John A Oates, M.D.

Official Affiliation: Pharmacology

Profile

Our research has focused on the participation of the oxygenated metabolites of arachidonic acid (eicosanoids) in the pathophysiology and treatment of human diseases. One pathway of arachidonic acid oxygenation leads to the formation of prostaglandins and related molecules; the initial step in their formation is catalyzed by one of the two cyclooxygenase enzymes, which are inhibited by aspirin and the nonsteroidal anti-inflammatory drugs. One of these enzymes, cyclooxygenase-2 (COX-2), is an inducible enzyme, the biosynthesis of which is stimulated by growth factors, cytokines, and endotoxin, and is inhibited by glucocorticoids.
We are investigating the mechanisms for interindividual variation in the effects of aspirin as an antiplatelet drug employed as a cardioprotective agent. This research is based on our discovery that the irrreversible inhibition of the platelet cycloxygenase-1 is regulated by the redox status of the enzyme. Also under study are the changes in the platelet proteome associated with loss of aspirin's effect on continued administration.
We have found that the delayed vasospasm that can cause severe neurological deficits in subarachnoid hemorrhage is temporally associated with and hypothetically caused by lipid peroxidation resulting from hemoglobin radicals. Our research has identified agents that can inhibit such hemoprotein lcatalyzed ipid peroxidation in vitro and in vivo. We are now investigating a series of hemprotein reductants to determine the compounds most potent in reducing hemoprotein catalyzed lipid peroxidation with the aim of developing a treatment strategy for not only subarachnoid hemorrhage, but also other diseases in which hemoprotein catalyzed lipid peroxidation contributes to the pathophysiology including rhabdomyolysis, myocardial infarction, sickle cell disease, and malaria.
Work on Alzheimer's disease addresses a highly reactive keto-aldehyde product of the cyclooxygenases called levuglandin. We discovered that levuglandins can greatly accelerate the oligomerization of amyloid beta and that the oligomers so formed are neurotoxic. Moreover, we have developed mass spectrometric methods for measuring protein adducts of the levuglandins, and find that they are increased by 12 fold in the brains of patients who died of Alzheimer's disease. W are now working with scavengers of the levuglandins that prevent their reaction with proteins to determine their effects in transgenic mouse models of Alzheimer's disease. Other work addresses mechanisms for decreasing amyloid beta biosynthesis by enhancing cleavage of its precursor protein by the alpha -secretase enzyme.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. On-tissue chemical derivatization of 3-methoxysalicylamine for MALDI-imaging mass spectrometry. Chacon A, Zagol-Ikapitte I, Amarnath V, Reyzer ML, Oates JA, Caprioli RM, Boutaud O (2011) J Mass Spectrom 46(8): 840-6
    › Primary publication · 21834023 (PubMed) · PMC3174490 (PubMed Central)
  2. Determination of the Pharmacokinetics and Oral Bioavailability of Salicylamine, a Potent γ-Ketoaldehyde Scavenger, by LC/MS/MS. Zagol-Ikapitte IA, Matafonova E, Amarnath V, Bodine CL, Boutaud O, Tirona RG, Oates JA, Roberts LJ, Davies SS (2010) Pharmaceutics 2(1): 18-29
    › Primary publication · 21822464 (PubMed) · PMC3150493 (PubMed Central)
  3. Cardiovascular risk markers and mechanisms in targeting the COX pathway for colorectal cancer prevention. Oates JA (2011) Cancer Prev Res (Phila) 4(8): 1145-8
    › Primary publication · 21816843 (PubMed)
  4. Determination of 3-methoxysalicylamine levels in mouse plasma and tissue by liquid chromatography-tandem mass spectrometry: application to in vivo pharmacokinetics studies. Zagol-Ikapitte I, Amarnath V, Jadhav S, Oates JA, Boutaud O (2011) J Chromatogr B Analyt Technol Biomed Life Sci 879(15-16): 1098-104
    › Primary publication · 21489890 (PubMed) · PMC3091354 (PubMed Central)
  5. Functional characterization of mutations in inherited human cPLA₂ deficiency. Reed KA, Tucker DE, Aloulou A, Adler D, Ghomashchi F, Gelb MH, Leslie CC, Oates JA, Boutaud O (2011) Biochemistry 50(10): 1731-8
    › Primary publication · 21247147 (PubMed) · PMC3051024 (PubMed Central)
  6. Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2α differently for cyclooxygenase-1 and 12-lipoxygenase catalysis. Holinstat M, Boutaud O, Apopa PL, Vesci J, Bala M, Oates JA, Hamm HE (2011) Arterioscler Thromb Vasc Biol 31(2): 435-42
    › Primary publication · 21127289 (PubMed) · PMC3035574 (PubMed Central)
  7. Kindred with prominent corneal nerves associated with a mutation in codon 804 of RET on chromosome 10q11. Ong DS, Lakhani V, Oates JA, O'Day DM (2010) Arch Ophthalmol 128(2): 247-9
    › Primary publication · 20142552 (PubMed)
  8. Characterization of scavengers of gamma-ketoaldehydes that do not inhibit prostaglandin biosynthesis. Zagol-Ikapitte I, Amarnath V, Bala M, Roberts LJ, Oates JA, Boutaud O (2010) Chem Res Toxicol 23(1): 240-50
    › Primary publication · 20041722 (PubMed) · PMC2831641 (PubMed Central)
  9. Characterization of covalent adducts of nucleosides and DNA formed by reaction with levuglandin. Carrier EJ, Amarnath V, Oates JA, Boutaud O (2009) Biochemistry 48(45): 10775-81
    › Primary publication · 19824699 (PubMed) · PMC2824920 (PubMed Central)
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Keywords & MeSH Terms

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Key: MeSH Term Keyword

Acetaminophen Allergens Alzheimer's disease Aspirin Base Sequence Blood Pressure Cells, Cultured Chromosomes, Human, Pair 19 cyclooxygenases Cytochrome P-450 Enzyme Inhibitors Free Radicals Health Histocytological Preparation Techniques Hypotension Injections, Intraperitoneal Leukotrienes Lipid Peroxides Macrophages Malignant Carcinoid Syndrome Meclofenamic Acid Mice Nicotinic Acids Pancreatic Neoplasms Pheochromocytoma Phylogeny Platelet Factor 4 Premedication Prostaglandins G Prostaglandins H Protein Binding Pyridoxamine Reproducibility of Results Subarachnoid hemorrhage Translational research Thromboxanes