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1.
J Membr Biol ; 253(1): 43-55, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31820013

RESUMO

Lysophosphatidylcholine (LPC) is a major atherogenic lipid that stimulates an increase in mitochondrial reactive oxygen species (mtROS) and the release of cytokines under inflammasome activation. However, the potential receptors of LPC in macrophages are poorly understood. Members of the transient receptor potential (TRP) channel superfamily, which is crucially involved in transducing environmental irritant stimuli into nociceptor activity, are potential receptors of LPC. In this study, we investigated whether LPC can induce the activation of transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily. The functional expression of TRPA1 was first detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and calcium imaging in human acute monocytic leukemia cell line (THP-1)-derived macrophages. The mechanism by which LPC induces the activation of macrophages through TRPA1 was verified by cytoplasmic and mitochondrial calcium imaging, mtROS detection, a JC-1 assay, enzyme-linked immunosorbent assay, the CCK-8 assay and the lactate dehydrogenase (LDH) cytotoxic assay. LPC induced the activation of THP-1-derived macrophages via calcium influx, and this activation was suppressed by potent and selective inhibitors of TRPA1. These results indicated that TRPA1 can mediate mtROS generation, mitochondrial membrane depolarization, the secretion of IL-1ß and cytotoxicity through cellular and mitochondrial Ca2+ influx in LPC-treated THP-1-derived macrophages. Therefore, the inhibition of TRPA1 may protect THP-1-derived macrophages against LPC-induced injury.

2.
Genes Brain Behav ; : e12625, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730264

RESUMO

Temperature sensing is an important adaptive mechanism for warm-blooded animals such as humans. ThermoTRP ion channels are activated by distinct but overlapping physiological temperatures. Our previous research demonstrated that sorting nexin 11 (SNX11) regulates lysosomal degradation of plasma membrane TRPV3, one of ThermoTRP ion channel proteins. Here, we found that SNX11, a vesicular trafficking protein, modulates mouse behaviour in response to temperature changes. Snx11-knockout mice exhibit a stronger preference for mild temperatures along with enhanced sensitivity to harmful heat. Mechanistically, keratinocytes from Snx11-knockout mice exhibit a larger temperature-gated TRPV3 membrane current and have enhanced thermoTRPV3 expression in the plasma membrane compared to wild-type keratinocytes. Additionally, Snx11-knockout mice show higher endogenous TRPV3 protein levels in skin tissues than wild-type mice do. Therefore, our results indicate that SNX11 may regulate thermal perception via alteration of functional thermoTRPV3 on the plasma membrane of thermally sensitive cells, which is the first link between vesicular trafficking and thermal transduction.

3.
Stem Cell Res ; 40: 101571, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31520889

RESUMO

Autism spectrum disorder (ASD) is a neurological disorder with complex etiologies. In this study, urine cells were collected from a 16-year-old male with ASD and reprogrammed with the human SKOM transcription factors. The patient has a heterozygous C > T mutation of FCGR1B gene that was confirmed by sequencing analysis. The pluripotency was verified by gene expression and capacity of differentiation towards the three germ layers. This kind of iPSC will be valuable for further understanding the pathogenesis of ASD and help to develop drugs for treating ASD.

4.
FEBS Open Bio ; 9(2): 206-225, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30761248

RESUMO

Some members of the transient receptor potential vanilloid (TRPV) subfamily of cation channels are thermosensitive. Earlier studies have revealed the distribution and functions of these thermo-TRPVs (TRPV1-4) in various organs, but their expression and function in the human esophagus are not fully understood. Here, we probed for the expression of the thermo-TRPVs in one nontumor human esophageal squamous cell line and two esophageal squamous cell carcinoma (ESCC) cell lines. TRPV1, TRPV2, and TRPV4 proteins were found to be upregulated in ESCC cells, while TRPV3 was not detectable in any of these cell lines. Subsequently, channel function was evaluated via monitoring of Ca2+ transients by Ca2+ imaging and nonselective cation channel currents were recorded by whole-cell patch clamp. We found that TRPV4 was activated by heat at 28 °C-35 °C, whereas TRPV1 and TRPV2 were activated by higher, noxious temperatures (44 °C and 53 °C, respectively). Furthermore, TRPV1 was activated by capsaicin (EC 50 = 20.32 µm), and this effect was antagonized by AMG9810; TRPV2 was activated by a newly developed cannabinoid compound, O1821, and inhibited by tranilast. In addition, TRPV4 was activated by hypotonic solutions (220 m Osm), and this effect was abolished by ruthenium red. The effects of TRPV1 and TRPV4 on ESCC were also explored. Our data, for the first time, showed that the overactivation of TRPV1 and TRPV4 promoted the proliferation and/or migration of ESCC cells. In summary, TRPV1, TRPV2, and TRPV4 were functionally expressed in human esophageal squamous cells, and thermo-TRPVs might play an important role in the development of ESCC.

5.
Brain Behav ; 7(10): e00768, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29075556

RESUMO

INTRODUCTION: Decision making as a complex cognitive process involves assessing risk, reward, and costs. Typically, it has been studied in nonsocial contexts. We have developed a novel laboratory model used with rodents to detect food-foraging decision-making strategies in different social settings. However, the brain regions that mediate these behaviors are not well identified. Substantial evidence shows that the anterior cingulate cortex (ACC) participates in evaluation of social information and in decision making. METHODS: In this study, we investigated the effect of bilateral lesions in the ACC on established behaviors. Kainic acid (KA) was administered bilaterally to induce ACC lesions, and saline microinjection into the ACC was used in the sham group. RESULTS: In contrast to the sham-lesioned animals, when faced with the choice of foraging under a social context, rats with ACC lesions preferred foraging for the less desirable food. Moreover, in these situations, the total amount of food foraged by the ACC-lesioned group was less than the amount foraged by the sham group. Notably, neither social interactions nor social agonistic behaviors were affected by ACC lesions. CONCLUSIONS: These data suggest that the ACC is a key region underlying neural processing of social decision-making, specifically tending to compete for foraging high predictive reward food.


Assuntos
Tomada de Decisões/fisiologia , Giro do Cíngulo , Comportamento Social , Animais , Comportamento Animal/fisiologia , Comportamento Alimentar/psicologia , Giro do Cíngulo/metabolismo , Giro do Cíngulo/patologia , Ácido Caínico/farmacologia , Masculino , Modelos Animais , Ratos , Ratos Sprague-Dawley
6.
ACS Appl Mater Interfaces ; 9(14): 12592-12600, 2017 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-28322542

RESUMO

The Mn3CuN/n-Si heterojunction device is first designed in the antiperovskite compound, and excellent rectifying characteristics are obtained. The rectification ratio (RR) reaches as large as 38.9 at 10 V, and the open-circuit voltage Voc of 1.13 V is observed under temperature of 410 K. The rectifying behaviors can be well described by the Shockley equation, indicating the existence of a Schottky diode. Simultaneously, a particular semiconductor-metal transition (SMT) behavior at 250 K is also observed in the Mn3CuN/n-Si heterojunction. The interfacial band bending induced inversion layer, which is clarified by the interfacial schematic band diagrams, is believed to be responsible for the SMT and rectifying effects. This study can develop a new class of materials for heterojunction, rectifying devices, and SMT behaviors.

7.
Adv Mater ; 28(19): 3761-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27007214

RESUMO

A baromagnetic effect in a novel tetragonal magnetic structure is introduced by vacancies in Mn3 Ga0.95 N0.94 , due to the change of the Mn-Mn distance and their spin re-orientation induced by a pressure field. This effect is proven for the first time in antiperovskite compounds by neutron powder diffraction analysis. This feature will enable wide applications in magnetoelectric devices and intelligent instruments.

9.
Neurosci Lett ; 585: 166-70, 2015 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-25445352

RESUMO

The effects of the vitamin E isomer δ-tocopherol on neural stem cell (NSC) differentiation have not been investigated until now. Here we investigated the effects of δ-tocopherol on NSC neural differentiation, maturation and its possible mechanisms. Neonatal rat NSCs were grown in suspended neurosphere cultures, and were identified by their expression of nestin protein and their capacity for self-renewal. Treatment with a low concentration of δ-tocopherol induced a significant increase in the percentage of ß-III-tubulin-positive cells. δ-Tocopherol also stimulated morphological maturation of neurons in culture. We further observed that δ-tocopherol stimulation increased the expression of voltage-dependent Ca(2+) channels. Moreover, a L-type specific Ca(2+) channel blocker verapamil reduced the percentage of differentiated neurons after δ-tocopherol treatment, and blocked the effects of δ-tocopherol on NSC differentiation into neurons. Together, our study demonstrates that δ-tocopherol may act through elevation of L-type calcium channel activity to increase neuronal differentiation.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Tocoferóis/farmacologia , Vitaminas/farmacologia , Animais , Animais Recém-Nascidos , Bloqueadores dos Canais de Cálcio/farmacologia , Diferenciação Celular , Células Cultivadas , Células-Tronco Neurais/citologia , Neurônios/citologia , Ratos Wistar , Verapamil/farmacologia
10.
Sci Rep ; 4: 5404, 2014 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-24953032

RESUMO

Human induced pluripotent stem cells (iPSC) can be used to understand the pathological mechanisms of human disease. These cells are a promising source for cell-replacement therapy. However, such studies require genetically defined conditions. Such genetic manipulations can be performed using the novel Transcription Activator-Like Effector Nucleases (TALENs), which generate site-specific double-strand DNA breaks (DSBs) with high efficiency and precision. Combining the TALEN and iPSC methods, we developed two iPS cell lines by generating the point mutation A5768G in the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1 α subunit. The engineered iPSC maintained pluripotency and successfully differentiated into neurons with normal functional characteristics. The two cell lines differ exclusively at the epilepsy-susceptibility variant. The ability to robustly introduce disease-causing point mutations in normal hiPS cell lines can be used to generate a human cell model for studying epileptic mechanisms and for drug screening.


Assuntos
Epilepsia/genética , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Mutagênese Sítio-Dirigida/métodos , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Células Cultivadas , Desoxirribonucleases/genética , Humanos , Engenharia de Proteínas/métodos
11.
Eur J Neurosci ; 37(10): 1714-25, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23432732

RESUMO

Deposition of ß -amyloid (Aß) peptides, cleavage products of ß-amyloid precursor protein (APP) by ß-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aß approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aß peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aß efficacy. The present study compared active γ-secretase binding sites with Aß deposition in aged and AD human cerebrum, and explored the possibility of Aß production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and ß-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aß40 and Aß42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aß, probably at reduced levels in AD.


Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Cérebro/metabolismo , Plexo Corióideo/metabolismo , Fragmentos de Peptídeos/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Ligação Proteica , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley
12.
Neurotox Res ; 24(1): 1-14, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23055086

RESUMO

The spinal cord is composed of distinct neuronal groups with well-defined anatomic connections. In some transgenic (Tg) models of Alzheimer's disease (AD), amyloid plaques develop in this structure, although the underlying cellular mechanism remains elusive. We attempted to explore the origin, evolution, and modulation of spinal ß-amyloid (Aß) deposition using Tg mice harboring five familiar AD-related mutations (5XFAD) as an experiential model. Dystrophic neuritic elements with enhanced ß-secretase-1 (BACE1) immunoreactivity (IR) appeared as early as 2 months of age, and increased with age up to 12 months examined in this study, mostly over the ventral horn (VH). Extracellular Aß IR emerged and developed during this same period, site-specifically co-existing with BACE1-labeled neurites often in the vicinity of large VH neurons that expressed the mutant human APP. The BACE1-labeled neurites almost invariably colocalized with ß-amyloid precursor protein (APP) and synaptophysin, and frequently with the vesicular glutamate transporter-1 (VGLUT). Reduced IR for the neuronal-specific nuclear antigen (NeuN) occurred in the VH by 12 months of age. In 8-month-old animals surviving 6 months after a unilateral sciatic nerve transection, there were significant increases of Aß, BACE1, and VGLUT IR in the VN of the ipsilateral relative to contralateral lumbar spinal segments. These results suggest that extracellular Aß deposition in 5XFAD mouse spinal cord relates to a progressive and amyloidogenic synaptic pathology largely involving presynaptic axon terminals from projection neurons in the brain. Spinal neuritic plaque formation is enhanced after peripheral axotomy, suggesting a retrograde transneuronal modulation on pathogenesis.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Traumatismos dos Nervos Periféricos/patologia , Placa Amiloide/patologia , Degeneração Retrógrada , Medula Espinal/patologia , Fatores Etários , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Proteínas de Ligação a DNA , Masculino , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Placa Amiloide/metabolismo , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/patologia , Nervo Isquiático/lesões , Medula Espinal/metabolismo , Sinaptofisina/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
13.
PLoS One ; 7(11): e48782, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23155407

RESUMO

The comorbidity between epilepsy and Alzheimer's disease (AD) is a topic of growing interest. Senile plaques and tauopathy are found in epileptic human temporal lobe structures, and individuals with AD have an increased incidence of spontaneous seizures. However, why and how epilepsy is associated with enhanced AD-like pathology remains unknown. We have recently shown ß-secretase-1 (BACE1) elevation associated with aberrant limbic axonal sprouting in epileptic CD1 mice. Here we sought to explore whether BACE1 upregulation affected the development of Alzheimer-type neuropathology in mice expressing mutant human APP, presenilin and tau proteins, the triple transgenic model of AD (3×Tg-AD). 3×Tg-AD mice were treated with pilocarpine or saline (i.p.) at 6-8 months of age. Immunoreactivity (IR) for BACE1, ß-amyloid (Aß) and phosphorylated tau (p-tau) was subsequently examined at 9, 11 or 14 months of age. Recurrent convulsive seizures, as well as mossy fiber sprouting and neuronal death in the hippocampus and limbic cortex, were observed in all epileptic mice. Neuritic plaques composed of BACE1-labeled swollen/sprouting axons and extracellular AßIR were seen in the hippocampal formation, amygdala and piriform cortices of 9 month-old epileptic, but not control, 3×Tg-AD mice. Densities of plaque-associated BACE1 and AßIR were elevated in epileptic versus control mice at 11 and 14 months of age. p-Tau IR was increased in dentate granule cells and mossy fibers in epileptic mice relative to controls at all time points examined. Thus, pilocarpine-induced chronic epilepsy was associated with accelerated and enhanced neuritic plaque formation and altered intraneuronal p-tau expression in temporal lobe structures in 3×Tg-AD mice, with these pathologies occurring in regions showing neuronal death and axonal dystrophy.


Assuntos
Doença de Alzheimer/patologia , Epilepsia do Lobo Temporal/patologia , Placa Amiloide/patologia , Lobo Temporal/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Morte Celular , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neuritos/metabolismo , Neuritos/patologia , Neurônios/metabolismo , Neurônios/patologia , Pilocarpina , Placa Amiloide/genética , Placa Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Lobo Temporal/metabolismo , Regulação para Cima , Proteínas tau/genética , Proteínas tau/metabolismo
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