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1.
Cell Biol Int ; 45(8): 1644-1653, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33760350

RESUMO

Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/ß-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/ß-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Neoplasias da Mama/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Molécula de Adesão da Célula Epitelial/biossíntese , Transição Epitelial-Mesenquimal/fisiologia , Proteínas de Neoplasias/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Molécula de Adesão da Célula Epitelial/antagonistas & inibidores , Molécula de Adesão da Célula Epitelial/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Mitoxantrona/farmacologia , Proteínas de Neoplasias/genética , RNA Interferente Pequeno/administração & dosagem
2.
Bioorg Med Chem Lett ; 44: 128106, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33991630

RESUMO

Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC50 = 0.010 µM) and the activity of iNOS (IC50 = 0.082 µM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Descoberta de Drogas , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Doença Aguda , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Carragenina , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
3.
Cereb Cortex ; 30(6): 3717-3730, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-31907535

RESUMO

Angiogenesis in the developing cerebral cortex accompanies cortical neurogenesis. However, the precise mechanisms underlying cortical angiogenesis at the embryonic stage remain largely unknown. Here, we show that radial glia-derived vascular cell adhesion molecule 1 (VCAM1) coordinates cortical vascularization through different enrichments in the proximal and distal radial glial processes. We found that VCAM1 was highly enriched around the blood vessels in the inner ventricular zone (VZ), preventing the ingrowth of blood vessels into the mitotic cell layer along the ventricular surface. Disrupting the enrichment of VCAM1 surrounding the blood vessels by a tetraspanin-blocking peptide or conditional deletion of Vcam1 gene in neural progenitor cells increased angiogenesis in the inner VZ. Conversely, VCAM1 expressed in the basal endfeet of radial glial processes promoted angiogenic sprouting from the perineural vascular plexus (PNVP). In utero, overexpression of VCAM1 increased the vessel density in the cortical plate, while knockdown of Vcam1 accomplished the opposite. In vitro, we observed that VCAM1 bidirectionally affected endothelial cell proliferation in a concentration-dependent manner. Taken together, our findings identify that distinct concentrations of VCAM1 around VZ blood vessels and the PNVP differently organize cortical angiogenesis during late embryogenesis.


Assuntos
Proliferação de Células/genética , Córtex Cerebral/embriologia , Células Endoteliais/metabolismo , Células Ependimogliais/metabolismo , Neovascularização Fisiológica/genética , Molécula 1 de Adesão de Célula Vascular/genética , Animais , Proliferação de Células/efeitos dos fármacos , Córtex Cerebral/irrigação sanguínea , Ventrículos Cerebrais/irrigação sanguínea , Ventrículos Cerebrais/embriologia , Células Endoteliais/citologia , Células Ependimogliais/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Técnicas In Vitro , Camundongos , Camundongos Knockout , Neovascularização Fisiológica/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
4.
Mol Pain ; 15: 1744806919842464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30987515

RESUMO

Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs have been recently linked to many diseases, including neuropathic pain. However, the role of miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation rat model. After establishment of spinal nerve ligation rat models, rats were infected with adeno-associated virus-neurofilament light polypeptide, adeno-associated virus-miR-7a or treated with metformin. The paw withdrawal threshold and paw withdrawal latency were assessed afterward, and the expression of miR-7a and neurofilament light polypeptide as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of neurofilament light polypeptide on neuropathic pain was detected using plasmid overexpressing neurofilament light polypeptide. Spinal nerve ligation rat model exhibited upregulation of neurofilament light polypeptide but downregulation of miR-7a. In addition, neurofilament light polypeptide accumulation or miR-7a inhibition decreased paw withdrawal threshold and paw withdrawal latency. Then, neurofilament light polypeptide accumulation or miR-7a inhibition was observed to increase the phosphorylation level of signal transducer and activator of transcription. miR-7a was found to directly target neurofilament light polypeptide and downregulate neurofilament light polypeptide. In addition, inhibiting the signal transducer and activator of transcription signaling pathway was also revealed to increase paw withdrawal threshold and paw withdrawal latency. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the signal transducer and activator of transcription signaling pathway by repressing neurofilament light polypeptide. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.


Assuntos
MicroRNAs/metabolismo , Neuralgia/genética , Proteínas de Neurofilamentos/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Nervos Espinhais/patologia , Animais , Sequência de Bases , Modelos Animais de Doenças , Regulação para Baixo/genética , Ligadura , Masculino , MicroRNAs/genética , Modelos Biológicos , Proteínas de Neurofilamentos/genética , Ratos Sprague-Dawley , Regulação para Cima/genética
5.
J Org Chem ; 84(16): 10490-10500, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31333031

RESUMO

A versatile protocol for the direct thiolation of an inert sp2 C-H bond is presented via a catalytic amount of copper catalysis, by switching related Brønsted bases and regulating the reaction time, and the corresponding mono- and dithiolation products can be obtained selectively in moderate to good yields. The reaction exhibits a relatively broad substrate scope and a good functional group tolerance, even with different heterocyclic amides and alkyl thiols.

6.
Org Biomol Chem ; 17(9): 2341-2345, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30758028

RESUMO

Here, we present an unprecedented pathway to α-sulfenylated carbonyl compounds from commercially available thiols and universally employed TEMPO and its analogues, which act as C3 synthons through skeletal rearrangement under simple and metal-free conditions. Mechanism studies suggest that this reaction involves a consecutive radical oxidation and cation coupling process. TEMPO analogues and thiols serve as oxidants and reductive reagents, respectively, along the radical process, while in the coupling process, the former ones afford C3 synthons to couple with related sulfur sources.

7.
Biol Reprod ; 98(5): 683-694, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29409020

RESUMO

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and its etiology has not been characterized. Growth differentiation factor 8 (GDF8) is a member of the transforming growth factor-ß superfamily that plays a critical role in the regulation of ovarian functions. However, the expression pattern of GDF8 in the human ovary is not yet clear. This study examined the cellular distribution of GDF8 and its putative cellular receptors (ACVR2A, ACVR2B, and ALK5) in a series of normal (n = 34) and PCOS ovaries (n = 14). The immunostaining of GDF8, ACVR2A, ACVR2B, and ALK5 was detected in the oocytes regardless of the developmental stage. All these proteins were localized in antral follicles in normal and PCOS ovaries, and the expression of these proteins increased with increasing follicle diameter. A significantly higher expression of GDF8 was detected in the granulosa cells than in the matched theca cells (TCs). These proteins were also localized in the luteal cells of the corpus luteum. Granulosa cells and TCs of large antral follicles in PCOS ovaries display a higher expression of these proteins. The higher expression levels of GDF8 and its functional receptors (ACVR2A, ACVR2B, and ALK5) in antral follicles of PCOS ovaries than those in normal ovaries suggest the possible involvement of dysregulated GDF8 in the pathogenesis of PCOS.


Assuntos
Receptores de Activinas Tipo II/metabolismo , Miostatina/metabolismo , Folículo Ovariano/metabolismo , Síndrome do Ovário Policístico/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Adulto , Corpo Lúteo/metabolismo , Feminino , Células da Granulosa/metabolismo , Humanos , Ovário/metabolismo , Células Tecais/metabolismo
8.
Dig Dis Sci ; 60(11): 3283-92, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26108418

RESUMO

BACKGROUND: Perineural invasion (PNI) is one of the important routes for local spread of gastric carcinoma associated with poor prognosis. However, the exact cellular characteristics and molecular mechanisms of PNI are still unclear. AIM: To identify the interaction between gastric carcinoma cells and neural cells, and whether vascular cell adhesion molecule-1 (VCAM1) is involved in this process. METHODS: We adopted in vitro cell coculture assays to investigate the cellular and molecular interaction between gastric cancer cells and neural cells. RESULTS: We find upregulation of VCAM1 in clinical gastric cancer tissue samples. In in vitro tumor-neural cell coculture system, gastric cancer cells with high level of VCAM1 promote proliferation of neural progenitor cells and induce the process outgrowth and branching of neural cells. Reciprocally, neural cells enhance neurotropic migration and mobility of tumor cells. Repressing VCAM1 function through VCAM1 blocking antibody can attenuate these effects. CONCLUSIONS: Our study indicates that VCAM1 is significantly involved in tumor invasion via mediating nerve-tumor interaction, which is a mutually beneficial process. It is possible that interaction between neural cells and tumor cells might contribute to PNI of gastric carcinoma. Inhibiting the activity of VCAM1 could be a potential strategy targeting PNI in gastric carcinoma therapy.


Assuntos
Adenocarcinoma/metabolismo , Comunicação Celular , Movimento Celular , Células-Tronco Neurais/metabolismo , Neoplasias Gástricas/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Técnicas de Cocultura , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células NIH 3T3 , Invasividade Neoplásica , Células-Tronco Neurais/patologia , Transdução de Sinais , Neoplasias Gástricas/patologia , Regulação para Cima
9.
Anal Bioanal Chem ; 406(28): 7221-31, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25260404

RESUMO

Thermal preparation of lysozyme-imprinted microspheres was firstly investigated by using biocompatible ionic liquid (IL) as a thermal stabilizer. The imprinted microspheres made with IL could obtain the good recognition ability to template protein, whereas the imprinted polymer synthesized in the absence of it had a similar adsorption capacity to the non-imprinted one. Furthermore, the preparation conditions of imprinted polymers (MIPs) including the content of IL, temperature of polymerization, and types of functional monomers and crosslinkers were systematically analyzed via circular dichroism spectrum and activity assay. The results illustrated that using hydroxyethyl acrylate as the functional monomer, ethylene glycol dimethacrylate as the crosslinker, 5 % IL as the stabilizer, and 75 °C as the reaction temperature could retain the structure of template protein as much as possible. The obtained MIPs showed excellent recognition ability to the template protein with the separation factor and selectivity factor value of 4.30 and 2.21, respectively. Consequently, it is an effective way to accurately imprint and separate template protein by cooperatively using circular dichroism spectroscopy and activity assay during the preparation of protein MIPs. The method of utilizing IL to stabilizing protein at high temperature would offer a good opportunity for various technologies to improve the development of macromolecules imprinting.


Assuntos
Líquidos Iônicos , Microesferas , Impressão Molecular , Muramidase/química , Muramidase/metabolismo , Animais , Galinhas , Dicroísmo Circular , Polímeros , Extração em Fase Sólida , Temperatura
10.
Front Genet ; 15: 1436469, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39092432

RESUMO

A dicentric chromosome is an abnormal chromosome with two centromeres on the same chromosome. It has been reported that dicentric chromosomes are specific biomarkers of radiation exposure, but dicentric chromosomes are rarely identified in newborns with multiple congenital anomalies. At 16 weeks of gestation, a 39-year-old pregnant woman (gravida 2, para 1) was referred to the prenatal diagnosis center for genetic counseling. The fetal ultrasonography indicated multiple anomalies. Subsequently, amniocentesis was performed, and the G-banding karyotype analysis showed a rare type of mosaicism. The C-banding karyotype analysis indicated a pseudo-dicentric chromosome X [psu dic (X; 18) (p11.2; p11.2)]. A single-nucleotide polymorphism array (SNP array) revealed three pathogenic copy number variations (CNVs). After genetic counseling, the parents chose to terminate this pregnancy. This study provides new evidence for a better understanding of the diagnosis of dicentric chromosomes and emphasizes on the importance of genetic counseling.

11.
Cell Physiol Biochem ; 31(4-5): 649-58, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23652731

RESUMO

BACKGROUND/AIMS: Water channels, also named aquaporins (AQPs), play crucial roles in cellular water homeostasis. METHODS: RT-PCR indicated the mRNA expression of AQPs 1-5, 7, 9, and 11-12, but not AQPs 0, 6, 8, and 10 in the 2∼8-cell stage human embryos. AQP3 and AQP7 were further analyzed for their mRNA expression and protein expression in the oocyte, zygote, 2-cell embryo, 4-cell embryo, 8-cell embryo, morula, and blastocyst from both human and mouse using RT-PCR and immunofluorescence, respectively. RESULTS: AQP3 and AQP7 were detected in all these stages. Knockdown of either AQP3 or AQP7 by targeted siRNA injection into 2-cell mouse embryos significantly inhibited preimplantation embryo development. However, knockdown of AQP3 in JAr spheroid did not affect its attachment to Ishikawa cells. CONCLUSION: These data demonstrate that multiple aquaporins are expressed in the early stage human embryos and that AQP3 and AQP7 may play a role in preimplantation mouse embryo development.


Assuntos
Aquaporina 3/metabolismo , Aquaporinas/metabolismo , Embrião de Mamíferos/metabolismo , Animais , Aquaporina 3/antagonistas & inibidores , Aquaporina 3/genética , Aquaporinas/antagonistas & inibidores , Aquaporinas/genética , Blastocisto/metabolismo , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário , Feminino , Humanos , Camundongos , Camundongos Endogâmicos ICR , Oócitos/metabolismo , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Zigoto/metabolismo
12.
Cereb Cortex ; 21(9): 2158-65, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21339379

RESUMO

Neuron-restrictive silencer factor (NRSF), also known as repressor element-1 silencing transcription factor, is a transcriptional repressor that plays important roles in embryonic development and neurogenesis. Recent findings show that NRSF is upregulated after seizures activity however, the link between NRSF and epileptogenesis remains poorly understood. To investigate the role of NRSF in epilepsy, we employed a Cre-loxp system to specifically delete NRSF in excitatory neurons of the postnatal mouse forebrain. In the kindling model of epileptogenesis, conditional NRSF knockout (NRSF-cKO) mice exhibited dramatically accelerated seizure progression and prolonged afterdischarge duration compared with control mice. Moreover, seizures activity-induced mossy fiber sprouting was enhanced in the NRSF-cKO mice. The degree of upregulation of Fibroblast growth factor 14 and Brain-derived neurotrophic factor (BDNF) following kainic acid-induced status epilepticus was significantly increased in the cortex of NRSF-cKO mice compared with control mice. Furthermore, the derepression of BDNF was associated by activation of PLCγ and PI(3)K signaling pathways. These findings indicate that NRSF functions as an intrinsic repressor of limbic epileptogenesis.


Assuntos
Epilepsia/fisiopatologia , Excitação Neurológica/fisiologia , Neurônios/fisiologia , Prosencéfalo/citologia , Prosencéfalo/fisiologia , Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Animais , Comportamento Animal/fisiologia , Western Blotting , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Fenômenos Eletrofisiológicos , Ativação Enzimática/fisiologia , Fatores de Crescimento de Fibroblastos/genética , Deleção de Genes , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Knockout , Fibras Musgosas Hipocampais/fisiologia , Proteína Oncogênica v-akt/fisiologia , Fosfatidilinositol 3-Quinases/genética , Fosfolipase C gama/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Estado Epiléptico/genética , Estado Epiléptico/fisiopatologia
13.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 32(11): 1521-5, 2012 Nov.
Artigo em Zh | MEDLINE | ID: mdl-23359978

RESUMO

OBJECTIVE: To observe the cytotoxicity of indirubin derivative PHII-7 against human breast cancer MCF-7 cells and to study its primary mechanisms. METHODS: The proliferation of MCF-7 cells was detected using MTT colorimetry. Annexin V/PI double staining was applied to detect the apoptosis rate of MCF-7 cells. The distribution of cell cycles was detected using PI staining and flow cytometry (FCM). The levels of reactive oxygen species (ROS) in MCF-7 cells were detected by DCFH-DA staining. The mRNA and protein levels of c-fos were detected using RT-PCR and Westem blot analysis. RESULTS: PHII-7 at different concentrations inhibited the proliferation of MCF-7 cells in a concentration-dependent manner, with the inhibitory rate ranging from 43.13% to 90.90% (P < 0.05). The inhibition was strengthened along with increased concentrations. PHII-7 at different concentrations could induce the apoptosis of MCF-7 cells. The early apoptosis rate was 1.43% +/- 0.02%, 9.14% +/- 0.36%, and 45.79% +/- 8.46%, respectively with the action of 1.25, 2.50, and 5.00 micromol/L PHII-7, respectively, showing dose-dependent manner. FCM analysis found that the proportion of MCF-7 cells in the G0/G1 phase and the S phase decreased after treatment with PHII-7, and the ratio of MCF-7 cells in the G2/M phase obviously increased (P < 0.01). The intra-cellular ROS level was significantly elevated 2 h after pretreatment with PHII-7. The levels of the protooncogene c-fos mRNA and protein were down-regulated in a dose-dependent manner after action of PHII-7. CONCLUSIONS: PHII-7 exerted obvious in vitro cytotoxic effects on MCF-7 cells. Its mechanisms might be associated with arresting the cell cycle, regulating the redox equilibrium, and down-regulating the expression of the protooncogene.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Indóis/farmacologia , Feminino , Humanos , Células MCF-7
14.
Reprod Sci ; 29(4): 1368-1378, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34580843

RESUMO

High maternal serum estradiol (E2) levels in the first trimester of pregnancy are associated with a high incidence of low birth weight (LBW) and small for gestational age (SGA). This study aimed to investigate the effect of first-trimester high maternal serum E2 levels on fetal growth and the underlying mechanisms in multiple pregnancies. Maternal serum E2 levels of women at 8 weeks of gestation were measured. The expression levels of imprinted genes and DNMT1 were determined by RT-qPCR, and KvDMR1 methylation in embryo tissue, placenta, and newborn cord blood samples was examined by bisulfite sequencing PCR. The effect of E2 on CDKN1C expression was investigated in HTR8 cells. The incidence of SGA was significantly higher in multiple pregnancies reduced to singleton than that in primary singleton pregnancies (11.4% vs. 2.9%) (P < 0.01) and multiple pregnancies reduced to twins than primary twins (38.5% vs. 27.3%) (P < 0.01). The maternal serum E2 level at 8 weeks of gestation increased with the number of fetuses and was negatively correlated with offspring birth weight. CDKN1C and DNMT1 expression was significantly upregulated in embryo tissue, placenta, and cord blood from multiple pregnancies. Furthermore, there was a positive correlation between CDKN1C mRNA expression and KvDMR1 methylation levels. In HTR8 cells, DNMT1 mediated the estrogen-induced upregulation of CDKN1C, which might contribute to SGA. To minimize the risks of LBW and SGA, our findings suggest that abnormally high maternal serum E2 levels should be avoided during the first trimester of multiple pregnancies from assisted reproductive technology (ART).


Assuntos
Recém-Nascido Pequeno para a Idade Gestacional , Inibidor de Quinase Dependente de Ciclina p57/genética , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , DNA (Citosina-5-)-Metiltransferase 1 , Estradiol , Feminino , Retardo do Crescimento Fetal/etiologia , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , Gravidez Múltipla , Regulação para Cima
15.
Epilepsia ; 52(9): 1609-16, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21762439

RESUMO

PURPOSE: The ketogenic diet (KD) has been used as an effective antiepileptic treatment for nearly a century. Inhibition of glycolysis and increased levels of ketone bodies are both known to contribute to the antiepileptic effects of the KD. Neuron-restrictive silencer factor (NRSF), also known as RE-1 silencing transcription factor (REST), is implicated in the antiepileptic effects of the glycolytic inhibitor 2-deoxy-d-glucose (2DG). Glycolytic inhibition is a common feature of the KD and 2DG treatment, leading to the hypothesis that NRSF might also be involved in the antiepileptic effect of the KD. To test this hypothesis, the present study was designed to investigate the role of NRSF in the antiepileptic effect of 2DG, the KD, and acetone in vivo. METHODS: Kindling was used as a model to test the antiepileptic effects of 2DG, the KD, and acetone on control and NRSF conditional knockout mice (NRSF-cKO; from the intercross of CamKIIα-iCre and NRSF exon 2 floxed mice). After recovery from electrode implantation, adult mice were stimulated twice a day at afterdischarge threshold (ADT) current intensity. In the 2DG- (500 mg/kg) and acetone- (10 mmol/kg) treated groups, drugs were injected intraperitoneally 20 min before each stimulus. In the 2DG group, mice were pretreated with intraperitoneal injections for 3 days in addition to the injections administered before the regular kindling stimulation. In the KD group, mice were fed the KD instead of a control diet until the end of stimulations. KEY FINDINGS: Compared with control mice, the antiepileptic effect of 2DG was abolished in NRSF-cKO mice, indicating that NRSF is required for the antiepileptic effect of 2DG. In the KD-fed group, kindling development was retarded in both control and NRSF-cKO mice. In the acetone-treated group, inhibition of kindling-induced epileptogenesis was observed in both control and NRSF-cKO mice, similar to the action of the KD. SIGNIFICANCE: These findings imply that NRSF repression complex is not essential for the antiepileptic effect of the ketogenic diet.


Assuntos
Anticonvulsivantes/administração & dosagem , Dieta Cetogênica/métodos , Epilepsia/terapia , Excitação Neurológica/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Acetona/uso terapêutico , Animais , Antimetabólitos/administração & dosagem , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Desoxiglucose/administração & dosagem , Estimulação Elétrica/efeitos adversos , Epilepsia/etiologia , Epilepsia/genética , Excitação Neurológica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Repressoras/deficiência
16.
Reprod Sci ; 28(3): 785-793, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33211273

RESUMO

BNC1 is a transcription factor that is crucial for spermatogenesis and male fertility, although the underlying mechanism remains unclear. To study BNC1's specific role in spermatogenesis, we characterized a previously developed mouse model carrying a truncating mutation in Bnc1 (termed Bnc1+/tr for heterozygotes and Bnc1tr/tr for homozygotes) and found that the mutation decreased BNC1 protein levels and resulted in germ cell loss by apoptosis. Given that loss of functional Bnc1 is known to result in decreased expression of the spermatogenesis genes Ybx2 and Papolb, we aimed to explore whether and how BNC1 promotes transcription of Ybx2 and Papolb to mediate its role in spermatogenesis. We confirmed significant reduction in YBX2 and PAPOLB protein levels in testis tissue from Bnc1+/tr and Bnc1tr/tr males compared with wild-type mice (Bnc1+/+). Consistently, knockdown of Bnc1 led to downregulation of Ybx2 and Papolb in CRL-2196 cells in vitro. To investigate if BNC1 directly induces Ybx2 and Papolb gene expression, chromatin immunoprecipitation using mouse testicular tissue and luciferase reporter assays in HEK293 cells were used to identify functional binding of BNC1 to the Ybx2 and Papolb promoters at defined BNC1 binding sites. Taken together, this study reveals a mechanism for BNC1's role in spermatogenesis by directly binding to BNC1 binding elements in the promoter regions of both Ybx2 and Papolb and inducing transcription of these important spermatogenesis genes.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Polinucleotídeo Adenililtransferase/metabolismo , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/metabolismo , Espermatogênese , Espermatozoides/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Animais , Apoptose , Sítios de Ligação , Proliferação de Células , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Polinucleotídeo Adenililtransferase/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética
17.
Cereb Cortex ; 19(7): 1504-14, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18832330

RESUMO

Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20-25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabolic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation.


Assuntos
Modelos Animais de Doenças , Epilepsia/fisiopatologia , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/patologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Sistema Límbico/patologia , Sistema Límbico/fisiopatologia , Animais , Proteína do X Frágil da Deficiência Intelectual/genética , Humanos , Masculino , Camundongos , Camundongos Knockout
18.
Stem Cell Reports ; 14(6): 1093-1106, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32521248

RESUMO

Active neural stem cells (aNSCs) and quiescent neural stem cells (qNSCs) are two distinct subpopulations found in the adult hippocampal dentate gyrus (DG). However, to date, no cell surface marker has been established to identify and profile qNSCs in the adult hippocampus. Here, we identified expression of vascular cell adhesion molecule 1 (VCAM1) on the cell surface of NSCs, through which we identified a previously unrecognized subpopulation of NSCs in the adult mouse DG. Interestingly, most VCAM1-expressing NSCs were largely quiescent. By injecting virus into Ai14 reporter mice to conduct lineage tracing in the adult DG, we confirmed that VCAM1-expressing cells were multipotent and capable of generating neurons and astrocytes. Furthermore, depletion of Vcam1 during the embryonic or adult stage impaired spatial learning and memory in mice, accompanied by a reduced number of radial glial-like cells and proliferating NSCs in the subgranular zone of Vcam1 knockout mice.


Assuntos
Hipocampo/metabolismo , Células-Tronco Neurais/metabolismo , Memória Espacial , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Células Cultivadas , Hipocampo/citologia , Hipocampo/fisiologia , Camundongos , Células-Tronco Neurais/citologia , Neurogênese , Molécula 1 de Adesão de Célula Vascular/genética
19.
Cell Rep ; 30(8): 2489-2500.e5, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101730

RESUMO

Emerging evidence suggests that crosstalk between glioma cells and the brain microenvironment may influence brain tumor growth. To date, known reciprocal interactions among these cells have been limited to the release of paracrine factors. Combining a genetic strategy with longitudinal live imaging, we find that individual gliomas communicate with distinct sets of non-glioma cells, including glial cells, neurons, and vascular cells. Transfer of genetic material is achieved mainly through extracellular vesicles (EVs), although cell fusion also plays a minor role. We further demonstrate that EV-mediated communication leads to the increase of synaptic activity in neurons. Blocking EV release causes a reduction of glioma growth in vivo. Our findings indicate that EV-mediated interaction between glioma cells and non-glioma brain cells alters the tumor microenvironment and contributes to glioma development.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Comunicação Celular , Vesículas Extracelulares/metabolismo , Glioma/patologia , Animais , Astrócitos/patologia , Encéfalo/fisiopatologia , Neoplasias Encefálicas/fisiopatologia , Fusão Celular , Linhagem Celular Tumoral , DNA de Neoplasias/genética , Fenômenos Eletrofisiológicos , Vesículas Extracelulares/ultraestrutura , Glioma/fisiopatologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Nus , Neurônios/patologia , Imagem com Lapso de Tempo
20.
Neurorehabil Neural Repair ; 23(8): 837-46, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19531605

RESUMO

BACKGROUND: The effect of using robots to improve motor recovery has received increased attention, even though the most effective protocol remains a topic of study. OBJECTIVE: . The objective was to compare the training effects of treatments on the wrist joint of subjects with chronic stroke with an interactive rehabilitation robot and a robot with continuous passive motion. METHODS: . This study was a single-blinded randomized controlled trial with a 3-month follow-up. Twenty-seven hemiplegic subjects with chronic stroke were randomly assigned to receive 20-session wrist training with a continuous electromyography (EMG)-driven robot (interactive group, n = 15) and a passive motion device (passive group, n = 12), completed within 7 consecutive weeks. Training effects were evaluated with clinical scores by pretraining and posttraining tests (Fugl-Meyer Assessment [FMA] and Modified Ashworth Score [MAS]) and with session-by-session EMG parameters (EMG activation level and co-contraction index). RESULTS: . Significant improvements in FMA scores (shoulder/elbow and wrist/hand) were found in the interactive group (P < .05). Significant decreases in the MAS were observed in the wrist and elbow joints for the interactive group and in the wrist joint for the passive group (P < .05). These MAS changes were associated with the decrease in EMG activation level of the flexor carpi radialis and the biceps brachii for the interactive group (P < .05). The muscle coordination on wrist and elbow joints was improved in the interactive groups in the EMG co-contraction indexes across the training sessions (P < .05). CONCLUSIONS: . The interactive treatment improved muscle coordination and reduced spasticity after the training for both the wrist and elbow joints, which persisted for 3 months. The passive mode training mainly reduced the spasticity in the wrist flexor.


Assuntos
Eletromiografia/métodos , Modalidades de Fisioterapia/instrumentação , Amplitude de Movimento Articular , Robótica/instrumentação , Reabilitação do Acidente Vascular Cerebral , Articulação do Punho/fisiologia , Algoritmos , Doença Crônica , Articulação do Cotovelo/fisiologia , Humanos , Modelos Biológicos , Recuperação de Função Fisiológica/fisiologia , Articulação do Ombro/fisiologia , Acidente Vascular Cerebral/fisiopatologia
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