Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
EMBO J ; : e103111, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32187724

RESUMO

The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.

2.
J Neuroinflammation ; 17(1): 45, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007102

RESUMO

BACKGROUND: G-protein-coupled estrogen receptor (GPER/GPR30) is a novel membrane-associated estrogen receptor that can induce rapid kinase signaling in various cells. Activation of GPER can prevent hippocampal neuronal cell death following transient global cerebral ischemia (GCI), although the mechanisms remain unclear. In the current study, we sought to address whether GPER activation exerts potent anti-inflammatory effects in the rat hippocampus after GCI as a potential mechanism to limit neuronal cell death. METHODS: GCI was induced by four-vessel occlusion in ovariectomized female SD rats. Specific agonist G1 or antagonist G36 of GPER was administrated using minipump, and antisense oligonucleotide (AS) of interleukin-1ß receptor antagonist (IL1RA) was administrated using brain infusion kit. Protein expression of IL1RA, NF-κB-P65, phosphorylation of CREB (p-CREB), Bcl2, cleaved caspase 3, and microglial markers Iba1, CD11b, as well as inflammasome components NLRP3, ASC, cleaved caspase 1, and Cle-IL1ß in the hippocampal CA1 region were investigated by immunofluorescent staining and Western blot analysis. The Duolink II in situ proximity ligation assay (PLA) was performed to detect the interaction between NLRP3 and ASC. Immunofluorescent staining for NeuN and TUNEL analysis were used to analyze neuronal survival and apoptosis, respectively. We performed Barnes maze and Novel object tests to compare the cognitive function of the rats. RESULTS: The results showed that G1 attenuated GCI-induced elevation of Iba1 and CD11b in the hippocampal CA1 region at 14 days of reperfusion, and this effect was blocked by G36. G1 treatment also markedly decreased expression of the NLRP3-ASC-caspase 1 inflammasome and IL1ß activation, as well as downstream NF-κB signaling, the effects reversed by G36 administration. Intriguingly, G1 caused a robust elevation in neurons of a well-known endogenous anti-inflammatory factor IL1RA, which was reversed by G36 treatment. G1 also enhanced p-CREB level in the hippocampus, a transcription factor known to enhance expression of IL1RA. Finally, in vivo IL1RA-AS abolished the anti-inflammatory, neuroprotective, and anti-apoptotic effects of G1 after GCI and reversed the cognitive-enhancing effects of G1 at 14 days after GCI. CONCLUSIONS: Taken together, the current results suggest that GPER preserves cognitive function following GCI in part by exerting anti-inflammatory effects and enhancing the defense mechanism of neurons by upregulating IL1RA.

3.
PeerJ ; 7: e7132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632844

RESUMO

Background: Many recent studies have demonstrated the predominant role chronic inflammation plays in cancer cell propagation, angiogenesis and immunosuppression. Cancer-related inflammation (CRI) has been shown to correlate with poor cancer prognosis. Our study aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with hepatocellular carcinoma (HCC) who have undergone liver resection. Methods: Between 2012 and 2015, 239 patients with HCC who had undergone liver resection at XiangYa Hospital Central South University were included in this study. The values of simple inflammatory markers, including the NLR and PLR, used in predicting the long-term outcomes of these patients were evaluated using Kaplan-Meier curves and Cox regression models. Results: The cutoff values of the NLR and PLR were 2.92 and 128.1, respectively. In multivariate Cox regression analysis, high NLR (≥2.92) and high PLR (≥128.1) were independent risk factors predicting poorer outcomes in patients with HCC. However, high NLR and high PLR were prognostic factors in tumor size and tumor number. Conclusions: In this study, we identified that high NLR (≥2.92) and high PLR (≥128.1) are useful prognostic factors in predicting outcomes in patients with HCC whom underwent liver resection.

4.
World J Clin Cases ; 7(16): 2238-2246, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31531318

RESUMO

BACKGROUND: Muscular atrophy is the basic defect of neurogenic clubfoot. Muscle atrophy of clubfoot needs more scientific and reasonable imaging measurement parameters to evaluate. The Hippo pathway and myostatin pathway may be directly correlated in myogenesis. In this study, we will use congenital neurogenic clubfoot muscle atrophy model to verify in vivo. Further, the antagonistic mechanism of TAZ on myostatin was studied in the C2C12 cell differentiation model. AIM: To identify muscle atrophy in fetal neurogenic clubfoot by ultrasound imaging and detect the expression of TAZ and myostatin in gastrocnemius muscle. To elucidate the possible mechanisms by which TAZ antagonizes myostatin-induced atrophy in an in vitro cell model. METHODS: Muscle atrophy in eight cases of fetal unilateral clubfoot with nervous system abnormalities was identified by 2D and 3D ultrasound. Western blotting and immunostaining were performed to detect expression of myostatin and TAZ. TAZ overexpression in C2C12 myotubes and the expression of associated proteins were analyzed by western blotting. RESULTS: The maximum cross-sectional area of the fetal clubfoot on the varus side was reduced compared to the contralateral side. Myostatin was elevated in the atrophied gastrocnemius muscle, while TAZ expression was decreased. They were negatively correlated. TAZ overexpression reversed the diameter reduction of the myotube, downregulated phosphorylated Akt, and increased the expression of forkhead box O4 induced by myostatin. CONCLUSION: Ultrasound can detect muscle atrophy of fetal clubfoot. TAZ and myostatin are involved in the pathological process of neurogenic clubfoot muscle atrophy. TAZ antagonizes myostatin-induced myotube atrophy, potentially through regulation of the Akt/forkhead box O4 signaling pathway.

5.
Math Biosci Eng ; 16(5): 3393-3410, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31499620

RESUMO

In 2017, the low pathogenic avian influenza H7N9 virus in China had mutated into high pathogenicity to domestic poultry, and led to a large number of poultry death and human cases. To evaluate the effect of virus mutation on the transmission of avian influenza H7N9 virus, this paper takes Guangdong province for the research area, takes domestic poultry, virus in the domestic poultry survival environment and human beings for the research objects, and establishes a non-autonomous dynamical model. By fitting model with the newly confirmed human cases in Guangdong province, the model we established is confirmed and applied to explain the dynamics of historical human cases. By carrying on parameter estimation, it is deduced that at least 5279376 human beings in Guangdong province had been infected with avian influenza H7N9 virus from March 2013 to September 2017, but most of them were not confirmed, since they had no obvious symptoms or had been cured as common influenza. And comparing with the low pathogenic avian influenza H7N9 virus (H7N9 LPAIV), the transmission rate of the highly pathogenic avian influenza H7N9 virus (H7N9 HPAIV) to human is almost unchanged, but to domestic poultry is about 3.87 times higher. Also, we calculate the basic reproduction number ℜ0 = 1.3042, which indicates that the virus will persist in Guangdong province with time. Besides, we also perform some sensitivity analysis of the newly confirmed human cases and ℜ0 in terms of model parameters and conclude that reducing the birth population of domestic poultry, speeding up the circulation of domestic poultry in the market and raising the rate of disease-related death of domestic poultry are benefit to control the transmission of the avian influenza H7N9 virus.

6.
J Cancer ; 10(17): 3893-3898, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417632

RESUMO

Background: Numerous studies have shown that circular RNAs (circRNAs) play vital roles in tumor progression. However, how circRNAs function in hepatocellular cancer (HCC) remains mostly unclear. Methods: We analyzed HCC circRNA expression via a microarray, and the expression of an upregulated circRNA, circABCC2, was detected. We next explored the function of circABCC2 in HCC via a series of experiments. We performed RNA immunoprecipitation (RIP) and luciferase assays to explore the competing endogenous RNA (ceRNA) function of circABCC2 in HCC. Results: qRT-PCR verified that circABCC2 was overexpressed in HCC. Inhibition of circABCC2 suppressed HCC cell proliferation and invasion, but promoted apoptosis. Luciferase assays and RIP showed that circABCC2 and ABCC2 could directly bind to miR-665 and that circABCC2 could regulate ABCC2 expression by sponging miR-665. Conclusions: In summary, circABCC2 regulates ABCC2 expression and HCC progression by sponging miR-665. circABCC2 could be used as a biomarker and therapeutic target in HCC.

7.
Int J Biol Sci ; 15(5): 909-918, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182912

RESUMO

The really interesting new gene (RING) finger protein 8 (RNF8) is a central factor in DNA double strand break (DSB) signal transduction. DSB damage is the most toxic type of DNA damage to cells and is related to genomic instability. Multiple roles for RNF8 have been identified in DNA damage response as well as in other functions, such as telomere protection, cell cycle control and transcriptional regulation. These functions are closely correlated to tumorigenesis and cancer progression. Indeed, deficiency of RNF8 caused spontaneous tumorigenesis in a mouse model. Deciphering these mechanisms of RNF8 may shed light on strategies for cancer treatment. In this review, we summarize the current understanding of both classical and nonclassical functions of RNF8, and discuss its roles in the pathogenesis and progression of tumor.

8.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(3): 315-321, 2019 Mar 28.
Artigo em Chinês | MEDLINE | ID: mdl-30971525

RESUMO

OBJECTIVE: To investigate the risk factors for hypoparathyroidism after thyroidectomy.
 Methods: Clinical data of 492 patients, who underwent thyroidectomy from April 2015 to December 2016 from Xiangya Hospital of Central South University, were studied retrospectively. Chi-square test and multivariable logistic regression were performed to find the risk factors for postoperative hypoparathyroidism.
 Results: The incidence of postoperative hypoparathyroidism was 43.5%, and the incidence of temporary and permanent hypoparathyroidism was 43.1% and 0.4%, respectively. Univariate analysis showed that tumor pathology, thyroidectomy types, the extent of lymph node dissection, application of carbon nanoparticles, and merged Hashimoto's thyroiditis were risk factors for postoperative hypoparathyroidism (all P<0.01). Logistic regression analysis showed that: thyroidectomy types (OR=0.149, 95% CI 0.078 to 0.28), the extent lymph node dissection (OR=0.779, 95% CI 0.617 to 0.983) and application of carbon nanoparticles (OR=1.729, 95% CI 1.067 to 2.801) were independent risk factors for postoperative hypoparathyroidism (all P<0.05).
 Conclusion: Hypoparathyroidism is a common complication after thyroidectomy. The incidence of postoperative hypoparathyroidism is significantly increased in patients underwent total thyroidectomy and cervical lymph node dissection. Application of carbon nanoparticles intraoperatively can reduce the incidence of postoperative hypoparathyroidism.


Assuntos
Hipoparatireoidismo , Humanos , Hipoparatireoidismo/cirurgia , Complicações Pós-Operatórias , Estudos Retrospectivos , Fatores de Risco , Neoplasias da Glândula Tireoide , Tireoidectomia
9.
Diabetes Metab Res Rev ; 35(7): e3168, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974033

RESUMO

AIMS: To evaluate the association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the risk of bone fracture in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We conducted a systematic literature search in PubMed, Embase, the Cochrane Library, and Web of Science from inception to 28 February 2018 and identified eligible randomized controlled trials. The following data were extracted from each study: first author, year of publication, sample size, patient characteristics, study design, intervention drug, control drug, follow-up time, and incident bone fracture events. A meta-analysis was conducted using Review Manager 5.3 software to calculate the odds ratio (OR) and 95% confidence intervals (CI) for dichotomous variables. RESULTS: A total of 38 studies with 39 795 patients with T2DM were included. There were 241 incident bone fracture cases (107 in the GLP-1 RAs group and 134 in the control group). Compared with patients who received placebo and other anti-diabetic drugs, those who received GLP-1 RAs treatment showed a pooled OR of 0.71 (95% CI, 0.56-0.91) for bone fracture. Subgroup analysis showed that treatments with liraglutide and lixisenatide were associated with significantly reduced risk of bone fractures (ORs, 0.56; 95% CI, 0.38-0.81 and 0.55; 95% CI, 0.31-0.97, respectively). However, other GLP-1 RAs did not show superiority to placebo or other anti-diabetic drugs. Moreover, these beneficial effects were dependent on the duration of GLP-1 RAs treatment, only a GLP-1 RAs treatment period of more than 52 weeks could significantly lower the risk of bone fracture in patients with T2DM (OR, 0.71; 95% CI, 0.56-0.91). CONCLUSIONS: Compared with placebo and other anti-diabetic drugs, liraglutide and lixisenatide were associated with a significant reduction in the risk of bone fractures, and the beneficial effects were dependent on the duration of treatment.

10.
Acta Pharmacol Sin ; 40(8): 999-1009, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30796355

RESUMO

Promoting white adipose tissue (WAT) browning and enhancing brown adipose tissue (BAT) activity are attractive therapeutic strategies for obesity and its metabolic complications. Targeting sympathetic innervation in WAT and BAT represents a promising therapeutic concept. However, there are few reports on extracellular microenvironment remodeling, especially changes in nerve terminal connections. Identifying the key molecules mediating the neuro-adipose synaptic junctions is a key point. In this study, we used bioinformatics methods to identify the differentially expressed predicted secreted genes (DEPSGs) during WAT browning and BAT activation. These DEPSGs largely reflect changes of cytokines, extracellular matrix remodeling, vascularization, and adipocyte-neuronal cross-talk. We then performed functional enrichment and cellular distribution specificity analyses. The upregulated and downregulated DEPDGs during WAT browning displayed a distinctive biological pattern and cellular distribution. We listed a cluster of adipocyte-enriched DEPSGs, which might participate in the cross-talk between mature adipocytes and other cells; then identified a synaptogenic adhesion molecule, Clstn3, as the top gene expressed enriched in both mature white and brown adipocytes. Using Q-PCR and immunohistochemistry, we found significantly increased Clstn3 expression level during WAT browning and BAT activation in mice subjected to cold exposure (4 °C). We further demonstrated that treatment with isoproterenol significantly increased Clstn3 and UCP1 expression in differentiated white and beige adipocytes in vitro. In conclusion, our study demonstrates that the secretion pattern was somewhat different between WAT browning and BAT activation. We reveal that Clstn3 may be a key gene mediating the neuro-adipose junction formation or remodeling in WAT browning and BAT activation process.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas de Membrana/metabolismo , Células 3T3-L1 , Animais , Biologia Computacional , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sinapses/metabolismo , Transcriptoma
11.
Sensors (Basel) ; 18(11)2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30463356

RESUMO

The aircraft full-scale fatigue test is widely used in the modern aircraft industry for the safety of flight. Generally, the aircraft full-scale fatigue test is achieved by structural loading; multiple hydraulic actuators are used to apply load for force control. The fatigue loading test takes approximately several years. A key challenge is how to accelerate the loading frequency to shorten the total test time. Nevertheless, when pluralities of hydraulic actuator simultaneously increase the loading frequency, the mutual coupling force from the low rigidity of the aircraft structure will cause a large loading error, meaning that the test cannot be implemented. Although it is possible to reduce error by adding sensors, the force sensors need to connect several kilometers of cable. This paper proposed a novel motion synchronous composite decoupling control strategy with fewer sensors. The control method compensates the negative coupling effect of the channels by integrating the command signals and feedback signals of all channels. It can suppress coupling force and reduce errors at higher frequencies, thereby shortening the experiment time. Opposed to traditional decoupling control methods, advantages of this strategy are that it only needs force sensors and it does not need additional displacement or velocity and acceleration sensors to collect state variables for building the state space. Furthermore, it has been experimentally verified that the new motion synchronous composite decoupling control method can indeed guarantee sufficient control accuracy when the test frequency is increased. The method has great economic significance for shortening test duration.

12.
Am J Otolaryngol ; 39(6): 746-750, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30197157

RESUMO

PURPOSE: To assess the value of 24-hour intact parathyroid hormone (iPTH), serum calcium, and decreases in both were evaluated against preoperative values (iPTH and serum calcium decline) and used to determine the existence of permanent hypoparathyroidism (pHPP) after total thyroidectomy (TT). MATERIALS AND METHODS: The clinical data of patients who underwent total thyroidectomy in our hospital between September 2014 and July 2015 were retrospectively analyzed. RESULTS: There were 42 cases with normal parathyroid function, 58 cases with temporary HPP, and 10 cases with pHPP. When iPTH and serum calcium were administered at 24 h after surgery, iPTH decline and calcium decline differed significantly among the three groups above (P < .01). The accuracy and positive predictive value of 24 h iPTH for pHPP were higher than any one of the others. The sensitivity, specificity, false positive rate, and accuracy were 100%, 95%, 33.33%, and 94.45%, respectively. The AUC was 0.982 when 24-hour iPTH was equal to or <3.15 pg/mL. The use of blood calcium equal to or <2.03 mmol/L (8.12 mg/dL) pointed to a diagnosis of pHPP, with a sensitivity of 100%, specificity of 63%, false positive rate of 78.72%, and accuracy of 66.36%. CONCLUSIONS: Measurement of the postoperative 24-h intact parathyroid hormone and serum calcium concentration can predict the occurrence of permanent hypoparathyroidism and the former is more advantageous. Postoperative 24-h intact parathyroid hormone equal to or <3.15 pg/mL is a reliable index, and it is suitable for the prediction of postoperative permanent hypoparathyroidism.


Assuntos
Cálcio/sangue , Hipoparatireoidismo/etiologia , Hormônio Paratireóideo/sangue , Complicações Pós-Operatórias/etiologia , Doenças da Glândula Tireoide/cirurgia , Tireoidectomia/efeitos adversos , Adulto , Feminino , Humanos , Hipoparatireoidismo/sangue , Hipoparatireoidismo/diagnóstico , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/diagnóstico , Valor Preditivo dos Testes , Estudos Retrospectivos , Doenças da Glândula Tireoide/sangue , Fatores de Tempo
13.
J Exp Clin Cancer Res ; 37(1): 172, 2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30053867

RESUMO

BACKGROUD: Accumulating evidences indicate that circular RNAs (circRNAs), a class of non-coding RNAs, play important roles in tumorigenesis. However, the function of circRNAs in hepatocellular cancer (HCC) is largely unknown. METHODS: We performed circRNA microarrays to identify circRNAs that are aberrantly expressed in HCC tissues. Expression levels of a significantly upregulated circRNA, circFBLIM1, was detected by quantitative real-time PCR (qRT-PCR) in HCC cell lines and tissues. Then, we examined the functions of circFBLIM1 in HCC by cell proliferation, apoptosis, invasion and mouse xenograft assay. In addition, luciferase assay and RNA immunoprecipitation (RIP) assay were used to explore the miRNA sponge function of circFBLIM1 in HCC. RESULTS: Microarray analysis and qRT-PCR verified a circRNA termed circFBLIM1 that was upregulated in HCC tissues and cell lines. Knockdown of circFBLIM1 inhibited proliferation, invasion and promoted apoptosis in HCC. Via luciferase reporter assays, circFBLIM1 and FBLIM1 were observed to directly bind to miR-346. Subsequent experiments showed that circFBLIM1 and FBLIM1 regulated the expression of each other by sponging miR-346. CONCLUSIONS: Taken together, we conclude that circFBLIM1 may function as a competing endogenous RNA (ceRNA) to regulate FBLIM1 expression through sponging miR-346 to exert regulatory functions in HCC. circFBLIM1 may be a diagnostic biomarker and potential target for HCC therapy.


Assuntos
Carcinoma Hepatocelular/genética , Moléculas de Adesão Celular/genética , Proteínas do Citoesqueleto/genética , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , RNA/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Moléculas de Adesão Celular/biossíntese , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas do Citoesqueleto/biossíntese , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/biossíntese , MicroRNAs/genética , Análise em Microsséries , RNA/biossíntese , RNA/genética , Transfecção
14.
Int J Biol Sci ; 13(8): 1092-1099, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28924389

RESUMO

SMC1 (Structural Maintenance of Chromosomes protein 1), well known as one of the SMC superfamily members, has been explored to function in many activities including chromosome dynamics, cell cycle checkpoint, DNA damage repair and genome stability. Upon being properly assembled as part of cohesin, SMC1 can be phosphorylated by ATM and mediate downstream DNA damage repair after ionizing irradiation. Abnormal gene expression or mutation of SMC1 can cause defect in the DNA damage repair pathway, which has been strongly associated with tumorigenesis. Here we focus to discuss SMC1's role in genome stability maintenance and tumorigenesis. Deciphering the underlying molecular mechanism can provide insight into novel strategies for cancer treatment.


Assuntos
Carcinogênese/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Instabilidade Genômica/fisiologia , Animais , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Proteínas Cromossômicas não Histona/genética , Dano ao DNA/genética , Dano ao DNA/fisiologia , Reparo do DNA/genética , Reparo do DNA/fisiologia , Feminino , Instabilidade Genômica/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilação/genética , Fosforilação/fisiologia
15.
Neuropsychopharmacology ; 40(7): 1569-79, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25662838

RESUMO

An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLAST(CreERT2/+)/GLT1(flox/flox), iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.


Assuntos
Córtex Cerebral/patologia , Transtornos Traumáticos Cumulativos/genética , Transtornos Traumáticos Cumulativos/patologia , Transportador 1 de Aminoácido Excitatório/deficiência , Transportador 2 de Aminoácido Excitatório/deficiência , Sinapses/genética , Animais , Animais Recém-Nascidos , Ansiedade/genética , Transtornos Traumáticos Cumulativos/complicações , Transtornos Traumáticos Cumulativos/tratamento farmacológico , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Transportador 1 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/genética , Potenciais Pós-Sinápticos Excitadores/genética , Feminino , Regulação da Expressão Gênica/genética , Hiperalgesia/genética , Masculino , Camundongos , Camundongos Transgênicos , Degeneração Neural/etiologia , Degeneração Neural/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas/genética , Convulsões/genética
16.
Mol Brain ; 6: 34, 2013 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-23902942

RESUMO

BACKGROUND: Loss of retinal ganglion cells (RGCs) is a hallmark of various retinal diseases including glaucoma, retinal ischemia, and diabetic retinopathy. N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR)-mediated excitotoxicity is thought to be an important contributor to RGC death in these diseases. Native NMDARs are heterotetramers that consist of GluN1 and GluN2 subunits, and GluN2 subunits (GluN2A-D) are major determinants of the pharmacological and biophysical properties of NMDARs. All NMDAR subunits are expressed in RGCs in the retina. However, the relative contribution of the different GluN2 subunits to RGC death by excitotoxicity remains unclear. RESULTS: GluN2B- and GluN2D-deficiency protected RGCs from NMDA-induced excitotoxic retinal cell death. Pharmacological inhibition of the GluN2B subunit attenuated RGC loss in glutamate aspartate transporter deficient mice. CONCLUSIONS: Our data suggest that GluN2B- and GluN2D-containing NMDARs play a critical role in NMDA-induced excitotoxic retinal cell death and RGC degeneration in glutamate aspartate transporter deficient mice. Inhibition of GluN2B and GluN2D activity is a potential therapeutic strategy for the treatment of several retinal diseases.


Assuntos
N-Metilaspartato/toxicidade , Neurotoxinas/toxicidade , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/metabolismo , Retina/patologia , Animais , Morte Celular/efeitos dos fármacos , Transportador 1 de Aminoácido Excitatório/deficiência , Transportador 1 de Aminoácido Excitatório/metabolismo , Deleção de Genes , Marcação In Situ das Extremidades Cortadas , Isoquinolinas/farmacologia , Camundongos , Subunidades Proteicas/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Retina/efeitos dos fármacos
17.
Mol Brain ; 6: 25, 2013 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-23688253

RESUMO

BACKGROUND: Bergmann glia (BG) are unipolar cerebellar astrocytes. The somata of mature BG reside in the Purkinje cell layer and extend radially arranged processes to the pial surface. BG have multiple branched processes, which enwrap the synapses of Purkinje cell dendrites. They migrate from the ventricular zone and align next to the Purkinje cell layer during development. Previously, we reported that Notch1, Notch2, and RBPj genes in the BG play crucial roles in the monolayer formation and morphogenesis of BG. However, it remains to be determined which ligand activates Nocth1 and Notch 2 on BG. Delta-like 1 (Dll1) is a major ligand of Notch receptors that is expressed in the developing cerebellum. RESULTS: In this study, we used human glial fibrillary acidic protein (hGFAP) promoter-driven Cre-mediated recombination to delete Dll1 in BG. Dll1-conditional mutant mice showed disorganization of Bergmann fibers, ectopic localization of BG in the molecular layer and a reduction in the number of BG. CONCLUSION: These results suggest that Dll1 is required for the formation of the BG layer and its morphological maturation, apparently through a Notch1/2-RBPj dependent signaling pathway.


Assuntos
Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neuroglia/metabolismo , Envelhecimento/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Proteínas de Ligação ao Cálcio , Contagem de Células , Diferenciação Celular , Cerebelo/anormalidades , Deleção de Genes , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Integrases/metabolismo , Camundongos , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Receptores Notch/metabolismo , Transdução de Sinais
18.
Mol Brain ; 6: 22, 2013 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-23641686

RESUMO

BACKGROUND: N-methyl-D-aspartate receptors (NMDARs) are critical for neuronal development and synaptic plasticity. Dysregulation of NMDARs is implicated in neuropsychiatric disorders. Native NMDARs are heteromultimeric protein complexes consisting of NR1 and NR2 subunits. NR2 subunits (NR2A-D) are the major determinants of the functional properties of NMDARs. Most research has focused on NR2A- and/or NR2B-containing receptors. A recent study demonstrated that NR2C- and/or NR2D-containing NMDARs are the primary targets of memantine, a drug that is widely prescribed to treat Alzheimer's disease. Our laboratory demonstrated that memantine prevents the loss of retinal ganglion cells (RGCs) in GLAST glutamate transporter knockout mice, a model of normal tension glaucoma (NTG), suggesting that NR2D-containing receptors may be involved in RGC loss in NTG. RESULTS: Here we demonstrate that NR2D deficiency attenuates RGC loss in GLAST-deficient mice. Furthermore, Dock3, a guanine nucleotide exchange factor, binds to the NR2D C-terminal domain and reduces the surface expression of NR2D, thereby protecting RGCs from excitotoxicity. CONCLUSIONS: These results suggest that NR2D is involved in the degeneration of RGCs induced by excitotoxicity, and that the interaction between NR2D and Dock3 may have a neuroprotective effect. These findings raise the possibility that NR2D and Dock3 might be potential therapeutic targets for treating neurodegenerative diseases such as Alzheimer's disease and NTG.


Assuntos
Proteínas de Transporte/metabolismo , Citoproteção/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Neurotoxinas/toxicidade , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Transportador 1 de Aminoácido Excitatório/deficiência , Transportador 1 de Aminoácido Excitatório/metabolismo , Glutamatos/toxicidade , Fatores de Troca do Nucleotídeo Guanina , Células HEK293 , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Camundongos , N-Metilaspartato/toxicidade , Neurônios/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Retina/efeitos dos fármacos , Retina/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia
19.
Eur J Endocrinol ; 162(4): 661-6, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20061334

RESUMO

OBJECTIVE: To investigate whether 4-month preoperative lanreotide treatment would improve the surgical cure rate of newly diagnosed acromegalic patients with macroadenomas. DESIGN: A prospective, randomised study. METHODS: After a baseline evaluation, patients were randomly assigned to 4-month preoperative treatment with lanreotide (starting with 30 mg/2 weeks i.m. and increasing to 30 mg/week i.m. at week 8 if mean GH >2.5 microg/l on GH day curves; pretreatment group, Group 1) or to transsphenoidal surgery (direct surgery group, Group 2). Cure was evaluated 4 months postoperatively primarily by fasting IGF1 less than or equal to age-adjusted upper limit of normal. RESULTS: A pool of 108 patients was randomly divided into two groups. Five patients in each group were lost to follow-up during the study period, so 49 patients in each group were analysed. At baseline, no difference was observed between the two groups. Cure was established in 24 of 49 (49.0%, 95% confidence interval (CI), 35.0-63.0%) pretreated patients (Group 1) versus 9 of 49 (18.4%, 95% CI, 7.6-29.2%) direct surgery patients (Group 2; P=0.001). Surgical morbidity was recorded in 12 patients (12.2%) and was similar in Group 1 and 2 patients (14.3 and 10.2% respectively; P=0.538). The postoperative hospital stay was similar between groups: being 4.5+/-1.6 days in Group 1 vs 4.8+/-1.9 days in Group 2 (P=0.328). CONCLUSIONS: Pretreatment with lanreotide before transsphenoidal surgery improves surgical cure rates in patients with GH-secreting pituitary macroadenomas. Pretreatment does not affect surgical complications or duration of hospital stay (ClinicalTrials.gov number, NCT00993356).


Assuntos
Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Neoplasias Hipofisárias/tratamento farmacológico , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/cirurgia , Adenoma/sangue , Adenoma/cirurgia , Adulto , Distribuição de Qui-Quadrado , Terapia Combinada , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/cirurgia , Cuidados Pré-Operatórios , Estudos Prospectivos , Somatostatina/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA