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1.
Cell Death Differ ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907392

RESUMO

Vps35 (vacuolar protein sorting 35) is a key component of retromer that regulates transmembrane protein trafficking. Dysfunctional Vps35 is a risk factor for neurodegenerative diseases, including Parkinson's and Alzheimer's diseases. Vps35 is highly expressed in developing pyramidal neurons, and its physiological role in developing neurons remains to be explored. Here, we provide evidence that Vps35 in embryonic neurons is necessary for axonal and dendritic terminal differentiation. Loss of Vps35 in embryonic neurons results in not only terminal differentiation deficits, but also neurodegenerative pathology, such as cortical brain atrophy and reactive glial responses. The atrophy of neocortex appears to be in association with increases in neuronal death, autophagosome proteins (LC3-II and P62), and neurodegeneration associated proteins (TDP43 and ubiquitin-conjugated proteins). Further studies reveal an increase of retromer cargo protein, sortilin1 (Sort1), in lysosomes of Vps35-KO neurons, and lysosomal dysfunction. Suppression of Sort1 diminishes Vps35-KO-induced dendritic defects. Expression of lysosomal Sort1 recapitulates Vps35-KO-induced phenotypes. Together, these results demonstrate embryonic neuronal Vps35's function in terminal axonal and dendritic differentiation, reveal an association of terminal differentiation deficit with neurodegenerative pathology, and uncover an important lysosomal contribution to both events.

2.
Biol Trace Elem Res ; 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31838737

RESUMO

Sodium para-aminosalicylic acid (PAS-Na) has been used to treat patients with manganism, a neurological disease caused by manganese (Mn) toxicity, although the exact molecular mechanisms are yet unclear. The present study aims to investigate the effect of PAS-Na on glutamate (Glu) turnover of Mn-exposed rats. The results showed that Mn concentrations in the hippocampus, thalamus, striatum, and globus pallidus were increased in Mn-exposed rats. Moreover, the results also demonstrated that subacute Mn exposure (15 mg/kg for 4 weeks) interrupted the homeostasis of Glu by increasing Glu levels but decreasing glutamine (Gln) levels in the hippocampus, thalamus, striatum, and globus pallidus in male Sprague-Dawley rats. These effects lasted even after Mn exposure had been ceased for a period of 6 weeks. Meanwhile the main Glu turnover enzymes [Gln synthetase (GS) and phosphate-activated glutaminase (PAG)] and transporters [Glu/aspartate transporter (GLAST) and Glu transporter-1 (GLT-1)] were also affected by Mn treatment. Additionally, PAS-Na treatment recovered the aforementioned changes induced by Mn. Taken together, these results indicate that Glu turnover might be involved in Mn-induced neurotoxicity. PAS-Na treatment could promote Mn excretions and recover the changes in Glu turnover induced by Mn, and a prolonged PAS-Na treatment may be more effective.

3.
PLoS Biol ; 17(10): e3000461, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600191

RESUMO

Dendritic spine development is crucial for the establishment of excitatory synaptic connectivity and functional neural circuits. Alterations in spine morphology and density have been associated with multiple neurological disorders. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. However, the role of DIP2A in the brain remains largely unknown. In this study, we found that deletion of Dip2a in mice induced defects in spine morphogenesis along with thin postsynaptic density (PSD), and reduced synaptic transmission of pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. Furthermore, Dip2a knockout (KO) mice exhibited autism-like behaviors, including excessive repetitive behaviors and defects in social novelty. Importantly, acetylation mimetic cortactin restored the impaired synaptic transmission and ameliorated repetitive behaviors in these mice. Altogether, our findings establish an initial link between DIP2A gene variations in autism spectrum disorder (ASD) and highlight the contribution of synaptic protein acetylation to synaptic processing.

4.
Exp Ther Med ; 18(4): 2739-2745, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31572521

RESUMO

Interleukin (IL)-37 has an important role in autoimmune diseases by suppressing immunity and inflammation; however, the role of IL-37 in immune thrombocytopenia (ITP) has remained largely elusive. The present study aimed to investigate the expression of IL-37 and its potential role in the pathogenesis of ITP. The plasma levels and expression of IL-37 in the peripheral blood mononuclear cells of patients with active ITP, ITP patients in remission and healthy controls were measured by ELISA and reverse transcription-quantitative PCR, respectively. The levels of IL-37 in patients with ITP treated with and without glucocorticoids were also determined by ELISA. Specific anti-platelet glycoprotein (GP)IIb/IIIa and/or GPIb/IX autoantibodies were assayed by modified monoclonal antibody-specific immobilization of platelet antigens. The mean value of plasma IL-37 in ITP patients was slightly higher than that in healthy controls, but this was not statistically significant. There was no correlation between IL-37 and anti-platelet autoantibodies, and no significant difference in the IL-37 concentration was identified between patients treated with and without glucocorticoids. In addition, the correlation between IL-37 and the platelet count was analyzed, with no statistical significance observed. It was therefore concluded that IL-37 may not have a pivotal role in the development of ITP. However, the lack of significant differences may be due to the limited number of patients in different groups. A larger number of ITP patients should be enrolled in the future work and achieve more accurate results.

5.
Biomed Res Int ; 2019: 9013904, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275989

RESUMO

Background: It has been documented that vitamin D supplementation showed an improvement of symptoms of diabetic nephropathy; however, the underlying mechanisms remain unknown. We here tested the hypothesis that active vitamin D is able to up-regulate AKT/UCP2 signaling to alleviate oxidative stress of renal tubular cell line HK2. Methods: There are eight groups in the present study: normal glucose, osmotic control (5.5 mmol/L D-glucose+24.5 mmol/L D-mannitol), NAC control (30 mmol/L D-glucose + 1.0 mmol/L N-Methylcysteine), high glucose, high glucose+VD, high glucose (HG)+VD+siVDR, HG+VD+AKT inhibitor (AI), and high glucose+VD+UCP2 inhibitor (Gelipin). Concentration of superoxide dismutase (SOD) and malondialdehyde (MDA) was analyzed by ELISA. Reactive oxygen species (ROS), mitochondrial membrane potential and apoptosis were measured by flow cytometry. JC-1 was evaluated by flow cytometry. The presence of VDR, AKT, and UCP2 in HK cells was assessed using RT-PCR and western blot analyses. Results: VD administration significantly upregulated the SOD activation and downregulated MDA levels compared to HG group. siVDR, AKT inhibitor, and UCP2 inhibitor significantly suppressed the activation of SOD and increased the expression of MDA compared to VD group. ROS generation and apoptosis of HK2 cells in HG+VD group were significantly lower than those in HG, HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group. ΔΨm in HG+VD group was obviously higher than those in HG, HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group. Decreased mRNA and protein levels of VDR, p-AKT, and UCP2 were observed in HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group compared to those in HG+VD group. Conclusions: siVDR, AKT inhibitor, and UCP2 inhibitor elevated the ROS and apoptosis of HK2 cells while attenuating the mitochondrial membrane potential, suggesting that vitamin D protects renal tubular cell from high glucose by AKT/UCP2 signaling pathway.


Assuntos
Glucose/toxicidade , Túbulos Renais/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Calcitriol/metabolismo , Transdução de Sinais , Proteína Desacopladora 2/metabolismo , Vitamina D/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
6.
Cells ; 8(5)2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108937

RESUMO

ß-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and ß-amyloid (Aß) production, a critical step in the pathogenesis of Alzheimer's disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity at acidic pH and GFP variant-pHluorin-displays pH dependence. In light of these observations, we generated three tandem fluorescence-tagged BACE1 fusion proteins, named pHluorin-BACE1-mCherry, BACE1-mCherry-pHluorin and BACE1-mCherry-EGFP. Comparing the fluorescence characteristics of these proteins in response to intracellular pH changes induced by chloroquine or bafilomycin A1, we found that pHluorin-BACE1-mCherry is a better pH sensor for BACE1 because its fluorescence intensity responds to pH changes more dramatically and more quickly. Additionally, we found that (pro)renin receptor (PRR), a subunit of the v-ATPase complex, which is critical for maintaining vesicular pH, regulates pHluorin's fluorescence and BACE1 activity in pHluorin-BACE1-mCherry expressing cells. Finally, we found that the expression of Swedish mutant APP (APPswe) suppresses pHluorin fluorescence in pHluorin-BACE1-mCherry expressing cells in culture and in vivo, implicating APPswe not only as a substrate but also as an activator of BACE1. Taken together, these results suggest that the pHluorin-BACE1-mCherry fusion protein may serve as a useful tool for visualizing active/inactive BACE1 in culture and in vivo.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Proteínas Luminescentes/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Fluorescência , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Macrolídeos/farmacologia , Masculino , Camundongos , Receptores de Superfície Celular/metabolismo , Transfecção , ATPases Vacuolares Próton-Translocadoras/metabolismo
7.
Cereb Cortex ; 29(6): 2737-2747, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30843060

RESUMO

Chronic stress has been observed to increase the risk of developing depression and induce neuronal alterations of synaptic plasticity, yet the underlying molecular mechanisms remain unclear. Here, we found that the ubiquitously expressed RNA-binding protein HuR was up-regulated in the medial prefrontal cortex (mPFC) of mice following chronic stress. In adult mice, AAV-Cre-mediated knockout of HuR in the mPFC prevented anxiety-like and depression-like behaviors induced by chronic stress. HuR was also required for the stress-induced dendritic spine loss and synaptic transmission deficits. Moreover, HuRflox/flox;Nex-Cre mice, which induce HuR loss of function from embryonic development, exhibited enhanced synaptic functions. Notably, we ascertained RhoA signaling to be regulated by HuR and involved in the modulation of structural synaptic plasticity in response to chronic stress. Our results demonstrate HuR is a critical modulator for the regulation of stress-induced synaptic plasticity alterations and depression, providing a potential therapeutic target for the treatment of depressive disorders.

8.
Biochem Biophys Res Commun ; 511(2): 369-373, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30803756

RESUMO

Substance P is one of the major neuropeptides released by striatal neurons; however, its function in the striatum remains unclear. In this study, we found substance P triggers spontaneous neurotransmitter release and rapid synaptic vesicle exocytosis in cultured striatal neurons, as substance P knockdown in these neurons impaired spontaneous neurotransmitter release and calcium-dependent rapid synaptic neurotransmission. Furthermore, treatment with exogenous substance P completely rescued the synaptic dysfunction phenotype in striatal neurons lacking this neuropeptide. On the other hand, substance P knockdown had no effect on the size of the readily releasable pool of synaptic vesicles, but decreased the probability of presynaptic release of synaptic vesicles in cultured striatal neurons. Treatment with CP96345, a NK1 receptor antagonist, also resulted in synaptic defects in cultured striatal neurons. In summary, we propose substance P is critical for synaptic transmission in striatal neurons.


Assuntos
Neurônios/metabolismo , Substância P/metabolismo , Transmissão Sináptica , Animais , Células Cultivadas , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Camundongos , Neurônios/citologia , Terminações Pré-Sinápticas/metabolismo , Vesículas Sinápticas/metabolismo
9.
J Sports Med Phys Fitness ; 59(11): 1798-1804, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30722652

RESUMO

BACKGROUND: Stereopsis is the most important part of depth perception, especially in athletic population. At present, there are few studies on how to comprehensively evaluate athletes' stereoscopic function and how the impairment of stereoscopic function affects sports performance. METHODS: Twenty-two professional table-tennis players from Sichuan Province Team were recruited as player group and 23 age-matched students were recruited as the controls. All subjects were measured the habitual visual acuity, best corrected visual acuity, dominant eye, retinoscopy and three stereo acuity tests. Both groups completed two motor skills tasks: Purdue Pegboard and beads threading with habitual binocular viewing and monocular viewing by covering dominant eye. In addition, the player group was asked to complete a brief questionnaire and catch balls served by the auto table-tennis machine under two viewing conditions. RESULTS: The player group had better stereo acuity with median values of 60, 25 and 40 arc sec in TNO, Butterfly, and Frisby tests, respectively. There had statistically correlations between stereo acuity and two motor skills tasks. Both the two tasks were statistically significant different between binocular and monocular viewings in both groups. The player group had better performance on Purdue Pegboard task with binocular viewing (16±1.1, P=0.006) compared to the control group, while no statistical difference was found under monocular condition in beads threading task. In player group, the brief questionnaire demonstrated very negative feeling of players under monocular viewing and the number of catching balls had statistically significant difference between binocular (9.9±0.3) and monocular (6.9±1.6) viewings (P<0.001). CONCLUSIONS: Stereopsis plays an important role in sports performance, the stereo tests combined with Purdue pegboard can be used to evaluate athletes' stereoscopic function comprehensively.

10.
Cell Biol Int ; 43(4): 421-428, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30672040

RESUMO

Disconnected interacting protein 2 (DIP2) is a highly conserved protein family among invertebrates and vertebrates, but its function remains unclear. In this paper, we summarized the conservation of gene sequences and protein domains of DIP2 family members and predicted that they may have a similar functional role in acetyl-coenzyme A (acetyl-CoA) synthesis. We then used the most characterized member, disconnected interacting protein 2 homolog A (DIP2A), for further study. DIP2A is a cytoplasmic protein that is preferentially localized to mitochondria, and its acetyl-CoA synthetase activity has been demonstrated in vitro. Furthermore, the level of acetyl-CoA in HEK293 cells overexpressing DIP2A was increased, which is consistent with its metabolically related function. Together, these data enrich the evolutionary and functional characterization of dip2 genes and provide significant insights into the identification and application of other homologs of DIP2.


Assuntos
Proteínas do Tecido Nervoso/genética , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , China , Biologia Computacional/métodos , Células HEK293 , Humanos , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo
11.
Harmful Algae ; 81: 65-76, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30638500

RESUMO

Athecate dinoflagellate Karlodinium veneficum is a universal toxic species possessing karlotoxins recognized especially as ichthyotoxic as well as cytotoxic and hemolytic. Blooms of K. veneficum, both single-species or accompanied with other species, occurred more frequently worldwide in recent years, including the coastal region of China. Normally, K. veneficum present in relatively low abundance in phytoplankton communities in estuary regions. Being small and difficult to identify with light microscopy, it has been ignored for a long time till its blooming and toxins being confirmed. How it presents in background level and what is its relationship with critical geological and hydrological environment factors are basically not clear. In this study, the paper reports the application of a real-time quantitative PCR (qPCR) method to investigate the abundance and distribution of K. veneficum in the coastal waters of Xiangshan Bay in the East China Sea (ECS), a typical bay area of harmful algae blooms and heavily affected by anthropogenic activities. The real-time qPCR assay came out being an efficient method at detecting even low cell densities of K. veneficum of different genotypes. A total of 38 field samples of surface (0.5 m) and bottom water (9-100 m in depth) were analyzed and 12 samples were found positive for K. veneficum. At least 3 genotypes of K. veneficum present in this region. Temperatures in sites of K. veneficum positive ranged from 21.7 to 23.4 °C, and salinity levels were between 21.1 and 26.3. The K. veneficum distributed quite extensively in the waters of Xiangshan Bay, cell abundance varied from a low of 4 cells/L to a maximum of 170 cells/L. Most of the samples containing K. veneficum were collected from bottom water in different sites. At three of the 19 sampling sites, K. veneficum was detected in both surface and bottom water samples. Especially at sampling site near Beilun port, where the water is typically muddy with low transparency, relative high cell numbers of K. veneficum were found in both surface and bottom waters. Mixotrophy and vertical migration of K. veneficum could be important eco-physiological factors to consider in terms of understanding these distribution characteristics. The ideal conditions for K. veneficum growth and aggregation in this area still needs further study.

12.
J Cell Mol Med ; 23(2): 1622-1627, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30484953

RESUMO

Disabled-1 (Dab1) is best known as an adaptor protein regulating neuron migration and lamination during development. However, the exact function of Dab1 in breast cancer is unknown. In this study, we examined the expression of Dab1 in 38 breast cancer paraffin sections, as well as 60 paired frozen breast cancer and their adjacent tissues. Our results showed that Dab1 was reduced in breast cancer, and its compromised expression correlated with triple negative breast cancer phenotype, poor differentiation, as well as lymph node metastasis. Functional analysis in breast cancer cell lines demonstrated that Dab1 promoted cell apoptosis, which, at least partially, depended on its regulation of NF-κB/Bcl-2/caspase-9 pathway. Our study strongly suggests that Dab1 may be a potential tumour suppressor gene in breast cancer.

13.
Bioinformatics ; 35(9): 1469-1477, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247625

RESUMO

MOTIVATION: Transcription termination is an important regulatory step of gene expression. If there is no terminator in gene, transcription could not stop, which will result in abnormal gene expression. Detecting such terminators can determine the operon structure in bacterial organisms and improve genome annotation. Thus, accurate identification of transcriptional terminators is essential and extremely important in the research of transcription regulations. RESULTS: In this study, we developed a new predictor called 'iTerm-PseKNC' based on support vector machine to identify transcription terminators. The binomial distribution approach was used to pick out the optimal feature subset derived from pseudo k-tuple nucleotide composition (PseKNC). The 5-fold cross-validation test results showed that our proposed method achieved an accuracy of 95%. To further evaluate the generalization ability of 'iTerm-PseKNC', the model was examined on independent datasets which are experimentally confirmed Rho-independent terminators in Escherichia coli and Bacillus subtilis genomes. As a result, all the terminators in E. coli and 87.5% of the terminators in B. subtilis were correctly identified, suggesting that the proposed model could become a powerful tool for bacterial terminator recognition. AVAILABILITY AND IMPLEMENTATION: For the convenience of most of wet-experimental researchers, the web-server for 'iTerm-PseKNC' was established at http://lin-group.cn/server/iTerm-PseKNC/, by which users can easily obtain their desired result without the need to go through the detailed mathematical equations involved.

14.
J Cell Mol Med ; 22(6): 3259-3263, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29575613

RESUMO

Single-chain variable fragment (scFv) antibodies are the smallest immunoglobulins with high antigen-binding affinity. We have previously reported that fibroblast growth factor 1 played pivotal roles in cancer development and generated a mouse scFv (mscFv1C9) could effectively prohibit cancer cell proliferation in vitro and in vivo. Here, we further humanized this scFv (hscFv1C9) using a structure-guided complementarity determining region grafting strategy. The purified hscFv1C9 maintained similar antigen-binding affinity and specificity as mscFv1C9, and it was capable of inhibiting growth of different tumours in vitro and in vivo. These data strongly suggested that hscFv1C9 has antitumour potentials.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/antagonistas & inibidores , Glioma/tratamento farmacológico , Anticorpos de Cadeia Única/farmacologia , Sequência de Aminoácidos/genética , Animais , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Fator 1 de Crescimento de Fibroblastos/química , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/imunologia , Glioma/genética , Glioma/patologia , Xenoenxertos , Humanos , Camundongos , Anticorpos de Cadeia Única/imunologia
15.
Cell Rep ; 22(13): 3598-3611, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29590626

RESUMO

Newborn neurons undergo inside-out migration to their final destinations during neocortical development. Reelin-induced tyrosine phosphorylation of disabled 1 (Dab1) is a critical mechanism controlling cortical neuron migration. However, the roles of Reelin-independent phosphorylation of Dab1 remain unclear. Here, we report that deleted in colorectal carcinoma (DCC) interacts with Dab1 via its P3 domain. Netrin 1, a DCC ligand, induces Dab1 phosphorylation at Y220 and Y232. Interestingly, knockdown of DCC or truncation of its P3 domain dramatically delays neuronal migration and impairs the multipolar-to-bipolar transition of migrating neurons. Notably, the migration delay and morphological transition defects are rescued by the expression of a phospho-mimetic Dab1 or a constitutively active form of Fyn proto-oncogene (Fyn), a member of the Src-family tyrosine kinases that effectively induces Dab1 phosphorylation. Collectively, these findings illustrate a DCC-Dab1 interaction that ensures proper neuronal migration during neocortical development.


Assuntos
Receptor DCC/metabolismo , Neocórtex/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Animais , Animais Recém-Nascidos , Movimento Celular/fisiologia , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/citologia , Neocórtex/metabolismo , Netrina-1/metabolismo , Fosforilação , Domínios Proteicos
16.
Cell Death Dis ; 9(1): 8, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29311593

RESUMO

Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.


Assuntos
Transtorno Depressivo/prevenção & controle , Proteínas de Membrana/genética , Neurogênese , Animais , Proliferação de Células , Células Cultivadas , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Transtorno Depressivo/patologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Hipocampo/citologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Tamoxifeno/farmacologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
17.
Sci Rep ; 7(1): 16417, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-29180800

RESUMO

Gestational diabetes mellitus (GDM) is conventionally confirmed with oral glucose tolerance test (OGTT) in 24 to 28 weeks of gestation, but it is still uncertain whether it can be predicted with secondary use of electronic health records (EHRs) in early pregnancy. To this purpose, the cost-sensitive hybrid model (CSHM) and five conventional machine learning methods are used to construct the predictive models, capturing the future risks of GDM in the temporally aggregated EHRs. The experimental data sources from a nested case-control study cohort, containing 33,935 gestational women in West China Second Hospital. After data cleaning, 4,378 cases and 50 attributes are stored and collected for the data set. Through selecting the most feasible method, the cost parameter of CSHM is adapted to deal with imbalance of the dataset. In the experiment, 3940 samples are used for training and the rest 438 samples for testing. Although the accuracy of positive samples is barely acceptable (62.16%), the results suggest that the vast majority (98.4%) of those predicted positive instances are real positives. To our knowledge, this is the first study to apply machine learning models with EHRs to predict GDM, which will facilitate personalized medicine in maternal health management in the future.


Assuntos
Diabetes Gestacional/epidemiologia , Registros Eletrônicos de Saúde , Adulto , Algoritmos , Análise Custo-Benefício , Bases de Dados Factuais , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/etiologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Idade Gestacional , Humanos , Modelos Estatísticos , Gravidez , Prognóstico , Curva ROC , Fluxo de Trabalho
18.
Biomed Res Int ; 2017: 2984826, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29075643

RESUMO

Some reports have shown that nicotinamide N-methyltransferase (NNMT) is associated with the body mass index (BMI) and energy metabolism. Here we explored the association between NNMT gene polymorphisms and obesity. The subjects were recruited from male Chinese Han college student. 289 of them (19 ≤ body fat percentage (BF%)) were selected as the high body fat group (HBFG), 494 of them (3 ≤ BF% < 13.5) were selected as the low body fat group (LBFG), and then a case-control study (fat versus thin) was carried out to explore the association between the NNMT gene polymorphism and the body composition using tagSNPs method. A tagSNP (rs10891644) in NNMT gene was found significantly associated with the body composition (P < 0.0026). At this locus, the BF% for the genotype GT, TT, and GG were 14.56 ± 8.35, 13.47 ± 8.11, and 12.42 ± 7.50, respectively, and the differences between the GT and the GG + TT were highly significant (P < 0.01); the ORadjusted value of the GT versus (GG + TT) was 1.716 (Padjusted = 0.002, 95% CI = 1.240-2.235). Therefore, the variation of the tagSNP, rs10891644, is significantly associated with obesity and the GT carriers are the susceptible population.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Nicotinamida N-Metiltransferase/genética , Obesidade/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Índice de Massa Corporal , Metabolismo Energético/genética , Feminino , Genótipo , Humanos , Masculino , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
Sci Rep ; 7(1): 5454, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28710382

RESUMO

Gliomas, a common type of brain tumor, are characterized by aggressive infiltration, making it difficultly to cure by surgery. Netrin-1, an extracellular guidance cue critical for neuronal axon path-finding, has been reported to play an important role in cell invasion and migration in several types of cancers. However, the role of netrin-1 in glioma remains largely unknown. Here, we provide evidence suggested that Netrin-1 has a critical role in glioma growth. We found that netrin-1 was significantly increased in glioma samples and positively correlated with cell proliferation, tumor grade and malignancy. Netrin-1 knockdown reduced cell proliferation and attenuated tumor growth in a xenograft mouse model. Further studies found that netrin-1 induced NF-κB p65ser536 phosphorylation and c-Myc expression in vitro and in vivo. Interestingly, activation of NF-κB by netrin-1 was dependent on UNC5A receptor, because suppression of UNC5A significantly inhibited NF-κB p65ser536 phosphorylation, c-Myc up-regulation and reduced cell proliferation. Taken together, these results suggested netrin-1 promotes glioma cell proliferation by activating NF-κB signaling via UNC5A, netrin-1 may be a potential therapeutic target for the treatment of glioma.


Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , NF-kappa B/genética , Netrina-1/genética , Receptores de Superfície Celular/genética , Adulto , Idoso , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Gradação de Tumores , Netrina-1/antagonistas & inibidores , Netrina-1/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
20.
PLoS One ; 12(6): e0179047, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28591194

RESUMO

In the developing neocortex, cells in the ventricular/subventricular zone are largely multipotent neural stem cells and neural progenitor cells. These cells undergo self-renewal at the early stage of embryonic development to amplify the progenitor pool and subsequently differentiate into neurons. It is thus of considerable interest to investigate mechanisms controlling the switch from neural stem cells or neural progenitor cells to neurons. Here, we present evidence that Kif2a, a member of the Kinesin-13 family, plays a role in regulating the proliferation and differentiation of neural stem cells or neural progenitor cells at embryonic day 13.5. Silencing Kif2a by use of in utero electroporation of Kif2a shRNA reduced neural stem cells proliferation or self-renewal but increased neuronal differentiation. We further found that knockdown of Kif2a decreased the protein level of ß-catenin, which is a critical molecule for neocortical neurogenesis. Together, these results reveal an important function of Kif2a in embryonic neocortical neurogenesis.


Assuntos
Cinesina/genética , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Proteínas Repressoras/genética , beta Catenina/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Feminino , Humanos , Camundongos , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Neurônios/metabolismo , Gravidez , RNA Interferente Pequeno/genética
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