Artículos (Fisiología)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10874

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Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
(American Society for Clinical Investigation, 2021-10-01) Nakanishi, Tomoko; Pigazzini, Sara; Degenhardt, Frauke; Cordioli, Mattia; Butler-Laporte, Guillaume; Maya Miles, Douglas; Romero Gómez, Manuel; Ganna, Andrea; Calderón Sandubete, Enrique José; Gallego Durán, Rocío; Medrano Ortega, Francisco Javier; Ampuero Herrojo, Javier; Morilla Romero de la Osa, Rubén; Fisiología; Medicina; Enfermería; Junta de Andalucía; European Union; Consejo Superior de Investigaciones Científicas (CSIC)
Background. There is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition. Methods. We combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank. Results. We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2–1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6–2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2–2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2–2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8–3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2–1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors. Conclusions. The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.
Phenotype-Specific Mitochondrial Responses to Mediterranean Diet and Exercise in Elderly Obesity
(MDPI, 2026-02-01) Carrillo-Fernández, Paloma; Silva-Soto, María Ángeles; Gallego Durán, Rocío; Medina-Jiménez, Elena; Vilches-Pérez, Alberto; Mogaburo-Alba, Juan Francisco; Maya Miles, Douglas; Romero Gómez, Manuel; Bernal-López, María Rosa; Medicina; Fisiología; Instituto de Biomedicina de Sevilla (IBIS); Instituto de Salud Carlos III; Centros de Investigación En Red (CIBER); European Union (UE); Programa “Nicolás Monardes”; Junta de Andalucía; PFIS; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); “Acciones Individuales MSCA—Sello de Excelencia ISCIII-HEALTH 2022”; CTS1106: Enfermedades Hepáticas y Digestivas
Background/Objectives: While excessive body fat is commonly linked to metabolic disorders (metabolically unhealthy obesity, MUO), a subset of individuals remain metabolic healthy despite obesity (metabolically healthy obesity, MHO). This work aims to determine how these phenotypes influence responses to lifestyle modification (LSM) in older adults. Methods: A 12-month lifestyle modification (LSM) intervention based on the Mediterranean Diet (MedDiet) and regular physical activity (PA) was conducted in 43 older adults (70% women) classified according to World Health Organization (WHO) criteria as MHO (22 subjects) or MUO (21 subjects). Clinical, dietary, and PA parameters were assessed at baseline and follow-up. Peripheral blood mononuclear cells were analyzed for mitochondrial fusion (OPA1, MFN2), mitophagy (PINK1), biogenesis (TFAM), and the respiratory chain (COX IV) using Western blot and RT-qPCR techniques. Results: At baseline, MUO showed significant lower OPA1-L, MFN2, and TFAM along with MFN2 degradation products and PINK1 accumulation. After 12 months of LSM, MUO participants exhibited greater metabolic profile improvements, such as significantly reduced MFN2 degradation products and higher COX IV. Changes in mitochondrial proteins were associated with nutrient intake and PA and clinical parameters with phenotype-specific patterns. In MUO, protein and cholesterol intake improved MFN2 fusion (rho = 0.446, p = 0.043; rho = 0.581, p = 0.006), while carbohydrates were negatively associated with OPA1 in MHO (rho = −0.596, p = 0.025). PA was positively related to fusion proteins in both phenotypes. Clinically, significant improvements in BMI, waist circumference, and HDL were found in MUO but not in MHO. Conclusions: Older adults with obesity show phenotype-specific mitochondrial impairments that shape distinct responses to LSM, highlighting the relevance of tailoring LSM interventions by metabolic phenotype.
Wild and cultivated olive trees: Nutraceutical insights of extra virgin olive oils in cardiovascular and ocular diseases
(Elsevier, 2024-01) Reyes Goya, Claudia; Santana Garrido, Álvaro; Espinosa-Martin, P.; Vázquez Cueto, Carmen María; Mate Barrero, Alfonso; Fisiología
Extra virgin olive oil (EVOO) from Olea europaea (cultivated olive tree) and the oil obtained from the wild olive variety or acebuche (ACE oil from Olea oleaster) contain an extraordinary number of bioactive molecules. These include oleic acid, sterols, tocopherols, triterpene compounds, and polyphenols. Both oils are known for their healthy properties and are considered to be a nutraceutical tool against cardiovascular diseases, including arterial hypertension, preeclampsia, and ocular diseases such as glaucoma or diabetic retinopathy. The benefits of EVOO and ACE oil stem from their anti-inflammatory, antioxidant, and anti-cancer properties. They also have potential as prebiotic compounds. In this update, we synthesise and illustrate the various characteristics and beneficial effects of olive oils from different varieties of olive trees, with special emphasis on Olea oleaster, also known as Olea europaea, L. var. sylvestris.
Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
(Springer Nature, 2023-08-10) Zheng, Kang; Hao, Fengjie; Medrano García, Sandra; Chen, Chaobo; Guo, Feifei; Gallego Durán, Rocío; Maya Miles, Douglas; Ampuero Herrojo, Javier; Romero Gómez, Manuel; Cubero, Francisco Javier; Fisiología; Medicina; Ministerio de Ciencia e Innovación (MICIN). España; European Union (UE); Comunidad Autónoma de Madrid
Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.
Transcription and FACT facilitate the restoration of replication-coupled chromatin assembly defects
(Nature Research, 2023-07-14) Barrientos Moreno, Marta; Maya Miles, Douglas; Murillo Pineda, Marina; Fontalva Ostio, Sara; Pérez Alegre, Mónica; Andújar, Eloísa; Prado, Félix; Fisiología; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE); Junta de Andalucía
Genome duplication occurs through the coordinated action of DNA replication and nucleosome assembly at replication forks. Defective nucleosome assembly causes DNA lesions by fork breakage that need to be repaired. In addition, it causes a loss of chromatin integrity. These chromatin alterations can be restored, even though the mechanisms are unknown. Here, we show that the process of chromatin restoration can deal with highly severe chromatin defects induced by the absence of the chaperones CAF1 and Rtt106 or a strong reduction in the pool of available histones, and that this process can be followed by analyzing the topoisomer distribution of the 2µ plasmid. Using this assay, we demonstrate that chromatin restoration is slow and independent of checkpoint activation, whereas it requires the action of transcription and the FACT complex. Therefore, cells are able to “repair” not only DNA lesions but also chromatin alterations associated with defective nucleosome assembly.
The Calcium-Binding Protein S100A10 (p11) Is Required for Normal Motor Performance by Regulating Vesicle Dynamics at Excitatory Synapses
(Wiley, 2026-01-12) Vilches-Herrando, Esther; Rodríguez-Bey, Guillermo; García Hernández, Rosendo Miguel; Gento-Caro, Ángela; Pastor Loro, Ángel Manuel; Campos-Caro, Antonio; González-Forero, David; Moreno-López, Bernardo; Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
AIM: Identifying interactors in sensorimotor processing and neurotransmission remains a current challenge for understanding neural information processing and brain function. METHODS: To evaluate the role of p11 in sensorimotor processing and excitatory synaptic neurotransmission, neuron-specific lentivirus-directed p11 silencing, small interfering RNA (siRNAp11)-induced p11 deletion, unitary extracellular recordings of hypoglossal motor neurons (HMNs), western blot, co-immunoprecipitation, multiple immunolabeling, proximity ligation (PLA) assays, electron microscopy, and whole-cell patch-clamp recording of AMPA receptor-mediated excitatory postsynaptic currents in adult and/or neonatal rat HMNs were performed. RESULTS: p11 knockdown depressed baseline and chemoreceptor-modulated inspiratory-related activity in HMNs. Co-immunoprecipitation and PLA assays indicated that p11 interacts with Munc13-1, a presynaptic active zone (AZ) protein for vesicle priming, presumably at excitatory inputs in the hypoglossal nucleus. Interference with p11 resulted in Munc13-1 downregulation, reduction in AZ length, and increased vesicle accumulation at excitatory boutons on HMNs, without affecting the number of docked vesicles at the AZ. p11 knockdown robustly reduced the synaptic strength of excitatory neurotransmission incoming to HMNs by affecting both the synchronous and asynchronous phases of neurotransmitter release. The decrease in synaptic strength was concurrent with a reduction in the size of the "functional" pool of readily releasable (RRP) vesicles and with the slowing down of the vesicle recruitment rate to replenish RRP. CONCLUSION: p11 is proposed as a relevant mediator in the neurotransmitter release by regulating vesicle dynamics at central excitatory synapses. Here, p11 is highlighted as a multifaceted factor involved in neurotransmission and synaptic plasticity and, therefore, central for neural information processing.
Inhibition of ex vivo VEGF-induced angiogenesis by tyrosol and hydroxytyrosol: a quantitative three-dimensional mouse aortic ring model
(Royal Society of Chemistry, 2025-09-19) Cerezo López, Ana Belén; Gallardo Fernández, Marta; Santana Garrido, Álvaro; Hornedo Ortega, Ruth; Vázquez Cueto, Carmen María; Troncoso González, Ana María; García Parrilla, María del Carmen; Nutrición y Bromatología, Toxicología y Medicina Legal; European Union (UE); Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España
Mediterranean diet foods such as olives, virgin olive oil and wine are sources of tyrosol (TOL) and hydroxytyrosol (HT), which are bioactive compounds. HT has already shown in vitro anti-angiogenic effects in HUVECs. Since TOL is structurally closely related to HT, the aim of the present study was firstly to evaluate the anti-angiogenic properties of TOL regarding inhibition of VEGF-induced VEGFR2 phosphorylation as well as its effects on the intracellular signaling cascade (PLCγ1, Akt and eNOS). Additionally, this paper aims to demonstrate the anti-angiogenic effects of HT and TOL using the ex vivo gold standard mouse aortic ring model. Our results demonstrated that TOL significantly inhibits VEGF-induced VEGFR2 activation in HUVECs, with an IC50 value of 38.33 μM. Additionally, TOL completely blocked PLCγ1 activation, a key component of the VEGFR-2-mediated signalling pathway, while simultaneously increasing the phosphorylation of Akt and eNOS, critical molecules in the regulation of angiogenesis and vasodilation. This study is the first to use the mouse aortic ring model to demonstrate the anti-angiogenic effects of TOL and HT. A significant reduction of capillary sprouting at 68% and 96% was observed for TOL and HT, respectively. These results not only support the potential of TOL and HT as natural anti-angiogenic agents but also offer a new perspective on how diet, especially the Mediterranean diet, may influence the prevention and treatment of angiogenesis-related diseases, such as cancer and cardiovascular diseases.
Long non-coding RNA H19 as a biomarker for hepatocellular carcinoma
(Wiley, 2022-06) Rojas, Ángela; Gil Gómez, Antonio; Cruz Ojeda, Patricia de la; Muñoz Hernández, Rocío; Sánchez Torrijos, Yolanda María; Gallego Durán, Rocío; Maya Miles, Douglas; Muntané Relat, Jordi; Ampuero Herrojo, Javier; Padillo Ruiz, Francisco Javier; Romero Gómez, Manuel; Fisiología; Medicina; Cirugía; Instituto de Biomedicina de Sevilla (IBIS); Junta de Andalucía; Instituto de Salud Carlos III; Sara Borrell postdoctoral fellowships (Instituto de Salud Carlos III); CTS1106: Enfermedades Hepáticas y Digestivas; CTS1098: Mecanismos Moleculares del Hepatocarcinoma y Sus Estrategias Terapéuticas; CTS664: Cirugía Avanzada y Trasplantes. Terapia Celular y Bioingeniería Aplicada a la Cirugía
Background and Aims: Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer. Methods: LncRNA-H19 expression levels and the functional assays were conducted in EpCAM+CD133+ CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort. Results: EpCAM+CD133+ cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025). Conclusion: LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC.
Dysregulated GluA2-Y876 phosphorylation contributes to loss of synaptic upscaling in GRIP1 mutant mice with reduced sociability and increased repetitive behavior
(2025-12-13) Han, Mei; Tan, Han L.; Mejías Estévez, Rebeca María; Chiu, Shu-Ling; Kim, Juhyun; Huganir, Richard L; Wang, Tao; Fisiología; Ministerio de Ciencia y TIC
Loss of synaptic upscaling, a post-synaptic homeostatic plasticity, has been reported in mouse models of autism, but the underlying mechanism remains unknown. Glutamate receptor interacting protein 1 (GRIP1) binds AMPA receptor 2 (GluA2) through its PDZ domains 4-6 where gain-of-function variants were described in autism. We characterized mice carrying one variant, GRIP1-I586L (murine I507L), that shows increased binding with GluA2. Grip1-I507L mice exhibit impaired social interaction and increased repetitive behaviors, increased neuronal excitability and excitatory-to-inhibitory ratio in the medial prefrontal cortex. Grip1-I507L cortical neurons show a loss of synaptic upscaling to tetrodotoxin-induced inactivity. Basal phosphorylation of GluA2-Y876 is increased, which is consistent with increased binding to GluA2 while lack of further induction to inactivity contributes to loss of synaptic upscaling. Phosphorylation of GluA2-S880 that regulates Hebbian plasticity is not altered. These results support that gain-of-function GRIP1 variants are a novel cause of autism-related impaired social interaction and increased repetitive behavior and implicate that dysregulated phosphorylation of GluA2-Y876 is a novel mechanism for loss of synaptic upscaling.
Creatine differently prevents chronic colitis-induced motor deficits, anxiety and depressive behaviors, neuroinflammation, and microglial activation in male and female rats
(American Chemical Society (ACS), 2025-08-18) Sotelo Parrilla, Gema; Ruiz Calero, Alejandro; García Miranda, Pablo; Calonge Castrillo, María Luisa; Vázquez Carretero, María Dolores; Peral, María José; Fisiología; Ministerio de Ciencia e Innovación (MICIN). España
Creatine has been reported to exhibit neuroprotective and anti-inflammatory properties and alleviate symptoms of affective disorders. In this study, we used a chronic colitis model in male and female rats, using a dextran sulfate sodium treatment that mimics the remitting–relapsing phases of human ulcerative colitis. The results showed that in rats with colitis, oral creatine supplementation reduced the severity of colitis symptoms and prevented motor deficits, anxiety, and depression-like behaviors. These effects of creatine were consistent throughout the development of chronic colitis, remaining independent of remitting–relapsing periods. In response to creatine supplementation, colon and brain creatine levels increased in rats with chronic colitis without sex differences. Furthermore, at the end of the treatment, when chronic colitis was established, creatine ameliorated injury of colonic surface epithelial and prevented chronic colitis-associated neuroinflammation, evidenced by a decrease in the pro-inflammatory cytokines IL-1β, IL-6, and TNF mRNA, as well as microglial activation in the prefrontal and motor cortices of rats of both sexes. In general, creatine supplementation was more effective in females. In conclusion, creatine supplementation had sex-specific effects and could serve as a nutritional strategy to reduce the severity of colitis and its associated motor and mood disturbances, neuroinflammation, and microglial activation.
Association of First-Trimester Maternal Biomarkers with Preeclampsia and Related Maternal and Fetal Severe Adverse Events
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-07-11) Camacho Carrasco, Ana; Muñoz Hernández, Rocío; García Díaz, Lutgardo; Stiefel García-Junco, Pablo Enrique; Mate Barrero, Alfonso; Vázquez Cueto, Carmen María; Vallejo Vaz, Antonio Javier; Beltrán Romero, Luis Matías; Fisiología; Medicina; Cirugía; Junta de Andalucía
To assess the association between known (PlGF, sFlt-1, betaHCG, PAPPA) and novel (cell-free DNA, cfDNA, and total endothelial and platelet microvesicles, MVs) maternal blood biomarkers measured at the first trimester with the later development of preeclampsia (PE) and PE-related severe adverse events (SAE), we conducted a retrospective case–control study including women with an established diagnosis of preeclampsia (cases) and healthy pregnant women (controls). Biomarkers were measured from first-trimester blood samples stored in a hospital biobank. A total of 89 women, 54 women with PE and 35 controls were included. PlGF showed good performance for diagnosing overall preeclampsia (AUC: 0.71; 95% CI 0.59–0.82), early-onset preeclampsia (AUC 0.80; 95% CI 0.68–0.9) and fetal-neonatal SAEs (AUC: 0.73; 95% CI 0.63–0.84). Multivariate models including clinical variables, PlGF and other biomarkers showed good to very good discrimination for the development of PE, early-onset PE and fetal-neonatal SAEs (AUCs of 0.87, 0.89 and 0.79, respectively). Platelet-derived MVs were the best isolated biomarker for late-onset PE and, combined with systolic blood pressure, showed good discrimination (AUC: 0.81; 95% CI 0.71–0.92). For maternal SAEs, a model incorporating cfDNA and sFlt-1 provided excellent discrimination (AUC 0.92; 95% CI 0.82–1.00). Our findings suggest that multivariate models incorporating both clinical variables and first-trimester biomarkers may improve risk stratification for PE, especially for late-onset PE and for identifying women at risk of severe maternal or fetal complications. Notably, the inclusion of novel biomarkers such as cfDNA and MVs added value in clinical scenarios where the predictive performance of existing tools remains suboptimal.
Binge drinking as a potential cardiometabolic risk factor during adolescence in rats: novel protective antinitrosative mechanism of folic acid via caveolin-1
(Springer Nature, 2025-11-19) Gallego López, María del Carmen; Nogales Bueno, Fátima; Romero Herrera, Inés; Carreras Sánchez, Olimpia; Ojeda Murillo, María Luisa; Fisiología; Junta de Andalucía
Binge drinking (BD) is the predominant pattern of alcohol consumption among adolescents. It is clinically associated with cardiovascular and hepatic alterations due to its strong pro-oxidant effects. Folic acid (FA), a cardioprotective vitamin, is related to caveolins (Cav), proteins involved in cellular nitrosative balance. This study aims to evaluate BD as a possible cardiometabolic risk factor (CMRF) during adolescence by examining its effects on cardiac nitrosative equilibrium as well as the potential of FA supplementation to mitigate these effects. Four groups of adolescent rats were employed: control, BD (intraperitoneal alcohol), control FA-supplemented, and BD-FA-supplemented. Diets contained 2 ppm FA (control) or 8 ppm FA (supplemented). BD promoted several CMRFs, including insulin resistance. BD also induced cardiac oxidative stress, primarily through NADPH oxidase (NOX) activation. Notably, BD caused cardiac nitrosative stress by increasing nitric oxide synthase (NOS) isoforms (iNOS and eNOS), resulting in abnormally high NO levels. This redox imbalance affected cardiac function by increasing heart rate (HR). BD further led to vascular dysfunction with decreased systemic NO and elevated VEGF and Cav-1, increasing mean blood pressure (MBP). FA supplementation restored cardiac oxidative/nitrosative homeostasis, normalizing NO levels. Consequently, HR and MBP decreased, vascular function improved, and CMRFs were attenuated. The action of FA was partly mediated by increased Cav-1 levels in the heart and serum. These findings suggest that FA supplementation could be a promising strategy to mitigate cardiovascular alterations induced by BD in adolescents and potentially prevent the development of future cardiometabolic diseases.
Rat models of fetal alcohol spectrum disorders for studying the critical role of cerebellar damage: A scoping review
(Wiley, 2025-08-04) Nogales Bueno, Fátima; Jotty, Karick; Pascual-Vaca, Diego; Gallego López, María del Carmen; Carreras Sánchez, Olimpia; Ojeda Murillo, María Luisa; Fisiología; Universidad de Sevilla
Background Fetal alcohol spectrum disorder (FASD) refers to the neurodevelopmental condition of lifelong cognitive, emotional, and behavioral challenges that can occur in individuals exposed to alcohol before birth. FASD is a preventable, chronic condition with no direct diagnosis and no treatment, and is considered the leading cause of developmental cognitive impairment in Western countries. The best-known effects of prenatal alcohol exposure (PAE) are those that affect the brain. Among these structures, the cerebellum, a key coordinative tissue, is particularly sensitive to PAE, leading to motor and cognitive disorders. Since 1994, the use of different rat models of FASD has greatly influenced the understanding of the effects of perinatal alcohol exposure on cerebellum development. Methods We conducted a scoping review of research from the past 30 years to answer an important question for the scientific community: “Which rat model of Fetal Alcohol Spectrum Disorders (FASD) offers the most relevant insights for selecting an appropriate experimental design, specifically for investigating alcohol-induced effects on the cerebellum?” Results Considering the unique developmental characteristics of the cerebellum, five developmental time windows have been identified in rats for studying its state after ethanol exposure. In each window, the route and dose of ethanol administration result in different blood alcohol concentration (BAC) levels, each with distinct advantages and disadvantages. This information is presented in three tables, which also indicate the type of study conducted: morphological, biochemical, electrophysiological, or behavioral. Conclusions The third-trimester equivalent period is the most susceptible to alcohol-induced cerebellar damage and is thus the most widely studied by researchers. More research is needed on the effects of alcohol during lactation.
Microbiome-centered therapies for the management of metabolic dysfunction-associated steatotic liver disease
(Korean Association for the Study of the Liver (KASL), 2024-11-28) Saeed, Huma; Díaz, Luis Antonio; Gil Gómez, Antonio; Burton, Jeremy; Bajaj, Jasmohan S.; Romero Gómez, Manuel; Khan, Mohammad Qasim; Fisiología; Medicina; Fondo Nacional de Desarrollo Científico y Tecnológico. Chile; Instituto de Salud Carlos III
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant global health issue, affecting over 30% of the population worldwide due to the rising prevalence of metabolic risk factors such as obesity and type 2 diabetes mellitus. This spectrum of liver disease ranges from isolated steatosis to more severe forms such as steatohepatitis, fibrosis, and cirrhosis. Recent studies highlight the role of gut microbiota in MASLD pathogenesis, showing that dysbiosis significantly impacts metabolic health and the progression of liver disease. This review critically evaluates current microbiome-centered therapies in MASLD management, including prebiotics, probiotics, synbiotics, fecal microbiota transplantation, and emerging therapies such as engineered bacteria and bacteriophage therapy. We explore the scientific rationale, clinical evidence, and potential mechanisms by which these interventions influence MASLD. The gut-liver axis is crucial in MASLD, with notable changes in microbiome composition linked to disease progression. For instance, specific microbial profiles and reduced alpha diversity are associated with MASLD severity. Therapeutic strategies targeting the microbiome could modulate disease progression by improving gut permeability, reducing endotoxin-producing bacteria, and altering bile acid metabolism. Although promising, these therapies require further research to fully understand their mechanisms and optimize their efficacy. This review integrates findings from clinical trials and experimental studies, providing a comprehensive overview of microbiome-centered therapies’ potential in managing MASLD. Future research should focus on personalized strategies, utilizing microbiome features, blood metabolites, and customized dietary interventions to enhance the effectiveness of these therapies.
Potential Noninvasive Biomarkers to Assess the Aging Process
(Cambridge University Press, 2025-09-15) Pérez Muñoz, Álvaro; González-Serna Martín, Manuel Alejandro; Cano Rodríguez, Mercedes; Fisiología; Ministerio de Unviersidades
Aging is a process preserved in all living beings, progressive over time and inexorable. Despite the existence of several theories that attempt to explain changes associated with aging, scientists have not managed to satisfactorily explain the causes of aging. However, during the last decade, several cellular processes involved in the aging process have been shown to be involved, allowing scientists to identify new biomolecules as aging biomarkers and control the progression of aging. Currently, there is no single biomarker sensitive and specific enough to predict aging, so it is necessary to find a set of specific biomarkers of cellular processes involved in aging. These biomarkers must be accessible for quantification in biological samples in a noninvasive way to implement them in clinical practice. By 2050, it is estimated that approximately one in six people in the world will be over 65 years old, doubling the percentage of population over 60 years old. Therefore, the research of new biomarkers represents a novel strategy to counteract against aging and improve quality of life. In this review we summarize the potential biomarkers of aging that could be used in a noninvasive manner.
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.

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