Now showing 1 - 3 of 3
  • 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.
      301
  • 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.
      362
  • 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.
      482