Examinando por Autor "Hermoso, Marcela A"

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    Dysregulated immune responses in COVID-19 patients correlating with disease severity and invasive oxygen requirements.
    (Frontiers Media S.A., 2021-10-21) García-González, Paulina; Tempio, Fabian; Fuentes, Camila; Merino, Consuelo; Vargas, Leonardo; Simon, Valeska; Ramirez-Pereira, Mirliana; Rojas, Verónica; Tobar, Eduardo; Landskron, Glauben; Araya, Juan Pablo; Navarrete, Mariela; Bastias, Carla; Tordecilla, Rocío; Varas, Macarena A; Maturana, Pablo; Marcoleta, Andrés E; Allende, Miguel L; Naves, Rodrigo; Hermoso, Marcela A; Salazar-Onfray, Flavio; Lopez, Mercedes; Bono, María-Rosa; Osorio, Fabiola
    The prognosis of severe COVID-19 patients has motivated research communities to uncover mechanisms of SARS-CoV-2 pathogenesis also on a regional level. In this work, we aimed to understand the immunological dynamics of severe COVID-19 patients with different degrees of illness, and upon long-term recovery. We analyzed immune cellular subsets and SARS-CoV-2-specific antibody isotypes of 66 COVID-19 patients admitted to the Hospital Clínico Universidad de Chile, which were categorized according to the WHO ten-point clinical progression score. These included 29 moderate patients (score 4-5) and 37 severe patients under either high flow oxygen nasal cannula (18 patients, score 6), or invasive mechanical ventilation (19 patients, score 7-9), plus 28 convalescent patients and 28 healthy controls. Furthermore, six severe patients that recovered from the disease were longitudinally followed over 300 days. Our data indicate that severe COVID-19 patients display increased frequencies of plasmablasts, activated T cells and SARS-CoV-2-specific antibodies compared to moderate and convalescent patients. Remarkably, within the severe COVID-19 group, patients rapidly progressing into invasive mechanical ventilation show higher frequencies of plasmablasts, monocytes, eosinophils, Th1 cells and SARS-CoV-2-specific IgG than patients under high flow oxygen nasal cannula. These findings demonstrate that severe COVID-19 patients progressing into invasive mechanical ventilation show a distinctive type of immunity. In addition, patients that recover from severe COVID-19 begin to regain normal proportions of immune cells 100 days after hospital discharge and maintain high levels of SARS-CoV-2-specific IgG throughout the study, which is an indicative sign of immunological memory. Thus, this work can provide useful information to better understand the diverse outcomes of severe COVID-19 pathogenesis.
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    Liver X receptor unlinks intestinal regeneration and tumorigenesis
    (Springer Nature, 2024-10-17) Das, Srustidhar; Parigi S., Martina; Luo, Xinxin; Fransson, Jennifer; Kern, Bianca C.; Okhovat, Ali; Diaz, Oscar E.; Sorini, Chiara; Czarnewski, Paulo; Webb, Anna T.; Morales, Rodrigo A; Lebon, Sacha; Monasterio, Gustavo; Castillo, Francisca; Tripathi, Kumar P.; He, Ning; Pelczar, Penelope; Schaltenberg, Nicola; De la Fuente, Marjorie; López-Köstner, Francisco; Nylén, Susanne; Larsen, Hjalte List; Kuiper, Raoul; Antonson, Per; Hermoso, Marcela A; Huber, Samuel; Biton, Moshe; Scharaw, Sandra; Gustafsson, Jan-Åke; Katajisto, Pekka; Villablanca, Eduardo J.
    Uncontrolled regeneration leads to neoplastic transformation1-3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.
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    Pannexin-1 expression in tumor cells correlates with colon cancer progression and survival
    (Elsevier, 2024) Fierro Arenas, Aaron; Landskron, Glauben; Camhi-Vainroj, Ilan; Basterrechea, Benjamin; Parada Venegas, Daniela; Lobos Gonzalez, Lorena; Dubois Camacho, Karen; Araneda, Catalina; Romero, Camila; Dominguez, Antonia; Vasquez, Gonzalo; Lopez K, Francisco; Alvarez, Karin; Gonzalez, Carlos M; Hager Ribeiro, Carolina; Balboa, Elisa; Eugenin, Eliseo; Hermoso, Marcela A; De la Fuente, Marjorie
    Aims: Pannexin-1 (PANX1) is a hemichannel that releases ATP upon opening, initiating inflammation, cell proliferation, and migration. However, the role of PANX1 channels in colon cancer remains poorly understood, thus constituting the focus of this study. Main methods: PANX1 mRNA expression was analyzed using multiple cancer databases. PANX1 protein expression and distribution were evaluated by immunohistochemistry on primary tumor tissue and non-tumor colonic mucosa from colon cancer patients. PANX1 inhibitors (probenecid or 10Panx) were used to assess colon cancer cell lines viability. To study the role of PANX1 in vivo, a subcutaneous xenograft model using HCT116 cells was performed in BALB/c NOD/SCID immunodeficient mice to evaluate tumor growth under PANX1 inhibition using probenecid. Key findings: PANX1 mRNA was upregulated in colon cancer tissue compared to non-tumor colonic mucosa. Elevated PANX1 mRNA expression in tumors correlated with worse disease-free survival. PANX1 protein abundance was increased on tumor cells compared to epithelial cells in paired samples, in a cancer stagedependent manner. In vitro and in vivo experiments indicated that blocking PANX1 reduced cell viability and tumor growth. Significance: PANX1 can be used as a biomarker of colon cancer progression and blocking PANX1 channel opening could be used as a potential therapeutic strategy against this disease.
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    Regulation of the intestinal extra-adrenal steroidogenic pathway component LRH-1 by glucocorticoids in ulcerative colitis
    (MDPI, 2022-06-12) Landskron, Glauben; Dubois-Camacho, Karen; Orellana-Serradell, Octavio; De la Fuente, Marjorie; Parada-Venegas, Daniela; Bitrán, Mirit; Díaz-Jiménez, David; Tang, Shuang; Cidlowski, John A; Li, Xiaoling; Molina, Héctor; González, Carlos M; Simian, Daniela; Lubascher, Jaime; Pola, Victor; Montecino, Martín; Blokzijl, Tjasso; Faber, Klaas Nico; González, María-Julieta; Quera, Rodrigo; Hermoso, Marcela A
    Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GRiKO) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.