Browsing by Author "Carrasco, Gonzalo"
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- ItemEffects of bile acid sequestration on hepatic steatosis in obese mice(2014) Solís, Nancy; Pizarro Rojas, Margarita Alicia; Quintero, Pablo; Arab Verdugo, Juan Pablo; Riquelme Pérez, Arnoldo; Padilla Pérez, Oslando; Carrasco, Gonzalo; Pirola, Carlos J.; Sookoian, Silvia; Arrese Jiménez, Marco
- ItemFarnesoid X Receptor Critically Determines the Fibrotic Response in Mice but Is Expressed to a Low Extent in Human Hepatic Stellate Cells and Periductal Myofibroblasts(ELSEVIER SCIENCE INC, 2009) Fickert, Peter; Fuchsbichler, Andrea; Moustafa, Tarek; Wagner, Martin; Zollner, Gernot; Halilbasic, Emina; Stoeger, Ulrike; Arrese, Marco; Pizarro, Margarita; Solis, Nancy; Carrasco, Gonzalo; Caligiuri, Alessandra; Sombetzki, Martina; Reisinger, Emil; Tsybrovskyy, Oleksiy; Zatloukal, Kurt; Denk, Helmut; Jaeschke, Hartmut; Pinzani, Massimo; Trauner, MichaelThe nuclear bile acid receptor, farnesoid X receptor (FXR), may play a pivotal role in liver fibrosis. We tested the impact of genetic FXR ablation in four different mouse models. Hepatic fibrosis was induced in wild-type and FXR knock-out mice (FXR-/-) by CCl4 intoxication, 3,5-diethoxycarbonyl-1,4-dihydrocollidine feeding, common bile duct ligation, or Schistosoma mansoni (S.m.)-infection. In addition, we determined nuclear receptor expression levels (FXR, pregnane X receptor (PXR), vitamin D receptor, constitutive androstane receptor (CAR), small heterodimer partner (SHP)) in mouse hepatic stellate cells (HSCs), portal myofibroblasts (MFBs), and human HSCs. Cell type-specific FXR protein expression was determined by immunohistochemistry in five mouse models and prototypic human fibrotic liver diseases. Expression of nuclear receptors was much lower in mouse and human HSCs/MFBs compared with total liver expression with the exception of vitamin D receptor. FXR protein was undetectable in mouse and human HSCs and MFBs. FXR loss had no effect in CCl4-intoxicated and S. m.-infected mice, but significantly decreased liver fibrosis of the bitiary type (common bile duct ligation, 3,5-diethoxycarbonyl-1,4-dihydrocoUidine). These data suggest that FXR loss significantly reduces fibrosis of the biliary type, but has no impact on non-cholestatic liver fibrosis. Since there is no FXR expression in HSCs and MFBs in liver fibrosis, our data indicate that these cells may not represent direct therapeutic targets for FXR ligands. (Am J Pathol 2009, 175;2392-2405; DOI: 10.2353/ajpath.2009.090114)
- ItemHelicobacter pylori -induced chronic gastritis and assessing risks for gastric cancer(2013) Carrasco, Gonzalo; Corvalán R., AlejandroChronic gastritis is an inflammation of the gastric mucosa and has multiple etiologies. Here we discuss the pathological alterations induced by Helicobacter pylori (HP) leading to chronic gastritis and the epigenetic bases underlying these changes. We review the histology of the normal gastric mucosa and overview the role of HP in the multistep cascade of GC. We attempt to define the role of the Operative Link for Gastritis Assessment (OLGA) staging system in assessing the risk of GC. The epigenetic bases of chronic gastritis, mainly DNA methylation, are presented through examples such as (i) the methylation of the promoter region of E-cadherin in HP-induced chronic gastritis and its reversion after HP eradication and (ii) the association of methylation of the promoter region of Reprimo, a p53-mediated cell cycle arrest gene, with aggressive HP strains in high risk areas for GC. In addition, we discuss the finding of RPRM as a circulating cell-free DNA, offering the opportunity for noninvasive risk assessment of GC. Finally, the integration of OLGA and tissue biomarkers, by systems pathology approach, suggests that severe atrophy has a greater risk for GC development if, in addition, overexpressed p73. This trial is registered with ClinicalTrials.gov NCT01774266.
- ItemHelicobacter pylori-Induced Loss of the Inhibitor-of-Apoptosis Protein Survivin Is Linked to Gastritis and Death of Human Gastric Cells(OXFORD UNIV PRESS INC, 2010) Valenzuela, Manuel; Perez Perez, Guillermo; Corvalan, Alejandro H.; Carrasco, Gonzalo; Urra, Hery; Bravo, Denisse; Toledo, Hector; Quest, Andrew F. G.Helicobacter pylori infects the human stomach and modifies signaling pathways that affect gastric epithelial cell proliferation and viability. Chronic exposure to this pathogen contributes to the onset of gastric atrophy, an early event in the genesis of gastric cancer associated with H. pylori infection. Susceptibility to H. pylori-induced cell death ultimately depends on the presence of protective host cell factors. Although expression of the inhibitor-of-apoptosis protein survivin in adults is frequently linked to the development of cancer, evidence indicating that the protein is present in normal gastric mucosa is also available. Thus, we investigated in human gastric tissue samples and cell lines whether H. pylori infection is linked to loss of survivin and increased cell death. Our results show that infection with H. pylori decreased survivin protein levels in the mucosa of patients with gastritis. Furthermore, survivin down-regulation correlated with apoptosis and loss of cell viability in gastrointestinal cells cocultured with different H. pylori strains. Finally, overexpression of survivin in human gastric cells was sufficient to reduce cell death after infection. Taken together, these findings implicate survivin as an important survival factor in the gastric mucosa of humans.
- ItemNiemann-Pick C2 Protein Expression Regulates Lithogenic Diet-Induced Gallstone Formation and Dietary Cholesterol Metabolism in Mice(SPRINGER HEIDELBERG, 2012) Balboa, Elisa; Morales, Gabriela; Aylwin, Paula; Carrasco, Gonzalo; Amigo, Ludwig; Castro, Juan; Rigotti, Attilio; Zanlungo, SilvanaNiemann-Pick C2 protein (NPC2) is a lysosomal soluble protein that is highly expressed in the liver; it binds to cholesterol and is involved in intracellular cholesterol trafficking, allowing the exit of lysosomal cholesterol obtained via the lipoprotein endocytic pathway. Thus, this protein may play an important role in controlling hepatic cholesterol transport and metabolism. The aim of this work was to study the relevance of NPC2 protein expression in hepatic cholesterol metabolism, biliary lipid secretion and gallstone formation by comparing NPC2 hypomorph [NPC2 (h/h)] and wild-type mice fed control, 2% cholesterol, and lithogenic diets. NPC2 (h/h) mice exhibited resistance to a diet-induced increase in plasma cholesterol levels. When consuming the chow diet, we observed increased biliary cholesterol and phospholipid secretions in NPC2 (h/h) mice. When fed the 2% cholesterol diet, NPC2 (h/h) mice exhibited low and high gallbladder bile cholesterol and phospholipid concentrations, respectively. NPC2 (h/h) mice fed with the lithogenic diet showed reduced biliary cholesterol secretion, gallbladder bile cholesterol saturation, and cholesterol crystal and gallstone formation. This work indicates that hepatic NPC2 expression is an important factor in the regulation of diet-derived cholesterol metabolism and disposal as well as in diet-induced cholesterol gallstone formation in mice.
- ItemOverexpression of 11 beta-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue and portal hypercortisolism in non-alcoholic fatty liver disease(WILEY, 2012) Candia, Roberto; Riquelme, Arnoldo; Baudrand, Rene; Carvajal, Cristian A.; Morales, Mauricio; Solis, Nancy; Pizarro, Margarita; Escalona, Alex; Carrasco, Gonzalo; Boza, Camilo; Perez, Gustavo; Padilla, Oslando; Cerda, Jaime; Fardella, Carlos E.; Arrese, MarcoBackground: The enzyme 11 beta-hydroxysteroid-dehydrogenase type 1 (11 beta HSD1) catalyses the reactivation of intracellular cortisol. We explored the potential role of 11 beta-HSD1 overexpression in visceral adipose tissue (VAT) in non-alcoholic fatty liver disease (NAFLD) assessing sequential changes of enzyme expression, in hepatic and adipose tissue, and the occurrence of portal hypercortisolism in obese mice. 11 beta-HSD1 expression was also assessed in tissues from obese patients undergoing bariatric surgery. Methods: Peripheral and portal corticosterone levels and liver histology were assessed in ob/ob mice at two time points (8-12 weeks of age). 11 beta-HSD1 tissue expression was assessed in by RT-pcr in ob/ob mice and in 49 morbidly obese patients. Results: Portal corticosterone serum levels were higher in obese mice with a 26% decrease between 8 and 12 weeks of age (controls: 78.3 +/- 19.7 ng/ml, 8-week-old ob/ob: 167.5 +/- 14.5 ng/ml and 12-week-old ob/ob: 124.3 +/- 28 ng/ml, P < 0.05). No significant differences were found in peripheral corticosterone serum levels. Expression of 11b-HSD1 was lower in the liver [-45% at 8 weeks and -35% at 12-weeks (P = 0.0001)] and highly overexpressed in VAT in obese mice, compared to controls (128-fold higher in 8-week-old ob/ob and 41-fold higher in 12-week-old ob/ob, P < 0.01). No significant differences were seen in the expression of 11 beta-HSD1 in subcutaneous adipose tissue. In multivariate analysis, human 11 beta-HSD1 expression in VAT (OR: 1.385 +/- 1.010-1.910) was associated with NAFLD. Conclusion: Murine NAFLD is associated with portal hypercortisolism and 11 beta-HSD1 overexpression in VAT. In humans, 11 beta-HSD1 VAT expression was associated with the presence of NAFLD. Thus, local corticosteroid production in VAT may contribute to NAFLD pathogenesis.
- ItemOverexpression of p73 as a Tissue Marker for High-Risk Gastritis(AMER ASSOC CANCER RESEARCH, 2010) Carrasco, Gonzalo; Diaz, Jose; Valbuena, Jose R.; Ibanez, Paulina; Rodriguez, Paz; Araya, Gabriela; Rodriguez, Carolina; Torres, Javiera; Duarte, Ignacio; Aravena, Edmundo; Mena, Fernando; Barrientos, Carlos; Corvalan, Alejandro H.Purpose: Histologic assessment of high-risk gastritis for the development of gastric cancer is not well defined. The identification of tissue markers together with the integration of histologic features will be required for this assessment.
- ItemPlasminogen activator inhibitor type 1 serum levels and 4G/5G gene polymorphism in morbidly obese Hispanic patients with non-alcoholic fatty liver disease(Elsevier España, 2011) Espino Espino, Alberto Antonio; Villagran Torres, Andrea Alejandra; Vollrath Reyes, Valeska Yolanda; Hanckes Mayo, Maria Paulina; Salas Ocaranza, Roberto Ignacio; Farah Samaan, Andrea Catherina; Solis, Nancy; Pizarro Rojas, Margarita Alicia; Escalona Perez, Alex Gamaliel; Boza Wilson, Camilo; Perez, Gustavo; Carrasco, Gonzalo; Padilla, Orlando; Francisco Miguel, Juan; Nervi Oddone, Flavio; Chavez Tapia, Norberto C.; Arab Verdugo, Juan Pablo; Alvarez Lobos, Manuel Marcelo; Arrese Jimenez, Marco Antonio; Riquelme Perez, Arnoldo JavierBackground. The plasminogen activator inhibitor type-1 (PAI-1) has been implicated in the regulation of fibrinolysis and extracellular matrix components. The single base pair guanine insertion/deletion polymorphism (4G/5G) within the promoter region of the PAI-1 gene influences PAI-1 synthesis and may modulate hepatic fibrogenesis. Aim. To evaluate the influence of PAI-1 serum levels and 4G/5G polymorphism on the risk of liver fibrosis associated to non-alcoholic fatty liver disease (NAFLD) in morbidly obese patients. Material and methods. Case-control study of 50 obese patients undergoing bariatric surgery and 71 non-obese subjects matched by age and sex. Anthropometric and biochemical measurements were performed, including PAI-1 serum levels. Genomic DNA was obtained to assess the presence of 4G/5G polymorphism. Results. BMI, insulinemia, triglycerides, HOMA-IR, hypertension and diabetes were significantly higher in obese patients compared to control subjects. PAI-1 serum levels observed in obese patients were significantly lower (10.63 +/- 4.82) compared to controls (14.26 +/- 11.4; p < 0.05). No differences were observed in the PAI-1 4G/5G promoter genotypes frequencies (p = 0.12). No differences were observed in PAI-1 plasma levels among obese patients with liver fibrosis (10.64 +/- 4.35) compared to patients without liver fibrosis (10.61 +/- 5.2; p = 0.985). PAI-1 4G/5G promoter genotypes frequencies were similar in patients with or without liver fibrosis associated to NASH (p = 0.6). Conclusions. Morbidly obese patients had significantly Lower PAI-1 serum levels with similar PAI-1 4G/5G genotypes frequencies compared to non-obese subjects. The frequency of 4G/5G genotypes in Chilean Hispanic healthy subjects was similar to that described in other populations. No association was found between PAI-1 serum levels or 4G/5G genotype with liver fibrosis in obese patients.
- ItemSyphilitic tonsillitis presenting as an ulcerated tonsillar tumor with ipsilateral lymphadenopathy(ELSEVIER SCIENCE INC, 2007) Oddo, David; Carrasco, Gonzalo; Capdeville, Felipe; Ayala, Maria FernandaWe describe a 49-year-old man who presented with a cervical mass of a week's evolution, which clinically mimicked a tumoral expansion. Physical examination showed a left cervical mass of 6 x 4 x 2 cm, associated to a left ulcerated tonsillar tumor. The presumptive diagnosis was a tonsillar cancer with lymph node involvement. An amygdalectomy and a frozen section biopsy of the cervical tumor were performed. The biopsy displayed a reactive lymphadenopathy with follicular and interfollicular hyperplasia rich in plasma cells, epithelioid areas, and an outstanding parcel fibrosis of subcapsular, interfollicular, and perifollicular distribution associated to an isolated focus of polymorphonuclear leukocytes and obliterative parietal angiovascular proliferation. The tonsil presented a similar but ulcerated process. These results suggested an infectious reactive process, probably luetic. A Warthin-Starry stain revealed spirochetes in the tonsillar ulcer. Laboratory examinations revealed a positive VDRL test and negative serology for HIV. In conclusion, a primary syphilis of the oropharyngeal tonsil with a syphilic lymphadenopathy was diagnosed. The literature about tonsillar syphilis is reviewed. (C) 2007 Elsevier Inc. All rights reserved.