Artículos (Fisiología)

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Deciphering the role of ammonia in MASLD: From a neurotoxin to a metabolic by-product
(Elsevier, 2026-04) Zurita Palomo, Carola; Martín Bermudo, Franz; Maya Miles, Douglas; Ampuero Herrojo, Javier; Romero Gómez, Manuel; Gallego Durán, Rocío; Fisiología; Medicina; Instituto de Salud Carlos III; Agencia Estatal de Investigación. España; European Union (UE)
Expanding HIV clinical monitoring: the role of CD4, CD8, and CD4/CD8 ratio in predicting non-AIDS events
(Elsevier, 2023-09) Martínez-Sanz, Javier; Díaz-Álvarez, Jorge; Rosas, Marta; Ron, Raquel; Iribarren, José Antonio; Bernal, Enrique; Gutiérrez, Félix; Ruiz Sancho, Andrés; Cabello, Noemi; Olalla, Julián; Moreno, Santiago; Serrano-Villar, Sergio; CoRIS; González-Serna Martín, Manuel Alejandro; Macías Sánchez, Juan; Fisiología; Medicina; Consorcio Centro de Investigación Biomédica en Red; Instituto de Salud Carlos III
Background While a low CD4/CD8 ratio during HIV treatment correlates with immunosenescence, its value in identifying patients at an increased risk for clinical events remains unclear. Methods We analyzed data from the CoRIS cohort to determine whether CD4 count, CD8 count, and CD4/CD8 ratio at year two of antiretroviral therapy (ART) could predict the risk of serious non-AIDS events (SNAEs) during the next five years. These included major adverse cardiovascular events, non-AIDS-defining malignancies, and non-accidental deaths. We used pooled logistic regression with inverse probability weighting to estimate the survival curves and cumulative risk of clinical events. Findings The study included 4625 participants, 83% male, of whom 200 (4.3%) experienced an SNAE during the follow-up period. A CD4/CD8 ratio <0.3 predicted an increased risk of SNAEs during the next five years (OR 1.63, 95% CI 1.03–2.58). The effect was stronger at a CD4/CD8 ratio cut-off of <0.2 (OR 3.09, 95% CI 1.57–6.07). Additionally, low CD4 count at cut-offs of <500 cells/μL predicted an increased risk of clinical events. Among participants with a CD4 count ≥500 cells/μL, a CD8 count ≥1500 cells/μL or a CD4/CD8 ratio <0.4 predicted increased SNAE risk. Interpretation Our results support the use of the CD4/CD8 ratio and CD8 count as predictors of clinical progression. Patients with CD4/CD8 ratio <0.3 or CD8 count ≥1500/μL, regardless of their CD4 count, may benefit from closer monitoring and targeted preventive interventions.
Effectiveness and tolerability of dolutegravir/lamivudine for the treatment of HIV-1 infection in clinical practice
(Oxford University Press, 2023-06) Suarez-Garcia, Ines; Alejos, Belen; Hernando, Victoria; Vinuela, Laura; Vera Garcia, Mar; Rial-Crestelo, David; Perez Elias, Maria Jesus; Albendin Iglesias, Helena; Peraire, Joaquim; Tiraboschi, Juan; Diaz, Asuncion; Moreno, Santiago; Jarrin, Inma; CoRIS; González-Serna Martín, Manuel Alejandro; Macías Sánchez, Juan; Fisiología; Medicina; Instituto de Salud Carlos III
Objectives To assess the effectiveness and tolerability of dolutegravir (DTG)/lamivudine (3TC) among treatment-naive and virologically suppressed treatment-experienced individuals in the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) during the years 2018–2021. Methods We used multivariable regression models to compare viral suppression (VS) [HIV RNA viral load (VL) <50 copies/mL] and the change in CD4 cell counts at 24 and 48 (±12) weeks after initiation with dolutegravir/lamivudine or other first-line ART regimens. Results We included 2160 treatment-naive subjects, among whom 401 (18.6%) started with dolutegravir/lamivudine. The remaining subjects started bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (n = 949, 43.9%), DTG + FTC/tenofovir disoproxil fumarate (TDF) (n = 282, 13.1%), DTG/3TC/abacavir (ABC) (n = 255, 11.8%), darunavir (DRV)/cobicistat(COBI)/FTC/TAF (n = 147, 6.8%) and elvitegravir (EVG)/COBI/FTC/TAF (n = 126, 5.8%). At 24 and 48 weeks after starting dolutegravir/lamivudine, 91.4% and 93.8% of the subjects, respectively, achieved VS. The probability of achieving VS with dolutegravir/lamivudine was not significantly different compared with any other regimen at 24 or 48 weeks, with the exception of a lower chance of achieving VS at 24 weeks for DRV/COBI/FTC/TAF (adjusted OR: 0.47; 95% CI: 0.30–0.74) compared with dolutegravir/lamivudine. For the analysis of treatment-experienced virally suppressed subjects we included 1456 individuals who switched to dolutegravir/lamivudine, among whom 97.4% and 95.5% maintained VS at 24 and 48 weeks, respectively. During the first 48 weeks after dolutegravir/lamivudine initiation, 1.0% of treatment-naive and 1.5% of treatment-experienced subjects discontinued dolutegravir/lamivudine due to an adverse event. Conclusions In this large multicentre cohort, effectiveness and tolerability of dolutegravir/lamivudine were high among treatment-naive and treatment-experienced subjects.
Targeting epidermal growth factor receptor signaling to facilitate cortical injury repair?
(Medknow Publications, 2024-05) Gómez Oliva, Ricardo; Núñez Abades, Pedro Antonio; Castro, Carmen; Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Union (UE); Junta de Andalucía
Characterization of a novel interaction of the Nup159 nucleoporin with asymmetrically localized spindle pole body proteins and its link with autophagy
(Public Library of Science, 2023-08-03) García de Oya, Inés; Manzano López, Javier; Álvarez Llamas, Alejandra; Vázquez Aroca, María de la Paz; Cepeda García, Cristina; Monje Casas, Fernando; Fisiología
Both the spindle microtubule-organizing centers and the nuclear pore complexes (NPCs) are convoluted structures where many signaling pathways converge to coordinate key events during cell division. Interestingly, despite their distinct molecular conformation and overall functions, these structures share common components and collaborate in the regulation of essential processes. We have established a new link between microtubule-organizing centers and nuclear pores in budding yeast by unveiling an interaction between the Bfa1/Bub2 complex, a mitotic exit inhibitor that localizes on the spindle pole bodies, and the Nup159 nucleoporin. Bfa1/Bub2 association with Nup159 is reduced in metaphase to not interfere with proper spindle positioning. However, their interaction is stimulated in anaphase and assists the Nup159-dependent autophagy pathway. The asymmetric localization of Bfa1/Bub2 during mitosis raises the possibility that its interaction with Nup159 could differentially promote Nup159-mediated autophagic processes, which might be relevant for the maintenance of the replicative lifespan.
The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control
(MDPI, 2020-01-20) Manzano López, Javier; Monje Casas, Fernando; Fisiología; European Union (UE); Ministerio de Economia, Industria y Competitividad (MINECO). España
The Cdc14 phosphatase is a key regulator of mitosis in the budding yeast Saccharomyces cerevisiae. Cdc14 was initially described as playing an essential role in the control of cell cycle progression by promoting mitotic exit on the basis of its capacity to counteract the activity of the cyclin-dependent kinase Cdc28/Cdk1. Acompiling body of evidence, however, has later demonstrated that this phosphatase plays other multiple roles in the regulation of mitosis at di erent cell cycle stages. Here, we summarize our current knowledge about the pivotal role of Cdc14 in cell cycle control, with a special focus in the most recently uncovered functions of the phosphatase.
Polo-like kinase acts as a molecular timer that safeguards the asymmetric fate of spindle microtubule-organizing centers
(eLife Sciences Publications, 2020-11-02) Matellán Fernández, Laura; Manzano López, Javier; Monje Casas, Fernando; Fisiología; European Union (UE); Ministerio de Economía y Competitividad (MINECO). España
The microtubules that form the mitotic spindle originate from microtubule-organizing centers (MTOCs) located at either pole. After duplication, spindle MTOCs can be differentially inherited during asymmetric cell division in organisms ranging from yeast to humans. Problems with establishing predetermined spindle MTOC inheritance patterns during stem cell division have been associated with accelerated cellular aging and the development of both cancer and neurodegenerative disorders. Here, we expand the repertoire of functions Polo-like kinase family members fulfill in regulating pivotal cell cycle processes. We demonstrate that the Plk1 homolog Cdc5 acts as a molecular timer that facilitates the timely and sequential recruitment of two key determinants of spindle MTOCs distribution, that is the g-tubulin complex receptor Spc72 and the protein Kar9, and establishes the fate of these structures, safeguarding their asymmetric inheritance during Saccharomyces cerevisiae mitosis.
Asymmetric inheritance of spindle microtubule-organizing centers preserves replicative lifespan
(Nature Research, 2019-07-29) Manzano López, Javier; Matellán, Laura; Álvarez Llamas, Alejandra; Blanco Mira, José Carlos; Monje Casas, Fernando; Fisiología; European Union (UE); Ministerio de Ciencia, Innovación y Universidades (MICIU). España
The differential distribution of the microtubule-organizing centers (MTOCs) that orchestrate spindle formation during cell division is a fascinating phenomenon originally described in Saccharomyces cerevisiae and later found to be conserved during stem cell divisions in organisms ranging from Drosophila to humans. Whether pre-determined MTOC inheritance patterns fulfill any biological function is however so far unknown. Using a genetically-designed S. cerevisiae strain that displays a constitutively inverted MTOC fate, we demonstrate that the asymmetric segregation of these structures is critical to ensure normal levels of the Sir2 sirtuin and a correct localization of the mitochondrial inheritance regulator Mfb1, and therefore to properly distribute functional mitochondria and protein aggregates between the mother and daughter cells. Consequently, interfering with this process severely accelerates cellular aging.
¿Qué es docencia con perspectiva de género? Punto de partida
(Editorial Universidad de Sevilla, 2025) Casado Mejía, Rosa María; Gaytán Guía, Susana Pilar; Rebollo Catalán, María Ángeles; Enfermería; Fisiología; Métodos de Investigación y Diagnóstico en Educación; SEJ066: Mujeres, Bienestar y Ciudadanía; TIC203: Ingeniería Biomédica; HUM833: Desarrollo e Innovación de Modelos Educativos (Dime)
Excitotoxicity in amyotrophic lateral sclerosis: a key pathogenic mechanism
(Oxford University Press, 2026-03-20) Silva Hucha, Silvia; García Hernández, Rosendo Miguel; Baena López, Diego; Fernández de Sevilla, María Estrella; Paradas, Carmen; Morcuende, Sara; Fisiología
Amyotrophic lateral sclerosis is a complex neurodegenerative disease affecting motor neurons, characterized by the involvement of various factors, including oxidative stress, inflammatory processes, glutamate excitotoxicity, mitochondrial dysfunction, protein aggregation, axonal transport abnormalities, and apoptosis. The complexity of amyotrophic lateral sclerosis arises from its multifactorial aetiology involving diverse genetic, protein, metabolic, and cellular alterations. Mutations of different genes, such as SOD1, C9ORF72, TARDBP, and FUS, have been identified as critical contributors to disease pathophysiology through their facilitation of aberrant protein misfolding and aggregation. All these factors disrupt glutamate homeostasis, leading to calcium-mediated neurotoxicity. Under oxidative stress, motor neurons exhibit a diminished capacity to regulate calcium influx, along with impaired functioning of the mitochondria and endoplasmic reticulum, further compromising cellular integrity. Dysregulation of glutamate signalling also triggers astrocytic stress responses, leading to reduced glutamate clearance, thus worsening neuronal damage through excitotoxic mechanisms. These factors contribute to the excessive production of reactive oxygen species, which exacerbates glutamate imbalance and establishes a detrimental cycle of neuronal damage and glial dysfunction, ultimately intensifying excitotoxicity. This review aims to highlight the role of excitotoxicity in motor neuronal degeneration and to explore the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis. It also examines current therapeutic approaches, including approved treatments and ongoing clinical trials to reduce excitotoxicity, while emphasizing the urgent need for novel, targeted strategies. Given the lack of definitive diagnostic tools and curative therapies, advancing our understanding of the molecular mechanisms driving excitotoxicity and neurodegeneration is, therefore, crucial for the development of more effective, disease-modifying treatments to slow amyotrophic lateral sclerosis progression.
Classical Proprioceptors and Palisade Endings Have Distinct Molecular Profiles in Pig Eye Muscles
(Association for Research in Vision and Ophthalmology, 2026-03) Carrero Rojas, Genova; Petersen, Arzu; Yildiz, Erdem; Martín Calvo, Paula; García Hernández, Rosendo Miguel; Streicher, Johannes; Rodríguez de la Cruz, Rosa María; Pastor Loro, Ángel Manuel; Blumer, Roland; Fisiología; Austrian Science Fund (FWF); Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE)
PURPOSE. Classical proprioceptors, such as muscle spindles and Golgi tendon organs, are absent from the extraocular muscles (EOMs) of most mammals, whereas palisade endings are present in most mammalian EOMs. Even-toed ungulates such as pigs are the only species with classical proprioceptors together with palisade endings in their EOMs. This study aimed to compare the molecular phenotype of classical proprioceptors and palisade endings in pig EOMs. METHODS. EOMs from both eyes of nine pigs were analyzed. EOM cross sections and EOM whole mount preparations were immunolabeled with antibodies against neurofilament, glucose transporter 1 (GLUT1), choline acetyltransferase (ChAT), synaptophysin, synaptobrevin, complexin, and vesicular glutamate transporter 1 (VGLUT1). These were used together with the toxins phalloidin and α-bungarotoxin. The analyses were conducted using confocal laser scanning microscopy. RESULTS. A capsule, expressing GLUT1, was present in muscle spindles and Golgi tendon organs but not in palisade endings. Conversely, palisade endings express ChAT, whereas muscle spindles and Golgi tendon organs lack it. An exception was the paraequatorial and polar regions of muscle spindles, where ChAT immunoreactivity was present. VGLUT1 was present in Golgi tendon organs and muscle spindles but absent from palisade endings. In classical proprioceptors as well as palisade endings, nerve terminals exhibited synaptophysin, synaptobrevin, and complexin immunoreactivity. Alphabungarotoxin was present in the motor terminal of the muscle spindle’s paraequatorial and polar regions. CONCLUSIONS. Palisade endings and classical proprioceptors in pig EOMs differ regarding the capsular envelope and neurotransmitters. However, they equate each other with respect to proteins implicated in neurotransmitter release.
Care Pathways for Metabolic Dysfunction- Associated Steatotic Liver Disease (MASLD): A State- of- The- Art Review
(John Wiley & Sons, Inc., 2026-04) van Eekhout, Kirsi M. A.; Broekman, Leonard D.; De Jong, Vivian D.; Michel, Maurice; Grobbee, Rick; Maya Miles, Douglas; Romero Gómez, Manuel; Holleboom, Adriaan G.; Medicina; Instituto de Biomedicina de Sevilla (IBIS); Fisiología; Innovative Health Initiative; CTS1106: Enfermedades hepáticas y digestivas
Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is a growing clinical challenge, necessitating effective diagnostic strategies to identify advanced liver fibrosis while minimising unnecessary referrals of mild cases. Current clinical guidelines recommend care pathways utilising non-invasive tests (NITs) to stratify patients, but the optimal diagnostic algorithm across care settings remains unclear. This state-of-the-art review systematically examines studies describing clinical care pathways for detecting advanced fibrotic MASLD and stratifying patients at risk. A comprehensive literature search of MEDLINE, Embase, Cochrane Library, and Scopus, finalised in January 2026, identified nine relevant studies that met predefined criteria including structured care plans and applicability beyond diagnosis alone. Pathway populations included patients at risk for MASLD (type 2 diabetes (n = 4) or broad range cardiometabolic risk factors (n = 1)) or confirmed MASLD (n = 4). The most frequently employed NITs were FIB- 4 and vibration-controlled transient elastography (VCTE). Numbers needed to screen (NNS) for hepatology referral and advanced fibrosis detection varied considerably across pathways and populations, reflecting heterogeneity in design and ibrosis assessment methods. All studies reported improved patient risk stratification; attendance rates declined at each pathway step. Findings suggest that NIT-based clinical care pathways can effectively align patient management and optimise transmural care for MASLD. Nonetheless, heterogeneity in pathway design and fibrosis determination highlights the need for standardised protocols and validation in larger, at-risk cohorts to strengthen evidence supporting widespread adoption. This review contributes to advancing MASLD management within evolving clinical frameworks.
Ulcerative colitis model triggers gut α-Synuclein aggregation without brain involvement or neuronal loss in female rats
(Frontiers Media SA, 2026) Espinosa Oliva, Ana María; Vázquez Carretero, María Dolores; Ruiz Laza, Rocío; Roca-Ceballos, María A.; García Miranda, Pablo; Peral Rubio, María José; Sarmiento Soto, Manuel; Herrera Carmona, Antonio José; Venero Recio, José Luis; Martínez de Pablos, Rocío; Bioquímica y Biología Molecular; Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; European Union (UE)
Introduction: Despite being the second most common neurodegenerative disorder, the mechanisms underlying the onset and progression of Parkinson’s disease (PD) remain poorly understood, and no curative treatment is currently available. The Braak hypothesis offers an intriguing framework for explaining both the origin and development of the disease, proposing that PD begins in the gut and subsequently spreads to the brain. Methods: In previous studies, our group developed a novel PD model in which peripheral inflammation, triggered by administering dextran sodium sulphate (DSS) in the drinking water of male Wistar rats, recapitulates key features of PD in both the gut and the brain. This model supports the Braak hypothesis and highlights the relevance of the gut-brain axis. Using the same model, the present study aimed to determine whether sex influences peripheral inflammation and the resulting neuropathology in the substantia nigra (SN) of female Wistar rats. Results: Our findings show that while DSS treatment induces comparable levels of colonic inflammation and phosphorylated a-synuclein accumulation in both sexes, it does not produce a-synuclein aggregation or dopaminergic neuronal loss in the SN pars compacta of female rats. Conclusion: These results underscore the critical importance of considering sex differences in experimental PD models and in clinical practice, as such differences may significantly influence PD pathogenesis.
Low rate of vaccination and risk of incident hepatitis A among HIV-infected men who have sex with men in Seville, Southern Spain
(Elsevier, 2024-05) Fernández-Fuertes, Marta; Macías Sánchez, Juan; Corma-Gómez, Anaïs; Salazar-González, Adolfo; González-Serna Martín, Manuel Alejandro; Rincón, Pilar; Arriaza-Estévez, María J.; Fuentes-López, Ana; Real Navarrete, Luis Miguel; Pineda Vergara, Juan Antonio; Medicina; Fisiología; Bioquímica Médica y Biología Molecular e Inmunología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Background Periodic outbreaks of hepatitis A (HAV) infection in men who have sex with men (MSM) have been reported. Low vaccination uptake in HIV-infected individuals could drive new outbreaks. We aimed at evaluating the incidence of and risk factors for HAV infection in people living with HIV (PLWH) in our area. We also assessed the rates of HAV vaccination. Methods This was a prospective cohort study. 915 patients were included, 272 (30%) of them were anti-HAV seronegative at baseline. Results Twenty-six (9.6%) susceptible individuals became infected. Incident cases peaked in 2009–2010 and 2017–2018. Incident HAV infection was independently associated with MSM [adjusted odds ratio (95% confidence ratio): 4.39 (1.35–14.27), p = 0.014]. One hundred and five (38.6%) HAV seronegative patients were vaccinated, 21 (20%) of them did not respond, and one (1%) patient lost immunity against HAV. Four (29%) non-responders to vaccination showed incident HAV 5–9 years afterwards. Conclusions The incidence of HAV infection in a cohort of well-controlled PLWH remains low and stable, with intermittent outbreaks involving mainly non-immunized MSM. A significant proportion of PLWH remain susceptible to HAV infection due to insufficient vaccine uptake and limited response to vaccination. Importantly, patients not responding to HAV vaccination continue at risk of infection.
Real-world management and outcome of patients with pancreatic adenocarcinoma. Results of the Spanish RETUD gastrointestinal registry
(Elsevier, 2025) Macarulla, T; Muñoz, A.; Castro, EM de; Castillo, A.; Cano, MT; Castet, F; Vidal, R; Ferrández, A; Gallego Jiménez, Isabel; Aranda, E; Fisiología
Background: Patient registries better reflect real-world management and outcomes of pancreatic cancer (PC) compared with clinical trials. Patients and methods: The main objective was to characterize patterns of care and outcomes in patients with exocrine PC included in the Spanish gastrointestinal RETUD registry. All analyses are descriptive in nature; therefore, P values are not reported. Results: A total of 1438 patients with a median age of 68.7 years (range: 34-94 years) were included between 1 January 2019 and 31 December 2022. 79.7% of patients had an Eastern Cooperative Oncology Group performance status of 0-1. 54.9% of resectable patients received adjuvant chemotherapy after upfront surgery, with a median overall survival (mOS) of 33.3 months (range: 26.1 months-not reached) for those treated with Folfirinox. 79.5% of metastatic patients received first-line chemotherapy, primarily gemcitabine and nab-paclitaxel (62.6%), with a mOS of 8.7 months (range: 7.1-9.6 months). Overall, 1- and 3-year net survival rates were 46% and 9%, respectively, with a clear increase for resectable/borderline stages. KRAS, microsatellite instability (MSI), and germline BRCA1/2 were determined in 16.4% (81.8% mutated), 21.2% (1.6% MSI-high), and 9.2% (12.8% mutated) of patients, respectively. Conclusions: Our study provides a real-world perspective on PC patients in Spain, revealing very poor survival similar to those reported in population-based and epidemiological studies. Notably, resectable PC patients receiving adjuvant chemotherapy had lower survival compared with those in clinical trials, a trend not observed in more advanced stages. Adherence to international guidelines varied, and clinical trial participation was low. Additionally, access to molecular testing was limited, remaining a significant challenge.
The ansa cervicalis and superior cervical ganglion contribute to the fiber composition of the human hypoglossal nerve and its branches
(Nature Research, 2026-01-21) Didava, Giorgi; Petersen, Arzu; Carrero Rojas, Génova; Pruidze, Paata; Pastor Loro, Ángel Manuel; Weninger, Wolfgang J.; Blumer, Roland; Fisiología
The hypoglossal nerve is considered a pure motor nerve. Yet, there are indications that it contains sensory and sympathetic fibers in the periphery. We analyzed changes in the fiber composition along the human hypoglossal nerve, delineating the pathways through which non-motor fibers enter this nerve and describing the direction in which these fibers extend. Five key positions along the nerve were selected for fiber analyses. Position 1 was intracranial. Positions 2–5 were extracranial and in relation to the C1 component of the ansa cervicalis, which is attached to the hypoglossal nerve. Nerve samples were subjected to multicolor immunofluorescence and quantitative analyses. Intracranially, all axons of the hypoglossal nerve were motor. The extracranial portion of the hypoglossal nerve has a mixed fibers composition of motor, sensory, and sympathetic fibers. The number of all types of fibers increased, reaching a maximum after the C1 component of the ansa branched off from the hypoglossal nerve. At this position, the proportion of motor fibers, sensory fibers, and sympathetic fibers was 63: 11: 26. Our findings suggest that sensory and sympathetic fibers enter the hypoglossal nerve via the ansa cervicalis. Most fibers extend in a distal direction, reaching the tongue, while a smaller number extend in a proximal direction, most likely to become integrated in the meningeal branch of thehypoglossal nerve.
ErbB signaling in brain injury regeneration: Pathway interactions and therapeutic potential
(Medknow Publications, 2025-07-05) Pérez García, Patricia; Martínez Gómez, Nora; Vázquez de Górgolas, Sonia; Chamorro Francisco, Andrea; Pardillo Díaz, Ricardo; Núñez Abades, Pedro Antonio; Castro, Carmen; Carrascal Moreno, María Livia; Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; European Union (UE)
The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury. This review provides a comprehensive overview of ErbB receptors and their ligands, highlighting canonical and non-canonical signaling mechanisms relevant to brain damage. We explore how ErbB signaling is dynamically regulated following injury and how it orchestrates processes such as neuroinflammation, gliosis, and neural repair. Special attention is given to its interplay with other critical pathways, including Notch signaling, and its roles within adult neurogenic niches, where it modulates neural stem cell behavior in response to damage. Based on accumulating preclinical evidence, we propose two therapeutic strategies for targeting ErbB signaling in brain injury: (1) dampening neuroinflammation through ErbB inhibition and (2) promoting neuroprotection and neurogenesis via neuregulin-1-mediated activation. The first strategy is supported by studies, which demonstrate that inhibition of ErbB1 limits neuroinflammation and supports neural repair in preclinical models. The latter strategy is supported by emerging studies demonstrating the significant potential of novel protein kinase C activating diterpenes in modulating ErbB signaling pathways through the regulation of neuregulin-1 release. Diterpenes, by influencing the ErbB pathway, may uniquely bridge the gap between neuroprotection and regeneration. Their potential to modulate inflammation and promote pro-regenerative cellular environments positions them as promising tools in the development of targeted therapies. By dissecting these mechanisms, we aim to shed light on the translational potential of ErbB-targeted therapies and their capacity to enhance endogenous repair processes in the injured brain.
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.

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