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Controlling active transport of water through membrane channels is essential for advanced nanofluidic devices. Despite advancements in water nanopump design using techniques like short-range invasion and subnanometer-level control, challenges remain facilely and remotely realizing massive waters active transport. Herein, using molecular dynamic simulations, we propose an ultrahigh-flux nanopump, powered by frequency-specific terahertz stimulation, capable of unidirectionally transporting massive water through asymmetric-wettability membrane channels at room temperature without any external pressure. The key physics behind this terahertz-powered water nanopump is revealed to be the energy flow resulting from the asymmetric optical absorption of water.
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The adsorbed nanobubbles inside the nanochannels can cause fluid transport blockages, which will obviously degrade the nanodevice performance and reduce the lifetime. However, due to small-scale effects, the removal of nanobubbles is a huge challenge at the nanoscale. Herein, molecular dynamics simulations are carried out to study the effect of the electrostatic field on underwater nitrogen nanobubbles confined in nanochannels. It is found that the nanobubbles will collapse under an appropriate electrostatic field, thereby unblocking the transport of water in the nanochannels. The formation of ordered water structures induced by electrostatic fields plays an important role in the removal of nanobubbles from the nanochannels. Our findings provide a convenient, controllable, and remote way to address the blockage problem of nanobubbles in nanochannels, which may have potential applications in improving the performance of fuel cells.
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Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.
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Antineoplásicos , Neoplasias , Animais , Camundongos , Proteína Supressora de Tumor p53/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ciclo Celular , Antineoplásicos/farmacologia , Divisão CelularRESUMO
Ammonia (NH3) plays a vital role in the formation of fine particulate matter (PM2.5). Prior studies have primarily focused on the control of agricultural NH3 emissions, the dominant source of anthropogenic NH3 emissions. The air quality impact from vehicular NH3 emissions, which could be particularly important in urban areas, has not been adequately evaluated. We developed high-resolution vehicular NH3 emission inventories for Beijing and Shanghai based on detailed link-level traffic profiles and conducted atmospheric simulations of ambient PM2.5 concentrations contributed by vehicular NH3 emissions. We found that vehicular NH3 emissions shared high proportions among total anthropogenic NH3 emissions in the urban areas of Beijing (86%) and Shanghai (45%), where vehicular NH3 was primarily emitted by gasoline vehicles. Local vehicular NH3 emissions could be responsible for approximately 3% of urban PM2.5 concentrations during wintertime, and the contributions could be much higher during polluted periods (â¼3 µg m-3). We also showed that controlling vehicular NH3 emissions will be effective and feasible to alleviate urban PM2.5 pollution for megacities in the near future.
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Poluentes Atmosféricos , Poluição do Ar , Emissões de Veículos/análise , Amônia/análise , Poluentes Atmosféricos/análise , Cidades , Monitoramento Ambiental , China , Poluição do Ar/análise , Material Particulado/análiseRESUMO
China's civil aviation market has rapidly expanded, becoming the world's second-largest. However, the air quality and health impacts caused by its aircraft emissions have been inadequately assessed. Here, we leverage an updated emission inventory of air pollutants with improved temporal and spatial resolution based on hundreds of thousands of flight trajectories and simulate aviation-attributable contributions to ground-level air pollution in China. We find that in 2017, the annual-average aviation-attributed PM2.5 and O3 concentrations were 0.4-1.5 and 10.6-14.5 µg·m-3, respectively, suggesting that aviation emissions have become an increasingly important source of ambient air pollution. The contributions attributable to high-altitude emissions (climb/cruise/descent) were comparable to those at low altitudes (landing and takeoff). Aviation-attributed ambient PM2.5 and O3 exposures are estimated to have caused about 67,000 deaths in China in 2017, with populous coastal regions in Eastern China suffering the most due to the dense aviation activity. We recommend that industrial and policy stakeholders expedite an agenda of regulating air pollutants harmonized with decarbonization efforts for a more sustainable aviation future.
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Poluentes Atmosféricos , Poluição do Ar , Aviação , Humanos , Material Particulado/análise , Monitoramento Ambiental , Poluição do Ar/análise , Poluentes Atmosféricos/análise , ChinaRESUMO
Polo-like kinase 1 (PLK1) is an attractive therapeutic target for the treatment of tumors, as it is an essential cell-cycle regulator frequently overexpressed in tumor tissues. PLK1 can promote tumor invasion and metastasis, and is often associated with poor prognosis in cancer patients. However, no PLK1 inhibitor has been granted marketing approval until now. Therefore, more potentially promising PLK1 inhibitors need to be investigated. In this study, a series of novel inhibitors targeting PLK1 was designed and optimized derived from a new scaffold. After synthesis and characterization, we obtained the structure-activity relationship and led to the discovery of the most promising compound 30e for PLK1. The antiproliferative activity against HCT116 cells (IC50 = 5 nM versus 45 nM for onvansertib) and the cellular permeability and efflux ratio were significantly improved (PappAâB = 2.03 versus 0.345 and efflux ratio = 1.65 versus 94.7 for 30e and onvansertib, respectively). Further in vivo studies indicated that 30e had favorable antitumor activity with 116.2% tumor growth inhibition (TGI) in comparison with TGI of 43.0% for onvansertib. Furthermore, 30e improved volume of tumor tissue distribution in mice as compared to onvansertib. This initial study on 30e holds promise for further development of an antitumor agent.
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Neoplasias , Inibidores de Proteínas Quinases , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinases , Linhagem Celular Tumoral , Proliferação de Células , Quinase 1 Polo-LikeRESUMO
As a key component in non-enzyme resistance system, flavonoids play a crucial role in the plant growth and defenses, which are significantly affected by biotic and abiotic factors such as fungi, bacteria, viruses, heavy metals, and atmospheric CO2. Arbuscular mycorrhizal fungi (AMF) play an important role in enhancing plant tolerance to adverse environments, which can significantly affect the synthesis of flavonoids by forming mycorrhizal symbionts with plant roots. However, few studies explored the combined effects of AMF, elevated CO2, and heavy metals on flavonoids in plants. Here, we investigated the adaptive response of flavonoids accumulation in Robinia pseudoacacia L. seedlings affected by the contamination of cadmium (Cd) and elevated CO2 to arbuscular mycorrhizal symbiosis. The results showed that G. mosseae decreased (p < 0.05) Cd content in leaves by 62.2% under elevated CO2. Moreover, G. mosseae colonization led to significant decreases in robinin, quercetin, kaempferol and acacetin by 17.4%, 11.1%, 15.5% and 23.1% under elevated CO2 + Cd, respectively. Additionally, G. mosseae down-regulated (p < 0.05) expression levels of phenylalanine ammonia-lyase (PAL) and chalcone synthase (CHS) genes under elevated CO2 + Cd, and CHS and uridine diphosphate flavonoid glucosyltransferase (UFGT) activities decreased (p < 0.05). Quercetin, kaempferol and acacetin showed positive (p < 0.05) correlation with PAL and CHS genes expression and PAL, CHS, and UFGT activities. Cadmium, C/N ratio, carotenoids, leaf biomass, total chlorophyll, P, and starch in leaves and G. mosseae colonization rate in roots influenced (p < 0.05) flavonoids content. Overall, G. mosseae reduced flavonoids synthesis by down-regulating gene expression levels and activities of key enzymes under elevated CO2 + Cd. The results improved our understanding of the regulation of AMF on non-enzymatic resistance of plants grown in heavy metal-contaminated soils under increasing atmospheric CO2 scenarios.
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Micorrizas , Robinia , Cádmio/toxicidade , Quercetina , Dióxido de Carbono , Quempferóis , Simbiose , FlavonoidesRESUMO
PLK-1 (Polo-like kinase-1) plays an essential role in cytokinesis, and its aberrant expression is considered to be keenly associated with a wide range of cancers. It has been selected as an appealing target and small-molecule inhibitors have been developed and studied in clinical trials. Unfortunately, most have been declared as failures due to the poor therapeutic response and off-target toxicity. In the present study, a novel potent PLK-1 inhibitor, compound 7a, was designed and synthetized. 1H NMR, 13C NMR, 19F NMR and mass spectrum were comprehensively used for the compound characterization. The compound exhibited higher potency against PLK-1 kinase, HCT-116 and NCI-H2030 cell lines than the positive control. Molecular docking indicated that the binding mode that the ATP binding site of PLK-1 was occupied by the compound. Then, a UHPLC-MS/MS method was established and validated to explore the pharmacokinetic behavior of the drug candidate. The method had good selectivity, high sensitivity and wide linearity. The exposure increased linearly with the dose, but the oral bioavailability was not satisfactory enough. Then, the metabolism was studied using liver microsomes by UHPLC-Q-Orbitrap/HRMS. Our research first studied the pharmacokinetic metabolic characteristics of 7a and may serve as a novel lead compound for the development of PLK-1 inhibitors.
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Metaboloma , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Simulação de Acoplamento Molecular , Disponibilidade BiológicaRESUMO
AIM: Brain microvascular endothelial cells (BMVECs), as the important structure of blood-brain barrier (BBB), play a vital role in ischemic stroke. Pyroptosis of different cells in the brain may aggravate cerebral ischemic injury, and PGC-1α plays a major role in pyroptosis. However, it is not known whether BMVECs undergo pyroptosis after ischemic stroke and whether PGC-1α activator Medioresinol (MDN) we discovered may be useful against pyroptosis of endothelial cells and ischemic brain injury. METHODS: For in vitro experiments, the bEnd.3 cells and BMVECs under oxygen and glucose-deprivation (OGD) were treated with or without MDN, and the LDH release, tight junction protein degradation, GSDMD-NT membrane location and pyroptosis-associated proteins were evaluated. For in vivo experiments, mice underwent transient middle cerebral artery occlusion (tMCAO) for ischemia model, and the neuroprotective effects of MDN were measured by infarct volume, the permeability of BBB and pyroptosis of BMVECs. For mechanistic study, effects of MDN on the accumulation of phenylalanine, mitochondrial reactive oxygen species (mtROS) were tested by untargeted metabolomics and MitoSOX Red probe, respectively. RESULTS: BMVECs underwent pyroptosis after ischemia. MDN dose-dependently activated PGC-1α, significantly reduced pyroptosis, mtROS and the expressions of pyroptosis-associated proteins (NLRP3, ASC, cleaved caspase-1, IL-1ß, GSDMD-NT), and increased ZO-1 and Occludin protein expressions in BMVECs. In tMCAO mice, MDN remarkably reduced brain infarct volume and the permeability of BBB, inhibited pyroptosis of BMVECs, and promoted long-term neurobehavioral functional recovery. Mechanistically, MDN promoted the interaction of PGC-1α with PPARα to increase PPARα nuclear translocation and transcription activity, further increased the expression of GOT1 and PAH, resulting in enhanced phenylalanine metabolism to reduce the ischemia-caused phenylalanine accumulation and mtROS and further ameliorate pyroptosis of BMVECs. CONCLUSION: In this study, we for the first time discovered that pyroptosis of BMVECs was involved in the pathogenesis of ischemic stroke and MDN as a novel PGC-1α activator could ameliorate the pyroptosis of endothelial cells and ischemic brain injury, which might attribute to reduction of mtROS through PPARα/GOT1 axis in BMVECs. Taken together, targeting endothelial pyroptosis by MDN may provide alternative therapeutics for brain ischemic stroke.
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Aspartato Aminotransferase Citoplasmática/metabolismo , Endotélio Vascular/efeitos dos fármacos , AVC Isquêmico/tratamento farmacológico , Lignanas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/agonistas , Piroptose/efeitos dos fármacos , Animais , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Imunofluorescência , Cromatografia Gasosa-Espectrometria de Massas , Células HEK293/efeitos dos fármacos , Humanos , Lignanas/farmacologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-DawleyRESUMO
Aims: To determine how consistently Chinese glioblastoma multiforme (GBM) patients were treated according to the Stupp regimen. Patients and methods: The proportion of treatments conforming to the Stupp regimen and reasons for nonconformity were evaluated in 202 newly diagnosed GBM patients. Results: Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations were temozolomide dosages >75 mg/m2 (58/120; 48.3%) and treatment durations <42 days (84/120; 70.0%) in the concomitant phase and temozolomide dosages <150 mg/m2 (89/101; 88.1%) in the maintenance phase. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments. Conclusion: Increased conformity to the Stupp regimen is needed for GBM patients in China.
Lay abstract In 2005 the European Organization for Research and Treatment of Cancer 26981 study led to US FDA approval for the use of temozolomide in combination with radiotherapy to treat glioblastoma multiforme (GBM). The Stupp regimen consists of fractionated focal irradiation in daily fractions of 2 Gy given 5 days/week for 6 weeks (a total of 60 Gy), plus concomitant daily temozolomide (75 mg/m2/day, 7 days/week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150200 mg/m2/day for 5 days during each 28-day cycle). In 2012 the Chinese guidelines for the diagnosis and treatment of glioma of the CNS recommended the Stupp regimen as first-line therapy for newly diagnosed GBM. In the present study, compliance of GBM treatments with the Stupp regimen in 28 Chinese centers from 20122016 was evaluated. Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations related to temozolomide dosages and treatment durations in the concomitant and maintenance phases. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments.
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Neoplasias Encefálicas/terapia , Quimiorradioterapia/estatística & dados numéricos , Glioblastoma/terapia , Fidelidade a Diretrizes/estatística & dados numéricos , Temozolomida/administração & dosagem , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Quimiorradioterapia/métodos , Quimiorradioterapia/normas , China/epidemiologia , Fracionamento da Dose de Radiação , Esquema de Medicação , Feminino , Seguimentos , Glioblastoma/mortalidade , Humanos , Masculino , Oncologia/normas , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Intervalo Livre de Progressão , Adulto JovemRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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OBJECTIVES: Deep brain stimulation (DBS) for Parkinson's disease (PD) has been applied to clinic for approximately 30 years. The goal of this review is to explore the similarities and differences between "awake" and "asleep" DBS techniques. METHODS: A comprehensive literature review was carried out to identify relevant studies and review articles describing applications of "awake" or "asleep" DBS for Parkinson's disease. The surgical procedures, clinical outcomes, costs and complications of each technique were compared in detail through literature review. RESULTS: The surgical procedures of awake and asleep DBS surgeries rely upon different methods for verification of intended target acquisition. The existing research results demonstrated that the stereotactic targeting accuracy of lead placement obtained by either method is reliable. There were no significant differences in clinical outcomes, costs, or complications between the two techniques. CONCLUSION: The surgical and clinical outcomes of asleep DBS for PD are comparable to those of awake DBS.
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Estimulação Encefálica Profunda/métodos , Doença de Parkinson/terapia , Resultado do Tratamento , Anestesia Geral , Anestesia Local , Humanos , Inconsciência , VigíliaRESUMO
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA contributing to protect the blood-brain barrier (BBB) after stroke. We searched for small molecules that may up-regulate MALAT1 and focused on polydatin (PD), a natural product, as a possible candidate. PD enhanced MALAT1 gene expression in rat brain microvascular endothelial cells, reducing cell toxicity and apoptosis after oxygen and glucose deprivation (OGD). These effects correlated with reduction of inflammatory factors and enhancement of expression of BBB markers. We found opposite changes after MALAT1 silencing. We determined that C/EBPß is a key transcription factor for PD-mediated MALAT1 expression. PPARγ activity is involved in MALAT1 protective effects through its coactivator PGC-1α and the transcription factor CREB. This suggests that PD activates the MALAT1/CREB/PGC-1α/PPARγ signaling pathway to protect endothelial cells against ischemia. PD administration to rats subjected to brain ischemia by transient middle cerebral artery occlusion (tMCAO) reduced cerebral infarct volume and brain inflammation, protected cerebrovascular endothelial cells and BBB integrity. These effects correlated with increased expression of MALAT1, C/EBPß, and PGC-1α. Our results strongly suggest that the beneficial effects of PD involve the C/EBPß/MALAT1/CREB/PGC-1α/PPARγ pathway, which may provide a novel therapeutic strategy for brain ischemic stroke.
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Encéfalo/irrigação sanguínea , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Glucosídeos/uso terapêutico , Microvasos/metabolismo , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Longo não Codificante/genética , Estilbenos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Sequência de Bases , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Glucosídeos/química , Glucosídeos/farmacologia , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Modelos Biológicos , RNA Longo não Codificante/metabolismo , Ratos Sprague-Dawley , Estilbenos/química , Estilbenos/farmacologia , Fatores de TempoRESUMO
We sought to calibrate mechanical properties of left ventricle (LV) based on three-dimensional (3D) speckle tracking echocardiographic imaging data recorded from 16 segments defined by American Heart Association (AHA). The in vivo data were used to create finite element (FE) LV and biventricular (BV) models. The orientation of the fibers in the LV model was rule based, but diffusion tensor magnetic resonance imaging (MRI) data were used for the fiber directions in the BV model. A nonlinear fiber-reinforced constitutive equation was used to describe the passive behavior of the myocardium, whereas the active tension was described by a model based on tissue contraction (Tmax). isight was used for optimization, which used abaqus as the forward solver (Simulia, Providence, RI). The calibration of passive properties based on the end diastolic pressure volume relation (EDPVR) curve resulted in relatively good agreement (mean error = -0.04 ml). The difference between the experimental and computational strains decreased after segmental strain metrics, rather than global metrics, were used for calibration: for the LV model, the mean difference reduced from 0.129 to 0.046 (circumferential) and from 0.076 to 0.059 (longitudinal); for the BV model, the mean difference nearly did not change in the circumferential direction (0.061) but reduced in the longitudinal direction from 0.076 to 0.055. The calibration of mechanical properties for myocardium can be improved using segmental strain metrics. The importance of realistic fiber orientation and geometry for modeling of the LV was shown.
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Oxidative stress is a great challenge to neurons following cerebral ischemia. PGC-1α has been shown to act as a potent modulator of oxidative metabolism. In this study, the effects of ZLN005, a small molecule that activate PGC-1α, against oxygen-glucose deprivation (OGD)- or ischemia-induced neuronal injury in vitro and in vivo were investigated. Transient middle cerebral artery occlusion (tMCAO) was performed in rats and ZLN005 was administered intravenously at 2 h, 4 h, or 6 h after ischemia onset. Infarct volume and neurological deficit score were detected to evaluate the neuroprotective effects of ZLN005. Well-differentiated PC12 cells, which were subjected to OGD for 2 h followed by reoxygenation for 22 h, were used as an in vitro ischemic model. Changes in expression of PGC-1α, its related genes, and antioxidant genes were determined by real-time quantitative PCR. The results showed that ZLN005 reduced cerebral infarct volume and improved the neurological deficit in rat with tMCAO, and significantly protected OGD-induced neuronal injury in PC12 cells. Furthermore, ZLN005 enhanced expression of PGC-1α in PC12 cells and in the ipsilateral hemisphere of rats with tMCAO. Additionally, ZLN005 increased antioxidant genes, including SOD1 and HO-1, and significantly prevented the ischemia-induced decrease in SOD activity. Taking together, the PGC-1α activator ZLN005 exhibits neuroprotective effects under ischemic conditions and molecular mechanisms possibly involve activation of PGC-1α signaling pathway and cellular antioxidant systems.
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Benzimidazóis/farmacologia , Isquemia Encefálica/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Isquemia Encefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Isquemia/tratamento farmacológico , Isquemia/metabolismo , Masculino , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Neuroinflammation plays a vital role in the pathological process of cerebral ischemic stroke, but currently there is no effective treatment. After ischemia, microglia-produced proinflammatory mediator expression contributes to the aggravation of neuroinflammation, while anti-inflammatory activation of microglia develops an anti-neuroinflammatory effect via secretion of anti-inflammatory factor. Promoting the anti-inflammatory activation of microglia might be an effective treatment of stroke. Previously, we discovered one derivative of the natural product (+)-balasubramide, compound 3C, that exhibits a remarkably anti-neuroinflammatory effect in vitro with unknown mechanisms. Thus in this study, we aimed to clarify its molecular mechanisms and determine whether compound 3C has a neuroprotective effect after ischemia via regulation on microglial inflammation. We found that compound 3C promoted the anti-inflammatory mediator expression and reduced the proinflammatory mediator expression in LPS-stimulated BV2 cells and mouse primary microglia cells, which were reversed by AMP-activated protein kinase (AMPK) inhibition or AMPK upstream calmodulin-dependent protein kinase kinase beta (CaMKKß) inhibition. Compound 3C also prevented LPS-stimulated JNK activation and enhanced PGC-1α activation in microglia, which was attenuated by AMPK inhibition. Additionally, compound 3C ameliorated depressive behaviors in LPS-induced neuroinflammatory mice by promoting the anti-inflammatory activation of microglia. Furthermore, we found that compound 3C markedly reduced brain infarct volume, improved the neurological deficit in rats with ischemia and reduced the activated microglia/macrophage cells in the ischemic area, which concomitantly enhanced the anti-inflammatory mediator expression. A mechanistic study showed that the compound 3C-mediated activation of CaMKKß, AMPK and PGC-1α is involved in the anti-neuroinflammatory and neuroprotective effects of 3C in the brain of LPS-treated mice and ischemic rats. Taken together, our results show that compound 3C could suppress neuroinflammation in vitro and in vivo by modulating microglial activation state through the CaMKKß-dependent AMPK/PGC-1α signaling pathway, and maybe further be developed as a promising new drug candidate for the treatment of brain disorders such as stroke associated with brain inflammation.
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Proteínas Quinases Ativadas por AMP/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Encefalite/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Microglia/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Depressão , Encefalite/prevenção & controle , Infarto da Artéria Cerebral Média/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Elastin is a peculiar elastomer in that it requires water to maintain resilience, and its mechanical properties are closely associated with the immediate aqueous environment. The bulk, extra- and intrafibrillar water plays important roles in both elastic and viscoelastic properties of elastin. In this study, a two-stage liquid-vapor method was developed to investigate the effects of water loss on the mechanical properties of porcine aortic elastin. The tissue samples started in a phosphate-buffered saline (PBS) solution at their fully hydrated condition, with a gravimetric water content of 370±36%. The hydration level was reduced by enclosing the tissue in dialysis tubing and submerging it in polyethylene glycol (PEG) solution at concentrations of 10%, 20%, 30%, and 45% w/v, which reduced the water content of the samples to 258±34%, 224±20%, 109±9%, and 58±3%, respectively. The samples were then transferred to a humidity chamber to maintain the hydration level while the samples underwent equi-biaxial tensile and stress relaxation tests. The concentration of 10% PEG treatment induced insignificant changes in tissue dimensions and stiffness, indicating that the removal of bulk water has less effect on elastin. Significant increases in tangent modulus were observed after 20% and 30% PEG treatment due to the decreased presence of extrafibrillar water. Elastin treated with 45% PEG shows a very rigid behavior as most of the extrafibrillar water is eliminated. These results suggest that extrafibrillar water is crucial for elastin to maintain its elastic behavior. It was also observed that the anisotropy of elastin tends to decrease with water loss. An increase in stress relaxation was observed for elastin treated with 30% PEG, indicating a more viscous behavior of elastin when the amount of extrafibrillar water is significantly reduced. Results from this study shed light on the close association between the bulk, extra- and intrafibrillar water pools and the mechanics of elastin.
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Aorta Torácica/metabolismo , Elastina/metabolismo , Fenômenos Mecânicos , Água/metabolismo , Animais , Fenômenos Biomecânicos , Teste de Materiais , SuínosRESUMO
Lamprey angiotensinogen (l-ANT) is a hormone carrier in the regulation of blood pressure, but it is also a heparin-dependent thrombin inhibitor in lamprey blood coagulation system. The detailed mechanisms on how angiotensin is carried by l-ANT and how heparin binds l-ANT and mediates thrombin inhibition are unclear. Here we have solved the crystal structure of cleaved l-ANT at 2.7 Å resolution and characterized its properties in heparin binding and protease inhibition. The structure reveals that l-ANT has a conserved serpin fold with a labile N-terminal angiotensin peptide and undergoes a typical stressed-to-relaxed conformational change when the reactive center loop is cleaved. Heparin binds l-ANT tightly with a dissociation constant of â¼10 nm involving â¼8 monosaccharides and â¼6 ionic interactions. The heparin binding site is located in an extensive positively charged surface area around helix D involving residues Lys-148, Lys-151, Arg-155, and Arg-380. Although l-ANT by itself is a poor thrombin inhibitor with a second order rate constant of 500 m-1 s-1, its interaction with thrombin is accelerated 90-fold by high molecular weight heparin following a bell-shaped dose-dependent curve. Short heparin chains of 6-20 monosaccharide units are insufficient to promote thrombin inhibition. Furthermore, an l-ANT mutant with the P1 Ile mutated to Arg inhibits thrombin nearly 1500-fold faster than the wild type, which is further accelerated by high molecular weight heparin. Taken together, these results suggest that heparin binds l-ANT at a conserved heparin binding site around helix D and promotes the interaction between l-ANT and thrombin through a template mechanism conserved in vertebrates.
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Angiotensinas/química , Proteínas de Peixes/química , Heparina/química , Lampreias , Trombina/química , Angiotensinas/genética , Angiotensinas/metabolismo , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Heparina/genética , Heparina/metabolismo , Mutação , Domínios Proteicos , Estrutura Secundária de Proteína , Trombina/genética , Trombina/metabolismoRESUMO
Giant pituitary adenomas (diameter >4 cm) are a challenge to treat, and there is no consensus on the optimal surgical strategy. We report here our experience in surgical management of these lesions. Adult patients with giant pituitary adenomas (n = 62; 54 non-functioning and eight hormone-secreting adenomas) who underwent surgical resection at our hospital from 2009 to 2015 were retrospectively reviewed. Surgical and clinical outcomes were analyzed. Single transsphenoidal and transcranial approaches were used in 43 (69.4%) and four (6.5%) patients, respectively. A combined transsphenoidal and transcranial approach was used in 13 patients (20.9%) and in two patients (3.2%), a transcranial procedure was followed 3 months later by a transsphenoidal approach. Greater than 90% resection was achieved in 47 cases (75.8%). During a mean follow-up period of 46.9 months, 49 patients (79%) showed improved visual impairment scores, while none experienced visual deterioration. There was no post-operative hemorrhage or mortality. A total of 27 patients (43.5%) received adjuvant medical and/or radiation therapy. At last follow-up, eight patients (12.9%) had recurrence. For giant pituitary adenoma, the transsphenoidal and transcranial approaches should be combined flexibly based on the characteristics of the tumor. In certain cases, a simultaneous combined approach can maximize tumor extirpation and lower the risk of swelling and bleeding of the residual tumor.
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Adenoma/cirurgia , Nanismo Hipofisário/cirurgia , Procedimentos Neurocirúrgicos/métodos , Nariz/cirurgia , Crânio/cirurgia , Resultado do Tratamento , Adenoma/diagnóstico por imagem , Adulto , Idoso , Nanismo Hipofisário/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Anxiety and depression have been identified as common psychological distresses faced by the majority of patients with cancer. However, no studies have investigated the relationship between positive psychological variables (hope, optimism and general self-efficacy) and anxiety and depression among patients with central nervous system (CNS) tumors in China. Our hypothesis is that the patients with higher levels of hope, optimism or general self-efficacy have lower levels of anxiety and depression when encountered by stressful life events such as CNS tumors. METHODS: Questionnaires, including the Hospital Anxiety and Depression Scale, the Herth Hope Index, the Life Orientation Scale-Revised and the General Self-Efficacy Scale, and demographic and clinical records were used to collect information about patients with CNS tumors in Liaoning Province, China. The study included 222 patients (effective response rate: 66.1%). Hierarchical linear regression analyses were performed to explore the associations among hope, optimism, general self-efficacy and anxiety/depression. RESULTS: Prevalence of anxiety and depression were 42.8 and 32.4%, respectively, among patients with CNS tumors. Hope and optimism both were negatively associated with anxiety and together accounted for 21.4% of variance in anxiety. Similarly, hope and optimism both were negatively associated with depression and accounted for 32.4% of variance in depression. CONCLUSIONS: The high prevalence of anxiety and depression among patients with CNS tumors should receive more attention in Chinese medical settings. To help reduce anxiety and depression, health care professionals should develop interventions to promote hope and optimism based on patients' specific needs.