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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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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： maría Norte-Muñoz maría portela-Lomba paloma Sobrado-Calvo Diana Simón Johnny Di pierdomenico Alejandro Gallego-Ortega mar pérez JoséMCabrera-Maqueda Javier Sierra Manuel Vidal-Sanz maría Teresa Moreno-Flores marta 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

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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 maría JoséMorillo-Bargues Carla perpiñá-Clérigues Francisco García-García Victoria Moreno-Manzano Consuelo Guerri maría 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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Abscisic acid, a promising therapeutic molecule to prevent Alzheimer’s and neurodegenerative diseases

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Neural Regeneration Research 2020年第6期15卷 1035-1036页

作者： Ana maría Sánchez-pérez Department of Medicine Universitat Jaume I

Neuroinflammatory processes induce neuronal damage and underlie the onset of neurodegenerative pathologies,including Alzheimer’s disease(AD)(Calsolaro and Edison,2016).Several conditions,ranging from emotional stress to metabolic syndrome,including traumatic brain injury,chronic infections or gut microbiota disruption can cause or aggravate ***,aging is the major factor associated with neurodegenerative diseases.

关键词： degenerative Alzheimer diseases

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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 maría 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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Antioxidant role of heme oxygenase-1 in prehepatic portal hypertensive rats

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World Journal of Gastroenterology 2006年第26期12卷 4149-4155页

作者： Soledad Gonzales maría Julia pérez Juan C perazzo maría Luján Tomaro Department of Biological Chemistry School of pharmacy and Biochemistry University of Buenos AiresBuenos Aires 1113Argentina Laboratory of portal Hypertension Department of Biological Science School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos Aires 1113Argentina

AIM： To study the effect of bilirubin on the oxidative liver status and the activity and expression of heine oxygenase-1 （HO-1） in rat liver injury induced by prehepatic portal hypertension. METHODS： Wistar male rats, weighing 200-250 g, were divided at random into two groups： one group with prehepatic portal hypertension （pH） induced by regulated prehepatic portal vein ligation （ppVL） and the other group corresponded to sham operated rats. portal pressure, oxidative stress parameters, antioxidant enzymes, HO-1 activity and expression and hepatic sinusoidal vasodilatation were measured. RESULTS： In ppVL rats oxidative stress was evidenced by a marked increase in thiobarbituric acid reactive substances （TBARS） content and a decrease in reduced glutathione （GSH） levels. The activities of liver antioxidant enzymes, superoxide dismutase （SOD）, catalase （CAT） and glutathione peroxidase （GSH-px） were also diminished while activity and expression of HO-1 were enhanced. Administration of bilirubin （5μmol/kg body weight） 24 h before the end of the experiment entirely prevented all these effects. pretreatment with Sn-protoporphyrin IX （Sn-ppIX）（100 μg/kg body weight, i.p.）, a potent inhibitor of HO, completely abolished the oxidative stress and provoked a slight decrease in liver GSH levels as well as an increase in lipid peroxidation. Besides, carbon monoxide, another heme catabolic product, induced a significant increase in sinusoidal hepatic areas in ppVL group. pretreatment of ppVL rats with Sn-ppIX totally prevented this effect CONCLUSION： These results suggest a beneficial role of HO-1 overexpression in prehepatic portal hypertensive rats.

关键词： Heme oxygenase-1 portal hypertensive rats Liver oxidative stress

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Common misconceptions about 5-aminosalicylates and thiopurines in inflammatory bowel disease

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World Journal of Gastroenterology 2011年第30期17卷 3467-3478页

作者： Javier p Gisbert maría Chaparro Fernando Gomollón Gastroenterology Unit Hospital Universitario de La PrincesaInstituto de Investigación SanitariaPrincesa(IP)and Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas28006 MadridSpain Gastroenterology Unit Hospital Clínico Universitario and Centro de Investigación Biomédica en Redde Enfermedades Hepáticasy DigestivasIACS50009 ZaragozaSpain

Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate *** of errors needs knowledge to avoid making such errors through ***,the amount of knowledge is increasing so quickly that one new danger is an overabundance of *** is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical *** regard to the use of 5-aminosalicylates,the best practice may to be consider abandoning the use of these drugs in patients withsmall bowel Crohn's *** combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis;once-daily treatment should be offered as a first choice regimen due to its better compliance and higher *** regard to thiopurines,they seem to be as effective in ulcerative colitis as in Crohn's *** of thiopurines is a form of *** should probably be continued indefinitely because their withdrawal is associated with a high risk of *** is a safe alternative in patients with digestive intolerance or hepatotoxicity due to ***,thiopurine methyltransferase(TpMT)screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TpMT-related.

关键词： Crohn' s disease Ulcerative colitis Inflam-matory bowel disease Aminosalicylates Steroids Azathioprine Mercaptopurine Misconceptions

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Calibration of the DEM sliding friction and rolling friction parameters of a cohesionless bulk material

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particuology 2024年第9期92卷 126-139页

作者： Jonatan marín pérez Tugrul Comlekci Yevgen Gorash Donald MacKenzie University of Strathclyde 75 Montrose StreetG11XJGlasgowUnited Kingdom

The discrete element method(DEM)has become a valuable tool for understanding the mechanical behaviour of granular assemblies,however,the accuracy of the DEM simulations depends on several interaction parameters such as the sliding friction and rolling friction ***,these parameters are estimated using bulk calibration approach(BCA)where the draw down test has been suggested as an effective way to approach these *** test provides up to four bulk criteria,the angle of repose,shear angle,mass flow rate and the mass loss which are used to narrow down the possible ***,there is still more research needed around it to fully understand how this methodology *** experimental and numerical study was carried out using the draw down test to assess the influence of different mass flow rates and particle shapes on DEM parameters for a cohesionless bulk *** is concluded that use of multi-sphere particles and three aperture sizes in the draw down test to calibrate the sliding and rolling friction parameters of a cohesionless bulk material can converge to a small feasible region in which a single combination of the friction coefficients can be *** calibrated sliding and rolling friction coefficients were validated using multi-sphere particles,where the maximum deviation was 5.9%from the experimental values.

关键词： Discrete element method Calibration Draw down Sliding friction Rolling friction particle shape

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Combination of Interleaved Single-input Multiple-output DC-DC Converters

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CSEE Journal of power and Energy Systems 2022年第1期8卷 132-142页

作者： Eladio Dur´an Aranda Salvador p´erez Litr´an mar´ıa Bella Ferrera prieto Electronic Engineering Computer Systems and Automation DepartmentUniversity of HuelvaHuelvaSpain Electrical and Thermal Engineering Design and Projects DepartmentUniversity of HuelvaHuelvaSpain

This paper analyses,simulates and verifies an experimental prototype of a four-phase interleaved DC-DC *** is based on a SEpIC-Cuk *** developed prototype has been used in single-input multiple-output(SIMO)*** combined converter allows obtaining dual output voltages of the same value,from a single input DC voltage and with only a power *** interleaved DC-DC converters achieve a better dynamic response and low ripple,maintaining their *** converter is connected in parallel,thereby managing their losses by distributing them between more components,which facilitates the thermal management of the multiphase converter and allows handling high power values in small sizes with respect to solutions for a single *** control strategies were applied:synchronous operation mode(SOM)and interleaved operation mode(IOM).The simulation results allow the comparison of both operational modes,verifying that the IOM presents advantages with respect to the ripple at the input and output *** experimental prototype was designed for a distributed power architecture and bipolar DC microgrid(MG).

关键词： Bipolar DC DC-DC converter interleaved

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Adalimumab-induced interstitial pneumonia in a patient with Crohn's disease

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World Journal of Gastroenterology 2015年第7期21卷 2260-2262页

作者： maría José Casanova maría Chaparro Claudia Valenzuela Carolina Cisneros Javier p Gisbert Gastroenterology Department Hospital Universitario de La Princesa Instituto de Investigación Sanitaria Princesa (IIS-IP) Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) pneumology Department Hospital Universitario de La Princesa

There are several reports of anti-tumor necrosis factor(TNF)-induced lung disease,especially in patients with rheumatologic *** is an antiTNF drug used to induce and maintain remission in patients with immune-mediated diseases,such as Crohn’s *** pulmonary disorders could be an extra-intestinal manifestation of inflammatory bowel disease,biologic therapy could also be a cause of lung *** few cases of adalimumab-induced lung toxicity have been reported,and the majority of them were in patients with rheumatologic *** injury secondary to anti-TNF therapy should,after ruling out other etiologies,be considered in patients who have a temporal association between the onset of respiratory symptoms and the exposure to these drugs.A compatible pattern in the biopsy and the clinical improvement after discontinuation of the anti-TNF drug would strongly support the diagnosis.

关键词： Adalimumab Anti-tumor necrosis factor Crohn’s dise

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