RESUMO
White matter injury (WMI) causes oligodendrocyte precursor cell (OPC) differentiation arrest and functional deficits, with no effective therapies to date. Here, we report increased expression of growth hormone (GH) in the hypoxic neonatal mouse brain, a model of WMI. GH treatment during or post hypoxic exposure rescues hypoxia-induced hypomyelination and promotes functional recovery in adolescent mice. Single-cell sequencing reveals that Ghr mRNA expression is highly enriched in vascular cells. Cell-lineage labeling and tracing identify the GHR-expressing vascular cells as a subpopulation of pericytes. These cells display tip-cell-like morphology with kinetic polarized filopodia revealed by two-photon live imaging and seemingly direct blood vessel branching and bridging. Gain-of-function and loss-of-function experiments indicate that GHR signaling in pericytes is sufficient to modulate angiogenesis in neonatal brains, which enhances OPC differentiation and myelination indirectly. These findings demonstrate that targeting GHR and/or downstream effectors may represent a promising therapeutic strategy for WMI.
Assuntos
Bainha de Mielina , Neovascularização Fisiológica , Pericitos , Animais , Pericitos/metabolismo , Pericitos/efeitos dos fármacos , Camundongos , Bainha de Mielina/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/farmacologia , Animais Recém-Nascidos , Hipóxia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Receptores da Somatotropina/metabolismo , Receptores da Somatotropina/genética , AngiogêneseRESUMO
The exciplex-thermally activated delayed fluorescence (exciplex-TADF) system is an excellent candidate for the fabrication of high-efficiency organic light-emitting diodes (OLEDs) because of its more easily achieved small singlet-triplet energy splitting (ΔEST) and doping control. However, exciplex-TADF is still faced with the problems of low external quantum efficiency (ηext) and unclear effect of structure modification in electron acceptors. Herein, we provide a steric hindrance increase strategy to obtain high-efficiency exciplex emissions. Through introducing a 9-phenylfluorene group into N-ethylcarbazole of the dicyano-substituted 9-phenylfluorene, an electron acceptor material with increased steric hindrance is obtained, which helps the exciplex harvest a larger driving force and higher emission efficiencies. Encouragingly, the obtained OLED displays a maximum ηext of 25.8%, which is one of the best efficiency values among reported exciplex-OLEDs, simultaneously possessing excellent current efficiency of 83.6 cd A-1 and power efficiency of 93.7 lm W-1. It is expected that this work will offer a new avenue for designing electron acceptors for highly efficient exciplex emissions.
RESUMO
Diabetic rats display cognition impairments accompanied by activation of NF-κB signalling and increased Aß expression. Ghrelin has been suggested to improve cognition in diabetic rats. In this study, we investigated the role of ghrelin on cognition and NF-κB mediated Aß production in diabetic rats. A diabetic rat model was established with streptozotocin (STZ) injection, and diabetic rats were intracerebroventricularly administered with ghrelin or (D-lys3)-GHRP-6 (DG). Our results showed that diabetic rats had cognition impairment in the Morris water maze test, accompanied by the higher expression of Aß in the hippocampus. Western blot analysis showed that diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aß production, and improved cognition in STZ-induced diabetic rats. These effects were reversed by DG. Then, primary rat hippocampal neurons were isolated and treated with high glucose, followed by Ghrelin and DG, PP1 or IKK. Similar to the in vivo results, high glucose suppressed the expression levels of GHSR-1a and PP1, activated the IKK/NF-κB/BACE1 pathway, increased Aß production. Ghrelin suppressed IKK/NF-κB/BACE1 induced Aß production. This improvement was reversed by DG and a PP1 antagonist and was enhanced by the IKK antagonist. Our findings indicated that chronic ghrelin administration can suppress IKK/NF-κB/BACE1 mediated Aß production in primary neurons with high glucose treatment and improve the cognition via PP1 upregulation in diabetic rats.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Cognição/fisiologia , Diabetes Mellitus Experimental/metabolismo , Grelina/metabolismo , Neurônios/metabolismo , Proteína Fosfatase 1/metabolismo , Transdução de Sinais , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Cognição/efeitos dos fármacos , Diabetes Mellitus Experimental/psicologia , Grelina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Quinase I-kappa B/metabolismo , Masculino , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/administração & dosagem , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura , Regulação para CimaRESUMO
Activation of glutamate receptors and followed increase of intracellular calcium concentration is a key pathological mechanism involved in secondary neuronal injury after traumatic brain injury (TBI). Stromal interaction molecule (STIM) proteins are considered to be important players in regulating neuronal Ca(2+) homeostasis under normal aging and pathological conditions. Here, we investigated the role of STIM1 in regulating metabotropic glutamate receptor 1 (mGluR1)-related Ca(2+) signaling and neuronal survival by using an in vitro traumatic neuronal injury (TNI) model. The expression of STIM1 was significantly increased at both mRNA and protein levels after TNI. Down-regulation of STIM1 by specific small interfere RNA significantly preserved neuronal viability, decreased lactate dehydrogenase release, and inhibited apoptotic cell death after traumatic injury. Moreover, knockdown of STIM1 significantly alleviated the mGluR1-related increase of cytoplasmic Ca(2+) levels after TNI. By analyzing Ca(2+) imaging in Ca(2+)-free conditions, we demonstrated that the mGluR1-dependent inositol trisphosphate receptor and/or ryanodine receptor-mediated Ca(2+) release from the endoplasmic reticulum after TNI is strongly attenuated in the absence of STIM1. Together, our results demonstrate that in the mammalian nervous system, STIM1 is a key regulator of mGluR1-dependent Ca(2+) signaling and knockdown of STIM1 might be an effective intervention target in TBI.
Assuntos
Canais de Cálcio/metabolismo , Sinalização do Cálcio , Córtex Cerebral/patologia , Técnicas de Silenciamento de Genes , Neurônios/metabolismo , Neurônios/patologia , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Apoptose , Sobrevivência Celular , Retículo Endoplasmático/metabolismo , Espaço Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Molécula 1 de Interação EstromalRESUMO
Green's functions play an important role in electroelastic analyses of piezoelectric media. However, most works available on the topic are for the case of uniform temperature. Based on the compact 2-D general solution of orthotropic piezothermoelectric material, which is expressed in harmonic functions, and employing the trial-and-error method, the 2-D Green's function for a steady line heat source in a semi-infinite piezothermoelectric plane is presented by four newly induced harmonic functions. All components of the coupled field are expressed in terms of elementary functions and are convenient to use. Numerical results are given graphically by contours.
RESUMO
In this paper, the axisymmetric general solutions of transversely isotropic magnetoelectroelastic media are expressed with four harmonic displacement functions at first. Then, based on the solutions, the analytical three-dimensional solutions are provided for a simply supported magnetoelectroelastic circular plate subjected to uniform loads. Finally, the example of circular plate is presented.