Late-onset renal TMA and tubular injury in cobalamin C disease: a report of three cases and literature review.

BACKGROUND: Mutation of MMACHC gene causes cobalamin C disease (cblC), an inherited metabolic disorder, which presents as combined methylmalonic aciduria (MMA-uria) and hyperhomocysteinaemia in clinical. Renal complications may also be present in patients with this inborn deficiency. The most common histological change is thrombotic microangiopathy (TMA). However, to our acknowledge, renal tubular injury in the late-onset presentation of cblC is rarely been reported. This study provides a detailed description of the characteristics of kidney disease in cblC deficiency, aiming to improve the early recognition of this treatable disease for clinical nephrologists. CASE PRESENTATION: Here we described three teenage patients who presented with hematuria, proteinuria, and hypertension in clinical presentation. They were diagnosed with renal involvement due to cblC deficiency after laboratory tests revealing elevated serum and urine homocysteine, renal biopsy showing TMA and tubular injury, along with genetic testing showing heterogeneous compound mutations in MMACHC. Hydroxocobalamin, betaine, and L-carnitine were administered to these patients. All of them got improved, with decreased homocysteine, controlled blood pressure, and kidney outcomes recovered. CONCLUSIONS: The clinical diagnosis of cblC disease associated with kidney injury should be considered in patients with unclear TMA accompanied by a high concentration of serum homocysteine, even in teenagers or adults. Early diagnosis and timely intervention are vital to improving the prognosis of cobalamin C disease. CLINICAL TRIAL NUMBER: Not applicable.

Clinical use of 0.1% polyhexanide and propylbetaine on acute and hard-to-heal wounds: a literature review.

OBJECTIVE: To summarise the findings on the effect of the clinical use of 0.1% polyhexanide-propylbetaine (PHMB/betaine) solution/gel on acute and hard-to-heal (chronic) wound healing. METHOD: A literature search was conducted in MEDLINE, CINAHL, Embase, Scopus and the CENTRAL Trials Registry of the Cochrane Collaboration. Paired reviewers conducted title and abstract screening and full-text screening to identify experimental, quasi-experimental and observational studies. Study quality and risk of bias were not formally evaluated. RESULTS: A total of 17 studies met the eligibility criteria. The findings from 12 studies indicated that the use of 0.1% PHMB/betaine solution/gel had: a low risk of contact sensitivity; could help debridement during wound cleansing; aided effective wound bed preparation; reduced wound size, odour and exudate; improved pain control; reduced microbial load; and enhanced wound healing. The results of three studies indicated that both 0.1% PHMB and saline solution were effective in reducing bacterial load, while another showed that adding 0.1% PHMB to tie-over dressings had no effect on reducing bacterial loads in wounds. Another study concluded that disinfection and granulation of pressure ulcers with hydrobalance dressing with 0.3% PHMB was faster and more effective than using 0.1% PHMB/betaine. CONCLUSION: The findings of this literature review showed that 0.1% PHMB/betaine solution/gel appeared to be useful and safe for wound cleansing, was effective in removing soft debris and slough from the wound bed, and created a wound environment optimal for healing. Although these actions cannot be attributed solely to this treatment modality, these results do highlight the unique action of this combined product. However, more robust studies are needed to confirm these results.

Quality of life case series review: wound bed preparation from a UK perspective.

Previous studies have reported that polyhexamethylene biguanide (PHMB) and betaine solution and gels remove biofilm, improve wound healing and reduce infection rates. Quality of life (QoL) outcomes are not commonly reported on when it comes to wound care. This review aims to summarise QoL data from a cohort of case studies previously published on chronic lower limb ulcers using PHMB products (Prontosan® Solution, Prontosan® Wound Gel X and Prontosan® Debridement Pad). Here, we report on and review a total of 38 case studies describing 56 wounds. From these 38 case studies, 36 reported that all the wounds involved had either healed or improved by the end of their respective study period. QoL themes explore malodour, slough, and exudate, pain, mobility, hair growth, antibiotic intake, return to work, social life and mood. This case series demonstrates that treatment with Prontosan® products improves many QoL outcomes for patients with non-healing wounds.

Cost-Effectiveness of PHMB & betaine wound bed preparation compared with standard care in venous leg ulcers: A cost-utility analysis in the United Kingdom.

BACKGROUND: Wounds cost £8.3 billion per year in the United Kingdom (UK) annually. Venous leg ulcers (VLUs) account for 15% of wounds and can be complicated to heal, increasing nurse visits and resource costs. Recent wound bed preparation consensus recommends wound cleansing and biofilm disrupting agents. However, inert cleansers such as tap water or saline are inexpensive, an evaluation of evidence is required to justify the higher upfront costs of treatment with active cleansers. We undertook a cost-effectiveness analysis of the use of a biofilm disrupting and cleansing solution and gel, Prontosan® Solution and Gel X, (PSGX) (B Braun Medical), as compared to the standard practice of using saline solution, for treating VLUs. METHODS: A Markov model was parameterised to one-year costs and health-related quality of life consequences of treating chronic VLUs with PSGX versus saline solution. Costs are viewed from a UK healthcare payer perspective, include routine care and management of complications. A systematic literature search was performed to inform the clinical parameters of the economic model. Deterministic univariate sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were undertaken. RESULTS: For PSGX an Incremental Net Monetary Benefit (INMB) of £1,129.65 to £1,042.39 per patient (with a Maximum Willingness to Pay of £30k and £20k per QALY respectively), of which cost savings are £867.87 and 0.0087 quality-adjusted life years (QALYs) gain per patient. PSA indicates a 99.3% probability of PSGX being cost-effective over saline. CONCLUSIONS: PSGX for the treatment of VLUs is dominant compared with saline solution in the UK with expected cost-savings within a year and improved patient outcomes.

Betaine attenuate chronic restraint stress-induced changes in testicular damage and oxidative stress in male mice.

SCOPE: Male fertility and sperm quality are negatively affected by psychological stress. Chronic restraint stress (CRS) is a common psychological stress that has a negative effect on sperm. Betaine (BET), an active ingredient isolated from Lycium barbarum, has anti-oxidant, anti-inflammatory and other pharmacological activities. This study aims to explore whether betaine has a therapeutic effect on sperm deformity and vitality under CRS and its mechanism. METHODS AND RESULTS: Chronic restraint stress was induced in 8-week-old male C57BL/6 J mice by fixation for 6 h a day for 35 days. Mice were intraperitoneally injected with betaine (BET) or normal saline (NS) for 14 days. Thirty-five days later, the animals were sacrificed. The results showed that the detrimental effects of CRS on testes as evident by disrupted histoarchitecture, increased oxidative stress, inflammation and apoptosis that compromised male fertility. BET injections can reverse these symptoms. CONCLUSIONS: BET can improve spermatogenesis dysfunction caused by CRS, which may provide potential dietary guidance.

Preventive Effect of Betaine Against Cognitive Impairments in Amyloid ß Peptide-Injected Mice Through Sirtuin1 in Hippocampus.

In the pathophysiology of Alzheimer's disease, the deposition of amyloid ß peptide (Aß) is associated with oxidative stress, leading to cognitive impairment and neurodegeneration. We have already reported that betaine (glycine betaine), an osmolyte and methyl donor in cells, prevents the development of cognitive impairment in mice with intracerebroventricular injection of Aß25-35, an active fragment of Aß, associated with oxidative stress in the hippocampus, but molecular mechanisms of betaine remain to be determined. Here, to investigate a key molecule underlying the preventive effect of betaine against cognitive impairments in Aß25-35-injected mice, cognitive tests and qPCR assays were performed in Aß25-35-injected mice with continuous betaine intake, in which intake was started a day before Aß25-35 injection, and then continued for 8 days. The Aß25-35 injection impaired short-term and object recognition memories in the Y-maze and object recognition tests, respectively. PCR assays revealed the down-regulation of Sirtuin1 (SIRT1), a NAD+-dependent deacetylase that mediates metabolic responses, in the hippocampus of Aß25-35-injected mice, whereas betaine intake prevented memory deficits as well as the decrease of hippocampal SIRT1 expression in Aß25-35-injected mice. Further, sirtinol, an inhibitor of the Sirtuin family, blocked the preventive effect of betaine against memory deficits. On the other hand, resveratrol, the potent compound that activates SIRT1, also prevented memory impairments in Aß25-35-injected mice, suggesting that SIRT1 plays a causative role in the preventive effect of betaine against memory deficits caused by Aß exposure.

Betaine in ameliorating alcohol-induced hepatic steatosis.

Alcohol-associated liver disease (AALD) is one of most common chronic liver diseases. Hepatic steatosis is the earliest stage in AALD pathological spectrum, reversible by alcohol abstinence. Untreated steatosis can progress to steatohepatitis, fibrosis and/or cirrhosis. Considering the difficulties in achieving complete abstinence, challenges in disease reversal at advanced stages, high costs of AALD management and lack of standardised prescribed medications for treatment, it is essential to explore low-cost natural compounds that can target AALD at an early stage and halt or decelerate disease progression. Betaine is a non-hazardous naturally occurring nutrient. Here, we address the mechanisms of alcohol-induced hepatic steatosis, the role of betaine in reversing the effects i.e., its action against hepatic steatosis in animal models and humans, and the associated cellular and molecular processes. Accordingly, the review discusses how betaine restores the alcohol-induced reduction in methylation potential by elevating the levels of S-adenosylmethionine and methionine. It details how betaine reinstates alcohol-induced alterations in the expressions and/or activities of protein phosphtase-2A, FOXO1, PPAR-α, AMPK, SREBP-1c, fatty acid synthase, diacylglycerol transferase-2, adiponectin and nitric oxide. Interrelationships between these factors in preventing de novo lipogenesis, reducing hepatic uptake of adipose-tissue-derived free fatty acids, promoting VLDL synthesis and secretion, and restoring ß-oxidation of fatty acids to attenuate hepatic triglyceride accumulation are elaborated. Despite its therapeutic potential, very few clinical trials have examined betaine's effect on alcohol-induced hepatic lipid accumulation. This review will provide further confidence to conduct randomised control trials to enable maximum utilisation of betaine's remedial properties to treat alcohol-induced hepatic steatosis.

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.

Effects of betaine on non-alcoholic liver disease.

The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) poses a growing challenge in terms of its prevention and treatment. The 'multiple hits' hypothesis of multiple insults, such as dietary fat intake, de novo lipogenesis, insulin resistance, oxidative stress, mitochondrial dysfunction, gut dysbiosis and hepatic inflammation, can provide a more accurate explanation of the pathogenesis of NAFLD. Betaine plays important roles in regulating the genes associated with NAFLD through anti-inflammatory effects, increased free fatty oxidation, anti-lipogenic effects and improved insulin resistance and mitochondrial function; however, the mechanism of betaine remains elusive.

Wound cleansing for treating venous leg ulcers.

BACKGROUND: Leg ulcers are open skin wounds that occur below the knee but above the foot. The majority of leg ulcers are venous in origin, occurring as a result of venous insufficiency, where the flow of blood through the veins is impaired; they commonly arise due to blood clots and varicose veins. Compression therapy, using bandages or stockings, is the primary treatment for venous leg ulcers. Wound cleansing can be used to remove surface contaminants, bacteria, dead tissue and excess wound fluid from the wound bed and surrounding skin, however, there is uncertainty regarding the effectiveness of cleansing and the best method or solution to use. OBJECTIVES: To assess the effects of wound cleansing, wound cleansing solutions and wound cleansing techniques for treating venous leg ulcers. SEARCH METHODS: In September 2019 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) comparing wound cleansing with no wound cleansing, or RCTs comparing different wound cleansing solutions, or different wound cleansing techniques. DATA COLLECTION AND ANALYSIS: We screened studies for their appropriateness for inclusion, assessed their risk of bias using the Cochrane 'Risk of bias' tool, and used GRADE methodology to determine the certainty of evidence. Two review authors undertook these tasks independently, using predetermined criteria. We contacted study authors for missing data where possible. MAIN RESULTS: We included four studies with a total of 254 participants. All studies included comparisons between different types of cleansing solutions, and three of these reported our primary outcomes of complete wound healing or change in ulcer size over time, or both. Two studies reported the secondary outcome, pain. One study (27 participants), which compared polyhexamethylene biguanide (PHMB) solution with saline solution for cleansing venous leg ulcers, did not report any of the review's primary or secondary outcomes. We did not identify any studies that compared cleansing with no cleansing, or that explored comparisons between different cleansing techniques. One study (61 participants) compared aqueous oxygen peroxide with sterile water. We are uncertain whether aqueous oxygen peroxide makes any difference to the number of wounds completely healed after 12 months of follow-up (risk ratio (RR) 1.88, 95% confidence interval (CI) 1.10 to 3.20). Similarly, we are uncertain whether aqueous oxygen peroxide makes any difference to change in ulcer size after eight weeks of follow-up (mean difference (MD) -1.38 cm2, 95% CI -4.35 to 1.59 cm2). Finally, we are uncertain whether aqueous oxygen peroxide makes any difference to pain reduction, assessed after eight weeks of follow-up using a 0 to 100 pain rating, (MD 3.80, 95% CI -10.83 to 18.43). The evidence for these outcomes is of very low certainty (we downgraded for study limitations and imprecision; for the pain outcome we also downgraded for indirectness). Another study (40 participants) compared propyl betaine and polihexanide with a saline solution. The authors did not present the raw data in the study report so we were unable to conduct independent statistical analysis of the data. We are uncertain whether propyl betaine and polihexanide make any difference to the number of wounds completely healed, change in ulcer size over time, or wound pain reduction. The evidence is of very low certainty (we downgraded for study limitations and imprecision). The final study (126 participants) compared octenidine dihydrochloride/phenoxyethanol (OHP) with Ringer's solution. We are uncertain whether OHP makes any difference to the number of wounds healed (RR 0.96, 95% CI 0.53 to 1.72) or to the change in ulcer size over time (we were unable to conduct independent statistical analysis of available data). The evidence is of very low certainty (we downgraded for study limitations and imprecision). None of the studies reported patient preference, ease of use of the method of cleansing, cost or health-related quality of life. In one study comparing propyl betaine and polihexanide with saline solution the authors do not report any adverse events occurring. We are uncertain whether OHP makes any difference to the number of adverse events compared with Ringer's solution (RR 0.58, 95% CI 0.29 to 1.14). The evidence is of very low certainty (we downgraded for study limitations and imprecision). AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence to guide decision making about the effectiveness of wound cleansing compared with no cleansing and the optimal approaches to cleansing of venous leg ulcers. From the four studies identified, there is insufficient evidence to demonstrate whether the use of PHMB solution compared with saline solution; aqueous oxygen peroxide compared with sterile water; propyl betaine and polihexanide compared with a saline solution; or OHP compared with Ringer's solution makes any difference in the treatment of venous leg ulcers. Evidence from three of the studies is of very low certainty, due to study limitations and imprecision. One study did not present data for the primary or secondary outcomes. Further well-designed studies that address important clinical, quality of life and economic outcomes may be important, based on the clinical and patient priority of this uncertainty.

ANTECEDENTES: Las úlceras de la pierna son heridas cutáneas abiertas que se producen por debajo de la rodilla, pero por encima del pie. La mayoría de las úlceras de la pierna son de origen venoso, y se producen como resultado de la insuficiencia venosa, en la que el flujo de sangre a través de las venas se ve afectado; suelen surgir debido a coágulos de sangre y venas varicosas. El tratamiento de compresión (vendas o medias) es el tratamiento principal para las úlceras venosas de la pierna. La limpieza de la herida se puede utilizar para eliminar los contaminantes superficiales, las bacterias, el tejido muerto y el exceso de líquido de la base de la úlcera y de la piel circundante; sin embargo, no se sabe con certeza cuál es la efectividad de la limpieza ni cuál es el mejor método o solución a utilizar. OBJETIVOS: Evaluar los efectos de la limpieza de heridas, las soluciones de limpieza de heridas y las técnicas de limpieza de heridas para el tratamiento de las úlceras venosas de la pierna. MÉTODOS DE BÚSQUEDA: En septiembre de 2019 se hicieron búsquedas en el Registro especializado del Grupo Cochrane de Heridas (Cochrane Wounds Group), en el Registro Cochrane central de ensayos controlados (CENTRAL); Ovid MEDLINE (incluido In­Process & Other Non­Indexed Citations); Ovid Embase y EBSCO CINAHL Plus. También se buscaron estudios en curso y no publicados en los registros de ensayos clínicos, y se examinaron las listas de referencias de los estudios incluidos pertinentes, así como de las revisiones, los metanálisis y los informes de tecnología sanitaria para identificar estudios adicionales. No hubo restricciones en cuanto al idioma, la fecha de publicación ni el contexto de los estudios. CRITERIOS DE SELECCIÓN: Se consideraron los ensayos controlados aleatorizados (ECA) que compararon la limpieza de heridas con ninguna limpieza de heridas, o ECA que compararon diferentes soluciones de limpieza de heridas o diferentes técnicas de limpieza de heridas. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se examinaron los estudios para determinar si eran adecuados para inclusión, el riesgo de sesgo se evaluó mediante la herramienta Cochrane "Risk of bias" y se utilizó el método GRADE para determinar la certeza de la evidencia. Dos autores de la revisión realizaron estas tareas de forma independiente, utilizando criterios predeterminados. Cuando fue posible, se estableció contacto con los autores de los estudios para obtener los datos faltantes. RESULTADOS PRINCIPALES: Se incluyeron cuatro estudios con un total de 254 participantes. Todos los estudios incluyeron comparaciones entre diferentes tipos de soluciones de limpieza, y tres de ellos informaron sobre los desenlaces principales de esta revisión, cicatrización completa de la herida o cambio en el tamaño de la úlcera con el tiempo, o ambos. Dos estudios informaron sobre el desenlace secundario de dolor. Un estudio (27 participantes), que comparó la solución de polihexametileno biguanida (PHMB) con el suero fisiológico para la limpieza de las úlceras venosas de la pierna, no informó sobre ninguno de los desenlaces principales ni secundarios de la revisión. No se identificaron estudios que compararan la limpieza con ninguna limpieza, o que explorara comparaciones entre diferentes técnicas de limpieza. Un estudio (61 participantes) comparó el peróxido de oxígeno acuoso con el agua estéril. No hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en el número de heridas completamente cicatrizadas tras 12 meses de seguimiento (razón de riesgos [RR] 1,88; intervalo de confianza [IC] del 95%: 1,10 a 3,20). Del mismo modo, no hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en el cambio del tamaño de la úlcera tras ocho semanas de seguimiento (diferencia de medias [DM] ­1,38 cm2; IC del 95%: ­4,35 a 1,59 cm2). Por último, no hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en la reducción del dolor, evaluada tras ocho semanas de seguimiento mediante una calificación del dolor de 0 a 100 (DM 3,80; IC del 95%: ­10,83 a 18,43). La evidencia para estos desenlaces es de certeza muy baja (se disminuyó la calificación por las limitaciones del estudio y la imprecisión; para el desenlace dolor también se disminuyó la calificación por medidas indirectas). Otro estudio (40 participantes) comparó la propil betaína y la polihexanida con una solución salina. Los autores no presentaron los datos brutos en el informe del estudio, por lo que no fue posible realizar un análisis estadístico independiente de los datos. No se sabe si la propil betaína y la polihexanida suponen alguna diferencia en el número de heridas completamente cicatrizadas, en el cambio del tamaño de la úlcera con el tiempo o en la reducción del dolor de la herida. La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). El último estudio (126 participantes) comparó el dihidrocloruro de octenidina/fenoxietanol (OHP) con la solución de Ringer. No hay certeza de que el OHP suponga alguna diferencia en el número de heridas cicatrizadas (RR 0,96; IC del 95%: 0,53 a 1,72) ni en el cambio del tamaño de la úlcera con el tiempo (no fue posible realizar un análisis estadístico independiente de los datos disponibles). La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). Ninguno de los estudios informó sobre la preferencia de los pacientes, la facilidad de uso del método de limpieza, el coste o la calidad de vida relacionada con la salud. En un estudio en el que se compara la propil betaína y la polihexanida con la solución salina, los autores no informaron la aparición de eventos adversos. No hay certeza de que el OHP suponga alguna diferencia en el número de eventos adversos en comparación con la solución de Ringer (RR 0,58; IC del 95%: 0,29 a 1,14). La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). CONCLUSIONES DE LOS AUTORES: En la actualidad se carece de evidencia de ECA para guiar la toma de decisiones sobre la efectividad de la limpieza de heridas en comparación con ninguna limpieza y los enfoques óptimos para la limpieza de las úlceras venosas de la pierna. A partir de los cuatro estudios identificados, no hay evidencia suficiente para demostrar si el uso de la solución PHMB en comparación con el suero fisiológico; el peróxido de oxígeno acuoso en comparación con el agua estéril; la betaína propil y la polihexanida en comparación con un suero fisiológico; o el OHP en comparación con la solución de Ringer supone alguna diferencia en el tratamiento de las úlceras venosas de la pierna. La evidencia de tres de los estudios es de certeza muy baja, debido a las limitaciones de los estudios y a la imprecisión. Un estudio no presentó datos para los desenlaces principales ni secundarios. Podría ser importante realizar más estudios bien diseñados que aborden desenlaces clínicos, de calidad de vida y económicos importantes, sobre la base de la prioridad clínica y para el paciente de esta falta de certeza.

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.

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.

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.

Food, Acid Supplementation and Drug Absorption - a Complicated Gastric Mix: a Randomized Control Trial.

PURPOSE: The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastric pH. METHODS: This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500 mg, 3000 mg and 4500 mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food. RESULTS: Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0 min. Administering 4500 mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9 min. AUCpH of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55. CONCLUSION: The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500 mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02758015.

Anticataractogenic effect of betaine in chick embryo hydrocortisone-induced cataract model.

Background & objectives: Cataract is one of the leading causes of blindness in the world. The aim of the present study was to investigate anticataractogenic effect of betaine in chick embryo hydrocortisone (HC)-induced cataract model. Methods: The study included 60 fertilized eggs divided into six groups each having 10 eggs: one group treated with only HC (HC group); three treated with both HC and different doses of betaine (HC/B 1.00, HC/B 0.50 and HC/B 0.25 groups) and two non-HC groups treated with only phosphate-buffered saline (PBS group) or betaine (B group). After the injections, lenses of the embryos were removed and classified into five stages according to the lens opacification. The amounts of reduced glutathione (GSH) in the removed lenses were measured. Results: All the lenses in non-HC-treated groups were clear, whereas in the HC-treated group, 90 per cent of the lenses had cataract (stages 4 and 5). The mean score of lens opacity was significantly lower in all HC/B groups compared to HC group (2.4-3.5 vs. 4.4, P<0.05). Among HC/B groups, the HC/B 0.25 group had significantly lower mean score of lens opacity compared to remaining HC/B groups treated with higher doses of betaine. In addition, the mean reduced GSH level was significantly higher in HC/B 0.25 group compared to HC, HC/B 1.00 and HC/B 0.50 groups (P<0.001). Interpretation & conclusions: The present results show beneficial anti-cataract and anti-oxidant effects of 0.25 µmol/egg betaine on HC-induced cataract in the chick embryo.

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.

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.

Analytic Approaches for the Treatment of Hyperhomocysteinemia and Its Impact on Vascular Disease.

Homocysteine is an intermediary metabolite in the methionine cycle. Accumulation of homocysteine is caused either by mutation of relevant genes or by nutritional depletion of related vitamin(s). This review covers the historical background of hyperhomocysteinemia in which indispensable subjects in relation to underlying pathophysiological processes are discussed with the view of metabolism and genetics of folate and methionine cycles. This review emphasizes the unique role of homocysteine that is clearly distinct from other risk factors, particularly cholesterol in the development of vascular disease. The critical issue in understanding the role of homocysteine is the relation with plasma folic acid. The majority of subjects with homocysteine > 15 µmol/L exhibit plasma folate < 9 nmol/ L, indicating that depletion of folate is the main cause of hyperhomocysteinemia irrespective of the presence or absence of vascular disease. Furthermore, only the group of subjects with homocysteine levels > 15 µmol/L demonstrated a higher prevalence of vascular disease. Analytic approaches to treat hyperhomocysteinemia are discussed in which stepwise administration with nutritional doses of folic acid, 5-methyitetrahydrofolate (5-MTHF), and betaine is provided singly or by combined manner based on clinical and laboratory evaluations. Whether correction of hyperhomocysteinemia is able to prevent the development of homocysteine-associated vascular disease remains an unresolved issue. The review discussed a biochemical and mechanistic approach to resolve questions involved in the relation between homocysteine and the development of atherosclerotic vascular disease.

Betaine chemistry, roles, and potential use in liver disease.

BACKGROUND: Betaine is the trimethyl derivative of glycine and is normally present in human plasma due to dietary intake and endogenous synthesis in liver and kidney. Betaine is utilized in the kidney primarily as an osmoprotectant, whereas in the liver its primary role is in metabolism as a methyl group donor. In both organs, a specific betaine transporter mediates cellular uptake of betaine from plasma. The abundance of both betaine and the betaine transporter in liver greatly exceeds that of other organs. SCOPE OF REVIEW: The remarkable contributions of betaine to normal human and animal health are summarized together with a discussion of the mechanisms and potential beneficial effects of dietary betaine supplements on liver disease. MAJOR CONCLUSIONS: A significant amount of data from animal models of liver disease indicates that administration of betaine can halt and even reverse progression of the disruption of liver function. Betaine is well-tolerated, inexpensive, effective over a wide range of doses, and is already used in livestock feeding practices. GENERAL SIGNIFICANCE: The accumulated data indicate that carefully controlled additional investigations in humans are merited. The focus should be on the long-term use of betaine in large patient populations with liver diseases characterized by development of fatty liver, especially non-alcoholic fatty liver disease and alcoholic liver disease.