Hua Zou

Nanfang Hospital, Shengcheng, Guangdong, China

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Publications (6)15.88 Total impact

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    ABSTRACT: Autism spectrum disorder (ASD) is a heterogeneous grouping of neurodevelopmental disorders characterized by impairment in social interaction, verbal communication and repetitive/stereotypic behaviors. Much evidence suggests that ASD is multifactorial with a strong genetic basis, but the underlying mechanisms are far from clear. Recent advances in genetic technologies are beginning to shed light on possible etiologies of ASD. This review discusses current evidence for several widely studied candidate ASD genes, as well as various rare genes that supports their relationship to the etiology of ASD. The majority of the data are based on molecular, cytogenetic, linkage and association studies of autistic subjects, but newer methods, including whole-exome sequencing, are also beginning to make significant contributions to our understanding of autism.
    Brain research bulletin 06/2012; 88(6):543-52. · 2.97 Impact Factor
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    ABSTRACT: Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. A number of studies have shown that the Ras/Raf/ERK1/2 (extracellular signal-regulated kinase) signaling pathway plays important roles in the genesis of neural progenitors, learning and memory. Ras/Raf/ERK1/2 and ERK5 have also been shown to have death-promoting apoptotic roles in neural cells. Recent studies have shown a possible association between neural cell death and autism. In addition, two recent studies reported that a deletion of a locus on chromosome 16, which included the mitogen-activated protein kinase 3 (MAPK3) gene that encodes ERK1, is associated with autism. Most recently, our laboratory detected that Ras/Raf/ERK1/2 signaling activities were significantly enhanced in the brain of BTBR mice that model autism, as they exhibit many autism-like behaviors. We thus hypothesized that Ras/Raf/ERK1/2 signaling and ERK5 could be abnormally regulated in the brain of autistic subjects. In this study, we show that the expression of Ras protein was significantly elevated in the frontal cortex of autistic subjects. C-Raf phosphorylation was increased in the frontal cortex, while both C-Raf and A-Raf activities were enhanced in the cerebellum of autistic subjects. We also detected that both the protein expression and activities of ERK1/2 were significantly upregulated in the frontal cortex of autistic subjects, but not in the cerebellum. Furthermore, we showed that ERK5 protein expression is upregulated in both frontal cortex and cerebellum of autistic subjects. These results suggest that the upregulation of Ras/Raf/ERK1/2 signaling and ERK5 activities mainly found in the frontal cortex of autistic subjects may be critically involved in the pathogenesis of autism.
    Genes Brain and Behavior 08/2011; 10(8):834-43. · 3.60 Impact Factor
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    ABSTRACT: Preeclampsia is a prevalent and potentially devastating complication of pregnancy. Intercellular adhesion molecule-1 (ICAM-1) was reported to be involved in the pathogenesis of the disease. Therefore we hypothesized anti-ICAM-1 monoclonal antibody (mAb) could be a therapeutic choice for preeclampsia. The objective of this study was to evaluate its therapeutic effects using a rat model of preeclampsia. Timed pregnant Wistar rats were intravenously injected endotoxin and then randomized to receive either anti-ICAM-1 mAb or saline. The effects of antibody on blood pressure, urinary protein, levels of alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, uric acid, weight of placenta were measured. Pregnancy outcomes were evaluated. Anti-ICAM-1 mAb significantly decreased the levels of blood pressure, urinary protein, maternal BUN, creatnine and uric acid comparing with untreated preeclamptic rats. And the antibody therapy significantly improved pregnancy outcomes. After five days of mAb treatment, most of the parameters in mAb-treated group approached normal levels. Our data prove anti-ICAM-1 mAb therapy as a promising choice for preeclampsia.
    The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 08/2011; 25(6):855-9. · 1.36 Impact Factor
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    ABSTRACT: Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. BTBR mouse is currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Growing evidence suggests that Ras/Raf/ERK1/2 signaling plays death-promoting apoptotic roles in neural cells. Recent studies showed a possible association between neural cell death and autism. In addition, two studies reported that a deletion of a locus on chromosome 16, which includes the MAPK3 gene that encodes ERK1, is associated with autism. We thus hypothesized that Ras/Raf/ERK1/2 signaling could be abnormally regulated in the brain of BTBR mice that models autism. In this study, we show that expression of Ras protein was significantly elevated in frontal cortex and cerebellum of BTBR mice as compared with B6 mice. The phosphorylations of A-Raf, B-Raf and C-Raf were all significantly increased in frontal cortex of BTBR mice. However, only C-Raf phosphorylation was increased in the cerebellum of BTBR mice. In addition, we further detected that the activities of both MEK1/2 and ERK1/2, which are the downstream kinases of Ras/Raf signaling, were significantly enhanced in the frontal cortex. We also detected that ERK1/2 is significantly over-expressed in frontal cortex of autistic subjects. Our results indicate that Ras/Raf/ERK1/2 signaling is upregulated in the frontal cortex of BTBR mice that model autism. These findings, together with the enhanced ERK1/2 expression in autistic frontal cortex, imply that Ras/Raf/ERK1/2 signaling activities could be increased in autistic brain and involved in the pathogenesis of autism.
    Genes Brain and Behavior 05/2011; 10(5):615-24. · 3.60 Impact Factor
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    ABSTRACT: Background: Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. BTBR mice are a model for understanding mechanisms that may be responsible for the pathogenesis of autism, since they exhibit many autism-like behaviors. A number of studies have shown that the Ras/Raf/ERK1/2 signaling pathway plays important roles in the genesis of neural progenitors, learning, and memory. Ras/Raf/ERK1/2 and ERK5 have also been shown to have death-promoting apoptotic roles in neural cells. Recent studies have demonstrated a possible association between neural cell death and autism. In addition, two recent studies reported that a deletion of a locus on chromosome 16, which included the MAPK3 gene that encodes ERK1, is associated with autism. We thus hypothesized that Ras/Raf/ERK1/2 signaling and ERK5 could be abnormally regulated in the brain of autistic subjects and the abnormality could be modeled in BTBR mice. Objectives: The aim of this study is to determine how Ras/Raf/ERK1/2 signaling pathway is regulated in the brain of both autistic subjects and BTBR mice. Methods: Frozen human brain tissues of six autistic subjects (mean age 8.3 ± 3.8 years) and six age-matched normal subjects (mean age 8 ± 3.7 years) were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders. Donors with autism fit the diagnostic criteria of the Diagnostic and Statistical Manual-IV, as confirmed by the Autism Diagnostic Interview-Revised. Six female BTBR T+tfJ (BTBR) and six B6 were obtained from Jackson Laboratories (Bar Harbor, ME). All procedures were conducted in compliance with the NIH Guidelines for the Care and Use of Laboratory Animals. In this study, Western Blot Analyses were used to detect the protein expression and activity levels of Ras, A-Raf, B-Raf, C-Raf, MEK1/2 and ERK1/2. Immunohistochemistry studies were carried out to determine the protein expression and phosphorylation of MEK1/2. Enzyme-linked Immunosorbent Assay (Elisa) was carried out to determine the activity level of ERK1/2. Results: We show that expression of Ras protein was significantly elevated in the frontal cortex of autistic subjects and BTBR mice. C-Raf phosphorylation, as well as both B-Raf and C-Raf phosphorylation were increased correspondently in autistic subjects and BTBR mice. ERK1/2 and ERK5 protein expression were significantly up-regulated in autistic frontal cortex, and the kinase activities of MEK1/2 and ERK1/2 were found to be increased in the frontal cortex of BTBR mice. These results suggest that Ras/Raf/ERK1/2 signaling activities are up-regulated in the frontal cortex of autistic subjects and BTBR mice as compared with their controls. Furthermore, we also examined the Ras/Raf/ERK1/2 pathway in the cerebellum of autistic subjects and BTBR mice. We did not detect significant changes in the protein expression and activities of MEK1/2 and ERK1/2 in autistic cerebellum, as well as in the cerebellum of BTBR mice, which indicates that this pathways is not abnormally regulated in the cerebellum of autistic subjects and BTBR mice. Conclusions: Our findings suggest that up-regulated Ras/Raf/ERK1/2 signaling and ERK5 activities in the frontal cortex could be one of the cellular mechanisms responsible for the autism phenotype.
    International Meeting for Autism Research 2011; 05/2011
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    ABSTRACT: Although the cellular mechanisms responsible for the pathogenesis of autism are not understood, a growing number of studies have suggested that localized inflammation of the central nervous system (CNS) may contribute to the development of autism. Recent evidence shows that IL-6 has a crucial role in the development and plasticity of CNS. Immunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO-PRO-3 staining and immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively. In this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses. Our results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism.
    Journal of Neuroinflammation 01/2011; 8:52. · 4.35 Impact Factor