Protective Effects of Notoginsenoside R1 via Regulation of the PI3K-Akt-mTOR/JNK Pathway in Neonatal Cerebral Hypoxic-Ischemic Brain Injury.

Notoginsenoside R1 (NGR1) is a predominant phytoestrogen extracted from Panax notoginseng that has recently been reported to play important roles in the treatment of cardiac dysfunction, diabetic kidney disease, and acute liver failure. Studies have suggested that NGR1 may be a viable treatment of hypoxic-ischemic brain damage (HIBD) in neonates by reducing endoplasmic reticulum stress via estrogen receptors (ERs). However, whether NGR1 has other neuroprotective mechanisms or long-term neuroprotective effects is unclear. In this study, oxygen-glucose deprivation/reoxygenation (OGD/R) in primary cortical neurons and unilateral ligation of the common carotid artery (CCL) in 7-day-old postnatal Sprague Dawley (SD) rats followed by exposure to a hypoxic environment were used to mimic an HIBD episode. We assessed the efficacy of NGR1 by measuring neuronal damage with MTT assay and assessed brain injury by TTC staining and brain water content detection 24-48 h after OGD/HIE. Simultaneously, we measured the long-term neurophysiological effects using the beam walking test (5 weeks after HI) and Morris water maze test 5-6 weeks after HI. Expression of PI3K-Akt-mTOR/JNK (24 h after HI or OGD/R) proteins was detected by Western blotting after stimulation with HI, NGR1, LY294002 (PI3K inhibitor), 740Y-P (PI3K agonist), or ICI 182780(estrogen receptors inhibitor). The results indicated that NGR1 exerted neuroprotective effects by inhibiting neuronal apoptosis and promoting cell survival via the PI3K-Akt-mTOR/JNK signaling pathways by targeting ER in neonatal hypoxic-ischemic injury.

[Protective effect of notoginsenoside R1 on neuron injury induced by OGD/R through ATF6/Akt signaling pathway].

Notoginsenoside R1(NGR1),a critical compound in traditional herb Panax notoginseng, is a kind of estrogen receptor agonist.It is reported to exhibit anti-apoptotic,anti-oxidative and anti-inflammatory properties activity, so it is widely used for treatment of various diseases.In order to investigate the potential neuroprotective effect of NGR1 in hypoxic-ischemic brain damage(HIBD), primary cortical neurons were used in this study to establish oxygen-glucose deprivation/reoxygenation(OGD/R) injury models. They were treated with NGR1 and estrogen receptor inhibitor ICI-182780 respectively, then the neuronal survival, cell membrane integrity and apoptosis were assessed by MTT assay,lactate dehydrogenase test(LDH) and Hoechst 33342 stain respectively, while the protein expression levels of ATF6α,p-Akt,Akt,Bax and Cleaved Caspase-3 were measured by Western blotting. Results indicated that as compared with the blank control group,OGD/R could induce cell injury and apoptosis(P<0.05), reduce relative integrity of cell membrane(P<0.05), decrease protein expression of ATF6α,p-Akt(P<0.05), and increase protein expression of Bax and Cleaved Caspase-3(P<0.05) in the primary cortical cells. After NGR1 treatment, the expression levels of ATF6α,p-Akt were obviously increased, and the expression levels of Bax and Cleaved Caspase-3 and the apoptosis of neuron were decreased(P<0.05). However, these neuroprotective properties of NGR1 against ODG/R-induced cell damage could be blocked by ICI-182780. This finding indicated that NGR1 may protect the primary cortical neurons against OGD/R induced injury,and the mechanism may be associated with accelerating the activation of the ATF6/Akt signaling pathway via estrogen receptors.

Notoginsenoside R1 Protects against Neonatal Cerebral Hypoxic-Ischemic Injury through Estrogen Receptor-Dependent Activation of Endoplasmic Reticulum Stress Pathways.

Notoginsenoside R1 (NGR1) is a phytoestrogen that is isolated from Panax notoginseng It is used in China to treat many diseases, including hypoxic-ischemic encephalopathy (HIE), and it has been shown to target estrogen receptors. Endoplasmic reticulum (ER) stress plays an important role in the development of cell apoptosis during ischemia, and ER stress is known to be regulated by estrogen; however, the neuroprotective mechanisms of NGR1 in neonatal HIE is unclear. In this study, oxygen-glucose deprivation/reoxygenation (OGD/R) in primary cortical neurons and unilateral ligation of the common carotid artery (CCL), followed by exposure to a hypoxic environment in 7-day-old postnatal Sprague-Dawley rats were used to mimic HIE episodes. Potential neuroprotective effects of NGR1 against neonatal HIE and its mechanisms were examined. After HIE conditions in vitro and in vivo, we administered NGR1 or the estrogen receptor inhibitor ICI-182780 and measured cell apoptosis, brain injury by MTT assay, TTC stain, and so forth. Expression of estrogen receptors α (ERα) and ß (ERß), ER stress-associated proteins was detected by Western blot upon stimulation with HIE, NGR1, or ICI-182780. Results showed that after HIE, ER chaperone GRP78 was activated, ER stress-associated proapoptotic proteins (CHOP, PERK, ERO1-α, and IRE1α) were increased, caspase-12 was increased, and BCL-2 was decreased. The ER stress response and neuronal apoptosis were attenuated by NGR1 treatment. However, neuroprotective properties of NGR1 against HIE-induced apoptosis and ER stress were attenuated by ICI-182780. These results suggest that NGR1 may be an effective treatment of HIE by reducing ER stress-induced neuronal apoptosis and brain injury via estrogen receptors.

Stromal cell-derived factor-1 enhances wound healing through recruiting bone marrow-derived mesenchymal stem cells to the wound area and promoting neovascularization.

Stromal cell-derived factor-1 (SDF-1) is a potent chemokine for bone marrow-derived stromal stem cells (BMSCs) that express CXCR4, the receptor for SDF-1. SDF-1 is considered to play an important role in the trafficking of BMSCs. We investigated the contribution of SDF-1 to the recruitment of BMSCs to the wound area and its promotion of wound repair and neovascularization. BMSCs were pretreated with or without anti-CXCR4 blocking antibody and combined with CM-DiI label, and injected via the tail vein into mice with full-thickness skin wounds on the dorsum. Simultaneously, anti-SDF-1 antibody was injected into local wounds in another group of mice. The results show that blockade of CXCR4 on either infused BMSCs or SDF-1 in the host wounds (1) dramatically impaired the number of infused BMSCs being recruited to the injured tissue, (2) reduced the expression of growth factors involved in the repair of injured tissue such as vascular endothelial growth factor, basic fibroblast growth factor and transforming growth factor beta 1, (3) decreased the resultant neovascularization, and (4) retarded wound healing. Taken together, the findings indicate that the SDF-1/CXCR4 signal pathway facilitates wound healing through augmenting BMSC recruitment to wound tissues, responsive secretion of growth factors by BMSCs and neovascularization in the wound area.

[Study on molecular target promoting human neural stem cells of ginsenoside Rg1 by gene chip].

OBJECTIVE: To screen out main molecular target promoting human neural stem cells (NSCs) of ginsenoside Rg1 by using the gene chip technology. METHOD: First, MTT assay was adopted to screen out the optimal concentration of Rg1-promoted NSC proliferation (120 mg x L(-1)). Then, on the 7th day after the Rg1-promoted NSC proliferation, the expression of target genes was observed by the gene chip technology. The most important target gene and signal transduction pathways were screened out through the data calculations. RESULT: On the 7th day after the Rg1-promoted NSC proliferation, obtained 440 differential genes, 266 significantly upregulated genes and 174 significantly down-regulated genes. HES1 gene, CAMP (cyclic adenosine monophosphate)-PKA (protein kinase A) and PI3K (phosphatidylinositol 3 kinase)-AKT signal transduction pathways were closely related to the NSC proliferation. CONCLUSION: The differentially expressed genes screened out by gene chip may provide new clues for studies on molecular mechanism of ginsenoside Rg1-promoted NSCs proliferation.

Public acceptance of residential photovoltaic installation: A case study in China.

Residential photovoltaics (PV) presents an effective means of achieving low-carbon development, owing to its installation flexibility and resource-saving properties. To explore the residents' behavioral intentions to purchase and install residential PV systems, this study collected 1424 samples and analyze the impact of different policies on residents' adoption of residential PV using the theory of TPB and the Partial Least Squares Structural Equation Model (PLS-SEM). The main conclusions are summarized as follows: (1) Bungalow residents exhibit a stronger inclination to install residential PV than building residents. (2) Perceived reward (PR) affects installation intention (II) more than perceived guide (PG) among bungalow residents. (3) Both PR and PG indirectly affect II through Perceived behavioral control (PBC) among bungalow residents. Economic policies, represented by PR, are likely to have more substantial indirect effects than propaganda and guidance policies. The findings suggest that China's recent residential PV installation policies should increase users' trust and guide the future decline of subsidy policy.

Vitamin D receptor-deficient keratinocytes-derived exosomal miR-4505 promotes the macrophage polarization towards the M1 phenotype.

Background: The vitamin D receptor (VDR) has a low level of expression in the keratinocytes of patients with psoriasis and plays a role in the development of the disease. Furthermore, the crosstalk between macrophages and psoriatic keratinocytes-derived exosomes is critical for psoriasis progression. However, the effects of VDR-deficient keratinocytes-derived exosomes (Exos-shVDR) on macrophages and their underlying mechanisms remain largely unknown. Methods: VDR-deficient keratinocytes were constructed by infecting HaCaT cells with a VDR-targeting lentivirus, mimicking the VDR-deficient state observed in psoriatic keratinocytes. Exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blot. The effect of Exos-shVDR on macrophage proliferation, apoptosis, and M1/M2 polarization was assessed using cell counting kit-8 assay (CCK-8), flow cytometer, real-time quantitative polymerasechain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The mechanism underlying the effect of Exos-shVDR on macrophage function was elucidated through data mining, bioinformatics, RT-qPCR, and rescue experiments. Results: Our results revealed that both Exos-shVDR and Exos-shNC exhibited typical exosome characteristics, including a hemispheroid shape with a concave side and particle size ranging from 50 to 100 nm. The levels of expression of VDR were significantly lower in Exos-shVDR than in Exos-shNC. Functional experiments demonstrated that Exos-shVDR significantly promoted macrophage proliferation and polarization towards the M1 phenotype while inhibiting macrophage apoptosis. Moreover, miR-4505 was highly expressed in the skin tissue of patients with psoriasis. Its overexpression significantly increased macrophage proliferation and polarization towards M1 and inhibited apoptosis. Furthermore, the effects of Exos-shVDR on macrophage function occur through miR-4505. Conclusions: Exos-shVDR exacerbates macrophage proliferation, promotes polarization towards the M1 phenotype, and inhibits macrophage apoptosis by increasing the levels of miR-4505. These results indicate that modulation of macrophage function is a potential strategy for developing new drugs for the treatment of psoriasis.

Does the Pro-Environmental Behavior of Household PV Installation Contribute to the Shaping of Users' Green Purchasing Behavior?-Evidence from China.

In order to achieve the "dual carbon goal", the Chinese government is actively encouraging the adoption of household photovoltaic (PV) systems. While there has been considerable research on residents' inclination to install PV, limited attention has been given to understanding how the installation and utilization of PV systems influence pro-environmental behaviors. Therefore, this paper aims to investigate the potential impact of pro-environmental behavior resulting from household PV installation on users' green purchasing behavior. Based on the "learning by doing" theory, a survey was conducted with 1249 participants, and the generalized structural equation model was employed as our analytical approach. The findings of this research indicate that the adoption and utilization of household photovoltaic (PV) systems have a positive impact on green consumption. The test results demonstrate that the overall effect coefficient is 0.03, indicating that current PV promotion policies have an indirect impact on green consumption. Moreover, economic incentive policies have a more substantial influence than environmental publicity policies, with total indirect effect coefficients of 0.005 and 0.002, respectively. Based on the findings above, the following recommendations are proposed: (1) It is recommended to maintain stable economic incentives to promote the adoption of household PV systems. (2) Emphasizing the dissemination of knowledge and skills for promoting environmental protection should be prioritized. (3) Efforts should be made to align personal interests and societal interests with low-carbon policies.

Effects of chronic sleep restriction on the neuro-phenotypes of Ctnnd2 knockout mice.

INTRODUCTION: Sleep abnormalities are highly correlated with neurodevelopmental disorders, such as intellectual disability, attention deficit hyperactivity disorder, and autism spectrum disorders (ASD). The severity of behavioral abnormalities is correlated with the presence of sleep abnormalities. Based on previous research, we investigated that Ctnnd2 gene deletion in mice lead to ASD-like behaviors and cognitive defects. Given the importance of sleep in individuals with ASD, this study aimed to determine the effects of chronic sleep restriction (SR) on wild-type (WT) mice and on Ctnnd2 deletion-induced, neurologically related phenotypes in mice. METHOD: WT and Ctnnd2 knockout (KO) mice were both subjected to manual SR (5 h per day) for 21 consecutively days separately, then we compared neurologically related phenotypes of WT mice, WT mice subjected to SR, KO mice, and KO mice subjected to SR using a three-chamber assay, direct social interaction test, open-field test, Morris water maze, Golgi staining, and Western blotting. RESULTS: The effects of SR on WT and KO mice were different. After SR, social ability and cognition were impaired in both WT and KO mice. Repetitive behaviors were increased, and exploration abilities were decreased in KO mice but not in WT mice. Moreover, SR reduced the density and area of mushroom-type dendritic spines in WT rather than KO mice. Finally, the PI3K/Akt-mTOR pathway was found to be involved in the effects induced by SR-impaired phenotypes in WT and KO mice. CONCLUSION: Overall, results of the present study may have implications for the role of disrupted sleep in patients with CTNND2 gene-related autism and the evolution of neurodevelopmental disorders.

Melatonin ameliorates sleep-wake disturbances and autism-like behaviors in the Ctnnd2 knock out mouse model of autism spectrum disorders.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by atypical patterns of social interaction and communication, as well as restrictive and repetitive behaviors. In addition, patients with ASD often presents with sleep disturbances. Delta (δ) catenin protein 2 (CTNND2) encodes δ-catenin protein, a neuron-specific catenin implicated in many complex neuropsychiatric diseases. Our previous study demonstrated that the deletion of Ctnnd2 in mice led to autism-like behaviors. However, to our knowledge, no study has investigated the effects of Ctnnd2 deletion on sleep in mice. In this study, we investigated whether the knockout (KO) of exon 2 of the Ctnnd2 gene could induce sleep-wake disorders in mice and identified the effects of oral melatonin (MT) supplementation on Ctnnd2 KO mice. Our results demonstrated that the Ctnnd2 KO mice exhibited ASD-like behaviors and sleep-wake disorders that were partially attenuated by MT supplementation. Overall, our current study is the first to identify that knockdown of Ctnnd2 gene could induce sleep-wake disorders in mice and suggests that treatment of sleep-wake disturbances by MT may benefit to autism-like behaviors causing by Ctnnd2 gene deletion.

[Effect of ginsenoside Rg1 on functional expression of human neural stem cells: a patch clamp study].

OBJECTIVE: To observe the effects of ginsenoside Rg1 on the functional expression of human neural stem cells (hNSCs). METHOD: The membrane electrophysiological properties and sodium and potassium ion channels in the hNSCs induced by Rg1 were analyzed using the whole-cell patch-clamp. RESULT: On the 7th day, the neuron-like cells derived from ginsenoside Rg1 (20 mg x L(-1))-induced NSCs show: (1) The resting membrane potential: (-45.70 +/- 2.63) mV, the membrane capacitance: (26.89 +/- 1.91) pF, the membrane input impedance: (877.51 +/- 20.44) MH (P < 0.05 compared with the control group, respectively); (2) The detection rate of inward sodium current which is rapidly activated and inactivated in voltage-dependence was 50%, and its average peak value was (711.48 +/- 158.03) pA (P < 0.05 compared with the control group); (3) The outward potassium currents were composed of rapidly activated and inactivated transient outward potassium current and delayed rectifier outward potassium current, and its average peak value was (1 070.42 +/- 177.18) pA (P < 0.05 compared with the control group). CONCLUSION: Ginsenoside Rg1 can promote the functional expression and maturity of hNSCs.

[Study on mechanism of ginsenoside Rg1-induced human neural stem cells differentiation by genechip].

OBJECTIVE: The molecular targets of ginsenoside Rg1-induced neural stem cells (NSCs) differentiation were screened by genechip. METHOD: 7th day following ginsenoside Rg1 induced human neural stem cells to neurons the gene expression was observed by genechip. The purpose gene and signal transduction pathways were selected by the data calculations, and then confirmed by western blot and immunohistochemical method. RESULT: 7th day following Rg1-induced NSCs differentiation, there were about 675 different genes, 255 genes of which were up-regulated and 420 genes down-regulated obviously. Meanwhile the ERK1/2 (extracellular signal-regulated protein kinase) in MAPK (mitogen-activated protein kinase) pathway was related with the NSCs differentiation. The Western blot and immunohistochemistry detection confirmed that ERK 1/2 protein and its phosphorylation were significantly increased, which can be blocked by PD98059 (ERK1/2 inhibitor). In addition, differentiation rate of NSCs was also decreased obviously in ginsenoside Rg1-induced differentiated NSCs when ERK blocker PD98059 was used. CONCLUSION: ERK1/2 is an important molecular target in ginsenoside Rg1-induced NSC differentiation. The selected differentially expressed genes by genechip may provide new clues to study of ginsenoside Rg1-induced NSCs differentiation.

Overexpression of miR-149-5p Attenuates Cerebral Ischemia/Reperfusion (I/R) Injury by Targeting Notch2.

Ischemic stroke is one of the leading causes of death and disability worldwide. Although miR-149-5p downregulation is observed in rats after ischemia/reperfusion (I/R) injury, its function and role in ischemic stroke remain unclear. This study aimed to investigate the roles of miR-149-5p in I/R injury. The results showed that miR-149-5p was significantly downregulated in brain tissues of rats subjected to middle cerebral artery occlusion (MCAO) and primary cortical neurons subject to oxygen and glucose deprivation (OGD). MiR-149-5p overexpression effectively reduced MCAO/R-induced infarct volume, neurological score, and brain water content as well as OGD/R-induced cortical neurons apoptosis and OGD/R-induced expression of TNF-α, IL-4, IL-6, IL-1ß, and COX-2. Moreover, Notch2 was identified as a target of miR-149-5p and Notch2 overexpression significantly attenuated the inhibitory effects of miR-149-5p mimics on inflammation and apoptosis. Taken together, our study revealed that miR-149-5p overexpression protects the rat brain against I/R injury by regulating Notch2-mediated inflammation and apoptosis pathway.

Progranulin improves neural development via the PI3K/Akt/GSK-3ß pathway in the cerebellum of a VPA-induced rat model of ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disease featuring social interaction deficits and repetitive/stereotyped behaviours; the prevalence of this disorder has continuously increased. Progranulin (PGRN) is a neurotrophic factor that promotes neuronal survival and differentiation. However, there have not been sufficient studies investigating its effect in animal models of autism. This study investigated the effects of PGRN on autistic phenotypes in rats treated with valproic acid (VPA) and assessed the underlying molecular mechanisms. PGRN was significantly downregulated in the cerebellum at postnatal day 14 (PND14) and PND35 in VPA-exposed rats, which simultaneously showed defective social preference, increased repetitive behaviours, and uncoordinated movements. When human recombinant PGRN (r-PGRN) was injected into the cerebellum of newborn ASD model rats (PND10 and PND17), some of the behavioural defects were alleviated. r-PGRN supplementation also reduced cerebellar neuronal apoptosis and rescued synapse formation in ASD rats. Mechanistically, we confirmed that PGRN protects neurodevelopment via the PI3K/Akt/GSK-3ß pathway in the cerebellum of a rat ASD model. Moreover, we found that prosaposin (PSAP) promoted the internalisation and neurotrophic activity of PGRN. These results experimentally demonstrate the therapeutic effects of PGRN on a rat model of ASD for the first time and provide a novel therapeutic strategy for autism.

Treatment with Z-ligustilide, a component of Angelica sinensis, reduces brain injury after a subarachnoid hemorrhage in rats.

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype accounting for approximately 3 to 7% of cases each year. Despite its rarity among the various stroke types, SAH is still responsible for approximately 25% of all stroke fatalities. Although various preventative and therapeutic interventions have been explored for potential neuroprotection after SAH, a considerable percentage of patients still experience serious neurologic and/or cognitive impairments as a result of the primary hemorrhage and/or secondary brain damage that occurs. Z-ligustilide (LIG), the primary lipophilic component of the Chinese traditional medicine radix Angelica sinensis, has been shown to reduce ischemic brain injury via antiapoptotic pathways. Accordingly, in our study, we investigated the neuroprotective potential of LIG after experimental SAH in rats. Rats with SAH that was induced using the established double hemorrhage model were studied with and without LIG treatment. Mortality, neurobehavioral evaluation, brain water content, blood-brain barrier (BBB) permeability, and vasospasm assessment of the basilar artery were measured on days 3 and 7 after injury. Additional testing was done to evaluate for apoptosis using TdT-mediated dUTP-biotin nick end labeling staining as well as immunohistochemistry and Western blotting to identify key proapoptotic/survival proteins, i.e., p53, Bax, Bcl-2, and cleaved caspase-3. The results showed that LIG treatment reduced mortality, neurobehavioral deficits, brain edema, BBB permeability, and cerebral vasospasm. In addition, treatment reduced the number of apoptotic cells in the surrounding brain injury site, which accompanied a marked down-regulation of proapoptotic proteins, p53, and cleaved caspase-3. Our data suggest that LIG may be an effective therapeutic modality for SAH victims by altering apoptotic mechanisms.

Treatment with ginsenoside rb1, a component of panax ginseng, provides neuroprotection in rats subjected to subarachnoid hemorrhage-induced brain injury.

OBJECTIVE: recent trials have shown Ginsenoside Rb1 (GRb1), an active component of a well known Chinese medicine Panax Ginseng, plays a significant role in improving the complications seen after an ischemic brain event. In the present study, we investigated the use of GRb1 as a treatment modality to reduce brain edema, reduce arterial vasospasm, and improve neurobehavioral function after subarachnoid hemorrhage-induced brain injury (SAH) in rats. METHOD: male Sprague-Dawley rats weighing between 250 and 300 g were randomly assigned to three groups: (1) Sham group (n = 10), (2) Vehicle group (SAH + no treatment; n = 12); (3) Treatment group (SAH + GRb1 treatment at 20 mg/kg; n = 11). Subarachnoid hemorrhage was induced using the modified double hemorrhage model followed by treatment administration intravenously. Post-operative assessment included neurobehavioral testing using the spontaneous activity scoring system, brain water content, and histological examination of the basilar artery. RESULTS: post-operative findings indicated treatment with GRb1 had significantly reduced brain edema and improved neurobehavioral functioning. In addition, histological examination revealed a significant reduction in basilar artery vasospasm and lumen thickness with treatment. CONCLUSION: the results of the study suggest that GRb1 treatment reduces brain edema, improves neurobehavioral function, and blocks vasculature thickening and spasm after SAH in rats. Given the novelty of the study, further research will be needed to confirm the benefits of treatment and mechanisms behind neuroprotection.

Abnormal spatiotemporal expression pattern of progranulin and neurodevelopment impairment in VPA-induced ASD rat model.

Some environmental risk factors have been proven to contribute to the etiology of autism spectrum disorder (ASD). Exposure to the antiepileptic drug valproic acid (VPA) during pregnancy significantly increases the risk of ASD in humans, and consequently is utilized as a validated animal model of ASD in rodents; however, the precise molecular and cellular mechanisms remain ill-defined. In the present study, we investigated the effect of prenatal VPA exposure on the spatiotemporal dynamics of Progranulin (PGRN) expression, neuronal apoptosis, synapse density, and AKT/GSK-3ß pathway activation in the brains of VPA-exposed offspring. Results from behavioral tests were consistent with prior studies showing impaired sociability, restricted interests and increased repetitive behaviors in VPA rats at postnatal days 28-32. Our data also indicated that VPA exposure resulted in abnormal dynamics of PGRN expression in different brain regions at the different development stages. The temporal and spatial patterns of PGRN expression were consistent with the spatiotemporal regularity of abnormalities, which observed in apoptosis-related protein levels, neuron numbers, dendritic spine density, synapse-related protein levels, and AKT/GSK-3ß phosphorylation in VPA rats. It suggests that prenatal VPA exposure may affect the spatiotemporal regularity of neuronal apoptosis and synaptic development/regression via interfering with the spatiotemporal process of PGRN expression and downstream AKT/GSK-3ß pathway activation. This may be a potential mechanism of the abnormal neuroanatomical changes and ASD-like behaviors in VPA-induced ASD.

Rictor is involved in Ctnnd2 deletion-induced impairment of spatial learning and memory but not autism-like behaviors.

Background: The CTNND2 gene which encodes a δ-catenin protein (CTNND2) is associated with multiple severe neurological disorders. However, the specific role of CTNND2 in spatial cognition and related mechanisms remains obscure. Methods: In this study, we generated a new line of Ctnnd2-Knock out (KO) mice with its exon2 deleted, and then characterized their behavioral phenotypes and explore the Biological mechanism. Results: Ctnnd2-KO mice were with typical autism-like behaviors as evidenced by reduced social interaction in three-chamber sociability test, more frequent stereotypic behaviors (self-grooming), and deficits in spatial learning and memory tested by the Morris water maze. Furthermore, the expression of Rictor protein, a core component of the mTORC2 complex, was significantly decreased in the hippocampus of mutant mice. ShRNA-induced knockdown of Rictor protein in the hippocampus of both Ctnnd2-KO mice and wild-type mice exacerbated spatial learning and memory deficits but did not affect their autism-like behaviors. Mechanistically, the hippocampal CA1 neurons of Ctnnd2-KO mice showed decreased actin polymerization, postsynaptic spine density. Down-regulation of Rictor resulted in altered expression of post-synaptic proteins such as GluR1 and ELKS, but not presynaptic protein Synapsin1, implying abnormal synaptic changes in KO mice. Conclusion: The CTNND2 gene is involved in spatial learning and memory via Rictor-mediated actin polymerization and synaptic plasticity. Our study provides a novel insight into the role and mechanisms of the Ctnnd2 gene in cognition at the molecular and synaptic levels.

Regulation of progranulin expression and location by sortilin in oxygen-glucose deprivation/reoxygenation injury.

Progranulin is a secreted glycoprotein expressed in neurons and microglial cells that is involved in maintaining physiological functions. Many studies have found that progranulin may play a protective role against ischemic brain injury, but little is known about how the expression level and cellular localization status of progranulin is regulated after hypoxia-ischemia. Research has confirmed that sortilin, encoded by SORT1, can bind with progranulin and deliver a mature secretory isoform of progranulin to lysosomes, and progranulin is then cleaved. In the present study, we aimed to figure out whether sortilin could affect the expression and cellular localization of progranulin and regulate cell apoptosis during hypoxia-ischemia. In this study, oxygen-glucose deprivation/reoxygenation (OGD/R) in primary cortical neurons was used to mimic hypoxic-ischemic episodes. After OGD/R, the neuroprotective effects of progranulin against hypoxia-ischemia were examined, and primary cortical neurons were transduced with a SORT1 knockdown lentivirus to inhibit the expression of sortilin. The results showed that sortilin inhibition increased PGRN expression and alleviated cell injury induced by hypoxia-ischemia. Additionally, sortilin inhibition was associated with less PGRN localization in lysosomes. All of these findings suggest that sortilin can regulate the expression of PGRN, most likely by transporting it to lysosomes and affecting the cell injury in hypoxia-ischemia.

[Improvement of a mouse model of valproic acid-induced autism].

OBJECTIVE: To establish an improved mouse model of valproic acid (VPA)-induced autism that better mimics human autism. METHODS: We established mouse models of autism in female C57 mice by intraperitoneal injection of sodium valproate either at a single dose (600 mg/kg) on day 12.5 after conception (conventional group) or in two doses of 300 mg/kg each on days 10 and 12 after conception (modified group), and the control mice were injected with saline only on day 12.5. The responses of the mice to VPA injection, the uterus, mortality rate, and abortion rate were compared among the 3 groups. The morphology and development of the offspring mice were assessed, and their behavioral ontogeny was evaluated using 3- chambered social test, social test, juvenil play test, and open field test. RESULTS: The mortality and abortion rates were significantly lower in the modified model group than in the conventional group (P < 0.01). Compared with those in the control group, the offspring mice in both the conventional group and the modified group showed developmental disorders (P < 0.05). The mortality rate of the newborn mice was significantly lower in the modified group than in the conventional group with a rate of curvy tail of up to 100% (P < 0.001). The offspring mice in both the modified group and conventional group exhibited autism-like behavioral abnormalities, including social disorder and repetitive stereotyped behavior (P < 0.05). CONCLUSIONS: The mouse model of autism established using the modified method better mimics human autism with reduced mortality and abortion rates of the pregnant mice and also decreased mortality rate of the newborn mice.