Artículos (Fisiología)

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Sunitinib-induced oxidative imbalance and retinotoxic effects in rats
(Elsevier, 2020-09-15) Santana Garrido, Álvaro; Reyes Goya, Claudia; André, Helder; Aramburu Bodas, Oscar; Mate Barrero, Alfonso; Vázquez Cueto, Carmen María; Universidad de Sevilla. Departamento de Fisiología; Junta de Andalucía
Aims Sunitinib (Su), a tyrosine kinase inhibitor, is one of the most commonly used anti-angiogenic drugs. Some studies have described retinal detachment and photoreceptor damage following systemic exposure to Su, despite beneficial effects achieved with local treatment of ocular pathologies. The aim of this study was to explore the role of NADPH oxidase system and oxidative stress in eyes from Su-treated animals. Main methods Male Wistar rats were administered 25 mg Su/kg body weight/day incorporated in the chow for 3 weeks. Upon treatment completion, NADPH oxidase activity and ROS levels were measured in ocular tissue by chemiluminescence and dihydroethidium (DHE) staining, respectively. The expression of NADPH oxidase isoforms (NOX1, NOX2 and NOX4), antioxidant enzymes and endothelial/inducible nitric oxidase isoforms (eNOS/iNOS) in the eyecup and/or retina were measured via immunofluorescence, immunoblotting and RT-qPCR. Key findings NADPH oxidase activity/expression increased in eyecup and retinas from Su-treated rats. Immunohistofluorescence studies in retinal layer confirmed a higher signal of NADPH oxidase isoforms after Su treatment. Treated animals also presented with reductions in NO levels and eNOS expression, whereas iNOS was upregulated. Finally, a significant depletion of antioxidant enzyme glutathione peroxidase was measured in eyecups of rats following Su exposure, and the opposite pattern was seen for glutathione reductase and superoxide dismutase. Significance This study demonstrates that Su treatment is associated with NADPH oxidase-derived oxidative stress in the eye. Long-term treatment of Su should be properly monitored to avoid retinotoxic effects that might result in ocular pathologies and sight-threatening conditions.
Navigating the Link Between Non-alcoholic Fatty Liver Disease/ Non-alcoholic Steatohepatitis and Cardiometabolic Syndrome
(Radcliffe Medical Media, 2024) Gato, S.; García Fernández, V.; Gil Gómez, A.; Rojas, A.; Montero Vallejo, R.; Muñoz Hernández, Rocío; Romero Gómez, Manuel; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Medicina; Instituto de Salud Carlos III; Junta de Andalucía
The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.
A chronically implantable device for the controlled delivery of substances, and stimulation and recording of activity in severed nerves
(Elsevier, 2008-01-30) Davis López de Carrizosa, María América; Tena, Juan J.; Benítez Temiño, Beatriz; Morado Díaz, Camilo José; Pastor Loro, Ángel Manuel; Rodríguez de la Cruz, Rosa María; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Educación y Ciencia (MEC). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
We describe the use of an implantable device for peripheral nerves that allows chronic simultaneous delivery of small volumes of solution, recording of both field and multiunit potentials, and electrical stimulation. This custom-made multifunctional device was attached to the cut end of the abducens (VIth) nerve for stimulation, recording and injection purposes. Our device consists of a polyethylene chamber with two electrodes that can be used for stimulation and recording and two Teflon tubes that serve as inlet and outlet for administering chemicals to the nerve fitted inside. Since the device is implanted in a retro-orbital position, we herein will refer to it as an intraorbitary device (IOD). The applicability of the IOD is demonstrated with an electrophysiological and anatomical account of the properties of the abducens nerve. Furthermore, it is shown that certain neuronal discharge properties can be inferred from the nerve recordings. The IOD can also be efficiently used for the delivery of small volume of pharmacological substances or conventional retrograde markers.
Targeting pro-senescence mitogen activated protein kinase (Mapk) enzymes with bioactive natural compounds
(Elsevier, 2019-09) Cano Rodríguez, María Mercedes; Guerrero Castilla, Angélica; Nabavi, Seyed Mohammad; Ayala Gómez, Antonio; Argüelles Castilla, Sandro; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla
Aging is a multifactorial universal process characterized by a gradual decrease in physiological and biochemical functions. Given that life expectancy is on the rise, a better understanding of molecular mechanisms of the aging process is necessary in order to develop anti-aging interventions. Uncontrolled cellular senescence promotes persistent inflammation and accelerates the aging process by decreasing tissue renewal, repair and regeneration. Senescence of immune cells, immunesenescence, is another hallmark of aging. Targeting pro-senescent enzymes increases survival and therefore the lifespan. Although the upregulation of Mitogen Activated Protein Kinases (MAPK) enzymes in aging is still controversial, increasing evidence shows that dysregulation of those enzymes are associated with biological processes that contribute to aging such as irreversible senescence. In this manuscript components of the MAPK pathway will be summarized, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38, as well as natural flavonoids, phenolic and diterpenoids with anti-senescence activity that shows positive effects on longevity and MAPK inhibition. Although more studies using additional aging models are needed, we suggest that these selected natural bioactive compounds that regulate MAPK enzymes and reduce senescent cells can be potentially used to improve longevity and prevent/treat age-related diseases.
Adipose-derived stem cells decreased microglia activation and protected dopaminergic loss in rat lipopolysaccharide model
(John Wiley & Sons, 2019-08) Muñoz Pinto, Mario Faustino; Argüelles Castilla, Sandro; Medina, Rafael; Cano Rodríguez, María Mercedes; Ayala Gómez, Antonio; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Junta de Andalucía
Adult stem cell therapy is being used extensively to rejuvenate damaged tissue. One important tissue source to obtain these cells is adipose, which contains cells called adipose-derived stem cells (ADSCs). These cells have a great therapeutic potential not only for their multipotent properties as well as for immunomodulatory effects on the immune system. Parkinson's disease is characterized as neurodegenerative disorder which etiology is undoubtedly related to neuroinflammation process. The properties of ADSCs can be used as a new tool in stem cells therapy to treat neurodegenerative disorders. However, their efficacies are still controversial. Some authors have reported neuroprotection effects, while others did not find differences or stem cells increased the damage. Our previous study showed that ADSCs can survive long time after transplantation, suggesting us some biological effects could need more time to be repaired. In this study, we assessed the neuroprotection 6 months after transplantation. Our results suggest ADSCs can protect the dopaminergic loss after lipopolysaccharide (LPS) injection both reducing the microglia activation and differentiating into dopaminergic cells.
Hepatic steatosis after switching to integrase inhibitor-based regimens does not parallel short-term weight gain
(Wolters Kluwer Health, 2023-11-15) González-Serna Martín, Manuel Alejandro; Macías Sánchez, Juan; Rincón, Pilar; Arriaza, María José; Corma-Gómez, Anais; Santos, Marta; Fernández-Fuertes, Marta; Pineda Vergara, Juan Antonio; Real Navarrete, Luis Miguel; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Medicina; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (MICINN). España
We studied hepatic steatosis in people with HIV (PWH) who switched to an integrase inhibitor (INSTI)-based regimen. One hundred and fifty-four PWH were included. After 48 weeks, median (Q1-Q3) weight gain was 1.2 (-0.6 to 3.8) kg and median (Q1-Q3) controlled attenuation parameter (CAP) change was -4 (-33 to 27) dB/m. Weight gain was weakly correlated with CAP change [R2 95% confidence interval (CI) = 0.144 (-0.014 to 0.296); P = 0.074)]. Changes in hepatic steatosis after switching to INSTI-based regimens do not seem to parallel weight gain after 1 year.
Liver stiffness change with HCV cure in HIV-infected patients on non-nucleoside analogues
(Oxford University Press, 2021-09-01) González-Serna Martín, Manuel Alejandro; Corma-Gómez, A.; Téllez, F.; García-Martín, S.; Rivero-Juárez, A.; Frías, M; Vera-Méndez, F. J.; Santos, I. de los; Macías Sánchez, Juan; Pineda Vergara, Juan Antonio; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Medicina; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Instituto de Salud Carlos III; Junta de Andalucía
Background: Liver stiffness (LS) at sustained viral response (SVR) is strongly associated with a lower incidence of subsequent hepatic events. HIV NNRTIs may have a beneficial impact on fibrogenesis. Objectives: Our aim was to analyse the influence of NNRTI-based therapy on the change in LS from starting direct-acting antiviral (DAA) therapy to achieving SVR in HIV/HCV-coinfected patients. Methods: Three hundred and thirteen HIV/HCV-coinfected patients who fulfilled the following criteria were included: (i) had achieved SVR with an IFN-free, DAA-including regimen; (ii) LS 9.5 kPa before therapy; (iii) LS measurement available at SVR; (iv) seronegative for HBsAg; and (v) ART containing 2 NRTIs plus either 1 NNRTI or 1 integrase inhibitor (INI) or 1 2 NRTIs plus 1 PI. LS changes were assessed. Results: Seventy-four patients received NNRTI-based combinations [53 (71.6%) rilpivirine and 16 (21.6%) efavirenz] and 239 patients received other regimens. At baseline, the median (IQR) LS was 16.7 kPa (11.8 25.6) in the NNRTI group and 17.3 kPa (11.9 27.4) in the non-NNRTI group (P = 0.278). The median (IQR) percentage of LS decrease from baseline to SVR was 35.2% (18.2% 52.3%) for NNRTI-based therapy and 29.5% (10% 45.9%) for PI- or INI-based therapy (P = 0.018). In multivariate analysis, adjusted for sex, age, HCV genotype, NRTI backbone and propensity score for HIV therapy, NNRTI-based regimen use was associated with a higher LS decrease [b = 11.088 (95% CI = 1.67 20.51); P = 0.021]. Conclusions: Treatment with NNRTI plus 2 NRTI combinations is associated with a higher LS decline than other ART combinations in HIV/HCV-coinfected patients receiving DAA-based therapy.
Spatial localization and projection densities of brainstem mossy fibre afferents to the forelimb C1 zone of the rat cerebellum
(John Wiley & Sons, 2012-02) Herrero Rama, Luis Jacinto; Pardoe, Joanne; Cerminara, Nadia L.; Apps, Richard; Universidad de Sevilla. Departamento de Fisiología
The present study uses a double retrograde tracer technique in rats to examine the spatial localization and pattern of axonal branching in mossy fibres arising from three major sources in the medulla-the external cuneate nucleus, the sensory trigeminal nucleus and the reticular formation, to two electrophysiologically-identified parts of the cerebellar cortex that are linked by common climbing fibre input - the forelimb-receiving parts of the C1 zone in lobulus simplex and the paramedian lobule. In each experiment a small injection of rhodamine-tagged beads was injected into one cortical region and an injection of fluorescein-tagged beads was injected into the other region. The main findings were: (i) the proportion of double-labelled cells in each of the three precerebeller sources of mossy fibres was positively correlated with those in the inferior olive; and (ii) the C1 zone in lobulus simplex was found to receive a greater density of projections from all three sources of mossy fibres than the C1 zone in the paramedian lobule. These data suggest that two rostrocaudally separated but somatotopically corresponding parts of the C1 zone receive common mossy fibre and climbing fibre inputs. However, the differences in projection densities also suggest that the two parts of the zone differ in the extent to which they receive mossy fibre signals arising from the same precerebellar nuclei. This implies differences in function between somatotopically corresponding parts of the same cortical zone, and could enable a higher degree of parallel processing and integration of information within them.
Afferent and Efferent Connections of the Mesencephalic Reticular Formation in Goldfish
(Elsevier, 2008) Luque Laó, María Ángeles; Pérez Pérez, M. P.; Herrero Rama, Luis Jacinto; Torres Ruiz, Blas; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Educación y Cultura (MEC). España
The physiology of the mesencephalic reticular formation (MRF) in goldfish suggests its contribution to eye and body movements, but the afferent and efferent connections underlying such movements have not been determined. Therefore, we injected the bidirectional tracer biotinylated dextran amine into functionally identified MRF sites. We found retrogradely labelled neurons and anterogradely labelled boutons within nuclei of the following brain regions: (1) the telencephalon: a weak and reciprocal connectivity was confined to the central zone of area dorsalis and ventral nucleus of area ventralis; (2) the diencephalon: reciprocal connections were abundant in the ventral and dorsal thalamic nuclei; the central pretectal nucleus was also reciprocally wired with the MRF, but only boutons were present in the superficial pretectal nucleus; the preoptic and suprachiasmatic nuclei showed abundant neurons and boutons; the MRF was reciprocally connected with the preglomerular complex and the anterior tuberal nucleus; (3) the mesencephalon: neurons and boutons were abundant within deep tectal layers; reciprocal connections were also present within the torus semicircularis and the contralateral MRF; neurons were abundant within the nucleus isthmi; and (4) the rhombencephalon: the superior and middle parts of the reticular formation received strong projections from the MRF, while the projection to the inferior area was weaker; sparse neurons were present throughout the reticular formation; a reciprocal connectivity was observed with the sensory trigeminal nucleus; the medial and magnocellular nuclei of the octaval column projected to the MRF. These results support the participation of the MRF in the orienting response. The MRF could also be involved in other motor tasks triggered by visual, auditory, vestibular, or somatosensory signals.
Postnatal Development Enhances the Effects of Cholinergic Inputs on Recruitment Threshold and Firing Rate of Rat Oculomotor Nucleus Motoneurons
(Elsevier, 2010) Carrascal Moreno, María Livia; Luque Laó, María Ángeles; Sobrino Cabello, Verónica; Torres Ruiz, Blas; Núñez Abades, Pedro Antonio; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
Changes in the electrophysiological and morphological characteristics of motoneurons (Mns) of the oculomotor nucleus during postnatal development have been reported, however synaptic modifications that take place concurrently with postnatal development in these Mns are yet to be elucidated. We investigated whether cholinergic inputs exert different effects on the recruitment threshold and firing rate of Mns during postnatal development. Rat oculomotor nucleus Mns were intracellularly recorded in brain slice preparations and separated in neonatal (4-7 postnatal days) and adult (20-30 postnatal days) age groups. Stimulation of the medial longitudinal fasciculus evoked a monosynaptic excitatory potential in Mns that was attenuated with atropine (1.5 μM, a muscarinic antagonist). Mns were silent at their resting membrane potential, and bath application of carbachol (10 μM, a cholinergic agonist) induced depolarization of the membrane potential and a sustained firing rate that were more pronounced in adult Mns. Pharmacological and immunohistochemical assays showed that these responses were attributable to muscarinic receptors located in the membrane of Mns. In addition, compared to control Mns, carbachol-exposed Mns exhibited a higher firing rate in response to the injection of the same amount of current, and a decrease in the current threshold required to achieve sustained firing. These latter effects were more pronounced in adult than in neonatal Mns. In conclusion, our findings suggest that cholinergic synaptic inputs are already present in neonatal Mns, and that the electrophysiological effects of such inputs on recruitment threshold and firing rate are enhanced with the postnatal development in oculomotor nucleus Mns. We propose that cholinergic input maturation could provide a greater dynamic range in adult Mns to encode the output necessary for graded muscle contraction.
Impact of nonalcoholic fatty liver disease on the survival of people living with HIV
(Wiley, 2024-11-27) Macías Sánchez, Juan; Frias, M; Pineda, JA; Corona-Mata, D; Corma-Gomez, A; Rivero-Juarez, A; González-Serna Martín, Manuel Alejandro; Real Navarrete, Luis Miguel; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Salud Carlos III; European Commission. Fondo Social Europeo (FSO); Junta de Andalucía; Gobierno de España
Background: Nonalcoholic fatty liver disease (NAFLD) is an increasing concern for people living with HIV (PLWH). However, information on the impact of NAFLD on the prognosis of PLWH is very scarce. Aims: To investigate the influence of NAFLD on the overall and liver- related mortality in PLWH. Methods: PLWH followed in three Spanish centres were included in a prospective cohort at the date of the first transient elas tography evaluation. Survival data were recorded, and the causes of death were centrally monitored. The risk of all- cause death and liver- related death was evaluated by applying time- to- event analyses. Results: A total of 2151 PLWH were included in the cohort and followed for a median (Q1–Q3) of 7.3 (3.5–10.4) years. There were 174 (8.1%) deaths. The probability of overall death and liver- related death was associated with liver stiffness measure ment (LSM) and with FibroScan- AST (FAST) score. Among 844 PLWH with potential for NALFD, LSM was independently associated with all- cause mortality (adjusted hazard ratio [AHR], by 1 kPa increase: 1.06; 95% confidence interval [95% CI]: 1.04–1.08; p < 0.001). In a separate model and after adjustment, FAST score ≥ 0.67 was related to survival (AHR: 1.87; 95% CI: 1.40–2.50; p < 0.001). The AUROC (95% CI) of the models were based on LSM, 0.812 (0.739–0.885); and FAST, 0.825 (0.753–0.897) (p = 0.386). Conclusions: For PLWH, advanced liver fibrosis increases the risk of overall death and liver- related death. LSM and the FAST score are similar predictors of survival for PLWH with potential for NAFLD.
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.

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