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1.
Curr Med Chem ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34477508

RESUMO

Exosomes are a heterogeneous group of nano-sized natural membrane vesicles released from various cells and exist in body fluids. Different from the previous understanding of the function of exosomes as "garbage bins", exosomes act as carriers with many kinds of bioactive molecules (e.g., proteins, lipids, and nucleic acids) to play an important role in cell-cell communication. Growing evidence in recent years has suggested that exosomes also play some roles in the pathogenesis, diagnosis, and treatment modalities of some brain diseases, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and brain cancers. Exosomes as therapeutic drug carriers for brain drug delivery have received extensive attention as well as exosomes can overcome the blood-brain barrier (BBB). However, the low targeting ability and size-dependent cellular uptake of native exosomes could profoundly affect the delivery performance of exosomes. Recent studies have indicated that engineered exosomes can increase the drug uptake efficiency and the subsequent drug efficacy. In the present paper, we will briefly introduce the engineering methods and applications of engineered exosomes in the treatment of brain diseases, and then focus on discussing the advantages and challenges of exosome-based drug delivery platforms to further enrich and boost the development of exosomes as a promising drug delivery strategy for brain diseases.

2.
Stem Cell Reports ; 16(10): 2548-2564, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34506726

RESUMO

The specification of inhibitory neurons has been described for the mouse and human brain, and many studies have shown that pluripotent stem cells (PSCs) can be used to create interneurons in vitro. It is unclear whether in vitro methods to produce human interneurons generate all the subtypes found in brain, and how similar in vitro and in vivo interneurons are. We applied single-nuclei and single-cell transcriptomics to model interneuron development from human cortex and interneurons derived from PSCs. We provide a direct comparison of various in vitro interneuron derivation methods to determine the homogeneity achieved. We find that PSC-derived interneurons capture stages of development prior to mid-gestation, and represent a minority of potential subtypes found in brain. Comparison with those found in fetal or adult brain highlighted decreased expression of synapse-related genes. These analyses highlight the potential to tailor the method of generation to drive formation of particular subtypes.

3.
Nat Commun ; 12(1): 4876, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385436

RESUMO

While the printed circuit board (PCB) has been widely considered as the building block of integrated electronics, the world is switching to pursue new ways of merging integrated electronic circuits with textiles to create flexible and wearable devices. Herein, as an alternative for PCB, we described a non-printed integrated-circuit textile (NIT) for biomedical and theranostic application via a weaving method. All the devices are built as fibers or interlaced nodes and woven into a deformable textile integrated circuit. Built on an electrochemical gating principle, the fiber-woven-type transistors exhibit superior bending or stretching robustness, and were woven as a textile logical computing module to distinguish different emergencies. A fiber-type sweat sensor was woven with strain and light sensors fibers for simultaneously monitoring body health and the environment. With a photo-rechargeable energy textile based on a detailed power consumption analysis, the woven circuit textile is completely self-powered and capable of both wireless biomedical monitoring and early warning. The NIT could be used as a 24/7 private AI "nurse" for routine healthcare, diabetes monitoring, or emergencies such as hypoglycemia, metabolic alkalosis, and even COVID-19 patient care, a potential future on-body AI hardware and possibly a forerunner to fabric-like computers.


Assuntos
Técnicas Biossensoriais/instrumentação , Medicina de Precisão/instrumentação , Têxteis , Dispositivos Eletrônicos Vestíveis , Tecnologia sem Fio/instrumentação , Técnicas Biossensoriais/métodos , COVID-19/diagnóstico , COVID-19/prevenção & controle , COVID-19/virologia , Desenho de Equipamento , Humanos , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Medicina de Precisão/métodos , SARS-CoV-2/fisiologia , Suor/fisiologia
4.
Small ; 17(29): e2100949, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34145743

RESUMO

Single atom catalysts (SACs) are promising electrocatalysts for CO2 reduction reaction (CO2 RR), in which the coordination environment plays a crucial role in intrinsic catalytic activity. Taking the regular Fe porphyrin (Fe-N4 porphyrin) as a probe, the study reveals that the introduction of opposable S atoms into N coordination (Fe-N2 S2 porphyrin) allows for an appropriate electronic structural optimization on active sites. Owing to the additional orbitals around the Fermi level and the abundant Fe d z 2 orbital occupation after S substitution, N, S cocoordination can effectively tune SACs and thus facilitating protonation of intermediates during CO2 RR. CO2 RR mechanisms lead to possible C1 products via two-, six-, and eight-electron pathways are systematically elucidated on Fe-N4 porphyrin and Fe-N2 S2 porphyrin. Fe-N4 porphyrin yields the most favorable product of HCOOH with a limiting potential of -0.70 V. Fe-N2 S2 porphyrin exhibits low limiting potentials of -0.38 and -0.40 V for HCOOH and CH3 OH, respectively, surpassing those of most Cu-based catalysts and SACs. Hence, the N, S cocoordination might provide better catalytic environment than regular N coordination for SACs in CO2 RR. This work demonstrates Fe-N2 S2 porphyrin as a high-performance CO2 RR catalyst, and highlights N, S cocoordination regulation as an effective approach to fine tune high atomically dispersed electrocatalysts.


Assuntos
Porfirinas , Dióxido de Carbono , Catálise , Ferro
5.
Methods Appl Fluoresc ; 9(2): 025003, 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33524966

RESUMO

A dual-functional nanosysterm is developed by means of Chlorin e6 (Ce6) as photosensitizer and 1,3-Diphenylisobenzofuran (DPBF) as fluorescent singlet oxygen (1O2) probe. Under 660 nm laser irradiation, Ce6 exhibites efficient 1O2 generation, and subsequently the production of 1O2 is assessed by the ratiometric fluorescence of PFO and DPBF under one-photon and two-photon excitation mode. The nanoparticles with excellent biocompatibility can be internalized into Hela cells and applied for tumor treatment. For intracellular PDT, the nanoparticles perform a high phototoxicity, while the PDT proccess can be evaluated in time by monitoring fluorescence signals of DPBF. This theranostic nanosysterm provides a facile strategy to fabricate 1O2-detection PDT, which can realize accurate and efficient photodynamic therapy based on singlet oxygen detection.


Assuntos
Antineoplásicos/farmacologia , Corantes Fluorescentes/química , Nanopartículas/química , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete/análise , Oxigênio Singlete/farmacologia , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Benzofuranos/química , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Luz , Nanopartículas/efeitos da radiação , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Polímeros/química , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/efeitos da radiação , Oxigênio Singlete/química
6.
J Neurosci ; 41(5): 991-1004, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33268544

RESUMO

Mossy cells (MCs) of the dentate gyrus (DG) are a major group of excitatory hilar neurons that are important for regulating activity of dentate granule cells. MCs are particularly intriguing because of their extensive longitudinal connections within the DG. It has generally been assumed that MCs in the dorsal and ventral DG have similar patterns of termination in the inner one-third of the dentate molecular layer. Here, we demonstrate that axonal projections of MCs in these two regions are considerably different. MCs in dorsal and ventral regions were labeled selectively with Cre-dependent eYFP or mCherry, using two transgenic mouse lines (including both sexes) that express Cre-recombinase in MCs. At four to six weeks following unilateral labeling of MCs in the ventral DG, a dense band of fibers was present in the inner one-fourth of the molecular layer and extended bilaterally throughout the rostral-caudal extent of the DG, replicating the expected distribution of MC axons. In contrast, following labeling of MCs in the dorsal DG, the projections were more diffusely distributed. At the level of transfection, fibers were present in the inner molecular layer, but they progressively expanded into the middle molecular layer and, most ventrally, formed a distinct band in this region. Optical stimulation of these caudal fibers expressing ChR2 demonstrated robust EPSCs in ipsilateral granule cells and enhanced the effects of perforant path stimulation in the ventral DG. These findings suggest that MCs in the dorsal and ventral DG differ in the distribution of their axonal projections and possibly their function.SIGNIFICANCE STATEMENT Mossy cells (MCs), a major cell type in the hilus of the dentate gyrus (DG), are unique in providing extensive longitudinal and commissural projections throughout the DG. Although it has been assumed that all MCs have similar patterns of termination in the inner molecular layer of the DG, we discovered that the axonal projections of dorsal and ventral MCs differ. While ventral MC projections exhibit the classical pattern, with dense innervation in the inner molecular layer, dorsal MCs have a more diffuse distribution and expand into the middle molecular layer where they overlap and interact with innervation from the perforant path. These distinct locations and patterns of axonal projections suggest that dorsal and ventral MCs may have different functional roles.


Assuntos
Axônios/química , Axônios/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Fibras Musgosas Hipocampais/química , Fibras Musgosas Hipocampais/fisiologia , Animais , Giro Denteado/química , Giro Denteado/citologia , Giro Denteado/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética/métodos
7.
Environ Sci Technol ; 54(20): 12850-12859, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32915549

RESUMO

Due to developmental toxicity, prenatal exposure to per- and polyfluoroalkyl substances (PFASs) in animals may result in adverse effects on the fetus. However, little information is available on PFASs presence in the human cord plasma. Here, we measured the levels of 37 emerging and legacy PFASs in 650 cord plasma samples collected every 5 years spanning 1998 to 2018 by the Beijing Cord Blood Bank and evaluated changes in PFASs concentrations using generalized additive models. We observed an increase in the concentrations of 24 PFASs (Σ24PFASs) from 1998 to 2003 followed by a decrease every 5 years from 2003 to 2018. For legacy PFASs, similar trends were observed for PFOS, whereas PFOA levels did not decline until 2013. For emerging chemicals, 6:2 Cl-PFESA showed a similar trend as PFOS, and prenatal exposure to 6:2 Cl-PFESA could be traced back to 1998, with a median concentration of 0.411 ng/mL in plasma. Our data showed that prenatal exposure to legacy PFASs has gradually decreased in cord plasma from the Beijing Cord Blood Bank in recent years, and the discovery of the presence of emerging chemicals in 1998 suggested that further evaluation is needed to assess possible health risks to pregnant women and fetuses.


Assuntos
Ácidos Alcanossulfônicos , Poluentes Ambientais , Fluorcarbonetos , Efeitos Tardios da Exposição Pré-Natal , Animais , Pequim , Bancos de Sangue , China , Feminino , Fluorcarbonetos/análise , Humanos , Plasma/química , Gravidez
8.
JCI Insight ; 5(4)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31999649

RESUMO

In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-ß receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line-derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-ß-rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Neoplasias/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Fatores de Transcrição Forkhead/fisiologia , Humanos , Camundongos , Camundongos Knockout , Neoplasias/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Mater Chem B ; 8(5): 1033-1039, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31939981

RESUMO

Photothermal therapy following microscopic temperature detection can avoid overheating effects or insufficient heating, and thus improve therapeutic efficacy. In this study, biocompatible dual-functional nanoparticles (NPs) are constructed from polypyrrole (PPy) and rhodamine B (RB) by a one-step modified polymerization method. The polypyrrole serves as a photothemal agent, and rhodamine B acts as a temperature-sensing probe. The polypyrrole-rhodamine B (PPy-RB) NPs possess a high photothermal effect on irradiation by 808 nm laser, and a competent temperature sensitivity for the real-time temperature monitoring based on the emission intensity response of rhodamine B. After acting on HepG2 cells, the PPy-RB NPs can effectively induce cancer cell death, and the microscopic temperature is monitored by fluorescence feedback from rhodamine B during PTT by laser confocal microscopy. Hence, the proposed approach can supply a facile and promising way for the fabrication of effective theranostic nanoplatforms assisted by self-monitoring of cancer therapeutic processes.


Assuntos
Nanopartículas/química , Terapia Fototérmica , Polímeros/farmacologia , Pirróis/farmacologia , Rodaminas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Teste de Materiais , Tamanho da Partícula , Polímeros/química , Pirróis/química , Rodaminas/química , Propriedades de Superfície , Temperatura , Células Tumorais Cultivadas
10.
Oncoimmunology ; 9(1): 1824643, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-33457103

RESUMO

Chimeric antigen receptor T (CAR-T) cell therapy has been applied successfully in treating hematologic malignancies; however, it shows very limited efficacy in treating solid tumors. Adenosine is one of the key immunosuppressive metabolites in tumor microenvironment (TME) of solid tumors. Although the effect of adenosine has been well studied using mouse CAR-T cells, its effect on human CAR-T cells has not been fully elucidated. In particular, there was no evaluation of the CAR-T cells with blocked adenosine signaling in tumor xenograft animal model, which is essential for determining the feasibility of future clinical trials. In this study, we found the expression of A2a receptor (A2AR) and A2b receptor (A2BR) both upregulated in human-derived CAR-T cells, and only A2AR was responsible for adenosine-induced impairment of CAR-T cell function. Disrupting A2AR gene in human CAR-T cells with CRISPR-Cas9 increased the anti-tumor function and prevented the exhaustion of CAR-T cells in vitro. Furthermore, CRL5826-CDX model and two patient-derived xenograft solid tumor models were applied to evaluate the efficacy of A2AR knock-out CAR-T cells, which showed superior capability of inhibiting tumor growth. Taken together, these results demonstrate that A2AR knock-out CAR-T cells have the potential of being an improved CAR-T cell therapy in treating solid tumors.


Assuntos
Adenosina , Receptores de Antígenos Quiméricos , Animais , Imunoterapia Adotiva , Camundongos , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais , Linfócitos T
11.
Diagn Pathol ; 14(1): 116, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31647020

RESUMO

BACKGROUND: Gastrointestinal stromal tumors (GISTs), a type of mesenchymal tumor in the gastrointestinal tract, are believed to be closely associated with PDGFRA and C-KIT mutations. Schwannoma in the stomach, which is an unusual location, is a rare disorder. The simultaneous occurrence of the two diseases is rarer than metachronous occurrences, and its pathological characteristics have not been reported to date. We present a case report on a patient with simultaneous coexistence of gastric schwannoma and GISTs. CASE PRESENTATION: A 39-year-old female visited our hospital complaining of intermittent abdominal pain for the previous 3 months. CT revealed a 3.4 cm slight homogeneous enhancement in the lesser curvature of the stomach; the mass was nodular soft tissue, which was removed by radical surgery. Two solid tumors with different volumes were located in the stomach. Histologically and immunohistochemically different, the larger tumor consisted of spindle cells surrounded by a peripheral lymphoid cuff, and was positive for S-100. The larger tumor was therefore classified as a gastric schwannoma. The smaller tumor was composed of medium-sized round, oval cells with amphiphilic granular cytoplasm; vacuolization was also observed. The tumor cells were positive for DOG1 and sporadically positive for CD34 and CD117. Hence, the smaller tumor was diagnosed as epithelioid GISTs. Sanger sequencing revealed that the GIST tumor cells contained a deletion mutation (c.2527_2538 del12,843-846del4), which was located in exon 18 of PDGFRA. CONCLUSION: GISTs combined with gastric schwannoma are a considerably rare subgroup of gastric tumors. Related clinical research is comparatively weak, and the mechanism remains unknown. We reviewed related articles to provide knowledge to improve the correct identification, diagnosis and management of patients with gastric cancer. All pathologists involved in the diagnosis and clinicians involved in the treatment should be aware of this new kind of disease pattern to improve their understanding of the disease.


Assuntos
Tumores do Estroma Gastrointestinal/patologia , Neurilemoma/patologia , Neoplasias Gástricas/patologia , Estômago/patologia , Adulto , Éxons , Feminino , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/genética , Humanos , Neurilemoma/diagnóstico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Deleção de Sequência/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética
13.
Neuropharmacology ; 148: 11-20, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30594698

RESUMO

24S-hydroxycholesterol (24HC) is the major metabolic breakdown product of cholesterol in the brain. Among its other effects on neurons, 24HC modulates N-methyl-d-aspartate (NMDA or GluN) receptors, but our understanding of this mechanism is poor. We used whole-cell patch clamp recordings and various pharmacological approaches in mouse brain slices to record isolated NMDAR-mediated (INMDA) tonic and evoked synaptic currents. 24HC (1 µΜ) significantly enhanced tonic, but not evoked, INMDA of dentate gyrus granule cells. The INMDA had both GluN2A and GluN2B-mediated components. Preincubation of the slices with PEAQX (a GluN2A antagonist) or Ro25-6981 (a GluN2B antagonist) dramatically changed the INMDA modulatory potential of 24HC. Ro25-6981 blocked the enhancing effect of 24HC on tonic INMDA, while preincubation with PEAQX had no effect. In cholesterol 24-hydroxylase (CYP46A1) knockout mice, in sharp contrast to WT, 24HC slightly decreased the tonic INMDA of granule cells. Furthermore, 24HC had no effect on tonic INMDA of dentate gyrus parvalbumin interneurons (PV-INs), known to express different GluN subunits than granule cells. Taken together, our results revealed a specific enhancement of GluN2B-containing NMDARs by 24HC, indicating a novel endogenous pathway to influence a subclass of NMDARs critically involved in cortical plasticity and in numerous neurological and psychiatric disorders.


Assuntos
Giro Denteado/fisiologia , Hidroxicolesteróis/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Colesterol 24-Hidroxilase/genética , Giro Denteado/efeitos dos fármacos , Potenciais Evocados/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fenóis/farmacologia , Piperidinas/farmacologia , Quinoxalinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Potenciais Sinápticos/fisiologia
15.
J Med Genet ; 56(1): 10-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30030293

RESUMO

BACKGROUND: Chimeric antigen receptor T (CAR-T) cells engineered with lentiviral and retroviral vectors have been successfully applied to treat patients with B cell malignancy. However, viral integration in T cells has the potential risk of mutagenesis, and viral vector production demands effort and is costly. Using non-integrative episomal vector such as minicircle vector to generate integration-free CAR-T cells is an attractive option. METHODS AND RESULTS: We established a novel method to generate minicircle vector within a few hours using simple molecular biology techniques. Since no bacteria is involved, we named these vectors bacteria-free (BF) minicircle. In comparison with plasmids, BF minicircle vector enabled higher transgene expression and improved cell viability in human cell line, stem cells and primary T cells. Using BF minicircle vector, we generated integration-free CAR-T cells, which eliminated cancer cells efficiently both in vitro and in vivo. CONCLUSION: BF minicircle vector will be useful in basic research as well as in clinical applications such as CAR-T and gene therapy. Although the transgene expression of minicircle vector lasts apparently shorter than that of insertional lentivirus, multiple rounds of BF minicircle CAR-T cell infusion could eliminate cancer cells efficiently. On the other hand, a relatively shorter CAR-T cell persistence provides an opportunity to avoid serious side effects such as cytokine storm or on-target off-tumour toxicity.


Assuntos
DNA Bacteriano , DNA Circular , Técnicas de Transferência de Genes , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Animais , Linhagem Celular , Vetores Genéticos/genética , Xenoenxertos , Humanos , Imunoterapia Adotiva , Camundongos , Modelos Animais , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Transgenes
16.
Metab Brain Dis ; 33(4): 1069-1079, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29542038

RESUMO

Taxifolin is a potent flavonoid with anti-inflammatory activity. Taxifolin has been reported to decrease the accumulation of ß-amyloid (Aß), and reduce Aß-induced neurotoxicity. However, the detail molecular mechanism of taxifolin against Aß-induced neurotoxicity is largely unknown. In this study, we revealed the protective effects and the underlying mechanisms of taxifolin on the impairments of cognitive function and synapse formation induced by soluble Aß oligomers. Our results showed that taxifolin prevented neuronal cell death in a concentration-dependent manner. The recognition memory in novel object recognition tasks and the spatial memory in Morris water maze tests are significantly lower in the Alzheimer's disease (AD) model mice induced by hippocampal injection of Aß42. Taxifolin treatment prevented the recognitive and spatial memory deficits of the AD mice. 10 mg/kg taxifolin treatment also significantly prevented the decreased expression levels of PSD 95 induced by Aß42. Live cell imaging study showed that 2 h pre-treatment of taxifolin prevented the decrease in the number of filopodium and spine induced by Aß42 oligomers. Aß42 oligomers significantly increased the production of cytosolic phospholipase A2 (cPLA2), a crucial enzyme of pro-inflammatory mediator, and prostaglandin E2 (PGE2), a neuroinflammatory molecule. Taxifolin significantly reduced the content of cPLA2 and PGE2 induced by Aß42 both in the primary hippocampal neurons and hippocampal tissues. These results indicated that taxifolin might prevent Aß42 oligomer-induced synapse and cognitive impairments through decreasing cPLA2 and PGE2. Our study provided novel insights into the cellular mechanisms for the protective effects of taxifolin on AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Citosol/metabolismo , Dinoprostona/metabolismo , Transtornos da Memória/metabolismo , Fosfolipases A2/metabolismo , Quercetina/análogos & derivados , Sinapses/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular Tumoral , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Quercetina/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Sinapses/metabolismo
17.
Front Med ; 11(4): 554-562, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28625015

RESUMO

T cells engineered with chimeric antigen receptor (CAR) have been successfully applied to treat advanced refractory B cell malignancy. However, many challenges remain in extending its application toward the treatment of solid tumors. The immunosuppressive nature of tumor microenvironment is considered one of the key factors limiting CAR-T efficacy. One negative regulator of Tcell activity is lymphocyte activation gene-3 (LAG-3). We successfully generated LAG-3 knockout Tand CAR-T cells with high efficiency using CRISPR-Cas9 mediated gene editing and found that the viability and immune phenotype were not dramatically changed during in vitro culture. LAG-3 knockout CAR-T cells displayed robust antigen-specific antitumor activity in cell culture and in murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates an efficient approach to silence immune checkpoint in CAR-T cells via gene editing.


Assuntos
Antígenos CD/imunologia , Sistemas CRISPR-Cas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Edição de Genes/métodos , Tolerância Imunológica/imunologia , Camundongos , Camundongos Knockout , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Neural Plast ; 2017: 5196958, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28255459

RESUMO

Bisphenol-A (BPA), a widely used synthetic compound in plastics, disrupts endocrine function and interferes with physiological actions of endogenous gonadal hormones. Chronic effects of BPA on reproductive function, learning and memory, brain structure, and social behavior have been intensively investigated. However, less is known about the influence of BPA on long-term potentiation (LTP), one of the major cellular mechanisms that underlie learning and memory. In the present study, for the first time we investigated the effect of different doses of BPA on hippocampal LTP in rat brain slices. We found a biphasic effect of BPA on LTP in the dentate gyrus: exposure to BPA at a low dose (100 nM) enhanced LTP and exposure to BPA at a high dose (1000 nM) inhibited LTP compared with vehicle controls. The rapid facilitatory effect of low-dose BPA on hippocampal LTP required membrane-associated estrogen receptor (ER) and involved activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Coadministration of 17ß-estradiol (E2, the primary estrogen hormone) and BPA (100 nM) abolished both the BPA-induced enhancement of LTP and the E2-induced enhancement of baseline fEPSP, suggesting a complex interaction between BPA- and E2-mediated signaling pathways. Our investigation implies that even nanomolar levels of endocrine disrupters (e.g., BPA) can induce significant effects on hippocampal LTP.


Assuntos
Compostos Benzidrílicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fenóis/farmacologia , Receptores de Estrogênio/fisiologia , Animais , Compostos Benzidrílicos/administração & dosagem , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiologia , Relação Dose-Resposta a Droga , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Fulvestranto , Masculino , Fenóis/administração & dosagem , Ratos , Ratos Wistar , Receptores de Estrogênio/antagonistas & inibidores
20.
Mol Med Rep ; 14(2): 1061-6, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27277949

RESUMO

The aim of the present study was to examine the effect of small interfering RNA (siRNA) methods on the expression of N­ethylmaleimide sensitive factor (NSF) and Weibel­Palade body (WPB) release in endothelial cells. A small hairpin RNA (shRNA), mediated with an adenovirus vector, was designed to target the N­terminal functional area of NSF. Subsequently, viruses were transfected into human aortic endothelial cells. The mRNA and protein expression levels of NSF were detected using reverse transcription­quantitative polymerase chain reaction and Western blot analyses, respectively, and the release of WPBs in the endothelial cells was examined using immunofluorescence. The mRNA expression of NSF in the endothelial cells, which were transfected with the adenoviruses carrying the NSF­shRNA was significantly decreased, compared with the negative control group (P=0.035) and blank control group (P=0.02). In addition, the mRNA expression of NSF was gradually decreased as duration increased; there were marked differences between the 24, 48 and 72 h groups (P<0.05). The protein expression of NSF was significantly decreased in the experimental group, compared with the negative control group (P=0.004) and blank control group (P=0.031), however, no difference was observed between the negative control and blank control groups (P=0.249). The immunofluorescence staining showed that the release of WPBs in the endothelial cells induced with thrombin was inhibited markedly following transfection with the virus carrying the NSF­shRNA. Therefore NSF­siRNA inhibited the mRNA and protein expression levels of NSF, and inhibited the release of WPBs in endothelial cells induced with thrombin. These results suggested that NSF-siRNA may be valuable for preventing and treating atherosclerosis and acute coronary syndrome.


Assuntos
Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Proteínas Sensíveis a N-Etilmaleimida/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Corpos de Weibel-Palade/metabolismo , Adenoviridae/genética , Células Cultivadas , Expressão Gênica , Vetores Genéticos/genética , Humanos , Transdução Genética
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