Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis: Hepatology

We identified in the transcriptome analysis of patients with alcoholic hepatitis (AH) osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, Western blotting and ELISA. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN−/− mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH compared to normal livers and other types of chronic liver diseases and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and MMP-7) and cleaved-OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C SNP of the OPN gene compared to patients with alcohol abuse without liver disease. Importantly, OPN−/− mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by LPS and stimulated inflammatory actions in hepatic stellate cells

Targeting UBC9-Mediated Protein Hyper-SUMOylation in Cystic Cholangiocytes Halts Polycystic Liver Disease in Experimental Models

BACKGROUND & AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Herein, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting. METHODS: Levels and functional effects of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated invitro, invivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry. RESULTS: Most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. Invitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered proteasome hyperactivity in cystic cholangiocytes, leading to activation of the unfolded protein response and stress-related apoptosis. CONCLUSIONS: Cystic cholangiocytes exhibit increased SUMOylation of proteins involved in cell survival and proliferation, thus promoting hepatic cystogenesis. Inhibition of protein SUMOylation with SAMe halts PLD, representing a novel therapeutic strategy. LAY SUMMARY: Protein SUMOylation is a dynamic post-translational event implicated in numerous cellular processes. This study revealed dysregulated protein SUMOylation in polycystic liver disease, which promotes hepatic cystogenesis. Administration of S-adenosylmethionine (SAMe), a natural UBC9-dependent SUMOylation inhibitor, halted polycystic liver disease in experimental models, thus representing a potential therapeutic agent for patients.Spanish Carlos III Health Institute (ISCIII) [J.M. Banales (FIS PI12/00380, PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129 and CPII19/00008); M.J. Perugorria (FIS PI14/00399, PI17/00022 and PI20/00186); P.M. Rodrigues (Sara Borrell CD19/00254)] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); Ministerio de Ciencia, Innovación y Universidades (MICINN; M.L. Martinez-Chantar: SAF2017-87301-R); “Instituto de Salud Carlos III” [CIBERehd: J.M. Banales, M.J. Perugorria, M.L. Martinez-Chantar and L. Bujanda], Spain; “Diputación Foral Gipuzkoa” (J.M. Banales: DFG15/010, DFG16/004), Department of Health of the Basque Country (M.J. Perugorria: 2019111024, 2015111100 and J.M. Banales: 2017111010), “Euskadi RIS3” (J.M. Banales: 2016222001, 2017222014, 2018222029, 2019222054, 2020333010), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales and M.L. Martinez-Chantar) and Department of Industry of the Basque Country (J.M. Banales: Elkartek: KK-2020/00008). La Caixa Scientific Foundation (J.M. Banales and M.L. Martinez-Chantar: HR17-00601). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to J.M. Banales and M.L. Martinez-Chantar). “Ayudas para apoyar grupos de investigación del Sistema Universitario Vasco” (IT971-16 to P.A.). Università Politecnica delle Marche PSA2017_UNIVPM grant (to M. Marzioni). National Institutes of Health (NIH) of United States of America (DK24031 to N.F. LaRusso). MJ Perugorria was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Program RYC-2015-17755), P.Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award 2017), F.J. Caballero-Camino by the Spanish Ministry of Science and Innovation (BES-2014-069148), and P. Olaizola and A. Santos-Laso by the Basque Government (PRE_2016_1_0269, PRE_2015_1_0126). We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). The funding sources had no involvement in study design, data collection and analysis, decision to publish, or preparation of the article

Comparative study of paediatric prescription drug utilization between the spanish and immigrant population

<p>Abstract</p> <p>Background</p> <p>The immigrant population has increased greatly in Spain in recent years to the point where immigrants made up 12% of the infant population in 2008. There is little information available on the profile of this group with regard to prescription drug utilization in universal public health care systems such as that operating in Spain. This work studies the overall and specific differences in prescription drug utilization between the immigrant and Spanish population.</p> <p>Methods</p> <p>Use was made of the Aragonese Health Service databases for 2006. The studied population comprises 159,908 children aged 0-14 years, 13.6% of whom are foreign nationals. Different utilization variables were calculated for each group. Prescription-drug consumption is measured in Defined Daily Doses (DDD) and DDD/1000 persons/day/(DID).</p> <p>Results</p> <p>A total of 833,223 prescriptions were studied. Utilization is lower for immigrant children than in Spanish children for both DID (66.27 v. 113.67) and average annual expense (€21.55 v. €41.14). Immigrant children consume fewer prescription drugs than Spanish children in all of the therapy groups, with the most prescribed (in DID) being: respiratory system, anti-infectives for systemic use, nervous system, sensory organs. Significant differences were observed in relation to the type of drugs and the geographical background of immigrants.</p> <p>Conclusion</p> <p>Prescription drug utilization is much greater in Spanish children than in immigrant children, particularly with reference to bronchodilators (montelukast and terbutaline) and attention-disorder hyperactivity drugs such as methylphenidate. There are important differences regarding drug type and depending on immigrants' geographical backgrounds that suggest there are social, cultural and access factors underlying these disparities.</p

A protective personal factor against disability and dependence in the elderly: an ordinal regression analysis with nine geographically-defined samples from Spain

Background Sense of Coherence (SOC) is defined as a tendency to perceive life experiences as comprehensible, manageable and meaningful. The construct is split in three major domains: Comprehensibility, Manageability, and Meaningfulness. SOC has been associated with successful coping strategies in the face of illness and traumatic events and is a predictor of self-reported and objective health in a variety of contexts. In the present study we aim to evaluate the association of SOC with disability and dependence in Spanish elders. Methods A total of 377 participants aged 75 years or over from nine locations across Spain participated in the study (Mean age: 80.9 years; 65.3% women). SOC levels were considered independent variables in two ordinal logistic models on disability and dependence, respectively. Disability was established with the World health Organization-Disability Assessment Schedule 2.0 (36-item version), while dependence was measured with the Extended Katz Index on personal and instrumental activities of daily living. The models included personal (sex, age, social contacts, availability of an intimate confidant), environmental (municipality size, access to social resources) and health-related covariates (morbidity). Results High Meaningfulness was a strong protective factor against both disability (Odds Ratio [OR] = 0.50; 95% Confidence Interval [CI] = 0.29–0.87) and dependence (OR = 0.33; 95% CI = 0.19–0.58) while moderate and high Comprehensibility was protective for disability (OR = 0.40; 95% CI = 0.22–0.70 and OR = 0.39; 95%CI = 0.21–0.74), but not for dependence. Easy access to social and health resources was also highly protective against both disability and dependence. Conclusions Our results are consistent with the view that high levels of SOC are protective against disability and dependence in the elderly. Elderly individuals with limited access to social and health resources and with low SOC may be a group at risk for dependence and disability in Spain.This project was partially funded by a research contract in support of the project “Epidemiological Study of Dementia in Spain” signed by the Pfizer Foundation and Carlos III Institute of HealthS

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Análisis del comportamiento de programas multihilo en sistemas NUMA

&lt;p&gt;Los sistemas NUMA son una opción escalable en sistemas de memoria compartida, comprender su comportamiento en relación con la localidad de los datos y la afinidad de los hilos es clave para optimizar su eficiencia. Este trabajo examina los sistemas NUMA multihilo, centrándose en cómo la disposición de dos hilos en nodos impacta en la ejecución de programas con predominio de operaciones de acceso a memoria. Estudiamos la localidad evaluando un solo hilo haciendo operaciones de memoria locales y remotas, luego introducimos un segundo hilo para evaluar los efectos de la compartición de recursos, y finalmente analizamos la afinidad observando efectos del acceso paralelo a un único vector de datos.&nbsp;&lt;/p&gt;&lt;p&gt;Tras realizarse pruebas sobre un sistema NUMA de 4 nodos e interconexiones homogéneas se observó que; primero, el acceso local a los datos ofrece un rendimiento hasta 3 veces superior a los accesos remotos; segundo, la compartición de recursos puede penalizar rendimiento en programas con acceso intensivo a datos; y tercero, los tiempos de acceso a datos compartidos pueden verse afectados por los protocolos de coherencia caché, sincronizándose los hilos a aquel de acceso más lento. Este último efecto puede mitigarse retrasando la ejecución de un hilo, limitando conflictos de acceso a memoria, permitiendo que el hilo adelantado se aproxime al rendimiento aislado y el hilo con el retardo mejore sus tiempos de ejecución gracias a la precarga de datos.&lt;/p&gt;&lt;p&gt;Ası́, este estudio identifica pérdidas de rendimiento y sugiere posibles soluciones mediante planificación de accesos y migración de hilos/datos.&lt;/p&gt;&lt;p&gt;Este trabajo ha recibido el apoyo económico del Consellerı́a de Cultura, Educación y Ordenación Universitaria de la Xunta de Galicia (acreditaciones ED431C 2022/16 y ED431G 2019/04) y el Fondo Europeo de Desarrollo Regional (FEDER), que reconoce al CiTIUS de la Universidad de Santiago de Compostela como Centro de Investigación del Sistema Universitario de Galicia. Este trabajo también fue apoyado por el Ministerio de Economı́a y Competitividad del Gobierno de España (Proyecto PID2019-104834GB-I00).&lt;/p&gt

Genetic HLA Study of Kurds in Iraq, Iran and Tbilisi (Caucasus, Georgia): Relatedness and Medical Implications

Kurds from Iraq (Dohuk and Erbil Area, North Iraq) have been analyzed for HLA genes. Their HLA genetic profile has been compared with that of other Kurd groups from Iran and Tbilisi (Georgia, Caucasus) and also Worldwide populations. A total of 7,746 HLA chromosomes have been used. Genetic distances, NJ dendrograms and correspondence analyses have been carried out. Haplotype HLA-B*52-DRB1*15 is present in all three analyzed Kurd populations. HLA-A*02-B*51-DRB1*11 is present in Iraq and Georgia Kurds. Haplotypes common to Iran and Iraq Kurds are HLA DRB1*11-DQB1*03, HLA DRB1*03-DQB1*02 and others in a lower frequency. Our HLA study conclusions are that Kurds most probably belong to an ancient Mediterranean / Middle East / Caucasian genetic substratum and that present results and those previously obtained by us in Kurds may be useful for Medicine in future Kurd transplantation programs, HLA Epidemiology (HLA linked diseases) and Pharmacogenomics (HLA-associated drug side effects) and also for Anthropology. It is discussed that one of the most ancient Kurd ancestor groups is in Hurrians (2,000 years BC)

MicroRNA-506 promotes primary biliary cholangitis–like features in cholangiocytes and immune activation

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although PBC etiopathogenesis still remains obscure, development of anti-mitochondrial auto-antibodies against pyruvate dehydrogenase complex-E2 (PDC-E2) is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but their functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl(-) /HCO3(-) anion exchanger 2 (AE2) and type III inositol 1,4,5-trisphosphate receptor (InsP3R3), leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several pro-inflammatory cytokines overexpressed in PBC livers [such as IL8, IL12, IL17, IL18 and TNFα] stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506: i) induced dedifferentiation with downregulation of biliary and epithelial markers together with upregulation of mesenchymal, pro-inflammatory and pro-fibrotic markers; ii) impaired cell proliferation and adhesion; iii) increased oxidative and endoplasmic reticulum (ER) stress; iv) caused DNA damage; and v) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less ATP production) and PDC-E2 overexpression. Co-culture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. different pro-inflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells. MiR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. This article is protected by copyright. All rights reserve