Prenatal Nutritional Intervention Reduces Autistic-Like Behavior Rates Among Mthfr-Deficient Mice

The causes and contributing factors of autism spectrum disorders (ASD) are poorly understood. One gene associated with increased risk for ASD is methylenetetrahydrofolate-reductase (MTHFR), which encodes a key enzyme in one carbon (C1) metabolism. The MTHFR 677C > T polymorphism reduces the efficiency of methyl group production with possible adverse downstream effects on gene expression. In this study, the effects of prenatal and/or postnatal diets enriched in C1 nutrients on ASD-like behavior were evaluated in Mthfr-deficient mice. Differences in intermediate pathways between the mice with and without ASD-like behaviors were tested. The findings indicate that maternal and offspring Mthfr deficiency increased the risk for an ASD-like phenotype in the offspring. The risk of ASD-like behavior was reduced in Mthfr-deficient mice supplemented with C1 nutrients prenatally. Specifically, among offspring of Mthfr+/- dams, prenatal diet supplementation was protective against ASD-like symptomatic behavior compared to the control diet with an odds ratio of 0.18 (CI:0.035, 0.970). Changes in major C1 metabolites, such as the ratios between betaine/choline and SAM/SAH in the cerebral-cortex, were associated with ASD-like behavior. Symptomatic mice presenting ASD-like behavior showed decreased levels of GABA pathway proteins such as GAD65/67 and VGAT and altered ratios of the glutamate receptor subunits GluR1/GluR2 in males and NR2A/NR2B in females. The altered ratios, in turn, favor receptor subunits with higher sensitivity to neuronal activity. Our study suggests that MTHFR deficiency can increase the risk of ASD-like behavior in mice and that prenatal dietary intervention focused on MTHFR genotypes can reduce the risk of ASD-like behavior

Usual intake of one-carbon metabolism nutrients in a young adult population aged 19–30 years: a cross-sectional study

One-carbon nutrients play an important role in epigenetic mechanisms and cellular methylation reactions. Inadequate intake of these nutrients is linked to metabolic perturbations, yet the current intake levels of these nutrients have rarely been studied in Asia. This cross-sectional study surveyed the usual dietary intake of one-carbon nutrients (folate, choline and vitamins B2, B6 and B12) among Thai university students aged 19–30 years (n 246). Socioeconomic background, health information, anthropometric data and 24-h dietary recall data were collected. The long-term usual intake was estimated using the multiple-source method. The average usual intake levels for men and women were (mean ± sd) 1⋅85 ± 0⋅95 and 2⋅42 ± 8⋅7 mg/d of vitamin B2, 1⋅96 ± 1⋅0 and 2⋅49 ± 8⋅7 mg/d of vitamin B6, 6⋅20 ± 9⋅5 and 6⋅28 ± 12 μg/d of vitamin B12, 195 ± 154 and 155 ± 101 μg dietary folate equivalent/d of folate, 418 ± 191 and 337 ± 164 mg/d of choline, respectively. Effect modification by sex was observed for vitamin B2 (P-interaction = 0⋅002) and choline (P-interaction = 0⋅02), where every 1 mg increase in vitamin B2 and 100 mg increase in choline intake were associated with a 2⋅07 (P = 0⋅01) and 0⋅81 kg/m2 (P = 0⋅04) lower BMI, respectively, in men. The study results suggest that Thai young adults meet the recommended levels for vitamins B2, B6 and B12. The majority of participants had inadequate folate intake and did not achieve recommended intake levels for choline. The study was approved by the Ethics Committee at the Faculty of Medicine, Chiang Mai University. This trial was registered at www.thaiclinicaltrials.gov (TCTR20210420007)

RELATIONSHIP OF CHOLINE AND TRIMETHYLAMINE-N-OXIDE INTAKE WITH METABOLIC AND HEALTH OUTCOMES IN HUMANS

This dissertation is focused on dietary choline and its derivative trimethylamine-N-oxide (TMAO). Recent discoveries have implicated circulating TMAO as a candidate risk factor for cardiovascular disease (CVD) among patients, but whether TMAO and dietary choline play a causative role in the disease process remains controversial. This dissertation describes 1) the production of TMAO from its dietary precursors (TMAO, choline and L-carnitine) in healthy individuals, 2) its metabolic fate within the body, and 3) the relationship between dietary choline and high blood pressure, a major risk factor for CVD. In Chapter 1, a randomized crossover feeding study was conducted where 40 healthy men consumed a test meal consisting of either fish (TMAO), eggs (choline), beef (choline and L-carnitine) or a fruit control. Postprandial blood collected for 6 hours after consumption of the test meal revealed that fish consumption yielded the highest increase in plasma TMAO metabolites among the test meals. Furthermore, production of TMAO following consumption of eggs or beef varied among individuals and correlated with the gut microbiome. The overall findings show that TMAO can be temporarily elevated in healthy individuals following consumption of various foods, especially heart-healthy fish. High variation in plasma TMAO in response to the same meals indicates metabolic differences among individuals that may be due to other factors such as composition of the gut microbiome. In Chapter 2, the metabolic fate of dietary TMAO was investigated. Participants enrolled in the feeding study consumed 50 mg deuterium-labeled methyl d9-TMAO (d9-TMAO) in the fruit control arm. We found that d9-TMAO entered circulation within 15 min and that 96% of the tracer was excreted in urine within 24 hours. These results demonstrate rapid absorption of intact TMAO along with its efficient elimination from the human body. In Chapter 3 the hypothesis that increased choline intake may increase CVD risk through elevated blood pressure was investigated. Using cross-sectional 2007-10 National Health and Nutrition Examination Survey, we examined the relationship of choline intake with blood pressure and prevalence odds of hypertension in a general U.S. population. We found a borderline inverse association between choline intake and odds of hypertension in women but not in men. Furthermore, supplemental choline use by both sexes showed a significant inverse association with hypertension. We concluded that choline intake is not associated with blood pressure, a risk factor of CVD, in this population. Taken together, evidence in this dissertation does not support the hypothesis that dietary choline increases disease risks by elevating baseline circulating TMAO in healthy adults. More epidemiologic and experimental evidence are still needed to further confirm or dispute this hypothesis

Choline and one-carbon metabolite response to egg, beef and fish among healthy young men: A short-term randomized clinical study

Background: Homeostatic mechanisms that regulate long-term circulating concentrations of choline and one-carbon metabolites can obscure the relationship between diet and nutritional response. As such, we sought to determine the acute response of one-carbon metabolites to animal source foods enriched in one-carbon nutrients. Methods: As part of a crossover feeding trial with one-week washout intervals, healthy young men (n = 40) were randomized to animal food sources of choline (eggs, beef and fish) and a fruit control. A panel of one-carbon metabolites was measured in blood and urine samples collected at baseline and throughout the 6-h study period. Results: Consumption of the test foods yielded 1.1–2.7 times higher (P < 0.0001) maximum peak circulating concentrations of choline, betaine, dimethylglycine (DMG) and methionine relative to the fruit control. Similarly, urinary excretion was 1.5–2.6 times higher (P < 0.0001) for these same metabolites across the 6-h study period. Of the test foods, eggs had the greatest effects on plasma choline and betaine, while fish had the greatest effects on plasma methionine. Nutritional response across the study period was modified by time with a delay in peak plasma concentrations of choline and betaine after egg consumption. In addition, the FMO3 G472A genotype (rs 2266782) modified plasma DMG, urinary trimethylamine-N-oxide and urinary methionine responses to the test foods (P < 0.05). Conclusion: Consumption of animal source foods of choline improves circulating concentrations of choline and other one-carbon metabolites in a manner that is influenced by time and the FMO3 G472A genotype. This trial was registered at clinicaltrials.gov as NCT02558673

Inhibitory Effects of Saponin-Rich Extracts from <i>Pouteria cambodiana</i> against Digestive Enzymes α-Glucosidase and Pancreatic Lipase

Pouteria cambodiana is a perennial plant that has a wide distribution in tropical regions. It is commonly referred to as ’Nom-nang’ in the northern region of Thailand. The bark of this plant has been used for the purpose of promoting lactation among breastfeeding mothers. Moreover, P. cambodiana bark has a high nutraceutical potential due to the presence of saponins, which are secondary metabolites. The purpose of this study was to determine the optimal conditions for ultrasound-assisted extraction (UAE) of saponins from the bark of P. cambodiana and to assess the in vitro inhibitory activities of saponin-rich extracts. The most effective extraction conditions involved a temperature of 50 °C and a 50% concentration level of ethanol as the solvent, which allowed the extraction of saponin at a concentration of 36.04 mg/g. Saponin-rich extracts and their hydrolysates from P. cambodiana bark were evaluated for their ability to inhibit α-glucosidase and pancreatic lipase. The IC50 values for saponin- and sapogenin-rich extracts inhibiting α-glucosidase were 0.10 and 2.98 mg/mL, respectively. Non-hydrolysed extracts also had a stronger inhibitory effect than acarbose. In the case of pancreatic lipase, only the hydrolysed extracts exhibited inhibitory effects on pancreatic lipase (IC 50 of 7.60 mg/mL). Thus, P. cambodiana bark may be an applicable natural resource for preparing ingredients for functional products with inhibitory activity against α-glucosidase and pancreatic lipase. The phenolic contents, saponin contents, and antioxidant activities of the dried extract stored at a low temperature of 25 °C for 2 months showed the best stability, with more than 90% retention.</p

Choline metabolome response to prenatal choline supplementation across pregnancy: A randomized controlled trial.

Pregnancy places a unique stress upon choline metabolism, requiring adaptations to support both maternal and fetal requirements. The impact of pregnancy and prenatal choline supplementation on choline and its metabolome in free-living, healthy adults is relatively uncharacterized. This study investigated the effect of prenatal choline supplementation on maternal and fetal biomarkers of choline metabolism among free-living pregnant persons consuming self-selected diets. Participants were randomized to supplemental choline (as choline chloride) intakes of 550&nbsp;mg/d (500&nbsp;mg/d d0-choline + 50&nbsp;mg/d methyl-d9-choline; intervention) or 25&nbsp;mg/d d9-choline (control) from gestational week (GW) 12-16 until Delivery. Fasting blood and 24-h urine samples were obtained at study Visit 1 (GW 12-16), Visit 2 (GW 20-24), and Visit 3 (GW 28-32). At Delivery, maternal and cord blood and placental tissue samples were collected. Participants randomized to 550 (vs. 25) mg supplemental choline/d achieved higher (p&nbsp;&lt;&nbsp;.05) plasma concentrations of free choline, betaine, dimethylglycine, phosphatidylcholine (PC), and sphingomyelin at one or more study timepoint. Betaine was most responsive to prenatal choline supplementation with increases (p&nbsp;≤&nbsp;.001) in maternal plasma observed at Visit 2-Delivery (relative to Visit 1 and control), as well as in the placenta and cord plasma. Notably, greater plasma enrichments of d3-PC and LDL-C were observed in the intervention (vs. control) group, indicating enhanced PC synthesis through the de novo phosphatidylethanolamine N-methyltransferase pathway and lipid export. Overall, these data show that prenatal choline supplementation profoundly alters the choline metabolome, supporting pregnancy-related metabolic adaptations and revealing biomarkers for use in nutritional assessment and monitoring during pregnancy

Optimization of Ultrasonic-Assisted Bioactive Compound Extraction from Green Soybean (<i>Glycine max</i> L.) and the Effect of Drying Methods and Storage Conditions on Procyanidin Extract

Green soybean (Glycine max L.) seeds (GSS) are rich in various antioxidants and phytonutrients that are linked to various health benefits. Ultrasound-assisted extraction (UAE) technology was used for extracting the effective components from GSS. A response surface method (RSM) was used to examine the influence of liquid-to-solid ratio and extraction temperature on the bioactive compounds and antioxidant characteristics. The optimal conditions were a liquid-to-solid ratio of 25:1 and a UAE temperature of 40 °C. The observed values coincided well with the predicted values under optimal conditions. Additionally, the effects of drying methods on the procyanidins and antioxidant activities of GSS extract were evaluated. The spray-dried GSS extract contained the highest levels of procyanidins (21.4 ± 0.37 mg PC/g), DPPH (199 ± 0.85 µM Trolox eq/g), and FRAP (243 ± 0.26 µM Trolox eq/g). Spray drying could be the most time- and energy-efficient technique for drying the GSS extract. The present study also assessed the effects of storage temperature and time on procyanidins and antioxidant activities in GSS extract powder. Procyanidins were found to degrade more rapidly at 45 °C than at 25 °C and 35 °C. Storage under 25 °C was appropriate for maintaining the procyanidin contents, DPPH, and FRAP activities in the GSS extract powder. This study contributed to the body of knowledge by explaining the preparation of procyanidin extract powder from GSS, which might be employed as a low-cost supply of nutraceutical compounds for the functional food industry and pharmaceutical sector

Technology-based strategic marketing planning for Pi-Pe

In this paper, we present a strategic marketing plan combined with Technology-Based Marketing approach (TBM) and Competitive Strategy approach for an intelligent travel planning system named Pi-Pe which uses artificial intelligence to help users easily create their one-day trip schedule with three simple steps: (1) Select the date and time (2) State the starting location and (3) Pick the destinations. The purpose of the paper is to develop a set of technology-based marketing plan for Pi-Pe in the pursuit of competitive advantage to drive up product value and create sustained commercial advantage