Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.
TL;DR: Estimates can be used to more fully understand the redox biochemistry that results from oxidative stress, which hopefully will provide a rationale and understanding of the cellular mechanisms associated with cell growth and development, signaling, and reductive or oxidative stress.
About: This article is published in Free Radical Biology and Medicine.The article was published on 2001-06-01. It has received 4274 citations till now. The article focuses on the topics: RoGFP & Redox.
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TL;DR: Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, rheumatoid arthritis, and ageing.
12,240 citations
Cites background from "Redox environment of the cell as vi..."
...The glutathione (2GSH/GSSG couple) represents the major cellular redox buffer and therefore is a representative indicator for the redox environment of the cell (Dröge, 2002; Schafer & Buettner, 2001)....
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...Thus each cell is characterised by a particular concentration of electrons (redox state) stored in many cellular constituents and the redox state of a cell and its oscillation determines cellular functioning (Schafer & Buettner, 2001)....
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...In view of these findings, cancer is characterised by a more reducing environment of the cell and can be considered as a disturbed balance between cell proliferation and cell death shifted more greatly towards cell proliferation (Schafer & Buettner, 2001)....
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...As menioned above, the cell cycle is characterised by fluctuations in the redox environment of a cell, mediated, in particular by intracellular changes in concentration of glutathione (Arrigo, 1999; Kern & Kehrer, 2005; Schafer & Buettner, 2001)....
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...A 30 mV change in the redox state means a 10-fold change in the ratio between reductant and oxidant species (Schafer & Buettner, 2001)....
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TL;DR: The description outlined here facilitates the understanding of factors that favour mitochondrial ROS production and develops better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
Abstract: The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The flux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2•− production is far lower. The generation of O2•− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2•− generation by mitochondria in vivo from O2•−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
6,371 citations
TL;DR: This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process and the role of enzymatic and non-enzymatic antioxidants in the process of carcinogenesis as well as the antioxidant interactions with various regulatory factors.
5,937 citations
TL;DR: It is argued that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
Abstract: Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
4,369 citations
Cites background from "Redox environment of the cell as vi..."
...A moderate increase in ROS can promote cell proliferation and differentiatio...
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TL;DR: A full understanding of the redox control of apoptotic initiation and execution could underpin the development of therapeutic interventions targeted at oxidative stress-associated disorders.
2,834 citations
Cites background from "Redox environment of the cell as vi..."
...Reduced GSH is the biological active form that is oxidized to glutathione disulfide (GSSG) during oxidative stress, and the ratio of GSH-to-GSSG thus offers a simple and convenient expression of cellular oxidative stress [23]....
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References
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TL;DR: Cells undergoing apoptosis in vivo showed increased release of cy tochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c.
5,128 citations
TL;DR: In this article, the authors used one-electron reduction potentials to predict a pecking order, or hierarchy, for free radical reactions, which is in agreement with experimentally observed free radical electron (hydrogen atom) transfer reactions.
2,359 citations
TL;DR: Thomas Buttke and Paul Sandstrom suggest that eukaryotic cells may benefit from this perilous existence by invoking oxidative stress as a common mediator of apoptosis.
2,204 citations
TL;DR: The efficacy of different antioxidants to favorably influence the molecular mechanisms implicated in human disease should be a critical determinant of its selection for clinical studies.
Abstract: Reactive oxygen species (ROS) are implicated in the pathogenesis of a wide variety of human diseases. Recent evidence suggests that at moderately high concentrations, certain forms of ROS such as H202 may act as signal transduction messengers. To develop a better understanding of the exact mechanisms that underlie ROS-dependent disorders in biological systems, recent studies have investigated the regulation of gene expression by oxidants, antioxidants, and other determinants of the intracellular reduction-oxidation (redox) state. At least two well-defined transcription factors, nuclear factor (NF) kappa B and activator protein (AP) -1 have been identified to be regulated by the intracellular redox state. The regulation of gene expression by oxidants, antioxidants, and the redox state has emerged as a novel subdiscipline in molecular biology that has promising therapeutic implications. Binding sites of the redox-regulated transcription factors NF-kappa B and AP-1 are located in the promoter region of a large variety of genes that are directly involved in the pathogenesis of diseases, e.g., AIDS, cancer, atherosclerosis and diabetic complications. Biochemical and clinical studies have indicated that antioxidant therapy may be useful in the treatment of disease. Critical steps in the signal transduction cascade are sensitive to oxidants and antioxidants. Many basic events of cell regulation such as protein phosphorylation and binding of transcription factors to consensus sites on DNA are driven by physiological oxidant-antioxidant homeostasis, especially by the thiol-disulfide balance. Endogenous glutathione and thioredoxin systems, and the exogenous lipoate-dihydrolipoate couple may therefore be considered to be effective regulators of redox-sensitive gene expression. The efficacy of different antioxidants to favorably influence the molecular mechanisms implicated in human disease should be a critical determinant of its selection for clinical studies.
1,975 citations
"Redox environment of the cell as vi..." refers background in this paper
...Changes in the cellular redox environment can alter signal transduction, DNA and RNA synthesis, protein synthesis, enzyme activation, and even regulation of the cell cycle [31,52, 74–82]....
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TL;DR: Results suggest that the demonstrated preferential transport of GSSG compared to GSH into the ER lumen may contribute to this redox compartmentation.
Abstract: The redox state of the endoplasmic reticulum (ER) was measured with the peptide N-Acetyl-Asn-Tyr-Thr-Cys-NH2. The peptide diffused across cellular membranes; some became glycosylated and thus trapped within the secretory pathway, and its cysteine residue underwent reversible thiol-disulfide exchanges with the surrounding redox buffer. Glycosylated peptides from cells were disulfide-linked to glutathione, indicating that glutathione is the major redox buffer in the secretory pathway. The redox state of the secretory pathway was more oxidative than that of the cytosol; the ratio of reduced glutathione to the disulfide form (GSH/GSSG) within the secretory pathway ranged from 1:1 to 3:1, whereas the overall cellular GSH/GSSG ratio ranged from 30:1 to 100:1. Cytosolic glutathione was also transported into the lumen of microsomes in a cell-free system. Although how the ER maintains an oxidative environment is not known, these results suggest that the demonstrated preferential transport of GSSG compared to GSH into the ER lumen may contribute to this redox compartmentation.
1,831 citations
"Redox environment of the cell as vi..." refers background in this paper
...The ratio of GSH/GSSG appears to range from 1:1 to 3:1 [53]....
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