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1.
Phytother Res ; 35(3): 1621-1633, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33150724

RESUMO

The consequences of increased industrialization increased the risk of asthma and breathing difficulties due to increased particulate matter in the air. We aim to investigate the therapeutic properties of Hypericum ascyron L. extract (HAE) in airway inflammation and unravel its mechanism of action. We conducted nitric oxide and cell viability assay, real-time PCR and western blot analyses along with in vitro studies. in vivo studies include a model of coal fly ash and diesel exhaust particle (CFD)-induced airway inflammation in mice. HAE reduced coal fly ash (CFA)-induced nitric oxide secretion without exhibiting cytotoxicity in MH-S cells. HAE also reduced the mRNA expression of pro-inflammatory cytokines and reduced the expression of proteins in the NFκB and MAPK pathways. In a mice model of CFD-induced airway inflammation, HAE effectively reduced neutrophil infiltration in bronchoalveolar lavage fluid (BALF) and increased the amount of T cells in the BALF, lungs, and blood while reducing all other immune cell subtypes to reduce airway inflammatory response. CXCL-1, IL-17, MIP-2, and TNF-α expression in the BALF were also reduced. HAE effectively reduced MIP-2 and TNF-α mRNA expression in the lung tissue of mice. In a nutshell, HAE is effective in preventing airway inflammation induced by CFA in MH-S cells, as well as inflammation induced by CFD in mice.


Assuntos
Hypericum/química , Inflamação/tratamento farmacológico , Material Particulado/química , Animais , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Camundongos
2.
Development ; 144(22): 4159-4172, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28993397

RESUMO

GTPase regulator associated with focal adhesion kinase 1 (GRAF1) is an essential component of the GPI-enriched endocytic compartment (GEEC) endocytosis pathway. Mutations in the human GRAF1 gene are associated with acute myeloid leukemia, but its normal role in myeloid cell development remains unclear. We show that Graf, the Drosophila ortholog of GRAF1, is expressed and specifically localizes to GEEC endocytic membranes in macrophage-like plasmatocytes. We also find that loss of Graf impairs GEEC endocytosis, enhances EGFR signaling and induces a plasmatocyte overproliferation phenotype that requires the EGFR signaling cascade. Mechanistically, Graf-dependent GEEC endocytosis serves as a major route for EGFR internalization at high, but not low, doses of the predominant Drosophila EGFR ligand Spitz (Spi), and is indispensable for efficient EGFR degradation and signal attenuation. Finally, Graf interacts directly with EGFR in a receptor ubiquitylation-dependent manner, suggesting a mechanism by which Graf promotes GEEC endocytosis of EGFR at high Spi. Based on our findings, we propose a model in which Graf functions to downregulate EGFR signaling by facilitating Spi-induced receptor internalization through GEEC endocytosis, thereby restraining plasmatocyte proliferation.


Assuntos
Proteínas de Transporte/metabolismo , Compartimento Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Endocitose , Receptores ErbB/metabolismo , Glicosilfosfatidilinositóis/metabolismo , Hematopoese , Receptores de Peptídeos de Invertebrados/metabolismo , Animais , Proliferação de Células , Clatrina/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Hemócitos/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismo , Modelos Biológicos , Mutação/genética , Ligação Proteica , Proteólise , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Ubiquitina/metabolismo , Ubiquitinação , Proteínas ras/metabolismo
3.
Molecules ; 25(22)2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33182623

RESUMO

Ginseng is a vastly used herbal supplement in Southeast Asian countries. Red ginseng extract enriched with Rg3 (Rg3-RGE) is a formula that has been extensively studied owing to its various biological properties. Persicaria tinctoria (PT), belonging to the Polygonaceae family, has also been reported for its anti-inflammatory properties. Ulcerative colitis (UC) is inflammation of the large intestine, particularly in the colon. This disease is increasingly common and has high probability of relapse. We investigated, separately and in combination, the effects of Rg3-RGE and PT using murine exemplary of UC induced by DSS (Dextran Sulfate Sodium). For in vitro and in vivo experiments, nitric oxide assay, qRT-Polymerase Chain Reaction (PCR), Western blot, ulcerative colitis introduced by DSS, Enzyme Linked Immunosorbent Assay (ELISA), and flow cytometry analysis were performed. The results obtained demonstrate that treatment with Rg3-RGE + PT showed synergism to suppress inflammation (in vitro) in RAW 264.7 cells via mitogen-activated protein kinase and nuclear factor κB pathways. Moreover, in C57BL/6 mice, this mixture exhibits strong anti-inflammatory effects in restoring colon length, histopathological damage, pro-inflammatory mediators, and cytokines amount, and decreasing levels of NLRP3 inflammasome (in vivo). Our results recommend that this mixture can be used for the prevention of UC as a prophylactic/therapeutic supplement.


Assuntos
Caryophyllales/química , Colite Ulcerativa/tratamento farmacológico , Panax/química , Extratos Vegetais/farmacologia , Equilíbrio Th1-Th2 , Animais , Anti-Inflamatórios , Ensaio de Imunoadsorção Enzimática , Inflamação , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/química , Células RAW 264.7 , Transdução de Sinais
4.
Molecules ; 25(20)2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33081281

RESUMO

A 'remedy for all' natural product widely known in the Korean Peninsula is called Panax Ginseng Meyer. Globalization represents a persistent risk to the ozone layer, leading to bountiful amounts of Ultra-Violet B beams (UVB). The variety in human skin hues is ascribed to the characteristic color called Melanin. However, Melanin overproduction due to UVB beams promotes skin staining and tumorigenesis, a process called photo aging, which damages skin quality. To assess the effects of Korean Red Ginseng Oil (KGO) on photo aging, the murine melanoma cell lines B16/F10 were used in vitro and HRM-2 hairless mice exposed to UVB were studied in vivo. Our results revealed that KGO reduced tyrosinase activity and melanin production in B16/F10 cells along with the suppression of upstream factors involved in the melanin production pathway, both transcriptionally and transitionally. In the in vivo studies, KGO suppressed the expression of Matrix Metalloproteinase (MMP) and Interleukins along with a reduction of depth in wrinkle formation and reduced collagen degradation. Moreover, the feed intake and feed efficiency ratio that decreased as a result of UVB exposure was also improved by KGO treatment. In light of our results, we conclude that KGO can have considerable benefits due to its various properties of natural skin enhancement.


Assuntos
Carcinogênese/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Panax/química , Óleos de Plantas/farmacologia , Animais , Carcinogênese/efeitos da radiação , Fibroblastos/efeitos dos fármacos , Humanos , Melaninas/biossíntese , Melaninas/efeitos da radiação , Camundongos , Camundongos Pelados , Ozônio/efeitos adversos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Óleos de Plantas/química , Pele/efeitos dos fármacos , Pele/metabolismo , Raios Ultravioleta/efeitos adversos
5.
Platelets ; 30(5): 589-598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29870296

RESUMO

Panax ginseng (P. ginseng), one of the most valuable medicinal plants, is known for its healing and immunobooster properties and has been widely used in folk medicine against cardiovascular diseases, including stroke and heart attack. In this study, we explored the anti-platelet activity of gintonin (a recently discovered non-saponin fraction of ginseng) against agonist-induced platelet activation. In vitro effects of gintonin on agonist-induced human and rat platelet aggregation, granule secretion, integrin αIIbß3 activation, and intracellular calcium ion ([Ca2+]i) mobilization were examined. Western blot analysis and immunoprecipitation techniques were used to estimate the expression of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and interaction of glycoprotein VI (GPVI) signaling pathway molecules such as Src family kinases (SFK), tyrosine kinase Syk, and PLCγ2. In vivo effects were studied using acute pulmonary thromboembolism model in mice. Gintonin remarkably inhibited collagen-induced platelet aggregation and suppressed granule secretion, [Ca2+]i mobilization, and fibrinogen binding to integrin αIIbß3 in a dose-dependent manner and clot retraction. Gintonin attenuated the activation of MAPK molecules and PI3K/Akt pathway. It also inhibited SFK, Syk, and PLCγ2 activation and protected mice from thrombosis. Gintonin inhibited agonist-induced platelet activation and thrombus formation through impairment in GPVI signaling molecules, including activation of SFK, Syk, PLCγ2, MAPK, and PI3K/Akt; suggesting its therapeutic potential against platelet related CVD.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trombose/metabolismo , Animais , Biomarcadores , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/ultraestrutura , Modelos Animais de Doenças , Humanos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Panax/química , Fosfatidilinositol 3-Quinase/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Trombose/tratamento farmacológico , Trombose/etiologia
6.
Phys Chem Chem Phys ; 19(2): 976-985, 2017 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-27711559

RESUMO

Boron nitride nanotubes (BNNTs) are ceramic compounds which are hardly oxidized below 1000 °C due to their superior thermal stability. Also, they are electrically almost insulators with a large band gap of 5 eV. Thus, it is a challenging task to etch BNNTs at low temperature and to convert their electrical properties to a conductive behavior. In this study, we demonstrate that BNNTs can be easily etched at low temperature by catalytic oxidation, resulting in an electrically conductive behavior. For this, multi-walled BNNTs (MWBNNTs) impregnated with Co precursor (Co(NO3)2·6H2O) were simply heated at 350 °C under air atmosphere. As a result, diverse shapes of etched structures such as pits and thinned walls were created on the surface of MWBNNTs without losing the tubular structure. The original crystallinity was still kept in the etched MWBNNTs in spite of oxidation. In the electrical measurement, MWBNNTs with a large band gap were converted to electrical conductors after etching by catalytic oxidation. Theoretical calculations indicated that a new energy state in the gap and a Fermi level shift contributed to MWBNNTs being conductive.

7.
Nanotechnology ; 27(40): 405704, 2016 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-27581367

RESUMO

The performance of carbon nanotube (CNT)-based devices strongly depends on the adhesion of CNTs to the substrate on which they were directly grown. We report on the bond strength of CNTs grown on a carbon fiber (T700SC Toray), measured via in situ pulling of individual CNTs inside a transmission electron microscope. The bond strength of an individual CNT, obtained from the measured pulling force and CNT cross-section, was very high (∼200 MPa), 8-10 times higher than that of an adhesion model assuming only van der Waals interactions (25 MPa), presumably due to carbon-carbon interactions between the CNT (its bottom atoms) and the carbon substrate.

8.
Nano Lett ; 15(6): 4129-34, 2015 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-26000901

RESUMO

Atomic-scale defects strongly influence the electrical and optical properties of materials, and their impact can be more pronounced in localized dimensions. Here, we directly demonstrate that strain triggers the formation of oxygen vacancies in complex oxides by examining the tilt boundary of SrTiO3 bicrystals. Through transmission electron microscopy and electron energy loss spectroscopy, we identify strains along the tilt boundary and oxygen vacancies in the strain-imposed regions between dislocation cores. First-principles calculations support that strains, irrespective of their type or sign, lower the formation energy of oxygen vacancies, thereby enhancing vacancy formation. Finally, current-voltage measurements confirm that such oxygen vacancies at the strained boundary result in a decrease of the nonlinearity of the I-V curve as well as the resistivity. Our results strongly indicate that oxygen vacancies are preferentially formed and are segregated at the regions where strains accumulate, such as heterogeneous interfaces and grain boundaries.

9.
Materials (Basel) ; 16(20)2023 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-37895734

RESUMO

In this paper, we investigate the structural, microstructural, dielectric, and energy storage properties of Nd and Mn co-doped Ba0.7Sr0.3TiO3 [(Ba0.7Sr0.3)1-xNdxTi1-yMnyO3 (BSNTM) ceramics (x = 0, 0.005, and y = 0, 0.0025, 0.005, and 0.01)] via a defect dipole engineering method. The complex defect dipoles (MnTi"-VO∙∙)∙ and (MnTi"-VO∙∙) between acceptor ions and oxygen vacancies capture electrons, enhancing the breakdown electric field and energy storage performances. XRD, Raman, spectroscopy, XPS, and microscopic investigations of BSNTM ceramics revealed the formation of a tetragonal phase, oxygen vacancies, and a reduction in grain size with Mn dopant. The BSNTM ceramics with x = 0.005 and y = 0 exhibit a relative dielectric constant of 2058 and a loss tangent of 0.026 at 1 kHz. These values gradually decreased to 1876 and 0.019 for x = 0.005 and y = 0.01 due to the Mn2+ ions at the Ti4+- site, which facilitates the formation of oxygen vacancies, and prevents a decrease in Ti4+. In addition, the defect dipoles act as a driving force for depolarization to tailor the domain formation energy and domain wall energy, which provides a high difference between the maximum polarization of Pmax and remnant polarization of Pr (ΔP = 10.39 µC/cm2). Moreover, the complex defect dipoles with optimum oxygen vacancies in BSNTM ceramics can provide not only a high ΔP but also reduce grain size, which together improve the breakdown strength from 60.4 to 110.6 kV/cm, giving rise to a high energy storage density of 0.41 J/cm3 and high efficiency of 84.6% for x = 0.005 and y = 0.01. These findings demonstrate that defect dipole engineering is an effective method to enhance the energy storage performance of dielectrics for capacitor applications.

10.
Nanotechnology ; 23(43): 435603, 2012 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-23059535

RESUMO

Today, state-of-the-art III-Ns technology has been focused on the growth of c-plane nitrides by metal-organic chemical vapor deposition (MOCVD) using a conventional two-step growth process. Here we show that the use of graphene as a coating layer allows the one-step growth of heteroepitaxial GaN films on sapphire in a MOCVD reactor, simplifying the GaN growth process. It is found that the graphene coating improves the wetting between GaN and sapphire, and, with as little as ~0.6 nm of graphene coating, the overgrown GaN layer on sapphire becomes continuous and flat. With increasing thickness of the graphene coating, the structural and optical properties of one-step grown GaN films gradually transition towards those of GaN films grown by a conventional two-step growth method. The InGaN/GaN multiple quantum well structure grown on a GaN/graphene/sapphire heterosystem shows a high internal quantum efficiency, allowing the use of one-step grown GaN films as 'pseudo-substrates' in optoelectronic devices. The introduction of graphene as a coating layer provides an atomic playground for metal adatoms and simplifies the III-Ns growth process, making it potentially very useful as a means to grow other heteroepitaxial films on arbitrary substrates with lattice and thermal mismatch.

11.
Materials (Basel) ; 15(10)2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35629672

RESUMO

Z-type hexagonal ferrites have recently received attention for their room-temperature magnetoelectric (ME), which is activated when the temperature at which the transverse-conical spin-state transitions to a ferrimagnetic state is increased. The changes in the magnetic domain structure at the transition have been well-documented; however, they are still not understood in detail. In the present study, Lorentz transmission electron microscopy (TEM) analysis combined with an in situ heating experiment was conducted to demonstrate the shift in magnetic domain structure during the transition from the transverse-conical spin arrangement to a ferrimagnetic spin order. The dynamics of the magnetic domain structure changes with the increasing temperature were acquired in real-time. At 490 K, the magnetization transition from the transverse-conical spin state to the ferromagnetic state was demonstrated. Cross-tie domain walls formed during the magnetic transition process. The increased effect of the demagnetizing field applied to the 180° magnetic domains was caused by a lower magnetocrystalline anisotropy (MCA) at the easy axis of magnetization.

12.
Materials (Basel) ; 15(7)2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35407995

RESUMO

Real-time structural changes in Na-ß″-alumina were observed in situ using transmission electron microscopy (TEM) with electron beam irradiation. Na-ß″-alumina has been widely investigated as a solid electrolyte material for sodium-sulfur secondary batteries owing to its high ionic conductivity. This high conductivity is known to be due to the Na+ ions on the loosely packed conduction planes of Na-ß″-alumina. In the present study, we acquired real-time videos of the generation of spinel blocks caused by the conduction of Na+ ions. In addition, by observing Na extraction during electron beam irradiation, we experimentally confirmed that spinel block generation originates from the Na+ ion conduction, which has been a subject of recent debate.

13.
Sci Rep ; 12(1): 7204, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504925

RESUMO

To learn spatiotemporal representations and anomaly predictions from geophysical data, we propose STANet, a spatiotemporal neural network with a trainable attention mechanism, and apply it to El Niño predictions for long-lead forecasts. The STANet makes two critical architectural improvements: it learns spatial features globally by expanding the network's receptive field and encodes long-term sequential features with visual attention using a stateful long-short term memory network. The STANet conducts multitask learning of Nino3.4 index prediction and calendar month classification for predicted indices. In a comparison of the proposed STANet performance with the state-of-the-art model, the accuracy of the 12-month forecast lead correlation coefficient was improved by 5.8% and 13% for Nino3.4 index prediction and corresponding temporal classification, respectively. Furthermore, the spatially attentive regions for the strong El Niño events displayed spatial relationships consistent with the revealed precursor for El Niño occurrence, indicating that the proposed STANet provides good understanding of the spatiotemporal behavior of global sea surface temperature and oceanic heat content for El Niño evolution.


Assuntos
El Niño Oscilação Sul , Redes Neurais de Computação , Previsões , Aprendizagem
14.
Biomol Ther (Seoul) ; 30(1): 80-89, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34887366

RESUMO

The targeting of DNA methylation in cancer using DNA hypomethylating drugs has been well known to sensitize cancer cells to chemotherapy and immunotherapy by affecting multiple pathways. Herein, we investigated the combinational effects of DNA hypomethylating drugs and ionizing radiation (IR) in human sarcoma cell lines both in vitro and in vivo. Clonogenic assays were performed to determine the radiosensitizing properties of two DNA hypomethylating drugs on sarcoma cell lines we tested in this study with multiple doses of IR. We analyzed the effects of 5-aza-dC or SGI-110, as DNA hypomethylating drugs, in combination with IR in vitro on the proliferation, apoptosis, caspase-3/7 activity, migration/invasion, and Western blotting using apoptosis- or autophagy-related factors. To confirm the combined effect of DNA hypomethylating drugs and IR in our in vitro experiment, we generated the sarcoma cells in nude mouse xenograft models. Here, we found that the combination of DNA hypomethylating drugs and IR improved anticancer effects by inhibiting cell proliferation and by promoting synergistic cell death that is associated with both apoptosis and autophagy in vitro and in vivo. Our data demonstrated that the combination effects of DNA hypomethylating drugs with radiation exhibited greater cellular effects than the use of a single agent treatment, thus suggesting that the combination of DNA hypomethylating drugs and radiation may become a new radiotherapy to improve therapeutic efficacy for cancer treatment.

15.
Materials (Basel) ; 15(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36556714

RESUMO

High-Mn lightweight steel, Fe-0.9C-29Mn-8Al, was manufactured using steelmaking, ingot-making, forging, and rolling processes. After the final rolling process, a typical austenite single phase was observed on all sides of the thick plate. The microstructural changes after annealing and aging heat-treatments were observed, using optical and transmission electron microscopy. The annealed coupon exhibited a typical austenite single phase, including annealing twins in several grains; the average grain size was 153 µm. After aging heat treatment, κ-carbide was observed within the grains and on the grain boundaries. Additionally, the effect of aging heat treatment on the mechanical properties was analyzed, using a tensile test. The fine κ-carbide that precipitated within the grains in the aged coupon improved the 0.2% offset yield and the tensile stresses, as compared to the as-annealed coupon. To estimate the applicability of high-Mn lightweight steel for low-pressure (LP) steam turbine blades, a low-cycle fatigue (LCF) test was carried out at room temperature. At a total strain amplitude of 0.5 to 1.2%, the LCF life of high-Mn lightweight steel was approximately three times that of 12% Cr steel, which is used in commercial LP steam turbine blades. The LCF behavior of high-Mn lightweight steel followed the Coffin-Manson equation. The LCF life enhancement in the high-Mn lightweight steel results from the planar dislocation gliding behavior.

16.
J Neurosci ; 30(24): 8138-50, 2010 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-20554864

RESUMO

The bone morphogenetic protein (BMP) ligand Glass bottom boat (Gbb) acts as a retrograde growth signal at the Drosophila neuromuscular junction (NMJ). Endocytic regulation of presynaptic BMP receptors has been proposed to attenuate retrograde BMP signaling. However, it remains unknown whether the Gbb signal is also regulated by postsynaptic mechanisms. Here, we provide evidence that Drosophila Cdc42-interacting protein 4 (dCIP4) functions postsynaptically to inhibit synaptic growth. dCIP4 is localized postsynaptically at NMJs. dcip4 mutations lead to synaptic overgrowth and increased presynaptic phosphorylated mothers against decapentaplegic (Mad) levels, and these defects are rescued by muscle-specific expression of dCIP4. Biochemical and genetic analyses demonstrate that dCIP4 acts downstream of Cdc42 to activate the postsynaptic Wsp-Arp2/3 pathway. We also show that BMP signaling is necessary for synaptic overgrowth in larvae lacking postsynaptic dcip4 or wsp. Finally, dCIP4 and Wsp inhibit Gbb secretion. Thus, we propose that dCIP4 restrains synaptic growth by inhibiting postsynaptic Gbb secretion through the Wsp-Arp2/3 pathway.


Assuntos
Proteínas de Transporte/fisiologia , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Junção Neuromuscular/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Análise de Variância , Animais , Animais Geneticamente Modificados , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Drosophila , Proteínas de Drosophila/genética , Proteínas de Fluorescência Verde/genética , Humanos , Microscopia Confocal/métodos , Biologia Molecular/métodos , Mutação/genética , Proteínas do Tecido Nervoso/genética , Junção Neuromuscular/citologia , Junção Neuromuscular/efeitos dos fármacos , Fosforilação , Terminações Pré-Sinápticas/metabolismo , Interferência de RNA/fisiologia , Transdução de Sinais/genética , Transfecção/métodos , Fator de Crescimento Transformador beta/genética
17.
Mol Brain ; 14(1): 73, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892766

RESUMO

Loss-of-function mutations in the human oligophrenin-1 (OPHN1) gene cause intellectual disability, a prevailing neurodevelopmental condition. However, the role OPHN1 plays during neuronal development is not well understood. We investigated the role of the Drosophila OPHN1 ortholog Graf in the development of the mushroom body (MB), a key brain structure for learning and memory in insects. We show that loss of Graf causes abnormal crossing of the MB ß lobe over the brain midline during metamorphosis. This defect in Graf mutants is rescued by MB-specific expression of Graf and OPHN1. Furthermore, MB α/ß neuron-specific RNA interference experiments and mosaic analyses indicate that Graf acts via a cell-autonomous mechanism. Consistent with the negative regulation of epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) signaling by Graf, activation of this pathway is required for the ß-lobe midline-crossing phenotype of Graf mutants. Finally, Graf mutants have impaired olfactory long-term memory. Our findings reveal a role for Graf in MB axon development and suggest potential neurodevelopmental functions of human OPHN1.


Assuntos
Axônios/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Memória de Longo Prazo/fisiologia , Corpos Pedunculados/metabolismo , Olfato/fisiologia , Animais , Encéfalo/metabolismo , Proteínas de Transporte/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Endocitose , Epistasia Genética , Receptores ErbB/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Ligantes , Metamorfose Biológica , Mutação/genética , Regiões Promotoras Genéticas/genética , Transdução de Sinais
18.
Artigo em Inglês | MEDLINE | ID: mdl-33953788

RESUMO

Background and Objective. Epimedium koreanum Nakai is a medicinal plant known for its health beneficial effects on impotence, arrhythmia, oxidation, aging, osteoporosis, and cardiovascular diseases. However, there is no report available that shows its effects on platelet functions. Here, we elucidated antiplatelet and antithrombotic effects of ethyl acetate fraction of E. koreanum. Methodology. We analyzed the antiplatelet properties using standard in vitro and in vivo techniques, such as light transmission aggregometry, scanning electron microscopy, intracellular calcium mobilization measurement, dense granule secretion, and flow cytometry to assess integrin α IIb ß 3 activation, clot retraction, and Western blot, on washed platelets. The antithrombotic effects of E. koreanum were assessed by arteriovenous- (AV-) shunt model in rats, and its effects on hemostasis were analyzed by tail bleeding assay in mice. Key Results. E. koreanum inhibited platelet aggregation in agonist-stimulated human and rat washed platelets, and it also reduced calcium mobilization, ATP secretion, and TXB2 formation. Fibrinogen binding, fibronectin adhesion, and clot retraction by attenuated integrin α IIb ß 3-mediated inside-out and outside-in signaling were also decreased. Reduced phosphorylation of extracellular signal-regulated kinases (ERK), Akt, PLCγ2, and Src was observed. Moreover, the fraction inhibited thrombosis. HPLC results revealed that the fraction predominantly contained icariin. Conclusion and Implications. E. koreanum inhibited platelet aggregation and thrombus formation by attenuating calcium mobilization, ATP secretion, TXB2 formation, and integrin α IIb ß 3 activation. Therefore, it may be considered as a potential candidate to treat and prevent platelet-related cardiovascular disorders.

19.
J Cell Biol ; 220(5)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33683284

RESUMO

Mutations in the human ALS2 gene cause recessive juvenile-onset amyotrophic lateral sclerosis and related motor neuron diseases. Although the ALS2 protein has been identified as a guanine-nucleotide exchange factor for the small GTPase Rab5, its physiological roles remain largely unknown. Here, we demonstrate that the Drosophila homologue of ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway. dALS2 loss causes structural defects in the postsynaptic subsynaptic reticulum (SSR), recapitulating the phenotypes observed in FNI pathway mutants. Consistently, these developmental phenotypes are rescued by postsynaptic expression of the signaling-competent C-terminal fragment of Drosophila Frizzled-2 (dFz2). We further demonstrate that dALS2 directs early to late endosome trafficking and that the dFz2 C terminus is cleaved in late endosomes. Finally, dALS2 loss causes age-dependent progressive defects resembling ALS, including locomotor impairment and brain neurodegeneration, independently of the FNI pathway. These findings establish novel regulatory roles for dALS2 in endosomal trafficking, synaptic development, and neuronal survival.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Endossomos/metabolismo , Endossomos/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Densidade Pós-Sináptica/metabolismo , Densidade Pós-Sináptica/fisiologia , Esclerose Lateral Amiotrófica/genética , Animais , Transporte Biológico/fisiologia , Morte Celular/genética , Sobrevivência Celular/genética , Células Cultivadas , Drosophila/genética , Drosophila/metabolismo , Drosophila/fisiologia , Endossomos/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Mutação/genética , Fenótipo , Densidade Pós-Sináptica/genética , Proteínas rab5 de Ligação ao GTP/genética , Proteínas rab5 de Ligação ao GTP/metabolismo
20.
Sci Rep ; 11(1): 14468, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262073

RESUMO

We investigated the effect of κ-carbide precipitates on the strain hardening behavior of aged Fe-Mn-Al-C alloys by microstructure analysis. The κ-carbides-strengthened Fe-Mn-Al-C alloys exhibited a superior strength-ductility balance enabled by the recovery of the strain hardening rate. To understand the relation between the κ-carbides and strain hardening recovery, dislocation gliding in the aged alloys during plastic deformation was analyzed through in situ tensile transmission electron microscopy (TEM). The in situ TEM results confirmed the particle shearing mechanism leads to planar dislocation gliding. During deformation of the 100 h-aged alloy, some gliding dislocations were strongly pinned by the large κ-carbide blocks and were prone to cross-slip, leading to the activation of multiple slip systems. The abrupt decline in the dislocation mean free path was attributed to the activation of multiple slip systems, resulting in the rapid saturation of the strain hardening recovery. It is concluded that the planar dislocation glide and sequential activation of slip systems are key to induce strain hardening recovery in polycrystalline metals. Thus, if a microstructure is designed such that dislocations glide in a planar manner, the strain hardening recovery could be utilized to obtain enhanced mechanical properties of the material.

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