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Recent meta-analyses have found no association between heart disease and dietary saturated fat; however, higher proportions of plasma saturated fatty acids (SFA) predict greater risk for developing type-2 diabetes and heart disease. These observations suggest a disconnect between dietary saturated fat and plasma SFA, but few controlled feeding studies have specifically examined how varying saturated fat intake across a broad range affects circulating SFA levels. Sixteen adults with metabolic syndrome (age 44.9±9.9 yr, BMI 37.9±6.3 kg/m2) were fed six 3-wk diets that progressively increased carbohydrate (from 47 to 346 g/day) with concomitant decreases in total and saturated fat. Despite a distinct increase in saturated fat intake from baseline to the low-carbohydrate diet (46 to 84 g/day), and then a gradual decrease in saturated fat to 32 g/day at the highest carbohydrate phase, there were no significant changes in the proportion of total SFA in any plasma lipid fractions. Whereas plasma saturated fat remained relatively stable, the proportion of palmitoleic acid in plasma triglyceride and cholesteryl ester was significantly and uniformly reduced as carbohydrate intake decreased, and then gradually increased as dietary carbohydrate was re-introduced. The results show that dietary and plasma saturated fat are not related, and that increasing dietary carbohydrate across a range of intakes promotes incremental increases in plasma palmitoleic acid, a biomarker consistently associated with adverse health outcomes.

Obesity-related cardiometabolic disorders are driven by inflammation, oxidative stress, and gut dysbiosis. Green tea catechins protect against cardiometabolic disorders by anti-inflammatory, antioxidant, and prebiotic activities. However, whether obesity alters catechin bioavailability remains unknown. We hypothesized that obesity would decrease catechin bioavailability due to altered gut microbiota composition. Obese and healthy persons completed a pharmacokinetics trial in which a confection formulated with green tea extract (GTE; 58% epigallocatechin gallate, 17% epigallocatechin, 8% epicatechin, 6% epicatechin gallate) was ingested before collecting plasma and urine at timed intervals for up to 24 h. Stool samples were collected prior to confection ingestion. Catechins and γ-valerolactones were assessed by LC-MS. Obesity reduced plasma area under the curve (AUC0-12h) by 24–27% and maximum plasma concentrations by 18–36% for all catechins. Plasma AUC0-12h for 5′-(3′,4′-dihydroxyphenyl)-γ-valerolactone and 5′-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone, as well as total urinary elimination of all catechins and valerolactones, were unaffected. ⍺-Diversity in obese persons was lower, while Slackia was the only catechin-metabolizing bacteria that was altered by obesity. Ascorbic acid and diversity metrics were correlated with catechin/valerolactone bioavailability. These findings indicate that obesity reduces catechin bioavailability without affecting valerolactone generation, urinary catechin elimination, or substantially altered gut microbiota populations, suggesting a gut-level mechanism that limits catechin absorption.

Ascorbate (vitamin C) is an essential micronutrient in humans. The severe chronic deficiency of ascorbate, termed scurvy, has long been associated with increased susceptibility to infections. How ascorbate affects the immune system at the cellular and molecular levels remained unclear. From a micronutrient analysis, we identified ascorbate as a potent enhancer for antibody response by facilitating the IL-21/STAT3-dependent plasma cell differentiation in mouse and human B cells. The effect of ascorbate is unique as other antioxidants failed to promote plasma cell differentiation. Ascorbate is especially critical during early B cell activation by poising the cells to plasma cell lineage without affecting the proximal IL-21/STAT3 signaling and the overall transcriptome. As a cofactor for epigenetic enzymes, ascorbate facilitates TET2/3-mediated DNA modification and demethylation of multiple elements at the Prdm1 locus. DNA demethylation augments STAT3 association at the Prdm1 promoter and a downstream enhancer, thus ensuring efficient gene expression and plasma cell differentiation. The results suggest that an adequate level of ascorbate is required for antibody response and highlight how micronutrients may regulate the activity of epigenetic enzymes to regulate gene expression. Our findings imply that epigenetic enzymes can function as sensors to gauge the availability of metabolites and influence cell fate decisions.

Introduction Acute aerobic exercise prevents sitting-induced impairment of flow-mediated dilation (FMD). Further, evidence suggests that sitting-induced impairment of FMD occurs via an oxidative stress-dependent mechanism that disrupts endothelial function. Purpose We hypothesized that acute aerobic exercise would prevent impairment of femoral artery FMD by limiting oxidative stress responses that increase endothelin-1 (ET-1) levels and disrupt nitric oxide (NO) status. Methods In a randomized, cross-over study, healthy men ( n  = 11; 21.2 ± 1.9 years) completed two 3 h sitting trials that were preceded by 45 min of either quiet rest (REST) or a single bout of continuous treadmill exercise (65% maximal oxygen consumption) (EX). Superficial femoral artery FMD, plasma glucose, malondialdehyde (MDA), ET-1, arginine (ARG) and its related metabolites [homoarginine (HA), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA)] were assessed at baseline, 1 h following EX (or REST) (0 h), and at 1 h intervals during 3 h of uninterrupted sitting. Data were analyzed using repeated measures ANOVA. Results During REST, femoral artery FMD declined from baseline (2.6 ± 1.8%) at 1, 2, and 3 h of sitting and resting shear rate decreased at 3 h. In contrast, when sitting was preceded by EX, femoral artery FMD (2.7 ± 2.0%) and resting shear rate responses were unaffected. No between trial differences were detected for plasma glucose, MDA, ET-1, ARG, HA, ADMA, or SDMA. Conclusion Prior aerobic exercise prevented the decline in femoral artery FMD that is otherwise induced by prolonged sitting independent of changes in oxidative stress, ET-1, and NO status.

Quercetin bioavailability exhibits high interindividual variation for reasons that remain unclear. We conducted a 24-h pharmacokinetic study to investigate whether individual differences in circulating antioxidants, oxidative stress and inflammation, and intestinal permeability affect quercetin bioavailability. Healthy adults (n = 9 M/7 F; 34.3 ± 4.5 y; 27.0 ± 1.7 kg/m2) ingested 1095 mg quercetin aglycone with a standardized meal. Plasma antioxidants, biomarkers of oxidative stress and inflammation, and endotoxin were measured at baseline (0 h), and quercetin and its methylated metabolites isorhamnetin and tamarixetin were measured at timed intervals for 24 h. Plasma pharmacokinetics of quercetin, isorhamnetin and tamarixetin were highly variable between participants (CVinter = 37–96%). Plasma vitamin C concentrations (34.6 ± 2.5 μmol/L), but no other antioxidants, were inversely correlated to the Cmax and AUC0 to 24 h of total quercetin (Qtotal; sum of quercetin, isorhamnetin and tamarixetin; r = −0.52 to −0.53; P < 0.05). Plasma endotoxin (0.13 ± 0.01 EU/mL), a surrogate marker of intestinal permeability, was correlated to Qtotal Cmax (r = 0.45; P < 0.05) and tended to be correlated to Qtotal AUC0 to 24 h (r = 0.38; P = 0.07). Additionally, vitamin C was inversely related to C-reactive protein, myeloperoxidase, and endotoxin (r = −0.46 to −0.55; P < 0.05), whereas endotoxin was positively correlated to C-reactive protein (r = 0.73; P < 0.05). These findings suggest that vitamin C status and plasma endotoxin may be associated with interindividual variations in quercetin bioavailability. Greater quercetin absorption and bioavailability may be associated with poor vitamin C status and increased intestinal permeability in healthy adults.

Whey protein intake reduces CVD risk, but little is known whether whey-derived bioactive peptides regulate vascular endothelial function (VEF). We determined the impact of a whey-derived extract (NOP-47) on VEF in individuals with an increased cardiovascular risk profile. Men and women with impaired brachial artery flow-mediated dilation (FMD) (n 21, age 55 (sem 1·3) years, BMI 27·8 (sem 0·6) kg/m2, FMD 3·7 (sem 0·4) %) completed a randomised, cross-over study to examine whether ingestion of NOP-47 (5 g) improves postprandial VEF. Brachial artery FMD, plasma amino acids, insulin, and endothelium-derived vasodilators and vasoconstrictors were measured for 2 h after ingestion of NOP-47 or placebo. Acute NOP-47 ingestion increased FMD at 30 min (4·6 (sem 0·5) %) and 120 min (5·1 (sem 0·5) %) post-ingestion (P< 0·05, time × trial interaction), and FMD responses at 120 min were significantly greater in the NOP-47 trial compared with placebo (4·3 (sem 0·5) %). Plasma amino acids increased at 30 min following NOP-47 ingestion (P< 0·05). Serum insulin increased at 15, 30 and 60 min (P< 0·001) following NOP-47 ingestion. No changes were observed between the trials for plasma NO∙ and prostacyclin metabolites or endothelin-1. Ingestion of a rapidly absorbed extract derived from whey protein improved endothelium-dependent dilation in older adults by a mechanism independent of changes in circulating vasoactive compounds. Future investigation is warranted in individuals at an increased CVD risk to further elucidate potential health benefits and the underlying mechanisms of extracts derived from whey.

Brain alpha-tocopherol (αT) concentration was previously reported to be inversely associated with neurofibrillary tangle (NFT) counts in specific brain structures from centenarians. However, the contribution of natural or synthetic αT stereoisomers to this relationship is unknown. In this study, αT stereoisomers were quantified in the temporal cortex (TC) of 47 centenarians in the Georgia Centenarian Study (age: 102.2 ± 2.5 years, BMI: 22.1 ± 3.9 kg/m2) and then correlated with amyloid plaques (diffuse and neuritic plaques; DPs, NPs) and NFTs in seven brain regions. The natural stereoisomer, RRR-αT, was the primary stereoisomer in all subjects, accounting for >50% of total αT in all but five subjects. %RRR was inversely correlated with DPs in the frontal cortex (FC) (ρ = −0.35, p = 0.032) and TC (ρ = −0.34, p = 0.038). %RSS (a synthetic αT stereoisomer) was positively correlated with DPs in the TC (ρ = 0.39, p = 0.017) and with NFTs in the FC (ρ = 0.37, p = 0.024), TC (ρ = 0.42, p = 0.009), and amygdala (ρ = 0.43, p = 0.008) after controlling for covariates. Neither RRR- nor RSS-αT were associated with premortem global cognition. Even with the narrow and normal range of BMIs, BMI was correlated with %RRR-αT (ρ = 0.34, p = 0.021) and %RSS-αT (ρ = −0.45, p = 0.002). These results providing the first characterization of TC αT stereoisomer profiles in centenarians suggest that DP and NFT counts, but not premortem global cognition, are influenced by the brain accumulation of specific αT stereoisomers. Further study is needed to confirm these findings and to determine the potential role of BMI in mediating this relationship.

F 2 -Isoprostanes (F 2 -IsoPs), regio- and stereoisomers of prostaglandin F 2α (PGF 2α ), and urinary F 2 -IsoP metabolites including 2,3-dinor-5,6-dihydro-8- iso -PGF 2α [2,3-dinor-8- iso -PGF 1α (2,3-dinor-F1)] and 2,3 dinor-8- iso -PGF 2α (2,3-dinor-F2), have all been used as biomarkers of oxidative stress. A novel method was developed to measure these biomarkers using a single solid phase extraction (SPE) cartridge, separation by HPLC, and detection by negative mode selected reaction monitoring (SRM) mass spectrometry (MS), using authentic standards of PGF 2α ; 8- iso -PGF 2α ; 2,3-dinor-F1 and 2,3-dinor-F2 to identify specific chromatographic peaks. The method was validated in a population of healthy, college-aged nonsmokers ( n  = 6 M/8F) and smokers ( n  = 6 M/5F). Urinary F 2 -IsoP concentrations were ~0.2–1.5 μg/g creatinine, 2,3-dinor-F1 was ~1–3 μg/g and 2,3-dinor-F2 was ~3–5 μg/g. Additional F 2 -IsoPs metabolites were identified using SRM. The sum of all urinary F 2 -IsoP metabolites was 50–100 μg/g creatinine indicating their greater abundance than F 2 -IsoPs. Women had higher F 2 -IsoP metabolite concentrations than did men (MANOVA, main effect P  = 0.003); cigarette smokers had higher concentrations than did nonsmokers (main effect P  = 0.036). For men or women, respectively, smokers had higher metabolite concentrations than did nonsmokers ( P  < 0.05). Thus, our method simultaneously allows measurement of urinary F 2 -IsoPs and their metabolites for the determination of oxidative stress.

Background Whey protein is a potential source of bioactive peptides. Based on findings from in vitro experiments indicating a novel whey derived peptide (NOP-47) increased endothelial nitric oxide synthesis, we tested its effects on vascular function in humans. Methods A randomized, placebo-controlled, crossover study design was used. Healthy men (n = 10) and women (n = 10) (25 ± 5 y, BMI = 24.3 ± 2.3 kg/m 2 ) participated in two vascular testing days each preceded by 2 wk of supplementation with a single dose of 5 g/day of a novel whey-derived peptide (NOP-47) or placebo. There was a 2 wk washout period between trials. After 2 wk of supplementation, vascular function in the forearm and circulating oxidative stress and inflammatory related biomarkers were measured serially for 2 h after ingestion of 5 g of NOP-47 or placebo. Macrovascular and microvascular function were assessed using brachial artery flow mediated dilation (FMD) and venous occlusion strain gauge plethysmography. Results Baseline peak FMD was not different for Placebo (7.7%) and NOP-47 (7.8%). Placebo had no effect on FMD at 30, 60, and 90 min post-ingestion (7.5%, 7.2%, and 7.6%, respectively) whereas NOP-47 significantly improved FMD responses at these respective postprandial time points compared to baseline (8.9%, 9.9%, and 9.0%; P < 0.0001 for time × trial interaction). Baseline reactive hyperemia forearm blood flow was not different for placebo (27.2 ± 7.2%/min) and NOP-47 (27.3 ± 7.6%/min). Hyperemia blood flow measured 120 min post-ingestion (27.2 ± 7.8%/min) was unaffected by placebo whereas NOP-47 significantly increased hyperemia compared to baseline (29.9 ± 7.8%/min; P = 0.008 for time × trial interaction). Plasma myeloperoxidase was increased transiently by both NOP-47 and placebo, but there were no changes in markers inflammation. Plasma total nitrites/nitrates significantly decreased over the 2 hr post-ingestion period and were lower at 120 min after placebo (-25%) compared to NOP-47 (-18%). Conclusion These findings indicate that supplementation with a novel whey-derived peptide in healthy individuals improves vascular function.

BACKGROUND: Preliminary evidence indicates that subclinical cardiometabolic abnormalities are present in apparently healthy nonobese young adults. Poor dietary habits may be a contributing factor. OBJECTIVE: The objective of this study was to examine the presence of cardiometabolic abnormalities in apparently healthy college students and to assess the relationship between diet quality and cardiometabolic risk factors. METHODS: Cross-sectional anthropometric, lipidemia, and glucose tolerance, blood pressure, and dietary Healthy Eating Index (HEI) data were collected (April 2015). Participants were undergraduate students. Ordinary least squares regression was used to examine associations between diet quality and cardiometabolic risk factors. RESULTS: Participants (n = 147) were primarily nonHispanic Caucasian between 18 and 22 years and largely nonobese (95.0% of females, 85.1% of males). Total HEI score was 56.1 ± 16.1 for females and 53.2 ± 15.0 for males. Mean biochemical and clinical outcomes fell within normal limits. However, 71.0% of females and 80.9% of males met ≥1 or more metabolic syndrome criteria. HEI was not related to health outcomes. CONCLUSIONS: Cardiometabolic abnormalities are present in a large proportion of apparently healthy undergraduates which may place them at risk for future cardiometabolic complications. There was no relationship between diet quality and cardiometabolic health.