Artículos (Fisiología Médica y Biofísica)

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Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer’s disease
(Elsevier, 2024-03) Maccioni, Riccardo; Travisan, Caterina; Badman, Jack; Zerial, Stefania; Wagener, Annika; Andrade-Talavera, Yuniesky; Picciau, Federico; Grassi, Caterina; Chen, Gefei; Lemoine, Laetitia; Tambaro, Simone; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Academy of Finland (AKA); Ahlen-stiftelsen; Alzheimerfonden; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG); DFG; Formas; Gamla tjanarinnor; Lindhes Advokatbyra Stiftelse; Olle Engkvists Stiftelse
Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aβ cascade. Exogenous Aβ42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of AppNL-G-F knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in AppNL-G-F mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aβ production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aβ-induced upregulation of SPPL2b may enhance Aβ production in a vicious cycle, further aggravating Aβ pathology. Therefore, SPPL2b emerges as a potential anti-Aβ drug target.
Human adolescent brain similarity development is different for paralimbic versus neocortical zones
(National Academy of Sciences, 2024-08-09) Dorfschmidt, Lena; Váša, František; White, Simon R.; Romero García, Rafael; Kitzbichler, Manfred G.; Alexander-Bloch, Aaron F.; Cieslak, Matthew; Mehta, Kahini; Satterthwaite, Theodore D.; Bethlehem, Richard A.I.; Seidlitz, Jakob; Vértes, Petra E.; Bullmore, Edward T.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España
Adolescent development of human brain structural and functional networks is increasingly recognized as fundamental to emergence of typical and atypical adult cognitive and emotional processes. We analysed multimodal magnetic resonance imaging (MRI) data collected from N 300 healthy adolescents (51%; female; 14 to 26 y) each scanned repeatedly in an accelerated longitudinal design, to provide an analyzable dataset of 469 structural scans and 448 functional MRI scans. We estimated the morphometric similarity between each possible pair of 358 cortical areas on a feature vector comprising six macro- and microstructural MRI metrics, resulting in a morphometric similarity network (MSN) for each scan. Over the course of adolescence, we found that morphometric similarity increased in paralimbic cortical areas, e.g., insula and cingulate cortex, but generally decreased in neocortical areas, and these results were replicated in an independent developmental MRI cohort (N 304). Increasing hubness of paralimbic nodes in MSNs was associated with increased strength of coupling between their morphometric similarity and functional connectivity. Decreasing hubness of neocortical nodes in MSNs was associated with reduced strength of structure–function coupling and increasingly diverse functional connections in the corresponding fMRI networks. Neocortical areas became more structurally differentiated and more functionally integrative in a metabolically expensive process linked to cortical thinning and myelination, whereas paralimbic areas specialized for affective and interoceptive functions became less differentiated, as hypothetically predicted by a developmental transition from periallocortical to proisocortical organization of the cortex. Cytoarchitectonically distinct zones of the human cortex undergo distinct neurodevelopmental programs during typical adolescence.
Handshaking for ultrafast endocytosis: Dynamin1xA and Endophilin A1 sealed the deal
(Nature Pub. Group, 2024-08) López-Begines, Santiago; Fernández-Chacón, Rafael; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Agencia Estatal de Investigación. España
Brain function relies on quick inter-neuron communication at specialized points of contact termed synapses. In the latest issue of The EMBO Journal, Imoto, Xue, et al (2024) report the discovery of a novel, regulated interaction between two major endocytosis players which supports the notion of a preassembled protein machinery at presynaptic nerve terminals that can explain how the high speed of ultrafast endocytosis is possible
Brain tumour microstructure is associated with post-surgical cognition
(Nature Publishing Group, 2024-03-07) Aznarez-Sanado, Maite; Romero García, Rafael; Li, Chao; Morris, Rob C.; Price, Stephen J.; Manly, Thomas; Santarius, Thomas; Erez, Yaara; Hart, Michael G.; Suckling, John; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Junta de Andalucía; Cancer Research Cambridge Centre. United Kingdom
Brain tumour microstructure is potentially predictive of changes following treatment to cognitive functions subserved by the functional networks in which they are embedded. To test this hypothesis, intra-tumoural microstructure was quantified from diffusion-weighted MRI to identify which tumour subregions (if any) had a greater impact on participants’ cognitive recovery after surgical resection. Additionally, we studied the role of tumour microstructure in the functional interaction between the tumour and the rest of the brain. Sixteen patients (22–56 years, 7 females) with brain tumours located in or near speech-eloquent areas of the brain were included in the analyses. Two different approaches were adopted for tumour segmentation from a multishell diffusion MRI acquisition: the first used a two-dimensional four group partition of feature space, whilst the second used data-driven clustering with Gaussian mixture modelling. For each approach, we assessed the capability of tumour microstructure to predict participants’ cognitive outcomes after surgery and the strength of association between the BOLD signal of individual tumour subregions and the global BOLD signal. With both methodologies, the volumes of partially overlapped subregions within the tumour significantly predicted cognitive decline in verbal skills after surgery. We also found that these particular subregions were among those that showed greater functional interaction with the unaffected cortex. Our results indicate that tumour microstructure measured by MRI multishell diffusion is associated with cognitive recovery after surgery.
A novel long non-coding RNA connects obesity to impaired adipocyte function
(Elsevier, 2024-12) Lluch, Aina; Latorre, Jèssica; Oliveras-Cañellas, Núria; Fernández-Sánchez, Ana; Moreno-Navarrete, José M.; Castells-Nobau, Anna; Comas, Ferran; Buxò, Maria; Rodríguez-Hermosa, José I.; Ballester, María Pilar; Espadas, Isabel; Ortega, Francisco J.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España
Background Long non-coding RNAs (lncRNAs) can perform tasks of key relevance in fat cells, contributing, when defective, to the burden of obesity and its sequelae. Here, scrutiny of adipose tissue transcriptomes before and after bariatric surgery (GSE53378) granted identification of 496 lncRNAs linked to the obese phenotype. Only expression of linc-GALNTL6-4 displayed an average recovery over 2-fold and FDR-adjusted p-value <0.0001 after weight loss. The aim of the present study was to investigate the impact on adipocyte function and potential clinical value of impaired adipose linc-GALNTL6-4 in obese subjects. Methods We employed transcriptomic analysis of public dataset GSE199063, and cross validations in two large transversal cohorts to report evidence of a previously unknown association of adipose linc-GALNTL6-4 with obesity. We then performed functional analyses in human adipocyte cultures, genome-wide transcriptomics, and untargeted lipidomics in cell models of loss and gain of function to explore the molecular implications of its associations with obesity and weight loss. Results The expression of linc-GALNTL6-4 in human adipose tissue is adipocyte-specific and co-segregates with obesity, being normalized upon weight loss. This co-segregation is demonstrated in two longitudinal weight loss studies and two cross-sectional samples. While compromised expression of linc-GALNTL6-4 in obese subjects is primarily due to the inflammatory component in the context of obesity, adipogenesis requires the transcriptional upregulation of linc-GALNTL6-4, the expression of which reaches an apex in terminally differentiated adipocytes. Functionally, we demonstrated that the knockdown of linc-GALNTL6-4 impairs adipogenesis, induces alterations in the lipidome, and leads to the downregulation of genes related to cell cycle, while propelling in adipocytes inflammation, impaired fatty acid metabolism, and altered gene expression patterns, including that of apolipoprotein C1 (APOC1). Conversely, the genetic gain of linc-GALNTL6-4 ameliorated differentiation and adipocyte phenotype, putatively by constraining APOC1, also contributing to the metabolism of triglycerides in adipose. Conclusions Current data unveil the unforeseen connection of adipocyte-specific linc-GALNTL6-4 as a modulator of lipid homeostasis challenged by excessive body weight and meta-inflammation.
The carotid body oxygen sensor
(Elsevier, 2025-06) Gao Chen, Lin; Moreno Domínguez, Alejandro; Ortega Sáenz, Patricia; López Barneo, José; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; European Research Council (ERC)
Carotid body (CB) chemoreceptor glomus cells sense hypoxia through the inhibition of plasmalemmal K+ channels, which leads to the opening of Ca2+ channels, Ca2+ influx, and neurotransmitter release. The mechanism of O2 sensing and the regulation of membrane ion channels by O2 have remained undefined and a subject of debate. Here, we summarize the molecular pathway that underlies acute O2 sensing in the CB. This process does not rely on a single-molecule O2 sensor expressed in glomus cells but rather on HIF2α-dependent genetically specialized mitochondria that can detect changes in O2 tension, within physiological ranges, and generate biochemical signals that regulate membrane ion channels. The acute O2-sensing pathway in glomus cells could provide new targets for respiratory and cardiovascular pharmacology.
Predicting clinical and functional trajectories in individuals with first-episode psychosis by baseline deviations in grey matter volume
(Royal College of Psychiatrists ; Cambridge University Press, 2025-06-16) Alemán Morillo, C.; Muñoz-Caracuel, Manuel; García-San-Martín, Natalia; Garrido-Torres, Nathalia; Alemany-Navarro, María; Bethlehem, Richard A. I.; Ruiz Veguilla, Miguel; Crespo Facorro, Benedicto; Romero García, Rafael; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Universidad de Sevilla. Departamento de Psiquiatría; Gobierno de España; Junta de Andalucía; Instituto de Salud Carlos III; Universidad de Sevilla. TIC245: Topological Pattern Analysis, Recognition and Learning; Universidad de Sevilla. CTS1086: Psiquiatría Traslacional
Background Predicting long-term outcome trajectories in psychosis remains a crucial and challenging goal in clinical practice. The identification of reliable neuroimaging markers has often been hindered by theclinical and biological heterogeneity of psychotic disorders and the limitations of traditional case-control methodologies, which often mask individual variability. Recently, normative brain charts derived from extensive magnetic resonance imaging (MRI) data-sets covering the human lifespan have emerged as a promising biologically driven solution, offering a more individualised approach. Aims To examine how deviations from normative cortical and subcortical grey matter volume (GMV) at first-episode psychosis (FEP) onset relate to symptom and functional trajectories. Method We leveraged the largest available brain normative model (N > 100 000) to explore normative deviations in a sample of over 240 patients with schizophrenia spectrum disorders who underwent MRI scans at the onset of FEP and received clinical follow-up at 1, 3 and 10 years. Results Our findings reveal that deviations in regional normative GMV at FEP onset are significantly linked to overall long-term clinical trajectories, modulating the effect of time on both symptom and functional outcome. Specifically, negative deviations in the left superior temporal gyrus and Broca’s area at FEP onset were notably associated with a more severe progression of positive and negative symptoms, as well as with functioning trajectories over time. Conclusions These results underscore the potential of brain developmental normative approaches for the early prediction of disorder progression, and provide valuable insights for the development of preventive and personalised therapeutic strategies.
Synaptic vulnerability to amyloid-β and tau pathologies differentially disrupts emotional and memory neural circuits
(Nature Pub. Group, 2025-01-30) Capilla-López, María Dolores; Deprada, Ángel; Andrade-Talavera, Yuniesky; Martínez-Gallego, Irene; Coatl-Cuaya, Heriberto; Sotillo, Paula; Rodríguez-Álvarez, José; Rodríguez-Moreno, Antonio; Parra-Damas, Arnaldo; Saura, Carlos A.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Agencia Estatal de Investigación. España; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Junta de Andalucía; Instituto de Salud Carlos III; European Union
Alzheimer’s disease (AD) is characterized by memory loss and neuropsychiatric symptoms associated with cerebral amyloid-β (Aβ) and tau pathologies, but whether and how these factors differentially disrupt neural circuits remains unclear. Here, we investigated the vulnerability of memory and emotional circuits to Aβ and tau pathologies in mice expressing mutant human amyloid precursor protein (APP), Tau or both APP/Tau in excitatory neurons. APP/Tau mice develop age- and sex-dependent Aβ and phosphorylated tau pathologies, the latter exacerbated at early stages, in vulnerable brain regions. Early memory deficits were associated with hippocampal tau pathology in Tau and APP/Tau mice, whereas anxiety and fear appeared linked to intracellular Aβ in the basolateral amygdala (BLA) of APP and APP/Tau mice. Transcriptome hippocampal profiling revealed gene changes affecting myelination and RNA processing in Tau mice, and inflammation and synaptic-related pathways in APP/Tau mice at 6 months. At 9 months, we detected common and region-specific changes in astrocytic, microglia and 63 AD-associated genes in the hippocampus and BLA of APP/Tau mice. Spatial learning deficits were associated with synaptic tau accumulation and synapse disruption in the hippocampus of Tau and APP/Tau mice, whereas emotional disturbances were linked to Aβ pathology but not synaptic tau in the BLA. Interestingly, Aβ and tau exhibited synergistic detrimental effects in long-term potentiation (LTP) in the hippocampus but they counteract with each other to mitigate LTP impairments in the amygdala. These findings indicate that Aβ and tau pathologies cause region-specific effects and synergize to induce synaptic dysfunction and immune responses, contributing to the differing vulnerability of memory and emotional neural circuits in AD.
Polygenic scores for autism are associated with reduced neurite density in adults and children from the general population
(Nature Pub. Group, 2025-02-24) Gu, Yuangu; Stauffer, Eva María; Saashi A., Bedford; Romero García, Rafael; Grove, Jackob; Børglum, Anders D.; Martin, Hilary; Baron-Cohen, Simon; Bethlehem, Richard A. I.; Warrier, Varun; APEX Consortium; iPSYCH-Autism Consortium; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; European Union (UE). H2020
Genetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.
Pharmacological Inhibition of Microglial Proliferation Supports Blood–Brain Barrier Integrity in Experimental Autoimmune Encephalomyelitis
(MDPI, 2025-03-12) Borjini, Nozha; Fernandez, Mercedes; Giardino, Luciana; Sorokin, Lydia; Calzà, Laura; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; European Union (UE)
Blood–brain barrier dysfunction (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). We have previously shown that blocking microglial proliferation using GW2580, a selective inhibitor of CSF1R (Colony stimulating factor 1 receptor), reduced disease progression and severity and prevented the relapse phase. However, whether this was due to effects of GW2580 on the functional integrity of the BBB was not determined. Therefore, here, we examine BBB properties in rats during EAE under GW2580 treatment. Our data suggest that blocking early microglial proliferation through selective targeting of CSF1R signaling has a therapeutic effect in EAE by protecting BBB integrity and reducing peripheral immune cell infiltration. Taken together, our results identify a novel mechanism underlying the effects of GW2580, which could offer a novel therapy for MS.
Intracellular signalling in arterial chemoreceptors during acute hypoxia and glucose deprivation: role of ATP
(Willey-Blackwell, 2025-03-01) Torres López, María; González Rodríguez, Patricia; Colinas Miranda, Olalla; Rho, Hee-Sool; Torres Torrelo, Hortensia; Castellano Orozco, Antonio Gonzalo; Gao Chen, Lin; Ortega Sáenz, Patricia; López Barneo, José; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; European Research Council (ERC)
The carotid body (CB) is the main oxygen (O2) sensing organ that mediates reflex hyperventilation and increased cardiac output in response to hypoxaemia. Acute O2 sensing is an intrinsic property of CB glomus cells, which contain special mitochondria to generate signalling molecules (NADH and H2O2) that modulate membrane K+ channels in response to lowered O2 tension (hypoxia). In parallel with these membrane-associated events, glomus cells are highly sensitive to mitochondrial electron transport chain (ETC) inhibitors. It was suggested that a decrease in oxidative production of ATP is a critical event mediating hypoxia-induced cell depolarization. Here, we show that rotenone [an inhibitor of mitochondrial complex (MC) I] activates rat and mouse glomus cells but abolishes their responsiveness to hypoxia. Rotenone does not prevent further activation of the cells by cyanide (a blocker of MCIV) or glucose deprivation. Responsiveness to glucose deprivation is enhanced in O2-insenstive glomus cells with genetic disruption of MCI. These findings suggest that acute O2 sensing requires a functional MCI but that a decrease in intracellular ATP, presumably produced by the simultaneous inhibition of MCI and MCIV, is not involved in hypoxia signalling. In support of this concept, ATP levels in single glomus cells were unaltered by hypoxia, but rapidly declined following exposure of the cells to low glucose or to inhibitors of oxidative phosphorylation. These observations indicate that a reduction in intracellular ATP does not participate in physiological acute O2 sensing. However, local decreases in ATP of glycolytic origin may contribute to low glucose signalling in glomus cells.
Filamin A C-terminal fragment modulates Orai1 expression by inhibition of protein degradation
(American Physiological Society, 2025-01-07) Macias-DÍaz, Alvaro; Nieto-Felipe, Joel; Jardin, Isaac; Camello, Pedro J.; Martinez-Quintana, Eva M.; Salido, Gines M.; Smani Hajami, Tarik; Lopez, Jose J.; Rosado, Juan A.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Junta de Extremadura; Ministerio de Ciencia e Innovación (MICIN). España
Filamin A (FLNA) is an actin-binding protein that has been reported to interact with STIM1 modulating the activation of Orai1 channels. Cleaving of FLNA by calpain leads to a C-terminal fragment that is involved in a variety of functional and pathological events, including pro-oncogenic activity in different types of cancer. Here, we show that full-length FLNA is downregulated in samples from patients with colon cancer as well as in the adenocarcinoma cell line HT-29. This is consistent with an increased calpain-dependent FLNA cleaving with enhanced expression of the C-terminal FLNA fragment accompanied by enhanced expression of Orai1 and STIM1, as well as store-operated Ca2+ entry (SOCE). To further explore the mechanism underlying the enhancement of SOCE by the C-terminal FLNA fragment, we expressed in HEK-293 cells the C-terminal FLNA region encompassing repeats 16–24 (FLNA16–24 fragment), which enhanced both Orai1 and STIM1 as well as SOCE. Transfection of the FLNA16–24 fragment attenuates Orai1 and STIM1 protein degradation, and, specifically, abrogates Orai1α lysosomal degradation and retains this channel in the plasma membrane. However, the C-terminal FLNA fragment did not induce a detectable modification in Orai1β degradation. Due to the relevance of SOCE in cell physiology, our results provide evidence of a novel mechanism for the regulation of Ca2+ influx with relevant pathophysiological implications
Early Myocardial Strain Reduction and miR-122-5p Elevation Associated with Interstitial Fibrosis in Anthracycline-Induced Cardiotoxicity
(MDPI, 2024-12-27) Caballero-Valderrama, María de Regla; Bevilacqua, Elisa; Echevarría Irusta, Miriam; Salvador Bofill, Francisco Javier; Ordóñez Fernández, José Antonio; López Haldón, José Eduardo; Smani Hajami, Tarik; Calderón-Sánchez, Eva M; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Agencia Estatal de Investigación. España; Junta de Andalucía
Echocardiographic myocardial strain is crucial for early detection of anthracycline-induced cardiotoxicity, particularly in patients at moderate or high risk. Background/ Objectives: This study investigates changes in global longitudinal strain (GLS) in breast cancer patients with low baseline risk for cardiotoxicity during cancer therapy. We also examined the relationship between echocardiographic strain, structural myocardial changes, and microRNA (miRNA) dysregulation associated with cancer treatment using an animal model. Methods: Echocardiography and blood tests were examined in 33 breast cáncer patients with low baseline risk for cardiotoxicity during anthracycline treatment, with a follow-up at 12 months. Additionally, 16 Wistar rats received epirubicin (20 mg/kg over 4 weeks) to examine cardiac strain and structural changes. Moreover, circulating miRNA levels were assessed in patients’ serum using microarray at the end of the treatment and further analyzed in peripheral blood from the animal model. Results: Pathological GLS values were observed in 27.27% of patients after four cycles, with 15.15% showing reduced left ventricular ejection fraction (LVEF) after 12 months. In the animal model, epirubicin-induced circumferential strain (CS) decrease correlates with myocardial fibrosis assessed histologically and by a significant increase in COL1 and TGFB2 expression. Furthermore, we found a significant decrease in aquaporin1 expression associated with the presence of vacuoles in treated rats. Furthermore, dysregulation in the expression of miRNAs was observed in patients with cardiotoxicity. Among them, hsa-miR-122-5p is increased in both patient and rat serum post-treatment. Conclusions: A notable percentage of low-risk patients exhibited cardiac strain reduction due to cardiotoxicity. Epirubicin treatment caused structural heart changes in rats, highlighting miR-122-5p as a potential fibrosis marker that correlated with echocardiographic parameters.
Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging
(Cell Press (Elsevier), 2019-09-05) Ho, Ya Hsuan; Toro Estévez, Raquel del; Rivera-Torres, José; Rak, Justyna; Korn, Claudia; García-García, Andrés; Macías, David; Méndez-Ferrer, Simón; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Unión Europea; Comunidad de Madrid; Universidad de Sevilla. CTS1134: Investigación Traslacional en la Fisiopatología Cardiovascular; Universidad de Sevilla. CTS1138: Hipoxia y Enfermedades Asociadas al Envejecimiento
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.
Fast neurogenesis from carotid body quiescent neuroblasts accelerates adaptation to hypoxia
(Springer Nature, 2018-01-16) Sobrino Cabello, Verónica; González Rodríguez, Patricia; Annese, Valentina; López Barneo, José; Pardal Redondo, Ricardo; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Economía y Competitividad (MINECO). España; Instituto de Salud Carlos III
Unlike other neural peripheral organs, the adult carotid body (CB) has a remarkable structural plasticity, as it grows during acclimatization to hypoxia. The CB contains neural stem cells that can differentiate into oxygen-sensitive glomus cells. However, an extended view is that, unlike other catecholaminergic cells of the same lineage (sympathetic neurons or chromaffin cells), glomus cells can divide and thus contribute to CB hypertrophy. Here, we show that O2-sensitive mature glomus cells are post-mitotic. However, we describe an unexpected population of pre-differentiated, immature neuroblasts that express catecholaminergic markers and contain voltage-dependent ion channels, but are unresponsive to hypoxia. Neuroblasts are quiescent in normoxic conditions, but rapidly proliferate and differentiate into mature glomus cells during hypoxia. This unprecedented “fast neurogenesis” is stimulated by ATP and acetylcholine released from mature glomus cells. CB neuroblasts, which may have evolved to facilitate acclimatization to hypoxia, could contribute to the CB oversensitivity observed in highly prevalent human diseases.
Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD
(Nature Publishing Group; Springernature, 2014-04-17) González-Rodríguez, A.; Mayoral, R.; Agra, N.; Valdés Pardo, V. G.; Valdecantos, M. P.; Miquilena-Colina, M. E.; Muntané Relat, Jordi; Valverde, A. M.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Comunidad de Madrid; Ministerio de Economia, Industria y Competitividad (MINECO). España; Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM, ISCIII, Barcelona, Spain); Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD, ISCIII); Universidad de Sevilla. CTS1098: Mecanismos Moleculares del Hepatocarcinoma y Sus Estrategias Terapéuticas
The pathogenic mechanisms underlying the progression of non-alcoholic fatty liver disease (NAFLD) are not fully understood. In this study, we aimed to assess the relationship between endoplasmic reticulum (ER) stress and autophagy in human and mouse hepatocytes during NAFLD. ER stress and autophagy markers were analyzed in livers from patients with biopsy-proven non alcoholic steatosis (NAS) or non-alcoholic steatohepatitis (NASH) compared with livers from subjects with histologically normal liver, in livers from mice fed with chow diet (CHD) compared with mice fed withhigh fat diet (HFD) or methionine-choline-deficient (MCD) diet and in primary and Huh7 humanhepatocytesloadedwith palmitic acid (PA). In NASH patients, significant increases in hepatic messenger RNA levels of markers of ER stress (activating transcription factor 4 (ATF4), glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP)) and autophagy (BCN1) were found compared with NAS patients. Likewise, protein levels of GRP78, CHOP and p62/SQSTM1 (p62) autophagic substrate were significantly elevated in NASH compared with NAS patients. In livers from mice fed with HFD or MCD, ER stress-mediated signaling was parallel to the blockade of the autophagic flux assessed by increases in p62, microtubule-associated protein 2 light chain 3 (LC3-II)/LC3-I ratio and accumulation of autophagosomes compared with CHD fed mice. In Huh7 hepatic cells, treatment with PA for 8h triggered activation of both unfolding protein response and the autophagic flux. Conversely, prolonged treatment with PA (24h) induced ERstress and cell death together with a blockade of the autophagic flux. Under these conditions, cotreatment with rapamycin or CHOP silencing ameliorated these effects and decreased apoptosis. Our results demonstrated that the autophagic flux is impaired in the liver from both NAFLD patients and murine models of NAFLD, as well as in lipid-overloaded human hepatocytes, and it could be due to elevated ER stress leading to apoptosis. Consequently, therapies aimed to restore the autophagic flux might attenuate or prevent the progression of NAFLD.
Antisense therapeutics in oncology: current status
(Dove Medical Press Ltd, 2014-11-03) Farooqi, Ammad Ahmad; Rehman, Zia ur; Muntané Relat, Jordi; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Universidad de Sevilla. CTS1098: Mecanismos Moleculares del Hepatocarcinoma y Sus Estrategias Terapéuticas
There is increasing progress in translational oncology and tremendous breakthroughs have been made as evidenced by preclinical and clinical trials. Data obtained from high-throughput technologies are deepening our understanding about the molecular and gene network in cancer cells and rapidly emerging in vitro and in vivo evidence is highlighting the role of antisense agents as specific inhibitors of the expression of target genes, thus modulating the response of cancer cells to different therapeutic strategies. Much information is continuously being added into various facets of molecular oncology and it is now understood that overexpression of antiapoptotic proteins, oncogenes, oncogenic microRNAs (miRNA), and fusion proteins make cancer cells difficult to target. Delivery of antisense oligonucleotides has remained a challenge and technological developments have helped in overcoming hurdles by improving the ability to penetrate cells, effective and targeted binding to gene sequences, and downregulation of target gene function. Different delivery systems, including stable nucleic acid lipid particles, have shown potential in enhancing the delivery of cargo to the target site. In this review, we attempt to summarize the current progress in the development of antisense therapeutics and their potential in medical research. We partition this multicomponent review into introductory aspects about recent breakthroughs in antisense therapeutics. We also discuss how antisense therapeutics have shown potential in resensitizing resistant cancer cells to apoptosis by targeted inhibition of antiapoptotic proteins, oncogenic miRNAs, and BCR-ABL.
Redox regulation of metabolic and signaling pathways by thioredoxin and glutaredoxin in NOS-3 overexpressing hepatoblastoma cells
(Elsevier Science Bv, Elsevier, 2015-07-17) González, Raúl; López-Grueso, M. José; Muntané Relat, Jordi; Bárcena, J. A.; Padilla, C. Alicia; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Junta de Andalucía; Gobierno de España; Universidad de Sevilla. CTS1098: Mecanismos Moleculares del Hepatocarcinoma y Sus Estrategias Terapéuticas
Nitric oxide (NO) plays relevant roles in signal transduction in physiopathology and its effects are de pendent on several environmental factors. NO has both pro-apoptotic and anti-apoptotic functions but the molecular mechanisms responsible for these opposite effects are not fully understood. The action of NO occurs mainly through redox changes in target proteins, particularly by S-nitrosylation of reactive cysteine residues. Thioredoxin (Trx) and glutaredoxin (Grx) systems are the main cellular controllers of the thiolic redox state of proteins exerting controversial effects on apoptosis with consequences for the resistance to or the development of cancer. The aim of this study was to ascertain whether Trx and/or Grx systems mediate the antiproliferative effect of NO on hepatoblastoma cells by modulating the redox-state of key proteins. Proliferation decreased and apoptosis increased in HepG2 cells overexpressing Nitric Oxide Synthase 3 (NOS-3) as a result of multilevel cellular responses to the oxidative environment generated by NO. Enzyme levels and cysteine redox state at several metabolic checkpoints were consistent with promi nence of the pentose phosphate pathway to direct the metabolic flux toward NADPH for antioxidant defense and lowering of nucleotide biosynthesis and hence proliferation. Proteins involved in cell sur vival pathways, proteins of the redoxin systems and phosphorylation of MAPK were all significantly increased accompanied by a shift of the thiolic redox state of Akt1, Trx1 and Grx1 to more oxidized. Silencing of Trx1 and Grx1 neutralized the increases in CD95, Akt1 and pAkt levels induced by NO and produced a marked increase in caspase-3 and-8 activities in both control and NOS-3 overexpressing cells concomitant with a decrease in the number of cells. These results demonstrate that the antiproliferative effect of NO is actually hampered by Trx1 and Grx1 and support the strategy of weakening the thiolic antioxidant defenses when designing new an titumoral therapies.
Modulation of autophagy by sorafenib: effects on treatment response
(Frontiers Media SA, 2016-06-08) Prieto-Domínguez, Nestor; Ordóñez, Raquel; Fernández, Anna; García-Palomo, Andres; Muntané Relat, Jordi; González-Gallego, Javier; Mauriz, José L.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Gobierno de España; Universidad de Sevilla. CTS1098: Mecanismos Moleculares del Hepatocarcinoma y Sus Estrategias Terapéuticas
The multikinase inhibitor sorafenib is, at present, the only drug approved for the treatment of hepatocellular carcinoma (HCC), one of the most lethal types of cancer worldwide. However, the increase in the number of sorafenib tumor resistant cells reduces efficiency. A better knowledge of the intracellular mechanism of the drug leading to reduced cell survival could help to improve the benefits of sorafenib therapy. Autophagy is a bulk cellular degradation process activated in a broad range of stress situations, which allows cells to degrade misfolded proteins or dysfunctional organelles. This cellular route can induce survival or death, depending on cell status and media signals. Sorafenib, alone or in combination with other drugs is able to induce autophagy, but cell response to the drug depends on the complex integrative crosstalk of different intracellular signals. In cancerous cells, autophagy can be regulated by different cellular pathways (Akt-related mammalian target of rapamycin (mTOR) inhibition, 5′ AMP-activated protein kinase (AMPK) induction, dissociation of B-cell lymphoma 2 (Bcl-2) family proteins from Beclin-1), or effects of some miRNAs. Inhibition of mTOR signaling by sorafenib and diminished interaction between Beclin-1 and myeloid cell leukemia 1 (Mcl-1) have been related to induction of autophagy in HCC. Furthermore, changes in some miRNAs, such as miR-30α, are able to modulate autophagy and modify sensitivity in sorafenib-resistant cells. However, although AMPK phosphorylation by sorafenib seems to play a role in the antiproliferative action of the drug, it does not relate with modulation of autophagy. In this review, we present an updated overview of the effects of sorafenib on autophagy and its related activation pathways, analyzing in detail the involvement of autophagy on sorafenib sensitivity and resistance.
Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation
(Public Library Science, 2017-03-28) González, Raúl; Rosa, Ángel J. de la; Rufini, Alessandro; Rodríguez-Hernández, María A.; Navarro-Villarán, Elena; Marchal, Trinidad; Pascasio Acevedo, Juan Manuel; Gómez Bravo, Miguel Ángel; Muntané Relat, Jordi; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Fisiología médica y biofísica; Junta de Andalucía; Instituto de Salud Carlos III; Universidad de Sevilla. CTS664: Cirugía Avanzada y Trasplantes. Terapia Celular y Bioingeniería Aplicada a la Cirugía; Universidad de Sevilla. CTS1098: Mecanismos Moleculares del Hepatocarcinoma y Sus Estrategias Terapéuticas
Background & Aims Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines. Methods HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells. Results The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation. Conclusions The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.

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