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    Measures of insulin sensitivity, leptin, and adiponectin concentrations in cats in diabetic remission compared to healthy control cats
    Gottlieb, S ; Rand, JS ; Ishioka, K ; Dias, DA ; Boughton, BA ; Roessner, U ; Ramadan, Z ; Anderson, ST (FRONTIERS MEDIA SA, 2022-07-29)
    OBJECTIVES: Firstly, to compare differences in insulin, adiponectin, leptin, and measures of insulin sensitivity between diabetic cats in remission and healthy control cats, and determine whether these are predictors of diabetic relapse. Secondly, to determine if these hormones are associated with serum metabolites known to differ between groups. Thirdly, if any of the hormonal or identified metabolites are associated with measures of insulin sensitivity. ANIMALS: Twenty cats in diabetic remission for a median of 101 days, and 21 healthy matched control cats. METHODS: A casual blood glucose measured on admission to the clinic. Following a 24 h fast, a fasted blood glucose was measured, and blood sample taken for hormone (i.e., insulin, leptin, and adiponectin) and untargeted metabolomic (GC-MS and LC-MS) analysis. A simplified IVGGT (1 g glucose/kg) was performed 3 h later. Cats were monitored for diabetes relapse for at least 9 months (270 days). RESULTS: Cats in diabetic remission had significantly higher serum glucose and insulin concentrations, and decreased insulin sensitivity as indicated by an increase in HOMA and decrease in QUICKI and Bennett indices. Leptin was significantly increased, but there was no difference in adiponectin (or body condition score). Several significant correlations were found between insulin sensitivity indices, leptin, and serum metabolites identified as significantly different between remission and control cats. No metabolites were significantly correlated with adiponectin. No predictors of relapse were identified in this study. CONCLUSION AND CLINICAL IMPORTANCE: Insulin resistance, an underlying factor in diabetic cats, persists in diabetic remission. Cats in remission should be managed to avoid further exacerbating insulin resistance.
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    Mapping carbon fate during bleaching in a model cnidarian symbiosis: the application of 13C metabolomics
    Hillyer, KE ; Dias, DA ; Lutz, A ; Roessner, U ; Davy, SK (WILEY, 2017-06)
    Coral bleaching is a major threat to the persistence of coral reefs. Yet we lack detailed knowledge of the metabolic interactions that determine symbiosis function and bleaching-induced change. We mapped autotrophic carbon fate within the free metabolite pools of both partners of a model cnidarian-dinoflagellate symbiosis (Aiptasia-Symbiodinium) during exposure to thermal stress via the stable isotope tracer (13 C bicarbonate), coupled to GC-MS. Symbiont photodamage and pronounced bleaching coincided with substantial increases in the turnover of non13 C-labelled pools in the dinoflagellate (lipid and starch store catabolism). However, 13 C enrichment of multiple compounds associated with ongoing carbon fixation and de novo biosynthesis pathways was maintained (glucose, fatty acid and lipogenesis intermediates). Minimal change was also observed in host pools of 13 C-enriched glucose (a major symbiont-derived mobile product). However, host pathways downstream showed altered carbon fate and/or pool composition, with accumulation of compatible solutes and nonenzymic antioxidant precursors. In hospite symbionts continue to provide mobile products to the host, but at a significant cost to themselves, necessitating the mobilization of energy stores. These data highlight the need to further elucidate the role of metabolic interactions between symbiotic partners, during the process of thermal acclimation and coral bleaching.
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    Lipidomics reveal the protective effects of a vegetable-derived isothiocyanate against retinal degeneration
    Kwa, FA ; Dulull, NK ; Roessner, U ; Dias, DA ; Rupasinghe, TW (F1000 Research Ltd, 2020-02-20)
    Background:Age-related macular degeneration (AMD) is a leading cause of blindness in the ageing population. Without effective treatment strategies that can prevent disease progression, there is an urgent need for novel therapeutic interventions to reduce the burden of vision loss and improve patients’ quality of life. Dysfunctional innate immune responses to oxidative stress observed in AMD can be caused by the formation of oxidised lipids, whilst polyunsaturated fatty acids have shown to increase the risk of AMD and disease progression in affected individuals. Previously, our laboratory has shown that the vegetable-derived isothiocyanate, L-sulforaphane (LSF), can protect human adult pigment epithelial cells from oxidative damage by upregulating gene expression of the oxidative stress enzyme Glutathione-S-Transferase µ1. This study aims to validate the protective effects of LSF on human retinal cells under oxidative stress conditions and to reveal the key players in fatty acid and lipid metabolism that may facilitate this protection.Methods:Thein vitrooxidative stress model of AMD was based on the exposure of an adult retinal pigment epithelium-19 cell line to 200µM hydrogen peroxide. Percentage cell proliferation following LSF treatment was measured using tetrazolium salt-based assays. Untargeted fatty acid profiling was performed by gas chromatography-mass spectrometry. Untargeted lipid profiling was performed by liquid chromatography-mass spectrometry.Results:Under hydrogen peroxide-induced oxidative stress conditions, LSF treatment induced dose-dependent cell proliferation. The key fatty acids that were increased by LSF treatment of the retinal cells include oleic acid and eicosatrienoic acid. LSF treatment also increased levels of the lipid classes phosphatidylcholine, cholesteryl ester and oxo-phytodienoic acid but decreased levels of phosphatidylethanolamine lipids.Conclusions:We propose that retinal cells at risk of oxidative damage and apoptosis can be pre-conditioned with LSF to regulate levels of selected fatty acids and lipids known to be implicated in the pathogenesis and progression of AMD.
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    Lipidomics reveal the protective effects of a vegetable-derived isothiocyanate against retinal degeneration
    Kwa, FA ; Dulull, NK ; Roessner, U ; Dias, DA ; Rupasinghe, TW (F1000 Research Ltd, 2020-08-04)
    Background:Age-related macular degeneration (AMD) is a leading cause of blindness in the ageing population. Without effective treatment strategies that can prevent disease progression, there is an urgent need for novel therapeutic interventions to reduce the burden of vision loss and improve patients’ quality of life. Dysfunctional innate immune responses to oxidative stress observed in AMD can be caused by the formation of oxidised lipids, whilst polyunsaturated fatty acids have shown to increase the risk of AMD and disease progression in affected individuals. Previously, our laboratory has shown that the vegetable-derived isothiocyanate, L-sulforaphane (LSF), can protect human adult pigment epithelial cells from oxidative damage by upregulating gene expression of the oxidative stress enzyme Glutathione-S-Transferase µ1. This study aims to validate the protective effects of LSF on human retinal cells under oxidative stress conditions and to reveal the key players in fatty acid and lipid metabolism that may facilitate this protection.Methods:Thein vitrooxidative stress model of AMD was based on the exposure of an adult retinal pigment epithelium-19 cell line to 200µM hydrogen peroxide. Percentage cell proliferation following LSF treatment was measured using tetrazolium salt-based assays. Untargeted fatty acid profiling was performed by gas chromatography-mass spectrometry. Untargeted lipid profiling was performed by liquid chromatography-mass spectrometry.Results:Under hydrogen peroxide-induced oxidative stress conditions, LSF treatment induced dose-dependent cell proliferation. The key fatty acids that were increased by LSF treatment of the retinal cells include oleic acid and eicosatrienoic acid. LSF treatment also increased levels of the lipid classes phosphatidylcholine, cholesteryl ester and oxo-phytodienoic acid but decreased levels of phosphatidylethanolamine lipids.Conclusions:We propose that retinal cells at risk of oxidative damage and apoptosis can be pre-conditioned with LSF to regulate levels of selected fatty acids and lipids known to be implicated in the pathogenesis and progression of AMD.
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    Lipidomics reveal the protective effects of a vegetable-derived isothiocyanate against retinal degeneration.
    Kwa, FA ; Dulull, NK ; Roessner, U ; Dias, DA ; Rupasinghe, TW (F1000 Research Ltd, 2019)
    Background: Age-related macular degeneration (AMD) is a leading cause of blindness in the ageing population. Without effective treatment strategies that can prevent disease progression, there is an urgent need for novel therapeutic interventions to reduce the burden of vision loss and improve patients' quality of life. Dysfunctional innate immune responses to oxidative stress observed in AMD can be caused by the formation of oxidised lipids, whilst polyunsaturated fatty acids have shown to increase the risk of AMD and disease progression in affected individuals. Previously, our laboratory has shown that the vegetable-derived isothiocyanate, L-sulforaphane (LSF), can protect human adult pigment epithelial cells from oxidative damage by upregulating gene expression of the oxidative stress enzyme Glutathione-S-Transferase µ1. This study aims to validate the protective effects of LSF on human retinal cells under oxidative stress conditions and to reveal the key players in fatty acid and lipid metabolism that may facilitate this protection. Methods: The in vitro oxidative stress model of AMD was based on the exposure of an adult retinal pigment epithelium-19 cell line to 200µM hydrogen peroxide. Percentage cell proliferation following LSF treatment was measured using tetrazolium salt-based assays. Untargeted fatty acid profiling was performed by gas chromatography-mass spectrometry. Untargeted lipid profiling was performed by liquid chromatography-mass spectrometry. Results: Under hydrogen peroxide-induced oxidative stress conditions, LSF treatment induced dose-dependent cell proliferation. The key fatty acids that were increased by LSF treatment of the retinal cells include oleic acid and eicosatrienoic acid. LSF treatment also increased levels of the lipid classes phosphatidylcholine, cholesteryl ester and oxo-phytodienoic acid but decreased levels of phosphatidylethanolamine lipids. Conclusions: We propose that retinal cells at risk of oxidative damage and apoptosis can be pre-conditioned with LSF to regulate levels of selected fatty acids and lipids known to be implicated in the pathogenesis and progression of AMD.
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    A Historical Overview of Natural Products in Drug Discovery
    Dias, DA ; Urban, S ; Roessner, U (MDPI, 2012-06)
    Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed.
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    Root spatial metabolite profiling of two genotypes of barley (Hordeum vulgare L.) reveals differences in response to short-term salt stress
    Shelden, MC ; Dias, DA ; Jayasinghe, NS ; Bacic, A ; Roessner, U (OXFORD UNIV PRESS, 2016-06)
    Barley (Hordeum vulgare L.) is the most salt-tolerant cereal crop and has excellent genetic and genomic resources. It is therefore a good model to study salt-tolerance mechanisms in cereals. We aimed to determine metabolic differences between a cultivated barley, Clipper (tolerant), and a North African landrace, Sahara (susceptible), previously shown to have contrasting root growth phenotypes in response to the early phase of salinity stress. GC-MS was used to determine spatial changes in primary metabolites in barley roots in response to salt stress, by profiling three different regions of the root: root cap/cell division zone (R1), elongation zone (R2), and maturation zone (R3). We identified 76 known metabolites, including 29 amino acids and amines, 20 organic acids and fatty acids, and 19 sugars and sugar phosphates. The maintenance of cell division and root elongation in Clipper in response to short-term salt stress was associated with the synthesis and accumulation of amino acids (i.e. proline), sugars (maltose, sucrose, xylose), and organic acids (gluconate, shikimate), indicating a potential role for these metabolic pathways in salt tolerance and the maintenance of root elongation. The processes involved in root growth adaptation and the underlying coordination of metabolic pathways appear to be controlled in a region-specific manner. This study highlights the importance of utilizing spatial profiling and will provide us with a better understanding of abiotic stress response(s) in plants at the tissue and cellular level.
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    Metabolic Profiling of Diabetic Cats in Remission
    Gottlieb, S ; Rand, J ; Anderson, ST ; Morton, JM ; Dias, DA ; Boughton, BA ; Roessner, U ; Ramadan, Z (FRONTIERS MEDIA SA, 2020-05-15)
    Background: The majority of diabetic cats in remission have abnormal glucose tolerance, and approximately one third relapse within 1 year. Greater understanding of the metabolic characteristics of diabetic cats in remission, and predictors of relapse is required to effectively monitor and manage these cats. Objectives: To identify and compare differences in plasma metabolites between diabetic cats in remission and healthy control cats using a metabolomics approach. Secondly, to assess whether identified metabolites are predictors of diabetic relapse. Animals: Twenty cats in diabetic remission for a median of 101 days, and 22 healthy matched control cats. Methods: Cats were admitted to a clinic, and casual blood glucose was recorded. After a 24 h fast, blood glucose concentration was measured, then a blood sample was taken for metabolomic (GCMS and LCMS) analyses. Three hours later, a simplified intravenous glucose tolerance test (1 g glucose/kg) was performed. Cats were monitored for diabetes relapse for at least 9 months (270 days) after baseline testing. Results: Most cats in remission continued to display impaired glucose tolerance. Concentrations of 16 identified metabolites differed (P ≤ 0.05) between remission and control cats: 10 amino acids and stearic acid (all lower in remission cats), and glucose, glycine, xylitol, urea and carnitine (all higher in remission cats). Moderately close correlations were found between these 16 metabolites and variables assessing glycaemic responses (most |r| = 0.31 to 0.69). Five cats in remission relapsed during the study period. No metabolite was identified as a predictor of relapse. Conclusion and clinical importance: This study shows that cats in diabetic remission have abnormal metabolism.
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    Metabolic profiling of a transgenic Caenorhabditis elegans Alzheimer model
    Van Assche, R ; Temmerman, L ; Dias, DA ; Boughton, B ; Boonen, K ; Braeckman, BP ; Schoofs, L ; Roessner, U (SPRINGER, 2015-04)
    Despite decades of research, no early-onset biomarkers are currently available for Alzheimer's disease, a cureless neurodegenerative disease afflicting millions worldwide. In this study, transgenic Caenorhabditis elegans were used to investigate changes in the metabolome after induced expression of amyloid-β. GC- and LC-MS-based platforms determined a total of 157 differential features. Some of these were identified using in-house (GC-MS) or public libraries (LC-MS), revealing changes in allantoin, cystathionine and tyrosine levels. Since C. elegans is far better suited to metabolomics studies than most other model systems, the accordance of these findings with vertebrate literature is promising and argues for further use of C. elegans as a model of human pathology in the study of AD.