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Pathological and therapeutic effects of extracellular vesicles in neurological and neurodegenerative diseases

Neural Regeneration Research 2024年第1期19卷 55-61页

作者： Paula lzquierdo-Altarejos Victoria Moreno-Manzano Vicente Felipo Laboratory of Neurobiology Centro Investigación Príncipe FelipeValenciaSpain Neuronal and Tissue Regeneration Laboratory Centro Investigación Príncipe FelipeValenciaSpain

Extracellular vesicles are released by all cell types and contain proteins,microRNAs,mRNAs,and other bioactive molecules.Extracellular vesicles play an important role in intercellular communication and in the modulation of the immune system and neuroinflammation.The cargo of extra cellular vesicles(e.g.,proteins and microRNAs)is altered in pathological situations.Extracellular vesicles contribute to the pathogenesis of many pathologies associated with sustained inflammation and neuroinflammation,including cance r,diabetes,hype rammonemia and hepatic encephalopathy,and other neurological and neurodegenerative diseases.Extracellular vesicles may cross the blood-brain barrier and transfer pathological signals from the periphery to the brain.This contributes to inducing neuroinflammation and cognitive and motor impairment in hyperammonemia and hepatic encephalopathy and in neurodegenerative diseases.The mechanisms involved are beginning to be unde rstood.For example,increased tumor necrosis factor a in extracellular vesicles from plasma of hype rammonemic rats induces neuroinflammation and motor impairment when injected into normal rats.Identifying the mechanisms by which extracellular vesicles contribute to the pathogenesis of these diseases will help to develop new treatments and diagnostic tools for their easy and early detection.In contrast,extra cellular vesicles from mesenchymal stem cells have therapeutic utility in many of the above pathologies,by reducing inflammation and neuroinflammation and improving cognitive and motor function.These extra cellular vesicles recapitulate the beneficial effects of mesenchymal stem cells and have advantages as therapeutic tools:they are less immunoge nic,may not diffe rentiate to malignant cells,cross the blood-brain barrier,and may reach more easily target organs.Extracellular vesicles from mesenchymal stem cells have beneficial effects in models of ischemic brain injury,Alzheimer's and Parkinson's diseases,hyperammonemia,and hepatic encephalopathy.Extracellular vesicles f

关键词： extracellular vesicles inflammation cognitive function mesenchymal stem cells neurodegenerative diseases neuroinflammation therapy transforming growth factor-β

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Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy

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World Journal of Gastroenterology 2006年第48期12卷 7737-7743页

作者： Vicente Felipo Laboratory of Neurobiology Centro de Investigacion Principe Felipe Valencia Spain

Patients with liver disease may present hepatic enceph- alopathy (HE), a complex neuropsychiatric syndrome covering a wide range of neurological alterations, including cognitive and motor disturbances. HE reduces the quality of life of the patients and is associated with poor prognosis. In the worse cases HE may lead to coma or death. The mechanisms leading to HE which are not well known are being studied using animal models. The neurological alterations in HE are a consequence of impaired cerebral function mainly due to alterations in neurotransmission. We review here some studies indicating that alterations in neurotransmission associated to different types of glutamate receptors are responsible for some of the cognitive and motor alterations present in HE. These studies show that the function of the signal transduction pathway glutamate-nitric oxide-cGMP associated to the NMDA type of glutamate receptors is impaired in brain in vivo in HE animal models as well as in brain of patients died of HE. Activation of NMDA receptors in brain activates this pathway and increases cGMP. In animal models of HE this increase in cGMP induced by activation of NMDA receptors is reduced, which is responsible for the impairment in learning ability in these animal models. Increasing cGMP by pharmacological means restores learning ability in rats with HE and may be a new therapeutic approach to improve cognitive function in patients with HE. However, it is necessary to previously assess the possible secondary effects.Patients with HE may present psychomotor slowing, hypokinesia and bradykinesia. Animal models of HE also show hypolocomotion. It has been shown in rats with HE that hypolocomotion is due to excessive activation of metabotropic glutamate receptors (mGluRs) in substantia nigra pars reticulata. Blocking mGluR1 in this brain area normalizes motor activity in the rats, suggesting that a similar treatment for patients with HE could be useful to treat psychomotor slowing and hypokinesia. However, the possible secondary effec

关键词：信号转导谷氨酸盐肝性脑病神经

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Neuroinflammation and neurological alterations in chronic liver diseases

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Neuroimmunology and Neuroinflammation 2015年第1期2卷 138-144页

作者： Carmina Montoliu Marta Llansola Vicente Felipo Research Foundation of the Clinic Hospital of Valencia Health Research Institute-INCLIVA46010 ValenciaSpain Laboratory of Neurobiology Prince Felipe Research Center46012 ValenciaSpain

Several million people with chronic liver diseases(cirrhosis,hepatitis)show neurological alterations,named hepatic encephalopathy(HE)with cognitive and motor alterations that impair quality of life and reduces life span.Inflammation acts synergistically with hyperammonemia to induce cognitive and motor alterations in patients with chronic liver disease and minimal hepatic encephalopathy(MHE).Previous studies in animal models have suggested that neuroinflammation is a major player in HE.This would also be the case in patients with liver cirrhosis or hepatitis C with HE.Rats with MHE show microglial activation and neuroinflammation that is associated with cognitive impairment and hypokinesia.The anti-inflammatory drug ibuprofen reduces microglial activation and neuroinflammation and restores cognitive and motor functions in rats with MHE.Chronic hyperammonemia per se induces neuroinflammation.Both peripheral inflammation and hyperammonemia would contribute to neuroinflammation in chronic liver failure.Therefore,neuroinflammation may be a key therapeutic target to improve the cognitive and motor alterations in MHE and overt HE.Identifying new targets to reduce neuroinflammation in MHE without inducing secondary effects would serve to develop new therapeutic tools to reverse the cognitive and motor alterations in patients with HE associated with chronic liver diseases.

关键词： Cognitive impairment hepatic encephalopathy hyperammonemia inflammation motor function neuroinflammation

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Non invasive blood flow measurement in cerebellum detects minimal hepatic encephalopathy earlier than psychometric tests

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World Journal of Gastroenterology 2014年第33期20卷 11815-11825页

作者： Vicente Felipo Amparo Urios Carla Giménez-Garzó Omar Cauli Maria-Jesús Andrés-Costa Olga González Miguel A Serra Javier Sánchez-González Roberto Aliaga Remedios Giner-Durán vicente Belloch Carmina Montoliu Laboratory of Neurobiology Centro Investigación Príncipe Felipe 46012Valencia Spain Fundación Investigación Hospital Clínico de Valencia. Instituto de Investigación Sanitaria INCLIVA 46010 Valencia Spain Servicio DigestivoHospital Arnau de Vilanova 46015 Valencia Spain Grupo Hepatología Servicio Aparato Digestivo Hospital Clínico de Valencia 46010 Valencia Spain Philips Healthcare Iberia 28050 Madrid Spain ERESA Unidad RM 46015 Valencia Spain Departamento de Patología Facultad de Medicina Universidad de Valencia 46010 Valencia Spain

AIM: To assess whether non invasive blood flow measurement by arterial spin labeling in several brain regions detects minimal hepatic encephalopathy. METHODS: Blood flow(BF) was analyzed by arterial spin labeling(ASL) in different brain areas of 14 controls, 24 cirrhotic patients without and 16 cirrhotic patients with minimal hepatic encephalopathy(MHE). Images were collected using a 3 Tesla MR scanner(Achieva 3T-TX, Philips, Netherlands). Pulsed ASL was performed. Patients showing MHE were detected using the battery Psychometric Hepatic Encephalopathy Score(PHES) consisting of five tests. Different cognitive and motor functions were also assessed: alterations in selective attention were evaluated using the Stroop test. Patients and controls also performed visuo-motor and bimanual coordination tests. Several biochemical parameters were measured: serum pro-inflammatory interleukins(IL-6 and IL-18), 3-nitrotyrosine, cGMP and nitrates+nitrites in plasma, and blood ammonia. Bivariate correlations were evaluated.RESULTS: In patients with MHE, BF was increased in cerebellar hemisphere(P = 0.03) and vermis(P = 0.012) and reduced in occipital lobe(P = 0.017). BF in cerebellar hemisphere was also increased in patients without MHE(P = 0.02). Bimanual coordination was impaired in patients without MHE(P = 0.05) and much more in patients with MHE(P < 0.0001). Visuo-motor coordination was impaired only in patients with MHE(P < 0.0001). Attention was slightly affected in patients without MHE and more strongly in patients with MHE(P< 0.0001). BF in cerebellar hemisphere and vermis correlated with performance in most tests of PHES [(number connection tests A(NCT-A), B(NCT-B)and line tracing test] and in the congruent task of Stroop test. BF in frontal lobe correlated with NCT-A. Performance in bimanual and visuomotor coordination tests correlated only with BF in cerebellar hemisphere. BF in occipital lobe correlates with performance in the PHES battery and with CFF. BF in cerebellar hemisphere correlates with plasma cGMP and nitr

关键词： Arterial spin labelling Neurological impair-ment B

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Phosphate-activated glutaminase activity is enhanced in brain, intestine and kidneys of rats following portacaval anastomosis

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World Journal of Gastroenterology 2006年第15期12卷 2406-2411页

作者： Manuel Romero-Gómez María Jover Daniel Díaz-Gómez Laura Collantes de Terán Regina Rodrigo Inés Camacho Miriam Echevarría Vicente Felipo Juan D Bautista Unit for the Clinical Management of Digestive Diseases Hospital Universitario de Valme SevillaSpain Department of Biochemistry Bromatology and Toxicology Faculty of PharmacyUniversity of SevilleSpain Laboratory of Neurobiology Fundación Valenciana de Investigaciones Biomédicas ValenciaSpain Biochemistry Unit Hospital Universitario de Valme SevillaSpain Instituto de Investigaciones Biomédicas Departament of Physiology University of SevilleSpain Laboratory of Neurobiology Fundación Valenciana de Investigaciones Biomédicas ValenciaSpain

瞄准：估计在老鼠的门腔静脉吻合(PCA ) 是否在肾影响蛋白质表示或谷酰胺酶的活动，肠并且在外皮的三个大脑区域，基础轧了神经胶质和小脑并且解释在肝的脑病发现的神经病学的改变(他) 。方法：称 250-350 g 的十六只男 Wistar 老鼠被... 详细信息

瞄准：估计在老鼠的门腔静脉吻合(PCA ) 是否在肾影响蛋白质表示或谷酰胺酶的活动，肠并且在外皮的三个大脑区域，基础轧了神经胶质和小脑并且解释在肝的脑病发现的神经病学的改变(他) 。方法：称 250-350 g 的十六只男 Wistar 老鼠被组织进假冒操作的控制(n=8 ) 或 portacaval (n=8 ) 。在过程以后的 28 天，动物被牺牲。十二指肠，肾和大脑被移开， homogenised 和线粒体被孤立。氨在大脑和血被测量。激活磷酸盐的谷酰胺酶(PAG ) 活动被与 O-phthalaldehyde (OPA ) 和每蛋白质(蛋白质的 mukat/g ) 的克以单位表示的特殊活动在 37 摄氏度测量氨生产追随者孵化一个小时决定。蛋白质表示被弄污的免疫测量。结果：十二指肠并且和蛋白质内容的肾 PAG 活动比在 PCA 组是显著地更高的在控制或假冒操作老鼠(十二指肠 PAG 活动是在 PCA 老鼠对在假冒操作老鼠的蛋白质的 429.19+/-126.92mukat/g 的蛋白质的 976.95+/-268.87 mukat/g；肾 PAG 活动是在 PCA 老鼠对在控制的蛋白质的 669.67+/-400.8 mukat/g 的 1259.18+/-228.79 mukat/g 蛋白质， P<0.05；十二指肠的蛋白质内容：173% 在 PCA 对假冒操作老鼠；在肾，蛋白质的内容在 PCA 对假冒操作老鼠是 152%) 。在 PCA 老鼠的 PAG 活动和蛋白质表示在外皮是更高的并且基础在假冒操作老鼠比那些轧了神经胶质(外皮：蛋白质的 6646.6+/-1870.4 mukat/g 对在控制老鼠的蛋白质的 3573.8+/-2037.4 mukat/g， P<0.01；基础轧了神经胶质， PAG 活动是在 PCA 老鼠对在假冒的操作老鼠的蛋白质的 2271.2+/-384 mukat/g 的蛋白质的 3657.3+/-1469.6 mukat/g， P<0.05；在小脑，分别地， PAG 活动是蛋白质的 2471.6+/-701.4 mukat/g 对在 PCA 和假冒的老鼠的蛋白质的 1452.9+/-567.8 mukat/g P<0.05；蛋白质的内容：大脑皮质：162%+/-40% 对 100%+/-26% ， P<0.009；并且基础轧了神经胶质：140%+/-39% 对 100%+/-14% ， P<0.05；然而并非在里面小脑：100%+/-25% 对 100%+/-16% ， P=ns ) 。结论：在肾和十二指肠的增加的 PAG 活动能在 PCA 老鼠显著地作出贡献到 hyperammonaemia，脑病的动物模型。PAG 从外皮在 non-synaptic 线粒体被增加并且基础轧了神经胶质并且能在肝的脑病的致病被含有。因此， PAG 能是为处理的一个可能的目标他或肝机能障碍。

关键词：磷酸谷氨酰胺酶酶活性脑疾病门腔静脉吻合术

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Diversity and Phenology of the Braconid Community (Hymenoptera: Braconidae) in the Mediterranean Protected Landscape of Sierra Calderona (Spain)

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Open Journal of Ecology 2014年第4期4卷 174-181页

作者： Jose vicente Falcó-Garí Francisco Javier Peris-felipo Ricardo Jiménez-Peydró Laboratory of Entomology and Pest Control Institute Cavanilles of Biodiversity and Evolutionary Biology Valencia Spain

The diversity of the Braconidae subfamilies (Hymenoptera) in the protected landscape of the Natural Park of Sierra Calderona (Eastern Spain) is analysed. Samplings have been carried out along 2010 in three different habitats: almond crop, Oak forest (Quercus suber L.) and Pine forest (Pinus halepensis Miller). In total, 2166 braconid specimens, belonging to 23 subfamilies, have been captured. Alpha, beta and gamma diversities are analysed. As a result, almond crop habitat is proven to show the greatest diversity. The structure of the community and the phenology in each habitat are also analysed.

关键词： Braconidae Diversity Community Mediterranean Landscapes Spain

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PM_(2.5) chemical composition and health risks by inhalation near a chemical complex

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Journal of Environmental Sciences 2023年第2期124卷 860-874页

作者： Celia Alves Margarita Evtyugina Estela vicente Ana vicente Ismael Casotti Rienda Ana Sanchez de la Campa Mario Tome Iola Duarte Department of Environment Centre for Environmental and Marine Studies(CESAM)University of Aveiro3810-193 AveiroPortugal Associate Unit CSIC-University of Huelva“Atmospheric Pollution” Centre for Research in Sustainable Chemistry-CIQSOUniversity of HuelvaE21071 HuelvaSpain Department of Mining MechanicEnergetic and Construction EngineeringETSIUniversity of Huelva21071 HuelvaSpain PROMETHEUS School of Technology and Management(ESTG)Polytechnic Institute of Viana do Castelo4900-348 Viana do CasteloPortugal Department of Chemistry CICECO-Aveiro Institute of MaterialsUniversity of Aveiro3810-193 AveiroPortugal

Particulate matter(PM_(2.5))samples were collected in the vicinity of an industrial chemical pole and analysed for organic and elemental carbon(OC and EC),47 trace elements and around 150 organic constituents.On average,OC and EC accounted for 25.2% and 11.4% of the PM_(2.5) mass,respectively.Organic compounds comprised polycyclic aromatic hydrocarbons(PAHs),alkylated PAHs,anhydrosugars,phenolics,aromatic ketones,glycerol derivatives,aliphatic alcohols,sterols,and carboxyl groups,including aromatic,carboxylic and dicarboxylic acids.Enrichment factors>100 were obtained for Pb,Cd,Zn,Cu,Sn,B,Se,Bi,Sb and Mo,showing the contribution of industrial emissions and nearby major roads.Principal component analysis revealed that vehicle,industrial and biomass burning emissions accounted for 66%,11% and 9%,respectively,of the total PM_(2.5)-bound PAHs.Some of the detected organic constituents are likely associated with plasticiser ingredients and thermal stabilisers used in the manufacture of PVC and other plastics in the industrial complex.Photooxidation products of both anthropogenic(e.g.,toluene)and biogenic(e.g.,isoprene and pinenes)precursors were also observed.It was estimated that biomass burning accounted for 13.8%of the PM_(2.5) concentrations and that secondary OC represented 37.6% of the total OC.The lifetime cancer risk from inhalation exposure to PM_(2.5)-bound PAHs was found to be negligible,but it exceeded the threshold of 10−6 for metal(loi)s,mainly due to Cr and As.

关键词： PM_(2.5) OC/EC Organic speciation Trace elements Cancer and non-cancer risks

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A building energy models calibration methodology based on inverse modelling approach

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Building Simulation 2022年第11期15卷 1883-1898页

作者： vicente Gutiérrez González Carlos Fernández Bandera Installations construction and structuresSchool of ArchitectureUniversity of NavarraCampus UniversitarioPamplona31009NavarraSpain

Nowadays,building energy models(BEMs)are widely used,particularly in the assessment of energy consumption in buildings to address the potential savings that can be generated.The realisation of a dynamic energy model based on high-fidelity physics(white-box models)requires a tuning process to fit the model to reality,due to many uncertainties involved.Currently some research trends try to reduce this performance gap by modulating different types of experimental parameters such as:capacitances or infiltration.The EnergyPlus simulation software,in its latest versions,has implemented an object:HybridModel:Zone that calculates the infiltration and internal mass of buildings using an inverse modelling approach that employs only the measured indoor temperature data to invert the heat balance equation for the zone under study.The main objective of this paper is to reduce the execution time and uncertainties in the development of quality energy models by generating a new calibration methodology that implements this approach.This uses,as a starting point,a research created by the authors of this study,which was empirically and comparatively validated against the energy models developed by the participants in Annex 58.It is also worth highlighting the empirical validation of the HybridModel:Zone object,since it was activated in all scenarios where its execution is possible:periods of seven days or more of free oscillation and periods in which the building is under load.The findings are promising.The data generated with the new methodology,if compared with those produced by the baseline model,improve their resemblance to the real ones by 22.9%.While those of its predecessor did it by 15.6%.For this study,the two dwellings foreseen in Annex 58 of the IEA ECB project have been modelled and their real monitoring data have been used.

关键词： internal thermal mass energy simulation EnergyPlus inverse model Annex 58 infiltration

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Whole-rock geochemical, U-Pb and Sm-Nd isotope characteristics of the Dongueni Mont nepheline syenite intrusion, Mozambique

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地学前缘：英文版 2017年第5期8卷 1063-1071页

作者： vicente Albino Manjate Instituto Nacional de Minas Av24 de Julho 1895 Maputo Mozambique

The Dongueni Mont nepheline syenite intrudes migmatitic paragneisses and siliciclastic metasediments of the Barue Complex, Mozambique. This study reports the whole-rock geochemical, U-Pb and Nd isotopic data of the nepheline syenite. The ferroan and alkalic geochemical characteristics are typical of alkaline rocks formed in a within-plate setting. The strong depletion in high field strength elements(HFSEs)(e.g. Ba, Nb, P,and Ti) and enrichment in large ion lithophile elements(LILEs)(e.g. Rb, Th, K, and Pb) are consistent with magmatism in a continental alkaline magmatic province associated with intracontinental rifting. Zircon U-Pb data yielded crystallization ages from 498 ± 19 to 562± 14 Ma,consistent with the Pan-African Orogeny and the inherited zircons yield an age of 1040 Ma, which supports the presence of a Mesoproterozoic crust. Theε_(Nd)(t) values from the nepheline syenite samples range from-15.1 to-16.1 and the T_(DM)values from 1.77 to 1.67 Ga, which indicate that the initial nepheline syenite magma formed from a tholeiitic or mantle source in a within-plate setting with crustal assimilation.

关键词： Orogeny Geochronology Model age Nepheline syenite Crystallization

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How are children with medical complexity being identified in epidemiological studies?A systematic review

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World Journal of Pediatrics 2023年第10期19卷 928-938页

作者： Patrícia vicente Oliveira Carla C.Enes Luciana B.Nucci Postgraduate Program in Health Sciences Center for Life SciencesPontifical Catholic University of CampinasAv.John Boyd Dunlop s/nCampinasCEP 13060-904Brazil Postgraduate Program in Health Sciences School of NutritionPontifical Catholic University of CampinasSão PauloBrazil Postgraduate Program in Health Sciences School of MedicinePontifical Catholic University of CampinasSão PauloBrazil

Background There are different definitions to identify/classify children with medical complexity(CMC).We aimed to investigate and describe the definitions used to classify CMC in epidemiological studies.Methods PubMed,SciELO,LILACS,and EMBASE were searched from 2015 to 2020(last updated September 15th,2020)for original studies that presented the definition used to classify/identify CMC in the scientific research method.We applied the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology.From the included studies,the following were identified:first author,year of publication,design,population,study period,the definition of CMC used,limitations,and strengths.Results Nine hundred and sixty-seven records were identified in the searched databases,and 42 met the inclusion criteria.Of the 42 studies included,the four most frequent definitions used in the articles included in this review were classification of CMC into nine diagnostic categories based on the International Classification of Diseases,Ninth Revision(ICD-9)(35.7%,15 articles);update of the previous classification for ICD-10 codes with the inclusion of other conditions in the definition(21.4%,nine articles);definition based on a medical complexity algorithm for classification(16.7%,seven articles);and a risk rating system(7.1%,three articles).Conclusions CMC definitions using diagnostic codes were more frequent.However,several limitations were found in its uses.Our research highlighted the need to improve health information systems to accurately characterize the CMC population and promote the provision of comprehensive care.

关键词： Children with medical complexity Complex chronic conditions Epidemiologic studies Pediatrics Systematic review

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