Artículos (Biología Celular)

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In vitro toxicity of two functionalized reduced graphene oxide materials with potential application in food packaging
(Elsevier, 2025-01) Cebadero Domínguez, Óscar; Díez-Quijada Jiménez, Leticia; López Martín, Sergio; Prieto, Alejandro; Puerto Rodríguez, María; Cameán Fernández, Ana María; Jos Gallego, Ángeles Mencía; Nutrición y Bromatología, Toxicología y Medicina Legal; Biología Celular; Junta de Andalucía
Functionalized graphene materials have been proposed as nanofillers in food packaging applications as they improve the characteristics of the resulting nanocomposites. But food contact materials require a toxicity evaluation previous their authorization and use. In this sense, reduced graphene oxide functionalized with dodecyl amine (DA-rGO), and [2-(methacryloyloxy) ethyl] trimethylammonium chloride (MTAC-rGO) were characterized and their internalization and cytotoxicity in Caco-2 and HepG2 cultures evaluated. Cell viability decreased from 100 μg/mL in all experimental trials, and oxidative stress by means of a reduction in glutathione levels was evidenced as one of the potential toxicity mechanisms involved. Moreover, both materials were subjected to an in vitro digestion process to investigate their potential changes along the gastrointestinal tract. Digested samples were characterized, and the cytotoxicity also evaluated showing an exacerbation. These results raise concerns about the impact of these materials after oral exposure, and therefore further research is necessary.
Shaping current European mitochondrial haplogroup frequency in response to infection: the case of SARS-CoV-2 severity
(Nature Briefing, 2025-01) Cabrera Alarcón, José Luis; Cruz, Raquel; Rosa-Moreno, Marina; Latorre-Pellicer, Ana; Diz de Almeida, Silvia; SCOURGE cohort group; Medrano Ortega, Francisco Javier; Rodríguez Hernández, María A.; Morilla Romero de la Osa, Rubén; Valido Morales, Agustín S.; Enríquez, José Antonio; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Enfermería; Instituto de Biomedicina de Sevilla (IBIS)
The frequency of mitochondrial DNA haplogroups (mtDNA-HG) in humans is known to be shaped by migration and repopulation. Mounting evidence indicates that mtDNA-HG are not phenotypically neutral, and selection may contribute to its distribution. Haplogroup H, the most abundant in Europe, improved survival in sepsis. Here we developed a random forest trained model for mitochondrial haplogroup calling using data procured from GWAS arrays. Our results reveal that in the context of the SARS-CoV-2 pandemic, HV branch were found to represent protective factors against the development of critical SARS-CoV-2 in an analysis of 14,349 patients. These results highlight the role of mtDNA in the response to infectious diseases and support the proposal that its expansion and population proportion has been influenced by selection through successive pandemics.
Virgin olive oil and its phenol fraction modulate monocyte/macrophage functionality: a potential therapeutic strategy in the treatment of systemic lupus erythematosus
(Cambridge University Press, 2018-07-31) Aparicio Soto, Marina; Montserrat de la Paz, Sergio; Sánchez Hidalgo, Marina; Cárdeno Galván, Ana; Bermúdez Pulgarín, Beatriz; García Muriana, Francisco José; Alarcón de la Lastra Romero, Catalina; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Universidad de Sevilla
Monocytes and macrophages are critical effectors and regulators of inflammation and innate immune response, which appear altered in different autoimmune diseases such as systemic lupus erythematosus (SLE). Recent studies suggested that virgin olive oil (VOO) and particularly its phenol compounds might possess preventive effects on different immune-inflammatory diseases, including SLE. Here, we evaluated the effects of VOO (and sunflower oil) on lipopolysaccharide (LPS)-activated peritoneal macrophages from a model of pristane-induced SLE in BALB/c mice, as well as those of the phenol fraction (PF) from VOO on the immune-inflammatory activity and plasticity in monocytes and monocyte-derived macrophages from healthy volunteers. The release of nitrite and inflammatory cytokines was lower in LPS-treated peritoneal macrophages from pristane-SLE mice fed the VOO diet when compared with the sunflower oil diet. PF from VOO similarly decreased the secretion of nitrite and inflammatory cytokines and expression of inducible nitric oxide, PPARγ and Toll-like receptor 4 in LPS-treated human monocytes. PF from VOO also prevented the deregulation of human monocyte subset distribution by LPS and blocked the genetic signature of M1 macrophages while favouring the phenotype of M2 macrophages upon canonical polarisation of naïve human macrophages. For the first time, our study provides several lines of in vivo and in vitro evidence that VOO and PF from VOO target and counteract inflammatory pathways in the monocyte–macrophage lineage of mice with pristane-induced SLE and of healthy subjects, which is a meaningful foundation for further development and application in preclinical and clinical use of PF from VOO in patients with SLE.
Three Decades of the Spanish Society for Developmental Biology (SEBD): Insights and Emerging Perspectives from the 18th Spanish Society for Developmental Biology Meeting (SEBD 2024)
(Universidad del País Vasco, 2024-04-15) Herrera, Eloisa; Acosta, Sandra; Almuedo, María; Borrell, Victor; Cañestro, Cristian; Casas Tintó, Sergio; Escudero Cuadrado, Luis María; Araújo, Sofia J.; Universidad de Sevilla. Departamento de Biología Celular
The Spanish Society for Developmental Biology,(SEBD) organized its 18th meeting in October 2024 (hereafter,SEBD2024), coinciding with the society’s 30th anniversary and,serving as the stage for its celebrations. This article provides an,overview of the event, including the speakers, scientific sessions,and the different activities related to the anniversary.
SUMO2/3 modification of transcription-associated proteins controls cell viability in response to oxygen and glucose deprivation-mediated stress
(Springer, 2025-05-10) Gallardo Chamizo, Francisco de Asis; González Prieto, Román; Jafari, Vahid; Luna Peláez, Noelia; Vertegaal, Alfred C.O.; García-Domínguez, Mario; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE)
Because limited oxygen and glucose supply to tissues is a serious challenge that cells must properly measure to decide between,surviving or triggering cell death, organisms have developed accurate mechanisms for sensing and signaling these conditions. In,recent years, signaling through posttranslational modification of proteins by covalent attachment of the Small Ubiquitin-like,Modifier (SUMO) is gaining notoriety. Enhanced sumoylation in response to oxygen and glucose deprivation (OGD) constitutes a,safeguard mechanism for cells and a new avenue for therapeutic intervention. However, indiscriminate global sumoylation can limit,the therapeutic potential that a more precise action on selected targets would have. To clear up this, we have conducted a,proteomic approach in P19 cells to identify specific SUMO targets responding to OGD and to investigate the potential that these,targets and their sumoylation have in preserving cells from death. Proteins undergoing sumoylation in response to OGD are mostly,related to transcription and RNA processing, and the majority of them are rapidly desumoylated when restoring oxygen and,glucose (ROG), confirming the high dynamics of this modification. Since OGD is linked to brain ischemia, we have also studied cells,differentiated into neurons. However, no major differences have been observed between the SUMO-proteomes of proliferating and,differentiated cells. We show that the overexpression of the transcription factor SOX2 or the SUMO ligase PIAS4 has a manifest cell,protective effect largely depending on their sumoylation, and that maintaining the sumoylation capacity of the coregulator NAB2 is,also important to face OGD. Conversely, sumoylation of the pluripotency factor OCT4, which is sumoylated under OGD, and is a,target of the SUMO protease SENP7 for desumoylation after ROG, seems to block its cell survival-promoting capacity. Thus, better,outcomes in cell protection would rely on the appropriate combination of sumoylated and non-sumoylated forms of selected,factors.
Apico-basal intercalations enable the integrity of curved epithelia
(Elsevier, 2025) Anbari, Samira; Gómez Gálvez, Pedro; Vicente Munuera, Pablo; Escudero Cuadrado, Luis María; Buceta, Javier; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; Consejo Superior de Investigaciones Científicas (CSIC)
Non-invasive force inference based on imaging data has significantly advanced our understanding of the mechanical cues driving morphogenesis. In 2D studies of confluent tissues, these methods allow for the computation of forces acting on cells by analyzing their geometrical features. Here, we present a novel approach for 3D force and energy inference in curved epithelia. Specifically, we focus on tubular epithelia, which form the foundation of many vital organs, including the lungs, kidneys, and vasculature. Our technique analyzes the average mechanical behavior of cells along their apico-basal axis and is based on an optimal parametrization of a vertex model aimed at obtaining effective tissue parameters. We apply our method to in silico data to investigate the mechanical consequences of different 3D cellular packing scenarios. Our results reveal that in squamous epithelia, prismatic cellular shapes are mechanically stable. However, in cubic/columnar tubes, prismatic shapes are incompatible with the adhesion required to maintain tissue integrity. In conclusion, this study indicates that in cubic/columnar epithelia, stability can only be achieved if cells undergo apico-basal intercalations and adopt an alternative shape: the scutoid.
The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity article
(Springer Nature, 2018-02-15) Mellado Gil, José Manuel; Fuente Martín, Esther; Lorenzo, Petra I.; Cobo Vuilleumier, Nadia; López Noriega, Livia; Martín Montalvo, Alejandro; Gracia Herrera Gómez, Irene de; Ceballos Chávez, María; Gómez-Jaramillo, Laura; Campos-Caro, Antonio; Romero-Zerbo, Silvana Y.; Rodríguez-Comas, Júlia; Hmadcha, Abdelkrim; Aguilar-Diosdado, Manuel; Universidad de Sevilla. Departamento de Biología Celular; Junta de Andalucía; Ministerio de Economía y Competitividad (MINECO). España; Instituto de Salud Carlos III
HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the HMG20A gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that HMG20A is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased HMG20A transcript levels, a result also observed in islets of gestating mice. In contrast, HMG20A expression was not altered in islets from diet-induced obese and pre-diabetic mice. The T2DM-associated rs7119 SNP, located in the 3′ UTR of the HMG20A transcript reduced the luciferase activity of a reporter construct in the human beta 1.1E7 cell line. Depletion of Hmg20a in the rat INS-1E cell line resulted in decreased expression levels of its neuronal target gene NeuroD whereas Rest and Pax4 were increased. Chromatin immunoprecipitation confirmed the interaction of HMG20A with the Pax4 gene promoter. Expression levels of Mafa, Glucokinase, and Insulin were also inhibited. Furthermore, glucose-induced insulin secretion was blunted in HMG20A-depleted islets. In summary, our data demonstrate that HMG20A expression in islet is essential for metabolism-insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as NeuroD and Mafa and that depletion induces expression of genes such as Pax4 and Rest implicated in beta cell de-differentiation. More importantly we assign to the T2DM-linked rs7119 SNP the functional consequence of reducing HMG20A expression likely translating to impaired beta cell mature function.
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.
A Rfa1-MN-based system reveals new factors involved in the rescue of broken replication forks
(Public Library of Science, 2025-04-01) Amiama Roig, Ana; Barrientos Moreno, Marta; Cruz Zambrano, Esther; López Ruiz, Luz M.; González Prieto, Román; Ríos Orelogio, Gabriel; Prado, Félix; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España
The integrity of the replication forks is essential for an accurate and timely completion of genome duplication. However, little is known about how cells deal with broken replication forks. We have generated in yeast a system based on a chimera of the largest subunit of the ssDNA binding complex RPA fused to the micrococcal nuclease (Rfa1-MN) to induce double-strand breaks (DSBs) at replication forks and searched for mutants affected in their repair. Our results show that the core homologous recombination (HR) proteins involved in the formation of the ssDNA/Rad51 filament are essential for the repair of DSBs at forks, whereas non-homologous end joining plays no role. Apart from the endonucleases Mus81 and Yen1, the repair process employs fork-associated HR factors, break-induced replication (BIR)-associated factors and replisome components involved in sister chromatid cohesion and fork stability, pointing to replication fork restart by BIR followed by fork restoration. Notably, we also found factors controlling the length of G1, suggesting that a minimal number of active origins facilitates the repair by converging forks. Our study has also revealed a requirement for checkpoint functions, including the synthesis of Dun1-mediated dNTPs. Finally, our screening revealed minimal impact from the loss of chromatin factors, suggesting that the partially disassembled nucleosome structure at the replication fork facilitates the accessibility of the repair machinery. In conclusion, this study provides an overview of the factors and mechanisms that cooperate to repair broken forks.
Hypoxia Tolerant Species: The Wisdom of Nature Translated into Targets for Stroke Therapy
(MDPI, 2021-10-15) Río Mercado, Carmen del; Montaner, Joan; Universidad de Sevilla. Departamento de Biología Celular; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Human neurons rapidly die after ischemia and current therapies for stroke management are limited to restoration of blood flow to prevent further brain damage. Thrombolytics and mechanical thrombectomy are the available reperfusion treatments, but most of the patients remain untreated. Neuroprotective therapies focused on treating the pathogenic cascade of the disease have widely failed. However, many animal species demonstrate that neurons can survive the lack of oxygen for extended periods of time. Here, we reviewed the physiological and molecular pathways inherent to tolerant species that have been described to contribute to hypoxia tolerance. Among them, Foxo3 and Eif5A were reported to mediate anoxic survival in Drosophila and Caenorhabditis elegans, respectively, and those results were confirmed in experimental models of stroke. In humans however, the multiple mechanisms involved in brain cell death after a stroke causes translation difficulties to arise making necessary a timely and coordinated control of the pathological changes. We propose here that, if we were able to plagiarize such natural hypoxia tolerance through drugs combined in a pharmacological cocktail it would open new therapeutic opportunities for stroke and likely, for other hypoxic conditions.
Diet Supplementation with Polyphenol-Rich Salicornia ramosissima Extracts Protects against Tissue Damage in Experimental Models of Cerebral Ischemia
(MDPI, 2022-11-29) García Rodríguez, Paula; Ma, Feifei; Río Mercado, Carmen del; Romero Bernal, Marina; Najar Moyano, Ana María; Cádiz Gurrea, María de la Luz; Montaner, Joan; Universidad de Sevilla. Departamento de Biología Celular; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
Strokes are the second most common cause of death worldwide and a leading cause of disability. Regular consumption of polyphenols has been shown to reduce the risk of suffering a cardiovascular event. For this reason, we have investigated the protective effect of Salicornia ramosissima, a seasonal halophyte that synthetizes high amounts of bioactive compounds, including polyphenols, in response to environmental stress. Aqueous, hydroalcoholic, and ethanolic extracts were prepared to investigate if dietary supplementation prior to ischemic challenge can prevent subsequent damage using two animal models. First, we screened the protective effect against hypoxia–reoxygenation in Drosophila melanogaster and observed that both ethanolic and hydroalcoholic extracts protected flies from the deleterious effects of hypoxia. Second, we confirmed the protective effect of S. ramosissima ethanolic extract against brain ischemia using the transient middle cerebral artery occlusion mice model. Four weeks of oral supplementation with the ethanolic extract before artery occlusion reduced infarct volume and lowered the plasma levels of the DNA peroxidant product 8-hydroxydeoxyguanosine. Phytochemical profiling of S. ramosissima ethanolic extract revealed 50 compounds. Thus, it represents a valuable source of bioactive compounds that show promising disease-modifying activities and could be further developed as an effective food supplement for the prevention or treatment of neurovascular disorders.
A Review on Polyphenols in Salicornia ramosissima with Special Emphasis on Their Beneficial Effects on Brain Ischemia
(MDPI, 2023-02-03) Najar Moyano, Ana María; Romero Bernal, Marina; Río Mercado, Carmen del; Montaner, Joan; Universidad de Sevilla. Departamento de Biología Celular; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
There has been an increasing interest in the consumption of halophytes as a healthy food in the last few years. Salicornia ramosissima is a seasonal Mediterranean halophyte with an interesting profile of bioactive compounds, including more than 60 identified polyphenols with a broad range of biological activities. Accumulating evidence supports the role of dietary polyphenols in the prevention of cardiovascular diseases, such as stroke. Stroke is the second cause of death worldwide and it is estimated that a substantial proportion of stroke incidence and recurrence may be prevented by healthier dietary patterns. Here, we have grouped the phenolic acids and flavonoids identified in S. ramosissima and reviewed their potential protective effect on brain ischemia, which are mostly related to the reduction of oxidative stress and inflammation, the inhibition of cell death pathways and their role in the preservation of the vascular function. Despite the fact that most of these compounds have been reported to be neuroprotective through multiple mechanisms, human studies are still scarce. Given the safe profile of polyphenols identified in S. ramosissima, this halophyte plant could be considered as a source of bioactive compounds for the nutraceutical industry.
LRH-1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype
(Wiley, 2024-12-19) Cobo Vuilleumier, Nadia; Rodríguez Fernández, Silvia; López Noriega, Livia; Lorenzo, Petra I.; Franco, Jaime M.; Lachaud, Christian Claude; Dorronsoro, Akaitz; González Prieto, Román; Gauthier, Benoit R.; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Background The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross-talk between the immune system and insulin-producing beta cells, has hindered the development of effective disease-modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH-1/NR5A2 activation and improve islet survival. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH-1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T-cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001-target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co-cultures of PBMCs and iPSCs-derived islet organoids were performed to assess the impact of BL001 on beta cell viability. Results LRH-1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro-inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro-inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro-inflammatory to an anti-inflammatory/tolerogenic state, resulting in the inhibition of CD4+ and CD8+ T-cell proliferation. BL001 treatment also increased CD4+/CD25+/FoxP3+ regulatory T-cells and Th2 cells within PBMCs while decreasing CD8+ T-cell proliferation. Additionally, BL001 alleviated PBMC-induced apoptosis and maintained insulin expression in human iPSC-derived islet organoids. Conclusion These findings demonstrate the potential of LRH-1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach.
Evaluation of Bioactive Effects of Five Plant Extracts with Different Phenolic Compositions against Different Therapeutic Targets
(MDPI, 2024-02-08) Villegas Aguilar, María del Carmen; Sánchez Marzo, Noelia; Río Mercado, Carmen del; Montaner, Joan; Micol, Vicente; Fernández Ochoa, Álvaro; Segura Carretero, Antonio; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Plant extracts rich in phenolic compounds have been reported to exert different bioactive properties. Despite the fact that there are plant extracts with completely different phenolic compositions, many of them have been reported to have similar beneficial properties. Thus, the structure–bioactivity relationship mechanisms are not yet known in detail for specific classes of phenolic compounds. In this context, this work aims to demonstrate the relationship of extracts with different phenolic compositions versus different bioactive targets. For this purpose, five plant matrices (Theobroma cacao, Hibiscus sabdariffa, Silybum marianum, Lippia citriodora, and Olea europaea) were selected to cover different phenolic compositions, which were confirmed by the phytochemical characterization analysis performed by HPLC-ESI-qTOF-MS. The bioactive targets evaluated were the antioxidant potential, the free radical scavenging potential, and the inhibitory capacity of different enzymes involved in inflammatory processes, skin aging, and neuroprotection. The results showed that despite the different phenolic compositions of the five matrices, they all showed a bioactive positive effect in most of the evaluated assays. In particular, matrices with very different phenolic contents, such as T. cacao and S. marianum, exerted a similar inhibitory power in enzymes involved in inflammatory processes and skin aging. It should also be noted that H. sabdariffa and T. cacao extracts had a low phenolic content but nevertheless stood out for their bioactive antioxidant and anti-radical capacity. Hence, this research highlights the shared bioactive properties among phenolic compounds found in diverse matrices. The abundance of different phenolic compound families highlights their elevated bioactivity against diverse biological targets.
Evaluating the Clinical Impact of a Polyphenol-Rich Extract from Salicornia ramosissima on Patients with Transient Ischemic Attack and Minor Stroke
(MDPI, 2024-12-13) Najar Moyano, Ana María; López Azcárate, Cristina; Domínguez Ruiz, Carmen; Núñez Jurado, David; Torres, Reyes de; López, Reyes; Camino Moya, Miriam; Magni, Eleonora; Río Mercado, Carmen del; Pérez Sánchez, Soledad; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Enfermería; European Union (UE); Instituto de Salud Carlos III; Junta de Andalucía; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Ministerio de Sanidad. España
Transient ischemic attack (TIA) is a well-established risk factor for future strokes, making interventions that target recovery and vascular risk crucial. This study aimed to assess the safety and clinical effects of a polyphenol-rich Salicornia ramosissima extract in post-TIA patients. A randomized, triple-blind, placebo-controlled trial was conducted with participants who had a history of TIA or minor stroke and who received 1 g of Salicornia extract or placebo over 11 months. Biochemical analyses, neuropsychological assessments (MOCA test), and gait and aerobic performance tests were conducted at the beginning and the end of the study. A total of 118 individuals were screened, with 80 finally included. Importantly, no significant adverse events were reported throughout the study. A neurological analysis showed an improvement in MOCA scores in patients treated with the Salicornia extract for 11 months. The treatment did not affect spatiotemporal gait parameters, but it significantly reduced blood pressure at baseline and after the aerobic performance test. Biochemically, both groups exhibited mild hyperhomocysteinemia at baseline; however, Salicornia treatment significantly lowered homocysteine levels, bringing them within the normal range. These findings highlight the safety of the Salicornia extract in patients at a high cerebrovascular risk and suggest it as a potential therapeutic option for managing vascular risk factors, such as hyperhomocysteinemia and hypertension. However, further studies are required to confirm the underlying mechanisms and explore broader clinical applications.
Dietary supplementation with polyphenol-rich Salicornia ramosissima extracts: Assessing safety, efficacy, and impact on cardiovascular health biomarkers in healthy volunteers
(MDPI, 2024-10-30) Najar Moyano, Ana María; Pérez Sánchez, Soledad; Río Mercado, Carmen del; Domínguez, Carmen; López Azcárate, Cristina; Torres, Reyes de; Montaner, Joan; Universidad de Sevilla. Departamento de Biología Celular; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía; Ministerio de Sanidad. España
The importance of diet in preventing non-communicable diseases is well established, with polyphenol consumption suggested to impact cardiovascular disease development. Salicornia ramosissima synthesizes high amounts of phytochemicals under environmental stress. In a randomized controlled clinical trial on 90 healthy volunteers, we evaluated the safety of supplementation with 1 g of polyphenol-rich S. ramosissima extracts from salt marshes and hydroponic sources over three months. No differences in adverse effects were observed between extract-treated and placebo subjects. Salicornia extract from marshes (SM) increased glomerular filtration rate and reduced LDL cholesterol. SM treatment also modulated plasma markers related to cardiovascular disease: MERTK, Gal-9, ADM, TF, PRSS27, HAOX1, IL-18, PAPPA, TNFRSF1A, TIE2 and FGF-21 proteins were downregulated while SRC levels were upregulated. Therefore, under the studied conditions of use, Salicornia extracts consumption is safe and SM induced biochemical and proteomic changes related to cardiovascular health.
Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
(MDPI, 2024-12-15) Domínguez Martín, Helena; Gavilán Dorronzoro, Elena; Parrado, Celia; Burguillos García, Miguel Ángel; Daza Navarro, María Paula; Ruano Caballero, Diego; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Junta de Andalucía; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; Unión Europea NextGeneration; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Sevilla. CTS257: Envejecimiento y Neurodegeneración.
first_pagesettingsOrder Article Reprints Open AccessArticle Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines by Helena Domínguez-Martín 1,2,†,Elena Gavilán 1,2,†ORCID,Celia Parrado 1,Miguel A. Burguillos 1,2ORCID,Paula Daza 3 andDiego Ruano 1,2,* 1 Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla (US), 41012 Sevilla, Spain 2 Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla (US), 41013 Sevilla, Spain 3 Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla (US), 41012 Sevilla, Spain * Author to whom correspondence should be addressed. † These authors contributed equally to this work and share first authorship. Cells 2024, 13(24), 2069; https://doi.org/10.3390/cells13242069 Submission received: 4 November 2024 / Revised: 10 December 2024 / Accepted: 13 December 2024 / Published: 15 December 2024 (This article belongs to the Special Issue Understanding the Interplay Between Autophagy and Neurodegeneration) Downloadkeyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract Autophagy is a catabolic process involved in different cellular functions. However, the molecular pathways governing its potential roles in different cell types remain poorly understood. We investigated the role of autophagy in the context of proteotoxic stress in two central nervous system cell types: the microglia-like cell line BV2 and the neuronal-like cell line N2a. Proteotoxic stress, induced by proteasome inhibition, produced early apoptosis in BV2 cells, due in part to a predominant activation of the PERK-CHOP pathway. In contrast, N2a cells showcased greater resistance and robust induction of the IRE1α-sXbp1 arm of the UPR. We also demonstrated that proteotoxic stress activated autophagy in both cell lines but with different kinetics and cellular functions. In N2a cells, autophagy restored cellular proteostasis, while in BV2 cells, it participated in regulating phagocytosis. Finally, proteotoxic stress predominantly activated the mTORC2-AKT-FOXO1-β-catenin pathway in BV2 cells, while N2a cells preferentially induced the PDK1-AKT-FOXO3 axis. Collectively, our findings suggest that proteotoxic stress triggers cell-specific responses in microglia and neurons, with different physiological outcomes.
Hyperhomocysteinemia: Underlying Links to Stroke and Hydrocephalus, with a Focus on Polyphenol-Based Therapeutic Approaches
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-12-26) Ortiz Salguero, Carmen; Romero Bernal, Marina; González Díaz, Ángela; Doush, Elaheh Sobh; Río Mercado, Carmen del; Echevarría Irusta, Miriam; Montaner, Joan; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía
Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine (HCys) levels, is associated with increased risks of neurovascular diseases such as stroke or hydrocephalus. HHcy promotes oxidative stress, neuroinflammation, and endothelial dysfunction, disrupting the blood–brain barrier and accelerating neurodegeneration. These processes highlight HCys as both a biomarker and a potential therapeutic target in vascular-related neurological disorders. Current research suggests that polyphenols, known for their antioxidant and anti-inflammatory properties, may reduce HCys levels and offer neuroprotection. Polyphenols have demonstrated effectiveness in modulating oxidative stress and inflammatory pathways triggered by HHcy. These compounds may also upregulate enzymatic functions involved in HCys metabolism, thus reducing neurotoxicity. Furthermore, polyphenol-rich diets, like the Mediterranean diet, have been linked to lower HCys levels and a reduced incidence of neurovascular disorders. This review provides an overview of HHcy’s role in neurovascular pathologies and examines the therapeutic potential of polyphenols in managing HCys levels and preventing HCys-induced neurovascular damage.
Absence of Aquaporin-4 (AQP4) Prolongs the Presence of a CD11c+ Microglial Population during Postnatal Corpus Callosum Development
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-07-30) Mayo Leon, Francisco; González Vinceiro, Lourdes; Hiraldo González, Laura; Calle Castillejo, Claudia; Torres Rubio, Ismael; Mayo León, Manuel; Ramírez Lorca, Reposo; Echevarría Irusta, Miriam; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Física Atómica, Molecular y Nuclear; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía
Aquaporin-4 (AQP4) expression is associated with the development of congenital hydrocephalus due to its structural role in the ependymal membrane. Gene expression analysis of periaqueductal tissue in AQP4-knockout (KO) mice at 11 days of age (P11) showed a modification in ependymal cell adhesion and ciliary protein expression that could alter cerebrospinal fluid homeostasis. A microglial subpopulation of CD11c+ cells was overexpressed in the periaqueductal tissue of mice that did not develop hydrocephalus, suggesting a possible protective effect. Here, we verified the location of this CD11c+ expression in the corpus callosum (CC) and cerebellum of AQP4-KO mice and analysed its time course. Immunofluorescence labelling of the CD11c protein in the CC and cerebellum of WT and KO animals at P3, P5, P7 and P11 confirmed an expanded presence of these cells in both tissues of the KO animal; CD11c+ cells appeared at P3 and reached a peak at P11, whereas in the WT animal, they appeared at P5, reached their peak at P7 and were undetectable by P11. The gene expression analysis in the CC samples at P11 confirmed the presence of CD11c+ microglial cells in this tissue. Among the more than 4000 overexpressed genes, Spp1 stood out with the highest differential gene expression (≅600), with other genes, such as Gpnmb, Itgax, Cd68 and Atp6v0d2, also identified as overexpressed. Therefore, CD11c+ cells appear to be necessary for normal corpus callosum development during postnatal life, and the absence of AQP4 prolonged its expression in this tissue.
The Coffee Constituent Chlorogenic Acid Induces Cellular DNA Damage and Formation of Topoisomerase I– and II–DNA Complexes in Cells
(American Chemical Society, 2012-07-13) Burgos Morón, Estefanía; Calderón Montaño, José Manuel; Orta Vázquez, Manuel Luis; Pastor Carrillo, Nuria María; Pérez Guerrero, María Concepción; Austin, Caroline; Mateos Cordero, Santiago; López Lázaro, Miguel; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Biología Celular
Chlorogenic acid (CGA) is a plant polyphenol with known antioxidant properties. Although some studies suggest that CGA has anticancer properties, others indicate that this dietary constituent may cause DNA damage and induce carcinogenic effects. Because CGA is widely consumed in the form of coffee, it is important to further evaluate the putative DNA-damaging activity of CGA. Here we have employed two standard techniques commonly used for DNA damage detection (the comet assay and the γ- H2AX focus assay) and observed that CGA (0.5–5 mM) induces DNA damage in normal and cancer cells. We report for the first time that CGA induces high levels of topoisomerase I- and topoisomerase II-DNA complexes in cells (TARDIS assay). Catalase pretreatment abolished the formation of these topoisomerase-DNA complexes and reduced the cytotoxic activity of CGA, therefore indicating that hydrogen peroxide plays an important role in these activities. Lung cancer cells (A549) were more sensitive than normal lung fibroblasts (MRC5) to the cytotoxic activity of CGA, supporting previous findings that CGA may induce selective killing of cancer cells. Taking into consideration our results and the pharmacokinetic profile of CGA, the possible cancer preventive, carcinogenic and therapeutic potential of this dietary agent are discussed.

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