Choline-Mediated Lipid Reprogramming as a Dominant Salt Tolerance Mechanism in Grass Species Lacking Glycine Betaine.

Choline, as a precursor of glycine betaine (GB) and phospholipids, is known to play roles in plant tolerance to salt stress, but the downstream metabolic pathways regulated by choline conferring salt tolerance are still unclear for non-GB-accumulating species. The objectives were to examine how choline affects salt tolerance in a non-GB-accumulating grass species and to determine major metabolic pathways of choline regulating salt tolerance involving GB or lipid metabolism. Kentucky bluegrass (Poa pratensis) plants were subjected to salt stress (100 mM NaCl) with or without foliar application of choline chloride (1 mM) in a growth chamber. Choline or GB alone and the combined application increased leaf photochemical efficiency, relative water content and osmotic adjustment and reduced leaf electrolyte leakage. Choline application had no effects on the endogenous GB content and GB synthesis genes did not show responses to choline under nonstress and salt stress conditions. GB was not detected in Kentucky bluegrass leaves. Lipidomic analysis revealed an increase in the content of monogalactosyl diacylglycerol, phosphatidylcholine and phosphatidylethanolamine and a decrease in the phosphatidic acid content by choline application in plants exposed to salt stress. Choline-mediated lipid reprogramming could function as a dominant salt tolerance mechanism in non-GB-accumulating grass species.

Dynamics of Choline-Containing Phospholipids in Traumatic Brain Injury and Associated Comorbidities.

The incidences of traumatic brain injuries (TBIs) are increasing globally because of expanding population and increased dependencies on motorized vehicles and machines. This has resulted in increased socio-economic burden on the healthcare system, as TBIs are often associated with mental and physical morbidities with lifelong dependencies, and have severely limited therapeutic options. There is an emerging need to identify the molecular mechanisms orchestrating these injuries to life-long neurodegenerative disease and a therapeutic strategy to counter them. This review highlights the dynamics and role of choline-containing phospholipids during TBIs and how they can be used to evaluate the severity of injuries and later targeted to mitigate neuro-degradation, based on clinical and preclinical studies. Choline-based phospholipids are involved in maintaining the structural integrity of the neuronal/glial cell membranes and are simultaneously the essential component of various biochemical pathways, such as cholinergic neuronal transmission in the brain. Choline or its metabolite levels increase during acute and chronic phases of TBI because of excitotoxicity, ischemia and oxidative stress; this can serve as useful biomarker to predict the severity and prognosis of TBIs. Moreover, the effect of choline-replenishing agents as a post-TBI management strategy has been reviewed in clinical and preclinical studies. Overall, this review determines the theranostic potential of choline phospholipids and provides new insights in the management of TBI.

Role of Choline in Ocular Diseases.

Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma, and dry eye syndrome. Choline supplementation may be effective for treating these diseases.

Sphingomyelin synthase 2 loss suppresses steatosis but exacerbates fibrosis in the liver of mice fed with choline-deficient, L-amino acid-defined, high-fat diet.

Sphingomyelin synthase 2 (SMS2) regulates sphingomyelin synthesis and contributes to obesity and hepatic steatosis. Here, we investigated the effect of SMS2 deficiency on liver fibrosis in mice fed with choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) or injected with carbon tetrachloride (CCl4), respectively. SMS2 deficiency suppressed hepatic steatosis, but exacerbated fibrosis induced by CDAHFD feeding. Sphingosine 1-phosphate (S1P), which is a key lipid mediator induces fibrosis in various organs, was increased in the liver of mice fed with CDAHFD. The increase of S1P became prominent by SMS2 deficiency. Meanwhile, SMS2 deficiency had no impact on CCl4-induced liver injury, fibrosis and S1P levels. Our findings demonstrated that SMS2 deficiency suppresses steatosis but worsens fibrosis in the liver in a specific condition with CDAHFD feeding.

Choline-mediated modulation of hippocampal sharp wave-ripple complexes in vitro.

The cholinergic system is critically involved in the modulation of cognitive functions, including learning and memory. Acetylcholine acts through muscarinic (mAChRs) and nicotinic receptors (nAChRs), which are both abundantly expressed in the hippocampus. Previous evidence indicates that choline, the precursor and degradation product of Acetylcholine, can itself activate nAChRs and thereby affects intrinsic and synaptic neuronal functions. Here, we asked whether the cellular actions of choline directly affect hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R) and can induce gamma oscillations. In addition, choline reduces synaptic transmission between hippocampal subfields CA3 and CA1. Surprisingly, these effects are mediated by activation of both mAChRs and α7-containing nAChRs. Most nicotinic effects became only apparent after local, fast application of choline, indicating rapid desensitization kinetics of nAChRs. Effects were still present following block of choline uptake and are, therefore, likely because of direct actions of choline at the respective receptors. Together, choline turns out to be a potent regulator of patterned network activity within the hippocampus. These actions may be of importance for understanding state transitions in normal and pathologically altered neuronal networks. In this study we asked whether choline, the precursor and degradation product of acetylcholine, directly affects hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R). In addition, choline reduces synaptic transmission between hippocampal subfields. These effects are mediated by direct activation of muscarinic as well as nicotinic cholinergic pathways. Together, choline turns out to be a potent regulator of patterned activity within hippocampal networks.

The role of folic acid fortification in neural tube defects: a review.

The worldwide prevalence of neural tube defects (NTDs) has fallen noticeably during the past 30 years, but the specific etiology and causative mechanism of NTDs remain unknown. Since introduction of mandatory fortification of grains with folic acid, a further decrease in NTD prevalence has been reported in North America and other countries with large variations among ethnic subgroups. However, a significant portion of NTDs still persists. Population data suggest that women of childbearing age may not yet be adequately targeted, while the general population may be overfortified with folic acid. While an excessive folate intake may be associated with adverse effects, there remains uncertainty about the minimum effective folate intake and status required for NTD prevention, and the safe upper folate level. Besides folate, several other lifestyle and environmental factors as well as genetic variations may influence NTD development, possibly by affecting one-carbon metabolism and thus epigenetic events. In conclusion, mandatory folic acid fortification plays a significant part in the reduction of NTD prevalence, but possibly at a cost and with a portion of NTDs remaining. More effective preventive strategies require better understanding of the etiology of this group of birth defects.

α7 nicotinic ACh receptors as a ligand-gated source of Ca(2+) ions: the search for a Ca(2+) optimum.

The spatiotemporal distribution of cytosolic Ca(2+) ions is a key determinant of neuronal behavior and survival. Distinct sources of Ca(2+) ions including ligand- and voltage-gated Ca(2+) channels contribute to intracellular Ca(2+) homeostasis. Many normal physiological and therapeutic neuronal functions are Ca(2+)-dependent, however an excess of cytosolic Ca(2+) or a lack of the appropriate balance between Ca(2+) entry and clearance may destroy cellular integrity and cause cellular death. Therefore, the existence of optimal spatiotemporal patterns of cytosolic Ca(2+) elevations and thus, optimal activation of ligand- and voltage-gated Ca(2+) ion channels are postulated to benefit neuronal function and survival. Alpha7 nicotinic -acetylcholine receptors (nAChRs) are highly permeable to Ca(2+) ions and play an important role in modulation of neurotransmitter release, gene expression and neuroprotection in a variety of neuronal and non-neuronal cells. In this review, the focus is placed on α7 nAChR-mediated currents and Ca(2+) influx and how this source of Ca(2+) entry compares to NMDA receptors in supporting cytosolic Ca(2+) homeostasis, neuronal function and survival.

Choline and betaine in health and disease.

Choline is an essential nutrient, but is also formed by de novo synthesis. Choline and its derivatives serve as components of structural lipoproteins, blood and membrane lipids, and as a precursor of the neurotransmitter acetylcholine. Pre-and postnatal choline availability is important for neurodevelopment in rodents. Choline is oxidized to betaine that serves as an osmoregulator and is a substrate in the betaine-homocysteine methyltransferase reaction, which links choline and betaine to the folate-dependent one-carbon metabolism. Choline and betaine are important sources of one-carbon units, in particular, during folate deficiency. Choline or betaine supplementation in humans reduces concentration of total homocysteine (tHcy), and plasma betaine is a strong predictor of plasma tHcy in individuals with low plasma concentration of folate and other B vitamins (B2, B6, and B12) in combination TT genotype of the methylenetetrahydrofolate reductase 677 C->T polymorphism. The link to one-carbon metabolism and the recent availability of food composition data have motivated studies on choline and betaine as risk factors of chronic diseases previously studied in relation to folate and homocysteine status. High intake and plasma level of choline in the mother seems to afford reduced risk of neural tube defects. Intake of choline and betaine shows no consistent relation to cancer or cardiovascular risk or risk factors, whereas an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations in plasma. Thus, choline and betaine showed opposite relations with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline oxidation to betaine as part of the mitochondrial dysfunction in metabolic syndrome.

Multimodality molecular imaging of apoptosis in oncology.

OBJECTIVE: The purposes of this review are to describe the signaling pathways of and the cellular changes that occur with apoptosis and other forms of cell death, summarize tracers and modalities used for imaging of apoptosis, delineate the relation between apoptosis and inhibition of protein translation, and describe spectroscopic technologies that entail high-frequency ultrasound and infrared and midinfrared light in characterizing the intracellular events of apoptosis. CONCLUSION: Apoptosis is a highly orchestrated set of biochemical and morphologic cellular events. These events present many potential targets for the imaging of apoptosis in vivo. Imaging of apoptosis can facilitate early assessment of anticancer treatment before tumor shrinkage, which may increase the effectiveness of delivery of chemotherapy and radiation therapy and speed drug development.

[Importance of choline in cognitive function]. / Importancia de la colina en la función cognitiva.

INTRODUCTION: Choline is a critical nutrient for cognitive development, metabolism and liver function, and regulation of homocysteine metabolism. It is necessary for the synthesis of the neurotransmitter acetylcholine, the synthesis of betaine and that of phosphatidylcholine. In the perinatal stage, the contribution of choline is essential to guarantee optimal cognitive development and prevent neural tube defects. In adults and the elderly, choline intake has been associated with better performance in some cognitive functions and a lower incidence of dementia. Despite their important role in health, most groups of the population do not reach their adequate intake of choline, and even some groups, such as pregnant women or childbearing women, have a higher risk of having suboptimal intakes. The main dietary sources of choline are eggs, dairy and meats, so reducing or limiting the consumption of these foods negatively impacts on the intake of this nutrient. Given the need to improve the intake of this vitamin, it is necessary to increase the knowledge that the population has about this nutrient, raising awareness about the importance of choline for health, and its main food sources.

INTRODUCCIÓN: La colina es un nutriente crítico para el desarrollo cognitivo, el metabolismo y la función hepática y la regulación del metabolismo de la homocisteína. Es necesaria para la síntesis del neurotransmisor acetilcolina, la síntesis de betaína y la de fosfatidilcolina. En la etapa perinatal el aporte de colina es fundamental para garantizar el desarrollo cognitivo y prevenir defectos del tubo neural. En adultos mayores y ancianos la ingesta de colina se ha asociado a mejor rendimiento en algunas funciones cognitivas y menor incidencia de demencia. A pesar de su importante papel en la salud, la mayoría de los colectivos no alcanza sus ingestas adecuadas (IA) de colina, aunque algunos colectivos, como gestantes o mujeres en edad fértil, tienen un mayor riesgo de tener ingestas subóptimas. Las principales fuentes dietéticas de esta vitamina son los huevos, lácteos y carnes, y disminuir o limitar el consumo de estos alimentos impacta negativamente en la ingesta de este nutriente. Dada la necesidad de mejorar la ingesta de esta vitamina, es necesario mejorar el conocimiento que tiene la población sobre este nutriente, concienciándola sobre la importancia de la colina para la salud y sus principales fuentes alimentarias.

Plasma methionine metabolic profile is associated with longevity in mammals.

Methionine metabolism arises as a key target to elucidate the molecular adaptations underlying animal longevity due to the negative association between longevity and methionine content. The present study follows a comparative approach to analyse plasma methionine metabolic profile using a LC-MS/MS platform from 11 mammalian species with a longevity ranging from 3.5 to 120 years. Our findings demonstrate the existence of a species-specific plasma profile for methionine metabolism associated with longevity characterised by: i) reduced methionine, cystathionine and choline; ii) increased non-polar amino acids; iii) reduced succinate and malate; and iv) increased carnitine. Our results support the existence of plasma longevity features that might respond to an optimised energetic metabolism and intracellular structures found in long-lived species.

Physiological concentrations of choline activate native alpha7-containing nicotinic acetylcholine receptors in the presence of PNU-120596 [1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea].

The use of PNU-120596 [1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea], a positive allosteric modulator of alpha7 nicotinic acetylcholine receptor (nAChR), may be beneficial for enhancing cholinergic therapies. However, the effects of PNU-120596 on activation of native alpha7-containing nAChRs by physiological concentrations of choline are not known and were investigated in this study using patch-clamp electrophysiology and histaminergic tuberomammillary neurons in hypothalamic slices. In the presence of PNU-120596, subthreshold (i.e., inactive) physiological concentrations of choline ( approximately 10 microM) elicited repetitive step-like whole-cell responses reminiscent of single ion channel openings that were reversibly blocked by 20 nM methyllycaconitine, a selective alpha7 nAChR antagonist. The effects of choline and PNU-120596 were synergistic as administration of 10 to 40 microM choline or 1 to 4 muM PNU-120596 alone did not elicit responses. In voltage clamp at -60 mV, the persistent activation of alpha7-containing nAChRs by 10 microM choline plus 1 microM PNU-120596 was estimated to produce a sustained influx of Ca(2+) ions at a rate of 8.4 pC/min ( approximately 0.14 pA). In the presence of PNU-120596 in current clamp, transient step-like depolarizations ( approximately 5 mV) enhanced neuronal excitability and triggered voltage-gated conductances; a single opening of an alpha7-containing nAChR channel appeared to transiently depolarize the entire neuron and facilitate spontaneous firing. Therefore, this study tested and confirmed the hypothesis that PNU-120596 enhances the effects of subthreshold concentrations of choline on native alpha7-containing nAChRs, allowing physiological levels of choline to activate these receptors and produce whole-cell responses in the absence of exogenous nicotinic agents. In certain neurological disorders, this activation may be therapeutically beneficial, more efficacious, and safer than treatments with nAChR agonists.

Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia.

The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between alpha7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed.

Choline: An Essential Nutrient for Skeletal Muscle.

BACKGROUND: Choline is an essential micronutrient with a pivotal role in several metabolic pathways contributing to liver, neurological, and hematological homeostasis. Although choline is commonly administered to improve physical performance, its effects on muscle are still unclear. The aim of this scoping review is to analyze the role of choline on skeletal muscle in terms of biological effects and clinical implications. METHODS: A technical expert panel (TEP) of 6 medical specialists with expertise in muscle physiology and skeletal muscle disorders performed the review following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) model. The TEP planned a research on PubMed selecting "choline" as MeSH (Medical Subject Headings) term adding to PubMed Search Builder the terms "skeletal muscle" and "muscle striated". TEP considered for eligibility articles published in the last 30 years, including original researches, particularly in vitro studies, and animal and clinical studies in the English language. RESULTS: From the 1239 studies identified, TEP included 14 studies, 3 in vitro, 9 animal, and 2 clinical studies. CONCLUSIONS: Our scoping review elucidates and summarizes the crucial role of choline in modulating muscle fat metabolism, muscle proteins homeostasis, and the modulation of inflammation and autophagy.

Role of teichoic acid choline moieties in the virulence of Streptococcus pneumoniae.

In recent reports it was shown that genetically modified choline-free strains of Streptococcus pneumoniae (D39Cho(-)licA64 and D39ChiplicB31) expressing the type II capsular polysaccharide were virtually avirulent in the murine sepsis model, in sharp contrast to the isogenic and highly virulent strains D39Cho(-) and D39Chip, which have retained the choline residues at their surface. We now demonstrate that this choline-associated virulence is independent of Toll-like receptor 2 recognition. Also, despite the lack of virulence, choline-free strains of S. pneumoniae were able to activate splenic dendritic cells, induce secretion of proinflammatory cytokines, and produce specific protective immunity against subsequent challenge. However, after this transient engagement of the immune system the choline-free bacteria were rapidly cleared from the blood, while the isogenic virulent strain D39Cho(-) continued to grow, accompanied by prolonged expression of cytokines, eventually killing the experimental animals. The critical contribution of choline residues to the virulence potential of pneumococci appears to be the role that these amino alcohol residues play in a pneumococcal immune evasion strategy, the mechanism of which is unknown at the present time.

The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor.

A protein secreted by cultured rat heart cells can direct the choice of neurotransmitter phenotype made by cultured rat sympathetic neurons. Structural analysis and biological assays demonstrated that this protein is identical to a protein that regulates the growth and differentiation of embryonic stem cells and myeloid cells, and that stimulates bone remodeling and acute-phase protein synthesis in hepatocytes. This protein has been termed D factor, DIA, DIF, DRF, HSFIII, and LIF. Thus, this cytokine, like IL-6 and TGF beta, regulates growth and differentiation in the embryo and in the adult in many tissues, now including the nervous system.

Choline and cholinergic neurons.

Mammalian neurons can synthesize choline by methylating phosphatidylethanolamine and hydrolyzing the resulting phosphatidylcholine. This process is stimulated by catecholamines. The phosphatidylethanolamine is synthesized in part from phosphatidylserine; hence the amino acids methionine (acting after conversion to S-adenosylmethionine) and serine can be the ultimate precursors of choline. Brain choline concentrations are generally higher than plasma concentrations, but depend on plasma concentrations because of the kinetic characteristics of the blood-brain-barrier transport system. When cholinergic neurons are activated, acetylcholine release can be enhanced by treatments that increase plasma choline (for example, consumption of certain foods).

Survival of adult basal forebrain cholinergic neurons after loss of target neurons.

Target cells are thought to regulate the survival of afferent neurons during development by supplying limiting amounts of neurotrophic factors, but the degree to which afferent neurons remain dependent on target-derived support in the adult is uncertain. In this study, uninjured basal forebrain cholinergic neurons did not die after excitotoxic ablation of their target neurons in young adult rats, indicating that they are either not dependent on neurotrophic factors for survival or can obtain trophic support from other sources after target neurons are lost. This finding suggests that cholinergic cell death in neurodegenerative conditions such as Alzheimer's disease is not due solely to a loss of target neurons or factors provided by them.

Choline: Exploring the Growing Science on Its Benefits for Moms and Babies.

The importance of ensuring adequate choline intakes during pregnancy is increasingly recognized. Choline is critical for a number of physiological processes during the prenatal period with roles in membrane biosynthesis and tissue expansion, neurotransmission and brain development, and methyl group donation and gene expression. Studies in animals and humans have shown that supplementing the maternal diet with additional choline improves several pregnancy outcomes and protects against certain neural and metabolic insults. Most pregnant women in the U.S. are not achieving choline intake recommendations of 450 mg/day and would likely benefit from boosting their choline intakes through dietary and/or supplemental approaches.

Cholinergic nervous system and glaucoma: From basic science to clinical applications.

The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, and arachidonic acid contents of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.