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Novel Pannexin-1-Coupled Signaling Cascade Involved in the Control of Endothelial Cell Function and NO-Dependent Relaxation
(2021)
Mauricio A. Lillo
;
Pablo S. Gaete
;
Mariela Puebla
;
Pía C. Burboa
;
Inés Poblete
<jats:p>Deletion of pannexin-1 (Panx-1) leads not only to a reduction in endothelium-derived hyperpolarization but also to an increase in NO-mediated vasodilation. Therefore, we evaluated the participation of Panx-1-formed channels in the control of membrane potential and [Ca2+]i of endothelial cells. Changes in NO-mediated vasodilation, membrane potential, superoxide anion (O2⋅–) formation, and endothelial cell [Ca2+]i were analyzed in rat isolated mesenteric arterial beds and primary cultures of mesenteric endothelial cells. Inhibition of Panx-1 channels with probenecid (1 mM) or the Panx-1 blocking peptide 10Panx (60 μM) evoked an increase in the ACh (100 nM)-induced vasodilation of KCl-contracted mesenteries and in the phosphorylation level of endothelial NO synthase (eNOS) at serine 1177 (P-eNOSS1177) and Akt at serine 473 (P-AktS473). In addition, probenecid or 10Panx application activated a rapid, tetrodotoxin (TTX, 300 nM)-sensitive, membrane potential depolarization and [Ca2+]i increase in endothelial cells. Interestingly, the endothelial cell depolarization was converted into a transient spike after removing Ca2+ ions from the buffer solution and in the presence of 100 μM mibefradil or 10 μM Ni2+. As expected, Ni2+ also abolished the increment in [Ca2+]i. Expression of Nav1.2, Nav1.6, and Cav3.2 isoforms of voltage-dependent Na+ and Ca2+ channels was confirmed by immunocytochemistry. Furthermore, the Panx-1 channel blockade was associated with an increase in O2⋅– production. Treatment with 10 μM TEMPOL or 100 μM apocynin prevented the increase in O2⋅– formation, ACh-induced vasodilation, P-eNOSS1177, and P-AktS473 observed in response to Panx-1 inhibition. These findings indicate that the Panx-1 channel blockade triggers a novel complex signaling pathway initiated by the sequential activation of TTX-sensitive Nav channels and Cav3.2 channels, leading to an increase in NO-mediated vasodilation through a NADPH oxidase-dependent P-eNOSS1177, which suggests that Panx-1 may be involved in the endothelium-dependent control of arterial blood pressure.</jats:p>
7Scopus© Citations 13
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Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats
(2021)
Andrea Tapia-Bustos
;
Carolyne Lespay-Rebolledo
;
Valentina Vío
;
Ronald Pérez-Lobos
;
Emmanuel Casanova-Ortiz
<jats:p>The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 μL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.</jats:p>
Scopus© Citations 7 2
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Analyzing Olfactory Neuron Precursors Non-Invasively Isolated through NADH FLIM as a Potential Tool to Study Oxidative Stress in Alzheimer’s Disease
(2021)
Laura Gómez-Virgilio
;
Alejandro Luarte
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Daniela P. Ponce
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Bárbara A. Bruna
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BEHRENS PELLEGRINO, MARIA ISABEL
<jats:p>Among all the proposed pathogenic mechanisms to understand the etiology of Alzheimer’s disease (AD), increased oxidative stress seems to be a robust and early disease feature where many of those hypotheses converge. However, despite the significant lines of evidence accumulated, an effective diagnosis and treatment of AD are not yet available. This limitation might be partially explained by the use of cellular and animal models that recapitulate partial aspects of the disease and do not account for the particular biology of patients. As such, cultures of patient-derived cells of peripheral origin may provide a convenient solution for this problem. Peripheral cells of neuronal lineage such as olfactory neuronal precursors (ONPs) can be easily cultured through non-invasive isolation, reproducing AD-related oxidative stress. Interestingly, the autofluorescence of key metabolic cofactors such as reduced nicotinamide adenine dinucleotide (NADH) can be highly correlated with the oxidative state and antioxidant capacity of cells in a non-destructive and label-free manner. In particular, imaging NADH through fluorescence lifetime imaging microscopy (FLIM) has greatly improved the sensitivity in detecting oxidative shifts with minimal intervention to cell physiology. Here, we discuss the translational potential of analyzing patient-derived ONPs non-invasively isolated through NADH FLIM to reveal AD-related oxidative stress. We believe this approach may potentially accelerate the discovery of effective antioxidant therapies and contribute to early diagnosis and personalized monitoring of this devastating disease.</jats:p>
7Scopus© Citations 9
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Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage
(2021)
Elisa Balboa
;
Tamara Marín
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Juan Esteban Oyarzún
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Pablo S. Contreras
;
Robert Hardt
<jats:p>Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.</jats:p>
Scopus© Citations 9 1
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Prácticas y preferencias alimentarias y de actividad física en niños y niñas: Una aproximación desde los Parlamentos Escolares en establecimientos educacionales
(2023)
Tito Pizarro
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Macarena Jara
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Daisy Margarit
;
José Luis Palacios
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PINHEIRO FERNANDES, ANNA CHRISTINA
<jats:p>En Chile la malnutrición por exceso continúa en aumento, afectando especialmente a la población infantil. Solucionar esta problemática de salud pública requiere desarrollar estrategias de promoción y prevención que consideren las propuestas de las comunidades, especialmente la de los propios niños y niñas. Objetivo: Conocer las opiniones y sugerencias de niños y niñas de tercero y cuarto básico de escuelas de la zona sur de Santiago de Chile, respecto de sus prácticas alimentarias y de actividad física, en el marco del proyecto FONDEF IT 1810016. Sujetos y Método: Se desarrollaron siete parlamentos escolares en siete escuelas mediante una metodología cualitativa participativa, recogiendo las opiniones de 176 niños y niñas acerca de sus hábitos y preferencias tanto de alimentos como de actividad física. Resultados: Los alimentos más consumidos y preferidos son aquellos fáciles de preparar y de alta disponibilidad, como pan, tallarines y leche. Los alimentos que requieren preparación, como pescado, legumbres, frutas, verduras y preparaciones caseras, son menos consumidos y tienen menos preferencia. En las actividades físicas recreativas destacan los videojuegos y el fútbol. Los estudiantes proponen aumentar las horas de educación física, los recreos y mejorar la disponibilidad y acceso a alimentos saludables en los entornos escolares como estrategia de solución al problema de la malnutrición por exceso. Conclusiones: Los Parlamentos Escolares como estrategia participativa aportan en la generación conjunta de conocimiento. La necesidad de incluir a las comunidades como partes interesadas en las iniciativas de salud, reconoce a través de su participación, a los niños y las niñas como actores sujetos de derechos.</jats:p>
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Eco-epidemiology of rodent-associated trombiculid mites and infection with Orientia spp. in Southern Chile
(2023)
María Carolina Silva de la Fuente
;
Caricia Pérez
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Constanza Martínez-Valdebenito
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Pérez Ball, Ruth
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VIAL COX, MARIA CECILIA
<jats:sec id="sec001"> <jats:title>Background</jats:title> <jats:p>Scrub typhus is a potentially severe infection caused by bacteria of the genus <jats:italic>Orientia</jats:italic>, endemic in Asia-Pacific and recently discovered in southern Chile. The presented study aimed to determine the prevalence and species richness of rodent-associated trombiculid mites and their infection with <jats:italic>Orientia</jats:italic> spp. in different areas of two regions in southern Chile.</jats:p> </jats:sec> <jats:sec id="sec002"> <jats:title>Methodology/Principal findings</jats:title> <jats:p>During summer 2020, trombiculid mites were collected from rodents captured in three areas in southern Chile known to be endemic for scrub typhus (Cochamó and Chiloé Island in the Los Lagos Region and Tortel in the Aysén Region). A total of 132 rodents belonging to five species were captured using Sherman-like traps; 89.4% were infested with trombiculids. Mite specimens were morphologically identified and subsequently tested by <jats:italic>Orientia</jats:italic>-specific qPCR. Six mite species were identified. Among chigger-infested rodents, 33.9% carried <jats:italic>Orientia</jats:italic>-positive mites; this rate was higher in Tortel (63.8%) than in Cochamó (45.0%) and Chiloé Island (2.0%). The analysis of individual mites (n = 901) revealed that 31.2% of <jats:italic>Herpetacarus antarctica</jats:italic> samples (n = 202) were positive for <jats:italic>Orientia</jats:italic> DNA; the prevalence was 7.0% in <jats:italic>Paratrombicula neuquenensis</jats:italic> (n = 213), 6.9% in <jats:italic>Herpetacarus eloisae</jats:italic> (n = 144), 3.6% in <jats:italic>Argentinacarus expansus</jats:italic> (n = 55), and 0% in <jats:italic>Paratrombicula goffi</jats:italic> (n = 110) and <jats:italic>Quadraseta chiloensis</jats:italic> (n = 177). The southernmost site (Tortel) showed the highest rates of trombiculid infestation, trombiculid load, and <jats:italic>Orientia</jats:italic> infection in the captured rodents.</jats:p> </jats:sec> <jats:sec id="sec003"> <jats:title>Conclusions/Significance</jats:title> <jats:p>Our study provides new insights into the trombiculid fauna and prevalence of <jats:italic>Orientia</jats:italic> in mites collected from wild rodents in southern Chile. <jats:italic>Orientia</jats:italic> DNA was detected in four of the six mite species. Rates of infestation, mite loads, and <jats:italic>Orientia</jats:italic> prevalences differed geographically and were highest in the Aysén Region. Our data improve our knowledge on possible vectors of scrub typhus and their distribution in Chile.</jats:p> </jats:sec>
1Scopus© Citations 9 2
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A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids
(2023)
Anyelo Durán
;
David A. Priestman
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Macarena Las Las Heras
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Boris Rebolledo-Jaramillo
;
Valeria Olguín
<jats:p>Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.</jats:p>
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Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine
(2023)
Luis A. Cea
;
Walter Vásquez
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Romina Hernández-Salinas
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Alejandra Z. Vielma
;
Mario Castillo-Ruiz
<jats:p>Individuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. In the present work, the atrophy of skeletal myofibers from streptozotocin-induced diabetic rats was prevented with boldine, suggesting that non-selective channels inhibited by this alkaloid are involved in this process, as has previously shown for other muscular pathologies. Accordingly, we found a relevant increase in sarcolemma permeability of skeletal myofibers of diabetic animals in vivo and in vitro due to de novo expression of functional connexin hemichannels (Cx HCs) containing connexins (Cxs) 39, 43, and 45. These cells also expressed P2X7 receptors, and their inhibition in vitro drastically reduced sarcolemma permeability, suggesting their participation in the activation of Cx HCs. Notably, sarcolemma permeability of skeletal myofibers was prevented by boldine treatment that blocks Cx43 and Cx45 HCs, and now we demonstrated that it also blocks P2X7 receptors. In addition, the skeletal muscle alterations described above were not observed in diabetic mice with myofibers deficient in Cx43/Cx45 expression. Moreover, murine myofibers cultured for 24 h in high glucose presented a drastic increase in sarcolemma permeability and levels of NLRP3, a molecular member of the inflammasome, a response that was also prevented by boldine, suggesting that, in addition to the systemic inflammatory response found in diabetes, high glucose can promote the expression of functional Cx HCs and activation of the inflammasome in skeletal myofibers. Therefore, Cx43 and Cx45 HCs play a critical role in myofiber degeneration, and boldine could be considered a potential therapeutic agent to treat muscular complications due to diabetes.</jats:p>
5Scopus© Citations 18

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