1,720,964 research outputs found
Dysregulation of the Scribble/YAP/β-catenin axis sustains the fibroinflammatory response in a PKHD1-/- mouse model of congenital hepatic fibrosis
No full text: Congenital hepatic fibrosis (CHF), a genetic cholangiopathy characterized by fibropolycystic changes in the biliary tree, is caused by mutations in the PKHD1 gene, leading to defective fibrocystin (FPC), changes in planar cell polarity (PCP) and increased β-catenin-dependent chemokine secretion. In this study, we aimed at understanding the role of Scribble (a protein involved in PCP), Yes-associated protein (YAP), and β-catenin in the regulation of the fibroinflammatory phenotype of FPC-defective cholangiocytes. Immunohistochemistry showed that compared with wild type (WT) mice, in FPC-defective (Pkhd1del4/del4 ) mice nuclear expression of YAP/TAZ in cystic cholangiocytes, significantly increased and correlated with connective tissue growth factor (CTGF) expression and pericystic fibrosis, while Scribble expression on biliary cyst cells was markedly decreased. Cholangiocytes isolated from WT mice showed intense Scribble immunoreactivity at the membrane, but minimal nuclear expression of YAP, which conversely increased, together with CTGF, after small interfering RNA (siRNA) silencing of Scribble. In FPC-defective cholangiocytes, inhibition of YAP nuclear import reduced β-catenin nuclear expression, and CTGF, integrin β6, CXCL1, and CXCL10 mRNA levels, whereas inhibition of β-catenin signaling did not affect nuclear translocation of YAP. Notably, siRNA silencing of Scribble and YAP in WT cholangiocytes mimics the fibroinflammatory changes of FPC-defective cholangiocytes. Conditional deletion of β-catenin in Pkhd1del4/del4 mice reduced cyst growth, inflammation and fibrosis, without affecting YAP nuclear expression. In conclusion, the defective anchor of Scribble to the membrane facilitates the nuclear translocation of YAP and β-catenin with gain of a fibroinflammatory phenotype. The Scribble/YAP/β-catenin axis is a critical factor in the sequence of events linking the genetic defect to fibrocystic trait of cholangiocytes in CHF
Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium
No full textThe most studied physiological function of biliary epithelial cells (cholangiocytes) is to regulate bile flow and composition, in particular the hydration and alkalinity of the primary bile secreted by hepatocytes. After almost three decades of studies it is now become clear that cholangiocytes are also involved in epithelial innate immunity, in inflammation, and in the reparative processes in response to liver damage. An increasing number of evidence highlights the ability of cholangiocyte to undergo changes in phenotype and function in response to liver damage. By participating actively to the immune and inflammatory responses, cholangiocytes represent a first defense line against liver injury from different causes. Indeed, cholangiocytes express a number of receptors able to recognize pathogen- or damage-associated molecular patterns (PAMPs/DAMPs), such as Toll-like receptors (TLR), which modulate their pro-inflammatory behavior. Cholangiocytes can be both the targets and the initiators of the inflammatory process. Derangements of the signals controlling these mechanisms are at the basis of the pathogenesis of different cholangiopathies, both hereditary and acquired, such as cystic fibrosis-related liver disease and sclerosing cholangiti
Bioactive signaling lipids as drivers of chronic liver diseases
No full textLipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases. In this review, we focus specifically on the roles of bioactive lipids derived from phospholipids (lyso-phospholipids) and poly-unsaturated fatty acids (eicosanoids, pro-resolving lipid mediators and endocannabinoids) in prevalent chronic liver diseases (alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma). We discuss the balance between pathogenic and beneficial bioactive lipids as well as potential therapeutic targets related to the agonism or antagonism of their receptors. (c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved
β-Catenin and interleukin-1β–dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis
No full textCongenital hepatic fibrosis (CHF), a genetic disease caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, encoding for the protein fibrocystin/polyductin complex, is characterized by biliary dysgenesis, progressive portal fibrosis, and a protein kinase A-mediated activating phosphorylation of β-catenin at Ser675. Biliary structures of Pkhd1del4/del4 mice, a mouse model of CHF, secrete chemokine (C-X-C motif) ligand 10 (CXCL10), a chemokine able to recruit macrophages. The aim of this study was to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF/Caroli disease and to understand the mechanisms leading to increased CXCL10 secretion. We demonstrate that treatment of Pkhd1del4/del4 mice for 3 months with AMG-487, an inhibitor of CXC chemokine receptor family 3, the cognate receptor of CXCL10, reduces the peribiliary recruitment of alternative activated macrophages (cluster of differentiation 45+ F4/80+ cells), spleen size, liver fibrosis (sirius red), and cyst growth (cytokeratin 19-positive area), consistent with a pathogenetic role of CXCL10. Furthermore, we show that in fibrocystin/polyductin complex-defective cholangiocytes, isolated from Pkhd1del4/del4 mice, CXCL10 production is mediated by Janus kinase/signal transducer and activator of transcription 3 in response to interleukin 1beta (IL-1β) and β-catenin. Specifically, IL-1β promotes signal transducer and activator of transcription 3 phosphorylation, whereas β-catenin promotes its nuclear translocation. Increased pro-IL-1β was regulated by nuclear factor kappa-light-chain-enhancer of activated B cells, and increased secretion of active IL-1β was mediated by the activation of Nod-like receptors, pyrin domain containing 3 inflammasome (increased expression of caspase 1 and Nod-like receptors, pyrin domain containing 3).
CONCLUSION:
In fibrocystin/polyductin complex-defective cholangiocytes, β-catenin and IL-1β are responsible for signal transducer and activator of transcription 3-dependent secretion of CXCL10; in vivo experiments show that the CXCL10/CXC chemokine receptor family 3 axis prevents the recruitment of macrophages, reduces inflammation, and halts the progression of the disease; the increased production of IL-1β highlights the autoinflammatory nature of CHF and may open novel therapeutic avenues
Animal models of cholangiocarcinoma: What they teach us about the human disease
No full textDespite recent advances, pathogenesis of cholangiocarcinoma, a highly lethal cancer, remains enigmatic. Furthermore, treatment options are still limited and often disappointing. For this reason, in the last few years there has been a mounting interest towards the generation of experimental models able to reproduce the main features associated with this aggressive behavior. Toxic and infestation-induced, genetically engineered and cell implantation rodent models have been generated, contributing to a deeper understanding of the complex cell biology of the tumor, sustained by multiple cell interactions and driven by a huge variety of molecular perturbations. Herein, we will overview the most relevant animal models of biliary carcinogenesis, highlighting the methodological strategy, the molecular, histological and clinical phenotypes consistent with the human condition, their particular strengths and weaknesses and the novel therapeutic approaches that have been developed
Lipid, DNA and protein oxidative stress markers in chronic livel diseases
No full textReactive oxygen and nitrogen species (ROS/RNS) are involved in liver damage induced by several conditions such as alcohol abuse, viral hepatitis and metabolic disorders. The aim of our study was to determine whether oxidant stress is a feature of early liver disease and to examine the effect of therapy, hepatic necrosis and fibrogenesis to the levels of oxidative stress markers in blood and urine of patients with various forms of chronic liver diseases. The concentrations of isoprostane, aldehydes such as malonaldialdehyde and 4-hydroxynonenal, protein carbonyls, 3-nitrotyrosine, 8-hydroxydeoxygouanosine, glutathione and the activities of myeloperoxidase, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase were estimated. Measurements were performed in 49 patients with Autoimmune Cholestatic liver disease, 36 patients with Autoimmune Hepatitis, 49 patients with Chronic Hepatitis B, 47 patients with Chronic Hepatitis C, 29 patients with Alcoholic Liver Disease and 28 patients with Non Alcoholic Steatohepatitis. The results were compared with those from 75 healthy controls matched for age and sex. To our knowledge, it is the first time in the literature that a significant number of many biomarkers of both oxidants and antioxidants were determined in patients with in autoimmune liver diseases, Chronic Hepatitis B patients and especially in chronic inactive HBsAg carriers. Free radical production was found to be the highest in Alcoholic Liver Disease and the lowest in Chronic Hepatitis B. Oxidant stress is a significant feature of Autoimmune Hepatitis and Autoimmune Cholestatic liver disease. lnactive HBsAg carriers demonstrated free radical production. Βlood glutathione concentration was significantly lower in all groups of patients compared to controls. Furthermore all the oxidative injury products and the most activities of antioxidant enzymes were increased in all groups of patients with elevated hepatic injury markers compared to patients with normal hepatic injury markers. All the activities of the antioxidants enzymes were reduced whereas the majority of oxidative injury products were increased in cirrhotic patients compared to non cirrhotic. Therapy reduced the markers of oxidative stress in normal levels only in the patients with Chronic Hepatitis C. Treatment for Autoimmune Hepatitis was more effective to ameliorate the production of free radicals than treatment with Autoimmune Cholestatic liver disease. Four major findings have emerged from the present study. Firstly, disturbances in antioxidant enzymes activity seem to be involved in the progress of disease to decompensated liver cirrhosis. Secondly, the generation of ROS/RNS was shown to occur from early stage of all chronic liver diseases. Third, therapy ameliorates the production of free radicals. Fourth, we demonstrated a significant correlation between multiple markers of oxidant stress and histologically assessed liver damage in autoimmune and viral liver diseases.Οι δραστικές μορφές οξυγόνου και αζώτου (ΔΜΟ/ΔΜΑ) εμπλέκονται στην ηπατική βλάβη που επάγεται από αρκετές καταστάσεις όπως είναι η κατάχρηση οινοπνεύματος, η ιογενής ηπατίτιδα και μεταβολικές διαταραχές. Ο σκοπός της παρούσης μελέτης ήταν να προσδιοριστεί το κατά πόσο το οξειδωτικό στρες είναι ένα χαρακτηριστικό του αρχικού σταδίου των ηπατικών νοσημάτων και να εξεταστεί η επίδραση της θεραπείας, της ηπατικής νέκρωσης και ινογένεσης στα επίπεδα των δεικτών οξειδωτικού στρες στο αίμα και στα ούρα ασθενών με διάφορα χρόνια νοσήματα του ήπατος. Εκτιμήθηκαν τα επίπεδα των ισοπροστανίων, των αλδεϋδών (4-ύδροξυνονεννάλη και μηλονική διαλδεΰδη), των πρωτεϊνικών καρβονυλίων, της 3-νιτροτυροσίνης, της 8-υδρόξυ-δεοξυγουανοσίνης, της γλουταθειόνης και οι δραστικότητες της μυελοϋπεροξειδάσης, της υπεροξειδάσης της γλουταθειόνης, της αναγωγάσης της γλουταθειόνης, της υπεροξειδικής δισμουτάσης και της καταλάσης. Οι μετρήσεις πραγματοποιήθηκαν σε 36 ασθενείς με Αυτοάνοση Ηπατίτιδα, 49 ασθενείς με Αυτοάνοσα Χολοστατικά Νοσήματα, 49 ασθενείς με Χρόνια Ηπατίτιδα Β, 47 ασθενείς με Χρόνια Ηπατίτιδα C, 29 ασθενείς με Αλκοολική Ηπατοπάθεια και σε 28 ασθενείς με Μη Αλκοολική Στεατοηπατίτιδα. Τα αποτελέσματα συσχετίσθηκαν με 75 υγιείς εθελοντές παρόμοιας ηλικίας και φύλλου. Είναι η πρώτη φορά στη βιβλιογραφία που μετρώνται τόσοι πολλοί δείκτες οξειδωτικών και αντιοξειδωτικών στα αυτοάνοσα νοσήματα του ήπατος, στη χρόνια Ηπατίτιδα Β και ειδικά στους χρόνιους ανενεργούς φορείς της Ηπατίτιδας Β. Η παραγωγή των ελευθέρων ριζών βρέθηκε να είναι υψηλότερη στην Αλκοολική Ηπατοπάθεια και χαμηλότερη στη Χρόνια Ηπατίτιδα Β. Το οξειδωτικό στρες είναι ένα σημαντικό χαρακτηριστικό της Αυτοάνοσης Ηπατίτιδας και των Αυτοάνοσων Χολοστατικών νοσημάτων του ήπατος. Οι χρόνιοι ανενεργοί φορείς της Ηπατίτιδας Β παρουσίαζαν παραγωγή ελευθέρων ριζών. Η συγκέντρωση της γλουταθειόνης ήταν σημαντικά χαμηλότερη σε όλες τις ομάδες των ασθενών συγκριτικά με τους μάρτυρες. Επιπλέον, όλα τα προϊόντα οξειδωτικής βλάβης και οι δραστικότητες των περισσοτέρων αντιοξειδωτικών ενζύμων αυξήθηκαν στους ασθενείς με αυξημένους δείκτες ηπατικής βλάβης σε σχέση με τους ασθενείς με φυσιολογικούς δείκτες ηπατικής βλάβης. Όλες οι δραστικότητες των αντιοξειδωτικών ενζύμων μειώθηκαν ενώ τα περισσότερα προϊόντα οξειδωτικής βλάβης αυξήθηκαν στους κιρρωτικούς σε σχέση με τους μη κιρρωτικούς. Η θεραπεία μείωσε τους δείκτες οξειδωτικού στρες σε φυσιολογικά επίπεδα μόνο στους ασθενείς με Χρόνια Ηπατίτιδα C. Η θεραπεία των ασθενών με Αυτοάνοση Ηπατίτιδα ήταν πιο αποτελεσματική στο να μειώνει την παραγωγή ελευθέρων ριζών από ότι η θεραπεία των ασθενών με Αυτοάνοσα Χολοστατικά Νοσήματα. Τέσσερα κύρια ευρήματα προκύπτουν από την παρούσα μελέτη. Πρώτον, η διαταραχή της λειτουργίας της αντιοξειδωτικής άμυνας εμπλέκεται στην εξέλιξη των νοσημάτων σε κίρρωση. Δεύτερον, η παραγωγή ΔΜΟ/ΔΜΑ συμβαίνει από τα αρχικά στάδια των χρόνιων ηπατικών νοσημάτων. Τρίτον, η θεραπεία μειώνει ως ένα βαθμό τα προϊόντα οξειδωτικής βλάβης και τέταρτον υπάρχει σημαντική συσχέτιση μεταξύ ποικίλων δεικτών οξειδωτικού στρες και της ιστολογικά εκτιμούμενης ηπατικής βλάβης στα αυτοάνοσα και στα ιογενή νοσήματα του ήπατος
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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