Now showing 1 - 8 of 8
  • Publication
    Sulfur-containing amino acids: a neurochemical perspective
    (Nova Science Publishers Inc., 2016)
    This review charts recent developments in understanding the neurochemistry of endogenous sulfur-containing amino acids as neuromodulators, metabolic intermediates and potential toxins. The amino acids discussed include L-cysteine, L-cysteine sulfinic acid, L-cysteic acid, L-homocysteine, L-homocysteine sulfinic acid, L-homocysteic acid and taurine. Particular emphasis is placed on examining the mechanism and regulation of biochemical pathways that contribute to the synthesis and metabolism of cysteine, especially in its capacity as precursor of glutathione, taurine and hydrogen sulfide. Evidence concerning the role of cysteine and its oxidised form, cystine, in the control of intracellular and extracellular redox potentials and in the response of cells to oxidative stress is presented. Lastly, the therapeutic potential of intervention in the pathways of sulfur-containing amino acid metabolism in the brain is discussed.
      253
  • Publication
    Cysteine, Glutathione and Thiol Redox Balance in Astrocytes
    (MDPI (Multidisciplinary Digital Publishing Institute), 2017-08-03)
    This review discusses the current understanding of cysteine and glutathione redox balance in astrocytes. Particular emphasis is placed on the impact of oxidative stress and astrocyte activation on pathways that provide cysteine as a precursor for glutathione. The effect of the disruption of thiol-containing amino acid metabolism on the antioxidant capacity of astrocytes is also discussed.
      298Scopus© Citations 93
  • Publication
    The transsulfuration pathway : a source of cysteine for glutathione in astrocytes
    (Springer, 2012-01)
    Astrocyte cells require cysteine as a substrate for glutamate cysteine ligase (γ-glutamylcysteine synthase; EC 6.3.2.2) catalyst of the rate-limiting step of the γ-glutamylcycle leading to formation of glutathione (l-γ-glutamyl-l-cysteinyl-glycine; GSH). In both astrocytes and glioblastoma/astrocytoma cells, the majority of cysteine originates from reduction of cystine imported by the x c − cystine-glutamate exchanger. However, the transsulfuration pathway, which supplies cysteine from the indispensable amino acid, methionine, has recently been identified as a significant contributor to GSH synthesis in astrocytes. The purpose of this review is to evaluate the importance of the transsulfuration pathway in these cells, particularly in the context of a reserve pathway that channels methionine towards cysteine when the demand for glutathione is high, or under conditions in which the supply of cystine by the x c − exchanger may be compromised.
      1019Scopus© Citations 155
  • Publication
    Astrocytes and the regulation of cerebral cysteine/cystine redox potential: implications for cysteine neurotoxicity
    (Nova Publishers, 2012-02-28)
    The sulfur amino acid, cysteine plays an essential role in maintaining cellular redox potential and is a key constituent of the antioxidant, glutathione. Cysteine is highly reactive and readily oxidises to the disulfide form, cystine, producing oxygen radicals as a by-product. Extracellular oxidising conditions favour cystine, whereas cysteine is the dominant intracellular form of the amino acid. In the brain, astrocytes control the extracellular thiol redox potential by actively taking up cystine and exporting cysteine. Particularly, astrocytes up-regulate the cysteine/cystine cycle in response to oxidative stress, which is essential for preventing damage to neuronal function arising from loss of redox balance. Recent evidence shows that the extracellular cysteine/cystine redox state may have a significant role in a number of processes that affect synaptic activity, including signal transduction and receptor activation and may be implicated in a number of neurodegenerative diseases, for example Alzheimer’s and Parkinson’s. This review charts recent developments in understanding the role of astrocytes in neuroprotection via management of the extracellular thiol redox potential in normal brain function and provides an up-to-date account of cysteine neurotoxicity and its significance in the aetiology of neurodegenerative disease.
      385
  • Publication
    The thiol redox system in glioma biology : clinical target and significance in resistance to glioma chemotherapy
    (Nova Science Publishers, 2013-07)
    Sulfur-containing compounds play an essential role in maintaining redox balance in glioma cells. Chief amongst these are the reduced and oxidised (disulfide) forms of cysteine (cysteine/cystine) and glutathione (GSH /GSSG) as well as thioredoxin and glutaredoxin, members of the thiol-disulfide oxidoreductases. GSH is also important as an antioxidant, as a ‘safe’ storage form of cysteine and for detoxification reactions involving the GSH sulfur transferase family of enzymes. Glioma cells contain a high concentration of GSH, compared to normal astrocytes, which renders these cells particularly resistant to chemotherapeutic agents. The rate of synthesis of GSH is controlled by the availability of cysteine, which is imported in its oxidised form, cystine, through specialized channels in the plasma membrane. These channels, known as the cystine-glutamate xc- exchanger, operate by taking up cystine in exchange for glutamate, which is released into the extracellular medium. Glioma cells export large quantities of glutamate by this mechanism, which, if unchecked, causes damage and eventual death of surrounding neurones. Thus, GSH synthesis in glioma cells fuels resistance to chemotherapy and, at the same time, kills off surrounding neurones thereby providing space for tumor cell growth. Much is now known of the molecular mechanism of cystine import and of GSH synthesis in glioma cells. In particular, a number of therapeutic strategies that target the cystine-glutamate exchanger have been proposed on the basis that this would inhibit synthesis of GSH and remove the source of glutamate release. This review describes new developments in the field of glioma cell redox balance and evaluates the potential for clinical intervention at the level of cysteine and GSH biosynthesis that may prove effective in combating brain tumor growth and development.
      274
  • Publication
    Thiol redox homeostasis in neurodegenerative disease
    This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc− cystine–glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed.
      343Scopus© Citations 100
  • Publication
    Glutathione depletion causes a JNK and p38MAPK-mediated increase in expression of cystathionine-gamma-lyase and upregulation of the transsulfuration pathway in C6 glioma cells
    Cancer cells have a high demand for cysteine as precursor of the antioxidant, glutathione, that is required to promote cell growth and division. Uptake of cystine by the View the MathML source cystine-glutamate exchanger provides the majority of cysteine, but a significant percentage may be derived from methionine, via a transsulfuration pathway. Our aim was to evaluate the relative contribution of the exchanger and the transsulfuration pathway to glutathione synthesis in astrocytoma/glioblastoma cells, using the C6 glioma cell line as a model system. Blockade of the View the MathML source exchanger with the gliotoxins l-αaminoadipate or l-β-N-oxalylamino-l-alanine (400 μM) caused a loss of cellular cysteine and depletion in glutathione to 51% and 54% of control, respectively, after 24 h. Inhibition of the transsulfuration pathway with propargylglycine (1 mM, 24 h) depleted glutathione to 77% of control. Co-incubation of cells with gliotoxin and propargylglycine reduced glutathione to 39% of control at 24 h and to 20% at 48 h. Expression of cystathionine-γ-lyase, the rate-limiting enzyme of the transsulfuration pathway, was significantly increased following incubation of the cells with gliotoxins. Incubation of C6 cells with diethylmaleate for 3 h led to a significant reduction in glutathione (63%), whereas expression of cystathionine-γ-lyase was increased by 1.5-fold. Re-feeding methionine to diethylmaleate-treated cells incubated in the absence of cystine or methionine resulted in a significant recovery in glutathione that was blocked by propargylglycine. Co-incubation of C6 cells with diethylmaleate and the JNK-inhibitor, SP600125, abolished the increase in expression of cystathionine-γ-lyase that had been observed in the presence of diethylmaleate alone. Similar results were obtained with the p38MAPK inhibitor, SB203580. It is concluded that glutathione depletion causes a JNK- and p38MAPK-mediated increase in expression of cystathionine-γ-lyase that promotes flux through the transsulfuration pathway to compensate for loss of glutathione in C6 glioma cells.
      339Scopus© Citations 44
  • Publication
    Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance
    Neurodegenerative diseases are characterized by chronic microglial over-activation and oxidative stress. It is now beginning to be recognized that reactive oxygen species (ROS) produced by either microglia or the surrounding environment not only impact neurons but also modulate microglial activity. In this review, we first analyze the hallmarks of pro-inflammatory and anti-inflammatory phenotypes of microglia and their regulation by ROS. Then, we consider the production of reactive oxygen and nitrogen species by NADPH oxidases and nitric oxide synthases and the new findings that also indicate an essential role of glutathione (γ-glutamyl-l-cysteinylglycine) in redox homeostasis of microglia. The effect of oxidant modification of macromolecules on signaling is analyzed at the level of oxidized lipid by-products and sulfhydryl modification of microglial proteins. Redox signaling has a profound impact on two transcription factors that modulate microglial fate, nuclear factor kappa-light-chain-enhancer of activated B cells, and nuclear factor (erythroid-derived 2)-like 2, master regulators of the pro-inflammatory and antioxidant responses of microglia, respectively. The relevance of these proteins in the modulation of microglial activity and the interplay between them will be evaluated. Finally, the relevance of ROS in altering blood brain barrier permeability is discussed. Recent examples of the importance of these findings in the onset or progression of neurodegenerative diseases are also discussed. This review should provide a profound insight into the role of redox homeostasis in microglial activity and help in the identification of new promising targets to control neuroinflammation through redox control of the brain
      415Scopus© Citations 218