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Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2−/− mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36−/− and Mertk−/− mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

Subsequent to the dietary uptake of nitrate/nitrite in combination with acetaldehyde/ethanol, combination effects resulting from the sustained endogenous exposure to nitrite and acetaldehyde may be expected. This may imply locoregional effects in the upper gastrointestinal tract as well as systemic effects, such as a potential influence on endogenous formation of N-nitroso compounds (NOC). Salivary concentrations of the individual components nitrate and nitrite and acetaldehyde are known to rise after ingestion, absorption and systemic distribution, thereby reflecting their respective plasma kinetics and parallel secretion through the salivary glands as well as the microbial/enzymatic metabolism in the oral cavity. Salivary excretion may also occur with certain drug molecules and food constituents and their metabolites. Therefore, putative combination effects in the oral cavity and the upper digestive tract may occur, but this has remained largely unexplored up to now. In this Guest Editorial, published evidence on exposure levels and biokinetics of nitrate/nitrite/NOx, NOC and acetaldehyde in the organism is reviewed and knowledge gaps concerning combination effects are identified. Research is suggested to be initiated to study the related unresolved issues. published

Ageing is a biological process guided by genetic and environmental factors that ultimately lead to adverse outcomes for organismal lifespan and healthspan. Determination of molecular pathways that are affected with age and increase disease susceptibility is crucial. The gene expression profile of the ideal ageing model, namely the nematode Caenorhabditis elegans mapped with the microarray technology initially led to the identification of age-dependent gene expression alterations that characterize the nematode's ageing process. The list of differentially expressed genes was then utilized to construct a network of molecular interactions with their first neighbors/interactors using the interactions listed in the WormBase database. The subsequent network analysis resulted in the unbiased selection of 110 candidate genes, among which well-known ageing regulators appeared. More importantly, our approach revealed candidates that have never been linked to ageing before, thus suggesting promising potential targets/ageing regulators.

Objective Current data regarding the roles of branched-chain amino acids (BCAA) in metabolic health are rather conflicting, as positive and negative effects have been attributed to their intake. Methods To address this, individual effects of leucine and valine were elucidated in vivo (C57BL/6JRj mice) with a detailed phenotyping of these supplementations in high-fat (HF) diets and further characterization with in vitro approaches (C2C12 myocytes). Results Here, we demonstrate that under HF conditions, leucine mediates beneficial effects on adiposity and insulin sensitivity, in part due to increasing energy expenditure—likely contributing partially to the beneficial effects of a higher milk protein intake. On the other hand, valine feeding leads to a worsening of HF-induced health impairments, specifically reducing glucose tolerance/insulin sensitivity. These negative effects are driven by an accumulation of the valine-derived metabolite 3-hydroxyisobutyrate (3-HIB). Higher plasma 3-HIB levels increase basal skeletal muscle glucose uptake which drives glucotoxicity and impairs myocyte insulin signaling. Conclusion These data demonstrate the detrimental role of valine in an HF context and elucidate additional targetable pathways in the etiology of BCAA-induced obesity and insulin resistance.

A low folate or low thiamine status may be associated with the risk of preterm delivery, small for gestational age (SGA) offspring and adverse pregnancy outcomes.5-Methyltetrahydrofolate (5MTHF) and thiamine diphosphate (TDP) were measured directly in cord-blood erythrocytes (CBEs) of early preterm (n=26;32 weeks gestational age; including 50% multiple births), late preterm (n=38; 32 to37 weeks; including 24% multiple births) and term newborns (n=60, 37-42 weeks) via high-performance liquid chromatography and fluorescence detection. Associations between 5MTHF and TDP with gestational age, newborn anthropometrics (birth weight, newborn's length and head circumference) and risk of being SGA were explored.Group comparison as well as multivariate linear regression analysis of cord-blood vitamins revealed that 5MTHF was significantly lower in late preterms compared with terms but did not differ between singletons and multiples. TDP tended to be higher in preterms than in terms and lower in multiples than in singletons in both early and late preterms. Multivariate analysis on birth outcomes showed that 5MTHF was significantly positively associated with gestational age, birth weight and newborn's length. 5MTHF, increasing gestational age and parity were associated with a significantly reduced risk for being SGA, while TDP, multiple births and gender were not associated with the risk for being SGA.Higher CBE concentrations of 5MTHF were associated with improved birth outcomes. Lower TDP concentrations were observed in multiple births. Future studies evaluating cord-blood vitamin concentrations and their associations with birth outcomes should additionally include dietary intakes and maternal blood concentrations at different stages of pregnancy.

In this study we compared biomarkers of oxidative stress, stress response, antioxidant defence and inflammation between mice (n = 10 per group, female, 7 months old) with an accelerated (SAMP8) and a normal ageing phenotype (SAMR1). As compared to SAMR1 mice, SAMP8 mice exhibited higher levels of lipid peroxides and protein carbonyls as well as a lower activity of the proteasomal subunit beta-5. Furthermore, heme oxygenase-1 and paraoxonase-1 (PON-1) status was lower in SAMP8 mice indicating impaired stress response. Biomarkers of inflammation such as C-reactive protein and serum amyloid P were elevated in SAMP8 mice. Interestingly, impaired stress response and increased inflammation in SAMP8 mice were associated with elevated concentrations of ascorbic acid and alpha-tocopherol in the liver. An age-dependent increase in hepatic vitamin E and a decline in PON-1 gene expression were also observed in aged compared to young C57BL/6 mice.

The accumulation of oxidized proteins is known to be linked to some severe neurodegenerative diseases like Alzheimer's, Parkinson's and Huntington's disease. Furthermore, the aging process is also accompanied by an ongoing aggregation of misfolded and damaged proteins. Therefore, mammalian cells have developed potent degradation systems, which selectively degrade damaged and misfolded proteins. The proteasomal system is largely responsible for the removal of oxidatively damaged proteins form the cellular environment. Not only cytosolic proteins are prone to oxidative stress, also nuclear proteins are readily oxidized. The nuclear proteasomal system is responsible for the degradation of these proteins. This review is focused on the specific degradation of oxidized nuclear proteins, the role of the proteasome in this process and the regulation of the nuclear proteasomal system under oxidative conditions.

Curcumin from Curcuma longa may exert putative neuroprotective properties in the brain. Impaired mitochondrial function is implicated in Alzheimer’s disease and the presence of the apolipoprotein (APO) E4 genotype, which is a risk factor for late-onset Alzheimer’s disease, may aggravate mitochondrial malfunction. Here, we report that in the brain of 16-month-old APOE4-targeted replacement mice, adenosine triphosphate (ATP) concentrations were significantly lower than in APOE3 mice. A 3-month dietary supplementation of 0.2 % curcumin numerically increased ATP concentrations in APOE3 and significantly in APOE4 mice compared to the respective controls. Curcumin significantly induced the transcription of peroxisome proliferator-activated receptor (PPAR) γ and mitochondrial transcription factor A (TFAM) in APOE3, but not in APOE4 mice. Moreover, PPARγ coactivator (PGC)-1α and guanine–adenine repeat binding protein α (GABPa) mRNA was only increased in APOE3 mice. Consistent with these observations, protein expression of mitochondrial respiratory complexes, especially of complex IV, also appeared to be increased in APOE3 mice. In conclusion, we provide evidence that curcumin affects mitochondrial function and gene and protein expression in the murine brain despite its low bioavailability and carriers of the Alzheimer’s disease-risk genotype APOE4 may be less responsive to dietary curcumin than APOE3 carriers.

Oxygen free radicals and other oxidants are causing potential danger for intracellular proteins during the lifetime of cells and organisms. Therefore, protein oxidation is one of the natural consequences of aerobic life. The degradation of non-functional, oxidized proteins is an essential part of the antioxidant defenses of cells. The major proteolytic system responsible for the removal of oxidized cytosolic proteins is the proteasomal system. This system consists of the 20S 'core' proteasome and a multitude of various regulators. It is known that certain components of this system are regulated during oxidative stress and aging. One of the highlights of age-related changes of cellular metabolism is the accumulation of oxidized proteins. The question whether the accumulation of oxidized proteins during aging is due to a malfunction of the intracellular proteolytic machinery of the cell remains still unsolved. The information available about an age-related decline of the proteasomal system is very contradictory. The current literature about the proteasomal system, the regulation of this system during oxidative stress and the age-related changes are in the focus of this review.

For quantitative evaluation of lipid peroxidation after perinatal hypoxia in umbilical arterial cord blood samples from 109 healthy, acidotic, and asphyctic neonates with a gestational age ranging from 26 to 41 wk, the levels of aldehydic lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynon-2-enal (HNE) were measured. Furthermore, the concentrations of oxidized and reduced glutathione (GSSH and GSH) and the purine compounds hypoxanthine and uric acid were determined. With increasing gestational age MDA and HNE levels increased. Furthermore, an increased level of GSH was also found. After perinatal hypoxia the concentrations of MDA and HNE rose distinctly (p < 0.001), reflecting sensitively the extent of in vivo lipid peroxidation. HNE is proposed to be a new parameter for quantitative evaluation of posthypoxic cellular damage in the perinatal period. HNE is a more specific parameter for estimation of lipid peroxidation processes in comparison with MDA. Additionally, HNE is cytotoxic and mutagenic at nanomolar concentrations. The increased levels of both MDA and HNE were accompanied by a strong decrease of GSH concentrations (p < 0.001), indicating the rapid consumption of GSH via a glutathione peroxidase reaction but additionally the high reactivity of HNE with sulfhydryl groups. During oxygen deficiency, increased levels of hypoxanthine (p < 0.01) and uric acid (p < 0.05) were due to the accelerated degradation of purine nucleotides. The rate of purine degradation including xanthine oxidase reactions characterizes the extent of an important radical source during oxygen deficiency, contributing to peroxidation of polyunsaturated fatty acids and the formation of peroxidation of polyunsaturated fatty acids and the formation of secondary aldehydic lipid peroxidation products.

During the transition of Ehrlich mouse ascites tumour cells from the proliferating to the resting state of growth a large loss of purine and pyrimidine compounds occurs. This decrease is accompanied by a change in the amount of protein in the supernate of ascites fluid, which is known from the study of the ATP-consumption during protein synthesis. The ascites fluid was investigated by anion-exchange and size-exclusion chromatography (SEC). SDS-PAGE (sodium, dodecyl sulfate-polyacrylamide gel electrophoresis) data were compared with SEC data. The total amount of protein increased by 50% between day 5 and 12 of growth. At least 5 new peaks are observed in the chromatograms of an ion-exchange separation of Ehrlich ascites fluid at day 12 postinoculation. The amounts of transferrin, albumin and IgG (immunoglobulin G) were increased to 132, 134, 157%, respectively duringin vivo growth.

Objective and Design: The study was designed to elucidate whether cyclosporine A (Cy A) induces oxidative stress in heart, liver and kidney.¶Material and Treatment: Male Wistar rats were treated with NaCl (n = 7), cremophor (vehicle for Cy A; n = 7) and 30 mg/kg b.w. Cy A in cremophor (n = 7) daily for 4 weeks.¶Methods: Oxidized (GSSG) and reduced (GSH) glutathione, lipid peroxides and superoxide dismutase were measured in the organs.¶Results: Increases in GSSG [nmol/mg prot.] and a compensatory rise in total GSH [nmol/mg prot.] indicating Cy A-induced oxidative stress were found in kidney (0.39 ± 0.09 vs. 0.47 ± 0.14 vs. 0.64 ± 0.18; 20.71 ± 3.86 vs. 21.07 ± 3.86 vs. 28.14 ± 3.37) and liver (0.51 ± 0.11 vs. 0.51 ± 0.09 vs. 0.65 ± 0.25; 33.35 ± 5.06 vs. 32.88 ± 5.12 vs. 44.12 ± 6.06) but not in heart.¶Conclusion: Cy A-induced oxidative stress may contribute to the hepatotoxicity and nephrotoxicity of this drug. After heart transplantation, accelerated allograft atherosclerosis limits transplantation success. We did not find any evidence that Cy A induces oxidative stress in the heart which might favour atherogenesis.

During the degradation of lipid hydroperoxides as primary products of free radical-initiated lipid peroxidation aldehydic compounds are generated. 4-Hydroxynonenal (HNE) is a major aldehydic lipid peroxidation product which is formed from omega 6-PUFA. It exhibits cytotoxic, mutagenic, and genotoxic properties [1]. Increased levels of HNE were found in plasma and tissues under conditions of oxidative stress [ 2 4]. HNE is rapidly metabolized in eucaryotic cells. The aim of this study was the investigation of the different pathways of HNE metabolism. That includes the development of sensitive analytical procedures for the qualitative and quantitative determination of metabolic HNE products.

The analysis of two metabolite groups, nucleotides and aldehydes, is necessary for assessment of oxygen radical metabolism during hypoxia and reoxygenation.

Three groups of metabolites were analyzed in extracts of rat hepatocytes by an HPLC method: (i) nucleotides (ATP, ADP, AMP, GTP, GDP, UTP, UDP, IMP, UMP), (ii) nucleosides and nucleobases (adenosine, adenine, guanosine, inosine, xanthine, hypoxanthine, uridine) and (iii) inhibitors of xanthine oxidoreductase (oxypurinol, allopurinol). Perchloric acid extracts were neutralized with K2CO3/triethanolamine and analyzed at 254 nm by reversed-phase ion-pair high-performance liquid chromatography. The nucleotides and their derivatives were separated with a gradient elution using 10 mM NH4H2PO4/2 mM t-butylammonium-phosphate and acetonitrile. Recovery values were estimated for the extraction procedure used. The method was applied to the investigation of nucleotide metabolism of hepatocytes of starved rats at anoxia and reoxygenation.