29 research outputs found
Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment
No full textPolycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.</jats:p
How Did You Do It? Shared Experiences of Birth Activism on the Issue of Obstetric Violence: Interview with Ibone Olza
No full textIbone Olza is a Spanish mother activist, psychiatrist, and author involved in childbirth advocacy and research at the national and international level. In the present interview, she talks about her experiences within Spanish mothers’ movement, specifically in relation to the phenomenon and the concept of “obstetric violence”—a form of gender-based violence exercised on women within maternity healthcare. The interviewer Elena Skoko is a fellow mother activist operating in Italy. The conversation herein represents a milestone for the Italian mothers’ movement because it has influenced the use of the term “obstetric violence” in Italy, which has resulted in the creation of a new public awareness and a new national movement of mothers
The role of TREM-2 receptor in cholestasis and fibrosis-associated hepatocellular carcinoma (HCC)
No full text346 p.La progresión de enfermedades hepatobiliares crónicas, tales como las enfermedades colestásicas (entrelas que destacan la colangitis biliar primaria y la colangitis esclerosante primaria), así como el carcinomahepatocelular (HCC), es un proceso complejo en el cual participan distintos mecanismos moleculares. Laseñalización derivada de productos bacterianos que se translocan del intestino al hígado, se propone comoun mecanismo clave en esta progresión. El receptor TREM2 (tiggering receptor expressed on myeloidcells 2) modula estas señales por su acción en los receptores TLR (toll like receptors). En esta tesisdoctoral se ha investigado el papel del receptor TREM2 en el desarrollo de la colestasis y el carcinomahepatocelular. Nuestros resultados muestran que la expresión de TREM2 incrementa en el tejido hepáticode pacientes con colestasis en comparación a tejido hepático sano, esta observación se confirma enhígado de ratón. Además ratones deficientes en Trem2 muestran una respuesta exacerbada, caracterizadapor una mayor expansión biliar, muerte celular e inflamación, ante el daño inducido por colestasis endistintos modelos murinos de esta condición patológica. Estos efectos son en parte dependientes de laacción de TREM2 sobre la señalización derivada de productos bacterianos en TLRs. Además, losreceptores TREM1 y TREM2 median algunos de los efectos beneficiosos del ácido ursodeoxicólico enlas células de kupffer, siendo el UDCA un ácido biliar endógeno que se considera el tratamiento dereferencia para las enfermedades colestasicas. En tumores de HCC, TREM2 se expresa mayormente enmacrófagos residentes e infiltrados, y en modelos murinos de HCC asociado a fibrosis, ratonesdeficientes en Trem2 muestran una mayor carcinogénesis hepática. En conclusión, TREM2 se presentacomo una nueva diana terapéutica en el tratamiento de diversas enfermedades hepáticas, ya que actúacomo un freno natural en la inflamación tras la lesión hepatocelular, siendo un regulador crítico endiversos tipos de lesión hepatobiliar y carcinogénesis.BioDonosti
The role of TREM-2 receptor in cholestasis and fibrosis-associated hepatocellular carcinoma (HCC)
No full text346 p.La progresión de enfermedades hepatobiliares crónicas, tales como las enfermedades colestásicas (entrelas que destacan la colangitis biliar primaria y la colangitis esclerosante primaria), así como el carcinomahepatocelular (HCC), es un proceso complejo en el cual participan distintos mecanismos moleculares. Laseñalización derivada de productos bacterianos que se translocan del intestino al hígado, se propone comoun mecanismo clave en esta progresión. El receptor TREM2 (tiggering receptor expressed on myeloidcells 2) modula estas señales por su acción en los receptores TLR (toll like receptors). En esta tesisdoctoral se ha investigado el papel del receptor TREM2 en el desarrollo de la colestasis y el carcinomahepatocelular. Nuestros resultados muestran que la expresión de TREM2 incrementa en el tejido hepáticode pacientes con colestasis en comparación a tejido hepático sano, esta observación se confirma enhígado de ratón. Además ratones deficientes en Trem2 muestran una respuesta exacerbada, caracterizadapor una mayor expansión biliar, muerte celular e inflamación, ante el daño inducido por colestasis endistintos modelos murinos de esta condición patológica. Estos efectos son en parte dependientes de laacción de TREM2 sobre la señalización derivada de productos bacterianos en TLRs. Además, losreceptores TREM1 y TREM2 median algunos de los efectos beneficiosos del ácido ursodeoxicólico enlas células de kupffer, siendo el UDCA un ácido biliar endógeno que se considera el tratamiento dereferencia para las enfermedades colestasicas. En tumores de HCC, TREM2 se expresa mayormente enmacrófagos residentes e infiltrados, y en modelos murinos de HCC asociado a fibrosis, ratonesdeficientes en Trem2 muestran una mayor carcinogénesis hepática. En conclusión, TREM2 se presentacomo una nueva diana terapéutica en el tratamiento de diversas enfermedades hepáticas, ya que actúacomo un freno natural en la inflamación tras la lesión hepatocelular, siendo un regulador crítico endiversos tipos de lesión hepatobiliar y carcinogénesis.BioDonosti
TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation
No full textBackground & Aims: Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis.Methods: TREM-2 expression was analyzed in the livers of pa-tients with primary biliary cholangitis (PBC) or primary scle-rosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Pri-mary cultured Kupffer cells were incubated with lipopolysac-charide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed.Results: TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/-mice. This was characterized by enhanced necroptotic cell death, in-flammatory responses and biliary expansion. Antibiotic treat-ment partially abrogated the effects observed in Trem-2-/-mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and damp-ened inflammatory gene transcription via a TREM-2-dependent mechanism.Conclusions: TREM-2 acts as a negative regulator of inflamma-tion during cholestasis, representing a novel potential thera-peutic target.Lay summary: Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (spe-cifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.Spanish Carlos III Health Institute (ISCIII) [J.M. Banales (FIS PI18/01075, PI21/00922 and Miguel Servet Program CPII19/00008); M.J. Perugorria (FIS PI14/00399, PI17/00022 and PI20/00186); J.J.G. Marin (FIS PI16/00598 and PI19/00819); P.M. Rodrigues (Sara Borrell CD19/00254)] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); “Instituto de Salud Carlos III” [CIBERehd: M.J. Monte, J.J.G. Marin, J.M. Banales, M.J. Perugorria, P. Aspichueta, P.M. Rodrigues and L. Bujanda], Spain; “Diputación Foral de Gipuzkoa” (M.J. Perugorria: DFG18/114), Department of Health of the Basque Country (M.J. Perugorria: 2019111024, 2015111100 and J.M. Banales: 2021111021), “Euskadi RIS3” (J.M. Banales: 2019222054, 2020333010, 2021333003), and Department of Industry of the Basque Country (J.M. Banales: Elkartek: KK-2020/00008); “Junta de Castilla y Leon” (J.J.G. Marin: SA063P17). La Caixa Scientific Foundation (J.M. Banales: HR17-00601). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); “Centro Internacional sobre el Envejecimiento” (J.J.G. Marin: OLD-HEPAMARKER, 0348_CIE_6_E); Fundació Marato TV3 (J.J.G. Marin: Ref. 201916-31). O Sharif was funded by the Austrian Science Fund (FWF-P35168). Work in the lab of T. Luedde was funded by the European Research Council (ERC) (Grant Agreement 771083), the German Research Foundation (DFG – LU 1360/3-2 (279874820), LU 1360/4-(1461704932) and SFB-CRC 1382-Project A01) and the German Ministry of Health (BMG – DEEP LIVER 2520DAT111). Contributions of M. Marzioni were funded by the Università Politecnica delle Marche PSA2017_UNIVPM grant. Contributions of DAM were supported by programme grants from CRUK (C18342/A23390) and MRC (MR/K0019494/1 and MR/R023026/1). MJ Perugorria was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Programme RYC-2015-17755), I. Labiano, A. Agirre-Lizaso, P. Olaizola, A. Echebarria and F. González-Romero by the Basque Government (PRE_2016_1_0152, PRE_2018_1_0184, PRE_2016_1_0269 PRE_2020_1_0080, PRE_2018_1_0120, respectively), I. Olaizola by the Ministry of Universities (FPU 19/03327) and A. Esparza-Baquer by the University of the Basque Country (PIF2014/11). The funding sources had no involvement in study design, data collection and analysis, decision to publish, or preparation of the article
La mujer y los Juegos Olímpicos: análisis a través de los medios de comunicación: retos para Beijing 2008
No full textDespués de un recorrido por la historia de los Juegos Olímpicos, el documento analiza el papel de la mujer en los Juegos de Sydney 2000 y Atenas 2004 , y elabora una serie de retos para los futuros Juegos de Beijing 2008. Este trabajo fue presentado por la autora en la Academia Olímpica Española, en la convocatoria 2005.Després d’un recorregut per la història dels Jocs Olímpics, el document analitza el paper de la dona als Jocs de Sidney 2000 i Atenes 2004, i elabora una sèrie de reptes pels futurs Jocs de Beijing 2008. Aquest treball va ser presentat a l’Acadèmia Olímpica Espanyola, en la convocatòria 2005.After reviewing the history of the Olympic Games, the document analyses the role of women in Sydney 2000 and Athens 2004 Olympic Games and pose challenges for the upcoming Beijing 2008 Summer Games. This essay was submitted by the author to the Spanish Olympic Academy in 2005
Ageing-related expression of Twinfilin-1 regulates cholangiocyte biological response to injury
No full textDisorders of the biliary tree develop and progress differently according to patient age. It is currently not known whether the ageing process affects the response to injury of cholangiocytes
Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma
No full textBACKGROUND & AIMS: Metabolic and transcriptional programs respond to extracellular matrix-derived cues in complex environments, such as the tumor microenvironment. Here, we demonstrate how lysyl oxidase (LOX), a known factor in collagen crosslinking, contributes to the development and progression of cholangiocarcinoma (CCA).METHODS: Transcriptomes of 209 human CCA tumors, 143 surrounding tissues, and single-cell data from 30 patients were analyzed. The recombinant protein and a small molecule inhibitor of the LOX activity were used on primary patient-derived CCA cultures to establish the role of LOX in migration, proliferation, colony formation, metabolic fitness, and the LOX interactome. The oncogenic role of LOX was further investigated by RNAscope and in vivo using the AKT/NICD genetically engineered murine CCA model.RESULTS: We traced LOX expression to hepatic stellate cells and specifically hepatic stellate cell-derived inflammatory cancer-associated fibroblasts and found that cancer-associated fibroblast-driven LOX increases oxidative phosphorylation and metabolic fitness of CCA, and regulates mitochondrial function through transcription factor A, mitochondrial. Inhibiting LOX activity in vivo impedes CCA development and progression. Our work highlights that LOX alters tumor microenvironment-directed transcriptional reprogramming of CCA cells by facilitating the expression of the oxidative phosphorylation pathway and by increasing stemness and mobility.CONCLUSIONS: Increased LOX is driven by stromal inflammatory cancer-associated fibroblasts and correlates with diminished survival of patients with CCA. Modulating the LOX activity can serve as a novel tumor microenvironment-directed therapeutic strategy in bile duct pathologies.</p
High-fat diet overfeeding promotes nondetrimental liver steatosis infemale mice
No full textHigh-fat diet (HFD) feeding or leptin-deficient mice are extensively used as models resembling features of human nonalcoholic fatty liver disease (NAFLD). The concurrence of experimental factors as fat content and source or total caloric intake leads to prominent differences in the development of the hepatic steatosis and related disturbances. In this work, we characterized the hepatic lipid accumulation induced by HFD in wild-type (WT) and ob/ob mice with the purpose of differentiating adaptations to HFD from those specific of increased overfeeding due to leptin deficiency-associated hyperphagia. Given that most published works have been done in male models, we used female mice with the aim of increasing the body of evidence regarding NAFLD in female subjects. HFD promoted liver lipid accumulation only in the hyperphagic strain. Nevertheless, a decrease of lipid droplet-associated cholesteryl ester (CE) in both WT and obese animals was observed. These changes were accompanied by an improvement in the profile of lipoproteins that transport cholesterol and liver function markers in plasma from ob/ob mice and a lower hepatic index. Using primary hepatocytes from female mice, overaccumulation of CE induced by 0.4 mM oleic acid reversed in the presence of a specific Takeda G protein-coupled bile acid receptor agonist. Nevertheless, hepatocytes from male mice were not responsive. This study suggests that enterohepatic circulation of bile acids might be one of the factors that can affect sex dimorphism in NAFLD development, which underlines the importance of including female models in the NAFLD research field.This research was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-64352-R), the Basque Country Government (IT-336-10 and IT-971-16), the University of the Basque Country UPV/EHU (UFI11/20), and the Jesús de Gangoiti Barrera Foundation. L. Arisqueta and H. Navarro-Imaz were recipients of research training fellowships from the Basque Country Government
La mujer y los Juegos Olímpicos : análisis a través de los medios de comunicación : retos para Beijing 2008
No full textDespués de un recorrido por la historia de los Juegos Olímpicos, el documento analiza el papel de la mujer en los Juegos de Sydney 2000 y Atenas 2004 , y elabora una serie de retos para los futuros Juegos de Beijing 2008. Este trabajo fue presentado por la autora en la Academia Olímpica Española, en la convocatoria 2005.Després d'un recorregut per la història dels Jocs Olímpics, el document analitza el paper de la dona als Jocs de Sidney 2000 i Atenes 2004, i elabora una sèrie de reptes pels futurs Jocs de Beijing 2008. Aquest treball va ser presentat a l'Acadèmia Olímpica Espanyola, en la convocatòria 2005.After reviewing the history of the Olympic Games, the document analyses the role of women in Sydney 2000 and Athens 2004 Olympic Games and pose challenges for the upcoming Beijing 2008 Summer Games. This essay was submitted by the author to the Spanish Olympic Academy in 2005
