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Jonay Poveda,Ana B Sanz,Susana Carrasco,Marta Ruiz-Ortega,Pablo Cannata-Ortiz,Maria D Sanchez-Niño,Alberto Ortiz 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-
Acute kidney injury (AKI) is characterized by tubular cell death and interstitial inflammation. TWEAK promotes experimental kidney injury and activates the transcription factor NF-κB, a key regulator of genes involved in cell survival and inflammatory response. In search of potential therapeutic targets for AKI, we compared a transcriptomics database of NF-κB-related genes from murine AKI-kidneys with a transcriptomics database of TWEAK-stimulated cultured tubular cells. Four out of twenty-four (17%) genes were significantly upregulated (false discovery rate, FDRo0.05), while nine out of twenty-four (37%) genes were significantly upregulated at FDR o0.1 in both databases. Bcl3 was the top upregulated NF-κB-related gene in experimental AKI and one of the most upregulated genes in TWEAK-stimulated tubular cells. Quantitative reverse transcription PCR (qRT-PCR), western blot and immunohistochemistry confirmed Bcl3 upregulation in both experimental conditions and localized increased Bcl3 expression to tubular cells in AKI. Transcriptomics database analysis revealed increased Bcl3 expression in numerous experimental and human kidney conditions. Furthermore, systemic TWEAK administration increased kidney Bcl3 expression. In cultured tubular cells, targeting Bcl3 by siRNA resulted in the magnification of TWEAK-induced NF-κB transcriptional activity, chemokine upregulation and Klotho downregulation, and in the sensitization to cell death induced by TWEAK/TNFα/interferon-γ. In contrast, Bcl3 overexpression decreased NF-κB transcriptional activity, inflammatory response and cell death while dampening the decrease in Klotho expression. In conclusion, Bcl3 expressed in response to TWEAK stimulation decreases TWEAK-induced inflammatory and lethal responses. Therefore, therapeutic upregulation of Bcl3 activity should be explored in kidney disease because it has advantages over chemical inhibitors of NF-κB that are known to prevent inflammatory responses but can also sensitize the cells to apoptosis.
Pleural effusion secondary to minoxidil in a peritoneal dialysis patient
Palomar, Rosa,Morales, Pedro,Sanz de Castro, Saturnino,Tasis, Ana,Rodrigo, Emilio,Piñ,era, Celestino,Ruiz, Juan Carlos,Ferná,ndez-Fresnedo, Gema,Martin de Francisco, Angel Luis,Arias, Manu Oxford University Press 2004 Nephrology, dialysis, transplantation Vol.19 No.10
New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells
Begoña Alburquerque-González,Manuel Bernabé-García,Silvia Montoro-García,Ángel Bernabé-García,Priscila Campioni Rodrigues,Javier Ruiz Sanz,Fernando F. López-Calderón,Irene Luque,Francisco José Nicolas 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-
Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors.