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1.
Nano Lett ; 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39241022

RESUMEN

This work presents a new strategy to achieve the growth of copper sulfide nanoclusters with high nuclearity. Through a phosphine-assisted C-S reductive cleavage approach, an intrinsically chiral [Cu4] cluster passes through a [S-Cu9] cluster and transforms into a higher-nuclearity [S-Cu36] cluster, which features a core-shell structure with a [Cu4]4+ core encapsulated by a chiral [Cu20S12] shell. Interestingly, the spiral arrangement of the bidental ligands on the surface of the [S-Cu36] cluster leads to the L-/R-enantiomeric configurations. Moreover, by utilization of [Na(THF)6]+ as a chiral adaptive counterion, [S-Cu36] can be interlocked separately, thus enabling the isolation of homochiral clusters. Theoretical calculation suggests that the configuration transition between two enantiomeric [Na(THF)6]+ species is favorable at room temperature, thereby promoting the cocrystallization of resulting chiral products. This study introduces a novel perspective on the synthesis of chiral copper sulfide nanoclusters and presents an innovative approach to achieving the chiral separation of nanoclusters.

2.
J Transl Med ; 22(1): 25, 2024 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-38183140

RESUMEN

Acute lung injury (ALI) is a complex disease with numerous causes. This review begins with a discussion of disease development from direct or indirect pulmonary insults, as well as varied pathogenesis. The heterogeneous nature of ALI is then elaborated upon, including its epidemiology, clinical manifestations, potential biomarkers, and genetic contributions. Although no medication is currently approved for this devastating illness, supportive care and pharmacological intervention for ALI treatment are summarized, followed by an assessment of the pathophysiological gap between human ALI and animal models. Lastly, current research progress on advanced nanomedicines for ALI therapeutics in preclinical and clinical settings is reviewed, demonstrating new opportunities towards developing an effective treatment for ALI.


Asunto(s)
Lesión Pulmonar Aguda , Ciencia Traslacional Biomédica , Animales , Humanos , Lesión Pulmonar Aguda/tratamiento farmacológico , Modelos Animales
3.
BMC Med ; 21(1): 336, 2023 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-37667332

RESUMEN

BACKGROUND: Colorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of sporadic colorectal cancer cases worldwide. Currently, recurrent CA can only be treated with repeated invasive polypectomies, while safe and promising pharmaceutical invention strategies are still missing due to the lack of reliable in vitro model for CA-related drug screening. METHODS: We have established a large-scale patient-derived high-risk colorectal adenoma organoid (HRCA-PDO) biobank containing 37 PDO lines derived from 33 patients and then conducted a series of high-throughput and high-content HRCA drug screening. RESULTS: We established the primary culture system with the non-WNT3a medium which highly improved the purity while maintained the viability of HRCA-PDOs. We also proved that the HRCA-PDOs replicated the histological features, cellular diversity, genetic mutations, and molecular characteristics of the primary adenomas. Especially, we identified the dysregulated stem genes including LGR5, c-Myc, and OLFM4 as the markers of adenoma, which are well preserved in HRCA-PDOs. Based on the HRCA-PDO biobank, a customized 139 compound library was applied for drug screening. Four drugs including metformin, BMS754807, panobinostat and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. As a representative, metformin was discovered to hinder HRCA-PDO growth in vitro and in vivo by restricting the stemness maintenance. CONCLUSIONS: This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.


Asunto(s)
Adenoma , Neoplasias Colorrectales , Metformina , Humanos , Bancos de Muestras Biológicas , Evaluación Preclínica de Medicamentos , Organoides , Adenoma/tratamiento farmacológico , Adenoma/genética , Neoplasias Colorrectales/tratamiento farmacológico
4.
J Nanobiotechnology ; 21(1): 457, 2023 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-38031152

RESUMEN

MicroRNA (miRNA) delivery by extracellular vesicles (EVs) has recently inspired tremendous developments in cancer treatments. However, hybridization between miRNA and its target mRNA is still difficult to be imaged in vivo to assess the therapeutic effects in time. Herein we design a nano-scale fluorescent "off-on" complex encapsulated by small extracellular vesicles (sEVs) for real-time visualization and evaluation of gene therapy efficiency in human gastric cancer cells and murine xenograft tumor models. The complex is formed by π-π stacking between graphene quantum dots (GQDs) and tumor suppressor miR-193a-3p conjugated fluorescent tag whose signals remain off when binding to GQDs. Loaded into sEVs using tunable sonication techniques, the GQDs/Cy5-miR particles enter the tumor cells and promote miR-193a-3p escape from endosomes. The miR-193a-3p in GQDs/Cy5-miR is unleashed to pair the specific target oncogene cyclin D1 (CCND1), therefore turning on the fluorescence of miRNA tags. We find out that GQDs/Cy5-miR@sEVs can activate the "turn-on" fluorescent signal and exhibit the longest retention time in vivo, which suggests a minimized degradation of miR-193a-3p in dynamic processes of miRNA-mRNA binding. More importantly, GQDs/Cy5-miR@sEVs significantly promote cancer apoptosis in vitro and in vivo via the enhanced cellular uptake. Our study demonstrates that GQDs/Cy5-miR@sEVs represent an efficient and refined theranostic platform for gene therapy in cancers.


Asunto(s)
Vesículas Extracelulares , MicroARNs , Neoplasias , Humanos , Ratones , Animales , MicroARNs/genética , MicroARNs/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Vesículas Extracelulares/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias/terapia , Neoplasias/metabolismo
5.
Oral Dis ; 29(4): 1668-1679, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-35255186

RESUMEN

Long non-coding RNAs (lncRNAs) are thought to play important roles in non-syndromic orofacial clefts (NSOFC). Clinical diagnosis was categorized as either non-syndromic cleft lip with or without cleft palate (NSCL/P), or non-syndromic cleft palate only (NSCPO). Tissues excised from the trimmed wound edge were reserved as experimental samples; adjacent normal control was used as a positive control, and tissue from healthy individuals was used as a blank control. Target lncRNAs in the collected tissues were identified using microarrays and quantitative reverse transcription PCR (RT-qPCR). Immunohistochemical (IHC) staining and RT-qPCR were used to verify the target mRNAs. Pathway, gene ontology (GO) enrichment, and TargetScan predictions were employed to construct competing endogenous RNA networks (ceRNA networks) and explore their potential functions. RNA-Seq revealed 24 upregulated and 43 downregulated lncRNAs; MALAT1 and NEAT1 were screened and validated using RT-qPCR. Common NSOFC risk factors were positively correlated with MALAT1 and NEAT1 expression. Bioinformatics predicted four ceRNA networks; GO enrichment focused on their potential functions. RT-qPCR and IHC data were consistent with respect to expression levels of proteins and the mRNAs that encode them. As MALAT1 and NEAT1 are associated with the severity of NSOFC, they represent potential therapeutic targets and prognostic biomarkers.


Asunto(s)
Labio Leporino , Fisura del Paladar , MicroARNs , ARN Largo no Codificante , Humanos , Labio Leporino/genética , Fisura del Paladar/genética , ARN Largo no Codificante/genética , Factores de Riesgo , MicroARNs/genética
6.
Molecules ; 28(12)2023 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-37375185

RESUMEN

The sensitive and accurate determination of glyphosate (Glyp) is urgently demanded because it is closely correlated with human health and environmental safety. In this work, we proposed a sensitive and convenient colorimetric assay by employing copper ion peroxidases for the detection of Glyp in the environment. Free Cu(II) ions displayed high peroxidase activity and can catalytically oxidize the colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxTMB, resulting in an obviously visible discoloration reaction. Once the Glyp is added, the ability of copper ions to mimic peroxidase can be largely suppressed because of the generation of Glyp-Cu2+ chelate. The favorable selectivity and sensitivity were demonstrated in the colorimetric analysis of Glyp. Furthermore, this rapid and sensitive method was successfully applied in the accurate and reliable determination of glyphosate in the real sample, holding promising applications in pesticide determination in the environment.


Asunto(s)
Colorimetría , Peroxidasa , Humanos , Colorimetría/métodos , Cobre/análisis , Oxidorreductasas , Peroxidasas , Iones , Peróxido de Hidrógeno , Glifosato
7.
New Phytol ; 234(2): 422-434, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35048364

RESUMEN

Root anatomical traits play crucial roles in understanding root functions and root form-function linkages. However, the root anatomy and form-function linkages of monocotyledonous and dicotyledonous herbs remain largely unknown. We measured order-based anatomical traits and mycorrhizal colonization rates of 32 perennial herbs of monocotyledons and dicotyledons in a temperate steppe. For monocots, relative constant proportion of cortex and mycorrhizal colonization rates, but increased cell-wall thickening of the endodermis and proportion of stele were observed across root orders, indicating a slight reduction in absorption capacity and improvement in transportation capacity across orders. For dicots, the cortex and mycorrhizal colonization disappeared in the fourth-order and/or fifth-order roots, whereas the secondary vascular tissue increased markedly, suggesting significant transition of root functions from absorption to transportation across root orders. The allometric relationships between stele and cortex differed across root orders and plant groups, suggesting different strategies to coordinate the absorption and transportation functions among plant groups. In summary, our results revealed different functional transition patterns across root orders and distinct strategies for coordinating the absorption and transportation of root system between monocots and dicots. These findings will contribute to our understanding of the root form and functions in herbaceous species.


Asunto(s)
Magnoliopsida , Micorrizas , Magnoliopsida/anatomía & histología , Fenotipo , Raíces de Plantas/anatomía & histología , Plantas
8.
J Xray Sci Technol ; 30(2): 343-364, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35095013

RESUMEN

In computed tomography (CT) image reconstruction problems, exterior CT is an important application in industrial non-destructive testing (NDT). Different from the limited-angle problem that misses part of the rotation angle, the rotation angle of the exterior problem is complete, but for each rotation angle, the projection data through the central region of the object cannot be collected, so that the exterior CT problem is ill-posed inverse problem. The results of traditional reconstruction methods like filtered back-projection (FBP) and simultaneous algebra reconstruction technique (SART) have artifacts along the radial direction edges for exterior CT reconstruction. In this study, we propose and test an anisotropic relative total variation in polar coordinates (P-ARTV) model for addressing the exterior CT problem. Since relative total variation (RTV) can effectively distinguish edges from noises, and P-ARTV with different weights in radial and tangential directions can effectively enhance radial edges, a two-step iteration algorithm was developed to solve the P-ARTV model in this study. The fidelity term and the regularization term are solved in Cartesian and polar coordinate systems, respectively. Numerical experiments show that our new model yields better performance than the existing state-of-the-art algorithms.


Asunto(s)
Procesamiento de Imagen Asistido por Computador , Tomografía Computarizada por Rayos X , Algoritmos , Artefactos , Procesamiento de Imagen Asistido por Computador/métodos , Fantasmas de Imagen , Tomografía Computarizada por Rayos X/métodos
9.
New Phytol ; 229(3): 1481-1491, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32645210

RESUMEN

Root anatomy plays important roles in the control of leaf water relations. However, few studies have evaluated whether and how anatomical traits of absorptive roots influence leaf physiology of herbaceous species in a temperate grassland. We measured absorptive root anatomical traits and leaf physiological traits of 15 herbaceous species in a temperate steppe and monitored their responses to increased precipitation in a field stimulating experiment. Root anatomical and leaf physiological traits differed among monocotyledonous grasses, monocotyledonous liliaceous species and dicotyledonous forbs. The species with higher stele: root diameter, lower root diameter and cortex thickness exhibited higher transpiration rates and stomatal conductance, but lower intrinsic water-use efficiency. Increased precipitation enhanced transpiration and stomatal conductance of forbs and lilies, but it enhanced photosynthesis in lilies exclusively. The sensitive response of lilies to precipitation may be related to their large root diameter and cortex thickness. In summary, we observed distinct differences in anatomical traits of absorptive roots among plant groups in temperate steppes. These differences drove variations in leaf physiological traits and their diverse responses to precipitation change. These findings highlight the important roles of root anatomical traits in driving leaf-level physiological processes in temperate grasslands.


Asunto(s)
Magnoliopsida , Hojas de la Planta , Fotosíntesis , Plantas , Poaceae
10.
Langmuir ; 37(19): 5776-5782, 2021 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-33966385

RESUMEN

Nonspecific protein adsorption-resistant materials, the so-called nonfouling materials, are crucial biomaterials in biomedical applications. Up-to-date, little attention was paid to the biodegradability of these materials. In this work, nonfouling zwitterionic copolymerized peptides composed of the N-l-glumatyl-l-lysine dimer (EK) and δ-l-lysinyl-l-glutamic acid dimer (E-K, glutamic acid with the lysine side chain) at various ratios were synthesized to investigate the enzymatic degradation rate. Two types of proteases (trypsin and alkaline protease), which represent a site-specific and less site-specific cleavage protease, respectively, were used to demonstrate the adjustable degradability by tracking the molecular weight (Mw) at different digestion times. Results showed that higher compositions of the E-K dimer lead to slower degradation rates by both proteases and larger fragments after 120 min digestion. With the composition of the E-K dimer over 50%, the degradation of copolymerized peptides by both proteases becomes very slow. This indicated that the bulky lysinyl side chain on E-K can alter the enzymolysis process for adjusting the enzymatic degradability of the newly synthesized zwitterionic copolymerized peptides, which could be promising candidates for biomedical applications in vivo.


Asunto(s)
Ácido Glutámico , Lisina , Péptidos , Polímeros , Tripsina
11.
BMC Cancer ; 20(1): 815, 2020 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-32854652

RESUMEN

BACKGROUND: Trophoblast cell surface antigen 2 (TROP2) is overexpressed in many squamous cell carcinomas and promotes tumor development and invasion. The association between TROP2 expression and occurrence and development of oral squamous cell carcinoma (OSCC) remains to be understood. METHODS: We investigated the role of TROP2 in OSCC patients using a combination of biophysical approaches. A total of 108 OSCC patient specimens with varying degrees of differentiation were subjected to hematoxylin and eosin staining, immunohistochemistry, Kaplan-Meier survival curve analysis, and atomic force microscopy to analyze TROP2 expression, morphology, and mechanical properties of OSCC tissues. RESULTS: TROP2 was overexpressed in 34% of poorly differentiated OSCC samples. High levels of TROP2 were associated with 10.2% survival rate lower than 45.4% and patient age (odds ratio [OR] = 0.437, P = 0.039, 95% confidence interval [CI, 0.198-0.966]), tumor size (OR = 13.148, P = 0.000, 95% CI [5.060-34.168]), and TNM stage (OR = 0.141, P = 0.000, 95% CI [0.082-0.244]). Average surface roughness of low, medium, and highly differentiated OSCC tissues were 448.9 ± 54.8, 792.7 ± 83.6, and 993.0 ± 104.3 nm, respectively. The Pearson coefficient revealed a negative association between tumor stiffness and TROP2 expression (r = - 0.84, P < 0.01). CONCLUSION: Overexpression of TROP2 negatively associated with patient survival, degree of tumor differentiation, and tissue mechanics. Taken together, our findings demonstrated that TROP2 may be an indicator of OSCC differentiation leading to the altered mechanical properties of OSCC tissues.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/metabolismo , Diferenciación Celular , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Estadificación de Neoplasias , Pronóstico , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Tasa de Supervivencia , Carga Tumoral
12.
BMC Med Educ ; 20(1): 272, 2020 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-32811485

RESUMEN

BACKGROUND: This research aims to investigate the evaluation methods of teaching oral implant clinical courses and estimate the effectiveness of a virtual simulation platform. METHODS: Eighty second- and third-year undergraduates in Lanzhou University were recruited and randomized to either three experimental groups or one control group. The subjects undertook theoretical examinations to test their basic level of knowledge after training in similarly unified knowledge courses. Each student group then participated in an eight-hour operating training session. An operation test on pig mandible was conducted, followed by a second theoretical examination. The assessment consists of three distinct parts: a subjective operating score by a clinical senior teacher, an implant accuracy analysis in cone-beam computed tomography (angular, apical, and entrance deviation), and comparison of the two theoretical examinations. Finally, students completed a questionnaire gauging their understanding of the virtual simulation. RESULTS: There was no significant difference between the four groups in first theoretical examination (P > 0.05); the second theoretical scores of the V-J and J-V group (62.90 ± 3.70, 60.05 ± 2.73) were significantly higher than the first time (57.05 ± 3.92, P < 0.05), while no difference between the V (57.10 ± 3.66) and J (56.89 ± 2.67) groups was found. Thus, the combination of V-J was effective in improving students' theoretical scores. The V-J and J-V groups had higher scores on operation (73.98 ± 4.58, 71.85 ± 4.67) and showed better implant precision. CONCLUSION: Virtual simulation education, especially with a jaw simulation model, could improve students' implantology achievements and training. Currently study found that the V-J group may performed better than the J-V group in oral implant teaching.


Asunto(s)
Competencia Clínica , Evaluación Educacional , Animales , Simulación por Computador , Escolaridad , Humanos , Estudiantes , Porcinos
14.
J Xray Sci Technol ; 26(3): 481-498, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29562578

RESUMEN

PURPOSES: Restricted by the scanning environment in some CT imaging modalities, the acquired projection data are usually incomplete, which may lead to a limited-angle reconstruction problem. Thus, image quality usually suffers from the slope artifacts. The objective of this study is to first investigate the distorted domains of the reconstructed images which encounter the slope artifacts and then present a new iterative reconstruction method to address the limited-angle X-ray CT reconstruction problem. METHODS: The presented framework of new method exploits the structural similarity between the prior image and the reconstructed image aiming to compensate the distorted edges. Specifically, the new method utilizes l0 regularization and wavelet tight framelets to suppress the slope artifacts and pursue the sparsity. New method includes following 4 steps to (1) address the data fidelity using SART; (2) compensate for the slope artifacts due to the missed projection data using the prior image and modified nonlocal means (PNLM); (3) utilize l0 regularization to suppress the slope artifacts and pursue the sparsity of wavelet coefficients of the transformed image by using iterative hard thresholding (l0W); and (4) apply an inverse wavelet transform to reconstruct image. In summary, this method is referred to as "l0W-PNLM". RESULTS: Numerical implementations showed that the presented l0W-PNLM was superior to suppress the slope artifacts while preserving the edges of some features as compared to the commercial and other popular investigative algorithms. When the image to be reconstructed is inconsistent with the prior image, the new method can avoid or minimize the distorted edges in the reconstructed images. Quantitative assessments also showed that applying the new method obtained the highest image quality comparing to the existing algorithms. CONCLUSIONS: This study demonstrated that the presented l0W-PNLM yielded higher image quality due to a number of unique characteristics, which include that (1) it utilizes the structural similarity between the reconstructed image and prior image to modify the distorted edges by slope artifacts; (2) it adopts wavelet tight frames to obtain the first and high derivative in several directions and levels; and (3) it takes advantage of l0 regularization to promote the sparsity of wavelet coefficients, which is effective for the inhibition of the slope artifacts. Therefore, the new method can address the limited-angle CT reconstruction problem effectively and have practical significance.


Asunto(s)
Algoritmos , Procesamiento de Imagen Asistido por Computador/métodos , Tomografía Computarizada por Rayos X , Artefactos , Simulación por Computador , Humanos , Procesamiento de Imagen Asistido por Computador/instrumentación , Fantasmas de Imagen , Relación Señal-Ruido , Tórax/diagnóstico por imagen , Tomografía Computarizada por Rayos X/instrumentación , Análisis de Ondículas
15.
J Cardiovasc Pharmacol ; 67(6): 465-73, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26657715

RESUMEN

As one of the main risk factors for cardiovascular diseases, ageing plays an important role in the alterations of vascular structure and function. Early vascular ageing refers to a condition in patients with impaired endothelial function and increased arterial stiffness that can be assessed before the overt clinical manifestations, such as hypertension and atherosclerosis. Both epidemiological and experimental data indicate that the biological age of endothelial cells in patients with cardiovascular diseases is older than their chronological age. In fact, endothelial senescence is present at the early stage of vascular ageing and contributes to the development of endothelial dysfunction and arterial stiffness. Sirtuin 1 (SIRT1), the mammalian ortholog of yeast longevity regulator Sir2, is a nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase that elicits a variety of vasoprotective functions. Overexpression of SIRT1 in endothelium prevents cellular senescence, enhances vasodilatory responses, and attenuates ageing-induced vascular damages. The present review summarizes the recent progresses related to SIRT1-mediated beneficial effects on the prevention of early vascular ageing and discusses the potential of SIRT1 in endothelial cells as an antivascular ageing target.


Asunto(s)
Envejecimiento/metabolismo , Células Endoteliales/metabolismo , Sirtuina 1/biosíntesis , Animales , Arterias/metabolismo , Aterosclerosis/fisiopatología , Senescencia Celular/fisiología , Humanos , Rigidez Vascular/fisiología
17.
ScientificWorldJournal ; 2015: 125736, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26495414

RESUMEN

Mars500 study was a psychological and physiological isolation experiment conducted by Russia, the European Space Agency, and China, in preparation for an unspecified future manned spaceflight to the planet Mars. Its intention was to yield valuable psychological and medical data on the effects of the planned long-term deep space mission. In this paper, we present data mining methods to mine medical data collected from the crew consisting of six spaceman volunteers. The synthesis of the four diagnostic methods of TCM, inspection, listening, inquiry, and palpation, is used in our syndrome differentiation. We adopt statistics method to describe the syndrome factor regular pattern of spaceman volunteers. Hybrid optimization based multilabel (HOML) is used as feature selection method and multilabel k-nearest neighbors (ML-KNN) is applied. According to the syndrome factor statistical result, we find that qi deficiency is a base syndrome pattern throughout the entire experiment process and, at the same time, there are different associated syndromes such as liver depression, spleen deficiency, dampness stagnancy, and yin deficiency, due to differences of individual situation. With feature selection, we screen out ten key factors which are essential to syndrome differentiation in TCM. The average precision of multilabel classification model reaches 80%.


Asunto(s)
Medicina Tradicional China , Nave Espacial , Algoritmos , Humanos , Modelos Biológicos , Síndrome
18.
Acta Pharmacol Sin ; 35(8): 1082-92, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25047514

RESUMEN

AIM: Aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). METHODS: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. RESULTS: The Z' value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 µmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 µmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein. CONCLUSION: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.


Asunto(s)
Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales/métodos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Aromatasa/química , Aromatasa/metabolismo , Mama/efectos de los fármacos , Mama/enzimología , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Flavonoides/química , Flavonoides/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Simulación del Acoplamiento Molecular , Quinolinas/química , Quinolinas/farmacología , Espectrometría de Fluorescencia/métodos
19.
Front Microbiol ; 15: 1348027, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38601930

RESUMEN

Background: Previous studies have suggested that the gut microbiota (GM) is closely associated with the development of autoimmune cholestatic liver disease (ACLD), but limitations, such as the presence of confounding factors, have resulted in a causal relationship between the gut microbiota and autoimmune cholestatic liver disease that remains uncertain. Thus, we used two-sample Mendelian randomization as a research method to explore the causal relationship between the two. Methods: Pooled statistics of gut microbiota from a meta-analysis of genome-wide association studies conducted by the MiBioGen consortium were used as an instrumental variable for exposure factors. The Pooled statistics for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) were obtained from the R9 version of the FinnGen database (https://r9.finngen.fi/). Inverse-variance Weighted (IVW), cML-MA, MR-Egger regression, Weighted median (WME), Weighted mode (WM), and Simple mode (SM) were used to detect the association between intestinal flora and the causal relationship between intestinal flora and ACLD, in which IVW method was dominant, was assessed based on the effect indicator dominance ratio (odds ratio, OR) and 95% confidence interval (CI). Sensitivity analysis, heterogeneity test, gene pleiotropy test, MR pleiotropy residual sum and outlier test (MR-PRESSO) were combined to verify the stability and reliability of the results. Reverse Mendelian randomization analysis was performed on gut microbiota and found to be causally associated with ACLD. Results: The IVW results showed that the relative abundance of the genus Clostridium innocuum group, genus Butyricicoccus, and genus Erysipelatoclostridium was negatively correlated with the risk of PBC, that is, increased abundance reduced the risk of PBC and was a protective, and the relative abundance of the genus Eubacterium hallii was positively correlated with the risk of PSC, which is a risk factor for PSC. Family Clostridiaceae1 and family Lachnospiraceae were negatively correlated with the risk of PSC, which is a protective factor for PSC. Conclusion: This study found a causal relationship between gut microbiota and ACLD. This may provide valuable insights into gut microbiota-mediated pathogenesis of ACLD. It is necessary to conduct a large-sample randomized controlled trial (RCT) at a later stage to validate the associated role of the relevant gut microbiota in the risk of ACLD development and to explore the associated mechanisms.

20.
ACS Appl Mater Interfaces ; 16(1): 1225-1233, 2024 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-38112452

RESUMEN

Constructing high-performance solution-processed organic light-emitting diodes (OLEDs) based on thermally activated delayed fluorescence (TADF) conjugated polymers remains a challenging issue. The electron-withdrawing ability of acceptors in TADF units significantly affects the TADF properties of the conjugated polymers. Herein, we have designed three TADF conjugated polymers, in which phenoxazine donors and anthracen-9(10H)-one acceptors are incorporated into the polymeric backbones and side chains, respectively, and the carbazole derivative is copolymerized as the host. By incorporating different heteroatoms, such as nitrogen, oxygen, or sulfur, with slightly different electronegativities into anthracen-9(10H)-one, the effect of the electron-withdrawing ability of the acceptor on the performance of conjugated TADF polymer-based OLEDs is thus systematically studied. It is found that the introduction of a nitrogen atom can enhance the spin-orbital coupling and RISC process due to the modulated energy levels and nature of the excited states. As a result, the solution-processed OLEDs based on the prepared polymer p-PXZ-XN display an excellent comprehensive performance with an EQEmax of 17.6%, a low turn-on voltage of 2.8 V, and a maximum brightness of 14750 cd m-2. Notably, the efficiency roll-off is quite low, maintaining 15.1% at 1000 cd m-2, 12.1% at 3000 cd m-2, and 6.1% at 10000 cd m-2, which ranks in the first tier among the reported TADF conjugated polymers. This work provides a guideline for constructing high-efficiency TADF polymers.

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