1,721,016 research outputs found
Cellular and molecular mechanisms of intestinal fibrosis
No full text"Fibrosis is a chronic and progressive process characterized. by an excessive accumulation of extracellular matrix. (ECM) leading to stiffening and\/or scarring of the. involved tissue. Intestinal fibrosis may develop in several. different enteropathies, including inflammatory bowel. disease. It develops through complex cell, extracellular. matrix, cytokine and growth factor interactions. Distinct. cell types are involved in intestinal fibrosis, such as. resident mesenchymal cells (fibroblasts, myofibroblasts. and smooth muscle cells) but also ECM-producing cells. derived from epithelial and endothelial cells (through a. process termed epithelial- and endothelial-mesenchymal. transition), stellate cells, pericytes, local or bone. marrow-derived stem cells. The most important soluble. factors that regulate the activation of these cells include. cytokines, chemokines, growth factors, components of. the renin-angiotensin system, angiogenic factors, peroxisome. proliferator-activated receptors, mammalian. target of rapamycin, and products of oxidative stress.. It soon becomes clear that although inflammation is. responsible for triggering the onset of the fibrotic process,. it only plays a minor role in the progression of this. condition, as fibrosis may advance in a self-perpetuating. fashion. Definition of the cellular and molecular. mechanisms involved in intestinal fibrosis may provide. the key to developing new therapeutic approaches.
Can we prevent, reduce or reverse intestinal fibrosis in IBD?
No full textIntestinal fibrosis is a common complication of in inflammatory bowel disease
(IBD) and can occur in both ulcerative colitis (UC) and Crohn’s disease (CD), but is much more prevalent in CD. Fibrosis is a consequence of local chronic inflammation and is characterized by
abnormal deposition of extracellular matrix (ECM) proteins producted by activated myofibroblasts.
Current anti-inflammatory therapies used in IBD do not prevent nor they reverse established fibrosis and strictures. Despite the therapeutic advance in the treatment of IBD in the
last two decades, the incidence of intestinal strictures in CD has not significantly changed. This
implies that control of intestinal inflammation
does not necessarily affect the associated fibrotic
process. The conventional view that intestinal
fibrosis is an inevitable and irreversible process in patients with IBD is progressively changing in
light of improved understanding of the cellular
and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the
mechanisms of intestinal fibrosis may pave the way for the developments of anti-fibrotic agents
and of new possible therapeutic approches in
IBD. Nevertheless, there are important clinical issues
that need further investigations, in particular
the identification of factors relevant for the development
of the intestinal fibrosis in IBD and the need of accurate and effective monitoring of the fibrotic progression and of effectiveness of the
new proposed treatments
PPAR-gamma improves intestinal fibrosis by targeting the EMT-activator ZEB1.
No full textINTRODUCTION: Intestinal fibrosis is a common consequence of Inflammatory Bowel Disease (IBD), in which excessive extracellular matrix (ECM) components deposition causes obstruction and loss of function. Our previous data show inhibition of TGF- 1/Smad pathway mediated by a new transrepressive PPAR modulator, GED-0507-34 Levo, and relative improvement of fibrotic disease in a DSS model o the prototypical pathway regulating epithelial to mesenchymal transition (EMT) in fibrosis. PPAR is highly expressed in intestinal epithelial cells (IEC) and its GED-mediated activation may inhibit TGF- induced phenotypic EMT and in particular the over-expression of Zinc finger E-box-binding homeobox 1 (ZEB1), a pivotal epithelial markers transcriptional repressor.
AIMS&METHODS: Aim: To evaluate the role of GED-induced PPAR activation to reverse the progression of TGF- induced EMT, and to determine its ability to downregulate ZEB1 expression in intestinal epithelial cells.
Methods: Intestinal epithelial cells (HT29) differentiated by a 4 day treatment with TGF- 1 (10 ng/ml) were stimulated with GED 1mM. A PPAR knockdown HT29 (ShPPAR HT29) cell line was included in the study to confirm the PPAR -dependence of GED effect. After 4 day of combined treatments EMT was determined by quantitative real-time PCR analysis of A33 and Cytokeratin 20 (two specific intestinal epithelial markers) aSMA, Collagen, Fibronectin and ZEB1. Collagen deposition was evaluated by Picrosirius red staining.
RESULTS: TGF- 1 induced phenotypic EMT in cultured HT29 and ShPPARg HT29 cell line via significantly reduced A33 and Cytokeratin 20 expression (p50.05) and significantly increased expression of mesenchymal differentiation markers, -SMA and Fibronectin (p50.01) in association with the loss of epithelial morphology. GED reduced SMA and Fibronectin mRNA expression (1.2 fold and 2.5 fold vs TGF- , respectively. p50.05) and restored specific IECs markers. GED determined a 65% reduction of TGF -induced collagen deposition (p50.05). ZEB1 mRNA expression was downregulated by GED in TGF-b treated IEC by 2.2 fold (p50.05) compared to TGF- treated cells. Significant effects of GED treatment were not observed in ShPPAR HT29.
CONCLUSION: GED reversed all EMT markers in a PPAR -dependent manner. The present study could represent a useful start point to better highlight the action spectrum of PPARg in prevention and care of intestinal fibrosis and to identify new specific molecular target to develop efficient therapeutic strategies.
REFERENCES:
1. Speca S et al. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol. 2012; 18: 3635-61.
2. Rousseaux C, Desreumaux P. The peroxisome-proliferator-activated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD). J Soc Biol 2006; 200: 121-131
3. Dubuquoy L, et al. PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut. 2006; 55:1341-9
4. Das S, et al. Reversal of transforming growth factor- induced epithelial-tomesenchymal transition and the ZEB proteins. Fibrogenesis Tissue Repair. 2012; 5 Suppl 1: S28.f chronic colitis. TGF- 1/Smad i
Expression of pro-fibrotic and anti-fibrotic molecules in dimethylnitrosamine-induced hepatic fibrosis
No full textBackground: Hepatic fibrosis is characterized by a progressive accumulation of fibrillar extracellular
matrix (ECM) proteins, produced by activated myofibroblasts which are modulated by both profibrotic
and antifibrotic factors.
Objective: To evaluate in vivo the expression of pro-fibrotic molecules like av6 integrin, transforming
growth factor- (TGF-), Smad3, connective tissue growth factor (CTGF) and mammalian target of
Rapamycin (mTOR), as well as anti-fibrotic peroxisome proliferator-activated receptor- (PPAR) in an
experimental model of chronic hepatitis-associated fibrosis induced by intraperitoneal administration
of dimethylnitrosamine (DMN) in mice.
Methods: Chronic hepatitis was induced in 12 Smad3 wild-type (WT) and 12 knock-out (KO) mice by
intraperitoneal DMN administration. Histological, morphometric and immunohistochemical analyses
using -smooth muscle actin (-SMA), collagen types I–III, TGF-1, Smad3, av6 integrin, CTGF, mTOR
and PPAR antibodies were performed.
Results: The liver of DMN-treated Smad3 WT mice showed a higher degree of hepatic accumulation of
connective tissue compared to KO mice. The expression of -SMA, collagen I–III and CTGF was increased
in Smad3 WT compared to KO mice treated with DMN, associated with a concomitant up-regulation of
av6, TGF, Smad3, and mTOR and a reduction in PPAR expression.
Conclusions: These results suggest a possible interaction between pro-fibrotic and anti-fibrotic molecules
in the development of hepatic fibrosis.Background Hepatic fibrosis is characterized by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins, produced by activated myofibroblasts which are modulated by both profibrotic and antifibrotic factors. Objective To evaluate in vivo the expression of pro-fibrotic molecules like avβ6 integrin, transforming growth factor-β (TGF-β), Smad3, connective tissue growth factor (CTGF) and mammalian target of Rapamycin (mTOR), as well as anti-fibrotic peroxisome proliferator-activated receptor-γ (PPARγ) in an experimental model of chronic hepatitis-associated fibrosis induced by intraperitoneal administration of dimethylnitrosamine (DMN) in mice. Methods Chronic hepatitis was induced in 12 Smad3 wild-type (WT) and 12 knock-out (KO) mice by intraperitoneal DMN administration. Histological, morphometric and immunohistochemical analyses using α-smooth muscle actin (α-SMA), collagen types I–III, TGF-β1, Smad3, avβ6 integrin, CTGF, mTOR and PPARγ antibodies were performed. Results The liver of DMN-treated Smad3 WT mice showed a higher degree of hepatic accumulation of connective tissue compared to KO mice. The expression of α-SMA, collagen I–III and CTGF was increased in Smad3 WT compared to KO mice treated with DMN, associated with a concomitant up-regulation of avβ6, TGFβ, Smad3, and mTOR and a reduction in PPARγ expression. Conclusions These results suggest a possible interaction between pro-fibrotic and anti-fibrotic molecules in the development of hepatic fibrosis
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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