Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’...Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.展开更多
Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain met...Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.展开更多
The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous syst...The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.展开更多
The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regul...The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.展开更多
Over the past few decades,the Sonic Hedgehog protein has become a pivotal player in many biological processes,including tumourigenesis,embryonic development,and protective mechanisms after cerebral damage.The Sonic He...Over the past few decades,the Sonic Hedgehog protein has become a pivotal player in many biological processes,including tumourigenesis,embryonic development,and protective mechanisms after cerebral damage.The Sonic Hedgehog signaling pathway is crucial in the central nervous system,with implications in a diverse range of diseases,including Parkinson's disease,Alzheimer's disease,spinal cord injury,traumatic brain injury,depression,Sonic Hedgehog medulloblastoma,and stroke.In this comprehensive review,we examined Sonic Hedgehog from the perspective of canonical and non-canonical pathways,elucidating their complex connections to the central nervous system.Subsequently,we summarize the latest advancements in drug therapies that offer novel strategies for treating neurological diseases by modulating the Sonic Hedgehog protein.Finally,we summarize and extend the technologies and tools for studying the Sonic Hedgehog signaling field,with the aim of providing new research ideas and methods.展开更多
The optimal development,function,and maintenance of the central nervous system(CNS)are determined by the dynamic and continuous crosstalk between its components.Neurons and glial cells,the cellular constituents of the...The optimal development,function,and maintenance of the central nervous system(CNS)are determined by the dynamic and continuous crosstalk between its components.Neurons and glial cells,the cellular constituents of the CNS,orchestrate a wide range of essential activities(Allen and Lyons,2018).Notably,glial cells,which outnumber neurons,constitute the major population within the CNS.This population comprises astrocytes,microglia,oligodendrocytes,and ependymal cells,each fulfilling specialized functions that contribute to neural homeostasis and overall CNS integrity.Astrocytes are pivotal in preserving structural and functional integrity through the regulation of synaptic function,the clearance of neurotransmitters,and ion balance.Moreover,they provide metabolic support to neurons.展开更多
The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzh...The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.展开更多
In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,...In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,allowing them to target deep brain lesions.Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines,mRNAs,and disease-related proteins,thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects.However,exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells.This limitation can lead to side effects and toxicity when they interact with non-specific cells.Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases.In this review,we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases.Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases.We introduce the strategies being used to enhance exosome targeting,including genetic engineering,chemical modifications(both covalent,such as click chemistry and metabolic engineering,and non-covalent,such as polyvalent electrostatic and hydrophobic interactions,ligand-receptor binding,aptamer-based modifications,and the incorporation of CP05-anchored peptides),and nanomaterial modifications.Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases.However,several challenges remain in the clinical application of exosomes.Improvements are needed in preparation,characterization,and optimization methods,as well as in reducing the adverse reactions associated with their use.Additionally,the range of applications and the safety of exosomes require further research and evaluation.展开更多
Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown t...Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARαplays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.展开更多
Oligodendrocyte precursor cells(OPCs)tile the central nervous system ubiquitously,accounting for about 5%of the total cell population in the central nervous system.Beyond their role in myelination,OPCs actively shape ...Oligodendrocyte precursor cells(OPCs)tile the central nervous system ubiquitously,accounting for about 5%of the total cell population in the central nervous system.Beyond their role in myelination,OPCs actively shape neural circuits(Fang and Bai,2023),by releasing neuromodulators,pruning synapses,maintaining the homeostasis of extracellular potassium concentration,and interacting with endothelial cells.展开更多
Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indice...Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indices,has provided a fresh perspective and valuable insight into the study of freezing of gait in Parkinson's disease.It has been revealed that Parkinson's disease is accompanied by widespread irregularities in inherent brain network activity.However,the effective integration of the multi-level indices of resting-state functional magnetic resonance imaging into clinical settings for the diagnosis of freezing of gait in Parkinson's disease remains a challenge.Although previous studies have demonstrated that radiomics can extract optimal features as biomarkers to identify or predict diseases,a knowledge gap still exists in the field of freezing of gait in Parkinson's disease.This cross-sectional study aimed to evaluate the ability of radiomics features based on multi-level indices of resting-state functional magnetic resonance imaging,along with clinical features,to distinguish between Parkinson's disease patients with and without freezing of gait.We recruited 28 patients with Parkinson's disease who had freezing of gait(15 men and 13 women,average age 63 years)and 30 patients with Parkinson's disease who had no freezing of gait(16 men and 14 women,average age 64 years).Magnetic resonance imaging scans were obtained using a 3.0T scanner to extract the mean amplitude of low-frequency fluctuations,mean regional homogeneity,and degree centrality.Neurological and clinical characteristics were also evaluated.We used the least absolute shrinkage and selection operator algorithm to extract features and established feedforward neural network models based solely on resting-state functional magnetic resonance imaging indicators.We then performed predictive analysis of three distinct groups based on resting-state functional magnetic resonance imaging indicators indicators combined with clinical features.Subsequently,we conducted 100 additional five-fold cross-validations to determine the most effective model for each classification task and evaluated the performance of the model using the area under the receiver operating characteristic curve.The results showed that when differentiating patients with Parkinson's disease who had freezing of gait from those who did not have freezing of gait,or from healthy controls,the models using only the mean regional homogeneity values achieved the highest area under the receiver operating characteristic curve values of 0.750(with an accuracy of 70.9%)and 0.759(with an accuracy of 65.3%),respectively.When classifying patients with Parkinson's disease who had freezing of gait from those who had no freezing of gait,the model using the mean amplitude of low-frequency fluctuation values combined with two clinical features achieved the highest area under the receiver operating characteristic curve of 0.847(with an accuracy of 74.3%).The most significant features for patients with Parkinson's disease who had freezing of gait were amplitude of low-frequency fluctuation alterations in the left parahippocampal gyrus and two clinical characteristics:Montreal Cognitive Assessment and Hamilton Depression Scale scores.Our findings suggest that radiomics features derived from resting-state functional magnetic resonance imaging indices and clinical information can serve as valuable indices for the identification of freezing of gait in Parkinson's disease.展开更多
Neural cell differentiation and maturation is a critical step during central nervous system devel-opment. The oligodendrocyte transcription family （Olig family） is known to be an important factor in regulating neura...Neural cell differentiation and maturation is a critical step during central nervous system devel-opment. The oligodendrocyte transcription family （Olig family） is known to be an important factor in regulating neural cell differentiation. Because of this, the Olig family also affects acute and chronic central nervous system diseases, including brain injury, multiple sclerosis, and even gliomas. Improved understanding about the functions of the Olig family in central nervous system development and disease will greatly aid novel breakthroughs in central nervous system diseases. This review investigates the role of the Olig family in central nervous system develop- ment and related diseases.展开更多
Microglia serve as brain-resident myeloid cells that affect cerebral development, ischemia, neurodegeneration, and neuro-viral infection. MicroRNAs play a key role in central nervous system disease through post-transc...Microglia serve as brain-resident myeloid cells that affect cerebral development, ischemia, neurodegeneration, and neuro-viral infection. MicroRNAs play a key role in central nervous system disease through post-transcriptional regulation. Indeed, evidence shows that microRNAs are one of the most important regulators mediating microglial activation, polarization, and autophagy, and subsequently affecting neuroinflammation and the outcome of central nervous system disease. In this review, we provide insight into the function of microRNAs, which may be an attractive strategy and influential treatment for microglia-related central nervous system dysfunction. Moreover, we comprehensively describe how microglia fight against central nervous system disease via multiple functional microRNAs.展开更多
Extracellular vesicles,including exosomes and microvesicles,play a fundamental role in the activity of the nervous system,participating in signal transmission between neurons and providing the interaction of central n...Extracellular vesicles,including exosomes and microvesicles,play a fundamental role in the activity of the nervous system,participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems.In many neurodegenerative diseases,neurons pack toxic substances into vesicles and release them into the extracellular space,which leads to the spread of misfolded neurotoxic proteins.The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system,and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases.Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier.Today,the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis,specificallyα-synuclein,tau protein,superoxide dismutase 1,FUS,leucine-rich repeat kinase 2,as well as some synaptic proteins,has been well evidenced.Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles,which are important in the onset and development of many neurodegenerative diseases.Depending on parental cell type,extracellular vesicles may have different therapeutic properties,including neuroprotective,regenerative,and anti-inflammatory.Due to nano size,biosafety,ability to cross the blood-brain barrier,possibility of targeted delivery and the lack of an immune response,extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain.This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles.展开更多
Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular funct...Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular functions such as migration, survival, proliferation, and differentiation. Oligodendrocytes are the myelin-forming cells in the central nervous system and play critical roles in the conduction of action potentials, supply of metabolic components for axons, and other functions. Emerging evidence suggests that both oligodendrocytes and oligodendrocyte precursor cells are vulnerable to cytokines released under pathological conditions. This review mainly summarizes the effects of cytokines on oligodendrocyte lineage cells in central nervous system diseases. A comprehensive understanding of the effects of cytokines on oligodendrocyte lineage cells contributes to our understanding of central nervous system diseases and offers insights into treatment strategies.展开更多
Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,...Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive molecules.Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders.These exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic effects.Furthermore,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug encapsulation.Consequently,researchers have turned their attention to exosomes as a novel therapeutic avenue.Nonetheless,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application.To overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system.By exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier.Notably,exosomes,owing to their small size,can readily access the nerve pathways using this method.As a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments.In this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases.Furthermore,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.展开更多
Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phen...Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes;these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer’s disease. Our literature search found that phenotypic changes occur continuously in Alzheimer’s disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer’s disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer’s disease.展开更多
Photobiomodulation using light in the red or near-infrared region is an innovative treatment strategy for a wide range of neurological and psychological conditions.Photobiomodulation can promote neurogenesis and elici...Photobiomodulation using light in the red or near-infrared region is an innovative treatment strategy for a wide range of neurological and psychological conditions.Photobiomodulation can promote neurogenesis and elicit anti-apoptotic,antiinflammatory and antioxidative responses.Its therapeutic effects have been demonstrated in studies on neurological diseases,peripheral nerve injuries,pain relief and wound healing.We conducted a comprehensive literature review of the application of photobiomodulation in patients with central nervous system diseases in February 2019.The NCBI PubMed database,EMBASE database,Cochrane Library and ScienceDirect database were searched.We reviewed 95 papers and analyzed.Photobiomodulation has wide applicability in the treatment of stroke,traumatic brain injury,Parkinson’s disease,Alzheimer’s disease,major depressive disorder,and other diseases.Our analysis provides preliminary evidence that PBM is an effective therapeutic tool for the treatment of central nervous system diseases.However,additional studies with adequate sample size are needed to optimize treatment parameters.展开更多
Programmed cell death protein 1(PD-1)is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment.Accumulating evid...Programmed cell death protein 1(PD-1)is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment.Accumulating evidence suggests an important role of PD-1 in the central nervous system(CNS).PD-1 has been implicated in CNS disorders such as brain tumors,Alzheimer’s disease,ischemic stroke,spinal cord injury,multiple sclerosis,cognitive function,and pain.PD-1 signaling suppresses the CNS immune response via resident microglia and infiltrating peripheral immune cells.Notably,PD-1 is also widely expressed in neurons and suppresses neuronal activity via downstream Src homology 2 domain-containing protein tyrosine phosphatase 1 and modulation of ion channel function.An improved understanding of PD-1 signaling in the cross-talk between glial cells,neurons,and peripheral immune cells in the CNS will shed light on immunomodulation,neuromodulation,and novel strategies for treating brain diseases.展开更多
Although there are challenges in treating traumatic central nervous system diseases,mesenchymal stem cell-de rived extracellular vesicles(MSC-EVs) have recently proven to be a promising non-cellular the rapy.We compre...Although there are challenges in treating traumatic central nervous system diseases,mesenchymal stem cell-de rived extracellular vesicles(MSC-EVs) have recently proven to be a promising non-cellular the rapy.We comprehensively evaluated the efficacy of mesenchymal stem cell-de rived extracellular vesicles in traumatic central nervous system diseases in this meta-analysis based on preclinical studies.Our meta-analysis was registered at PROSPERO(CRD42022327904,May 24,2022).To fully retrieve the most relevant articles,the following databases were thoro ughly searched:PubMed,Web of Science,The Cochrane Library,and Ovid-Embase(up to April 1,2022).The included studies were preclinical studies of mesenchymal stem cell-derived extracellular vesicles for traumatic central nervous system diseases.The Systematic Review Centre for Laboratory Animal Experimentation(SYRCLE)’s risk of bias tool was used to examine the risk of publication bias in animal studies.After screening 2347studies,60 studies were included in this study.A meta-analysis was conducted for spinal co rd injury(n=52) and traumatic brain injury(n=8).The results indicated that mesenchymal stem cell-derived extracellular vesicles treatment prominently promoted motor function recovery in spinal co rd injury animals,including rat Basso,Beattie and Bresnahan locomotor rating scale scores(standardized mean difference [SMD]:2.36,95% confidence interval [CI]:1.96-2.76,P <0.01,I2=71%) and mouse Basso Mouse Scale scores(SMD=2.31,95% CI:1.57-3.04,P=0.01,I2=60%) compared with controls.Further,mesenchymal stem cell-de rived extracellular vesicles treatment significantly promoted neurological recovery in traumatic brain injury animals,including the modified N eurological Severity Score(SMD=-4.48,95% CI:-6.12 to-2.84,P <0.01,I2=79%) and Foot Fault Test(SMD=-3.26,95% CI:-4.09 to-2.42,P=0.28,I2=21%) compared with controls.Subgroup analyses showed that characteristics may be related to the therapeutic effect of mesenchymal stem cell-de rived extra cellular vesicles.For Basso,Beattie and Bresnahan locomotor rating scale scores,the efficacy of allogeneic mesenchymal stem cell-derived extracellular vesicles was higher than that of xenogeneic mesenchymal stem cell-derived extracellular vesicles(allogeneic:SMD=2.54,95% CI:2.05-3.02,P=0.0116,I2=65.5%;xenogeneic:SMD:1.78,95%CI:1.1-2.45,P=0.0116,I2=74.6%).Mesenchymal stem cellde rived extracellular vesicles separated by ultrafiltration centrifugation combined with density gradient ultra centrifugation(SMD=3.58,95% CI:2.62-4.53,P <0.0001,I2=31%) may be more effective than other EV isolation methods.For mouse Basso Mouse Scale scores,placenta-derived mesenchymal stem cell-de rived extracellular vesicles worked better than bone mesenchymal stem cell-derived extracellular vesicles(placenta:SMD=5.25,95% CI:2.45-8.06,P=0.0421,I2=0%;bone marrow:SMD=1.82,95% CI:1.23-2.41,P=0.0421,I2=0%).For modified Neurological Severity Score,bone marrow-derived MSC-EVs worked better than adipose-derived MSC-EVs(bone marrow:SMD=-4.86,95% CI:-6.66 to-3.06,P=0.0306,I2=81%;adipose:SMD=-2.37,95% CI:-3.73 to-1.01,P=0.0306,I2=0%).Intravenous administration(SMD=-5.47,95% CI:-6.98 to-3.97,P=0.0002,I2=53.3%) and dose of administration equal to 100 μg(SMD=-5.47,95% CI:-6.98 to-3.97,P <0.0001,I2=53.3%)showed better res ults than other administration routes and doses.The heterogeneity of studies was small,and sensitivity analysis also indicated stable results.Last,the methodological quality of all trials was mostly satisfactory.In conclusion,in the treatment of traumatic central nervous system diseases,mesenchymal stem cell-derived extracellular vesicles may play a crucial role in promoting motor function recovery.展开更多
基金supported by the National Key R&D Program of China,No.2021YFC2501200(to PC).
文摘Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.
基金supported by the National Natural Science Foundation of China, No.82274616the Key Laboratory Project for General Universities in Guangdong Province, No.2019KSYS005Guangdong Province Science and Technology Plan International Cooperation Project, No.2020A0505100052 (all to QW)。
文摘Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.
文摘The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.
基金supported by grants from Simons Foundation (SFARI 479754),CIHR (PJT-180565)the Scottish Rite Charitable Foundation of Canada (to YL)funding from the Canada Research Chairs program。
文摘The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.
基金supported by the National Natural Science Foundation of China,No.82474468the Science and Technology Innovation Program of Hunan Province,No.2024RC3200+3 种基金the Health Commission Talent Project of Hunan Province,No.20240304118the Scientific Research Project of Hunan Department of Education,No.23A0281the Open Fund for Chinese Medicine Powder and Innovative Drugs in the Cultivation Base of the Provincial-Ministry Jointly Established State Key Laboratory of Chinese Medicine,No.23PTKF1013the Training Plan of Outstanding Innovative Youth of Changsha,No.kq2009018(all to PM)。
文摘Over the past few decades,the Sonic Hedgehog protein has become a pivotal player in many biological processes,including tumourigenesis,embryonic development,and protective mechanisms after cerebral damage.The Sonic Hedgehog signaling pathway is crucial in the central nervous system,with implications in a diverse range of diseases,including Parkinson's disease,Alzheimer's disease,spinal cord injury,traumatic brain injury,depression,Sonic Hedgehog medulloblastoma,and stroke.In this comprehensive review,we examined Sonic Hedgehog from the perspective of canonical and non-canonical pathways,elucidating their complex connections to the central nervous system.Subsequently,we summarize the latest advancements in drug therapies that offer novel strategies for treating neurological diseases by modulating the Sonic Hedgehog protein.Finally,we summarize and extend the technologies and tools for studying the Sonic Hedgehog signaling field,with the aim of providing new research ideas and methods.
基金supported by Linea D.1.2023-24 UniversitàCattolica del S.Cuore(to MTV).
文摘The optimal development,function,and maintenance of the central nervous system(CNS)are determined by the dynamic and continuous crosstalk between its components.Neurons and glial cells,the cellular constituents of the CNS,orchestrate a wide range of essential activities(Allen and Lyons,2018).Notably,glial cells,which outnumber neurons,constitute the major population within the CNS.This population comprises astrocytes,microglia,oligodendrocytes,and ependymal cells,each fulfilling specialized functions that contribute to neural homeostasis and overall CNS integrity.Astrocytes are pivotal in preserving structural and functional integrity through the regulation of synaptic function,the clearance of neurotransmitters,and ion balance.Moreover,they provide metabolic support to neurons.
基金supported by ANR(ANR-21CE16-0008-01)ANR(ANR-21-CE16-0008-02 and ANR-23CE52-0007)+1 种基金UNADEV(A22018CS)(to HN)UNADEV(A22020CS)(to SB)。
文摘The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.
基金supported by the National Natural Science Foundation of China,No.22103055(to JG)the Natural Science Foundation of Hebei Province,No.F2024110001(to HC)Open Project of Tianjin Key Laboratory of Optoelectronic Detection Technology and System,Nos.2024LODTS215(to NL),2024LODTS216(to XS).
文摘In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,allowing them to target deep brain lesions.Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines,mRNAs,and disease-related proteins,thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects.However,exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells.This limitation can lead to side effects and toxicity when they interact with non-specific cells.Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases.In this review,we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases.Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases.We introduce the strategies being used to enhance exosome targeting,including genetic engineering,chemical modifications(both covalent,such as click chemistry and metabolic engineering,and non-covalent,such as polyvalent electrostatic and hydrophobic interactions,ligand-receptor binding,aptamer-based modifications,and the incorporation of CP05-anchored peptides),and nanomaterial modifications.Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases.However,several challenges remain in the clinical application of exosomes.Improvements are needed in preparation,characterization,and optimization methods,as well as in reducing the adverse reactions associated with their use.Additionally,the range of applications and the safety of exosomes require further research and evaluation.
基金supported by grants from Tianjin Scientific Research Project in Key Areas of Traditional Chinese Medicine,Tianjin Municipal Health Commission,No.2024012(to JL)Tianjin Municipal Education Commission Project,No.2021KJ217(to CS)。
文摘Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARαplays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.
基金supported by DeutscheForschungsgemeinschaft(BA 8014/1-1 to XB)University of Saarland(NanoBioMed Young Investigatorgrant 2021 to XB,Anschubsfinanzierung2024to XB,HOMFORExzellenz2025 andAnschubsfinanzierung2025 to LPF)the ChinaPharmaceutical University(UndergraduateInternship Program to YZ).
文摘Oligodendrocyte precursor cells(OPCs)tile the central nervous system ubiquitously,accounting for about 5%of the total cell population in the central nervous system.Beyond their role in myelination,OPCs actively shape neural circuits(Fang and Bai,2023),by releasing neuromodulators,pruning synapses,maintaining the homeostasis of extracellular potassium concentration,and interacting with endothelial cells.
基金supported by the National Natural Science Foundation of China,No.82071909(to GF)the Natural Science Foundation of Liaoning Province,No.2023-MS-07(to HL)。
文摘Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indices,has provided a fresh perspective and valuable insight into the study of freezing of gait in Parkinson's disease.It has been revealed that Parkinson's disease is accompanied by widespread irregularities in inherent brain network activity.However,the effective integration of the multi-level indices of resting-state functional magnetic resonance imaging into clinical settings for the diagnosis of freezing of gait in Parkinson's disease remains a challenge.Although previous studies have demonstrated that radiomics can extract optimal features as biomarkers to identify or predict diseases,a knowledge gap still exists in the field of freezing of gait in Parkinson's disease.This cross-sectional study aimed to evaluate the ability of radiomics features based on multi-level indices of resting-state functional magnetic resonance imaging,along with clinical features,to distinguish between Parkinson's disease patients with and without freezing of gait.We recruited 28 patients with Parkinson's disease who had freezing of gait(15 men and 13 women,average age 63 years)and 30 patients with Parkinson's disease who had no freezing of gait(16 men and 14 women,average age 64 years).Magnetic resonance imaging scans were obtained using a 3.0T scanner to extract the mean amplitude of low-frequency fluctuations,mean regional homogeneity,and degree centrality.Neurological and clinical characteristics were also evaluated.We used the least absolute shrinkage and selection operator algorithm to extract features and established feedforward neural network models based solely on resting-state functional magnetic resonance imaging indicators.We then performed predictive analysis of three distinct groups based on resting-state functional magnetic resonance imaging indicators indicators combined with clinical features.Subsequently,we conducted 100 additional five-fold cross-validations to determine the most effective model for each classification task and evaluated the performance of the model using the area under the receiver operating characteristic curve.The results showed that when differentiating patients with Parkinson's disease who had freezing of gait from those who did not have freezing of gait,or from healthy controls,the models using only the mean regional homogeneity values achieved the highest area under the receiver operating characteristic curve values of 0.750(with an accuracy of 70.9%)and 0.759(with an accuracy of 65.3%),respectively.When classifying patients with Parkinson's disease who had freezing of gait from those who had no freezing of gait,the model using the mean amplitude of low-frequency fluctuation values combined with two clinical features achieved the highest area under the receiver operating characteristic curve of 0.847(with an accuracy of 74.3%).The most significant features for patients with Parkinson's disease who had freezing of gait were amplitude of low-frequency fluctuation alterations in the left parahippocampal gyrus and two clinical characteristics:Montreal Cognitive Assessment and Hamilton Depression Scale scores.Our findings suggest that radiomics features derived from resting-state functional magnetic resonance imaging indices and clinical information can serve as valuable indices for the identification of freezing of gait in Parkinson's disease.
基金the National Natural Science Foundation of China,No.81171859the Natural Science Foundation of Chongqing,No.cstc2012jjA10058the Chongqing Health Bureau Project,No.2011-2-172
文摘Neural cell differentiation and maturation is a critical step during central nervous system devel-opment. The oligodendrocyte transcription family （Olig family） is known to be an important factor in regulating neural cell differentiation. Because of this, the Olig family also affects acute and chronic central nervous system diseases, including brain injury, multiple sclerosis, and even gliomas. Improved understanding about the functions of the Olig family in central nervous system development and disease will greatly aid novel breakthroughs in central nervous system diseases. This review investigates the role of the Olig family in central nervous system develop- ment and related diseases.
基金supported by the National Natural Science Foundation of China,No.81401084(to XHW)Beijing Municipal Administration of Hospital Ascent Plan,No.DFL20150802(to TLW)+2 种基金Beijing 215 High Level Healthcare Talent Plan Academic Leader,No.008-0027(to TLW)Beijing Municipal Commission of Health and Family Planning,No.PXM2017_026283_000002(to TLW)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding,No.ZYLX201706(to TLW)
文摘Microglia serve as brain-resident myeloid cells that affect cerebral development, ischemia, neurodegeneration, and neuro-viral infection. MicroRNAs play a key role in central nervous system disease through post-transcriptional regulation. Indeed, evidence shows that microRNAs are one of the most important regulators mediating microglial activation, polarization, and autophagy, and subsequently affecting neuroinflammation and the outcome of central nervous system disease. In this review, we provide insight into the function of microRNAs, which may be an attractive strategy and influential treatment for microglia-related central nervous system dysfunction. Moreover, we comprehensively describe how microglia fight against central nervous system disease via multiple functional microRNAs.
基金financially supported by the Russian Government Program of Competitive Growth of Kazan Federal Universitysupported by state assignment 20.5175.2017/6.7 of the Ministry of Education and Science of Russian Federationthe President of the Russian Federation grant НШ-3076.2018.4
文摘Extracellular vesicles,including exosomes and microvesicles,play a fundamental role in the activity of the nervous system,participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems.In many neurodegenerative diseases,neurons pack toxic substances into vesicles and release them into the extracellular space,which leads to the spread of misfolded neurotoxic proteins.The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system,and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases.Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier.Today,the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis,specificallyα-synuclein,tau protein,superoxide dismutase 1,FUS,leucine-rich repeat kinase 2,as well as some synaptic proteins,has been well evidenced.Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles,which are important in the onset and development of many neurodegenerative diseases.Depending on parental cell type,extracellular vesicles may have different therapeutic properties,including neuroprotective,regenerative,and anti-inflammatory.Due to nano size,biosafety,ability to cross the blood-brain barrier,possibility of targeted delivery and the lack of an immune response,extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain.This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles.
基金supported by the Natural Science Foundation of Zhejiang Province,No.LQ23C090003 (to CZ)the Major Project on Brain Science and Analog Brain Research of Ministry of Science and Technology of China,No.2022ZD0204701 (to MQ)the National Natural Science Foundation of China,No.32170969 (to MQ)。
文摘Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular functions such as migration, survival, proliferation, and differentiation. Oligodendrocytes are the myelin-forming cells in the central nervous system and play critical roles in the conduction of action potentials, supply of metabolic components for axons, and other functions. Emerging evidence suggests that both oligodendrocytes and oligodendrocyte precursor cells are vulnerable to cytokines released under pathological conditions. This review mainly summarizes the effects of cytokines on oligodendrocyte lineage cells in central nervous system diseases. A comprehensive understanding of the effects of cytokines on oligodendrocyte lineage cells contributes to our understanding of central nervous system diseases and offers insights into treatment strategies.
基金supported by KAKENHI under grant number 23K08535,22K09274(to MK)。
文摘Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive molecules.Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders.These exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic effects.Furthermore,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug encapsulation.Consequently,researchers have turned their attention to exosomes as a novel therapeutic avenue.Nonetheless,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application.To overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system.By exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier.Notably,exosomes,owing to their small size,can readily access the nerve pathways using this method.As a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments.In this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases.Furthermore,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.
基金supported by the National Natural Science Foundation of China,Nos. 82004028 (to LJS) and 81473577 (to CGM)China Postdoctoral Science Foundation,No. 2020M680912 (to LJS)+4 种基金Shanxi Applied Basic Research Project,No. 201901D211538 (to LJS)Leading Team of Medical Science and Technology of Shanxi Province,No. 2020TD05 (to CGM)Funds for Construction of Key Disciplines from Shanxi University of Chinese Medicine,Young Scientists Cultivation Project of Shanxi University of Chinese Medicine No. 2021PYQN-09 (to LJS)Basic Research Project of the Cultivation Plan of Scientific and Technological Innovation Ability of Shanxi University of Chinese Medicine,No. 2020PY-JC-02 (to LJS)Cardiovascular Special Fund Project of National Regional Traditional Chinese Medicine Medical Center of Affiliated Hospital of Shanxi University of Chinese Medicine in 2021, No. XGZX202115 (to LJS)。
文摘Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes;these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer’s disease. Our literature search found that phenotypic changes occur continuously in Alzheimer’s disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer’s disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer’s disease.
文摘Photobiomodulation using light in the red or near-infrared region is an innovative treatment strategy for a wide range of neurological and psychological conditions.Photobiomodulation can promote neurogenesis and elicit anti-apoptotic,antiinflammatory and antioxidative responses.Its therapeutic effects have been demonstrated in studies on neurological diseases,peripheral nerve injuries,pain relief and wound healing.We conducted a comprehensive literature review of the application of photobiomodulation in patients with central nervous system diseases in February 2019.The NCBI PubMed database,EMBASE database,Cochrane Library and ScienceDirect database were searched.We reviewed 95 papers and analyzed.Photobiomodulation has wide applicability in the treatment of stroke,traumatic brain injury,Parkinson’s disease,Alzheimer’s disease,major depressive disorder,and other diseases.Our analysis provides preliminary evidence that PBM is an effective therapeutic tool for the treatment of central nervous system diseases.However,additional studies with adequate sample size are needed to optimize treatment parameters.
基金The work related to this review was partially supported by Duke University Fund.
文摘Programmed cell death protein 1(PD-1)is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment.Accumulating evidence suggests an important role of PD-1 in the central nervous system(CNS).PD-1 has been implicated in CNS disorders such as brain tumors,Alzheimer’s disease,ischemic stroke,spinal cord injury,multiple sclerosis,cognitive function,and pain.PD-1 signaling suppresses the CNS immune response via resident microglia and infiltrating peripheral immune cells.Notably,PD-1 is also widely expressed in neurons and suppresses neuronal activity via downstream Src homology 2 domain-containing protein tyrosine phosphatase 1 and modulation of ion channel function.An improved understanding of PD-1 signaling in the cross-talk between glial cells,neurons,and peripheral immune cells in the CNS will shed light on immunomodulation,neuromodulation,and novel strategies for treating brain diseases.
文摘Although there are challenges in treating traumatic central nervous system diseases,mesenchymal stem cell-de rived extracellular vesicles(MSC-EVs) have recently proven to be a promising non-cellular the rapy.We comprehensively evaluated the efficacy of mesenchymal stem cell-de rived extracellular vesicles in traumatic central nervous system diseases in this meta-analysis based on preclinical studies.Our meta-analysis was registered at PROSPERO(CRD42022327904,May 24,2022).To fully retrieve the most relevant articles,the following databases were thoro ughly searched:PubMed,Web of Science,The Cochrane Library,and Ovid-Embase(up to April 1,2022).The included studies were preclinical studies of mesenchymal stem cell-derived extracellular vesicles for traumatic central nervous system diseases.The Systematic Review Centre for Laboratory Animal Experimentation(SYRCLE)’s risk of bias tool was used to examine the risk of publication bias in animal studies.After screening 2347studies,60 studies were included in this study.A meta-analysis was conducted for spinal co rd injury(n=52) and traumatic brain injury(n=8).The results indicated that mesenchymal stem cell-derived extracellular vesicles treatment prominently promoted motor function recovery in spinal co rd injury animals,including rat Basso,Beattie and Bresnahan locomotor rating scale scores(standardized mean difference [SMD]:2.36,95% confidence interval [CI]:1.96-2.76,P <0.01,I2=71%) and mouse Basso Mouse Scale scores(SMD=2.31,95% CI:1.57-3.04,P=0.01,I2=60%) compared with controls.Further,mesenchymal stem cell-de rived extracellular vesicles treatment significantly promoted neurological recovery in traumatic brain injury animals,including the modified N eurological Severity Score(SMD=-4.48,95% CI:-6.12 to-2.84,P <0.01,I2=79%) and Foot Fault Test(SMD=-3.26,95% CI:-4.09 to-2.42,P=0.28,I2=21%) compared with controls.Subgroup analyses showed that characteristics may be related to the therapeutic effect of mesenchymal stem cell-de rived extra cellular vesicles.For Basso,Beattie and Bresnahan locomotor rating scale scores,the efficacy of allogeneic mesenchymal stem cell-derived extracellular vesicles was higher than that of xenogeneic mesenchymal stem cell-derived extracellular vesicles(allogeneic:SMD=2.54,95% CI:2.05-3.02,P=0.0116,I2=65.5%;xenogeneic:SMD:1.78,95%CI:1.1-2.45,P=0.0116,I2=74.6%).Mesenchymal stem cellde rived extracellular vesicles separated by ultrafiltration centrifugation combined with density gradient ultra centrifugation(SMD=3.58,95% CI:2.62-4.53,P <0.0001,I2=31%) may be more effective than other EV isolation methods.For mouse Basso Mouse Scale scores,placenta-derived mesenchymal stem cell-de rived extracellular vesicles worked better than bone mesenchymal stem cell-derived extracellular vesicles(placenta:SMD=5.25,95% CI:2.45-8.06,P=0.0421,I2=0%;bone marrow:SMD=1.82,95% CI:1.23-2.41,P=0.0421,I2=0%).For modified Neurological Severity Score,bone marrow-derived MSC-EVs worked better than adipose-derived MSC-EVs(bone marrow:SMD=-4.86,95% CI:-6.66 to-3.06,P=0.0306,I2=81%;adipose:SMD=-2.37,95% CI:-3.73 to-1.01,P=0.0306,I2=0%).Intravenous administration(SMD=-5.47,95% CI:-6.98 to-3.97,P=0.0002,I2=53.3%) and dose of administration equal to 100 μg(SMD=-5.47,95% CI:-6.98 to-3.97,P <0.0001,I2=53.3%)showed better res ults than other administration routes and doses.The heterogeneity of studies was small,and sensitivity analysis also indicated stable results.Last,the methodological quality of all trials was mostly satisfactory.In conclusion,in the treatment of traumatic central nervous system diseases,mesenchymal stem cell-derived extracellular vesicles may play a crucial role in promoting motor function recovery.
