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Modulation of the Nogo signaling pathway to overcome amyloid-β-mediated neurite inhibition in human pluripotent stem cell-derived neurites

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Neural Regeneration Research 2025年第9期20卷 2645-2654页

作者： Kirsty Goncalves Stefan Przyborski Department of biosciences Durham UniversityDurhamUK Reprocell Europe Ltd. GlasgowUK

Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer's *** accumulation of amyloid-βpeptides,a key hallmark of Alzheimer's disease,is believed to induce neuritic abnormalities,including reduced growth,extension,and abnormal growth cone morphology,all of which contribute to decreased ***,the precise cellular and molecular mechanisms governing this response remain *** this study,we used an innovative approach to demonstrate the effect of amyloid-βon neurite dynamics in both two-dimensional and three-dimensional cultu re systems,in order to provide more physiologically relevant culture *** utilized various methodologies,including the addition of exogenous amyloid-βpeptides to the culture medium,growth substrate coating,and the utilization of human-induced pluripotent stem cell technology,to investigate the effect of endogenous amyloid-βsecretion on neurite outgrowth,thus paving the way for potential future applications in personalized ***,we also explore the involvement of the Nogo signaling cascade in amyloid-β-induced neurite *** demonstrate that inhibition of downstream ROCK and RhoA components of the Nogo signaling pathway,achieved through modulation with Y-27632(a ROCK inhibitor)and Ibuprofen(a Rho A inhibitor),respectively,can restore and even enhance neuronal connectivity in the presence of amyloid-β.In summary,this study not only presents a novel culture approach that offers insights into the biological process of neurite growth and inhibition,but also proposes a specific mechanism for reduced neural connectivity in the presence of amyloid-βpeptides,along with potential intervention points to restore neurite ***,we aim to establish a culture system that has the potential to serve as an assay for measuring preclinical,predictive outcomes of drugs and their ability to promote neurite outgrowth,both generally and in a patie

关键词： Alzheimer's disease induced pluripotent stem cell neurite outgrowth neuron Nogo Rho A ROCK stem cell three-dimensional culture

Polyethylene glycol fusion repair of severed sciatic nerves accelerates recovery of nociceptive sensory perceptions in male and female rats of different strains

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Neural Regeneration Research 2025年第9期20卷 2667-2681页

作者： Liwen Zhou Karthik Venkudusamy Emily A.Hibbard Yessenia Montoya Alexa Olivarez Cathy Z.Yang Adelaide Leung Varun Gokhale Guhan Periyasamy Zeal Pathak Dale R.Sengelaub George D.Bittner Department of Neuroscience University of TexasAustinTXUSA Program in Neuroscience Indiana UniversityBloomingtonINUSA Department of Molecular biosciences University of TexasAustinTXUSA

Successful polyethylene glycol fusion(PEG-fusion)of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1)rapidly restore electrophysiological continuity;(2)prevent distal Wallerian Degeneration and maintain their myelin sheaths;(3)promote primarily motor,voluntary behavioral recoveries as assessed by the Sciatic Functional Index;and,(4)rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex(e.g.,toe twitch)or voluntary *** preceding companion paper describes sensory terminal field reo rganization following PEG-fusion repair of sciatic nerve transections or ablations;howeve r,sensory behavioral recovery has not been explicitly explored following PEG-fusion *** the current study,we confirmed the success of PEG-fusion surgeries according to criteria(1-3)above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis *** nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the *** von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve *** withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not *** thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated *** sciatic transection,all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the ***,PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative

关键词： autophagia axotomy collateral sprouting neuropathic pain peripheral nerve repair polyethylene glycol fusion(PEG-fusion) saphenous nerve sensory neurons sex and strain Wallerian degeneration

Polyethylene glycol has immunoprotective effects on sciatic allografts, but behavioral recovery and graft tolerance require neurorrhaphy and axonal fusion

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Neural Regeneration Research 2025年第4期20卷 1192-1206页

作者： Tyler A.Smith Liwen Zhou Cameron L.Ghergherehchi Michelle Mikesh Cathy Z.Yang Haley O.Tucker JuliAnne Allgood Jared S.Bushman George D.Bittner Department of Molecular biosciences University of Texas at AustinAustinTXUSA Department of Neuroscience University of Texas at AustinAustinTXUSA Division of Pharmaceutical Sciences University of WyomingLaramieWYUSA

Behavioral recovery using(viable)peripheral nerve allografts to repair ablation-type(segmental-loss)peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal ***,such peripheral nerve allografts undergo immunological rejection by the host immune *** contrast,peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks,reduced immune responses,and many axons do not undergo Wallerian *** relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this *** hypothesized that polyethylene glycol might have some immune-protective effects,but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral *** examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal ***-type sciatic nerve injuries in outbred Sprague–Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts,but peripheral nerve allografts were loose-sutured(loose-sutured polyethylene glycol)with an intentional gap of 1–2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host *** to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts,animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days *** morphological signs of rejection,such as col

关键词： allograft rejection axotomy macrophage myelin nerve repair polyethylene glycol(PEG) sciatic nerve T cell transplantation Wallerian degeneration

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

Tilting homeostatic and dyshomeostatic microglial balance in health and disease:transforming growth factor-beta1 as a critical protagonist

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Neural Regeneration Research 2025年第10期20卷 2895-2897页

作者： Nicolas Hugues Yu Luo Department of Molecular and Cellular biosciences University of CincinnatiCincinnatiOHUSA Neuroscience Graduate Program University of CincinnatiCincinnatiOHUSA Division of Immunobiology Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiOHUSA

Adult microglia,by continuously sensing changes in their environment and communicating with nearly all brain cell types,are considered to be the immune sentinels of the *** the healthy central nervous system(CNS),microglia display a unique molecular homeostatic signature(i.e.,Tmem119,P2ry12,Sall1,Siglech,Gpr34,and Hexb)(Figure 1A).

关键词： Figure signature critical

Dendritic Cells as a Pharmacological Target of Traditional Chinese Medicine

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Cellular & Molecular Immunology 2006年第6期3卷 401-410页

作者： Xin Chen Lu Yang O. M. Zack Howard Joost J. Oppenheim Basic Research Program SAIC-Frededck Inc. NCI-Frederick imquest biosciences Inc. 7340 Executive Way Frederick MD 21704 Laboratory of Molecular Immunoregulation Center for Cancer Research NCI-Frederick Frederick Maryland 21702-120

Dendritic cells （DCs） represent a heterogeneous population of professional antigen-presenting cells （APCs） that play a central role in the initiation and regulation of immune responses. There is considerable evidence that DCs can be used as therapeutic targets for pharmacological modulation of immune responses. Traditional Chinese medicine （TCM） has a long-standing history of using herbal medicine in the treatment of variety of human diseases. Many of the clinical effects of TCM have reportedly been attributed to the up- or down-regulation of immune responses. Accumulating evidence indicates that TCM and its components can interfere with immune responses at the earliest stage by targeting key functions of DCs. Here, we review those published studies of TCM with respect to their effects on immunobiological functions of DCs. Investigations based on both chemical entities derived from TCM as well as TCM herbal mixtures are presented. These studies suggest that various TCM herbal medicines have the capacity to inhibit or promote major functions of DCs, such as differentiation, maturation, cytokine production, survival, antigen uptake and presentation as well as trafficking. These studies have revealed novel biological effects of TCM and documented the utility of this approach to discover novel biological modifier of DC functions derived from natural sources.

关键词： dendritic cell traditional Chinese medicine

Mechanism of Cd(II) adsorption by macrofungus Pleurotus platypus

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Journal of Environmental Sciences 2011年第2期23卷 288-293页

作者： R.Vimala Nilanjana Das School of biosciences and Technology VIT University

The mechanism of Cd（Ⅱ） uptake by the dead biomass of macrofungus Pleurotus platypus was investigated using different chemical and instrumental techniques. Sequential removal of cell wall components of the biosorbent revealed that structural polysaccharides play a predominant role in the biosorption of Cd（Ⅱ）. The adsorption kinetics fitted well with the pseudo second-order model suggested that the adsorption of Cd（Ⅱ） on P. platypus involved a chemisorption process. Transmission electron microscopy of the cadmium exposed biomass confirmed the deposition of the metal mainly in the metal loaded biosorbent confirmed the participation of-OH, - the cell wall. Fourier transform infrared spectroscopic analysis of NH and C-O-C groups in the uptake of Cd（Ⅱ）. Energy dispersive X-ray analysis of the biosorbent before and after metal uptake revealed that the main mechanism of adsorption was ion-exchange. The effectiveness of CaCl2 in the desorption of cadmium perhaps suggested the exchange of Ca^2＋ with Cd（Ⅱ）.

关键词： biosorption mechanism ion-exchange Pleurotus platypus macrofungus cadmium

PEX16 contributions to peroxisome import and metabolism revealed by viable Arabidopsis pex16 mutants

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Journal of Integrative Plant Biology 2019年第7期61卷 853-870页

作者： Sarah E.Burkhart Roxanna J.Llinas Bonnie Bartel Department of biosciences Rice University

Peroxisomes rely on peroxins(PEX proteins) for biogenesis, importing membrane and matrix proteins, and fission. PEX16, which is implicated in peroxisomal membrane protein targeting and forming nascent peroxisomes from the endoplasmic reticulum(ER), is unusual among peroxins because it is inserted co-translationally into the ER and localizes to both ER and peroxisomal membranes. PEX16 mutations in humans, yeast, and plants confer some common peroxisomal defects; however, apparent functional differences have impeded the development of a unified model for PEX16 action. The only reported pex16 mutant in plants, the Arabidopsis shrunken seed1 mutant, is inviable,complicating analysis of PEX16 function after embryogenesis. Here, we characterized two viable Arabidopsis pex16 alleles that accumulate negligible PEX16 protein levels. Both mutants displayed impaired peroxisome function-slowed consumption of stored oil bodies, decreased import of matrix proteins, and increased peroxisome size. Moreover,one pex16 allele exhibited reduced growth that could be alleviated by an external fixed carbon source, decreased responsiveness to peroxisomally processed hormone precursors, and worsened or improved peroxisome function in combination with other pex mutants. Because the mutations impact different regions of the PEX16 gene, these viable pex16 alleles allow assessment of the importance of Arabidopsis PEX16 and its functional domains.

关键词： pex16 mutants peroxisome metabolism

The plant N-degron pathways of ubiquitinmediated proteolysis

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Journal of Integrative Plant Biology 2020年第1期62卷 70-89页

作者： Michael John Holdsworth Jorge Vicente Gunjan Sharma Mohamad Abbas Agata Zubrycka School of biosciences University of Nottingham

The amino-terminal residue of a protein(or amino-terminus of a peptide following protease cleavage)can be an important determinant of its stability,through the Ubiquitin Proteasome System associated N-degron *** contain a unique combination of N-degron pathways(previously called the N-end rule pathways)E3 ligases,PROTEOLYSIS(PRT)6 and PRT1,recognizing non-overlapping sets of amino-terminal residues,and others remain to be *** only very few substrates of PRT1 or PRT6 have been identified,substrates of the oxygen and nitric oxide sensing branch of the PRT6 N-degron pathway include key nuclear-located transcription factors(ETHYLENE RESPONSE FACTOR VIIs and LITTLE ZIPPER 2)and the histone-modifying Polycomb Repressive Complex 2 component VERNALIZATION *** response to reduced oxygen or nitric oxide levels(and other mechanisms that reduce pathway activity)these stabilized substrates regulate diverse aspects of growth and development,including response to flooding,salinity,vernalization(cold-induced flowering)and shoot apical meristem *** N-degron pathways show great promise for use in the improvement of crop performance and for biotechnological *** proteases,components of the different pathways and associated substrates still remain to be identified and characterized to fully appreciate how regulation of protein stability through the amino-terminal residue impacts plant biology.

关键词： stability residue cleavage