The Role of DNA Methylation in Stroke Recovery.

Epigenetic alterations affect the onset of ischemic stroke, brain injury after stroke, and mechanisms of poststroke recovery. In particular, DNA methylation can be dynamically altered by maintaining normal brain function or inducing abnormal brain damage. DNA methylation is regulated by DNA methyltransferase (DNMT), which promotes methylation, DNA demethylase, which removes methyl groups, and methyl-cytosine-phosphate-guanine-binding domain (MBD) protein, which binds methylated DNA and inhibits gene expression. Investigating the effects of modulating DNMT, TET, and MBD protein expression on neuronal cell death and neurorepair in ischemic stroke and elucidating the underlying mechanisms can facilitate the formulation of therapeutic strategies for neuroprotection and promotion of neuronal recovery after stroke. In this review, we summarize the role of DNA methylation in neuroprotection and neuronal recovery after stroke according to the current knowledge regarding the effects of DNA methylation on excitotoxicity, oxidative stress, apoptosis, neuroinflammation, and recovery after ischemic stroke. This review of the literature regarding the role of DNA methylation in neuroprotection and functional recovery after stroke may contribute to the development and application of novel therapeutic strategies for stroke.

The Role of NOX4 in Parkinson's Disease with Dementia.

The neuropathology of Parkinson's disease with dementia (PDD) has been reported to involve heterogeneous and various disease mechanisms. Alpha-synuclein (α-syn) and amyloid beta (Aß) pathology are associated with the cognitive status of PDD, and NADPH oxidase (NOX) is known to affect a variety of cognitive functions. We investigated the effects of NOX on cognitive impairment and on α-syn and Aß expression and aggregation in PDD. In the 6-hydroxydopamine (6-OHDA)-injected mouse model, cognitive and motor function, and the levels of α-syn, Aß, and oligomer A11 after inhibition of NOX4 expression in the hippocampal dentate gyrus (DG) were measured by the Morris water maze, novel object recognition, rotation, and rotarod tests, as well as immunoblotting and immunohistochemistry. After 6-OHDA administration, the death of nigrostriatal dopamine neurons and the expression of α-syn and NOX1 in the substantia nigra were increased, and phosphorylated α-syn, Aß, oligomer A11, and NOX4 were upregulated in the hippocampus. 6-OHDA dose-dependent cognitive impairment was observed, and the increased cognitive impairment, Aß expression, and oligomer A11 production in 6-OHDA-treated mice were suppressed by NOX4 knockdown in the hippocampal DG. Our results suggest that increased expression of NOX4 in the hippocampal DG in the 6-OHDA-treated mouse induces Aß expression and oligomer A11 production, thereby reducing cognitive function.

Sequential Transcriptome Changes in the Penumbra after Ischemic Stroke.

To investigate the changes in the expression of specific genes that occur during the acute-to-chronic post-stroke phase, we identified differentially expressed genes (DEGs) between naive cortical tissues and peri-infarct tissues at 1, 4, and 8 weeks after photothrombotic stroke. The profiles of DEGs were subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology analyses, followed by string analysis of the protein-protein interactions (PPI) of the products of these genes. We found 3771, 536, and 533 DEGs at 1, 4, and 8 weeks after stroke, respectively. A marked decrease in biological-process categories, such as brain development and memory, and a decrease in neurotransmitter synaptic and signaling pathways were observed 1 week after stroke. The PPI analysis showed the downregulation of Dlg4, Bdnf, Gria1, Rhoa, Mapk8, and glutamatergic receptors. An increase in biological-process categories, including cell population proliferation, cell adhesion, and inflammatory responses, was detected at 4 and 8 weeks post-stroke. The KEGG pathways of complement and coagulation cascades, phagosomes, antigen processing, and antigen presentation were also altered. CD44, C1, Fcgr2b, Spp1, and Cd74 occupied a prominent position in network analyses. These time-dependent changes in gene profiles reveal the unique pathophysiological characteristics of stroke and suggest new therapeutic targets for this disease.

Effect of Inhibition of DNA Methylation Combined with Task-Specific Training on Chronic Stroke Recovery.

To develop new rehabilitation therapies for chronic stroke, this study examined the effectiveness of task-specific training (TST) and TST combined with DNA methyltransferase inhibitor in chronic stroke recovery. Eight weeks after photothrombotic stroke, 5-Aza-2'-deoxycytidine (5-Aza-dC) infusion was done on the contralesional cortex for four weeks, with and without TST. Functional recovery was assessed using the staircase test, the cylinder test, and the modified neurological severity score (mNSS). Axonal plasticity and expression of brain-derived neurotrophic factor (BDNF) were determined in the contralateral motor cortex. TST and TST combined with 5-Aza-dC significantly improved the skilled reaching ability in the staircase test and ameliorated mNSS scores and cylinder test performance. TST and TST with 5-Aza-dC significantly increased the crossing fibers from the contralesional red nucleus, reticular formation in medullar oblongata, and dorsolateral spinal cord. Mature BDNF was significantly upregulated by TST and TST combined with 5-Azd-dC. Functional recovery after chronic stroke may involve axonal plasticity and increased mature BDNF by modulating DNA methylation in the contralesional cortex. Our results suggest that combined therapy to enhance axonal plasticity based on TST and 5-Aza-dC constitutes a promising approach for promoting the recovery of function in the chronic stage of stroke.

Au nanoparticle@hollow mesoporous carbon with FeCo/graphitic shell nanoparticls as a magnetically recyclable yolk-shell nanocatalyst for catalytic reduction of nitroaromatics.

We have developed a highly stable and magnetically recyclable yolk-shell nanocatalyst for catalytic reduction of nitroaromatics. This nanocatalyst is composed of a ~13 nm Au nanoparticle encapsulated in a hollow mesoporous carbon (hmC) shell with a diameter of ~120 nm and a thickness of ~15 nm. The hmC shell contains ~6 nm FeCo/graphitic carbon shell (FeCo/GC) nanoparticles. We have synthesized the Au@hmC-FeCo/GC nanocatalyst by thermal decomposition of Fe and Co precursors in silica of a solid core/mesoporous shell structure containing a Au nanoparticle within the core, subsequent ethylene chemical vapor deposition (CVD), and then removal of the silica by treatment with aqueous HF. The Au@hmC-FeCo/GC has superparamagnetism and high saturation magnetization (29.2 emu g-1) at room temperature. It also shows a type IV sorption isotherm, typical for mesoporous carbon (pore diameter = 3.5 nm), thereby ensuring ready accessibility to the Au core by substrates. We have shown that the Au@hmC-FeCo/GC catalyses the reduction of 4-nitrophenol and 4-nitrotoluene more efficiently than Au nanoparticles do, can be separated very quickly from the reaction mixture using an magnet, and can be reused for the same reduction reaction at least five times without loss of the initial level of catalytic activity.

Highly stable mesoporous silica nanospheres embedded with FeCo/graphitic shell nanocrystals as magnetically recyclable multifunctional adsorbents for wastewater treatment.

Highly stable and magnetically separable mesoporous silica nanospheres (MSNs) embedded with 4.6 ± 0.8 nm FeCo/graphitic carbon shell nanocrystals (FeCo/GC NCs@MSNs) were synthesized by thermal decomposition of metal precursors in MSNs and subsequent methane CVD. The FeCo/GC NCs@MSNs had a high specific surface area (442 m2 g-1), large pore volume (0.65 cm3 g-1), and tunable size (65 nm, 130 nm, and 270 nm). Despite the low magnetic metal content (8.35 wt%), the FeCo/GC NCs@MSNs had a sufficiently high saturation magnetization (17.1 emu g-1). This is due to the superior magnetic properties of the FeCo/GC NCs, which also enable fast magnetic separation of the nanospheres. The graphitic carbon shell on the FeCo NCs not only protects the alloy core against oxidation and acid etching in 35% HCl(aq), but also facilitates non-covalent, hydrophobic interactions with the hydrocarbon chains of organic dyes such as methyl orange and methylene blue. Surface functionalization of the FeCo/GC NCs@MSNs with thiol groups provides efficient capacity for binding with Hg2+ ions. We have shown that the thiol-functionalized FeCo/GC NCs@MSNs (FeCo/GC NCs@MSNs-SH) work as multifunctional adsorbents for organic dyes (target organic pollutants) and Hg2+ ions (target inorganic pollutant). We also demonstrated that the FeCo/GC NCs@MSNs-SH are excellent recyclable adsorbents for methyl orange.

Sulfur-Doped Porphyrinic Carbon Nanostructures Synthesized with Amorphous MoS2 for the Oxygen Reduction Reaction in an Acidic Medium.

To develop doped carbon nanostructures as non-precious metal cathode catalysts, nanocomposites were synthesized by using SBA-15 and 5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin-iron(III) chloride with different ratios of amorphous MoS2 precursor. From various analyses, it was found that, during pyrolysis at 900 °C under an N2 atmosphere, the amorphous MoS2 precursor decomposed into Mo and S, facilitating the formation of graphene sheet-like carbon with MoC and doping of sulfur in the carbon. In the nanocomposite formed from 10 wt % MoS2 precursor (denoted as Mo/S/PC-10), most of the MoS2 was decomposed, thus forming S-doped carbon, which was grown on the MoC phase without crystalline MoS2 . Furthermore, Mo/S/PC-10 exhibited better performance in the oxygen reduction reaction (specific activity of 1.23 mA cm-2 at 0.9 V and half-wave potential of 0.864 V) than a commercial Pt catalyst, owing to a heteroatom-doped carbon nanostructure with a fairly high specific surface area. In the polarization curve of the unit-cell performance measured at 80 °C under ambient pressure, Mo/S/PC-10 as a cathode catalyst exhibited an optimal power density of 314 mW cm-2 and a current density of 280 mA cm-2 at 0.6 V.

High-Performance Chemically Regenerative Redox Fuel Cells Using a NO3- /NO Regeneration Reaction.

In this study, we proposed high-performance chemically regenerative redox fuel cells (CRRFCs) using NO3- /NO with a nitrogen-doped carbon-felt electrode and a chemical regeneration reaction of NO to NO3- via O2 . The electrochemical cell using the nitrate reduction to NO at the cathode on the carbon felt and oxidation of H2 as a fuel at the anode showed a maximal power density of 730 mW cm-2 at 80 °C and twofold higher power density of 512 mW cm-2 at 0.8 V, than the target power density of 250 mW cm-2 at 0.8 V in the H2 /O2 proton exchange membrane fuel cells (PEMFCs). During the operation of the CRRFCs with the chemical regeneration reactor for 30 days, the CRRFCs maintained 60 % of the initial performance with a regeneration efficiency of about 92.9 % and immediately returned to the initial value when supplied with fresh HNO3 .

Effect of task-specific training on Eph/ephrin expression after stroke.

Recent evidence indicates that the ephrin receptors and ephrin ligands (Eph/ephrin) expression modulate axonal reorganization and synaptic plasticity in stroke recovery. To investigate the effect of task-specific training (TST) on Eph/ephrin expression in the corticospinal tract (CST) after stroke, we compared Eph/ephrin expression in the peri-infarct cortex, pyramid, and spinal cord of a photothrombotic stroke model of rat brains treated with or without TST. The TST treatment showed significantly better recovery in the behavioral tests compared with no treatment. The significant upregulation of ephrin-A1 and ephrin-A5 observed in activated astrocytes of the CST at 2 weeks' post-stroke was decreased by TST. At 5 weeks, post-stroke, the elevated ephrin-A5 levels were decreased in the ipsilateral pyramid and spinal cord by TST. Glial fibrillary acidic protein was upregulated concomitantly with the altered ephrin expression after stroke, and the expression of these proteins was attenuated by TST. These data suggest that TST alters the expression of ephrin ligands in the CST after stroke. [BMB Reports 2016; 49(11): 635-640].

Prenatal maternal distress affects atopic dermatitis in offspring mediated by oxidative stress.

BACKGROUND: Recent evidence suggests that prenatal maternal distress increases the risk of allergic diseases in offspring. However, the effect of prenatal maternal depression and anxiety on atopic dermatitis (AD) risk remains poorly understood. OBJECTIVE: We investigated whether prenatal maternal distress is associated with AD risk in offspring and whether the mechanism is mediated by reactive oxygen species. METHODS: Two general population-based birth cohorts formed the study. One cohort (Cohort for Childhood Origin of Asthma and Allergic Diseases [COCOA]) consisted of 973 mother-baby dyads, and the other (Panel Study on Korean Children [PSKC]) consisted of 1531 mother-baby dyads. The association between prenatal distress and AD was assessed by using Cox proportional hazards and logistic regression models. In COCOA placental 11ß-hydroxysteroid dehydrogenase type 2 and glutathione levels and serum IgE levels in 1-year-old children were measured. RESULTS: In COCOA and PSKC AD occurred in 30.6% (lifetime prevalence) and 11.6% (1 year prevalence) of offspring, respectively. Prenatal maternal distress increased the risk of AD in offspring, both in COCOA (hazard ratio for depression, 1.31 [95% CI, 1.02-1.69]; hazard ratio for anxiety, 1.41 [95% CI, 1.06-1.89]) and PSKC (odds ratio for distress, 1.85 [95% CI, 1.06-3.25]). In COCOA both prenatal maternal depression and anxiety scores were positively related to the predicted probability of AD (P < .001 in both). Prenatal distress decreased placental glutathione to glutathione disulfide ratios (P = .037) and, especially in those who later had AD, decreased placental 11ß-hydroxysteroid dehydrogenase type 2 levels (P = .010) and increased IgE levels at 1 year of age (P = .005). CONCLUSION: Prenatal maternal depression and anxiety promote risk of AD in offspring. Maternal distress increases the predicted probability of AD. The mechanism might involve chronic stress, abnormal steroid levels, and reactive oxygen species.

The effect of perinatal anxiety on bronchiolitis is influenced by polymorphisms in ROS-related genes.

BACKGROUND: Exposure to perinatal anxiety affects disease susceptibility in offspring but studies on the association between perinatal anxiety and gene polymorphisms are lacking. This study aimed to elucidate the interaction between perinatal anxiety and polymorphisms in antioxidant defense and innate immunity genes on the development of respiratory tract infections (RTIs) during early infancy. METHODS: Trait anxiety levels in 440 women were assessed by the State-Trait Anxiety Inventory during late gestation. The occurrence of RTIs, including bronchiolitis, during the first year of life was assessed by parent-reported doctor diagnosis. Polymorphisms in glutathione S-transferase P-1 (GSTP1, rs1695) and CD14 (rs2569190) were genotyped using the TaqMan assay. Copy number variations of GSTT1 were measured by real-time polymerase chain reaction. RESULTS: Exposure to high levels of perinatal anxiety increased the risk of bronchiolitis in the first year of life (adjusted odds ratio [aOR], 1.30; 95% confidence interval [CI]: 1.00-1.80), in particular among children with the AG + GG genotype of GSTP1 or the GSTT1 null genotype (aOR 3.36 and 2.79). In infants with the TC + CC genotype of CD14, high levels of perinatal anxiety were associated with an increased risk of upper RTI, lower RTI, and bronchiolitis (aOR 2.51, 4.60, and 4.31, respectively). CONCLUSIONS: Perinatal maternal anxiety levels affect the occurrence of bronchiolitis in offspring. The effect of perinatal anxiety on the occurrence of bronchiolitis during infancy was influenced by genetic polymorphisms in antioxidant defense and innate immunity genes.

Prenatal maternal depression is associated with low birth weight through shorter gestational age in term infants in Korea.

BACKGROUND: Maternal prenatal depression is associated with lower offspring birth weight, yet the impact of gestational age on this association remains inadequately understood. AIMS: We aimed to investigate the effect of prenatal depression on low birth weight, gestational age, and weight for gestational age at term. STUDY DESIGN: Prospective cohort study. SUBJECT: Data were collected from 691 women in their third trimester of pregnancy who went on to give birth to a singleton at term without perinatal complications. One hundred and fifty-two women had a Center for Epidemiologic Studies Depression Scale-10 score ≥10 and were classed as prenatally depressed. OUTCOME MEASURES: Low birth weight (<2500g), gestational age at birth, and birth weight percentile for gestational age. RESULTS: Offspring of prenatally depressed women were more likely to be low birth weight (Odds ratio [OR] 2.94, 95% confidence interval [CI] 1.14-7.58) than offspring of prenatally non-depressed women, but the association was attenuated (OR 1.66, 95% CI 0.55-5.02) when adjusted for gestational age. Offspring of prenatally depressed women had lower gestational age in weeks (OR for one week increase in gestational age: 0.66, 95% CI 0.47-0.93) than offspring of prenatally non-depressed women. There was no association between prenatal depression and birth weight percentile for gestational age. CONCLUSIONS: Prenatal depression was not associated with low birth weight at term, but was associated with gestational age, suggesting that association between maternal depression and birth weight may be a reflection of the impact of depression on offspring gestational age.

Ultra-small, uniform, and single bcc-phased Fe(x)Co(1-x)/graphitic shell nanocrystals for T1 magnetic resonance imaging contrast agents.

We have synthesized ultra-small and uniform Fe(x)Co(1-x)/graphitic carbon shell (Fe(x)Co(1-x)/GC) nanocrystals (x=0.13, 0.36, 0.42, 0.50, 0.56, and 0.62, respectively) with average diameters of <4 nm by thermal decomposition of metal precursors in approximately 60 nm MCM-41 and methane CVD. The composition of the Fe(x)Co(1-x)/GC nanocrystals can be tuned by changing the Fe:Co ratios of the metal precursors. The Fe(x)Co(1-x)/GC nanocrystals show superparamagnetic properties at room temperature. The Fe(0.50)Co(0.50)/GC, Fe(0.56)Co(0.44)/GC, and Fe(0.62)Co(0.38)/GC nanocrystals have a single bcc FeCo structure, whereas the Fe(0.13)Co(0.87)/GC, Fe(0.36)Co(0.64)/GC, and Fe(0.42)Co(0.58)/GC nanocrystals have a mixed structure of bcc FeCo and fcc Co. The single bcc-phased Fe(x)Co(1-x)/GC nanocrystals functionalized with phospholipid-poly(ethylene glycol) (PL-PEG) in phosphate buffered saline (PBS) are demonstrated to be excellent T(1) MRI contrast agents.