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1.
Cell ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38968937

RESUMO

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.

2.
Biol Res ; 57(1): 9, 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38491377

RESUMO

BACKGROUND: Parkinson's disease (PD) is characterized by death of dopaminergic neurons leading to dopamine deficiency, excessive α-synuclein facilitating Lewy body formation, etc. Latroeggtoxin-VI (LETX-VI), a proteinaceous neurotoxin discovered from the eggs of spider L. tredecimguttatus, was previously found to promote the synthesis and release of PC12 cells, showing a great potential as a drug candidate for PD. However, the relevant mechanisms have not been understood completely. The present study explored the mechanism underlying the effects of LETX-VI on dopamine and α-synuclein of PC12 cells and the implications for PD. RESULTS: After PC12 cells were treated with LETX-VI, the level of dopamine was significantly increased in a dose-dependent way within a certain range of concentrations. Further mechanism analysis showed that LETX-VI upregulated the expression of tyrosine hydroxylase (TH) and L-dopa decarboxylase to enhance the biosynthesis of dopamine, and downregulated that of monoamine oxidase B to reduce the degradation of dopamine. At the same time, LETX-VI promoted the transport and release of dopamine through modulating the abundance and/or posttranslational modification of vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT). While the level of dopamine was increased by LETX-VI treatment, α-synuclein content was reduced by the spider toxin. α-Synuclein overexpression significantly decreased the dopamine level and LETX-VI efficiently alleviated the inhibitory action of excessive α-synuclein on dopamine. In the MPTP-induced mouse model of PD, application of LETX-VI ameliorated parkinsonian behaviors of the mice, and reduced the magnitude of MPTP-induced α-synuclein upregulation and TH downregulation. In addition, LETX-VI displayed neuroprotective effects by inhibiting MPTP-induced decrease in the numbers of TH-positive and Nissl-stained neurons in mouse brain tissues. CONCLUSIONS: All the results demonstrate that LETX-VI promotes the synthesis and release of dopamine in PC12 cells via multiple mechanisms including preventing abnormal α-synuclein accumulation, showing implications in the prevention and treatment of PD.


Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Ratos , Camundongos , Animais , Dopamina/metabolismo , Doença de Parkinson/tratamento farmacológico , alfa-Sinucleína/metabolismo , Células PC12 , Camundongos Endogâmicos C57BL
3.
Mol Hortic ; 3(1): 7, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37789495

RESUMO

The quantitative control of FLOWERING LOCUS T (FT) activation is important for the floral transition in flowering plants. However, the flowering regulation mechanisms in the day-neutral, summer-flowering chrysanthemum plant remain unclear. In this study, the chrysanthemum BBX7 homolog CmBBX7 was isolated and its flowering function was identified. The expression of CmBBX7 showed a diurnal rhythm and CmBBX7 exhibited higher expression levels than CmBBX8. Overexpression of CmBBX7 in transgenic chrysanthemum accelerated flowering, whereas lines transfected with a chimeric repressor (pSRDX-CmBBX7) exhibited delayed flowering. Yeast single hybridization, luciferase, electrophoretic mobility shift, and chromatin immunoprecipitation assays showed that CmBBX7 directly targets CmFTL1. In addition, we found that CmBBX7 and CmBBX8 interact to positively regulate the expression of CmFTL1 through binding to its promoter. Collectively, these results highlight CmBBX7 as a key cooperator in the BBX8-FT module to control chrysanthemum flowering.

4.
BMC Genomics ; 24(1): 517, 2023 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-37667188

RESUMO

BACKGROUND: Previous preliminary work found that Latroeggtoxin-VI (LETX-VI), a proteinaceous neurotoxin from the eggs of spider Latrodectus tredecimguttatus, could promote the synthesis and release of dopamine in PC12 cells. However, the underlying mechanisms have not been fully clear. Here, the effects of LETX-VI on the gene expression profile and dopamine in PC12 cells were analyzed with the differential transcriptome-based strategies. RESULTS: After treatment of PC12 cells with LETX-VI for 24 h, a total of 356 differentially expressed transcripts were identified. Of them 165 were up-regulated and 191 down-regulated. Relevant GO analysis indicated that LETX-VI modulated the expression of certain genes and thereby affected multiple biological processes in PC12 cells, including protein metabolism, nucleic acid metabolism, substance transport, signaling, neurotransmitter metabolism and release. When western blot analysis was employed to confirm the abundance levels of synaptojanin 1 and synuclein alpha interacting protein, the representatives of highly up- and down-regulated transcript-encoded proteins that are closely related with dopamine respectively, it was found that the level of synaptojanin 1 in the PC12 cells treated with LETX-VI was increased, whereas that of synuclein alpha interacting protein was not obviously altered, suggesting that synaptojanin 1 may be much more involved in the effects of LETX-VI on dopamine. After synaptojanin 1 level was knocked down using siRNA, the levels of both total and released dopamine were significantly decreased, indicating that synaptojanin 1 is a protein positively modulating the synthesis and secretion of dopamine. When the PC12 cells with knocked down synaptojanin 1 were treated by LETX-VI, the adverse effects of synaptojanin 1 knockdown on dopamine were attenuated, confirming that LETX-VI promotes the synthesis and secretion of dopamine at least partially by enhancing the expression of the gene SYNJ1 encoding synaptojanin 1. CONCLUSIONS: This work demonstrates that LETX-VI exerts multiple regulatory effects on the cellular processes in PC12 cells by altering the gene expression profile. LETX-VI modulates the expression of the genes closely related to the synthesis, transport and release of neurotransmitters especially dopamine in PC12 cells, with the gene SYNJ1 encoding synaptojanin 1 as a main target.


Assuntos
Dopamina , Neurotoxinas , Monoéster Fosfórico Hidrolases , Animais , Ratos , Células PC12 , RNA Interferente Pequeno , Sinucleínas , Proteínas de Artrópodes/toxicidade , Proteínas do Ovo/toxicidade
5.
J Cell Commun Signal ; 17(4): 1309-1321, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37702818

RESUMO

Latroeggtoxin-VI (LETX-VI) is an active protein and was previously demonstrated to have effects on the synthesis and release of dopamine. Hererin, the involvement of Ca2+ signaling in the effects of LETX-VI on dopamine was systematically investigated, using PC12 cells as a neuron model. LETX-VI was shown to promote dopamine release from PC12 cells both in the presence and absence of extracellular Ca2+; however the presence of extracellular Ca2+ was favorable for enhancing the promoting effects of LETX-VI on dopamine, because LETX-VI facilitated the influx of extracellular Ca2+ through the L-type calcium channels in plasma membrane (PM) to increase cytosolic Ca2+ concentration. LETX-VI was able to penetrate the PM of PC12 cells to act on the Ca2+ channel proteins IP3Rs and RyRs in the endoplasm reticulum (ER) membrane, opening the Ca2+ channels and promoting the release of ER Ca2+ to elevate cytosolic Ca2+ level. With the help of intracellular Ca2+ chelator BAPTA, the elevated cytosolic Ca2+ level was proven to play crucial role for the enhanced promoting effects of LETX-VI on dopamine. Taken together, LETX-VI is able to open the Ca2+ channels in both PM and ER membrane simultaneously to facilitate extracellular Ca2+ influx and ER Ca2+ release, and thus increases the cytosolic Ca2+ concentration to enhance the promoting effects on the synthesis and release of dopamine.

6.
Front Immunol ; 14: 1171351, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37256144

RESUMO

Depression has a high incidence and seriously endangers human health. Accumulated evidence indicates that targeting neuroinflammation is a potential avenue for neuroprotection and thus depression prevention. Herein, the effects of latroeggtoxin-VI (LETX-VI), a bioactive protein from the eggs of spider Latrodectus tredecimguttatus, on lipopolysaccharide (LPS)-induced inflammation and depression were systematically investigated using RAW264.7 macrophages and depression mouse model. Pretreatment with LETX-VI suppressed LPS-evoked NF-κB signaling pathway activation, inhibited LPS-induced over-production of NO, iNOS, IL-6 and TNF-α; at the same time LETX-VI mitigated the inhibitory effect of LPS on the expression of anti-inflammatory factors such as Arg-1, thereby suppressing oxidative stress and excessive inflammation. Culture of PC12 cells with the conditioned medium of RAW264.7 cells pretreated with LETX-VI demonstrated the neuroprotective effect of LETX-VI due to its anti-inflammation effect. In the LPS-induced depression mouse model, pretreatment with LETX-VI improved the LPS-induced depression-like behaviors, inhibited the activation of microglia and astrocytes, prevented the down-regulation of Nurr1 expression and alleviated the LPS-caused adverse changes in the brain tissues. Taken together, these in vitro and in vivo findings provide powerful insights into the anti-inflammation-based neuroprotective and antidepressant mechanisms of LETX-VI, which is helpful to deeply reveal the biological effects and potential applications of LETX-VI.


Assuntos
Depressão , NF-kappa B , Ratos , Camundongos , Animais , Humanos , NF-kappa B/metabolismo , Depressão/metabolismo , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Inflamação/metabolismo , Anti-Inflamatórios/uso terapêutico , Neurônios/metabolismo
7.
Plant Cell Environ ; 46(2): 440-450, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36367211

RESUMO

Plants employ several endogenous and exogenous signals to guarantee timely floral transitions with floral integrators. To avoid premature flowering, flowering plants must control the balance between vegetative and floral development. As a Group II member of BBX family, CmBBX8 promotes flowering by directly activating CmFTL1 in summer-flowering chrysanthemum. However, the mechanisms underlying this floral transition is yet to be elucidated. Here, we report that the chrysanthemum ERF3 homologue, CmERF3, physically interacts with CmBBX8 through yeast two-hybrid (Y2H), bimolecular fluorescence complementation (BiFC), pull-down, and luciferase complementation (LCI) assays. We found that CmERF3 was highly expressed at the vegetative stage and rarely expressed in the reproductive phase, indicating that CmERF3 may play a critical role in maintaining vegetative growth to prevent premature flowering. Rhythm analysis revealed that CmERF3 had a different response to rhythm compared to CmBBX8. Knockdown of CmERF3 facilitated floral initiation, whereas overexpression of CmERF3 delayed floral transition. We further found that CmERF3 repressed the transactivation activity of CmBBX8 on the downstream CmFTL1 gene. Collectively, our results indicate that the CmERF3-CmBBX8 transcriptional complex is a crucial module that balances the vegetative growth and reproductive development of chrysanthemum.


Assuntos
Chrysanthemum , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Chrysanthemum/genética , Chrysanthemum/metabolismo , Flores/fisiologia , Regulação da Expressão Gênica de Plantas , Etilenos/metabolismo
8.
Life Sci ; 309: 120995, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36167148

RESUMO

Ca2+-triggered neurotransmitter release involves complex regulatory mechanisms, including a series of protein-protein interactions. Three proteins, synaptobrevin (VAMP), synaptosomal-associated protein of 25kDa (SNAP-25) and syntaxin, constitute the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) core complex that plays key roles in controlling vesicle fusion and exocytosis. Many other proteins participate in the regulation of the processes via direct and/or indirect interaction with the SNARE complex. Although much effort has been made, the regulatory mechanism for exocytosis is still not completely clear. Accumulated evidence indicates that the small GTPase Rab3 and synaptotagmin proteins play important regulatory roles during vesicle fusion and neurotransmitter release. This review outlines our present understanding of the two regulatory proteins, with the focus on the interaction of Rab3 with synaptotagmin in the regulatory process.


Assuntos
Proteínas Monoméricas de Ligação ao GTP , Proteínas do Tecido Nervoso , Sinaptotagminas , Proteínas de Ligação a Fator Solúvel Sensível a N-Etilmaleimida/metabolismo , Proteína 25 Associada a Sinaptossoma/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Exocitose/fisiologia , Proteínas R-SNARE , Proteínas Qa-SNARE/metabolismo , Neurotransmissores , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Cálcio/metabolismo
9.
Int J Biol Macromol ; 216: 906-915, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35914553

RESUMO

Latroeggtoxin-VI (LETX-VI), a proteinaceous neurotoxin mined from the egg transcriptome of spider L. tredecimguttatus, was previously found to promote the release of dopamine from PC12 cells. However, the relevant molecular mechanism has not been fully clear. Here LETX-VI was demonstrated to rapidly penetrate the plasma membrane of PC12 cells via the vesicle exocytosis/endocytosis cycle, during which vesicular transmembrane protein synaptotagmin 1 (Syt1) functions as a receptor, with its vesicle luminal domain interacting with the C-terminal region of LETX-VI. The C-terminal sequence of LETX-VI is the functional region for both entering cells and promoting dopamine release. After gaining entry into the PC12 cells, LETX-VI down-regulated the phosphorylation levels of Syt1 at T201 and T195, thereby facilitating vesicle fusion with plasma membrane and thus promoting dopamine release. The relevant mechanism analysis indicated that LETX-VI has a protein phosphatase 2A (PP2A) activator activity. The present work has not only probed into the Syt1-mediated action mechanism of LETX-VI, but also revealed the structure-function relationship of the toxin, thus suggesting its potential applications in the drug transmembrane delivery and treatment of the diseases related to dopamine release and PP2A activity deficiency.


Assuntos
Dopamina , Sinaptotagmina I , Animais , Cálcio/metabolismo , Membrana Celular/metabolismo , Endocitose , Fusão de Membrana , Ratos , Sinaptotagmina I/genética , Sinaptotagmina I/metabolismo , Sinaptotagminas
10.
J Biochem Mol Toxicol ; 35(8): e22825, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34047418

RESUMO

Latroeggtoxin-VI (LETX-VI) is a peptide neurotoxin discovered from Latrodectus tredecimguttatus eggs. In the current study, the action features of the neurotoxin on PC12 cells were systematically investigated. LETX-VI could promote dopamine release from PC12 cells in the absence and presence of Ca2+, involving an even more complex action mechanism in the presence of Ca2+ and when the treatment time was longer. Although LETX-VI enchanced the autophagy and secretion activity in PC 12 cells, it showed no remarkable influence on the proliferation, cell cycle, apoptosis and ultrastructure of the cells. Pulldown combined with CapLC-MS/MS analysis suggested that LETX-VI affected PC12 cells by interacting with multiple proteins involved in the metabolism, transport, and release of neurotransmitters, particularly dopamine. The low cytotoxicity and effective regulatory action of LETX-VI on PC12 cells suggest the potential of the active peptide in the development of drugs for the treatment of some dopamine-related psychotic diseases and cancers.


Assuntos
Proteínas de Artrópodes/farmacologia , Citotoxinas/farmacologia , Proteínas do Ovo/farmacologia , Neoplasias , Transtornos Psicóticos , Animais , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Células PC12 , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/patologia , Ratos
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(5): 469-471, 2021 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-33974258

RESUMO

OBJECTIVE: To explore the clinical and genetic characteristics of a child with X-linked hypohidrotic ectodermal dysplasia (XLHED). METHODS: Clinical data of the child was collected. Peripheral blood samples were taken from the child and his parents with informed consent and subjected to copy number variation (CNV) analysis and whole exome sequencing (WES). RESULTS: The male infant manifested sparse hair, anhidrosis, anuresis due to polycystic kidney dysplasia, external genital malformation and anal atresia. WES has revealed a 406 bp hemizygous deletion at Xq13 (68 836 147-68 836 553) in the proband, which encompassed exon 1 of the EDA gene. A heterozygous deletion at the same site was detected in the mother, while no deletion or duplication of the site was detected in the father. CONCLUSION: The hemizygous deletion of EDA gene exon 1 probably underlay the ectodermal dysplasia in the proband. Above result has provided a basis for genetic counseling and prenatal diagnosis for the family.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1 , Displasia Ectodérmica , Criança , Variações do Número de Cópias de DNA , Displasia Ectodérmica/genética , Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Testes Genéticos , Humanos , Lactente , Masculino , Linhagem
12.
Hum Mutat ; 42(8): 990-1004, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34015165

RESUMO

Neurodevelopmental disorders (NDDs) are a genetically heterogeneous group of diseases, affecting 1%-3% of children. Whole-exome sequencing (WES) has been widely used as a first-tier tool for identifying genetic causes of rare diseases. Trio-WES was performed in a cohort of 74 pedigrees with NDDs. Exome-based copy number variant (CNV) calling was incorporated into the traditional single-nucleotide variant (SNV) and small insertion/deletion (Indel) analysis pipeline for WES data. An overall positive diagnostic yield of 54.05% (40/74) was obtained in the pipeline of combinational SNV/Indel and CNV analysis, including 35.13% (26/74) from SNV/Indel analysis and 18.92% (14/74) from exome-based CNV analysis, respectively. In total, SNV/Indel analysis identified 38 variants in 28 different genes, of which 24 variants were novel; exome-based CNV analysis identified 14 CNVs, including 2 duplications and 12 deletions, which ranged from 440 bp (single exon) to 16.86 Mb (large fragment) in size. In particular, a hemizygous deletion of exon 1 in the SLC16A2 gene was detected. Based on the diagnostic results, two families underwent prenatal diagnosis and had unaffected babies. The incorporation of exome-based CNV detection into conventional SNV/Indel analysis for a single trio-WES test significantly improved the diagnostic rate, making WES a more powerful, practical, and cost-effective tool in the clinical diagnosis of NDDs.


Assuntos
Transtornos do Neurodesenvolvimento , Simportadores , Criança , Variações do Número de Cópias de DNA , Exoma/genética , Feminino , Humanos , Transportadores de Ácidos Monocarboxílicos/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Gravidez , Estudos Retrospectivos , Simportadores/genética , Sequenciamento do Exoma
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(3): 275-277, 2021 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-33751541

RESUMO

OBJECTIVE: To explore the genetic basis for a child affected with Bainbridge-Ropers syndrome. METHODS: Genomic DNA was extracted from peripheral venous blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out to detect genetic variant of the proband. Candidate variant was verified by Sanger sequencing. RESULTS: The 3-year-old boy presented with psychomotor retardation, linguistic difficulties, mental retardation and peculiar craniofacial phenotype. A de novo heterozygous nonsense variant of the ASXL3 gene, c.3106C>T, was identified by WES in the proband, and the same mutation was not found among his parents. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.3106C>T variant was predicted to be pathogenic (PVS1+PS2+PP4). CONCLUSION: The heterozygous variant c.3106C>T of the ASXL3 gene probably underlies the Bainbridge-Ropers syndrome in the patient. Above result has enabled the clinical diagnosis and genetic counseling for the family.


Assuntos
Deficiência Intelectual , Fatores de Transcrição , Criança , Pré-Escolar , Heterozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Mutação , Fenótipo , Fatores de Transcrição/genética , Sequenciamento do Exoma
14.
Toxins (Basel) ; 13(2)2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673184

RESUMO

Latroeggtoxin-VI (LETX-VI) is a peptide neurotoxin newly found from the eggs of spider L. tredecimguttatus. To explore the mechanism of action of the LETX-VI on nerve cells, the effects of LETX-VI on PC12 cells, a commonly used neuron model, were analyzed using a pull-down assay-guided strategy. LETX-VI was shown to interact with 164 PC12 cell proteins that have diverse molecular functions such as binding, catalysis, regulation, structural activity, etc., thereby extensively affecting the biological processes in the PC12 cells, particularly protein metabolism, response to stimulus, substance transport, and nucleic acid metabolism, with 56.71%, 42.07%, 29.88% and 28.66% of the identified proteins being involved in these biological processes, respectively. By interacting with the relevant proteins, LETX-VI enhanced the synthesis of dopamine; positively regulated cell division and proliferation; and negatively regulated cell cycle arrest, cell death, and apoptotic processes, and therefore has limited cytotoxicity against the PC12 cells, which were further experimentally confirmed. In general, the effects of LETX-VI on PC12 cells are more regulatory than cytotoxic. These findings have deepened our understanding of the action mechanism of LETX-VI on nerve cells and provided valuable clues for further related researches including those on Parkinson's disease.


Assuntos
Proteínas de Artrópodes/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Mapeamento de Interação de Proteínas , Proteoma , Proteômica , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Células PC12 , Ligação Proteica , Ratos , Transdução de Sinais
15.
Sci Rep ; 10(1): 17445, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060836

RESUMO

CHARGE syndrome, a rare multiple congenital anomaly condition, is caused by haploinsufficiency of the chromatin remodeling protein gene CHD7 (Chromodomain helicase DNA binding protein 7). Brain abnormalities and intellectual disability are commonly observed in individuals with CHARGE, and neuronal differentiation is reduced in CHARGE patient-derived iPSCs and conditional knockout mouse brains. However, the mechanisms of CHD7 function in nervous system development are not well understood. In this study, we asked whether CHD7 promotes gene transcription in neural progenitor cells via changes in chromatin accessibility. We used Chd7 null embryonic stem cells (ESCs) derived from Chd7 mutant mouse blastocysts as a tool to investigate roles of CHD7 in neuronal and glial differentiation. Loss of Chd7 significantly reduced neuronal and glial differentiation. Sholl analysis showed that loss of Chd7 impaired neuronal complexity and neurite length in differentiated neurons. Genome-wide studies demonstrated that loss of Chd7 leads to modified chromatin accessibility (ATAC-seq) and differential nascent expression (Bru-Seq) of neural-specific genes. These results suggest that CHD7 acts preferentially to alter chromatin accessibility of key genes during the transition of NPCs to neurons to promote differentiation. Our results form a basis for understanding the cell stage-specific roles for CHD7-mediated chromatin remodeling during cell lineage acquisition.


Assuntos
Cromatina/química , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/citologia , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Neurais/citologia , Neurônios/citologia , Animais , Blastocisto/metabolismo , Diferenciação Celular , Elementos Facilitadores Genéticos , Epigênese Genética , Perfilação da Expressão Gênica , Camundongos , Camundongos Knockout , Fatores de Transcrição/metabolismo
16.
Sci Transl Med ; 12(537)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238574

RESUMO

Abundant decidual natural killer (dNK) cells at the maternal-fetal interface are important during early pregnancy. However, functional subsets of dNK cells remain poorly understood. We describe a CD49a+PBX homeobox 1 (PBX1)+ dNK cell subset that promotes fetal development in humans and mice. The expression of PBX1 in dNK cells is up-regulated via the activated AKT1 pathway through the interaction of major histocompatibility complex G with the immunoglobulin-like transcript 2 receptor. PBX1 drives pleiotrophin and osteoglycin transcription in dNK cells, further promoting fetal development. Decreased PBX1 expression or the PBX1G21S mutant correlated with fetal growth restriction and pregnancy failure in patients with unexplained recurrent spontaneous abortion (URSA). Inactivation of Pbx1 in mouse dNK cells impairs fetal development by decreasing growth-promoting factors from CD49a+PBX1+ dNK cells. Impairment of PBX1 in dNK cells has positive correlation with URSA pathogenesis and may provide a potential marker for this condition.


Assuntos
Decídua , Desenvolvimento Fetal , Células Matadoras Naturais , Animais , Decídua/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Gravidez , Útero
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(12): 1153-1157, 2019 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-31813136

RESUMO

OBJECTIVE: The phenotype and genetics of three patients with autosomal recessive polycystic kidney disease (ARPKD) at childhood, teenage and advanced age were analyzed. METHODS: Next generation sequencing (NGS) was applied to all the probands. PCR and Sanger sequencing were used to verify the suspicious gene variants screened by NGS in the probands and their family members, and one of the family got prenatal diagnosis. RESULTS: Through NGS, PCR and Sanger sequencing, the 5-yr proband in pedigree 1 was shown to carry compound heterozygous variants of c.5935G>A(p.G1979R) and c.5428G>T(p.E1810X) of PKHD1, originated from his parents; In pedigree 2, the 17-ys proband was detected with c.5512T>C(p.Y1838H) and c.5935G>A(p.G1979R) variants of PKHD1 orginated from her parents, and her mother also got prenatal diagnosis during the second trimester; In pedigree 3, the 70-ys female proband was found with variants c.11314C>T (p.R3772X) and c.3860T>G (p.V1287G) of PKHD1. CONCLUSION: The three pedigrees were diagnosed as ARPKD caused by PKHD1 variants. Five types of variants were detected, c.5935G>A and c.11314C>T were the known pathogenic variants, while c.5512T>C, c.5428G>T and c.3860T>G were not reported previously. Considering the complexity of the genetics and phenotypes of the cystic renal diseases, genetic diagnosis is crucial to give accurate etiological diagnosis, which may benefit the clinic management.


Assuntos
Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Adolescente , Idoso , Pré-Escolar , Feminino , Humanos , Masculino , Mutação , Fenótipo , Gravidez
18.
Nanoscale ; 11(8): 3718-3724, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30742189

RESUMO

In recent years, upconversion materials have attracted considerable attention because of their unique physicochemical features. Numerous studies have focused on the synthesis of upconversion materials with different colors. However, an easier way to vary the upconversion colors without changing the materials' components has not been extensively studied. In this study, we realized the in situ color variation of the designed upconversion material with the help of a three-state fluorescence switching hybrid device. The device was composed of Prussian blue and upconversion materials; the former element functioned as a fluorescence resonance energy transfer acceptor and the latter acted as a donor. Smartly applying the RGB color model guaranteed multicolor of the device. Moreover, the highest fluorescence contrast of the three-state fluorescence switching system was 86% (larger than the result of a previous study), and the three-state reversibility was remarkable; this was probably owing to the unique layer-by-layer dripping/electrodepositing assembly method. To the best of our knowledge, the in situ reversible color variation of the ready-made upconversion material has been demonstrated for the first time.

19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(6): 808-811, 2018 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-30512151

RESUMO

OBJECTIVE: To detect potential mutation in a Chinese pedigree affected with split hand/split foot malformation (SHFM). METHODS: The patients were screened for genome-wide copy number variations with single nucleotide polymorphism (SNP) microarray. Copy number variations were verified by real-time fluorescence quantitative PCR. RESULTS: There were 3 SHFM patients from three generations, which conformed to an autosomal dominant inheritance. SNP microarray assay revealed that all patients have carried a 0.34 Mb duplication in 10q24.31-q24.32 (102 993 649-103 333 271) encompassing the BTRC and DPCD genes. The result was verified by real-time fluorescence quantitative PCR, confirming that the duplication has co-segregated with the SHFM phenotype in the pedigree. CONCLUSION: The 10q24.31-q24.32 duplication probably underlies the pathogenesis of SHFM in this pedigree. Tiny copy number variations can result in diseases featuring autosomal dominant inheritance.


Assuntos
Cromossomos Humanos Par 10/genética , Variações do Número de Cópias de DNA , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Povo Asiático , China , Duplicação Cromossômica , Humanos , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único
20.
Reprod Biol Endocrinol ; 16(1): 28, 2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29580253

RESUMO

BACKGROUND: Excessive nerve growth factor (NGF) is commonly found in the follicular fluid of patients with polycystic ovary syndrome (PCOS). Furthermore, oocytes from PCOS patients exhibit lower developmental competence. The purpose of this study was to explore the association between excessive NGF and low oocyte competence in vitro. METHODS: Excessive NGF was added to mouse cumulus oocyte complexes (COCs) cultured in vitro to investigate meiotic maturation of the oocyte. After culture, mRNA expression levels of Pfkp and Ldha genes in cumulus cells (CCs) and Gdf9, Bmp15 and Fgf8 genes in oocytes, were determined by real-time quantitative polymerase chain reaction (qPCR). We also investigated the mRNA content of Pfkp and Ldha in CCs from PCOS and non-PCOS patients. RESULTS: Excessive NGF significantly inhibited oocyte meiotic maturation. The inhibitory effect was mediated by the NGF high-affinity receptor, NTRK1. mRNA content of Pfkp and Ldha genes in CCs was significantly reduced by excessive NGF stimulation. Moreover, the expression levels of Gdf9, Bmp15 and Fgf8 were also decreased in oocytes, and was induced by excessive NGF-stimulated CCs. In addition, lower expression levels of Pfkp and Ldha in CCs were identified in Chinese PCOS patients with excessive NGF (PCOS, 22 ± 2.63 ng/ml, n = 13; non-PCOS, 7.18 ± 2.42 ng/ml, n = 9; p < 0.01) in the follicular fluid, suggesting a potential association between excessive NGF and decreased glycolysis in the CCs of women with PCOS. CONCLUSIONS: Excessive NGF impairs bidirectional communication between oocyte and cumulus cells, which might be related to low oocyte competence.


Assuntos
Comunicação Celular/efeitos dos fármacos , Células do Cúmulo/fisiologia , Fator de Crescimento Neural/administração & dosagem , Oócitos/fisiologia , Adulto , Animais , Células Cultivadas , China , Células do Cúmulo/química , Relação Dose-Resposta a Droga , Feminino , Líquido Folicular/química , Glicólise/efeitos dos fármacos , Humanos , Técnicas de Maturação in Vitro de Oócitos , Meiose/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Fator de Crescimento Neural/análise , RNA Mensageiro/análise , Receptor trkA/análise
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