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1.
Int Immunopharmacol ; 79: 106175, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918060

RESUMO

Acute lung injury (ALI) is one of the severe complications in patients with traumatic brain injury (TBI), contributing to the high mortality. Ghrelin has protective effects against various inflammatory diseases, but the effects of Ghrelin on TBI-induced ALI and its mechanisms remain unknown. In this study, Ghrelin administration was performed on the mice with TBI, then histological change in cortex and lung tissues, lung vascular permeability and macrophage number in bronchoalveolar lavage fluid (BALF) were examined, respectively. Simultaneously, the alterations of proinflammatory factors and pyroptosis-related proteins in lung tissues were detected. As a result, TBI-induced ALI was ameliorated after Ghrelin treatment, which was demonstrated by improved histology, reduced lung vascular permeability, and peripheral macrophage number. Furthermore, Ghrelin decreased the mRNA levels of proinflammatory factors (IL-1ß, IL-6, TNF-α and IL-18), the protein levels of pyroptosis-related proteins (NLRP3, Caspase1-P20, HMGB1 and Gasdermin D), and the phosphorylation levels of NF-κB in lung tissues. These results showed that Ghrelin attenuating TBI-induced ALI might be via ameliorating inflammasome-induced pyroptosis by blocking NF-κB signal, which are important for the prevention and treatment of TBI-induced ALI.

2.
Pathol Res Pract ; 216(2): 152790, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31864713

RESUMO

BACKGROUND: Glioma is the most common primary malignant tumor with poor prognosis due to the lack of understanding the mechanism underlying the disease and the early diagnosis indexs. It is necessary to identify molecular signatures for predicting the overall prognosis of glioma. Adipocyte enhancer binding protein1 (AEBP1) acts as a transcriptional repressor and plays a role in adipogenesis and smooth muscle cell differentiation. However, its role in glioma remains unclear. MATERIALS AND METHODS: AEBP1 expression was analyzed by bioinformatics using the public database and by qPCR and western blotting in human glioma tissues. AEBP1 downregulation was performed by lipofectamine3000-mediated siRNA transfection. Cell proliferation and invasion were determined by cell counting kit-8 and transwell assays, while early cell apoptosis was determined by flow cytometry. The proteins of downstream NF-κB signaling pathway were determined by western blotting. RESULTS: AEBP1 is highly expressed in human gliomas. Lipofectamine 3000-mediated siRNA transfection stably and efficiently suppressed AEBP1 mRNA and protein expression in human glioma cells. AEBP1 downregulation inhibited cell proliferation and invasion, but promoted early cell apoptosis. Also, AEBP1 knockdown in glioma cells decreased the expression of NF-κB1. Furthermore, the downstream of NF-κB signaling pathway, Bax, caspase-3 are increased, while MMP2 and Bcl-2 are decreased in glioma cells. CONCLUSION: Elevated AEBP1 is positively associated with poor prognosis of glioma. AEBP1 downregulation suppressed cell proliferation and invasion, but promoted early cell apoptosis. AEBP1 downregulation suppressed the cell proliferation and invasion may by inhibiting the NF-κB signaling pathway.

3.
Micromachines (Basel) ; 10(11)2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31718029

RESUMO

This paper proposes a novel microdroplet generator based on the dielectrophoretic (DEP) force. Unlike the conventional continuous microfluidic droplet generator, this droplet generator is more like "invisible electric scissors". It can cut the droplet off from the fluid matrix and modify droplets' length precisely by controlling the electrodes' length and position. These electrodes are made of liquid metal by injection. By applying a certain voltage on the liquid-metal electrodes, the electrodes generate an uneven electric field inside the main microfluidic channel. Then, the uneven electric field generates DEP force inside the fluid. The DEP force shears off part from the main matrix, in order to generate droplets. To reveal the mechanism, numerical simulations were performed to analyze the DEP force. A detailed experimental parametric study was also performed. Unlike the traditional droplet generators, the main separating force of this work is DEP force only, which can produce one droplet at a time in a more precise way.

4.
J Craniofac Surg ; 30(7): 2239-2244, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31503116

RESUMO

BACKGROUND: A skull fracture widely occurs in patients with traumatic brain injury, leading to intracranial hematoma, brain contusion, and intracranial infection. It also influences the prognosis and death of patients. This study aimed to discuss cases of patients with comminuted skull fractures. METHODS: From October 2015 to December 2018, 38 patients with comminuted skull fractures were admitted to the hospital. All patients underwent three-dimensional reconstruction of computed tomography scan images. Digital subtraction angiography or magnetic resonance venography was performed to find out the venous sinus. The clinical findings of the patients were significant regarding gender, age, injury mechanism, location, admission Glasgow Coma Scale (GCS), combined epidural, subdural, cerebral contusion, intracranial pneumatosis, maximum depth of depression, admission to surgery, dural tear, post-operative cerebrospinal fluid leakage, post-operative infection, and Glasgow Outcome Scale (GOS) 3 months after surgery. RESULTS: The incidence of traffic accidents, fall from a height, railway accidents, fall of an object, and chop injury was 60.5%, 18.4%, 13.2%, 5.3%, and 2.6%, respectively. Intra-operative dural trar negatively correlated with epidural hematoma, cerebral contusion, and subdural hematoma. Also, post-operative infection negatively correlated with intracranial pneumatosis, depth of fracture depression, and pre-operative cerebrospinal fluid leakage. No correlation was found between contusion, subdural hematoma, intracranial pneumatosis, depth of fracture depression, and post-operative infection. The GOS score positively correlated with age, pre-operative cerebrospinal fluid leakage, and admission GCS score. CONCLUSIONS: A perfect pre-operative examination is a key to successful surgery. Further studies should be conducted to find out more effective treatments for traumatic comminuted skull fractures.


Assuntos
Fratura do Crânio com Afundamento/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vazamento de Líquido Cefalorraquidiano/etiologia , Contusões , Feminino , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Fratura do Crânio com Afundamento/complicações , Fratura do Crânio com Afundamento/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
5.
World Neurosurg ; 132: e391-e398, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31476468

RESUMO

OBJECTIVE: To compare clinical and radiologic characteristics and prognosis of patients with chronic subdural hematoma (CSDH) with and without a history of head trauma. METHODS: Clinical and radiologic characteristics and prognosis of patients with CSDH with a history of head trauma (HT group) and without a history of head trauma (WHT group) were comparatively analyzed. RESULTS: Mean age in the WHT group was 70.23 ± 11.53 years, which was significantly older than mean age 67.56 ± 11.18 years in the HT group (P = 0.008). Stroke, uremia, anticoagulant therapy, and antiplatelet therapy were encountered more often in the WHT group than the HT group. Motor weakness was more prevalent in the WHT group (P = 0.011). Modified Rankin Scale score of 2-3 was more common in the WHT group (P = 0.03), whereas a score of 4-5 was more common in the HT group (P = 0.014). Hematoma density on CT was mainly homogeneous in the 2 groups, with significantly more homogeneous density in the HT group compared with the WHT group (P = 0.014). There was significantly more mixed density in the WHT group (P = 0.001). Patients with CSDH in the WHT group had higher mortality (P = 0.026) and lower Glasgow Outcome Scale score (P = 0.033). CONCLUSIONS: Patients with CSDH with or without a history of head trauma presented with different clinical and radiologic characteristics. Patients with CSDH without a history of head trauma had a higher mortality and lower GOS score, which indicates these patients warrant more attention.


Assuntos
Traumatismos Craniocerebrais/complicações , Hematoma Subdural Crônico/etiologia , Hematoma Subdural Crônico/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hematoma Subdural Crônico/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Injury ; 50(10): 1634-1640, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31445831

RESUMO

BACKGROUND: Chronic subdural hematoma (CSDH) is commonly encountered in the elderly patients and the recurrence rate is still high, therefore, identifying risk factors for CSDH recurrence is essential. The present study aimed to identify clinical and radiological factors predicting the recurrence of CSDH. METHODS: We retrospectively identified 461 patients with CSDH who underwent surgical evacuation in our department. Univariable analyses were performed at first, variables with a P-value of <0.05 were entered into multivariable logistic regression model. Kendall's tau-b test was used to evaluate the relationship between brain atrophy and postoperative pneumocephalus. RESULTS: Univariable analyses revealed that patients with the following characteristics have a higher recurrence rate, including age ≥80 years, antiplatelet and/or anticoagulant use, GOS = 3, the volume of drainage ≥100 ml, midline shift ≥10 mm, severe brain atrophy, severe postoperative pneumocephalus. Multivariable logistic regression demonstrated that midline shift ≥10 mm, severe brain atrophy, severe postoperative pneumocephalus, and volume of drainage ≥100 ml were independent risk factors for CSDH recurrence. Kendall's tau-b test revealed that there was no correlation between brain atrophy and postoperative pneumocephalus. CONCLUSIONS: Midline shift ≥10 mm, severe brain atrophy, severe postoperative pneumocephalus, and volume of drainage ≥100 ml were independent risk factors for CSDH recurrence, CSDH patients with these characteristics should be taken precautions of recurrence and a closely follow-up should be carried out.

7.
World Neurosurg ; 130: e133-e139, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31203079

RESUMO

BACKGROUND: Most patients with bilateral chronic subdural hematomas (bCSDH) undergo initial bilateral evacuation. Risk factors associated with the recurrence of bCSDH after initial bilateral evacuation have not been published to date. In this study, we aimed to identify risk factors related to recurrence of bCSDH after initial bilateral evacuation, and to develop a prognostic grading system for clinical reference. METHODS: This study included 102 patients with bCSDH who underwent initial bilateral evacuation. Predictors of recurrence were identified via univariate analysis and multivariate logistic regression analysis. A prognostic grading system was created based on the independent predictors combined with a cutoff value. All cases were scored according to the prognostic grading system, and the recurrence rates of the different scores were reanalyzed. RESULTS: Anticoagulant use (odds ratio [OR], 84.266; 95% confidence interval [CI], 13.113-541.522; P < 0.001), severe brain atrophy (OR, 11.551; 95% CI, 2.558-52.163; P = 0.001), and postoperative pneumocephalus volume (PostPV) (OR, 0.978; 95% CI, 0.957-1.000; P = 0.049) were independent risk factors for the recurrence of bCSDH after initial bilateral evacuation. The cutoff value of PostPV was >20.9484 cm3. A prognostic grading system was then developed, and the recurrence rates based on score were determined. Rates were 2.8% for a score of 0-1, 28.1% for a score of 2-3, and 100% for a score of 4-5, showing a significant increase in risk with increasing score (P < 0.001). CONCLUSIONS: Anticoagulant use, severe brain atrophy, and PostPV were identified as independent risk factors for recurrence of bCSDH after initial bilateral evacuation. The prognostic grading system for recurrence of bCSDH after initial bilateral evacuation is reliable and applicable for clinical reference.


Assuntos
Encéfalo/cirurgia , Hematoma Subdural Crônico/diagnóstico , Hematoma Subdural Crônico/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Atrofia/complicações , Atrofia/diagnóstico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Feminino , Hematoma Subdural Crônico/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Pneumocefalia/complicações , Pneumocefalia/diagnóstico , Complicações Pós-Operatórias/etiologia , Recidiva , Fatores de Risco , Sensibilidade e Especificidade
8.
Sci Rep ; 9(1): 7397, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089197

RESUMO

Supplying exogenous sulfur-rich compounds increases the content of glutathione(GSH) and phytochelatins(PCs) in plant tissues, enabling plants to enhance their cellular defense capacity and/or compartmentalize Cadmium(Cd) into vacuoles. However, the mechanism by which surplus S modulates tolerance to Cd stress in different tissues need further investigation. In the present study, we found that supplementing the tartary buckwheat(Fagopyrum tararicum) exposed to Cd with surplus S reversed Cd induced adverse effects, and increased Cd concentrations in roots, but decreased in leaves. Further analysis revealed that exogenous S significantly mitigated Cd-induced oxidative stress with the aids of antioxidant enzymes and agents both in leaves and roots, including peroxidase(POD), ascorbate peroxidase(APX), glutathione peroxidase(GPX), glutathione S-transferase(GST), ascorbic acid(AsA), and GSH, but not superoxide dismutase(SOD) and catalase(CAT). The increased Cd uptake in root vacuoles and decreased translocation in leaves of exogenous S treated plants could be ascribed to the increasing Cd binding on cell walls, chelation and vacuolar sequestration with helps of non-protein thiols(NPT), PCs and heavy metal ATPase 3(FtHMA3) in roots, and inhibiting expression of FtHMA2, a transporter that helps Cd translocation from roots to shoots. Results provide the fundamental information for the application of exogenous S in reversal of heavy metal stress.

9.
World Neurosurg ; 126: e773-e778, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30853519

RESUMO

OBJECTIVE: To find risk factors for contralateral hematoma progression (CHP) in bilateral chronic subdural hematomas after initial unilateral evacuation. METHODS: We retrospectively analyzed 53 patients with bilateral chronic subdural hematomas who underwent unilateral surgical evacuation in our department. Risk factors for CHP were identified by univariate analysis, a P value <0.05 were entered into multivariate logistic regression model and a predictive receiver operating characteristic curve model. RESULTS: The progression rate was 32.08%, the average progression interval was 2.32 months. The progression rate of the homogeneous hypodense group was significantly higher than that of the other density group (P = 0.017). The limited type of contralateral hematoma had a significantly lower progression rate than that of the widespread type (P = 0.001). Both pre- and postoperative volume of contralateral hematoma were significantly more in the CHP group compared with the contralateral hematoma without progression group (P = 0.031 and P = 0.001, respectively). Of the 4 risk factors, only postoperative volume of contralateral hematoma was an independent risk factor in multivariate logistic regression model (P = 0.033; 95% confidence interval, 1.005-1.124). The cut-off values of contralateral hematoma volume before and after operation were 29.27 cm3 and 37.84 cm3, respectively. CONCLUSIONS: Contralateral hematoma volume after operation is an independent risk predictor for CHP after unilateral evacuation. An additional surgery on contralateral hematoma or medical treatment should be taken into consideration if the volume is >37.84 cm3 in the first cranial computed tomography scan after surgery.


Assuntos
Encéfalo/cirurgia , Hematoma Subdural Crônico/cirurgia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Craniotomia , Progressão da Doença , Feminino , Hematoma Subdural Crônico/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Complicações Pós-Operatórias , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X , Resultado do Tratamento
10.
J Neurosci ; 39(15): 2776-2791, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30705102

RESUMO

Calpains are calcium-dependent, cytosolic proteinases active at neutral pH. They do not degrade but cleave substrates at limited sites. Calpains are implicated in various pathologies, such as ischemia, injuries, muscular dystrophy, and neurodegeneration. Despite so, the physiological function of calpains remains to be clearly defined. Using the neuromuscular junction of Drosophila of both sexes as a model, we performed RNAi screening and uncovered that calpains negatively regulated protein levels of the glutamate receptor GluRIIA but not GluRIIB. We then showed that calpains enrich at the postsynaptic area, and the calcium-dependent activation of calpains induced cleavage of GluRIIA at Q788 of its C terminus. Further genetic and biochemical experiments revealed that different calpains genetically and physically interact to form a protein complex. The protein complex was required for the proteinase activation to downregulate GluRIIA. Our data provide a novel insight into the mechanisms by which different calpains act together as a complex to specifically control GluRIIA levels and consequently synaptic function.SIGNIFICANCE STATEMENT Calpain has been implicated in neural insults and neurodegeneration. However, the physiological function of calpains in the nervous system remains to be defined. Here, we show that calpain enriches at the postsynaptic area and negatively and specifically regulates GluRIIA, but not IIB, level during development. Calcium-dependent activation of calpain cleaves GluRIIA at Q788 of its C terminus. Different calpains constitute an active protease complex to cleave its target. This study reveals a critical role of calpains during development to specifically cleave GluRIIA at synapses and consequently regulate synaptic function.

11.
Sensors (Basel) ; 19(2)2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646594

RESUMO

A handy, flexible micro-thermocouple using low-melting-point metal alloys is proposed in this paper. The thermocouple has the advantages of simple fabrication and convenient integration. Bismuth/gallium-based mixed alloys are used as thermocouple materials. To precisely inject the metal alloys to the location of the sensing area, a micro-polydimethylsiloxane post is designed within the sensing area to prevent outflow of the metal alloy to another thermocouple pole during the metal-alloy injection. Experimental results showed that the Seebeck coefficient of this thermocouple reached -10.54 µV/K, which was much higher than the previously reported 0.1 µV/K. The thermocouple was also be bent at 90° more than 200 times without any damage when the mass ratio of the bismuth-based alloy was <60% in the metal-alloy mixture. This technology mitigated the difficulty of depositing traditional thin⁻film thermocouples on soft substrates. Therefore, the thermocouple demonstrated its potential for use in microfluidic chips, which are usually flexible devices.

12.
Biochem Biophys Res Commun ; 509(1): 182-187, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30587343

RESUMO

BACKGROUND: Glioma is the most common malignancy in brain carcinoma with poor prognosis due to the lack of understanding of the mechanism underlying the disease. γ-interferon-inducible lysosomal thiol reductase (GILT) plays a critical role in the process of antigen processing. However, the role of GILT in the tumorigenesis of glioma remains unknown. MATERIALS AND METHODS: The expression of GILT was analyzed by bioinformatics using the public database and by qPCR in three human glioma cell lines. Cell growth and viability were determined by Celigo and MTT assays, while cell cycle arrest and apoptosis were determined using flow cytometry. Giemsa staining was used to analyze the colony formation, while cell motility was assessed using transwell migration and invasion assays, as well as, using tumor growth in nude mice. RESULTS: GILT was highly expressed as observed in the public database on human gliomas and two human glioma cell lines, U373MG and U87MG cells. The downregulation of GILT by lentiviral-mediated silencing inhibits the cell growth, colony formation, and migration but promotes apoptosis and results in cell cycle arrest at the G0/G1 phase in the U373MG cells. Also, the knockdown of GILT inhibits tumor growth in vivo. CONCLUSION: Elevated GILT is positively associated with glioma progression. GILT silencing suppresses cell proliferation, colony formation, migration, and tumor growth, and induces apoptosis and cell cycle arrest. GILT may serve as a potential target for the treatment of glioma.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Animais , Apoptose , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Técnicas de Silenciamento de Genes , Glioma/patologia , Humanos , Lentivirus/genética , Camundongos Endogâmicos BALB C , Camundongos Nus
13.
Elife ; 72018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30355446

RESUMO

Lipids are structural components of cellular membranes and signaling molecules that are widely involved in development and diseases, but the underlying molecular mechanisms are poorly understood, partly because of the vast variety of lipid species and complexity of synthetic and turnover pathways. From a genetic screen, we identify that mannosyl glucosylceramide (MacCer), a species of glycosphingolipid (GSL), promotes synaptic bouton formation at the Drosophila neuromuscular junction (NMJ). Pharmacological and genetic analysis shows that the NMJ growth-promoting effect of MacCer depends on normal lipid rafts, which are known to be composed of sphingolipids, sterols and select proteins. MacCer positively regulates the synaptic level of Wnt1/Wingless (Wg) and facilitates presynaptic Wg signaling, whose activity is raft-dependent. Furthermore, a functional GSL-binding motif in Wg exhibiting a high affinity for MacCer is required for normal NMJ growth. These findings reveal a novel mechanism whereby the GSL MacCer promotes synaptic bouton formation via Wg signaling.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Glicoesfingolipídeos/metabolismo , Junção Neuromuscular/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt1/metabolismo , Animais
14.
Front Neurosci ; 12: 445, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30026681

RESUMO

Traumatic brain injury (TBI) is a primary cause of disability and mortality. Ghrelin, a gastrointestinal hormone, has been found to have protective effects for the brain, but the molecular mechanism of these neuroprotective effects of ghrelin remains unclear. In this study, an electronic cortical contusion impactor was used to establish a rat TBI model and we investigated the effect of ghrelin on brain repair by neurological severity score and histological examination. An antibody array was employed to uncover the molecular mechanism of ghrelin's neuroprotective effects by determining the alterations of multiple proteins in the brain cortex. As a result, ghrelin attenuated brain injury and promoted brain functional recovery. After TBI, 13 proteins were up-regulated in the brain cortex, while basic fibroblast growth factor (bFGF) and fibroblast growth factor-binding protein (FGF-BP) were down-regulated after ghrelin treatment. It is known that bFGF can induce angiogenesis in the brain and accelerate wound healing, which can be further enhanced by FGF-BP. Based on the previous studies, it is hypothesized that the exogenous ghrelin curing TBI might cause the closure of bFGF and FGF-BP functions on wound healing, or ghrelin might exert the neuroprotective effects by competitively inhibiting bFGF/FGF-BP-induced neovascularization. Whether the combinational administration of ghrelin and bFGF/FGF-BP can enhance or weaken the therapeutic effect on TBI requires further research.

15.
J Neurosci ; 37(48): 11592-11604, 2017 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-29074576

RESUMO

Human genetic studies support that loss-of-function mutations in the SH3 domain and ankyrin repeat containing family proteins (SHANK1-3), the large synaptic scaffolding proteins enriched at the postsynaptic density of excitatory synapses, are causative for autism spectrum disorder and other neuropsychiatric disorders in humans. To better understand the in vivo functions of Shank and facilitate dissection of neuropathology associated with SHANK mutations in human, we generated multiple mutations in the Shank gene, the only member of the SHANK family in Drosophila melanogaster Both male and female Shank null mutants were fully viable and fertile with no apparent morphological or developmental defects. Expression analysis revealed apparent enrichment of Shank in the neuropils of the CNS. Specifically, Shank coexpressed with another PSD scaffold protein, Homer, in the calyx of mushroom bodies in the brain. Consistent with high expression in mushroom body calyces, Shank mutants show an abnormal calyx structure and reduced olfactory acuity. These morphological and functional phenotypes were fully rescued by pan-neuronal reexpression of Shank, and only partially rescued by presynaptic but no rescue by postsynaptic reexpression of Shank. Our findings thus establish a previously unappreciated presynaptic function of Shank.SIGNIFICANCE STATEMENT Mutations in SHANK family genes are causative for idiopathic autism spectrum disorder. To understand the neural function of Shank, a large scaffolding protein enriched at the postsynaptic densities, we examined the role of Drosophila Shank in synapse development at the peripheral neuromuscular junctions and the central mushroom body calyx. Our results demonstrate that, in addition to its conventional postsynaptic function, Shank also acts presynaptically in synapse development in the brain. This study offers novel insights into the synaptic role of Shank.


Assuntos
Proteínas do Tecido Nervoso/fisiologia , Proteínas do Tecido Nervoso/ultraestrutura , Terminações Pré-Sinápticas/fisiologia , Terminações Pré-Sinápticas/ultraestrutura , Animais , Animais Geneticamente Modificados , Drosophila , Feminino , Masculino , Corpos Pedunculados/fisiologia , Corpos Pedunculados/ultraestrutura , Junção Neuromuscular/fisiologia , Junção Neuromuscular/ultraestrutura
16.
PLoS Genet ; 12(5): e1006062, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27232889

RESUMO

Altered expression of the E3 ubiquitin ligase UBE3A, which is involved in protein degradation through the proteasome-mediated pathway, is associated with neurodevelopmental and behavioral defects observed in Angelman syndrome (AS) and autism. However, little is known about the neuronal function of UBE3A and the pathogenesis of UBE3A-associated disorders. To understand the in vivo function of UBE3A in the nervous system, we generated multiple mutations of ube3a, the Drosophila ortholog of UBE3A. We found a significantly increased number of total boutons and satellite boutons in conjunction with compromised endocytosis in the neuromuscular junctions (NMJs) of ube3a mutants compared to the wild type. Genetic and biochemical analysis showed upregulation of bone morphogenetic protein (BMP) signaling in the nervous system of ube3a mutants. An immunochemical study revealed a specific increase in the protein level of Thickveins (Tkv), a type I BMP receptor, but not other BMP receptors Wishful thinking (Wit) and Saxophone (Sax), in ube3a mutants. Ube3a was associated with and specifically ubiquitinated lysine 227 within the cytoplasmic tail of Tkv, and promoted its proteasomal degradation in Schneider 2 cells. Negative regulation of Tkv by Ube3a was conserved in mammalian cells. These results reveal a critical role for Ube3a in regulating NMJ synapse development by repressing BMP signaling. This study sheds new light onto the neuronal functions of UBE3A and provides novel perspectives for understanding the pathogenesis of UBE3A-associated disorders.


Assuntos
Síndrome de Angelman/genética , Proteínas de Drosophila/biossíntese , Proteínas de Drosophila/genética , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/biossíntese , Receptores de Superfície Celular/biossíntese , Ubiquitina-Proteína Ligases/genética , Síndrome de Angelman/patologia , Animais , Proteínas Morfogenéticas Ósseas/biossíntese , Proteínas Morfogenéticas Ósseas/genética , Modelos Animais de Doenças , Drosophila/genética , Endocitose/genética , Regulação da Expressão Gênica/genética , Humanos , Junção Neuromuscular/genética , Junção Neuromuscular/patologia , Neurônios/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de Superfície Celular/genética , Transdução de Sinais , Sinapses/genética , Ubiquitina-Proteína Ligases/biossíntese
17.
J Genet Genomics ; 43(1): 11-24, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26842990

RESUMO

Fragile X syndrome (FraX), the most common form of inherited mental retardation, is caused by the absence of the evolutionally conserved fragile X mental retardation protein (FMRP). While neuronal functions of FMRP have been intensively studied for the last two decades, its role in non-neuronal cells remains poorly understood. Piwi, a key component of the Piwi-interacting RNA (piRNA) pathway, plays an essential role in germline development. In the present study, we report that similar to piwi, dfmr1, the Drosophila homolog of human FMR1, is required for transposon suppression in the germlines. Genetic analyses showed that dfmr1 and piwi act synergistically in heterochromatic silencing, and in inhibiting the differentiation of primordial germline cells and transposon expression. Northern analyses showed that roo piRNA expression levels are reduced in dfmr1 mutant ovaries, suggesting a role of dfmr1 in piRNA biogenesis. Biochemical analysis demonstrated a physical interaction between dFMRP and Piwi via their N-termini. Taken together, we propose that dFMRP cooperates with Piwi in maintaining genome integrity by regulating heterochromatic silencing in somatic cells and suppressing transposon activity via the piRNA pathway in germlines.


Assuntos
Proteínas Argonauta/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Animais , Proteínas Argonauta/química , Proteínas Cromossômicas não Histona/metabolismo , Drosophila/crescimento & desenvolvimento , Drosophila/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Feminino , Proteína do X Frágil de Retardo Mental/química , Proteína do X Frágil de Retardo Mental/genética , Inativação Gênica , Genoma de Inseto , Mutação , Ovário/crescimento & desenvolvimento , Óvulo/citologia , Proteínas do Grupo Polycomb/metabolismo , RNA Interferente Pequeno/metabolismo , Retroelementos
18.
Tumour Biol ; 37(7): 9663-70, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26801671

RESUMO

MicroRNAs (miRNAs), a kind of endogenous non-coding RNAs, regulate gene expression through binding to the 3'-untranslational region (UTR) of target messenger RNAs (mRNAs) and act as endogenous agents of RNA interference, resulting in either mRNA degradation or translational repression. MiR-31 has been demonstrated to be associated with the development and progression of glioma. However, the underlying molecular mechanism remains largely unclear. In the present study, we demonstrated that miR-31 only inhibited the cell migration and invasion, as well as the expression of a known miR-31 target oncogene radixin, in U251 glioma cells that expressed low level of p21; however, miR-31 showed no above effects on glioma SHG44 cells that highly expressed p21. Moreover, upregulation of p21 in U251 cells reversed the suppressive effects of miR-31 on the cell migration and invasion, suggesting that low p21 level is necessary for the miR-31-mediated inhibitory effects on glioma. Furthermore, analysis for 35 glioma specimens showed that the expression of radixin was negatively correlated with the miR-31 level in glioma tissues with low p21 expression; however, no such correlation was found in glioma tissues with high p21 level, further supporting that the low p21 level is necessary for the suppressive effect of miR-31 on the expression of its target oncogenes. In summary, our study demonstrates that the suppressive effect of miR-31 on glioma cell migration and invasion is p21-dependent, and suggests that miR-31 may be used for the treatment of patients with p21-deficent glioma.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Glioma/genética , MicroRNAs/genética , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas do Citoesqueleto/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Regulação para Cima/genética
19.
Brain Pathol ; 26(2): 167-76, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25976060

RESUMO

Parkinson's disease (PD) is the most prevalent movement disorder characterized by selective loss of midbrain dopaminergic (DA) neurons. MicroRNA-124 (miR-124) is abundantly expressed in the DA neurons and its expression level decreases in the 1-methyl-4-pheny-1, 2, 3, 6-tetrahydropyridine (MPTP) model of PD. However, whether the upregulation of miR-124 could attenuate neurodegeneration remains unknown. Here, we employed miR-124 agomir and miR-124 mimics to upregulate miR-124 expression in MPTP-treated mice and MPP(+) -intoxicated SH-SY5Y cells, respectively. We found that loss of DA neurons and striatal dopamine in MPTP-treated mice was significantly reduced by upregulating miR-124. In addition, we identified a target of miR-124, Bim that mediated the neuroprotection of miR-124. Indeed, treatment of miR-124 agomir in MPTP-treated mice inhibited Bim expression, thus suppressing Bax translocation to mitochondria. Moreover, impaired autophagy process in MPTP-treated mice and MPP(+) -intoxicated SH-SY5Y cells characterized as autophagosomes (AP) accumulation and lysosomal depletion were alleviated by the upregulation of miR-124. Taken together, these results indicate that upregulation of miR-124 could regulate apoptosis and impaired autophagy process in the MPTP model of PD, thus reducing the loss of DA neurons.


Assuntos
Proteína 11 Semelhante a Bcl-2/metabolismo , Intoxicação por MPTP/metabolismo , MicroRNAs/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Linhagem Celular Tumoral , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Intoxicação por MPTP/patologia , Masculino , Camundongos Endogâmicos C57BL , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
20.
Sensors (Basel) ; 15(12): 30340-50, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26690146

RESUMO

It is necessary to detect the target reflections in ground penetrating radar (GPR) images, so that surface metal targets can be identified successfully. In order to accurately locate buried metal objects, a novel method called the Multiresolution Monogenic Signal Analysis (MMSA) system is applied in ground penetrating radar (GPR) images. This process includes four steps. First the image is decomposed by the MMSA to extract the amplitude component of the B-scan image. The amplitude component enhances the target reflection and suppresses the direct wave and reflective wave to a large extent. Then we use the region of interest extraction method to locate the genuine target reflections from spurious reflections by calculating the normalized variance of the amplitude component. To find the apexes of the targets, a Hough transform is used in the restricted area. Finally, we estimate the horizontal and vertical position of the target. In terms of buried object detection, the proposed system exhibits promising performance, as shown in the experimental results.

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