Papel de las células madre de la médula ósea en hepatología: estudios in vivo e in vitro

El hígado es el único órgano capaz de desencadenar un proceso regenerativo tras sufrir un daño o lesión restableciendo así su funcionalidad tisular. La regeneración hepática es un proceso complejo en el que interaccionan todos los componentes celulares del hígado con distintos elementos reguladores permitiendo la activación de diversas cascadas de señalización intracelular que activan la división celular en el parénquima hepático. En los últimos años, se ha postulado la posible participación de las células madre adultas de médula ósea (BM-SC) en la regeneración hepática tras una insuficiencia hepática. La bibliografía ha demostrado ampliamente la capacidad de diferenciación de las BM-SC hacia células semejantes a hepatocitos. Sin embargo, se desconoce cuáles son los mecanismos de señalización que podrían regular este proceso de diferenciación. La ruta Wnt/ß-catenina juega un papel fundamental en el destino final que alcanzan las BM-SC, y podría ser clave una inactivación de esta ruta para la obtener la diferenciación final a hepatocitos funcionales. Sin embargo, la translocación nuclear de ß-catenina ha sido también relacionada con el desarrollo de procesos tumorales como el carcinoma hepatocelular o el hepatoblastoma. Pese al elevado número de publicaciones en torno al papel de las BM-SC durante la regeneración hepática aún es desconocido el grado de implicación de estas células con el proceso regenerativo en el hígado. Se ha postulado que inmediatamente después de producirse un daño en el parénquima hepático se desencadenaría diversos mecanismos de señalización que liberarían a las BM-SC desde su reservorio en la médula ósea (MO) hasta el torrente sanguíneo a través del cuál alcanzarían el hígado. Este proceso migratorio se conoce como ¿Mobilización celular¿ y se sabe que está estrictamente regulada por el eje SDF-1/CXCR-4. Pese a todo, se desconoce cuál podría ser la señal que dispare este proceso. Se ha propuesto a la resección hepática o la patología subyacente como elementos clave para activar los procesos de mobilización aunque en este sentido la bibliografía es contradictoria. Por otro lado, en la actualidad han surgido numerosas estrategias para mejorar a través del uso de distintos tipos de células madre la enfermedad hepática. Estas células madre han sido infundidas en varios modelos experimentales de daño hepático. Los resultados obtenidos ponen de manifiesto que las BM-SC tras alojarse en el hígado podrían ser capaces de diferenciarse a hepatocitos funcionales. No obstante, existen indicios para pensar que el efecto de las BM-SC no es directo, sino través de mecanismos de señalización paracrinos. De hecho, recientemente se han conseguido restaurar la funcionalidad hepática tras la infusión de un concentrado de medio de cultivo de MSC, que es rico en factores secretados por esta población

Residual stresses in Al2O3-ZrO2 multilayered ceramics: nature, evaluation and influence on the structural integrity

[ES] El presente trabajo comprende el diseño y procesamiento por colaje de suspensiones de sistemas multicapa basados en capas gruesas de alúmina y capas finas de alúmina-circona. Durante el enfriamiento desde la temperatura de sinterización se generan tensiones residuales en las capas debido a la expansión asociada a la transformación martensítica de la circona. En esta investigación se estudian los parámetros de procesamiento para la fabricación de estos sistemas laminados y se caracterizan microestructuralmente las capas que lo componen. Como resultado se obtienen multicapas cerámicas con diferente relación de espesores entre capas adyacentes utilizando como método de control las cinéticas de colaje de los correspondientes monolíticos. Adicionalmente, se determinan analíticamente las tensiones residuales generadas en los laminados por medio de las diferencias volumétricas determinadas en ensayos dilatométricos y del módulo elástico de cada capa. Se encuentra que en las capas delgadas se desarrollan elevadas tensiones de compresión mientras que en las gruesas se inducen tensiones residuales de tracción. El efecto de estas tensiones sobre la integridad mecánica del material se discute en términos de las observaciones de fenómenos de fisuración intrínseca: tanto de grietas de borde o “edge cracks” en la superficie libre de las capas delgadas como de fisuras túnel o “tunneling cracks” en las capas gruesas.[EN] This work studies the design and processing by slip casting of multilayered systems based on thick alumina and thin aluminazirconia layers. During cooling from the sintering temperature residual stresses may arise due to expansion associated to the martensitic transformation of the zirconia. In this investigation, the processing parameters involved in the fabrication of theses layered systems are studied and the respective layers microstructurally characterized. As a result, several multilayered ceramics in terms of thickness ratio between adjacent layers are obtained by means of the casting kinetics of the corresponding monoliths. Additionally, the residual stresses generated in the laminates are analytically determined through the difference in shrinkage assessed with dilatometric tests and the elastic modulus corresponding to each layer. It is found that in the thin layers elevated residual compressive stresses are generated whilst in the thick ones tensile residual stresses are induced. The effect of these stresses on the mechanical integrity of the material is discussed in terms of the observations of intrinsic cracking phenomena: both edge cracks at the free surface of the thin layers and tunneling cracks in the thick layers.El presente trabajo ha sido financiado por el Ministerio de Ciencia y Tecnología (MCYT) en el marco del proyecto Nº MAT2002-00368, así como por el programa de la Comunidad Europea bajo el contrato HPRN-CT-2002-00203, [SICMAC].Peer reviewe

El juego tradicional: ¿puente entre culturas? De lo posible a la realidad

Los juegos tradicionales dentro de una sociedad cumplen una función de enculturación, conservan y transmiten los valores profundos de la cultura popular, proporcionan una actividad motriz acorde con las características de sus practicantes, propician y facilitan las relaciones sociales entre los miembros de una misma generación y entre los de diferentes generaciones, y ayudan a conservar tradiciones de transmisión oral y el patrimonio lúdico, siendo considerados elementos de la cultura. El artículo se centra en las percepciones que los docentes tienen acerca de del juego tradicional como puente entre culturas para abordar la diversidad cultural existente en las aulas. Es por ello que el artículo se subtitula ‘de lo posible a la realidad’. Se abordará desde una investigación realizada a partir de tres grupos de discusión con maestros de entornos urbanos, de la periferia y rurales respectivamente, llevada a cabo en Granada con docentes de centros públicos y privados, y con contextos diferentes (marginales y normalizados). Se concluye con que existe un sentimiento de falta de preparación para abordar el tratamiento de la diversidad cultural y que en general hay una falta de sensibilidad hacia la pérdida de tradiciones de transmisión oral y vivencial ya que si bien se plantea con insistencia que hay que recuperar los juegos tradicionales, no hay ninguna alusión a los aspectos culturales que conllevan los mismo

Procaine Inhibits Osteo/Odontogenesis through Wnt/β-Catenin Inactivation

Introduction Periodontitis is a complex pathology characterized by the loss of alveolar bone. The causes and the mechanisms that promote this bone resorption still remain unknown. The knowledge of the critical regulators involved in the alteration of alveolar bone homeostasis is of great importance for developing molecular therapies. Procaine is an anesthetic drug with demethylant properties, mainly used by dentists in oral surgeries. The inhibitor role of Wnt signaling of procaine was described in vitro in colon cancer cells. Methods In this work we evaluated the role of procaine (1 uM) in osteo/odontogenesis of rat bone marrow mesenchymal stem cells. Similarly, the mechanisms whereby procaine achieves these effects were also studied. Results Procaine administration led to a drastic decrease of calcium content, alkaline phosphatase activity, alizarin red staining and an increase in the expression of Matrix Gla Protein. With respect to osteo/odontogenic markers, procaine decreased early and mature osteo/odontogenic markers. In parallel, procaine inhibited canonical Wnt/β-catenin pathway, observing a loss of nuclear β-catenin, a decrease in Lrp5 and Frizzled 3, a significant increase of sclerostin and Gsk3β and an increase of phosphorylated β-catenin. The combination of osteo/ odontogenic stimuli and Lithium Chloride decreased mRNA expression of Gsk3β, recovered by Procaine. Furthermore it was proved that Procaine alone dose dependently increases the expression of Gsk3β and β-catenin phosphorylation. These effects of procaine were also observed on mature osteoblast. Interestingly, at this concentration of procaine no demethylant effects were observed. PLO

Pathogenic pathways and therapeutic approaches targeting inflammation in diabetic nephropathy

Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several antiinflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.The authors work has been supported by grants from Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130, PI17/01495, PI19/00588, ERA-PerMed-JTC2018-PERSTIGAN AC18/00071), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and Cardiovascular (CIBERCV), Fondecyt Project (No. 1160465), Spanish Ministry of Science and Innovation (RTI2018-098788-B-100, DTS17/00203, DTS19/00093, RYC-2017-22369), and Spanish Societies of Cardiology (SEC), Nephrology (SEN) and Atherosclerosis (SEA). The “PFIS” and “Sara Borrell” training program of the ISCIII supported the salary of MGH (FI18/00310), SR-M (CD19/00021) and CH-B (CP16/00017). Córdoba University supported the salary of C.G.C

Nuclear Translocation of b-Catenin during Mesenchymal Stem Cells Differentiation into Hepatocytes Is Associated with a Tumoral Phenotype

Wnt/b-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated the role of Wnt/b-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, b-catenin nuclear translocation, up-regulation of genes related to the Wnt/b-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/b-catenin inactivation. Hepatocytes with nuclear translocation of b-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase b-chain were up-regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin b-chain were downregulated in this protocol. In conclusion, our results suggest that activation of the Wnt/b-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotyp

Toll-like receptors in acute kidney injury

Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent AKI bouts, cardiovascular events, and chronic kidney disease. However, there are no specific treatments to decrease the adverse consequences of AKI. Epidemiological and preclinical studies show the pathological role of inflammation in AKI, not only at the acute phase but also in the progression to chronic kidney disease. Toll-like receptors (TLRs) are key regulators of the inflammatory response and have been associated to many cellular processes activated during AKI. For that reason, a number of anti-inflammatory agents targeting TLRs have been analyzed in preclinical studies to decrease renal damage during AKI. In this review, we updated recent knowledge about the role of TLRs, mainly TLR4, in the initiation and development of AKI as well as novel compounds targeting these molecules to diminish kidney injury associated to this pathological conditionThe authors work has been supported by grants from Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130, PI17/01495, PI20/00375, PI20/00487), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and Cardiovascular (CIBERCV), Spanish Ministry of Science and Innovation (RTI2018-099114-B-100, RTI2018-098788-B-100, DTS19/00093, RYC-2017-22369), and Spanish Societies of Cardiology (SEC), Nephrology (SEN) and Atherosclerosis (SEA). The “PFIS” and “Sara Borrell” training program of the ISCIII supported the salary of MGH (FI18/00310), SR-M (CD19/00021) and CH-B (CP16/00017). Córdoba University supported the salary of C.G.C

In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/β-catenin activation

The present study investigates the differential effect of two vitamin D receptor agonists, calcitriol and paricalcitol, on human aortic smooth muscle cells calcification in vitro. Human vascular smooth muscle cells were incubated in a high phosphate (HP) medium alone or supplemented with either calcitriol 10−8M (HP + CTR) or paricalcitol 3·10−8 M (HP + PC). HP medium induced calcification, which was associated with the upregulation of mRNA expression of osteogenic factors such as bone morphogenetic protein 2 (BMP2), Runx2/Cbfa1, Msx2, and osteocalcin. In these cells, activation of Wnt/β-catenin signaling was evidenced by the translocation of β-catenin into the nucleus and the increase in the expression of direct target genes as cyclin D1, axin 2, and VCAN/versican. Addition of calcitriol to HP medium (HP + CTR) further increased calcification and also enhanced the expression of osteogenic factors together with a significant elevation of nuclear β-catenin levels and the expression of cyclin D1, axin 2, and VCAN. By contrast, the addition of paricalcitol (HP + PC) not only reduced calcification but also downregulated the expression of BMP2 and other osteoblastic phenotype markers as well as the levels of nuclear β-catenin and the expression of its target genes. The role of Wnt/β-catenin on phosphate- and calcitriol-induced calcification was further demonstrated by the inhibition of calcification after addition of Dickkopf-related protein 1 (DKK-1), a specific natural antagonist of the Wnt/β-catenin signaling pathway. In conclusion, the differential effect of calcitriol and paricalcitol on vascular calcification appears to be mediated by a distinct regulation of the BMP and Wnt/β-catenin signaling pathways

Protective role of nrf2 in renal disease

Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression remain an unmet need. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a key role in protection against oxidative stress and regulation of the inflammatory response. Consequently, the use of compounds targeting Nrf2 has generated growing interest for nephrologists. Pre-clinical and clinical studies have demonstrated that Nrf2-inducing strategies prevent CKD progression and protect from acute kidney injury (AKI). In this article, we review current knowledge on the protective mechanisms mediated by Nrf2 against kidney injury, novel therapeutic strategies to induce Nrf2 activation, and the status of ongoing clinical trials targeting Nrf2 in renal diseasesThe authors’work has been supported by grants FIS/Fondos FEDER (PI17/00130, PI17/00257, PI17/01495, PI18/01386, PI19/00815, PI20/00375, PI20/00487 ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and Cardiovascular (CIBERCV), Spanish Ministry of Science and Innovation (RTI2018-098788-B-100, DTS17/00203, DTS19/00093, RYC-2017-22369, FJC2019-042028), The “PFIS” and “Sara Borrell” training program of the ISCIII supported the salary of MGH (FI18/00310), SR-M (CD19/00021), and CH-B (CP16/00017). Spanish Ministerio de Ciencia, Innovación y Universidades (MICIU) grant RTI2018-100695-B-I00, Junta de Andalucía grants P18-RT-4264, 1263735-R and BIO-276, the FEDER Funding Program from the European Union, and Universidad de Córdoba (to J.M.V.