Maternal methyl donor supplementation: A potential therapy for metabolic disorder in offspring.

The prevalences of diabetes mellitus and obesity are increasing yearly and has become a serious social burden. In addition to genetic factors, environmental factors in early life development are critical in influencing the prevalence of metabolic disorders in offspring. A growing body of evidence suggests the critical role of early methyl donor intervention in offspring health. Emerging studies have shown that methyl donors can influence offspring metabolism through epigenetic modifications and changing metabolism-related genes. In this review, we focus on the role of folic acid, betaine, vitamin B12, methionine, and choline in protecting against metabolic disorders in offspring. To address the current evidence on the potential role of maternal methyl donors, we summarize clinical studies as well as experimental animal models that support the impact of maternal methyl donors on offspring metabolism and discuss the mechanisms of action that may bring about these positive effects. Given the worldwide prevalence of metabolic disorders, these findings could be utilized in clinical practice, in which methyl donor supplementation in the early life years may reverse metabolic disorders in offspring and block the harmful intergenerational effect.

Guanidinoacetic acid provides superior cardioprotection to its combined use with betaine and (or) creatine in HIIT-trained rats.

This study aimed to determine how guanidinoacetic acid (GAA) or its combined administration with betaine (B) or creatine (C) influences the cardiac function, morphometric parameters, and redox status of rats subjected to high-intensity interval training (HIIT). This research was conducted on male Wistar albino rats exposed to HIIT for 4 weeks. The animals were randomly divided into five groups: HIIT, HIIT + GAA, HIIT + GAA + C, HIIT + GAA + B, and HIIT + GAA + C + B. After completing the training protocol, GAA (300 mg/kg), C (280 mg/kg), and B (300 mg/kg) were applied daily per os for 4 weeks. GAA supplementation in combination with HIIT significantly decreased the level of both systemic and cardiac prooxidants ( O 2 - , H2O2, NO 2 - , and thiobarbituric acid reactive substances) compared with nontreated HIIT (p < 0.05). Also, GAA treatment led to an increase in glutathione and superoxide dismutase levels. None of the treatment regimens altered cardiac function. A larger degree of cardiomyocyte hypertrophy was observed in the HIIT + GAA group, which was reflected through an increase of the cross-sectional area of 27% (p < 0.05) and that of the left ventricle wall thickness of 27% (p < 0.05). Since we showed that GAA in combination with HIIT may ameliorate oxidative stress and does not alter cardiac function, the present study is a basis for future research exploring the mechanisms of cardioprotection induced by this supplement in an HIIT scenario.

Chemoprevention Agents to Reduce Mammographic Breast Density in Premenopausal Women: A Systematic Review of Clinical Trials.

Background: Higher mammographic breast density (MBD) is associated with an increased risk of breast cancer when compared with lower MBD, especially in premenopausal women. However, little is known about the effectiveness of chemoprevention agents in reducing MBD in premenopausal women without a history of breast cancer. Findings from this review should provide insight on how to target MBD in breast cancer prevention in premenopausal women with dense breasts. Methods: We searched 9 electronic databases for clinical trials in English, Spanish, French, or German published until January 2020. Articles evaluating the association of pharmacological agents and MBD were included. Data were extracted on methods, type and dose of intervention, outcomes, side effects, and follow up. Quality of the studies was assessed using the US Preventive Services Task Force criteria. Results: We identified 7 clinical trials evaluating the associations of 6 chemoprevention agents with changes in MBD in premenopausal women without history of breast cancer. The studies evaluated selective estrogen-receptor modulators (n = 1); gonadotropin-releasing hormone agonists (n = 2); isoflavones (n = 1); vitamin D (n = 1); and Boswellia, betaine, and mayo-inositol compound (n = 1). Hormonal interventions were associated with net reductions in percent density (tamoxifen [13.4%], leuprolide acetate [8.9%], and goserelin [2.7%]), whereas nonhormonal (vitamin D and isoflavone) interventions were not. However, MBD returned to preintervention baseline levels after cessation of gonadotropin-releasing hormone agonists. Conclusions: A limited number of chemoprevention agents have been shown to reduce MBD in premenopausal women. Identification of new and well-tolerated chemoprevention agents targeting MBD and larger studies to confirm agents that have been studied in small trials are urgent priorities for primary breast cancer prevention in premenopausal women with dense breasts.

Betaine supplementation to rats alleviates disturbances induced by high-fat diet: pleiotropic effects in model of type 2 diabetes.

Betaine is a biologically active compound exerting beneficial effects in the organism, however, the exact mechanisms underlying its action are not fully elucidated. The present study aimed to explore, whether betaine alleviates disorders induced by feeding rats a high-fat diet (HFD). Rats were divided into 3 groups: control, fed an HFD and fed an HFD and receiving betaine (2% water solution for 8 weeks). Betaine improved glucose tolerance, decreased blood levels of non-esterified fatty acids and prevented lipid accumulation in the skeletal muscle of rats on an HFD. Betaine reduced activities of blood alanine aminotransferase, blood levels of bilirubin and hepatic lipid content. Expression of fatty acid synthase in the liver and the skeletal muscle was decreased in response to feeding an HFD, and this effect was deepened by betaine in the muscle tissue. Hepatic and muscular expression of genes related to insulin signaling were unchanged in HFD-fed rats. Lipolysis stimulated by epinephrine (an adrenergic receptor agonist), forskolin (an activator of adenylate cyclase), dibutyryl-cAMP (an activator of protein kinase A) and DPCPX (an adenosine A1 receptor antagonist) was diminished in the adipocytes of rats fed an HFD, however, this effect was alleviated by betaine. Moreover, blood leptin levels in HFD-fed rats were elevated, whereas leptinemia have normalized by betaine supplementation. Betaine prevented the increase in expression of N-methyl D-aspartate receptors in the hippocampus and in the cerebral cortex. These results indicate that betaine positively affects the insulin-sensitive tissues: liver (hepatoprotective effects), skeletal muscle (reduced lipid accumulation) and adipose tissue (a rise in lipolysis), which is associated with improved insulin sensitivity. Betaine-induced prevention of hyperleptinemia indicates restoration of leptin action, and changes in the brain reveal neuroprotective properties. Our results show that betaine induces positive changes in HFD-fed rats, its action is pleiotropic and involves different tissues.

Betaine Supplementation Moderately Increases Total Cholesterol Levels: A Systematic Review and Meta-Analysis.

Betaine is used to lower elevated plasma homocysteine levels, which are a risk factor for cardiovascular diseases (CVD). However, some studies have shown that betaine may have a negative effect on blood lipids. Betaine supplementation is becoming more and more common, but the relationship between betaine supplementation and blood lipoprotein levels are unclear. The purpose of the study described here was thus to perform a meta-analysis of randomized placebo-controlled trials on the effects of betaine supplementation at a daily dose of at least 4 g on blood lipids in adults. Six randomized controlled trials published between 2002 and 2018 were identified. All six studies used adult participants supplemented with at least 4 g/d of betaine for six to twenty-four weeks. A meta-analysis was carried out using a random-effects model, and the overall effect size was calculated for changes in plasma total cholesterol (TC), HDL cholesterol, LDL cholesterol, and triglycerides (TG). The pooled estimate of the effects of betaine supplementation compared to placebo on TC was 0.34 mmol/L (95% CI: 0.02, 0.65), p = 0.0352. No significant effect was observed for LDL, HDL, or TG. Supplementation with at least 4 g/d of betaine for a minimum of six weeks may moderately increase plasma TC, which might be important in the context of cardiovascular health.

Adult-onset methylenetetrahydrofolate reductase deficiency.

Severe hyperhomocysteinemia (>100 µmol/L) is often associated with inborn errors of homocysteine metabolism. It manifests typically in neonatal period with developmental delay, hypotonia, feeding problems or failure to thrive. Adult-onset forms are rare and include less severe manifestations. Early diagnosis is crucial because effective treatment is available. A 23-year-old man presented with a 3-week history of speech and gait impairment, and numbness in lower limbs. Neurological examination revealed dysarthria, decreased vibratory sensation in both legs and appendicular and gait ataxia. Brain MRI revealed T2-hyperintense symmetric white matter lesions and cortical atrophy. He had folate and vitamin B12 deficiency, a markedly elevated serum homocysteine and low methionine. Despite vitamin supplementation homocysteine levels remained elevated. Molecular studies of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene revealed a new pathogenic mutation (c.1003C>T (p.Arg335Cys)) and a polymorphism (C677T (p.Ala222Val)) associated with hyperhomocysteinemia, both in homozygosity. The patient started betaine with clinical and biochemical improvement.

POSITIVE EFFECT OF BETAINE-ARGININE SUPPLEMENT ON IMPROVED HYPERHOMOCYSTEINEMIA TREATMENT IN MARRIED COUPLES WITH REPRODUCTIVE DISORDERS.

Treatment of hereditary hyperhomocysteinemia and the achievement of optimal folate status is necessary for persons of reproductive age in order to increase live birth rate. Patients are usually advised to take folic acid, a key nutrient in homocysteine remethylation. The results of study showed risk factors for hyperhomocysteinemia development in investigated married couples: male gender, MTHFR, MTR1 genes variants, lower vitamin B12 blood serum and no additional intake of vitamin B12. Since MTHFR, MTR1 genes variants affect to decrease the efficiency of homocysteine metabolic transformations, to contribute also to endothelial dysfunction in one of patients group we used betargine combined with folic acids and vitamin B12 administration. Patients group with combined administration including betargine within 2 weeks, in comparison with the group without its supplement, had significantly decreased level of homocysteine in plasma, less than 12 µmol/l (81.03% and 50% of cases, respectively). Folic acid and vitamin B12 mean values in blood serum was significantly increased in patients after two week vitamins administration including betargin. Further research is needed to establish the duration of betaine-arginine intake until the target homocysteine level will be reached, as well as to estimate the durability of clinical effect achieved after consumption.

Effect of Betaine on Reducing Body Fat-A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Animal studies have shown the beneficial effect of betaine supplementation on reducing body fat, while the data from human studies are controversial and inconsistent. The objective of the present systematic review was to investigate the effects of betaine intervention on treating obesity in humans and quantitatively evaluate the pooled effects based on randomized controlled trials with a meta-analysis. The PubMed and Scopus databases, and the Cochrane Library, were searched up to September 2019. Weighted mean differences were calculated for net changes in obesity-related indices by using a random-effects model. Publication bias was estimated using Begg's test. Six studies with 195 participants were identified. Betaine supplementation significantly reduced the total body fat mass (-2.53 kg; 95% CI: -3.93, -0.54 kg; I2 = 6.6%, P = 0.36) and body fat percentage (-2.44%; 95% CI: -4.20, -0.68%; I2 = 0.0%, P = 0.44). No changes were observed regarding body weight (-0.29 kg; 95% CI: -1.48, 0.89 kg; I2 = 0.00%, P = 0.99) and body mass index (-0.10 kg/m2; 95% CI: -5.13, 0.31 kg/m2; I2 = 0.00%, P = 0.84). The results suggested that dietary betaine supplementation might be an effective approach for reducing body fat.

A novel nutritional supplement to reduce plasma homocysteine in nonpregnant women: A randomised controlled trial in The Gambia.

BACKGROUND: Infant DNA methylation profiles are associated with their mother's periconceptional nutritional status. DNA methylation relies on nutritional inputs for one-carbon metabolic pathways, including the efficient recycling of homocysteine. This randomised controlled trial in nonpregnant women in rural Gambia tests the efficacy of a novel nutritional supplement designed to improve one-carbon-related nutrient status by reducing plasma homocysteine, and assesses its potential future use in preconception trials. METHODS AND FINDINGS: We designed a novel drink powder based on determinants of plasma homocysteine in the target population and tested it in a three-arm, randomised, controlled trial. Nonpregnant women aged between 18 and 45 from the West Kiang region of The Gambia were randomised in a 1:1:1 allocation to 12 weeks daily supplementation of either (a) a novel drink powder (4 g betaine, 800 µg folic acid, 5.2 µg vitamin B12, and 2.8 mg vitamin B2), (b) a widely used multiple micronutrient tablet (United Nations Multiple Micronutrient Preparation [UNIMMAP]) containing 15 micronutrients, or (c) no intervention. The trial was conducted between March and July 2018. Supplementation was observed daily. Fasted venepuncture samples were collected at baseline, midline (week 5), and endline (week 12) to measure plasma homocysteine. We used linear regression models to determine the difference in homocysteine between pairs of trial arms at midline and endline, adjusted for baseline homocysteine, age, and body mass index (BMI). Blood pressure and pulse were measured as secondary outcomes. Two hundred and ninety-eight eligible women were enrolled and randomised. Compliance was >97.8% for both interventions. At endline (our primary endpoint), the drink powder and UNIMMAP reduced mean plasma homocysteine by 23.6% (-29.5 to -17.1) and 15.5% (-21.2 to -9.4), respectively (both p < 0.001), compared with the controls. Compared with UNIMMAP, the drink powder reduced mean homocysteine by 8.8% (-15.8 to -1.2; p = 0.025). The effects were stronger at midline. There was no effect of either intervention on blood pressure or pulse compared with the control at endline. Self-reported adverse events (AEs) were similar in both intervention arms. There were two serious AEs reported over the trial duration, both in the drink powder arm, but judged to be unrelated to the intervention. Limitations of the study include the use of a single targeted metabolic outcome, homocysteine. CONCLUSIONS: The trial confirms that dietary supplements can influence metabolic pathways that we have shown in previous studies to predict offspring DNA methylation. Both supplements reduced homocysteine effectively and remain potential candidates for future epigenetic trials in pregnancy in rural Gambia. TRIAL REGISTRATION: Clinicaltrials.gov Reference NCT03431597.

Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline-deficient rats.

Methyl-donor deficiency is a risk factor for neurodegenerative diseases. Dietary deficiency of the methyl-donors methionine and choline [methionine-choline-deficient (MCD) diet] is a well-established model of nonalcoholic steatohepatitis (NASH), yet brain metabolism has not been studied in this model. We hypothesized that supplemental betaine would protect both the liver and brain in this model and that any benefit to the brain would be due to improved liver metabolism because betaine is a methyl-donor in liver methylation but is not metabolically active in the brain. We fed male Sprague-Dawley rats a control diet, MCD diet, or betaine-supplemented MCD (MCD+B) diet for 8 wk and collected blood and tissue. As expected, betaine prevented MCD diet-induced NASH. However, contrary to our prediction, it did not appear to do so by stimulating methylation; the MCD+B diet worsened hyperhomocysteinemia and depressed liver methylation potential 8-fold compared with the MCD diet. Instead, it significantly increased the expression of genes involved in ß-oxidation: fibroblast growth factor 21 and peroxisome proliferator-activated receptor α. In contrast to that of the liver, brain methylation potential was unaffected by diet. Nevertheless, several phospholipid (PL) subclasses involved in stabilizing brain membranes were decreased by the MCD diet, and these improved modestly with betaine. The protective effect of betaine is likely due to the stimulation of ß-oxidation in liver and the effects on PL metabolism in brain.-Abu Ahmad, N., Raizman, M., Weizmann, N., Wasek, B., Arning, E., Bottiglieri, T., Tirosh, O., Troen, A. M. Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline-deficient rats.

Role of betaine in liver injury induced by the exposure to ionizing radiation.

Oxidative stress, apoptosis, and fibrosis may play a major role in the development of radiation-induced liver damage. Betaine, a native compound widely present in beetroot, was reported to possess hepato-protective properties. The objective of this study was to investigate the influence of betaine on radiation-induced liver damage. Animals were exposed to 9 Gy applied in 3 doses of 3 Gy/wk. Betaine (400 mg/kg/d), was orally supplemented to rats after the first radiation dose, and daily during the irradiation period. Animals were sacrificed 1 day after the last dose of radiation. The results showed that irradiation has induced oxidative stress in the liver denoted by a significant elevation in malondialdehyde, protein carbonyl, and 8-hydroxy-2-deoxyguanosine with a significant reduction in catalase activity and glutathione (GSH) content. The activity of the detoxification enzyme cytochrome P450 (CYP450) increased while GSH transferase (GSH-T) decreased. The activity of the apoptotic marker caspase-3 increased concomitant with increased hyaluronic acid, hydroxyproline, laminin (LN), and collagen IV. These alterations were associated with a significant increase of gamma-glutamyl transferase, alkaline phosphatase and alanine and aspartate aminotransferase markers of liver dysfunction. Betaine treatment has significantly attenuated oxidative stress, decreased the activity of CYP450, enhanced GSH-T, reduced the activity of caspase-3, and the level of fibrotic markers concomitant with a significant improvement of liver function. In conclusion, betaine through its antioxidant activity and by enhancing liver detoxification and reducing apoptosis may alleviate the progression of liver fibrosis and exert a beneficial impact on radiation-induced liver damage.

Inhibition of Bromelain Activity During Enzymatic Debridement of Burn Wounds Pretreated With Frequently Used Products.

An enzyme mixture containing bromelain (NexoBrid®) was found to be suitable for enzymatic debridement of burn wounds, as determined by the criteria of patient comfort and pain, selectivity, and efficiency. Nevertheless, daily experience showed that pretreatment of burn wounds with several other clinical agents may inhibit debridement efficiency. Therefore, the current study was performed to identify those agents and evaluate their debridement inhibition capabilities. The impact of several common agents as well pH, on NexoBrid® debridement efficiency was evaluated in vitro. A collagen-based dermal substitute (MatriDerm®) was exposed to NexoBrid® in the presence of different agents of varying concentrations. Digestion was documented. The criteria used for judging digestion were independently classified by 3 investigators at least 3 times in succession. When a low concentration (1.0 mg/ml) of NexoBrid® was used, a ≥ 50% concentration of Prontosan® had an impact on enzymatic activity. Comparable results were obtained when even lower concentrations of Octenisept® (≥ 10%) were used. A 100-µmol/L concentration of copper inhibited the enzymatic activity of both a low (1.0 mg/ml) and high (10 mg/ml) concentration of NexoBrid®. Silver-sulfadiazine at concentrations of 10% and 90% inhibited the activity of 1 mg/ml NexoBrid®. No complete inhibition of NexoBrid® activity occurred at any concentration of iron. We recommend using polyhexanide-containing agents (Prontosan®) to rinse and presoak burn wounds. Pretreatment of burn wounds with agents containing silver and copper should be avoided. Experimentally, we found a partial inhibition of NexoBrid® activity at the distinct pH values of 3 and 11.

Corticosterone-Induced Lipogenesis Activation and Lipophagy Inhibition in Chicken Liver Are Alleviated by Maternal Betaine Supplementation.

Background: We have shown previously that in ovo betaine injection can prevent nonalcoholic fatty liver induced by glucocorticoid exposure in chickens; yet it remains unknown whether feeding betaine to laying hens may exert similar effects in their progeny. Objective: In this study, we fed laying hens a betaine-supplemented diet, and the progeny were later exposed chronically to corticosterone (CORT) to test hepatoprotective effects and further elucidate underlying mechanisms. Methods: Rugao yellow-feathered laying hens (n = 120) were fed a basal (control, C) diet or a 0.5% betaine-supplemented (B) diet for 28 d before their eggs were collected for incubation. At 49 d of age, male chickens selected from each group were daily injected subcutaneously with solvent (15% ethanol; vehicle, VEH) or CORT (4.0 mg/kg body mass) for 7 d to establish a fatty liver model. Chickens in the 4 groups (C-VEH, C-CORT, B-VEH, and B-CORT) were killed at day 57. Plasma and hepatic triglyceride (TG) concentrations, as well as the hepatic expression of genes involved in lipogenesis and lipophagy, were determined. Results: CORT induced a 1.6-fold increase in the plasma TG concentration (P < 0.05) and a 1.8-fold increment in the hepatic TG concentration (P < 0.05), associated with activation of lipogenic genes (70-780%). In contrast, lipophagy and mitochondrial ß-oxidation genes were inhibited by 30-60% (P < 0.05) in CORT-treated chickens. These CORT-induced changes were completely normalized by maternal betaine supplementation or were partially normalized to intermediate values that were significantly different from those in the C-VEH and C-CORT groups. These effects were accompanied by modifications in CpG methylation and glucocorticoid receptor binding to the promoters of major lipogenic and lipophagic genes (P < 0.05). Conclusions: These results indicate that maternal betaine supplementation protects male juvenile chickens from CORT-induced TG accumulation in the liver via epigenetic modulation of lipogenic and lipophagic genes.

Betaine Supplementation Enhances Lipid Metabolism and Improves Insulin Resistance in Mice Fed a High-Fat Diet.

Obesity is a major driver of metabolic diseases such as nonalcoholic fatty liver disease, certain cancers, and insulin resistance. However, there are no effective drugs to treat obesity. Betaine is a nontoxic, chemically stable and naturally occurring molecule. This study shows that dietary betaine supplementation significantly inhibits the white fat production in a high-fat diet (HFD)-induced obese mice. This might be due to betaine preventing the formation of new white fat (WAT), and guiding the original WAT to burn through stimulated mitochondrial biogenesis and promoting browning of WAT. Furthermore, dietary betaine supplementation decreases intramyocellular lipid accumulation in HFD-induced obese mice. Further analysis shows that betaine supplementation reduced intramyocellular lipid accumulation might be associated with increasing polyunsaturated fatty acids (PUFA), fatty acid oxidation, and the inhibition of fatty acid synthesis in muscle. Notably, by performing insulin-tolerance tests (ITTs) and glucose-tolerance tests (GTTs), dietary betaine supplementation could be observed for improvement of obesity and non-obesity induced insulin resistance. Together, these findings could suggest that inhibiting WAT production, intramyocellular lipid accumulation and inflammation, betaine supplementation limits HFD-induced obesity and improves insulin resistance.

Association between malnutrition and hyperhomocysteine in Alzheimer's disease patients and diet intervention of betaine.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, which is associated with malnutrition and hyperhomocysteine. The current study aimed to analyze the relationship between malnutrition and hyperhomocysteine in AD patients, and effects of diet intervention with betaine on the disease. METHODS: The nutritional statuses of the AD patients were assessed by short form mini nutritional assessment (MNA-SF). The levels of Hcy, tau hyperphosphorylation, synaptic proteins, blood inflammatory factors were measured by enzymatic cycling assay, Western blot and ELISA. The cognitive function was measured by AD assessment scale (ADAS-cog). RESULTS: There was a significant difference in mental status between normal people and AD patients (P<.05). Overall, malnutrition was reported in a larger proportion of AD patients and high level of Hcy was closely associated with malnutrition. Betaine decreased the levels of phosphorylated tau, elevated PP2Ac activity and inhibited Aß accumulation (P<.05). The levels of IL-lß and TNF-α were significantly higher in the untreatment group while much lower in the intervention group (P<.05). After intervention of betaine treatment, the expression level of Hcy can be restored and betaine can effectively suppress inflammation as well as trigger an increase in memory-related proteins. ADAS-Cog suggested that significant improvement was found after the intervention of betaine. CONCLUSIONS: AD was associated with both malnutrition and higher levels of Hcy. Betaine could restore Hcy expression to normal level in AD patient, which might ameliorate memory deficits.

Prenatal alcohol-induced neuroapoptosis in rat brain cerebral cortex: protective effect of folic acid and betaine.

PURPOSE: Alcohol consumption in pregnancy may cause fetal alcohol syndrome (FAS) in the infant. This study aims to investigate prenatal alcohol exposure related neuroapoptosis on the cerebral cortex tissues of newborn rats and possible neuroprotective effects of betaine, folic acid, and combined therapy. METHODS: Pregnant rats were divided into five experimental groups: control, ethanol, ethanol + betaine, ethanol + folic acid, and ethanol + betaine + folic acid combined therapy groups. We measured cytochrome c release, caspase-3, calpain and cathepsin B and L. enzyme activities. In order to observe apoptotic cells in the early stages, TUNEL method was chosen together with histologic methods such as assessing the diameters of the apoptotic cells, their distribution in unit volume and volume proportion of cortical intact neuron nuclei. RESULTS: Calpain, caspase-3 activities, and cytochrome c levels were significantly increased in alcohol group while cathepsin B and L. activities were also found to be elevated albeit not statistically significant. These increases were significantly reversed by folic acid and betaine + folic acid treatments. While ethanol increased the number of apoptotic cells, this increase was prevented in ethanol + betaine and ethanol + betaine + folic acid groups. Morphometric examination showed that the mean diameter of apoptotic cells was increased with ethanol administration while this increase was reduced by betaine and betaine + folic acid treatments. CONCLUSION: We observed that ethanol is capable of triggering apoptotic cell death in the newborn rat brains. Furthermore, folic acid, betaine, and combined therapy of these supplements may reduce neuroapoptosis related to prenatal alcohol consumption, and might be effective on preventing fetal alcohol syndrome in infants.

Choline and betaine consumption lowers cancer risk: a meta-analysis of epidemiologic studies.

A number of human and animal in vitro or in vivo studies have investigated the relationship between dietary choline and betaine and cancer risk, suggesting that choline and betaine consumption may be protective for cancer. There are also a few epidemiologic studies exploring this relationship, however, with inconsistent conclusions. The PubMed and Embase were searched, from their inception to March 2016, to identify relevant studies and we brought 11 articles into this meta-analysis eventually. The pooled relative risks (RRs) of cancer for the highest versus the lowest range were 0.82 (95% CI, 0.70 to 0.97) for choline consumption only, 0.86 (95%CI, 0.76 to 0.97) for betaine consumption only and 0.60 (95%CI, 0.40 to 0.90) for choline plus betaine consumption, respectively. Significant protective effect of dietary choline and betaine for cancer was observed when stratified by study design, location, cancer type, publication year, sex and quality score of study. An increment of 100 mg/day of choline plus betaine intake helped reduce cancer incidence by 11% (0.89, 95% CI, 0.87 to 0.92) through a dose-response analysis. To conclude, choline and betaine consumption lowers cancer incidence in this meta-analysis, but further studies are warranted to verify the results.

Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial.

Although the role of homocysteine (HCys) in secondary cardiovascular prevention has been scaled down, hyper-homocysteinemia remains a risk factor for cerebrovascular events. The aim of this study was to investigate the efficacy of nutraceuticals in lowering HCys serum levels versus a conventional vitamin supplementation in hypertensive subjects at low cardiovascular risk. One-hundred and four patients (mean age 62.8±14.5 years, 63.5% males), 52 for each treatment group, were enrolled. The study recruited patients with stage 1 essential hypertension and hyper-homocysteinemia (HCys ≥15 µmol/L), without a history of cardiovascular and cerebrovascular disease. They were sequentially randomized to receive a combined nutraceutical containing 400 µg folate-6-5-methyltetrahydrofolate, 3 mg vitamin B6, 5 µg vitamin B12, 2.4 mg vitamin B2, 12.5 mg zinc and 250 mg betaine (Normocis400®) once daily for two months, or supplementation with highly dosed folic acid (5 mg/day) (control group). Differences in serum HCys values were compared by ANOVA for repeated measures. A significant HCys reduction in comparison to baseline was found in both groups at the end of the study treatment, from 21.5±8.7 to 10.0±1.7 µmol/L for Normocis400® subjects (p less than 0.0001), and from 22.6±6.2 to 14.3±2.8 µmol/L for controls (p less than 0.0001). HCys reduction was significantly higher among patients treated with Normocis400® (p less than 0.035). The ideal HCys level (i.e. less than 10 µmol/L) was reached in 55.8% of cases in theNormocis400® group, and it was significantly higher than in controls. No side effects were observed in either treatment group. Randomized clinical trials are ongoing to test the effect of folate, B6, and B12 supplementation in primary prevention of cardiovascular and cerebrovascular events. In the meantime, especially when the ideal HCys level is far from being reached, Normocis400® appears to be safe, well tolerated and effective in reducing HCys levels.

A randomized trial of Boswellia in association with betaine and myo-inositol in the management of breast fibroadenomas.

OBJECTIVE: Breast fibroadenoma is a common finding in young women and actually accounts for the majority of benign breast lumps. Fibroadenoma does not require any treatment unless clinical symptoms (mostly mastalgia) or histological markers of cancer risk (atypia) impose specific medical or surgical intervention. In symptomatic fibroadenoma, anti-estrogenic treatments provided evidence of success. Yet, these therapies are often associated with relevant side effects that lead to drug treatment discontinuation. Additionally, in such cases, relapse is a frequent issue. Therefore, an optimal strategy is still warranted. Boswellia, betaine and myo-inositol have already been proved to modulate different pathways - inflammatory, metabolic, oxidative and endocrine processes - in a wide array of human tissues. Based on that background, we hypothesized that these substances can effectively synergize in inducing the regression of fibroadenoma. PATIENTS AND METHODS: We included 64 patients ≤ 30 years of age with fibroadenoma. The patients were randomized into two groups. The experimental group was treated with an association of Boswellia, betaine, myo-inositol, B-group vitamins and N-acetylcysteine for 6 months; otherwise, the placebo group was treated only with B-group vitamins and N-acetylcysteine. Patients were monitored at the enrollment and the end of the study for evaluating the clinical response. RESULTS: A significant clinical improvement was observed in the experimental arm. Fibroadenoma median volume reduction averaged 17.86% in the experimental group and 5.96% in the placebo group. Moreover, 14 out of 36 (38.88%) patients showed a reduction of fibroadenoma volume compared to 5/28 (17.85%) observed in the placebo group (p = 0.005). CONCLUSIONS: A supplementation with Boswellia, betaine and myo-inositol reduces fibroadenoma dimension in young women. No relevant side effects have been recorded.