Artículos (Fisiología)

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The role of Smad2 in adult neuroplasticity as seen through hippocampal-dependent spatial learning/memory and neurogenesis
(Society for Neuroscience, 2021-08-11) Gradari, Simona; Herrera, Antonio; Tezanos, Patricia; Fontán Lozano, Ángela del Carmen; Pons, Sebastián; Trejo, José Luis; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Economía y Competitividad (MINECO). España
Adult neural plasticity is an important and intriguing phenomenon in the brain, and adult hippocampal neurogenesis is directly involved in modulating neural plasticity by mechanisms that are only partially understood. We have performed gain-of-function and loss-of-function experiments to study Smad2, a transcription factor selected from genes that are demethylated after exercise through the analysis of an array of physical activity-induced factors, and their corresponding gene expression, and an efficient inducer of plasticity. In these studies, changes in cell number and morphology were analyzed in the hippocampal dentate gyrus (cell proliferation and survival, including regional distribution, and structural maturation/differentiation, including arborization, dendritic spines, and neurotransmitter-specific vesicles) of sedentary male mice, after evaluation in a battery of behavioral tests. As a result, we reveal a role for Smad2 in the balance of proliferation versus maturation of differentiating immature cells (Smad2 silencing increases both the proliferation and survival of cycling cells in the dentate granule cell layer), and in the plasticity of both newborn and mature neurons in mice (by decreasing dendritic arborization and dendritic spine number). Moreover, Smad2 silencing specifically compromises spatial learning in mice (through impairments of spatial tasks acquisition both in long-term learning and working memory). These data suggest that Smad2 participates in adult neural plasticity by influencing the proliferation and maturation of dentate gyrus neurons.
Kv7/M Channel Dysfunction Produces Hyperexcitability in Hippocampal CA1 Pyramidal Cells of Fmr1 Knockout Mice
(John Wiley & Sons, 2024) Luque Laó, María Ángeles; Morcuende Fernández, Sara R.; Torres Ruiz, Blas; Herrero Rama, Luis Jacinto; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla; Asociacion Sindrome X Fragil Pais Vasco
Abstract: Fragile X syndrome (FXS), the most frequent monogenic form of intellectual disability, is caused by transcriptional silencing of the FMR1 gene that could render neuronal hyperexcitability. Here we show that pyramidal cells (PCs) in the dorsal CA1 region of the hippocampus elicited a larger action potential (AP) number in response to suprathreshold stimulation in juvenile Fmr1 knockout (KO) than wild-type (WT) mice. Because Kv7/M channels modulate CA1 PC excitability in rats, we investigated if their dysfunction produces neuronal hyperexcitability in Fmr1 KO mice. Immunohistochemical and western blot analyses showed no differences in the expression of Kv7.2 and Kv7.3 channel subunits between genotypes; however, the current mediated by Kv7/M channels was reduced in Fmr1 KO mice. In both genotypes, bath application of XE991 (10 μM), a blocker of Kv7/M channels: produced an increased AP number, produced an increased input resistance, produced a decreased AP voltage threshold and shaped AP medium afterhyperpolarization by increasing mean velocities. Retigabine (10 μM), an opener of Kv7/M channels, produced opposite effects to XE991. Both XE991 and retigabine abolished differences in all these parameters found in control conditions between genotypes. Furthermore, a low concentration of retigabine (2.5 μM) normalized CA1 PC excitability of Fmr1 KO mice. Finally, ex vivo seizure-like events evoked by 4-aminopyiridine (200 μM) in the dorsal CA1 region were more frequent in Fmr1 KO mice, and were abolished by retigabine (5–10 μM). We conclude that CA1 PCs of Fmr1 KO mice exhibit hyperexcitability, caused by Kv7/M channel dysfunction, and increased epileptiform activity, which were abolished by retigabine. (Figure presented.). Key points: Dorsal pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice exhibit hyperexcitability. Kv7/M channel activity, but not expression, is reduced in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice. Kv7/M channel dysfunction causes hyperexcitability in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice by increasing input resistance, decreasing AP voltage threshold and shaping medium afterhyperpolarization. A Kv7/M channel opener normalizes neuronal excitability in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice. Ex vivo seizure-like events evoked in the dorsal CA1 region were more frequent in Fmr1 KO mice, and such an epileptiform activity was abolished by a Kv7/M channel opener depending on drug concentration. Kv7/M channels may represent a therapeutic target for treating symptoms associated with hippocampal alterations in fragile X syndrome.
Grandfathers-to-Grandsons Transgenerational Transmission of Exercise Positive Effects on Cognitive Performance
(Society for Neuroscience, 2024) Cintado, Elisa; Tezanos, Patricia; De Las Casas, Manuela; Muela, Pablo; McGreevy, Kerry R.; Fontán Lozano, Ángela del Carmen; Sacristán Horcajada, Eva; Pignatelli, Jaime; de Ceballos, María L.; Del Hierro, María Jesús; Fernández Punzano, Julia; Montoliu, Lluís; Trejo, José Luis; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Economía y Competitividad (MINECO). España; Ministerio de Ciencia e Innovación (MICIN). España
Physical exercise is a robust lifestyle intervention known for its enhancement of cognitive abilities. Nevertheless, the extent to which these benefits can be transmitted across generations (intergenerational inheritance to F1, and transgenerational to F2 and beyond) remains a topic of limited comprehension. We have already shown that cognitive improvements resulting from physical exercise can be inherited from parents to their offspring, proving intergenerational effects. So, we set out to explore whether these enhancements might extend transgenerationally, impacting the F2 generation. In this study, we initially examined the behavioral traits of second generation (F2) male mice, whose grandfathers (F0) had an exercise intervention. Our findings revealed that F2 mice with physically active grandpaternal F0 progenitors displayed significantly improved memory recall, encompassing both spatial and non-spatial information when compared to their counterparts from sedentary F0 progenitors, and proving for the first time the transgenerational inheritance of physical exercise induced cognitive enhancement. Surprisingly, while F2 memory improved (as was the case with F1), adult hippocampal neurogenesis remained unchanged between experimental and control groups (unlike in F1). Additionally, our analysis of small RNA sequences in the hippocampus identified 35 differentially expressed miRNAs linked to important brain function categories. Notably, two of these miRNAs, miRNA-144 and miRNA-298, displayed a robust negative correlation with cognitive performance. These findings highlight the enduring transgenerational transmission of cognitive benefits associated with exercise, even after two generations, suggesting that moderate exercise training can have lasting positive effects, possibly orchestrated by a specific set of miRNAs that exert their influence across multiple generations.
Fibroblast Growth Factor 21 is a Hepatokine involved in MASLD Progression
(John Wiley & Sons, 2024) Gallego Durán, Rocío; Ampuero Herrojo, Javier; Maya Miles, Douglas; Pastor Ramírez, Helena; Montero Vallejo, Rocío; Rivera Esteban, Jesús; Álvarez Amor, Leticia; Pareja, María Jesús; Rico, María Carmen; Millán, Raquel; Muñoz Hernández, Rocío; Romero Gómez, Manuel; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Medicina; Junta de Andalucía; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (MINECO). España
Aim: We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level. Methods: We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA. Results: A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD. Conclusions: Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.
Challenging Sarcopenia: Exploring AdipoRon in Aging Skeletal Muscle as a Healthspan-Extending Shield
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-09-03) Selvais, Camille M.; Davis López de Carrizosa, María América; Versele, Romain; Dubuisson, Nicolas; Noel, Laurence; Brichard, Sonia M.; Abou-Samra, Michel; Universidad de Sevilla. Departamento de Fisiología; Fonds National de la Recherche Scientifique (FNRS)
Sarcopenia, characterized by loss of muscle mass, quality, and function, poses significant risks in aging. We previously demonstrated that long-term treatment with AdipoRon (AR), an adiponectin receptor agonist, alleviated myosteatosis and muscle degeneration in middle-aged obese mice. This study aimed to determine if a shorter AR treatment could effectively offset sarcopenia in older mice. Two groups of old mice (20–23 months) were studied, one untreated (O) and one orally-treated with AR (O-AR) at 50 mg/kg/day for three months, compared with control 3-month-old young mice (Y) or 10-month-old young-adult mice (C-10). Results showed that AR remarkably inversed the loss of muscle mass by restoring the sarcopenia index and fiber count, which were greatly diminished with age. Additionally, AR successfully saved muscle quality of O mice by halving the accumulation of tubular aggregates and aberrant mitochondria, through AMPK pathway activation and enhanced autophagy. AR also bolstered muscle function by rescuing mitochondrial activity and improving exercise endurance. Finally, AR markedly curbed muscle fibrosis and mitigated local/systemic inflammation. Thus, a late three-month AR treatment successfully opposed sarcopenia and counteracted various hallmarks of aging, suggesting AR as a promising anti-aging therapy for skeletal muscles, potentially extending healthspan.
VEGF, but Not BDNF, Prevents the Downregulation of KCC2 Induced by Axotomy in Extraocular Motoneurons
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-09-14) Pastor Loro, Ángel Manuel; García Hernández, Rosendo Miguel; Carrero Rojas, Genova; Martín Calvo, Paula; Álvarez, F. J.; Rodríguez de la Cruz, Rosa María; Pastor Loro, Ángel Manuel; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Agencia Estatal de Investigación (AEI); Junta de Andalucía; National Institutes of Health (NIH). Estados Unidos
The potassium–chloride cotransporter KCC2 is the main extruder of Cl- in neurons. It plays a fundamental role in the activity of the inhibitory neurotransmitters (GABA and glycine) since low levels of KCC2 promote intracellular Cl- accumulation, leading to the depolarizing activity of GABA and glycine. The downregulation of this cotransporter occurs in neurological disorders characterized by hyperexcitability, such as epilepsy, neuropathic pain, and spasticity. KCC2 is also downregulated after axotomy. If muscle reinnervation is allowed, the KCC2 levels recover in motoneurons. Therefore, we argued that target-derived neurotrophic factors might be involved in the regulation of KCC2 expression. For this purpose, we performed the axotomy of extraocular motoneurons via the monocular enucleation of adult rats, and a pellet containing either VEGF or BDNF was chronically implanted in the orbit. Double confocal immunofluorescence of choline acetyl-transferase (ChAT) and KCC2 was carried out in the brainstem sections. Axotomy led to a KCC2 decrease in the neuropil and somata of extraocular motoneurons, peaking at 15 days post-lesion, with the exception of the abducens motoneuron somata. VEGF administration prevented the axotomy-induced KCC2 downregulation. By contrast, BDNF either maintained or reduced the KCC2 levels following axotomy, suggesting that BDNF is involved in the axotomy-induced KCC2 downregulation in extraocular motoneurons. The finding that VEGF prevents KCC2 decrease opens up new possibilities for the treatment of neurological disorders coursing with neuronal hyperactivity due to KCC2 downregulation.
Motor, mood, and memory impairments persist during remission periods in chronic colitis and are influenced by neuroinflammation and sex
(John Wiley & Sons, 2024-10-31) Sotelo Parrilla, Gema; Ruiz Calero, Alejandro; García Miranda, Pablo; Calonge Castrillo, María Luisa; Vázquez Carretero, María Dolores; Peral Rubio, María José; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Ciencia e Innovación (MICIN). España
Ulcerative colitis is a chronic pathology characterized by relapsing–remitting phasesof intestinal inflammation. Additionally, some patients develop neuropsychiatricdisorders, such as depression and anxiety, or cognitive deficits. We aimed to inves-tigate whether the development of chronic colitis elicits memory, locomotion, andmood impairments. It further examined whether these impairments are influencedby the relapsing–remitting phases of the colitis or by sex. Here, we used a chroniccolitis model in male and female rats, induced with sodium dextran sulfate, mirror-ing the phases of human ulcerative colitis. Our results revealed that the severity ofcolitis was slightly higher in males than females. Chronic colitis triggered motor andshort-term memory deficits and induced anxiety- and depression-like behaviors thatremained throughout the development of the disease. There are also sex differencesunder control or inflammatory conditions. Therefore, in both situations, femalescompared to males displayed: (i) slightly lower locomotion, (ii) increased anxiety-likebehaviors, (iii) similar depression-like behaviors, and (iv) similar short-term memorydeficit. Additionally, under control conditions, the mRNA levels of IL-1β, IL-6, andTNF-α were higher in the female hippocampus. In both sexes, when chronic colitiswas established, the neuroinflammation was evidenced by increased mRNA levels ofthese three cytokines in the hippocampus and in the motor and prefrontal cortices.Interestingly, this neuroinflammation was slightly greater in males. In summary, weshow that the development of chronic colitis caused persistent behavioral abnormali-ties, highlighting sex differences, and that could be a consequence, at least in part, ofthe increase in IL-1β, IL-6, and TNF-α in the brain.
Proceedings of the 5th Meeting of Translational Hepatology, organized by the Spanish Association for the Study of the Liver (AEEH)V Reunión de Hepatología Traslacional, organizada por la Asociación Española para el Estudio del Hígado (AEEH)
(Elsevier, 2024) Alvarado Tapias, Edilmar; Maya Miles, Douglas; Albillos, Agustin; Aller, Rocio; Ampuero Herrojo, Javier; Andrade, Raul J.; Arechederra, Maria; Aspichueta, Patricia; Banales, Jesús M.; Blas García, Ana; Carrillo Vico, Antonio; Muñoz Hernández, Rocío; Romero Gómez, Manuel; Gahete, Manuel D.; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Medicina
Characterization, Number, and Spatial Organization of Nerve Fibers in the Human Cervical Vagus Nerve and its Superior Cardiac Branch
(Elsevier, 2024) Kronsteiner, Bettina; Carrero Rojas, Génova; Reissig, Lukas F.; Moghaddam, Atieh Seyedian; Schwendt, Karoline M.; Gerges, Sylvia; Maierhofer, Udo; Aszmann, Oskar C.; Pastor Loro, Ángel Manuel; Kiss, Attila; Podesser, Bruno K.; Birkfellner, Wolfgang; Moscato, Francesco; Blumer, Roland; Weninger, Wolfgang J.; Universidad de Sevilla. Departamento de Fisiología; European Union (UE). H2020
Background: Electrical stimulation of the vagus nerve (VN) is a therapy for epilepsy, obesity, depression, and heart diseases. However, whole nerve stimulation leads to side effects. We examined the neuroanatomy of the mid-cervical segment of the human VN and its superior cardiac branch to gain insight into the side effects of VN stimulation and aid in developing targeted stimulation strategies. Methods: Nerve specimens were harvested from eight human body donors, then subjected to immunofluorescence and semiautomated quantification to determine the signature, quantity, and spatial distribution of different axonal categories. Results: The right and left cervical VN (cVN) contained a total of 25,489 ± 2781 and 23,286 ± 3164 fibers, respectively. Two-thirds of the fibers were unmyelinated and one-third were myelinated. About three-quarters of the fibers in the right and left cVN were sensory (73.9 ± 7.5 % versus 72.4 ± 5.6 %), while 13.2 ± 1.8 % versus 13.3 ± 3.0 % were special visceromotor and parasympathetic, and 13 ± 5.9 % versus 14.3 ± 4.0 % were sympathetic. Special visceromotor and parasympathetic fibers formed clusters. The superior cardiac branches comprised parasympathetic, vagal sensory, and sympathetic fibers with the left cardiac branch containing more sympathetic fibers than the right (62.7 ± 5.4 % versus 19.8 ± 13.3 %), and 50 % of the left branch contained sensory and sympathetic fibers only. Conclusion: The study indicates that selective stimulation of vagal sensory and motor fibers is possible. However, it also highlights the potential risk of activating sympathetic fibers in the superior cardiac branch, especially on the left side.
Effect of lathyrane-type diterpenoids in neural stem cell physiology: Microbial transformations, molecular docking and dynamics studies
(Elsevier, 2024-12) Escobar Montaño, Felipe; Gómez Oliva, Ricardo; Ezzanad, Abdellah; Vázquez de Górgolas, Sonia; Zorrilla, David; Macías Sánchez, Antonio J.; Botubol Ares, José M.; Núñez Abades, Pedro Antonio; Castro, Carmen; Durán Patrón, Rosa; Hernández Galán, Rosario; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
Promoting endogenous neurogenesis for brain repair is emerging as a promising strategy to mitigate the functional impairments associated with various neurological disorders characterized by neuronal death. Diterpenes featuring tigliane, ingenane, jatrophane and lathyrane skeletons, frequently found in Euphorbia plant species, are known protein kinase C (PKC) activators and exhibit a wide variety of pharmacological properties, including the stimulation of neurogenesis. Microbial transformation of these diterpenes represents a green and sustainable methodology that offers a hitherto little explored approach to obtaining novel derivatives and exploring structure–activity relationships. In the present study, we report the biotransformation of euphoboetirane A (4) and epoxyboetirane A (5), two lathyrane diterpenoids isolated from Euphorbia boetica, by Mucor circinelloides MC NRRL3631. Our findings revealed the production of nine biotransformation products (6–14), including jatrophane derivatives originated through an unprecedented rearrangement from the parent lathyranes. The chemical structures and absolute configurations of the new compounds were elucidated through comprehensive analysis using NMR and ECD spectroscopy, as well as MS. The study evaluated how principal metabolites and their derivatives affect TGFα and NRG1 release, as well as their potential to promote proliferation or differentiation in cultures of NSC isolated from the SVZ of adult mice. In order to shed some light on the mechanisms underlying the ability of 12 as a neurogenic compound, the interactions of selected compounds with PKC δ-C1B were analyzed through molecular docking and molecular dynamics. Based on these, it clearly appears that the ability of compound 12 to form both acceptor and donor hydrogen bonds with certain amino acid residues in the enzyme pocket leads to a higher affinity compound-PKC complex, which correlates with the observed biological activity.
Alteraciones fisiológicas en los transtornos de la conducta alimentaria
(Real e Ilustre Colegio Oficial de Farmacéuticos de Sevilla, 2022) Benítez Vidal, L.; Cano Rodríguez, María Mercedes; Universidad de Sevilla. Departamento de Fisiología
Los trastornos de la conducta alimentaria (TCA) engloban a una serie de enfermedades men- tales graves que cada vez afectan a más personas. Dentro de este trastorno encontramos varias enferme- dades, pero, todas tienen en común que presentan una alteración en la conducta alimentaria. Las más importantes son anorexia nerviosa, bulimia nerviosa y trastorno por atracón. Los TCA se consideran trastornos multifactoriales puesto que están implicados numerosos factores en su aparición como fac- tores socioculturales, biológicos, neuroendocrinológicos y psicológicos. Además, aunque son trastornos que pueden aparecer en cualquier persona independientemente de la edad o el sexo, es de destacar que son más frecuentes en mujeres jóvenes. La anorexia se caracteriza por un terror al aumento del peso y una imagen distorsionada de la figura corporal lo que lleva a que realicen dietas muy estrictas. Por su parte, la bulimia se caracteriza por la presencia de atracones y, posteriormente, conductas compensato- rias para evitar el aumento del peso corporal. Por último, el trastorno por atracón es similar a la bulimia nerviosa, ya que aparecen los atracones característicos, pero no se realizan conductas compensatorias para evitar el aumento del peso corporal. El objetivo del presente trabajo fue realizar una revisión bi- bliográfica sobre estas patologías y sus consecuencias fisiológicas. Estos comportamientos específicos conllevan la aparición de múltiples complicaciones médicas que acaban afectando al funcionamiento de distintos sistemas fisiológicos, así como a la actividad psicosocial del paciente e incluso pueden llevar a la muerte. La anorexia es la que presenta consecuencias más graves, de las cuales, las más importantes desde el punto de vista de la peligrosidad son las óseas, cardiovasculares y endocrinas. Por otro lado, en la bulimia las complicaciones más frecuentes son las del tracto digestivo debido a las conductas purgati- vas y, por último, en el trastorno por atracón la complicación más frecuente es la obesidad.
Daily Consumption of Wild Olive (Acebuche) Oil Reduces Blood Pressure and Ameliorates Endothelial Dysfunction and Vascular Remodelling in Rats with NG-nitro-L-arginine Methyl Ester-induced Hypertension
(Cambridge, 2022) Reyes Goya, Claudia; Santana Garrido, Álvaro; Aguilar Espejo, Gema; Pérez-Camino, María del Carmen; Mate Barrero, Alfonso; Vázquez Cueto, Carmen María; Universidad de Sevilla. Departamento de Fisiología; Junta de Andalucía; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Ministerio de Ciencia e Innovación (MICIN). España
Despite numerous reports on the beneficial effects of olive oil in the cardiovascular context, very little is known about the olive tree’s wild counterpart (Olea europaea, L. var. sylvestris), commonly known as acebuche (ACE) in Spain. The aim of this study was to analyse the possible beneficial effects of an extra virgin ACE oil on vascular function in a rodent model of arterial hypertension (AH) induced by NG-nitro-l-arginine methyl ester (L-NAME). Four experimental groups of male Wistar rats were studied: (1) normotensive rats (Control group); (2) normotensive rats fed a commercial diet supplemented with 15 % (w/w) ACE oil (Acebuche group); (3) rats made hypertensive following administration of L-NAME (L-NAME group); and (4) rats treated with L-NAME and simultaneously supplemented with 15 % ACE oil (LN + ACE group). All treatments were maintained for 12 weeks. Besides a significant blood pressure (BP)-lowering effect, the ACE oil-enriched diet counteracted the alterations found in aortas from hypertensive rats in terms of morphology and responsiveness to vasoactive mediators. In addition, a decrease in hypertension-related fibrotic and oxidative stress processes was observed in L-NAME-treated rats subjected to ACE oil supplement. Therefore, using a model of AH via nitric oxide depletion, here we demonstrate the beneficial effects of a wild olive oil based upon its vasodilator, antihypertensive, antioxidant, antihypertrophic and antifibrotic properties. We postulate that regular inclusion of ACE oil in the diet can alleviate the vascular remodelling and endothelial dysfunction processes typically found in AH, thus resulting in a significant reduction of BP.
The Gap Junction Inhibitor Octanol Decreases Proliferation and Increases Glial Differentiation of Postnatal Neural Progenitor Cells
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-06-07) Talaverón Aguilocho, Rocío; Morado Díaz, Camilo José; Herrera Delgado, Alejandro; Gálvez, Victoria; Pastor Loro, Ángel Manuel; Rodríguez Matarredona, Esperanza; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Microbiología; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
Neural precursor cells (NPCs) that persist in the postnatal/adult subventricular zone (SVZ) express connexins that form hemichannels and gap junctions. Gap junctional communication plays a role in NPC proliferation and differentiation during development, but its relevance on postnatal age remains to be elucidated. In this work we aimed to evaluate the effect of the blockade of gap junctional communication on proliferation and cell fate of NPCs obtained from the SVZ of postnatal rats. NPCs were isolated and expanded in culture as neurospheres. Electron microscopy revealed the existence of gap junctions among neurosphere cells. Treatment of cultures with octanol, a broad-spectrum gap junction blocker, or with Gap27, a specific blocker for gap junctions formed by connexin43, produced a significant decrease in bromodeoxyuridine incorporation. Octanol treatment also exerted a dose-dependent antiproliferative effect on glioblastoma cells. To analyze possible actions on NPC fate, cells were seeded in the absence of mitogens. Treatment with octanol led to an increase in the percentage of astrocytes and oligodendrocyte precursors, whereas the percentage of neurons remained unchanged. Gap27 treatment, in contrast, did not modify the differentiation pattern of SVZ NPCs. Our results indicate that general blockade of gap junctions with octanol induces significant effects on the behavior of postnatal SVZ NPCs, by reducing proliferation and promoting glial differentiation.
Uncovering the Role of Selenite and Selenium Nanoparticles (SeNPs) in Adolescent Rat Adipose Tissue beyond Oxidative Balance: Transcriptomic Analysis
(Multidisciplinary Digital Publishing Institute (MDPI), 2024) Nogales Bueno, Fátima; Pajuelo Domínguez, Eloísa; Romero Herrera, Inés; Carreras Sánchez, Olimpia; Merchán Ignacio, Francisco; Carrasco López, José Antonio; Ojeda Murillo, María Luisa; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Microbiología y Parasitología; Junta de Andalucía; Ministerio de Ciencia, Innovación y Universidades (MICINN). España
Studies on adolescent rats, when body composition is changing deeply, reveal that the administration of sodium selenite and selenium nanoparticles (SeNPs), at the same dose, have opposite effects on adipogenesis in white adipose tissue (WAT). To investigate the mechanisms involved in these contrasting effects by means of transcriptomic analysis, three groups of male adolescent rats (n = 18) were used: control (C), selenite supplemented (S), and SeNPs supplemented (NS). Both treated groups received a twofold increase in Se dose compared to the control group through water intake for three weeks. Following treatment, WAT was removed and frozen at −80 °C until subsequent use for RNA extraction, endogenous antioxidant enzymatic activities determination, and quantification of H2O2 and malondialdehyde. NS rats displayed a larger number of differentially expressed genes and cellular processes impacted than S rats. Remarkably, these changes involved upregulation of gene expression associated with the immune system, catabolism, mitochondrial function, and oxidative balance. NS rats presented an increase in antioxidant enzymes activity, alongside an accumulation of H2O2 and malondialdehyde levels. The expression level of 81 genes related to oxidative stress was significantly affected in NS rats. Analyzing the KEGG pathway enrichment revealed that NS rats exhibited increased activity in key catabolic pathways and decreased activity in crucial growth signaling processes. These changes contribute to the mass decrease in WAT found in NS rats. These results suggest a possible application of SeNPs in WAT reduction and induction of the immune response during adolescence.
Experimental Models to Study Immune Dysfunction in the Pathogenesis of Parkinson’s Disease
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-04-14) Saponjic, Jasna; Mejías Estévez, Rebeca María; Nikolovski, Neda; Dragic, Milorad; Canak, Asuman; Papoutsopoulou, Stamatia; Gürsoy-Özdemir, Yasemin; Fladmark, Kari E.; Ntavaroukas, Panagiotis; Bayar Muluk, Nuray; Zeljkovic Jovanovic, Milica; Fontán Lozano, Ángela del Carmen; Comi, Cristoforo; Marino, Franca; Universidad de Sevilla. Departamento de Fisiología
Parkinson’s disease (PD) is a chronic, age-related, progressive multisystem disease associated with neuroinflammation and immune dysfunction. This review discusses the methodological approaches used to study the changes in central and peripheral immunity in PD, the advantages and limitations of the techniques, and their applicability to humans. Although a single animal model cannot replicate all pathological features of the human disease, neuroinflammation is present in most animal models of PD and plays a critical role in understanding the involvement of the immune system (IS) in the pathogenesis of PD. The IS and its interactions with different cell types in the central nervous system (CNS) play an important role in the pathogenesis of PD. Even though culture models do not fully reflect the complexity of disease progression, they are limited in their ability to mimic long-term effects and need validation through in vivo studies. They are an indispensable tool for understanding the interplay between the IS and the pathogenesis of this disease. Understanding the immune-mediated mechanisms may lead to potential therapeutic targets for the treatment of PD. We believe that the development of methodological guidelines for experiments with animal models and PD patients is crucial to ensure the validity and consistency of the results.
Dietary Selenium and Its Antioxidant Properties Related to Growth, Lipid and Energy Metabolism
(MDPI, 2022) Ojeda Murillo, María Luisa; Nogales Bueno, Fátima; Universidad de Sevilla. Departamento de Fisiología
The Anti-Inflammatory and Antioxidant Properties of Acebuche Oil Exert a Retinoprotective Effect in a Murine Model of High-Tension Glaucoma
(MDPI, 2024) Lucchesi, Martina; Marracci, Silvia; Amato, Rosario; Lapi, Dominga; Santana Garrido, Álvaro; Espinosa Martín, Pablo; Vázquez Cueto, Carmen María; Mate Barrero, Alfonso; Dal Monte, Massimo; Universidad de Sevilla. Departamento de Fisiología; Italian Ministry of Universities and Research; University of Pisa
Glaucoma is characterized by cupping of the optic disc, apoptotic degeneration of retinal ganglion cells (RGCs) and their axons, and thinning of the retinal nerve fiber layer, with patchy loss of vision. Elevated intraocular pressure (IOP) is a major risk factor for hypertensive glaucoma and the only modifiable one. There is a need to find novel compounds that counteract other risk factors contributing to RGC degeneration. The oil derived from the wild olive tree (Olea europaea var. sylvestris), also called Acebuche (ACE), shows powerful anti-inflammatory, antioxidant and retinoprotective effects. We evaluated whether ACE oil could counteract glaucoma-related detrimental effects. To this aim, we fed mice either a regular or an ACE oil-enriched diet and then induced IOP elevation through intraocular injection of methylcellulose. An ACE oil-enriched diet suppressed glaucoma-dependent retinal glia reactivity and inflammation. The redox status of the glaucomatous retinas was restored to a control-like situation, and ischemia was alleviated by an ACE oil-enriched diet. Notably, retinal apoptosis was suppressed in the glaucomatous animals fed ACE oil. Furthermore, as shown by electroretinogram analyses, RGC electrophysiological functions were almost completely preserved by the ACE oil-enriched diet. These ameliorative effects were IOP-independent and might depend on ACE oil’s peculiar composition. Although additional studies are needed, nutritional supplementation with ACE oil might represent an adjuvant in the management of glaucoma.
The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study)
(Elsevier, 2024) Martín Sierra, Carmen; José Bravo, María; Sáez, María E.; de Rojas, Itziar; Santos, Marta; Martín Carmona, Jesica; González-Serna Martín, Manuel Alejandro; Pineda Vergara, Juan Antonio; Macías Sánchez, Juan; Real Navarrete, Luis Miguel; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Medicina; Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica; Junta de Andalucía; CIBERINFEC; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (MICIN). España; European Union (UE)
Background & aims: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/ HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). Objective: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. Patients and methods: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-eronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. Results: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. Conclusions: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.
Influence of High-Intensity Interval Training on Neuroplasticity Markers in Post-Stroke Patients: Systematic Review
(MDPI, 2024) Montero-Almagro, Ginés; Bernal Utrera, Carlos; Geribaldi Doldan, Noelia; Núñez Abades, Pedro Antonio; Castro, Carmen; Rodríguez Blanco, Cleofás; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Fisioterapia; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Background: Exercise has shown beneficial effects on neuronal neuroplasticity; therefore, we want to analyze the influence of high-intensity interval training (HIIT) on neuroplasticity markers in post-stroke patients. Methods: A systematic review of RCTs including studies with stroke participants was conducted using the following databases (PubMed, LILACS, ProQuest, PEDro, Web of Science). Searches lasted till (20/11/2023). Studies that used a HIIT protocol as the main treatment or as a coadjutant treatment whose outcomes were neural plasticity markers were used and compared with other exercise protocols, controls or other kinds of treatment. Studies that included other neurological illnesses, comorbidities that interfere with stroke or patients unable to complete a HIIT protocol were excluded. HIIT protocol, methods to assess intensity, neuroplasticity markers (plasmatic and neurophysiological) and other types of assessments such as cognitive scales were extracted to make a narrative synthesis. Jadad and PEDro scales were used to assess bias. Results: Eight articles were included, one included lacunar stroke (less than 3 weeks) and the rest had chronic stroke. The results found here indicate that HIIT facilitates neuronal recovery in response to an ischemic injury. This type of training increases the plasma concentrations of lactate, BDNF and VEGF, which are neurotrophic and growth factors involved in neuroplasticity. HIIT also positively regulates other neurophysiological measurements that are directly associated with a better outcome in motor learning tasks. Conclusions: We conclude that HIIT improves post-stroke recovery by increasing neuroplasticity markers. However, a limited number of studies have been found indicating that future studies are needed that assess this effect and include the analysis of the number of intervals and their duration in order to maximize this effect.
New pharmacological tools: the use of diterpenes to promote adult hippocampal neurogenesis
(Wolters Kluwer Medknow Publications, 2024-08) Gómez Oliva, Ricardo; Nuñez Abades, Pedro Antonio; Castro, Carmen; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía

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