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Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

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Neural Regeneration Research 2023年第12期18卷 2573-2581页

作者： sílvia sousa Chambel Célia Duarte Cruz Experimental Biology Unit Department of BiomedicineFaculty of Medicine of PortoUniversity of PortoPortoPortugal Translational NeuroUrology Instituto de Investigação e Inovação em Saúde-i3S and IBMCUniversidade do PortoPortoPortugal

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory prot

关键词： chondroitin sulphate proteoglycans collapsin response mediator protein 2 inhibitory molecules leucine-rich repeat and Ig domain containing 1 leucocyte common antigen related myelin-associated glycoprotein neurite outgrowth inhibitor A Nogo receptor 1 Nogo receptor 3 oligodendrocyte myelin glycoprotein p75 neurotrophin receptor Plexin A2 Ras homolog family member A/Rho-associated protein kinase receptor protein tyrosine phosphataseσ repulsive guidance molecule A spinal cord injury tumour necrosis factor receptor superfamily member 19

MYC and KRAs cooperation:from historical challenges to therapeutic opportunities in cancer

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signal Transduction and Targeted Therapy 2024年第9期9卷 3840-3869页

作者： sílvia Casacuberta-serra Íñigo González-Larreategui Daniel Capitán-Leo Laura soucek Peptomyc s.L. BarcelonaSpain Models of cancer therapies Laboratory Vall d’Hebron Institute of OncologyCellex CentreHospital University Vall d’Hebron CampusBarcelonaSpain InstitucióCatalana de Recerca i Estudis Avançats BarcelonaSpain Department of Biochemistry and Molecular Biology Universitat Autonoma de BarcelonaBellaterraSpain

RAs and MYC rank amongst the most commonly altered oncogenes in cancer,with RAs being the most frequently mutated and MYC the most *** cooperative interplay between RAs and MYC constitutes a complex and multifaceted phenomenon,profoundly influencing tumor *** and individually,these two oncogenes regulate most,if not all,hallmarks of cancer,including cell death escape,replicative immortality,tumor-associated angiogenesis,cell invasion and metastasis,metabolic adaptation,and immune *** to their frequent alteration and role in tumorigenesis,MYC and RAs emerge as highly appealing targets in cancer ***,due to their complex nature,both oncogenes have been long considered“undruggable”and,until recently,no drugs directly targeting them had reached the *** review aims to shed light on their complex partnership,with special attention to their active collaboration in fostering an immunosuppressive milieu and driving immunotherapeutic resistance in *** this review,we also present an update on the different inhibitors targeting RAs and MYC currently undergoing clinical trials,along with their clinical outcomes and the different combination strategies being explored to overcome drug *** recent clinical development suggests a paradigm shift in the long-standing belief of RAs and MYC“undruggability”,hinting at a new era in their therapeutic targeting.

关键词： therapeutic overcome Together

Revisiting cerebral endothelial cells in Alzheimer’s disease

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Neural Regeneration Research 2025年第10期20卷 2911-2912页

作者： Amira s.Hanafy Department of Neurosurgery University Hospital BonnBonnGermany

Alzheimer’s disease(AD)is the most common neurodegenerative disorder characterized by slow and progressive decline of cognitive and memory *** only approximately 5%of the cases,AD is familial,as often predisposed by genetic mutations(Hoogmartens et al.,2021),while sporadic AD accounts for approximately 95%of the *** amyloid cascade hypothesis is one of the fundamental hypotheses put out to explain AD pathogenesis as dysregulated homeostasis of amyloid-β(Aβ)peptides that leads to the accumulation of Aβplaques in the parenchyma,an anatomical hallmark of AD.

关键词： Alzheimer Aβ cerebral

Near-infrared leaf reflectance modeling of Annona emarginata seedlings for early detection of variations in nitrogen concentration

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Journal of Forestry Research 2023年第1期34卷 269-282页

作者： Rafaela Lancas Gomes Marília Caixeta sousa Felipe Girotto Campos Carmen sílvia Fernandes Boaro José Raimundo de souza Passos Gisela Ferreira Bioestatistic Plant BiologyParasitology and Zoology DepartmentBioscience Institute(IBB)Universidade Estadual Paulista(UNESP)BotucatuSao PauloBrazil

Nitrogen(N)monitoring is essential in nurseries to ensure the production of high-quality *** spectroscopy(NIRs)is an instantaneous,nondestructive method to monitor *** data such as NIRs can also provide the basis for developing a new vegetation spectral index(VsI).Here,we evaluated whether NIRs combined with statistical modeling can accurately detect early variations in N concentration in leaves of young plants of Annona emargiaata and developed a new VsI for this *** were grown in a hydroponics system with 0,2.75,5.5or 11 mM N for 45 *** we measured gas exchange,chlorophylla fluorescence,and pigments in leaves;analyzed complete leaf nutrients,and recorded spectral data for leaves at 966 to 1685 nm using *** a statistical learning approach,the dimensionality of the spectral data was reduced,then models were generated using two classes(N deficiency,N)or four classes(0,2.75,5.5,11 mM N).The best combination of techniques for dimensionality reduction and classification,respectively,was stepwise regression(PROC sTEPDIsC)and linear discriminant *** was possible to detect N deficiency in seedlings leaves with 100%precision,and the four N concentrations with93.55%accuracy before photosynthetic damage to the plant ***,NIRs combined with statistical modeling of multidimensional data is effective for detecting N variations in seedlings leaves of ***.

关键词： Mineral nutrition of plants Near-infrared spectroscopy spectral vegetation index Digital signature statistical learning Fluorescence of chlorophylla

A systematic review of progenitor survival and maturation in Parkinsonian models

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Neural Regeneration Research 2025年第11期20卷 3172-3178页

作者： Giulia Comini Eilís Dowd Pharmacology&Therapeutics and Galway Neuroscience Center University of GalwayGalwayIreland

stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell *** current therapeutic options for patients,this approach has the potential to provide longterm stem cell–derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to *** ultimate clinical success of stem cell–derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian *** the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies,the aim of this systematic review was to assess these parameters in human stem cell-derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease.A defined systematic search of the PubMed database was completed to identify relevant studies published up to March *** screening,76 articles were included in the analysis from which 178 separate transplant studies were *** these,graft survival could be assessed in 52 studies and differentiation in 129 ***,we found that graft survival ranged froms transplanted,with a median of 51%of transplanted cells surviving in the brain;while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%.This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell-derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.

关键词： cell replacement therapy differentiation embryonic stem cells graft induced pluripotent stem cells Parkinson's disease survival transplant

Deciphering the mechanobiology of microglia in traumatic brain injury with advanced microsystems

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Neural Regeneration Research 2025年第8期20卷 2304-2306页

作者： Anthony Procès sylvain Gabriele Univ.Grenoble Alpes InsermU1216Grenoble Institut des NeurosciencesGrenobleFrance Mechanobiology&Biomaterials Group CIRMAPResearch Institute for BiosciencesUniversity of MonsMonsBelgium

Advanced microsystems in traumatic brain injury research:Traumatic brain injury(TBI)results from a mechanical insult to the brain,leading to neuronal and axonal damage and subsequently causing a secondary *** minutes ... 详细信息

关键词： traumatic injury damage

Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael s.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-stay-Trim,”“sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

Radiation and concomitant chemotherapy for patients with glioblastoma multiforme

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Chinese Journal of Cancer 2014年第1期33卷 25-31页

作者： salvador Villà Carme Balaà sílvia Comas Radiation Oncology Catalan Institute of Oncology HU Germans TriasBadalona 08916 Catalonia Spain Medical Oncology Catalan Institute of Oncology HU Germans TriasBadalona 08916 Catalonia Spain

Postoperative external beam radiotherapy was considered the standard adjuvant treatment for patients with glioblastoma multiforme until the advent of using the drug temozolomide(TMZ) in addition to radiotherapy. High-dose volume should be focal, minimizing whole brain irradiation. Modern imaging, using several magnetic resonance sequences, has improved the planning target volume definition. The total dose delivered should be in the range of 60 Gy in fraction sizes of 1.8-2.0 Gy. Currently, TMZ concomitant and adjuvant to radiotherapy has become the standard of care for glioblastoma multiforme patients. Radiotherapy dose-intensification and radiosensitizer approaches have not improved the outcome. In spite of the lack of high quality evidence, stereotactic radiotherapy can be considered for a selected group of patients. For elderly patients, data suggest that the same survival benefit can be achieved with similar morbidity using a shorter course of radiotherapy(hypofractionation). Elderly patients with tumors that exhibit methylation of the O-6-methylguanine-DNA methyltransferase promoter can benefit from TMZ alone.

关键词：母细胞患者放疗胶质多形性 DNA甲基转移酶化疗放射治疗

Evaluation of the effectiveness of horizontal subsurface flow constructed wetlands for different media

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Journal of Environmental sciences 2010年第6期22卷 820-825页

作者： Antonio Albuquerque José Oliveira sabrina semitela Leonor amaral Department of Civil Engineering and Architecture and C-MADE University of Beira Interior Municipality of Penamacor Department of sciences and Environmental Engineering Faculty of Sciences and TechnologyNew University of Lisbon

Two media bed （gravel and Filtralite NR） were tested in a mesocosm to evaluate the removal of organic matter （as chemical oxygen demand （COD））, ammonia （NH4-N）, nitrite, nitrate and solid matter （as total suspended solids （Tss）） for a synthetic wastewater （acetate-based） and a domestic wastewater. The use of Filtralite allowed average removal rates （6--16.8 g COD/（m^2·day）, 0.8-1.1 g NH4-N/（m^2·day） and 3.1 g Tss/（m^2·day）） and removal efficiencies （65%-93%, 57%-85% and 78% for COD, NH4-N and Tss, respectively）, higher than that observed in the experiments with gravel. The applied loads of COD, ammonia, nitrate and Tss seem to influence the respective removal rates but only for the treatment of domestic wastewater with nigher correlation coefficients for Filtralite. Regardless the type of media bed and the type of wastewater, nitrate was completely removed for nitrogen loading rates up to 1.3 g NO3-N/（m^2·day）. There was no evidence of the influence of nitrate loads on the removal of organic matter.

关键词： media bed constructed wetlands pollutants removal rates