Inhibiting miR-466b-5p Attenuates Neonatal White Matter Injury by Targeting Lpar1.

miR-466b-5p is aberrantly upregulated in oligodendrocyte precursor cells (OPCs) after white matter injury (WMI). However, its roles in neonatal WMI pathogenesis are unknown. In this study, P3 rats were subjected to hypoxia-ischemia to establish a neonatal WMI model. A bioinformatic analysis was conducted to predict the possible target of miR-466b-5p as Lpar1. RT-PCR was performed to validate the expression of miR-466b-5p and Lpar1 mRNA. The miR-466b-5p antagomir was intracerebroventricularly administrated to inhibit miR-466b-5p; OPC differentiation, apoptosis, proliferation, and myelination were analyzed using immunofluorescence staining, western blotting, and electron microscopy. In addition, the behavioral performance of the rats was measured with the Morris water maze test. Sox10 expression and PLP trafficking were examined to elucidate the mechanism by which miR-466b-5p regulates WMI pathogenesis. We found that after inhibiting miR-466b-5p, the Edg2 protein was increased, OPC differentiation and myelinated axon formation were enhanced, and the rats' behavioral performance was improved, whereas OPC proliferation and apoptosis were not affected. Furthermore, the expression of Sox10 was promoted while PLP trafficking was attenuated after miR-466b-5p inhibition. We conclude that miR-466b-5p is involved in the regulation of WMI pathogenesis, partly through the Lpar1/Edg2/Sox10 and Lpar1/Edg2/PLP signaling pathways.

The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury.

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that plays an important role in stabilizing nucleosomes and DNA repair. HMGB1 can be passively released from necrotic neurons or actively secreted by microglia, macrophages/monocytes, and neutrophils. Cerebral ischemia is a major cause of mortality and disability worldwide, and its outcome depends on the number of neurons dying due to hypoxia in the ischemic area. HMGB1 contributes to the pathogenesis of cerebral ischemia via mediating neuroinflammatory responses to cerebral ischemic injury. Extracellular HMGB1 regulates many neuroinflammatory events by interacting with its different cell surface receptors, such as receptors for advanced glycation end products, toll-like receptor (TLR)-2, and TLR-4. Additionally, HMGB1 can be redox-modified, thus exerting specific cellular functions in the ischemic brain and has different roles in the acute and late stages of cerebral ischemic injury. However, the role of HMGB1 in cerebral ischemia is complex and remains unclear. Herein, we summarize and review the research on HMGB1 in cerebral ischemia, focusing especially on the role of HMGB1 in hypoxic ischemia in the immature brain and in white matter ischemic injury. We also outline the possible mechanisms of HMGB1 in cerebral ischemia and the main strategies to inhibit HMGB1 pertaining to its potential as a novel critical molecular target in cerebral ischemic injury.

Could the inhibitor of DNA binding 2 and 4 play a role in white matter injury?

White matter injury (WMI) prevents the normal development of myelination, leading to central nervous system myelination disorders and the production of chronic sequelae associated with WMI, such as chronic dyskinesia, cognitive impairment and cerebral palsy. This results in a large emotional and socioeconomic burden. Decreased myelination in preterm infant WMI is associated with the delayed development or destruction of oligodendrocyte (OL) lineage cells, particularly oligodendrocyte precursor cells (OPCs). The development of cells from the OL lineage involves the migration, proliferation and different stages of OL differentiation, finally leading to myelination. A series of complex intrinsic, extrinsic and epigenetic factors regulate the OPC cell cycle withdrawal, OL lineage progression and myelination. We focus on the inhibitor of DNA binding 2 (ID2), because it is widely involved in the different stages of OL differentiation and genesis. ID2 is a key transcription factor for the normal development of OL lineage cells, and the pathogenesis of WMI is closely linked with OL developmental disorders. ID4, another family member of the IDs protein, also plays a similar role in OL differentiation and genesis. ID2 and ID4 belong to the helix-loop-helix family; they lack the DNA-binding sequences and inhibit oligodendrogenesis and OPC differentiation. In this review, we mainly discuss the roles of ID2 in OL development, especially during OPC differentiation, and summarize the ID2-mediated intracellular and extracellular signaling pathways that regulate these processes. We also discuss ID4 in relation to bone morphogenetic protein signaling and oligodendrogenesis. It is likely that these developmental mechanisms are also involved in the myelin repair or remyelination in human neurological diseases.

Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis.

BACKGROUND: Acetaminophen is a widely used medication for fever and pain management during pregnancy. However, recent studies have found a possible connection between maternal prenatal acetaminophen use and attention deficit/hyperactivity disorder in children. OBJECTIVE: We aimed to explore the association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring. DATA SOURCES: PubMed, Embase, Web of Science and Cochrane Library were searched from their initial publications through November 2018 for studies. STUDY SELECTION: We included all studies that examined the association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring if the authors reported odds ratios, risk ratios, hazard ratios, regression coefficient, standard error and 95% confidence intervals. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data on the definition of exposure and outcome, exposed, non-exposed and total number of participants in the sample population, adjusted potential confounders and outcome parameters. Study quality was also assessed. RESULTS: Eight cohort studies with a total of 244,940 participants were included. Maternal exposure to acetaminophen during pregnancy increased the risk of attention deficit/hyperactivity disorder in offspring with a pooled adjusted risk ratio of 1.25 (95% confidence interval = [1.17, 1.34]). Children exposed prenatally to acetaminophen in the third trimester seemed to have the greatest risk of developing attention deficit/hyperactivity disorder (risk ratio: 1.26; 95% confidence interval = [1.08, 1.47]). In addition, a longer duration of maternal acetaminophen use during pregnancy was correlated with a higher risk ratio. Children whose mothers used acetaminophen for 28 or more days during gestation had a higher risk of developing attention deficit/hyperactivity disorder (risk ratio: 1.63; 95% confidence interval = [1.23, 2.16]). CONCLUSION: There is an association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring. The timing and duration of acetaminophen use during pregnancy may have a major effect on the risk of attention deficit/hyperactivity disorder.

Maternal chorioamnionitis and neurodevelopmental outcomes in preterm and very preterm neonates: A meta-analysis.

CONTEXT: No consensus exists regarding the association between maternal chorioamnionitis and neurodevelopmental outcomes in preterm and very preterm neonates. OBJECTIVES: To investigate whether maternal chorioamnionitis affects neurodevelopmental outcomes and to identify the factors that may explain these effects. DATA SOURCES: We used Ovid Medline, EMBASE and Web of Science to conduct a meta-analysis of studies published in English before August 25, 2017, with titles or abstracts that discussed an association between maternal chorioamnionitis and mental/motor development. STUDY SELECTION: Among the 603 initially identified studies, we selected those that addressed an association between maternal chorioamnionitis and mental/motor development according to our preselected inclusion criteria as follows: (1) the study compared infants with and without exposure to maternal chorioamnionitis and (2) the neurodevelopmental outcome was followed up using the Bayley Scales of Infant Development 2nd edition. DATA SYNTHESIS: Our meta-analysis included 10 studies. According to a random effect model, infants with maternal chorioamnionitis exposure had poorer mental development (d = -2.25 [95%CI, -4.33, -0.17], p<0.05) than infants without maternal chorioamnionitis, and infants with maternal clinical chorioamnionitis exposure had poorer motor development (d = -2.37 [95%CI, -4.62 to -0.12], p<0.05) than infants without maternal clinical chorioamnionitis exposure. Factors in the meta-analysis that showed differences between the two patient groups included an MDI assessment blinded to medical history, MDI assessment at the correct age, and time of the MDI assessment. CONCLUSION: This study suggests that maternal chorioamnionitis may affect mental development in preterm and very preterm neonates, and that maternal clinical chorioamnionitis may affect motor development in offspring. Further studies are required to confirm these results and to detect the influence of variables across studies.

Association between bronchopulmonary dysplasia and cerebral palsy in children: a meta-analysis.

OBJECTIVE: To investigate the association between bronchopulmonary dysplasia (BPD) and the risk of cerebral palsy (CP) in children. DATA SOURCES: We used EMBASE, PubMed and Web of Science to conduct a meta-analysis of studies published before 1 September 2017, written in English whose titles or abstracts discussed an association between BPD and CP. STUDY SELECTION: Observational studies, for example, case-control and cohort studies were included. DATA EXTRACTION AND SYNTHESIS: All review stages were conducted by two reviewers independently. Data synthesis was undertaken via meta-analysis of available evidence. MAIN OUTCOMES AND MEASURES: The prevalence of developing CP was measured after exposure to BPD. RESULTS: Among 1234 initially identified studies, we selected those that addressed an association between BPD and CP according to our preselected inclusion criteria. Our meta-analysis included 11 studies. According to a random effect model, BPD was significantly associated with CP (ORs 2.10; 95% CI 1.57 to 2.82) in preterm infants. Factors explaining differences in the study results included study design, the definition of BPD, the time of diagnosis of CP and whether the studies adjusted for potential confounders. CONCLUSION: This study suggests that BPD is a risk factor for CP. Further studies are required to confirm these results and to detect the influence of variables across studies.

The association between vitamin D status and tuberculosis in children: A meta-analysis.

BACKGROUND: Vitamin D deficiency (VDD) has been implicated in the pathogenesis of tuberculosis (TB), but most studies have not reported a significant association. We conducted a meta-analysis to explore the association between vitamin D status and TB in children. METHODS: Web of Science, Ovid Medline, and EMBASE were searched for studies in English that discussed vitamin D status and TB in children before January 22, 2018. RESULTS: From the 585 initially identified studies, we selected those that addressed an association between vitamin D status and TB according to our preselected inclusion criteria. Our meta-analysis included 10 studies. According to the random effects model, TB was significantly associated with VDD (ORs, 1.70; 95% CI, 1.20-2.42; P < .05) in children. Vitamin D levels were significantly lower in TB patients than in controls, with a mean difference d = -5.49 nmol/L (95% CI, -10.42 to -0.55; P < .05), indicating that VDD was significantly associated with TB (OR, 1.78; 95% CI, 1.30-2.44; P < .05) in children. CONCLUSION: This study suggests that vitamin D levels are significantly lower in children with TB/latent TB infection than in controls. TB may contribute to VDD in children. Therefore, VDD may be associated with TB in children.