Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 78
Filtrar
1.
Am J Med Genet B Neuropsychiatr Genet ; 186(1): 28-39, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33522098

RESUMO

Schizophrenia is a severe mental disease characterized with positive symptoms, negative symptoms, and cognitive impairments. Although recent genome-wide association studies (GWASs) have identified over 145 risk loci for schizophrenia, pinpointing the causal variants and genes at the reported loci and elucidating their roles in schizophrenia remain major challenges. Here we identify a functional single-nucleotide polymorphism (SNP; rs213237) in ZNF323 promoter by using functional fine-mapping. We found that allelic differences at rs213237 affected the ZNF323 promoter activity significantly. Consistently, expression quantitative trait loci (eQTL) analysis showed that rs213237 was significantly associated with ZNF323 expression in diverse human brain tissues, suggesting that rs213237 may contribute to schizophrenia risk through regulating ZNF323 expression. Interestingly, we found that ZNF323 protein was localized in the nucleus and knockdown of ZNF323 in macaque neural stem cells (mNSCs) significantly impaired proliferation and survival of mNSCs. We further showed that stable knockdown of ZNF323 in SH-SY5Y cells resulted in significant decrease of the tyrosine hydroxylase (TH) protein expression. Finally, transcriptome analysis revealed that ZNF323 may regulate pivotal schizophrenia risk genes (including VIPR2 and NPY) and schizophrenia-associated pathways (including PI3K-AKT and NOTCH signaling pathways), suggesting that ZNF323 may be a major regulator of schizophrenia risk genes. Our study reveals how a genetic variant in ZNF323 promoter contributes to schizophrenia risk through regulating ZNF323 expression. More importantly, our findings demonstrate that ZNF323 may have a pivotal role in schizophrenia pathogenesis through regulating schizophrenia risk genes and schizophrenia-associated biological processes (including neurodevelopment, PI3K-AKT, and NOTCH signaling pathways).

2.
Sensors (Basel) ; 21(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430379

RESUMO

Speed judgment is a vital component of autonomous driving perception systems. Automobile drivers were able to evaluate their speed as a result of their driving experience. However, driverless automobiles cannot autonomously evaluate their speed suitability through external environmental factors such as the surrounding conditions and traffic flows. This study introduced the parameter of overtaking frequency (OTF) based on the state of the traffic flow on both sides of the lane to reflect the difference between the speed of a driverless automobile and its surrounding traffic to solve the above problem. In addition, a speed evaluation algorithm was proposed based on the long short-term memory (LSTM) model. To train the LSTM model, we extracted OTF as the first observation variable, and the characteristic parameters of the vehicle's longitudinal motion and the comparison parameters with the leading vehicle were used as the second observation variables. The algorithm judged the velocity using a hierarchical method. We conducted a road test by using real vehicles and the algorithms verified the data, which showed the accuracy rate of the model is 93%. As a result, OTF is introduced as one of the observed variables that can support the accuracy of the algorithm used to judge speed.

3.
Org Lett ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33263254

RESUMO

An asymmetric [3 + 2]-cycloaddition reaction of α,ß-unsaturated 2-acyl imidazoles with spirovinylcyclopropanyl-2-oxindoles catalyzed synergistically by an achiral palladium(0) catalyst and a chiral-at-metal rhodium(III) complex has been developed. A series of biologically important 3-spirocyclopentane-2-oxindoles with four contiguous stereocenters were synthesized in high yields (up to 99%) with excellent stereoselectivities (up to 99% ee, 20:1 dr).

4.
J Med Genet ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32900838

RESUMO

The association between NOTCH4 and schizophrenia has been repeatedly reported. However, the results from different genetic studies are inconsistent, and the role of NOTCH4 in schizophrenia pathogenesis remains unknown. Here, we provide convergent lines of evidence that support NOTCH4 as a schizophrenia risk gene. We first performed a meta-analysis and found that a genetic variant (rs2071287) in NOTCH4 was significantly associated with schizophrenia (a total of 125 848 subjects, p=8.31×10-17), with the same risk allele across all tested samples. Expression quantitative trait loci (eQTL) analysis showed that rs2071287 was significantly associated with NOTCH4 expression (p=1.08×10-14) in human brain tissues, suggesting that rs2071287 may confer schizophrenia risk through regulating NOTCH4 expression. Sherlock integrative analysis using a large-scale schizophrenia GWAS and eQTL data from human brain tissues further revealed that NOTCH4 was significantly associated with schizophrenia (p=4.03×10-7 in CMC dataset and p=3.06×10-6 in xQTL dataset), implying that genetic variants confer schizophrenia risk through modulating NOTCH4 expression. Consistently, we found that NOTCH4 was significantly downregulated in brains of schizophrenia patients compared with controls (p=2.53×10-3), further suggesting that dysregulation of NOTCH4 may have a role in schizophrenia. Finally, we showed that NOTCH4 regulates proliferation, self-renewal, differentiation and migration of neural stem cells, suggesting that NOTCH4 may confer schizophrenia risk through affecting neurodevelopment. Our study provides convergent lines of evidence that support the involvement of NOTCH4 in schizophrenia. In addition, our study also elucidates a possible mechanism for the role of NOTCH4 in schizophrenia pathogenesis.

5.
J Genet Genomics ; 47(5): 233-248, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32712163

RESUMO

The Psychiatric Genomics Consortium (PGC) has recently identified 10 potential functional coding variants for schizophrenia. However, how these coding variants confer schizophrenia risk remains largely unknown. Here, we investigate the associations between eight potential functional coding variants identified by PGC and schizophrenia in a large Han Chinese sample (n = 4022 cases and 9270 controls). Among the eight tested single nucelotide polymorphisms (SNPs), rs3617 (a missense variant, p.K315Q in the ITIH3 gene) showed genome-wide significant association with schizophrenia in the Han Chinese population (P = 8.36 × 10-16), with the same risk allele as in PGC. Interestingly, rs3617 is located in a genomic region that is highly evolutionarily conserved, and its schizophrenia risk allele (C allele) was associated with lower ITIH3 mRNA and protein expression. Intriguingly, mouse neural stem cells stably overexpressing ITIH3 with different alleles of rs3617 exhibited significant differences in proliferation, migration, and differentiation, suggesting the impact of rs3617 on neurodevelopment. Subsequent transcriptome analysis found that the differentially expressed genes in neural stem cells stably overexpressing different alleles of rs3617 were significantly enriched in schizophrenia-related pathways, including cell adhesion, synapse assembly, MAPK and PI3K-AKT pathways. Our study provides convergent lines of evidence suggesting that rs3617 in ITIH3 likely affects protein function and neurodevelopment and thereby confers risk of schizophrenia.

6.
Mol Psychiatry ; 25(9): 1926-1945, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32214206

RESUMO

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and a leading cause of disability worldwide. Though recent genome-wide association studies (GWAS) have identified multiple risk variants for MDD, how these variants confer MDD risk remains largely unknown. Here we systematically characterize the regulatory mechanism of MDD risk variants using a functional genomics approach. By integrating chromatin immunoprecipitation sequencing (ChIP-Seq) (from human brain tissues or neuronal cells) and position weight matrix (PWM) data, we identified 34 MDD risk SNPs that disrupt the binding of 15 transcription factors (TFs). We verified the regulatory effect of the TF binding-disrupting SNPs with reporter gene assays, allelic-specific expression analysis, and CRISPR-Cas9-mediated genome editing. Expression quantitative trait loci (eQTL) analysis identified the target genes that might be regulated by these regulatory risk SNPs. Finally, we found that NEGR1 (regulated by the TF binding-disrupting MDD risk SNP rs3101339) was dysregulated in the brains of MDD cases compared with controls, implying that rs3101339 may confer MDD risk by affecting NEGR1 expression. Our findings reveal how genetic variants contribute to MDD risk by affecting TF binding and gene regulation. More importantly, our study identifies the potential MDD causal variants and their target genes, thus providing pivotal candidates for future mechanistic study and drug development.

7.
Transl Psychiatry ; 9(1): 333, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819045

RESUMO

Major depressive disorder (MDD) is recognized as a primary cause of disability worldwide, and effective management of this illness has been a great challenge. While genetic component is supposed to play pivotal roles in MDD pathogenesis, the genetic and phenotypic heterogeneity of the illness has hampered the discovery of its genetic determinants. In this study, in an independent Han Chinese sample (1824 MDD cases and 3031 controls), we conducted replication analyses of two genetic loci highlighted in a previous Chinese MDD genome-wide association study (GWAS), and confirmed the significant association of a single nucleotide polymorphism (SNP) rs12415800 near SIRT1. Subsequently, using hypothesis-free whole-brain analysis in two independent Han Chinese imaging samples, we found that individuals carrying the MDD risk allele of rs12415800 exhibited aberrant gray matter volume in the left posterior cerebellar lobe compared with those carrying the non-risk allele. Besides, in independent Han Chinese postmortem brain and peripheral blood samples, the MDD risk allele of rs12415800 predicted lower SIRT1 mRNA levels, which was consistent with the reduced expression of this gene in MDD patients compared with healthy subjects. These results provide further evidence for the involvement of SIRT1 in MDD, and suggest that this gene might participate in the illness via affecting the development of cerebellum, a brain region that is potentially underestimated in previous MDD studies.


Assuntos
Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Estudo de Associação Genômica Ampla , Substância Cinzenta/patologia , Sirtuína 1/genética , Adulto , Alelos , Estudos de Casos e Controles , China , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Loci Gênicos , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Adulto Jovem
8.
Small ; 15(50): e1905080, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721436

RESUMO

Two-photon photodynamic therapy (TP-PDT) is emerging as a powerful strategy for stereotactic targeting of diseased areas, but ideal photosensitizers (PSs) are currently lacking. This work reports a smart PS with aggregation-induced emission (AIE) feature, namely DPASP, for TP-PDT with excellent performances. DPASP exhibits high affinity to mitochondria, superior photostability, large two-photon absorption cross section as well as efficient reactive oxygen species generation, enabling it to achieve photosensitization both in vitro and in vivo under two-photon excitation. Moreover, its capability of stereotactic ablation of targeted cells with high-precision is also successfully demonstrated. All these merits make DPASP a promising TP-PDT candidate for accurate ablation of abnormal tissues with minimal damages to surrounding areas in the treatment of various diseases.


Assuntos
Fotoquimioterapia , Fótons , Fármacos Fotossensibilizantes/farmacologia , Células A549 , Animais , Humanos , Camundongos Nus , Fenômenos Ópticos
9.
J Org Chem ; 84(23): 15201-15211, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31661265

RESUMO

An enantioselective three-component cascade reduction-Michael addition reaction catalyzed by chiral-at-metal Rh(III) complexes has been developed. With a Hantzsch ester as the hydride source, a number of malononitrile derivatives were prepared in good yields and excellent enantioselectivities. A model that accounts for the origin and influence factors of the stereoselectivity has been proposed based on experiments.

10.
Chem Commun (Camb) ; 55(52): 7458-7461, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31184643

RESUMO

The development of a sensitive and reliable method for the detection of bioaccumulated heavy metal toxins is highly desirable for biotoxicity evaluation. However, the conventional biotoxicity evaluation method based on luminescent bacteria suffers from only being able to detect the overall toxicity without selectivity in light-off detection mode. Although various synthetic fluorescent probes have been developed for the selective detection of heavy metal ions, they usually suffer from aggregation-caused quenching after local accumulation in biological systems. To tackle these challenges, we herein develop a dual detection strategy for bioaccumulated Hg2+ based on turn-off of the bioluminescence of P. phosphoreum bacteria by disrupting the quorum sensing system and turn-on of the photoluminescence of an aggregation-induced emission (AIE) probe by forming aggregates with Hg2+ inside the bacteria. It is expected that the dual detection strategy would find broad applications in the evaluation of bioaccumulated toxins.


Assuntos
Mercúrio/química , Photobacterium/química , Corantes Fluorescentes/química , Íons/química , Luz , Medições Luminescentes/métodos , Mercúrio/farmacologia , Microscopia Confocal , Photobacterium/isolamento & purificação , Teoria Quântica , Percepção de Quorum/efeitos dos fármacos
11.
Neuropsychopharmacology ; 44(9): 1542-1551, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30771789

RESUMO

Major depressive disorder (MDD) is the most prevalent mental disorder that affects more than 200 million people worldwide. Recent large-scale genome-wide association studies (GWAS) have identified multiple risk variants that show robust association with MDD. Nevertheless, how the identified risk variants confer risk of MDD remains largely unknown. To identify risk variants that are associated with gene expression in human brain and to identify genes whose expression change may contribute to the susceptibility of MDD, we systematically integrated the genetic associations from a large-scale MDD GWAS (N = 480,359) and brain expression quantitative trait loci (eQTL) data (N = 494) using a Bayesian statistical framework (Sherlock). Sherlock integrative analysis showed that FLOT1 was significantly associated with MDD (P = 6.02 × 10-6), suggesting that risk variants may contribute to MDD susceptibility through affecting FLOT1 expression. We further examined the expression level of FLOT1 in MDD cases and controls and found that FLOT1 was significantly upregulated in brains and peripheral blood of MDD cases compared with controls (European sample). Interestingly, we found that FLOT1 expression was also significantly upregulated in peripheral blood of first-episode drug-naive MDD cases compared with controls (P = 1.01 × 10-7, Chinese sample). Our study identified FLOT1 as a novel MDD risk gene whose expression level may play a role in MDD. In addition, our findings also suggest that risk variants may confer risk of MDD through affecting expression of FLOT1. Further functional investigation of FLOT1 may provide new insights for MDD pathogenesis.


Assuntos
Transtorno Depressivo Maior/genética , Proteínas de Membrana/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Teorema de Bayes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Adulto Jovem
12.
Nat Commun ; 10(1): 670, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737407

RESUMO

Genome-wide association studies (GWASs) have identified over 180 independent schizophrenia risk loci. Nevertheless, how the risk variants in the reported loci confer schizophrenia susceptibility remains largely unknown. Here we systematically investigate the gene regulatory mechanisms underpinning schizophrenia risk through integrating data from functional genomics (including 30 ChIP-Seq experiments) and position weight matrix (PWM). We identify 132 risk single nucleotide polymorphisms (SNPs) that disrupt transcription factor binding and we find that 97 of the 132 TF binding-disrupting SNPs are associated with gene expression in human brain tissues. We validate the regulatory effect of some TF binding-disrupting SNPs with reporter gene assays (9 SNPs) and allele-specific expression analysis (10 SNPs). Our study reveals gene regulatory mechanisms affected by schizophrenia risk SNPs (including widespread disruption of POLR2A and CTCF binding) and identifies target genes for mechanistic studies and drug development. Our results can be accessed and visualized at SZDB database ( http://www.szdb.org/ ).


Assuntos
Genômica/métodos , Esquizofrenia/genética , Alelos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/patologia
13.
J Mater Chem B ; 7(15): 2434-2441, 2019 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32255120

RESUMO

Alzheimer's disease (AD) is one of the most serious health threats in our aging society. The major pathological feature of AD is excessive extracellular aggregation of ß-amyloid (Aß) protein in the form of Aß fibrils or plaques. The simultaneous detection of Aß fibrils and inhibition of their neurotoxicity is highly desirable for study of Alzheimer's disease. Although various fluorophores have been developed for imaging of Aß fibrils or plaques, they suffer from serious self-quenching at high concentration and a lack of neuroprotective functions. To tackle these challenges, we herein develop a multi-functional probe of Cur-N-BF2 with aggregation-induced emission (AIE) characteristics for light-up detection of Aß fibrils and plaques, inhibition of Aß fibrillation, disassembly of preformed Aß fibrils, and protection of neuronal cells. The AIE-active theranostic probe is thus promising for study of Aß fibrils and plaques in Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/química , Curcumina/química , Curcumina/farmacologia , Luz , Neurônios/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Animais , Encéfalo/citologia , Linhagem Celular , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Camundongos , Modelos Moleculares , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia
14.
Am J Transl Res ; 11(12): 7410-7421, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31934288

RESUMO

BACKGROUND: The aim of this study was to explore the effects of irisin on human visceral adipose tissue and adipocytes functions. METHODS: Fresh human visceral white adipose tissues derived from 11 donors were used to examine the effects of irisin on browning, adipogenesis and osteogenesis gene expression, and anti-inflammatory properties. Preadipocytes were also used to examine the effects of irisin on mitochondrial respiration, adipogenic differentiation, and osteogenic differentiation. KEY RESULTS: Irisin significantly increased cellular mitochondrial energy metabolism in differentiated visceral adipocytes. Irisin also increased mRNA levels of transcriptional regulators of brite/beige adipocytes (UCP-1, PGC1α, PRDM16, TMEM26, and CD137) in subcutaneous white adipose tissue but not in visceral/brown adipose tissue or their derived mature adipocytes. In parallel, irisin increased the protein levels of UCP-1 in subcutaneous white adipose tissue, but had no effect on the expression of this protein in visceral white adipose tissue and perirenal brown adipose tissue. However, irisin inhibited adipogenic differentiation, promoted osteogenic differentiation in visceral adipocytes, down-regulated adipogenesis, and upregulated osteogenesis genes expression in visceral fat tissue. Moreover, administration of irisin reduced the expression of proinflammatory marker mRNAs in both visceral and subcutaneous white adipose tissue. CONCLUSIONS: Our data suggest that (1) irisin may increase mitochondrial respiration and glycolysis in visceral adipocytes by a UCP-1 independent pathway; (2) irisin promotes anti-inflammatory activity on fat tissue.

15.
Chem Sci ; 9(31): 6497-6502, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30310579

RESUMO

Luminogens with aggregation-induced emission (AIEgens) characteristics have been well developed and applied in various areas such as bio-imaging, theranostics, organic photoelectronics and chemo/bio sensors. However, most of the reported AIEgens suffer from the disadvantages of complex organic synthesis and high cost, as well as being environmentally unfriendly and hard to degrade, which have largely limited their real applications. In this work, we discovered berberine chloride, a natural isoquinoline alkaloid isolated from Chinese herbal plants, as an unconventional rotor-free AIEgen with bright solid-state emission and water-soluble characteristics. Single crystal structure analysis and optical property, viscosity, and host-guest interaction studies suggested that intramolecular vibration and twisted intramolecular charge transfer were responsible for the AIE phenomenon of berberine chloride. Moreover, berberine chloride was biocompatible and could specifically target lipid droplets in a fluorescence turn-on and wash-free manner, demonstrating the great potential of natural products as promising AIE probes.

16.
ACS Sens ; 3(11): 2218-2222, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30350949

RESUMO

Optical cross-reactive sensor arrays have recently been proven to be a powerful tool for high-throughput bioanalytes identification. Nevertheless, identification and classification of microbes, especially using microbial lysates as the analytes, still is a great challenge due to their complex composition. Herein, we achieve this goal by using luminogens featuring aggregation-induced emission characteristics (AIEgens) and graphene oxide (GO) to construct a microbial lysate responsive fluorescent sensor array. The combination of AIEgen with GO not only reduces the background signal but also induces the competition interactions among AIEgen, microbial lysates, and GO, which highly improves the discrimination ability of the sensor array. As a result, six microbes, including two fungi, two Gram-positive bacteria, and two Gram-negative bacteria are precisely identified. Thus, this work provides a new way to design safer and simpler sensor arrays for the discrimination of complex analytes.


Assuntos
Técnicas de Tipagem Bacteriana/métodos , Corantes Fluorescentes/química , Técnicas de Tipagem Micológica/métodos , Bacillus subtilis/isolamento & purificação , Candida albicans/isolamento & purificação , Escherichia coli/isolamento & purificação , Grafite/química , Análise de Componente Principal , Pseudomonas aeruginosa/isolamento & purificação , Reprodutibilidade dos Testes , Saccharomyces cerevisiae/isolamento & purificação , Staphylococcus aureus/isolamento & purificação , Estilbenos/química
17.
Chem Commun (Camb) ; 54(74): 10479-10482, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30156593

RESUMO

The asymmetric Michael addition of diphenylbutazone and its analogues to α,ß-unsaturated 2-acyl imidazoles has been developed with a chiral-at-metal Rh(iii) complex as a catalyst. The corresponding adducts were obtained in good yields (89-98%) with excellent enantioselectivities (up to >99%). The reaction can be conducted on a gram-scale with a low catalyst loading (0.04 mol%) without impacting its efficiency. Moreover, the adducts can be converted into other useful synthetic building blocks.

18.
Chem Sci ; 9(26): 5730-5735, 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30079182

RESUMO

Photoactivatable fluorescent probes are ideal tools for organelle study with a significant advantage of high spatiotemporal resolution. However, conventional photo-caged fluorophores for organelle-specific imaging suffer from several drawbacks, such as aggregation-caused quenching (ACQ), instability under ambient light, low photoactivation efficiency, and toxic photo-cleavage byproducts. Herein, we propose a strategy for in situ generation of photoactivatable aggregation-induced emission (AIE) probes of 2-(2-hydroxyphenyl)-benzothiazolines from easily available disulfide and thiol substrates through tandem S-S bond reduction and intramolecular cyclization reaction. Because the photoactivatable AIE probes can be in situ generated in a quantitative yield, they can be directly used for bio-imaging without complicated separation steps. Under both one- and NIR two-photon irradiation, excellent spatiotemporal resolution and high photoactivation efficiency were achieved for specific imaging of lipid droplets and lysosomes, respectively. Based on their in situ generation and adjustable organelle-targeting ability, the photoactivatable AIE probes could become an easy-to-use imaging tool in the study of the biological functions of organelles.

19.
ACS Appl Mater Interfaces ; 10(17): 14410-14417, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29671572

RESUMO

The fluorescent probe for the detection of calcium ions is an indispensable tool in the biomedical field. The millimolar order of Ca(II) ions is associated with many physiological processes and diseases, such as hypercalcemia, soft tissue calcification, and bone microcracks. However, the conventional fluorescent probes are only suitable for imaging Ca(II) ions in the nanomolar to micromolar range, which can be because of their high affinities toward Ca(II) ions and aggregation-caused quenching drawbacks. To tackle this challenge, we herein develop an aggregation-induced emission (AIE) probe SA-4CO2Na for selective and light-up detection of Ca(II) ions in the millimolar range (0.6-3.0 mM), which can efficiently distinguish between hypercalcemic (1.4-3.0 mM) and normal (1.0-1.4 mM) Ca2+ ion levels. The formation of fibrillar aggregates between SA-4CO2Na and Ca(II) ions was clearly verified by fluorescence, scanning electron microscopy, and transmission electron analysis. Moreover, this AIE-active probe can be used for wash-free and light-up imaging of a high concentration of Ca(II) ions even in the solid analytes, including calcium deposits in psammomatous meningioma slice, microcracks on bovine bone surface, and microdefects on hydroxyapatite-based scaffold. It is thus expected that this AIE-active probe would have broad biomedical applications through light-up imaging and sensing of Ca(II) ions at the millimolar level.


Assuntos
Cálcio/química , Animais , Cátions Bivalentes , Bovinos , Fluorescência , Corantes Fluorescentes
20.
Onco Targets Ther ; 11: 1767-1776, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29662316

RESUMO

Background: CD19-chimericantigen receptor (CAR) modified T cells (CD19-CAR T cells) have been well documented to possess potent anti-tumor properties against CD19-expressingleukemia cells. As a traditional medicine, metformin has been widely used to treat type II diabetes mellitus and more recently has become a candidate for the treatment of cancer. However, no report has revealed the direct effect of metformin on CD19-CAR T cell biological function and its underling mechanisms. Purpose: The purpose of this research was to explore the effect of metformin on CD19-CAR T cell biological function and the mechanisms involved. Methods: CD19-CAR T cells proliferation, apoptosis and cytotoxicity were mainly tested by CCK-8 assay, flow cytometry and ELISA. The detection of mechanism primarily used western blot. Bioluminescence imaging is the main application technology of animal studies. Results: In the current study, it was found that metformin inhibited CD19-CAR T cell proliferation and cytotoxicity and induced apoptosis. Furthermore, our study revealed that metformin activated AMPK and suppressed mTOR and HIF1α expression. By using an AMPK inhibitor, compound C, we demonstrated the crucial roles of AMPK in CD19-CAR T cells when they were treated with metformin. Finally, we verified that metformin suppressed the cytotoxicity of CD19-CAR T cell in vivo. Conclusion: Taken together, these results indicated that metformin may play an important role in modulating CD19-CAR T cell biological functions in an AMPK-dependent and mTOR/HIF1α-independent manner.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...