Glutathione: An Old and Small Molecule with Great Functions and New Applications in the Brain and in Alzheimer's Disease

Haddad, Mohamed; Hervé, Vincent; Khedher, Mohamed Raâfet Ben; Rabanel, Jean‐Michel; Ramassamy, Charles

doi:10.1089/ars.2020.8129

Cited by 35 publications

(31 citation statements)

References 218 publications

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“…Regarding AD, while serum GSH levels are significantly lower in patients than controls, its plasma concentration has been correlated with cognitive decline, and it is able to discriminate between MCI subjects and healthy volunteers [ 163 , 164 ]. Despite these data, L-cysteine prodrug supplementation, or oral γ-glutamylcysteine administration, did not prevent AD alterations, nor did it restore GSH and oxidative markers, thus underscoring the need for further studies [ 178 ]. Similarly, serum glucose-6-phosphate dehydrogenase (G6PD), an enzyme that protects red blood cells from oxidative stress, has been found to nearly double in AD subjects relative to healthy individuals, although more studies are required to strengthen these results [ 165 ].…”

Section: Resultsmentioning

confidence: 99%

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

Varesi

Carrara

Pires

et al. 2022

Cells

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Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1–42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease.

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Section: Resultsmentioning

confidence: 99%

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

Varesi

Carrara

Pires

et al. 2022

Cells

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“…CAT is located primarily in the peroxisomes and is a widespread and highly efficient antioxidant enzyme present in almost all living organisms, which uses either iron or manganese as a cofactor ( 31 ). The GSH system, which is composed of glutathione reductase (GR), GSH and NADPH, is the most abundant cellular thiol antioxidant system and is regulated by its biosynthesis, redox state and cellular export ( 32 ). Its redox cycle is regulated by GPX and GR ( 33 ).…”

Section: Molecular Mechanisms and Pathways Of Oxidative Stressmentioning

confidence: 99%

Molecular pathways associated with oxidative stress and their potential applications in radiotherapy (Review)

Bian

Liu

et al. 2022

Int J Mol Med

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Radiotherapy is an essential and effective treatment modality for cancer. Excessive levels of reactive oxygen species (ROS) induced by ionizing radiation disrupt the redox homeostasis and lead to oxidative stress that may result in cell death. However, the tumor cell microenvironment is dynamic and responds to radiotherapy by activating numerous cellular signaling pathways. By scavenging excess ROS, the activity levels of the endogenous antioxidant enzymes result in radioresistance and worsen the clinical outcomes. To assess the full potential of radiotherapy, it is essential to explore the underlying mechanisms of oxidative stress in radiotherapy for potential target identification. The present review article summarized recent data demonstrating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) as a powerful transcription factor and one of the major cellular defense mechanisms that protect against oxidative stress in response to radiotherapy; the glutathione (GSH) and thioredoxin (Trx) systems complement each other and are effective antioxidant mechanisms associated with the protection of cancer cells from radiation damage. In addition, it is suggested that dual targeting to inhibit GSH and Trx enzymes may be a potential strategy for the development of radiosensitive and radioprotective drugs.

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“…However, another possibility that became apparent in our previous work with xCT-KO xenografts is cell-to-cell interplay which, in the case of xCT-KO cells, provides them with the source of reduced cysteine [28,38]. Although the degradation of GSH in vivo is just as intensive as in vitro [35,[39][40][41], the continuous flux of GSH from adjacent cells might be a sufficient source of GSH for GCLc-KO cells to survive and thrive in vivo. Indeed, our data showed that the co-culturing of GCLc-KO cells in the presence of the WT secretome had a partial rescue effect even in in vitro conditions (Figure 6C).…”

Section: Discussionmentioning

confidence: 94%

Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth

Daher

Meira

Durivault

et al. 2022

Cancers

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The conceptualization of a novel type of cell death, called ferroptosis, opens new avenues for the development of more efficient anti-cancer therapeutics. In this context, a full understanding of the ferroptotic pathways, the players involved, their precise role, and dispensability is prerequisite. Here, we focused on the importance of glutathione (GSH) for ferroptosis prevention in pancreatic ductal adenocarcinoma (PDAC) cells. We genetically deleted a unique, rate-limiting enzyme for GSH biosynthesis, γ-glutamylcysteine ligase (GCL), which plays a key role in tumor cell proliferation and survival. Surprisingly, although glutathione peroxidase 4 (GPx4) has been described as a guardian of ferroptosis, depletion of its substrate (GSH) led preferentially to apoptotic cell death, while classical ferroptotic markers (lipid hydroperoxides) have not been observed. Furthermore, the sensitivity of PDAC cells to the pharmacological/genetic inhibition of GPx4 revealed GSH dispensability in this context. To the best of our knowledge, this is the first time that the complete dissection of the xCT-GSH-GPx4 axis in PDAC cells has been investigated in great detail. Collectively, our results revealed the necessary role of GSH in the overall redox homeostasis of PDAC cells, as well as the dispensability of this redox-active molecule for a specific, antioxidant branch dedicated to ferroptosis prevention.

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Glutathione: An Old and Small Molecule with Great Functions and New Applications in the Brain and in Alzheimer's Disease

Cited by 35 publications

References 218 publications

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

Molecular pathways associated with oxidative stress and their potential applications in radiotherapy (Review)

Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth

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