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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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Physiological effects of amyloid precursor protein and its derivatives on neural stem cell biology and signaling pathways involved

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Neural Regeneration Research 2019年第10期14卷 1661-1671页

作者： Raquel Coronel Charlotte Palmer Adela Bernabeu-Zornoza María Monteagudo Andreea Rosca Alberto Zambrano Isabel Liste Unidad de Regeneración Neural Unidad Funcional de Investigación de Enfermedades Crónicas Instituto de Salud Carlos Ⅲ (ISCⅢ)

The pathological implication of amyloid precursor protein(APP)in Alzheimer’s disease has been widely documented due to its involvement in the generation of amyloid-β ***,the physiological functions of APP are still poorly *** is considered a multimodal protein due to its role in a wide variety of processes,both in the embryo and in the adult ***,APP seems to play a key role in the proliferation,differentiation and maturation of neural stem *** addition,APP can be processed through two canonical processing pathways,generating different functionally active fragments:soluble APP-α,soluble APP-β,amyloid-β peptide and the APP intracellular C-terminal *** fragments also appear to modulate various functions in neural stem cells,including the processes of proliferation,neurogenesis,gliogenesis or cell ***,the molecular mechanisms involved in these effects are still *** this review,we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells,as well as the possible signaling pathways that could be implicated in these *** knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer’s disease is essential to advance the understanding of the pathogenesis of Alzheimer’s disease,and in the search for potential therapeutic targets.

关键词： amyloid precursor protein APP soluble APP alpha soluble APP beta amyloid beta peptide APP intracellular domain neural stem cells neural progenitor cells neurogenesis signaling pathways

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Mechanisms of retinal neuroprotection of calcium dobesilate：therapeutic implications

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Neural Regeneration Research 2017年第10期12卷 1620-1622页

作者： Olga Simó-Servat Cristina Solà-Adell Patricia Bogdanov Cristina Hernández Rafael Simó Diabetes and Metabolism Research Unit Vall d'Hebron Research InstituteCIBERDEM(Instituto de Salud CarlosⅢ)BarcelonaSpain

Current treatments for diabetic retinopathy （DR） are based on laser photocoagulation and intravitreal injections of corti- costeroids or anti-vascular endothelial growth factor （VEGF） agents. These treatments are applicable only at advanced stages of the disease. In addition, they are expensive, require a vitreo- retinal specialist and are associated with significant adverse ef- fects. Therefore, new pharmacological treatments for the early stages of the disease are needed.

关键词： Ca Mechanisms of retinal neuroprotection of calcium dobesilate:therapeutic implications

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Intravitreal stem cell paracrine properties as a potential neuroprotective therapy for retinal photoreceptor neurodegenerative diseases

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Neural Regeneration Research 2020年第9期15卷 1631-1638页

作者： Kevin Puertas-Neyra Ricardo Usategui-Martín Rosa MCoco Ivan Fernandez-Bueno instituto Universitario de Oftalmobiologia Aplicada Universidad de ValladolidValladolidSpain Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y Leon ValladolidSpain Red Tematica de Investigacion Cooperativa en salud OftaredInstituto de Salud CarlosⅢValladolidSpain

Retinal degenerations are the leading causes of irreversible visual loss worldwide. Many pathologies included under this umbrella involve progressive degeneration and ultimate loss of the photoreceptor cells, with age-related macular degeneration and inherited and ischemic retinal diseases the most relevant. These diseases greatly impact patients' daily lives, with accompanying marked social and economic consequences. However, the currently available treatments only delay the onset or slow progression of visual impairment, and there are no cures for these photoreceptor diseases. Therefore, new therapeutic strategies are being investigated, such as gene therapy, optogenetics, cell replacement, or cell-based neuroprotection. Specifically, stem cells can secrete neurotrophic, immunomodulatory, and anti-angiogenic factors that potentially protect and preserve retinal cells from neurodegeneration. Further, neuroprotection can be used in different types of retinal degenerative diseases and at different disease stages, unlike other potential therapies. This review summarizes stem cell-based paracrine neuroprotective strategies for photoreceptor degeneration, which are under study in clinical trials, and the latest preclinical studies. Effective retinal neuroprotection could be the next frontier in photoreceptor diseases, and the development of novel neuroprotective strategies will address the unmet therapeutic needs.

关键词： clinical trials growth factors intraocular injection intravitreal injection neuroprotection paracrine properties photoreceptors preclinical models retinal diseases stem cells

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Physiological and pathological effects of amyloid-β species in neural stem cell biology

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Neural Regeneration Research 2019年第12期14卷 2035-2042页

作者： Adela Bernabeu-Zornoza Raquel Coronel Charlotte Palmer María Monteagudo Alberto Zambrano Isabel Liste Unidad de Regeneración Neural Unidad Funcional de Investigación de Enfermedades Crónicas. Instituto de Salud Carlos Ⅲ(ISCⅢ) Majadahonda Madrid Spain

Although amyloid-β peptide is considered neurotoxic, it may mediate several physiological processes during embryonic development and in the adult brain. The pathological function of amyloid-β peptide has been extensively studied due to its implication in Alzheimer’s disease, but its physiological function remains poorly understood. Amyloid-β peptide can be detected in non-aggregated (monomeric) and aggregated (oligomeric and fibrillary) forms. Each form has different cytotoxic and/or physiological properties, so amyloid-β peptide and its role in Alzheimer’s disease need to be studied further. Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer’s disease. In this review, we provide an outline of the effects of amyloid-β peptide, in monomeric and aggregated forms, on the biology of neural stem cells/neural precursor cells, and discuss the controversies. We also describe the possible molecular targets that could be implicated in these effects, especially GSK3β. A better understanding of amyloid-β peptide (both physiological and pathological), and the signaling pathways involved are essential to advance the field of Alzheimer’s disease.

关键词： amyloid-β peptide Aβ neural stem cells neural progenitor cells Alzheimer's disease amyloid precursor protein toxicity neurogenesis gliogenesis GSK3β

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SPINOPHILIN: A multiplayer tumor suppressor

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Genes & Diseases 2023年第1期10卷 187-198页

作者： Eva M.Verdugo-Sivianes Amancio Carnero instituto de Biomedicina de Sevilla IBISHospital Universitario Virgen del RocioConsejo Superior de Investigaciones CientificasUniversidad de SevillaSeville 41013Spain CIBERONC Instituto de Salud Carlos IlMadrid 28029Spain

SPINOPHILIN(SPN,PPP1R9B or NEURABIN-2)is a multifunctional protein that regulates protein-protein interactions in different cell signaling *** is also one of the regulatory subunits of protein phosphatase 1(PP1),implicated in the dephosphorylation of retinoblastoma protein(pRB)during cell *** SPN gene has been described as a tumor suppressor in different human tumor contexts,in which low levels of SPN are correlated with a higher grade and worse *** addition,mutations of the SPN protein have been reported in human ***,an oncogenic mutation of sPN,A566V,was described,which affects both the SPN-PP1 interaction and the phosphatase activity of the holoenzyme,and promotes p53-dependent tumorigenesis by increasing the cancer stem cell(CsC)pool in breast ***,the loss or mutation of SPN could be late events that promotes tumor progression by increasing the CSC pool and,eventually,the malignant behavior of the tumor.

关键词： Cancer therapy Phosphatase PP1 SPINOPHILIN Tumor suppressor Tumorigenesis

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Autochthonous Hepatitis E Virus Infection in Europe:A Matter of Concern for Public Health?

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Journal of Clinical and Translational Hepatology 2014年第1期2卷 7-14页

作者： José-Manuel Echevarría department of Virology National Centre of Microbiology Instituto de Salud Carlos Ⅲ Madrid Spain

Human hepatitis E virus (HHEV) is the proposed name for a diverse group of RNA viruses from the family Hepeviridae that cause acute hepatitis among *** strains are regularly imported into Europe by international travelers,and virus transmission of zoonotic strains via contaminated aliments is involved in autochthonous ***,in Europe,hepatitis E displays a unique dual character,having features of both imported and autochthonous *** involvement of waterborne and zoonotic diseases puts alimentary safety at *** addition,it may lead to serious health problems derived from persistent infection among patients with immune impairment due to organ transplant,cancer,or human immunodeficiency virus *** the European health authorities know at present that HHEV represents a problem worthy of consideration,the actual incidence of the disease in Europe is unknown,and attempts to ascertain the prevalence of the infection is hampered by unresolved technical *** order to determine the burden of hepatitis E in Europe,the World Health Organization Regional Office and the European Centre for Disease Prevention and Control should pay specific attention to hepatitis E,and research efforts in the continent should be transnational and *** of a specific European network for hepatitis E would help to achieve these goals.

关键词： Hepatitis Hepatitis E virus Epidemiology Europe Human

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Hepatoprotective effects of antioxidants in chronic hepatitis C

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World Journal of Gastroenterology 2010年第15期16卷 1937-1938页

作者： Ricardo Moreno-Otero María Trapero-Marugán Digestive Diseases Service and CIBEREHD (instituto de salud carlos ⅲ) University Hospital La Princesa Autonomous University of Ma-drid

We have read with interest the paper published in issue 2, volume 16 of World Journal of Gastroenterology 2010 by Nakamura et al, demonstrating that the antioxidant resveratrol (RVT) enhances hepatitis C virus (HCV) replication, consequently, they conclude that RVT is not a suitable antioxidant therapy for HCV chronic infection. The data raise some concern regarding the use of complementary and alternative medicine since the most frequent supplements taken by these patients are antioxidants or agents that may be beneficial for different chronic liver diseases. A recent study by Vidali et al on oxidative stress and steatosis in the progression of chronic hepatitis C concludes that oxidative stress and insulin resistance contribute to steatosis, thus accelerating the progression of fibrosis. We are particularly interested in investigating how the oxidative and nitrosative stress mechanisms are involved in the pathogenesis of different chronic liver diseases.

关键词： Antioxidant Chronic hepatitis C Resveratrol Sadenosylmethionine Nitric oxide Nacetylcysteine

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Implication of salivary lactoferrin and periodontal-mediated infections in Alzheimer's disease

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Neural Regeneration Research 2023年第12期18卷 2691-2692页

作者： Cristina Municio Eva Carro Group of Neurodegenerative Diseases Hospital Universitario 12 de Octubre Research Institute(imas12)MadridSpainNetwork Center for Biomedical Research in Neurodegenerative Diseases(CIBERNED)Instituto de Salud Carlos IIIMadridSpain Neurobiology of Alzheimer’s disease Unit Functional Unit for Research into Chronic DiseasesInstituto de Salud Carlos IIIMadridSpainNetwork Centre for Biomedical Research in Neurodegenerative Diseases(CIBERNED)Instituto de Salud Carlos IIIMadridSpain

Lactoferrin is an antimicrobial prote in characterized by the exertion of many protective functions,including antibacterial,antifungal,antiviral,and antiparasitic properties,as well as anti-inflammatory and immunomodulatory activities(Kruzel et al.,2017).Lactoferrin is one of the major proteins present in exocrine secretions,including saliva,and is therefore associated with host defense against oral pathogens and control of the oral *** recent years,it has become clear that alterations in the oral microbiome may contribute to opportunistic pathogen infections in the brains of Alzheimer’s disease(AD)patients and thus participate in or contribute to the development of this neurodegenerative disease(Sureda et al.,2020).Pathogenic oral microbes can affect neurological processes by entering brain tissue through various pathways and directly damaging the central nervous *** the central nervous system,oral microbes may trigger an immune response that increases amyloidβ(Aβ)production and may even trigger the Aβcascade to promote the onset of AD,as we discuss in our previous study supporting the“infectious hypothesis”in AD(González-Sánchez et al.,2020).

关键词： Alzheimer infections protective

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Aquaporin 5 in Alzheimer’s disease:a link between oral and brain pathology?

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Neural Regeneration Research 2023年第7期18卷 1491-1492页

作者： Cristina Municio Eva Carro Group of Neurodegenerative Diseases Hospital Universitario 12 de Octubre Research Institute(imas12)MadridSpain Network Center for Biomedical Research in Neurodegenerative Diseases(CIBERNED) Instituto de Salud Carlos IIIMadridSpain Neurobiology of Alzheimer’s Disease Unit Functional Unit for Research into Chronic DiseasesInstituto de Salud Carlos IIIMadridSpain

The involvement of aquaporins(AQPs)in the development of diseases has been widely described(Azad et al.,2021).AQP5 has been described in astrocytes changing after traumatic brain injuries(Chai et al.,2013),but the precise role of AQP5 in Alzheimer’s disease(AD)pathology is yet to be *** have recently reported that AQP5 expression changes during the development of AD(Antequera et al.,2022).The AQP5 expression in salivary glands is decreased in 6-month-old APP/PS1 mice and AD *** decrease in AQP5 expression could be involved in the mechanism of salivary gland dysfunction described in a previous study(Antequera et al.,2021).Now,we propose a new indirect role of AQP5 in the connection between infection-induced oral dysbiosis and AD(Sureda et al.,2020).Here,we suggest that the proinflammatory response induced by oral pathogen infection results in the downregulation of AQP5 contributing to the salivary gland secretory *** these alterations destabilize the peripheral immune-inflammatory balance and exacerbate neuroinflammation and neurodegeneration leading to AD pathology.

关键词： salivary pathology Alzheimer

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