Intranasal administration of stem cell-derived exosomes for central nervous system diseases

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.

Oligodendrocytes in central nervous system diseases:the effect of cytokine regulation

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.

Role of CD36 in central nervous system diseases

CD36 is a highly glycosylated integral membrane protein that belongs to the scavenger receptor class B family and regulates the pathological progress of metabolic diseases.CD36 was recently found to be widely expressed in various cell types in the nervous system,including endothelial cells,pericytes,astrocytes,and microglia.CD36 mediates a number of regulatory processes,such as endothelial dysfunction,oxidative stress,mitochondrial dysfunction,and inflammatory responses,which are involved in many central nervous system diseases,such as stroke,Alzheimer’s disease,Parkinson’s disease,and spinal cord injury.CD36 antagonists can suppress CD36 expression or prevent CD36 binding to its ligand,thereby achieving inhibition of CD36-mediated pathways or functions.Here,we reviewed the mechanisms of action of CD36 antagonists,such as Salvianolic acid B,tanshinone IIA,curcumin,sulfosuccinimidyl oleate,antioxidants,and small-molecule compounds.Moreover,we predicted the structures of binding sites between CD36 and antagonists.These sites can provide targets for more efficient and safer CD36 antagonists for the treatment of central nervous system diseases.

Targeting nuclear factor erythroid 2-related factor 2-regulated ferroptosis to treat nervous system diseases

By critically examining the work,we conducted a comprehensive bibliometric analysis on the role of nuclear factor erythroid 2-related factor 2(NRF2)in nervous system diseases.We also proposed suggestions for future bibliometric studies,including the integration of multiple websites,analytical tools,and analytical approaches,The findings presented provide compelling evidence that ferroptosis is closely associated with the therapeutic challenges of nervous system diseases.Targeted modulation of NRF2 to regulate ferroptosis holds substantial potential for effectively treating these diseases.Future NRF2-related research should not only focus on discovering new drugs but also on designing rational drug delivery systems.In particular,nanocarriers offer substantial potential for facilitating the clinical translation of NRF2 research and addressing existing issues related to NRF2-related drugs.

Microglia lactylation in relation to central nervous system diseases

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.

Vimentin as a potential target for diverse nervous system diseases

Vimentin is a major type Ⅲ intermediate filament protein that plays important roles in several basic cellular functions including cell migration, proliferation, and division. Although vimentin is a cytoplasmic protein, it also exists in the extracellular matrix and at the cell surface. Previous studies have shown that vimentin may exert multiple physiological effects in different nervous system injuries and diseases. For example, the studies of vimentin in spinal cord injury and stroke mainly focus on the formation of reactive astrocytes. Reduced glial scar, increased axonal regeneration, and improved motor function have been noted after spinal cord injury in vimentin and glial fibrillary acidic protein knockout(GFAPVIM) mice. However, attenuated glial scar formation in post-stroke in GFAP–/– VIM–/– mice resulted in abnormal neuronal network restoration and worse neurological recovery. These opposite results have been attributed to the multiple roles of glial scar in different temporal and spatial conditions. In addition, extracellular vimentin may be a neurotrophic factor that promotes axonal extension by interaction with the insulin-like growth factor 1 receptor. In the pathogenesis of bacterial meningitis, cell surface vimentin is a meningitis facilitator, acting as a receptor of multiple pathogenic bacteria, including E. coli K1, Listeria monocytogenes, and group B streptococcus. Compared with wild type mice, VIMmice are less susceptible to bacterial infection and exhibit a reduced inflammatory response, suggesting that vimentin is necessary to induce the pathogenesis of meningitis. Recently published literature showed that vimentin serves as a double-edged sword in the nervous system, regulating axonal regrowth, myelination, apoptosis, and neuroinflammation. This review aims to provide an overview of vimentin in spinal cord injury, stroke, bacterial meningitis, gliomas, and peripheral nerve injury and to discuss the potential therapeutic methods involving vimentin manipulation in improving axonal regeneration, alleviating infection, inhibiting brain tumor progression, and enhancing nerve myelination.

Mesenchymal stem cell-derived extracellular vesicles therapy in traumatic central nervous system diseases:a systematic review and meta-analysis

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.

Emerging trends and hotspots of Nuclear factor erythroid 2-related factor 2 in nervous system diseases

BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this field's research hotspots and evolution rules.AIM To investigate the research hotspots,evolution patterns,and future research trends in this field in recent years.METHODS We conducted a comprehensive literature search in the Web of Science Core Collection database using the following methods:(((((TS=(NFE2 L2))OR TS=(Nfe2 L2 protein,mouse))OR TS=(NF-E2-Related Factor 2))OR TS=(NRF2))OR TS=(NFE2L2))OR TS=(Nuclear factor erythroid2-related factor 2)AND(((((((TS=(neurological diseases))OR TS=(neurological disorder))OR TS=(brain disorder))OR TS=(brain injury))OR TS=(central nervous system disease))OR TS=(CNS disease))OR TS=(central nervous system disorder))OR TS=(CNS disorder)AND Language=English from 2010 to 2022.There are just two forms of literature available:Articles and reviews.Data were processed with the software Cite-Space(version 6.1.R6).RESULTS We analyzed 1884 articles from 200 schools in 72 countries/regions.Since 2015,the number of publications in this field has increased rapidly.China has the largest number of publications,but the articles published in the United States have better centrality and H-index.Among the top ten authors with the most published papers,five of them are from China,and the author with the most published papers is Wang Handong.The institution with the most articles was Nanjing University.To their credit,three of the top 10 most cited articles were written by Chinese scholars.The keyword co-occurrence map showed that"oxidative stress","NRF2","activation","expression"and"brain"were the five most frequently used keywords.CONCLUSION Research on the role of NRF2 in neurological diseases continues unabated.Researchers in developed countries published more influential papers,while Chinese scholars provided the largest number of articles.There have been numerous studies on the mechanism of NRF2 transcription factor in neurological diseases.NRF2 is also emerging as a potentially effective target for the treatment of neurological diseases.However,despite decades of research,our knowledge of NRF2 transcription factor in nervous system diseases is still limited.Further studies are needed in the future.

Research progress of sphingosine 1-phosphate and its signal transduction in central nervous system diseases

Sphingosine 1-phosphate(S1P),as a sphingolipid metabolite,has become a key substance in regulating various physiological processes,involved in differentiation,proliferation,migration,morphogenesis,cytoskeleton formation,adhesion,apoptosis,etc.process.Sphingosine 1-phosphate can not only activate the S1P-S1PR signaling pathway by binding to the corresponding receptors on the cell membrane,but also play a role in the cell.In recent years,studies have found that there is a certain relationship between its level changes and the occurrence and development of central nervous system diseases.This article reviews the latest knowledge of sphingosine-1-phosphate in the occurrence and treatment of nervous system diseases,and further clarifies its molecular mechanism in the treatment and development of central nervous system diseases.

Advances of Research on Auricular Vagus Nerve Stimulation for Treatment of Nervous System Diseases

As a new type of nerve regulation technology, Vagus Nerve Stimulation is currently used in the treatment of nervous system diseases. Auricular Vagus Nerve Stimulation has become one of the research hotspots in this field, because there is no implantation risk. However, there is no unified standard for the treatment parameters of aVNS for nervous system diseases. In this paper, the research progress of the anatomical structure and parameters of the vagus nerve and its role in nervous system diseases are reviewed to provide basis for further research.

MicroRNAs of microglia： wrestling with central nervous system disease

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.

Targeting cholesterol trafficking to mitigate axonal degeneration in hereditary spastic paraplegia

Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia(HSP),a genetically and clinically diverse group of disorders characterized by spasticity and weakness of the lower extremities.HSP is one significant cause of chronic neurodisability due to the lack of effective treatments and a wide range of onset ages from early childhood to 70 years.

Changing trends in nervous system diseases among hospitalized children in the Chongqing region

OBJECTIVE： To investigate the changing trends of nervous system diseases among hospitalized children and the risk factors of death. METHOD： The disease was statistically classified according to the International Statistical Classification of Disease and Health Problem （ICD10）. The retrospective investigation includes demographic characteristics, as well as categories and fatality rates for nervous system diseases. All data was statistically analyzed. RESULTS： The percentage of nervous system diseases among inpatients in all wards was 2.4% （2 537/ 107 250） between January 1993 and December 1999, and 3.6% （6 082/170 619） between January 2000 and December 2006. The first ten patterns of various etiologic forms of nervous system diseases were identical-epilepsies and seizures, infections of the central nervous system, autoimmune and demyelination disorders, cerebral palsy, motor unit disorders, hypoxic-ischemic encephalopathy, hydrocephalus, extra-pyramidal disorders, congenital abnormalities of nervous system, and headache. Epilepsies and seizures took first place in both year groups, with 29.4% and 35%, respectively. Bacterial infections were responsible for the majority of cranial infections in both year groups, with 78.9% and 63.6% respectively. The death rate in the year group January 2000 to December 2006 was significantly less than in the year group January 1993 to December 1999 （ Х^2 = 27.832, P 〈 0.01 ）. CONCLUSION： Among all nervous system diseases, epilepsies and seizures were among the most common with the lowest fatality rate.

Review on the Effect of Resveratrol on Central Nervous System Disease

Resveratrol (3,5,4’-trihydroxy-trans-stilbene, RV) is a kind of phytoalexin found in many kinds of plants and food. As a natural antioxidant, RV shows significant biological activity, including anti-tumor activity, antitubulin activity, cardiovascular disease resistance activity, etc. Many experiments confirm that resveratrol displays a wide range of beneficial effects on human diseases including heart disease and cancer, especially in the treatment of central nervous system disease, such as Huntington’s disease (HD), Alzheimer’s disease (AD) and Parkinson’s disease (PD). This paper summarizes the positive effects of RV on several central nervous system diseases.

Editor's Choice—Meta analysis of acupuncture efficacy for the treatment of nervous system diseases

Meta analysis of randomized, controlled, clinical studies of acupuncture for the treatment of nervous system diseases has demonstrated that acupuncture effectively treats optic atrophy and depression. However, the quality of selected studies is low and evidence is inadequate. Therefore,

Telemedicine and digital management in repair and regeneration after nerve injury and in nervous system diseases

To the editor, We read with interest the article, ＂Facilitating transparency in spinal cord injury studies using data standards and ontol- ogles＂ by Professor Vance E Lemmon, University of Miami, USA （Lemmon et al., 2014） and would like to add to the discussion on digital management in spinal cord injury. We have analyzed the advancements in the treatment of spinal cord injury, traumatic brain jury. Encouraging outcomes injury and peripheral nerve in- have been achieved in the area of regulating axon growth in vivo and in vitro. However, such a large amount of information neither provides in-depth insight for other scholars nor provides detailed therapeutic nrotocols for clinical studies.

Extracellular vesicles in the diagnosis and treatment of central nervous system diseases

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.

Research progress of the relationship between microvesicles derived from stem cells and nervous system diseases

Microvesicles, also called microparticles, are membranous vesicles released from the cell membrane surface or by exocytose. Almost any type of cells can secrete vesicles, especially stem cells. Recent years, stem cells are becoming a research hotspot of cytotherapy for their capacity of self-renewing, expansion and proliferation in vitro and the microvesicles derived from the conditioned medium of stem cells have been widely used to regenerative medicine because they are safer, easily obtained, measurable and cause no obvious immune rejection. Stem cells derived microvesicles have been confirmed to be closely related to the progress and treatment of atherosclerosis, diabetes, inflammation and tumor. This review focuses on the new progress of stem cells derived microvesicles treating various nervous system diseases and its application in biological therapy and the behind molecule mechanisms.

Rapid genetic screening of Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies patients

We used the allele-specific PCR-double digestion method on peripheral myelin protein 22 （PMP22） to determine duplication and deletion mutations in the proband and family members of one family with Charcot-Marie-Tooth disease type 1 and one family with hereditary neuropathy with liability to pressure palsies. The proband and one subclinical family member from the Charcot-Marie-Tooth disease type 1 family had a PMP22 gene duplication; one patient from the hereditary neuropathy with liability to pressure palsies family had a PMP22 gene deletion. Electron microscopic analysis of ultrathin sections of the superficial peroneal nerve from the two probands demonstrated demyelination and myelin sheath hyperplasia, as well as an ＇onion-like＇ structure in the Charcot-Marie-Tooth disease type 1A patient. We observed an irregular thickened myelin sheath and ＇mouse-nibbled＇-Iike changes in the patient with hereditary neuropathy with liability to pressure palsies. In the Charcot-Marie-Tooth disease type 1A patient, nerve electrophysiological examination revealed moderate-to-severe reductions in the motor and sensory conduction velocities of the bilateral median nerve, ulnar nerve, tibial nerve, and sural nerve. Moreover, the compound muscle action potential amplitude was decreased. In the patient with hereditary neuropathy with liability to pressure palsies, the nerve conduction velocity of the bilateral tibial nerve and sural nerve was moderately reduced, and the nerve conduction velocity of the median nerve and ulnar nerve of both upper extremities was slightly reduced.

Meningeal lymphatic vessel crosstalk with central nervous system immune cells in aging and neurodegenerative diseases

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.