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Oxidative stress and the guanosine n...

University of Montana., Biomedical Sciences.

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Oxidative stress and the guanosine nucleotide triphosphate pool: Implications for a biomarker and mechanism of impaired cell function.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Oxidative stress and the guanosine nucleotide triphosphate pool: Implications for a biomarker and mechanism of impaired cell function./
作者:	Bolin, Celeste Maree.
面頁冊數:	201 p.
附註:	Adviser: Fernando Cardozo-Pelaez.
Contained By:	Dissertation Abstracts International69-03B.
標題:	Biology, Neuroscience. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3303745
ISBN:	9780549505266

Oxidative stress and the guanosine nucleotide triphosphate pool: Implications for a biomarker and mechanism of impaired cell function.
Bolin, Celeste Maree.

Oxidative stress and the guanosine nucleotide triphosphate pool: Implications for a biomarker and mechanism of impaired cell function. - 201 p.

Adviser: Fernando Cardozo-Pelaez.

Thesis (Ph.D.)--University of Montana, 2008.

Oxidation of the guanosine (G) moiety, yielding the oxidized lesion 8-hydroxy-2'-deoxyguanosine (oxo82dG), in DNA has become a hallmark biomarker in assessing cellular outcomes induced by oxidative stress. It is well established that the guanosine nucleotide triphosphate pool is also susceptible to oxidative stress and suggested to be more available for oxidation than DNA due to the lack of protective histones and robust repair mechanisms for reducing the levels of all the products of oxidation. The oxidation of guanosine in the nucleotide triphosphate pool, resulting in oxidized guanosine 5'-triphoshate (oxo8GTP), has been overlooked due to the lack of a reliable method. Oxo8GTP has been shown to precede oxidation to G incorporated into DNA and modulate cell processes such as G-protein signaling and RNA synthesis. Evidence is presented in this study of a reliable method to quantify oxo 8GTP, a proposed mechanism for the oxidative modification of GTP in the presence of copper and L-ascorbic acid, and evidence of oxo8GTP as an inhibitor of soluble guanylyl cyclase (sGC). A significant induction of oxo8GTP in cell-free preparations as well as in PC12 and HEK 293T cells exposed to physiologically relevant oxidative conditions generated with 10 muM copper sulphate and 1mM L-Ascorbic Acid (Cu/Asc) is also reported. Exposure to oxidative conditions by Cu/As leads to elevations in oxo 8GTP significant enough to result in a reduction of the sGC product, cyclic guanosine monophosphate (cGMP), by as much as half in pure sGC and PC12 cells. GTP is protected from oxidation in the presence of reduced glutathione and this subsequently rescues sGC activity. This suggests that oxo 8GTP is produced by free radicals in vivo and can significantly impact neuronal cell functions regulated by sGC activity in the central nervous system such as synaptic plasticity. Alterations in copper homeostasis and oxidative stress have been implicated in several neurodegenerative disorders including Alzheimer's and Parkinson's diseases as well as Amyotrophic Lateral Sclerosis. Based upon evaluation of the data presented herein, we hypothesize that neuronal deficiencies in such disorders might be due to oxidation of the GTP pool and the ensuing effects on neuronal function.

ISBN: 9780549505266Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Oxidative stress and the guanosine nucleotide triphosphate pool: Implications for a biomarker and mechanism of impaired cell function.
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520 $a Oxidation of the guanosine (G) moiety, yielding the oxidized lesion 8-hydroxy-2'-deoxyguanosine (oxo82dG), in DNA has become a hallmark biomarker in assessing cellular outcomes induced by oxidative stress. It is well established that the guanosine nucleotide triphosphate pool is also susceptible to oxidative stress and suggested to be more available for oxidation than DNA due to the lack of protective histones and robust repair mechanisms for reducing the levels of all the products of oxidation. The oxidation of guanosine in the nucleotide triphosphate pool, resulting in oxidized guanosine 5'-triphoshate (oxo8GTP), has been overlooked due to the lack of a reliable method. Oxo8GTP has been shown to precede oxidation to G incorporated into DNA and modulate cell processes such as G-protein signaling and RNA synthesis. Evidence is presented in this study of a reliable method to quantify oxo 8GTP, a proposed mechanism for the oxidative modification of GTP in the presence of copper and L-ascorbic acid, and evidence of oxo8GTP as an inhibitor of soluble guanylyl cyclase (sGC). A significant induction of oxo8GTP in cell-free preparations as well as in PC12 and HEK 293T cells exposed to physiologically relevant oxidative conditions generated with 10 muM copper sulphate and 1mM L-Ascorbic Acid (Cu/Asc) is also reported. Exposure to oxidative conditions by Cu/As leads to elevations in oxo 8GTP significant enough to result in a reduction of the sGC product, cyclic guanosine monophosphate (cGMP), by as much as half in pure sGC and PC12 cells. GTP is protected from oxidation in the presence of reduced glutathione and this subsequently rescues sGC activity. This suggests that oxo 8GTP is produced by free radicals in vivo and can significantly impact neuronal cell functions regulated by sGC activity in the central nervous system such as synaptic plasticity. Alterations in copper homeostasis and oxidative stress have been implicated in several neurodegenerative disorders including Alzheimer's and Parkinson's diseases as well as Amyotrophic Lateral Sclerosis. Based upon evaluation of the data presented herein, we hypothesize that neuronal deficiencies in such disorders might be due to oxidation of the GTP pool and the ensuing effects on neuronal function.
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