Lecanda, J. (Jon)
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- La Crisis Antropológica de la Innovación Científica(Universidad Nicolás Copérnico de Torun, 2014) Vargas, A.I. (Alberto Ignacio); Lecanda, J. (Jon)Proponemos que la actual crisis de innovación en la ciencia moderna radica en las limitaciones que aparecen en el método experimental cuando se ejerce al margen de la integralidad de la persona humana. La conciencia crítica de los filósofos de la ciencia del siglo XX ha puesto de manifiesto esta despersonalización de la ciencia y ha detectado los límites del método científico; sin embargo, al no encontrar alternativas de superación ha dejado a la ciencia en una situación de desesperanza. La noción de crisis a partir de la Antropología Trascendental de Leonardo Polo permite además de detectar el límite abandonarlo y abrir el conocimiento a temas de novedad irrestricta: la libertad y el amor. Tres son las distinciones que aborda este trabajo: 1) estar en crisis y la conciencia crítica, 2) la conciencia crítica desesperada y la conciencia crítica solucionadora; 3) el límite y su abandono.
- HNF1alpha upregulates the human AE2 anion exchanger gene (SLC4A2) from an alternate promoter(Elsevier, 2003) Medina, J.F. (Juan Francisco); Ciesielczyk, P. (Pawel); Raquel; Melero, S. (Saida); Prieto, J. (Jesús); Lecanda, J. (Jon)The human AE2 gene (SLC4A2) is transcribed in a widespread fashion from the upstream promoter, the resultant full-length transcript AE2a being encountered in most tissues. Moreover, alternate promoter sequences within intron 2 may drive tissue-restricted expression of variants AE2b(1) and AE2b(2), mainly in liver and kidney. AE2b(2) proximal promoter sequences are highly active in transfected liver-derived HepG2 cells and contain an HNF1 motif. Mutation-disruption of this motif dramatically decreased alternate promoter activity in HepG2 cells but not in prostate-derived PC-3 cells. Electromobility shift and supershift assays indicated that HNF1alpha from HepG2 nuclear extracts binds the HNF1 sequence. Transactivation studies in PC-3 cells showed enhanced activity of the wild-type construct upon cotransfection with an HNF1alpha expression plasmid, while activity of the HNF1-mutated construct remained unaffected. Since liver AE2 is putatively involved in the biliary secretion of bicarbonate, HNF1alpha may have a role in increasing bicarbonate secretion in response to certain stimuli.
- The day the music died. Una revaloración íntima del ocio en la juventud posmoderna(2010) Rodríguez-Sedano, A. (Alfredo); Vargas, A.I. (Alberto Ignacio); Otero, J. (J.); Sainz-de-Aja, F. (F.); Christe, I. (I.); Delgado, L. (L.); Lecanda, J. (Jon)Nowadays youth leisure is facing many challenges seeking a deep and true way to find the meaning of life and real happiness. Unfortunately most of the alternatives available push the youth to a sick leisure marked by self pleasure, and those that are willing to keep rowing upstream are forced to live a boring life and stay away from the addicting world. We would like to offer a Christian choice that could rescue the real meaning of leisure in the times with a classical thought. What would happen if today we were to meet with John Paul II and Seneca, in Piazza Navona, and over a cup of coffee chat about attractive alternatives that recover the real and transcendental leisure that makes life an exciting adventure? --------------------------- En esta ponencia se aborda el tema del ocio en la juventud contemporánea que en muchos casos está planteado en términos de evasión. A través de un diálogo entre un joven contemporáneo, Juan Pablo II y Séneca, intentamos poner de manifiesto que el cristianismo puede dar distintas soluciones al problema del ocio. También hemos utilizado el símil de Don Maclean en la canción American Pie, para darnos cuenta de que el ocio divertido y sano no ha muerto sino que está siempre ahí esperando que alguien lo reencuentre y lo vuelva a “poner de moda”. A todo esto concluimos que el ocio que propone el cristianismo no está pasado de moda y que tiene sentido en nuestra cultura actual. Con la visión cristiana el ocio trasciende convirtiéndose en una muy buena alternativa que ayuda al hombre a realizarse tanto como ser humano, como hombre. También nos hemos dado cuenta que necesitamos de jóvenes que con espíritu de sacrificio estén dispuestos a remar contracorriente dando testimonio de que es posible ser cristiano y ser verdaderamente joven y por tanto profundamente feliz.
- El paradigma neurogenómico: La libertad y las dimensiones antropológicas del paciente(Universidad Nicolás Copérnico de Torun, 2015) Vargas, A.I. (Alberto Ignacio); Lecanda, J. (Jon)La ciencia experimental introduce sistemáticamente una división entre cuerpo- mente-espíritu. La unidad antropológica está ausente en el curso de la aplicación del método. Esta crisis incrementa la incidencia de enfermedades con entidad epidémica para las que cualquier sistema sanitario es insuficiente. Un cuidado terapéutico abierto a la integración de la libertad y otras dimensiones antropológicas consigue superar las distorsiones en la comprensión del paciente generadas por un omnipresente paradigma terapéutico limitado.
- Shared apical sorting of anion exchanger isoforms AE2a, AE2b1, and AE2b2 in primary hepatocytes(Elsevier, 2004) Banales, J.M. (Jesús M.); Medina, J.F. (Juan Francisco); Melero, S. (Saida); Prieto, J. (Jesús); Aranda-Calleja, V. (Victoria); Lecanda, J. (Jon); Martinez, I. (Íñigo)AE2 (SLC4A2) is the member of the Na(+)-independent anion exchanger (AE) family putatively involved in the secretion of bicarbonate to bile. In humans, three variants of AE2 mRNA have been described: the full-length transcript AE2a (expressed from the upstream promoter in most tissues), and alternative transcripts AE2b(1) and AE2b(2) (driven from alternate promoter sequences in a tissue-restricted manner, mainly in liver and kidney). These transcripts would result in AE protein isoforms with short N-terminal differences. To ascertain their translation, functionality, and membrane sorting, we constructed expression vectors encoding each AE2 isoform fused to GFP at the C-terminus. Transfected HEK293 cells showed expression of functional GFP-tagged AE2 proteins, all three isoforms displaying comparable AE activities. Primary rat hepatocytes transfected with expression vectors and repolarized in a collagen-sandwich configuration showed a microtubule-dependent apical sorting of each AE2 isoform. This shared apical sorting is liver-cell specific, as sorting of AE2 isoforms was basolateral in control experiments on polarized kidney MDCK cells. Hepatocytic apical targeting of AE2 isoforms suggests that they all may participate in the canalicular secretion of bicarbonate to bile.
- Oral methylthioadenosine administration attenuates fibrosis and chronic liver disease progression in Mdr2-/- mice(Public Library of Science, 2010) Latasa, M.U. (María Ujué); Banales, J.M. (Jesús M.); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Gil-Puig, C. (Carmen); Avila, M.A. (Matías Antonio); Rodriguez-Ortigosa, C.M. (Carlos M.); Goñi, S. (Saioa); Recio, J.A. (Juan A.); Lotersztajn, S. (Sophie); Raquel; Prieto, J. (Jesús); Juanarena, N. (Nerea); García-Fernández-de-Barrena, M. (Maite); Mendez, M. (Miriam); Lecanda, J. (Jon); Arcelus, S. (Sara)BACKGROUND: Inflammation and fibrogenesis are directly related to chronic liver disease progression, including hepatocellular carcinoma (HCC) development. Currently there are few therapeutic options available to inhibit liver fibrosis. We have evaluated the hepatoprotective and anti-fibrotic potential of orally-administered 5'-methylthioadenosine (MTA) in Mdr2(-/-) mice, a clinically relevant model of sclerosing cholangitis and spontaneous biliary fibrosis, followed at later stages by HCC development. METHODOLOGY: MTA was administered daily by gavage to wild type and Mdr2(-/-) mice for three weeks. MTA anti-inflammatory and anti-fibrotic effects and potential mechanisms of action were examined in the liver of Mdr2(-/-) mice with ongoing fibrogenesis and in cultured liver fibrogenic cells (myofibroblasts). PRINCIPAL FINDINGS: MTA treatment reduced hepatomegaly and liver injury. α-Smooth muscle actin immunoreactivity and collagen deposition were also significantly decreased. Inflammatory infiltrate, the expression of the cytokines IL6 and Mcp-1, pro-fibrogenic factors like TGFβ2 and tenascin-C, as well as pro-fibrogenic intracellular signalling pathways were reduced by MTA in vivo. MTA inhibited the activation and proliferation of isolated myofibroblasts and down-regulated cyclin D1 gene expression at the transcriptional level. The expression of JunD, a key transcription factor in liver fibrogenesis, was also reduced by MTA in activated myofibroblasts. CONCLUSIONS/SIGNIFICANCE: Oral MTA administration was well tolerated and proved its efficacy in reducing liver inflammation and fibrosis. MTA may have multiple molecular and cellular targets. These include the inhibition of inflammatory and pro-fibrogenic cytokines, as well as the attenuation of myofibroblast activation and proliferation. Downregulation of JunD and cyclin D1 expression in myofibroblasts may be important regarding the mechanism of action of MTA. This compound could be a good candidate to be tested for the treatment of (biliary) liver fibrosis.
- VEGF elicits epithelial-mesenchymal transition (EMT) in prostate intraepithelial neoplasia (PIN)-like cells via an autocrine loop(Elsevier, 2010) Gonzalez-Moreno, O. (Óscar); Lecanda, J. (Jon); Green, J.E. (Jeffrey E.); Segura, V. (Víctor); Catena, R. (R.); Serrano-Tejero, D. (Diego); Calvo-González, A. (Alfonso)Vascular endothelial growth factor (VEGF) is overexpressed during the transition from prostate intraepithelial neoplasia (PIN) to invasive carcinoma. We have mimicked such a process in vitro using the PIN-like C3(1)/Tag-derived Pr-111 cell line, which expresses low levels of VEGF and exhibits very low tumorigenicity in vivo. Elevated expression of VEGF164 in Pr-111 cells led to a significant increase in tumorigenicity, invasiveness, proliferation rates and angiogenesis. Moreover, VEGF164 induced strong changes in cell morphology and cell transcriptome through an autocrine mechanism, with changes in TGF-beta1- and cytoskeleton-related pathways, among others. Further analysis of VEGF-overexpressing Pr-111 cells or following exogenous addition of recombinant VEGF shows acquisition of epithelial-mesenchymal transition (EMT) features, with an increased expression of mesenchymal markers, such as N-cadherin, Snail1, Snail2 (Slug) and vimentin, and a decrease in E-cadherin. Administration of VEGF led to changes in TGF-beta1 signaling, including reduction of Smad7 (TGF-beta inhibitory Smad), increase in TGF-betaR-II, and translocation of phospho-Smad3 to the nucleus. Our results suggest that increased expression of VEGF in malignant cells during the transition from PIN to invasive carcinoma leads to EMT through an autocrine loop, which would promote tumor cell invasion and motility. Therapeutic blockade of VEGF/TGF-beta1 in PIN lesions might impair not only tumor angiogenesis, but also the early dissemination of malignant cells outside the epithelial layer.
- Epithelial to mesenchymal transition and cancer stem cell phenotypes leading to liver metastasis are abrogated by the novel TGFb1-targeting peptides P17 and P144(Elsevier, 2013) Zubeldia, I.G. (Idoia G.); Bleau, A.M. (Anne-Marie); Redrado, M. (Miriam); Serrano-Tejero, D. (Diego); Agliano, A. (Alice); Gil-Puig, C. (Carmen); Vidal-Vanaclocha, F. (Fernando); Lecanda, J. (Jon); Calvo-González, A. (Alfonso)Colorectal cancer (CRC) frequently metastasizes to the liver, a phenomenon that involves the participation of transforming-growth-factor-β(1) (TGFβ(1)). Blockade of the protumorigenic effects elicited by TGFβ(1) in advanced CRC could attenuate liver metastasis. We aimed in the present study to assess the antimetastatic effect of TGFβ(1)-blocking peptides P17 and P144, and to study mechanisms responsible for this activity in a mouse model. Colon adenocarcinoma cells expressing luciferase were pretreated with TGFβ(1) (Mc38-luc(TGFβ1) cells), injected into the spleen of mice and monitored for tumor development. TGFβ(1) increased primary tumor growth and liver metastasis, whereas systemic treatment of mice with either P17 or P144 significantly reduced tumor burden (p<0.01). In metastatic nodules, mitotic/apoptotic ratio, mesenchymal traits and angiogenesis (evaluated by CD-31, as well as circulating endothelial and progenitor cells) induced by TGFβ(1) were consistently reduced following injection of peptides. In vitro experiments revealed a direct effect of TGFβ(1) in Mc38 cells, which resulted in activation of Smad2, Smad3 and Smad1/5/8, and increased invasion and transendothelial migration, whereas blockade of TGFβ(1)-signaling reverted these features. Because TGFβ(1)-mediated epithelial-mesenchymal transition (EMT) has been suggested to induce a cancer stem cell (CSC) phenotype, we analyzed the ability of this cytokine to induce tumorsphere formation and the expression of CSC markers. In TGFβ(1)-treated cells, tumorspheres were enriched in CD44 and SOX2, which were diminished in the presence of P17. Our data provide a preclinical rationale to evaluate P17 and P144 as potential therapeutic options for the treatment of metastatic CRC.