5 research outputs found
Reaction between Peroxynitrite and Triphenylphosphonium-Substituted Arylboronic Acid Isomers: Identification of Diagnostic Marker Products and Biological Implications
Aromatic
boronic acids react rapidly with peroxynitrite (ONOO<sup>–</sup>) to yield phenols as major products. This reaction
was used to monitor ONOO<sup>–</sup> formation in cellular
systems. Previously, we proposed that the reaction between ONOO<sup>–</sup> and arylboronates (PhBÂ(OH)<sub>2</sub>) yields a phenolic
product (major pathway) and a radical pair PhBÂ(OH)<sub>2</sub>O<sup>•–</sup>···<sup>•</sup>NO<sub>2</sub> (minor pathway). [Sikora, A. et al. (2011) Chem. Res. Toxicol. 24, 687−697]. In this
study, we investigated the influence of a bulky triphenylphosphonium
(TPP) group on the reaction between ONOO<sup>–</sup> and mitochondria-targeted
arylboronate isomers (<i>o</i>-, <i>m</i>-, and <i>p</i>-MitoPhBÂ(OH)<sub>2</sub>). Results from the electron paramagnetic
resonance (EPR) spin-trapping experiments unequivocally showed the
presence of a phenyl radical intermediate from <i>meta</i> and <i>para</i> isomers, and not from the <i>ortho</i> isomer. The yield of <i>o</i>-MitoPhNO<sub>2</sub> formed
from the reaction between <i>o</i>-MitoPhBÂ(OH)<sub>2</sub> and ONOO<sup>–</sup> was not diminished by phenyl radical
scavengers, suggesting a rapid fragmentation of the <i>o</i>-MitoPhBÂ(OH)<sub>2</sub>O<sup>•–</sup> radical anion
with subsequent reaction of the resulting phenyl radical with <sup>•</sup>NO<sub>2</sub> in the solvent cage. The DFT quantum
mechanical calculations showed that the energy barrier for the dissociation
of the <i>o</i>-MitoPhBÂ(OH)<sub>2</sub>O<sup>•–</sup> radical anion is significantly lower than that of <i>m</i>-MitoPhBÂ(OH)<sub>2</sub>O<sup>•–</sup> and <i>p</i>-MitoPhBÂ(OH)<sub>2</sub>O<sup>•–</sup> radical
anions. The nitrated product, <i>o</i>-MitoPhNO<sub>2</sub>, is not formed by the nitrogen dioxide radical generated by myeloperoxidase
in the presence of the nitrite anion and hydrogen peroxide, indicating
that this specific nitrated product may be used as a diagnostic marker
product for ONOO<sup>–</sup>. Incubation of <i>o-</i>MitoPhBÂ(OH)<sub>2</sub> with RAW 264.7 macrophages activated to produce
ONOO<sup>–</sup> yielded the corresponding phenol <i>o-</i>MitoPhOH as well as the diagnostic nitrated product, <i>o-</i>MitoPhNO<sub>2</sub>. We conclude that the <i>ortho</i> isomer probe reported here is most suitable for specific detection
of ONOO<sup>–</sup> in biological systems
Bioavailability of ticagrelor and AR-C124910XX over time in patients with STEMI and NSTEMI.
<p>Plasma concentrations of (A) ticagrelor and (B) AR-C124910XX during the first 6 h after oral administration of a 180 mg ticagrelor loading dose in patients with STEMI and NSTEMI. NSTEMI: non-ST-elevation myocardial infarction, STEMI: ST-elevation myocardial infarction.</p
Baseline characteristics of study participants.
<p>Baseline characteristics of study participants.</p
Platelet reactivity over time in STEMI and NSTEMI patients.
<p>Platelet reactivity evaluated with (A) the VASP assay and (B) Multiplate at baseline, and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 12 h after administration of a 180 mg ticagrelor loading dose in patients with STEMI and NSTEMI. NSTEMI: non-ST-elevation myocardial infarction, STEMI: ST-elevation myocardial infarction, VASP: vasodilator-stimulated phosphoprotein.</p
Prevalence of high platelet reactivity over time in STEMI and NSTEMI patients.
<p>Proportion of patients with high platelet reactivity assessed with (A) the VASP assay and Multiplate (B) at baseline, and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 12 h after administration of a 180 mg ticagrelor loading dose in patients with STEMI and NSTEMI. HPR: high platelet reactivity, NSTEMI: non-ST-elevation myocardial infarction, STEMI: ST-elevation myocardial infarction, VASP: vasodilator-stimulated phosphoprotein.</p