27-Hydroxycholesterol inhibits trophoblast fusion during placenta development by activating PI3K/AKT/mTOR signaling pathway.

Trophoblast cell syncytialization is essential for placental and fetal development. Abnormal trophoblast cell fusion leads to pregnancy pathologies, such as preeclampsia (PE), intrauterine growth restriction (IUGR), and miscarriage. 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in human peripheral blood synthesized by sterol 27-hydroxylase (CYP27A1) and is considered a critical mediator between hypercholesterolemia and a variety of related disorders. Gestational hypercholesterolemia was associated with spontaneous preterm delivery and low birth weight (LBW) in term infants, yet the mechanism is unclear. In this study, two trophoblast cell models and CD-1 mice were used to evaluate the effects of 27-OHC on trophoblast fusion during placenta development. Two different kinds of trophoblast cells received a dosage of 2.5, 5, or 10 uM 27-OHC. Three groups of pregnant mice were randomly assigned: control, full treatment (E0.5-E17.5), or late treatment (E13.5-E17.5). All mice received daily intraperitoneal injections of saline (control group) and 27-OHC (treatment group; 5.5 mg/kg). In vitro experiments, we found that 27-OHC inhibited trophoblast cell fusion in primary human trophoblasts (PHT) and forskolin (FSK)-induced BeWo cells. 27-OHC up-regulated the expression of the PI3K/AKT/mTOR signaling pathway-related proteins. Moreover, the PI3K inhibitor LY294002 rescued the inhibitory effect of 27-OHC. Inhibition of trophoblast cell fusion by 27-OHC was also observed in CD-1 mice. Furthermore, fetal weight and placental efficiency decreased and fetal blood vessel development was inhibited in pregnant mice treated with 27-OHC. This study was the first to prove that 27-OHC inhibits trophoblast cell fusion by Activating PI3K/AKT/mTOR signaling pathway. This study reveals a novel mechanism by which dyslipidemia during pregnancy results in adverse pregnancy outcomes.

Nuclear Binding Protein 2/Nesfatin-1 Affects Trophoblast Cell Fusion during Placental Development via the EGFR-PLCG1-CAMK4 Pathway.

Previous studies have shown that nuclear binding protein 2 (NUCB2) is expressed in the human placenta and increases with an increase in the syncytialization of trophoblast cells. This study aimed to investigate the role of NUCB2 in the differentiation and fusion of trophectoderm cells. In this study, the expression levels of NUCB2 and E-cadherin in the placentas of rats at different gestation stages were investigated. The results showed that there was an opposite trend between the expression of placental NUCB2 and E-cadherin in rat placentas in different trimesters. When primary human trophoblast (PHT) and BeWo cells were treated with high concentrations of Nesfatin-1, the trophoblast cell syncytialization was significantly inhibited. The effects of NUCB2 knockdown in BeWo cells and Forskolin-induced syncytialization were investigated. These cells showed a significantly decreased cell fusion rate. The mechanism underlying NUCB2-regulated trophoblast cell syncytialization was explored using RNA-Seq and the results indicated that the epidermal growth factor receptor (EGFR)-phospholipase C gamma 1 (PLCG1)-calmodulin-dependent protein kinase IV (CAMK4) pathway might be involved. The results suggested that the placental expression of NUCB2 plays an important role in the fusion of trophoblasts during differentiation via the EGFR-PLCG1-CAMK4 pathway.

Association of maternal HDL2-c concentration in the first trimester and the risk of large for gestational age birth.

BACKGROUND: Maternal lipid levels during pregnancy are critical for fetal development. Recent studies revealed that high-density lipoprotein cholesterol (HDL-c) levels during pregnancy were negatively correlated with birthweight. High-density lipoprotein 2 cholesterol (HDL2-c) is one of the major subclasses of HDL-c, and its relationship with birthweight is unclear. Association of HDL2-c concentration in the first trimester and risk of large for gestational age (LGA) was explored. METHODS: This study recruited pregnant women who registered in Fuxing Hospital from October 2018 to January 2020, had regular obstetric examinations during pregnancy, and delivered between June 2019 and September 2020. Finally, 549 participants were recruited for the study. Maternal demographic characteristics and venous blood were collected at the 6th-14th gestational week, and serum total cholesterol (TC), triglyceride (TG), HDL-c, HDL2-c, high-density lipoprotein 3 cholesterol (HDL3-c), and low-density lipoprotein cholesterol (LDL-c) concentrations were detected. Neonatal characteristics were collected at delivery. A logistic regression model was used to explore the relationship between the first trimester HDL2-c concentration and LGA incidence. A nomogram was developed, and the performance was evaluated with a concordance index. RESULTS: Seventy-five mothers delivered LGA infants, and the LGA incidence was 13.66%. LGA mothers had significantly lower serum HDL-c and HDL2-c concentrations than appropriate for gestational age (AGA) mothers. A logistic regression model showed that HDL2-c concentration was negatively correlated with LGA risk (odds ratio (OR) = 0.237, 95% confidence intervals (CI): 0.099-0.567, P = 0.001) when adjusted for age, prepregnancy body mass index (BMI), and parity. A nomogram was generated using all these risk factors. The area under the curve (AUC) was 0.663 (95% CI: 0.593-0.732). CONCLUSIONS: Maternal HDL2-c concentration in the first trimester was negatively correlated with the risk of LGA.

Changes in serum TG levels during pregnancy and their association with postpartum hypertriglyceridemia: a population-based prospective cohort study.

BACKGROUND: Blood lipid increases during gestation are considered a physiological adaption, and decrease after delivery. However, some adverse pregnancy outcomes are thought to be related to gestational lipid levels. Therefore, it is necessary to have a reference range for lipid changes during gestation. The present study aims to describe triglyceride (TG) changes during pregnancy and 42 days postpartum and to find cut-off points for TG levels during the first, second, and third trimesters. METHODS: A total of 908 pregnant women were followed from recruitment to 42 days postpartum, and their serum lipids were collected at gestational weeks 6-8, 16, 24, and 36 and 42 days postpartum. The major outcome was postpartum hypertriglyceridemia. The association between gestational and postpartum TG levels was analysed by stepwise multiple linear regression. A two-stage approach including a linear mixed-effect model and linear or logistic regression was conducted to explore the contribution of the changes in TG over time in pregnancy to postpartum hypertriglyceridemia. Logistic regression was constructed to examine the association between gestational TG levels and postpartum hypertriglyceridemia. Cut-off points were calculated by receiver operating characteristic (ROC) curves. RESULTS: There was a tendency for serum TG to increase with gestational age and decrease at 42 days postpartum. Prepregnancy overweight, obesity, and GDM intensified this elevation. Higher TG levels at gestational weeks 6-8, 16, 24, and 36 were positively associated with a higher risk of postpartum hypertriglyceridemia [OR 4.962, 95 % CI (3.007-8.189); OR 2.076, 95 % CI (1.303-3.309); OR 1.563, 95 % CI (1.092-2.236); and OR 1.534, 95 % CI (1.208-1.946), respectively]. The trend of the change in TG over time was positively associated with the TG level and risk of postpartum hypertriglyceridemia [OR 11.660, 95 % CI (6.018-22.591)]. Based on ROC curves, the cut-off points of serum TG levels were 1.93, 2.35, and 3.08 mmol/L at gestational weeks 16, 24, and 36, respectively. Stratified analysis of prepregnancy body mass index (pre-BMI) and GDM showed that higher gestational TG was a risk factor for postpartum hypertriglyceridemia in women with normal pre-BMI and without GDM. CONCLUSIONS: Gestational TG and its elevation were risk and predictive factors of postpartum hypertriglyceridemia, especially in pregnant women with normal pre-BMI or without GDM.

Dietary Nucleotides Supplementation and Liver Injury in Alcohol-Treated Rats: A Metabolomics Investigation.

BACKGROUND: Previous studies suggested that nucleotides were beneficial for liver function, lipid metabolism and so on. The present study aimed to investigate the metabolic response of dietary nucleotides supplementation in alcohol-induced liver injury rats. METHODS: Five groups of male Wistar rats were used: normal control group (basal diet, equivalent distilled water), alcohol control group (basal diet, 50% alcohol (v/v)), dextrose control group (basal diet, isocaloric amount of dextrose), and 0.04% and 0.16% nucleotides groups (basal diet supplemented with 0.4 g and 1.6 g nucleotides kg(-1) respectively, 50% alcohol (v/v)). The liver injury was measured through traditional liver enzymes, expression of oxidative stress markers and histopathological examination. Ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to identify liver metabolite profiles. RESULTS: Nucleotides supplementation prevented the progression of hepatocyte steatosis. The levels of total proteins, globulin, alanine aminotransferase, aspartate aminotransferase, total cholesterol triglyceride, as well as the oxidative stress markers altered by alcohol, were improved by nucleotides supplementation. Elevated levels of liver bile acids (glycocholic acid, chenodeoxyglycocholic acid, and taurodeoxycholic acid), as well as lipids (stearic acid, palmitic acid, oleic acid, phosphatidylcholine, and lysophosphatidylethanolamine) in alcohol-treated rats were reversed by nucleotides supplementation. In addition, supplementation with nucleotides could increase the levels of amino acids, including valyl-Leucine, L-leucine, alanyl-leucine and L-phenylalanine. CONCLUSION: These data indicate potential biomarkers and confirm the benefit of dietary nucleotides on alcoholic liver injury.

Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase-silent mating type information regulation 2 homologue 1-PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine.

Grape seed procyanidin B2 (GSPB2), an antioxidative and anti-inflammatory polyphenol in grape seed, has been found to have protective effects on diabetic nephropathy. Based on its favourable biological activities, in the present study, we aimed to investigate whether GSPB2 could inhibit apoptosis in rat mesangial cells treated with glucosamine (GlcN) under high-dose conditions. The results showed that the administration of GSPB2 (10 µg/ml) significantly increased the viability of mesangial cells treated with GlcN at a dose of 15 mM. We found that GSPB2 inhibited apoptosis in mesangial cells using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphates (dUTP) nick-end labelling staining and flow cytometry technique (P< 0·05 for both). GSPB2 treatment also suppressed oxidative stress by elevating the activity of glutathione peroxidase (P< 0·05) and superoxide dismutase (P< 0·01), as well as prevented cellular damage. GSPB2 enhanced the mRNA expression of nuclear respiratory factor 1, mitochondrial transcription factor A and mitochondrial DNA copy number in mesangial cells as determined by real-time PCR (P< 0·05 for each). Finally, GSPB2 treatment activated the protein expression of PPARγ co-activator-1α (PGC-1α), silent mating type information regulation 2 homologue 1 (SIRT1) and AMP-activated protein kinase (AMPK) in mesangial cells. These findings suggest that GSPB2 markedly ameliorates mitochondrial dysfunction and inhibits apoptosis in rat mesangial cells treated with high-dose GlcN. This protective effect could be, at least in part, due to the activation of the AMPK-SIRT1-PGC-1α axis.

Effect of oat intake on glycaemic control and insulin sensitivity: a meta-analysis of randomised controlled trials.

The present meta-analysis of randomised controlled trials (RCT) aimed to investigate the effect of oat intake on glycaemic control and insulin sensitivity. A literature search was carried out in PubMed, ScienceDirect Online and The Cochrane Library (up to October 2013) for RCT that assessed the effect of oat intake on glucose control and insulin sensitivity. A total of fifteen articles with 673 subjects met the inclusion criteria. A random-effects model was used when the overall pooled studies exhibited significant heterogeneity. Otherwise, a fixed-effects model was used. Compared with controls, oat intake significantly reduced the concentrations of fasting insulin by - 6·29 (95 % CI - 12·32, - 0·27) pmol/l (P= 0·04) and the values of glucose AUC (GAUC; 0-120 min) by - 30·23 (95 % CI - 43·65, - 16·81) min × mmol/l (P< 0·0001). There was a slight decrease in fasting glucose concentrations, glycated Hb concentrations and homeostatic model assessment-insulin resistance values in subjects who consumed oats, but the difference was not significant. In conclusion, oat intake significantly lowers fasting insulin concentrations and GAUC values. To further investigate the effect of oat intake on fasting glucose concentrations, additional long-term and high-quality RCT with a parallel design are required.

Dosage-effect of selenium supplementation on blood glucose and oxidative stress in type 2 diabetes mellitus and normal mice.

BACKGROUND: The effectiveness of selenium (Se) supplementation on glycemic control is disparate. OBJECTIVE: This study aims to evaluate the effects of different dosages of Se diets on the blood glucose in type 2 diabetes mellitus (T2DM, db/db) and normal (db/m) mice. METHODS: The db/db and db/m mice were fed with different dosages of Se supplemented diets (0, 0.1, 0.3, 0.9, 2.7 mg/kg) for 12 weeks, respectively. Se concentrations of tissues, physical and biochemical characteristics, oxidative stress indexes and gene expression related to glucose, lipid metabolism and Se transporters of liver were detected. RESULTS: The Se concentrations in tissues were related to the dosages of Se supplementation in db/db (blood: slope=11.69, r = 0.924; skeletal muscle: slope=0.36, r = 0.505; liver: slope=22.12, r = 0.828; kidney: slope=11.81, r = 0.736) and db/m mice (blood: slope=19.89, r = 0.876; skeletal muscle: slope=2.80, r = 0.883; liver: slope=44.75, r = 0.717; kidney: slope=60.15, r = 0.960). Compared with Se2.7 group, the fasting blood glucose (FBG) levels of Se0.1 and Se0.3 group were decreased at week3 in db/db mice. Compared with control (Se0) group, the FBG levels of Se2.7 group were increased from week6 to week12 in db/m mice. The oral glucose tolerance test (OGTT) showed that the area under the curve (AUC) of Se0.3 group was lower than that of Se0.9 and Se2.7 group in db/m mice. Furthermore, compared with control group, the malondialdehyde (MDA) level in skeletal muscle of Se0.1 group was decreased, while that of Se2.7 group was increased in db/db mice; the glutathione peroxidase (GPx) activity in skeletal muscle of Se0.3, Se0.9 and Se2.7 group was increased both in db/db and db/m mice. For db/db mice, glucose-6-phosphatase catalytic (G6pc) expression of other groups were lower and fatty acid synthase (Fasn) expression of Se0.9 group were lower compared with Se0.3 group. For db/m mice, compared with Se0.3 group, (peroxisome proliferative activated receptor gamma coactivator 1 alpha) Pgc-1α expression of control and Se0.9 group were higher; (phosphoenolpyruvate carboxykinase 1) Pck1 expression of Se0.1, Se0.9, and Se2.7 group were higher. CONCLUSION: Low dosages (0.1 and 0.3 mg/kg) of Se supplementation exerted beneficial effects on FBG levels and glucose tolerance through regulating hepatic glycolysis and gluconeogenesis and inhibit the oxidative stress while high dosages of Se (0.9 and 2.7 mg/kg) supplementation enhanced FBG levels, impaired glucose tolerance and aggravate oxidative stress.

Quercetin but not quercitrin ameliorates tumor necrosis factor-alpha-induced insulin resistance in C2C12 skeletal muscle cells.

Skeletal muscle is a major site for glucose metabolism and its injury by cytokines can induce insulin resistance leading to type 2 diabetes. It has been suggested that quercetin may act as an anti-diabetic agent, however, the effects of quercetin on insulin resistance in skeletal muscle remain unknown. We aimed to investigate the role of quercetin and its glycoside, quercitrin in tumor necrosis factor-alpha (TNF-α) induced C2C12 skeletal muscle cell impairment. Quercetin, but not quercitrin moderately attenuated the effects of TNF-α and enhanced the basal and insulin stimulated uptake of glucose in a dose-dependent manner via the activation of the protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways. Furthermore, the underlying mechanism also involved the suppression of nuclear factor-κB (NF-κB) signaling and the nitric oxide (NO)/inducible nitric oxide synthase (iNOS) system, downstream of AMPK transduction. In summary, quercetin exhibited its effect of improving glucose uptake and insulin sensitivity in skeletal muscle cells via the two independent signaling pathways of Akt and AMPK, and can be developed as a potential anti-diabetic agent.

Oat ß-glucan supplementation pre- and during pregnancy alleviates fetal intestinal immunity development damaged by gestational diabetes in rats.

Oat ß-glucan (OG) has been shown to improve intestinal microecology in gestational diabetes mellitus (GDM), but the effect on fetal intestine health is unknown. Herein, we aimed to investigate the effects of OG supplementation during gestation in GDM dams on fetal intestinal immune development. OG was supplemented one week before mating until the end of the experiment. GDM rats were made with a high-fat diet (HFD) with a minimal streptozotocin (STZ) dose. The fetal intestines were sampled at gestation day (GD) 19.5, and the intestinal morphology, chemical barrier molecules, intraepithelial immune cell makers, and levels of inflammatory cytokines were investigated. The results showed that OG supplementation alleviated the decrease of the depth of fetal intestinal villi and crypts, the number of goblet cells (GCs), protein expression of mucin-1 (Muc1) and Muc2, the mRNA levels of Gpr41, Gpr43, and T cell markers, and increased the number of paneth cells (PCs), the mRNA levels of defensin-6 (defa6), and macrophage (Mø) marker and the expression of cytokines induced by GDM. In addition, OG supplementation alleviated the function of immune cell self-proliferation, chemotaxis and assembly capabilities, protein, fat, folic acid, and zinc absorption damaged by GDM. As indicated by these findings, OG supplementation before and during pregnancy improved the fetal intestinal chemical barriers, immune cells, cytokines, and the metabolism of nutrients to protect the fetal intestinal immunity.

Lipid Metabolic Genes and Maternal Supraphysiological Hypercholesterolemia: An Analysis of Maternal-fetal Interaction.

CONTEXT: The joint associations of maternal and fetal single nucleotide polymorphisms (SNPs) of lipid metabolic genes with the risk of maternal supraphysiological hypercholesterolemia (MSPH) are unclear. OBJECTIVE: This study aims to investigate the associations of maternal/fetal SNPs of APOE, LPL, LDLR, PCSK9, and SCARB1 with the risk of MSPH and explore whether the maternal-fetal pairing pattern of the risk alleles can affect MSPH risk. METHODS: A nested case-control study was conducted that included 182 pregnant women with MSPH and 182 with maternal physiological hypercholesterolemia. Maternal venous and umbilical venous blood were collected to detect the SNPs of genes. The primary outcome was MSPH. Logistic regression model was used to determine the associations of SNPs with risk of MSPH. RESULTS: The C-allele in maternal APOE rs429358 T > C (adjusted odds ratio [OR] = 1.72, P = 0.033), G-allele in fetal APOE rs440446 C > G (adjusted OR = 1.62, P = 0.012) and T-allele in fetal LPL rs263 C > T (adjusted OR = 1.53, P = 0.011) increased the risk of MSPH. The A-allele in maternal LDLR rs7258950 G > A decreased the risk of MSPH (adjusted OR = 0.67, P = 0.028). For maternal-fetal pairing analysis, the variant concordance of PCSK9 rs2149041, rs7523141, rs7523242, rs7525649, and LDLR rs7258950 were associated with the decreased risk of MSPH under the dominant model. The variant concordance of other SNPs of PCSK9, APOE, LDLR, LPL, and SCARB1 were associated with the increased risk of MSPH. CONCLUSION: This study supports the hypothesis that maternal and fetal genetic polymorphisms of lipid metabolic genes are associated with the risk of MSPH. The maternal-fetal variant concordance is also associated with this risk.

Health effects of high serum calcium levels: Updated phenome-wide Mendelian randomisation investigation and review of Mendelian randomisation studies.

BACKGROUND: Calcium plays a role in a wide range of biological functions. Here we conducted a phenome-wide Mendelian randomisation (MR-PheWAS) analysis and a systematic review for MR studies to comprehensively investigate the health effects of serum calcium. METHODS: One-hundred and thirty genetic variants strongly associated with serum calcium levels were used as instrumental variables. A phenome-wide association analysis (PheWAS) was conducted to examine the associations of genetically predicted serum calcium with 1473 distinct phenotypes in the UK Biobank including 339,197 individuals. Observed associations in PheWAS were further tested for replication in two-sample MR replication analysis. A systematic review for MR studies on serum calcium was performed to synthesize the published evidence and compare with the current MR-PheWAS findings. FINDINGS: Higher genetically predicted calcium levels were associated with decreased risk of 5 diseases in dermatologic and musculoskeletal systems and increased risk of 17 diseases in circulatory, digestive, endocrine, genitourinary and immune systems. Eight associations were replicated in two-sample MR analysis. These included decreased risk of osteoarthritis and increased risk of coronary artery disease, myocardial infarction, coronary atherosclerosis, hyperparathyroidism, disorder of parathyroid gland, gout, and calculus of kidney and ureter with increased serum calcium. Systematic review of 25 MR studies provided supporting evidence on five out of the eight disease outcomes, while the increased risk of gout, hyperparathyroidism and disorder of parathyroid gland were novel findings. INTERPRETATION: This study found wide-ranged health effects of high serum calcium, which suggests that the benefits and adversities of strategies promoting calcium intake should be assessed. FUNDING: ET is supported by a CRUK Career Development Fellowship (C31250/A22804). XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province. SCL acknowledges research funding from the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Cancer Society (Cancerfonden).

Gut microbiota-derived metabolite trimethylamine-N-oxide and multiple health outcomes: an umbrella review and updated meta-analysis.

BACKGROUND: Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced from dietary nutrients. Many studies have discovered that circulating TMAO concentrations are linked to a wide range of health outcomes. OBJECTIVES: This study aimed to summarize health outcomes related to circulating TMAO concentrations. METHODS: We searched the Embase, Medline, Web of Science, and Scopus databases from inception to 15 February, 2022 to identify and update meta-analyses examining the associations between TMAO and multiple health outcomes. For each health outcome, we estimated the summary effect size, 95% prediction CI, between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate the evidence credibility of the identified associations. RESULTS: This umbrella review identified 24 meta-analyses that investigated the association between circulating TMAO concentrations and health outcomes including all-cause mortality, cardiovascular diseases (CVDs), diabetes mellitus (DM), cancer, and renal function. We updated these meta-analyses by including a total of 82 individual studies on 18 unique health outcomes. Among them, 14 associations were nominally significant. After evidence credibility assessment, we found 6 (33%) associations (i.e., all-cause mortality, CVD mortality, major adverse cardiovascular events, hypertension, DM, and glomerular filtration rate) to present highly suggestive evidence. CONCLUSIONS: TMAO might be a novel biomarker related to human health conditions including all-cause mortality, hypertension, CVD, DM, cancer, and kidney function. Further studies are needed to investigate whether circulating TMAO concentrations could be an intervention target for chronic disease.This review was registered at www.crd.york.ac.uk/prospero/ as CRD42021284730.

Nobiletin Inhibits Hypoxia-Induced Placental Damage via Modulating P53 Signaling Pathway.

In this study, we aimed to evaluate the effect of Nobiletin (NOB) on the placenta of Sprague-Dawley (SD) rats that had undergone reduced uterine perfusion pressure (RUPP) surgery and to evaluate the safety of NOB intervention during pregnancy. The results showed that NOB alleviated placental hypoxia, attenuated placental cell apoptosis, and inhibited placental damage in RUPP rats. No side effect of NOB intervention during pregnancy was observed. BeWo cell lines with P53 knockdown were then constructed using lentiviral transfection, and the P53 signaling pathway was found to be essential for NOB to reduce hypoxia-induced apoptosis of the BeWo cell lines. In summary, NOB attenuated hypoxia-induced placental damage by regulating the P53 signaling pathway, and those findings may contribute some insights into the role of NOB in placental development and the prevention of placental-related diseases.

[Influence of exogenous 5'-nucleotides on acute alcohol intoxication in rats].

OBJECTIVE: To investigate effects of exogenous 5'-nucleotides on acute alcohol intoxication in SD rats. METHODS: In our study, 24 male SD rats were randomly divided into 4 groups which included a control group treated with normal saline and three experimental groups treated with low, medium and high doses of exogenous 5'-nucleotides (0.2, 0.8, 3.2 g/kg body weight). All the rats were gavaged with 50% ethanol 30 minutes after treatment. Then rotarod test and open field test were taken to assess rats' neurobehavior changes; Tail blood samples were collected to test blood ethanol concentration; Then all the rats were anesthetized and killed to collect blood and liver samples. Contents of serum alanine amino transferase, aspartate amino transferase, triglyceride, total cholesterol, high density lipoprotein cholesterol, total protein and albumin were tested; Their serum superoxide dismutase activity, malondialdehyde content and liver alcohol dehydrogenase activity were measured. RESULTS: Compared with the controls, high dose nucleotides treated rats had lower serum ethanol concentration [(0.56±0.18 g/L)vs.(1.11±0.44 g/L), P<0.05]. However, exogenous 5'-nucleotides had no impact on neurobehavior and serum biochemical indicators; No difference was found in liver alcohol dehydrogenase activity, serum superoxide dismutase activity and malondialdehyde content were also found no different between the groups. CONCLUSION: Exogenous 5'-nucleotides have no protective properties for acute alcohol intoxication in rats.

Vitamin D3 alleviates cognitive impairment through regulating inflammatory stress in db/db mice.

Patients with type 2 diabetes mellitus (T2DM) have a higher risk to develop cognitive impairment. Several studies reported the potential roles of vitamin D in prevention of cognitive impairment, but the mechanism remains unclear. The present study aims to investigate the protective effects of vitamin D3 on cognitive impairment in db/db mice and to explore the possible mechanism. Twelve-week-old male db/db mice were randomly administrated with low, medium, and high dose of vitamin D3 (LVD, MVD, and HVD groups, respectively) and equivalent volume vitamin D3 solvent (corn oil, DM group) intragastrically. Eight age-matched db/m mice were given equivalent volume corn oil as normal group. After 16 weeks of vitamin D3 treatment, the concentrations of fasting serum glucose in three vitamin D3 groups (especially the 1,000 IU/kg·bw dose) were significantly decreased compared with DM group. Pathology revealed that the neuron damage was reduced in vitamin D3 groups. MVD intervention significantly shortened the escape latency on day 5 and extended time in the target quadrant. Mice in HVD group had significantly higher exploration time and discrimination index compared with the DM group mice. Moreover, vitamin D3 treatment has increased the phosphorylation of cAMP-response element-binding protein and the expression of brain-derived neurotrophic factor and vitamin D receptor. This treatment, meanwhile, has decreased the expression of tumor necrosis factor-α, the phosphorylation of inhibitor kappa Bα (IκBα), and nuclear factor-κB p65 (NF-κB p65) in the hippocampus of db/db mice. These results suggest that vitamin D3 alleviated cognitive impairment in the hippocampus of db/db mice. Down-regulation of the NF-κB signaling pathway-related proteins IκBα and p65 might be one of the possible mechanisms.

Lipidomic profiles of maternal blood at the earlier stage of gestation and umbilical venous blood in response to supraphysiological hypercholesterolemia versus physiological hypercholesterolemia: An evidence of potential biomarkers and early intervention.

BACKGROUND: To our knowledge, we lack a complete understanding of the lipidomes alterations caused by maternal supraphysiological hypercholesterolemia (MSPH) at the third trimester. OBJECTIVES: The aim of this study was to investigate lipidomes alterations in maternal and umbilical venous (UV) serum and explore the association between these alterations and MSPH. METHODS: We conducted a nest case-control study between maternal physiological hypercholesterolemia (MPH) and MSPH subjects during pregnancy. Lipidomic profiling of maternal serum at the first trimester of gestation and UV serum was performed by ultra-high-performance liquid chromatography system connected to a quadrupole time-of-light/mass spectrometer. RESULTS: Several glycerophospholipids and sphingolipids (C18 sphingoid base) species were distinctly altered in maternal serum and/or UV serum with MSPH versus MPH. Glycerophospholipid metabolism, sphingolipid metabolism and propanoate metabolism were the main pathways that involved the most of discriminate metabolites. Higher HDL-c and phosphatidylcholine (16:0/0:0) (PC (16:0/0:0)) during pregnancy, higher PC (16:0/0:0) and lower cholesterol ester 20:4(8Z,11Z,14Z,17Z) (CE (20:4(8Z,11Z,14Z,17Z))) in the UV serum may be the risk factors for the increased placental circulation resistance. The total cholesterol levels of maternal serum both at the first trimester and at the third trimester were significantly correlated with some lipid species of UV serum. CONCLUSION: This study clarifies the differential lipid profiles to distinguish MSPH from MPH and the pathway which is influenced under the condition of MSPH. Also, it provides a resource to look for potential therapeutic targets for MSPH.

Ginseng (Panax ginseng Meyer) Oligopeptides Protect Against Binge Drinking-Induced Liver Damage through Inhibiting Oxidative Stress and Inflammation in Rats.

Panax ginseng C.A. Meyer (ginseng) is an edible and traditional medicinal herb, which is reported to have a wide range of biological activity and pharmaceutical properties. There were more studies on ginsenoside and polysaccharides, but fewer on ginseng oligopeptides (GOPs), which are small molecule oligopeptides extracted from ginseng. The present study was designed to investigate the effects and underlying mechanism of ginseng oligopeptide (GOPs) on binge drinking-induced alcohol damage in rats. Sprague Dawley rats were randomly assigned to six groups (n = 10), rats in normal control group and alcohol model group was administered distilled water; rats in four GOPs intervention groups (at a dose of 0.0625, 0.125, 0.25, 0.5 g/kg of body weight, respectively) were administered GOPs once a day for 30 days. Experiment rats were intragastrically administered ethanol at a one-time dose of 7 g/kg of body weight after 30 days. The liver injury was measured through traditional liver enzymes, inflammatory cytokines, expression of oxidative stress markers, and histopathological examination. We found that the GOPs treatment could significantly improve serum alanine aminotransferase and aspartate aminotransferase, plasma lipopolysaccharide, and inflammatory cytokine levels, as well as the oxidative stress markers that were altered by alcohol. Moreover, GOPs treatment inhibited the protein expression of toll-like receptor 4, and repressed the inhibitor kappa Bα and nuclear factor-κB p65 in the liver. These findings suggested that GOPs have a significant protective effect on binge drinking-induced liver injury, and the mechanism possibly mediated by the partial inhibition of lipopolysaccharide-toll-like receptor 4-nuclear factor-κB p65 signaling in the liver.

Milk Powder Co-Supplemented with Inulin and Resistant Dextrin Improves Glycemic Control and Insulin Resistance in Elderly Type 2 Diabetes Mellitus: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial.

SCOPE: The objective of the present study is to evaluate the effects of milk powder co-supplemented with inulin and resistant dextrin (MPCIR) on elderly patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A randomized, double-blind, placebo-controlled clinical trial is carried out among elderly T2DM patients. The subjects recruited from the community are randomly assigned to either the MPCIR group or placebo group for 12 weeks intervention. Each group receives 45 g milk powder with or without inulin and resistant dextrin. Anthropometric and metabolic variables are measured. For the MPCIR group, systolic blood pressure (BP) and diastolic BP are reduced significantly by 5.45 and 4.56 mm Hg (p < 0.001, vs placebo group), respectively. Compared with the placebo group, the fasting and 2-h postprandial plasma glucose levels, glycosylated serum protein, and insulin resistance index of the MPCIR group are significantly decreased by 0.96 mmol L-1 , 1.47 mmol L-1 , 16.33 µmol L-1 , and 0.65 respectively (p < 0.001). The MPCIR group shows an increase by 7.09 µIU mL-1 and 20.43 in 2-h postprandial insulin (p = 0.016) and ß-cell function index (p < 0.001), respectively. CONCLUSION: MPCIR supplementation helps to improve glycemic control, insulin resistance, and blood pressure.

Quercetin alleviates cell apoptosis and inflammation via the ER stress pathway in vascular endothelial cells cultured in high concentrations of glucosamine.

Glucosamine is a possible cause of vascular endothelial injury in the initial stages of atherosclerosis, through endoplasmic reticulum (ER) stress resulting in fatty streaks in the vascular wall. Quercetin is an anti­diabetic and cardiovascular protective agent that has previously been demonstrated to reduce ER stress in human umbilical vein endothelial cells (HUVECs). The present study aimed to investigate whether quercetin prevents glucosamine­induced apoptosis and inflammation via ER stress pathway in HUVECs. The effect of quercetin on cell viability, apoptosis, and protein expression levels of inflammatory cytokines and ER stress markers was investigated in glucosamine­supplemented HUVECs. Quercetin was demonstrated to protect against glucosamine­induced apoptosis, improved cell viability, and inhibited expression of pro­inflammatory factors and endothelin­1. Quercetin treatment also reduced the expression levels of glucose­regulated protein 78, phosphorylated protein kinase­like ER kinase, phosphorylated c­Jun N­terminal kinase and C/EBP homologous protein. In conclusion, quercetin may have auxiliary therapeutic potential against glucosamine­induced cell apoptosis and inflammation, which may be partially due to alleviation of ER stress.