Skeletal muscle (1) H MRSI before and after prolonged exercise. II. visibility of free carnitine

Carnitine (Car) buffers excess acetyl-CoA through the formation of acetylCar (AcCar). AcCar's acetyl group (AG-AcCar) gives rise to a peak at 2.13 ppm in ¹H MR spectra of skeletal muscle, whereas the trimethylammonium (TMA) groups of both, AcCar and Car, are thought to contribute to the TMA peak at 3.23 ppm. Surprisingly, in previous studies both resonances, AG-AcCar and TMA, increased after exercise. The aim of this study was to assess if the exercise-related TMA increase correlated with AcCar production. Magnetic resonance spectroscopic imaging (pulse repetition time/echo time = 1200/35 ms) was performed before and after prolonged exercise in the lower leg and thigh of eight runners and eight cyclists, respectively. TMA and AG-AcCar increased after exercise (P < 0.001). TMA's increase correlated with the AG-AcCar increase (R² = 0.73, P < 0.001, lower leg; R² = 0.28, P < 0.001, thigh). The correlation of ΔTMA with ΔAG-AcCar suggests that the TMA increase is due to AcCar formation. As total Car (Car + AcCar) remains unchanged with exercise, these findings suggest that the contribution of free Car to the TMA peak is limited and, therefore, is partly invisible in muscle ¹H MR spectra. This indicates that the biochemically relevant cytosolic content of free Car is considerably lower than the overall concentration determined by radioisotopic assays, a potentially important result with respect to regulation of substrate oxidation.

Efficient Oxidation of Cysteine and Glutathione Catalyzed by a Dinuclear Areneruthenium Trithiolato Anticancer Complex

The highly cytotoxic diruthenium complex [(p-MeC(6)H(4)Pr(1))(2)Ru(2)(SC(6)H(4)-p-Me)(3)](+) (1), water-soluble as the chloride salt, is shown to efficiently catalyze oxidation of the thiols cysteine and glutathione to give the corresponding disulfides, which may explain its high in vitro anticancer activity.

Constraining global methane emissions and uptake by ecosystems

Natural methane (CH4) emissions from wet ecosystems are an important part of today's global CH4 budget. Climate affects the exchange of CH4 between ecosystems and the atmosphere by influencing CH4 production, oxidation, and transport in the soil. The net CH4 exchange depends on ecosystem hydrology, soil and vegetation characteristics. Here, the LPJ-WHyMe global dynamical vegetation model is used to simulate global net CH4 emissions for different ecosystems: northern peatlands (45°–90° N), naturally inundated wetlands (60° S–45° N), rice agriculture and wet mineral soils. Mineral soils are a potential CH4 sink, but can also be a source with the direction of the net exchange depending on soil moisture content. The geographical and seasonal distributions are evaluated against multi-dimensional atmospheric inversions for 2003–2005, using two independent four-dimensional variational assimilation systems. The atmospheric inversions are constrained by the atmospheric CH4 observations of the SCIAMACHY satellite instrument and global surface networks. Compared to LPJ-WHyMe the inversions result in a~significant reduction in the emissions from northern peatlands and suggest that LPJ-WHyMe maximum annual emissions peak about one month late. The inversions do not put strong constraints on the division of sources between inundated wetlands and wet mineral soils in the tropics. Based on the inversion results we diagnose model parameters in LPJ-WHyMe and simulate the surface exchange of CH4 over the period 1990–2008. Over the whole period we infer an increase of global ecosystem CH4 emissions of +1.11 Tg CH4 yr−1, not considering potential additional changes in wetland extent. The increase in simulated CH4 emissions is attributed to enhanced soil respiration resulting from the observed rise in land temperature and in atmospheric carbon dioxide that were used as input. The long-term decline of the atmospheric CH4 growth rate from 1990 to 2006 cannot be fully explained with the simulated ecosystem emissions. However, these emissions show an increasing trend of +3.62 Tg CH4 yr−1 over 2005–2008 which can partly explain the renewed increase in atmospheric CH4 concentration during recent years.

Oxidative stress precedes peak systemic inflammatory response in pediatric patients undergoing cardiopulmonary bypass operation

Oxidative stress seems to contribute to cardiopulmonary bypass (CPB)-related postoperative complications. Pediatric patients are particularly prone to these complications. With this in mind, we measured oxidative stress markers in blood plasma of 20 children undergoing elective heart surgery before, during, and up to 48 h after cessation of CPB, along with inflammatory parameters and full analysis of iron status. Ascorbate levels were decreased by approximately 50% (P < 0.001) at the time of aorta cross-clamp removal (or pump switch-off in 4 patients with partial CPB), and associated with corresponding increases in dehydroascorbate (P < 0.001, r = -0.80) and malondialdehyde (P < 0.01, r = -0.59). In contrast to the immediate oxidative response, peak levels of IL-6 and IL-8 were not observed until 3-12 h after CPB cessation. The early loss of ascorbate correlated with duration of CPB (P < 0.002, r = 0.72), plasma hemoglobin after cross-clamp removal (P < 0.001, r = 0.70), and IL-6 and IL-8 levels at 24 and 48 h after CPB (P < 0.01), but not with postoperative lactate levels, strongly suggesting that hemolysis, and not inflammation or ischemia, was the main cause of early oxidative stress. The correlation of ventilation time with early changes in ascorbate (P < 0.02, r = 0.55), plasma hemoglobin (P < 0.01, r = 0.60), and malondialdehyde (P < 0.02, r = 0.54) suggests that hemolysis-induced oxidative stress may be an underlying cause of CPB-associated pulmonary dysfunction. Optimization of surgical procedures or therapeutic intervention that minimize hemolysis (e.g., off-pump surgery) or the resultant oxidative stress (e.g., antioxidant treatment) should be considered as possible strategies to lower the rate of postoperative complications in pediatric CPB.

Gamma-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation

Gamma-tocopherol (gammaT) complements alpha-tocopherol (alphaT) by trapping reactive nitrogen oxides to form a stable adduct, 5-nitro-gammaT [Christen et al., PNAS 94:3217-3222; 1997]. This observation led to the current investigation in which we studied the effects of gammaT supplementation on plasma and tissue vitamin C, vitamin E, and protein nitration before and after zymosan-induced acute peritonitis. Male Fischer 344 rats were fed for 4 weeks with either a normal chow diet with basal 32 mg alphaT/kg, or the same diet supplemented with approximately 90 mg d-gammaT/kg. Supplementation resulted in significantly higher levels of gammaT in plasma, liver, and kidney of control animals without affecting alphaT, total alphaT+gammaT or vitamin C. Intraperitoneal injection of zymosan caused a marked increase in 3-nitrotyrosine and a profound decline in vitamin C in all tissues examined. Supplementation with gammaT significantly inhibited protein nitration and ascorbate oxidation in the kidney, as indicated by the 29% and 56% reduction of kidney 3-nitrotyrosine and dehydroascorbate, respectively. Supplementation significantly attenuated inflammation-induced loss of vitamin C in the plasma (38%) and kidney (20%). Zymosan-treated animals had significantly higher plasma and tissue gammaT than nontreated pair-fed controls, and the elevation of gammaT was strongly accentuated by the supplementation. In contrast, alphaT did not significantly change in response to zymosan treatment. In untreated control animals, gammaT supplementation lowered basal levels of 3-nitrotyrosine in the kidney and buffered the starvation-induced changes in vitamin C in all tissues examined. Our study provides the first in vivo evidence that in rats with high basal amounts of alphaT, a moderate gammaT supplementation attenuates inflammation-mediated damage, and spares vitamin C during starvation-induced stress without affecting alphaT.

Inhibition by interferon-gamma of human mononuclear cell-mediated low density lipoprotein oxidation. Participation of tryptophan metabolism along the kynurenine pathway

In this study we examined the potential inhibition by interferon-gamma (IFN gamma) of the early stages of low density lipoprotein (LDL) oxidation mediated by human peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) in Ham's F-10 medium supplemented with physiological amounts of L-tryptophan (Trp). We assessed LDL oxidation by measuring the consumption of LDL's major antioxidant (i.e., alpha-tocopherol) and targets for oxidation (cholesteryllinoleate and cholesterylarachidonate), together with the accumulation of cholesterylester hydroperoxides and the increase in relative electrophoretic mobility of the lipoprotein particle. Exposure of PBMC or MDM to IFN gamma induced the degradation of extracellular Trp with concomitant accumulation of kynurenine, anthranilic and 3-hydroxyanthranilic acid (3HAA) in the culture medium. Formation of 3HAA, but neither Trp degradation nor formation of kynurenine and anthranilic acid, was inhibited by low amounts of diphenylene iodonium (DPI) in a concentration-dependent manner. In contrast to oxidative Trp metabolism, exposure of human PBMC or MDM to IFN gamma failed to induce degradation of arginine, and nitrite was not detected in the cell supernatant, indicating that nitric oxide synthase was not induced under these conditions. Incubation of LDL in Trp-supplemented F-10 medium resulted in a time-dependent oxidation of the lipoprotein that was accelerated in the presence of PBMC or MDM but inhibited strongly in the presence of both cells and IFN gamma, i.e., when Trp degradation and formation of 3HAA were induced. In contrast, when IFN gamma was added to PBMC or MDM in F-10 medium that was virtually devoid of Trp, inhibition of cell-accelerated LDL oxidation was not observed. Exogenous 3HAA added to PBMC or purified monocytes in the absence of IFN gamma also strongly and in a concentration-dependent manner inhibited LDL oxidation. Selective inhibition of IFN gamma-induced formation of 3HAA by DPI caused reversion of the inhibitory action of this cytokine on both PBMC- and MDM-mediated LDL oxidation. These results show that IFN gamma treatment of human PBMC or MDM in vitro attenuates the extent of LDL oxidation caused by these cells, and indicate that Trp degradation with formation of 3HAA is a major contributing factor to this inhibitory activity.