Liver transplant as a curative treatment in a pediatric patient with classic homocystinuria: A case report.

We report a patient with homocystinuria and hyperoxaluria who was cured of homocystinuria-related disease following liver transplant. The patient was diagnosed with homocystinuria as a newborn and was treated with dietary modifications and supplements. At 22 months, he passed a calcium oxalate stone and was found to have numerous bilateral kidney stones. Genetic testing confirmed primary hyperoxaluria, type 1. He underwent preemptive liver transplant at age four to treat primary hyperoxaluria. Following transplant, his serum methionine and homocysteine levels normalized, thus, demonstrating resolution of homocystinuria. Methionine and homocysteine levels remained normal 6 years later. Homocystinuria is associated with ophthalmologic, skeletal, neurologic, and thromboembolic complications. As cystathionine beta-synthase resides in the liver, transplant was hypothesized to be an effective treatment. Primary hyperoxaluria generally progresses to chronic kidney disease and is treated with combined kidney-liver transplant at the time of end stage kidney disease. Given this patient's dual diagnoses, we proceeded with preemptive liver transplantation. Three prior cases of patients with homocystinuria treated with liver transplantation have been reported. In all cases, transplant resolved metabolic effects. However, our case represents a pediatric patient without disease-related complications prior to transplant. This case supports liver-targeted gene therapies as an effective treatment for homocystinuria.

Plasma Sulfur Amino Acids and Risk of Cerebrovascular Diseases: A Nested Case-Control Study in the EPIC-Norfolk Cohort.

BACKGROUND AND PURPOSE: B-vitamin supplements lower circulating concentrations of homocysteine and may reduce stroke incidence. Homocysteine concentrations are associated with the incidence of stroke but other sulfur-containing compounds in the related metabolic pathway have not yet been investigated for an association with incident cerebrovascular diseases. METHODS: Nested within the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk cohort, we established a case-control study with 480 incident cases of cerebrovascular diseases and 480 controls matched by age, sex, and year of baseline examination (1993-1997). Using baseline plasma samples, we assayed sulfur-containing compounds including methionine, homocysteine, cystathionine, cysteine, glutathione, and taurine with liquid chromatography-tandem mass spectrometry. We examined the association of concentrations of each of the compounds and the ratio of methionine to homocysteine (representing activity of one-carbon metabolism) with risk of incident cerebrovascular diseases, adjusted for potential confounders. RESULTS: Plasma methionine and the methionine/homocysteine ratio were inversely associated with risk of cerebrovascular diseases, with odds ratios per 1 SD of 0.83 (95% CI, 0.72-0.96) and 0.82 (95% CI, 0.71-0.95), respectively. The association of methionine remained significant after adjustment for homocysteine. None of the other examined compounds was significantly associated with incident cerebrovascular diseases. CONCLUSIONS: These findings suggest that greater availability of methionine, an essential amino acid, may play a role in the prevention of cerebrovascular diseases and explain the previously recognized link between elevated homocysteine and stroke. Further research is needed to determine causation and the potential of circulating methionine as a target in cerebrovascular disease prevention.

The Appetite-Suppressant and GLP-1-Stimulating Effects of Whey Proteins in Obese Subjects are Associated with Increased Circulating Levels of Specific Amino Acids.

The satiating effect of whey proteins depends upon their unique amino acid composition because there is no difference when comparing whey proteins or a mix of amino acids mimicking the amino acid composition of whey proteins. The specific amino acids underlying the satiating effect of whey proteins have not been investigated to date. AIMS AND METHODS: The aim of the present study was to evaluate the appetite-suppressant effect of an isocaloric drink containing whey proteins or maltodextrins on appetite (satiety/hunger measured by a visual analogue scale or VAS), anorexigenic gastrointestinal peptides (circulating levels of glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY)) and amino acids (circulating levels of single, total [TAA] and branched-chain amino acids [BCAA]) in a cohort of obese female subjects (n = 8; age: 18.4 ± 3.1 years; body mass index, BMI: 39.2 ± 4.6 kg/m2). RESULTS: Each drink significantly increased satiety and decreased hunger, the effects being more evident with whey proteins than maltodextrins. Similarly, circulating levels of GLP-1, PYY and amino acids (TAA, BCAA and alanine, arginine, asparagine, citrulline, glutamine, hydroxyproline, isoleucine, histidine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tyrosine, and valine) were significantly higher with whey proteins than maltodextrins. In subjects administered whey proteins (but not maltodextrins), isoleucine, leucine, lysine, methionine, phenylalanine, proline, tyrosine, and valine were significantly correlated with hunger (negatively), satiety, and GLP-1 (positively). CONCLUSIONS: Eight specific amino acids (isoleucine, leucine, lysine, methionine, phenylalanine, proline, tyrosine, and valine) were implicated in the appetite-suppressant and GLP-1-stimulating effects of whey proteins, which may be mediated by their binding with nutrient-sensing receptors expressed by L cells within the gastrointestinal wall. The long-term satiating effect of whey proteins and the effectiveness of a supplementation with these amino acids (i.e., as a nutraceutical intervention) administered during body weight reduction programs need to be further investigated.

Sulfur-containing amino acid supplementation to gilts from late pregnancy to lactation altered offspring's intestinal microbiota and plasma metabolites.

Maternal nutrition during late pregnancy and lactation is highly involved with the offspring's health status. The study was carried out to evaluate the effects of different ratios of methionine and cysteine (Met/Cys: 46% Met, 51% Met, 56% Met, and 62% Met; maintained with 0.78% of total sulfur-containing amino acids; details in "Materials and methods") supplements in the sows' diet from late pregnancy to lactation on offspring's plasma metabolomics and intestinal microbiota. The results revealed that the level of serum albumin, calcium, iron, and magnesium was increased in the 51% Met group compared with the 46% Met, 56% Met, and 62% Met groups. Plasma metabolomics results indicated that the higher ratios of methionine and cysteine (0.51% Met, 0.56% Met, and 0.62% Met)-supplemented groups enriched the level of hippuric acid, retinoic acid, riboflavin, and δ-tocopherol than in the 46% Met group. Furthermore, the 51% Met-supplemented group had a higher relative abundance of Firmicutes compared with the other three groups (P < 0.05), while the 62% Met-supplemented group increased the abundance of Proteobacteria compared with the other three groups (P < 0.05) in piglets' intestine. These results indicated that a diet consisting with 51% Met is the optimum Met/Cys ratio from late pregnancy to lactation can maintain the offspring's health by improving the serum biochemical indicators and altering the plasma metabolomics profile and intestinal gut microbiota composition, but higher proportion of Met/Cys may increase the possible risk to offspring's health.

Reproductive and Productive Efficiency of Maghrebi Dairy She-Camels Fed Diets Supplemented with Zinc-Methionine.

This study is aimed at evaluating the effect of dietary zinc-methionine (Zn-Met) supplementation during 3 months prepartum up to 9 months postpartum on reproductive performance, blood biochemical, and milk production of lactating she-camels besides growth performance of their calves. Twenty pregnant Maghrebi she-camels (439.49 ± 11.57 kg; 3-5 parties) were divided into four similar groups. Animals were fed the basal diet (G1) or the basal diet supplemented with Zn-Met at levels of 30 mg (G2), 40 mg (G3), and 50 mg (G4)/kg diet. Results revealed that IgA, IgM, and IgG concentrations in colostrum, monthly milk yield, and lactation period were significantly increased in Zn-Met-supplemented groups. Milk contents of fat, ash, and total solids improved (P < 0.05) in G4 as compared with other groups. Pre- and postpartum Zn, T3, T4, P4, and E2 concentrations in plasma and milk Zn level were higher (P < 0.05) in all Zn-Met-supplemented groups. Postpartum first estrus interval, number of services/conception, days open, pregnancy rate, duration of placental drop, and calving interval improved (P < 0.05) in G4. Weaning weight and average daily gain of calves were enhanced all in Zn-Met-supplemented groups. Conclusively, the inclusion of Zn-Met especially at a level of 50 mg/kg diet, 3 months prepartum up to 9 months postpartum, led to better productive and reproductive performance, immunity of she-camels, and growth performance of their offspring.

Association of Methionine to Homocysteine Status With Brain Magnetic Resonance Imaging Measures and Risk of Dementia.

Importance: Impairment of methylation status (ie, methionine to homocysteine ratio) may be a modifiable risk factor for structural brain changes and incident dementia. Objective: To investigate the association of serum markers of methylation status and sulfur amino acids with risk of incident dementia, Alzheimer disease (AD), and the rate of total brain tissue volume loss during 6 years. Design, Setting, and Participants: This population-based longitudinal study was performed from March 21, 2001, to October 10, 2010, in a sample of 2570 individuals aged 60 to 102 years from the Swedish Study on Aging and Care in Kungsholmen who were dementia free at baseline and underwent comprehensive examinations and structural brain magnetic resonance imaging (MRI) on 2 to 3 occasions during 6 years. Data analysis was performed from March 1, 2018, to October 1, 2018. Main Outcomes and Measures: Incident dementia, AD, and the rate of total brain volume loss. Results: This study included 2570 individuals (mean [SD] age, 73.1 [10.4] years; 1331 [56.5%] female). The methionine to homocysteine ratio was higher in individuals who consumed vitamin supplements (median, 1.9; interquartile range [IQR], 1.5-2.6) compared with those who did not (median, 1.8; IQR, 1.3-2.3; P < .001) and increased per each quartile increase of vitamin B12 or folate. In the multiadjusted model, an elevated baseline serum total homocysteine level was associated with an increased risk of dementia and AD during 6 years: for the highest homocysteine quartile compared with the lowest, the hazard ratios (HRs) were 1.60 (95% CI, 1.01-2.55) for dementia and 2.33 (95% CI, 1.26-4.30) for AD. In contrast, elevated concentrations of methionine were associated with a decreased risk of dementia (HR, 0.54; 95% CI, 0.36-0.81) for the highest quartile compared with the lowest. Higher values of the methionine to homocysteine ratio were significantly associated with lower risk of dementia and AD: for the fourth methionine-homocysteine quartile compared with the first quartile, the HR was 0.44 (95% CI, 0.27-0.71) for incident dementia and 0.43 (95% CI, 0.23-0.80) for AD. In the multiadjusted linear mixed models, a higher methionine to homocysteine ratio was associated with a decreased rate of total brain tissue volume loss during the study period (ß [SE] per 1-SD increase, 0.038 [0.014]; P = .007). Conclusions and Relevance: The methionine to homocysteine status was associated with dementia development and structural brain changes during the 6-year study period, suggesting that a higher methionine to homocysteine ratio may be important in reducing the rate of brain atrophy and decreasing the risk of dementia in older adults.

Evaluation of tracer labelled methionine load test in vitamin B-12 deficient adolescent women.

BACKGROUND: Methionine loading test (MLT) has been used primarily to identify defects in transsulfuration of homocysteine in cystathionine beta synthase deficiency. It may not be as useful to evaluate remethylation pathway, in vitamin B-12 and folate deficiencies. OBJECTIVE: We used tracer isotope labelled MLT to interrogate transsulfuration and remethylation independently in vitamin B-12 deficiency. DESIGN: We studied vitamin B-12 deficient women with a tracer labelled MLT before and eleven months after treatment with vitamin B-12. The fractional contribution of [13C]homocysteine to breath CO2 was used as a measure of transsulfuration, and difference in the intracellular enrichment of [13C]methionine and that of [C2H3]methionine as a measure of remethylation of homocysteine. Combined pre- and post-treatment results were analyzed to investigate the association between plasma vitamin B-12 concentrations and measures of homocysteine metabolism. RESULTS: The subjects were 17 years old, with a BMI of 19.4 kg/m2. Treatment with vitamin B-12, 2µg/day increased plasma B-12 from 93 (78.7, 106.2) [median (25th, 75th centiles)] to 161.5 (125.5, 226.2) pmol/L; 44% were below <150pmol/L after treatment. Fasting homocysteine concentration was significantly lower and that of cysteine higher in subjects with B-12 levels >150pmol/L. The tracer estimated transsulfuration of homocysteine was lower and remethylation higher with B-12 levels >150pmol/L when compared with those <150pmol/L. CONCLUSIONS: The tracer labelled MLT in combination with fasting parameters is a robust way to estimate parameters of methionine metabolism and can be used in the field where prime-constant rate infusion studies cannot be done efficiently.

A Novel Concept of Amino Acid Supplementation to Improve the Growth of Young Malnourished Male Rats.

BACKGROUNDS/AIMS: This study was aimed at understanding the relationship between plasma amino acids and protein malnutrition and at determining whether amino acid supplementation associated with malnutrition and growth improves linear growth in growing rats. METHODS: Body length and plasma amino acids were measured in young male rats that were fed the following diet for 3 weeks, mimicking a low and imbalanced protein diets based on maize, a major staple consumed in developing countries: a 70% calorically restricted cornmeal-based diet (C), C + micronutrients (CM), CM + casein (CMC), CM + soy protein (CMS) or CMS + 0.3% lysine. RESULTS: A correlation analysis of linear growth and plasma amino acids indicated that lysine, tryptophan, branched-chain amino acids, methionine, and phenylalanine significantly correlated with body length. Supplementation with these 5 amino acids (AA1) significantly improved the body length in rats compared to CMC treatment whereas, nitrogen-balanced amino acid supplemented controls (AA2) did not (CM +1.2 ± 0.2, CMC +2.7 ± 0.3, CMS +2.1 ± 0.3, AA1 +2.8 ± 0.2, and AA2 +2.5 ± 0.3 cm). CONCLUSION: With securing proper amino acid balance, supplementing growth-related amino acids is more effective in improving linear growth in malnourished growing male rats. Analysis of the correlation between plasma amino acids and growth represents a powerful tool to determine candidate amino acids for supplementation to prevent malnutrition. This technology is adaptable to children in developing countries.

Lifestyle, metabolite, and genetic determinants of formate concentrations in a cross-sectional study in young, healthy adults.

Background: Formate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants. Objective: This study aimed to define formate concentrations and their determinants in a healthy young population. Design: Serum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors. Results: Serum formate concentrations ranged from 8.7 to 96.5 µM, with a mean of 25.9 µM. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12. Conclusions: Formate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900.

Comparative effects of acute-methionine loading on the plasma sulfur-amino acids in NAC-supplemented HIV+ patients and healthy controls.

In this study, an acute overloading of methionine (MetLo) was used to investigate the trassulfuration pathway response comparing healthy controls and HIV+ patients under their usual diet and dietary N-acetyl-L-cysteine (NAC) supplementation. MetLo (0.1 g Met/kg mass weight) was given after overnight fasting to 20 non-HIV+ control subjects (Co) and 12 HIV+ HAART-treated patients. Blood samples were taken before and after the MetLo in two different 7-day dietary situations, with NAC (1 g/day) or with their usual diet (UD). The amino acids (Met, Hcy, Cys, Tau, Ser, Glu and Gln) and GSH were determined by HPLC and their inflow rate into circulation (plasma) was estimated by the area under the curve (AUC). Under UD, the HIV+ had lower plasma GSH and amino acids (excepting Hcy) and higher oxidative stress (GSSG/GSH ratio), similar remethylation (RM: Me/Hcy + Ser ratio), transmethylation (TM; Hcy/Met ratio) and glutaminogenesis (Glu/Gln ratio), lower transsulfuration (TS: Cys/Hcy + Ser ratio) and Cys/Met ratio and, higher synthetic rates of glutathione (GG: GSH/Cys ratio) and Tau (TG: Tau/Cys ratio). NAC supplementation changed the HIV pattern by increasing RM above control, normalizing plasma Met and TS and, increasing plasma GSH and GG above controls. However, plasma Cys was kept always below controls probably, associatively to its higher consumption in GG (more GSSG than GSH) and TG. The failure of restoring normal Cys by MetLo, in addition to NAC, in HIV+ patients seems to be related to increased flux of Cys into GSH and Tau pathways, probably strengthening the cell-antioxidant capacity against the HIV progression (registered at http://www.clinicaltrials.gov , NCT00910442).

Relevance of plasma levels of free homocysteine and methionine as risk predictors for ischemic stroke in the young.

BACKGROUND & AIMS: The debated vascular risk potential of total homocysteine (tHcy), due to failed clinical trials designed on B vitamin supplementation, raises many possible explanations like the higher risk potential of the deleterious, free form of homocysteine (fHcy) or, the unchecked confounding effects of B-vitamins in tHcy-based association studies. Additionally, the cardiovascular risk probability of altered status of the homocysteine precursor, methionine (tMet) could shed light on the causality of association between tHcy and cardiovascular diseases. Hence, we aimed to evaluate the risk associations of elevated plasma levels of tHcy, fHcy and low levels of tMet with premature, ischemic stroke. METHODS: We recruited 171 young, ischemic stroke patients (aged ≤45 years) and 249 age- and gender-matched healthy controls. Plasma levels of fHcy, tHcy, tMet and vitamin B6 were estimated using HPLC coupled with coulometric electrochemical detection. Plasma levels of vitamin B12 and folate were estimated by radioimmunoassay. RESULTS: Elevated fHcy (>2.9 µmol/L) was independently and strongly associated with the risk of premature, ischemic stroke (OR = 9.62, 95% CI = 3.51-26.40). On the contrary, association between premature ischemic stroke and elevated tHcy (>15.0 µmol/L) was found to attenuate when adjusted for vitamin B6 values (OR = 0.24, 95%, CI = 0.03-1.69). Interestingly, compromised B6-status (<59.2 nmol/l) was found to confer high risk of premature ischemic stroke (OR = 170.80, 95% CI = 58.22-501.06). We could not establish any significant correlation between fHcy and B-vitamin levels (P > 0.05). Low tMet (<13.86 µmol/L) was also not significantly associated with premature, ischemic stroke (OR = 2.53, 95% CI = 0.613-10.38). CONCLUSION: Our results indicate significant but not-correlated, independent associations of fHcy and vitamin B6 with risk of premature, ischemic stroke. However, the causality of these associations need prospective and large scale validations. Further, our findings highlight the crucial confounding effects of B-vitamins on risk association between tHcy and premature ischemic stroke.

Eggs early in complementary feeding increase choline pathway biomarkers and DHA: a randomized controlled trial in Ecuador.

Background: Choline status has been associated with stunting among young children. Findings from this study showed that an egg intervention improved linear growth by a length-for-age z score of 0.63.Objective: We aimed to test the efficacy of eggs introduced early in complementary feeding on plasma concentrations of biomarkers in choline pathways, vitamins B-12 and A, and essential fatty acids.Design: A randomized controlled trial, the Lulun ("egg" in Kichwa) Project, was conducted in a rural indigenous population of Ecuador. Infants aged 6-9 mo were randomly assigned to treatment (1 egg/d for 6 mo; n = 80) and control (no intervention; n = 83) groups. Socioeconomic data, anthropometric measures, and blood samples were collected at baseline and endline. Household visits were made weekly for morbidity surveillance. We tested vitamin B-12 plasma concentrations by using chemiluminescent competitive immunoassay and plasma concentrations of choline, betaine, dimethylglycine, retinol, essential fatty acids, methionine, dimethylamine (DMA), trimethylamine, and trimethylamine-N-oxide (TMAO) with the use of liquid chromatography-tandem mass spectrometry.Results: Socioeconomic factors and biomarker concentrations were comparable at baseline. Of infants, 11.4% were vitamin B-12 deficient and 31.7% marginally deficient at baseline. In adjusted generalized linear regression modeling, the egg intervention increased plasma concentrations compared with control by the following effect sizes: choline, 0.35 (95% CI: 0.12, 0.57); betaine, 0.29 (95% CI: 0.01, 0.58); methionine, 0.31 (95% CI: 0.03, 0.60); docosahexaenoic acid, 0.43 (95% CI: 0.13, 0.73); DMA, 0.37 (95% CI: 0.37, 0.69); and TMAO, 0.33 (95% CI: 0.08, 0.58). No significant group differences were found for vitamin B-12, retinol, linoleic acid (LA), α-linolenic acid (ALA), or ratios of betaine to choline and LA to ALA.Conclusion: The findings supported our hypothesis that early introduction of eggs significantly improved choline and other markers in its methyl group metabolism pathway. This trial was registered at clinicaltrials.gov as NCT02446873.

Association between Serum Unmetabolized Folic Acid Concentrations and Folic Acid from Fortified Foods.

OBJECTIVE: To investigate the association between serum unmetabolized folic acid (UMFA) concentrations and folic acid from fortified foods and nutrients known as dietary methyl-group donors (folate, methionine, choline, betaine and vitamins B2, B6 and B12) in participants exposed to mandatory fortification of wheat and maize flours with folic acid. METHODS: Cross-sectional study carried out with 144 healthy Brazilian participants, both sexes, supplement nonusers. Serum folate, UMFA, vitamin B12 and total plasma homocysteine (tHcy) were biochemically measured. Dietary intake was assessed by 2 non-consecutive 24-hour dietary recalls (24-HRs) and deattenuated energy-adjusted nutrient data were used for statistical analysis. RESULTS: Ninety eight (68.1%) participants were women. Median (interquartile range) age was 35.5 (28.0-52.0) years. Elevated serum folate concentrations (>45 nmol/L) were found in 17 (11.8%), while folate deficiency (<7 nmol/L) in 10 (6.9%) participants. No one had vitamin B12 deficiency (<148 pmol/L). An elevated serum UMFA concentration was defined as > 1 nmol/L (90th percentile). UMFA concentrations were positively correlated with folic acid intake and negatively correlated to choline, methionine and vitamin B6 intakes. Participants in the lowest quartile of UMFA concentrations had lower dietary intake of total folate (DFEs) and folic acid, and higher dietary intake of methionine, choline and vitamin B6 than participants in the highest quartile of UMFA. Folic acid intake (OR [95% CI] = 1.02 [1.01-1.04)] and being a male (OR [95% CI] = 0.40 [0.19-0.87) were associated with increased and reduced odds for UMFA concentrations > 0.55 nmol/L (median values), respectively. CONCLUSION: UMFA concentrations were directly influenced by folic acid intake from fortified foods in a healthy convenience sample of adult Brazilians exposed to mandatory flour fortification with folic acid.

Dietary methionine source and level affect hepatic sulfur amino acid metabolism of broiler breeder hens.

A study was carried out to investigate the effects of dietary methionine source and level on plasma free amino acids patterns and the expression of genes involved in hepatic methionine metabolism in broiler breeders. A total of 2184 broiler breeders were assigned to 13 dietary treatments, with eight replicates per treatment. The 13 treatments included one control group and 12 additional treatments employing two sources and six levels (0.05, 0.10, 0.15, 0.20, 0.25 and 1.00%). Higher plasma methionine concentration was measured for DL-methionine (DLM) treated hens. Plasma alanine concentration was linearly increased as DLM or 2-hydroxy-4-(methylthio) butanoic acid (HMTBA) supplementation level increased. There was a linear increase in concentrations of tyrosine, valine, glycine and serine as dietary DLM supplementation level increased. Hens treated with DLM had higher relative expression of ADA than those fed HMTBA. The expression of MS, ADA, SAHH and MAT2A changed quadratically as HMTBA supplementation level increased, while the expression of GNMT and SAHH changed quadratically as DLM supplementation level increased. In conclusion, the effects of HMTBA on plasma free amino acid patterns and the expression of hepatic genes involved with methionine are different from DLM.

Placentome Nutrient Transporters and Mammalian Target of Rapamycin Signaling Proteins Are Altered by the Methionine Supply during Late Gestation in Dairy Cows and Are Associated with Newborn Birth Weight.

Background: To our knowledge, most research demonstrating a link between maternal nutrition and both fetal growth and offspring development after birth has been performed with nonruminants. Whether such relationships exist in large ruminants is largely unknown.Objective: We aimed to investigate whether increasing the methionine supply during late pregnancy would alter uteroplacental tissue nutrient transporters and mammalian target of rapamycin (mTOR) and their relation with newborn body weight.Methods: Multiparous Holstein cows were used in a randomized complete block design experiment. During the last 28 d of pregnancy, cows were fed a control diet or the control diet plus ethylcellulose rumen-protected methionine (0.9 g/kg dry matter intake) (Mepron; Evonik Nutrition & Care GmbH) to achieve a 2.8:1 ratio of lysine to methionine in the metabolizable protein reaching the small intestine. We collected placentome samples at parturition and used them to assess mRNA and protein expression and the phosphorylation status of mTOR pathway proteins.Results: Newborn body weight was greater in the methionine group than in the control group (44.1 kg and 41.8 kg, respectively; P ≤ 0.05). Increasing the methionine supply also resulted in greater feed intake (15.8 kg/d and 14.6 kg/d), plasma methionine (11.9 µM and 15.3 µM), and plasma insulin (1.16 µg/L and 0.81 µg/L) in cows during late pregnancy. As a result, mRNA expression of genes involved in neutral amino acid transport [solute carrier (SLC) family members SLC3A2, SLC7A5, SLC38A1, and SLC38A10], glucose transport [SLC2A1, SLC2A3, and SLC2A4], and the mTOR pathway [mechanistic target of rapamycin and ribosomal protein S6 kinase B1] were upregulated (P ≤ 0.07) in methionine-supplemented cows. Among 6 proteins in the mTOR pathway, increasing the methionine supply led to greater (P ≤ 0.09) protein expression of α serine-threonine kinase (AKT), phosphorylated (p)-AKT, p-eukaryotic elongation factor 2, and the p-mTOR:mTOR ratio.Conclusion: Supplemental methionine during late gestation increases feed intake and newborn body weight in dairy cows, and this effect may be mediated by alterations in the uteroplacental transport of nondispensable and dispensable amino acids and glucose at least in part through changes in gene transcription and mTOR signaling.

High-protein goat's milk diet identified through newborn screening: clinical warning of a potentially dangerous dietetic practice.

OBJECTIVE: Breast-feeding is an unequalled way of providing optimal food for infants' healthy growth and development and the WHO recommends that infants should be exclusively breast-fed for the first 6 months of life. For mothers who are unable to breast-feed or who decide not to, infant formulas are the safest alternative. Despite recommendations, it is possible that parents make potentially harmful nutritional choices for their children because of cultural beliefs or misinformation on infant nutrition. We describe a possible health risk of not breast-feeding, highlighting a potentially dangerous dietetic practice. Design/Setting/Subjects We report the case of a newborn who was fed with undiluted goat's milk because her mother could not breast-feed and was not aware of infant formulas. RESULTS: The dietary mistake was detected because of a positive expanded newborn screening result, characterized by severe hypertyrosinaemia with high methionine and phenylalanine levels, a pattern suggestive of severe liver impairment. The pattern of plasma amino acids was related to a goat's milk diet, because of its very different composition compared with human milk and infant formula. CONCLUSIONS: Our experience demonstrates that, when breast-feeding is not possible or is not exclusive, infants may be at risk of dangerous nutritional practices, including diets with very high protein content, such as a goat's milk diet. Families of not breast-fed infants may need appropriate advice on safe alternatives for infant nutrition to avoid the risks of inappropriate diets.

Methionine tumor starvation by erythrocyte-encapsulated methionine gamma-lyase activity controlled with per os vitamin B6.

Erymet is a new therapy resulting from the encapsulation of a methionine gamma-lyase (MGL; EC number 4.4.1.11) in red blood cells (RBC). The aim of this study was to evaluate erymet potential efficacy in methionine (Met)-dependent cancers. We produced a highly purified MGL using a cGMP process, determined the pharmacokinetics/pharmacodynamics (PK/PD) properties of erymet in mice, and assessed its efficacy on tumor growth prevention. Cytotoxicity of purified MGL was tested in six cancer cell lines. CD1 mice were injected with single erymet product supplemented or not with vitamin B6 vitamer pyridoxine (PN; a precursor of PLP cofactor). NMRI nude mice were xenografted in the flank with U-87 MG-luc2 glioblastoma cells for tumor growth study following five intravenous (IV) injections of erymet with daily PN oral administration. Endpoints included efficacy and event-free survival (EFS). Finally, a repeated dose toxicity study of erymet combined with PN cofactor was conducted in CD1 mice. Recombinant MGL was cytotoxic on 4/6 cell lines tested. MGL half-life was increased from <24 h to 9-12 days when encapsulated in RBC. Conversion of PN into PLP by RBC was demonstrated. Combined erymet + PN treatment led to a sustained Met depletion in plasma for several days with a 85% reduction of tumor volume after 45 days following cells implantation, and a significant EFS prolongation for treated mice. Repeated injections in mice exhibited a very good tolerability with only minor impact on clinical state (piloerection, lean aspect) and a slight decrease in hemoglobin and triglyceride concentrations. This study demonstrated that encapsulation of methioninase inside erythrocyte greatly enhanced pharmacokinetics properties of the enzyme and is efficacy against tumor growth. The perspective on these results is the clinical evaluation of the erymet product in patients with Met starvation-sensitive tumors.

Effects of Chromium Methionine Supplementation with Different Sources of Zinc on Growth Performance, Carcass Traits, Meat Quality, Serum Metabolites, Endocrine Parameters, and the Antioxidant Status in Growing-Finishing Pigs.

This experiment was conducted to evaluate the effects of chromium methionine with/without zinc sulfate or zinc amino acid complex on the growth performance, carcass traits, meat quality, serum parameters, endocrine parameters, and antioxidant status of growing-finishing pigs. A total of 180 (32.0 ± 1.7 kg body weight, BW) crossbred pigs (Duroc × Landrace × Yorkshire) were used in a completely randomized design with three dietary treatments and 10 replicates per treatment (five pens of barrows and five pens of gilts with six pigs per replicate). Three treatments were corn-soybean meal-based diets supplemented with 100 mg Zn/kg from zinc sulfate (ZnSO4), 100 mg Zn/kg from ZnSO4 + 0.2 mg Cr/kg from chromium methionine complex (CrMet), or 50 mg Zn/kg from ZnSO4 + 50 mg Zn/kg from zinc amino acid complex (ZnAA) + 0.2 mg Cr/kg from CrMet, respectively. The experiment lasted 105 days, of which was divided into three stages including phase 1 (30 to 50 kg BW), phase 2 (50 to 80 kg BW), and phase 3 (80 to 110 kg BW). Results showed that supplementation with CrMet and ZnAA improved (P < 0.05) the feed conversion of the pigs in phase 2, phase 3, and the overall experiment. Hot carcass weight, dressing percentage, and a longissimus dorsi muscle area were increased (P < 0.05) in pigs fed with diets supplemented with both CrMet and ZnAA compared with pigs fed with diets containing only ZnSO4 (P < 0.05). There was also an increase (P < 0.01) pH24 h in the longissimus dorsi muscle in pigs fed with diets supplemented with CrMet and ZnAA. The concentration of serum glucose in pigs fed with diets containing CrMet and ZnAA was decreased (P < 0.05) compared with that in pigs fed with the diet containing ZnSO4. Supplementation with CrMet and ZnAA increased (P < 0.05) the circulating levels of insulin and decreased (P < 0.05) cortisol. There was an increase (P < 0.05) in total serum antioxidant capacity and Cu/Zn superoxide dismutase activity as well as a decrease (P < 0.05) in serum malondialdehyde concentrations in pigs fed with diets supplemented with CrMet and ZnAA compared with pigs fed with the diet supplemented only with ZnSO4. In conclusion, supplementation of CrMet only or CrMet together with ZnAA improved feed conversion, carcass traits, and meat quality in the growing-finishing pigs.

Chicoric acid attenuate a nonalcoholic steatohepatitis by inhibiting key regulators of lipid metabolism, fibrosis, oxidation, and inflammation in mice with methionine and choline deficiency.

SCOPE: Nonalcoholic fatty liver diseases (NAFLD) range histopathologically from hepatic steatosis to steatohepatitis. Chicoric acid has beneficial effects on obesity and liver injury, but its effects on nonalcoholic steatohepatitis (NASH) have not yet been determined. This study examined the effects of Crepidiastrum denticulatum extract (CDE) and its active compound chicoric acid in a mouse model of NASH and fibrosis. METHODS: CDE and chicoric acid were orally administrated to mice fed a methionine- and choline-deficient (MCD) diet. HepG2 and AML-12 cells in MCD medium were incubated with chicoric acid. MCD-fed mice developed the histopathological characteristics of human NASH, including altered regulation of lipid metabolism, inflammation, fibrosis, and oxidation-associated expression, along with augmented lipoperoxidation. Administration of CDE or chicoric acid to MCD-fed mice and HepG2 and AML-12 cells in MCD medium reduced oxidative stress by upregulating antioxidant enzymes and decreased inflammation by inhibiting proinflammatory cytokines and nuclear factor-κB activation. In addition, CDE or chicoric acid reduced fibrosis, apoptosis, and lipogenesis-related gene expression and increased AMP Kinase activation both in vivo and in vitro. CONCLUSIONS: CDE and chicoric acid may be effective in the treatment of NAFLD and NASH.

Methionine and Choline Supply during the Periparturient Period Alter Plasma Amino Acid and One-Carbon Metabolism Profiles to Various Extents: Potential Role in Hepatic Metabolism and Antioxidant Status.

The objective of this study was to profile plasma amino acids (AA) and derivatives of their metabolism during the periparturient period in response to supplemental rumen-protected methionine (MET) or rumen-protected choline (CHOL). Forty cows were fed from -21 through 30 days around parturition in a 2 × 2 factorial design a diet containing MET or CHOL. MET supply led to greater circulating methionine and proportion of methionine in the essential AA pool, total AA, and total sulfur-containing compounds. Lysine in total AA also was greater in these cows, indicating a better overall AA profile. Sulfur-containing compounds (cystathionine, cystine, homocystine, and taurine) were greater in MET-fed cows, indicating an enriched sulfur-containing compound pool due to enhanced transsulfuration activity. Circulating essential AA and total AA concentrations were greater in cows supplied MET due to greater lysine, arginine, tryptophan, threonine, proline, asparagine, alanine, and citrulline. In contrast, CHOL supply had no effect on essential AA or total AA, and only tryptophan and cystine were greater. Plasma 3-methylhistidine concentration was lower in response to CHOL supply, suggesting less tissue protein mobilization in these cows. Overall, the data revealed that enhanced periparturient supply of MET has positive effects on plasma AA profiles and overall antioxidant status.