Analysis of Betaine and Choline Contents of Aleurone, Bran, and Flour Fractions of Wheat (Triticum aestivum L.) Using 1H Nuclear Magnetic Resonance (NMR) Spectroscopy

In conventional milling, the aleurone layer is combined with the bran fraction. Studies indicate that the bran fraction of wheat contains the majority of the phytonutrients betaine and choline, with relatively minor concentrations in the refined flour. This present study suggests that the wheat aleurone layer (Triticum aestivum L. cv. Tiger) contains the greatest concentration of both betaine and choline (1553.44 and 209.80 mg/100 g of sample, respectively). The bran fraction contained 866.94 and 101.95 mg/100 g of sample of betaine and choline, respectively, while the flour fraction contained 23.30 mg/100 g of sample (betaine) and 28.0 mg/100 g of sample (choline). The betaine content for
the bran was lower, and the choline content was higher compared to previous studies, although it is known that there is large variation in betaine and choline contents between wheat cultivars. The ratio of betaine/choline in the aleurone fraction was approximately 7:1; in the bran, the ratio was approximately 8:1; and in the flour fraction, the ratio was approximately 1:1. The study further
emphasizes the superior phytonutrient composition of the aleurone layer.
INTRODUCTION
Wheat is a valuable source of betaine, choline (1, 2), B
vitamins, vitamin E, and a number of minerals, including iron,
zinc, magnesium, and phosphorus (3). Epidemiological studies
indicate that whole-grain consumption is protective against
several chronic diseases (4-12). It has not been fully elucidated
how whole-grain cereals or specific fractions (13) exert their
protective effect, but it is thought to be due to their content of
several nutrients associated with the reduced risk of disease.
Conventionally, whole grain is separated during milling into
bran, germ, and flour (14). The nutrient composition of these
fractions differ markedly; refined wheat flour contains approximately
50% less vitamins and minerals than whole-grain
flour (

Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

BACKGROUND: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.

METHODS: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.

RESULTS: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.

CONCLUSIONS: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.

Perinatal choline supplementation reveals a dissociation between two types of spatial strategies.

Choline supplementation improving memory functions in rodents is assumed to increase the synthesis and release of acetylcholine in the brain. We have found that a combined pre- and postnatal supplementation results in long-lasting facilitation of spatial memory in juvenile rats when training was conducted in presence of a local salient cue. The present work was aimed at analysing the effects of peri- and postnatal choline supplementation on spatial abilities of naive adult rats. Rats given a perinatal choline supplementation were trained in various cued procedures of the Morris navigation task when aged 5 months. The treatment had a specific effect of reducing the escape latency of the rats when the platform was at a fixed position in space and surrounded by a suspended cue. This effect was associated with an increased spatial bias when the cue and platform were removed. In this condition, the control rats showed impaired spatial discrimination following the removal of the target cue, most likely due to an overshadowing of the distant environmental cues. This impairment was not observed in the treated rats. Further training with the suspended cue at unpredictable places in the pool revealed longer escape latencies in the control than in the treated rats suggesting that this procedure induced a selective perturbation of the normal but not of the treated rats. A special probe trial with the cue at an irrelevant position and no escape platform revealed a significant bias of the control rats toward the cue and of the treated rats toward the uncued spatial escape position. This behavioural dissociation suggests that a salient cue associated with the target induces an alternative "non spatial" guidance strategy in normal rats, with the risk of overshadowing of the more distant spatial cues. In this condition, the choline supplementation facilities a spatial reliance on the cue, that is an overall facilitation of learning a set of spatial relations between several visual cues. As a consequence, the improved escape in presence of the cue is associated with a stronger memory of the spatial position following disappearance of the cue. This and previous observations suggest that a specific spatial attention process relies on the buffering of highly salient visual cues.to facilitate integration of their relative position in the environment.

Choline-PET in prostate cancer management: The point of view of the radiation oncologist.

Among PET radiotracers, FDG seems to be quite accepted as an accurate oncology diagnostic tool, frequently helpful also in the evaluation of treatment response and in radiation therapy treatment planning for several cancer sites. To the contrary, the reliability of Choline as a tracer for prostate cancer (PC) still remains an object of debate for clinicians, including radiation oncologists. This review focuses on the available data about the potential impact of Choline-PET in the daily clinical practice of radiation oncologists managing PC patients. In summary, routine Choline-PET is not indicated for initial local T staging, but it seems better than conventional imaging for nodal staging and for all patients with suspected metastases. In these settings, Choline-PET showed the potential to change patient management. A critical limit remains spatial resolution, limiting the accuracy and reliability for small lesions. After a PSA rise, the problem of the trigger PSA value remains crucial. Indeed, the overall detection rate of Choline-PET is significantly increased when the trigger PSA, or the doubling time, increases, but higher PSA levels are often a sign of metastatic spread, a contraindication for potentially curable local treatments such as radiation therapy. Even if several published data seem to be promising, the current role of PET in treatment planning in PC patients to be irradiated still remains under investigation. Based on available literature data, all these issues are addressed and discussed in this review.

N-acétyltransférase lysosomale : organisation, fonctionnement et défauts moléculaires chez les patients atteints du syndrome de Sanfilippo type C

L’acétylation des résidus de glucosamine terminaux par la N-acétyltransférase lysosomale (HGSNAT) est une étape essentielle de la dégradation catabolique de l’héparan sulfate. Des défauts dans cette réaction causent une maladie de surcharge lysosomale autosomale récessive rare : le désordre de Sanfilippo type C (SFC). À ce jour, 54 mutations ont été rapportées chez des patients SFC, incluant 13 mutations des sites d’épissage, 11 insertions et délétions, 8 mutations non-sens, 18 mutations faux-sens et 4 polymorphismes, avec différentes manifestations phénotypiques. Nous avons identifié 10 d’entre elles et effectué une étude exhaustive portant sur l’éventail des mutations SFC, leur distribution dans la population de patients, ainsi que leur impact potentiel sur la structure de la HGSNAT. Les erreurs d’épissage, les mutations non-sens, les insertions et les délétions devraient toutes entraîner un ARN non fonctionnel qui est rapidement dégradé par des mécanismes de contrôle qualité cellulaire. Les 4 polymorphismes identifiés sont des changements d'acides aminés qui ne modifient pas l'activité enzymatique, la glycosylation ou la localisation et n'ont donc pas de signification au niveau clinique. Au niveau des enzymes, les polymorphismes sont des changements d’acides aminés qui n’affectent pas la fonction, mais dans un contexte d’acides nucléiques ils peuvent être considérés comme des mutations faux-sens. Les dix-huit mutations faux-sens qui ont été exprimées ont produit des protéines inactives, en raison d'erreurs dans leur repliement. Ceci expliquerait donc la progression sévère de la maladie chez les personnes porteuses de ces mutations. Les protéines mutantes mal repliées sont anormalement glycosylées et conservées dans le réticulum endoplasmique. La thérapie par amélioration de l’activité enzymatique par des chaperonnes est une option thérapeutique potentielle, spécifiquement conçue pour exploiter l'activité enzymatique résiduelle de mutants mal repliés, afin d’éliminer les substrats stockés. Nous avons démontré que le traitement de plusieurs lignées de fibroblastes de patients SFC avec le chlorhydrate de glucosamine, un inhibiteur spécifique de la HGSNAT, a partiellement restauré l’activité de l'enzyme mutante, fournissant une preuve de l’utilité future de la thérapie par des chaperonnes dans le traitement de la maladie de SFC.

Fatty acid compositions of inositol and choline phospholipids of breast tumours and normal breast tissue

The fatty acid compositions of the -choline and -inositol phospholipids of breast tumours of women undergoing surgery for treatment of breast disease (malignant n = 12; benign n = 10) and normal breast tissue of women undergoing breast reduction surgery (n = 6) were determined. The fatty acid compositions of erythrocyte phospholipids were also determined in the same subjects and in an additional number of normal healthy volunteers (n = 16). Levels of oleic acid were lower in both phospholipid fractions of erythrocytes of women with breast disease and in the phosphatidylcholine fraction of breast tumours compared with normal breast tissue. Significantly higher levels of linoleic acid were found in erythrocytes of tumour-bearing subjects and a similar trend was evident in the phosphatidylcholine fraction of tumour compared with normal breast tissues. Conversely, lower levels of two of the products of linoleic acid chain elongation and desaturation, dihomogamma-linolenic and arachidonic acids, were found in the erythrocyte phospholipids of tumour-bearing subjects and in the choline phospholipids of breast tumour tissues. These data suggest that in women with breast disease, there may be inhibition of 6-desaturase, and enhanced activity of 9-desaturase, enzymes which play an important role in determining membrane phospholipid fatty acid composition. This pattern of altered fatty acid composition characteristic of erythrocyte phospholipids of tumour-bearing subjects and phosphatidylcholine of breast tumour tissue was less evident in the case of the breast tumour phosphatidylinositol in which differences other than those described were seen.

Effect of dietary fatty acid composition on inositol-, choline- and ethanolamine-phospholipids of mammary tissue and erythrocytes in the rat

The present study investigated the effect of feeding maize-oil, olive-oil and fish-oil diets, from weaning to adulthood, on rat mammary tissue and erythrocyte phospholipid fatty acid compositions. Effects of diet on the relative proportions of membrane phospholipids in the two tissues were also investigated. Mammary tissue phosphatidylinositol (PI) fatty acids were unaltered by diet, but differences in phosphatidylethanolamine (PE) and, to a lesser extent, phosphatidylcholine (PC) fractions were found between animals fed on different diets from weaning. Differences observed were those expected from the dietary fatty acids fed; n-6 fatty acids were found in greatest amounts in maize-oil-fed rats, n-9 in olive-oil-fed rats, and n-3 in fish-oil-fed rats. In erythrocytes the relative susceptibilities of the individual phospholipids to dietary modification were: PE > PC > PI, but enrichment with n-9 and n-3 fatty acids was not observed in olive-oil- and fish-oil-fed animals and in PC and PE significantly greater amounts of saturated fatty acids were found when animals fed on olive oil or fish oil were compared with maize-oil-fed animals. The polyunsaturated:saturated fatty acid ratios of PE and PC fractions were significantly lower in olive-oil- and fish-oil-fed animals. No differences in the relative proportions of phospholipid classes were found between the three dietary groups. It is suggested that differences in erythrocyte fatty acid composition may reflect dietary-induced changes in membrane cholesterol content and may form part of a homoeostatic response the aim of which is to maintain normal erythrocyte membrane fluidity. The resistance of mammary tissue PI fatty acids to dietary modification suggests that alteration of PI fatty acids is unlikely to underlie effects of dietary fat on mammary tumour incidence rates.

Effects of rumen-protected choline supplementation on metabolic and performance responses of transition dairy cows

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism

Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline-and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J approximate to C57BL/6J approximate to C3H/HeJ < 129S1/SvImJ approximate to CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor alpha (PPAR alpha)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPAR alpha-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice.-Tryndyak, V., de Conti, A., Kobets, T., Kutanzi, K., Koturbash, I., Han, T., Fuscoe, J. C., Latendresse, J. R., Melnyk, S., Shymonyak, S., Collins, L., Ross, S. A., Rusyn, I., Beland, F. A., Pogribny, I. P. Interstrain differences in the severity of liver injury induced by a choline-and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism. FASEB J. 26, 4592-4602 (2012). www.fasebj.org

Vitamin C and Vitamin E in Prevention of Nonalcoholic Fatty Liver Disease (NAFLD) in Choline Deficient Diet Fed Rats

Abstract Aim Oxidative stress has been implicated in the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD). Vitamin C and vitamin E are known to react with reactive oxygen species (ROS) blocking the propagation of radical reactions in a wide range of oxidative stress situations. The potential therapeutic efficacy of antioxidants in NAFLD is unknown. The aim of this study was to evaluate the role of antioxidant drugs (vitamin C or vitamin E) in its prevention. Methods Fatty liver disease was induced in Wistar rats by choline-deficient diet for four weeks. The rats were randomly assigned to receive vitamin E (n = 6) – (200 mg/day), vitamin C (n = 6) (30 mg/Kg/day) or vehicle orally. Results In the vehicle and vitamin E-treated rats, there were moderate macro and microvesicular fatty changes in periportal area without inflammatory infiltrate or fibrosis. Scharlach stain that used for a more precise identification of fatty change was strong positive. With vitamin C, there was marked decrease in histological alterations. Essentially, there was no liver steatosis, only hepatocellular ballooning. Scharlach stain was negative. The lucigenin-enhanced luminescence was reduced with vitamin C (1080 ± 330 cpm/mg/minx103) as compared to those Vitamin E and control (2247 ± 790; 2020 ± 407 cpm/mg/minx103, respectively) (p < 0.05). Serum levels of aminotransferases were unaltered by vitamin C or vitamin E. Conclusions 1) Vitamin C reduced oxidative stress and markedly inhibited the development of experimental liver steatosis induced by choline-deficient diet ; 2)Vitamin E neither prevented the development of fatty liver nor reduced the oxidative stress in this model.

The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer

Choline positron emission tomography (PET)/computed tomography (CT) is a currently used diagnostic tool in restaging prostate cancer (PCa) patients with increasing prostate-specific antigen (PSA) after either radical prostatectomy (RP) or external-beam radiation therapy (EBRT). However, no final recommendations have been made on the use of this modality for patient management.

Comparison of C-11 methionine and C-11 choline for PET imaging of brain metastases: a prospective pilot study

The aim of the study was the comparison of C-11 methionine (MET) and C-11 choline (CHO) in the positron emission tomography (PET) imaging of brain metastases in correlation to the histopathology findings in stereotactic biopsy.