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BACKGROUND: Paclitaxel (PTX) is a key drug used for chemotherapy for various cancers. The hy-droxylation metabolites of paclitaxel are different between humans and rats. Currently, there is little infor-mation available on the metabolic profiles of CYP450 enzymes in rats. OBJECTIVE: This study evaluated the dynamic metabolic profiles of PTX and its metabolites in rats and in vitro. METHODS: Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrome-try (UHPLC-Q-TOF-MS) and LC-MS/MS were applied to qualitative and quantitative analysis of PTX and its metabolites in rats' liver microsomes and recombinant enzyme CYP3A1/3A2. Ten specific inhibitors [NF (CYP1A1), FFL (CYP1A2), MOP (CYP2A6), OND (CYP2B6), QCT (CYP2C8), SFP (CYP2C9), NKT (CYP2C19), QND (CYP2D6), MPZ (CYP2E1) and KTZ (CYP3A4)] were used to identify the metabolic pathway in vitro. RESULTS: Four main hydroxylated metabolites of PTX were identified. Among them, 3'-p-OH PTX and 2-OH PTX were monohydroxylated metabolites identified in rats and liver microsome samples, and 6α-2-di-OH PTX and 6α-5"-di-OH PTX were dihydroxylated metabolites identified in rats. CYP3A recombinant enzyme studies showed that the CYP3A1/3A2 in rat liver microsomes was mainly responsible for metabolizing PTX into 3'-p-OH-PTX and 2-OH-PTX. However, 6α-OH PTX was not detected in rat plasma and liver microsome samples. CONCLUSION: The results indicated that the CYP3A1/3A2 enzyme, metabolizing PTX into 3'-p-OH-PTX and 2-OH-PTX, is responsible for the metabolic of PTX in rats. The CYP2C8 metabolite 6α-OH PTX in humans was not detected in rat plasma in this study, which might account for the interspecies metabolic differences between rats and humans. This study will provide evidence for drug-drug interaction research in rats.
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PURPOSE: This study aimed to investigate the underlying factors driving the onset of myopia, specifically the role of the ciliary muscle's contraction in the elongation of the axial length of the eye. METHODS: The retrospective study was conducted utilizing data from three ophthalmic centers in Shanghai and Beijing. Both Chinese and Caucasian children were involved. The axial length of the subjects' eyes was measured in both relaxed and contracted state of the ciliary muscle. A comprehensive mechanical model was also developed to observe the influence of ciliary muscle contraction on the axial length. RESULTS: This study included a sample of 198 right eyes of 198 myopic children. Of these, 97 were male and 101 were female, 126 were of Chinese ethnicity and 72 were Caucasian. The age of onset for myopia ranged from 5.9 to 16.9 years old. The axial length of the eye decreased 0.028 ± 0.007mm following dilation, indicating relaxation of the ciliary muscle (t paired student = 15.16, p = 6.72 x 10-35). In contrast, ciliary muscle contraction resulted in an increase in axial length. Considering proportionality, a significant 90.4% (179 eyes) exhibited a reduced axial length, while a minor 9.6% (19 eyes) demonstrated an increase post-mydriasis. Finite element modeling demonstrated that muscle contraction caused a tension force that transmits towards the posterior pole of the eye, causing it to extend posteriorly. CONCLUSION: The contraction of the ciliary muscle leads to an extension of the axial length. This could potentially be the initiating factor for myopia.
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Miopía , Niño , Humanos , Masculino , Femenino , Preescolar , Adolescente , Estudios Retrospectivos , China , Miopía/etiología , Cuerpo Ciliar , Músculo Liso , Longitud Axial del OjoRESUMEN
Purpose: We aimed to explore the effects of percutaneous coronary intervention (PCI) on the ophthalmic artery (OA) hemodynamics in patients with acute coronary syndrome (ACS). Methods: A total of 73 participants (Group0: healthy controls, Group1: Patients with ACS underwent PCI < 3 months, Group2: Patients with ACS underwent PCI ≥ 3 months) were enrolled. Computed tomographic angiography images were used to construct three-dimensional models of participants' OAs. Numerical simulations based on computational fluid dynamics were used to acquire hemodynamic parameters. Results: The angle between the OA and internal carotid artery in Group2 was significantly larger compared with Group0 and Group1 (P = 0.003 and P = 0.044). Hemodynamic simulation showed a significantly slower OA blood velocity in Group1 than in the control (P < 0.001) and Group2 (P = 0.033). Lower wall shear stress was found in Group1 than that in control (P = 0.040). Patients after PCI had a higher wall pressure than healthy controls (P = 0.012 and P = 0.004). Mass flow ratios were decreased in Group1 and Group2 (P = 0.021 and P = 0.002). The hemodynamic parameters of OA were correlated with several clinical indicators. Conclusions: The OA blood flow velocity of patients with ACS after PCI initially slowed down, which increased the risk of plaque formation, and then showed an increasing trend. There was a correlation between OA hemodynamic parameters and clinical indexes related to cardiac stress. Ischemia-reperfusion injury and changes in blood flow status after PCI may affect OA morphology and hemodynamics, leading to ocular lesions. Trial registration: ChiCTR2100050428.
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Background: Anoikis-related long non-coding RNAs (ARLs) play a critical role in tumor metastasis and progression, suggesting that they may serve as risk markers for cancer. This study aimed to investigate the prognostic value of ARLs in patients with lung adenocarcinoma (LUAD). Methods: Clinical data, RNA sequencing (RNA-seq) data, and mutation data from the LUAD project were obtained from The Cancer Genome Atlas (TCGA) database. The Molecular Signatures Database (MSigDB) and the GeneCard database were used to collect an anoikis-related gene (ARG) set. Pearson correlation analysis was performed to identify ARLs. LASSO and Cox regression were then used to establish a prognostic risk signature for ARLs. The median risk score served as the basis for categorizing patients into high and low-risk groups. Kaplan-Meier analysis was utilized to compare the prognosis between these two groups. The study also examined the associations between risk scores and prognosis, clinicopathological characteristics, immune status, tumor mutation burden (TMB), and chemotherapeutic agents. LncRNA expression was assessed using quantitative real-time PCR (qRT-PCR). Results: A total of 480 RNA expression profiles, 501 ARGs, and 2698 ARLs were obtained from the database. A prognostic ARL signature for LUAD was established, consisting of 9 lncRNAs. Patients in the low-risk group exhibited significantly better prognosis compared to those in the high-risk group (P < 0.001). The 9 lncRNAs from the ARL signature were identified as independent prognostic factors (P < 0.001). The signature demonstrated high accuracy in predicting LUAD prognosis, with area under the curve values exceeding 0.7. The risk scores for ARLs showed strong negative correlations with stroma score (P = 5.9E-07, R = -0.23), immune score (P = 9.7E-09, R = -0.26), and microenvironment score (P = 8E-11, R = -0.29). Additionally, the low-risk group exhibited significantly higher TMB compared to the high-risk group (P = 4.6E-05). High-risk status was significantly associated with lower half-maximal inhibitory concentrations for most chemotherapeutic drugs. Conclusion: This newly constructed signature based on nine ARLs is a useful instrument for the risk stratification of LUAD patients. The signature has potential clinical significance for predicting the prognosis of LUAD patients and guiding personalized immunotherapy.
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Tilt photography of unmanned aerial vehicles (UAVs) is widely used in urban management, cadastral mapping, disaster monitoring and other fields, but there are few innovative applications in online tourism. In this study, empirical design and usability testing methods were adopted, advanced positioning technology and Cesium engine were used to build a 3D real online travel application based on tilt photography, and the interactive function was realized through JavaScript language dynamic interactive function script. Meanwhile, combined with the questionnaire survey, the mobile application Rating Scale (MARS) was used to evaluate the function and quality of the application. The results show that engagement, functionality and aesthetics have no significant influence on user perception. Information quality and subjective quality of application have significant positive influence on user perception, and the influence of information quality is more significant. This study extends the application of oblique photography in tourism and provides experience for the development of tourism digitization.
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Turismo , Dispositivos Aéreos No Tripulados , Viaje , Fotograbar , TecnologíaRESUMEN
Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.
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Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR2 NAM) led to a series of analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for a PET tracer with convenient chemical handles for incorporation of a 11C or 18F radiolabel. [11C]MK-8056 was synthesized and evaluated in vivo and demonstrated appropriate affinity, selectivity, and physicochemical properties to be used as a positron emission tomography tracer for mGluR2.
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The present study aimed to explore the main active components and underlying mechanisms of Marsdenia tenacissima in the treatment of ovarian cancer(OC) through network pharmacology, molecular docking, and in vitro cell experiments. The active components of M. tenacissima were obtained from the literature search, and their potential targets were obtained from SwissTargetPrediction. The OC-related targets were retrieved from Therapeutic Target Database(TTD), Online Mendelian Inheritance in Man(OMIM), GeneCards, and PharmGKB. The common targets of the drug and the disease were screened out by Venn diagram. Cytoscape was used to construct an "active component-target-disease" network, and the core components were screened out according to the node degree. The protein-protein interaction(PPI) network of the common targets was constructed by STRING and Cytoscape, and the core targets were screened out according to the node degree. GO and KEGG enrichment analyses of potential therapeutic targets were carried out with DAVID database. Molecular docking was used to determine the binding activity of some active components to key targets by AutoDock. Finally, the anti-OC activity of M. tenacissima extract was verified based on SKOV3 cells in vitro. The PI3K/AKT signaling pathway was selected for in vitro experimental verification according to the results of GO function and KEGG pathway analyses. Network pharmacology results showed that 39 active components, such as kaempferol, 11α-O-benzoyl-12ß-O-acetyltenacigenin B, and drevogenin Q, were screened out, involving 25 core targets such as AKT1, VEGFA, and EGFR, and the PI3K-AKT signaling pathway was the main pathway of target protein enrichment. The results of molecular docking also showed that the top ten core components showed good binding affinity to the top ten core targets. The results of in vitro experiments showed that M. tenacissima extract could significantly inhibit the proliferation of OC cells, induce apoptosis of OC cells through the mitochondrial pathway, and down-regulate the expression of proteins related to the PI3K/AKT signaling pathway. This study shows that M. tenacissima has the characteristics of multi-component, multi-target, and multi-pathway synergistic effect in the treatment of OC, which provides a theoretical basis for in-depth research on the material basis, mechanism, and clinical application.
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Medicamentos Herbarios Chinos , Marsdenia , Neoplasias Ováricas , Humanos , Femenino , Simulación del Acoplamiento Molecular , Farmacología en Red , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Bases de Datos Genéticas , Extractos Vegetales , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
Optic nerve damage is a common cause of blindness. Optic nerve injury is often accompanied by fundus vascular disease, retinal ganglion cell apoptosis, and changes in retinal thickness. These changes can cause alterations in protein expression within neurons in the retina. Proteomics analysis offers conclusive evidence to decode a biological system. Furthermore, animal models of optic nerve injury made it possible to gain insight into pathological mechanisms, therapeutic targets, and effective treatment of such injuries. Proteomics takes the proteome as the research object and studies protein changes in cells and tissues. At present, a variety of proteomic analysis methods have been widely used in the research of optic nerve injury diseases. This review summarizes the application of proteomic research in optic nerve injury diseases and animal models of optic nerve injury. Additionally, differentially expressed proteins are summarized and analyzed. Various optic nerve injuries, including those associated with different etiologies, are discussed along with their potential therapeutic targets and future directions.
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BACKGROUND: Cerebral small vessel disease (CSVD) is a systemic disease, affecting not only the brain, but also eyes and other organs. The total CSVD score is a tool for comprehensive evaluation of brain lesions in patients with CSVD. The ophthalmic artery (OA) is a direct response to ocular blood flow. However, little is known about the correlation between CSVD and characteristics of OA. We investigated the OA morphologies and hemodynamics in patients with CSVD and the correlation between these changes and the total CSVD score. METHODS: This cross-sectional observational study included 34 eyes from 22 patients with CSVD and 10 eyes from 5 healthy controls. The total CSVD score was rated according to the CSVD signs on magnetic resonance imaging. OA morphological characteristics were measured on the basis of 3D OA model reconstruction. OA hemodynamic information was calculated using computational fluid dynamics simulations. RESULTS: The total CSVD score negatively correlated with the OA diameter, blood flow velocity, and mass flow ratio (all P < 0.05). After adjusting for potential confounding factors, the total CSVD score was still independently correlated with the OA blood velocity (ß = - 0.202, P = 0.005). The total CSVD score was not correlated with OA angle (P > 0.05). The presence of cerebral microbleeds and enlarged perivascular spaces was correlated with the OA diameter (both P < 0.01), while the lacunar infarcts and white matter hyperintensities were correlated with the OA blood velocity (both P < 0.001). CONCLUSIONS: The decrease of the blood velocity in the OA was associated with the increase in the total CSVD score. The changes of the OA diameter and velocity were associated with the presence of various CSVD signs. The findings suggest that more studies are needed in the future to evaluate CSVD by observing the morphologies and hemodynamics of OA.
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Enfermedades de los Pequeños Vasos Cerebrales , Accidente Vascular Cerebral Lacunar , Humanos , Estudios Transversales , Arteria Oftálmica/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Accidente Vascular Cerebral Lacunar/complicaciones , Imagen por Resonancia Magnética , HemodinámicaRESUMEN
With the development and support of modern technologies such as digital media and online live stream, it has become an effective way to promote the online transaction of museum cultural and creative products. Based on the Technology Acceptance Model combined with the Post-Acceptance Model of Information System Continuance and the theories on customer satisfaction index, this research introduces perceived interest (PI) and media richness (MR) as variables and constructs a model of the influencing factors of online consumers' persistent purchase (PP) of museum products. The research model and related hypotheses were verified through structural equation modeling (SEM). The research found that perceived value (PV) and satisfaction (SAT) are the key variables that have impact on the PP of consumers. Perceived quality, brand trust, MR, PI, and perceived usefulness have significant effects on PV and SAT. Involvement in purchasing decisions positively moderates the impact on SAT of PV. The conclusion can be referred to for operators and product developers.
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Air pollution in China is complex, and the formation mechanism of chemical components in particulate matter is still unclear. This study selected three consecutive heavy haze pollution episodes (HPEs) during winter in Beijing for continuous field observation, including an episode with heavy air pollution under red alert. Clean days during the observation period were selected for comparison. The HPE characteristics of Beijing in winter were: under the influence of adverse meteorological conditions such as high relative humidity, temperature inversion and low wind speed; and strengthening of secondary transformation reactions, which further intensified the accumulation of secondary aerosols and other pollutants, promoting the explosive growth of PM2.5. PM2.5/CO values, as indicators of the contribution of secondary transformation in PM2.5, were approximately 2 times higher in the HPEs than the average PM2.5/CO during the clean period. The secondary inorganic aerosols (sulfate nitrate and ammonium salt) were significantly enhanced during the HPEs, and the conversion coefficients were remarkably improved. In addition, it is interesting to observe that the production of sulfate tended to exceed that of nitrate in the late stage of all three HPEs. The existence of aqueous phase reactions led to the explosive growth sulfur oxidation ratio (SOR) and rapid generation of sulfate under high relative humidity (RH>70%).
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Contaminantes Atmosféricos , Contaminación del Aire , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Beijing , China , Monitoreo del Ambiente , Nitratos/análisis , Óxidos de Nitrógeno/análisis , Material Particulado/análisis , Estaciones del Año , Sulfatos/análisisRESUMEN
NH3, SO2, NOx and the inorganic ions of PM2.5 in winter 2009, 2014 and 2016 were examined to investigate the change in NH3 and aerosol chemistry in Beijing, China. NH3 concentrations showed an increase by 59% on average, in contrast to the decrease of SO2 by 63% from winter 2009 to 2016. The mean mass ratio of NH3/NHx was 0.83 ± 0.12 in 2016, which is higher than those obtained in 2009 and 2014, implying more NHx remaining as free NH3 in 2016 winter. Our findings suggest that vehicles exhaust emissions are an important NH3 source in urban central atmosphere of Beijing in winter. Despite the observed NOx presenting declining trends from 2014 to 2016, nitrate concentrations even exhibited a significant increasing trend, which may be largely attributable to high NH3 levels. An in-depth analysis of measured NH3 and aerosol species in a heavy pollution episode in December 2016, combined with the acidity predicted by ISORROPIA II model demonstrated abundant NH3 most of the time in air, where NH3 is not only a precursor for NH4+ but also effect the neutralization of SO42- and NO3- in PM2.5. With high RH and low photochemical activity, elevated NO3- concentration was attributed to an enhanced heterogeneous conversion of NOx to HNO3 to form NH4NO3 in pollution transport stage. The decrease in NOx from high level and the increase in NH3, with peaks of SO42- occurring were observed in pollution cumulative stage. The aqueous-phase oxidation of SO2 by NO2 to sulfate might play an important role with high pH values. Our results suggested that the simultaneous control of NH3 emissions in conjunction with SO2 and NOx emissions would be more effective in reducing particulate matter PM2.5 formation.
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The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.
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Regulación Alostérica/efectos de los fármacos , Agonistas Muscarínicos/farmacología , Piridinas/farmacología , Receptor Muscarínico M4/agonistas , Animales , Células CHO , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacología , Cricetulus , Humanos , Macaca mulatta , Agonistas Muscarínicos/química , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Tomografía de Emisión de Positrones , Piridinas/química , Receptor Muscarínico M4/metabolismoRESUMEN
Atmospheric ammonia (NH3) as the most important alkaline gas in the atmosphere has attracted much attention in recent years due to its critical role in haze formation, especially on the North China Plain (NCP). Comprehensive studies are needed for investigating diurnal variations of NH3 and underlying mechanisms in different seasons and their potential impacts on atmospheric chemistry. In this study, continuous long-term observation (Mar. 2016 to May 2017) of NH3 at a rural site in the NCP was used to characterize the diurnal variation of NH3 in different seasons and to unveil its causes and potential impacts on atmospheric chemistry. NH3 concentrations displayed rapid increases during the morning, reaching very prominent peaks mostly between 8:00 to 11:00 LT. Such frequent (55%) morning peaks were mainly caused by the evaporation of dew and guttation water droplets. Average dew and guttation water volume concentrations of 750 mL m-2 was estimated for spring, which resulted in approximate NH3 emissions of 800 ng m-2 s- 1. Such high emission fluxes from dew and guttation water evaporation have never been reported before, suggesting dew and guttation droplets to be significant night-time reservoirs and strong morning sources for NH3. In light of recent studies putting forward that NH3 can promote the heterogeneous formation of HONO and nitrate under high humidity conditions, we investigated the differences in HONO and aerosol chemical composition diurnal variations between days with and without NH3 morning spikes during November. HONO, nitrate and sulfate concentrations were significantly higher for days with NH3 morning spikes, with HONO displaying a morning peak near that of NH3. These results demonstrate that the prevailing NH3 morning spikes on the NCP have significant influences on aerosol formation and atmospheric chemistry. NH3 emission mitigation strategies and regulations are urgently needed.
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Aerosoles/análisis , Contaminantes Atmosféricos/análisis , Amoníaco/análisis , Monitoreo del Ambiente , ChinaRESUMEN
BACKGROUND: This study aimes to characterize the fundus structural changes in patients with nonarteritic anterior ischemic optic neuropathy (NAION) and the correlation between macular vessel density, retinal nerve fibre layer (RNFL) parameters and visual field sensitivity (VFS) in NAION patients. METHODS: A retrospective case control study was performed using 37 eyes with NAION, 30 uninvolved contralateral eyes, and 27 eyes of healthy age-matched subjects. Data on the retinas and choroidal vessel densities and VFS were compared among the three groups. RESULTS: The NAION group exhibited significantly lower RNFL thicknesses, lower ganglion cell complexes (GCC), larger global loss volume (GLV) values and focal loss volume (FLV) values when compared with both uninvolved eyes and healthy eyes (p < 0.01 for all comparisons). The superficial vessel density (SVD) valus (whole, parafovea, superior-hemi and inferior-hemi) were significantly lower in NAION eyes, followed by uninvolved eyes and healthy eyes (p < 0.01; LSD, p < 0.05 for all comparisons). The deep vessel density (DVD) values (parafovea, superior-hemi and inferior-hemi) were the lowest by a significant value in NAION eyes, followed by uninvolved eyes and healthy eyes (p < 0.01; LSD, p < 0.05 for all comparisons). However, DVD value measurements (whole and fovea) of healthy and uninvolved eyes were not significantly different. The average threshold deviation (TD) was - 11.02 ± 3.75 dB for the overall field region, - 6.01 ± 2.21 dB for the affected superior field region and - 9.98 ± 3.34 dB for the affected inferior field region in NAION eyes. A statistically significant correlation was found between the RNFL thickness and visual field(VF) loss (r = - 0.788, p < 0.001). CONCLUSION: In addition to peripapillary vascular changes occurring in NAION eyes, macular vessel density is also involved. Furthermore, NAION-uninvolved eyes exhibited abnormalities compared with healthy eyes. This indicates that vascular changes may occur before changes in retinal thickness at the early stages of NAION.
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Coroides/irrigación sanguínea , Mácula Lútea/irrigación sanguínea , Neuropatía Óptica Isquémica/fisiopatología , Vasos Retinianos/patología , Adulto , Anciano , Análisis de Varianza , Estudios de Casos y Controles , Femenino , Humanos , Mácula Lútea/diagnóstico por imagen , Microvasos/diagnóstico por imagen , Persona de Mediana Edad , Neuropatía Óptica Isquémica/diagnóstico por imagen , Estudios Retrospectivos , Agudeza Visual/fisiología , Campos Visuales/fisiologíaRESUMEN
PURPOSE: To determine the effect of osthole on the retina in a chronic cerebral hypoperfusion (CCH) rat model and to investigate its therapeutic activity. METHODS: Seventy-two rats were randomly allocated into 6 groups. CCH was induced by permanent bilateral common carotid artery occlusion (BCCAO) in five groups. Sham surgery was performed without occlusion of the artery in the sixth group (control group). Animals were administered with saline (model group), osthole (osthole-IG group), aspirin (aspirin group), or ginaton (ginaton group); the osthole-PI group was performed with peribulbar injection of osthole. Four rats in each group were sacrificed every 5 days after drug administration, and histopathology along with morphology of retina were observed. Fundus fluorescein angiography was performed before the animals were sacrificed at day 15. Retinal Akt, NF-κB, Bax, and Bcl-2 levels were assessed using immunohistochemistry, immunofluorescence, and reverse-transcription PCR; retinal injury was assessed using TUNEL in situ; retinal levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured. RESULTS: Fundus fluorescein angiography revealed the retinal vascular diameter in the osthole-IG group rats to be wider than that in the model, osthole-PI, aspirin, or ginaton group rats. Histological analysis of retinal tissue revealed an increase in retinal thickness in all treatment groups, and significant improvement was noticed in the osthole-IG group. TUNEL staining revealed fewer apoptotic cells in the osthole-IG and osthole-PI groups than in the other groups. For immunohistochemistry results, in the osthole-IG group, levels of NF-κB and Akt were lower than those in the other treated groups, while levels of the ratio Bcl-2/Bax were higher. Levels of MDA were lower and levels of SOD were higher in the osthole-IG group than in the other groups. CONCLUSIONS: Osthole protects the retina from ischemia injury secondary to CCH induced by BCCAO, mainly through anti-inflammatory, antioxidant, and antiapoptotic effects.
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Vascular remodeling is a characteristic pathological feature of hypertension, it can cause of increasing vascular resistance and decrease of compliance. Vascular smooth muscle cell (VSMCs) dysfunction is the important foundation of vascular remodeling. Increasing evidences have revealed that lncRNA is an important regulatory factor of VSMC function. In this paper, we explored the function of lncRNA TUG1 in vascular remodeling of hypertension. Here, we found that lncRNA TUG1 was highly expressed in aorta of spontaneously hypertensive rats (SHR) rats and promoted the proliferation and migration of VSMCs (SHR-VSMCs). Bioinformatics analyze showed that lncRNA TUG1 sequence had miR-145-5p binding sites. Luciferase reporter test, RNA pulldown and qRT-PCR showed that lncRNA TUG1 could bind miR-145-5p. Similarly, bioinformatics analyze found that FGF10 3 'UTR contained miR-145-5p binding sites. Luciferase reporter test, qRT-PCR and Western blot were shown that miR-145-5p inhibited FGF10 expression by binding to its 3 'UTR. MTT showed that miR-145-5p inhibited and FGF10 promoted SHR-VMSCs proliferation and migration. Overexpression of miR-145-5p or knocking down of FGF10 after overexpresion of lncRNA TUG1 could rescue the proliferation and migration promoted by lncRNA TUG1. LncRNA TUG1 and FGF10 promoted and miR-145-5p suppressed the expression of ß-catenin, TCF and LEF in SHR-VSMCs. Therefore, lncRNA TUG1/miR-145-5p/FGF10 promotes the proliferation and migration of VSMCs in hypertensive state by activating the Wnt/ß-catenin pathway.
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Aorta/patología , Factor 10 de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica , Hipertensión/genética , MicroARNs/genética , Miocitos del Músculo Liso/patología , ARN Largo no Codificante/genética , Animales , Aorta/citología , Aorta/metabolismo , Movimiento Celular , Proliferación Celular , Células Cultivadas , Hipertensión/patología , Masculino , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Remodelación VascularRESUMEN
Choroidal neovascularization(CNV) is the most severe complication in Age-related macular degeneration(AMD) and the most common cause of irreversible blindness in the elderly in developed world. The aim of this study was to identify the effect of transforming growth factor-ß(TGF-ß) and Smad2/3-VEGF/TNF-α signaling on CNV angiopoiesis, and to explore TGF-ß inhibitors on the development of CNV in a CNV mouse model. Fundus fluorescein angiography(FFA) was used to evaluate the laser-induced CNV formation. The histology of CNV lesions stained with hematoxylin-eosin(HE) was obtained. The immunofluorescent staining was performed to determine TGF-ß protein expression. The expressions of TGF-ß, phosphorylated Smad2/3, VEGF and TNF-α were determined by using Western blot analysis. The CNV areas were analyzed by using fluorescein stain on RPE/choroid-sclera flat mounts. We found the levels of TGF-ß protein expression increasingly reached the peak till 3rd week during the CNV development. The protein levels of VEGF and TNF-α also increased significantly in CNV mice, which were inhibited by a synthetic TGF-ß inhibitor LY2157299 or a natural TGF-ß inhibitor Decorin. The phosphorylated Smad2/3 levels increased significantly in CNV mice, but this response was profoundly suppressed by the TGF-ß inhibitors. Here we have demonstrated that TGF-ß/Smad signaling plays an important role in Laser-induced CNV formation through down-regulation of VEGF and TNF-α expressions, suggesting TGF-ß inhibitors may provide an alternative to traditional methods in wet AMD treatment.
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Neovascularización Coroidal/patología , Degeneración Macular/complicaciones , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Western Blotting , Modelos Animales de Enfermedad , Angiografía con Fluoresceína , Histocitoquímica , Rayos Láser , Ratones , Microscopía Fluorescente , Transducción de SeñalRESUMEN
To improve the understanding of NH3 variation in urban Beijing, high temporal resolution (1-min averaged) NH3 data derived during the summer of 2009 were analyzed. The results indicated that after rain there was generally an increase in NH3 concentration. The analysis of the 1-min data revealed that a weak but significant linear correlation existed between NH3 and NOx in August, indicating a connection between NH3 concentrations and traffic levels during summer. This was further supported by peak NH3 levels approximately coinciding with morning rush hours. The daily NH3 concentrations were weakly correlated with NH4+ concentrations, suggesting that NH3 played an important precursor role in NH4+ in PM2.5 formation. The mean mass ratio of NH3/NHx was 0.76±0.13. This revealed that NHx (NH3+NH4+) was influenced by local sources during the summer period and that NH3 dry deposition could contribute substantially to NHx deposition. A high temperature, relative humidity, and degree of oxidization could increase photochemical reactions and aqueous processing, having the important effect of SO2 to SO42- and NH3 to NH4+ conversion in summer. The back trajectory analysis indicates that the transport of air masses from the North China Plain region contributed to the atmospheric NH3 and NH4+ aerosol variations in Beijing.