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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 mar.a Fernanda González Ana mar.a 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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Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

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World Journal of Stem Cells 2021年第8期13卷 1134-1150页

作者： mar.a b monzón-nomdedeu Karl J Morten Elisa Oltra School of biotechnology Universidad Católica de Valencia San Vicente MártirValencia 46001Spain nuffield Department of Women's and Reproductive Health The Women CentreUniversity of OxfordOxford OX39DUUnited Kingdom Department of Pathology Universidad Católica de Valencia San Vicente MártirValencia 46001Spain Centro de Investigación Traslacional San Alberto Magno Universidad Católica de Valencia San Vicente MártirValencia 46001Spain

bACKGROUnD Fibromyalgia(FM)and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS)are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific *** patient heterogeneity linked to patient subgroups and variation in disease severity,anomalies are found in the blood and plasma of these patients when compared with healthy control *** seeming specificity of these“plasma factors”,as recently reported by Ron Davis and his group at Stanford University,CA,United States,and observations by our group,have led to the proposal that induced pluripotent stem cells(iPSCs)may be used as metabolic sensors for FM and ME/CFS,a hypothesis that is the basis for this indepth *** To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by *** A PRISMA(Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body *** MeSH terms“metabolomic”or“metabolites”in combination with FM and ME/CFS disease terms were screened against the PubMed *** original studies applying omics technologies,published in English,were *** data obtained were tabulated according to the disease and type of body fluid *** across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease *** Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body *** vitro cell-based assays have the potential to be developed as screening platforms,providing evidence for the existence of factors in patient body fluids capable of altering morphology,differentiation state and/or growth ***,they can be further develo

关键词： Myalgic encephalomyelitis/chronic fatigue syndrome Fibromyalgia Induced pluripotent stem cells Plasma factor Conditioned medium Sensor system

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The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal nLRP3 inflammation induced by binge-like ethanol treatment in adolescence

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neural Regeneration Research 2025年第4期20卷 1153-1163页

作者： Susana Mellado mar.a JoséMorillo-bargues Carla Perpiñá-Clérigues Francisco García-García Victoria Moreno-Manzano Consuelo Guerri mar.a Pascual Department of Physiology School of Medicine and DentistryUniversity of ValenciaValenciaSpain bioinformatics and biostatistics Unit Príncipe Felipe Research CenterValenciaSpain neuronal and Tissue Regeneration Laboratory Príncipe Felipe Research CenterValenciaSpain

Our previous studies have reported that activation of the nLRP3(nOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain *** stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent *** the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the nLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge *** demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal nLRP3 inflammasome complex and other nLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa b,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRnAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent *** analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and nOD-like receptor signaling *** together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with nLRP3 inflammasome activation induced by binge drinking in adolescence.

关键词： adolescence binge-like ethanol treatment extracellular vesicles hippocampus mesenchymal stem cells neuroinflammation nOD-,LRR-and pyrin domain-containing protein 3(nLRP3)

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The Fibrillar Matrix:novel Avenues for breast Cancer Detection and Treatment

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Engineering 2021年第10期7卷 1375-1380页

作者： Rasha Rezk Raquel marín-García Annica K.b.Gad Weston Park Cancer Centre Department of Oncology and MetabolismThe Medical SchoolThe University of SheffieldSheffield S102RXUnited Kingdom Department of Engineering University of CambridgeCambridge CB21PZUnited Kingdom Madeira Chemistry Research Center University of MadeiraFunchal 9020105Portugal

breast cancer is marked by large increases in the protein fibers around tumor *** fibers increase the mechanical stiffness of the tissue,which has long been used for tumor diagnosis by manual *** research in bioengineering has led to the development of novel biomaterials that model the mechanical and architectural properties of the tumor microenvironment and can be used to understand how these cues regulate the growth and spread of breast ***,we provide an overview of how the mechanical properties of breast tumor tissues differ from those of normal breast tissue and noncancerous *** also describe how biomaterial models make it possible to understand how the stiffness and viscosity of the extracellular environment regulate cell migration and breast cancer *** highlight the need for biomaterial models that allow independent analysis of the individual and different mechanical properties of the tumor microenvironment and that use cells derived from different regions within *** models will guide the development of novel mechano-based therapies against breast cancer metastasis.

关键词： breast cancer Tissue stiffness Cancer metastasis Cell migration bioengineered scaffold Viscosity

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Petrography and tectonic provenance of the Permian Tunas Formation:Implications on the paleotectonic setting during the ClaromecóForeland basin evolution,southwestern Gondwana margin,Argentina

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Journal of Palaeogeography 2022年第3期11卷 427-447页

作者： mar.a belén Febbo Renata n.Tomezzoli nora n.Cesaretti Giselle Choque natalia b.Fortunatti Guadalupe Arzadún Consejo nacional de Investigaciones Científicas y Técnicas(COnICET) Argentina Dpto.de Geología Universidad Nacional del SurAvenida Alem 1253B8000ICPBahía BlancaArgentina Centro de Geología Aplicada y Medio Ambiente(CGAMA CIC–UNS)Dpto.de GeologíaUniversidad Nacional del SurBahía BlancaArgentina Laboratorio de Paleomagnetismo“Daniel A.Valencio” Instituto de Geociencias BásicasAplicadas y Ambientales de Buenos Aires(IGEBA)Departamento de Ciencias GeológicasFacultad de Ciencias Exactas y Naturales(FCEyN)Universidad de Buenos Aires(UBA)Pabellón II(1428)CABAArgentina Laboratorio de Termocronología(La.Te Andes–COnICET) Las Moreras 310A4401XBAVaquerosSaltaArgentina

The Claromec o basin is located at the south-western sector of the buenos Aires province,*** basin is considered a foreland basin closely related to the evolution of the southwestern Gondwana *** contribution focuses on the provenance analysis of the Tunas Formation(Permian,Pillahuinc o Group),which represents the last filling stage for the Claromec o Foreland *** and tectonic provenance analyses were performed in sandstones recovered from subsurface(PAnG 0001 and PAnG0003 exploration wells)and outcrops located close to the basin center(Gonzales Chaves locality).In the subsurface,the analyzed succession is composed of medium-to fine-grained sandstones interbedded with tuffs,mudrocks,carbonaceous mudrocks and coal *** outcrops,the succession is dominated by mediumto fine-grained sandstones interbedded with *** composition patterns are distributed into the recycled orogen and transitionally recycled to mixed *** analyses,in addition to provenance and sedimentological studies,confirm that sedimentary material was derived from a mixed source,which largely comes from the Sierras Australes fold and thrust belt,located towards the W-SW,where the sedimentary succession is interbedded with volcanic *** Tunas Formation shows clear differences in its modal composition,paleocurrent direction and paleoenvironmental conditions with respect to the underlying units of the Pillahuinc o Group(Sauce Grande,Piedra Azul and bonete formations).Source areas changed from cratonic to mixed fold belt/arc-derived material,suggesting variations in the Claromec o basin configuration during the Late *** in the paleotectonic scenario during the deposition of the Tunas Formation have been interpreted as a consequence of a compressive post-collisional deformation event,the product of adjustment,accommodation and translation of terrains towards the equator during the Permian-Triassic to form Pangea.

关键词： Provenance area Petrography Tunas Formation ClaromecóForeland basin Southwestern Gondwana margin Permian Upper Paleozoic

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Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway:Providing understanding of the complex mechanisms of chemoresistance

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World Journal of Gastroenterology 2022年第26期28卷 3027-3046页

作者： mar.a belén novoa Díaz mar.a Julia martín Claudia Gentili Departamento de biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Argentina Departamento de Química Universidad Nacional del Sur(UNS)-INQUISUR(CONICET-UNS)Bahía Blanca 8000Argentina

Colorectal cancer(CRC)continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current *** of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer,including *** many subtypes of CRC,hyperactivation of theβ-catenin pathway is associated with mutations of the adenomatous polyposis coli ***,it can also be associated with other *** recent years,studies of the tumor microenvironment(TME)have demonstrated its importance in the development and progression of *** this tumor nest,several cell types,structures,and biomolecules interact with neoplastic cells to pave the way for the spread of the ***-communications between tumor cells and the TME are then established primarily through paracrine factors,which trigger the activation of numerous signaling *** advances in the field of oncology have been made in the last *** Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness,focusing on crosscommunication between CRC cells and the *** this analysis,our main objective was to increase the understanding of this complex disease considering a more global *** many treatments for advanced CRC fail due to mechanisms involving chemoresistance,the data here exposed and analyzed are of great interest for the development of novel and effective therapies.

关键词： Colorectal cancer β-catenin pathway Tumor stroma Tumor microenvironment factors Cancer progression Drug resistance

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Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease

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World Journal of Gastroenterology 2015年第40期21卷 11273-11281页

作者： Alicia C marín Javier P Gisbert mar.a Chaparro Gastro- enterology Unit Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria PrincesaCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas28021 MadridSpain

Inflammatory bowel disease(IbD) is an immunological disorder that is usually treated with immunosuppressive therapy,potentially leading to increases in vulnerability to infections. Although many infections can be pre-vented by vaccination,vaccination coverage in these patients in clinical practice is insufficient. Therefore,the seroprotection condition should be verified,even for routine vaccines,such as hepatitis b or pneu-mococcus. Response to vaccines in IbD patients is thought to be impaired due to the immunological alterations generated by the disease and to the immunomodulatory treatments. The immunogenicity of hepatitis b,influenza,and pneumococcal vaccines is impaired in IbD patients,whereas the response to papillomavirus vaccine seems similar to that observed in the healthy population. On the other hand,data on the immunogenicity of tetanus vaccine in IbD patients are conflicting. Studies assessing the response to measles-mumps-rubella,varicella,and herpes zoster vaccines in IbD patients are scarce. The cellular and molecular mechanisms responsible for the impairment of the response to vaccination in IbD patients are poorly understood. Studies aiming to assess the response to vaccines in IbD patients and to identify the mechanisms involved in their immunogenicity are warranted. A better understanding of the immune response,specifically to vaccines,in patients with immune-mediated diseases(such as IbD),is crucial when developing vaccines that trigger more potent immunologic responses.

关键词： Crohn’s disease Inflammatory bowel disease Tumor n

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Glutamine synthetase activity and glutamate uptake in hippocampus and frontal cortex in portal hypertensive rats

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World Journal of Gastroenterology 2009年第23期15卷 2893-2899页

作者： Gabriela beatriz Acosta mar.a Alejandra Fernández Diego martín Roselló mar.a Luján Tomaro Karina balestrasse Abraham Lemberg Institute of Pharmacological Research (InInFA) National Research Council of Argentina (CONICET) and University of Buenos Aires Junín 956. 5th floor C1113AAD Buenos Aires Argentina Laboratory of Portal Hypertension School of Pharmacy and Biochemistry University of Buenos Aires Junín 956. 5th floor C1113AAD Buenos Aires Argentina Department of biological Chemistry School of Pharmacy and Biochemistry University of Buenos Aires Junín 596. 5th floor C1113AAD Buenos Aires Argentina

AIM: To study glutamine synthetase (GS) activity and glutamate uptake in the hippocampus and frontal cortex (FC) from rats with prehepatic portal vein hypertension. METHODS: Male Wistar rats were divided into shamoperated group and a portal hypertension (PH) group with a regulated stricture of the portal vein. Animals were sacrificed by decapitation 14 d after portal vein stricture. GS activity was determined in the hippocampus and FC. Specific uptake of radiolabeled L-glutamate was studied using synaptosome-enriched fractions that were freshly prepared from both brain areas. RESULTS: We observed that the activity of GS increased in the hippocampus of PH rats, as compared to control animals, and decreased in the FC. A significant decrease in glutamate uptake was found in both brain areas, and was more marked in the hippocampus. The decrease in glutamate uptake might have been caused by a deficient transport function, signif icantly and persistent increase in this excitatory neurotransmitter activity. COnCLUSIOn: The presence of moderate ammonia blood levels may add to the toxicity of excitotoxic glutamate in the brain, which causes alterations in brain function. Portal vein stricture that causes portal hypertension modif ies the normal function in some brain regions.

关键词： Portal hypertension Glutamine synthetase Glutamate uptake Frontal cerebral cortex Hippocampus Rat

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Protein kinase clk/STY is differentially regulated during erythroleukemia cell differentiation: a bias toward the skipped splice variant characterizes postcommitment stages

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Cell Research 2005年第7期15卷 495-503页

作者： Ana GARCíA-SACRISTán■,mar.a J. FERnánDEZ-nESTOSA,Pablo HERnánDEZ,Jorge b.SCHVARTZMAn,Dora b. KRIMER Department of Cell and Developmental biology Centro de Investigaciones biológicas Consejo Superior de InvestigacionesCientíficas Ramiro de Maeztu 9 Madrid 28040 Spain Instiute of Molecular Medicine 1649-028 Lisbon Medical School Lisbon Portugal Department of Cell and Developmental biology Centro de Investigaciones biológicas Consejo Superior de InvestigacionesCientíficas Ramiro de Maeztu 9 Madrid 28040 Spain Department of Cell and Developmental biology Centro de Investigaciones biológicas Consejo Superior de InvestigacionesCientíficas Ramiro de Maeztu 9 Madrid 28040 Spain Department of Cell and Developmental biology Centro de Investigaciones biológicas Consejo Superior de InvestigacionesCientíficas Ramiro de Maeztu 9 Madrid 28040 Spain Department of Cell and Developmental biology Centro de Investigaciones biológicas Consejo Superior de InvestigacionesCientíficas Ramiro de Maeztu 9 Madrid 28040 Spain

Clk/STY is a LAMMER protein kinase capable to phosphorylate serine/arginine-rich (SR) proteins that modulate pre-mRnA splicing. Clk/STY alternative splicing generates transcripts encoding a full-length kinase and a truncated catalyti-cally inactive protein. Here we showed that clk/STY, as well as other members of the family (e.g. clk2, clk3 and clk4),are up-regulated during HMbA-induced erythroleukemia cell differentiation. mRnAs coding for the full-length and thetruncated forms were responsible for the overall increased expression. In clk/STY, however, a switch was observed forthe ratio of the two alternative spliced products. In undifferentiated cells the full-length transcript was more abundantwhereas the transcript encoding for the truncated form predominated at latter stages of differentiation. Surprisingly,overexpression of clk/STY did not alter the splicing switch upon differentiation in MEL cells. These results suggest thatclk/STY might contribute to control erythroid differentiation by a mechanism that implicates a balance between thesetwo isoforms.

关键词： clk/STY LAMMER kinase alternative splicing erythroleukemia cells.

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Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

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World Journal of Gastroenterology 2021年第41期27卷 7025-7040页

作者： mar.a belén novoa Díaz Pedro Matías Carriere mar.a Julia martín natalia Calvo Claudia Gentili Departamento de biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Buenos AiresArgentina Departamento de Química Universidad Nacional del Sur(UNS)-INQUISUR(CONICET-UNS)Bahía Blanca 8000Buenos AiresArgentina

Colorectal cancer(CRC)remains one of the leading causes of mortality from malignant diseases *** general terms,CRC presents high heterogeneity due to the influence of different genetic and environmental factors;also,the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells,known together as the tumor microenvironment(TME).bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine *** hormone-related peptide(PTHrP)is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological *** exerts its effects as a paracrine/autocrine factor,although its mode of action is mainly *** has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral *** years ago,when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors,the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited,and no articles had been published regarding to the paracrine action of PTHrP in CRC *** on this and on our previous findings regarding the role of PTH in CRC cells,our purpose in recent years has been to explore the role of PTHrP in *** analyzed the behavior of CRC cells treated with exogenous PTHrP,focalizing in the study of the following events:Survival,cell cycle progression and proliferation,migration,chemoresistance,tumor-associated angiogenesis,epithelial to mesenchymal transition program and other events also associated with invasion,such us the induction of cancer stem cells *** work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressiv

关键词： Parathyroid hormone-related protein Colorectal cancer Tumor biomarkers neoplastic processes Drug resistance Tumor microenvironment

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