Polyphenols bind to low density lipoprotein at biologically relevant concentrations that are protective for heart disease.

There is ample evidence in the epidemiological literature that polyphenols, the major non-vitamin antioxidants in plant foods and beverages, have a beneficial effect on heart disease. Until recently other mechanisms which polyphenols exhibit such as cell signaling and regulating nitric oxide bioavailability have been investigated. The oxidation theory of atherosclerosis implicates LDL oxidation as the beginning step in this process. Nine polyphenols from eight different classes and several of their O-methylether, O-glucuronide and O-sulfate metabolites have been shown in this study to bind to the lipoproteins and protect them from oxidation at lysosomal/inflammatory pH (5.2), and physiological pH (7.4). Polyphenols bind to the apoprotein at pH 7.4 with Kb > 106 M-1 and the number of molecules of polyphenols bound per LDL particle under saturation conditions varied from 0.4 for ferulic acid to 13.1 for quercetin. Competition studies between serum albumin and LDL show that substantial lipoprotein binding occurs even in the presence of a great molar excess of albumin, the major blood protein. These in vitro results are borne out by published human supplementation studies showing that polyphenol metabolites from red wine, olive oil and coffee are found in LDL even after an overnight fast. A single human supplementation with various fruit juices, coffee and tea also produced an ex vivo protection against lipoprotein oxidation under postprandial conditions. This in vivo binding is heart-protective based on published olive oil consumption studies. Relevant to heart disease, we hypothesize that the binding of polyphenols and metabolites to LDL functions as a transport mechanism to carry these antioxidants to the arterial intima, and into endothelial cells and macrophages. Extracellular and intracellular polyphenols and their metabolites are heart-protective by many mechanisms and can also function as potent "intraparticle" and intracellular antioxidants due to their localized concentrations that can reach as high as the micromolar level. Low plasma concentrations make polyphenols and their metabolites poor plasma antioxidants but their concentration in particles such as lipoproteins and cells is high enough for polyphenols to provide cardiovascular protection by direct antioxidant effects and by other mechanisms such as cell signaling.

Mechanism of O((3)P) formation from a hydroxyl radical pair in aqueous solution.

The reaction mechanism for the rapid formation of a triplet oxygen atom, O((3)P), from a pair of triplet-state hydroxyl radicals in liquid water is explored utilizing extensive Car-Parrinello MD simulations and advanced visualization techniques. The local solvation structures, the evolution of atomic charges, atomic separations, spin densities, electron localization functions, and frontier molecular orbitals, as well as free energy profiles, evidence that the reaction proceeds through a hybrid (hydrogen atom transfer and electron-proton transfer) and hemibond-assisted reaction mechanism. A benchmarking study utilizing high-level ab initio calculations to examine the interactions of a hydroxyl radical pair in the gas phase and the influence of a hemibonded water is also provided. The results presented here should serve as a foundation for further experimental and theoretical studies aimed at better understanding the role and potential applications of the triplet oxygen atom as a potent reactive oxygen species.

Aqueous production of oxygen atoms from hydroxyl radicals.

The behavior of the hydroxyl radical (OH*) in solution is significant to a broad range of scientific and technological fields. OH* is considered a highly reactive, short-lived species and previous studies have neglected the possibility of encounters of two OH* in solution. However, these encounters may be nonnegligible in environments with elevated local OH* concentrations, such as under many in vivo processes and within nuclear infrastructure. High concentrations of OH* in vivo are considered to be very dangerous; OH* has been related to many ailments ranging from cancer to Alzheimer's disease. Here we probe details of the reactions and interactions that can occur between two OH* in water by utilizing Car-Parrinello molecular dynamics simulations and advanced visualization techniques. The recombination reaction to form hydrogen peroxide is confirmed for the singlet electronic state. In contrast, the triplet state yields an oxygen atom, O(aq). This species has been previously detected in experimental water-radiolysis studies, but its origin could not be determined. O(aq) is a much more potent biradical than its parent OH* and its presence can impact many in vivo processes. This study also reveals that the hemibonded interaction plays key role in the behavior of OH*(aq). Our findings have major implications to the scientific understanding of the impacts of high local OH* concentrations, such during oxidative stress and in aging processes. Given its importance, this study will form the basis of further experimental and theoretical investigations exploring the role of O(aq) in a number of contexts.

Cross-talk between amino acid residues and flavonoid derivatives: insights into their chemical recognition.

Currently, there is a general consensus that flavonoids exert their antioxidant activity through their ability to interact with a broad range of proteins, enzymes and transcription factors rather than acting as conventional hydrogen-donating antioxidants. For this, the effect of different chemical groups of the conjugated flavonoid metabolites is apparently playing a pivotal role. Yet, many questions concerning the relevant molecular mechanisms still remain open. It is therefore crucial to gain a deeper insight into the amino acid residue-flavonoid interaction. Here we show extensive theoretical thermodynamic data and structural characteristics of the interaction of chalcone, genistein, epigallocatechin gallate, and quercetin and some of its metabolites with amino acid residues. By correlating (a) the binding energies of flavonoids-amino acid residues, (b) the hydrophobicity of amino acids, and (c) the abundance of amino acid residues in the binding sites of proteins, we can conclude that flavonoids appear to be strongly bonded to only few charged hydrophilic amino acids in the protein pockets, and rather weakly bonded to the majority of amino acid residues in the binding sites. This finding strongly impacts the understanding of the chemical recognition of flavonoids and their metabolites in their interaction with proteins and would contribute to a better design of further experimental studies. Particularly, the amino acids Phe, Leu, Ile and Trp seem to play a crucial role in the dynamics of flavonoid ligands in the binding sites of proteins.

Hydroxyl radicals in ice: insights into local structure and dynamics.

The hydroxyl radical and its reactivity within ice environments are crucial to many important atmospheric reactions. The associated molecular mechanisms are largely unknown due to challenges posed by direct experimental measurements and computational studies of this transient species. Here we report insights into the local structure and behaviour of the hydroxyl radical in bulk ice through an extensive study utilizing Car-Parrinello molecular dynamics simulations. Interstitial and in-lattice hydroxyl radicals in hexagonal ice were investigated at primarily 190 K. Our findings, utilizing both HCTH/120 and BLYP functionals, show that OH* can exhibit greater mobility than other ice defects (the trapping energy estimated to be only 0.09 eV). We observe the formation of a two-center three-electron hemibond structure between the hydroxyl radical and an in-lattice water molecule; while controversial, such a structure in ice may be amenable to experimental detection due to its relative stability. Our results show that interstitial water molecules can strongly influence the mobility of the hydroxyl radical in bulk ice through the displacement of the radical to an interstitial location. We also demonstrate that the H-transfer reaction from an interstitial water to the radical is a rare event in ice. Together, these results predict that the radical can be a reactive species in bulk ice, as both interstitial and in-lattice OH* can be available for reactions with other species. These microscopic insights should contribute to our understanding of the reactivity of OH* in ice and its implications to atmospheric reactions.

Mobility mechanism of hydroxyl radicals in aqueous solution via hydrogen transfer.

The hydroxyl radical (OH*) is a highly reactive oxygen species that plays a salient role in aqueous solution. The influence of water molecules upon the mobility and reactivity of the OH* constitutes a crucial knowledge gap in our current understanding of many critical reactions that impact a broad range of scientific fields. Specifically, the relevant molecular mechanisms associated with OH* mobility and the possibility of diffusion in water via a H-transfer reaction remain open questions. Here we report insights into the local hydration and electronic structure of the OH* in aqueous solution from Car-Parrinello molecular dynamics and explore the mechanism of H-transfer between OH* and a water molecule. The relatively small free energy barrier observed (~4 kcal/mol) supports a conjecture that the H-transfer can be a very rapid process in water, in accord with very recent experimental results, and that this reaction can contribute significantly to OH* mobility in aqueous solution. Our findings reveal a novel H-transfer mechanism of hydrated OH*, resembling that of hydrated OH(-) and presenting hybrid characteristics of hydrogen-atom and electron-proton transfer processes, where local structural fluctuations play a pivotal role.

Insights into the Solvation and Mobility of the Hydroxyl Radical in Aqueous Solution.

A detailed description of the local solvation structure and mobility of hydroxyl radicals (OH*) in aqueous solution near ambient conditions is provided by Car-Parrinello molecular dynamics simulations. Here, we demonstrate that for HCTH/120 and BLYP functionals, smaller systems (i.e., 31·H2O-OH*) are contaminated by system size effects, being biased for the presence of a three-electron two-centered hemibond structure between the oxygen atoms of a water molecule and the radical. Radial and spatial distribution functions of relatively large 63·H2O-OH* systems reveal the existence of a 4-fold coordinated "inactive" OH* structure with three H-bond donating neighbors and a strongly coordinated H-bond accepting neighbor. The local hydration structure around the radical exhibits more H-bond ordering than has been predicted by recent simulations employing classical force fields. Local structural fluctuations can end with spontaneous H-transfer reactions from the nearest H-bond donor water molecule, facilitated by the formation of an "active" OH* state, resembling the proton transfer mechanism of hydrated OH(-) (i.e., slight polarization of the (H3O2)* complex). A comparison of the free energy barriers for the H-transfer reaction obtained by both DFT functionals and for both system sizes is also provided, demonstrating that this can be a very rapid process in water.

Quantum chemical associations ligand-residue: their role to predict flavonoid binding sites in proteins.

A novel approach is applied for the prediction of potential binding sites in ligand-protein interactions. This methodology introduces an integral strategy based on the calculation of protein geometrical parameters and the use of a quantum mechanical descriptor, Binding Local Site (B(LS)). A screening of the most likely cavities in the protein crystal structure is carried out where the analysis of geometric cavities is performed, and the virtual centers for binding (VCB) are located. The VCB surrounding amino acid residues (AA) are evaluated through the calculation of the B(LS) by using the theoretical affinity order between the ligand and each AA. It includes a quantum scoring function based on the ligand-AA association energies and entropies. A contribution to the understanding of flavonoid-protein interactions is provided as well. The new bioinformatic strategy makes good predictions for flavonoid ligands. The calculated binding sites are quite in agreement with the crystal binding sites of 10 flavonoid binding proteins. This is a contribution of quantum mechanics in some phases of in silico drug design.

Biodistribución y farmacocinética de Taninos de Pinus caribaea Morelet y Casuarina equisetifolia en ratones / Biodistribution and pharmacokinetics of tannins from Pinus caribaea Morelet and Casuarina equisetifolia in mice

Se estudió la biodistribución y la farmacocinética de taninos condensados purificados y marcados radioisotópicamente, extraídos a partir de la corteza de las especies forestales Pinus caribaea Morelet var caribaea y Casuarina equisetifolia previa administración por vía oral y endovenosa, con el empleo de ratones como biomodelo. Los taninos estudiados, con una alta capacidad antioxidante y diferenciados por la propiedad de formar complejos con proteínas, presentaron una rápida biodistribución hacia los diferentes órganos y tejidos, con manifestaciones de un importante acúmulo en el estómago e intestinos. Los taninos de ambas especies describen una biodistribución que se ajusta a un modelo bicompartimental de distribución. Se reportan los parámetros farmacocinéticos como tiempo de residencia medio, aclaramiento total, área bajo la curva, biodisponibilidad e instante de tiempo en que ocurre la máxima incorporación a partir de las curvas del aclaramiento sanguíneo

Biodistribución y farmacocinética de Taninos de Pinus caribaea Morelet y Casuarina equisetifolia en ratones / Biodistribution and pharmacokinetics of tannins from Pinus caribaea Morelet and Casuarina equisetifolia in mice

Se estudió la biodistribución y la farmacocinética de taninos condensados purificados y marcados radioisotópicamente, extraídos a partir de la corteza de las especies forestales Pinus caribaea Morelet var caribaea y Casuarina equisetifolia previa administración por vía oral y endovenosa, con el empleo de ratones como biomodelo. Los taninos estudiados, con una alta capacidad antioxidante y diferenciados por la propiedad de formar complejos con proteínas, presentaron una rápida biodistribución hacia los diferentes órganos y tejidos, con manifestaciones de un importante acúmulo en el estómago e intestinos. Los taninos de ambas especies describen una biodistribución que se ajusta a un modelo bicompartimental de distribución. Se reportan los parámetros farmacocinéticos como tiempo de residencia medio, aclaramiento total, área bajo la curva, biodisponibilidad e instante de tiempo en que ocurre la máxima incorporación a partir de las curvas del aclaramiento sanguíneo(AU)