Plasma betaine concentrations correlate with plasma cortisol but not with C-reactive protein in an elderly population

Background: Low plasma betaine concentrations are a feature of seriously ill patients. Increased dietary betaine intake has been associated with lowered systemic inflammation. We aimed to compare plasma cortisol (a stress marker) and C-reactive protein (an inflammation marker) as statistical predictors of plasma betaine concentrations.
Methods: Plasma carnitine, cortisol and C-reactive protein concentrations, other biochemical measures and urine betaine excretion, were compared with plasma betaine concentration by correlation and in multiple regression models, using morning blood and urine samples from 64 ambulant elderly subjects and from 55 patients admitted to hospital with hip fractures.
Results: In the ambulant elderly without acute trauma, plasma cortisol (with negative coefficients) and carnitine (with positive coefficients) statistically predicted plasma betaine concentrations. C-reactive protein was not a predictor. In the patients, the significant predictors were plasma carnitine (positive coefficient) and plasma homocysteine (negative coefficient) and C-reactive protein again was not a predictor. In regression models using combined patient and control data there were large ranges of both cortisol and especially C-reactive protein; cortisol and homocysteine (negative coefficients) and carnitine (positive coefficient) were significant predictors but C-reactive protein was not significant.
Conclusions: Stress rather than inflammation may affect plasma betaine concentrations.

Lever, M., et al., Plasma betaine concentrations correlate with plasma cortisol but not with C-reactive protein in an elderly population. Clin Chem Lab Med, 2012. 50(9): p. 1635-40

Plasma choline and betaine correlate with serum folate, plasma S-adenosyl-methionine and S-adenosyl-homocysteine in healthy volunteers

Background: Choline is essential for mammalian cell function. It plays a critical role in cell membrane integrity, neurotransmission, cell signaling and lipid metabolism. Moreover, choline is involved in methylation in two ways: a) its synthesis requires methyl groups donated by S-adenosyl-methionine (AdoMet); and b) choline oxidation product betaine methylates homocysteine (Hcy) to methionine (Met) and produces dimethylglycine. This later donates one carbon units to tetrahydrofolate (THF).
Methods: To evaluate the correlations of choline and betaine with folate, AdoMet, S-anenosyl-homocysteine (AdoHcy), total homocysteine (tHcy), and DNA methylation, choline, betaine and dimethylglycine were measured by LC-MS/MS in plasma of 109 healthy volunteers, in whom folate, AdoMet, AdoHcy, tHcy, and DNA methylation have previously been reported.
Results: Using a bivariate model, choline and betaine showed strong positive correlations with folate (r=0.346 and r=0.226), AdoHcy (r=0.468 and r=0.296), and correlated negatively with AdoMet/AdoHcy ratio (r=-0.246 and r=-0.379). Only choline was positively correlated with AdoMet (r=0.453). Using a multivariate linear regression model, choline correlated strongly with folate (beta=17.416), AdoMet (beta=61.272), and AdoHcy (beta=9.215). Betaine correlated positively with folate (beta=0.133) and negatively with tHcy (beta=-0.194) ratio. Choline is an integral part of folate and methylation pathways.
Conclusions: Our data highlight the importance of integrating choline in studies concerning addressing pathological conditions related to folate, homocysteine and methylation metabolism.

Imbard, A., et al., Plasma choline and betaine correlate with serum folate, plasma S-adenosyl-methionine and S-adenosyl-homocysteine in healthy volunteers. Clin Chem Lab Med, 2012.

Early second trimester maternal plasma choline and betaine are related to measures of early cognitive development in term infants

BACKGROUND: The importance of maternal dietary choline for fetal neural development and later cognitive function has been well-documented in experimental studies. Although choline is an essential dietary nutrient for humans, evidence that low maternal choline in pregnancy impacts neurodevelopment in human infants is lacking. We determined potential associations between maternal plasma free choline and its metabolites betaine and dimethylglycine in pregnancy and infant neurodevelopment at 18 months of age.

METHODOLOGY: This was a prospective study of healthy pregnant women and their full-term, single birth infants. Maternal blood was collected at 16 and 36 weeks of gestation and infant neurodevelopment was assessed at 18 months of age for 154 mother-infant pairs. Maternal plasma choline, betaine, dimethylglycine, methionine, homocysteine, cysteine, total B12, holotranscobalamin and folate were quantified. Infant neurodevelopment was evaluated using the Bayley Scales of Infant Development-III. Multivariate regression, adjusting for covariates that impact development, was used to determine the associations between maternal plasma choline, betaine and dimethylglycine and infant neurodevelopment.

RESULTS: The maternal plasma free choline at 16 and 36 weeks gestation was median (interquartile range) 6.70 (5.78-8.03) and 9.40 (8.10-11.3) µmol/L, respectively. Estimated choline intakes were (mean ±SD) 383±98.6 mg/day, and lower than the recommended 450 mg/day. Betaine intakes were 142±70.2 mg/day. Significant positive associations were found between infant cognitive test scores and maternal plasma free choline (B = 6.054, SE = 2.283, p = 0.009) and betaine (B = 7.350, SE = 1.933, p = 0.0002) at 16 weeks of gestation. Maternal folate, total B12, or holotranscobalamin were not related to infant development.

CONCLUSION: We show that choline status in the first half of pregnancy is associated with cognitive development among healthy term gestation infants. More work is needed on the potential limitation of choline or betaine in the diets of pregnant women.

Wu, B.T., et al., Early second trimester maternal plasma choline and betaine are related to measures of early cognitive development in term infants. PLoS One, 2012. 7(8): p. e43448.

Betaine inhibits in vitro and in vivo angiogenesis through suppression of the NF-κB and Akt signaling pathways

Angiogenesis is defined as the formation of new blood vessels form existing vessels surrounding a tumor. The process of angiogenesis is an important step for tumor growth and metastasis, as is inflammation. Thus, angiogenesis inhibitors that suppress inflammation have been studied as an anticancer treatment. Recently, many research groups have investigated the anti-angiogenic activity of natural compounds since some have been demonstrated to have anticancer properties. Among many natural compounds, we focused on betaine, which is known to suppress inflammation. Betaine, trimethylglycine (TMG), was first discovered in the juice of sugar beets and was later shown to be present in wheat, shellfish and spinach. In Southeast Asia, betaine is used in traditional oriental medicine for the treatment of hepatic disorders. Here, we report the anti-angiogenic action of betaine. Betaine inhibited in vitro angiogenic cascade, tube formation, migration and invasion of human umbilical vein endothelial cells (HUVECs). Betaine also inhibited in vivo angiogenesis in the mouse Matrigel plug assay. The mRNA expression levels of basic fibroblast growth factor (bFGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in HUVECs were decreased by betaine treatment. In addition, betaine suppressed NF-kappaB and Akt activation.
Yi, E.Y. and Y.J. Kim, Betaine inhibits in vitro and in vivo angiogenesis through suppression of the NF-kappaB and Akt signaling pathways. Int J Oncol, 2012. 41(5): p. 1879-85

Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity

BACKGROUND: Maternal nutritional status has been evaluated to clarify its role in development of neural tube defects (NTDs). Maternal folate intake during pregnancy has been closely evaluated for its association with NTDs. The study objective was to examine associations between NTDs and other dietary periconceptional micronutrient intake, particularly nutrients involved in one-carbon metabolism or antioxidant activity.

METHODS: Using data from the National Birth Defects Prevention Study, 1997-2005, logistic regression models were used to estimate the relative risk of NTDs based on maternal micronutrient intake.

RESULTS: Results were stratified according to folic acid supplement use, race/ethnicity, and maternal body mass index. Analyses included 954 cases (300 with anencephaly, 654 with spina bifida) and 6268 controls. Higher intakes of folate, thiamin, betaine, iron, and vitamin A were associated with decreased risk of anencephaly among some ethnic and clinical groups. In some groups, higher intakes of thiamin, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, and retinol were associated with decreased risk of spina bifida.

CONCLUSION: In addition to folic acid, other micronutrients, including thiamin, betaine, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, iron, retinol, and vitamin A, may decrease the risk of NTD occurrence.

Chandler, A.L., et al., Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity. Birth Defects Res A Clin Mol Teratol, 2012. 94(11): p. 864-74

Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet.

Non-alcoholic fatty liver disease (NAFLD) is one of the first hepatic manifestations of metabolic syndrome, whose progression can lead to cirrhosis and hepatic carcinoma. Interestingly, methyl donor supplementation could improve obesogenic diet-induced hepatic triglyceride accumulation. The aim of this research is to describe methyl donor effects on a high-fat-sucrose (HFS) diet in both sexes and epigenetic changes induced on fatty acid synthase (FASN) promoter methylation pattern as well as gene expression of NAFLD key metabolic genes. Twenty-four male and 28 female Wistar rats were assigned to three dietary groups: control, HFS, and HFS supplemented with methyl donors (choline, betaine, vitamin B12, and folic acid). After 8 weeks of treatment, somatic, biochemical, mRNA, and epigenetic measurements were performed. Rats fed the HFS diet presented an overweight phenotype and alterations in plasma biochemical measurements. Methyl donor supplementation reverted the HFS-diet-induced hepatic triglyceride accumulation. Analysis of FASN promoter cytosine methylation showed changes in both sexes due to the obesogenic diet at -1,096, -780, -778, and -774 CpG sites with respect to the transcriptional start site. Methyl donor supplementation modified DNA methylation at -852, -833, -829, -743, and -733 CpGs depending on the sex. RT-PCR analysis confirmed that FASN expression tended to be altered in males. Our findings reinforce the hypothesis that methyl donor supplementation can prevent hepatic triglyceride accumulation induced by obesogenic diets in both sexes. Changes in liver gene expression profile and epigenetic-mediated mechanisms related to FASN DNA hypermethylation could be involved in methyl donor-induced NAFLD improvement.

Cordero, P., et al., Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet. Genes Nutr, 2012 (May 31)

Recognition of betaine as an inhibitor of lipopolysaccharide-induced nitric oxide production in activated microglial cells

Background: Neuroinflammation, as a major outcome of microglia activation, is an important factor for progression of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. Microglial cells, as the first-line defense in the central nervous system, act as a source of neurotoxic factors such as nitric oxide (NO), a free radical which is involved in neuronal cell death. The aim of this study was to inhibit production of NO in activated microglial cells in order to decrease neurological damages that threat the central nervous system. Methods: An in vitro model of a newborn rat brain cell culture was used to examine the effect of betaine on the release of NO induced by lipopolysaccharide (LPS). Briefly, primary microglial cells were stimulated by LPS and after 2 minutes, they were treated by different concentrations of betaine. The production of NO was assessed by the Griess assay while cell viability was determined by the MTT assay. Results: Our investigations indicated that LPS-induced NO release was attenuated by betaine, suggesting that this compound might inhibit NO release. The effects of betaine on NO production in activated microglial cells after 24 h were "dose-dependent". It means that microglial cells which were treated with higher concentrations of betaine, released lower amounts of NO. Also our observations showed that betaine compound has no toxic effect on microglial cells. Conclusion: Betaine has an inhibitory effect on NO release in activated microglial cells and may be an effective therapeutic component to control neurological disorders.

Amiraslani, B., et al., Recognition of betaine as an inhibitor of lipopolysaccharide-induced nitric oxide production in activated microglial cells. Iran Biomed J, 2012. 16(2): p. 84-9.