The C-terminal of Cx46 modulates the phosphorylation of Akt1 through protein-protein interactions.

Project Title

Partner Organisations

Facultad de Medicina Clínica Alemana Universidad del Desarrollo

Internal ID

1240485

Principal Investigator

RETAMAL LUCERO, MAURICIO ANTONIO

Status

VIGENTE

Start Date

April 1, 2024

End Date

March 31, 2027

Organisations

University of Talca

Fields of Science and Technology (OECD)

Natural sciences

Publications

Now showing 1 - 6 of 6

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Tumor hypoxia shapes natural killer cell anticancer activities
(Springer Science and Business Media LLC, 2025-05-30)
RETAMAL LUCERO, MAURICIO ANTONIO
;
Flavio Salazar-Onfray
;
Fermín E. González
;
Andrés Tittarelli
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Connexin46 in the nucleus of cancer cells: a possible role as transcription modulator
(Springer Science and Business Media LLC, 2025-03-27)
Ainoa Fernández-Olivares
;
Viviana P Orellana
;
Jesús Llanquinao
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NUÑEZ VASQUEZ, GONZALO ESTEBAN
;
Pablo Pérez-Moreno
Scopus© Citations 1 10
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Machine learning-based identification of efficient and restrictive physiological subphenotypes in acute respiratory distress syndrome
(Springer Science and Business Media LLC, 2025-03-01)
Gabriela Meza-Fuentes
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DELGADO BECERRA, OROZIMBA IRIS
;
Mario Barbé
;
Ignacio Sánchez
;
RETAMAL LUCERO, MAURICIO ANTONIO
Acute respiratory distress syndrome (ARDS) is a severe condition with high morbidity and mortality, characterized by significant clinical heterogeneity. This heterogeneity complicates treatment selection and patient inclusion in clinical trials. Therefore, the objective of this study is to identify physiological subphenotypes of ARDS using machine learning, and to determine ventilatory variables that can effectively discriminate between these subphenotypes in a bedside setting with high performance, highlighting potential utility for future clinical stratification approaches.</jats:p> Methodology A retrospective cohort study was conducted using data from our ICU, covering admissions from 2017 to 2021. The study included 224 patients over 18 years of age diagnosed with ARDS according to the Berlin criteria and undergoing invasive mechanical ventilation (IMV). Data on physiological and ventilatory variables were collected during the first 24 h IMV. We applied machine learning techniques to categorize subphenotypes in ARDS patients. Initially, we employed the unsupervised Gaussian Mixture Classification Model approach to group patients into subphenotypes. Subsequently, we applied supervised models such as XGBoost to perform root cause analysis, evaluate the classification of patients into these subgroups, and measure their performance.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Our models identified two ARDS subphenotypes with significant clinical differences and significant outcomes. Subphenotype Efficient (<jats:italic>n</jats:italic> = 172) was characterized by lower mortality, lower clinical severity and presented a less restrictive pattern with better gas exchange compared to Subphenotype Restrictive (<jats:italic>n</jats:italic> = 52), which showed the opposite. The models demonstrated high performance with an area under the ROC curve of 0.94, sensitivity of 94.2% and specificity of 87.5%, in addition to an F1 score of 0.85. The most influential variables in the discrimination of subphenotypes were distension pressure, respiratory frequency and exhaled carbon dioxide volume.Conclusion This study presents an approach to improve subphenotype categorization in ARDS. The generation of clustering and prediction models by machine learning involving clinical, ventilatory mechanics, and gas exchange variables allowed for more accurate stratification of patients. These findings have the potential to optimize individualized treatment selection and improve clinical outcomes in patients with ARDS.</jats:p> Graphical Abstract
Scopus© Citations 2 5
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The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression
(MDPI AG, 2025-01-04)
Macarena Díaz-Ubilla
;
RETAMAL LUCERO, MAURICIO ANTONIO
<jats:p>DUX4 is typically a repressed transcription factor, but its aberrant activation in Facioscapulohumeral Muscular Dystrophy (FSHD) leads to cell death by disrupting muscle homeostasis. This disruption affects crucial processes such as myogenesis, sarcolemma integrity, gene regulation, oxidative stress, immune response, and many other biological pathways. Notably, these disrupted processes have been associated, in other pathological contexts, with the presence of connexin (Cx) hemichannels—transmembrane structures that mediate communication between the intracellular and extracellular environments. Thus, hemichannels have been implicated in skeletal muscle atrophy, as observed in human biopsies and animal models of Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Dysferlinopathies, suggesting a potentially shared mechanism of muscle atrophy that has not yet been explored in FSHD. Despite various therapeutic strategies proposed to manage FSHD, no treatment or cure is currently available. This review summarizes the current understanding of the mechanisms underlying FSHD progression, with a focus on hormones, inflammation, reactive oxygen species (ROS), and mitochondrial function. Additionally, it explores the potential of targeting hemichannels as a therapeutic strategy to slow disease progression by preventing the spread of pathogenic factors between muscle cells.</jats:p>
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Lack of canonical activities of connexins in highly aggressive human prostate cancer cells
(Springer Science and Business Media LLC, 2024-12-19)
Catalina Asencio
;
Loreto Véliz
;
Emilia Flores-Faúndez
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Lorena Azócar
;
Carolina E. Echeverría
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>
Scopus© Citations 3 1
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Molecular Interplay Between Non-Coding RNAs and Connexins and Its Possible Role in Cancer
(MDPI AG, 2025-03-12)
Pablo Pérez-Moreno
;
Juan P. Muñoz
;
RETAMAL LUCERO, MAURICIO ANTONIO
Non-coding RNAs (ncRNAs) are sequences that do not encode for proteins and play key roles in different cellular processes, including cell proliferation and differentiation. On the other hand, connexins (Cxs) are transmembrane proteins that principally allow intercellular communication. In pathological conditions such as cancer, there is a deregulation in the expression and/or function of ncRNAs and Cxs, which in turn leads to an enhancement in the aggressive phenotype, such as a greater proliferative and invasive capacity. This suggests a plausible interplay between ncRNAs and Cxs. Based on that, this review aims to summarize the current knowledge regarding this relationship and to analyze how it may influence the development of aggressive traits in cancer cells and the clinicopathological features of cancer patients. Finally, we discuss the potential of ncRNAs and Cxs as promising clinical biomarkers for cancer diagnosis, prognosis, and therapeutic targeting.
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