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.

Weekly-specific ambient PM1 before and during pregnancy and the risk of gestational diabetes mellitus.

BACKGROUND: Exposure to fine or respirable particulate matter has been linked to an elevated risk of gestational diabetes mellitus (GDM). However, the association between exposure to particulate matter with an aerodynamic diameter ≤ 1 µm (PM1) and GDM has not been explored. METHODS: We conducted a cohort study involving 60,173 pregnant women from nine hospitals in Beijing, China, from February 2015 to April 2021. Daily concentrations of PM1 and ozone were obtained from a validated spatiotemporal artificial intelligence model. We used a modified Poisson regression combined with distributed lag models to estimate the association between weekly-specific PM1 exposure and the risk of GDM after adjusting for individual-level covariates. RESULTS: Among the 51,299 pregnant women included in the final analysis, 4008 were diagnosed with GDM. Maternal exposure to PM1 during preconception and gestational periods was generally associated with an increased risk of GDM. The most pronounced associations were identified during the 12th week before pregnancy, the 5th-8th weeks of the first trimester, and the 23rd-24th weeks of the second trimester. Each 10 µg/m3 increase in PM1 was associated with a relative risk of GDM of 1.65 (95 % CI: 1.59, 1.72) during the preconception period, 1.67 (95 % CI: 1.61, 1.73) in the first trimester, 1.52 (95 % CI: 1.47, 1.58) in the second trimester, and 2.54 (95 % CI: 2.45, 2.63) when considering the first and second trimester combined. CONCLUSIONS: Exposure to PM1 before and during pregnancy was associated with an increased risk of GDM, particularly during the 12 weeks before pregnancy and gestational weeks 5-8 and 23-24.

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.

Assessment of evidence on reported non-genetic risk factors of congenital heart defects: the updated umbrella review.

BACKGROUND: Congenital heart defect (CHD) is the leading cause of birth defects globally, which results in a great disease burden. It is still imperative to detect the risk factors of CHD. This umbrella review aimed to comprehensively summarize the evidence and grade the evidence of the associations between non-genetic risk factors and CHD. METHODS: Databases including Medline, Embase, Web of Science, Cochrane Library, and four Chinese databases were searched from inception to 18 Jan 2022. The reference lists of systematic reviews (SR) and meta-analyses (MA) were screened, which aimed to explore the non-genetic risk factors of CHD. Subsequently, titles and abstracts of identified records and full texts of selected SR/MA were screened by two independent reviewers based on predefined eligibility criteria. A priori developed extraction form was used to abstract relative data following the PRISMA 2020 and MOOSE guidelines. The risk of bias was assessed with the AMSTAR2 instrument. Data were synthesized using fixed-effects and random-effects meta-analyses, respectively. Finally, the evidence on the association of non-genetic risk factors and CHD was graded using Ioannidis's five-class evidence grade. RESULTS: A total of 56 SRs, encompassing 369 MAs, were identified. The risk factors included relative factors on air pollution, reproductive-related factors, parental age and BMI, parental life habits, working and dwelling environment, maternal drug exposure, and maternal disease. Based on AMSTAR2 criteria, only 16% (9/56) of SRs were classified as "Moderate". One hundred and two traceable positive association MAs involving 949 component individual studies were included in further analysis and grading of evidence. Family genetic history, number of abortions, maternal obesity, especially moderate or severe obesity, decoration materials, harmful chemicals, noise during pregnancy, folic acid supplementation, SSRIs, SNRIs, any antidepressants in the first trimester, maternal DM (including both PGDM and GDM), and gestational hypertension were convincing and highly suggestive factors for CHD. After sensitivity analyses based on cohort studies, some grades of evidence changed. CONCLUSION: The present umbrella review will provide evidence-based information for women of childbearing age before or during pregnancy to prevent CHD. In addition, sensitivity analysis based on cohort studies showed the changed evidence levels. Therefore, future SR/MA should concern the sensitivity analysis based on prospective birth cohort studies and case-control studies.

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.

Associations between maternal serum HDL-c concentrations during pregnancy and neonatal birth weight: a population-based cohort study.

BACKGROUND: To evaluate the associations between maternal serum concentrations of high-density lipoprotein cholesterol (HDL-c) throughout pregnancy and neonatal birth weight (BW) and small for gestational age (SGA) births. METHODS: A prospective cohort of 2241 pregnant women was followed from recruitment to delivery in three hospitals in Beijing, China between January 2014 and December 2017. Maternal fasting serum lipids concentrations were measured at gestational week 6-12, 16, 24 and 36. Major outcome was neonatal BW. The associations between maternal HDL-c and BW were estimated by linear regression and linear mixed-effects models. Odds ratios (ORs) and 95% confidence intervals of SGA births in relation to HDL-c were evaluated via logistic regression analysis. RESULTS: There was a tendency that mothers with higher HDL-c concentrations throughout gestation gave birth to infants with lower BW. A negative association was found between maternal HDL-c concentrations and BW at 24th and 36th gestational weeks (B = - 34.044, P = 0.034; B = - 53.528, P = 0.000). The HDL-c trend of change was inversely associated with BW (B = - 442.736, P = 0.000). Mothers with SGA neonates had higher serum HDL-c concentration at the 36th gestational week (P < 0.01). The incidences of SGA in the three groups (HDL-c: 1.84-2.23 mmol/L, 2.24-2.59 mmol/L and ≥ 2.60 mmol/L) were higher than the group with the lowest concentration of HDL-c (< 1.83 mmol/L) (P < 0.01, P < 0.01, P < 0.001) at 36th week. Higher maternal HDL-c concentrations at 36th week (HDL-c: 1.84-2.23 mmol/L, 2.24-2.59 mmol/L and ≥ 2.60 mmol/L) were positively associated with the incidence of SGA (OR = 1.900, P = 0.008; OR = 1.893, P = 0.008; OR = 1.975, P = 0.004). The HDL-c trend of change was positively associated with SGA births (OR = 9.772, P = 0.000). CONCLUSIONS: Maternal serum HDL-c concentrations were inversely associated with BW at 24th and 36th gestational weeks. The high concentrations of HDL-c at the 36th gestational week increased the risk of SGA. The maternal HDL-c trend of change across pregnancy was associated with smaller neonatal size.

The Effects of 5,6,7,8,3',4'-Hexamethoxyflavone on Apoptosis of Cultured Human Choriocarcinoma Trophoblast Cells.

5,6,7,8,3,4'-Hexamethoxyflavone, also called nobiletin (NOB), widely found in the citrus peel, is one of the main byproducts in citrus processing. NOB is considered safe, but its safety for women during pregnancy is unknown. Therefore, the effect of NOB on apoptosis in human choriocarcinoma trophoblast cells (BeWo cells) was evaluated. Cells were divided into four groups and cultured with different concentrations of NOB (0, 10, 33, and 100 µM) for 12, 24, 36, and 48 h respectively. Cell viability was detected by CCK-8 assay, cell morphology was detected by a Cell Imaging Multi-Mode Reader, and cell cycle and apoptosis were detected by flow cytometry. Cleaved PARP level, the expressions of B cell lymphoma 2 (BCL2) family proteins, and p53 pathway proteins were detected by Western blot. The results showed that after 48 h of cell culture, the cell viability was decreased significantly, but apoptosis was significantly increased. Compared to the cells without NOB treatment, the cells treated with NOB at 10 or 33 µΜ showed no significant differences in the number of suspended cells or late apoptosis rate, except the increase of cell viability. Treatment of NOB at the concentration of 100 µM improved cell viability, attenuated apoptosis, decreased suspended cells, and did not alter the G1 phase arrest, compared with the non-NOB-treated group after 48 h of culturing. The 100 µΜ NOB treatment increased the levels of BCL2 and BCLXL, and decreased p53 accumulation in BeWo cells at 48 h, but had no effect on the expression of BAX, BAK, BAD, p21, and G1 phase arrest. These findings provide evidence that NOB (10, 33, and 100 µΜ) was safe for BeWo cells. NOB at the concentration of 100 µΜ could attenuate apoptosis in BeWo cells, which might be helpful to prevent pregnancy-related diseases caused by apoptosis.

The high maternal TG level at early trimester was associated with the increased risk of LGA newborn in non-obesity pregnant women.

INTRODUCTION: Recent research had shown blood glucose was not the only cause of large for gestational age infant (LGA), the contributions of other fuels such as lipids also play an important role in fetal development. However the association between maternal triglyceride at early trimester and the risk of LGA has not yet been clearly elucidated. This research evaluated the association of maternal early trimester TG level with the risk of LGA infant in Chinese mothers. METHODS: 2839 pregnant women were recruited at the first visit of their perinatal health care and followed up prospectively till after delivery. The demographic, maternal characteristics were extracted from a questionnaire. Infant characteristics were collected at delivery. Maternal fasting serum total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (HDL-C)levels, were measured in 6~8th, 16th, 24th, and 36th gestational weeks. Fasting serum glucose levels were measured at 6~8th, 24th, and 36th gestational weeks. Logistic regression model was used to calculate the odds ratio (OR) and 95% confidence intervals. RESULTS: A consistently lower TG level was observed in mothers with non-LGA infant than mothers with LGA infant and TG level of mothers of LGA infants increased faster than that of control group. The incidence of LGA infants between two groups (TG<1.7 mmol/L and TG ≥ 1.7 mmol/L) was 14.46 and 26.63%, respectively. Mothers with the highest TG level (TG > 1.19 mmol/L) gave birth to infants with higher birth weight (BW) than the other two groups (TG < 0.70 mmol/L and TG:0.70~0.89 mmol/L). When stratified by pre-pregnancy body mass index (pre-BMI), a significantly positive association was founded between the maternal TG level at early trimester and the risk of LGA in non-overweight/obesity women (OR = 1.740, p = 0.034). CONCLUSIONS: The findings suggested that high maternal TG level at very early trimester was associated with the increased risk of LGA in non-overweight/obesity pregnant women. Moreover, high maternal TG level at first trimester may be an early predictor of LGA.

Sex-specific nonlinear associations between serum lipids and different domains of cognitive function in middle to older age individuals.

To examine how serum lipids relates to specific cognitive ability domains between the men and women in Chinese middle to older age individuals. A complete lipid panel was obtained from 1444 individuals, ages 50-65, who also underwent a selection of cognitive tests. Participants were 584 men and 860 women from Linyi city, Shandong province. Multiple linear regression analyses examined serum lipids level as quadratic predictors of sex-specific measure of performance in different cognitive domains, which were adjusted for sociodemographic and lifestyle characteristics. In men, a significant quadratic effect of total cholesterol (TC) was identified for Digit Symbol (B = -0.081, P = 0.044) and also quadratic effect of low density lipoprotein-cholesterol (LDL-C) was identified for Trail Making Test B (B = -0.082, P = 0.045). Differently in women, there were significant quadratic associations between high density lipoprotein-cholesterol (HDL-C) and multiple neuropsychological tests. The nonlinear lipid-cognition associations differed between men and women and were specific to certain cognitive domains and might be of potential relevance for prevention and therapy of cognitive decline.

Genistein Inhibits Aß25-35-Induced Synaptic Toxicity and Regulates CaMKII/CREB Pathway in SH-SY5Y Cells.

Genistein (Gen), as a functional food in human diet, has shown many beneficial effects on neurodegenerative diseases such as Alzheimer's disease (AD). But the neuroprotective mechanism of Gen is not clear. Because synaptic failure is considered as the earliest phase in the pathogenesis of AD, we try to validate our hypothesis that synapse may be one target of Gen on protecting neurons. In this study, SH-SY5Y cells were pre-incubated with or without Gen for 2 h followed by the incubation with Aß25-35 (25 µmol/L) for another 24 h. Flow cytometry, Western Blots, and RT-PCR analysis were used to test the synaptic factors. The data showed that Gen pre-treatment could reverse the Aß25-35-induced down-regulation of synaptophysin and postsynaptic marker postsynaptic density-95. In addition, the down-regulation of NR1 and NR2B induced by Aß25-35 which are subunits of N-methyl-D-aspartate receptor also could be antagonized by pre-treatment of Gen. Moreover, the factors of CaMKII/CREB signaling pathway were detected. The results showed that mRNA and protein expressions of (Ca(2+))/calmodulin(CaM), CaMKII/pCaMKII, and CREB/pCREB were significantly down-regulated by Aß25-35, but they were all restored by the pre-treatment of Gen. Furthermore, Gen also maintained the intracellular Ca(2+) concentration which was disturbed by Aß25-35. In conclusion, these results suggested that Gen could protect synaptic dysfunction induced by Aß, and the mechanism might be associated with the regulation of synaptic markers and Ca(2+) level through activating CaM/CaMK/CREB signaling pathway.

Relationship between oxysterols and mild cognitive impairment in the elderly: a case-control study.

BACKGROUND: To investigate the relationship between oxysterols and mild cognitive impairment (MCI) in a matched case-control study. METHODS: The plasma levels of four oxysterols, 27-hydroxycholesterol (27-OHC), 24S-hydroxycholesterol (24S-OHC), 7α-hydroxycholesterol (7α-OHC) and 7ß-hydroxycholesterol (7ß-OHC), were analyzed by High Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) and compared between 70 MCI patients and 140 matched controls with normal cognition. The odds ratio (OR) was calculated using logistic analyses to assess the association between oxysterols and MCI. RESULTS: Compared with controls with normal cognition, plasma level of 27-OHC was significantly higher in MCI patients. Logistic analyses suggested high plasma level of 27-OHC was significantly associated with MCI even after multivariate adjustment (OR = 2.86, 95 % CI: 1.52 ~ 5.37). CONCLUSIONS: Our findings suggested that the increased plasma level of 27-OHC was associated with MCI, suggesting high plasma levels of 27-OHC may pay an important role in the development of MCI.

The oxysterol 27-hydroxycholesterol increases oxidative stress and regulate Nrf2 signaling pathway in astrocyte cells.

The disturbance in cholesterol metabolism has been considered as a cause of alzheimer's disease (AD), which dues to the oxidative damage and cell apoptosis in the brain. We aimed to investigate the toxicity and mechanism of AD-like pathology caused by cholesterol oxidation metabolite 27-hydroxycholesterol (27-OHC) in astrocyte cells. C6 cells were treated with 0, 5, 10, 20 µM 27-OHC for 24 h (h). The cell viability was monitored by using methyl thiazolyl tetrazolium test, generation of reactive oxygen species (ROS) was measured by using 2', 7'-dichlorodihydrofluorescein diacetate fluorescent probe under flow cytometry. The concentrations of 8-hydroxyl deoxyguanosine, the anti-oxidative enzymes such as total superoxide dismutase (tSOD), reduced glutathione (rGSH) and glutathione peroxidase (GSH-Px) were tested by using enzyme-linked immunosorbent assay and enzymic method, respectively. The gene and protein expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone 1 (NQO1) and γ-glutamylcysteine synthetase (γ-GCS) in C6 cells were detected by quantitative western blot analysis and real-time PCR analysis. Moreover, the Nrf2 expressions in both of the cytoplasm and nucleus were detected with western blot analysis, and the localization of Nrf2 was performed by immunocytochemistry and confocal microscopy. 27-OHC increased the levels of ROS and decreased the levels of tSOD, rGSH, GSH-Px in C6 cells dose-dependently. In addition, 27-OHC down regulated the expressions of Nrf2, HO-1, NQO1 and γ-GCS at both of gene and protein levels, while Nrf2 expression in the cytoplasm showed decreased trend after incubated for 24 h with 27-OHC. The cholesterol metabolite 27-OHC is toxic to C6 cells and contributed to oxidative damage via regulating the Nrf2 signaling pathway. Our results suggest that 27-OHC may represent a common pathogenic factor in AD.

Global DNA methylation was changed by a maternal high-lipid, high-energy diet during gestation and lactation in male adult mice liver.

An epigenetic mechanism has been suggested to explain the effects of the maternal diet on the development of disease in offspring. The present study aimed to observe the effects of a maternal high-lipid, high-energy (HLE) diet on the DNA methylation pattern of male offspring in mice. Female C57BL/6J mice were fed an HLE diet during gestation and lactation. The genomic DNA methylations at promoter sites of genes in the liver, mRNA and protein levels of selected genes related to lipid and glucose metabolism were measured by microarray, real-time PCR and Western blot. The results indicated that the percentage of methylated DNA in offspring from dams that were fed an HLE diet was significantly higher than that from dams that were fed a chow diet, and most of these genes were hypermethylated in promoter regions. The nuclear protein content and mRNA levels of hypermethylated genes, such as PPARγ and liver X receptor α (LXRα), were decreased significantly in offspring in the HLE group. The results suggested that the DNA methylation profile in adult offspring livers was changed by the maternal HLE diet during gestation and lactation.

Soy isoflavone antagonizes the oxidative cerebrovascular injury induced by ß-amyloid peptides 1-42 in rats.

Numerous evidences have shown that the antioxidative properties of soy isoflavone (SIF) have beneficial effects on prophylaxis of neurodegeneration, however, the mechanism is still not fully illustrated. As cerebrovascular dysfunction could initiate a cascade of events leading to pathogenesis of Alzheimer's disease, we tried to investigate whether SIF could protect the cerebrovascular system due to antagonizing oxidative damage induced by Aß1-42 in present study. In addition, NF-E2-related factor 2 (Nrf2) signaling pathways in the cerebrovascular tissue of Wistar rats were investigated to identify the potential cerebrovascular protective targets of SIF. Research results showed that SIF reduced the excessive production of nitrotyrosine in cerebrovascular tissue induced by Aß1-42, and maintained redox homeostasis by increasing the level of GSH and GSH/GSSG. Moreover, SIF could alleviate the down-regulation of Nrf2, γ-glutamylcysteine synthetase, Heme oxygenase-1 expressions in cerebrovascular tissue induced by Aß1-42 and suppress the increase of Kelch like ECH protein-1 (Keap1). These data suggested that SIF might reduce the cerebrovascular oxidative damage induced by Aß1-42 through regulating the Nrf2 signaling pathway. The mechanisms of SIF modulating the potential target Nrf2 might be associated with Keap1 expression.

Lipid-focused dietary education intervention in pregnant women: study protocol for an open-label, parallel, randomised, intervention study addressing adverse pregnancy outcomes in China.

INTRODUCTION: The incidence of infants who are large-for-gestational-age (LGA) is on the rise in China, and its detrimental effects on health have received increasing attention. Diet-based interventions have the potential to reduce adverse birth outcomes, particularly in decreasing the occurrence of LGA infants. We aim to evaluate the effect of lipid-focused diet education based on the theories of behaviour change in pregnant women on maternal and offspring outcomes through a randomised controlled trial. METHODS AND ANALYSIS: We have designed an open-label, parallel, multicentre randomised controlled trial in collaboration with three hospitals in Beijing, China.Pregnant women will be recruited before reaching 12 weeks of gestation and will be randomised in a 1:1:1 ratio into three arms: (1) online education arm, (2) pregnancy nutrition checklist and 'one-page flyer' arm and (3) routine antenatal education. The primary outcome LGA will be recorded at birth. Demographic information, physical activity, sleep and medical history will be collected through questionnaires and case cards prior to enrolment. Questionnaires will also be used to collect dietary behaviours and psychosocial factors of pregnant women at enrolment, at 24-28 weeks and 34-36 weeks of gestation. Additionally, information on breastfeeding and complementary food supplementation for infants and young children will be obtained through questionnaires. Physical development indicators of children and taste tests will be assessed 3 years after delivery. ETHICS AND DISSEMINATION: The study has received ethical approval from the Capital Medical University Ethics Committee and other collaborating study centres. Informed consent will be introduced to pregnant women, and their consent will be obtained. The findings will be reported in relevant national and international academic conferences and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ChiCTR2300071126.

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.

Elevated serum cholesterol levels during pregnancy as predictors for postpartum hypercholesterolemia: A prospective cohort study.

OBJECTIVE: To identify the associations between gestational cholesterol levels and the risk of postpartum hypercholesterolemia, and to establish trimester-specific reference values. METHODS: Serum lipids at gestational weeks 6-8, 16, 24, and 36, and 42 days postpartum were derived from 905 pregnant women of a prospective cohort. The major outcome was postpartum hypercholesterolemia. Logistic regression and restricted cubic splines were conducted to estimate the associations between cholesterol levels at specific gestational ages and postpartum hypercholesterolemia. Associations of the trend of changes in cholesterol levels during pregnancy with postpartum hypercholesterolemia were evaluated by linear mixed-effect model and linear or logistic regression. Reference values were computed by the receiver operating characteristic curves. RESULTS: Serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and the ratios of TC/HDL-C and LDL-C/HDL-C all increased during pregnancy and decreased at 42 days postpartum. The elevated levels of TC and LDL-C, decreased levels of HDL-C in pregnancy, and their rapid change rates were positively associated with higher risks of postpartum hypercholesterolemia. The established reference values from the first to the third trimester were below 5.47, 6.35, and 7.22 mmol/L for TC; below 2.83, 3.82, and 4.21 mmol/L for LDL-C; and more than 1.50, 1.55, and 1.50 mmol/L for HDL-C, respectively. CONCLUSION: Maternal cholesterol levels and their trend of change during pregnancy were predictors of postpartum hypercholesterolemia. Trimester-specific reference values were established in a Chinese population.

Reliability and Validity of a Theory-Based Determinants of Eating and Physical Activity Behaviors Questionnaire for Chinese Elementary School Children.

OBJECTIVE: The primary objective of this study was to develop and validate a Social Cognitive Theory-based instrument to identify psychosocial factors that influence diet and physical activity among Chinese children aged 10-12 years. DESIGN: This is a cross-sectional study, with data collected from questionnaires. SETTING: Two elementary schools in Beijing, China. PARTICIPANTS: Fourth to sixth-grade students (N = 1,486) aged 10-12 years were recruited. VARIABLES MEASURED: Gender, height, weight, nation, and grade were collected. Energy-balanced eating behaviors and their related sociopsychological factors were surveyed. ANALYSIS: Confirmatory factor analysis, Pearson correlations, Cronbach α index, and mediation analysis were used. RESULTS: (1) Confirmatory factor analysis revealed a 6-factor solution (51 items) and all factor loadings > 0.32, indicating that the model fitness was acceptable. (2) All correlation coefficients are statistically significant. All of the Cronbach α indexes were > 0.65, indicating acceptable reliability. (3) The mediating effect of goal intention and outcome expectations between self-efficacy and habit strength was statistically significant (P < 0.01), verifying the theory structure. CONCLUSIONS AND IMPLICATIONS: This questionnaire exhibits good internal consistency, reliability, and structural validity. It can be effectively employed to investigate energy-balanced eating behaviors related to the Social Cognitive Theory in Chinese children.

The challenge and opportunity of gut microbiota-targeted nanomedicine for colorectal cancer therapy.

The gut microbiota is an integral component of the colorectal cancer (CRC) microenvironment and is intimately associated with CRC initiation, progression, and therapeutic outcomes. We reviewed recent advancements in utilizing nanotechnology for modulating gut microbiota, discussing strategies and the mechanisms underlying their design. For future nanomedicine design, we propose a 5I principle for individualized nanomedicine in CRC management.