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John A. Oates - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin h2 derived adducts of proteins correlate with alzheimer s disease severity
Journal of Neurochemistry, 2005Co-Authors: Irene Zagolikapitte, Olivier Boutaud, Tina S. Masterson, Ventkataraman Amarnath, Thomas J. Montine, Katrin Andreasson, John A. OatesAbstract:The formation of Cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the Cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
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Prostaglandin H2‐derived adducts of proteins correlate with Alzheimer's disease severity
Journal of Neurochemistry, 2005Co-Authors: Irene Zagol-ikapitte, Olivier Boutaud, Tina S. Masterson, Ventkataraman Amarnath, Thomas J. Montine, Katrin Andreasson, John A. OatesAbstract:The formation of Cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the Cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
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Prostaglandin H2 (PGH2) accelerates formation of amyloid β1−42 oligomers
Journal of Neurochemistry, 2002Co-Authors: Olivier Boutaud, Thomas J. Montine, Pierre Chaurand, Richard M. Caprioli, John A. OatesAbstract:Epidemiologic evidence implicates Cyclooxygenase activity in the pathogenesis of Alzheimer's disease, in which amyloid plaques have been found to contain increased levels of dimers and higher multimers of the amyloid beta peptide. The product of the oxygenation of arachidonic acid by the Cyclooxygenases, prostaglandin H2 (PGH2), rearranges non-enzymatically to several prostaglandins, including the highly reactive gamma-keto aldehydes, levuglandins E2 and D2. We demonstrate that PGH2 markedly accelerates the formation of dimers and higher oligomers of amyloid beta1-42. This is associated with the formation of levuglandin adducts of the peptide. These findings provide the molecular basis for a hypothesis linking Cyclooxygenase activity to the formation of oligomers of amyloid beta.
Lawrence J Marnett - One of the best experts on this subject based on the ideXlab platform.
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The influence of double bond geometry in the inhibition of Cyclooxygenases by sulindac derivatives.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Matthew J. Walters, Anna L. Blobaum, Philip J. Kingsley, Andrew S. Felts, Gary A. Sulikowski, Lawrence J MarnettAbstract:Sulindac sulfide is a benzylidene-indene that is a potent, time-dependent inhibitor of Cyclooxygenases-1 and -2. Removal of the 2'-methyl group from the indene ring dramatically reduces time-dependent inhibition of both enzymes but also changes the geometry of the benzylidene double bond from Z to E. Herein, we explore the importance of double bond geometry on Cyclooxygenase inhibition. The Z-isomer of 2'-des-methyl sulindac sulfide was synthesized by reduction of a bromoindene precursor or by photoisomerization of the E-isomer. The Z-isomer inhibited both Cyclooxygenases, but with diminished potency compared to sulindac sulfide. Thus, although the 2'-methyl group is a major determinant of time-dependent Cyclooxygenase inhibition, the geometry of the benzylidene double bond plays a role as well.
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biomarkers of oxidative stress study iii effects of the nonsteroidal anti inflammatory agents indomethacin and meclofenamic acid on measurements of oxidative products of lipids in ccl4 poisoning
Free Radical Biology and Medicine, 2005Co-Authors: Maria B Kadiiska, Garret A Fitzgerald, John A. Lawson, Samar Basu, Beth C Gladen, Donna D Baird, L B Graham, Carol E Parker, Bruce N Ames, Lawrence J MarnettAbstract:Plasma and urinary levels of malondialdehyde-like products (MDA) and isoprostanes were identified as markers of in vivo lipid peroxidation in an animal model of CCl4 poisoning. We sought to determine the extent to which the formation of these oxidation products is influenced by inhibition of the Cyclooxygenase enzymes which catalytically generate proinflammatory lipid peroxidation products known as prostaglandins and thromboxane. In the present studies, after induction of oxidant stress in rats with CCl4, lipid peroxidation products measured in plasma and urine demonstrate that isoprostanes and MDA can be partially inhibited by Cyclooxygenase inhibitors, albeit to different extents. The lowering of isoprostane and MDA formation, however, may not to due primarily to the diminution of catalytic generation of isoprostanes or MDA by the Cyclooxygenases but, rather, may be the result of the suppression of nonenzymatic lipid peroxidation. This is suggested since 8,12-iso-iPF2alpha-VI is also reduced by indomethacin, yet, unlike other isoprostanes and MDA, it is not generated catalytically by the Cyclooxygenase. Thus, although the two Cyclooxygenase inhibitors we tested have statistically significant effects on the measurements of both isoprostanes and MDA in this study, the results provide evidence that these lipid-degradation products primarily constitute markers of oxidative stress.
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Structural insights into the stereochemistry of the Cyclooxygenase reaction
Nature, 2000Co-Authors: James R. Kiefer, Jennifer L. Pawlitz, Kirby T. Moreland, Roderick A. Stegeman, William F. Hood, James K. Gierse, Anna M. Stevens, Douglas C. Goodwin, Scott W. Rowlinson, Lawrence J MarnettAbstract:Cyclooxygenases are bifunctional enzymes that catalyse the first committed step in the synthesis of prostaglandins, thromboxanes and other eicosanoids^ 1 , 2 , 3 . The two known Cyclooxygenases isoforms share a high degree of amino-acid sequence similarity^ 1 , 2 , 3 , 4 , structural topology^ 5 , 6 , 7 and an identical catalytic mechanism^ 1 , 2 , 3 . Cyclooxygenase enzymes catalyse two sequential reactions in spatially distinct, but mechanistically coupled active sites^ 8 , 9 , 10 , 11 . The initial Cyclooxygenase reaction converts arachidonic acid (which is achiral) to prostaglandin G_2 (which has five chiral centres). The subsequent peroxidase reaction reduces prostaglandin G_2 to prostaglandin H_2. Here we report the co-crystal structures of murine apo-Cyclooxygenase-2 in complex with arachidonic acid and prostaglandin. These structures suggest the molecular basis for the stereospecificity of prostaglandin G_2 synthesis.
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xenobiotic metabolizing cytochromes p450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen malondialdehyde
Journal of Biological Chemistry, 2000Co-Authors: John P Plastaras, Peter F Guengerich, Daniel W Nebert, Lawrence J MarnettAbstract:Abstract Cyclooxygenases catalyze the oxygenation of arachidonic acid to prostaglandin endoperoxides. Cyclooxygenase-2- and the xenobiotic-metabolizing cytochrome P450s 1A and 3A are all aberrantly expressed during colorectal carcinogenesis. To probe for a role of P450s in prostaglandin endoperoxide metabolism, we studied the 12-hydroxyheptadecatrienoate (HHT)/malondialdehyde (MDA) synthase activity of human liver microsomes and purified P450s. We found that human liver microsomes have HHT/MDA synthase activity that is concentration-dependent and inhibited by the P450 inhibitors, ketoconazole and clotrimazole with IC50values of 1 and 0.4 μm, respectively. This activity does not require P450 reductase. HHT/MDA synthase activity was present in purified P450s but not in heme alone or other heme proteins. The catalytic activities of various purified P450s were determined by measuring rates of MDA production from prostaglandin endoperoxide. At 50 μm substrate, the catalytic activities of purified human P450s varied from 10 ± 1 to 0.62 ± 0.02 min−1, 3A4 ≫ 2E1 > 1A2. Oxabicycloheptane analogs of prostaglandin endoperoxide, U-44069 and U-46619, induced spectral changes in human P450 3A4 with K s values of 240 ± 20 and 130 ± 10 μm, respectively. These results suggest that co-expression of Cyclooxygenase-2 and P450s in developing cancers may contribute to genomic instability due to production of the endogenous mutagen, MDA.
Olivier Boutaud - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin h2 derived adducts of proteins correlate with alzheimer s disease severity
Journal of Neurochemistry, 2005Co-Authors: Irene Zagolikapitte, Olivier Boutaud, Tina S. Masterson, Ventkataraman Amarnath, Thomas J. Montine, Katrin Andreasson, John A. OatesAbstract:The formation of Cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the Cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
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Prostaglandin H2‐derived adducts of proteins correlate with Alzheimer's disease severity
Journal of Neurochemistry, 2005Co-Authors: Irene Zagol-ikapitte, Olivier Boutaud, Tina S. Masterson, Ventkataraman Amarnath, Thomas J. Montine, Katrin Andreasson, John A. OatesAbstract:The formation of Cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the Cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
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Prostaglandin H2 (PGH2) accelerates formation of amyloid β1−42 oligomers
Journal of Neurochemistry, 2002Co-Authors: Olivier Boutaud, Thomas J. Montine, Pierre Chaurand, Richard M. Caprioli, John A. OatesAbstract:Epidemiologic evidence implicates Cyclooxygenase activity in the pathogenesis of Alzheimer's disease, in which amyloid plaques have been found to contain increased levels of dimers and higher multimers of the amyloid beta peptide. The product of the oxygenation of arachidonic acid by the Cyclooxygenases, prostaglandin H2 (PGH2), rearranges non-enzymatically to several prostaglandins, including the highly reactive gamma-keto aldehydes, levuglandins E2 and D2. We demonstrate that PGH2 markedly accelerates the formation of dimers and higher oligomers of amyloid beta1-42. This is associated with the formation of levuglandin adducts of the peptide. These findings provide the molecular basis for a hypothesis linking Cyclooxygenase activity to the formation of oligomers of amyloid beta.
Katrin Andreasson - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin h2 derived adducts of proteins correlate with alzheimer s disease severity
Journal of Neurochemistry, 2005Co-Authors: Irene Zagolikapitte, Olivier Boutaud, Tina S. Masterson, Ventkataraman Amarnath, Thomas J. Montine, Katrin Andreasson, John A. OatesAbstract:The formation of Cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the Cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
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Prostaglandin H2‐derived adducts of proteins correlate with Alzheimer's disease severity
Journal of Neurochemistry, 2005Co-Authors: Irene Zagol-ikapitte, Olivier Boutaud, Tina S. Masterson, Ventkataraman Amarnath, Thomas J. Montine, Katrin Andreasson, John A. OatesAbstract:The formation of Cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the Cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
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Neuronal overexpression of COX-2 results in dominant production of PGE_2 and altered fever response
NeuroMolecular Medicine, 2003Co-Authors: Svetlana Vidensky, Yan Zhang, Tracey Hand, Joe Goellner, Alex Shaffer, Peter Isakson, Katrin AndreassonAbstract:Cyclooxygenases catalyze the first committed step in the formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase-2 (COX-2), the inducible isoform of Cyclooxygenase, is expressed in brain selectively in neurons of hippocampus, cerebral cortex, amygdala, and hypothalamus. Prostaglandins function in many processes in the CNS, including fever induction, nociception, and learning and memory, and are upregulated in paradigms of excitotoxic brain injury such as stroke and epilepsy. To address the varied functions of COX-2 and its prostaglandin products in brain, we have developed a transgenic mouse model in which COX-2 is selectively overexpressed in neurons of the CNS. COX-2 transgenic mice demonstrate elevated levels of all prostaglandins and thromboxane, albeit with a predominant induction of PGE_2 over other prostaglandins, followed by more modest inductions of PGI_2, and relatively smaller increases in PGF_2α, PGD_2, and TxB_2. We also examined whether increased neuronal production of prostaglandins would affect fever induction in response to the bacterial endotoxin lipopolysaccharide. COX-2 induction in brain endothelium has been previously determined to play an important role in fever induction, and we tested whether neuronal expression of COX-2 in hypothalamus also contributed to the febrile response. We found that in mice expressing transgenic COX-2 in anterior hypothalamus, the febrile response was significantly potentiated in transgenic as compared to non-transgenic mice, with an accelerated onset of fever by 1–2 hours after LPS administration, suggesting a role for neuronally derived COX-2 in the fever response.
Thomas J. Montine - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin h2 derived adducts of proteins correlate with alzheimer s disease severity
Journal of Neurochemistry, 2005Co-Authors: Irene Zagolikapitte, Olivier Boutaud, Tina S. Masterson, Ventkataraman Amarnath, Thomas J. Montine, Katrin Andreasson, John A. OatesAbstract:The formation of Cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the Cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
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Prostaglandin H2‐derived adducts of proteins correlate with Alzheimer's disease severity
Journal of Neurochemistry, 2005Co-Authors: Irene Zagol-ikapitte, Olivier Boutaud, Tina S. Masterson, Ventkataraman Amarnath, Thomas J. Montine, Katrin Andreasson, John A. OatesAbstract:The formation of Cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the Cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
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Prostaglandin H2 (PGH2) accelerates formation of amyloid β1−42 oligomers
Journal of Neurochemistry, 2002Co-Authors: Olivier Boutaud, Thomas J. Montine, Pierre Chaurand, Richard M. Caprioli, John A. OatesAbstract:Epidemiologic evidence implicates Cyclooxygenase activity in the pathogenesis of Alzheimer's disease, in which amyloid plaques have been found to contain increased levels of dimers and higher multimers of the amyloid beta peptide. The product of the oxygenation of arachidonic acid by the Cyclooxygenases, prostaglandin H2 (PGH2), rearranges non-enzymatically to several prostaglandins, including the highly reactive gamma-keto aldehydes, levuglandins E2 and D2. We demonstrate that PGH2 markedly accelerates the formation of dimers and higher oligomers of amyloid beta1-42. This is associated with the formation of levuglandin adducts of the peptide. These findings provide the molecular basis for a hypothesis linking Cyclooxygenase activity to the formation of oligomers of amyloid beta.
