Browsing by Author "Cancino Lobos, Gonzalo Ignacio"

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    Loss of stimulator of interferon genes (STING) promotes accumulation of cholesterol and triglycerides throughout life in mice
    (2025) Riquelme, Ian; Carrillanca, Daniela; Sánchez-Pérez, Camila; Monterroza, Andrea; Hernández-Rojas, Bairon; Riadi, Gonzalo; Cancino Lobos, Gonzalo Ignacio; Murgas, Paola
    Background The Stimulator of Interferon Genes (STING) pathway is pivotal in innate immunity, facilitating the detection of cytosolic DNA and initiating type I interferon-dependent responses. In addition to its immunological roles, STING has been increasingly associated with metabolic regulation, since research indicates that its inhibition can diminish inflammation, lipid accumulation, and tissue damage in obesity and other metabolic disorders. The findings have prompted the suggestion of STING inhibition as a viable treatment approach for metabolic illness. Nonetheless, the physiological function of STING in lipid homeostasis under normal settings remains largely unexplored, as does the impact of its absence on metabolism throughout various life stages in the absence of disease. This information deficit is crucial, particularly in light of the increasing interest in the long-term pharmacological suppression of STING. Results To examine the function of STING in lipid metabolism during physiological, non-pathological conditions throughout the lifespan, we assessed WT and STINGKO mice at various ages and discovered that STING deficiency results in a consistent increase in body weight, independent of alterations in locomotor activity or food consumption. STINGKO mice exhibited markedly increased circulation levels of triglycerides and total cholesterol. Histological and morphological analysis demonstrated augmented fat accumulation in adipose and hepatic tissues, despite the lack of nutritional or genetic metabolic stress. These findings indicate a crucial function for STING in the control of lipid homeostasis across the lifespan. Conclusions In contrast to earlier research conducted under pathological conditions, our findings indicate that the total absence of STING expression in healthy contexts leads to heightened lipid accumulation in tissues and blood. These findings underscore an unforeseen function of STING as a modulator of lipid metabolism in the context of longevity. They caution against the prolonged use of STING inhibitors, as chronic STING suppression may lead to detrimental metabolic effects. This study offers new insights into the non-immune roles of STING, indicating its significance in preserving metabolic equilibrium throughout the lifetime.
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    Neural conditional ablation of the protein tyrosine phosphatase receptor Delta PTPRD impairs gliogenesis in the developing mouse brain cortex
    (Frontiers Media SA, 2024) Cornejo Castillo, Francisca Alejandra; Franchini, Nayhara; Cortes, Bastián I.; Elgueta, Daniela; Cancino Lobos, Gonzalo Ignacio
    Neurodevelopmental disorders are characterized by alterations in the development of the cerebral cortex, including aberrant changes in the number and function of neural cells. Although neurogenesis is one of the most studied cellular processes in these pathologies, little evidence is known about glial development. Genetic association studies have identified several genes associated with neurodevelopmental disorders. Indeed, variations in the PTPRD gene have been associated with numerous brain disorders, including autism spectrum disorder, restless leg syndrome, and schizophrenia. We previously demonstrated that constitutive loss of PTPRD expression induces significant alterations in cortical neurogenesis, promoting an increase in intermediate progenitors and neurons in mice. However, its role in gliogenesis has not been evaluated. To assess this, we developed a conditional knockout mouse model lacking PTPRD expression in telencephalon cells. Here, we found that the lack of PTPRD in the mouse cortex reduces glial precursors, astrocytes, and oligodendrocytes. According to our results, this decrease in gliogenesis resulted from a reduced number of radial glia cells at gliogenesis onset and a lower gliogenic potential in cortical neural precursors due to less activation of the JAK/STAT pathway and reduced expression of gliogenic genes. Our study shows PTPRD as a regulator of the glial/neuronal balance during cortical neurodevelopment and highlights the importance of studying glial development to understand the etiology of neurodevelopmental diseases.
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    Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice
    (Elsevier B.V., 2024) Chandía Cristi, América Valeska; Gutiérrez García, Daniela A.; Dulcey, Andrés E.; Lara, Marcelo; Vargas Rojas, Lina Marcela; Lin, Yi-Han; Jiménez Muñoz, Pablo Salvador; Larenas Barrera, Gabriela Paz; Xu, Xin; Wang, Amy; Owens, Ashley; Dextras, Christopher; Chen, YuChi; Pinto, Claudio; Marín Marín, Tamara Alejandra; Almarza Salazar, Hugo Alcester; Acevedo, Keryma; Cancino Lobos, Gonzalo Ignacio; Hu, Xin; Rojas, Patricio; Ferrer, Marc; Southall, Noel; Henderson, Mark J.; Zanlungo Matsuhiro, Silvana; Marugan, Juan J.; Álvarez Rojas, Alejandra
    The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-D-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.