Artículos (Fisiología)

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Adolescent binge drinking disrupts hepatic lipid homeostasis, leading to steatosis in rats: protective role of folic acid in cholesterol and fatty acid balance
(American Physiological Society Journals, 2025) Gallego López, María del Carmen; Nogales Bueno, Fátima; Romero Herrera, Inés; Santana Garrido, Álvaro; Carreras Sánchez, Olimpia; Ojeda Murillo, María Luisa; Fisiología; Junta de Andalucía
Alcohol liver damage (ALD) is increasing worldwide among adolescents, along with binge drinking (BD). BD is an acute alcohol consumption pattern, strongly pro-oxidant in the liver, and may be associated with steatosis, the first step in ALD. Folic acid (FA), an antioxidant crucial for liver function, shows compromised hepatic stores after BD. Therefore, this study aims to analyze the hepatic lipid changes associated with BD-induced steatosis during adolescence in rats and to evaluate the efficacy of FA supplementation in preventing these alterations. Four groups of adolescent rats were used: control, BD (intraperitoneal alcohol exposure), control FA-supplemented, and BD-FA-supplemented. FA content was 2 ppm in control diets and 8 ppm in supplemented groups. BD impaired liver function by increasing transaminases and UGT-1 expression. BD also induced dyslipidemia and an anabolic liver lipid state by increasing hepatic cholesteryl esters depots through dysregulation of cholesterol modulators (HMGCR, SREBP1, LDLR, SR-B1, ACAT-2, and Ces1d) and enhancing FXR expression, which affected liver bile acid balance. Furthermore, BD promoted all sources of hepatic free fatty acids (de novo synthesis, dietary source, and adipose tissue uptake) and impaired their hepatic clearance, contributing to steatosis as confirmed by microvesicular lipid droplet accumulation. FA supplementation, mainly by improving hepatic cholesterol balance and stimulating free fatty acid mobilization, partially prevented these alterations, with beneficial effects on cardiovascular health. In conclusion, this study demonstrates for the first time that BD in adolescents disturbs hepatic lipid homeostasis, leading to steatosis, and that FA therapy could be used to mitigate these deleterious effects.
Mitochondrial Haplogroups and Weight Gain After Initiating ART in Patients With HIV
(Oxford University Press, 2024-08-15) Berenguer, J.; Jarrín, I.; Bellón, J. M.; Díez, C.; Jiménez-Sousa, M. A.; López, J. C.; González-Serna Martín, Manuel Alejandro; Fisiología; Merck Sharp & Dhome; Consorcio Centro de Investigación Biomédica en Red; Instituto de Salud Carlos III
We studied the association of mitochondrial DNA (mtDNA) haplogroups with weight and body mass index (BMI) gain at 96 weeks in 1019 treatment-naive persons with HIV (PWH) who initiated first-line antiretroviral therapy (ART) since 2014. The mean increase in weight and BMI over the study period was 2.90 kg and 0.98 kg/m2, respectively. We found a significant adjusted association between the major UK mtDNA haplogroup and lower weight and BMI increase at 96 weeks after ART initiation. Our findings reveal a potential role for mitochondrial genetics in the complex phenomenon of weight gain after initial ART in PWH.
Metabolic dysfunction-associated steatotic liver disease alters brain function and behavior: Insights from liver-targeted siRNA therapy
(Amer assoc advancement science, 2025-10-22) Cardoso Delgado, Teresa; Martín-Cuevas, Celia; Sánchez Hidalgo, Ana C.; Gil Gómez, Antonio; Rejano Gordillo, Claudia M.; Landa, Jon; Gallego Durán, Rocío; Romero Gómez, Manuel; Crespo Facorro, Benedicto; Martínez-Chantar, María Luz; Medicina; Fisiología; Psiquiatría; Instituto de Biomedicina de Sevilla (IBIS); CTS1086: Psiquiatría Traslacional
Metabolic dysfunction-associated steatotic liver disease (MASLD), a liver-centric condition, is associated with cognitive impairment and sensorimotor alterations. However, it remains unclear whether MASLD is sufficient to drive central nervous system deficits. Here, using diet-induced mouse models, we showed that MASLD was associated with alterations in social memory, sensorimotor processing, and hippocampal function, including decreased parvalbumin-positive interneurons, reduced dendritic spine density, and diminished dentate gyrus neurogenesis and neuronal differentiation. Then, we selectively modulated liver metabolism through N-acetylgalactosamine small interfering RNA (siRNA) therapy against Cyclin M4 (CNNM4), a magnesium transporter dysregulated in MASLD. Liver-specific intervention with siRNA-Cnnm4 reversed impaired social memory and sensorimotor processing in association with recovery of hippocampal synaptogenesis and mitochondrial function pathways, alongside activation of neurogenesis-associated transcriptional programs. Our findings demonstrate that liver pathology is sufficient to drive neurobehavioral and hippocampal dysfunction in MASLD. Hepatic-specific intervention restores brain function, strongly supporting the existence of a causal and therapeutically targetable liver-brain axis for MASLD-associated neurological complications.
Endothelin-1 Signaling in the Kidney: Recent Advances and Remaining Gaps
(American Physiological Society, 2025) Brooks, Abigail J.; Gallego López, María del Carmen; De Miguel, Carmen; Fisiología; Deep South KUH PRIME; Universidad de Sevilla; Diabetes Research Connection; National Institute of Diabetes and Digestive and Kidney Diseases
The involvement of endothelin-1 (ET-1) in the maintenance of kidney function as well as its role in renal pathophysiology hasbeen appreciated for decades; however, there still exist important gaps in knowledge in our understanding of the mechanisticpathways activated by this system in the kidney. The purpose of this article is to review recent advances in the ﬁeld, as well asto underscore areas that need more investigation, with an emphasis on the interplay of ET-1 with inﬂammation, sex differences,circadian rhythms of renal function, the most recent clinical trials involving the ET-1 system, and the interaction betweenmicroRNAs and the ET-1 system.
Mathematical Modeling of Neuroblast Migration Toward the Olfactory Bulb
(Elsevier, 2025) Acosta Soba, Daniel; Castro, Carmen; Geribaldi Doldán, Noelia; Guillén González, Francisco Manuel; Núñez Abades, Pedro Antonio; Ortega Román, Noelia; Pérez García, Patricia; Rodríguez Galván, J. Rafael; Fisiología; Ecuaciones Diferenciales y Análisis Numérico; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Cádiz; University of Tennessee; Junta de Andalucía
This article is devoted to the mathematical modeling of the migration of neuroblasts, precursor cells of neurons, along the Rostral Migratory Stream (RMS), the pathway they usually follow before maturing. According to our model, this way is determined mainly by attraction forces to the olfactory bulb, and also by the heterogeneous mobility of neuroblasts in different regions of the brain. Carefully identifying them as solutions to partial differential equations allows us to determine the movement of neuroblasts along the RMS in a realistic fashion. For solving the equations we develop numerical schemes where the application of novel discontinuous Galerkin methods allows to maintain the properties of the continuous model such as the maximum principle. We present some successful computer tests including parameter adjustment to fit real data from rodent brains.
High rate of major drug–drug interactions of lopinavir–ritonavir for COVID-19 treatment
(Nature Publishing Group; Nature Portfolio, 2020-12-01) Macías Sánchez, Juan; Pinilla, Ana; Lao-Dominguez, Francisco A.; Corma, Anaïs; Contreras Macías, Enrique; González-Serna Martín, Manuel Alejandro; Morillo Verdugo, Ramón Alejandro; Real Navarrete, Luis Miguel; Pineda Vergara, Juan Antonio; Medicina; Fisiología; Farmacología; Bioquímica Médica y Biología Molecular e Inmunología
The impact of drug–drug interactions (DDI) between ritonavir-boosted lopinavir (LPV-r) to treat patients with coronavirus disease 2019 (COVID-19) and commonly used drugs in clinical practice is not well-known. Thus, we evaluated the rate and severity of DDI between LPV-r for COVID-19 treatment and concomitant medications. This was a cross-sectional study including all individuals diagnosed of SARS-CoV-2 infection treated with LPV-r and attended at a single center in Southern Spain (March 1st to April 30th, 2020). The frequency [95% confidence interval (95% CI)] of potential and major DDI were calculated. Overall, 469 patients were diagnosed of COVID-19, 125 (27%) of them were prescribed LPV-r. LPV-r had potential DDI with concomitant medications in 97 (78%, 95% CI 69–85%) patients, and in 33 (26%, 95% CI 19–35%) individuals showed major DDI. Twelve (36%) patients with major DDI and 14 (15%) individuals without major DDI died (p = 0.010). After adjustment, only the Charlson index was independently associated with death [adjusted OR (95% CI) for Charlson index ≥ 5: 85 (10–731), p < 0.001]. LPV-r was discontinued due to side effects in 31 (25%) patients. Management by the Infectious Diseases Unit was associated with a lower likelihood of major DDI [adjusted odds ratio (95% CI): 0.14 (0.04–0.53), p = 0.003). In conclusion, a high frequency of DDI between LPV-r for treating COVID-19 and concomitant medications was found, including major DDI. Patients with major DDI showed worse outcomes, but this association was explained by the older age and comorbidities. Patients managed by the Infectious Diseases Unit had lower risk of major DDI.
How do women living with HIV experience menopause? Menopausal symptoms, anxiety and depression according to reproductive age in a multicenter cohort
(Biomed central LTD, 2021-05-28) Suarez-Garcia, I.; Alejos, B.; Perez-Elias, M.J.; Iribarren, J.A.; Hernando, A.; Ramirez, M.; Hernando, V.; CoRIS Cohort; Pineda Vergara, Juan Antonio; Macías Sánchez, Juan; Merchante Gutiérrez, Nicolás; Real Navarrete, Luis Miguel; González-Serna Martín, Manuel Alejandro; Pousada, Guillermo; Medicina; Fisiología; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Instituto de Salud Carlos III a través de la Red Temática de Investigación Cooperativa en Asdi, Plan Nacional I+D+I; ISCIII-Subdireccion General de Evaluacion; Accion Estrategica en Salud Intramural
Background: To estimate the prevalence and severity of menopausal symptoms and anxiety/depression and to assess the differences according to menopausal status among women living with HIV aged 45-60 years from the cohort of Spanish HIV/AIDS Research Network (CoRIS). Methods: Women were interviewed by phone between September 2017 and December 2018 to determine whether they had experienced menopausal symptoms and anxiety/depression. The Menopause Rating Scale was used to evaluate the prevalence and severity of symptoms related to menopause in three subscales: somatic, psychologic and urogenital; and the 4-item Patient Health Questionnaire was used for anxiety/depression. Logistic regression models were used to estimate odds ratios (ORs) of association between menopausal status, and other potential risk factors, the presence and severity of somatic, psychological and urogenital symptoms and of anxiety/depression. Results: Of 251 women included, 137 (54.6%) were post-, 70 (27.9%) peri- and 44 (17.5%) pre-menopausal, respectively. Median age of onset menopause was 48 years (IQR 45-50). The proportions of pre-, peri- and post-menopausal women who had experienced any menopausal symptoms were 45.5%, 60.0% and 66.4%, respectively. Both peri- and post-menopause were associated with a higher likelihood of having somatic symptoms (aOR 3.01; 95% CI 1.38-6.55 and 2.63; 1.44-4.81, respectively), while post-menopause increased the likelihood of having psychological (2.16; 1.13-4.14) and urogenital symptoms (2.54; 1.42-4.85). By other hand, post-menopausal women had a statistically significant five-fold increase in the likelihood of presenting severe urogenital symptoms than pre-menopausal women (4.90; 1.74-13.84). No significant differences by menopausal status were found for anxiety/depression. Joint/muscle problems, exhaustion and sleeping disorders were the most commonly reported symptoms among all women. Differences in the prevalences of vaginal dryness (p = 0.002), joint/muscle complaints (p = 0.032), and sweating/flush (p = 0.032) were found among the three groups. Conclusions: Women living with HIV experienced a wide variety of menopausal symptoms, some of them initiated before women had any menstrual irregularity. We found a higher likelihood of somatic symptoms in peri- and post-menopausal women, while a higher likelihood of psychological and urogenital symptoms was found in post-menopausal women. Most somatic symptoms were of low or moderate severity, probably due to the good clinical and immunological situation of these women.
Effectiveness of the combination elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COB/TFV/FTC) plus darunavir among treatment-experienced patients in clinical practice: A multicentre cohort study
(Biomed Central Ltd, 2020-07-20) López Cortés, Luis Fernando; Macías Sánchez, Juan; Merchante Gutiérrez, Nicolás; Real Navarrete, Luis Miguel; González-Serna Martín, Manuel Alejandro; Suárez-García, Inés; Moreno, Cristina; Ruiz-Algueró, Marta; Pérez-Elías, María Jesús; Navarro, Marta; Díez Martínez, Marcos; Medicina; Bioquímica Médica y Biología Molecular e Inmunología; Fisiología; Instituto de Salud Carlos III; Gobierno de España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Background: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegra vir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods: Treatment experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014–2018 and with more than 24 weeks of follow up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen). Results: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with base line VL ≥ 50 copies/ml) changed due to virological failure. Conclusions: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment experienced patients with undetectable viral load as a simplification strategy, allowing once daily, two pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads.
Regulation of transcription elongation anticipates alternative gene expression strategies across the cell cycle
(Public Library of Science, 2025-05-07) Maya Miles, Douglas; García-Martínez, José; Cases, Idelfonso; Pasión, Rocío; Cruz Díaz, Jesús de la; Pérez-Ortín, José Enrique; Muñoz Centeno, María de la Cruz; Chávez de Diego, Sebastián; Genética; Fisiología
A growing body of evidence supports the idea that RNA polymerase II (RNAP II) activity during transcription elongation can be regulated to control transcription rates. Using genomic run-on and RNAP II chromatin immunoprecipitation, we measured both active and total RNAP II across the bodies of genes at three different stages of the mitotic cell cycle in Saccharomyces cerevisiae: G1, S, and G2/M. Comparison of active and total RNAP II levels at these stages revealed distinct patterns of transcription elongation control throughout the cell cycle. Previously characterized cycling genes were associated with some of these elongation patterns. A cluster of genes with highly divergent genomic run-on and RNAP II chromatin immunoprecipitation patterns was notably enriched in genes related to ribosome biogenesis and the structural components of the ribosome. We confirmed that the expression of ribosome biogenesis mRNAs increases after G1 but decreases following mitosis. Finally, we analyzed the contribution of mRNA stability to each cluster and found that a coordinated regulation of RNAP II activity and mRNA decay is necessary to fully understand the alternative strategies of gene expression across the cell cycle.
Sex-specific differences in preclinical models of advanced chronic liver disease and portal hypertension
(BioMed Central, 2025-06-03) Aristu Zabalza, Peio; Andrés Rozas, María; Boyer Díaz, Zoé; Al-Adra, David P.; Maya Miles, Douglas; Guixe Muntet, Sergi; Fernández Iglesias, Anabel; Gracia Sancho, Jordi; Fisiología; Instituto de Salud Carlos III; European Union (UE); Generalitat de Catalunya
Background Chronic liver disease is a major health concern, but sex-specific differences in its pathophysiology remain unclear. Preclinical studies have predominantly used male animals, limiting findings' relevance to both sexes. This project aimed to explore sex differences in cirrhosis and portal hypertension (PH) in rats, and to find similarities in human samples for translational relevance. Methods Advanced chronic liver disease (ACLD) was induced in male and female Sprague–Dawley rats using thioacetamide (TAA, 250 mg/kg; 12 weeks) or bile duct ligation (BDL; 28 days). Healthy rats served as controls (n = 11–18/group). We assessed in vivo hepatic and systemic hemodynamic parameters, hepatic microvascular function, and hepatic transcriptomic analyses, including sex-specific differences in cellular composition using gene deconvolution (n = 5/group). Two human sample cohorts were compared to preclinical data for translational insights. Results Both animal models showed PH. TAA males had similar portal pressure (PP) to females (14.2 vs 14.1 mmHg), but BDL males had significantly higher PP than females (14.5 vs 12.5 mmHg; p = 0.003). No differences were observed in hepatic microvascular function. In the BDL model, females had more fenestrae and porosity, and less fibrosis. Transcriptomic analysis revealed that TAA males had dysregulated metabolic pathways, while females had deregulated genes in hormone signaling. In the BDL model, males showed higher deregulation in platelet activation, protein degradation, vesicular transport, and disease-related pathways. Gene deconvolution showed males had a more specialized endothelial phenotype basally, with more changes in endothelial and macrophage phenotypes after injury. In MASLD patients, men had dysregulated metabolic pathways, while women showed deregulation in fibrosis, extracellular matrix, and endocrine regulation. In HBV patients, men had more dysregulation in fibrosis, inflammation, and immune response. Female MASLD patients had more activated hepatic stellate cells, and greater loss of endothelial phenotype compared to men. Conclusions This study highlights sex-dependent molecular differences in the pathophysiology of cirrhosis in two preclinical models. Further research in preclinical and human liver disease is essential to develop safe and effective treatments for ACLD in both sexes.
Unveiling Protective Mechanisms of Wild Olive (Acebuche) Oil in Retinal Pigment Epithelial Cells with Hypertensive Phenotype
(Wiley, 2025) Santana Garrido, Álvaro; Reyes Goya, Claudia; Espinosa Martín, P.; Troya Toledo, Rosa María; André, H.; Mate Barrero, Alfonso; Vázquez Cueto, Carmen María; Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Junta de Andalucía; Universidad de Sevilla; Ministerio de Ciencia e Innovación (MICIN). España
Arterial hypertension leads to oxidative and inflammatory imbalances, triggering hyper-tensive organ damage through several pathways. We have previously described the antioxidant andanti-inflammatory properties of olive oil extracted from the wild olive tree (Olea europaea var.sylvestris, acebuche, ACE) against hypertensive ocular damage. The aim of this study was to clarifythe molecular mechanisms involved in the beneficial effect of ACE oil on hypertensive eyes, focusingon nitric oxide (NO)/arginine metabolism. To this end, we used retinal pigment epithelial cells(ARPE19) treated with angiotensin II as a hypertensive-like model. These cells were also incubatedwith extracellular vesicles (EVs) isolated from animals fed diets enriched in either ACE oil or extravirgin olive oil (EVOO), with the latter serving as a reference oil for comparison. Our results showedthat circulating ACE oil- and EVOO-derived EVs can modulate the production of reactive oxygenspecies by both NADPH oxidase and mitochondria, the activity and expression of l-arginine trans-porter CAT-1, angiotensin AT1 and AT2 receptors, and arginases, as well as the levels of NO andasymmetric dimethylarginine. Our findings demonstrate that: (1) changes in NO metabolism areinvolved in the protective effects of wild olive oil against hypertension-related ocular oxidative stress,and (2) these modifications appear to be mediated by EVs.
Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders
(Soc Neuroscience, 2024-10-02) Wlodarczyk, Jakub; Bhattacharyya, Raja; Dore, Kim; Ho, Gary P. H.; Martin, Dale D. O.; Mejías Estévez, Rebeca María; Hochrainer, Karin; Fisiología
Palmitoylation, a lipid-based posttranslational protein modification, plays a crucial role in regulating various aspects of neuronal,function through altering protein membrane-targeting, stabilities, and protein–protein interaction profiles. Disruption of palmitoylation has recently garnered attention as disease mechanism in neurodegeneration. Many proteins implicated in neurodegenerative,diseases and associated neuronal dysfunction, including but not limited to amyloid precursor protein, β-secretase (BACE1),,postsynaptic density protein 95, Fyn, synaptotagmin-11, mutant huntingtin, and mutant superoxide dismutase 1, undergo,palmitoylation, and recent evidence suggests that altered palmitoylation contributes to the pathological characteristics of these,proteins and associated disruption of cellular processes. In addition, dysfunction of enzymes that catalyze palmitoylation and depalmitoylation has been connected to the development of neurological disorders. This review highlights some of the latest advances in,our understanding of palmitoylation regulation in neurodegenerative diseases and explores potential therapeutic implications.
Dissimilar Effects of Selenite and Selenium Nanoparticles on Skeletal Muscle Development Unrelated to GPx1 Activity During Adolescence in Rats
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-05-28) Nogales Bueno, Fátima; Pajuelo Domínguez, Eloísa; Gallego López, María del Carmen; Romero Herrera, Inés; Merchán Ignacio, Francisco; Carreras Sánchez, Olimpia; Ojeda Murillo, María Luisa; Fisiología; Microbiología y Parasitología; Junta de Andalucía; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Background/Objectives: During adolescence, the critical growth period, the antioxidant selenium (Se), either as sodium selenite or selenium nanoparticles (SeNPs), has shown contrasting effects on adipose tissue (AT) in rats, due to its role in insulin signaling. Since skeletal muscle (SKM) is also a key insulin-target tissue, this study aimed to assess whether a similar effect occurs in this tissue. Methods: Three groups of male adolescent rats (n = 18) were used: control (C), selenite supplemented (S), and SeNPs supplemented (NS). Low doses of Se were administered via drinking water in both supplemented groups. AT was utilized for transcriptomic analyses, while SKM was analyzed for oxidative balance, insulin-induced anabolic effects, and proteolysis. Myokine levels in serum were also determined. Results: SeNPs administration decreased SKM mass and protein content, increased serum creatinine, and decreased insulin levels, indicating impaired SKM development. Both supplemented groups upregulated genes related to creatine metabolism and muscle contraction. However, only the NS group showed upregulation of genes associated with glycogenolysis and glycolysis. Despite unchanged GPx1 expression, NS rats presented lower oxidation and insulin–pmTOR activation, and higher expression of proteins related to proteolysis (pAMPK, SIRT1, ULK1, FOXO3a, and MaFbx) and a myokine profile compatible to muscle atrophy, fatty acid oxidation, and impaired myoblast proliferation. Ultimately, the selenite group impaired SKM catabolism mainly by increasing insulin–pmTOR activation. Conclusions: Once again, the form of Se administration exerts opposing effects on metabolism tissues, suggests a potential therapeutic role for selenite in disorders that compromise muscle growth, such as muscular dystrophies, cachexia, or sarcopenia.
The Subventricular Zone Neurogenic Niche Provides Adult Born Functional Neurons to Repair Cortical Brain Injuries in Response to Diterpenoid Therapy
(BioMed Central, 2025) Pardillo Díaz, Ricardo; Pérez García, Patricia; Ortego Domínguez, María; Gómez Oliva, Ricardo; Martínez Gómez, Nora; Domínguez García, Samuel; García Cózar, Francisco; Muñoz Miranda, Juan Pedro; Hernández Galán, Rosario; Carrascal Moreno, María Livia; Castro, Carmen; Núñez Abades, Pedro Antonio; Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Introduction: Neural stem cells from the subventricular zone (SVZ) neurogenic niche provide neurons that integrate in the olfactory bulb circuitry. However, in response to cortical injuries, the neurogenic activity of the SVZ is significantly altered, leading to increased number of neuroblasts with a modified migration pattern that leads cells towards the site of injury. Despite the increased neurogenesis and migration, many newly generated neurons fail to survive or functionally integrate into the cortical circuitry. Providing the injured area with the adequate signaling molecules may improve both migration and functional integration of newly generated neurons. Methods: In here, we have studied the effect of a diterpene with the capacity to induce neuregulin release at promoting neurogenesis in a murine model of cortical brain injury. Using green fluorescent protein expressing vectors we have labeled SVZ cells and have studied the migration of newly generated neuroblasts toward the injury in response the treatment. In addition, using electrophysiological recordings we have studied the differentiation of these neuroblasts into mature neurons and their functional integration into the cortical circuitry. We have studied their electrical properties, their morphology and cortical location. Results: We have found that EOF2 treatment of adult mice with mechanical cortical injuries facilitates the delivery of neuroblasts into these injuries. The newly generated neurons develop features of fully functional neurons. Our results show that the newly generated neurons receive electrical inputs, fire action potentials, and undergo complete differentiation into neurons recapitulating the stages that distinguish ontogenic differentiation. These neurons develop features representative of neurons belonging the cortical layer in which they are situated. We have also studied that EOF2 facilitates neuregulin release in SVZ cells, a signaling factor that promotes neuronal differentiation. Neuregulin is expressed in microglial cells that reach the injury in response to the damage and its release is increased by EOF2 treatment. Conclusion: Promoting neuregulin release via diterpene treatment facilitates migration of SVZ-derived neuroblasts to cortical injuries stimulating their differentiation into mature functional neurons, which receive electrical inputs and develop features of cortical neurons. These findings highlight the role of diterpenoids as a potential therapy to repair cortical brain injuries.
Influence of Cellular Aging on Liver Stiffness in Patients With Hepatitis C Virus Achieving Sustained Viral Response
(Oxford, 2025) González-Serna Martín, Manuel Alejandro; Corma Gómez, Anaïs; Cano Rodríguez, María Mercedes; Rubio Sánchez, Ricardo; Martín Sierra, Carmen; Rincón, Pilar; Martín Carmona, Jesica; Pérez, Margarita; Pineda Vergara, Juan Antonio; Real, Luis Miguel; Macías Sánchez, Juan; Fisiología; Medicina; Instituto de Salud Carlos III
Background. Liver stiffness (LS) is not reduced in 10%–30% of patients who achieve sustained viral response (SVR) after hepatitis C virus (HCV) elimination with direct-acting antivirals (DAA). Our aim was to analyze whether the parameters associated with cellular aging measured at the DAA initiation date are related to LS reduction upon achieving SVR. Methods. In a prospective cohort study (GEHEP-011) we measured several parameters associated with cellular aging, such as telomere attrition, mitochondrial alterations, and soluble biomarkers associated with senescence-associated secretory phenotype at the DAA initiation date, and examined their associations with a significant (≥20%) LS decrease at the SVR time point. Results. In total, 175 individuals were included in this study. In 101 (57.7%) patients, the LS reduction was ≥20% at SVR. In the multivariate analysis adjusted for sex, age, CXCL10, hsPCR, and CCL11 levels, greater relative telomere length (RTL) emerged as the sole variable independently associated with a significant LS decrease in SVR (1.102; 95% confidence interval, 1.001–1.1214; P = .047). Furthermore, changes in LS, including significant decrease, decrease <20%, or increase, were congruently associated with RTL (P = .011). Conclusions. Greater RTL was independently associated with a significant LS reduction in SVR. Thus, increased cellular aging may be responsible for the absence of liver regeneration after HCV eradication. Further studies are required to assess the long-term effects of cellular aging after SVR.
Use of Marine Sponges as Stress Indicators in Marine Ecosystems at Algeciras Bay (Southern Iberian Peninsula)
(Inter-Research, 1996) Carballo Cenizo, Juan José Luis; Naranjo, S. A.; García Gómez, José Carlos; Fisiología
Infralittoral sponge fauna was studied as part of a multidisciplinary investigation of benthic communities in Algeciras Bay. On a monthly basis over 1 year, a series of environmental variables were measured (hydrodynamism silting suspended solids, dissolved organic matter, % organic matter in silt). The only abiotic variable that was significantly correlated with beta diversity was hydrodynamism, with a linear regression model between the 2 variables showing a correlation coefficient of 0.66. The distributional pattern of the sponges (based on the relative abundance matrix) was correlated with the environmental variables by matching sample similarities using the Spearman rank correlation, thus showing that the variable combination that best explains the patterns of distribution is hydrodynamism/organic matter in silt (ρ(s) = 0.6). Of the species considered, Phorbas fictitius, Cliona celata, C1iona viridis, Crella elegans, Oscarella lobularis, Dysidea fragilis were among those showing the greatest adaptive plasticity in their relationship to environmental variables, depth, and selection by substrate, and are categorized as eurytopic species present in areas subject to great environmental stress. Other species such as Phorbas tenacior, Reniera fulva, Reniera mucosa, Cliona rhodensis proved to be much more sensitive to these variables, and were categorized as stenotopic species, indicators of normal conditions. Due to the particular environmental conditions where it is located, Mycale micracanthoxea was categorized as a good indicator species in port environments. Others such as Dysidea avara, Halichondria bowerbanki or Crella elegans presented morphological differentiations which have permitted them to adapt to sedimentary environments.
Effects of Environmental Stress on Ascidian Populations in Algeciras Bay (Southern Spain). Possible Marine Bioindicators?
(Inter-Research, 1996) Naranjo, S. A.; Carballo Cenizo, Juan José Luis; García Gómez, José Carlos; Fisiología
The distribution and abundance of littoral ascidians were analyzed with respect to their possible relationships with environmental stress. As part of a multidisciplinary research project on the benthic communities in Algeciras Bay, southern Spain, a suite of environmental variables was measured (hydrodynamism, silting, suspended solids and organic matter). After displaying the similarities of fauna through clustering and ordination el sampling sites, the relationships between community differences anti changes in the abiotic component were established based on the BIO-ENV procedure and Canonical Correspondence Analysis. Hydrodynamism and the percentage of organic matter in the silt is the variable combination that best explains (Spearman correlation of 0.82) the biotic structure. While all ascidians show a certain tolerance to diverse environmental factors, some species such as Ciona intestinalis, Diplosoma spongiforme, Phallusia mammillata, Microcosmus squamiger, Styela plicata and Synoicum argus could be considered as indicators of areas which have been subject to intense stress (substrate transformation water stagnation and sedimentation excess) over long periods of time whereas others such as Aplidium conicum, Aplidium punctum, Clavelina dellavallei, Halocynthia papillosa and Stolonica socialis, which live only in natural and non-perturbed rock areas, could be categorized as species very sensitive to stress, as well as indicators of good conditions.
Striking Cardioprotective Effects of an Adiponectin Receptor Agonist in an Aged Mouse Model of Duchenne Muscular Dystrophy
(MDPI, 2024-12-18) Abou-Samra, Michel; Dubuisson, Nicolas; Marino, Alice; Selvais, Camille M.; Romain, Versele; Davis López de Carrizosa, María América; Horman, Sandrine; Fisiología; National Fund for Scientific Research (FNRS). Belgium
first_pagesettingsOrder Article Reprints Open AccessArticle Striking Cardioprotective Effects of an Adiponectin Receptor Agonist in an Aged Mouse Model of Duchenne Muscular Dystrophy by Michel Abou-Samra 1,*ORCID,Nicolas Dubuisson 1,2ORCID,Alice Marino 3ORCID,Camille M. Selvais 1,Versele Romain 1ORCID,Maria A. Davis-López de Carrizosa 1,4ORCID,Laurence Noel 1,Christophe Beauloye 3,5,Sonia M. Brichard 1 andSandrine Horman 3 1 Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research (IREC), Medical Sector, Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 55, 1200 Brussels, Belgium 2 Neuromuscular Reference Center, Department of Neurology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium 3 Pole of Cardiovascular Research, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 55, 1200 Brussels, Belgium 4 Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, 41012 Seville, Spain 5 Department of Cardiovascular Intensive Care, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium * Author to whom correspondence should be addressed. Antioxidants 2024, 13(12), 1551; https://doi.org/10.3390/antiox13121551 Submission received: 21 November 2024 / Revised: 11 December 2024 / Accepted: 13 December 2024 / Published: 18 December 2024 (This article belongs to the Topic Advances in Adiponectin) Downloadkeyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract Adiponectin (ApN) is a hormone with potent effects on various tissues. We previously demonstrated its ability to counteract Duchenne muscular dystrophy (DMD), a severe muscle disorder. However, its therapeutic use is limited. AdipoRon, an orally active ApN mimic, offers a promising alternative. While cardiomyopathy is the primary cause of mortality in DMD, the effects of ApN or AdipoRon on dystrophic hearts have not been investigated. Our recent findings demonstrated the significant protective effects of AdipoRon on dystrophic skeletal muscle. In this study, we investigated whether AdipoRon effects could be extended to dystrophic hearts. As cardiomyopathy develops late in mdx mice (DMD mouse model), 14-month-old mdx mice were orally treated for two months with AdipoRon at a dose of 50 mg/kg/day and then compared with untreated mdx and wild-type (WT) controls. Echocardiography revealed cardiac dysfunction and ventricular hypertrophy in mdx mice, which were fully reversed in AdipoRon-treated mice. AdipoRon also reduced markers of cardiac inflammation, oxidative stress, hypertrophy, and fibrosis while enhancing mitochondrial biogenesis via ApN receptor-1 and CAMKK2/AMPK pathways. Remarkably, treated mice also showed improved skeletal muscle strength and endurance. By offering protection to both cardiac and skeletal muscles, AdipoRon holds potential as a comprehensive therapeutic strategy for better managing DMD.
Selenium supplementation via modulation of selenoproteins ameliorates binge drinking- induced oxidative, energetic, metabolic, and endocrine imbalance in adolescent rats’ skeletal muscle
(Royal Society of Chemistry, 2020-07-10) Romero Herrera, Inés; Nogales Bueno, Fátima; Gallego López, María del Carmen; Diaz Castro, Javier; Carreras Sánchez, Olimpia; Ojeda Murillo, María Luisa; Fisiología; Junta de Andalucía; Universidad de Sevilla
Adolescence is characterized by increased vulnerability to addiction and ethanol (EtOH) toxicity, particularly through binge drinking (BD), a favored acute EtOH-ingestion pattern among teenagers. BD, highly pro-oxidant, induces oxidative stress (OS), affecting skeletal muscle (SKM), where selenium (Se), an antioxidant element and catalytic center of selenoproteins, is stored, among other tissues. Investigating the effects of Se supplementation on SKM after BD exposure holds therapeutic promise. For this, we randomised 32 adolescent Wistar rats into 4 groups, exposed or not to intermittent i.p. BD [BD and control (C)] (3 g EtOH per kg per day), and supplemented with selenite [BDSe and CSe] (0.4 ppm). In SKM, we examined the oxidative balance, energy status (AMPK, SIRT-1), protein turnover (IRS-1, Akt1, mTOR, IGF-1, NF-κB p65, MAFbx, ULK1, pelF2α), serum myokines (myostatin, IL-6, FGF21, irisin, BDNF, IL-15, fractalkine, FSTL-1, FABP-3), and selenoproteins (GPx1, GPx4, SelM, SelP). In the pancreas, we studied the oxidative balance and SIRT-1 expression. Selenite supplementation mitigated BD-induced OS by enhancing the expression of selenoproteins, which restored oxidative balance, notably stimulating protein synthesis and normalizing the myokine profile, leading to improved SKM mass growth and metabolism, and reduced inflammation and apoptosis (caspase-3). Selenite restoration of SelP's receptor LRP1 expression, reduced by BD, outlines the crucial role of SKM in the SelP cycle, linking Se levels to SKM development. Furthermore, Se attenuated pancreatic OS, preserving insulin secretion. Se supplementation shows potential for alleviating SKM damage from BD, with additional beneficial endocrine effects on the pancreas, adipose tissue, liver, heart and brain that position it as a broad-spectrum treatment for adolescent alcohol consumption, preventing metabolic diseases in adulthood.
Sunitinib-induced oxidative imbalance and retinotoxic effects in rats
(Elsevier, 2020-09-15) Santana Garrido, Álvaro; Reyes Goya, Claudia; André, Helder; Aramburu Bodas, Oscar; Mate Barrero, Alfonso; Vázquez Cueto, Carmen María; Fisiología; Junta de Andalucía
Aims Sunitinib (Su), a tyrosine kinase inhibitor, is one of the most commonly used anti-angiogenic drugs. Some studies have described retinal detachment and photoreceptor damage following systemic exposure to Su, despite beneficial effects achieved with local treatment of ocular pathologies. The aim of this study was to explore the role of NADPH oxidase system and oxidative stress in eyes from Su-treated animals. Main methods Male Wistar rats were administered 25 mg Su/kg body weight/day incorporated in the chow for 3 weeks. Upon treatment completion, NADPH oxidase activity and ROS levels were measured in ocular tissue by chemiluminescence and dihydroethidium (DHE) staining, respectively. The expression of NADPH oxidase isoforms (NOX1, NOX2 and NOX4), antioxidant enzymes and endothelial/inducible nitric oxidase isoforms (eNOS/iNOS) in the eyecup and/or retina were measured via immunofluorescence, immunoblotting and RT-qPCR. Key findings NADPH oxidase activity/expression increased in eyecup and retinas from Su-treated rats. Immunohistofluorescence studies in retinal layer confirmed a higher signal of NADPH oxidase isoforms after Su treatment. Treated animals also presented with reductions in NO levels and eNOS expression, whereas iNOS was upregulated. Finally, a significant depletion of antioxidant enzyme glutathione peroxidase was measured in eyecups of rats following Su exposure, and the opposite pattern was seen for glutathione reductase and superoxide dismutase. Significance This study demonstrates that Su treatment is associated with NADPH oxidase-derived oxidative stress in the eye. Long-term treatment of Su should be properly monitored to avoid retinotoxic effects that might result in ocular pathologies and sight-threatening conditions.

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