Inter-comparisons of VOC oxidation mechanisms based on box model: A focus on OH reactivity.

Volatile organic compounds (VOCs) oxidation processes play a very important role in atmospheric chemistry, and the chemical reactions are expressed in various manners in chemical mechanisms. To gain an improved understanding of VOCs evolution during oxidation processes and evaluate the discrepancies of VOCs oxidation schemes among different mechanisms, we used the total VOC reactivity as a diagnostic and evaluated tool to explore the differences for six widely used chemical mechanisms. We compared the total VOC reactivity evolution under high-NOx conditions for several sets of precursors, including n-pentane, toluene, ethene, isoprene and a mixture of 57 Photochemical Assessment Monitoring Stations (PAMS) species in a 0-D photochemical box model. Inter-comparison of total VOC reactivity of individual precursor simulations showed discrepancies to different extent of the oxidation schemes among the studied mechanisms, which are mainly attributed to the different lumping approaches for organic species. The PAMS simulation showed smaller discrepancy than individual precursor cases in terms of total VOC reactivity. SAPRC07 and RACM2 performances are found to better match the MCM for simulation of total VOC reactivity. Evidences suggest that the performance in simulating secondary organic products, OH concentrations and NOx concentrations are related to the OH reactivity discrepancies among various chemical mechanisms. Information in this study can be used in selection of chemical mechanisms to better model OH reactivity in different environments. The results in this study also provide directions to further improve the ability in modelling total VOC reactivity with the chemical mechanisms.

High Concentrations of Atmospheric Isocyanic Acid (HNCO) Produced from Secondary Sources in China.

Isocyanic acid (HNCO) is a potentially toxic atmospheric pollutant, whose atmospheric concentrations are hypothesized to be linked to adverse health effects. An earlier model study estimated that concentrations of isocyanic acid in China are highest around the world. However, measurements of isocyanic acid in ambient air have not been available in China. Two field campaigns were conducted to measure isocyanic acid in ambient air using a high-resolution time-of-flight chemical ionization mass spectrometer (ToF-CIMS) in two different environments in China. The ranges of mixing ratios of isocyanic acid are from below the detection limit (18 pptv) to 2.8 ppbv (5 min average) with the average value of 0.46 ppbv at an urban site of Guangzhou in the Pearl River Delta (PRD) region in fall and from 0.02 to 2.2 ppbv with the average value of 0.37 ppbv at a rural site in the North China Plain (NCP) during wintertime, respectively. These concentrations are significantly higher than previous measurements in North America. The diurnal variations of isocyanic acid are very similar to secondary pollutants (e.g., ozone, formic acid, and nitric acid) in PRD, indicating that isocyanic acid is mainly produced by secondary formation. Both primary emissions and secondary formation account for isocyanic acid in the NCP. The lifetime of isocyanic acid in a lower atmosphere was estimated to be less than 1 day due to the high apparent loss rate caused by deposition at night in PRD. Based on the steady state analysis of isocyanic acid during the daytime, we show that amides are unlikely enough to explain the formation of isocyanic acid in Guangzhou, calling for additional precursors for isocyanic acid. Our measurements of isocyanic acid in two environments of China provide important constraints on the concentrations, sources, and sinks of this pollutant in the atmosphere.

Quantifying the contributions of meteorology, emissions, and transport to ground-level ozone in the Pearl River Delta, China.

Ozone pollution presents a growing air quality threat in urban agglomerations in China. It remains challenge to distinguish the roles of emissions of precursors, chemical production and transportations in shaping the ground-level ozone trends, largely due to complicated interactions among these 3 major processes. This study elucidates the formation factors of ozone pollution and categorizes them into local emissions (anthropogenic and biogenic emissions), transport (precursor transport and direct transport from various regions), and meteorology. Particularly, we attribute meteorology, which affects biogenic emissions and chemical formation as well as transportation, to a perturbation term with fluctuating ranges. The Community Multiscale Air Quality (CMAQ) model was utilized to implement this framework, using the Pearl River Delta region as a case study, to simulate a severe ozone pollution episode in autumn 2019 that affected the entire country. Our findings demonstrate that the average impact of meteorological conditions changed consistently with the variation of ozone pollution levels, indicating that meteorological conditions can exert significant control over the degree of ozone pollution. As the maximum daily 8-hour average (MDA8) ozone concentrations increased from 20 % below to 30 % above the National Ambient Air Quality Standard II, contributions from emissions and precursor transport were enhanced. Concurrently, direct transport within Guangdong province rose from 13.8 % to 22.7 %, underscoring the importance of regional joint prevention and control measures under adverse weather conditions. Regarding biogenic emissions and precursor transport that cannot be directly controlled, we found that their contributions were generally greater in urban areas with high nitrogen oxides (NOx) levels, primarily due to the stronger atmospheric oxidation capacity facilitating ozone formation. Our results indicate that not only local anthropogenic emissions can be controlled in urban areas, but also the impacts of local biogenic emissions and precursor transport can be potentially regulated through reducing atmospheric oxidation capacity.

Neuregulin1beta1 antagonizes apoptosis via ErbB4-dependent activation of PI3-kinase/Akt in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid protein (Aß) and extensive neuronal cell death. Apoptosis plays a crucial role in loss of neurons in AD. Neuregulin1 (NRG1) has been found to protect neurons from oxygen glucose deprivation induced apoptosis and hypoxia ischemia induced apoptosis. However, the relationship between NRG1 and apoptosis related protein expression in AD and its mechanism remain uncertain. The present study explores the effects of NRG1 on Aß-induced apoptosis in AD. In this study, extracellular domain of NRG1beta1 (NRG1ß1-ECD) promoted the expression of p-ErbB4 receptor, p-Akt and increased the level of Bcl-2 both in APP/PS1 transgenic mice and in vitro. In primary culture of neurons, the level of Bcl-2 protein decreased significantly after Aß treatment. These changes were inhibited by pretreatment of neurons with NRG1ß1-ECD. A specific inhibitor of PI3-kinase/Akt pathway, wortmannin, significantly abrogated the effects of NRG1ß1-ECD on p-Akt and Bcl-2 levels. Furthermore, the expression of PI3-kinase/Akt by NRG1ß1-ECD was ErbB4-dependent. Our data demonstrated that NRG1ß1-ECD might serve as an obvious neuroprotection in AD, and the possible protective mechanism occurs most likely via ErbB4-dependent activation of PI3-kinase/Akt pathway.

Sources, size-resolved deposition in the human respiratory tract and health risks of submicron black carbon in urban atmosphere in Pearl River Delta, China.

Black carbon (BC) has a significantly negative impact on air quality, climate and human health. Here we investigated the sources and health effects of BC in urban area of the Pearl River Delta (PRD) based on online data measured by Aerodyne soot particle high-resolution time of flight aerosol mass spectrometer (SP-AMS). In urban PRD, BC particles mainly came from vehicle emissions especially heavy-duty vehicle exhausts (contributing 42.9 % of total BC mass concentration), long-range transport (27.6 %), and aged biomass combustion emissions (22.3 %). Indicated by source analysis using simultaneous aethalometer data, BC associated with local secondary oxidation and transport may also be originated from fossil fuel combustion, especially traffic sources in urban and surrounding areas. Size-resolved BC mass concentrations provided by SP-AMS, for the first time to our best knowledge, were used to calculate BC deposition in the human respiratory tract (HRT) of different populations (children, adults, and the elderly) by the Multiple-Path Particle Dosimetry (MPPD) model. We found that submicron BC was deposited more in the pulmonary (P) region (49.0-53.2 % of the total BC deposition dose), while less in the tracheobronchial (TB, 35.6-37.2 %) and head (HA, 11.2-13.8 %) regions. Adults suffered the highest BC deposition (1.19 µg day-1) than the elderly (1.09 µg day-1) and children (0.25 µg day-1). BC deposition rate was greater at night (especially 18:00-24:00) than during the daytime. The maximum deposition in the HRT was found for BC particles around 100 nm, mainly in deeper respiratory regions (TB and P), which may cause more serious health effects. Adults and the elderly group are confronted with the notable carcinogenic risk of BC in the urban PRD, up to 29 times higher than the threshold. Our study emphasizes the need to control BC pollution in the urban area, especially nighttime vehicle emissions.

[Compositional Characteristics of Volatile Organic Compounds in Typical Industrial Areas of the Pearl River Delta: Importance of Oxygenated Volatile Organic Compounds].

Volatile organic compounds (VOCs) are key components of tropospheric chemistry, of which industrial emissions are an important source of atmospheric VOCs. In this study, online measurements of 74 VOCs were made in a typical industrial area of the Pearl River Delta in southern China during the early summer of 2021. The mean volume mixing ratio of total volatile organic compounds (TVOC) was (81.9±45.4)×10-9 during the campaign. Among them, oxygenated volatile organic compounds (OVOCs) accounted for the largest fraction of TVOC, with an average of 51.5%, followed by aromatics, accounting for 19.4% of TVOC. The proportion of OVOCs in TVOC gradually increased with the increase in TVOC concentration. Industry-related emissions were the main contributors to aromatics and OVOCs in this region. Aromatics and OVOCs were the two major contributors to the ozone formation potential (OFP), accounting for 56.4% and 26.7%, respectively. Furthermore, OVOCs also contributed 40.0% of the total ·OH reactivity from VOCs. Xylenes, toluene, acrolein, and ethyl acetate had a greater contribution to the formation of secondary pollution; thus, these species should be given priority for controlling secondary pollution. Our results underscore the severity of OVOCs pollution in industrial areas and the important roles of OVOCs in secondary pollution.

Photolysis frequency of nitrophenols derived from ambient measurements.

Nitrophenols, a class of important intermediate products from the oxidation of aromatics, can participate in photochemistry and influence the atmospheric oxidative capacity. However, the reported photolysis frequencies of nitrophenols show considerable discrepancies. Here, measurements of nitrophenol, and methyl nitrophenol using a proton-transfer-reaction time-of-flight mass spectrometer (PTR-ToF-MS) at both urban and regional sites in southern China are used to constrain photolysis frequencies of nitrophenols. Considerable concentrations with a campaign average of 58 ± 32 ppt for nitrophenol and 97 ± 59 ppt for methyl nitrophenol were observed at the regional site. Based on the in-situ measurement dataset, a steady-state calculation was performed along with a zero-dimensional box model to analyze the budgets of nitrophenols. The result indicates that both primary emission and photolysis have significant impacts on nitrophenols. Primary emission contributes up to 88 % of the total nitrophenols production while photolysis accounts for up to 98 % of the total removal rate. The dominant sink of nitrophenols is photolysis with a rate of about 3.5 % ± 1.3 % of jNO2 for nitrophenol and 2.4 % ± 1.0 % of jNO2 for methyl nitrophenol. The results of this study suggest that using advanced mass spectrometry to accurately measure ambient nitrophenols, supplemented by an observation-based box model for budget analysis, provides an important indication for determining photolysis rate constants of nitrophenols.

Downregulating the canonical Wnt/ß-catenin signaling pathway attenuates the susceptibility to autism-like phenotypes by decreasing oxidative stress.

Although a growing body of evidence supports the importance of the Wnt/ß-catenin signaling pathway and oxidative stress in the pathogenesis of autism, it is unclear whether a relationship exists between the Wnt/ß-catenin pathway and oxidative homeostasis. The present study examines the effects of sulindac, a small molecule inhibitor of the Wnt/ß-catenin signaling pathway, on the oxidative status of rats that are prenatally exposed to valproic acid (VPA), which is used in an animal model of autism. Our data show that sulindac treatment downregulated the canonical Wnt/ß-catenin signaling pathway by enhancing the expression of Glycogen Synthase Kinase 3ß and attenuating the expression of ß-catenin in comparison to levels in VPA-treated rats. Concomitantly, a marker of lipid peroxidation, 4-hydroxynonenal, was reduced as well. Sulindac treatment ameliorated the pain threshold, repetitive/stereotypic activity, learning and memory abilities and behavioral abnormalities of rats in our autism model. Our working model suggests that the upregulation of the Wnt/ß-catenin signaling pathway induced by VPA administration during early pregnancy produces an imbalance of oxidative homeostasis that facilitates susceptibility to autism. This information may be instrumental in designing appropriate therapeutic regimens with small molecule inhibitors of the Wnt/ß-catenin pathway for the treatment of autism-like behavioral phenotypes.

Activation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels.

The synthetic Liver X receptor (LXR) activator T0901317 has been reported to exert neuroprotective effect in Alzheimer's disease, but the relationship between LXR activation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) remains uncertain. This study investigated the effect of T0901317 on membrane cholesterol levels, BACE1 expression and activity. We found that T0901317 decreased membrane cholesterol levels, reduced BACE1 expression and activity as well as ß-secretase cleaved C-terminal fragment (ß-CTF) levels in vivo and in vitro. Meanwhile, the expression of ATP-binding membrane cassette transport protein A1 (ABCA1) enhanced. Additionally, inhibition of ABCA1 abrogated the effects of T0901317 on membrane cholesterol levels and ß-secretase activity. Moreover, addition of LXR antagonist reversed the effect of T0901317 on ABCA1 mRNA expression, membrane cholesterol levels and ß-secretase activity. Our results suggest that activation of LXR may decrease BACE1 expression and activity through a pathway associated with ABCA1-mediated reduction in membrane cholesterol levels.

Quantifying the role of PM2.5 dropping in variations of ground-level ozone: Inter-comparison between Beijing and Los Angeles.

In recent decade the ambient fine particle (PM2.5) levels have shown a trend of distinct dropping in China, while ground-level ozone concentrations have been increasing in Beijing and many other Chinese mega-cities. The variation pattern in Los Angeles was markedly different, with PM2.5 and ozone decreasing together over past decades. In this study, we utilize observation-based methods to establish the parametric relationship between PM2.5 concentration and key aerosol physical properties (including aerosol optical depth and aerosol surface concentration), and an observation-based 1-D photochemical model to quantify the response of PM2.5 decline in enhancing ground-level ozone pollution over a large PM2.5 concentration range (10-120 µg m-3). We find that the significance of ozone enhancement due to PM2.5 dropping depends on both the PM2.5 levels and optical properties of particles. Ozone formation increased by 37% in 2006-2016 due to PM2.5 dropping in Beijing, while it becomes less important (7%) as PM2.5 reaches below 40 µg/m3, similar to Los Angeles since 1980s. Therefore, the two cities show the convergence of air pollutant characteristics. Hence a control strategy prioritizing reactive volatile organic compound abatement is projected to yield simultaneous ozone and PM2.5 reductions in Beijing, as experienced in Los Angeles.

(Z)-(1,3-Thia-zinan-2-ylideneamino)formo-nitrile.

In the title mol-ecule, C(5)H(7)N(3)S, the thia-zine ring shows a conformation close to a half-boat. The Cremer & Pople puckering parameters of the thia-zine ring are q2 = 0.4645 (2) Å, θ = 132.4 (3) and ϕ = 285.52 (2)°. The packing is stabilized by inter-molecular N-H⋯N and C-H⋯S inter-actions.

Neuroprotective effects of neuregulin-1 in rat models of focal cerebral ischemia.

The purpose of this study was to investigate the therapeutic efficacy and mechanism of recombinant human NRG-1 to attenuate ischemia/reperfusion brain injury. NRG-1(3.0 ng/kg) was applied intravascularly 10 min before middle cerebral artery occlusion (MCAO) and then focal cerebral ischemia for 90 min and reperfusion for 24 h. The rats were scored post-reperfusion for neurological deficits and infarct volume in the brain was assessed by 2,3,5-triphenyltetrazolium chloride(TTC). Apoptosis was evaluated by TUNEL staining. Reverse transcription polymerase chain reaction (RT-PCR) was used to measure changes of caspase-3 mRNA. The level of TNF-alpha was determined using enzyme-linked immunosorbent assay (ELISA). Our results demonstrated that recombinant human NRG-1 could reduce cerebral infarct volume by about 71% (P < 0.05) and TUNEL positive cells when given immediately before MCAO, and improved behavior of animals. Furthermore, we also showed that NRG-1 could also decrease the expression of caspase-3 mRNA and production of TNF-alpha protein. These data suggest that pre-administration of NRG-1 attenuates cerebral ischemia and reperfusion injury. This protective effect may be involved in the inhibition of caspase-3 and TNF-alpha.

Splenocytes derived from young WT mice prevent AD progression in APPswe/PSENldE9 transgenic mice.

Immunosenescence contributes to pathogenesis of Alzheimer's disease (AD) in the elderly. In this study, we explored the effects of young wild type (WT) splenocytes (ySCs) on Alzheimer's disease by transplanting ySCs into APPswe/PSENldE9 transgenic mice. Young WT splenocytes not only prevented AD, but also improved the spatial learning and memory of APPswe/PSENldE9 transgenic mice. Young WT splenocytes enhanced Aß clearance, decreased astrogliosis and increased systemic growth differentiation factor 11 (GDF11) levels. Splenocytes derived from old AD mouse promoted AD. There was an increased number of regulatory T cells (Tregs) among old AD splenocytes. We suggest that alterations of GDF11 and Tregs are involved in AD progression and that rejuvenation of the immune system is a potential therapeutic strategy in AD.

Combined treatment of amyloid-ß1₋42-stimulated bone marrow-derived dendritic cells plus splenocytes from young mice prevents the development of Alzheimer's disease in APPswe/PSENldE9 mice.

Anti-amyloid-ß (Aß) immunotherapy is a potential therapeutic strategy to reduce amyloid plaques and amyloid-associated pathologies in Alzheimer's disease (AD). Immune senescence with aging has also played a crucial role in AD pathogenesis and influences the effect of anti-Aß immunotherapy. In this study, a combined treatment of Aß1₋42-bone marrow-derived dendritic cells (BMDCs) with intraperitoneal injection of splenocytes from young mice was designed as a novel immunotherapy for AD in APPswe/PSEN1de9 transgenic mice models. The results showed that the combined treatment not only elevated the level of anti-Aß antibodies but also reduced amyloid plaques in brain and finally ameliorated deterioration of spatial learning and memory in AD mice. Additionally, the results revealed an increase of CD68 positive microglial cells in the vicinity of amyloid plaques in the mouse brain, which was responsible for the enhanced phagocytosis of Aß plaques. In conclusion, the Aß1₋42-BMDCs plus splenocytes treatment improved the phagocytosis of microglia and prevented AD pathology more effectively. This combined immunotherapy provided a promising treatment in preventing the progression of AD in clinical studies in the near future.

Changes in Otx2 and parvalbumin immunoreactivity in the superior colliculus in the platelet-derived growth factor receptor-ß knockout mice.

The superior colliculus (SC), a relay nucleus in the subcortical visual pathways, is implicated in socioemotional behaviors. Homeoprotein Otx2 and ß subunit of receptors of platelet-derived growth factor (PDGFR- ß ) have been suggested to play an important role in development of the visual system and development and maturation of GABAergic neurons. Although PDGFR- ß -knockout (KO) mice displayed socio-emotional deficits associated with parvalbumin (PV-)immunoreactive (IR) neurons, their anatomical bases in the SC were unknown. In the present study, Otx2 and PV-immunolabeling in the adult mouse SC were investigated in the PDGFR- ß KO mice. Although there were no differences in distribution patterns of Otx2 and PV-IR cells between the wild type and PDGFR- ß KO mice, the mean numbers of both of the Otx2- and PV-IR cells were significantly reduced in the PDGFR- ß KO mice. Furthermore, average diameters of Otx2- and PV-IR cells were significantly reduced in the PDGFR- ß KO mice. These findings suggest that PDGFR- ß plays a critical role in the functional development of the SC through its effects on Otx2- and PV-IR cells, provided specific roles of Otx2 protein and PV-IR cells in the development of SC neurons and visual information processing, respectively.

Transplantation of oligodendrocyte precursor cells improves locomotion deficits in rats with spinal cord irradiation injury.

Demyelination contributes to the functional impairment of irradiation injured spinal cord. One potential therapeutic strategy involves replacing the myelin-forming cells. Here, we asked whether transplantation of Olig2(+)-GFP(+)-oligodendrocyte precursor cells (OPCs), which are derived from Olig2-GFP-mouse embryonic stem cells (mESCs), could enhance remyelination and functional recovery after spinal cord irradiation injury. We differentiated Olig2-GFP-mESCs into purified Olig2(+)-GFP(+)-OPCs and transplanted them into the rats' cervical 4-5 dorsal spinal cord level at 4 months after irradiation injury. Eight weeks after transplantation, the Olig2(+)-GFP(+)-OPCs survived and integrated into the injured spinal cord. Immunofluorescence analysis showed that the grafted Olig2(+)-GFP(+)-OPCs primarily differentiated into adenomatous polyposis coli (APC(+)) oligodendrocytes (54.6±10.5%). The staining with luxol fast blue, hematoxylin & eosin (LFB/H&E) and electron microscopy demonstrated that the engrafted Olig2(+)-GFP(+)-OPCs attenuated the demyelination resulted from the irradiation. More importantly, the recovery of forelimb locomotor function was enhanced in animals receiving grafts of Olig2(+)-GFP(+)-OPCs. We concluded that OPC transplantation is a feasible therapy to repair the irradiated lesions in the central nervous system (CNS).

Expression of glial cell line-derived neurotrophic factor and its receptors in cultured retinal Müller cells under high glucose circumstance.

This study aimed to explore the effect of high glucose concentration on the expression of glial cell line-derived neurotrophic factor (GDNF) and its family ligand receptors (GFRs) GFRα1 and GFRα2 in Müller cells and the protective role of GDNF in cultured Müller cells under high glucose circumstance. Cultured Müller cells (untreated or treated with 200 ng/mL of GDNF) were exposed to high glucose conditions (20 mmol/L glucose). We found that the expression levels of GDNF and GFRα1 mRNA and protein increased gradually over time under high glucose and exogenous GDNF-treated conditions, whereas the upregulation in GFRα2 expression was observed only in the early stage of high glucose conditions. Exogenous GDNF not only decreased apoptosis in cultured Müller cells under high glucose circumstance, but also accelerated the levels and speed of synthesis of GDNF and GFRα1 proteins in Müller cells. These results suggest that Müller cells can synthesize GDNF and GFRs under high glucose conditions, and GDNF may play important role in protecting Müller cells during the early stage of diabetic retinopathy. The difference in GFRs expression indicated that GDNF and neurturin may exert different effects on Müller cells under high glucose circumstance.

MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice.

Wnt signaling is important in various neuropsychiatric diseases. However, its actions on modulating schizophrenia are largely unknown. Our previous study found that three SNPs in adenomatous polyposis coli (APC), a negative regulator of the Wnt signaling, were associated with schizophrenia, and the mRNA levels of APC in blood leucocytes of patients with schizophrenia were significantly increased. This prompted us to further investigate the effects of Wnt signaling components on the pathogenesis of schizophrenia. In our current study, mouse schizophrenia was induced by i.p. injection of MK-801 for 7days and the brain prefrontal cortex (PFC) and ventral tegmental area (VTA) were isolated to investigate the Wnt signaling pathway. Compared with control, schizophrenic mice had increased inhibitory phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) in PFC and VTA, which is disassociated with augmented beta-catenin phosphorylation. However, APC mRNA and protein in the PFC and VTA isolated from the schizophrenic group were increased and matched with increased beta-catenin phosphorylation. The total dendritic length was significantly increased in both PFC and VTA from MK-801-treated mice compared to control. By using cultured SK-N-SH and PC12 cells with and without transfection of APC siRNA, we found that the APC protein facilitates neurite growth in vitro. Our data suggested that MK-801-induced schizophrenia is associated with attenuated Wnt signaling pathway in the brain, which may be due to augmented APC protein during schizophrenia. APC facilitates neurite growth, potentially contributing to the pathology of schizophrenia.

Alterations of NMDA receptor subunits NR1, NR2A and NR2B mRNA expression and their relationship to apoptosis following transient forebrain ischemia.

Glutamate excitotoxicity mediated by NMDA receptor activation plays a key role in many aspects of ischemic brain injury, but the expression of NMDA receptor subunits NR1, NR2A and NR2B mRNA and their relationship to apoptosis is still unclear. In this study, we applied in situ hybridization and TUNEL staining to investigate the expression of NMDA receptor subunit mRNA and apoptosis in hippocampus of rats after transient forebrain ischemia. The results showed that in the CA1 region, NR1 mRNA expression was significantly increased following ischemia-reperfusion (IR), reaching peak levels at IR 24h, and then gradually decreasing until IR 7 days. NR2A and NR2B mRNA expression dropped to lowest levels at IR 6h and IR 12h, respectively, and then started to recover. The mRNA expression of both NR2A and NR2B then increased to peak levels at IR 48h, followed by a sustained decline until IR 7 days. In the CA3 region and dentate gyrus the range of variation in mRNA expression was significantly reduced gradually. At IR 24h, apoptosis-positive cells were observed mainly in the CA1 region. The number of apoptosis-positive cells continuously grew and showed a dramatic increase at IR 48h and peaked at IR 72h. Then, the number of apoptosis-positive cells started to decrease, but at IR 7 days the apoptosis-positive cells still remained. These results indicate that the alterations of NMDA receptor subunit mRNA expression may contribute to the ischemic apoptosis of hippocampus after transient forebrain ischemia.

Demethylation of specific Wnt/ß-catenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure.

Valproate (VPA) has been used for decades in the treatment of epilepsy and migraine. However, maternal administration of VPA during pregnancy increases susceptibility to autism spectrum disorders (ASDs) in the offspring. The aim of this study was to investigate the methylation modification and its effects on the activity of Wnt/ß-catenin pathway in the rat brain prenatally exposed to VPA. We exposed the rats in early pregnancy to VPA and found that the prenatal VPA exposure, in comparison with the prenatal vehicle exposure, induced demethylation in the promoter regions of wnt1 and wnt2, but not in those of Wnt inhibitory factor-1 and Dickkopf 1, in the prefrontal cortexes and hippocampi of the offspring. Consequently, both mRNA and protein expression of wnt1 and wnt2 were increased. Furthermore, the activity of Wnt/ß-catenin pathway was upregulated, as indicated by the increased levels of ß-catenin, hence the growing expression of its target genes. This work suggested an epigenetic action via which VPA, when administered in early pregnancy, induced dysregulation of signaling pathway, further facilitating susceptibility to ASDs.