Associations of Placental Inflammation and Oxidative Stress Biomarkers with Glucolipid Metabolism in Children: A Birth Cohort Study in China.

BACKGROUND: The maternal intrauterine immune environment may affect offspring long-term health. We aimed to investigate the association between the intrauterine placental immunological milieu and glycolipid metabolic health in children. METHODS AND RESULTS: This study enrolled 1803 mother-child pairs from the Ma'anshan birth cohort (2013-2014). Placental mRNA expression of inflammatory cytokines (interleukin-1ß [IL-1ß], IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-4, IL-6, IL-8, C-reactive protein, and interferon-γ) and oxidative stress biomarkers (heme oxygenase-1, hypoxia-inducible factor-1alpha, and glucose-related protein 78) was quantified using real-time quantitative polymerase chain reaction. Fasting blood glucose, insulin, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol were assessed at 5 to 6 years old. Statistical analyses included multiple linear regression, binary logistic regression, restricted cubic spline model, and the Bayesian kernel machine regression model. Placental inflammatory cytokines (IL-1ß, monocyte chemoattractant protein-1, C-reactive protein, IL-6, IL-8, IL-10) and oxidative stress biomarkers (heme oxygenase-1, hypoxia-inducible factor-1alpha, glucose-related protein 78) showed positive associations with children's fasting blood glucose levels. Heme oxygenase-1 and glucose-related protein 78 exhibited negative correlations with children's fasting insulin levels. Elevated IL-6, heme oxygenase-1, hypoxia-inducible factor-1alpha, and glucose-related protein 78 were associated with increased risk of prediabetes in children. Overall upregulation of placental proinflammatory cytokines and oxidative stress factors mRNA expression correlated with higher prediabetes risk in children. Bayesian kernel machine regression analysis indicated a joint positive effect of the 12 placental inflammation and oxidative stress mixtures on children's risk of high fasting blood glucose. CONCLUSIONS: This exploratory study underscores significant correlations between maternal intrauterine placental inflammation, oxidative stress markers, and offspring fasting blood glucose and insulin levels. These findings highlight the potential role of intrauterine holistic immunity in shaping offspring glucose metabolism health.

Association between Dietary Patterns during Pregnancy and Children's Neurodevelopment: A Birth Cohort Study.

BACKGROUND: Research studies have showed that maternal diet may influence fetal neurodevelopment, but most studies have only assessed single nutrients or food groups. OBJECTIVE: To investigate the impact of maternal prenatal dietary patterns during pregnancy on child neurodevelopment. METHODS: Study participants were obtained from the China National Birth Cohort. The Ages and Stages Questionnaire, Third Edition, was used to assess children's neurodevelopment at 36 months old. Maternal antenatal dietary data were collected over three trimesters using food frequency questionnaires. Five distinct maternal dietary patterns throughout pregnancy were identified by principal component analysis, namely protein- and micronutrient-rich dietary patterns, low-iron dietary patterns, pasta as the staple food dietary patterns, iron-rich dietary patterns, tubers, fruits, and baked food dietary patterns. Group-based trajectory modeling was performed for dietary patterns present in all three periods. Multiple linear regression models were used for statistical analysis. RESULTS: Children of mothers who followed a high protein- and micronutrient-rich dietary pattern trajectory during pregnancy presented better neurodevelopment, including higher gross motor and problem-solving scores. Furthermore, it was observed that children born of women with low-iron dietary patterns had poorer neurodevelopment. In detail, children born to mothers with a low-iron dietary pattern during the first trimester had lower problem-solving scores, while to those who were exposed to a low-iron dietary pattern in the second and third trimesters had lower gross motor scores. Additionally, children with mothers who had a low-iron dietary pattern in the third trimester had lower communication scores. CONCLUSIONS: A nutrition-balanced protein- and micronutrient-rich dietary pattern and adequate iron dietary pattern for mothers throughout pregnancy may be beneficial to children's neurodevelopment.

E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases.

T follicular helper (Tfh) cells are indispensable for the formation of germinal center (GC) reactions, whereas T follicular regulatory (Tfr) cells inhibit Tfh-mediated GC responses. Aberrant activation of Tfh cells contributes substantially to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). Nonetheless, the molecular mechanisms mitigating excessive Tfh cell differentiation are not fully understood. Herein we demonstrate that the adenovirus E4 promoter-binding protein (E4BP4) mediates a feedback loop and acts as a transcriptional brake to inhibit Tfh cell differentiation. Furthermore, we show that such an immunological mechanism is compromised in patients with SLE. Establishing mice with either conditional knockout (cKO) or knockin (cKI) of the E4bp4 gene in T cells reveals that E4BP4 strongly inhibits Tfh cell differentiation. Mechanistically, E4BP4 regulates Bcl6 transcription by recruiting the repressive epigenetic modifiers HDAC1 and EZH2. E4BP4 phosphorylation site mutants have limited capability with regard to inhibiting Tfh cell differentiation. In SLE, we detected impaired phosphorylation of E4BP4, finding that this compromised transcription factor is positively correlated with disease activity. These findings unveiled molecular mechanisms by which E4BP4 restrains Tfh cell differentiation, whose compromised function is associated with uncontrolled autoimmune reactions in SLE.