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8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

Acta Pharmaceutica Sinica B 2023年第5期13卷 2152-2175页

作者： Damijan Knez daniel diez-iriepa Mourad Chioua Andrea Gottinger Milica Denic Fabien Chantegreil Florian Nachon Xavier Brazzolotto Anna Skrzypczak-Wiercioch Ane Meden Anja Pilar Janko Kos Simon akelj Jure Stojan Kinga Saat Julia Serrano Ana Patricia Fernández Aitana Sánchez-García Ricardo Martínez-Murillo Claudia Binda Francisco López-Muoz Stanislav Gobec JoséMarco-Contelles University of Ljubljana Faculty of PharmacyLjubljana 1000Slovenia Laboratory of Medicinal Chemistry(Institute of Organic Chemistry CSIC)Madrid 28006Spain Departamento de Química Orgánicay Química Inorgánica Alcaláde HenaresMadrid 28871Spain Department of Biology and Biotechnology University of PaviaPavia 27100Italy Département de Toxicologie et Risques Chimiques Institut de Recherche Biomédicale des ArméesParis 91220France Department of Animal Anatomy and Preclinical Sciences University Centre of Veterinary Medicine JU-UAUniversity of Agriculture in KrakowKrakow 30-059Poland Institute of Biochemistry Faculty of MedicineUniversity of LjubljanaLjubljana 1000Slovenia Department of Pharmacodynamics Chair of PharmacodynamicsFaculty of PharmacyJagiellonian University Medical CollegeKrakow 30-688Poland Department of Translational Neurobiology Neurovascular Research GroupCajal Institute(CSIC)Madrid 28002Spain Biotechnology and Vegetal Biology Department Escuela Técnica Superior de Ingeniería AgronómicaAlimentaria y de BiosistemasUniversidad Politécnica de MadridMadrid 28040Spain Faculty of Health Camilo JoséCela University of Madrid(UCJC)Neuropsychopharmacology Unit“Hospital 12 de Octubre”Research InstituteMadrid 28692Spain

We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative *** identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available *** 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme *** 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's *** addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and ***,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of QN 19.

关键词： Quinolylnitrone Butyrylcholinesterase Monoamine oxidase B Alzheimer's disease Multifunctional ligands 6-Hydroxydopamine model Passive avoidance task Novel object recognition

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Gastric polyps are not created equal: Know your enemy

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World Journal of Gastroenterology 2025年第2期31卷 144-146页

作者： Fady daniel Department of Gastroenterology and Hepatology American University of Beirut Medical CenterBeirut 11072020Lebanon

Gastric polyps are commonly detected during upper gastrointestinal *** are most often benign and rarely become ***,adequate knowledge,diagnostic modalities,and management strategies should be the endoscopist’s readily available“weapons”to defeat the potentially malignant“enemies”.This article sheds light on the valuable effort by Costa et al to generate a new classification system of gastric polyps as“good”,“bad”,and“ugly”.This comprehensive overview provides clinicians with a simplified decision-making process.

关键词： Gastric polyps Polypoid subepithelial lesions Early gastric cancer Endoscopic ultrasonography Electronic chromoendoscopy

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Amyloid-β-induced disruption of axon-initial-segment mitochondria localization:consequences for TAU missorting in Alzheimer's disease pathology

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Neural Regeneration Research 2025年第5期20卷 1407-1408页

作者： daniel Adam Felix Langerscheidt Hans Zempel Institute of Human Genetics University Hospital CologneCologneGermany Center for Molecular Medicine Cologne(CMMC) University of CologneCologneGermany

TAU is a neuronal microtubule-associated protein preferentially located in *** a battery of neurodegenerative diseases termed"tauopathies,"including Alzheimer's disease (AD),TAU is missorted and abnormally phosphorylated,leading to filamentous accumulations of hyperphosphorylated TAU,a pathological hallmark and potential disease driver of AD and related tauopathies (Zempel,2024).

关键词： Alzheimer tau diseases

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Vascular endothelial growth factor:a double-edged sword in the development of white matter lesions

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Neural Regeneration Research 2025年第1期20卷 191-192页

作者： Narek Manukjan daniel Fulton Zubair Ahmed WMatthijs Blankesteijn Sébastien Foulquier Department of Pharmacology and Toxicology Maastricht UniversityMaastrichtThe Netherlands CARIM-School for Cardiovascular Diseases Maastricht UniversityMaastrichtThe Netherlands Neuroscience and Ophthalmology Institute of Inflammation and AgeingUniversity of BirminghamEdgbastonBirminghamUK Centre for Trauma Sciences Research University of BirminghamEdgbastonBirminghamUK MHeNs-School for Mental Health and Neuroscience Maastricht UniversityMaastrichtThe Netherlands Department of Neurology Maastricht University Medical CenterMaastrichtThe Netherlands

As the population ages,the burden of age-related diseases becomes ***,over 55 million people suffer from dementia worldwide,with Alzheimer’s disease being the most common ***,it is becoming clearer that underlying vascular pathology such as cerebral small vessel disease(cSVD)may be a more detrimental cause for dementia(Cuadrado-Godia et al.,2018).It is estimated that 10%-30%of the elderly population and 35%-90%of all dementia patients exhibit signs of *** term cSVD refers to pathology affecting the small vessels of the brain,which can lead to lacunar cerebral infarcts,enlarged perivascular spaces,and cortical hemorrhages(Cuadrado-Godia et al.,2018).CSVD is often associated with cognitive decline,gait problems,and dementia(Cuadrado-Godia et al.,2018).

关键词： pathology becoming white

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Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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Neural Regeneration Research 2025年第5期20卷 1324-1335页

作者： Hassan Saad Bachar El Baba Ali Tfaily Firas Kobeissy Juanmarco Gutierrez Gonzalez daniel Refai Gerald R.Rodts Christian Mustroph David Gimbel Jonathan Grossberg daniel L.Barrow Matthew F.Gary Ali M.Alawieh Department of Neurosurgery Emory University School of MedicineAtlantaGAUSA Department of Neurology Yale UniversityNew HavenCTUSA Center for Neurotrauma Multiomics&Biomarkers(CNMB)Morehouse School of MedicineAtlantaGAUSA

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this *** the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing *** this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the *** study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular *** effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord *** this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human *** review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

关键词： complement neuroinflammation neuroplasticity regeneration spinal cord injury targeted therapy

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Dysregulation of genes involved in the long-chain fatty acid transport in pancreatic ductal adenocarcinoma

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World Journal of Gastrointestinal Oncology 2025年第1期17卷 199-206页

作者： Radu Cristian Poenaru Elena Milanesi Andrei Marian Niculae Anastasia-Maria Dobre Catalina Vladut Mihai Ciocîrlan daniel Vasile Balaban Vlad Herlea Maria Dobre Mihail Eugen Hinescu Faculty of Medicine Carol Davila University of Medicine and PharmacyBucharest 050474Romania Department of Radiobiology Victor Babes National Institute of PathologyBucharest 050096Romania Department of Pathology Victor Babes National Institute of PathologyBucharest 050096Romania Department of Gastroenterology Prof.Dr.Agrippa Ionescu Clinical Emergency HospitalBucharest 011356Romania Department of Pathology Fundeni Clinical InstituteBucharest 022258Romania

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is an aggressive lethal malignancy with limited options for treatment and a 5-year survival rate of 11%in the United *** for other types of tumors,such as colorectal cancer,aberrant de novo lipid synthesis and reprogrammed lipid metabolism have been suggested to be associated with PDAC development and *** To identify the possible involvement of lipid metabolism in PDAC by analyzing in tumoral and non-tumoral tissues the expression level of the most relevant genes involved in the long-chain fatty acid(FA)import into *** A gene expression analysis of FASN,CD36,SLC27A1,SLC27A2,SLC27A3,SLC27A4,SLC27A5,ACSL1,and ACSL3 was performed by qRT-PCR in 24 tumoral PDAC tissues and 11 samples from non-tumoral pancreatic tissues obtained via fine needle aspiration or via surgical *** genes were considered significantly dysregulated between the groups when the p value was<0.05 and the fold change(FC)was≤0.5 and≥*** We found that three FA transporters and two long-chain acyl-CoA synthetases genes were significantly upregulated in the PDAC tissue compared to the non-tumoral tissue:SLC27A2(FC=5.66;P=0.033),SLC27A3(FC=2.68;P=0.040),SLC27A4(FC=3.13;P=0.033),ACSL1(FC=4.10;P<0.001),and ACSL3(FC=2.67;P=0.012).We further investigated any possible association between the levels of the analyzed mRNAs and the specific characteristics of the tumors,including the anatomic location,the lymph node involvement,and the presence of metastasis.A significant difference in the expression of SLC27A3(FC=3.28;P=0.040)was found comparing patients with and without lymph nodes involvement with an overexpression of this transcript in 17 patients presenting tumoral cells in the lymph *** Despite the low number of patients analyzed,these preliminary results seem to be *** lipid metabolism through a broad strategy could be a beneficial way to treat this *** in vitro and in vivo s

关键词： Carcinoma Pancreatic ductal Fatty acid transport Gene expression Biomarkers

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Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis,learning,and memory in a mouse model of Alzheimer’s disease

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Neural Regeneration Research 2025年第10期20卷 2969-2981页

作者： Mackenzie M.Spicer Jianqi Yang daniel Fu Alison N.DeVore Marisol Lauffer Nilufer S.Atasoy Deniz Atasoy Rory A.Fisher Department of Neuroscience and Pharmacology University of Iowa Carver College of MedicineIowa CityIAUSA Iowa Neuroscience Institute University of Iowa Carver College of MedicineIowa CityIAUSA Interdisciplinary Graduate Program in Molecular Medicine University of Iowa Carver College of MedicineIowa CityIAUSA Neural Circuits and Behavior Core University of Iowa Carver College of MedicineIowa CityIAUSA

Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s *** hippocampal neurogenesis is reduced in patients with Alzheimer’s *** stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s ***,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly ***,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in ***,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse *** found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control *** cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal *** hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor ***6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing ***,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.

关键词： adult hippocampal neurogenesis Alzheimer’s disease dentate gyrus exercise learning/memory neural precursor cells regulator of G protein signaling 6(RGS6)

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区域创新系统的管治框架演化——来自深圳和东莞的对比实证

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人文地理 2013年第4期28卷 83-88页

作者：符文颖 Javier Revilla diez daniel Schiller 华南师范大学地理科学学院广州510631 德国汉诺威大学经济与文化地理系汉诺威30167 德国下萨克森州经济研究所汉诺威30175

本文在电子企业问卷调查的基础上,对比分析深圳和东莞的区域创新机制,并进一步从管治角度构建区域创新机制差异的理论框架,在中国转型的体制背景下阐释管治的演化逻辑。结果显示,改革开放初期自上而下的管治模式相对于自下而上的管治,... 详细信息

本文在电子企业问卷调查的基础上,对比分析深圳和东莞的区域创新机制,并进一步从管治角度构建区域创新机制差异的理论框架,在中国转型的体制背景下阐释管治的演化逻辑。结果显示,改革开放初期自上而下的管治模式相对于自下而上的管治,在各自向网络化管治模式演化的过程中,由于先发制度优势和组织能力禀赋,更能顺利的推动工业基础薄弱地区向区域创新系统的转变。最后指出,演化视角分析必须注重时间和地理的特殊性。

关键词：管治自上而下自下而上区域创新系统演化

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探讨香港-珠江三角洲的联系：跨界的制度多样性如何促进电子企业的竞争力

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南方经济 2010年第5期39卷 69-80页

作者： Javier Revilla diez daniel Schiller Susanne Meyer 符文颖 Institute of Economic and Cultural Geography Leibniz University of Hanover 德国汉诺威大学经济与文化地理系

基于灵活性的假设下,香港和珠三角两地的企业问卷调查表明,为了应对商业环境变化对灵活性的需求,香港客户对珠三角供应商关系调整了管治模式,逐渐采取股权或非股权合作代替原先的完全控股。而在香港企业寻找新的客户、选择适当的生产合... 详细信息

基于灵活性的假设下,香港和珠三角两地的企业问卷调查表明,为了应对商业环境变化对灵活性的需求,香港客户对珠三角供应商关系调整了管治模式,逐渐采取股权或非股权合作代替原先的完全控股。而在香港企业寻找新的客户、选择适当的生产合作伙伴方面,正式和非正式制度之间存在互补性。研究结果证实,在现有的正式制度框架内充分应用非正式因素,可提高企业更灵活应对政治和商业环境迅速变化的能力,以维持在全球市场的竞争力。

关键词：灵活企业组织非正式制度

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Kernel-Based State-Space Kriging for Predictive Control

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IEEE/CAA Journal of Automatica Sinica 2023年第5期10卷 1263-1275页

作者： A.daniel Carnerero daniel R.Ramirez daniel Limon Teodoro Alamo the Department of System Engineering and Automation University of SevilleSevilla 41020Spain the School of Engineering Tokyo Institute of TechnologyTokyo 152-8552Japan Department of System Engineering and Automation University of SevilleSevilla 41020Spain

In this paper, we extend the state-space kriging(SSK) modeling technique presented in a previous work by the authors in order to consider non-autonomous systems. SSK is a data-driven method that computes predictions as linear combinations of past outputs. To model the nonlinear dynamics of the system, we propose the kernel-based state-space kriging(K-SSK), a new version of the SSK where kernel functions are used instead of resorting to considerations about the locality of the data. Also, a Kalman filter can be used to improve the predictions at each time step in the case of noisy measurements. A constrained tracking nonlinear model predictive control(NMPC) scheme using the black-box input-output model obtained by means of the K-SSK prediction method is proposed. Finally, a simulation example and a real experiment are provided in order to assess the performance of the proposed controller.

关键词： Data-driven methods model identification Kernel methods predictive control

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