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Impacts of PI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions

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neural Regeneration Research 2025年第4期20卷 1031-1041页

作者： Ramón Pérez-núñez María fernanda González Ana María Avalos Lisette Leyton Cellular Communication Laboratory Programa de Biología Celular y MolecularCenter for Studies on ExerciseMetabolism and Cancer(CEMC)Instituto de Ciencias Biomédicas(ICBM)Facultad de MedicinaUniversidad de ChileSantiagoChile Advanced Center for Chronic diseases(ACCdiS) Faculty of Chemical and Pharmaceutical Sciences&Faculty of MedicineUniversidad de ChileSantiagoChile Instituto de Ciencias Biomédicas Facultad de Ciencias de la SaludUniversidad Autónoma de ChileSantiagoChile

Astrocytes are the most abundant type of glial cell in the central nervous *** injury and inflammation,astrocytes become reactive and undergo morphological and functional *** on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,***,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and *** analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their *** actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune *** phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo *** astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory ***,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their *** highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and notch/PI3K/AKT *** targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial *** dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function *** review emphasizes the importance of employing astrocyte-exclusive models to underst

关键词： inflammation integrins neuroprotective neurotoxic phosphatidylinositol 3-kinase reactive astrocytes signal transduction Thy-1(Cd90)

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data-driven drug repositioning using olfactory omics profiles:challenges and perspectives in neurodegeneration

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neural Regeneration Research 2025年第7期20卷 1997-1998页

作者： Paz Cartas-Cejudo Adriana Cortés Mercedes Lachén-Montes Elena Anaya-Cubero Joaquín fern.n.ez-Irigoyen Enrique Santamaría Clinical neuroproteomics Unit Proteomics PlatformNavarrabiomedHospitalario Universitario de Navarra(HUN)Universidad Pública de Navarra(UPNA)IdiSNANavarra Institute for Health ResearchPamplonaSpain

data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous *** diseases are often characterized as proteinopathies,which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells,leading to their dysfunction and eventual *** the gain-of-function hypothesis related to the aggregation of these proteins,recently,an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining *** last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body(ezzat et al.,2023).It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased.

关键词： diseases drug amyloid

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Gene therapy for spinal muscular atrophy:perspectives on the possibility of optimizing SMn1 delivery to correct all neurological and systemic perturbations

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neural Regeneration Research 2025年第7期20卷 2011-2012页

作者： Sharon J.Brown Rafael J.Yáñez-Muñoz Heidi R.Fuller School of Pharmacy and Bioengineering Keele UniversityKeeleUK Wolfson Center for Inherited neuromuscular disease TORCH BuildingRJAH Orthopaedic HospitalOswestryUK *** Center of Gene and Cell TherapyDepartment of Biological SciencesSchool of Life Sciences and the EnvironmentRoyal Holloway University of LondonEghamUK

Spinal muscular atrophy(SMA)is a genetic condition that results in selective lower motor neuron loss with concomitant muscle weakness and *** genetic cause of SMA was understood in 1995 when loss or impairment of the survival motor neuron 1(SMn1)gene was identified as the main contributing factor(Lefebvre et al.,1995).This,in combination with the discovery that humans have a“back-up”gene,SMn2,which can produce low levels(approximately 10%)of the full-length functional SMn protein,has led to the generation of SMA-specific gene *** was traditionally classified according to age of symptom onset and developmental milestones achieved,with life expectancy and severity varying between ***,SMn2 copy number is used as a proxy for the prediction of disease severity,with higher SMn2 copy number typically being associated with reduced severity of SMA,although this relationship is not absolute:some individuals with low SMn2 copy number have less severe SMA phenotypes and vice ***,the etiology of SMA is further complicated by other factors,such as non-typical nucleotide variants and SMn2-independent modifiers of disease severity.

关键词： atrophy traditionally absolute

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Re-folded structure of syn-orogenic granitoids(Padrón dome, nW Iberia):Assessing rheological evolution of cooling continental crust in a collisional setting

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Geoscience Frontiers 2019年第2期10卷 651-669页

作者： Rubén díez fern.n.ez Francisco J.Rubio Pascual Luis Miguel Martín Parra departamento de Geodinámica Estratigrafía y PaleontologíaFacultad de Ciencias GeológicasUniversidad Complutense de Madrid Instituto Geológico y Minero de Espana

This contribution discusses about the rheological, kinematic and dynamic frameworks necessary to produce recumbent and upright folds from syn-orogenic granitic massifs that were formed during an early stage of magma genesis related to the onset of a migmatitic dome. Syn-kinematic granitoids occurring within the high-grade infrastructure of the Padron migmatitic dome(nW Iberia) are deformed into largescale recumbent folds(d_2) that are later affected by upright folds(d_3). Petrostructural analysis of a selected area of this dome reveals that after a period of crustal thickening(d_1), nnW-directed extensional flow gave way to recumbent folds and penetrative axial plane foliation(S_2). Superimposed subhorizontal compression resulted in upright folds(d_3). A closer view into the dynamics of the dome allows exploring the factors that may condition the nucleation of folds with contrasting geometries during progressive deformation of molten continental crust. The formation of folds affecting syn-kinematic granitoids suggests a cooling metamorphic path in migmatitic domes. Active and passive folding mechanisms require a crystallizing(cooling) magma to nucleate folds. A more competent metamorphic host inhibits fold nucleation from much less competent magmas. As it crystallizes, magma becomes more rigid(competent),and approaches viscosity values of its host. Passive folding is favored when no significant competence contrast exists between magma and host, so this folding mechanism is more likely shortly after magma genesis and emplacement. In such conditions, and under dominant subhorizontal flow accompanied by flattening(d_2),passive folding would produce isoclinal recumbent geometries. Further magma cooling introduces a shift into the rheological behavior of partially molten crust. Thereon, crystallizing magma bodies would represent significant competence contrasts relative to their host. At this point, buckling is a more likely folding mechanism, and more regular, buckle fo

关键词： Recumbent folds Migmatitic domes Partial melting Crustal-derived granitoids Orogenic collapse Variscan orogen

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distribution of dnA damage in the human sperm nucleus:implications of the architecture of the sperm head

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Asian Journal of Andrology 2020年第4期22卷 401-408页

作者： Silvia González-Rojo Cristina fern.n.ez-díez Marta Lombó María Paz Herráez department of Molecular Biology Faculty of BiologyUniversidad de LeónCampus de Vegazana s/n LeónLeón 24071Spain

The sperm nucleus is prone to sustain dnA damage before and after *** of the damage is not homogeneous,and the factors determining differential sensitivity among nuclear regions have not yet been *** sperm chromatin contains three structural domains,two of which are considered the most susceptible to dnA damage:the histone bound domain,harboring developmental related genes,and the domain associated with nuclear matrix *** a quantitative polymerase chain reaction(qPCR)approach,we analyzed the number of lesions in genes homeobox A3(HOXA3),homeobox B5(HOXB 5),sex-determining region Y(SRY)-box 2(SOX2),β-GLOBIn,rdnA 18S,and rdnA 28S in human sperm after ultraviolet irradiation(400μW cm−2,10 min),H2O2treatment(250 mmol l−1,20 min),and cryopreservation,which showed differential susceptibility to genetic *** vulnerability is dependent on the genotoxic agent and independent of the sperm nuclear proteins to which the chromatin is bound and of accessibility to the transcription *** of 8-hydroxy-2'-deoxyguanosine(8-OHdG)showed that the highest level of oxidation was observed after *** distribution of oxidative lesions also differed depending on the genotoxic agent.8-OHdG did not colocalize either with histone 3(H3)or with type IIα+βtopoisomerase(TOPO IIα+β)after H2O2treatment but matched perfectly with peroxiredoxin 6(PRdX6),which is involved in *** study reveals that the characteristics of the sperm head domains are responsible for access of the genotoxicants and cause differential degree of damage to nuclear areas,whereas chromatin packaging has a very limited *** histone-enriched genes analyzed cannot be used as biomarkers of oxidative dnA damage.

关键词： biomarkers dnA damage human sperm oxidative stress sperm chromatin sperm quality

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Frontier of the Paleo-Tethys Ocean in the western Mediterranean:Isotopic(Sm-nd)constraints on sources of devonian units from Menorca Island

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Geoscience Frontiers 2024年第5期15卷 323-338页

作者： Ricardo Arenas Jose M.Fuenlabrada Cristian Timoner Rubén díez fern.n.ez Esther Rojo-Pérez departamento de Mineralogía y Petrología and Instituto de Geociencias(UCM CSIC)Universidad ComplutenseMadridSpain Unidad de Geocronología(CAI de Ciencias de la Tierra y Arqueometría) Universidad ComplutenseMadridSpain Bayerisches Geoinstitut University of BayreuthBayreuthGermany Instituto Geológico y Minero de España–CSIC SalamancaSpain

The c.1000-m-thick pre-orogenic devonian mainly metapelitic sequence of north Menorca Island shows a fairly complete stratigraphic *** rocks of this sequence indicate gradually increasing deeper marine conditions of sedimentation towards its uppermost ***,the obtained sedimentary characteristics resemble those related to a deep and narrow basin-associated *** sills of Ti-augite-bearing alkaline gabbros occur within the devonian *** intensity of Variscan deformation increases downwards through the *** to the characteristics of the devonian sequence and its location within the Variscan Orogen,a correlation with similar units located in the southern sectors of the Central Iberian Zone(Iberian Massif)is *** devonian metapelitic rocks have geochemical characteristics suggesting that they represent moderately recycled mature siliciclastic sediments,generated from erosion of distant source areas belonging to an upper continental *** relatively narrow range of variation observed in initial^(143)nd/^(144)nd ratios supports a similar source for the Menorcan slates(0.51165–0.51182).However,a marked trend is observed in these isotope ratios,from lower values at the base of the stratigraphic column(minimum value of 0.511941)to higher values at the top(maximum value of 0.512131).The^(147)Sm/^(144)nd ratios vary between 0.1074 and 0.1238,within the range defined for siliciclastic rocks with felsic crustal *** nd model ages define a narrow range between 1496 Ma and 1754 Ma(Late Paleoproterozoic–Early Mesoproterozoic),and they are consistently younger *** data rule out a provenance from the erosion of the West Africa Craton,as they are more compatible with a provenance from regions located in the Trans-Saharan Belt or Sahara *** characteristics of the Menorcan devonian sequence are compatible with its deposition in a narrow and deep peri-Gondwanan transtensional basin,gener

关键词： Western Paleo-Tethys frontiers Menorca Island Sm-nd isotopic constraints devonian sequence provenance in Gondwana

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nucleoside modified mRnA-lipid nanoparticles as a new delivery platform for the repair of the injured spinal cord

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neural Regeneration Research 2025年第8期20卷 2311-2312页

作者： Krisztián Pajer Tamás Bellák Antal nógrádi department of Anatomy Histology and EmbryologyAlbert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary

Spinal cord injury and treatment opportunities:The adult mammalian spinal cord has a very limited capacity for spontaneous regeneration due to various intrinsic molecular and cellular *** the spinal cord neurons have the capacity to regenerate their axons,the expression of growth inhibitory factors,lack or suppression of proper guidance cues,and profound inflammatory responses do not permit successful regeneration(Khyeam et al.,2021).

关键词： injured capacity modified

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The Study of Carbamoyl Phosphate Synthetase 1 deficiency Sheds Light on the Mechanism for Switching On/Off the Urea Cycle

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Journal of Genetics and Genomics 2015年第5期42卷 249-260页

作者： Carmen díez-fern.n.ez José Gallego Johannes H?berle Javier Cervera Vicente Rubio Institute for Biomedicine of Valencia of the Spanish Research Council Medical School of the Catholic University of Valencia University Children's Hospital Zurich and Children's Research Center Centre for Biomedical networking Research on Rare diseases of the Carlos Ⅲ Health Institute

Carbamoyl phosphate synthetase i （CPS1） deficiency （CPS1d） is an inborn error of the urea cycle having autosomal （2q34） recessive inheritance that can cause hyperammonemia and neonatal death or mental retardation. We analyzed the effects on CPS1 activity, kinetic parameters and enzyme stability of missense mutations reported in patients with CPS1 deficiency that map in the 20-kda C-terminal domain of the enzyme. This domain turns on or off the enzyme depending on whether the essential allosteric activator of CPS 1, n-acetyl- L-glutamate （nAG）, is bound or is not bound to it. To carry out the present studies, we exploited a novel system that allows the expression in vitro and the purification of human CPS1, thus permitting site-directed mutagenesis. These studies have clarified disease causation by individual mutations, identifying functionally important residues, and revealing that a number of mutations decrease the affinity of the enzyme for nAG. Patients with nAG affinity-decreasing mutations might benefit from nAG site saturation therapy with n-carbamyl-L- glutamate （a registered drug, the analog of nAG）. Our results, together with additional present and prior site-directed mutagenesis data for other residues mapping in this domain, suggest an nAG-triggered conformational change in the 134-~4 loop of the C-terminal domain of this enzyme. This change might be an early event in the nAG activation process. Molecular dynamics simulations that were restrained according to the observed effects of the mutations are consistent with this hypothesis, providing further backing for this structurally plausible signaling mechanism by which nAG could trigger urea cycle activation via CPS1.

关键词： Urea cycle diseases Inborn errors Hyperammonemia Site-directed mutagenesis Restrained molecular dynamics Allosteric regulation Carbamoyl phosphate synthetase 1 Enzyme

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Sex differences in aging and injured brain

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neural Regeneration Research 2025年第10期20卷 2901-2902页

作者： Jordan n.Williamson Yuan Yang University of Illinois Urbana-Champaign Grainger College of EngineeringDepartment of BioengineeringUrbanaILUSA Carle Foundation Hospital Stephenson Family Clinical Research InstituteClinical Imaging Research CenterUrbanaILUSA University of Illinois Urbana-Champaign Beckman Institute for Advanced Science and TechnologyUrbanaILUSA northwestern University Department of Physical Therapy and Human Movement SciencesChicagoILUSA

Background:The prevalence,age of onset,and symptomatology of traumatic brain injury,stroke,and neurodegenerative diseases(such as Alzheimer’s disease(Ad),Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease)differ substantially between males and *** higher prevalence of these brain disorders has been attributed to females having a greater longevity compared with *** one of the greatest risk factors of acquired brain injury(such as stroke,traumatic brain injury caused by fall)and neurodegenerative disease is age.

关键词： Huntington prevalence traumatic

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Astrocytes, reactive astrogliosis, and glial scar formation in traumatic brain injury

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neural Regeneration Research 2025年第4期20卷 973-989页

作者： María Belén Cieri Alberto Javier Ramos Laboratorio de neuropatología Molecular IBCN UBA-CONICETFacultad de MedicinaUniversidad de Buenos AiresBuenos AiresArgentina

Traumatic brain injury is a global health crisis,causing significant death and disability *** that follows traumatic brain injury has serious consequences for neuronal survival and cognitive impairments,with astrocytes involved in this *** traumatic brain injury,astrocytes rapidly become reactive,and astrogliosis propagates from the injury core to distant brain *** astroglial proteins are downregulated near the traumatic brain injury core,while pro-inflammatory astroglial genes are *** altered gene expression is considered a pathological remodeling of astrocytes that produces serious consequences for neuronal survival and cognitive *** addition,glial scar formed by reactive astrocytes is initially necessary to limit immune cell infiltration,but in the long term impedes axonal reconnection and functional *** therapeutic strategies for traumatic brain injury are focused on preventing acute ***,cannabinoids,progesterone,beta-blockers,and cerebrolysin demonstrate neuroprotective benefits but most of them have not been studied in the context of *** this review,we discuss the cell signaling pathways activated in reactive astrocytes following traumatic brain injury and we discuss some of the potential new strategies aimed to modulate astroglial responses in traumatic brain injury,especially using cell-targeted strategies with miRnAs or lncRnA,viral vectors,and repurposed drugs.

关键词： astrocyte glial scar innate immunity neuroinflammation stab injury Toll-like receptors

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