A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.

Exogenous melatonin can be helpful for treatment of some sleep disorders. However, immediate-release formulations are rapidly absorbed and cleared from the body making it difficult to provide coverage for an entire sleep period. Extended-release melatonin formulations can better mimic the naturally occurring melatonin profile and increase efficacy, but few studies have reported on their pharmacokinetics. To assess the pharmacokinetics of extended-release melatonin, we conducted a randomized, double-blind, crossover study of extended-release melatonin (4 mg) compared to immediate-release melatonin (4 mg) in 18 healthy adults, ages 18-65 years. Participants received immediate-release or extended-release melatonin in clinic after an 8 h fast, and blood samples were taken over a 10-h period. After a 7-day washout period, the same procedures were repeated with the melatonin form not previously received. Extended-release melatonin had a longer time to peak concentration (1.56 vs 0.6 h) and elimination half-life (1.63 vs 0.95 h) compared with immediate-release melatonin. Maximum concentration was lower for extended-release melatonin compared with immediate-release melatonin (7581 pg/mL vs 13120 pg/mL). Extended-release melatonin raised melatonin levels in as little as 15 min and sustained elevated melatonin levels (>300 pg/mL) for 6 h before falling below 50 pg/mL by 9 h. No clinically relevant adverse events were observed, and safety parameters remained within normal ranges for both formulations. The pharmacokinetic profile of this extended-release melatonin formulation suggests that it could be used for future efficacy studies of melatonin and sleep outcomes. This trial is registered at ClinicalTrials.gov, NCT04067791.

Association of omega-3 levels and sleep in US adults, National Health and Nutrition Examination Survey, 2011-2012.

OBJECTIVE: To determine associations between serum long-chain (LC) omega-3 fatty acid levels and sleep parameters among adults (N = 1314) in NHANES 2011-2012. METHODS: Regression analyses accounting for the complex-survey design were used to assess associations between serum LC omega-3 fatty acid levels, sleep duration, difficulty falling sleeping and sleep disorder. RESULTS: Overall, 48.6% were male, the mean age was 47.2 years, 5% reported very short sleep, 29% short sleep, 63% normal sleep and 3% long sleep. The sum of LC omega-3 fatty acid levels was lower among adults with short versus normal sleep, although differences were attenuated with adjustment for sociodemographic factors. Relative to normal sleep, adults with very short sleep had lower levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and sum of LC omega-3 fatty acids. Differences remained significant (p < .05 for all) with adjustment for sociodemographic factors. No associations were observed with difficulty falling sleeping or sleep disorder. CONCLUSION: Our results suggest that omega-3 fatty acid levels are associated with healthy sleep duration, although, interventions are needed to clarify causality.

Brain α-Tocopherol Concentration and Stereoisomer Profile Alter Hippocampal Gene Expression in Weanling Mice.

BACKGROUND: Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood. OBJECTIVES: The objective was to determine the impact of bio-potency-adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice. METHODS: Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams. RESULTS: A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz). CONCLUSIONS: In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.

Micronutrient Inadequacy in Short Sleep: Analysis of the NHANES 2005-2016.

One third of U.S. adults report short sleep (<7 h), which has been linked to negative health outcomes. Inadequate intake of micronutrients across the U.S. adult population has been reported, and a relationship between sleep conditions and micronutrient intake is emerging. This cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES 2005-2016) (n = 26,211) showed that participants with short sleep duration had a lower usual intake (Food + Supplements) of calcium, magnesium, and vitamin D in all adults aged 19+ years, and vitamin K in adults aged 19-50 years, even after adjusting for covariates. In addition, participants reporting short sleep had a higher percentage of individuals with intake lower than the estimated average requirement (EAR) across multiple nutrients. Age and gender differences were observed in the prevalence of inadequate intake across multiple nutrients. Adults aged 51-99 years with short sleep duration had inadequate intake with respect to more nutrients. In females there was an association between short sleep and a higher prevalence of inadequate intake (Food + Spp) for calcium, magnesium, and vitamins A, C, D, E, and K (above adequate intake). Conversely, males reporting short sleep only had an inadequate intake of vitamin D. Overall, we demonstrate that short sleep is associated with increased nutrient inadequacy, emphasizing the possible need for dietary supplementation.

Choline and DHA in Maternal and Infant Nutrition: Synergistic Implications in Brain and Eye Health.

The aim of this review is to highlight current insights into the roles of choline and docosahexaenoic acid (DHA) in maternal and infant nutrition, with special emphasis on dietary recommendations, gaps in dietary intake, and synergistic implications of both nutrients in infant brain and eye development. Adequate choline and DHA intakes are not being met by the vast majority of US adults, and even more so by women of child-bearing age. Choline and DHA play a significant role in infant brain and eye development, with inadequate intakes leading to visual and neurocognitive deficits. Emerging findings illustrate synergistic interactions between choline and DHA, indicating that insufficient intakes of one or both could have lifelong deleterious impacts on both maternal and infant health.

Fructose decreases physical activity and increases body fat without affecting hippocampal neurogenesis and learning relative to an isocaloric glucose diet.

Recent evidence suggests that fructose consumption is associated with weight gain, fat deposition and impaired cognitive function. However it is unclear whether the detrimental effects are caused by fructose itself or by the concurrent increase in overall energy intake. In the present study we examine the impact of a fructose diet relative to an isocaloric glucose diet in the absence of overfeeding, using a mouse model that mimics fructose intake in the top percentile of the USA population (18% energy). Following 77 days of supplementation, changes in body weight (BW), body fat, physical activity, cognitive performance and adult hippocampal neurogenesis were assessed. Despite the fact that no differences in calorie intake were observed between groups, the fructose animals displayed significantly increased BW, liver mass and fat mass in comparison to the glucose group. This was further accompanied by a significant reduction in physical activity in the fructose animals. Conversely, no differences were detected in hippocampal neurogenesis and cognitive/motor performance as measured by object recognition, fear conditioning and rotorod tasks. The present study suggests that fructose per se, in the absence of excess energy intake, increases fat deposition and BW potentially by reducing physical activity, without impacting hippocampal neurogenesis or cognitive function.

Tracking deposition of a 14C-radiolabeled kudzu hairy root-derived isoflavone-rich fraction into bone.

Hairy roots were induced in four genotypes from three kudzu species (Pueraria montana var. lobata, P. lobata and P. phaseoloides) in vitro using Agrobacterium rhizogenes to stimulate rapid secondary metabolite synthesis. Hairy roots from P. montana var. lobata (United States Department of Agriculture no. PI 434246) yielded the highest puerarin and total isoflavone content and the greatest new biomass per growth cycle among the genotypes evaluated. Hairy roots from this genotype were selected for radiolabeling using (14)C-sucrose as a carbon source. Isoflavones from radiolabeled kudzu hairy root cultures were extracted with 80% methanol, partitioned by solvent extraction, and then subfractionated by Sephadex LH-20 gel filtration. Radiolabeled isoflavones were isolated in a highly enriched fraction, which contained predominantly puerarin, daidzin and malonyl-daidzin and had an average radioactivity of 8.614 MBq/g (232.8 µCi/g) dry fraction. The (14)C-radiolabeled, isoflavone-rich fraction was orally administered at a dose of 60 mg/kg body weight to male Sprague-Dawley rats implanted with a jugular catheter, a subcutaneous ultrafiltrate probe and a brain microdialysate probe. Serum, interstitial fluid, brain microdialysate, urine and feces were collected using a Culex(®) Automated Blood Collection System for 24 h. At the end of this period, rats were sacrificed and major tissues were collected. Analysis by a scintillation counter confirmed that a bolus dose of (14)C-radiolabeled, isoflavone-rich kudzu fraction reached bone tissues, which accumulated 0.011%, 0.09% and 0.003% of the administered dose in femur, tibia and vertebrae, respectively. Femurs extracted with 80% methanol were analyzed by high-performance liquid chromatography with electrospray ionization-mass spectrometry and were found to contain trace quantities of puerarin, daidzein and puerarin glucuronide. This study demonstrates that kudzu isoflavones and metabolites are capable of reaching bone tissues, where they may contribute to the prevention of osteoporosis and the promotion of bone health.

In vivo metabolic tracking of 14C-radiolabelled isoflavones in kudzu (Pueraria lobata) and red clover (Trifolium pratense) extracts.

Absorption, distribution and elimination of 14C-labelled isoflavone-containing extracts from kudzu (Pueraria lobata) root culture and red clover (Trifolium pratense) cell culture were investigated in an in vivo rat model. The predominant isoflavones in the kudzu extract were the glycosides puerarin, daidzin and malonyl daidzin, while in the red clover extract, the major isoflavones were formononetin and its derivatives, genistein and biochanin A, with radioactivities of 3.770 and 7.256 MBq/g, respectively. Male Sprague-Dawley rats, implanted with a jugular catheter and a subcutaneous ultrafiltrate probe, were orally administered with 14C-labelled isoflavone extracts from either kudzu or clover cell cultures. Serum, interstitial fluid (ISF), urine and faeces were collected using a Culex Automated Blood Collection System for 24 h. Analysis of bone tissues revealed that radiolabel accumulated in the femur, tibia and vertebrae at 0.04, 0.03 and 0.01 % of the administered dose, respectively, in both kudzu and red clover treatments. The liver accumulated the greatest concentration of radiolabel among the tissues tested, at 1.99 and 1.54 % of the administered kudzu and red clover extracts, respectively. Serum and ISF analysis showed that both extracts were rapidly absorbed, distributed in various tissues, and largely eliminated in the urine and faeces. Urine and faeces contained 8.53 and 9.06 % of the kudzu dose, respectively, and 3.60 and 5.64 % of the red clover dose, respectively. Serum pharmacokinetics suggest that extracts from kudzu may undergo enterohepatic circulation.