Browsing by Author "Azócar, Lorena"

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    Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry
    (2018) Bustos, Bernabé I.; Pérez Palma, Eduardo; Buch, Stephan; Azócar, Lorena; Riveras, Eleodoro; Ugarte, Giorgia D.; Toliat, Mohammad; Nürnberg, Peter; Lieb, Wolfgang; Franke, Andre; Hinz, Sebastian; Burmeister, Greta; von Schönfels, Witigo; Schafmayer, Clemens; Völzke, Henry; Völker, Uwe; Homuth, Georg; Lerch, Markus M.; Santos Martín, José Luis; Puschel Illanes, Klaus; Bambs S., Claudia; Gutiérrez Ilabaca, Rodrigo Antonio; Hampe, Jochen; de Ferrari, Giancarlo V.; Miquel, Juan Francisco
    Background Latin Americans and Chilean Amerindians have the highest prevalence of cholesterol gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however they only explain a small portion of the population-attributable risk of the disease.Methods We performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Latinos with Mapuche Native American Ancestry, followed by a replication analysis of 10 candidate single nucleotide polymorphisms (SNPs) with suggestive genome-wide significance (P<1×10−5) in 1,643 individuals. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Logistic regression analyses were adjusted for age, sex, BMI, Type 2 Diabetes and Amerindian ancestry. Associated variants were further examined in two large GSD European populations and in a Chilean gallbladder cancer (GBC) cohort. We determined the expression levels of a novel GSD-candidate gene in normal and GSD-tissue samples.Results We consistently replicated the ABCG8 gene (rs11887534; P=3.24×10−8, OR=1.74) associated with GSD in admixed Latinos and identified a novel candidate signal within the TRAF3 gene on chromosome 14 (rs12882491; P=1.11×10−7, OR=1.40). ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 levels were significantly decreased in the gallbladder (P=0.015) and the duodenal mucosa (P=0.001) of affected GSD individuals compared to healthy controls.Conclusions We confirmed ABCG8 and identified TRAF3 both associated with GSD and GBC in admixed Latinos. Decreased TRAF3 expression levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.
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    Endogenous Galectin-8 protects against Th17 infiltration and fibrosis following acute kidney injury
    (Springer Nature, 2025) Perez-Moreno, Elisa; Peña, Adely de la; Toledo, Tomás; Saez, Javiera; Pérez-Molina, Francisca; Espinoza, Sofía; Metz, Claudia; Díaz-Valdivia, Nicole; Azócar, Lorena; Prado, Carolina; Pacheco, Rodrigo; Segovia-Miranda, Fabian; Godoy, Alejandro S.; Amador, Cristian A.; Feuerhake González, Teo; González, Alfonso; Soza, Andrea
    Background Acute kidney injury (AKI) is a serious clinical condition characterized by a rapid decline in renal function, often progressing to chronic kidney disease (CKD) and fibrosis. The endogenous mechanisms influencing kidney injury resolution or maladaptive repair remain poorly understood. Galectin‑8 (Gal‑8), a tandem‑repeat β‑galactosidebinding lectin, plays a role in epithelial cell proliferation, epithelial‑mesenchymal transition, and immune regulation, all of which are critical in AKI outcomes. While exogenous Gal‑8 administration has shown renoprotective effects, its endogenous role in kidney injury progression and resolution remains unclear. Methods To investigate the endogenous role of Gal‑8 in AKI, we compared the responses of Gal‑8 knockout (Gal8‑KO; Lgals8−/− bearing a β‑gal cassette under the Lgals8 gene promoter) and wild‑type (Lgals8+/+) mice in a nephrotoxic folic acid (FA)‑induced AKI model. Renal Gal‑8 expression was assessed by β‑galactosidase staining, lectin‑marker colocalization, and RT‑qPCR. Renal function, structure, and immune responses were evaluated at the acute (day 2) and fibrotic (day 14) phases of injury. Plasma creatinine levels were measured to assess renal function, while histological analyses evaluated tubular damage, renal inflammation, and extracellular matrix deposition. Flow cytometry was performed to characterize the immune response, focusing on pro‑inflammatory T cells. Results Galectin‑8 was predominantly expressed in the renal cortex, localizing to tubules, glomeruli, and blood vessels, with its levels decreasing by half following AKI. Both Lgals8+/+ and Lgals8−/− mice exhibited similar renal function and structure impairments during the acute phase, though Lgals8+/+ mice showed slightly worse damage. By the fibrotic phase, Lgals8−/− mice exhibited more pronounced cortical damage and fibrosis, characterized by increased type I and III collagen deposition and enhanced Th17 cell infiltration, while myofibroblast activation remained comparable to that of Lgals8+/+ mice. Conclusions Endogenous Gal‑8 does not significantly protect the kidney during the acute phase and is dispensable for cell proliferation and death in response to AKI. However, it is crucial in preventing maladaptive repair by regulating.
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    Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus
    (2013) Von Kampen, Oliver; Buch, Stephan; Nothnagel, Michael; Azócar, Lorena; Molina, Héctor; Brosch, Mario; Erhart, Wiebke; Von Schöenfels, Witigo; Egberts, Jan; Seeger, Marcus; Miquel P., Juan Francisco; Puschel Illanes, Klaus
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    Lack of canonical activities of connexins in highly aggressive human prostate cancer cells
    (2024) Asencio Barría, Catalina Andrea; Véliz García, Loreto Pamela; Flores-Faúndez, Emilia; Azócar, Lorena; Echeverría, Carolina E.; Torres Estay, Verónica; Orellana, Viviana; Ramírez Santelices, Catalina; Sotomayor Fahrenkrog, Paula Camila Stefanía; Cancino, Jorge; Kerr, Bredford; Fernandez-Olivares, Ainoa; Retamal, Mauricio A.; Sáez, Juan C.; Godoy, Alejandro S.
    Abstract Connexins (Cxs) have the ability to form channels that allow the exchange of ions/metabolites between adjacent cells (gap junction channels, GJC) or between the intra- and extra-cellular compartments (hemichannels, HC). Cxs were initially classified as tumor suppressors. However, more recently, it has been shown that Cxs exert anti- and pro-tumorigenic effects depending on the cell and tissue context. In prostate cancer (PCa), the expression and functionality of Cxs remain highly controversial. Here, we analyzed the expression pattern of Cx26, Cx32, Cx37, Cx40, Cx43 and Cx45 in PCa cell lines with increasing levels of tumor aggressiveness (LNCaP < LNCaP-C4-2 < Du-145 < PC-3). In addition, GJ and HC activities were evaluated in the PCa cell lines using dye coupling and dye uptake assays, respectively. Lastly, the cellular localization of Cx26, Cx32, and Cx43 was analyzed in LNCaP and PC-3 cell lines using immunofluorescence analyses. Our results showed a positive association between the mRNA levels of Cx26, Cx37 and Cx45 and the degree of aggressiveness of PCa cells, a negative association in the case of Cx32 and Cx43, and no clear pattern for Cx40. At the protein level, a negative relationship between the expression of Cx26, Cx32 and Cx43 and the degree of aggressiveness of PCa cell lines was observed. No significant differences were observed for the expression of Cx37, Cx40, and Cx45 in PCa cell lines. At the functional level, only LNCaP cells showed moderate GJ activity and LNCaP and LNCaP-C4-2 cells showed HC activity. Immunofluorescence analyses confirmed that the majority of Cx26, Cx32, and Cx43 expression was localized in the cytoplasm of both LNCaP and PC3 cell lines. This data indicated that GJ and HC activities were moderately detected only in the less aggressive PCa cells, which suggest that Cxs expression in highly aggressive PCa cells could be associated to channel-independent roles.
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    Prediction of Extraintestinal Manifestations in Inflammatory Bowel Disease Using Clinical and Genetic Variables with Machine Learning in a Latin IBD Group
    (2025) Pérez Jeldres, Tamara de Lourdes; Reyes Pérez, Paula; González Hormazábal, Patricio; Avendaño Soriano, Cristóbal Raimundo; Segovia Melero, Roberto; Azócar, Lorena; Verónica Silva; Andrés de la Vega; Arriagada, Elizabeth; Hernández, Elisa; Aguilar, Nataly; Pavez Ovalle, Carolina Denisse; Hernández Rocha, Cristián Antonio; Candia Balboa, Roberto Andrés; Miquel Poblete, Juan Francisco; Álvarez Lobos, Manuel Marcelo; Valdés, Ivania; Medina Rivera, Alejandra; Bustamante, María Leonor
    Extraintestinal manifestations (EIMs) significantly increase morbidity in inflammatory bowel disease (IBD) patients. In this study, we examined clinical and genetic factors associated with EIMs in 414 Latin IBD patients, utilizing machine learning for predictive modeling. In our IBD group (314 ulcerative colitis (UC) and 100 Crohn’s disease (CD) patients), EIM presence was assessed. Clinical differences between patients with and without EIMs were analyzed using Chi-square and Mann–Whitney U tests. Based on the genetic data of 232 patients, we identified variants linked to EIMs, and the polygenic risk score (PRS) was calculated. A machine learning approach based on logistic regression (LR), random forest (RF), and gradient boosting (GB) models was employed for predicting EIMs. EIMs were present in 29% (120/414) of patients. EIM patients were older (52 vs. 45 years, p = 0.01) and were more likely to have a family history of IBD (p = 0.02) or use anti-TNF therapy (p = 0.01). EIMs were more common in patients with CD than in those with UC without reaching statistical significance (p = 0.06). Four genetic variants were associated with EIM risk (rs9936833, rs4410871, rs3132680, and rs3823417). While the PRS showed limited predictive power (AUC = 0.69), the LR, GB, and RF models demonstrated good predictive capabilities. Approximately one-third of IBD patients experienced EIMs. Significant risk factors included genetic variants, family history, age, and anti-TNF therapy, with predictive models effectively identifying EIM risk.
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    Salmonella enterica serovar Typhi and gallbladder cancer : a case control study and meta-analysis
    (2016) Koshiol, Jill; Wozniak Banchero, Aniela; Cook, María Paz; Adaniel, Christina; Acevedo, Johanna; Azócar, Lorena; Roa Strauch, Juan Carlos Enrique; Miquel P., Juan Francisco; Ferreccio Readi, Catterina; Díaz, Alfonso; Molina, Héctor; Miranda, Carolina; Castillo, Claudia
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    Transcriptomic profiles reveal differences in zinc metabolism, inflammation, and tight junction proteins in duodenum from cholesterol gallstone subjects
    (2020) Riveras Hernández, Eleodoro Javier; Azócar, Lorena; Moyano, Tomás C.; Ocares, Marcia; Molina, Héctor; Romero, Diego; Roa Strauch, Juan Carlos Enrique; Valbuena Mora, José Rafael; Gutiérrez, Rodrigo A.; Miquel P., Juan Francisco
    Cholesterol Gallstone Disease (GSD) is a common multifactorial disorder characterized by crystallization and aggregation of biliary cholesterol in the gallbladder. The global prevalence of GSD is similar to 10-20% in the adult population but rises to 28% in Chile (17% among men and 30% among women). The small intestine may play a role in GSD pathogenesis, but the molecular mechanisms have not been clarified. Our aim was to identify the role of the small intestine in GSD pathogenesis. Duodenal biopsy samples were obtained from patients with GSD and healthy volunteers. GSD status was defined by abdominal ultrasonography. We performed a transcriptome study in a discovery cohort using Illumina HiSeq. 2500, and qPCR, immunohistochemistry and immunofluorescence were used to validate differentially expressed genes among additional case-control cohorts. 548 differentially expressed genes between GSD and control subjects were identified. Enriched biological processes related to cellular response to zinc, and immune and antimicrobial responses were observed in GSD patients. We validated lower transcript levels of metallothionein, NPC1L1 and tight junction genes and higher transcript levels of genes involved in immune and antimicrobial pathways in GSD patients. Interestingly, serum zinc and phytosterol to cholesterol precursor ratios were lower in GSD patients. A significant association was observed between serum zinc and phytosterol levels. Our results support a model where proximal small intestine plays a key role in GSD pathogenesis. Zinc supplementation, modulation of proximal microbiota and/or intestinal barrier may be novel targets for strategies to prevent GSD.
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    Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry
    (2019) Bustos, Bernabé I.; Pérez-Palma, Eduardo; Buch, Stephan; Azócar, Lorena; Riveras Hernández, Eleodoro Javier; Ugarte, Giorgia D.; Gutiérrez Ilabaca, Rodrigo Antonio; Nürnberg, Peter; Lieb, Wolfgang; Franke, Andre; Hinz, Sebastian; Burmeister, Greta; Schönfels, Witigo von; Schafmayer, Clemens; Völzke, Henry; Völker, Uwe; Homuth, Georg; Lerch, Markus M.; Santos Martín, José Luis; Puschel Illanes, Klaus; Bambs S., Claudia; Roa Strauch, Juan Carlos Enrique; Toliat, Mohammad; Hampe, Jochen; Ferrari, Giancarlo V. de; Miquel P., Juan Francisco