Small fiber polyneuropathy is a well-recognized syndrome mitigated by somatic sensory afferent and autonomic efferent nerve fibers that respectively mediate pain, heat and cold temperature afferent and autonomic effer...Small fiber polyneuropathy is a well-recognized syndrome mitigated by somatic sensory afferent and autonomic efferent nerve fibers that respectively mediate pain, heat and cold temperature afferent and autonomic efferent function in the skin. A patient with low serum titers of neuronal acetylcholine receptor ganglionic antibodies and autonomic failure had symptomatic small fiber polyneuropathy late in life in the setting of autoimmune dementia and encephalopathy and prostate cancer. Large and small fiber polyneuropathy and dysautonomia were detected in routine electrodiagnostic and autonomic laboratory studies, and epidermal nerve fiber analysis of the calf and thigh. Clinical improvement for one year concomitant with intravenous immune globulin therapy preceded?a?clinical?decline in neurocognitive function and death. Postmortem examination showed typical features of Alzheimer disease with neuropathic neuropathological changes in the peripheral nervous system,?and viable autonomic ganglia consistent with a channelopathy mechanism involving postsynaptic neuronal nAChRs.展开更多
BACKGROUND A large ganglionic cyst extending from the hip joint to the intrapelvic cavity through the sciatic notch is a rare space-occupying lesion associated with compressive lower-extremity neuropathy.A cyst in the...BACKGROUND A large ganglionic cyst extending from the hip joint to the intrapelvic cavity through the sciatic notch is a rare space-occupying lesion associated with compressive lower-extremity neuropathy.A cyst in the pelvic cavity compressing the intrapelvic-sciatic nerve is easily missed in the diagnostic process because it usually presents as atypical symptoms of an extraperitoneal-intrapelvic tumor.We present a case of a huge ganglionic cyst that was successfully excised laparoscopically and endoscopically by a gynecologist and an orthopedic surgeon.CASE SUMMARY A 52-year-old woman visited our hospital complaining of pain and numbness in her left buttock while sitting.The pain began 3 years ago and worsened,while the numbness in the left lower extremity lasted 1 mo.She was diagnosed and unsuccessfully treated at several tertiary referral centers many years ago.Magnetic resonance imaging revealed a suspected paralabral cyst(5 cm×5 cm×4.6 cm)in the left hip joint,extending to the pelvic cavity through the greater sciatic notch.The CA-125 and CA19-9 tumor marker levels were within normal limits.However,the cyst was compressing the sciatic nerve.Accordingly,endoscopic and laparoscopic neural decompression and mass excision were performed simultaneously.A laparoscopic examination revealed a tennis-ball-sized cyst filled with gelatinous liquid,stretching deep into the hip joint.An excisional biopsy performed in the pelvic cavity and deep gluteal space confirmed the accumulation of ganglionic cysts from the hip joint into the extrapelvic intraperitoneal cavity.CONCLUSION Intra-or extra-sciatic nerve-compressing lesion should be considered in cases of sitting pain radiating down the ipsilateral lower extremity.This large juxta-articular ganglionic cyst was successfully treated simultaneously using laparoscopy and arthroscopy.展开更多
The number and diversity of inhibitory neurons(INs)increased substantially during mammalian brain evolution.However,the generative mechanisms of the vast repertoire of human INs remain elusive.We performed spatial and...The number and diversity of inhibitory neurons(INs)increased substantially during mammalian brain evolution.However,the generative mechanisms of the vast repertoire of human INs remain elusive.We performed spatial and single-cell transcriptomics of human medial ganglionic eminence(hMGE),a pivotal source of cortical and subpallial INs,and built the trajectories of hMGE-derived cells during brain development.We identified spatiotemporally and molecularly segregated progenitor cell populations fated to produce distinct IN types.展开更多
Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apopt...Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.展开更多
Globally,glaucoma stands as a primary cause of irreversible blindness,marked by intricate pathophysiological processes in which neuroinflammation plays a pivotal role.As the principal immune cells within the central n...Globally,glaucoma stands as a primary cause of irreversible blindness,marked by intricate pathophysiological processes in which neuroinflammation plays a pivotal role.As the principal immune cells within the central nervous system,microglia play a dual function in the progression of glaucoma.Under standard physiological states,microglia safeguard the retina by offering neurotrophic support and removing cellular debris.In the pathological progression of glaucoma,microglia become activated and release significant levels of inflammatory factors,resulting in retinal ganglion cell injury,cell death,and impaired neuroregeneration.This review focuses on examining the dual functions of microglia in glaucoma,evaluating their influence on retinal neurodegeneration and repair,and suggesting that modulating microglial activity could serve as a promising therapeutic strategy.Understanding the mechanisms of microglial action in glaucoma is crucial for unveiling the complex pathophysiological processes of the disease and developing new therapeutic strategies.展开更多
Glaucoma is characterized by chronic progressive optic nerve damage and retinal ganglion cell death.Although extensive research has been conducted on neuroprotection for retinal ganglion cells,there is still no treatm...Glaucoma is characterized by chronic progressive optic nerve damage and retinal ganglion cell death.Although extensive research has been conducted on neuroprotection for retinal ganglion cells,there is still no treatment for clinical use.Recent evidence shows that extracellular vesicles isolated from a variety of stem cells are efficacious in retinal ganglion cell neuroprotection.In this study,we tested the novel extracellular vesicle source of the retinal progenitor R-28 cell line in vitro and in vivo.We isolated and characterized extracellular vesicles from R-28 cells and tested their therapeutic efficacy in terms of retinal ganglion cell survival in vitro and in an in vivo glaucoma model,measuring retinal ganglion cell survival and preservation of their axons.Additionally,we tested extracellular vesicles for their neuroprotective capacity in retinal ganglion cells differentiated from human embryonic stem cells.Finally,we investigated miRNA changes in retinal ganglion cells with R-28 extracellular vesicle treatment,and predicted possible pathways that may be modulated.R-28 extracellular vesicles improved retinal ganglion cell survival but failed to preserve axons significantly.Moreover,the results also illustrated the neuroprotection of R-28 extracellular vesicles on human retinal ganglion cells.Finally,we also showed changes in hsa-miRNA-4443,hsa-miRNA-216a-5p,hsa-let-7e-5p,hsa-miRNA-374b-5p,hsa-miRNA-331-3p,and hsa-miRNA-421 expressions,which may have neuroprotective potential on retinal ganglion cell degeneration.This study will pave the way for miRNA and extracellular vesicle-based neuroprotective therapies for glaucoma.展开更多
To perform various functions in the body,skeletal muscle is controlled and coordinated as a whole by nerves.However,there has been little research into whether the nerve control characteristics of different muscles ar...To perform various functions in the body,skeletal muscle is controlled and coordinated as a whole by nerves.However,there has been little research into whether the nerve control characteristics of different muscles are different,and the importance of these potential differences.In the present study,we used a three-dimensional imaging of solvent-cleared organ-compatible multi-tracer technique to explore the spatial distribution patterns of sensory and sympathetic neurons that innervate limb muscles.We integrated transcriptome sequencing datasets from mouse limb muscles in public databases and performed correlation analysis with neuronal spatial distribution data to reveal the unique effects of different types of neurons on muscle functional pathways.In terms of spatial distribution patterns,sympathetic neurons exhibited a more concentrated distribution than sensory and motor neurons.In addition,the neuronal innervation of limb muscles exhibited four different characteristics:sympathetic neuron-rich muscle,sensory neuron-rich muscle,neuron-sparse muscle,and motor neuron-rich muscle.Sensory neuron density was mainly associated with muscle contractile structure and cell pH,whereas sympathetic neuron density was associated with protein kinase activity,muscle vasculature,muscle calcium-dependent protein kinase activity,lipid transport,and vesicle release.Motor neuron density was mainly associated with protein kinase activity,cell adhesion,oxidoreductase activity,and exocytosis.These findings may contribute to a deeper understanding of how nerves cooperate to endow muscles with diverse physiological functions,thereby providing new insights and experimental evidence for the treatment of various neuromuscular diseases.展开更多
Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene express...Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene expression patterns in the dorsal root ganglias of young adult and aged animals following sciatic nerve injury.In young adult animals,two transforming growth factor beta-related factors,activin A and angiopoietin 2,were found to be upregulated post nerve injury.Treatment of isolated dorsal root ganglia explants and cultured dorsal root ganglia neurons of neonatal and young adult rats with recombinant activin A or angiopoietin 2 protein stimulated neurite outgrowth and axonal elongation.The administration of recombinant activin A or angiopoietin 2 protein to sciatic nerve crush-injured dorsal root ganglias also supported the growth of sensory neurons and facilitated nerve regeneration in both young adult and aged rats.Using RNA sequencing,we characterized genetic changes in dorsal root ganglia neurons following recombinant activin A or angiopoietin 2 treatment,revealing the unique mechanisms of these transforming growth factor beta-related factors.Recombinant activin A elicited changes in the gene expression of cytoskeleton-related Gper1 and activated extracellular signal-regulated kinase signaling,while angiopoietin 2 increased the expression of the transcription factor gene E2f2.Our identification of activin A and angiopoietin 2 as crucial promotional factors of axonal regeneration may guide future therapeutic strategies for the treatment of nerve injury.展开更多
Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown ...Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.展开更多
Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglio...Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglion cells and their axons,leading to axonal transport dysfuntion,subsequently causing secondary damage to anterior or posterior ends of the visual system.Accordingly,recent evidence indicates that glaucoma is a degenerative disease of the central nervous system that causes damage throughout the visual pathway.However,the effects of glaucoma on synaptic plasticity in the primary visual cortex remain unclear.In this study,we established a mouse model of unilateral chronic ocular hypertension by injecting magnetic microbeads into the anterior chamber of one eye.We found that,after 4 weeks of chronic ocular hypertension,the neuronal somas were smaller in the superior colliculus and lateral geniculate body regions of the brain contralateral to the affected eye.This was accompanied by glial cell activation and increased expression of inflammatory factors.After 8 weeks of ocular hypertension,we observed a reduction in the number of excitatory and inhibitory synapses,dendritic spines,and activation of glial cells in the primary visual cortex contralateral to the affected eye.These findings suggest that glaucoma not only directly damages the retina but also induces alterations in synapses and dendritic spines in the primary visual cortex,providing new insights into the pathogenesis of glaucoma.展开更多
Neurodegenerative diseases account for a large and increasing health and economic burden worldwide.With an increasingly aged population,this burden is set to increase.Optic neuropathies make up a large proportion of n...Neurodegenerative diseases account for a large and increasing health and economic burden worldwide.With an increasingly aged population,this burden is set to increase.Optic neuropathies make up a large proportion of neurodegenerative diseases with glaucoma being highly prevalent.Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells and their axons which make up the optic nerve.It is the leading cause of irreversible vision loss and affects an estimated 80 million people.The mammalian central nervous system is non-regenerative and,once lost or injured,retinal ganglion cells cannot regenerate an axon into the optic nerve under basal conditions.Thus,strategies that provide neuroprotection to stressed,dysfunctional,or dying retinal ganglion cells are likely to be of high therapeutic and translational value.Advancing age,genetics,and elevated intraocular pressure are all major risk factors for glaucoma,however,all clinically available glaucoma treatments focus on intraocular pressure management and do not directly address the neurodegenerative component of glaucoma.展开更多
Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Ret...Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.展开更多
Retinal ganglion cells are the bridging neurons between the eye and the central nervous system,transmitting visual signals to the brain.The injury and loss of retinal ganglion cells are the primary pathological change...Retinal ganglion cells are the bridging neurons between the eye and the central nervous system,transmitting visual signals to the brain.The injury and loss of retinal ganglion cells are the primary pathological changes in several retinal degenerative diseases,including glaucoma,ischemic optic neuropathy,diabetic neuropathy,and optic neuritis.In mammals,injured retinal ganglion cells lack regenerative capacity and undergo apoptotic cell death within a few days of injury.Additionally,these cells exhibit limited regenerative ability,ultimately contributing to vision impairment and potentially leading to blindness.Currently,the only effective clinical treatment for glaucoma is to prevent vision loss by lowering intraocular pressure through medications or surgery;however,this approach cannot halt the effect of retinal ganglion cell loss on visual function.This review comprehensively investigates the mechanisms underlying retinal ganglion cell degeneration in retinal degenerative diseases and further explores the current status and potential of cell replacement therapy for regenerating retinal ganglion cells.As our understanding of the complex processes involved in retinal ganglion cell degeneration deepens,we can explore new treatment strategies,such as cell transplantation,which may offer more effective ways to mitigate the effect of retinal degenerative diseases on vision.展开更多
Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate followin...Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate following injury.Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage.To initiate repair after peripheral nerve injury,dorsal root ganglion(DRG) neurons mobilize a pro-regenerative gene expression program,which facilitates axon outgrowth.展开更多
Traumatic optic neuropathy is a form of optic neuropathy resulting from trauma.Its pathophysiological mechanisms involve primary and secondary injury phases,leading to progressive retinal ganglion cell loss and axonal...Traumatic optic neuropathy is a form of optic neuropathy resulting from trauma.Its pathophysiological mechanisms involve primary and secondary injury phases,leading to progressive retinal ganglion cell loss and axonal degeneration.Contributing factors such as physical trauma,oxidative stress,neuroinflammation,and glial scar formation exacerbate disease progression and retinal ganglion cell death.Multiple forms of cell death—including apoptosis,pyroptosis,necroptosis,and ferroptosis—are involved at different disease stages.Although current treatments,such as corticosteroid therapy and surgical interventions,have limited efficacy,cell-based therapies have emerged as a promising approach that simultaneously promotes neuroprotection and retinal ganglion cell regeneration.This review summarizes recent advances in cell-based therapies for traumatic optic neuropathy.In the context of cell replacement therapy,retinal ganglion cell-like cells derived from embryonic stem cells and induced pluripotent stem cells—via chemical induction or direct reprogramming—have demonstrated the ability to integrate into the host retina and survive for weeks to months,potentially improving visual function.Mesenchymal stem cells derived from various sources,including bone marrow,umbilical cord,placenta,and adipose tissue,have been shown to enhance retinal ganglion cell survival,stimulate axonal regeneration,and support partial functional recovery.Additionally,neural stem/progenitor cells derived from human embryonic stem cells offer neuroprotective effects and function as“neuronal relays,”facilitating reconnection between damaged regions of the optic nerve and the visual pathway.Beyond direct cell transplantation,cell-derived products,such as extracellular vesicles and cell-extracted solutions,have demonstrated promising neuroprotective effects in traumatic optic neuropathy.Despite significant progress,several challenges remain,including limited integration of transplanted cells,suboptimal functional vision recovery,the need for precise timing and delivery methods,and an incomplete understanding of the role of the retinal microenvironment and glial cell activation in neuroprotection and neuroregeneration.Furthermore,studies with longer observation periods and deeper mechanistic insights into the therapeutic effects of cell-based therapies remain scarce.Two Phase I clinical trials have confirmed the safety and potential benefits of cell-based therapy for traumatic optic neuropathy,with reported improvements in visual acuity.However,further studies are needed to validate these findings and establish significant therapeutic outcomes.In conclusion,cell-based therapies hold great promise for treating traumatic optic neuropathy,but critical obstacles must be overcome to achieve functional optic nerve regeneration.Emerging bioengineering strategies,such as scaffold-based transplantation,may improve cell survival and axonal guidance.Successful clinical translation will require rigorous preclinical validation,standardized protocols,and the integration of advanced imaging techniques to optimize therapeutic efficacy.展开更多
Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as ...Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target.In addition,the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure.To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides,we used a C57BL/6J mouse model treated with kanamycin.We found that the mice exhibited auditory deficits following the acute loss of outer hair cells.Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time.Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response,particularly those related to the NLRP3 inflammasome.Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed,accompanied by infiltration of macrophages and the release of proinflammatory cytokines.Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model.These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration.Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.展开更多
AIM:To comprehensively investigate the current state of research on the application of neurotrophic factors in glaucoma therapy and identify potential research hotspots.METHODS:On September 30,2023,a literature search...AIM:To comprehensively investigate the current state of research on the application of neurotrophic factors in glaucoma therapy and identify potential research hotspots.METHODS:On September 30,2023,a literature search was conducted on Scopus using specific keywords related to neurotrophic factors and glaucoma.Of the 918 articles retrieved,780 met the inclusion criteria.These articles were subsequently analyzed and visualized using Google Sheets,Biblioshiny 3.1,and VosViewer 1.6.18.RESULTS:A total of 780 studies published between 1989 and 2023 were included,and the global publication count showed an upward trend through 2023(projected to continue rising by 2030).The United States,China,Japan,Italy,and Australia were the most significant contributors to the publication output.Research in this field had been published in 313 journals,spanning categories such as pharmacology and drug development,ophthalmology,genetics and gene therapy,and neuroscience.A total of 2622 authors had contributed to these studies,with the most prolific author publishing 14 articles.The focus of research in this field had evolved sequentially from“glutamate”to“CNTF”and“GDNF”,and finally to“optic nerve injury”.Co-occurrence analysis identified five clusters:glaucoma and ocular health,neuroinflammation in ophthalmology,neuroprotection in ophthalmology,ocular drug delivery,and stem cell therapy.Several areas in this field require further exploration,including the neurophysiological mechanisms underlying glaucoma,ocular drug delivery systems,and the clinical value of specific neurotrophic factors.CONCLUSION:This study systematically reviews global research trends on neurotrophic factors in glaucoma therapy,clarifying the current research status and future directions.展开更多
Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limit...Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.展开更多
Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein ...Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.展开更多
文摘Small fiber polyneuropathy is a well-recognized syndrome mitigated by somatic sensory afferent and autonomic efferent nerve fibers that respectively mediate pain, heat and cold temperature afferent and autonomic efferent function in the skin. A patient with low serum titers of neuronal acetylcholine receptor ganglionic antibodies and autonomic failure had symptomatic small fiber polyneuropathy late in life in the setting of autoimmune dementia and encephalopathy and prostate cancer. Large and small fiber polyneuropathy and dysautonomia were detected in routine electrodiagnostic and autonomic laboratory studies, and epidermal nerve fiber analysis of the calf and thigh. Clinical improvement for one year concomitant with intravenous immune globulin therapy preceded?a?clinical?decline in neurocognitive function and death. Postmortem examination showed typical features of Alzheimer disease with neuropathic neuropathological changes in the peripheral nervous system,?and viable autonomic ganglia consistent with a channelopathy mechanism involving postsynaptic neuronal nAChRs.
文摘BACKGROUND A large ganglionic cyst extending from the hip joint to the intrapelvic cavity through the sciatic notch is a rare space-occupying lesion associated with compressive lower-extremity neuropathy.A cyst in the pelvic cavity compressing the intrapelvic-sciatic nerve is easily missed in the diagnostic process because it usually presents as atypical symptoms of an extraperitoneal-intrapelvic tumor.We present a case of a huge ganglionic cyst that was successfully excised laparoscopically and endoscopically by a gynecologist and an orthopedic surgeon.CASE SUMMARY A 52-year-old woman visited our hospital complaining of pain and numbness in her left buttock while sitting.The pain began 3 years ago and worsened,while the numbness in the left lower extremity lasted 1 mo.She was diagnosed and unsuccessfully treated at several tertiary referral centers many years ago.Magnetic resonance imaging revealed a suspected paralabral cyst(5 cm×5 cm×4.6 cm)in the left hip joint,extending to the pelvic cavity through the greater sciatic notch.The CA-125 and CA19-9 tumor marker levels were within normal limits.However,the cyst was compressing the sciatic nerve.Accordingly,endoscopic and laparoscopic neural decompression and mass excision were performed simultaneously.A laparoscopic examination revealed a tennis-ball-sized cyst filled with gelatinous liquid,stretching deep into the hip joint.An excisional biopsy performed in the pelvic cavity and deep gluteal space confirmed the accumulation of ganglionic cysts from the hip joint into the extrapelvic intraperitoneal cavity.CONCLUSION Intra-or extra-sciatic nerve-compressing lesion should be considered in cases of sitting pain radiating down the ipsilateral lower extremity.This large juxta-articular ganglionic cyst was successfully treated simultaneously using laparoscopy and arthroscopy.
文摘The number and diversity of inhibitory neurons(INs)increased substantially during mammalian brain evolution.However,the generative mechanisms of the vast repertoire of human INs remain elusive.We performed spatial and single-cell transcriptomics of human medial ganglionic eminence(hMGE),a pivotal source of cortical and subpallial INs,and built the trajectories of hMGE-derived cells during brain development.We identified spatiotemporally and molecularly segregated progenitor cell populations fated to produce distinct IN types.
基金supported by the National Natural Science Foundation of China,Nos.32271043(to ZW)and 82171047(to YM)the both Science and Technology Major Project of Shanghai,No.2018SHZDZX01 and ZJLabShanghai Center for Brain Science and Brain-Inspired Technology(to ZW)。
文摘Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.
基金supported by the Deutsche Forschungsgemeinschaft(DFG)with grants PR1569/1-1 and PR 1569/1-3(to VP).
文摘Globally,glaucoma stands as a primary cause of irreversible blindness,marked by intricate pathophysiological processes in which neuroinflammation plays a pivotal role.As the principal immune cells within the central nervous system,microglia play a dual function in the progression of glaucoma.Under standard physiological states,microglia safeguard the retina by offering neurotrophic support and removing cellular debris.In the pathological progression of glaucoma,microglia become activated and release significant levels of inflammatory factors,resulting in retinal ganglion cell injury,cell death,and impaired neuroregeneration.This review focuses on examining the dual functions of microglia in glaucoma,evaluating their influence on retinal neurodegeneration and repair,and suggesting that modulating microglial activity could serve as a promising therapeutic strategy.Understanding the mechanisms of microglial action in glaucoma is crucial for unveiling the complex pathophysiological processes of the disease and developing new therapeutic strategies.
基金supported by a Ph.D.scholarship from the YLSY program of the Republic of Turkiye,Ministry of National Educationfunded by Fight for Sight UK,grant reference#5183/5184。
文摘Glaucoma is characterized by chronic progressive optic nerve damage and retinal ganglion cell death.Although extensive research has been conducted on neuroprotection for retinal ganglion cells,there is still no treatment for clinical use.Recent evidence shows that extracellular vesicles isolated from a variety of stem cells are efficacious in retinal ganglion cell neuroprotection.In this study,we tested the novel extracellular vesicle source of the retinal progenitor R-28 cell line in vitro and in vivo.We isolated and characterized extracellular vesicles from R-28 cells and tested their therapeutic efficacy in terms of retinal ganglion cell survival in vitro and in an in vivo glaucoma model,measuring retinal ganglion cell survival and preservation of their axons.Additionally,we tested extracellular vesicles for their neuroprotective capacity in retinal ganglion cells differentiated from human embryonic stem cells.Finally,we investigated miRNA changes in retinal ganglion cells with R-28 extracellular vesicle treatment,and predicted possible pathways that may be modulated.R-28 extracellular vesicles improved retinal ganglion cell survival but failed to preserve axons significantly.Moreover,the results also illustrated the neuroprotection of R-28 extracellular vesicles on human retinal ganglion cells.Finally,we also showed changes in hsa-miRNA-4443,hsa-miRNA-216a-5p,hsa-let-7e-5p,hsa-miRNA-374b-5p,hsa-miRNA-331-3p,and hsa-miRNA-421 expressions,which may have neuroprotective potential on retinal ganglion cell degeneration.This study will pave the way for miRNA and extracellular vesicle-based neuroprotective therapies for glaucoma.
基金supported by the National Natural Science Foundation of China,No.82072162(to XY).
文摘To perform various functions in the body,skeletal muscle is controlled and coordinated as a whole by nerves.However,there has been little research into whether the nerve control characteristics of different muscles are different,and the importance of these potential differences.In the present study,we used a three-dimensional imaging of solvent-cleared organ-compatible multi-tracer technique to explore the spatial distribution patterns of sensory and sympathetic neurons that innervate limb muscles.We integrated transcriptome sequencing datasets from mouse limb muscles in public databases and performed correlation analysis with neuronal spatial distribution data to reveal the unique effects of different types of neurons on muscle functional pathways.In terms of spatial distribution patterns,sympathetic neurons exhibited a more concentrated distribution than sensory and motor neurons.In addition,the neuronal innervation of limb muscles exhibited four different characteristics:sympathetic neuron-rich muscle,sensory neuron-rich muscle,neuron-sparse muscle,and motor neuron-rich muscle.Sensory neuron density was mainly associated with muscle contractile structure and cell pH,whereas sympathetic neuron density was associated with protein kinase activity,muscle vasculature,muscle calcium-dependent protein kinase activity,lipid transport,and vesicle release.Motor neuron density was mainly associated with protein kinase activity,cell adhesion,oxidoreductase activity,and exocytosis.These findings may contribute to a deeper understanding of how nerves cooperate to endow muscles with diverse physiological functions,thereby providing new insights and experimental evidence for the treatment of various neuromuscular diseases.
基金supported by Major Program of National Natural Science Foundation of China,No.92368207Frontier Leading Technology BasicResearch Major Project of Jiangsu Province,No.BK20232023(both to XG).
文摘Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene expression patterns in the dorsal root ganglias of young adult and aged animals following sciatic nerve injury.In young adult animals,two transforming growth factor beta-related factors,activin A and angiopoietin 2,were found to be upregulated post nerve injury.Treatment of isolated dorsal root ganglia explants and cultured dorsal root ganglia neurons of neonatal and young adult rats with recombinant activin A or angiopoietin 2 protein stimulated neurite outgrowth and axonal elongation.The administration of recombinant activin A or angiopoietin 2 protein to sciatic nerve crush-injured dorsal root ganglias also supported the growth of sensory neurons and facilitated nerve regeneration in both young adult and aged rats.Using RNA sequencing,we characterized genetic changes in dorsal root ganglia neurons following recombinant activin A or angiopoietin 2 treatment,revealing the unique mechanisms of these transforming growth factor beta-related factors.Recombinant activin A elicited changes in the gene expression of cytoskeleton-related Gper1 and activated extracellular signal-regulated kinase signaling,while angiopoietin 2 increased the expression of the transcription factor gene E2f2.Our identification of activin A and angiopoietin 2 as crucial promotional factors of axonal regeneration may guide future therapeutic strategies for the treatment of nerve injury.
基金supported by the National Natural Science Foundation of China,Nos.82471123,82171053the Jilin Province Special Project for Talent in Medical and Health Sciences,No.2024WSXK-E01the Natural Science Foundation of Jilin Province,YDZJ202501ZYTS318(all to GL).
文摘Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.
基金supported by the National Natural Science Foundation of China,No.82271115(to MY).
文摘Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglion cells and their axons,leading to axonal transport dysfuntion,subsequently causing secondary damage to anterior or posterior ends of the visual system.Accordingly,recent evidence indicates that glaucoma is a degenerative disease of the central nervous system that causes damage throughout the visual pathway.However,the effects of glaucoma on synaptic plasticity in the primary visual cortex remain unclear.In this study,we established a mouse model of unilateral chronic ocular hypertension by injecting magnetic microbeads into the anterior chamber of one eye.We found that,after 4 weeks of chronic ocular hypertension,the neuronal somas were smaller in the superior colliculus and lateral geniculate body regions of the brain contralateral to the affected eye.This was accompanied by glial cell activation and increased expression of inflammatory factors.After 8 weeks of ocular hypertension,we observed a reduction in the number of excitatory and inhibitory synapses,dendritic spines,and activation of glial cells in the primary visual cortex contralateral to the affected eye.These findings suggest that glaucoma not only directly damages the retina but also induces alterations in synapses and dendritic spines in the primary visual cortex,providing new insights into the pathogenesis of glaucoma.
基金supported by St.Erik Eye Hospital philanthropic donations,Vetenskapsrådet 2022-00799(to PAW).
文摘Neurodegenerative diseases account for a large and increasing health and economic burden worldwide.With an increasingly aged population,this burden is set to increase.Optic neuropathies make up a large proportion of neurodegenerative diseases with glaucoma being highly prevalent.Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells and their axons which make up the optic nerve.It is the leading cause of irreversible vision loss and affects an estimated 80 million people.The mammalian central nervous system is non-regenerative and,once lost or injured,retinal ganglion cells cannot regenerate an axon into the optic nerve under basal conditions.Thus,strategies that provide neuroprotection to stressed,dysfunctional,or dying retinal ganglion cells are likely to be of high therapeutic and translational value.Advancing age,genetics,and elevated intraocular pressure are all major risk factors for glaucoma,however,all clinically available glaucoma treatments focus on intraocular pressure management and do not directly address the neurodegenerative component of glaucoma.
文摘Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.
基金supported by the National Key Research and Development Program of China,No.2019YFA0111200the National Natural Science Foundation of China,Nos.U23A20436,82371047+3 种基金Key Research Project in Shanxi Province,No.202302130501008Shanxi Provincial Science Fund for Distinguished Young Scholars,No.202103021221008Key Research and Development Program in Shanxi Province,No.202204051001023Shanxi Medical University Doctor’s Startup Fund Project,No.SD22028(all to YG)。
文摘Retinal ganglion cells are the bridging neurons between the eye and the central nervous system,transmitting visual signals to the brain.The injury and loss of retinal ganglion cells are the primary pathological changes in several retinal degenerative diseases,including glaucoma,ischemic optic neuropathy,diabetic neuropathy,and optic neuritis.In mammals,injured retinal ganglion cells lack regenerative capacity and undergo apoptotic cell death within a few days of injury.Additionally,these cells exhibit limited regenerative ability,ultimately contributing to vision impairment and potentially leading to blindness.Currently,the only effective clinical treatment for glaucoma is to prevent vision loss by lowering intraocular pressure through medications or surgery;however,this approach cannot halt the effect of retinal ganglion cell loss on visual function.This review comprehensively investigates the mechanisms underlying retinal ganglion cell degeneration in retinal degenerative diseases and further explores the current status and potential of cell replacement therapy for regenerating retinal ganglion cells.As our understanding of the complex processes involved in retinal ganglion cell degeneration deepens,we can explore new treatment strategies,such as cell transplantation,which may offer more effective ways to mitigate the effect of retinal degenerative diseases on vision.
基金supported by the Canada Foundation for Innovation (Project#44220)the Natural Sciences and Engineering Research Council of Canada (RGPIN-2024-03986)+3 种基金the Michael Smith Foundation for Health Research BCthe financial support of Health Canada,through the Canada Brain Research Fund,an innovative partnership between the Government of Canada (through Health Canada),Brain Canada Foundationthe Azrieli Foundationsupported by a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship–Master’s Award。
文摘Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate following injury.Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage.To initiate repair after peripheral nerve injury,dorsal root ganglion(DRG) neurons mobilize a pro-regenerative gene expression program,which facilitates axon outgrowth.
基金supported by the National Key Research and Development Program of China,No.2022YFA1105502(to PG)the National Natural Science Foundation of China,Nos.82271123(to PG),32200618(to ZT)。
文摘Traumatic optic neuropathy is a form of optic neuropathy resulting from trauma.Its pathophysiological mechanisms involve primary and secondary injury phases,leading to progressive retinal ganglion cell loss and axonal degeneration.Contributing factors such as physical trauma,oxidative stress,neuroinflammation,and glial scar formation exacerbate disease progression and retinal ganglion cell death.Multiple forms of cell death—including apoptosis,pyroptosis,necroptosis,and ferroptosis—are involved at different disease stages.Although current treatments,such as corticosteroid therapy and surgical interventions,have limited efficacy,cell-based therapies have emerged as a promising approach that simultaneously promotes neuroprotection and retinal ganglion cell regeneration.This review summarizes recent advances in cell-based therapies for traumatic optic neuropathy.In the context of cell replacement therapy,retinal ganglion cell-like cells derived from embryonic stem cells and induced pluripotent stem cells—via chemical induction or direct reprogramming—have demonstrated the ability to integrate into the host retina and survive for weeks to months,potentially improving visual function.Mesenchymal stem cells derived from various sources,including bone marrow,umbilical cord,placenta,and adipose tissue,have been shown to enhance retinal ganglion cell survival,stimulate axonal regeneration,and support partial functional recovery.Additionally,neural stem/progenitor cells derived from human embryonic stem cells offer neuroprotective effects and function as“neuronal relays,”facilitating reconnection between damaged regions of the optic nerve and the visual pathway.Beyond direct cell transplantation,cell-derived products,such as extracellular vesicles and cell-extracted solutions,have demonstrated promising neuroprotective effects in traumatic optic neuropathy.Despite significant progress,several challenges remain,including limited integration of transplanted cells,suboptimal functional vision recovery,the need for precise timing and delivery methods,and an incomplete understanding of the role of the retinal microenvironment and glial cell activation in neuroprotection and neuroregeneration.Furthermore,studies with longer observation periods and deeper mechanistic insights into the therapeutic effects of cell-based therapies remain scarce.Two Phase I clinical trials have confirmed the safety and potential benefits of cell-based therapy for traumatic optic neuropathy,with reported improvements in visual acuity.However,further studies are needed to validate these findings and establish significant therapeutic outcomes.In conclusion,cell-based therapies hold great promise for treating traumatic optic neuropathy,but critical obstacles must be overcome to achieve functional optic nerve regeneration.Emerging bioengineering strategies,such as scaffold-based transplantation,may improve cell survival and axonal guidance.Successful clinical translation will require rigorous preclinical validation,standardized protocols,and the integration of advanced imaging techniques to optimize therapeutic efficacy.
基金supported by the National Natural Science Foundation of China,Nos.81800919(to YX),82171140(to PW)the International Cooperation and Exchange of the National Natural Science Foundation of China,Nos.82020108008(to HS),81720108010(to SY).
文摘Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target.In addition,the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure.To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides,we used a C57BL/6J mouse model treated with kanamycin.We found that the mice exhibited auditory deficits following the acute loss of outer hair cells.Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time.Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response,particularly those related to the NLRP3 inflammasome.Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed,accompanied by infiltration of macrophages and the release of proinflammatory cytokines.Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model.These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration.Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.
文摘AIM:To comprehensively investigate the current state of research on the application of neurotrophic factors in glaucoma therapy and identify potential research hotspots.METHODS:On September 30,2023,a literature search was conducted on Scopus using specific keywords related to neurotrophic factors and glaucoma.Of the 918 articles retrieved,780 met the inclusion criteria.These articles were subsequently analyzed and visualized using Google Sheets,Biblioshiny 3.1,and VosViewer 1.6.18.RESULTS:A total of 780 studies published between 1989 and 2023 were included,and the global publication count showed an upward trend through 2023(projected to continue rising by 2030).The United States,China,Japan,Italy,and Australia were the most significant contributors to the publication output.Research in this field had been published in 313 journals,spanning categories such as pharmacology and drug development,ophthalmology,genetics and gene therapy,and neuroscience.A total of 2622 authors had contributed to these studies,with the most prolific author publishing 14 articles.The focus of research in this field had evolved sequentially from“glutamate”to“CNTF”and“GDNF”,and finally to“optic nerve injury”.Co-occurrence analysis identified five clusters:glaucoma and ocular health,neuroinflammation in ophthalmology,neuroprotection in ophthalmology,ocular drug delivery,and stem cell therapy.Several areas in this field require further exploration,including the neurophysiological mechanisms underlying glaucoma,ocular drug delivery systems,and the clinical value of specific neurotrophic factors.CONCLUSION:This study systematically reviews global research trends on neurotrophic factors in glaucoma therapy,clarifying the current research status and future directions.
基金supported by the National Natural Science Foundation of China,No.82271114the Natural Science Foundation of Zhejiang Province of China,No.LZ22H120001(both to ZLC).
文摘Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.
基金supported by the National Natural Science Foundation of China,Nos.82001178(to LW),81901129(to LH),82001175(to FX)Shanghai Sailing Program,No.20YF1439200(to LW)+1 种基金the Natural Science Foundation of Shanghai,China,No.23ZR1450800(to LH)and the Fundamental Research Funds for the Central Universities,No.YG2023LC15(to ZX)。
文摘Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.
