Association of breast milk-derived arachidonic acid-induced infant gut dysbiosis with the onset of atopic dermatitis.

OBJECTIVE: The specific breast milk-derived metabolites that mediate host-microbiota interactions and contribute to the onset of atopic dermatitis (AD) remain unknown and require further investigation. DESIGN: We enrolled 250 mother-infant pairs and collected 978 longitudinal faecal samples from infants from birth to 6 months of age, along with 243 maternal faecal samples for metagenomics. Concurrently, 239 corresponding breast milk samples were analysed for metabolomics. Animal and cellular experiments were conducted to validate the bioinformatics findings. RESULTS: The clinical findings suggested that a decrease in daily breastfeeding duration was associated with a reduced incidence of AD. This observation inspired us to investigate the effects of breast milk-derived fatty acids. We found that high concentrations of arachidonic acid (AA), but not eicosapentaenoic acid (EPA) or docosahexaenoic acid, induced gut dysbiosis in infants. Further investigation revealed that four specific bacteria degraded mannan into mannose, consequently enhancing the mannan-dependent biosynthesis of O-antigen and lipopolysaccharide. Correlation analysis confirmed that in infants with AD, the abundance of Escherichia coli under high AA concentrations was positively correlated with some microbial pathways (eg, 'GDP-mannose-derived O-antigen and lipopolysaccharide biosynthesis'). These findings are consistent with those of the animal studies. Additionally, AA, but not EPA, disrupted the ratio of CD4/CD8 cells, increased skin lesion area and enhanced the proportion of peripheral Th2 cells. It also promoted IgE secretion and the biosynthesis of prostaglandins and leukotrienes in BALB/c mice fed AA following ovalbumin immunostimulation. Moreover, AA significantly increased IL-4 secretion in HaCaT cells costimulated with TNF-α and INF-γ. CONCLUSIONS: This study demonstrates that AA is intimately linked to the onset of AD via gut dysbiosis.

Silencing of circCDC14A prevents cerebral ischemia-reperfusion injury via miR-23a-3p/CXCL12 axis.

Ischemic stroke is one of the main causes of death and disability. Circular RNAs (circRNAs) have received extensive attention in the pathogenesis of ischemic stroke. Here, we evaluated the role of circCDC14A in cerebral ischemia-reperfusion (CI/R) injury in vivo and in vitro. The expression of circCDC14A was significantly upregulated in the middle cerebral artery occlusion (MCAO) model and oxygen and glucose deprivation/reoxygenation (OGD/R)-treated HT22 cells. Knockdown of circCDC14A suppressed the cell viability reduction caused by OGD/R, as well as cell damage and apoptosis. Mechanistically, circCDC14A acted as a sponge for miR-23a-3p and promoted the expression of chemokine stromal-derived factor-1 (CXCL12) by negatively regulating miR-23a-3p. Rescue experiments further confirmed that miR-23a-3p inhibitor or circCDC14A-overexpression vectors blocked the beneficial effects of circCDC14A knockdown in OGD/R-induced HT22 cells. Moreover, knockdown of circCDC14A suppressed MCAO-induced cerebral infarction and neurological damage, as well as the brain tissue damage and neuronal apoptosis in vivo. Consistently, miR-23a-3p antagomir treatment abolished the cerebral protective effects of circCDC14A knockdown on MCAO mice. In conclusion, circCDC14A promoted CI/R injury by regulating the miR-23a-3p/CXCL12 axis, which suggested that circCDC14A may become a potential therapeutic target for CI/R injury.

N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung Development In Vivo and In Vitro.

Background. Intrauterine hypoxia is a common cause of fetal growth and lung development restriction. Although N-methyl-D-aspartate receptors (NMDARs) are distributed in the postnatal lung and play a role in lung injury, little is known about NMDAR's expression and role in fetal lung development. Methods. Real-time PCR and western blotting analysis were performed to detect NMDARs between embryonic days (E) 15.5 and E21.5 in fetal rat lungs. NMDAR antagonist MK-801's influence on intrauterine hypoxia-induced retardation of fetal lung development was tested in vivo, and NMDA's direct effect on fetal lung development was observed using fetal lung organ culture in vitro. Results. All seven NMDARs are expressed in fetal rat lungs. Intrauterine hypoxia upregulated NMDARs expression in fetal lungs and decreased fetal body weight, lung weight, lung-weight-to-body-weight ratio, and radial alveolar count, whereas MK-801 alleviated this damage in vivo. In vitro experiments showed that NMDA decreased saccular circumference and area per unit and downregulated thyroid transcription factor-1 and surfactant protein-C mRNA expression. Conclusions. The excessive activation of NMDARs contributed to hypoxia-induced fetal lung development retardation and appropriate blockade of NMDAR might be a novel therapeutic strategy for minimizing the negative outcomes of prenatal hypoxia on lung development.

MicroRNA expression profile in intrauterine hypoxia-induced pulmonary hypoplasia in rats.

Hypoxia is necessary for fetal development; however, excess hypoxia is detrimental. The mechanisms underlying the effects of hypoxia on lung development remain unclear, although important roles of microRNAs (miRNAs) during lung development have recently been established. However, the effect on lung development at an miRNA expression level, following changes in oxygen tension, have not yet been studied. In the present study, pregnant rats were exposed to a fraction of inspired oxygen of 10.5 or 21% for two days on gestation day 19, following which the body weight, lung wet weight, radial alveolar count (RAC) and mean linear intercept (Lm) of the newborn pups were analyzed on postnatal day 1. To define the role of miRNAs during lung development following intrauterine hypoxia exposure, the miRNA expression pattern was profiled using a miRNA microarray. The newborn rats in the hypoxic group exhibited statistically significant decreases in body weight, lung weight and the RAC, as well as a marked increase in the Lm. A total of 69 miRNAs were identified to have significant changes in expression, including 55 upregulated and 14 downregulated miRNAs. Quantitative polymerase chain reaction was used to validate the microarray results of six selected miRNAs. Therefore, the results indicated that late gestation intrauterine hypoxia exposure may cause lung injury and miRNAs may play important roles in this process.