Nursing & Health

Permanent URI for this collectionhttps://research.avondale.edu.au/handle/123456789/457

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    Inhibition of Indoleamine 2,3 Dioxygenase Activity by H2O2
    (2006-06-01) Smythe, George A.; Sachdev, Perminder; Walker, Mark J.; Truscott, Roger J.; Littlejohn, Tamantha K.; Takikawa, Osamu; Willows, Robert D.; Jamie, Joanne F.; Austin, Chris J.; Grant, Ross; Poljak, Anne

    Indoleamine 2,3-dioxygenase is the first and rate limiting enzyme of the kynurenine pathway of tryptophan metabolism, has potent effects on cell proliferation and mediates antimicrobial, antitumorogenic, and immunosuppressive effects. As a potent cytotoxic effector, the mechanisms of indoleamine 2,3-dioxygenase inhibition deserve greater attention. The work presented here represents the first systematic study exploring the mechanisms by which low levels of hydrogen peroxide (10–100 μM) inhibit indoleamine 2,3-dioxygenase in vitro. Following brief peroxide exposure both enzyme inhibition and structural changes were observed. Loss of catalysis was accompanied by oxidation of several cysteine residues to sulfinic and sulfonic acids, observed by electrospray and MALDI mass spectrometry. Enzyme activity could in part be preserved in the presence of sulfhydryl containing compounds, particularly DTT and methionine. However, these structural alterations did not prevent substrate (l-tryptophan) binding. Some enzyme activity could be recovered in the presence of thioredoxin, indicating that the inhibitory effect of H2O2 is at least partially reversible in vitro. We present evidence that cysteine oxidation represents one mechanism of indoleamine 2,3-dioxygenase inhibition.

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    Effects of Kynurenine Pathway Metabolites on Intracellular NAD+ Synthesis and Cell Death in Human Primary Astrocytes and Neurons
    (2009-01-01) Guillemin, Gilles; Jayasena, Tharusha; Adams, Seray; Brew, Bruce J.; Grant, Ross; Braidy, Nady

    The kynurenine pathway (KP) is a major route of L-tryptophan catabolism resulting in the production of the essential pyridine nucleotide nicotinamide adenine dinucleotide, (NAD+). Up-regulation of the KP during infl ammation leads to the release of a number of biologically active metabolites into the brain. We hypothesised that while some of the extracellular KP metabolites may be benefi cial for intracellular NAD+ synthesis and cell survival at physiological concentrations, they may contribute to neuronal and astroglial dysfunction and cell death at pathophysiological concentrations. In this study, we found that treatment of human primary neurons and astrocytes with 3-hydroxyanthranilic acid (3-HAA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC) at concentrations below 100 nM significantly increased intracellular NAD+ levels compared to non-treated cells. However, a dose dependent decrease in intracellular NAD+ levels and increased extracellular LDH activity was observed in human astrocytes and neurons treated with 3-HAA, 3-HK, QUIN and PIC at concentrations >100 nM and kynurenine (KYN), at concentrations above 1 μM. Intracellular NAD+ levels were unchanged in the presence of the neuroprotectant, kynurenic acid (KYNA), and a dose dependent increase in intracellular NAD+ levels was observed for TRP up to 1 mM. While anthranilic acid (AA) increased intracellular NAD+ levels at concentration below 10 μM in astrocytes. NAD+ depletion and cell death was observed in AA treated neurons at concentrations above 500 nM. Therefore, the differing responses of astrocytes and neurons to an increase in KP metabolites should be considered when assessing KP toxicity during neuroinfl ammation.[from article]

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    The Physiological Action of Picolinic Acid in the Human Brain
    (2009-01-01) Smythe, George A.; Coggan, S E.; Grant, Ross

    Picolinic Acid is an endogenous metabolite of L-tryptophan (TRP) that has been reported to possess a wide range of neuroprotective, immunological, and anti-proliferative affects within the body. However the salient physiological function of this molecule is yet to be established. The synthesis of picolinic acid as a product of the kynurenine pathway (KP) suggests that, similar to other KP metabolites, picolinic acid may play a role in the pathogenesis of inflammatory disorders within the CNS and possibly other organs. In this paper we review the limited body of literature dealing with the physiological actions of picolinic acid in the CNS and its associated synthesis via the kynurenine pathway in health and disease. Discrepancies and gaps in our current knowledge of picolinic acid are identified highlighting areas of research to promote a more complete understanding of its endogenous function in the brain.[from article]

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    The Relative Impact of a Vegetable-rich Diet on Key Markers of Health in a Cohort of Australian Adolescents
    (2008-03-01) Ashton, John; Hokin, Bevan; Pearce, Robyn; Guy, Trish; Zeuschner, Carol; Bilgin, Ayse; Grant, Ross

    Childhood obesity is a widespread health problem in Australia. Overweight in childhood can lead to adult overweight and the development of risk factors for cardiovascular disease (CVD). Effective strategies for reducing childhood obesity are urgently required. A vegetarian diet has been shown to be an effective prophylactic to many lifestyle diseases in the adult population and may therefore be beneficial in children. However the metabolic demands of adolescents are different to adults and the impact of a vegetarian diet on CVD markers in this demographic is not certain. We compared key physiological and biochemical markers of health against responses to a modified, Schools Physical Activity and Nutrition Survey (SPANS) using one-way and two-way Analysis of Variance. 215 adolescents (14-15yrs) from 5 Adventist secondary schools in the Sydney and Hunter regions of New South Wales, Australia, participated in this study. Adolescents consuming predominantly vegetarian foods showed significantly better scores on markers of cardiovascular health, including, body mass index (BMI), waist circumference, Cholesterol/High density lipoprotein ratio and low density lipoprotein. Adolescents consuming nuts more than once per week, also showed lower scores for BMI and serum glucose irrespective of their vegetarian status. Markers of general health including haemoglobin and average height were not different between groups; however a lower serum level of vitamin B12 was apparent in the vegetarian cohort. Surprisingly, exercise on its own was not statistically associated with any of the risk factors tested suggesting that diet may be the most significant factor in promoting health in this age group.

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    Promotion of Cellular NAD+ Anabolism: Therapeutic Potential for Oxidative Stress in Ageing and Alzheimer’s Disease
    (2008-01-01) Grant, Ross; Guillemin, Gilles; Braidy, Nady

    Oxidative imbalance is a prominent feature in Alzheimer’s disease and ageing. Increased levels of reactive oxygen species (ROS) can result in disordered cellular metabolism due to lipid peroxidation, protein-cross linking, DNA damage and the depletion of nicotinamide adenine dinucleotide (NAD+). NAD+ is a ubiquitous pyridine nucleotide that plays an essential role in important biological reactions, from ATP production and secondary messenger signalling, to transcriptional regulation and DNA repair. Chronic oxidative stress may be associated with NAD+ depletion and a subsequent decrease in metabolic regulation and cell viability. Hence, therapies targeted toward maintaining intracellular NAD+ pools may prove efficacious in the protection of age-dependent cellular damage, in general, and neurodegeneration in chronic central nervous system inflammatory diseases such as Alzheimer’s disease, in particular.

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    Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes
    (2009-01-01) Guillemin, Gilles J.; Brew, Bruce J.; Adams, Seray; Grant, Ross; Braidy, Nady

    There is growing evidence implicating the kynurenine pathway (KP) and particularly one of its metabolites, quinolinic acid (QUIN), as important contributors to neuroinflammation in several brain diseases. While QUIN has been shown to induce neuronal and astrocytic apoptosis, the exact mechanisms leading to cell death remain unclear. To determine the mechanism of QUIN-mediated excitotoxicity in human brain cells, we measured intracellular levels of nicotinamide adenine dinucleotide (NAD+) and poly(ADP-ribose) polymerase (PARP) and extracellular lactate dehydrogenase (LDH) activities in primary cultures of human neurons and astrocytes treated with QUIN. We found that QUIN acts as a substrate for NAD+ synthesis at very low concentrations (nM) in both neurons and astrocytes, but is cytotoxic at sub-physiological concentrations (>150 nM) in both the cell types. We have shown that the NMDA ion channel blockers, MK801 and memantine, and the nitric oxide synthase (NOS) inhibitor, L-NAME, significantly attenuate QUIN-mediated PARP activation, NAD+ depletion, and LDH release in both neurons and astrocytes. An increased mRNA and protein expression of the inducible (iNOS) and neuronal (nNOS) forms of nitric oxide synthase was also observed following exposure of both cell types to QUIN. Taken together these results suggests that QUIN-induced cytotoxic effects on neurons and astrocytes are likely to be mediated by an over activation of an NMDA-like receptor with subsequent induction of NOS and excessive nitric oxide (NO•)-mediated free radical damage. These results contribute significantly to our understanding of the pathophysiological mechanisms involved in QUIN neuro- and gliotoxicity and are relevant for the development of therapies for neuroinflammatory diseases.