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Highlights of ASS234: a novel and promising therapeutic agent for Alzheimer’s disease therapy

Neural Regeneration Research 2020年第1期15卷 30-35页

作者： Alejandro Romero JoséMarco-Contelles Eva Ramos Department of Pharmacology&Toxicology Faculty of Veterinary MedicineComplutense University of MadridMadridSpain Laboratory of Medicinal Chemistry Institute of General Organic Chemistry(CSIC)MadridSpain

There is no effective treatment to face Alzheimer’s disease complexity.Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression.In this context,N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine(ASS234)has been tested achieving promising results.ASS234 has demonstrated to cross the blood-brain barrier in vivo,and a good in silico safety profile being less toxic than donepezil.Besides,ASS234 reversibly inhibits human acetyl-and butyryl-cholinesterase,and irreversibly inhibits human monoamine oxidase A and B.Moreover,this multitarget molecule has antioxidant and neuroprotective properties,and inhibitsΑβ1–42 andΑβ1–40 self-aggregation.Inquiring about the mechanism of action,several signaling pathways related to Alzheimer’s disease had been explored showing that ASS234 induces the wingless-type MMTV integration site(Wnt)family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes.Finally,in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus,ameliorating scopolamine-induced learning deficits.Here we gather the information regarding ASS234 evaluated so far,showing its ability to face different targets,necessary to counteract a neurodegenerative disease as complex as the Alzheimer’s disease.

关键词： AChE BuChE gene expression heat shock proteins inflammation in silico toxicology MAO A/B neuroprotection oxidative stress Wnt signaling

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

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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 diseases.We identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 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 kinetics.Compound 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 disease.In 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 coordination.Importantly,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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What is the prognosis of emphysematous pyelonephritis associated with extended-spectrum beta-lactamases producing microorganisms?

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Asian Journal of Urology 2022年第2期9卷 146-151页

作者： joséIván Robles-Torres marco Alberto Ocaña-Munguía joséGustavo Arrambide-Herrera Adrián Mauricio Martínez-Fernández Rodrigo Romero-Mata Lauro Salvador Gómez-Guerra Urology Department Hospital Universitario"Dr.Jose´Eleuterio Gonza´lez"Universidad Auto´noma de Nuevo LeonMonterreyNuevo LeonMexico

Objective:To describe the microbiological characteristics in emphysematous pyelonephritis(EPN),demonstrate the frequency of extended-spectrum beta-lactamase(ESBL)microorganisms,and determine if these microorganisms are associated with the prognosis of patients with EPN.Methods:We conducted a retrospective study in patients with a diagnosis of EPN in a tertiary care hospital of the northeast region of Mexico during the period from January 2011 to January 2016.Clinical variables were analyzed to determine association with the presence of ESBL-producing microorganisms.Statistical significance was set with p<0.05.Results:A total of 63 patients were included;55(87.3%)of them were females,with a median age of 55(interquartile range:45-65)years.Conservative management was indicated in 38.1%;42.9%were treated with ureteral stent;12.7%with open or percutaneous drainage;15.8%with early nephrectomy;and 9.5%with delayed nephrectomy.Reported mortality was 13(20.6%)cases;23(36.5%)cases required admission to the intensive care unit.The most frequent microorganism isolated was Escherichia coli(n=34,53.9%).ESBL microorganisms were found in 31.7%of the population.No significant association of ESBL was found with admission to the intensive care unit,or with increased mortality.Conclusions:To our knowledge,this is the first study that evaluates ESBL microorganisms as a prognostic factor in EPN.Risk factors associated with a poor prognosis in patients with EPN have been described.The microbiological factors,specifically ESBL-producing bacteria,do not seem to influence in the prognosis of these patients.

关键词： Emphysematous pyelonephritis Extended spectrum betalactamase Mortality Intensive care unit admission

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Tissue-specific melt electrowritten polymeric scaffolds for coordinated regeneration of soft and hard periodontal tissues

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Bioactive Materials 2023年第1期19卷 268-281页

作者： Arwa Daghrery Jessica A.Ferreira Jinping Xu Nasim Golafshan Darnell Kaigler Sarit B.Bhaduri jos Malda Miguel Castilho marco C.Bottino Department of Cariology Restorative Sciencesand EndodonticsSchool of DentistryUniversity of MichiganAnn ArborMIUnited States Department of Restorative Dental Sciences School of DentistryJazan UniversityJazanKingdom of Saudi Arabia Department of Orthopedics University Medical Center UtrechtUtrechtthe Netherlands Regenerative Medicine Center Utrechtthe Netherlands Department of Periodontics and Oral Medicine School of DentistryUniversity of MichiganAnn ArborMIUnited States Department of Mechanical Industrial and Manufacturing EngineeringUniversity of ToledoToledoOHUnited States EEC Division Directorate of EngineeringThe National Science FoundationAlexandriaVAUnited States Department of Clinical Sciences Faculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands Department of Biomedical Engineering Eindhoven University of TechnologyEindhoventhe Netherlands Institute for Complex Molecular Systems Eindhoven University of TechnologyP.O.Box 5135600 MB Eindhoventhe Netherlands Department of Biomedical Engineering College of EngineeringUniversity of MichiganAnn ArborMIUnited States

Periodontitis is a chronic inflammatory condition that often causes serious damage to tooth-supporting tissues.The limited successful outcomes of clinically available approaches underscore the need for therapeutics that cannot only provide structural guidance to cells but can also modulate the local immune response.Here,three-dimensional melt electrowritten(i.e.,poly(ε-caprolactone))scaffolds with tissue-specific attributes were engineered to guide differentiation of human-derived periodontal ligament stem cells(hPDLSCs)and mediate macrophage polarization.The investigated tissue-specific scaffold attributes comprised fiber morphology(aligned vs.random)and highly-ordered architectures with distinct strand spacings(small 250μm and large 500μm).Macrophages exhibited an elongated morphology in aligned and highly-ordered scaffolds,while maintaining their round-shape on randomly-oriented fibrous scaffolds.Expressions of periostin and IL-10 were more pronounced on the aligned and highly-ordered scaffolds.While hPDLSCs on the scaffolds with 500μm strand spacing show higher expression of osteogenic marker(Runx2)over 21 days,cells on randomly-oriented fibrous scaffolds showed upregulation of M1 markers.In an orthotopic mandibular fenestration defect model,findings revealed that the tissue-specific scaffolds(i.e.,aligned fibers for periodontal ligament and highly-ordered 500μm strand spacing fluorinated calcium phosphate[F/CaP]-coated fibers for bone)could enhance the mimicking of regeneration of natural periodontal tissues.

关键词： Periodontitis Melt electrowriting 3D printing Inflammation Periodontal regeneration Scaffold

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Thermodynamic Dual Descriptor

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物理化学学报 2018年第6期34卷 683-691页

作者： FRANCO-PéREZ marco GáZQUEZ josé L. AYERS Paul W. VELA Alberto Departamento de Quimica Universidad Aut6noma Metropolitana-Iztapalapa Av. San Rafael Atlixco 186 Ciudad de Mexico 09340 Mexico. Department of Chemistry McMaster University Hamilton Ontario L8S 4M1 Canada. Departamento de Quimica Centro

A new definition of the dual descriptor,namely,thethermodynamic dual descriptor,is developed within the grand canonicalpotential formalism.This new definition is formulated to describe the same △f_r(r)=β/2C[f^+(r)-f^-(r)](C>0) physical phenomenon as the original definition proposed by Morell,Grand,and Toro-Labbé(J.Phys.Chem.A2005,109,205),which is characterized by a second-order response of the electron density towards an electron flux.To formulate the new definition,we performed two successive partial derivatives of the average electron density,one with respect to the average number of electrons,and the other with respect to the chemical potential of the electron reservoir.When the derivative is expressed in terms of the three-state ensemble model,in the regime of low temperatures up to temperatures of chemical interest,one finds that the thermodynamic dual descriptor can be expressed as?f_T(r)=(β/2)C[f^+(r)-f^-(r)],whereβ=1/k_BT,Cis a global quantity that depends on the temperature and global electronic properties of the molecule(the first ionization potential and the electron affinity),C=1 for systems with zero fractional charge,and C=C_ω>0(albeit very close to zero)for systems with nonzero fractional charge,,and f^+(r)and f^-(r)are the nucleophilic and electrophilic Fukui functions,respectively.The quantity within the square brackets is the original definition of the dual descriptor.As the local terms(the ones containing regioselectivity information)are equal to those of the dual descriptor,?f_T(r)has the same regioselectivity information,multiplied by the global quantity(β/2)C.This implies that the regioselectivity information contained in the original dual descriptor is preserved at all temperatures different from zero,and for any value of C>0.One of the most important features of this new definition is that it avoidsthe undesired Dirac delta behavior observed when the second order partial derivative of the average density is taken with respect to the average number of electrons,using the exact density depe

关键词： Dual descriptor Chemical stability Finite temperature chemical reactivity theory Fractional average number of electrons Amphiphilicity

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Activity-dependent remodeling of genome architecture in engram cells facilitates memory formation and recall

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Neural Regeneration Research 2022年第5期17卷 991-993页

作者： Asaf marco Neuro-Epigenetics Laboratory the Robert H.Smith Faculty of FoodEnvironment and Agriculturethe Hebrew University of JerusalemRehovol CampusIsrael

The formation and preservation of longterm memories critically depend upon coordinated activity of neuronal circuits,intracellular signaling cascades and synaptic remodeling(josselyn et al.,2015).These essential proce... 详细信息

关键词： remodeling ngram

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Measurement of vibration frequencies of ties in masonry arches by means of a robotic total station

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Earthquake Engineering and Engineering Vibration 2022年第2期21卷 489-500页

作者： marco Gatti Dipartimento di Ingegneria University of Ferraravia Saragat 144123 FerraraItaly

Measurement of the vibration frequencies of eight ties set in masonry arches of a church by means of a robotic total station is described.The instrument made continuous recordings(up to ten per second)of the three-dimensional positions of a reflector situated at 1/2 or 1/4 of the length of the tie during vertical oscillation induced by an impulsive load.The recording slips,vibration amplitudes(and their accuracy),hourly diagram and experimental spectra of vibrations,and the corresponding frequencies were calculated.The results were verified by comparing them with the vibration frequencies and indirectly the tension and fixed support constraint calculated from accelerometric measurements.The study provides interesting information on the accuracies of the reflector′s three-dimensional coordinates,but highlighted certain limits in the application of robotized total stations for measuring vibration frequencies of ties in masonry arches.

关键词： RTS frequency vibrations ties arches

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Overlapping approach Proton Pump Inhibitors/Nux vomica-Heel as new intervention for gastro-esophageal reflux management:Delphi consensus study

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World Journal of Gastroenterology 2024年第18期30卷 2467-2478页

作者： Edda Battaglia Luciano Bertolusso marco Del Prete marco Monzani marco Astegiano Gastroenterology Unit ASLTO4Ivrea 10015TurinItaly General Practitioner ASL CN2Alba-Bra 12051CuneoItaly Specialist in Nephrology International Academy of Physiological Regulating Medicine Milan 20100Italy Specialist in Endocrinology Territorial Social and Health Authority of BrianzaMonza 20900Italy Gastroenterology Specialist Retired from Gastroenterology and Hepatology UnitAOU Cittàdella Salute e della ScienzaTurin 10123Italy

BACKGROUND Gastro-esophageal reflux disease(GERD)may affect the upper digestive tract;up to 20%of population in Western nations are affected by GERD.Antacids,histamine H2-receptor antagonists,and Proton Pump Inhibitors(PPIs)are considered the referring medications for GERD.Nevertheless,PPIs must be managed carefully because their use,especially chronic,could be linked with some adverse effects.An effective and safe alternative pharmacological tool for GERD is needed.After the identification of potentially new medications to flank PPIs,it is mandatory to revise and improve good clinical practices even through a consensus process.AIM To optimize diagnosis and treatment guidelines for GERD through a consensus based on Delphi method.METHODS The availability of clinical studies describing the action of the multicomponent/multitarget medication Nux vomica-Heel,subject of the consensus,is the basic prerequisite for the consensus itself.A modified Delphi process was used to reach a consensus among a panel of Italian GERD specialists on the overlapping approach PPIs/Nux vomica-Heel as a new intervention model for the management of GERD.The Voting Consensus group was composed of 49 Italian Medical Doctors with different specializations:Gastroenterology,otolaryngology,geriatrics,and general medicine.A scientific committee analyzed the literature,determined areas that required investigation(in agreement with the multiple-choice questionnaire results),and identified two topics of interest:(1)GERD disease;and(2)GERD treatment.Statements for each of these topics were then formulated and validated.The Delphi process involved two rounds of questioning submitted to the panel experts using an online platform.RESULTS According to their routinary GERD practice and current clinical evidence,the panel members provided feedback to each questionnaire statement.The experts evaluated 15 statements and reached consensus on all 15.The statements regarding the GERD disease showed high levels of agreement,with consensus ranging from 70%to 92%.

关键词： Gastro-esophageal reflux disease Proton Pump Inhibitors Consensus Nux vomica-Heel Overlapping Decalage

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Comparative effects of different types of exercise on health-related quality of life during and after active cancer treatment:A systematic review and network meta-analysis

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Journal of Sport and Health Science 2023年第6期12卷 726-738页

作者： Vicente Martínez-Vizcaíno Iván Cavero-Redondo Sara Reina-Gutiérrez Luis Gracia-marco joséJGil-Cosano Bruno Bizzozero-Peroni Fernando Rodriguez-Artalejo Esther Ubago-Guisado Universidad de Castilla-La Mancha Health and Social Research CenterCuenca 16071Spain Facultad de Ciencias de la Salud Universidad Autónoma de ChileTalca 3460000Chile PROFITH(PROmoting FITness and Health through physical activity)Research Group Department of Physical Education and SportsFaculty of Sport SciencesSport and Health University Research Institute(iMUDS)University of GranadaGranada 18012Spain Higher Institute for Physical Education Universidad de la RepúblicaRivera 40000Uruguay Department of Preventive Medicine and Public Health School of MedicineUniversidad Autónoma de MadridMadrid 28029Spain IdiPaz(Instituto de Investigación Sanitaria Hospital Universitario La Paz) Madrid 28029Spain g Epidemiology and Control of Chronic Diseases CIBER of Epidemiology and Public Health(CIBERESP)Madrid 28029Spain Cancer Registry of Granada Escuela Andaluza de Salud PúblicaGranada 18011Spain Cancer Epidemiology Group Instituto de Investigación BiosanitariaGranada 18012Spain

Background The positive influence of most types of exercise has been reported repeatedly,but what the most effective exercise approaches are for improving health-related quality of life(HRQoL)in people with cancer remains unknown.The aim of this systematic review and network meta-analysis was to synthesize the evidence from intervention studies to assess the effects of different types of exercise on HRQoL during and after cancer treatment.Methods MEDLINE,SPORTDiscus,the Cochrane Library,Web of Science,and Scopus were searched for randomized controlled trials aimed at testing the effects of exercise interventions meant to improve HRQoL in people with cancer.Separate analyses were conducted for HRQoL as measured by general and cancer-specific questionnaires.We also evaluated whether the effects of exercise were different during and after cancer treatment in both the physical and mental HRQoL domains.Results In total,93 studies involving 7435 people with cancer were included.Network effect size estimates comparing exercise intervention vs.usual care were significant for combined exercise(0.35,95%confidence interval(95%CI):0.14–0.56)for HRQoL as measured by general questionnaires,and for combined(0.31,95%CI:0.13–0.48),mind–body exercise(0.54,95%CI:0.18–0.89),and walking(0.39,95%CI:0.04–0.74)for HRQoL as measured by cancer-specific questionnaires.Conclusion Exercise programs combining aerobic and resistance training can be recommended to improve HRQoL during and after cancer treatment.The scarcity and heterogeneity of these studies prevents us from making recommendations about other exercise modalities due to insufficient evidence.

关键词： Cancer Exercise HRQoL Physical activityTagedEnd

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Sarcoma stratification by combined pH2AX and MAP17(PDZK1IP1)levels for a better outcome on doxorubicin plus olaparib treatment

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Signal Transduction and Targeted Therapy 2020年第1期5卷 697-709页

作者： marco Perez joséManuel García-Heredia Blanca Felipe-Abrio Sandra Muñoz-Galván Javier Martín-Broto Amancio Carnero Instituto de Biomedicina de Sevilla(IBIS) Hospital Universitario Virgen del RocíoUniversidad de SevillaConsejo Superior de Investigaciones CientíficasSevillaSpain Ciber de Cancer IS Carlos IIIMadridSpain Departamento de Bioquímica Vegetal y Biología Molecular Universidad de SevillaSevillaSpain Departamento de Anatomía Patológica Hospital Universitario Virgen del RocíoSevillaSpain

Sarcomas constitute a rare heterogeneous group of tumors,including a wide variety of histological subtypes.Despite advances in our understanding of the pathophysiology of the disease,first-line sarcoma treatment options are still limited and new treatment approaches are needed.Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development.In this study,we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein,an inducer of DNA damage through ROS increase,as prognostic biomarkers in sarcoma tumors.Next,we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers.We evaluate retrospectively the levels of pH2AX(Ser139)and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features.We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival.Next,we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma.We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro,inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation,as a result of DNA damage.The synergism was corroborated in patient-derived xenografts(PDX)where the combination was effective in tumors with high levels of pH2AX and MAP17,suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.

关键词： H2AX doxorubicin treatment

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