AIM:To investigate the effects of Sonic hedgehog(Shh)gene-modified bone marrow mesenchymal stem cells(MSCs)on graft-induced retinal gliosis and retinal ganglion cells(RGCs)survival in diabetic mice.METHODS:Bone marrow...AIM:To investigate the effects of Sonic hedgehog(Shh)gene-modified bone marrow mesenchymal stem cells(MSCs)on graft-induced retinal gliosis and retinal ganglion cells(RGCs)survival in diabetic mice.METHODS:Bone marrow-derived MSCs were genetically modified with the Shh gene to generate a stably transfected cell line of Shh-modified MSCs(MSC-Shh).Intravitreal injections of MSC-Shh and green fluorescent protein-modified MSCs(MSC-Gfp;control)were administered in diabetic mice.After 4wk,the effects of MSC-Shh on retinal gliosis were evaluated using fundus photography,and markers of gliosis were examined by immunofluorescence and Western blotting.The neurotrophic factors expression and RGCs survival in the host retina were evaluated using Western blotting and immunofluorescence.The mechanisms underlying the effects of MSC-Shh was investigated.RESULTS:A significant reduction of proliferative vitreoretinopathy(PVR)was observed after intravitreal injection of MSC-Shh compared to MSC-Gfp.Significant downregulation of glial fibrillary acidic protein(GFAP)was demonstrated in the host retina after MSC-Shh administration compared to MSC-Gfp.The extracellular signal-regulated kinase 1/2(ERK1/2),protein kinase B(AKT)and phosphatidylin-ositol-3-kinase(PI3K)pathways were significantly downregulated after MSC-Shh administration compared to MSC-Gfp.Brain-derived neurotrophic factor(BDNF)and ciliary neurotrophic factor(CNTF)levels were significantly increased in the host retina,and RGCs loss was significantly prevented after MSC-Shh administration.CONCLUSION:MSC-Shh administration reduces graft-induced reactive gliosis following intravitreal injection in diabetic mice.The ERK1/2,AKT and PI3K pathways are involved in this process.MSC-Shh also increases the levels of neurotrophic factors in the host retina and promoted RGCs survival in diabetic mice.展开更多
AIM:To evaluate the effects of intravitreal slow-release dexamethasone on traumatic proliferative vitreoretinopathy(PVR)and Müller cell gliosis and preliminarily explored the possible inflammatory mechanism in a ...AIM:To evaluate the effects of intravitreal slow-release dexamethasone on traumatic proliferative vitreoretinopathy(PVR)and Müller cell gliosis and preliminarily explored the possible inflammatory mechanism in a rabbit model induced by penetrating ocular trauma.METHODS:Traumatic PVR was induced in the right eyes of pigmented rabbits by performing an 8-mm circumferential scleral incision placed 2.5 mm behind the limbus,followed by treatment with a slow-release dexamethasone implant(Ozurdex)or sham injection.Left eyes were used as normal controls.The intraocular pressure(IOP)was monitored using an iCare tonometer.PVR severity was evaluated via anatomical and histopathological examinations every week for 6wk;specific inflammatory cytokine and proliferative marker levels were measured by quantitative real-time polymerase chain reaction,Western blot,protein chip analysis,or immunofluorescence staining.RESULTS:During the observation period,PVR severity gradually increased.Intense Müller cell gliosis was observed in the peripheral retina near the wound and in the whole retina of PVR group.Ozurdex significantly alleviated PVR development and Müller cell gliosis.Post-traumatic inflammation fluctuated and was persistent.The interleukin-1β(IL-1β)mRNA level was significantly upregulated,peaking on day 3 and increasing again on day 21 after injury.The expression of nod-like receptor family pyrin domain containing 3(NLRP3)showed a similar trend that began earlier than that of IL-1βexpression.Ozurdex suppressed the expression of IL-1β,NLRP3,and phosphorylated nuclear factor-kappa B(NF-κB).The average IOP after treatment was within normal limits.CONCLUSION:The present study demonstrates chronic and fluctuating inflammation in a traumatic PVR rabbit model over 6wk.Ozurdex treatment significantly inhibites inflammatory cytokines expression and Müller cell gliosis,and thus alleviates PVR severity.This study highlights the important role of IL-1β,and Ozurdex inhibites inflammation presumably via the NF-κB/NLRP3/IL-1βinflammatory axis.In summary,Ozurdex provides a potential therapeutic option for traumatic PVR.展开更多
The authors regret an error in Fig.4I,where the wrong DAPI and merged images were inadvertently introduced in Rot group when composing the layouts.The authors have replaced the wrong images with the corrected ones,thi...The authors regret an error in Fig.4I,where the wrong DAPI and merged images were inadvertently introduced in Rot group when composing the layouts.The authors have replaced the wrong images with the corrected ones,this correction has not changed the results,interpretation,or conclusions of the article.The original data of these figures have been provided to the Editorial Office,and the corresponding authors can be contacted for original data access.The authors would like to apologize for any inconvenience caused.展开更多
A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to ...A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity.After 4 weeks of tail suspension,there were no notable alterations in retinal function and morphology,while after 8 weeks of tail suspension,significant reductions in retinal function were observed,and the outer nuclear layer was thinner,with abundant apoptotic cells.To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina,proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension.The results showed that the expression levels of fibroblast growth factor 2(also known as basic fibroblast growth factor)and glial fibrillary acidic protein,which are closely related to Müller cell activation,were significantly upregulated.In addition,Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks,respectively,of simulated weightlessness.These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.展开更多
Background In response to the injury of the central nervous system （CNS）, the astrocytes upregulate the expression of glial fibrillary acidic protein （GFAP）, which largely contributes to the reactive gliosis after...Background In response to the injury of the central nervous system （CNS）, the astrocytes upregulate the expression of glial fibrillary acidic protein （GFAP）, which largely contributes to the reactive gliosis after brain injury. The regulatory mechanism of this process is still not clear. In this study, we aimed to compare the ephrin-B2 deficient mice with the wild type ones with regard to qliosis after traumatic brain injury展开更多
Objective: Stroke is the second leading cause of death worldwide. This study aimed to investigate the neuroprotective effect of Paeoniae Radix Rubra(PRR) on ischemic stroke of mice.Methods: The focal ischemic stroke m...Objective: Stroke is the second leading cause of death worldwide. This study aimed to investigate the neuroprotective effect of Paeoniae Radix Rubra(PRR) on ischemic stroke of mice.Methods: The focal ischemic stroke model was produced via middle cerebral artery occlusion. The experimental mice were divided into four groups: vehicle-sham group, PRR-sham group, vehicle-ischemia group, and PRR-treated ischemia group. The cerebral infarction volume was detected with TTC staining.The number of neurons in the hippocampal CA1 of the ischemic side, and the activation of astrocytes and microglia were observed via immunohistochemical staining. Western blotting was used to determine the expression changes of SOD1, SOD2, and Catalase protein levels in the hippocampus.Results: PRR significantly reduced the cerebral infarct volume induced by ischemic injury and inhibited the astrocytes and microglia activation in the hippocampal CA1 region. The decreased levels of SOD1,SOD2, and Catalase that was induced by ischemic reperfusion were simultaneously improved after PRR treatment.Conclusion: PRR improved neuronal injuries that were induced by transient cerebral ischemia via inhibiting gliosis and elevating anti-oxidants.展开更多
Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neur...Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.展开更多
Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photo...Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide(Lb GP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of Lb GP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of Lb GP as a protective pre-treatment on days 1–7;intraperitoneal administration of 40 mg/kg N-methylN-nitrosourea to induce photoreceptor injury on day 7;and continuation of orally administered Lb GP on days 8–14. Treatment with Lb GP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. Lb GP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, Lb GP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration.展开更多
Objective The present study aimed to explore the role of P2Y1 receptor in glial fibrillary acidic protein （GFAP） production and glial cell line-derived neurotrophic factor （GDNF） secretion of astrocytes under isch...Objective The present study aimed to explore the role of P2Y1 receptor in glial fibrillary acidic protein （GFAP） production and glial cell line-derived neurotrophic factor （GDNF） secretion of astrocytes under ischemic insult and the related signaling pathways. Methods Using transient right middle cerebral artery occlusion （tMCAO） and oxygen-glucose-serum deprivation for 2 h as the model of ischemic injury in vivo and in vitro, immunofluorescence, quantitative real-time reverse transcription-polymerase chain reaction （RT-PCR）, Western blotting, enzyme linked immunosorbent assay （ELISA） were used to investigate location of P2Y1 receptor and GDNF, the expression of GFAP and GDNF, and the changes of signaling molecules. Results Blockage of P2Y1 receptor with the selective antagonist N^6-methyl-2′-deoxyadenosine 3′,5′-bisphosphate diammonium （MRS2179） reduced GFAP production and increased GDNF production in the antagonist group as compared with simple ischemic group both in vivo and in vitro. Oxygen-glucose-serum deprivation and blockage of P2Y1 receptor caused elevation of phosphorylated Akt and cAMP response element binding protein （CREB）, and reduction of phosphorylated Janus kinase2 （JAK2） and signal transducer and activator of transcription3 （STAT3, Ser727）. After blockage of P2Y1 receptor and deprivation of oxygen-glucose-serum, AG490 （inhibitor of JAK2） reduced phosphorylation of STAT3 （Ser727） as well as expression of GFAP; LY294002, an inhibitor of phosphatidylinositol 3-kinase （PI3-K）, decreased phosphorylation of Akt and CREB; the inhibitor of mitogen-activated protein kinase kinase 1/2 （MEK 1/2） U0126, an important molecule of Ras/extracellular signal- regulated kinase （ERK） signaling pathway, decreased the phosphorylation of JAK2, STAT3 （Ser727）, Akt and CREB. Conclusion These results suggest that P2Y1 receptor plays a role in the production of GFAP and GDNF in astrocytes under transient ischemic condition and the related signaling pathways may be JAK2/STAT3 and PI3-K/Akt/CREB, respectively, and that crosstalk probably exists between them.展开更多
Plastics such as polyvinyl chlorides （PVC） are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-（2-ethylhexyl） phthalates （DEHP）, can leach into the surrounding e...Plastics such as polyvinyl chlorides （PVC） are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-（2-ethylhexyl） phthalates （DEHP）, can leach into the surrounding environment. This study focused on DEHP＇s effect on the central nervous system by determining the precise DEHP content in mice brain tissue after exposure to the chemical, to evaluate the specific exposure range. Primary neuronal-astrocyte co-culture systems were used as in vitro models for chemical hazard identification of DEHP. Oxidative stress was hypothesized as a probable mechanism involved, and therefore the total reactive oxygen species （ROS） concentration was determined as a biomarker of oxidative stress. In addition, NeuriteTracer, a neurite tracing plugin with ImageJ, was used to develop an assay for neurotoxicity to provide quantitative measurements of neurological parameters, such as neuronal number, neuron count and neurite length, all of which could indicate neurotoxic effects. The results showed that with 1 nmol/L DEHP exposure, there was a significant increase in ROS concentrations, indicating that the neuronal-astrocyte cultures were injured due to exposure to DEHP. In response, astrocyte proliferation （gliosis） was initiated, serving as a mechanism to maintain a homeostatic environment for neurons and protect neurons from toxic chemicals. There is a need to assess the cumulative effects of DEHP in animals to evaluate the possible uotake and effects on the human neuronal system from exoosure to DEHP in the indoor environment.展开更多
A long-standing goal of spinal cord injury research is to develop effective repair strategies,which can restore motor and sensory functions to near-normal levels.Recent advances in clinical management of spinal cord i...A long-standing goal of spinal cord injury research is to develop effective repair strategies,which can restore motor and sensory functions to near-normal levels.Recent advances in clinical management of spinal cord injury have significantly improved the prognosis,survival rate and quality of life in patients with spinal cord injury.In addition,a significant progress in basic science research has unraveled the underlying cellular and molecular events of spinal cord injury.Such efforts enabled the development of pharmacologic agents,biomaterials and stem-cell based therapy.Despite these efforts,there is still no standard care to regenerate axons or restore function of silent axons in the injured spinal cord.These challenges led to an increased focus on another therapeutic approach,namely neuromodulation.In multiple animal models of spinal cord injury,epidural electrical stimulation of the spinal cord has demonstrated a recovery of motor function.Emerging evidence regarding the efficacy of epidural electrical stimulation has further expanded the potential of epidural electrical stimulation for treating patients with spinal cord injury.However,most clinical studies were conducted on a very small number of patients with a wide range of spinal cord injury.Thus,subsequent studies are essential to evaluate the therapeutic potential of epidural electrical stimulation for spinal cord injury and to optimize stimulation parameters.Here,we discuss cellular and molecular events that continue to damage the injured spinal cord and impede neurological recovery following spinal cord injury.We also discuss and summarize the animal and human studies that evaluated epidural electrical stimulation in spinal cord injury.展开更多
The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intr...The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.展开更多
Spinal cord injury（SCI） is a condition without a cure,affecting sensory and/or motor functions.The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permiss...Spinal cord injury（SCI） is a condition without a cure,affecting sensory and/or motor functions.The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration.Among these complex set of events are damage of the blood-brain barrier,edema formation,inflammation,oxidative stress,demyelination,reactive gliosis and apoptosis.The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival,regeneration,vascular reorganization and synaptic formation.Tamoxifen,a selective estrogen receptor modulator,is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition.Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI.Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant,anti-inflammatory and anti-gliotic responses.A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment.In addition,the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated.This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field.展开更多
Spinal cord injury represents a devastating central nervous system injury that could impair the mobility and sensory function of afflicted patients.The hallmarks of spinal cord injury include neuroinflammation,axonal ...Spinal cord injury represents a devastating central nervous system injury that could impair the mobility and sensory function of afflicted patients.The hallmarks of spinal cord injury include neuroinflammation,axonal degeneration,neuronal loss,and reactive gliosis.Furthermore,the formation of a glial scar at the injury site elicits an inhibitory environment for potential neuroregeneration.Besides axonal regeneration,a significant challenge in treating spinal cord injury is to replenish the neurons lost during the pathological process.However,despite decades of research efforts,current strategies including stem cell transplantation have not resulted in a successful clinical therapy.Furthermore,stem cell transplantation faces serious hurdles such as immunorejection of the transplanted cells and ethical issues.In vivo neuronal reprogramming is a recently developed technology and leading a major breakthrough in regenerative medicine.This innovative technology converts endogenous glial cells into functional neurons for injury repair in the central nervous system.The feasibility of in vivo neuronal reprogramming has been demonstrated successfully in models of different neurological disorders including spinal cord injury by numerous laboratories.Several reprogramming factors,mainly the pro-neural transcription factors,have been utilized to reprogram endogenous glial cells into functional neurons with distinct phenotypes.So far,the literature on in vivo neuronal reprogramming in the model of spinal cord injury is still small.In this review,we summarize a limited number of such reports and discuss several questions that we think are important for applying in vivo neuronal reprogramming in the research field of spinal cord injury as well as other central nervous system disorders.展开更多
Luteolin is neuroprotective for retinal ganglion cells and retinal pigment epithelial cells after oxidative injury,whereby it can inhibit microglial neurotoxicity.Therefore,luteolin holds the potential to be useful fo...Luteolin is neuroprotective for retinal ganglion cells and retinal pigment epithelial cells after oxidative injury,whereby it can inhibit microglial neurotoxicity.Therefore,luteolin holds the potential to be useful for treatment of retinal diseases.The purpose of this study was to investigate whether luteolin exhibits neuroprotective effects on rod cells in rd10 mice,a slow photoreceptor-degenerative model of retinitis pigmentosa.Luteolin(100 mg/kg)intraperitoneally injected daily from postnatal day 14(P14)to P25 significantly enhanced the visual performance and retinal light responses of rd10 mice at P25.Moreover,it increased the survival of photoreceptors and improved retinal structure.Mechanistically,luteolin treatment attenuated increases in reactive oxygen species,photoreceptor apoptosis,and reactive gliosis;increased mRNA levels of anti-inflammatory cytokines while lowering that of pro-inflammatory and chemoattractant cytokines;and lowered the ratio of phospho-JNK/JNK.Application of the JNK inhibitor SP600125 exerted a similar protective effect to luteolin,suggesting that luteolin delays photoreceptor degeneration and functional deterioration in rd10 mice through regulation of retinal oxidation and inflammation by inhibiting the JNK pathway.Therefore,luteolin may be useful as a supplementary treatment for retinitis pigmentosa.This study was approved by the Qualified Ethics Committee of Jinan University,China(approval No.IACUC-20181217-02)on December 17,2018.展开更多
The main pathological feature of the neurodegenerative diseases is represented by neuronal death that represents the final step of a cascade of adverse/hostile events.Early in the neurodegenerative process,glial cells...The main pathological feature of the neurodegenerative diseases is represented by neuronal death that represents the final step of a cascade of adverse/hostile events.Early in the neurodegenerative process,glial cells (including astrocytes,microglial cells,and oligodendrocytes) activate and trigger an insidious neuroinflammatory reaction,metabolic decay,blood brain barrier dysfunction and energy impairment,boosting neuronal death.How these mechanisms might induce selective neuronal death in specific brain areas are far from being elucidated.The last two decades of neurobiological studies have provided evidence of the main role of glial cells in most of the processes of the central nervous system,from development to synaptogenesis,neuronal homeostasis and integration into,highly specific neuro-glial networks.In this mini-review,we moved from in vitro and in vivo models of neurodegeneration to analyze the putative role of glial cells in the early mechanisms of neurodegeneration.We report changes of transcriptional,genetic,morphological,and metabolic activity in astrocytes and microglial cells in specific brain areas before neuronal degeneration,providing evidence in experimental models of neurodegenerative disorders,including Parkinson’s and Alzheimer’s diseases.Understanding these mechanisms might increase the insight of these processes and pave the way for new specific glia-targeted therapeutic strategies for neurodegenerative disorders.展开更多
In the present study, we aimed to explore the neuroprotective effect of dioscin, a natural steroid saponin, on transient focal cerebral ischemia induced by middle cerebral artery occlusion （MCAO） in mice and its rel...In the present study, we aimed to explore the neuroprotective effect of dioscin, a natural steroid saponin, on transient focal cerebral ischemia induced by middle cerebral artery occlusion （MCAO） in mice and its related mechanism, We observed that dioscin （1,5 mg/kg, intracerebroventricular injection 30 min before MCAO） dramatically reduced the cerebral infarct volume, leading to improved neurological symptoms and reduced death of neuron, astrocytes and microglia in the infarct region. The gliosis and the reduced expressions of SOD1 and SOD2 by MCAO in the hippocampal CA1 region were significantly elevated by 1.5 mg/kg dioscin administration. These findings suggested that pretreatment of dioscin had a neuroprotective effect on mice transient focal cerebral ischemia via inhibiting the gliosis and elevating the SOD levels.展开更多
Retinal damage in the adult zebrafish induces Müller glia reprogramming to produce neuronal progenitor cells that proliferate and differentiate into retinal neurons.Notch signaling,which is a fundamental mechanis...Retinal damage in the adult zebrafish induces Müller glia reprogramming to produce neuronal progenitor cells that proliferate and differentiate into retinal neurons.Notch signaling,which is a fundamental mechanism known to drive cell-cell communication,is required to maintain Müller glia in a quiescent state in the undamaged retina,and repression of Notch signaling is necessary for Müller glia to reenter the cell cycle.The dynamic regulation of Notch signaling following retinal damage also directs proliferation and neurogenesis of the Müller glia-derived progenitor cells in a robust regeneration response.In contrast,mammalian Müller glia respond to retinal damage by entering a prolonged gliotic state that leads to additional neuronal death and permanent vision loss.Understanding the dynamic regulation of Notch signaling in the zebrafish retina may aid efforts to stimulate Müller glia reprogramming for regeneration of the diseased human retina.Recent findings identified DeltaB and Notch3 as the ligand-receptor pair that serves as the principal regulators of zebrafish Müller glia quiescence.In addition,multi-omics datasets and functional studies indicate that additional Notch receptors,ligands,and target genes regulate cell proliferation and neurogenesis during the regeneration time course.Still,our understanding of Notch signaling during retinal regeneration is limited.To fully appreciate the complex regulation of Notch signaling that is required for successful retinal regeneration,investigation of additional aspects of the pathway,such as post-translational modification of the receptors,ligand endocytosis,and interactions with other fundamental pathways is needed.Here we review various modes of Notch signaling regulation in the context of the vertebrate retina to put recent research in perspective and to identify open areas of inquiry.展开更多
Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has sh...Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration,the role of lutein alone remains unclear.In this study,we administered intragastric lutein to Pde6brd10 model mice,which display degeneration of retinal photoreceptors,on postnatal days 17(P17)to P25,when rod apoptosis reaches peak.Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control.Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells,in line with an increased survival rate of photoreceptors.Functionally,lutein improved visual behavior,visual acuity,and retinal electroretinogram responses in Pde6brd10 mice.Mechanistically,lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells.The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects.This study was approved by the Laboratory Animal Ethics Committee of Jinan University(approval No.LACUC-20181217-02)on December 17,2018.展开更多
OBJECTIVE:To explore the underlying mechanism of acupuncture on nerve repair by investigating its effect on the differentiation of glial cells and the repair of glial scars.METHODS:Sprague-Dawley rats were randomly al...OBJECTIVE:To explore the underlying mechanism of acupuncture on nerve repair by investigating its effect on the differentiation of glial cells and the repair of glial scars.METHODS:Sprague-Dawley rats were randomly allocated to three groups:normal group,model group,and acupuncture group.Acupuncture was applied at Renzhong(GV26),Baihui(GV20),Fengfu(GV16),Yamen(GV15)and Hegu(LI4)within 12 h after TBI modeling with a frequency of one session per day for 4 weeks.Neurobehavioral assessment,hematoxylin and eosin staining,immunofluorescence detection,and magnetic resonance imaging scanning were performed on days 3,7,14,and 28 after modeling of traumatic brain injury(TBI).RESULTS:Acupuncture promoted the proliferation of glial cells and glial scars at an early stage but inhibited the proliferation of glial cells and glial scars at a late stage.Morphological observations and immunofluorescence histochemistry showed that the morphology of the perilesional cortex in the acupuncture group was improved and the number of neurons was increased when compared with the model group.The lesion size of ipsilateral brain parenchyma in the acupuncture group was smaller than in the model group on days 7,14,and 28(P<0.05)after TBI modeling.CONCLUSIONS:Acupuncture might have a bidirectional regulatory effect on glial scar repair after TBI by promoting the proliferation of glial cells and glial scars to limit the injured area and relieve nerve injury during the early stages,and by inhibiting glial scar hyperplasia to benefit the regeneration and repair of neurons and axons and promote neurological function recovery during the later stages.展开更多
基金Supported by the Natural Science Foundation of Guangdong Province(No.2018A0303130293,No.2023A1515012470).
文摘AIM:To investigate the effects of Sonic hedgehog(Shh)gene-modified bone marrow mesenchymal stem cells(MSCs)on graft-induced retinal gliosis and retinal ganglion cells(RGCs)survival in diabetic mice.METHODS:Bone marrow-derived MSCs were genetically modified with the Shh gene to generate a stably transfected cell line of Shh-modified MSCs(MSC-Shh).Intravitreal injections of MSC-Shh and green fluorescent protein-modified MSCs(MSC-Gfp;control)were administered in diabetic mice.After 4wk,the effects of MSC-Shh on retinal gliosis were evaluated using fundus photography,and markers of gliosis were examined by immunofluorescence and Western blotting.The neurotrophic factors expression and RGCs survival in the host retina were evaluated using Western blotting and immunofluorescence.The mechanisms underlying the effects of MSC-Shh was investigated.RESULTS:A significant reduction of proliferative vitreoretinopathy(PVR)was observed after intravitreal injection of MSC-Shh compared to MSC-Gfp.Significant downregulation of glial fibrillary acidic protein(GFAP)was demonstrated in the host retina after MSC-Shh administration compared to MSC-Gfp.The extracellular signal-regulated kinase 1/2(ERK1/2),protein kinase B(AKT)and phosphatidylin-ositol-3-kinase(PI3K)pathways were significantly downregulated after MSC-Shh administration compared to MSC-Gfp.Brain-derived neurotrophic factor(BDNF)and ciliary neurotrophic factor(CNTF)levels were significantly increased in the host retina,and RGCs loss was significantly prevented after MSC-Shh administration.CONCLUSION:MSC-Shh administration reduces graft-induced reactive gliosis following intravitreal injection in diabetic mice.The ERK1/2,AKT and PI3K pathways are involved in this process.MSC-Shh also increases the levels of neurotrophic factors in the host retina and promoted RGCs survival in diabetic mice.
基金Supported by National Natural Science Foundation of China(No.81974135,No.81900851)。
文摘AIM:To evaluate the effects of intravitreal slow-release dexamethasone on traumatic proliferative vitreoretinopathy(PVR)and Müller cell gliosis and preliminarily explored the possible inflammatory mechanism in a rabbit model induced by penetrating ocular trauma.METHODS:Traumatic PVR was induced in the right eyes of pigmented rabbits by performing an 8-mm circumferential scleral incision placed 2.5 mm behind the limbus,followed by treatment with a slow-release dexamethasone implant(Ozurdex)or sham injection.Left eyes were used as normal controls.The intraocular pressure(IOP)was monitored using an iCare tonometer.PVR severity was evaluated via anatomical and histopathological examinations every week for 6wk;specific inflammatory cytokine and proliferative marker levels were measured by quantitative real-time polymerase chain reaction,Western blot,protein chip analysis,or immunofluorescence staining.RESULTS:During the observation period,PVR severity gradually increased.Intense Müller cell gliosis was observed in the peripheral retina near the wound and in the whole retina of PVR group.Ozurdex significantly alleviated PVR development and Müller cell gliosis.Post-traumatic inflammation fluctuated and was persistent.The interleukin-1β(IL-1β)mRNA level was significantly upregulated,peaking on day 3 and increasing again on day 21 after injury.The expression of nod-like receptor family pyrin domain containing 3(NLRP3)showed a similar trend that began earlier than that of IL-1βexpression.Ozurdex suppressed the expression of IL-1β,NLRP3,and phosphorylated nuclear factor-kappa B(NF-κB).The average IOP after treatment was within normal limits.CONCLUSION:The present study demonstrates chronic and fluctuating inflammation in a traumatic PVR rabbit model over 6wk.Ozurdex treatment significantly inhibites inflammatory cytokines expression and Müller cell gliosis,and thus alleviates PVR severity.This study highlights the important role of IL-1β,and Ozurdex inhibites inflammation presumably via the NF-κB/NLRP3/IL-1βinflammatory axis.In summary,Ozurdex provides a potential therapeutic option for traumatic PVR.
文摘The authors regret an error in Fig.4I,where the wrong DAPI and merged images were inadvertently introduced in Rot group when composing the layouts.The authors have replaced the wrong images with the corrected ones,this correction has not changed the results,interpretation,or conclusions of the article.The original data of these figures have been provided to the Editorial Office,and the corresponding authors can be contacted for original data access.The authors would like to apologize for any inconvenience caused.
基金supported by the Army Laboratory Animal Foundation of China,No.SYDW[2020]22(to TC)the Shaanxi Provincial Key R&D Plan General Project of China,No.2022SF-236(to YM)the National Natural Science Foundation of China,No.82202070(to TC)。
文摘A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity.After 4 weeks of tail suspension,there were no notable alterations in retinal function and morphology,while after 8 weeks of tail suspension,significant reductions in retinal function were observed,and the outer nuclear layer was thinner,with abundant apoptotic cells.To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina,proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension.The results showed that the expression levels of fibroblast growth factor 2(also known as basic fibroblast growth factor)and glial fibrillary acidic protein,which are closely related to Müller cell activation,were significantly upregulated.In addition,Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks,respectively,of simulated weightlessness.These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.
文摘Background In response to the injury of the central nervous system （CNS）, the astrocytes upregulate the expression of glial fibrillary acidic protein （GFAP）, which largely contributes to the reactive gliosis after brain injury. The regulatory mechanism of this process is still not clear. In this study, we aimed to compare the ephrin-B2 deficient mice with the wild type ones with regard to qliosis after traumatic brain injury
基金supported by Special Financial Grant from the China Postdoctoral Science Foundation(2015T80592)General Financial Grant from the China Postdoctoral Foundation(2014M561720)+1 种基金Key University Science Research Project of Jiangsu Province(16KJA310006)Yangzhou University Student Academic Science and Technology Innovation Project(X20170835)
文摘Objective: Stroke is the second leading cause of death worldwide. This study aimed to investigate the neuroprotective effect of Paeoniae Radix Rubra(PRR) on ischemic stroke of mice.Methods: The focal ischemic stroke model was produced via middle cerebral artery occlusion. The experimental mice were divided into four groups: vehicle-sham group, PRR-sham group, vehicle-ischemia group, and PRR-treated ischemia group. The cerebral infarction volume was detected with TTC staining.The number of neurons in the hippocampal CA1 of the ischemic side, and the activation of astrocytes and microglia were observed via immunohistochemical staining. Western blotting was used to determine the expression changes of SOD1, SOD2, and Catalase protein levels in the hippocampus.Results: PRR significantly reduced the cerebral infarct volume induced by ischemic injury and inhibited the astrocytes and microglia activation in the hippocampal CA1 region. The decreased levels of SOD1,SOD2, and Catalase that was induced by ischemic reperfusion were simultaneously improved after PRR treatment.Conclusion: PRR improved neuronal injuries that were induced by transient cerebral ischemia via inhibiting gliosis and elevating anti-oxidants.
基金supported by the National Natural Science Foundation of China,No.82101493(to JY)。
文摘Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.
基金supported by Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology,No.20200730009 (to YX)the National Natural Science Foundation of China,No.82074169 (to XM)+2 种基金the Guangdong Basic and Applied Basic Research Foundation,No.2021A1515012473 (to XM)Project of Administration of Traditional Chinese Medicine of Guangdong Province,No.20202045 (to XM)Aier Eye Hospital Group,No.AF2019001 (to ST,KFS,YX,XM)。
文摘Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide(Lb GP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of Lb GP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of Lb GP as a protective pre-treatment on days 1–7;intraperitoneal administration of 40 mg/kg N-methylN-nitrosourea to induce photoreceptor injury on day 7;and continuation of orally administered Lb GP on days 8–14. Treatment with Lb GP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. Lb GP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, Lb GP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration.
基金the National Natural Science Foundation of China (No. 30500189)
文摘Objective The present study aimed to explore the role of P2Y1 receptor in glial fibrillary acidic protein （GFAP） production and glial cell line-derived neurotrophic factor （GDNF） secretion of astrocytes under ischemic insult and the related signaling pathways. Methods Using transient right middle cerebral artery occlusion （tMCAO） and oxygen-glucose-serum deprivation for 2 h as the model of ischemic injury in vivo and in vitro, immunofluorescence, quantitative real-time reverse transcription-polymerase chain reaction （RT-PCR）, Western blotting, enzyme linked immunosorbent assay （ELISA） were used to investigate location of P2Y1 receptor and GDNF, the expression of GFAP and GDNF, and the changes of signaling molecules. Results Blockage of P2Y1 receptor with the selective antagonist N^6-methyl-2′-deoxyadenosine 3′,5′-bisphosphate diammonium （MRS2179） reduced GFAP production and increased GDNF production in the antagonist group as compared with simple ischemic group both in vivo and in vitro. Oxygen-glucose-serum deprivation and blockage of P2Y1 receptor caused elevation of phosphorylated Akt and cAMP response element binding protein （CREB）, and reduction of phosphorylated Janus kinase2 （JAK2） and signal transducer and activator of transcription3 （STAT3, Ser727）. After blockage of P2Y1 receptor and deprivation of oxygen-glucose-serum, AG490 （inhibitor of JAK2） reduced phosphorylation of STAT3 （Ser727） as well as expression of GFAP; LY294002, an inhibitor of phosphatidylinositol 3-kinase （PI3-K）, decreased phosphorylation of Akt and CREB; the inhibitor of mitogen-activated protein kinase kinase 1/2 （MEK 1/2） U0126, an important molecule of Ras/extracellular signal- regulated kinase （ERK） signaling pathway, decreased the phosphorylation of JAK2, STAT3 （Ser727）, Akt and CREB. Conclusion These results suggest that P2Y1 receptor plays a role in the production of GFAP and GDNF in astrocytes under transient ischemic condition and the related signaling pathways may be JAK2/STAT3 and PI3-K/Akt/CREB, respectively, and that crosstalk probably exists between them.
基金supported by the Key Project of National Natural Science Foundation of China(No.51136002)China Key Technologies R&D Program(No.2012BAJ02B03)
文摘Plastics such as polyvinyl chlorides （PVC） are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-（2-ethylhexyl） phthalates （DEHP）, can leach into the surrounding environment. This study focused on DEHP＇s effect on the central nervous system by determining the precise DEHP content in mice brain tissue after exposure to the chemical, to evaluate the specific exposure range. Primary neuronal-astrocyte co-culture systems were used as in vitro models for chemical hazard identification of DEHP. Oxidative stress was hypothesized as a probable mechanism involved, and therefore the total reactive oxygen species （ROS） concentration was determined as a biomarker of oxidative stress. In addition, NeuriteTracer, a neurite tracing plugin with ImageJ, was used to develop an assay for neurotoxicity to provide quantitative measurements of neurological parameters, such as neuronal number, neuron count and neurite length, all of which could indicate neurotoxic effects. The results showed that with 1 nmol/L DEHP exposure, there was a significant increase in ROS concentrations, indicating that the neuronal-astrocyte cultures were injured due to exposure to DEHP. In response, astrocyte proliferation （gliosis） was initiated, serving as a mechanism to maintain a homeostatic environment for neurons and protect neurons from toxic chemicals. There is a need to assess the cumulative effects of DEHP in animals to evaluate the possible uotake and effects on the human neuronal system from exoosure to DEHP in the indoor environment.
基金This work was supported by the Medical Scientist Training Program T32GM007250Predoctoral Training in Molecular Therapeutics Program T32GM008803(to EHC).
文摘A long-standing goal of spinal cord injury research is to develop effective repair strategies,which can restore motor and sensory functions to near-normal levels.Recent advances in clinical management of spinal cord injury have significantly improved the prognosis,survival rate and quality of life in patients with spinal cord injury.In addition,a significant progress in basic science research has unraveled the underlying cellular and molecular events of spinal cord injury.Such efforts enabled the development of pharmacologic agents,biomaterials and stem-cell based therapy.Despite these efforts,there is still no standard care to regenerate axons or restore function of silent axons in the injured spinal cord.These challenges led to an increased focus on another therapeutic approach,namely neuromodulation.In multiple animal models of spinal cord injury,epidural electrical stimulation of the spinal cord has demonstrated a recovery of motor function.Emerging evidence regarding the efficacy of epidural electrical stimulation has further expanded the potential of epidural electrical stimulation for treating patients with spinal cord injury.However,most clinical studies were conducted on a very small number of patients with a wide range of spinal cord injury.Thus,subsequent studies are essential to evaluate the therapeutic potential of epidural electrical stimulation for spinal cord injury and to optimize stimulation parameters.Here,we discuss cellular and molecular events that continue to damage the injured spinal cord and impede neurological recovery following spinal cord injury.We also discuss and summarize the animal and human studies that evaluated epidural electrical stimulation in spinal cord injury.
文摘The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.
基金partially supported by COBRE(P20-GM103642)the MBRS-RISE Program(R25 GM061838)+1 种基金NIH-MARC(5T34GM007821-35)the RCMI program(5G12MD007600)
文摘Spinal cord injury（SCI） is a condition without a cure,affecting sensory and/or motor functions.The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration.Among these complex set of events are damage of the blood-brain barrier,edema formation,inflammation,oxidative stress,demyelination,reactive gliosis and apoptosis.The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival,regeneration,vascular reorganization and synaptic formation.Tamoxifen,a selective estrogen receptor modulator,is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition.Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI.Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant,anti-inflammatory and anti-gliotic responses.A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment.In addition,the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated.This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field.
基金supported by startup funds from Medical College of Georgia at Augusta University(to HL)National Institutes of Health R01NS117918,R21NS104394,and R21NS119732(to HL)。
文摘Spinal cord injury represents a devastating central nervous system injury that could impair the mobility and sensory function of afflicted patients.The hallmarks of spinal cord injury include neuroinflammation,axonal degeneration,neuronal loss,and reactive gliosis.Furthermore,the formation of a glial scar at the injury site elicits an inhibitory environment for potential neuroregeneration.Besides axonal regeneration,a significant challenge in treating spinal cord injury is to replenish the neurons lost during the pathological process.However,despite decades of research efforts,current strategies including stem cell transplantation have not resulted in a successful clinical therapy.Furthermore,stem cell transplantation faces serious hurdles such as immunorejection of the transplanted cells and ethical issues.In vivo neuronal reprogramming is a recently developed technology and leading a major breakthrough in regenerative medicine.This innovative technology converts endogenous glial cells into functional neurons for injury repair in the central nervous system.The feasibility of in vivo neuronal reprogramming has been demonstrated successfully in models of different neurological disorders including spinal cord injury by numerous laboratories.Several reprogramming factors,mainly the pro-neural transcription factors,have been utilized to reprogram endogenous glial cells into functional neurons with distinct phenotypes.So far,the literature on in vivo neuronal reprogramming in the model of spinal cord injury is still small.In this review,we summarize a limited number of such reports and discuss several questions that we think are important for applying in vivo neuronal reprogramming in the research field of spinal cord injury as well as other central nervous system disorders.
基金The work was supported by the National Natural Science Foundation of China,Nos.81470656(to YX),82071372(to AL),82074169(to XSM)Guangdong Grant Key Technologies for Treatment of Brain Disorders’,China,No.2018B030332001(to YX)+3 种基金Ningxia Key Research and Development Program Grant(Yinchuan,Ningxia Hui Autonomous Region,China)(to KFS)Program of Introducing Talents of Discipline to Universities,China,No.B14036(to YX,AL,KFS)Outstanding Scholar Program of Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory),No.2018GZR110102002(to KFS,AL)Science and Technology Program of Guangzhou,No.202007030012(to KFS and AL).
文摘Luteolin is neuroprotective for retinal ganglion cells and retinal pigment epithelial cells after oxidative injury,whereby it can inhibit microglial neurotoxicity.Therefore,luteolin holds the potential to be useful for treatment of retinal diseases.The purpose of this study was to investigate whether luteolin exhibits neuroprotective effects on rod cells in rd10 mice,a slow photoreceptor-degenerative model of retinitis pigmentosa.Luteolin(100 mg/kg)intraperitoneally injected daily from postnatal day 14(P14)to P25 significantly enhanced the visual performance and retinal light responses of rd10 mice at P25.Moreover,it increased the survival of photoreceptors and improved retinal structure.Mechanistically,luteolin treatment attenuated increases in reactive oxygen species,photoreceptor apoptosis,and reactive gliosis;increased mRNA levels of anti-inflammatory cytokines while lowering that of pro-inflammatory and chemoattractant cytokines;and lowered the ratio of phospho-JNK/JNK.Application of the JNK inhibitor SP600125 exerted a similar protective effect to luteolin,suggesting that luteolin delays photoreceptor degeneration and functional deterioration in rd10 mice through regulation of retinal oxidation and inflammation by inhibiting the JNK pathway.Therefore,luteolin may be useful as a supplementary treatment for retinitis pigmentosa.This study was approved by the Qualified Ethics Committee of Jinan University,China(approval No.IACUC-20181217-02)on December 17,2018.
基金supported by grants from Regione Campania(L.R.N.5 Bando 2003,to MP)the Italian Minister of Research and University(PRIN 2007,to MP+1 种基金 PRIN 2017,to GC and MP)UNIMIB(Progetto ID 2019-ATESP-0001 and Progetto ID 2018-CONV-0056,to AV)
文摘The main pathological feature of the neurodegenerative diseases is represented by neuronal death that represents the final step of a cascade of adverse/hostile events.Early in the neurodegenerative process,glial cells (including astrocytes,microglial cells,and oligodendrocytes) activate and trigger an insidious neuroinflammatory reaction,metabolic decay,blood brain barrier dysfunction and energy impairment,boosting neuronal death.How these mechanisms might induce selective neuronal death in specific brain areas are far from being elucidated.The last two decades of neurobiological studies have provided evidence of the main role of glial cells in most of the processes of the central nervous system,from development to synaptogenesis,neuronal homeostasis and integration into,highly specific neuro-glial networks.In this mini-review,we moved from in vitro and in vivo models of neurodegeneration to analyze the putative role of glial cells in the early mechanisms of neurodegeneration.We report changes of transcriptional,genetic,morphological,and metabolic activity in astrocytes and microglial cells in specific brain areas before neuronal degeneration,providing evidence in experimental models of neurodegenerative disorders,including Parkinson’s and Alzheimer’s diseases.Understanding these mechanisms might increase the insight of these processes and pave the way for new specific glia-targeted therapeutic strategies for neurodegenerative disorders.
基金The National Natural Science Foundation of China(Grant No.81401005)the Natural Science Foundation of Jiangsu Province of China(Grant No.BK20140494)the College Students’Practice Innovation Training Program Projects of Jiangsu Province(Grant No.201611117094X)
文摘In the present study, we aimed to explore the neuroprotective effect of dioscin, a natural steroid saponin, on transient focal cerebral ischemia induced by middle cerebral artery occlusion （MCAO） in mice and its related mechanism, We observed that dioscin （1,5 mg/kg, intracerebroventricular injection 30 min before MCAO） dramatically reduced the cerebral infarct volume, leading to improved neurological symptoms and reduced death of neuron, astrocytes and microglia in the infarct region. The gliosis and the reduced expressions of SOD1 and SOD2 by MCAO in the hippocampal CA1 region were significantly elevated by 1.5 mg/kg dioscin administration. These findings suggested that pretreatment of dioscin had a neuroprotective effect on mice transient focal cerebral ischemia via inhibiting the gliosis and elevating the SOD levels.
基金National Eye Institute R01-EY024519 and U01-EY027267(to DRH)the Center for Zebrafish Research,University of Notre Dame.
文摘Retinal damage in the adult zebrafish induces Müller glia reprogramming to produce neuronal progenitor cells that proliferate and differentiate into retinal neurons.Notch signaling,which is a fundamental mechanism known to drive cell-cell communication,is required to maintain Müller glia in a quiescent state in the undamaged retina,and repression of Notch signaling is necessary for Müller glia to reenter the cell cycle.The dynamic regulation of Notch signaling following retinal damage also directs proliferation and neurogenesis of the Müller glia-derived progenitor cells in a robust regeneration response.In contrast,mammalian Müller glia respond to retinal damage by entering a prolonged gliotic state that leads to additional neuronal death and permanent vision loss.Understanding the dynamic regulation of Notch signaling in the zebrafish retina may aid efforts to stimulate Müller glia reprogramming for regeneration of the diseased human retina.Recent findings identified DeltaB and Notch3 as the ligand-receptor pair that serves as the principal regulators of zebrafish Müller glia quiescence.In addition,multi-omics datasets and functional studies indicate that additional Notch receptors,ligands,and target genes regulate cell proliferation and neurogenesis during the regeneration time course.Still,our understanding of Notch signaling during retinal regeneration is limited.To fully appreciate the complex regulation of Notch signaling that is required for successful retinal regeneration,investigation of additional aspects of the pathway,such as post-translational modification of the receptors,ligand endocytosis,and interactions with other fundamental pathways is needed.Here we review various modes of Notch signaling regulation in the context of the vertebrate retina to put recent research in perspective and to identify open areas of inquiry.
基金supported by Aier Eye Hospital Group,Nos.AF2019001 and AF2019002(to SBT,KFS,YX and XSM)the National Natural Science Foundation of China,No.82074169(to XSM)+3 种基金Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology of China,No.20200730009(to YX)Guangdong Grant Key Technologies for Treatment of Brain Disorders,China,No.2018B030332001(to YX)Natural Science Foundation of Guangdong Province of China,No.2021A1515012473(to XSM)Project of Administration of Traditional Chinese Medicine of Guangdong Province,No.20202045(to XSM)。
文摘Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration,the role of lutein alone remains unclear.In this study,we administered intragastric lutein to Pde6brd10 model mice,which display degeneration of retinal photoreceptors,on postnatal days 17(P17)to P25,when rod apoptosis reaches peak.Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control.Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells,in line with an increased survival rate of photoreceptors.Functionally,lutein improved visual behavior,visual acuity,and retinal electroretinogram responses in Pde6brd10 mice.Mechanistically,lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells.The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects.This study was approved by the Laboratory Animal Ethics Committee of Jinan University(approval No.LACUC-20181217-02)on December 17,2018.
基金Supported by National Natural Science Foundation of China:Explore the Effect and Mechanism of Acupuncture for Neuroinflammation and Glial Scars After Traumatic Brain Injury Based on the Signaling Pathway of TLR2/4-NFκB(No.81574066)National Natural Science Foundation of China:Explore the Effect of Acupuncture on Brain Function Remodeling and the Benign Bidirectional Regulation to Autophagy After TBI(No.81873362)+4 种基金National Natural Science Foundation of China:Basing on the Theory of Bidirectional Benign Regulation to Investigate the Mechanism of Acupuncture Regulating Microglia-mediated Immune Imbalance to Promote Nerve Repair After TBI(No.82174483)National Natural Science Foundation of China:Based on Iron Metabolic Pathway to Explore the Mechanism of Electroacupuncture Inhibits Ferroptosis to Reduce TBI Nerve Injury(No.82205249)China Postdoctoral Science Foundation:the Effect and Mechanism of Electroacupuncture in Promoting Neural Function Repair by Regulating Iron Metabolism in Neurons of TBI Rats(2022M710912)Natural Science Foundation of Guangdong Province:the Effect and Mechanism of Acupuncture on the Linkage of Neuron Autophagy and Apoptosis after TBI Based on PI3K/AKT/mTOR Signaling Pathway(2021A1515011219)Natural Science Foundation of Guangdong Province:the Effect and Mechanism of Acupuncture on Microglial Polarization Mediated Immune Homeostasis After TBI Based on TREM2/STAT6/NFκB Signaling Pathway(2021A1515110146)。
文摘OBJECTIVE:To explore the underlying mechanism of acupuncture on nerve repair by investigating its effect on the differentiation of glial cells and the repair of glial scars.METHODS:Sprague-Dawley rats were randomly allocated to three groups:normal group,model group,and acupuncture group.Acupuncture was applied at Renzhong(GV26),Baihui(GV20),Fengfu(GV16),Yamen(GV15)and Hegu(LI4)within 12 h after TBI modeling with a frequency of one session per day for 4 weeks.Neurobehavioral assessment,hematoxylin and eosin staining,immunofluorescence detection,and magnetic resonance imaging scanning were performed on days 3,7,14,and 28 after modeling of traumatic brain injury(TBI).RESULTS:Acupuncture promoted the proliferation of glial cells and glial scars at an early stage but inhibited the proliferation of glial cells and glial scars at a late stage.Morphological observations and immunofluorescence histochemistry showed that the morphology of the perilesional cortex in the acupuncture group was improved and the number of neurons was increased when compared with the model group.The lesion size of ipsilateral brain parenchyma in the acupuncture group was smaller than in the model group on days 7,14,and 28(P<0.05)after TBI modeling.CONCLUSIONS:Acupuncture might have a bidirectional regulatory effect on glial scar repair after TBI by promoting the proliferation of glial cells and glial scars to limit the injured area and relieve nerve injury during the early stages,and by inhibiting glial scar hyperplasia to benefit the regeneration and repair of neurons and axons and promote neurological function recovery during the later stages.
