Michal K. Handzlik

Applications of the ETS-NOCV method in descriptions of chemical reactions

AbstractThe present study characterizes changes in the electronic structure of reactants during chemical reactions based on the combined charge and energy decomposition scheme, ETS-NOCV (extended transition state–natural orbitals for chemical valence). Decomposition of the activation barrier, ΔE#, into stabilizing (orbital interaction, ΔEorb, and electrostatic, ΔEelstat) and destabilizing (Pauli repulsion, ΔEPauli, and geometry distortion energy, ΔEdist) factors is discussed in detail for the following reactions: (I) hydrogen cyanide to hydrogen isocyanide, HCN → CNH isomerization; (II) Diels-Alder cycloaddition of ethene to 1,3-butadiene; and two catalytic processes, i.e., (III) insertion of ethylene into the metal-alkyl bond using half-titanocene with phenyl-phenoxy ligand catalyst; and (IV) B–H bond activation catalyzed by an Ir-containing catalyst. Various reference states for fragments were applied in ETS-NOCV analysis. We found that NOCV-based deformation densities (Δρi) and the corresponding energies ΔEorb(i) obtained from the ETS-NOCV scheme provide a very useful picture, both qualitatively and quantitatively, of electronic density reorganization along the considered reaction pathways. Decomposition of the barrier ΔE# into stabilizing and destabilizing contributions allowed us to conclude that the main factor responsible for the existence of positive values of ΔE# for all processes (I, II, III and IV) is Pauli interaction, which is the origin of steric repulsion. In addition, in the case of reactions II, III and IV, a significant degree of structural deformation of the reactants, as measured by the geometry distortion energy, plays an important role. Depending on the reaction type, stabilization of the transition state (relatively to the reactants) originating either from the orbital interaction term or from electrostatic attraction can be of vital importance. Finally, use of the ETS-NOCV method to describe catalytic reactions allows extraction of information on the role of catalysts in determination of ΔE#. FigureContours of dominant deformation density contributions, Δρ1, together with the corresponding energies ΔEorb(1) obtained from the ETS-NOCV method for the transition state (TS) and the product (cyclohexene) of Diels-Alder cycloaddition of ethene to 1,3-butadiene. Black and white colors used in the representation of Δρ1 indicate carbon and hydrogen atoms, respectively. The blue/red colors in the contours corresponds to accumulation/depletion of electron density upon bond formation

Likely Additive Ergogenic Effects of Combined Preexercise Dietary Nitrate and Caffeine Ingestion in Trained Cyclists

Aims. To evaluate the possible additive effects of beetroot juice plus caffeine on exercise performance. Methods. In a randomized, double-blinded study design, fourteen healthy well-trained men aged 22 ± 3 years performed four trials on different occasions following preexercise ingestion of placebo (PLA), PLA plus 5 mg/kg caffeine (PLA+C), beetroot juice providing 8 mmol of nitrate (BR), and beetroot juice plus caffeine (BR+C). Participants cycled at 60% maximal oxygen uptake (V˙O2max) for 30 min followed by a time to exhaustion (TTE) trial at 80% V˙O2max. Saliva was collected before supplement ingestion, before exercise, and after the TTE trial for salivary nitrate, nitrite, and cortisol analysis. Results. In beetroot trials, saliva nitrate and nitrite increased >10-fold before exercise compared with preingestion (P ≤ 0.002). TTE in BR+C was 46% higher than in PLA (P = 0.096) and 18% and 27% nonsignificant TTE improvements were observed on BR+C compared with BR and PLA+C alone, respectively. Lower ratings of perceived exertion during TTE were found during 80% V˙O2max on BR+C compared with PLA and PLA+C (P < 0.05 for both). Conclusions. Acute preexercise beetroot juice coingestion with caffeine likely has additive effects on exercise performance compared with either beetroot or caffeine alone.

Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance

The cardiac metabolic reprogramming seen in heart diseases such as myocardial infarction and hypertrophy shares similarities with that seen in chronic hypoxia, but understanding of how the hypoxic heart responds to further hypoxic challenge – hypoxic tolerance – is limited. The pyruvate dehydrogenase complex serves to control irreversible decarboxylation of pyruvate within mitochondria, and is a key regulator of substrate metabolism, potentially regulating hypoxic tolerance. Acute activation of the pyruvate dehydrogenase complex did not improve cardiac function during acute hypoxia; however, simultaneous activation of the pyruvate dehydrogenase complex during chronic hypoxic exposure improved tolerance to subsequent acute hypoxia. Activation of the pyruvate dehydrogenase complex during chronic hypoxia stockpiled cardiac acetylcarnitine, and this was used during acute hypoxia. This maintained cardiac ATP and glycogen, and improved hypoxic tolerance as a result. These findings demonstrate that pyruvate dehydrogenase complex activation can improve cardiac function under hypoxia.

The Role of Diacylglycerol Acyltransferase (DGAT) 1 and 2 in Cardiac Metabolism and Function

It is increasingly recognized that synthesis and turnover of cardiac triglyceride (TG) play a pivotal role in the regulation of lipid metabolism and function of the heart. The last step in TG synthesis is catalyzed by diacylglycerol:acyltransferase (DGAT) which esterifies the diacylglycerol with a fatty acid. Mammalian heart has two DGAT isoforms, DGAT1 and DGAT2, yet their roles in cardiac metabolism and function remain poorly defined. Here, we show that inactivation of DGAT1 or DGAT2 in adult mouse heart results in a moderate suppression of TG synthesis and turnover. Partial inhibition of DGAT activity increases cardiac fatty acid oxidation without affecting PPARα signaling, myocardial energetics or contractile function. Moreover, coinhibition of DGAT1/2 in the heart abrogates TG turnover and protects the heart against high fat diet-induced lipid accumulation with no adverse effects on basal or dobutamine-stimulated cardiac function. Thus, the two DGAT isoforms in the heart have partially redundant function, and pharmacological inhibition of one DGAT isoform is well tolerated in adult hearts.