Betaine Administration Research Articles

The BHMT-betaine methylation pathway epigenetically modulates oligodendrocyte maturation.

Research into the epigenome is of growing importance as a loss of epigenetic control has been implicated in the development of neurodegenerative diseases. Previous studies have implicated aberrant DNA and histone methylation in multiple sclerosis (MS) disease pathogenesis. We have previously reported that the methyl donor betaine is depleted in MS and is linked to changes in histone H3 trimethylation (H3K4me3) in neurons. We have also shown that betaine increases histone methyltransferase activity by activating chromatin bound betaine homocysteine S-methyltransferase (BHMT). Here, we investigated the role of the BHMT-betaine methylation pathway in oligodendrocytes. Immunocytochemistry in the human MO3.13 cell line, primary rat oligodendrocytes, and tissue from MS postmortem brain confirmed the presence of the BHMT enzyme in the nucleus in oligodendrocytes. BHMT expression is increased 2-fold following oxidative insult, and qRT-PCR demonstrated that betaine can promote an increase in expression of oligodendrocyte maturation genes SOX10 and NKX-2.2 under oxidative conditions. Chromatin fractionation provided evidence of a direct interaction of BHMT on chromatin and co-IP analysis indicates an interaction between BHMT and DNMT3a. Our data show that both histone and DNA methyltransferase activity are increased following betaine administration. Betaine effects were shown to be dependent on BHMT expression following siRNA knockdown of BHMT. This is the first report of BHMT expression in oligodendrocytes and suggests that betaine acts through BHMT to modulate histone and DNA methyltransferase activity on chromatin. These data suggest that methyl donor availability can impact epigenetic changes and maturation in oligodendrocytes.

Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport.

In schizophrenia (SCZ), neurons in the brain tend to undergo gross morphological changes, but the related molecular mechanism remains largely elusive. Using Kif3b+/- mice as a model with SCZ-like behaviors, we found that a high-betaine diet can significantly alleviate schizophrenic traits related to neuronal morphogenesis and behaviors. According to a deficiency in the transport of collapsin response mediator protein 2 (CRMP2) by the KIF3 motor, we identified a significant reduction in lamellipodial dynamics in developing Kif3b+/- neurons as a cause of neurite hyperbranching. Betaine administration significantly decreases CRMP2 carbonylation, which enhances the F-actin bundling needed for proper lamellipodial dynamics and microtubule exclusion and may thus functionally compensate for KIF3 deficiency. Because the KIF3 expression levels tend to be downregulated in the human prefrontal cortex of the postmortem brains of SCZ patients, this mechanism may partly participate in human SCZ pathogenesis, which we hypothesize could be alleviated by betaine administration.

Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to Lps/Galactosamine Liver Injury and Protection by Betaine Administration.

Simple SummaryPrevious studies from our laboratory have shown that chronic ethanol exposure-induced increase in apoptotic hepatocellular death is closely related to the ethanol-induced impairment in asialoglycoprotein receptor, a major component of liver sugar recognition system. The aim of this study was to examine whether the absence of this receptor confers increased susceptibility to fulminant liver failure induced by lipopolysaccharide/galactosamine. We further investigated whether treatment with betaine, a naturally occurring tertiary amine, prior to lipopolysaccharide/galactosamine injection is protective. Lipopolysaccharide/galactosamine injection caused a more pronounced liver damage in asialoglycoprotein receptor-deficient compared with the wild-type control mice. In addition, prior administration of betaine was found to significantly attenuate the lipopolysaccharide/galactosamine-induced increases in several liver injury parameters. Our work underscores the importance of normal functioning of asialoglycoprotein receptor in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.Background: Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. Methods: Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. Results: LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. Conclusion: Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.

Betaine prevented high-fat diet-induced NAFLD by regulating the FGF10/AMPK signaling pathway in ApoE-/- mice.

Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in developing countries. The pathogenesis is complex, and there is currently no effective treatment. Betaine is an essential intermediate in choline catabolism and an important component of the methionine cycle. Betaine deficiency is associated with NAFLD severity, and its mechanism needs to be further elaborated. In this study, an NAFLD mouse model was established by feeding ApoE-/- mice a high-fat diet. The effects of betaine on NAFLD were investigated, including its mechanism. In this study, after treatment with betaine, blood lipid levels and liver damage were significantly decreased in the NAFLD mouse model. The fat infiltration of the liver tissues of high-fat diet (HFD)-fed mice after betaine administration was significantly improved. Betaine treatment significantly upregulated AMP-activated protein kinase (AMPK), fibroblast growth factor 10 (FGF10), and adipose triglyceride lipase (ATGL) protein levels both in vivo and in vitro and suppressed lipid metabolism-related genes. Furthermore, the overexpression of FGF10 increased the protein level of AMPK and decreased lipid accumulation in HepG2 cells. Taken together, the data strongly suggest that betaine significantly prevents high-fat diet-induced NAFLD through the FGF10/AMPK signaling pathway in ApoE-/- mice.

Betaine Ameliorates Schizophrenic Traits by Functionally Compensating KIF3-Based CRMP2 Transport

Neurons in schizophrenia (SCZ) brains tend to undergo gross morphological changes, but its molecular mechanism is still largely elusive. Using Kif3b+/- mice as a SCZ model, here we show that high betaine diet can significantly remedy their schizophrenic traits in neuronal morphogenesis and social behavior. We identified significant reduction and restoration by betaine of lamellipodial dynamics in developing Kif3b+/- neurons as a cause of neurite hyperbranching, according to a local deficiency of collapsin response mediator protein 2 (CRMP2) transported by the KIF3 motor. Betaine administration significantly decreased the CRMP2 carbonylation, which enhanced its F-actin bundling activity necessary for proper lamellipodial dynamics and peripheral microtubule exclusion, and thus may functionally compensate the KIF3 deficiency. Because KIF3 expression levels tended to be downregulated in human prefrontal cortex of postmortem SCZ patient brains, this mechanism may also take part in human SCZ pathogenesis, which we propose will be remedied by betaine administration.

Hepatotoxicity and nephrotoxicity following long-term prenatal exposure of paracetamol in the neonatal rat: is betaine protective?

Abstract Background Paracetamol is one of the widely used antipyretic and analgesic drug around the world. Many researchers showed that paracetamol caused to hepatotoxicity or nephrotoxicity. Objective In the present study, we aimed to determine whether betaine has protective effects on hepatotoxicity and nephrotoxicity in neonate rats, following to long term maternal paracetamol exposure. Materials and methods Randomly chosen neonates, from the neonate pools, were divided into three groups; Control (n=13), APAP (n=13), and APAP+Betaine (n=13). Physiological saline, paracetamol (30 mg/kg/day), and paracetamol (30 mg/kg/day)+betaine (800 mg/kg/day) were orally administered to the relevant groups during the pregnancy period (approximately 21 day). Following to the birth, neonates were decapitated under anaesthesia and tissue samples were taken for biochemical and histological analyses. Results The statistical analysis showed that, malondialdehyde and nitric oxide levels increase significantly in APAP group, while paraoxonase, arylesterase activity and glutathione levels decrease. After the betaine administration, glutathione levels, paraoxonase and arylesterase activities increased while malondialdehyde and nitric oxide levels decreased in APAP+betaine group. These biochemical findings also were supported by histological results. Conclusion In this study, our biochemical and histological findings indicate that betaine can protect the tissue injury caused by paracetamol.

Alleviation of infectious-bursal-disease-virus-induced bursal injury by betaine is associated with DNA methylation in IL-6 and interferon regulatory factor 7 promoter

Infectious bursal disease virus (IBDV) often infects young chickens and causes severe immunosuppression and inflammatory injury. Betaine is an antiviral and anti-inflammatory ingredient that may exert functions through epigenetic regulation. However, the effects of betaine on an IBDV-induced bursal injury and their underlying mechanisms have not been investigated. In this study, betaine was supplemented to the drinking water of newly hatched commercial broilers for 3 wk. Afterward, the chickens were infected with the IBDV. After 5 D of infection, the bursal lesions were examined. The mRNA expression levels of IBDV VP2 gene, pro-inflammatory cytokines, and interferons were detected. Furthermore, the 5-methylcytosine level of the CpG island in the promoter region of IL-6 and interferon regulatory factor 7 (IRF7) were determined. The IBDV induced the depletion of lymphocytes and inflammation in the bursal follicles. IBDV infection considerably elevated the mRNA levels of VP2, IL-6, types I (IFNα and IFNβ) and II (IFNγ) interferons, and IRF7. The CpG island methylation in the promoter regions of IL-6 and IRF7 were substantially decreased after IBDV infection. Betaine administration attenuated the IBDV-induced bursal lesions. Meanwhile, the IBDV-induced mRNA expression levels of IL-6, IFNβ, and IRF7 were suppressed by betaine consumption. Furthermore, the hypomethylation effects of IBDV infection to the promoter regions of IL-6 and IRF7 genes were eliminated and relieved by betaine administration. Our results indicated that the IBDV-induced expression levels of IL-6 and IRF7 genes are associated with the suppression of methylation in the promoter region. Betaine administration through drinking water may alleviate the IBDV-induced bursal injury via epigenetic regulation.

Efficacy of betaine as carcass modifier in female broiler chickens to produce leaner carcass for human consumption

Betaine is a methyl group donor which involved in protein and energy metabolism, offering an opportunity to the poultry producers to satisfy consumer needs by producing leaner carcass. This study was conducted to investigate the efficacy of betaine as carcass modifier in female broiler chickens fed diet containing sufficient methyl group donor. Two hundred female day-old chicks (DOC) were allotted to four assay diets with 5 replicates of 10 birds. The starter and finisher diets contained 0.50 and 0.38% methionine as methyl group donor, respectively. The basal diets were fed without supplementation or supplemented with 0.10, 0.20 and 0.30% betaine. The assay diets were fed from the age 8–42 days. Two birds per replicate were slaughtered at the age of 42 days to measure the carcass characteristics. The fat content was derived from breast meat samples. Supplementation of betaine did not influence the slaughter weight, carcass and breast yield, indicating similar growth and carcass production. Furthermore, administration of betaine produced 29.8–42.5% lower abdominal fat pad deposition and 9.2 – 35.9% lower meat fat content than those without betaine administration (P<0.05). It can be concluded that betaine can modify carcass characteristic in female broiler chickens by lowering fat deposition.

Homocystinuria: Literature Review and Clinical Case Description

Homocystinuria is rare autosomal-recessive monogenic disorder associated with disturbance of methionine metabolism due to liver enzyme cystathionine--synthetase (CBS) deficit. That in turn causes elevated concentration of homocystein and its metabolites in blood and urine. The main clinical manifestations of homocystinuria are: myopia, ectopia lentis, psychomotor retardation, learning difficulties, mental retardation, mental illnesses, behaviour problems, paroxysms, extrapyramidal symptoms, skeletal anomalies (body height), long limbs — dolichostenomelia and arachnodactylia (Marfan Phenotype), pectus carinatum, valgus lower limbs, scoliosis, osteoporosis, thromboembolic disorders. Diagnostics of homocystinuria is based on clinical findings and laboratory changes (increase of methionine and homocysteine levels in serum). There is prenatal and DNA-diagnostics (genetic variants in CBS gene). Revealing of homocystinuria demands examination of first-degree relatives. Therapy of patients with homocystinuria includes not only diet therapy but also pyridoxine, folic acid, betaine administration. Syndromic concomitant therapy is also used. The description of the patient with severe B6-resistant form of homocystinuria is given in this article.

Evaluation of Betaine Neuroprotective Effects on 6-Hydroxydopamine-Induced hemi-Parkinsonism in Male Wistar Rats

BACKGROUND: Parkinson's disease (PD) is one of the prevalent debilitating neurodegenerative disor- ders. Accordingly, researchers are working on methods to modify PD progression. Previously, the neuro- protective effects of betaine, as a methyl donor agent in homocysteine metabolism, have been demonstrated in animal models of chronic cerebral hypoperfusion and memory deficits. OBJECTIVES: It was aimed to investigate the neuroprotective effects of betaine in an animal model of PD. METHODS: In male Wistar rats under two-week course of oral betaine administration (50, 100, and 200 mg/kg per day), the behavioral, biochemical, and histological evaluations were conducted one week follow- ing unilateral nigral 6-OHDA injection. RESUTLS: Betaine administration with dose of 200 mg/kg, one week before and after 6-OHDA lesioning, was associated with a meaningful reduction in the plasma levels of homocysteine (Hcy) in comparison with the control and sham groups (P < 0.05). Our evaluations revealed a remarkable improvement in motor asymmetry induced by apomorphine in the rats under treatment of betaine 200 mg/kg. Moreover, in this group, a significant decrease of malondyaldehyde (MDA) concentrations was detected in the brain tissues, as well as a significantly diminished neuronal cell loss (percent) in substantia nigra pars compacta (P < 0.05). The results of 50 and 100 mg/kg betaine groups were not significant. CONCLUSIONS: Altogether, our findings indicate the antioxidant neuroprotective effects of betaine in this animal model of PD and it is in concordance with betaine properties in decreasing the plasma levels and possible neurotoxic effects of Hcy.

Effect of betaine versus arsenite-induced alterations of testicular oxidative stress and circulating androgenic indices in rats.

The aim of this work was to study the alleviative role of betaine versus arsenite-provoked alterations in testis oxidative status and circulating androgenic indices. Twenty-four adult male rats (204.5±21g) were divided into four groups, equally. Control group was given basal diet and tap water. Group 2 rats received arsenite (100mg/L) in drinking water. Rats in group 3 received betaine (2% of the diet) during arsenite exposure. Group 4 received betaine at 2% of the diet during study period (30days). The results revealed significant decrease in testicular glutathione peroxidase, catalase and glutathione in arsenite-treated animals relative to controls. Significant increase in testicular malondialdehyde was also detected in arsenite-exposed group. Concurrent administration of betaine with arsenite significantly increased glutathione and catalase amounts in comparison with arsenite group. Arsenite exposure resulted in a significant decrease in plasma testosterone and dihydrotestosterone levels over control rats, whereas supplementation of betaine augmented the hormones concentrations to the levels that had no significant difference in comparison with controls. Concentration of all measured oxidative status and hormonal variables in the betaine plus arsenite and betaine groups was not significantly different relative to controls. Taken together, betaine may be proposed as an alleviative agent against arsenite-induced male reprotoxicity.

Betaine and ascorbic acid modulate indoor behavior and some performance indicators of broiler chickens in response to hot-dry season

Heat stress causes lipid peroxidation in poultry, necessitating antioxidant administration. The experiment evaluated the modulating effects of betaine and ascorbic acid (AA) on indoor behavior and some performance parameters of broiler chickens during the hot-dry season. Experimental groups were: Group I (control) was daily given sterile water; Group II, betaine at 250 mg/kg; Group III, AA (50 mg/kg), and Group IV, betaine (250 mg/kg) + AA (50 mg/kg), orally for 42 days. The natural occurring dry-bulb temperature (28.0–37.0 °C), relative humidity (69.0–93.0%), and temperature-humidity index (27.9–36.1 °C) were predominantly outside the thermo-neutral zone for broiler chickens, indicating heat stress conditions. Scan test, used to assess the percentage of birds sitting/lying, panting, feeding, drinking and spreading wings, was performed at 06:00 h, 13:00 h and 18:00 h on each of days 35 and 42. Feed intakes (FD), water consumption (WC), body weight, average daily weight gain (ADG) and feed-to-gain ratio (FGR) were obtained. Betaine+AA reduced (P < 0.05) percentage of birds panting; AA decreased (P < 0.05) percentage of birds spreading wing, compared with control. Finisher phase: betaine and/or AA, decreased FGR, increased ADG (P < 0.05); betaine reduced (P < 0.01) FD compared with control. Grower phase: betaine, either alone or with AA, lowered FGR and FD (P < 0.01); AA reduced (P < 0.01) FD, compared with control. Starter phase: betaine and/or AA decreased WC (P < 0.05); AA lowered FGR, compared with controls. Betaine administration decreased (P < 0.05) FD at 4 week-old, but its administration, either alone or with AA, reduced WC at 1 week-old, compared with control. Overall, betaine and/or AA group lowered FGR compared with controls. In conclusion, administration of betaine and/or AA to broiler chickens modulated indoor behavior, some performance indicators and water consumption during the hot-dry season.

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response.

Background: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. Several studies have demonstrated that betaine possesses outstanding anti-inflammatory effects. However, whether betaine exerts protective effects on PAH by inhibiting inflammatory responses in the lungs needs to be explored. To test our hypothesis, we aimed to investigate the effects of betaine on monocrotaline-induced PAH in rats and attempted to further clarify the possible mechanisms. Methods: PAH was induced by monocrotaline (50 mg/kg) and oral administration of betaine (100, 200, and 400 mg/kg/day). The mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricle hypertrophy index were used to evaluate the development of PAH. Hematoxylin and eosin staining and Masson staining were performed to measure the extents of vascular remodeling and proliferation in fibrous tissue. Monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were also detected by immunohistochemical staining. Nuclear factor-κB (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) were assessed by Western blot. Results: This study showed that betaine improved the abnormalities in right ventricular systolic pressure, mean pulmonary arterial pressure, right ventricle hypertrophy index, and pulmonary arterial remodeling induced by monocrotaline compared with the PAH group. The levels of MCP-1 and ET-1 also decreased. Western blot indicated that the protein expression levels of NF-κB, TNF-α, and IL-1β significantly decreased (p < 0.01). Conclusion: Our study demonstrated that betaine attenuated PAH through its anti-inflammatory effects. Hence, the present data may offer novel targets and promising pharmacological perspectives for treating monocrotaline-induced PAH.

Maternal betaine administration modulates hepatic type 1 iodothyronine deiodinase (Dio1) expression in chicken offspring through epigenetic modifications

As a feed additive, betaine is widely used in livestock production for its ability to promote growth. Our previous studies had reported that maternal betaine supplementation altered hepatic metabolism in offspring. But it remains unknown whether and how maternal betaine modulates metabolism of thyroid hormones in the offspring chickens by epigenetic modification. In this study, one hundred and twenty Rugao yellow-feathered laying hens were randomly divided into two groups, and were fed basal diet with or without 0.5% betaine supplementation for 28 days. After that, all the hens were artificially inseminated and then four hundreds fertilized eggs were selected. After hatching, the newborn chicks were raised until 56 days old. Betaine fed female chicks showed significantly lower body weight and lower level of biologically active thyroid hormone in plasma compared to control group, which was associated with significantly decrease in expression of type 1 iodothyronine deiodinase (Dio1). Moreover, betaine also changed hepatic expression of betaine-homocysteine -S-methyltransferase (BHMT) and DNA methyltransferase 1 (DNMT1), which may contribute to hypermethylation of the Dio1 promoter. Interestingly, betaine treatments of hens caused none of these effects in male chicks except Dio1 expression. These results indicate that maternal betaine administration effects growth of offspring through differential modification of Dio1 gene methylation and expression in liver and this model of transgenerational effects may help elucidate the mechanisms of maternal effects arise in natural systems.

Behavioral and hematological responses of broiler chickens administered with betaine and ascorbic acid during hot-dry season

ABSTRACTHeat stress is a major problem in poultry production in tropical regions. Assessing the impact of thermally stressful environmental conditions on the welfare of broiler chickens is of great importance. Behavioral responses in a novel environment and hematology of broiler chickens administered with betaine and/or ascorbic acid (AA) during the hot-dry season were evaluated. Broiler chickens were randomly divided into four groups: Group I (control) was given sterile water, Group II was given betaine, Group III was given AA, and Group IV received betaine + AA orally and daily for 42 days. An open-field test was used to assess behavior. Hematological parameters were obtained using a hematology auto-analyzer. The natural environmental conditions were predominantly outside the thermoneutral zone for broiler chickens. Results demonstrated that treated groups exhibited improved ability to adjust faster to a new environment and better hematological responses than controls, evidenced by enhanced behavioral responses, oxygen-carrying capacity, and immune responses of broiler chickens under unfavorable environmental conditions. Betaine and/or AA administration to broiler chickens improved some behavioral responses, hemoglobin concentrations, packed cell volume, and total leukocyte count during the hot-dry season.

Prenatal betaine exposure modulates hypothalamic expression of cholesterol metabolic genes in cockerels through modifications of DNA methylation

Cholesterol is essential for neuronal development and brain function. Previously we reported that in ovo administration of betaine modulates hepatic cholesterol metabolism in the chicken, yet it remains unknown whether maternal betaine affects the cholesterol content and the expression of cholesterol metabolic genes in chicken hypothalamus. In this study, eggs were injected with saline or betaine at 2.5 mg/egg, and the hatchlings were raised under the same condition until 64 d of age. Maternal betaine significantly (P = 0.05) increased the body weight and suppressed aggressive behavior of 64-day-old cockerels, in association with significantly (P < 0.05) up-regulated expression of 5-HTR1A receptor in the hypothalamus. Concurrently, betaine in ovo significantly increased (P < 0.05) the hypothalamic content of total cholesterol and cholesterol ester, which coincided with significantly up-regulated (P < 0.05) hypothalamic expression of cholesterol biosynthetic genes, such as sterol-regulatory element binding protein 2 and 3-hydroxy-3-methyl-glutaryl-CoA reductase as well as acetyl-CoA cholesterol acyltransferase 1, which converts free cholesterol to cholesterol ester for storage. In contrast, low density lipoprotein receptor, which mediates the cholesterol uptake, was significantly down-regulated (P < 0.05). In ovo betaine administration significantly enhanced the expression of betaine-homocysteine methyltransferase and DNA methyltransferase 1 (P < 0.05), which was associated with alterations of CpG methylation on the promoter of modified cholesterol metabolic genes. These results indicate that maternal betaine modulates hypothalamic cholesterol metabolism in cockerels through modifying DNA methylation on the promoter of cholesterol metabolic genes.

Rapidly progressive psychotic symptoms triggered by infection in a patient with methylenetetrahydrofolate reductase deficiency: a case report

BackgroundMethylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn error of metabolism inherited in autosomal recessive pattern and is associated with a wide spectrum of neurological abnormalities.Case presentationWe herein describe a 15-year-old boy with MTHFR deficiency who presented with a slowly progressive decline of school performance and a spastic gait. Rapidly deteriorating psychosis and repetitive seizures triggered by a febrile infection prompted neurological investigation. He had significantly elevated total plasma homocysteine and urinary homocystine levels, as well as a decreased plasma methionine level. Brain magnetic resonance imaging (MRI) revealed leukoencephalopathy. DNA gene sequencing showed c.446_447 del GC ins TT and c.137G > A, and c.665C > T heterozygous mutations in the MTHFR gene of the patient. Oral administration of betaine drastically improved his clinical symptoms within a few months. After 8 months of treatment, his total plasma homocysteine level moderately decreased; and the plasma methionine concentration became normalized. Furthermore, the white matter lesions on MRI had disappeared.ConclusionThis patient demonstrates the possibility that MTHFR deficiency should be considered in mentally retarded adolescents who display an abnormally elevated plasma level of homocysteine in association with progressive neurological dysfunction and leukoencephalopathy. Febrile infections may be an aggravating factor in patients with MTHFR deficiency.

Molecular Mechanism of Betaine on Hepatic Lipid Metabolism: Inhibition of Forkhead Box O1 (FoxO1) Binding to Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)

Betaine is a major water-soluble component of Lycium chinensis. Although there are reports about the protective effects of betaine on hepatic steatosis, the underlying mechanisms are unclear. We used db/db mice and HepG2 cells to examine the mechanism underlying betaine-mediated protection against hepatic steatosis. Here, we showed increased hepatic lipid accumulation in db/db mice, which is associated with increased activation of lipogenic transcription factors including forkhead box O1 (FoxO1) and peroxisome proliferator-activated receptor gamma (PPARγ), whereas betaine administration by oral gavage reversed these characteristics. We investigated whether betaine ameliorates hepatic steatosis by inhibiting FoxO1/PPARγ signaling in HepG2 cells. Although adenovirus-mediated FoxO1 overexpression notably increased mRNA expression levels of PPARγ and its target genes including FAS and ACC, betaine treatment reversed them. Furthermore, betaine inhibited FoxO1 binding to the PPARγ promoter and PPARγ transcriptional activity in HepG2 cells, which was previously shown to induce hepatic steatosis. We concluded that betaine ameliorates hepatic steatosis, at least in part, by inhibiting the FoxO1 binding to PPARγ and their downstream lipogenic signaling cascade.

Effect of Afobazole and Betaine on Cognitive Disorders in the Offspring of Rats with Streptozotocin-Induced Diabetes and Their Relationship with DNA Damage.

Cognitive activity in 60-day-old offspring of rats (intrauterine development in experimental streptozotocin-induced diabetes) was studied on the model of food-seeking behavior under conditions of free choice in a 6-arm maze. The formation of the food-procuring skill was significantly delayed, which attests to impairment of cognitive functions in these animals. Peroral administration of afobazole (10 and 50 mg/kg) and betaine (50 and 100 mg/kg) significantly and dose-dependently alleviated this disorder. Correlation analysis of the data on delayed formation of a food-procuring skill and results of DNA comet attests to a strong relationship between DNA damage in cells of the embryo and placenta during intrauterine development and cognitive dysfunction in the postnatal offspring of animals with streptozotocin-induced diabetes.

Pathobiological Insights into Neurological Involvement in Cobalamin C Deficiency

Cobalamin C (Cbl-C) defects are inherited autosomal recessive disorders of vitamin B 12 (or cyanocobalamin [CNCbl]) metabolism. These defects are caused by mutations in the methylmalonic aciduria and homocystinuria Cbl-C type ( MMACHC ; MIM # 609831) gene located on chromosome 1p34.1, which catalyzes the reductive decyanation of CNCbl, thus impairing the biosynthesis of 5′-deoxyadenosylcobalamin, adenosylcobalamin, and methylcobalamin. This impairment results in methylmalonic acidemia [MMA; MIM # 277400] combined with hyperhomocysteinemia and hypomethioninemia . Clinically, Cbl-C defects are characterized by a constellation of systemic signs and symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy, are common in the early-onset form of the disease, but are rare in its adult-onset counterpart. Administration of hydroxocobalamin (OHCbl), betaine, and folinic acid represents main therapeutic approaches. No proven efficacy has been demonstrated for carnitine and dietary protein restrictions. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adjustment exist. Despite these measures, the long-term outcome is unsatisfactory especially in patients with early onset, who experience frequent progression of their neurological and ocular impairment. The unfavorable outcome suggests that a better understanding of the pathophysiology of the disease is needed to improve treatment protocols and to develop new therapeutic approaches.