions as a critical region to inhibit cadmium translocation from the roots to shoots in oilseed rape (Brassica napus).
Li, JS, Suzui, N, Nakai, Y, Yin, YG, Ishii, S, Fujimaki, S, Kawachi, N, Rai, H, Matsumoto, T, Sato-Izawa, K, et al
Plant science : an international journal of experimental plant biology. 2021;:110822
Abstract
Glutathione (GSH) is a tripeptide involved in controlling heavy metal movement in plants. Our previous study showed that GSH, when site-specifically applied to plant roots, inhibits Cd translocation from the roots to shoots in hydroponically cultured oilseed rape (Brassica napus) plants. A factor that led to this inhibitory effect was the activation of Cd efflux from root cells. To further investigate the molecular mechanism triggered by root-applied GSH, Cd movement was non-invasively monitored using a positron-emitting tracer imaging system. The Cd absorption and efflux process in the roots were visualized successfully. The effects of GSH on Cd efflux from root cells were estimated by analyzing imaging data. Reanalysis of image data suggested that GSH applied to roots, at the shoot base, activated Cd return. Cutting the shoot base significantly inhibited Cd efflux from root cells. These experimental results demonstrate that the shoot base plays an important role in distributing Cd throughout the plant body. Furthermore, microarray analysis revealed that about 400 genes in the roots responded to root-applied GSH. Among these, there were genes for transporter proteins related to heavy metal movement in plants and proteins involved in the structure modification of cell walls.
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Chemopreventive effect of troxerutin against hydrogen peroxide-induced oxidative stress in human leukocytes through modulation of glutathione-dependent enzymes.
Cavalcanti, BC, Neto, JBA, Silva, AAS, Barreto, FS, Ferreira, JRO, Magalhães, HIF, Silva, CRD, Vieira, ÍGP, Ricardo, NMPS, Nobre Júnior, HV, et al
Journal of toxicology and environmental health. Part A. 2021;(4):137-151
Abstract
Troxerutin is a natural flavonoid present abundantly in tea, coffee, olives, wheat, and a variety of fruits and vegetables. Due to its diverse pharmacological properties, this flavonoid has aroused interest for treatment of various diseases, and consequently prompted investigation into its toxicological characteristics. The aim of this study was to evaluate the genotoxic and mutagenic effects and chemoprotective activity attributed to troxerutin using human peripheral blood leukocytes (PBLs) through several well-established experimental protocols based upon different parameters. Data demonstrated that troxerutin (100 to 1000 µM) induced no marked cytotoxic effect on PBLs after 24 hr, and did not produce strand breaks and mutagenicity. Regarding chemoprevention, this flavonoid attenuated cytotoxicity, genotoxicity, and mutagenicity initiated by hydrogen peroxide (H2O2) in human PBLs. Further, troxerutin demonstrated no marked cytotoxic effect on PBLs and exerted a protective effect against oxidative stress induced by H2O2 through modulation of GSH-dependent enzymes.
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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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tBHP treatment as a model for cellular senescence and pollution-induced skin aging.
Wedel, S, Martic, I, Hrapovic, N, Fabre, S, Madreiter-Sokolowski, CT, Haller, T, Pierer, G, Ploner, C, Jansen-Dürr, P, Cavinato, M
Mechanisms of ageing and development. 2020;:111318
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Accumulation of senescent cells promotes the development of age-related pathologies and deterioration. In human skin, senescent cells potentially impair structure and function by secreting a mixture of signaling molecules and proteases that influence neighboring cells and degrade extracellular matrix components, such as elastin and collagen. One of the key underlying mechanisms of senescence and extrinsic skin aging is the increase of intracellular reactive oxygen species and resulting oxidative stress. Tert-butyl hydroperoxide (tBHP) is a known inducer of oxidative stress and cellular damage, acting at least in part by depleting the antioxidant glutathione. Here, we provide a detailed characterization of tBHP-induced senescence in human dermal fibroblasts in monolayer culture. In addition, results obtained with more physiological experimental models revealed that tBHP treated 3D reconstructed skin and ex vivo skin developed signs of chronic tissue damage, displaying reduced epidermal thickness and collagen fiber thinning. We, therefore, propose that tBHP treatment can be used as a model to study the effects of extrinsic skin aging, focusing mainly on the influence of environmental pollution.