Artículos (Fisiología)

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The Subventricular Zone Neurogenic Niche Provides Adult Born Functional Neurons to Repair Cortical Brain Injuries in Response to Diterpenoid Therapy
(BioMed Central, 2025) Pardillo Díaz, Ricardo; Pérez García, Patricia; Ortego Domínguez, María; Gómez Oliva, Ricardo; Martínez Gómez, Nora; Domínguez García, Samuel; García Cózar, Francisco; Muñoz Miranda, Juan Pedro; Hernández Galán, Rosario; Carrascal Moreno, María Livia; Castro, Carmen; Núñez Abades, Pedro Antonio; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Introduction: Neural stem cells from the subventricular zone (SVZ) neurogenic niche provide neurons that integrate in the olfactory bulb circuitry. However, in response to cortical injuries, the neurogenic activity of the SVZ is significantly altered, leading to increased number of neuroblasts with a modified migration pattern that leads cells towards the site of injury. Despite the increased neurogenesis and migration, many newly generated neurons fail to survive or functionally integrate into the cortical circuitry. Providing the injured area with the adequate signaling molecules may improve both migration and functional integration of newly generated neurons. Methods: In here, we have studied the effect of a diterpene with the capacity to induce neuregulin release at promoting neurogenesis in a murine model of cortical brain injury. Using green fluorescent protein expressing vectors we have labeled SVZ cells and have studied the migration of newly generated neuroblasts toward the injury in response the treatment. In addition, using electrophysiological recordings we have studied the differentiation of these neuroblasts into mature neurons and their functional integration into the cortical circuitry. We have studied their electrical properties, their morphology and cortical location. Results: We have found that EOF2 treatment of adult mice with mechanical cortical injuries facilitates the delivery of neuroblasts into these injuries. The newly generated neurons develop features of fully functional neurons. Our results show that the newly generated neurons receive electrical inputs, fire action potentials, and undergo complete differentiation into neurons recapitulating the stages that distinguish ontogenic differentiation. These neurons develop features representative of neurons belonging the cortical layer in which they are situated. We have also studied that EOF2 facilitates neuregulin release in SVZ cells, a signaling factor that promotes neuronal differentiation. Neuregulin is expressed in microglial cells that reach the injury in response to the damage and its release is increased by EOF2 treatment. Conclusion: Promoting neuregulin release via diterpene treatment facilitates migration of SVZ-derived neuroblasts to cortical injuries stimulating their differentiation into mature functional neurons, which receive electrical inputs and develop features of cortical neurons. These findings highlight the role of diterpenoids as a potential therapy to repair cortical brain injuries.
Influence of Cellular Aging on Liver Stiffness in Patients With Hepatitis C Virus Achieving Sustained Viral Response
(Oxford, 2025) González-Serna Martín, Manuel Alejandro; Corma Gómez, Anaïs; Cano Rodríguez, María Mercedes; Rubio Sánchez, Ricardo; Martín Sierra, Carmen; Rincón, Pilar; Martín Carmona, Jesica; Pérez, Margarita; Pineda Vergara, Juan Antonio; Real, Luis Miguel; Macías Sánchez, Juan; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Medicina; Instituto de Salud Carlos III
Background. Liver stiffness (LS) is not reduced in 10%–30% of patients who achieve sustained viral response (SVR) after hepatitis C virus (HCV) elimination with direct-acting antivirals (DAA). Our aim was to analyze whether the parameters associated with cellular aging measured at the DAA initiation date are related to LS reduction upon achieving SVR. Methods. In a prospective cohort study (GEHEP-011) we measured several parameters associated with cellular aging, such as telomere attrition, mitochondrial alterations, and soluble biomarkers associated with senescence-associated secretory phenotype at the DAA initiation date, and examined their associations with a significant (≥20%) LS decrease at the SVR time point. Results. In total, 175 individuals were included in this study. In 101 (57.7%) patients, the LS reduction was ≥20% at SVR. In the multivariate analysis adjusted for sex, age, CXCL10, hsPCR, and CCL11 levels, greater relative telomere length (RTL) emerged as the sole variable independently associated with a significant LS decrease in SVR (1.102; 95% confidence interval, 1.001–1.1214; P = .047). Furthermore, changes in LS, including significant decrease, decrease <20%, or increase, were congruently associated with RTL (P = .011). Conclusions. Greater RTL was independently associated with a significant LS reduction in SVR. Thus, increased cellular aging may be responsible for the absence of liver regeneration after HCV eradication. Further studies are required to assess the long-term effects of cellular aging after SVR.
Use of Marine Sponges as Stress Indicators in Marine Ecosystems at Algeciras Bay (Southern Iberian Peninsula)
(Inter-Research, 1996) Carballo Cenizo, Juan José Luis; Naranjo, S. A.; García Gómez, José Carlos; Universidad de Sevilla. Departamento de Fisiología
Infralittoral sponge fauna was studied as part of a multidisciplinary investigation of benthic communities in Algeciras Bay. On a monthly basis over 1 year, a series of environmental variables were measured (hydrodynamism silting suspended solids, dissolved organic matter, % organic matter in silt). The only abiotic variable that was significantly correlated with beta diversity was hydrodynamism, with a linear regression model between the 2 variables showing a correlation coefficient of 0.66. The distributional pattern of the sponges (based on the relative abundance matrix) was correlated with the environmental variables by matching sample similarities using the Spearman rank correlation, thus showing that the variable combination that best explains the patterns of distribution is hydrodynamism/organic matter in silt (ρ(s) = 0.6). Of the species considered, Phorbas fictitius, Cliona celata, C1iona viridis, Crella elegans, Oscarella lobularis, Dysidea fragilis were among those showing the greatest adaptive plasticity in their relationship to environmental variables, depth, and selection by substrate, and are categorized as eurytopic species present in areas subject to great environmental stress. Other species such as Phorbas tenacior, Reniera fulva, Reniera mucosa, Cliona rhodensis proved to be much more sensitive to these variables, and were categorized as stenotopic species, indicators of normal conditions. Due to the particular environmental conditions where it is located, Mycale micracanthoxea was categorized as a good indicator species in port environments. Others such as Dysidea avara, Halichondria bowerbanki or Crella elegans presented morphological differentiations which have permitted them to adapt to sedimentary environments.
Effects of Environmental Stress on Ascidian Populations in Algeciras Bay (Southern Spain). Possible Marine Bioindicators?
(Inter-Research, 1996) Naranjo, S. A.; Carballo Cenizo, Juan José Luis; García Gómez, José Carlos; Universidad de Sevilla. Departamento de Fisiología
The distribution and abundance of littoral ascidians were analyzed with respect to their possible relationships with environmental stress. As part of a multidisciplinary research project on the benthic communities in Algeciras Bay, southern Spain, a suite of environmental variables was measured (hydrodynamism, silting, suspended solids and organic matter). After displaying the similarities of fauna through clustering and ordination el sampling sites, the relationships between community differences anti changes in the abiotic component were established based on the BIO-ENV procedure and Canonical Correspondence Analysis. Hydrodynamism and the percentage of organic matter in the silt is the variable combination that best explains (Spearman correlation of 0.82) the biotic structure. While all ascidians show a certain tolerance to diverse environmental factors, some species such as Ciona intestinalis, Diplosoma spongiforme, Phallusia mammillata, Microcosmus squamiger, Styela plicata and Synoicum argus could be considered as indicators of areas which have been subject to intense stress (substrate transformation water stagnation and sedimentation excess) over long periods of time whereas others such as Aplidium conicum, Aplidium punctum, Clavelina dellavallei, Halocynthia papillosa and Stolonica socialis, which live only in natural and non-perturbed rock areas, could be categorized as species very sensitive to stress, as well as indicators of good conditions.
Striking Cardioprotective Effects of an Adiponectin Receptor Agonist in an Aged Mouse Model of Duchenne Muscular Dystrophy
(MDPI, 2024-12-18) Abou-Samra, Michel; Dubuisson, Nicolas; Marino, Alice; Selvais, Camille M.; Romain, Versele; Davis López de Carrizosa, María América; Horman, Sandrine; Universidad de Sevilla. Departamento de Fisiología; National Fund for Scientific Research (FNRS). Belgium
first_pagesettingsOrder Article Reprints Open AccessArticle Striking Cardioprotective Effects of an Adiponectin Receptor Agonist in an Aged Mouse Model of Duchenne Muscular Dystrophy by Michel Abou-Samra 1,*ORCID,Nicolas Dubuisson 1,2ORCID,Alice Marino 3ORCID,Camille M. Selvais 1,Versele Romain 1ORCID,Maria A. Davis-López de Carrizosa 1,4ORCID,Laurence Noel 1,Christophe Beauloye 3,5,Sonia M. Brichard 1 andSandrine Horman 3 1 Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research (IREC), Medical Sector, Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 55, 1200 Brussels, Belgium 2 Neuromuscular Reference Center, Department of Neurology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium 3 Pole of Cardiovascular Research, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 55, 1200 Brussels, Belgium 4 Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, 41012 Seville, Spain 5 Department of Cardiovascular Intensive Care, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium * Author to whom correspondence should be addressed. Antioxidants 2024, 13(12), 1551; https://doi.org/10.3390/antiox13121551 Submission received: 21 November 2024 / Revised: 11 December 2024 / Accepted: 13 December 2024 / Published: 18 December 2024 (This article belongs to the Topic Advances in Adiponectin) Downloadkeyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract Adiponectin (ApN) is a hormone with potent effects on various tissues. We previously demonstrated its ability to counteract Duchenne muscular dystrophy (DMD), a severe muscle disorder. However, its therapeutic use is limited. AdipoRon, an orally active ApN mimic, offers a promising alternative. While cardiomyopathy is the primary cause of mortality in DMD, the effects of ApN or AdipoRon on dystrophic hearts have not been investigated. Our recent findings demonstrated the significant protective effects of AdipoRon on dystrophic skeletal muscle. In this study, we investigated whether AdipoRon effects could be extended to dystrophic hearts. As cardiomyopathy develops late in mdx mice (DMD mouse model), 14-month-old mdx mice were orally treated for two months with AdipoRon at a dose of 50 mg/kg/day and then compared with untreated mdx and wild-type (WT) controls. Echocardiography revealed cardiac dysfunction and ventricular hypertrophy in mdx mice, which were fully reversed in AdipoRon-treated mice. AdipoRon also reduced markers of cardiac inflammation, oxidative stress, hypertrophy, and fibrosis while enhancing mitochondrial biogenesis via ApN receptor-1 and CAMKK2/AMPK pathways. Remarkably, treated mice also showed improved skeletal muscle strength and endurance. By offering protection to both cardiac and skeletal muscles, AdipoRon holds potential as a comprehensive therapeutic strategy for better managing DMD.
Selenium supplementation via modulation of selenoproteins ameliorates binge drinking- induced oxidative, energetic, metabolic, and endocrine imbalance in adolescent rats’ skeletal muscle
(Royal Society of Chemistry, 2020-07-10) Romero Herrera, Inés; Nogales Bueno, Fátima; Gallego López, María del Carmen; Diaz Castro, Javier; Carreras Sánchez, Olimpia; Ojeda Murillo, María Luisa; Universidad de Sevilla. Departamento de Fisiología; Junta de Andalucía; Universidad de Sevilla
Adolescence is characterized by increased vulnerability to addiction and ethanol (EtOH) toxicity, particularly through binge drinking (BD), a favored acute EtOH-ingestion pattern among teenagers. BD, highly pro-oxidant, induces oxidative stress (OS), affecting skeletal muscle (SKM), where selenium (Se), an antioxidant element and catalytic center of selenoproteins, is stored, among other tissues. Investigating the effects of Se supplementation on SKM after BD exposure holds therapeutic promise. For this, we randomised 32 adolescent Wistar rats into 4 groups, exposed or not to intermittent i.p. BD [BD and control (C)] (3 g EtOH per kg per day), and supplemented with selenite [BDSe and CSe] (0.4 ppm). In SKM, we examined the oxidative balance, energy status (AMPK, SIRT-1), protein turnover (IRS-1, Akt1, mTOR, IGF-1, NF-κB p65, MAFbx, ULK1, pelF2α), serum myokines (myostatin, IL-6, FGF21, irisin, BDNF, IL-15, fractalkine, FSTL-1, FABP-3), and selenoproteins (GPx1, GPx4, SelM, SelP). In the pancreas, we studied the oxidative balance and SIRT-1 expression. Selenite supplementation mitigated BD-induced OS by enhancing the expression of selenoproteins, which restored oxidative balance, notably stimulating protein synthesis and normalizing the myokine profile, leading to improved SKM mass growth and metabolism, and reduced inflammation and apoptosis (caspase-3). Selenite restoration of SelP's receptor LRP1 expression, reduced by BD, outlines the crucial role of SKM in the SelP cycle, linking Se levels to SKM development. Furthermore, Se attenuated pancreatic OS, preserving insulin secretion. Se supplementation shows potential for alleviating SKM damage from BD, with additional beneficial endocrine effects on the pancreas, adipose tissue, liver, heart and brain that position it as a broad-spectrum treatment for adolescent alcohol consumption, preventing metabolic diseases in adulthood.
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.

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