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Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.
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Canagliflozina , Proliferación Celular , Hipertensión Pulmonar , Estrés Oxidativo , PPAR gamma , Animales , Masculino , Ratones , Ratas , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Proliferación Celular/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , PPAR gamma/metabolismo , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Ratas Sprague-Dawley , Remodelación Vascular/efectos de los fármacos , Serina/química , Serina/metabolismoRESUMEN
The right sinus of the Valsalva aneurysm (SVA) rupturing into the right atrium (RA) and dissecting into the interventricular septum (IVS) is rare. The disease can be definitively diagnosed using two-dimensional (2D) echocardiography and color Doppler ultrasonography. Real-time biplane imaging and three-dimensional (3D) echocardiography offer new perspectives for viewing and diagnosing this disease.
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Aneurisma Roto , Aneurisma de la Aorta , Disección Aórtica , Rotura de la Aorta , Seno Aórtico , Tabique Interventricular , Humanos , Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta/diagnóstico por imagen , Seno Aórtico/diagnóstico por imagen , Atrios Cardíacos/diagnóstico por imagenRESUMEN
The inner part of the oil pool flame could be divided into different combustion areas, and there have been a limited number of researches on the heat transfer characteristics within oil pool fire. Due to the lack of adequate researches on the characteristics of heat transfer in oil pool flame, this paper carries out an analytical study to pool flame spectrums of 92# gasolineï¼95# gasoline and lube by establishing flame infrared testing system. Spectral information about different combustion regions of oil pool fire is collected. The results show that three kinds of oil pool fire have similar spectral characteristics, with several characteristics emission bands of such combustion products as CO2, H2O and carbon black particles and that 3.4 µm CH stretching vibration peak is obvious; the main spectral characteristics of smoke zone is high temperature CO2 emission peak at the band range of 4ï½4.5µm, the heat exchange of flame and air is violent; the temperature changes unstably, and flame pulse frequency is high; spectral characteristics in the intermittent area is high temperature CO2 emission peak at 4ï½4.5 µm; and flame pulse frequency in intermittent zone is relatively lower compared with that in the smoke zone; compared with that in the flue gas zone and intermittent zone, the combustion in continuous zone is more stable, the spectral characteristics of the region is obvious, and carbon black particle emission intensity is high at 2.5ï½3 µm, and CH stretching vibration emission peak shows itself at 3.4 µm, which showed that the characteristic peak oil pool flame spectrum at 3.4 µm is caused by high temperature oil vapor steam. Spectral characteristics analysis of the oil pool flame in different combustion areas shows that the heat transfer is absorbed by the fuel rich layer on the surface of the oil pool flame, which leads to the change in the energy level of the oil vapor near 3.4 µm. The calculation of the emission spectrum intensity of oil pool flame in different combustion areas shows that the intensity in flame continuous zone is the largest, followed by the intermittent zone, that the connection between the flame smoke zone and the air is strong, and that the emission spectrum intensity is the lowest. The results in this study provide a reference for the modification of flame oil heat transfer model.
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In virtue of the severity and scale of the pollution caused by oil pool flame, space remote sensing can provide us a new way of monitoring in real time the oil pool flame pollution. Space remote sensing monitoring is based on the analysis of target spectrum characteristics. Due to lack of adequate researches on the characteristics of infrared spectrum of oil pool flame, this paper carries out the analytical study on flame spectrums of several types of oil, mixed oil and other combustible objects in outdoor space by establishing all-flame infrared testing system with the spectrum range of 1ï½14 µm. The results show that the spectrum curves of oil pool flame of 92# gasoline, 95# gasoline, 0# diesel, aviation kerosene and lube have similar features, that there exist characteristics emission peaks at the area of certain wave lengthsH2O characteristics emission peak for 1.1, 2.4, 2.8 and 6.3 µm, CO2 characteristics emission peak for 4.2 and 4.5 µm, CH stretching vibration emission peak for 3.4 µm, and no obvious characteristics peak for spectrum curves of 6.3 µm and above; that there is no obvious difference in the spectrum of oil pool flame among the mixtures of 92# gasoline and 0# diesel at different proportions, that the comparison of the flame spectrum of 92# gasoline with that of wood and paper shows that there appears a characteristics emission peak at 3.4 µm; that though the flame spectrum of alcohol has similar radiated emission near 3.4 µm, the proportion of its radiation intensity to that of CO2 at 4.5 µm is far less than that for the flame spectrum of 92# gasoline; that the flame spectrum of honeycomb briquette is similar to that of gray body radiation. The differences in flame spectrum among all kinds of combustible materials are closely linked to their chemical compositions and burning reaction mechanisms. Comparative analysis on the spectrum characteristics at continuous area, intermission area and flue gas area shows that CH stretching vibration peak only exists in continuous area, which proves that the emission peak is caused by the combustible reaction of oil and gas. This result is in line with the mechanism of oil pool combustion reaction. The experimental conclusion is of great significance in the remote-sensing recognition of oil pool flame based on the analysis of spectrum characteristics.
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Zika virus (ZIKV) is an emerging flavivirus that causes congenital syndromes including microcephaly and fetal demise in pregnant women. No commercial vaccines against ZIKV are currently available. We previously generated a chimeric ZIKV (ChinZIKV) based on the Chaoyang virus (CYV) by replacing the prME protein of CYV with that of a contemporary ZIKV strain GZ01. Herein, we evaluated this vaccine candidate in a mouse model and showed that ChinZIKV was totally safe in both adult and suckling immunodeficient mice. No viral RNA was detected in the serum of mice inoculated with ChinZIKV. All of the mice inoculated with ChinZIKV survived, while mice inoculated with ZIKV succumbed to infection in 8 days. A single dose of ChinZIKV partially protected mice against lethal ZIKV challenge. In contrast, all the control PBS-immunized mice succumbed to infection after ZIKV challenge. Our results warrant further development of ChinZIKV as a vaccine candidate in clinical trials.
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The genus Flavivirus is a group of arthropod-borne single-stranded RNA viruses, which includes important human and animal pathogens such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), Dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and Tick-borne encephalitis virus (TBEV). Reverse genetics has been a useful tool for understanding biological properties and the pathogenesis of flaviviruses. However, the conventional construction of full-length infectious clones for flavivirus is time-consuming and difficult due to the toxicity of the flavivirus genome to E. coli. Herein, we applied a simple, rapid, and bacterium-free circular polymerase extension reaction (CPER) method to synthesize recombinant flaviviruses in vertebrate cells as well as insect cells. We started with the de novo synthesis of the JEV vaccine strain SA-14-14-2 in Vero cells using CPER, and then modified the CPER method to recover insect-specific flaviviruses (ISFs) in mosquito C6/36 cells. Chimeric Zika virus (ChinZIKV) based on the Chaoyang virus (CYV) backbone and the Culex flavivirus reporter virus expressing green fluorescent protein (CxFV-GFP) were subsequently rescued in C6/36 cells. CPER is a simple method for the rapid generation of flaviviruses and other potential RNA viruses. A CPER-based recovery system for flaviviruses of different host ranges was established, which would facilitate the development of countermeasures against flavivirus outbreaks in the future.
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Atmospheric ammonia (NH3) and ammonium (NH4+) can substantially influence air quality, ecosystems, and climate. NH3 volatilization from fertilizers and wastes (v-NH3) has long been assumed to be the primary NH3 source, but the contribution of combustion-related NH3 (c-NH3, mainly fossil fuels and biomass burning) remains unconstrained. Here, we collated nitrogen isotopes of atmospheric NH3 and NH4+ and established a robust method to differentiate v-NH3 and c-NH3. We found that the relative contribution of the c-NH3 in the total NH3 emissions reached up to 40 ± 21% (6.6 ± 3.4 Tg N yr-1), 49 ± 16% (2.8 ± 0.9 Tg N yr-1), and 44 ± 19% (2.8 ± 1.3 Tg N yr-1) in East Asia, North America, and Europe, respectively, though its fractions and amounts in these regions generally decreased over the past decades. Given its importance, c-NH3 emission should be considered in making emission inventories, dispersion modeling, mitigation strategies, budgeting deposition fluxes, and evaluating the ecological effects of atmospheric NH3 loading.
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Contaminantes Atmosféricos , Contaminación del Aire , Amoníaco/análisis , Contaminantes Atmosféricos/análisis , Ecosistema , Monitoreo del Ambiente/métodos , Nitrógeno/análisis , ChinaRESUMEN
The films of vinylidene fluoride and trifluoroethylene (P(VDF-TrFE)) are widely used in piezoelectric tactile sensors, vibration energy harvesters, optical frequency conversion materials and organic photo-voltaic devices because of high electroactive, good optical and nonlinear optical properties, respectively. In this work, the multilayer structured ultrathin films were fabricated by the Langmuir-Blodgett technique, and the thickness per layer can be controlled accurately. It was found that as the collapse pressure of P(VDF-TrFE) (25:75) and the optimal dipping value are 60~70 mN/m and 15 mN/m, respectively, a high-density film can be obtained due to the compression of molecules. The surface topography and optical properties of the LB films were characterized by X-ray diffraction, white light interferometer and variable-angle spectrum ellipsometer. It was observed that the films are transparent in the visible region and IR-band, but show a high absorption in the UV band. Besides, the transmittance of the films ranges from 50% to 85% in the visible region, and it linearly decreases with the number of monolayers. The average thickness of per deposition layer is 2.447 nm, 2.688 nm and 2.072 nm, respectively, under three measurement methods. The calculated refractive index ranged from 1.443 to 1.598 (600~650 nm) by the Cauchy-model.
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Arginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.
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Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Proteína-Arginina N-Metiltransferasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas de Unión al ARN/genética , Proteínas Represoras/genética , Animales , Arginina , Carcinogénesis/genética , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Metilación , RatonesRESUMEN
Inflammatory bowel disease (IBD) is characterized by recurring inflammatory disorders in digestive system, and devoid of effective treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9), stimulated via inflammation whose inhibition could decrease secretion of inflammatory factors. We then determined whether inhibition of PCSK9 could improve the inflammation. First, rats model of colitis was first established via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS), and then verified via determination of body weight loss, myeloperoxidase (MPO) activity, and histopathological analysis of colonic damage. Results showed that treatment with TNBS induced a great body weight loss, MPO activity increase, and serious colonic damage, showing an obviously character of IBD. PCSK9 was elevated in TNBS-induced rats, and PCSK9 inhibition delivered by adenovirus vector increased the body weight, decreased MPO activity, and ameliorated histological change of colon. Second, the protective effect of PCSK9 inhibition against TNBS-induced colitis was accompanied by decrease of proinflammatory factors secretion, including tumor necrosis factor-α, interleukin-1ß, interleukin-6, intercellular adhesion molecule 1, and monocyte chemoattractant protein-1. TNBS could activate toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway, while PCSK9 inhibition suppressed activation of TLR4/NF-κB in TNBS-induced rats. In conclusion, PCSK9 inhibition attenuated TNBS-induced rat colitis through anti-inflammatory effect under inactivation of TLR4/NF-κB, suggesting potential therapeutic strategy in IBD.
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Colitis/prevención & control , Colon/metabolismo , FN-kappa B/genética , Proproteína Convertasa 9/genética , Receptor Toll-Like 4/genética , Adenoviridae/genética , Adenoviridae/metabolismo , Animales , Peso Corporal , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Colon/efectos de los fármacos , Colon/patología , Regulación de la Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Inflamación , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , FN-kappa B/metabolismo , Inhibidores de PCSK9 , Peroxidasa/genética , Peroxidasa/metabolismo , Proproteína Convertasa 9/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Wistar , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Ácido Trinitrobencenosulfónico/administración & dosificación , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Asymmetric allylic substitution of Morita-Baylis-Hillman (MBH) carbonates with less-nucleophilic phenols mediated by nucleophilic amine catalysis was successfully developed. A variety of substituted aryl allyl ethers were afforded with moderate to high yields with excellent enantioselectivities. The chiral MBH alcohol could be easily accessed from the corresponding aryl allyl ether.
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OBJECTIVE: To study the changes of amplitude of low-frequency fluctuation (ALFF) of the resting-fMRI in the mesial temporal lobe epilepsy (mTLE) with bilateral hippocampal sclerosis (HS), and discussed its underlying neuro-pathophysiological mechanism. METHODS: The resting-fMRI data of 20 TLE patients with HS and 20 normal volunteers were performed ALFF analysis. The amplitude of the blood oxygenation level-dependent activation of the resting-state brain was investigated. The brain structures showing increased and decreased ALFF in TLE patients were demonstrated by comparing to normal subjects with 2-sample t-test with threshold of P < 0.01. RESULTS: By comparison with that of normal subjects, the regions showing increased and decreased ALFF in TLE patients were distributed in the brain symmetrically and bilaterally. The regions showing increased ALFF were distributed with center of limbic system, such as parahippocampal gyri, amygdala, hypothalamus, dorsal anterior cingulate gyrus and part of posterior insular lobe, as well as the neocortices such as primary sensorimotor cortices, occipital cortices, inferior temporal gyri, orbital gyri, and the subcortical structures of verbal brainstem and mesial cerebellum. The point with maximal increased ALFF (T = 6.02) located in the right precentral gyru (15, - 12.51). While the regions showing decreased ALFF covered the areas of default mode, such as posterior cingulate cortex/ precuneus and medial prefrontal cortex /ventral anterior cingulate cortex, as well as other structures such as dorsal lateral prefrontal cortices, superior temporal gyri, caudate heads, dorsal brain stem and the posterior cerebellum (3, -78, -21) with the maximal decreased ALFF (T = -4.42). CONCLUSION: The method of ALFF allows the direct observation to the epileptic activation in TLE. The increased ALFF is considered the facilitation such as the epileptic activity generation and propagation; while the ALFF decrease is considered the function inhibition in these regions, especially implies the suspension in the default mode activity.
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Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/fisiopatología , Hipocampo/patología , Imagen por Resonancia Magnética/métodos , Adolescente , Adulto , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Epilepsia del Lóbulo Temporal/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis/complicaciones , Adulto JovenRESUMEN
Actinomycetes are well-known for producing numerous bioactive secondary metabolites. In this study, primary screening by antifungal activity assay found one actinomycete strain WA23-4-4 isolated from the intestinal tract of Periplaneta americana that exhibited broad spectrum antifungal activity. 16S rDNA gene analysis of strain WA23-4-4 revealed close similarity to Streptomyces nogalater (AB045886) with 86.6% sequence similarity. Strain WA23-4-4 was considered as a novel Streptomyces and the 16s rDNA sequence has been submitted to GenBank (accession no. KX291006). The maximum antifungal activity of WA23-4-4 was achieved when culture conditions were optimized to pH 8.0, with 12% inoculum concentration and 210 ml ISP2 medium, which remained stable between the 5th and the 9th day. 3-Acetyl benzoyl amide was isolated by ethyl acetate extraction of WA23-4-4 fermentation broth, and its molecular formula was determined as C9H9NO2 based on MS, IR, 1H, and 13C NMR analyses. The compound showed significant antifungal activity against Candida albicans ATCC 10231 (MIC: 31.25 µg/ml) and Aspergillus niger ATCC 16404 (MIC: 31.25 µg/ml). However, the compound had higher MIC values against Trichophyton rubrum ATCC 60836 (MIC: 500 µg/ml) and Aspergillus fumigatus ATCC 96918 (MIC: 1,000 µg/ml). SEM analysis showed damage to the cell membrane of Candida albicans ATCC 10231 and to the mycelium of Aspergillus niger ATCC 16404 after being treatment with 3-acetyl benzoyl amide. In conclusion, this is the first time that 3-acetyl benzoyl amide has been identified from an actinomycete and this compound exhibited antifungal activity against Candida albicans ATCC 10231 and Aspergillus niger ATCC 16404.
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Actinobacteria/química , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Benzamidas/aislamiento & purificación , Intestinos/microbiología , Periplaneta/microbiología , Actinobacteria/genética , Actinobacteria/aislamiento & purificación , Actinobacteria/metabolismo , Animales , Antifúngicos/química , Aspergillus fumigatus/efectos de los fármacos , Aspergillus niger/efectos de los fármacos , Aspergillus niger/ultraestructura , Benzamidas/química , Benzamidas/farmacología , Candida albicans/efectos de los fármacos , Candida albicans/ultraestructura , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Rastreo , Micelio/efectos de los fármacos , Micelio/ultraestructura , Periplaneta/anatomía & histología , ARN Ribosómico 16S/genética , Streptomyces/genéticaRESUMEN
The constituents of Cimicifuga plants have been extensively investigated, and the principal metabolites are 9,19-cyclolanostane triterpenoid glycosides, which are distributed widely in Cimicifuga plants, but not in other members of the Ranunculaceae family, and are considered to be characteristics of the Cimicifuga genus. This type of triterpenoid glycoside possesses several important biological activities. More than 120 cycloartane triterpene glycosides have been isolated from Cimicifuga simplex Wormsk. The aim of this review article is to summarize all the major findings based on the available scientific literatures on C. simplex, with a focus on the identified 9,19-cyclolanostane triterpenoid glycosides. Biological studies of cycloartane triterpene glycosides from Cimicifuga spp. are also discussed.