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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)

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

How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells

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World Journal of Stem Cells 2023年第5期15卷 281-301页

作者： mar.a belén novoa díaz Pedro Carriere Claudia Gentili departamento de Biología Bioquímica y FarmaciaUniversidad Nacional del SurBahía Blanca 8000Buenos AiresArgentina Instituto de Ciencias Biológicas y Biomédicas del Sur Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)-Universidad Nacional del Sur(UNS)Bahía Blanca 8000Buenos AiresArgentina

Colorectal cancer(CRC)remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant *** is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment ***,in the last decades,CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells(CCSC)with features like tumor initiation capacity,self-renewal capacity,and acquired multidrug *** data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic *** alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine *** is known that in the tumor niche,different cell types,structures,and biomolecules coexist and interact with cancer cells favoring cancer growth and ***,these components constitute the tumor microenvironment(TME).Most recently,researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa,collectively known as gut microbiota,on *** TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of *** in the last decade,crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC,the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.

关键词： Colorectal cancer Colorectal cancer stem cells Tumor microenvironment factors Tumor stroma Gut microbiota Cancer progression

differential response of injured and healthy retinas to syngeneic and allogeneic transplantation of a clonal cell line of immortalized olfactory ensheathing glia:a double-edged sword

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neural Regeneration Research 2025年第8期20卷 2395-2407页

作者： mar.a norte-Muñoz mar.a Portela-Lomba Paloma Sobrado-Calvo diana Simón Johnny di Pierdomenico Alejandro Gallego-Ortega mar Pérez JoséMCabrera-Maqueda Javier Sierra Manuel Vidal-Sanz mar.a Teresa Moreno-Flores mar.a Agudo-Barriuso Grupo de Investigación Oftalmología Experimental Departamento de OftalmologíaOptometríaOtorrinolaringología y Anatomía PatológicaFacultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la SaludMurciaSpain Experimental Sciences Faculty Universidad Francisco de VitoriaPozuelo de AlarcónMadridSpain Anatomy Histology and Neuroscience DepartmentMedicine FacultyUniversidad Autónoma de MadridMadridSpain Center of neuroimmunology Service of NeurologyLaboratory of Advanced Imaging in Neuroimmunological DiseasesHospital Clínic of BarcelonaInstitut d’Investigacions Biomèdiques August Pi i Sunyer(IDIBAPS)and Universitat de BarcelonaBarcelonaSpain Medicine Faculty Universidad Francisco de VitoriaPozuelo de AlarcónMadridSpain

Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic ***,it is unknown whether olfactory ensheathing glia also have neuroprotective *** ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion ***,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve *** ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive *** and gene expression analyses were *** bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡ*** and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an *** axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 *** these retinas,microglial anatomical activation was higher than after optic nerve crush *** intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or ***,neuroprotection of axotomized retinal ganglion cells did not improve with these *** different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.

关键词： cell therapy immune recognition major histocompatibility complex class II(MHCII) neuroprotection olfactory ensheathing glia retinal ganglion cells

Olfactory receptors in neural regeneration in the central nervous system

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neural Regeneration Research 2025年第9期20卷 2480-2494页

作者： Rafael Franco Claudia Garrigós Toni Capó Joan Serrano-marín Rafael Rivas-Santisteban Jaume Lillo Molecular neurobiology Laboratory Department of Biochemistry and Molecular BiomedicineFacultat de BiologiaUniversitat de BarcelonaBarcelonaSpain Ciberned network Center for Biomedical Research in neurodegenerative diseases Spanish National Health Institute Carlos ⅢMadridSpain School of Chemistry Universitat de BarcelonaBarcelonaSpain department of Biochemistry and Physiology School of Pharmacy and Food SciencesUniversitat de BarcelonaBarcelonaSpain Laboratory of Computational Medicine Biostatistics UnitFaculty of MedicineAutonomous University of BarcelonaCampus BellaterraBarcelonaSpain

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional *** receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental *** ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous *** gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent *** the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's *** ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian *** ectopic expression provides insights into the chemical structures that can activate olfactory *** addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing *** analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation *** review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative *** suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous syste

关键词： adenosine receptors adrenergic receptors ectopic expression G proteincoupled receptors glia neurons

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

Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide

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World Journal of Gastroenterology 2022年第26期28卷 3177-3200页

作者： mar.a belén novoa díaz Pedro Carriere Graciela Gigola Ariel Osvaldo Zwenger natalia Calvo Claudia Gentili departamento de Biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Buenos AiresArgentina Centro de Estudios Clínicos SAGA CEC SAGASantiago de Chile 8320000Chile

BACKGROUnd Parathyroid hormone-related peptide(PTHrP)plays a key role in the development and progression of many *** found that in colorectal cancer(CRC)HCT116 cells,the binding of PTHrP to its receptor PTHR type 1(PTHR1)activates events associated with an aggressive *** HCT116 cell xenografts,PTHrP modulates the expression of molecular markers linked to tumor *** evidence suggests that the Met receptor is involved in the development and evolution of *** on these data,we hypothesized that the signaling pathway trigged by PTHrP could be involved in the transactivation of Met and consequently in the aggressive behavior of CRC *** To elucidate the relationship among PTHR1,PTHrP,and Met in CRC *** For in vitro assays,HCT116 and Caco-2 cells derived from human CRC were incubated in the absence or presence of PTHrP(1-34)(10-8 M).Where indicated,cells were pre-incubated with specific kinase inhibitors or dimethylsulfoxide,the vehicle of the *** protein levels were evaluated by Western blot ***-time polymerase chain reaction(RT-qPCR)was carried out to determine the changes in gene *** healing assay and morpho logical monitoring were performed to evaluate cell migration and changes related to the epithelialmesenchymal transition(EMT),*** number of viable HCT116 cells was counted by trypan blue dye exclusion test to evaluate the effects of irinotecan(CPT-11),oxaliplatin(OXA),or doxorubicin(dOXO)with or without *** in vivo tests,HCT116 cell xenografts on 6-wk-old male n:nIH(S)_nu mice received daily intratumoral injections of PTHrP(40μg/kg)in 100μL phosphate-buffered saline(PBS)or the vehicle(PBS)as a control during 20 *** slaughter was carried out and the tumors were removed,weighed,and fixed in a 4%formaldehyde solution for subsequent treatment by *** evaluate the expression of molecular markers in human tumor samples,we studied 23 specimens ob

关键词： PTHrP MET receptor tyrosine kinase Parathyroid hormone receptor type 1 Colorectal cancer drug resistance

Survival effect of probiotics in a rat model of colorectal cancer treated with capecitabine

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World Journal of Gastrointestinal Oncology 2021年第10期13卷 1518-1531页

作者： Graciela Gigola Pedro Carriere mar.a belén novoa díaz Gabriela Perdigon Ariel Osvaldo Zwenger Claudia Gentili Biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Buenos Aires ProvinciaArgentina San Miguel de Tucumán 4000Argentina Centro de Estudios Clínicos SAGA CEC SAGASantiago de Chile 8320000Chile

BACKGROUnd Probiotics are used to manage a number of gastrointestinal disorders due to their beneficial *** reports showed that probiotics also improve the life quality of patients with colorectal cancer(CRC)subjected to oncologic *** a CRC animal model,probiotics supplementation has the potential to decrease the formation of aberrant crypts and ameliorate tumor malignancy,enhancing the antitumor effect of 5-fluorouracil(5-FU)*** on these data,we hypothesize that the administration of probiotics impact positively in the overall survival and life quality of rats with CRC under the treatment of capecitabine,which is the pro drug of *** To evaluate the probiotics effects in a rat CRC model treated with capecitabine and followed until the end of *** 1,2-dimethylhidrazine dihydrochloride(1,2-dMH)was employed as carcinogen inductor of *** male Wistar-Lewis rats were randomly assigned to one of five following groups:Control(n=5),Control+probiotics(Control-P group,n=5),1,2-dMH alone(dMH group,n=10),1,2-dMH+capecitabine(dMH-C group,n=10),1,2-dMH+probiotics(dMH-P group,n=10)and 1,2-dMH+capecitabine+probiotics(dMH-C-P group,n=10).All parametric data were expressed as the mean±*** statistical significance of differences was analyzed using one-way *** were analyzed with InfoStat *** results were considered statistically significant at Pd with the Kaplan-Meier estimator with the log-rank *** The data of mean overall survival for dMH,dMH-P,dMH-C,dMH-C-P,Control and Control-P groups were 250 d[95%confidence interval(CI):242.5-253.1],268 d(95%CI:246.3-271.4),380 d(95%CI:337.8-421.9),480 d(95%CI:436.9-530.7),588 d(95%CI:565.8-609.3)and 590 d(95%CI:564.3-612.9),respectively,with a significant difference between dMH-C and dMH-C-P groups(P=0.001).Comparing all groups by Kaplan-Meier estimator,we found a significantly different in the overall survival of dMH and dMH-

关键词： Colorectal cancer Capecitabine Probiotics Survival Life quality Animal experimentation

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)