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1.
Proc Natl Acad Sci U S A ; 119(18): e2202382119, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35476529

RESUMO

SignificanceSeawater is one of the most abundant resources on Earth. Direct electrolysis of seawater is a transformative technology for sustainable hydrogen production without causing freshwater scarcity. However, this technology is severely impeded by a lack of robust and active oxygen evolution reaction (OER) electrocatalysts. Here, we report a highly efficient OER electrocatalyst composed of multimetallic layered double hydroxides, which affords superior catalytic performance and long-term durability for high-performance seawater electrolysis. To the best of our knowledge, this catalyst is among the most active for OER and it advances the development of seawater electrolysis technology.

2.
Biomed Microdevices ; 25(1): 6, 2023 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-36695970

RESUMO

To our best knowledge, there are no non-invasive and painless means for the diagnosis and treatment of intestinal bleeding as of now, especially the segment of intestine that cannot be reached by endoscopy. We proposed an intelligent intestinal bleeding diagnosis and treatment capsule (IBDTC) system for the first time to diagnose and treat intestinal bleeding with low power consumption, estimated to be about 2.16mW. A hue-saturation-light (HSL) color space method was applied to diagnose bleeding according to H (hue) values of the film dyed by blood. A MEMS-based micro-igniter works as the critical component of the micro-thruster that houses the propellant (74.6% potassium nitrate, 11.9% sulfur, 13.5% charcoal) and the detonating agent (dinitrodiazophenol), to help release drug. Bleeding detection and ignition tests were performed to justify its feasibility and reliability. Results demonstrated that the bleeding diagnosis module of the IBDTC can effectively detect bleeding and the micro-igniter can successfully ignite the propellant. Owing to its simplicity and intelligence, the IBDTC system will pave a way for future accurate treatment of small intestinal bleeding with no injury, no pain, no complicated supporting equipment, no need for in vitro operation and positioning.


Assuntos
Endoscopia por Cápsula , Humanos , Reprodutibilidade dos Testes , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/terapia , Inteligência , Cor
3.
Langmuir ; 39(13): 4777-4788, 2023 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-36947690

RESUMO

Metal-directed interfacial self-assembly of well-defined coordination polymer (CP) ultrathin films can control the metal complex arrangement and distribution at the molecular level, providing a convenient route for the design and fabrication of novel opto-electrical devices and heterogeneous catalysts. Here, we report the assembly of two series of CP multilayers with the transition-metal ions of Fe2+, Co2+, Zn2+ and Tb3+ as connectors and tripodal terpyridyl ligands of 4,4',4″-(1,3,5-triazine-2,4,6-triyl)tris(1-(4-([2,2':6',2″-terpyridin]-4'-yl)benzyl)pyridin-1-ium) (TerPyTa) and 4,4',4″-(benzene-1,3,5-triyl)tris(1-(4-([2,2':6',2″-terpyridin]-4'-yl)benzyl)pyridin-1-ium) (TerPyBen) as linkers at the air-water interface. The as-prepared Langmuir-Blodgett (LB) films display strong luminescence, with the emission wavelength and relative intensity dependent on both the metal ions and linkers; among them, the Zn-TerPyTa and Zn-TerPyBen CPs give off the strongest luminescent emission centered at about 370 nm with an emission lifetime of approximately 0.2-0.3 ns. The Tb-TerPyTa CPs can give off emission at approximately 490, 546, 586, and 622 nm, attributed to the 5D4 to 7F3-6 electron transitions of typical Tb3+ ions. Finally, these CP LB films can act as efficient heterogeneous photocatalysts for the CO2 reduction to selectively produce CO. The catalytic efficiency can be optimized by adjusting the experimental conditions (light sensitizer, electron donor, and water content) and CP composition (metal ion and ligand) with an excellent yield of up to 248.1 mmol g-1. In particular, it is revealed that, under the same conditions, the catalytic efficiency of the Fe-TerPyTa CP LB film is nearly 2 to 3 orders of magnitude higher than that of the other metalated complexes investigated in the homogeneous system. UV-vis spectroscopy and cyclic voltammetry studies demonstrated that the dual active sites of Fe-terpyridine and TerPyTa units contribute to the enhanced catalytic activity. This work provides an effective method to introduce the earth-abundant metal complexes into CP films to construct efficient noble-metal-free photocatalysts for the CO2 reduction.

4.
Int J Vitam Nutr Res ; 2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37434308

RESUMO

Accumulating evidences have shown the beneficial effects of astaxanthin (AST) supplementation on metabolic diseases prevention and treatment. The goal of present study was to reveal the favorable interactions among AST supplementation, gut microbiota, and kidneys in vivo, so as to attenuate kidney impairment in diabetic mice. Twenty C57BL/6J mice were assigned to a normal control group and a diabetic model group induced by a high-fat diet plus low-dose streptozotocin, and then the diabetic mice were fed with a high-fat diet without or with AST [0.01% (AST_a) or 0.02% (AST_b)] for 12 weeks. When compared to the diabetes kidney disease (DKD) group, AST supplementation delayed the renal pathological progression, reduced fasting blood glucose (AST_b: 1.53-fold, p<0.05), repressed levels of lipopolysaccharide (LPS; AST_a: 1.24-fold, p=0.008; AST_b: 1.43-fold, p<0.001) and TMAO (AST_a: 1.51-fold, p=0.001; AST_b: 1.40-fold, p=0.003), inhibited IL-6 (AST_a: 1.40-fold, p=0.004; AST_b: 1.57-fold, p=0.001) and reactive oxygen species (ROS; AST_a: 1.30-fold, p=0.004; AST_b: 1.53-fold, p<0.001), as well as regulated the Sirt1/PGC-1α/NFκB p65 signaling pathway. Moreover, the results of 16S rRNA gene-based Illumina deep sequencing in each group revealed that dietary AST supplementation also favorably modulated the gut microbiota compared with the DKD group, as evidenced by the inhibition of the harmful bacteria Clostridium_sensu_stricto_1, Romboutsia, and Coriobacteriaceae_UCG-002, and the enhancement of the probiotics such as Lachnospiraceae_NK4A136_group, Roseburia, and Ruminococcaceae. Taken together, dietary AST supplementation could protect kidneys against inflammation and oxidative stress by adjusting the gut-kidney axis in diabetic mice.

5.
Anal Chem ; 94(49): 17334-17340, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36456915

RESUMO

Cell-cell fusion studies provide an experimental platform for evaluating disease progression and investigating cell infection. However, to realize sensitive and quantitative detection on cell-cell fusion is still a challenge. Herein, we report a facile molecular beacon (MB)-based method for precise detection on cell-cell fusion. By transfection of the spike protein (S protein) and enhanced green fluorescent protein (EGFP) in HEK 293 cells, the virus-mimicking fusogenic effector cells 293-S-EGFP cells were constructed to interact with target cells. Before mixing the effector cells with the target cells, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in 293-S-EGFP cells was silenced, and the MB for GAPDH mRNA detection was delivered into the GAPDH silenced 293-S-EGFP cells. Once cell-cell fusion occurred, MB migrated from the GAPDH silenced effector cells to the target cells and hybridized with GAPDH mRNA in the target cells to induce fluorescence emission. The cell-cell fusion can be easily visualized and quantitated by fluorescence microscopy and flow cytometry. The fluorescence intensity is strongly dependent on the number of fused target cells. This MB-based method can easily identify the differences in the cell fusions for various target cells with different angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) expression levels, resulting in dramatically different fluorescence intensities in fused target cells. Our study provides a convenient and efficient quantitative detection approach to study cell-cell fusion.


Assuntos
Fusão Celular , Humanos , Células HEK293 , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Transfecção , Citometria de Fluxo , RNA Mensageiro/genética
6.
Inorg Chem ; 61(24): 9318-9327, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35675572

RESUMO

Rational design and fabrication of efficient and low-cost catalysts for both the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) are crucial for hydrogen production from water electrolysis. Herein, we report heteroatom Fe-incorporated Ni5P4 (Fe-NiP) as an excellent bifunctional catalyst for overall water splitting. Density functional theory (DFT) calculations reveal that heteroatom Fe effectively steers the electronic structure of Ni5P4, which optimizes the hydrogen adsorption behavior. Additionally, the hierarchical conductive framework of Fe-NiP contributes to abundant active sites. Thus, the Fe-NiP catalyst shows robust performance with enhanced intrinsic catalytic activity. As a good bifunctional catalyst, it demands low overpotentials of 144 and 223 mV to deliver a current density of 10 mA cm-2 for HER and OER, respectively. Considering the good bifunctional activity, an outstanding electrolyzer has been successfully assembled, which is superior to the benchmark of a RuO2(+)//Pt/C(-) electrolyzer. This study sheds light on steering the electronic structure of electrocatalysts through a heteroatom modulation strategy.

7.
Rev Esp Enferm Dig ; 114(8): 461-467, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-34886676

RESUMO

BACKGROUND AND PURPOSE: abdominal tuberculosis (TB) is a common form of extrapulmonary TB but it is still a diagnostic dilemma in clinical practice. This study aimed to highlight the clinical features and diagnostic approaches for abdominal TB. METHODS: seventy cases of diagnosed abdominal TB were retrospectively collected between August 1st, 2015 and June 30th, 2020. They were classified as peritoneal TB, lymph node TB, gastrointestinal TB, visceral TB or mixed TB. RESULTS: eighteen patients were diagnosed with peritoneal TB, nine with lymph node TB, five with gastrointestinal TB, two with visceral TB and 36 with mixed TB. More than 65 % of the patients had tuberculosis of other sites except the abdomen. The median diagnosis time was 60 days. Ascites (58.6 %), abdominal distension (48.6 %), weight loss (44.3 %) and fever (42.9 %) were the most common symptoms. The overall microbiological and histological detection rates were 70.0 % and 38.6 %, respectively. The non-ascite samples yielded a higher microbiological confirmation rate (63.6 %) than the total samples (40.8 %). Diagnosis was confirmed histologically in 18 patients (69.2 %). Forty-five cases (64.3 %) were clinically diagnosed. Invasive procedures such as surgery (6/7), percutaneous biopsy (7/7) and endoscopy in lymph node TB (4/5) had high confirmation rates. CONCLUSIONS: the diagnosis of abdominal TB should be reached by a combination of clinical, laboratory, radiological, microbiological and pathological findings.


Assuntos
Peritonite Tuberculosa/epidemiologia , Tuberculose Gastrointestinal/epidemiologia , Tuberculose dos Linfonodos/epidemiologia , Abdome/diagnóstico por imagem , Ascite/diagnóstico , Ascite/epidemiologia , Ascite/patologia , Ascite/cirurgia , China/epidemiologia , Hospitais , Humanos , Peritonite Tuberculosa/diagnóstico , Peritonite Tuberculosa/patologia , Peritonite Tuberculosa/cirurgia , Estudos Retrospectivos , Fatores de Tempo , Tuberculose Gastrointestinal/diagnóstico , Tuberculose Gastrointestinal/patologia , Tuberculose Gastrointestinal/cirurgia , Tuberculose dos Linfonodos/diagnóstico , Tuberculose dos Linfonodos/patologia
8.
Pharmazie ; 76(8): 372-378, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34412736

RESUMO

Drug resistance caused by the extreme genetic variability of zhe hepatitis C virus has rendered effective combinations of drugs indispensable in the treatment of chronic hepatitis C (CHC). Herein, we developed a fixed-dose combination (FDC) treatment containing the NS5B inhibitor sofosbuvir (SOF) and the NS5A inhibitor fopitasvir (FOP). Then the dissolution behavior of FOP in FOP/SOF FDC was improved by co-micronizing FOP with lactose. The enhanced dissolution rate of FOP in the FDC was in good agreement with the behavior of the FOP singledrug tablet. In addition, pharmacokinetic studies showed that both FOP and SOF in the FDC exhibited similar characteristics (area under the curve, Cmax, Tmax, and T1/2) as those of tablets containing FOP or SOF alone. These results revealed that the FOP/SOF FDC represents a potential therapeutic option for the treatment of CHC.


Assuntos
Hepatite C Crônica , Sofosbuvir , Antivirais/farmacologia , Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Humanos , Sofosbuvir/farmacologia , Sofosbuvir/uso terapêutico , Comprimidos
9.
J Am Chem Soc ; 142(26): 11417-11427, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32506908

RESUMO

Oxygen-bearing copper (OBC) has been widely studied for enabling the C-C coupling of the electrocatalytic CO2 reduction reaction (CO2RR) since this is a distinctive hallmark of strongly correlated OBC systems and may benefit many other Cu-based catalytic processes. Unresolved problems, however, include the instability of and limited knowledge regarding OBC under realistic operating conditions, raising doubts about its role in CO2RR. Here, an atypical and stable OBC catalyst with a hierarchical pore and nanograin-boundary structure was constructed and was found to exhibit efficient CO2RR for the production of ethylene with a Faradaic efficiency of 45% at a partial current density of 44.7 mA cm-2 in neutral media, and the ethylene partial current density is nearly 26 and 116 times that of oxygen-free copper (OFC) and commercial Cu foam, respectively. More importantly, the structure-activity relationship in CO2RR was explored through a comprehensive analysis of experimental data and computational techniques, thus increasing the fundamental understanding of CO2RR. A systematic characterization analysis suggests that atypical OBC (Cu4O) was formed and that it is stable even at -1.00 V [(vs the reversible hydrogen electrode (RHE)]. Density functional theory calculations show that the atypical OBC enables control over CO adsorption and dimerization, making it possible to implement a preference for the electrosynthesis of ethylene (C2) products. These results provide insight into the synthesis and structural characteristics of OBC as well as its interplay with ethylene selectivity.

10.
Bioorg Med Chem Lett ; 30(20): 127479, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32784091

RESUMO

Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Piperazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
11.
Bioorg Chem ; 105: 104344, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091667

RESUMO

PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin's lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation.


Assuntos
Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Linfoma não Hodgkin/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Piperazinas/química , Purinas/síntese química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Xenoenxertos , Humanos , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Morfolinas/química , Neoplasias Experimentais , Fosforilação , Purinas/farmacologia
12.
Zhongguo Zhong Yao Za Zhi ; 45(22): 5518-5524, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33350214

RESUMO

At present, there are many difficulties in the development and production of traditional Chinese medicine(TCM) tablets. This work aimed to explore the feasibility of improving dissolution difficulty and large dosage of TCM tablets by co-spray drying TCM extract with a small amount of pore-foaming agent ammonium bicarbonate. A series of porous Fagopyri Dibotryis Rhizoma powders were prepared by co-spray drying Fagopyri Dibotryis Rhizoma with different amounts of ammonium bicarbonate, and their powder pro-perties and tablet properties were comparatively investigated. At the same time, Fagopyri Dibotryis Rhizoma commercial tablets and raw material tablets were used as control drugs, the improvement degree of its compressibility and dissolution rate was investigated. The results showed that there were higher porosity, specific surface area and hollow spheroidal particles structure of powders via co-spray drying Fagopyri Dibotryis Rhizoma with NH_4HCO_3. Compared to parent and commercial Fagopyri Dibotryis Rhizoma tablets, the dissolution rates and compressibility of porous Fagopyri Dibotryis Rhizoma tablets were significantly increasing. High compressibility could increase drug loading by reducing excipients in manufacturing of tablets and lower the dose of Fagopyri Dibotryis Rhizoma tablets.


Assuntos
Excipientes , Rizoma , Composição de Medicamentos , Porosidade , Pós , Comprimidos
13.
Small ; 15(6): e1804272, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30637939

RESUMO

Facile design of low-cost and high-efficiency catalysts with earth-abundant and cheap materials is desirable to replace platinum (Pt) for the hydrogen evolution reaction (HER) in water splitting, but the development of such HER catalysts with Pt-like activity using simple strategies remains challenging. A mesoporous hybrid catalyst of nickel phosphides nanoparticles and cobalt phosphosulfide/phosphide (CoS|Ni|P) nanosheet arrays for HER is reported here, which is developed by a facile three-step approach consisting of electrodeposition, thermal sulfurization, and phosphorization. This hybrid catalyst is highly robust and stable in acid for HER, and is distinguished by very low overpotentials of 41, 88, and 150 mV to achieve 10, 100, and 1000 mA cm-2 , respectively, as well as a small Tafel slope (45.2 mV dec-1 ), and a large exchange current density (964 µA cm-2 ). It is among the most efficient earth-abundant catalysts reported thus far for HER. More importantly, this electrocatalyst has electrochemical durability over 20 h under a wide range of current densities (up to 1 A cm-2 ) in acidic conditions, as well as very high turnover frequencies of 0.40 and 1.26 H2 s-1 at overpotentials of 75 and 100 mV, respectively, showing that it has great potential for practical applications in large-scale water electrolysis.

14.
Bioorg Med Chem Lett ; 29(19): 126577, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421967

RESUMO

Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, has been recognized as an attractive candidate target for the treatment targeting gene transcription in several types of cancers. In this study, two types of novel compounds were designed, synthesized and evaluated as BRD4 inhibitors. Therein, pyridone derivatives were more effective against BRD4 protein and human leukemia cell lines MV4-11. Among them, compounds 11d, 11e and 11f were the most potential ones with IC50 values of 0.55 µM, 0.86 µM and 0.80 µM against BRD4, and exhibited remarkable antiproliferative activities against MV4-11 cells with IC50 values of 0.19 µM, 0.32 µM and 0.12 µM, respectively. Moreover, in western blot assay, compound 11e induced down-regulation of C-Myc, which is a significant downstream gene of BRD4. Cell cycle analysis assay also showed that compound 11e could block MV4-11 cells at G0/G1 phase. Taken together, our results suggested that compound 11e and its derivatives were a class of novel structural potential BRD4 inhibitors and could serve as lead compounds for further exploration.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Fármacos , Isoxazóis/química , Leucemia/tratamento farmacológico , Piridonas/química , Fatores de Transcrição/antagonistas & inibidores , Ciclo Celular , Humanos , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Células Tumorais Cultivadas
15.
Bioorg Med Chem Lett ; 29(17): 2511-2515, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353295

RESUMO

New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation.


Assuntos
Antituberculosos/química , Oxazóis/química , Animais , Antituberculosos/síntese química , Antituberculosos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Permeabilidade/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade , Células Vero
16.
Pharmazie ; 74(6): 321-325, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31138367

RESUMO

The non-structural protein 4B (NS4B) of hepatitis C virus (HCV) has emerged as a promising target for chronic hepatitis C treatment. The thieno[2,3-b]pyridine HCV inhibitor 2 has demonstrated properties as a NS4B inhibitor. Subsequent hybridization of 2 with our recently published imidazo[2,1-b]thiazole NS4B inhibitor 3 resulted in the discovery of several more potent compounds with sub-micromolar EC50 against HCV genotype 1b replicon. More importantly, the resistant profile study of the new synthesized HCV inhibitors illustrated that the bicyclic scaffold would mediate the resistance of H3R and Q26R mutations, while the piperazinone motif would mediate the resistance of H94R, F98C and V105M mutations, and the C3- amino group would disrupt the interaction between piperazinone motif and NS4B. This structure-resistance relationship detail could help us to develop new NS4B inhibitors with higher resistant barrier in the future.


Assuntos
Antivirais/química , Piridinas/química , Piridinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Hepacivirus , Humanos , Replicação Viral/efeitos dos fármacos
17.
Artigo em Inglês | MEDLINE | ID: mdl-29686156

RESUMO

Tuberculosis is a major global health problem, and the emergence of multidrug-resistant and extensively drug-resistant strains has increased the difficulty of treating this disease. Among the novel antituberculosis drugs in the pipeline, decaprenylphosphoryl-beta-d-ribose-2-epimerase (DprE1) inhibitors such as BTZ043 and pBTZ169 exhibited extraordinary antituberculosis potency. Here, the metabolites of the new DprE1 inhibitor SKLB-TB1001 in vivo and its inhibition of cytochrome P450 isoforms and plasma protein binding (PPB) in vitro were studied. The results showed that rapid transformation and high PPB resulted in inadequate exposure in vivo and thus led to the moderate potency of SKLB-TB1001 in vivo This study provided explanations for the discrepant potency of this scaffold in vivo and in vitro Meanwhile, it also provides a rationale for lead optimization of this very promising scaffold of antituberculosis agents to prevent them from being metabolized, thus improving their exposure in vivo.


Assuntos
Antituberculosos/farmacocinética , Proteínas de Bactérias/metabolismo , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/química , Proteínas de Bactérias/genética , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem , Tuberculose/metabolismo
18.
Langmuir ; 34(12): 3694-3700, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29509429

RESUMO

Maintaining colloidal stability in unfriendly environments while retaining surface chemical properties is challenging for fundamental science and crucial for many applications. Here, we report for the first time that by using a low concentration of poly(sodium 4-styrenesulfonate) (PSS), graphene-based amphiphilic Janus nanosheets (AJNs) can be stabilized in high salt brine (3 wt % NaCl and 0.5 wt % CaCl2), whereas the interfacial behavior of the nanosheets is not affected. The adsorption of PSS on the hydrophilic and hydrophobic surfaces of AJNs in brine was investigated experimentally and by molecular dynamics simulations. Simulations further showed that the spatial configuration of absorbed PSS molecules with sulfonate functional groups facing outward favored the generation of electrosteric repulsive interactions. Calculations of the interaction energy between PSS molecules and the nanosheet revealed surface charge as a key parameter to stabilize AJNs in the salt environment, as demonstrated by the case of graphene oxide with higher surface charge. Simulations were also used to examine the interfacial behavior of graphene-based AJNs in biphasic systems. The AJNs, which exhibited asymmetry in surface wettability, remained at the oil/brine interface because of PSS detachment from the hydrophobic surface. The results were subsequently experimentally confirmed, consistent with our previously reported graphene-based AJN fluid prepared in fresh water. The process was thermodynamically supported by the demonstrated negative change of Gibbs free energy. We believe that such a strategy could benefit for the stabilization of other AJNs with surface chemical accessibility under harsh conditions.

19.
BMC Anesthesiol ; 18(1): 6, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29329510

RESUMO

BACKGROUND: Surgical patients are asked to fast for a sufficient duration to ensure that the amount of residual liquid in the stomach is within the safe range, thereby reducing the risk of gastric reflux perioperatively. The authors hypothesized that subjective hunger numerical rating scale (NRS) score could also help assess the process of gastric emptying and determine the amount of fluid remaining in the stomach. METHODS: The current study consisted of healthy volunteers recruited by advertisement and mutual introduction. Participants were asked to rate their subjective hunger feeling every 30 min after oral administration of 8 mL/kg carbohydrate nutrient solution that contained 10% maltodextrin and 2.5% sucrose. Consecutively, the gastric residual fluid was measured by magnetic resonance imagining (MRI). The Spearman's correlation coefficient, the ROC curves and the stepwise regression were used to analyze the predictive value of NRS for the gastric emptying process. RESULTS: The cohort consisted of 29 healthy volunteers enrolled in this study. The area under ROC curves estimated by the NRS score for the gastric residual volume of 2 mL/kg, 1 mL/kg, and 0.5 mL/kg were AUC2.0 = 0.78, AUC1.0 = 0.76, and AUC0.5 = 0.72, respectively. The correlation coefficient between the NRS score and the residual liquid in the stomach was -0.57 (P < 0.01). The correlation coefficient between the increase of the NRS score and the decrease of gastric liquid residual volume was 0.46 (P < 0.01). The standardized estimate of NRS score for the residual volume was -0.18 (P < 0.01) and the standardized estimate of fasting time was -0.73 (P < 0.01). CONCLUSIONS: The subjective hunger NRS score can not accurately predict the gastric residual volume, but it can provide a reference for clinicians to judge the gastric emptying process and it should be used as a second check after oral intake of clear fluids before surgery according to the new fasting protocol.


Assuntos
Esvaziamento Gástrico/fisiologia , Voluntários Saudáveis/psicologia , Fome/fisiologia , Polissacarídeos/administração & dosagem , Sacarose/administração & dosagem , Administração Oral , Adulto , Idoso , Escala de Avaliação Comportamental/estatística & dados numéricos , Feminino , Suco Gástrico/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
20.
Zhongguo Yi Liao Qi Xie Za Zhi ; 41(3): 170-174, 2017 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-29862760

RESUMO

In order to realize the requirement of precise eye tracking in clinical, a pupil center location algorithm based on the least square method is proposed. First, the eye image was captured by the camera under the infrared light, and then the two-valued image was obtained after preprocessing. Use the number of pixels that form the outline which was Extracting from the two-valued image to carry out the rough filtration of the pupil. The ellipse curve was fitting by the randomly select 6 pixels on the filtered contours, and then calculated the variance of distance between the center and the edge of the ellipse. The ellipse center is ellipse center, where the variance of the distance is Minimum. The algorithm has advantage of accurate identification the pupil center when there is white spot interference and squint. Experiments show that the pupil center can be located quickly and real-timely by this algorithm.


Assuntos
Algoritmos , Movimentos Oculares , Pupila , Humanos , Raios Infravermelhos , Análise dos Mínimos Quadrados
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