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    Genomic modifiers of neurological resilience in a Niemann‐Pick C family
    (Wiley, 2025-06-12)
    Macarena Las Heras
    ;
    Benjamín Szenfeld
    ;
    Valeria Olguín
    ;
    Juan Carlos Rubilar
    ;
    CALDERON GIADROSIC, JUAN FRANCISCO  
    Niemann-Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss-of-function variants in CCDC115, SLC4A5, DEPDC5, ETFDH, SNRNP200, and DOCK1 that co-segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC-like severity based on orthologous gene variants. RNA-seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1, enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target.
      6
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    Omega-3 Fatty Acids and Exercise in Obesity Management: Independent and Synergistic Benefits in Metabolism and Knowledge Gaps
    (MDPI AG, 2025-04-24)
    Viviana Sandoval
    ;
    Álvaro Vergara-Nieto
    ;
    Amanda Bentes
    ;
    Saulo Silva
    ;
    Carolina Núñez
    Obesity is a significant global health issue, profoundly affecting metabolic and cardiovascular health and other related chronic conditions. In Chile, the prevalence of obesity is among the highest within the Organisation for Economic Cooperation and Development (OECD) countries, highlighting a critical public health challenge. This narrative review examines current evidence on the independent and potential synergistic roles of omega-3 fatty acids and exercise in managing obesity-related metabolic dysfunction. Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA), have been shown to lower triglyceride levels, enhance lipid metabolism, and modulate inflammation via pathways involving peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). Exercise interventions, such as moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT), provide distinct yet complementary metabolic benefits. Specifically, MICT improves body fat distribution and mitochondrial efficiency, whereas HIIT has notable effects on metabolic adaptability and insulin signaling. Additionally, emerging evidence points toward a potential role of the kinin-kallikrein system, particularly kallikrein 7 (KLK7), in obesity-associated insulin resistance. Despite these promising findings, several knowledge gaps persist regarding optimal dosing, intervention timing, population-specific effects, and the exact mechanisms behind the potential synergistic interactions between omega-3 supplementation and structured exercise. This review emphasizes the importance of conducting further research, particularly controlled clinical trials, to clarify these combined interventions’ effectiveness and establish targeted therapeutic strategies tailored to individual metabolic profiles.
    Scopus© Citations 3  1
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      2
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    Dermatitis atópica severa en la infancia en la era de la medicina personalizada
    (2024)
    Rosario Agüero Ureta
    ;
    Edinson López Bravo
    ;
    María Trinidad Hasbún Zegpi
    <jats:p> La dermatitis atópica (DA) es una dermatosis crónica e inflamatoria no infecciosa, con prevalencia creciente en las últimas décadas. De curso crónico y recurrente, deteriora la calidad de vida de los pacientes y su familia. Los avances en la comprensión de la fisiopatología de la DA han impulsado el desarrollo de terapias dirigidas, como los anticuerpos monoclonales (mAb) y los inhibidores de la quinasa Janus (JAKis), las cuales modulan el sistema inmunológico a través de vías de señalización específicas, ofreciendo alternativas efectivas a los agentes inmunosupresores sistémicos tradicionales. En EE.UU. se han aprobado cuatro terapias dirigidas para el tratamiento de los casos severos/refractarios: dupilumab, tralokinumab, abrocitinib y upadacitinib. El objetivo de este manuscrito es presentar una actualización sobre la fisiopatología de la DA, describir los nuevos tratamientos disponibles y realizar un análisis de los resultados iniciales de la utilización de dichos tratamientos en pediatria. Se concluye que el alto costo de estos tratamientos suele limitar su prescripción a situaciones en las que los casos de DA son resistentes a otras opciones terapéuticas convencionales o cuando su curso es severo. Se resalta la importancia de toma de decisiones cuidadosa y precisa en la atención médica de la DA, con el fin de garantizar el uso eficiente de estos recursos terapéuticos. </jats:p>
      9
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    Scopus© Citations 1  4
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    MET Signaling Pathways, Resistance Mechanisms, and Opportunities for Target Therapies
    (2022)
    RIVAS VERA, SOLANGE VERÓNICA  
    ;
    Arnaldo Marín
    ;
    Suraj Samtani
    ;
    Evelin González-Feliú
    ;
    ARMISEN YAÑEZ, RICARDO AMADO  
    <jats:p>The MET gene, known as MET proto-oncogene receptor tyrosine kinase, was first identified to induce tumor cell migration, invasion, and proliferation/survival through canonical RAS-CDC42-PAK-Rho kinase, RAS-MAPK, PI3K-AKT-mTOR, and β-catenin signaling pathways, and its driver mutations, such as MET gene amplification (METamp) and the exon 14 skipping alterations (METex14), activate cell transformation, cancer progression, and worse patient prognosis, principally in lung cancer through the overactivation of their own oncogenic and MET parallel signaling pathways. Because of this, MET driver alterations have become of interest in lung adenocarcinomas since the FDA approval of target therapies for METamp and METex14 in 2020. However, after using MET target therapies, tumor cells develop adaptative changes, favoring tumor resistance to drugs, the main current challenge to precision medicine. Here, we review a link between the resistance mechanism and MET signaling pathways, which is not only limited to MET. The resistance impacts MET parallel tyrosine kinase receptors and signals shared hubs. Therefore, this information could be relevant in the patient’s mutational profile evaluation before the first target therapy prescription and follow-up to reduce the risk of drug resistance. However, to develop a resistance mechanism to a MET inhibitor, patients must have access to the drugs. For instance, none of the FDA approved MET inhibitors are registered as such in Chile and other developing countries. Constant cross-feeding between basic and clinical research will thus be required to meet future challenges imposed by the acquired resistance to targeted therapies.</jats:p>
    Scopus© Citations 15  16
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    Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research
    (2022)
    Valeria Olguín
    ;
    Anyelo Durán
    ;
    Macarena Las Heras
    ;
    Juan Carlos Rubilar
    ;
    Francisco A. Cubillos
    <jats:p>We are all similar but a bit different. These differences are partially due to variations in our genomes and are related to the heterogeneity of symptoms and responses to treatments that patients exhibit. Most animal studies are performed in one single strain with one manipulation. However, due to the lack of variability, therapies are not always reproducible when treatments are translated to humans. Panels of already sequenced organisms are valuable tools for mimicking human phenotypic heterogeneities and gene mapping. This review summarizes the current knowledge of mouse, fly, and yeast panels with insightful applications for translational research.</jats:p>
      46Scopus© Citations 8
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    Scopus© Citations 7  3