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PubMed1979

Fate of labeled choline administered intraruminally to pregnant ewes given manganese-deficient or -supplemented rations.

Tissue samples were taken from pregnant ewes and their 3-month fetuses 96 hours after intraruminal dosing of the ewes with tritiated choline. Starting 5 months before mating, one group of ewes had been given a manganese (Mn)-deficient ration and a second group had been given a Mn-supplemented (normal) ration. The results indicate that Mn depletion decreased the overall uptake of choline; the radioactivity of all tissues from the Mn-depleted group was lower than the radioactivity of the corresponding tissues from the group given a Mn-supplemented (normal) ration. The radioactivity of fetal tissues was also lower in the Mn-deficient group than it was in the Mn-supplemented group. Lower radioactivity concentrations were also observed in the whole plasma (sampled at various times after radioisotope dosing) and its lipid extract of Mn-depleted ewes than in the plasma and its lipid extract of Mn-supplemented ewes. There was no significant difference in the fatty acid composition of hepatic phosphatidyl choline between the two groups. However, the proportions of linoleic, stearic, and arachidonic acids were lower in fetal hepatic phosphatidyl choline than in maternal hepatic phosphatidyl choline.

Animal Feed↗
PubMed2002

Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology.

Chronic nutritional deficiencies in folate, choline, methionine, vitamin B-6 and/or vitamin B-12 can perturb the complex regulatory network that maintains normal one-carbon metabolism and homocysteine homeostasis. Genetic polymorphisms in these pathways can act synergistically with nutritional deficiencies to accelerate metabolic pathology associated with occlusive heart disease, birth defects and dementia. A major unanswered question is whether homocysteine is causally involved in disease pathogenesis or whether homocysteinemia is simply a passive and indirect indicator of a more complex mechanism. S-Adenosylmethionine and S-adenosylhomocysteine (SAH), as the substrate and product of methyltransferase reactions, are important metabolic indicators of cellular methylation status. Chronic elevation in homocysteine levels results in parallel increases in intracellular SAH and potent product inhibition of DNA methyltransferases. SAH-mediated DNA hypomethylation and associated alterations in gene expression and chromatin structure may provide new hypotheses for pathogenesis of diseases related to homocysteinemia.

Animals↗
PubMed1979

Lipid accumulation in the rat liver: a histological and biochemical study.

The sequential pattern of lipid accumulation and associated biochemical changes were studied in two commonly used experimental models of nutritional fatty liver in rats. Female rats were maintained for 8 weeks on high fat, low protein diets containing adequate methionine and choline, and drinking water ad libitum (Diet 1), or deficient in methionine and choline and containing 20% ethanol as a substitute for drinking water (Diet 2). Histologically, there was a progressive increase in liver lipids, mainly in the periportal areas. Occasional foci of liver cell necrosis with lipogranuloma formation occurred in areas of severe fatty change. These changes appeared earlier and were more marked in rats maintained on Diet 2. Electron micrographs revealed large lipid droplets in the liver cells, which sometimes contained myelin figures. The mitochondria were enlarged, distorted and appeared as amorphous structures with disorientated cristae in rats on Diet 1, whereas they had a condensed conformation in rats maintained on Diet 2. Rough endoplasmic reticulum was fragmented and degranulated particularly in rats on Diet 1, and smooth endoplasmic reticulum showed hyperplasia and vesiculation in rats on Diet 2. There was a progressive increase in the total liver lipids and triglycerides in both the groups of rats. This fatty change was accompanied by a significant increase in hepatic 3-hydroxybutyrate, acetoacetate, malate, 2-oxoglutarate, citrate, lactate, ammonia, glutamate, alanine and aspartate, and a significant decrease in oxaloacetate, urea and glucose concentrations. The mass action ratios for alanine aminotransferase, aspartate amino transferase, and glutamate dehydrogenase, generally moved in a parallel direction. Hepatic ATP content was considerably reduced accompanied by a decrease in [ATP]/[ADP] ratios and a significant increased in [lactate]/[pyruvate] and [3-hydroxybutyrate]/[acetoacetate] ratios. There was a corresponding decrease in the [NAD+]/[NADH] ratios both in the cytoplasmic and mitochondrial compartments. These biochemical changes were particularly severe in rats maintained on Diet 1 and Diet 2 for 8 weeks. There was a very good relationship between impaired mitochondrial and endoplasmic reticulum functions, redox and phosphorylation states, and the relevance of their changes to the fate of fatty liver cells.

Adenosine Triphosphate↗
PubMed2003

Choline acetyltransferase mutations in myasthenic syndrome due to deficient acetylcholine resynthesis.

The myasthenic syndrome due to abnormal acetylcholine resynthesis is characterized by early onset, recessive inheritance, and recurrent episodes of potentially fatal apnea. Mutations in the gene encoding choline acetyltransferase (CHAT) have been found to account for this condition. We have identified five patients from three independent families with features of this disease including, in four patients, a paradoxical worsening of symptoms with cold temperatures. Electrodiagnostic studies demonstrated impaired neuromuscular transmission in all patients. In vitro microelectrode studies performed in the anconeus muscle biopsies of two patients showed moderate reduction of quantal release. Electron microscopy of the neuromuscular junction was normal in both patients. Each patient had two heterozygous CHAT mutations including L210P and P211A (family 1), V194L and V506L (family 2), and R548stop and S694C (family 3). Three of these mutations have previously been reported and suggest that, in this syndrome, some molecular defects may be more prevalent than others.

Acetylcholine↗
PubMed2002

The prospective role of abnormal methyl metabolism in cadmium toxicity.

Several lines of evidence point to the probable role of abnormal methylation processes in the toxicology of metals and other xenobiotics. The spectrum of toxic effects exhibited by such metals as Ni, As, and Cd, as well as by Zn deficiency, often resemble those seen in animals chronically fed methyl-deficient diets. These metal-associated pathologies include cancer, atherosclerosis, birth defects, neurological disturbances, and pancreatic lesions. In addition, each of the above agents has been shown to alter normal methyl group metabolism in vivo or in vitro. In the present studies, we compared the effects on the enzyme DNA methyltransferase (MTase) of two metal ions: the essential metal Zn and the carcinogen Cd. MTase extracts were obtained from the hepatic nuclei of rats fed a methyl-deficient diet (lacking choline and folate) for 7 and 24 weeks. Control animals were fed the same diet supplemented with each of these vitamins. Zn and Cd both inhibited MTase in the nuclear extracts from both the control and the methyl-deficient rats. The inhibitory activity of Cd was greater than that of Zn regardless of whether the nuclear extracts were from the control or the deficient animals. In addition, the kinetics of Cd inhibition of MTase activity were different in the nuclear extracts from the control and methyl-deficient rats. The results provide evidence that the carcinogenic effects of Cd may be mediated in part through abnormal DNA methylation.

Administration, Oral↗
PubMed1981

On the mechanism of the inhibition of fast axonal transport caused by exposure of frog spinal ganglia to the sodium-deficient medium.

Substitution of choline or sucrose for Na+ in the medium surrounding frog spinal ganglia causes an inhibition of fast axonal transport in vitro. Since an increase Ca2+ influx into neurons does occur in these media, the present experiments examined the possibility that the effect on transport is mediated by an increase in intracellular free Ca2+. The combination of the choline substitution with a 3-fold increase in extracellular Ca2+ reduced transport of [3H] proteins to 75% of control (as compared to the 63% obtained previously with choline alone), thus providing no evidence of an enhancement of choline's effect by a second factor which promotes an increase in intracellular Ca2+. When Li+ was substituted for Na+, the quantity of [3H] proteins transported fell to 40% of control despite the fact that the Li+ substitution does not modify Ca+ fluxes across the plasma membrane in neurons of the frog spinal nerve. The present findings suggest that removal of Na+ interferes with fast axonal transport by a mechanism other than an increase in intracellular Ca2+

Animals↗
PubMed2006

Liver choline dehydrogenase and kidney betaine-homocysteine methyltransferase expression are not affected by methionine or choline intake in growing rats.

Choline dehydrogenase (CHDH) and betaine-homocysteine methyltransferase (BHMT) are 2 enzymes involved in choline oxidation. BHMT is expressed at high levels in rat liver and its expression is regulated by dietary Met and choline. BHMT is also found in rat kidney, albeit in substantially lower amounts, but it is not known whether kidney BHMT expression is regulated by dietary Met or choline. Similarly, CHDH activity is highest in the liver and kidney, but the regulation of its expression by diet has not been thoroughly investigated. Sprague Dawley rats ( approximately 50 g) were fed, for 9 d in 2 x 3 factorial design (n = 8), an l-amino acid-defined diet varying in l-Met (0.125, 0.3, or 0.8%) and choline (0 or 25 mmol/kg diet). Liver and kidney BHMT and CHDH were assessed using enzymatic, Western blot, and real-time PCR analyses. Liver samples were also fixed for histological analysis. Liver BHMT activity was 1.3-fold higher in rats fed the Met deficient diet containing choline, which was reflected in corresponding increases in mRNA content and immunodetectable protein. Independent of dietary choline, supplemental Met increased hepatic BHMT activity approximately 30%. Kidney BHMT and liver CHDH expression were refractory to these diets. Some degree of fatty liver developed in all rats fed a choline-devoid diet, indicating that supplemental Met cannot completely compensate for the lack of dietary choline in growing rats.

Animals↗
PubMed1994

Evidence for cholinergic neuronal loss in brain in congenital ornithine transcarbamylase deficiency.

Congenital ornithine transcarbamylase (OTC) deficiency in humans is associated with seizures and mental retardation. As part of a series of studies to delineate the neurochemical features of OTC deficiency, activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), respectively, were measured in brain regions of the congenitally hyperammonemic sparse-fur (spf) mouse, a mutant with an X-linked inherited defect of OTC. ChAT activities were reduced by 63% (P < 0.01) in cerebral cortex of spf mice compared with CD-1/Y controls. Activities of the GABA nerve terminal marker enzyme, glutamic acid decarboxylase, on the other hand, were within normal limits. Using an immunohistochemical technique with a monoclonal antibody to ChAT, a significant loss of ChAT-positive neurons was observed throughout the cerebral cortex, septal area and diagonal band of spf mice. These results suggest that a loss of forebrain cholinergic neurons is a feature of congenital OTC deficiency in these mutants. Possible pathogenetic mechanisms responsible for the cholinergic neuronal loss in congenital OTC deficiency include neurotoxic effects of ammonia and accumulation of quinolinic acid.

Acetylcholinesterase↗
PubMed1978

Leg bone abnormalities and histopathology of caged and floor reared broilers fed diets devoid of selected vitamins and minerals.

Summers et al., 1978, described an experiment in which performance and leg conditions of birds fed diets devoid of synthetic biotin, choline, folic acid, manganese, and miacin were observed and recoreded. This is a report on birds from the same experiment. Dyschondroplasia of the tibia was documented and the distal end of each tibia examined histologically. Metatarsal length and condyle depth of the distal tibia were also determined. Metatarsal length was influenced by vitamin deficiencies as well as the type of floor on which binds were raised. The depth of the intercondyle space was affected more by a manganese deficiency than by vitamin deficiencies and, in this case, was greater on plastic and litter as opposed to wire floors. There did not appear to be a correlation between the space depth and slipping of the tendons; however, a large number of birds should be examined to provide more data. Dyschondroplasia was more prevalent in choline deficient birds, particularly those birds raised on litter or plastic floors. Histology changes in relation to nutrient deficiencies were comparable to those reported previously.

Animals↗
PubMed1995

Methyl donors in the diet and responses to chemical carcinogens.

Dietary deficiency of labile methyl donors (choline and methionine) increases spontaneous and chemically induced hepatocarcinogenesis in rats. Chemical carcinogenesis in the colon, mammary gland, esophagus, and pancreas also may be increased. The mechanism of the dietary effect is not known but may be related to reduced methylation of DNA and RNA, hyperplasia of target cells, increased peroxidative damage, and altered carcinogen or promoter metabolism. Folate deficiency also is associated with increased carcinogenesis, an effect that may be mediated through participation in methyl metabolism; this has been less extensively studied. Deficiency of these three nutrients also may play a role in the elevated cancer risk in humans that is associated with ethanol intake.

Animals↗
PubMed1977

Chronic toxicity of methotrexate in rats: partial to complete projection of the liver by choline: Brief communication.

Methotrexate (MTX) inhibits the enzyme dihydrofolate reductase, which in turn limits the body's ability to perform transmethylation reactions. This study examined the hypothesis that the consequent deficiency of an important methylated compound, choline, may have contributed to the MTX-induced fatty change in the liver of W rats. Groups of rats were given MTX alone or MTX plus choline in varying dose combinations. All groups but one receiving the combined treatment showed a significantly lower triglyceride concentration in their livers and much less visible hepatocytic fat on histologic examination than did those given MTX alone. The protective effect of choline on the liver was dose related, the unaffected group having received a very small amount. Growth rate, survival, and hematopoietic depression due to MTX were unaltered by choline administration.

Animals↗
PubMed1976

Factors affecting liver lipid content in pyridoxing-deficient rats. I. Dietary protein levels.

Effects of choline fortification and various dietary protein levels on liver lipid content in pyridoxine-deficient rats were studied. Choline fortification did not prevent the accumulation of liver lipids in pyridoxine-deficient rats. Considerable accumulation of liver lipids was observed in the 70% casein pyridoxine-deprived group. Reducing the protein level in the diet decreased the extent of lipid accumulation. A highly negative correlation was found between liver lipid content and liver GPT activity, indicating that the fatty infiltration of the liver may be intimately related to the pyridoxine deficiency state. The time course of fatty liver induction upon feeding of a 70% casein pyridoxine-deficient diet was also studied. The liver lipid content increased gradually and reached the highest value by the third week with a concomitant decrease in food intake. Effect of change of dietary compositions on fatty liver caused by 70% casein pyridoxine-free diet was examined. Feeding of a 70% casein pyridoxine-supplemented diet or a 20% casein pyridoxine-free diet caused decreases in the liver lipids.

Alanine Transaminase↗
PubMed2005

Progesterone neuroprotection in spinal cord trauma involves up-regulation of brain-derived neurotrophic factor in motoneurons.

Progesterone (PROG) provides neuroprotection to the injured central and peripheral nervous system. These effects may be due to regulation of myelin synthesis in glial cells and also to direct actions on neuronal function. Both types of cells express classical intracellular PROG receptors (PR), while neurons additionally express the PROG membrane-binding site called 25-Dx. In motoneurons from rats with spinal cord injury (SCI), PROG restores to normal the deficient levels of choline acetyl-transferase and of alpha3 subunit Na,K-ATPase mRNA, while levels of the growth associated protein GAP-43 mRNA are further stimulated. Recent studies suggest that neurotrophins are possible mediators of hormone action, and in agreement with this assumption, PROG treatment of rats with SCI increases the expression of brain-derived neurotrophic factor (BDNF) at both the mRNA and protein levels in ventral horn motoneurons. In situ hybridization (ISH) has shown that SCI reduces BDNF mRNA levels by 50% in spinal motoneurons, while PROG administration to injured rats (4mg/kg/day during 3 days, s.c.) elicits a three-fold increase in grain density. In addition to enhancement of mRNA levels, PROG increases BDNF immunoreactivity in perikaryon and cell processes of motoneurons of the lesioned spinal cord, and also prevents the lesion-induced chromatolytic degeneration of spinal cord motoneurons as determined by Nissl staining. Our findings strongly indicate that motoneurons of the spinal cord are targets of PROG, as confirmed by the expression of PR and the regulation of molecular parameters. PROG enhancement of endogenous neuronal BDNF could provide a trophic environment within the lesioned spinal cord and might be part of the PROG activated-pathways to provide neuroprotection. Thus, PROG treatment constitutes a new approach to sustain neuronal function after injury.

Animals↗
PubMed2004

Tissue-specific contributions of pneumococcal virulence factors to pathogenesis.

We assessed the ability of Streptococcus pneumoniae mutants deficient in either choline binding protein A (CbpA), pneumolysin (Pln), pyruvate oxidase (SpxB), autolysin (LytA), pneumococcal surface protein A, or neuraminidase A (NanA) to replicate in distinct anatomical sites and translocate from one site to the next. Intranasal, intratracheal, and intravenous models of disease were assessed in 4-week-old BALB/cJ mice by quantitation of bacterial titers in the relevant organs. Mice were also observed by use of real-time bioluminescent imaging (BLI). BLI allowed visualization of the bacteria in sites not tested by sampling. All mutants were created in D39 Xen7, a fully virulent derivative of capsular type 2 strain D39 that contains an optimized luxABCDE cassette. NanA, SpxB, and, to a lesser extent, CbpA contributed to prolonged nasopharyngeal colonization, whereas CbpA and NanA contributed to the transition to the lower respiratory tract. Once lung infection was established, Pln, SpxB, and LytA contributed to bacterial replication in the lungs and translocation to the bloodstream. In the bloodstream, only Pln and LytA were required for high-titer replication, whereas CbpA was required for invasion of the cerebrospinal fluid. We conclude that transitions between body sites require virulence determinants distinct from those involved in organ-specific replication.

Animals↗
PubMed1997

Rhizobium meliloti mutants deficient in phospholipid N-methyltransferase still contain phosphatidylcholine.

Phosphatidylcholine (PC) is the major membrane-forming phospholipid in eukaryotes. In addition to this structural function, PC is thought to play a major role in lipid turnover and signalling in eukaryotic systems. In prokaryotes, only some groups of bacteria, among them the members of the family Rhizobiaceae, contain PC. To understand the role of PC in bacteria, we have studied Rhizobium meliloti 1021, which is able to form nitrogen-fixing nodules on its legume host plants and therefore has a very complex phenotype. R. meliloti was mutagenized with N-methyl-N'-nitro-N-nitrosoguanidine, and potential mutants defective in phospholipid N-methyltransferase were screened by using a colony autoradiography procedure. Filters carrying lysed replicas of mutagenized colonies were incubated with S-adenosyl-L-[methyl-14C]methionine. Enzymatic transfer of methyl groups to phosphatidylethanolamine (PE) leads to the formation of PC and therefore to the incorporation of radiolabel into lipid material. Screening of 24,000 colonies for reduced incorporation of radiolabel into lipids led to the identification of seven mutants which have a much-reduced specific activity of phospholipid N-methyltransferase. In vivo labelling of mutant lipids with [14C]acetate showed that the methylated PC biosynthesis intermediates phosphatidylmonomethylethanolamine and phosphatidyldimethylethanolamine are no longer detectable. This loss is combined with a corresponding increase in the potential methyl acceptor PE. These results indicate that PC biosynthesis via the methylation pathway is indeed blocked in the mutants isolated. However, mass spectrometric analysis of the lipids shows that PC was still present when the mutants had been grown on complex medium and that it was present in the mutants in wild-type amounts. In vivo labelling with [methyl-14C]methionine shows that in phospholipid N-methyltransferase-deficient mutants, the choline moiety of PC is not formed by methylation. These findings suggest the existence of a second pathway for PC biosynthesis in Rhizobium.

Acetates↗
PubMed1972

Effect of lidocaine hydrochloride on membrane conductance in mammalian cardiac Purkinje fibers.

Lidocaine depresses automaticity in cardiac Purkinje fibers by decreasing the slope of slow diastolic depolarization, but the mechanisms of this effect are poorly understood. To test the proposal that the antiautomatic effect of lidocaine might be mediated by an increase in membrane potassium conductance, transmembrane voltage (V(m)) was measured in Purkinje fibers perfused with sodium-deficient Tyrode containing choline as the major cation. V(m) was varied by altering the external potassium concentration, [K](o), from 0.5 to 150 mM before and after lidocaine, 2.14 x 10(-5) M, a concentration considered equivalent to clinical plasma antiarrhythmic levels. In Purkinje fibers, resting V(m) varies linearly with [K](o) plotted on a logarithmic scale from 4 to 150 mM, approximately as predicted by the Nernst equation. At [K](o) of 0.5-2.7 mM, resting V(m) diverges from the predicted potassium equilibrium potential (V(K)) resulting in an increased driving force for the outward K(+) current (V(m) - V(K)). In choline Tyrode at [K](o) of 2.7 mM or less, lidocaine caused a significant increase in V(m), the change being a positive linear function of (V(m) - V(K)) with a P < 0.01. This effect was more striking in Purkinje fibers with a V(m) reduced by stretch. These findings imply that lidocaine increased membrane chord conductance for the potassium ion (gK).Current-voltage relationships using intracellular current pulses were performed in choline Tyrode at [K](o) of 0.5, 2.0, and 4.0 mM and, at each [K](o), lidocaine was found to increase membrane slope conductance (GK). The increase in GK was even more apparent when the current-voltage relationships in long Purkinje fibers was corrected for cable complications or when experiments were done in short Purkinje fibers. To minimize complications due to membrane rectifier properties, GK was measured using intracellular application of small hyperpolarizing current pulses as V(m) was decreased from -90 to -60 mv by increasing the [K](o) from 3 to 15 mM before and after lidocaine. Lidocaine increased the GK over this range of V(m). These results suggest that lidocaine increases membrane potassium conductance within the range of V(m) where the pacemaker potential is seen, an action which can account for its ability to suppress automaticity, and, in part, for its ability to prevent reentrant arrhythmias.

Animals↗
PubMedDate not supplied

[Activation of reparative processes by phospholipid preparation in the affected organs and tissues in neonathal enteropathology of calves].

The peculiarities of dynamics of quantitative changes of some classes of lipid and phospholipid spectra of blood plasma of calves recovered after dyspepsia were studied. Obtained reliable changes of the blood plasma lipidogrammas testify to development of dyslipidemia. It is characterized by hypercholesterolemia and hypertriacylglycerolemia of recovered 30 days old calves 3 weeks after diseases symptoms past. These changes give evidence concerning deficiency of phosphatides choline fraction - main structural components of cell membranes. It was established that changes of lipid and phospholipid spectra of blood plasma caused by enteropathology can be corrected by the inclusion of reparative therapy preparations to dyspepsia treatment plan in particular--experimental phospholipid containing a drug, which is prepared on the basis of milk phospholipids--its natural source for newborn calves.

Animals↗