RESUMEN
Renal tubulointerstitial fibrosis (TIF) is one of the main pathological changes induced by diabetic kidney disease (DKD), and epithelial-to-mesenchymal transition (EMT) induced by high glucose (HG) can promote TIF. Our previous study has shown that ubiquitin-specific protease 22 (USP22) could affect the process of DKD by deubiquitinating and stabilizing Sirt1 in glomerular mesangial cells. However, whether USP22 could regulate EMT occurrence in renal tubular epithelial cells and further aggravate the pathological process of TIF in DKD remains to be elucidated. In this study, we found that USP22 expression was upregulated in kidney tissues of db/db mice and HG-treated NRK-52E cells. In vitro, USP22 overexpression promoted the EMT process of NRK-52E cells stimulated by HG and further increased the levels of extracellular matrix (ECM) components such as fibronectin, Collagen I, and Collagen â £. Meanwhile, USP22 deficiency exhibited the opposite effects. Mechanism studies showed that USP22, depending on its deubiquitinase activity, deubiquitinated and stabilized the EMT transcriptional factor Snail1. In vivo experiment showed that interfering with USP22 could improve the renal pathological damages and renal function of the db/db spontaneous diabetic mice by decreasing Snail1 expression, which could inhibit EMT occurrence, and reduce the production of ECM components. These results suggested that USP22 could accelerate renal EMT and promote the pathological progression of diabetic TIF by deubiquitinating Snail1, providing an experimental basis for using USP22 as a potential target for DKD.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Factores de Transcripción de la Familia Snail , Ubiquitina Tiolesterasa , Animales , Ratones , Colágeno/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/patología , Transición Epitelial-Mesenquimal , Fibrosis , Riñón , Ratas , Línea Celular , Factores de Transcripción de la Familia Snail/metabolismo , Ubiquitina Tiolesterasa/metabolismoRESUMEN
The aim of this study is to embed PANDA fiber into metal aluminum by using the ultrasonic additive manufacturing (UAM) technique. The functional sensing characteristics of the metallic structure were realized by structure design, precise positioning, and laying of the optical fiber and a tip coating (gold film) technique. The sensing characteristics of the metallic structure sensor including temperature, bending, tensile straining, and twist responses have been systematically investigated. Experimental results show that moderate sensitivity, good repeatability, and exactly linear spectral responses are obtained with -476.2pm/∘C for temperature, 1304pm/m-1 for bending, 0.6314pm/µÎµ for tensile straining, and -332.3pm/(rad/m) for twisting. Based on its simple fabrication process and multifunctional measurement, it is clearly demonstrated that the metallic matrix structure with embedded PANDA fiber produced by the UAM technique is a functional structure with capabilities to monitor the structure health conditions and mechanical operation changes in applications.
RESUMEN
A novel pressure vector sensor based on a short section of PANDA fiber with an orthogonal optical path Sagnac interferometer structure is proposed and experimentally demonstrated. The sensor structure was realized using a gold film, coated on the end of the fiber tip through the magnetron sputtering method. The birefringence-dependent interference dip is sensitive to external force. Therefore, pressure can be monitored by this sensor. The relationship between the force direction and the pressure sensitivity was studied. We embedded the sensor in aluminum, using ultrasonic consolidation technology, to investigate the application of its sensing properties in metal. Based on this, the influence of the embedding direction on the polarization characteristics of the fiber was analyzed. The experimental results showed that the sensor offered a high sensitivity of 2330 pm/(N·m) in its freeform and 780 pm/(N·m) after being embedded in aluminum. Due to its simple fabrication process, low cost, and high sensitivity, the pressure sensor described in this paper could be a competitive candidate in several pressure sensing applications.
RESUMEN
A series of novel arylpiperazine derivatives as α1A/1D-adrenergic receptors (AR) subtype selective antagonists were designed, synthesized and evaluated for their antagonistic activities towards α1-ARs (α1A, α1B, and α1D). Compounds 9, 12, 13, 15, 17, 18, 21, 22, 25 and 26 exerted strong antagonistic effects on α1A and/or α1D subtypes over α1B in vitro. SAR analysis indicated that chloride at the ortho-phenyl position for compound 17 was beneficial for the highest α1A/D-AR sub-selectivity. Moreover, molecular docking study of compound 17 with the homology-modeled α1-ARs (α1A, α1B, and α1D) structures exhibited differences of key amino resides in the docking pocket which may influence the subtype selectivity. ILE 193 of α1A was validated as the key residues for binding ligand. This work provides useful information for finding more new potential drugs in clinic in treating benign prostatic hyperplasia (BPH).
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Piperazinas/química , Piperazinas/farmacología , Receptores Adrenérgicos alfa 1/metabolismo , Humanos , Masculino , Simulación del Acoplamiento Molecular , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/metabolismo , Relación Estructura-ActividadRESUMEN
A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines (PC-3, LNCaP, and DU145) were evaluated by a CCK-8 assay. Compounds 10, 24 and 29 exhibited strong cytotoxic activities against LNCaP cells (IC50 <3µM). In addition, these compounds exhibited weak cytotoxic effects on human epithelial prostate normal cells RWPE-1. The structure-activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Piperazinas/síntesis química , Piperazinas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Neoplasias de la Próstata/patología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines (PC-3, LNCaP, and DU145) were evaluated by a CCK-8 assay. Compounds 9 and 15 exhibited strong cytotoxic activities against LNCaP cells (IC50<5 µM), and compound 8 (IC50=8.25 µM) possessed the most potent activity against DU145 cells. However, these compounds also exhibited cytotoxicity towards human epithelial prostate normal cells RWPE-1. The structure-activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data.
Asunto(s)
Piperazinas/administración & dosificación , Piperazinas/síntesis química , Neoplasias de la Próstata/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Piperazina , Piperazinas/química , Neoplasias de la Próstata/patología , Relación Estructura-ActividadRESUMEN
α1-Adrenoceptors (ARs; 1A, 1B, and 1D) have been determined to perform different prominent functions in the physiological responses of the sympathetic nervous system. A high-throughput screening assay (HTS) was set up to detect α1-AR subtype-selective agonists by a dual-luciferase reporter assay in HEK293 cells. Using the HTS assay, two novel compounds, CHE3 and CHK3, were discovered as α1-ARs agonists in α1-ARs expressed in HEK293 cells. These compounds also showed moderate/weak anti-proliferative activities against tested cancer cell lines. The HTS assay proposed in this study represents a potential method for discovering more α1-AR subtype-selective ligands.