Paraoxonase 1 polymorphism Q192R affects the pro-inflammatory cytokine TNF-alpha in healthy males

<p>Abstract</p> <p>Background</p> <p>Human paraoxonase 1 (PON1) is an HDL-associated enzyme with anti-oxidant/anti-inflammatory properties that has been suggested to play an important protective role against coronary heart diseases and underlying atherogenesis. The common <it>PON1 </it>Q192R polymorphism (<it>rs662</it>, A>G), a glutamine to arginine substitution at amino acid residue 192, has been analyzed in numerous association studies as a genetic marker for coronary heart diseases, however, with controversial results.</p> <p>Findings</p> <p>To get a better understanding about the pathophysiological function of PON1, we analyzed the relationships between the Q192R polymorphism, serum paraoxonase activity and serum biomarkers important for atherogenesis. Genotyping a cohort of 49 healthy German males for the Q192R polymorphism revealed an allele distribution of 0.74 and 0.26 for the Q and R allele, respectively, typical for Caucasian populations. Presence of the R192 allele was found to be associated with a significantly increased paraoxonase enzyme activity of 187.8 ± 11.4 U/l in comparison to the QQ192 genotype with 60.5 ± 4.9 U/l. No significant differences among the genotypes were found for blood pressure, asymmetric dimethylarginine, LDL, HDL, triglycerides, and cholesterol. As expected, MIP-2 alpha a cytokine rather not related to atherosclerosis is not affected by the <it>PON1 </it>polymorphism. In contrast to that, the pro-inflammatory cytokine TNF-alpha is enhanced in R192 carriers (163.8 ± 24.7 pg/ml vs 94.7 ± 3.2 pg/ml in QQ192 carriers).</p> <p>Conclusions</p> <p>Our findings support the hypothesis that the common <it>PON1 </it>R192 allele may be a genetic risk factor for atherogenesis by inducing chronic low-grade inflammation.</p

Erratum to: Two-dimensional linear-combination model fitting of magnetic resonance spectra to define the macromolecule baseline using FiTAID, a fitting tool for arrays of interrelated datasets

Object: To propose the determination of the macromolecular baseline (MMBL) in clinical 1H MR spectra based on T1 and T2 differentiation using 2D fitting in FiTAID, a general Fitting Tool for Arrays of Interrelated Datasets. Materials and methods: Series of localized inversion-recovery (IR) and 2DJ separation spectra of the brain were recorded at 3T. The MMBL was determined by three 2D evaluation methods based on (1) IR spectra only, (2) 2DJ spectra only, (3) both IR and 2DJ spectra (2DJ-IR). Their performance was compared using synthetic spectra and based on variability and reproducibility as obtained in vivo from 12 subjects in 20 examinations. Results: All methods performed well for synthetic data. In vivo, 2DJ-only yielded larger variations than the other methods. IR-only and 2DJ-IR yielded similar performance. FiTAID is illustrated with further applications where linear-combination model fitting of interrelated arrays of spectra is advantageous. Conclusion: 2D-Fitting offers the possibility to determine the MMBL based on a range of complementary experimental spectra not relying on smoothness criteria or global assumptions on T1. Since 2DJ-IR includes information from spectra with different inversion and echo times, it is expected to be more robust in cases with more variable data quality and overlap with lipid resonance

Stress Resistance and Longevity Are Not Directly Linked to Levels of Enzymatic Antioxidants in the Ponerine Ant Harpegnathos saltator

BACKGROUND: The molecular mechanisms of variations in individual longevity are not well understood, even though longevity can be increased substantially by means of diverse experimental manipulations. One of the factors supposed to be involved in the increase of longevity is a higher stress resistance. To test this hypothesis in a natural system, eusocial insects such as bees or ants are ideally suited. In contrast to most other eusocial insects, ponerine ants show a peculiar life history that comprises the possibility to switch during adult life from a normal worker to a reproductive gamergate, therewith increasing their life expectancy significantly. RESULTS: We show that increased resistance against major stressors, such as reactive oxygen species and infection accompanies the switch from a life-history trait with normal lifespan to one with a longer life expectancy. A short period of social isolation was sufficient to enhance stress resistance of workers from the ponerine ant species Harpegnathos saltator significantly. All ant groups with increased stress resistances (reproducing gamergates and socially isolated workers) have lower catalase activities and glutathione levels than normal workers. Therewith, these ants resemble the characteristics of the youngest ants in the colony. CONCLUSIONS: Social insects with their specific life history including a switch from normal workers to reproducing gamergates during adult life are well suited for ageing research. The regulation of stress resistance in gamergates seemed to be modified compared to foraging workers in an economic way. Interestingly, a switch towards more stress resistant animals can also be induced by a brief period of social isolation, which may already be associated with a shift to a reproductive trajectory. In Harpegnathos saltator, stress resistances are differently and potentially more economically regulated in reproductive individuals, highlighting the significance of reproduction for an increase in longevity in social insects. As already shown for other organisms with a long lifespan, this trait is not directly coupled to higher levels of enzymatic and non-enzymatic antioxidants

Effects of beta-alanine supplementation and interval training on physiological determinants of severe exercise performance

Introduction: We aimed to manipulate physiological determinants of severe exercise performance. We hypothesized that (1) beta-alanine supplementation would increase intramuscular carnosine and buffering capacity and dampen acidosis during severe cycling, (2) that high-intensity interval training (HIT) would enhance aerobic energy contribution during severe cycling, and (3) that HIT preceded by beta-alanine supplementation would have greater benefits. Methods: Sixteen active men performed incremental cycling tests and 90-s severe (110% peak power) cycling tests at three time points: before and after oral supplementation with either beta-alanine or placebo, and after an 11-days HIT block (9 sessions, 4×4min), which followed supplementation. Carnosine was assessed via MR spectroscopy. Energy contribution during 90-s severe cycling was estimated from the O2 deficit. Biopsies from m. vastus lateralis were taken before and after the test. Results: Beta-alanine increased leg muscle carnosine (32±13%, d=3.1). Buffering capacity and incremental cycling were unaffected, but during 90-s severe cycling, beta-alanine increased aerobic energy contribution (1.4±1.3%, d=0.5), concurrent with reduced O2 deficit (−5.0±5.0%, d=0.6) and muscle lactate accumulation (−23±30%, d=0.9), while having no effect on pH. Beta-alanine also enhanced motivation and perceived state during the HIT block. There were no between-group differences in adaptations to the training block, namely increased buffering capacity (+7.9±11.9%, p=0.04, d=0.6, n=14) and glycogen storage (+30±47%, p=0.04, d=0.5, n=16). Conclusions: Beta-alanine did not affect buffering considerably, but has beneficial effects on severe exercise metabolism as well as psychological parameters during intense training phases

Fermented Goat’s Milk Consumption Improves Duodenal Expression of Iron Homeostasis Genes during Anemia Recovery

Despite the crucial roles of duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), ferritin light chain (Ftl1), ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), and hepcidin antimicrobial peptide (Hamp) in Fe metabolism, no studies have investigated the modulations of these genes during Fe repletion with fermented milks. Analysis included Fe status markers and gene and protein expression in enterocytes of control and anemic animals fed fermented milks. Fermented goat’s milk up-regulated enterocyte Dcytb, DMT1, FPN1, and Ftl1 and down-regulated TfR1 and Hamp gene expression in control and anemic animals. Anemia decreased Dcytb, DMT1, and Ftl1 in animals fed fermented cow’s milk and up-regulated TfR1 and Hamp expression. Fe overload down-regulated Dcytb and TfR1 in animals fed fermented cow’s milk and up-regulated DMT1 and FPN1 gene expression. Fermented goat’s milk increased expression of duodenal Dcytb, DMT1, and FPN1 and decreased Hamp and TfR1, improving Fe metabolism during anemia recovery

Pulse consumption improves indices of glycemic control in adults with and without type 2 diabetes: a systematic review and meta-analysis of acute and long-term randomized controlled trials.

Funder: University of LeedsPURPOSE: Findings from randomized controlled trials (RCTs) evaluating the effect of pulse intake on glycemic control are inconsistent and conclusive evidence is lacking. The aim of this study was to systematically review the impact of pulse consumption on post-prandial and long-term glycemic control in adults with and without type 2 diabetes (T2D). METHODS: Databases were searched for RCTs, reporting outcomes of post-prandial and long-term interventions with different pulse types on parameters of glycemic control in normoglycemic and T2D adults. Effect size (ES) was calculated using random effect model and meta-regression was conducted to assess the impact of various moderator variables such as pulse type, form, dose, and study duration on ES. RESULTS: From 3334 RCTs identified, 65 studies were eligible for inclusion involving 2102 individuals. In acute RCTs, pulse intake significantly reduced peak post-prandial glucose concentration in participants with T2D (ES  - 2.90; 95%CI  - 4.60,  - 1.21; p ≤ 0.001; I2 = 93%) and without T2D (ES  - 1.38; 95%CI  - 1.78,  - 0.99; p ≤ 0.001; I2 = 86%). Incorporating pulse consumption into long-term eating patterns significantly attenuated fasting glucose in normoglycemic adults (ES  - 0.06; 95%CI  - 0.12, 0.00; p ≤ 0.05; I2 = 30%). Whereas, in T2D participants, pulse intake significantly lowered fasting glucose (ES  - 0.54; 95%CI  - 0.83,  - 0.24; p ≤ 0.001; I2 = 78%), glycated hemoglobin A1c (HbA1c) (ES  - 0.17; 95%CI  - 0.33, 0.00; p ≤ 0.05; I2 = 78) and homeostatic model assessment of insulin resistance (HOMA-IR) (ES  - 0.47; 95%CI  - 1.25,  - 0.31; p ≤ 0.05; I2 = 79%). CONCLUSION: Pulse consumption significantly reduced acute post-prandial glucose concentration > 1 mmol/L in normoglycemic adults and > 2.5 mmol/L in those with T2D, and improved a range of long-term glycemic control parameters in adults with and without T2D. PROSPERO REGISTRY NUMBER: (CRD42019162322)

Differential Effects of Betacyanin and Betaxanthin Pigments on Oxidative Stress and Inflammatory Response in Murine Macrophages

Scope: Betalain pigments are increasingly highlighted for their bioactive and anti-inflammatory properties, although research is lacking to demonstrate contributions of individual betalains. The work herein aimed to compare effects of four main betalains on inflammatory and cell-protective markers and to highlight potential structure-related relationships of the two main subgroups: betacyanins vs betaxanthins. Methods and results: Murine RAW 264.7 macrophages were stimulated with bacterial lipopolysaccharide following incubation with betacyanins (betanin, neobetanin) and betaxanthins (indicaxanthin, vulgaxanthin I) in concentrations from 1 to 100 µM. All betalains suppressed expression of pro-inflammatory markers IL-6, IL-1β, iNOS, and COX-2 with tendency for stronger effects of betacyanins compared to betaxanthins. In contrast, HO-1 and gGCS showed mixed and only moderate induction, while more emphasized effects were observed for betacyanins. While all betalains suppressed mRNA levels of NADPH oxidase 2 (NOX-2), a superoxide generating enzyme, only betacyanins were able to counteract hydrogen peroxide induced reactive oxygen species (ROS) generation, in alignment with their radical scavenging potential. Furthermore, betaxanthins exerted pro-oxidant properties, elevating ROS production beyond hydrogen peroxide stimulation. Conclusion: In summary, all betalains display anti-inflammatory properties, although only betacyanins demonstrate radical scavenging capacities, indicating potential differing responses under oxidative stress conditions, which requires further research

Experimental models for testing hypotheses about cumulative cultural evolution

The rapid appearance (over evolutionary time) of the cognitive skills and complex inventions of modern humans has been attributed to “cumulative cultural evolution” (henceforth CCE), the accumulation of knowledge and skills over generations. To date, researchers have only been able to speculate about the reasons for the apparent absence of this phenomenon in nonhumans, and it has not been possible to test hypotheses regarding the mechanisms underlying it. Here we show that it is possible to demonstrate CCE under laboratory conditions, by simulating generational succession through the repeated removal and replacement of human participants within experimental groups. We created “microsocieties” in which participants were instructed to complete simple tasks using everyday materials. In one of our procedures, participants were instructed to build a paper aeroplane which flew as far as possible, and in the other, they were instructed to construct a tower of spaghetti which was as tall as possible. We show that, in both cases, information accumulates within the groups such that later generations produce designs which are more successful than earlier ones. These methods offer researchers a window to understanding CCE, allowing for experimental manipulation and hypothesis testing

Effect of Quercetin on Paraoxonase 2 Levels in RAW264.7 Macrophages and in Human Monocytes––Role of Quercetin Metabolism

There is increasing evidence that the intracellular antioxidant enzyme paraoxonase 2 (PON2) may have a protective function in the prevention of atherogenesis. An enhancement of PON2 activity by dietary factors including flavonoids is therefore of interest. In the present study we determined the effect of quercetin on paraoxonase 2 levels in cultured murine macrophages in vitro and in overweight subjects with a high cardiovascular risk phenotype supplemented with 150 mg quercetin/day for 42 days in vivo. Supplementation of murine RAW264.7 macrophages in culture with increasing concentrations of quercetin (1, 10, 20 μmol/L) resulted in a significant increase in PON2 mRNA and protein levels, as compared to untreated controls. Unlike quercetin, its glucuronidated metabolite quercetin-3-glucuronide did not affect PON2 gene expression in cultured macrophages. However the methylated quercetin derivative isorhamnetin enhanced PON2 gene expression in RAW264.7 cells to similar extent like quercetin. Although supplementing human volunteers with quercetin was accompanied by a significant increase in plasma quercetin concentration, dietary quercetin supplementation did not change PON2 mRNA levels in human monocytes in vivo. Current data indicate that quercetin supplementation increases PON2 levels in cultured monocytes in vitro but not in human volunteers in vivo