Choline is an essential nutrient that plays an integral role in all stages of the life cycle, with increasing interest in the relationship between choline and neurodevelopment. Choline is a major component in the synthesis of phospholipids, phosphatidylcholine and sphingolipids, and is an essential nutrient for methyl metabolism, acetylcholine synthesis and cell signaling. Choline plays an important role in neurogenesis and neural migration during fetal development, potentially influencing the development and prognosis of neurological disorders, but its mechanism of action is not yet clear. This article reviews the source and metabolism of choline, the effects and mechanism of choline on neurodevelopment and central nervous system related disorders.
Humans ; Choline/metabolism* ; Phosphatidylcholines/metabolism* ; Central Nervous System/metabolism*

Objective: To characterize the relationship between the levels of plasma methyl donor and related metabolites (including choline, betaine, methionine, dimethylglycine and homocysteine) and fetal growth in twin pregnancies. Methods: A hospital-based cohort study was used to collect clinical data of 92 pregnant women with twin pregnancies and their fetuses who were admitted to Peking University Third Hospital from March 2017 to January 2018. Fasting blood was collected from the pregnant women with twin pregnancies (median gestational age: 18.9 weeks). The levels of methyl donors and related metabolites in plasma were quantitatively analyzed by high-performance liquid chromatography combined with mass spectrometry. The generalized estimation equation was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and neonatal outcomes of twins, and the generalized additive mixed model was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and fetal growth ultrasound indicators. Results: (1) General clinical data: of the 92 women with twin pregnancies, 66 cases (72%) were dichorionic diamniotic (DCDA) twin pregnancies, and 26 cases (28%) were monochorionic diamniotic (MCDA) twin pregnancies. The comparison of the levels of five plasma methyl donors and related metabolites in twin pregnancies with different basic characteristics showed that the median levels of plasma choline and betaine in pregnant women ≥35 years old were higher than those in pregnant women <35 years old, and the differences were statistically significant (all P<0.05). (2) Correlation between plasma methyl donor and related metabolites levels and neonatal growth indicators: after adjusting for confounding factors, plasma homocysteine level in pregnant women with twins was significantly negatively correlated with neonatal birth weight (β=-47.9, 95%CI:-94.3- -1.6; P=0.043). Elevated methionine level was significantly associated with decreased risks of small for gestational age infants (SGA; OR=0.5, 95%CI: 0.3-0.9; P=0.021) and low birth weight infants (OR=0.6, 95%CI: 0.4-0.9; P=0.020). Increased homocysteine level was associated with increased risks of SGA (OR=1.5, 95%CI: 1.0-2.2; P=0.029) and inconsistent growth in twin fetuses (OR=1.9, 95%CI: 1.0-3.7; P=0.049). (3) Correlation between the levels of plasma methyl donors and related metabolites and intrauterine growth indicators of twins pregnancies: for every 1 standard deviation increase in plasma choline level in pregnant women with twin pregnancies, fetal head circumference, abdominal circumference, femoral length and estimated fetal weight in the second trimester increased by 1.9 mm, 2.6 mm, 0.5 mm and 20.1 g, respectively, and biparietal diameter, abdominal circumference and estimated fetal weight increased by 0.7 mm, 3.0 mm and 38.4 g in the third trimester, respectively, and the differences were statistically significant (all P<0.05). (4) Relationship between plasma methyl donor and related metabolites levels in pregnant women with different chorionicity and neonatal birth weight and length: the negative correlation between plasma homocysteine level and neonatal birth weight was mainly found in DCDA twin pregnancy (β=-65.9, 95%CI:-110.6- -21.1; P=0.004). The levels of choline, betaine and dimethylglycine in plasma of MCDA twin pregnancy were significantly correlated with the birth weight and length of newborns (all P<0.05). Conclusion: Homocysteine level is associated with low birth weight in twins, methionine is associated with decreased risk of SGA, and choline is associated with fetal growth in the second and third trimesters of pregnancy.
Adult ; Female ; Humans ; Infant, Newborn ; Pregnancy/metabolism* ; Betaine/metabolism* ; Birth Weight/physiology* ; Choline/metabolism* ; Cohort Studies ; Fetal Development/physiology* ; Fetal Weight/physiology* ; Homocysteine/metabolism* ; Methionine/metabolism* ; Pregnancy, Twin/physiology* ; Biomarkers/metabolism* ; Pregnancy Trimesters/physiology* ; Pregnancy Outcome

The association among plasma trimethylamine-N-oxide (TMAO), FMO3 polymorphisms, and chronic heart failure (CHF) remains to be elucidated. TMAO is a microbiota-dependent metabolite from dietary choline and carnitine. A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction, with the longest follow-up of 7 years. The concentrations of plasma TMAO and its precursors, namely, choline and carnitine, were determined by liquid chromatography-mass spectrometry, and the FMO3 E158K polymorphisms (rs2266782) were genotyped. The top tertile of plasma TMAO was associated with a significant increment in hazard ratio (HR) for the composite outcome of cardiovascular death or heart transplantation (HR = 1.47, 95% CI = 1.13-1.91, P = 0.004) compared with the lowest tertile. After adjustments of the potential confounders, higher TMAO could still be used to predict the risk of the primary endpoint (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). This result was also obtained after further adjustment for carnitine (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). The FMO3 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort, and lower TMAO levels were found in the AA-genotype. Thus, higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders, and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.
Carnitine ; Choline/metabolism* ; Chronic Disease ; Heart Failure/genetics* ; Humans ; Methylamines ; Oxygenases ; Prospective Studies

OBJECTIVE: To explore the changes in Yes-associated protein (YAP) activity at the early stage of nonalcoholic steatohepatitis (NASH) and the spatiotemporal relationship between YAP and ductular reaction (DR). METHODS: Male C57BL/6J mouse models of NASH were established by feeding with a methionine- and choline-deficient (MCD) diet or a thioacetamide (TAA) diet for 12 weeks. At different time points during the feeding, liver histology of the mice was observed with HE and Masson trichrome staining. The mRNA expressions of YAP and its target genes (Ctgf, Cyr61, Acta2) were determined by qPCR, and the total protein expression level of YAP was measured with immunoblotting. The expression and distribution of YAP and the markers of DR (K19 and Sox9) were observed with immunohistochemical staining. RESULTS: At the early stage of NASH induced by MCD diet (1 to 4 weeks), the mRNA expression of YAP and its target genes and the total protein expression of YAP increased significantly (P < 0.01). The number of YAP-positive hepatocytes reached the peak level of 90.8 (cells per ×400 field of view) at week 2 and then decreased to 30.8 at week 4 (P < 0.001); YAP-positive ductular cells appeared near the portal area, where DR began to occur. From 8 to 12 weeks, numerous K19/Sox9-positive DR cells were observed in the hepatic lobules around the central vein (P < 0.01), while only a few YAP-positive hepatocytes were present in the liver tissue (P > 0.05), and the number of YAP-positive ductular cells gradually increased with time (P < 0.001). At the early stage of NASH induced by TAA diet (3 days to 2 weeks), the mRNA expression of YAP and its target genes and the total protein expression of YAP increased significantly (P < 0.05), and the number of YAP-positive hepatocytes reached the peak of 69.2 at week 2 and then decreased to 55.2 at week 4 (P < 0.001); YAP-positive ductular cells first appeared at the initial location of DR near the central vein. From 6 to 12 weeks, numerous K19/Sox9-positive DR cells occurred in the hepatic lobules around the central vein (P < 0.01). While the number of YAP-positive hepatocytes decreased (P < 0.001), the number of YAP-positive ductular cells continued to increase (P < 0.001). CONCLUSION During the development of NASH, YAP activation occurs earlier than DR but they are spatiotemporally correlated. YAP activation in hepatocytes may participate in DR by promoting hepatocyte dedifferentiation.
Animals ; Choline ; Disease Models, Animal ; Hepatocytes ; Liver/metabolism* ; Male ; Methionine/metabolism* ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/metabolism* ; RNA, Messenger/metabolism* ; Thioacetamide/metabolism* ; YAP-Signaling Proteins

OBJECTIVETo examine the effect of icariin (ICA) on the cognitive impairment induced by traumatic brain injury (TBI) in mice and the underlying mechanisms related to changes in hippocampal acetylation level.

METHODSThe modifified free-fall method was used to establish the TBI mouse model. Mice with post-TBI cognitive impairment were randomly divided into 3 groups using the randomised block method (n=7): TBI (vehicle-treated), low-dose (75 mg/kg) and high-dose (150 mg/kg) of ICA groups. An additional sham-operated group (vehicle-treated) was employed. The vehicle or ICA was administrated by gavage for 28 consecutive days. The Morris water maze (MWM) test was conducted. Acetylcholine (ACh) content, mRNA and protein levels of choline acetyltransferase (ChAT), and protein levels of acetylated H3 (Ac-H3) and Ac-H4 were detected in the hippocampus.

RESULTSCompared with the sham-operated group, the MWM performance, hippocampal ACh content, mRNA and protein levels of ChAT, and protein levels of Ac-H3 and Ac-H4 were signifificantly decreased in the TBI group (P<0.05). High-dose of ICA signifificantly ameliorated the TBI-induced weak MWM performance, increased hippocampal ACh content, and mRNA and protein levels of ChAT, as well as Ac-H3 protein level compared with the TBI group (P<0.05).

CONCLUSIONICA improved post-TBI cognitive impairment in mice by enhancing hippocampal acetylation, which improved hippocampal cholinergic function and ultimately improved cognition.

Acetylation ; Acetylcholine ; metabolism ; Animals ; Brain Injuries, Traumatic ; complications ; Choline O-Acetyltransferase ; genetics ; metabolism ; Cognitive Dysfunction ; drug therapy ; etiology ; Flavonoids ; chemistry ; pharmacology ; therapeutic use ; Hippocampus ; pathology ; Histones ; metabolism ; Homeostasis ; drug effects ; Male ; Maze Learning ; drug effects ; Mice ; RNA, Messenger ; genetics ; metabolism

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases currently in the context of obesity worldwide, which contains a spectrum of chronic liver diseases, including hepatic steatosis, non-alcoholic steatohepatitis and hepatic carcinoma. In addition to the classical "Two-hit" theory, NAFLD has been recognized as a typical gut microbiota-related disease because of the intricate role of gut microbiota in maintaining human health and disease formation. Moreover, gut microbiota is even regarded as a "metabolic organ" that play complementary roles to that of liver in many aspects. The mechanisms underlying gut microbiota-mediated development of NAFLD include modulation of host energy metabolism, insulin sensitivity, and bile acid and choline metabolism. As a result, gut microbiota have been emerging as a novel therapeutic target for NAFLD by manipulating it in various ways, including probiotics, prebiotics, synbiotics, antibiotics, fecal microbiota transplantation, and herbal components. In this review, we summarized the most recent advances in gut microbiota-mediated mechanisms, as well as gut microbiota-targeted therapies on NAFLD.
Animals ; Bile Acids and Salts ; metabolism ; Choline ; metabolism ; Dietary Supplements ; Energy Metabolism ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome ; Humans ; Insulin Resistance ; Intestines ; microbiology ; Non-alcoholic Fatty Liver Disease ; microbiology ; therapy

BACKGROUNDIn head and neck neoplasm survivors treated with brain irradiation, metabolic alterations would occur in the radiation-induced injury area. The mechanism of these metabolic alterations has not been fully understood, while the alternations could be sensitively detected by proton (1H) nuclear magnetic resonance spectroscopy (MRS). In this study, we investigated the metabolic characteristics of radiation-induced brain injury through a long-term follow-up after radiation treatment using MRS in vivo.

METHODSA total of 12 adult Sprague-Dawley rats received a single dose of 30 Gy radiation treatment to semi-brain (field size: 1.0 cm × 2.0 cm; anterior limit: binocular posterior inner canthus connection; posterior limit: external acoustic meatus connection; internal limit: sagittal suture). Conventional magnetic resonance imaging and single-voxel 1H-MRS were performed at different time points (in month 0 before irradiation as well as in the 1st, 3rd, 5th, 7th, and 9th months after irradiation) to investigate the alternations in irradiation field. N-acetylaspartate/choline (NAA/Cho), NAA/creatinine (Cr), and Cho/Cr ratios were measured in the bilateral hippocampus and quantitatively analyzed with a repeated-measures mixed-effects model and multiple comparison test.

RESULTSSignificant changes in the ratios of NAA/Cho (F = 57.37, P_{g < 0.001), NAA/Cr (F = 54.49, Pg < 0.001), and Cho/Cr (F = 9.78, Pg = 0.005) between the hippocampus region of the irradiated semi-brain and the contralateral semi-brain were observed. There were significant differences in NAA/Cho (F = 9.17, Pt < 0.001) and NAA/Cr (F = 13.04, Pt < 0.001) ratios over time. The tendency of NAA/Cr to change with time showed no significant difference between the irradiated and contralateral sides. Nevertheless, there were significant differences in the Cho/Cr ratio between these two sides.}

CONCLUSIONSMRS can sensitively detect metabolic alternations. Significant changes of metabolites ratio in the first few months after radiation treatment reflect the metabolic disturbance in the acute and early-delayed stages of radiation-induced brain injuries.

Animals ; Aspartic Acid ; analogs & derivatives ; metabolism ; Brain ; radiation effects ; Choline ; metabolism ; Male ; Proton Magnetic Resonance Spectroscopy ; methods ; Radiation Injuries ; diagnosis ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the preventive effect of different compatibilities of Ramulus Cinnamomi (RC) and Radix Paeomiae alba (RPA) in Guizhi Decoction (GZD) on neurotransmitters and their rate-limiting enzymes, and neurotrophic factors of cardiac sympathetic denervation model rats induced by 6-hydroxydopamine (6-OHDA).

METHODSTotally 54 male Wistar rats were randomly divided into 6 groups, i.e., the blank control group, the model group, the methycobal group, the 2:1 (RC/RPA) Guishao group, the 1:2 Guishao group, and the 1:1 Guishao group, 9 in each group. Sympathetic denervation was induced by intraperitoneal injection of 6-OHDA for three successive days. Rats in the methycobal group and GZD groups were administered with corresponding decoction by gastrogavage 1 week before modeling (methycobal at the daily dose 0.15 mg/kg; GZD at the daily dose of 4.0, 5.5, 5.5 g crude drugs/kg for GZD 1:1, 1:2, and 2:1 groups). All medication lasted for 10 successive days. Levels of norepinephrine (NE), tyrosine hydroxylase (TH), choline acetyl-transferase (ChAT), nerve growth factor (NGF), growth associated protein43 (GAP-43) and ciliary neurotrophic factor (CNTF) in myocar- dial homogenates of right atrium and ventricular septum were detected by ELISA.

RESULTSCompared with the blank control group, levels of NE, TH, TH/ChAT ratio, and GAP-43 in myocardial homogenates of right atrium and ventricular septum decreased in the model group, and level of NGF increased (P < 0.01, P < 0.05). Compared with the model group, levels of NE and GAP-43 increased in the right atrium and interventricular septum; NGF level of the ventricular septum decreased in the methycobal group and each GZD groups. TH and TH/ChAT ratio in the right atrium increased in the 2:1 Guishao group and the 1:2 Guishao group (P < 0.01, P < 0.05); NGF levels in the right atrium and interventricular septum decreased only in the 1:1 Guishao group (P < 0.01, P< 0.05). Compared with the methycobal group, levels of NE, TH, and GAP-43 in the right atrium and interventricular septum increased, and NGF levels in the right atrium and interventricular septum decreased in the 1:1 Guishao group (P < 0.05). Compared with the methycobal group, levels of NE and GAP-43 in interventricular septum increased in the 2:1 Guishao group (P < 0.05).

CONCLUSIONGZD (with the proportion between RC and RPA 2:1 and 1:1) could improve contents of neurotransmitters and their rate-limiting enzymes, as well as neurotrophic factors in cardiac sympathetic denervation model rats induced by 6-OHDA, alleviate cardiac sympathetic denervation induced by 6-OHDA, and maintain the balance of sympathetic-vagal nerve system.

Animals ; Choline O-Acetyltransferase ; metabolism ; Ciliary Neurotrophic Factor ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; GAP-43 Protein ; metabolism ; Heart ; drug effects ; innervation ; Male ; Myocardium ; metabolism ; Nerve Growth Factor ; metabolism ; Norepinephrine ; metabolism ; Oxidopamine ; adverse effects ; Random Allocation ; Rats ; Rats, Wistar ; Sympathectomy ; Tyrosine 3-Monooxygenase ; metabolism

OBJECTIVE: To explore the correlation between diabetic nephropathy (DN) and cognitive impairment through examining the cognitive function and the metabolism of the cerebrum in Type 2 diabetes mellitus patients at different stages of renal function.
 METHODS: Eighty six patients with Type 2 diabetes mellitus (T2DM) were enrolled for this study. According to the urinary albumin excretion rate (UAER), the patients were divided into a T2DM without DN group (DM group, n=33), an early DN group (DN-III group, n=26) and a clinical stage group (DN-IV group, n=27). Thirty healthy adults were selected as a control group (NC group). Biochemical indexes and UAER were measured, and glomerular filtration rate (GFR) was detected by single-photon emission computed tomography (SPECT). The cognitive function was measured by Montreal Cognitive Assessment (MoCA, Beijing version) and mini-mental state examination (MMSE). The peak areas of N-acetylasparte (NAA), creatine (Cr), choline-containing compounds (Cho) were detected by proton magnetic resonance spectroscopy (1H-MRS).
 RESULTS: 1) There was no statistical difference in MMSE scores between the DM group and the control group. The scores of MoCA in the DN-III group or in the DN-IV group were significant less than that in the NC group (F=3.66, P<0.05); 2) There was significant difference in left N-acetylaspartate (LNAA), left choline (LCho) among the diabetes groups. Compared with the DM group, the level of LNAA was decreased significantly (t=3.826, P<0.05) while the LCho was increased significantly (t=4.373, P<0.05) in the DN groups, with statistic difference between the 2 groups (t=3.693, P<0.05); 3) The MoCA scores of T2DM patients were negatively correlated with UAER (r=-0.285, P<0.05), while positively correlated with GFR (r=0.379, P<0.05); 4) Logistic regression analysis indicated that UAER and GFR were the major risky factors for diabetic cognitive impairment.
 CONCLUSION Diabetic cognitive impairment is closely correlated with the nephropathy in patients with Type 2 diabetes. With the decline in glomerular filtration function, the cognitive disorder tends to be aggravated. The hippocampal brain metabolism may have some changes in left side of Cho/Cr in patients with diabetic nephropathy.
Adult ; Aspartic Acid ; analogs & derivatives ; metabolism ; Case-Control Studies ; Cerebrum ; metabolism ; Choline ; metabolism ; Cognition ; Cognition Disorders ; epidemiology ; Creatine ; metabolism ; Diabetes Mellitus, Type 2 ; physiopathology ; Diabetic Nephropathies ; epidemiology ; Glomerular Filtration Rate ; Humans ; Neuropsychological Tests

OBJECTIVETo study the effects of Dipsacus total saponins on the ability of learning and memory and its mechanism of action.

METHODSForty rats were randomly divided into blank control group, model group, Dipsacus group and positive control group (n = 10), general situation of rats were observed, the ability of learning and memory of rats was tested by Square water maze, the activities of acetylcholinesterase (AChE)and choline acetyltransferase (ChAT) of hippocampus in rats were measured using double antibody sandwich method.

RESULTSDuring the period of treatment, general situation had no obvious change in model group, but general situation and the ability of activity were gradually improved in Dipsacus group and positive control group. Compared with blank control group, the swimming time was obviously prolonged and the number of mistakes was obviously increased at different time, the activity of AChE was significantly enhanced and the activity of ChAT was significantly decreased in model group. Compared with model group, the swimming time was obviously shortened and the number of mistakes was obviously reduced at different time, the activities of AChE were significantly decreased and the activities of ChAT were significantly enhanced in Dipsacus group and positive control group; Compared with positive control group, the swimming time and the number of mistakes at different time and the activities of AChE and ChAT had no significant difference in Dipsacus group.

CONCLUSIONDipsacus total saponins can improve the ability of learning and memory in Alzheimer' s disease(AD) rats, its mechanism of 'action may be related to regulating ACh metabolism of hippocampus.

Acetylcholine ; metabolism ; Acetylcholinesterase ; metabolism ; Alzheimer Disease ; drug therapy ; physiopathology ; Animals ; Choline O-Acetyltransferase ; metabolism ; Dipsacaceae ; chemistry ; Disease Models, Animal ; Hippocampus ; drug effects ; Learning ; drug effects ; Memory ; drug effects ; Rats ; Saponins ; pharmacology