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Maternal immune activation (MIA) during pregnancy has been increasingly recognized as a critical factor in the development of neurodevelopmental disorders, with potential sex-specific impacts that are not yet fully understood. In this study, we utilized a murine model to explore the behavioral and molecular consequences of MIA induced by lipopolysaccharide (LPS) administration on embryonic day 12.5. Our findings indicate that male offspring exposed to LPS exhibited significant increases in anxiety-like and depression-like behaviors, while female offspring did not show comparable changes. Molecular analyses revealed alterations in pro-inflammatory cytokine levels and synaptic gene expression in male offspring, suggesting that these molecular disruptions may underlie the observed behavioral differences. These results emphasize the importance of considering sex as a biological variable in studies of neurodevelopmental disorders and highlight the need for further molecular investigations to understand the mechanisms driving these sex-specific outcomes. Our study contributes to the growing evidence that prenatal immune challenges play a pivotal role in the etiology of neurodevelopmental disorders and underscores the potential for sex-specific preventative approaches of MIA.
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Comportamento Animal , Modelos Animais de Doenças , Lipopolissacarídeos , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Camundongos , Masculino , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Ansiedade/imunologia , Fatores Sexuais , Depressão/imunologia , Caracteres Sexuais , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVES: One of the largest health concerns, postpartum depression (PPD), has detrimental effects on new mothers, their child, and their family. Investigating under-researched risk factors for postpartum depression in Asian women is the goal of this review of the literature. METHODS: The literature was searched using a number of electronic research databases. This review included studies that meet the following requirements: (a) they evaluated risk variables; (b) they were conducted in Asian countries using quantitative or qualitative methods; and (c) they were published in English in peer-reviewed journals between 2007 and 2023. A total of 90 studies from 14 different countries were reviewed, compiled, and synthesized. RESULTS: In Asian countries, where rates ranged from 0.82 % to 93 %, South Korea and Japan had the lowest and highest rates of postpartum depression, respectively. The risk factors for postpartum depression were divided into five main categories: biological/physical (e.g., ABO blood group, oxytocin level), psychological (e.g., antenatal depression, body dissatisfaction, child care stress), obstetric/pediatric (e.g., loss of baby, abortions, pain), socio-demographic (e.g., low social support, poverty, loss of autonomy), and cultural (e.g., gender preference). CONCLUSION: This phenomenon is prevalent in Asian cultures as it is in European Countries. The repercussions of untreated postpartum depression can lead to long-term psychological and developmental issues in children and strain the familial bonds essential for a nurturing environment. Moreover, understanding the specific risk factors faced by Asian women can pave the way for culturally sensitive interventions and support systems designed to address and mitigate these challenges effectively.
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Depressão Pós-Parto , Humanos , Depressão Pós-Parto/etnologia , Feminino , Fatores de Risco , Ásia/etnologia , Povo Asiático/estatística & dados numéricosRESUMO
Purpose: Childbirth represents a significant life event, bringing about both physical and emotional transformations in a woman's life. Among other psychological aspects associated with childbirth, labor pain, death anxiety, and postpartum depression have garnered significant attention in the field of maternal and reproductive health. This study is intended to evaluate how the effectiveness of hypnobirthing training alleviates labor pain, mitigates death anxiety enhances postpartum well-being reduces labor hours, and how anxiety exacerbates the duration of labor. Methods: Data were collected from (N = 50) young and middle-aged postpartum women in the outpatient obstetrics and gynecology departments of the Civil Hospital, Waseer Gynecology Hospital and Basic Health Unit Jalal Ballagan in Gujranwala, Pakistan, by using the convenience sampling technique. Out of 50, women were divided into a control (N = 25) and an experimental group (N = 25). They were recruited during their 33 weeks of pregnancy until childbirth for hypnobirthing training. Numerical Pain Rating Scale (NPRS), Templer Death Anxiety Scale (TDAS), and Edinburgh Postnatal Depression Scale (EPDS) were used to collect participants' responses. Results: Findings proved hypnobirthing training as a catalyst in significantly reducing labor pain, death anxiety, and postpartum depression. Furthermore, the analysis indicated that death anxiety exacerbates the labor duration hours and hypnobirthing decreases the labor hours in the experimental group of women. Conclusion: It sheds light on the effectiveness of hypnobirthing training to enhance the birthing process. Findings underscore the significance of collaboration between obstetricians, psychologists, and mental health professionals to develop integrated care plans that address both physical and psychological aspects of childbirth.
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BACKGROUND: Most of the important biological mechanisms and functions of transmembrane proteins (TMPs) are realized through their interactions with non-transmembrane proteins(nonTMPs). The interactions between TMPs and nonTMPs in cells play vital roles in intracellular signaling, energy metabolism, investigating membrane-crossing mechanisms, correlations between disease and drugs. RESULTS: Despite the importance of TMP-nonTMP interactions, the study of them remains in the wet experimental stage, lacking specific and comprehensive studies in the field of bioinformatics. To fill this gap, we performed a comprehensive statistical analysis of known TMP-nonTMP interactions and constructed a deep learning-based predictor to identify potential interactions. The statistical analysis describes known TMP-nonTMP interactions from various perspectives, such as distributions of species and protein families, enrichment of GO and KEGG pathways, as well as hub proteins and subnetwork modules in the PPI network. The predictor implemented by an end-to-end deep learning model can identify potential interactions from protein primary sequence information. The experimental results over the independent validation demonstrated considerable prediction performance with an MCC of 0.541. CONCLUSIONS: To our knowledge, we were the first to focus on TMP-nonTMP interactions. We comprehensively analyzed them using bioinformatics methods and predicted them via deep learning-based solely on their sequence. This research completes a key link in the protein network, benefits the understanding of protein functions, and helps in pathogenesis studies of diseases and associated drug development.
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Biologia Computacional , Proteínas de Membrana , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Biologia Computacional/métodos , Aprendizado Profundo , Humanos , Mapas de Interação de ProteínasRESUMO
Fake news impacts individuals' behavior and decision-making while also disrupting political processes, perceptions of medical advice, and societal trends. Improving individuals' ability to accurately assess fake news can reduce its harmful effects. However, previous research on media literacy interventions designed for improving fake news credibility assessments has yielded inconsistent results. We systematically collected 33 independent studies and performed a meta-analysis to examine the effects of media literacy interventions on assessing fake news credibility (n = 36,256). The results showed that media literacy interventions significantly improved fake news credibility assessments (Hedges' g = 0.53, 95% confidence interval [0.29-0.78], p < 0.001). Gaming interventions were the most effective intervention form. Conversely, the intervention channel, outcome measurement, and subject characteristics (age, gender, and country development level) did not influence the intervention effects.
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Enganação , Meios de Comunicação de Massa , Humanos , ConfiançaRESUMO
Children with autism exhibit more pronounced symptoms of both problem behaviors and motor coordination difficulties. Yoga, recognized as an effective intervention modality, can be valuable after assessing its efficacy in addressing problem behaviors and motor coordination challenges, ultimately contributing to symptom alleviation in autism. The randomized controlled trial (RCT) was used to divide 17 children with autism into an intervention group (n = 9) and a control group (n = 8). The intervention group participated in an 8-week yoga intervention training (three sessions/week, 45-50 min/session), and the control group did not participate in yoga training but only in daily program activities. Pre-test, mid-test, post-test, and after delayed test, teachers assessed the effect of yoga intervention on problem behaviors of children with autism through the Aberrant Behavior Checklist (ABC) and the effect of yoga intervention on motor coordination through the Movement Assessment Battery for Children-Second Edition (MABC2). Results show that the yoga intervention is effective in reducing problem behaviors and improving motor coordination in children with autism. Yoga intervention significantly reduces irritability and social withdrawal in children with autism. Yoga intervention had the most significant improvement in ball skills and static and dynamic balance.
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HIV infection is known to have significant effects on central nervous system. This study conducted a meta-analysis of whole voxel-based morphometry (VBM) in HIV patients (Nâ¯=â¯435) and HIV-uninfected controls (Nâ¯=â¯397). This study observed a reduction of limbic lobe, cingulate gyrus, frontal lobe, middle frontal gyrus, sub-lobar, insula, inferior frontal gyrus and superior frontal gyrus volume in HIV patients. These morphological differences may be responsible for cognitive decline in HIV patients, as these brain regions are closely related to motor and memory functions. These results contribute to a better understanding of the neural mechanisms underlying brain injury in HIV patients and could help develop targeted brain targets, provide more personalized treatment and predict neurodevelopmental outcomes.
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Substância Cinzenta , Infecções por HIV , Humanos , Substância Cinzenta/diagnóstico por imagem , Infecções por HIV/complicações , Infecções por HIV/diagnóstico por imagem , Imageamento por Ressonância Magnética , Córtex Cerebral/diagnóstico por imagem , Encéfalo/diagnóstico por imagemRESUMO
BACKGROUND: The prevalence of misinformation poses a substantial threat to individuals' daily lives, necessitating the deployment of effective remedial approaches. One promising strategy is psychological inoculation, which pre-emptively immunizes individuals against misinformation attacks. However, uncertainties remain regarding the extent to which psychological inoculation effectively enhances the capacity to differentiate between misinformation and real information. OBJECTIVE: To reduce the potential risk of misinformation about digital health, this study aims to examine the effectiveness of psychological inoculation in countering misinformation with a focus on several factors, including misinformation credibility assessment, real information credibility assessment, credibility discernment, misinformation sharing intention, real information sharing intention, and sharing discernment. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we conducted a meta-analysis by searching 4 databases (Web of Science, APA PsycINFO, Proquest, and PubMed) for empirical studies based on inoculation theory and outcome measure-related misinformation published in the English language. Moderator analyses were used to examine the differences in intervention strategy, intervention type, theme, measurement time, team, and intervention design. RESULTS: Based on 42 independent studies with 42,530 subjects, we found that psychological inoculation effectively reduces misinformation credibility assessment (d=-0.36, 95% CI -0.50 to -0.23; P<.001) and improves real information credibility assessment (d=0.20, 95% CI 0.06-0.33; P=.005) and real information sharing intention (d=0.09, 95% CI 0.03-0.16; P=.003). However, psychological inoculation does not significantly influence misinformation sharing intention (d=-0.35, 95% CI -0.79 to 0.09; P=.12). Additionally, we find that psychological inoculation effectively enhances credibility discernment (d=0.20, 95% CI 0.13-0.28; P<.001) and sharing discernment (d=0.18, 95% CI 0.12-0.24; P<.001). Regarding health misinformation, psychological inoculation effectively decreases misinformation credibility assessment and misinformation sharing intention. The results of the moderator analyses showed that content-based, passive inoculation was more effective in increasing credibility and sharing intention. The theme of climate change demonstrates a stronger effect on real information credibility. Comparing intervention types showed that pre-post interventions are more effective for misinformation credibility assessment, while post-only interventions are better for credibility discernment. CONCLUSIONS: This study indicated that psychological inoculation enhanced individuals' ability to discern real information from misinformation and share real information. Incorporating psychological inoculation to cultivate an informed public is crucial for societal resilience against misinformation threats in an age of information proliferation. As a scalable and cost-effective intervention strategy, institutions can apply psychological inoculation to mitigate potential misinformation crises.
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Comunicação , Intenção , Humanos , Disseminação de Informação , Idioma , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Misinformation affects various aspects of people's lives, such as politics, entertainment, and social interactions. However, effective intervention measures to combat misinformation are lacking. The inoculation theory has become a prevalent measure of misinformation. This study employed inoculation theory and developed an interactive game to help the public counter misinformation. In this game, players take on the role of the misinformation spreader, intending to add more followers to their virtual accounts using different strategies. A total of 180 Chinese participants were randomly assigned to game-based inoculation, graphic-based inoculation, and control groups. The results indicated that both types of inoculation interventions significantly decreased the perceived credibility and sharing intention of misinformation. Game-based inoculation was more effective than graphic-based inoculation in terms of misinformation perceived credibility, and the intervention effects were stable after 2 weeks. The graphic-based inoculation contained the sleeper effect, which interventions required a period of time to take effect. Neither inoculation produced countereffects on perceived credibility and nor sharing intention of accurate information.
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Comunicação , Intenção , Humanos , PolíticaRESUMO
Structural magnetic resonance imaging (sMRI) studies have shown abnormalities in the brain structure of ASD patients, but the relationship between structural changes and social communication problems is still unclear. This study aims to explore the structural mechanisms of clinical dysfunction in the brain of ASD children through voxel-based morphometry (VBM). After screening T1 structural images from the Autism Brain Imaging Data Exchange (ABIDE) database, 98 children aged 8-12 years old with ASD were matched with 105 children aged 8-12 years old with typical development (TD). Firstly, this study compared the differences in gray matter volume (GMV) between the two groups. Then, this study evaluated the relationship between GMV and the subtotal score of communications and social interaction on the Autism Diagnostic Observation Schedule (ADOS) in ASD children. Research has found that abnormal brain structures in ASD include the midbrain, pontine, bilateral hippocampus, left parahippocampal gyrus, left superior temporal gyrus, left temporal pole, left middle temporal gyrus and left superior occipital gyrus. In addition, in ASD children, the subtotal score of communications and social interaction on the ADOS were only significantly positively correlated with GMV in the left hippocampus, left superior temporal gyrus and left middle temporal gyrus. In summary, the gray matter structure of ASD children is abnormal, and different clinical dysfunction in ASD children is related to structural abnormalities in specific regions.
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Background: Fetal ventriculomegaly (VM) is one of the most common abnormalities of the central nervous system (CNS), which can be significantly identified by brain anomalies prenatally by magnetic resonance imaging (MRI). Aberrant white blood cells (WBCs) levels indicate that the maternal is suffering from the infection. Previous studies have confirmed that prenatal infection can affect fetal brain structure, but there is no research revealed the association between maternal blood parameters with fetal VM until now. Methods: We measured the width of the lateral ventricle of 142 fetuses, which were divided into the fetal VM group (n = 70) and the normal lateral ventricle group (n = 72). We compared maternal blood cell levels between the two groups and investigate potential biomarkers of fetal VM. Result: High levels of maternal WBC and neutrophil (NE#) levels were observed in fetuses with VM (p < 0.001), while lymphocyte percentage, monocytes (MO#), neutrophil/lymphocyte ratio (NLR), and platelet were also increased in the fetal VM group (p = 0.033, 0.027, 0.034, and 0.025, respectively). receiver-operator curve (ROC) analysis suggested that WBC and NE# counts might be useful to distinguish fetuses with enlarged lateral ventricles (AUC = 0.688, 0.678, respectively). Conclusion: The current study emphasizes the importance of maternal infection for fetal brain growth, which could provide important information for prenatal diagnosis of CNS anomalies. Future research needs longitudinal analysis and exploration of the influence of maternal blood inflammatory marker levels on fetal brain development.
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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear etiology, and due to the lack of effective treatment, ASD patients bring enormous economic and psychological burden to families and society. In recent years, many studies have found that children with ASD are associated with gastrointestinal diseases, and the composition of intestinal microbiota (GM) is different from that of typical developing children. Thus, many researchers believe that the gut-brain axis may play an important role in the occurrence and development of ASD. Indeed, some clinical trials and animal studies have reported changes in neurological function, behavior, and comorbid symptoms of autistic children after rebalancing the composition of the GM through the use of antibiotics, prebiotics, and probiotics or microbiota transfer therapy (MMT). In view of the emergence of new therapies based on the modulation of GM, characterizing the individual gut bacterial profile evaluating the effectiveness of intervention therapies could help provide a better quality of life for subjects with ASD. This article reviews current studies on interventions to rebalance the GM in children with ASD. The results showed that Lactobacillus plantarum may be an effective strain for the probiotic treatment of ASD. However, the greater effectiveness of MMT treatment suggests that it may be more important to pay attention to the overall balance of the patient's GM. Based on these findings, a more thorough assessment of the GM is expected to contribute to personalized microbial intervention, which can be used as a supplementary treatment for ASD.
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Synaptic cytoskeleton dysfunction represents a common pathogenesis in neurodevelopmental disorders, such as autism spectrum disorder (ASD). The serine/threonine kinase PAK2 is a critical regulator of cytoskeleton dynamics. However, its function within the central nervous system and its role in ASD pathogenesis remain undefined. Here, we found that Pak2 haploinsufficiency resulted in markedly decreased synapse densities, defective long-term potentiation, and autism-related behaviors in mice. Phosphorylation levels of key actin regulators LIMK1 and cofilin, together with their mediated actin polymerization, were reduced in Pak2+/-mice. We identified one de novo PAK2 nonsense mutation that impaired PAK2 function in vitro and in vivo and four de novo copy-number deletions containing PAK2 in large cohorts of patients with ASD. PAK2 deficiency extensively perturbed functional networks associated with ASD by regulating actin cytoskeleton dynamics. Our genetic and functional results demonstrate a critical role of PAK2 in brain development and autism pathogenesis.
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Transtorno do Espectro Autista/genética , Pareamento Cromossômico/genética , Quinases Ativadas por p21/genética , Actinas/genética , Actinas/metabolismo , Animais , Transtorno do Espectro Autista/enzimologia , Citoesqueleto/enzimologia , Citoesqueleto/genética , Citoesqueleto/patologia , Células HEK293 , Haploinsuficiência , Humanos , Potenciação de Longa Duração , Masculino , Camundongos , Mutação de Sentido Incorreto , Comportamento Social , Comportamento Estereotipado , Quinases Ativadas por p21/metabolismoRESUMO
The CRISPR (clustered regularly interspaced short palindromic repeat)-Cas (CRISPR-associated protein) system, a prokaryotic RNA-based adaptive immune system against viral infection, is emerging as a powerful genome editing tool in broad research areas. To further improve and expand its functionality, various CRISPR delivery strategies have been tested and optimized, and key CRISPR system components such as Cas protein have been engineered with different purposes. Benefiting from more in-depth understanding and further development of CRISPR, versatile CRISPR-based platforms for genome editing have been rapidly developed to advance investigations in biology and biomedicine. In biological research area, CRISPR has been widely adopted in both fundamental and applied research fields, such as genomic and epigenomic modification, genome-wide screening, cell and animal research, agriculture transforming, livestock breeding, food manufacture, industrial biotechnology, and gene drives in disease agents control. In biomedical research area, CRISPR has also shown its extensive applicability in the establishment of animal models for genetic disorders, generation of tissue donors, implementation of antimicrobial and antiviral studies, identification and assessment of new drugs, and even treatment for clinical diseases. However, there are still several problems to consider, and the biggest concerns are the off-target effects and ethical issues of this technology. In this prospect article, after highlighting recent development of CRISPR systems, we outline different applications and current limitations of CRISPR in biological and biomedical investigation. Finally, we provide a perspective on future development and potential risks of this multifunctional technology. J. Cell. Biochem. 119: 52-61, 2018. © 2017 Wiley Periodicals, Inc.
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Sistemas CRISPR-Cas , Edição de Genes , Animais , Doença/genética , Variação Genética , Genômica , HumanosRESUMO
Proper neuronal migration is critical for the formation of the six-layered neocortex in the mammalian brain. However, the precise control of neuronal migration is not well understood. Heterotrimeric guanine nucleotide binding proteins (G proteins), composed of Gα and Gßγ, transduce signals from G protein-coupled receptors to downstream effectors and play crucial roles in brain development. However, the functions of individual subunits of G proteins in prenatal brain development remain unclear. Here, we report that Gß2 is expressed in the embryonic neocortex, with abundant expression in the intermediate zone, and is significantly upregulated in differentiated neurons. Perturbation of Gß2 expression impairs the morphogenetic transformation of migrating neurons from multipolar to bipolar and subsequently delays neuronal migration. Moreover, Gß2 acts as a scaffold protein to organize the MP1-MEK1-ERK1/2 complex and mediates the phosphorylation of ERK1/2. Importantly, expression of a constitutively active variant of MEK1 rescues the migration defects that are caused by the loss of Gß2. In conclusion, our findings reveal that Gß2 regulates proper neuronal migration during neocortex development by activating the ERK1/2 signaling pathway.
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Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Neocórtex/citologia , Neocórtex/embriologia , Neurônios/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Movimento Celular/genética , Polaridade Celular/fisiologia , Células Cultivadas , Feminino , Subunidades beta da Proteína de Ligação ao GTP/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nestina/metabolismo , Células-Tronco Neurais/fisiologia , Fosforilação/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismoRESUMO
The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, a simple and efficient tool for genome editing, has experienced rapid progress in its technology and applicability in the past two years. Here, we review the recent advances in CRISPR/Cas9 technology and the ways that have been adopted to expand our capacity for precise genome manipulation. First, we introduce the mechanism of CRISPR/Cas9, including its biochemical and structural implications. Second, we highlight the latest improvements in the CRISPR/Cas9 system, especially Cas9 protein modifications for customization. Third, we review its current applications, in which the versatile CRISPR/Cas9 system was employed to edit the genome, epigenome, or RNA of various organisms. Although CRISPR/Cas9 allows convenient genome editing accompanied by many benefits, we should not ignore the significant ethical and biosafety concerns that it raises. Finally, we discuss the prospective applications and challenges of several promising techniques adapted from CRISPR/Cas9.
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Proteínas Associadas a CRISPR/química , Sistemas CRISPR-Cas , Endodesoxirribonucleases/química , Edição de Genes , Proteínas Associadas a CRISPR/genética , Proteínas Associadas a CRISPR/metabolismo , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Mutação , Domínios ProteicosRESUMO
Proper brain function depends on correct neuronal migration during development, which is known to be regulated by cytoskeletal dynamics and cell-cell adhesion. Myosin X (Myo10), an uncharacteristic member of the myosin family, is an important regulator of cytoskeleton that modulates cell motilities in many different cellular contexts. We previously reported that Myo10 was required for neuronal migration in the developing cerebral cortex, but the underlying mechanism was still largely unknown. Here, we found that knockdown of Myo10 expression disturbed the adherence of migrating neurons to radial glial fibers through abolishing surface Neuronal cadherin (N-cadherin) expression, thereby impaired neuronal migration in the developmental cortex. Next, we found Myo10 interacted with N-cadherin cellular domain through its FERM domain. Furthermore, we found knockdown of Myo10 disrupted N-cadherin subcellular distribution and led to localization of N-cadherin into Golgi apparatus and endosomal sorting vesicle. Taking together, these results reveal a novel mechanism of Myo10 interacting with N-cadherin and regulating its cell-surface expression, which is required for neuronal adhesion and migration.
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During embryonic development of the mammalian cerebral cortex, postmitotic cortical neurons migrate radially from the ventricular zone to the cortical plate. Proper migration involves the correct orientation of migrating neurons and the transition from a multipolar to a mature bipolar morphology. Herein, we report that the 2 isoforms of Myosin-10 (Myo10) play distinct roles in the regulation of radial migration in the mouse cortex. We show that the full-length Myo10 (fMyo10) isoform is located in deeper layers of the cortex and is involved in establishing proper migration orientation. We also demonstrate that fMyo10-dependent orientation of radial migration is mediated at least in part by the netrin-1 receptor deleted in colorectal cancer. Moreover, we show that the headless Myo10 (hMyo10) isoform is required for the transition from multipolar to bipolar morphologies in the intermediate zone. Our study reveals divergent functions for the 2 Myo10 isoforms in controlling both the direction of migration and neuronal morphogenesis during radial cortical neuronal migration.
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Movimento Celular/genética , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Miosinas/metabolismo , Neurônios/fisiologia , Análise de Variância , Animais , Células Cultivadas , Receptor DCC , Eletroporação , Embrião de Mamíferos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Técnicas In Vitro , Antígeno Ki-67/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Miosinas/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese , Isoformas de Proteínas/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Tubulina (Proteína)/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Myosin X (Myo10) is an unconventional myosin associated with filopodia motility. Recent studies show that in addition to full-length Myo10, brain expresses a shorter form of Myo10 that lacks a myosin motor domain named headless Myo10. Herein, we analyzed and cloned 2-kb of the 5'-upstream sequences of mouse full-length Myo10 (fMyo10) and headless Myo10 (hMyo10) to understand the transcriptional regulation of the Myo10 gene. The putative transcription factor binding sites and CpG island were analyzed by a bioinformatic approach. Luciferase reporter assays showed that the 2-kb of 5'-upstream sequences of both fMyo10 and hMyo10 had promoter activities.
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Miosinas/genética , Regiões Promotoras Genéticas , Animais , Sequência de Bases , Clonagem Molecular , Ilhas de CpG , Camundongos , Ativação TranscricionalRESUMO
BACKGROUND: Dependence receptors have been proved to act as tumor suppressors in tumorigenesis. Neogenin, a DCC homologue, well known for its fundamental role in axon guidance and cellular differentiation, is also a dependence receptor functioning to control apoptosis. However, loss of neogenin has been reported in several kinds of cancers, but its role in glioma remains to be further investigated. METHODOLOGY/PRINCIPAL FINDINGS: Western blot analysis showed that neogenin level was lower in glioma tissues than in their matching surrounding non-neoplastic tissues (n = 13, p<0.01). By immunohistochemical analysis of 69 primary and 16 paired initial and recurrent glioma sections, we found that the loss of neogenin did not only correlate negatively with glioma malignancy (n = 69, p<0.01), but also glioma recurrence (n = 16, p<0.05). Kaplan-Meier plot and Cox proportional hazards modelling showed that over-expressive neogenin could prolong the tumor latency (n = 69, p<0.001, 1187.6 ± 162.6 days versus 687.4 ± 254.2 days) and restrain high-grade glioma development (n = 69, p<0.01, HR: 0.264, 95% CI: 0.102 to 0.687). By Methylation specific polymerase chain reaction (MSP), we reported that neogenin promoter was methylated in 31.0% (9/29) gliomas, but absent in 3 kinds of glioma cell lines. Interestingly, the prevalence of methylation in high-grade gliomas was higher than low-grade gliomas and non-neoplastic brain tissues (n = 33, p<0.05) and overall methylation rate increased as glioma malignancy advanced. Furthermore, when cells were over-expressed by neogenin, the apoptotic rate in SHG-44 was increased to 39.7% compared with 8.1% in the blank control (p<0.01) and 9.3% in the negative control (p<0.01). CONCLUSIONS/SIGNIFICANCE: These observations recapitulated the proposed role of neogenin as a tumor suppressor in gliomas and we suggest its down-regulation owing to promoter methylation is a selective advantage for glioma genesis, progression and recurrence. Furthermore, the induction of apoptosis in SHG-44 cells after overexpression of neogenin, indicated that neogenin could be a novel target for glioma therapy.