Interrelation between homocysteine metabolism and the development of autism spectrum disorder in children.

Evidence is emerging that dysregulation of circulating concentrations of homocysteine, an important intermediate in folate and vitamin B12 metabolism, is associated with autism spectrum disorder (ASD), but comprehensive assessments and correlations with disease characteristics have not been reported. Multivariate ordinal regression and restricted cubic spline (RCS) models were used to estimate independent correlations between serum homocysteine, folate, and vitamin B12 levels and clinical outcomes and severity of children with ASD. After adjusting for confounding factors, serum homocysteine levels were significantly higher in children with ASD than in healthy controls (ß: 0.370; 95% CI: 0.299~0.441, p < 0.001). Moreover, homocysteine had a good diagnostic ability for distinguishing children with ASD from healthy subjects (AUC: 0.899, p < 0.001). The RCS model indicated a positive and linear association between serum homocysteine and the risk of ASD. The lowest quartile of folate was positively associated with ASD severity (OR: 4.227, 95% CI: 1.022~17.488, p = 0.041) compared to the highest quartile, and serum folate showed a negative and linear association with ASD severity. In addition, decreased concentrations of folate and vitamin B12 were associated with poor adaptive behavior developmental quotients of the Gesell Developmental Schedules (p < 0.05). Overall, an increased homocysteine level was associated with ASD in a linear manner and is thus a novel diagnostic biomarker for ASD. Decreased concentrations of folate and vitamin B12 were associated with poor clinical profiles of children with ASD. These findings suggest that homocysteine-lowering interventions or folate and vitamin B12 supplementation might be a viable treatment strategy for ASD.

The effect of vitamin D supplementation in treatment of children with autism spectrum disorder: a systematic review and meta-analysis of randomized controlled trials.

Objective: The effect of vitamin D supplementation on the risk of Autism Spectrum Disorder (ASD) is conflicting. The aim of this study was to estimate the efficacy of vitamin D supplementation on ASD in children.Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) in which vitamin D supplementation was used as a therapy in children with ASD. The PubMed, PsychINFO, Cochrane CENTRAL library, Web of Science, and Cinahl databases were searched from inception to March 20, 2019, for all publications on vitamin D and ASD with no restrictions. Studies involving individuals aged <18 years diagnosed with ASD and with all functional outcomes assessed by measurement scales for ASD were included. Mean differences were pooled, and a meta-analysis was performed using a random-effects model due to differences between the individual RCTs.Results: There were five RCTs with 349 children with ASD in the review, of which three RCTs were included in the meta-analysis. Vitamin D supplementation indicated a small but significant improvement in hyperactivity scores (pooled MD: -3.20; 95% CI: [-6.06, -0.34]) with low heterogeneity (I2 = 10%, p = 0.33), but there were no other statistically significant differences in ASD symptoms between groups as measured by validated scales.Conclusion: Vitamin D supplementation appears to be beneficial for hyperactivity but not for core symptoms or other co-existing behaviors and conditions of ASD. Future RCTs with large sample sizes examining the effect of vitamin D supplementation on ASD among individuals with low serum vitamin D levels at baseline are needed.

Folic Acid and Risk of Preterm Birth: A Meta-Analysis.

The results from epidemiologic studies linking blood folate concentrations, folic acid supplementation, or dietary folate to the risk of preterm birth are inconsistent. In this study, we aimed to summarize the available evidence on these associations. A systematic search of the PubMed/MEDLINE, Google Scholar, Web of Science, and Cochrane Library databases up to October 20, 2018 was performed and reference lists of retrieved articles were screened. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the highest vs. the lowest levels of folate concentrations, folic acid supplementation, and dietary folate were calculated using random-effects models. Subgroup analyses and univariate meta-regression were performed to explore the sources of heterogeneity. Ten studies (six prospective cohort studies and four case-control studies) were included on folate concentrations, 13 cohort studies were included about folic acid supplementation, and 4 cohort studies were included regarding dietary folate intake. Higher maternal folate levels were associated with a 28% reduction in the risk of preterm birth (OR 0.72, 95% CI 0.56-0.93). Higher folic acid supplementation was associated with 10% lower risk of preterm birth (OR 0.90, 95% CI 0.85-0.95). In addition, a significant negative association was observed between dietary folate intake and the risk of preterm birth (OR 0.68, 95% CI 0.55-0.84), but no significant relation was seen between dietary folate and the risk of spontaneous preterm birth (OR 0.89, 95% CI 0.57-1.41). In the subgroup analysis, higher maternal folate levels in the third trimester were associated with a lower risk of preterm birth (OR 0.58, 95% CI 0.36-0.94). To initiate taking folic acid supplementation early before conception was adversely associated with preterm birth risk (OR 0.89, 95% CI 0.83-0.95). In conclusion, higher maternal folate levels and folic acid supplementation were significantly associated with a lower risk of preterm birth. The limited data currently available suggest that dietary folate is associated with a significantly decreased risk of preterm birth.

Iron Metabolism and Brain Development in Premature Infants.

Iron is important for a remarkable array of essential functions during brain development, and it needs to be provided in adequate amounts, especially to preterm infants. In this review article, we provide an overview of iron metabolism and homeostasis at the cellular level, as well as its regulation at the mRNA translation level, and we emphasize the importance of iron for brain development in fetal and early life in preterm infants. We also review the risk factors for disrupted iron metabolism that lead to high risk of developing iron deficiency and subsequent adverse effects on neurodevelopment in preterm infants. At the other extreme, iron overload, which is usually caused by excess iron supplementation in iron-replete preterm infants, might negatively impact brain development or even induce brain injury. Maintaining the balance of iron during the fetal and neonatal periods is important, and thus iron status should be monitored routinely and evaluated thoroughly during the neonatal period or before discharge of preterm infants so that iron supplementation can be individualized.

Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway.

Traumatic brain injury (TBI) is a principal cause of death and disability worldwide. Melatonin, a hormone made by the pineal gland, is known to have anti-inflammatory and antioxidant properties. In this study, using a weight-drop model of TBI, we investigated the protective effects of ramelteon, a melatonin MT1/MT2 receptor agonist, and its underlying mechanisms of action. Administration of ramelteon (10 mg/kg) daily at 10:00 a.m. alleviated TBI-induced early brain damage on day 3 and long-term neurobehavioral deficits on day 28 in C57BL/6 mice. Ramelteon also increased the protein levels of interleukin (IL)-10, IL-4, superoxide dismutase (SOD), glutathione, and glutathione peroxidase and reduced the protein levels of IL-1ß, tumor necrosis factor, and malondialdehyde in brain tissue and serum on days 1, 3, and 7 post-TBI. Similarly, ramelteon attenuated microglial and astrocyte activation in the perilesional cortex on day 3. Furthermore, ramelteon decreased Keap 1 expression, promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation, and increased levels of downstream proteins, including SOD-1, heme oxygenase-1, and NQO1 on day 3 post-TBI. However, in Nrf2 knockout mice with TBI, ramelteon did not decrease the lesion volume, neuronal degeneration, or myelin loss on day 3; nor did it mitigate depression-like behavior or most motor behavior deficits on day 28. Thus, timed ramelteon treatment appears to prevent inflammation and oxidative stress via the Nrf2-antioxidant response element pathway and might represent a potential chronotherapeutic strategy for treating TBI.

Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats.

Cranial radiotherapy is one of the most effective tools for treating children with brain tumors. However, radiotherapy-induced late-onset side effects have a significant impact on patients' quality of life. The purpose of this study was to investigate the effects of irradiation on metabolism and the possible molecular and cellular mechanisms behind such effects. Female Wistar rats were subjected to a single dose of 6-Gy whole-brain irradiation on postnatal day 11. The animals were sacrificed 6 h or 20 weeks after irradiation. Cell death and proliferation, microglial activation, and inflammation were analyzed and RNA sequencing was performed. We found that irradiation led to a significantly increased body weight from 15 weeks (p < 0.05) along with white adipose tissue accumulation and adipocyte hypertrophy at 20 weeks, and these changes were accompanied by glucose and lipid metabolic disturbances as indicated by reduced glucose tolerance, increased insulin resistance, increased serum triglycerides, and an increased leptin/adiponectin ratio. Furthermore, irradiation induced cell death, microglial activation, inflammation, and persistent astrocyte reactivity in the hypothalamus. Hypothalamic transcriptome analysis showed that 865 genes were downregulated and 290 genes were upregulated in the irradiated group 20 weeks after irradiation, and further pathway analysis showed that the insulin resistance-related PI3K-Akt signaling pathway and the energy expenditure-related adipocytokine signaling pathway were downregulated. Gene Ontology enrichment analysis showed that the expression of fatty acid metabolism-related proteins and effector proteins was significantly different in the irradiation group. This study demonstrates that ionizing radiation to the juvenile female brain induces hypothalamic damage that is likely to be associated with delayed metabolic abnormalities, and this critical vulnerability of the hypothalamus to irradiation should be taken into consideration in the development of future protective strategies for radiotherapy.

Luminal solutions protect mucosal barrier during extended preservation.

BACKGROUND: Mucosal barrier injury during intestinal preservation (IP) and transplantation favors life-threatening infections. Luminal delivery of solutions containing amino acids or polyethylene glycols (PEGs) may improve preservation results and reduce this injury. We tested if solutions containing glutamine and PEG influence the mucosal injury. MATERIALS AND METHODS: Rat intestines were perfused and stored in Viaspan-University of Wisconsin solution. Before IP, a PEG 3350 solution was introduced intraluminally alone (group 1) or supplemented with 40 mmol/L L-glutamine (group 2). Controls underwent vascular flush alone (group 3). Preservation injury was evaluated after 8, 14, and 24 h by histology and goblet cell count. Tight-junction proteins zonula occludens-1, claudin-3, claudin-4, and caveolin-1 were studied by immunofluorescence. Maltase and caspase-3 activity were also analyzed. RESULTS: Group 1 showed mild edema at 8 h and mucosal disruption by 24 h; these features were greatly improved in group 2 where continuous mucosa was found after 24 h of IP. Intestines in group 3 did worse at all time points with subepithelial edema (Park/Chiu grade 3) and marked goblet cell depletion; caspase-3 activity was lowest in group 2. Tight-junction proteins varied continuously during IP; zonula occludens-1 expression and colocalization with claudins decreased significantly in group 3 but not in other groups. Claudin-3 was distinctly localized in the membrane, but stained diffuse, cytoplasmic at later time-points. Claudin-4 changed to a cytoplasmic granular pattern. No caveolin-1 colocalization was observed. CONCLUSIONS: Luminal PEG and glutamine delay epithelial breakdown and preserve several important mucosal features during extended IP.

Electroacupuncture enhances cell proliferation and neuronal differentiation in young rat brains.

To investigate the effect of electroacupuncture on cell proliferation and differentiation in young rat hippocampus, postnatal day-14 rats were assigned randomly to control, ketamine anesthesia, nonacupoint, or acupoint electroacupuncture groups. Electroacupuncture was applied at bilateral acupoints (Quchi, Waiguan, Huantiao, and Zusanli) 30 min daily for 7 successive days. The proliferation and neuronal differentiation of proliferated surviving cells in the dentate gyrus were evaluated at 4 weeks after last stimulation. The stimulatory effect of electroacupuncture on cell proliferation had a long-lasting effect, as indicated by the increased phosphor-histone H3-positive cells. The number of proliferated and survival cells, indicated by BrdU labeling, was highest in the electroacupuncture group. The number of newly differentiated neurons, as indicated by BrdU/NeuN double labeling, was significantly higher in the electroacupuncture group than in any of the other groups. This finding provides a theoretical basis for the clinical application of acupuncture to cerebral injury rehabilitation in children.