Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory v...Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory versus degenerative dichotomy.This was based on a broad misconception regarding essentially all neurodegenerative conditions,depicting the degenerative process as passive and immune-independent occurring as a late byproduct of active inflammation in the central nervous system(CNS),which is(solely)systemically driven.展开更多
Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pa...Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.展开更多
Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple rol...Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood–brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.展开更多
Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-targe...Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the“therapeutic module”of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.展开更多
Multiple Sclerosis(MS)poses significant health risks.Patients may face neurodegeneration,mobility issues,cognitive decline,and a reduced quality of life.Manual diagnosis by neurologists is prone to limitations,making ...Multiple Sclerosis(MS)poses significant health risks.Patients may face neurodegeneration,mobility issues,cognitive decline,and a reduced quality of life.Manual diagnosis by neurologists is prone to limitations,making AI-based classification crucial for early detection.Therefore,automated classification using Artificial Intelligence(AI)techniques has a crucial role in addressing the limitations of manual classification and preventing the development of MS to advanced stages.This study developed hybrid systems integrating XGBoost(eXtreme Gradient Boosting)with multi-CNN(Convolutional Neural Networks)features based on Ant Colony Optimization(ACO)and Maximum Entropy Score-based Selection(MESbS)algorithms for early classification of MRI(Magnetic Resonance Imaging)images in a multi-class and binary-class MS dataset.All hybrid systems started by enhancing MRI images using the fusion processes of a Gaussian filter and Contrast-Limited Adaptive Histogram Equalization(CLAHE).Then,the Gradient Vector Flow(GVF)algorithm was applied to select white matter(regions of interest)within the brain and segment them from the surrounding brain structures.These regions of interest were processed by CNN models(ResNet101,DenseNet201,and MobileNet)to extract deep feature maps,which were then combined into fused feature vectors of multi-CNN model combinations(ResNet101-DenseNet201,DenseNet201-MobileNet,ResNet101-MobileNet,and ResNet101-DenseNet201-MobileNet).The multi-CNN features underwent dimensionality reduction using ACO and MESbS algorithms to remove unimportant features and retain important features.The XGBoost classifier employed the resultant feature vectors for classification.All developed hybrid systems displayed promising outcomes.For multiclass classification,the XGBoost model using ResNet101-DenseNet201-MobileNet features selected by ACO attained 99.4%accuracy,99.45%precision,and 99.75%specificity,surpassing prior studies(93.76%accuracy).It reached 99.6%accuracy,99.65%precision,and 99.55%specificity in binary-class classification.These results demonstrate the effectiveness of multi-CNN fusion with feature selection in improving MS classification accuracy.展开更多
Despite suggested shared pathophysiological mechanisms between coronavirus disease 2019(COVID-19)and multiple sclerosis(MS),the molecular pathways underlying their relationship remain unclear.Herein,gene expression pr...Despite suggested shared pathophysiological mechanisms between coronavirus disease 2019(COVID-19)and multiple sclerosis(MS),the molecular pathways underlying their relationship remain unclear.Herein,gene expression profiles of COVID-19(GSE171110,GSE152641)and MS(GSE66573,GSE159225)datasets were analyzed using Gene Ontology(GO)enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,and protein-protein interaction(PPI)network construction.A two-acsample Mendelian randomization(MR)study was performed to establish potential causal relationships.A total of 165 shared differentially expressed genes(DEGs)were identified,with significant enrichment in pathways related to humoral immune response,neutrophil migration,and cytokine-receptor interactions in both conditions.Validation by receiver operating characteristic(ROC)curve analysis demonstrated that the hub genes S100A8,S100A9,S100A12,and ALOX5AP achieved area under the curve(AUC)values above 0.7 for both diseases.Increased neutrophil infiltration was positively correlated with upregulated expression of these genes,particularly demonstrating significant associations between the hub gene expression and neutrophil activity pathways.MR analysis suggested a causal relationship between S100A8 expression and susceptibility to both conditions and neutrophil counts,while ALOX5AP was indicated as a potential MS risk factor.These findings suggest that COVID-19 and MS co-occurrence is associated with neutrophil infiltration,highlighting S100A8 as both a promising biomarker and therapeutic target.展开更多
AIM:To determine the diagnostic ability of various visual functions in patients with multiple sclerosis(MS)with and without optic neuritis(ON).METHODS:In this cross-sectional study,we assessed and compared refractive ...AIM:To determine the diagnostic ability of various visual functions in patients with multiple sclerosis(MS)with and without optic neuritis(ON).METHODS:In this cross-sectional study,we assessed and compared refractive error,visual acuity(VA),and contrast sensitivity(CS)between patients with MS and a matched control group of healthy individuals.The MS patients were further categorized into those with ON and those without.RESULTS:A total of 133 eyes from 133 participants were assessed,including 66 individuals diagnosed with MS.The mean ages for the MS group and the healthy control group were 37.5±4.27y and 38.45±4.60y,respectively(P=0.346).Among the 66 patients with MS,18 had ON.The presence of MS was associated with a decrease in best-corrected visual acuity(BCVA)and spherical component of refractive error(P<0.05),whereas ON did not lead to any further decline in these parameters(P>0.05).MS was linked to decreased CS at spatial frequencies of 6 and 18 cycles per degree(CPD;P<0.05),while ON in MS patients resulted in an additional decrease in CS at 3 CPD(P=0.03).The most significant sensitivity for distinguishing MS patients from healthy individuals as well as MS patients with ON from those without ON was found with cylindrical component[associated criterion(AC)>-0.75 D;71.21%]and CS at spatial frequency of 6 CPD(AC≤1.56;72.22%),respectively.Conversely,the highest specificity for these diagnostic measures was associated with BCVA(AC>0 logMAR;97.01%)and CS at a spatial frequency of 12 CPD(AC≤0.60;93.75%),respectively.CONCLUSION:MS significantly affects refractive error and CS,with ON further reducing CS.Assessing these visual parameters can improve MS monitoring and management.展开更多
BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a...BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a common site for MS plaques,and the medial olivocochlear(MOC)system is located in the superior olivary complex(SOC)of the brainstem.The cochlear nuclei are also involved in the MOC reflex arc.Additionally,the temporal cortex can modulate the SOC and cochlear nucleus,so lesions in the brainstem or temporal cortex may affect the MOC reflex in MS.AIM To investigate efferent auditory system activity in patients with multiple sclerosis via the MOC reflex.METHODS The study included 50 patients with MS and 50 healthy controls.Patients with MS were divided into three subgroups according to cranial magnetic resonance imaging findings:Patients with brainstem lesions(Group 1,n=20);patients with temporal cortex lesions without brainstem involvement(Group 2,n=20);and patients without any lesions in the brainstem or temporal cortex(Group 3,n=10).Tympanometry,acoustic stapedial reflex thresholds,pure-tone audiometry,and transientevoked otoacoustic emission(TEOAE)tests(with and without contralateral noise)were performed for all participants.RESULTS There was no significant difference in pure-tone hearing thresholds or baseline TEOAE amplitudes between the MS and control groups,indicating normal cochlear function in patients with MS;however,MOC reflex suppression was significantly reduced in patients with MS compared to controls(P=0.021).In particular,Group 1(MS with brainstem lesions)showed the lowest mean suppression values,which was significantly lower than that of Group 2 and the control group(P=0.002).By contrast,Group 2 and Group 3 did not significantly differ from controls.Additionally,patients with MS exhibited a sex difference in MOC function:Male patients had significantly lower suppression compared to female patients both within Group 1 and in the MS group as a whole.CONCLUSION The findings indicate that the efferent auditory system(specifically the MOC reflex)is affected by MS.MOC reflex activity was most significantly decreased in patients with MS with brainstem lesions,while temporal cortex lesions alone did not appear to notably impair the MOC reflex.Diminished MOC activity may underlie various auditory difficulties in patients with MS(e.g.,hearing in noise),and loss of efferent suppression could contribute to symptoms such as hyperacusis or tinnitus in this population.Further studies are needed to better understand the relationship between MOC dysfunction and auditory symptoms in MS,as well as the potential diagnostic value of MOC testing in MS.展开更多
Multiple sclerosis(MS)is a neurodegenerative disease,with aging being a significant risk factor that increases neural susceptibility to damage and reduces resilience.Cellular senescence(CS),a critical biological proce...Multiple sclerosis(MS)is a neurodegenerative disease,with aging being a significant risk factor that increases neural susceptibility to damage and reduces resilience.Cellular senescence(CS),a critical biological process of aging,also plays a pivotal role in MS pathogenesis.This study investigated the role of CS in MS by bioinformatics analyses,identifying key genes and potential therapeutic drugs.In differential gene expression(DEG)analysis,we identified 565 DEGs,comprising 166 upregulated and 399 downregulated genes(P<0.05,|LogFC|>1.5).Gene Set Enrichment Analysis(GSEA)revealed that these DEGs were enriched in pathways related to ribosomes,CS,and MAPK signaling.Weighted gene co-expression network analysis(WGCNA)identified the turquoise module,consisting of 164 genes,as having the strongest correlation with MS(R^(2)=0.54,P=1e^(–14)).KEGG pathway analysis indicated that this module was most enriched in autophagy,Salmonella infection,and apoptosis pathways.Intersecting the DEGs,WGCNA key module genes,and 1381 CS-associated genes,we identified 49 key genes involved in MS.Machine learning algorithms further pinpointed ATF7IP,ATR,BCL10,CTNNB1,PDCD1,PIK3CA,TNFSF13,MSH3,HTR2A,and ALPL as MS hub genes,which were validated using the GSE13732 testing set.Seven candidate gene-related drugs were identified from DrugBank and the Comparative Toxicogenomics Database(CTD).Molecular docking results indicated that the binding energies for ATF7IP,ATR,BCL10,HTR2A,and PDCD10 with these drugs ranged from–2.444 to–6.523 Kcal/mol.展开更多
Multiple sclerosis （MS） is an autoimmune disease. The etiology and pathogenesis of MS remain unclear. At present, there are substantial evidences to support the hypothesis that genetics plays a crucial role. The peo...Multiple sclerosis （MS） is an autoimmune disease. The etiology and pathogenesis of MS remain unclear. At present, there are substantial evidences to support the hypothesis that genetics plays a crucial role. The people who have genetic predisposing genes easily develop immune-mediated disorder, probably in conjunction with environmental factors. The aim of this review is to describe recent observations regarding the immunologic pathogenesis of MS.展开更多
This review focused on the diagnosis and clinical features of multiple sclerosis(MS) in China. We have identified the published researching information from 1976 to 2008 in China. The key issues related to the diagnos...This review focused on the diagnosis and clinical features of multiple sclerosis(MS) in China. We have identified the published researching information from 1976 to 2008 in China. The key issues related to the diagnosis and clinical features of MS in China were summarized. The first patient with MS in China was reported in 1926 from Xiehe hospital. Case reports on MS has been increasing during recent decades. Almost all the patients with MS were confirmed by the McDonald criteria(1977) before1984. After the...展开更多
Vitamin D is a seco-steroid involved in calcium and phosphorus metabolism,and bone formation and mineralization, through binding to a specific nuclear receptor,vitamin D receptor（VDR）.Besides its well-established fu...Vitamin D is a seco-steroid involved in calcium and phosphorus metabolism,and bone formation and mineralization, through binding to a specific nuclear receptor,vitamin D receptor（VDR）.Besides its well-established functions on bone health,multiple lines of evidence have indicated the immunomodulatory roles of vitamin D.Vitamin D can affect both innate and adaptive immunity,and prevent autoimmune responses efficiently.Vitamin D regulates the immune responses by suppressing T cell proliferation and modulating macrophage functions.Epidemiological studies have shown that vitamin D deficiency is associated with multiple diseases such as rickets and cancer.Moreover,associations between vitamin D and autoimmune diseases have been confirmed in multiple sclerosis（MS）,rheumatoid arthritis（RA）,etc.The present review mainly summarized the recent findings on the immunomodulatory role of vitamin D in various disorders,with special focus on its role in MS,an autoimmune disease of the nervous system.展开更多
Exciting new features have been described concerning neurogenic bowel dysfunction,including interactions between the central nervous system,the enteric nervous system,axonal injury,neuronal loss,neurotransmission of n...Exciting new features have been described concerning neurogenic bowel dysfunction,including interactions between the central nervous system,the enteric nervous system,axonal injury,neuronal loss,neurotransmission of noxious and non-noxious stimuli,and the fields of gastroenterology and neurology.Patients with spinal cord injury,myelomeningocele,multiple sclerosis and Parkinson's disease present with serious upper and lower bowel dysfunctions characterized by constipation,incontinence,gastrointestinal motor dysfunction and altered visceral sensitivity.Spinal cord injury is associated with severe autonomic dysfunction,and bowel dysfunction is a major physical and psychological burden for these patients.An adult myelomeningocele patient commonly has multiple problems reflecting the multisystemic nature of the disease.Multiple sclerosis is a neurodegenerative disorder in which axonal injury,neuronal loss,and atrophy of the central nervous system can lead to permanent neurological damage and clinical disability.Parkinson's disease is a multisystem disorder involving dopaminergic,noradrenergic,serotoninergic and cholinergic systems,characterizedby motor and non-motor symptoms.Parkinson's disease affects several neuronal structures outside the substantia nigra,among which is the enteric nervous system.Recent reports have shown that the lesions in the enteric nervous system occur in very early stages of the disease,even before the involvement of the central nervous system.This has led to the postulation that the enteric nervous system could be critical in the pathophysiology of Parkinson's disease,as it could represent the point of entry for a putative environmental factor to initiate the pathological process.This review covers the data related to the etiology,epidemiology,clinical expression,pathophysiology,genetic aspects,gastrointestinal motor dysfunction,visceral sensitivity,management,prevention and prognosis of neurogenic bowel dysfunction patients with these neurological diseases.Embryological,morphological and experimental studies on animal models and humans are also taken into account.展开更多
The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating a...The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system（CNS）.It has been shown that NF-κB is activated in multiple cell types in the CNS of MS patients,including T cells,microglia/macrophages,astrocytes,oligodendrocytes,and neurons.Interestingly,data from animal model studies,particularly studies of experimental autoimmune encephalomyelitis,have suggested that NF-κB activation in these individual cell types has distinct effects on the development of MS.In this review,we will cover the current literature on NF-κB and the evidence for its role in the development of MS and its animal model experimental autoimmune encephalomyelitis.展开更多
Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination....Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.展开更多
Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of auto...Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis （MS）, a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system （CNS）. Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis （EAE, a mouse model of MS）. Dysfunction of mitochondria that intensively influences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene （ATG） 5 and immune-related GTPase M （IRGM） 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin （mTOR）, ameliorates relapsing-remitting EAE. Inflammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-11/LC3-1 ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-inflammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinflammation associated with the pathogenesis of MS.展开更多
Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, th...Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells（OPCs） and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.展开更多
Multiple sclerosis （MS） is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, m...Multiple sclerosis （MS） is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.展开更多
Multiple sclerosis(MS)is an inflammatory demyelinating disease of the central nervous system.The disability caused by inflammatory demyelination clinically dominates the early stages of relapsing-remitting MS and is r...Multiple sclerosis(MS)is an inflammatory demyelinating disease of the central nervous system.The disability caused by inflammatory demyelination clinically dominates the early stages of relapsing-remitting MS and is reversible.Once there is considerable loss of axons,MS patients enter a secondary progressive stage.Disease-modifying drugs currently in use for MS suppress the immune system and reduce relapse rates but are not effective in the progressive stage.Various animal models of MS(mostly mouse and rat)have been established and proved useful in studying the disease process and response to therapy.The experimental autoimmune encephalomyelitis animal studies reviewed here showed that a chronic progressive disease can be induced by immunization with appropriate amounts of myelin oligodendrocyte glycoprotein together with mycobacterium tuberculosis and pertussis toxin in Freund's adjuvant.The clinical manifestations of autoimmune encephalomyelitis disease were prevented or reduced by treatment with certain pharmacological agents given prior to,at,or after peak disease,and the agents had protective effects as shown by inhibiting demyelination and damage to neurons,axons and oligodendrocytes.In the cuprizone-induced toxicity animal studies,the pharmacological agents tested were able to promote remyelination and increase the number of oligodendrocytes when administered therapeutically or prophylactically.A monoclonal IgM antibody protected axons in the spinal cord and preserved motor function in animals inoculated with Theiler's murine encephalomyelitis virus.In all these studies the pharmacological agents were administered singly.A combination therapy may be more effective,especially using agents that target neuroinflammation and neurodegeneration,as they may exert synergistic actions.展开更多
M ultiple sclerosis is a chro nic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation,genetic predisposition,and environmental fa ctors.The acti...M ultiple sclerosis is a chro nic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation,genetic predisposition,and environmental fa ctors.The activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology,playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and neurodegeneration.Even though reactive mic roglia can damage tissue and heighten deleterious effects and neurodegeneration,activated microglia also perform neuroprotective functions such as debris phagocytosis and growth fa ctor secretion.Astrocytes can be activated into pro-inflammato ry phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia,which could also mediate neurodegeneration.This A1 phenotype inhibits oligodendrocyte prolife ration and differe ntiation and is toxic to both oligodendrocytes and neurons.Howeve r,astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism.A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation,progression,and resolution of the disease.The colonystimulating facto r-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system microglia.Importantly,as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling,colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the brain.In this context,the present review discusses the impact of microglial depletion through colo ny-stimulating factor-1 receptor inhibition on demyelination,neurodegeneration,astroglial activation,and behavior in different multiple sclerosis models,highlighting the diversity of microglial effects on the progression of demyelinating diseases and the strengths and weaknesses of microglial modulation in therapy design.展开更多
文摘Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory versus degenerative dichotomy.This was based on a broad misconception regarding essentially all neurodegenerative conditions,depicting the degenerative process as passive and immune-independent occurring as a late byproduct of active inflammation in the central nervous system(CNS),which is(solely)systemically driven.
基金Private DonationLa Trobe Research Focus AreasMultiple Sclerosis Australia,Grant/Award Number:20-032。
文摘Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.
基金supported by the National Natural Science Foundation of China,Nos.82060219,82271234the Natural Science Foundation of Jiangxi Province,Nos.20212ACB216009,20212BAB216048+1 种基金Jiangxi Province Thousands of Plans,No.jxsq2019201023Youth Team Project of the Second Affiliated Hospital of Nanchang University,No.2019YNTD12003(all to FH)。
文摘Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood–brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.
基金supported by the National Natural Science Foundation of China(Grant Nos.:32271292,31872723,32200778,and 22377089)the Jiangsu Students Innovation and Entrepre-neurship Training Program,China(Program No.:202210285081Z)+6 种基金the Project of MOE Key Laboratory of Geriatric Diseases and Immunology,China(Project No.:JYN202404)Proj-ect Funded by the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions,Natural Science Foundation of Jiangsu Province,China(Project No.:BK20220494)Suzhou Medical and Health Technology Innovation Project,China(Grant No.:SKY2022107)the Clinical Research Center of Neuro-logical Disease in The Second Affiliated Hospital of Soochow University,China(Grant No.:ND2022A04)State Key Laboratory of Drug Research(Grant No.:SKLDR-2023-KF-05)Jiangsu Shuang-chuang Program for Doctor,Young Science Talents Promotion Project of Jiangsu Science and Technology Association(Program No.:TJ-2023-019)Young Science Talents Promotion Project of Suzhou Science and Technology Association,Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and startup funding(Grant Nos.:NH21500221,NH21500122,and NH21500123)to Qifei Cong.
文摘Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the“therapeutic module”of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.
文摘Multiple Sclerosis(MS)poses significant health risks.Patients may face neurodegeneration,mobility issues,cognitive decline,and a reduced quality of life.Manual diagnosis by neurologists is prone to limitations,making AI-based classification crucial for early detection.Therefore,automated classification using Artificial Intelligence(AI)techniques has a crucial role in addressing the limitations of manual classification and preventing the development of MS to advanced stages.This study developed hybrid systems integrating XGBoost(eXtreme Gradient Boosting)with multi-CNN(Convolutional Neural Networks)features based on Ant Colony Optimization(ACO)and Maximum Entropy Score-based Selection(MESbS)algorithms for early classification of MRI(Magnetic Resonance Imaging)images in a multi-class and binary-class MS dataset.All hybrid systems started by enhancing MRI images using the fusion processes of a Gaussian filter and Contrast-Limited Adaptive Histogram Equalization(CLAHE).Then,the Gradient Vector Flow(GVF)algorithm was applied to select white matter(regions of interest)within the brain and segment them from the surrounding brain structures.These regions of interest were processed by CNN models(ResNet101,DenseNet201,and MobileNet)to extract deep feature maps,which were then combined into fused feature vectors of multi-CNN model combinations(ResNet101-DenseNet201,DenseNet201-MobileNet,ResNet101-MobileNet,and ResNet101-DenseNet201-MobileNet).The multi-CNN features underwent dimensionality reduction using ACO and MESbS algorithms to remove unimportant features and retain important features.The XGBoost classifier employed the resultant feature vectors for classification.All developed hybrid systems displayed promising outcomes.For multiclass classification,the XGBoost model using ResNet101-DenseNet201-MobileNet features selected by ACO attained 99.4%accuracy,99.45%precision,and 99.75%specificity,surpassing prior studies(93.76%accuracy).It reached 99.6%accuracy,99.65%precision,and 99.55%specificity in binary-class classification.These results demonstrate the effectiveness of multi-CNN fusion with feature selection in improving MS classification accuracy.
基金Hunan Province College Students Research Learning and Innovative Experiment Project(S202410542120)。
文摘Despite suggested shared pathophysiological mechanisms between coronavirus disease 2019(COVID-19)and multiple sclerosis(MS),the molecular pathways underlying their relationship remain unclear.Herein,gene expression profiles of COVID-19(GSE171110,GSE152641)and MS(GSE66573,GSE159225)datasets were analyzed using Gene Ontology(GO)enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,and protein-protein interaction(PPI)network construction.A two-acsample Mendelian randomization(MR)study was performed to establish potential causal relationships.A total of 165 shared differentially expressed genes(DEGs)were identified,with significant enrichment in pathways related to humoral immune response,neutrophil migration,and cytokine-receptor interactions in both conditions.Validation by receiver operating characteristic(ROC)curve analysis demonstrated that the hub genes S100A8,S100A9,S100A12,and ALOX5AP achieved area under the curve(AUC)values above 0.7 for both diseases.Increased neutrophil infiltration was positively correlated with upregulated expression of these genes,particularly demonstrating significant associations between the hub gene expression and neutrophil activity pathways.MR analysis suggested a causal relationship between S100A8 expression and susceptibility to both conditions and neutrophil counts,while ALOX5AP was indicated as a potential MS risk factor.These findings suggest that COVID-19 and MS co-occurrence is associated with neutrophil infiltration,highlighting S100A8 as both a promising biomarker and therapeutic target.
文摘AIM:To determine the diagnostic ability of various visual functions in patients with multiple sclerosis(MS)with and without optic neuritis(ON).METHODS:In this cross-sectional study,we assessed and compared refractive error,visual acuity(VA),and contrast sensitivity(CS)between patients with MS and a matched control group of healthy individuals.The MS patients were further categorized into those with ON and those without.RESULTS:A total of 133 eyes from 133 participants were assessed,including 66 individuals diagnosed with MS.The mean ages for the MS group and the healthy control group were 37.5±4.27y and 38.45±4.60y,respectively(P=0.346).Among the 66 patients with MS,18 had ON.The presence of MS was associated with a decrease in best-corrected visual acuity(BCVA)and spherical component of refractive error(P<0.05),whereas ON did not lead to any further decline in these parameters(P>0.05).MS was linked to decreased CS at spatial frequencies of 6 and 18 cycles per degree(CPD;P<0.05),while ON in MS patients resulted in an additional decrease in CS at 3 CPD(P=0.03).The most significant sensitivity for distinguishing MS patients from healthy individuals as well as MS patients with ON from those without ON was found with cylindrical component[associated criterion(AC)>-0.75 D;71.21%]and CS at spatial frequency of 6 CPD(AC≤1.56;72.22%),respectively.Conversely,the highest specificity for these diagnostic measures was associated with BCVA(AC>0 logMAR;97.01%)and CS at a spatial frequency of 12 CPD(AC≤0.60;93.75%),respectively.CONCLUSION:MS significantly affects refractive error and CS,with ON further reducing CS.Assessing these visual parameters can improve MS monitoring and management.
文摘BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a common site for MS plaques,and the medial olivocochlear(MOC)system is located in the superior olivary complex(SOC)of the brainstem.The cochlear nuclei are also involved in the MOC reflex arc.Additionally,the temporal cortex can modulate the SOC and cochlear nucleus,so lesions in the brainstem or temporal cortex may affect the MOC reflex in MS.AIM To investigate efferent auditory system activity in patients with multiple sclerosis via the MOC reflex.METHODS The study included 50 patients with MS and 50 healthy controls.Patients with MS were divided into three subgroups according to cranial magnetic resonance imaging findings:Patients with brainstem lesions(Group 1,n=20);patients with temporal cortex lesions without brainstem involvement(Group 2,n=20);and patients without any lesions in the brainstem or temporal cortex(Group 3,n=10).Tympanometry,acoustic stapedial reflex thresholds,pure-tone audiometry,and transientevoked otoacoustic emission(TEOAE)tests(with and without contralateral noise)were performed for all participants.RESULTS There was no significant difference in pure-tone hearing thresholds or baseline TEOAE amplitudes between the MS and control groups,indicating normal cochlear function in patients with MS;however,MOC reflex suppression was significantly reduced in patients with MS compared to controls(P=0.021).In particular,Group 1(MS with brainstem lesions)showed the lowest mean suppression values,which was significantly lower than that of Group 2 and the control group(P=0.002).By contrast,Group 2 and Group 3 did not significantly differ from controls.Additionally,patients with MS exhibited a sex difference in MOC function:Male patients had significantly lower suppression compared to female patients both within Group 1 and in the MS group as a whole.CONCLUSION The findings indicate that the efferent auditory system(specifically the MOC reflex)is affected by MS.MOC reflex activity was most significantly decreased in patients with MS with brainstem lesions,while temporal cortex lesions alone did not appear to notably impair the MOC reflex.Diminished MOC activity may underlie various auditory difficulties in patients with MS(e.g.,hearing in noise),and loss of efferent suppression could contribute to symptoms such as hyperacusis or tinnitus in this population.Further studies are needed to better understand the relationship between MOC dysfunction and auditory symptoms in MS,as well as the potential diagnostic value of MOC testing in MS.
基金The Key R&D Plan of Xianyang Construction of Xianyang City’s in vitro rapid diagnostic reagent technology integration and pilot scale shared service platform(Grant No.2021ZDYF-SF-0012)。
文摘Multiple sclerosis(MS)is a neurodegenerative disease,with aging being a significant risk factor that increases neural susceptibility to damage and reduces resilience.Cellular senescence(CS),a critical biological process of aging,also plays a pivotal role in MS pathogenesis.This study investigated the role of CS in MS by bioinformatics analyses,identifying key genes and potential therapeutic drugs.In differential gene expression(DEG)analysis,we identified 565 DEGs,comprising 166 upregulated and 399 downregulated genes(P<0.05,|LogFC|>1.5).Gene Set Enrichment Analysis(GSEA)revealed that these DEGs were enriched in pathways related to ribosomes,CS,and MAPK signaling.Weighted gene co-expression network analysis(WGCNA)identified the turquoise module,consisting of 164 genes,as having the strongest correlation with MS(R^(2)=0.54,P=1e^(–14)).KEGG pathway analysis indicated that this module was most enriched in autophagy,Salmonella infection,and apoptosis pathways.Intersecting the DEGs,WGCNA key module genes,and 1381 CS-associated genes,we identified 49 key genes involved in MS.Machine learning algorithms further pinpointed ATF7IP,ATR,BCL10,CTNNB1,PDCD1,PIK3CA,TNFSF13,MSH3,HTR2A,and ALPL as MS hub genes,which were validated using the GSE13732 testing set.Seven candidate gene-related drugs were identified from DrugBank and the Comparative Toxicogenomics Database(CTD).Molecular docking results indicated that the binding energies for ATF7IP,ATR,BCL10,HTR2A,and PDCD10 with these drugs ranged from–2.444 to–6.523 Kcal/mol.
基金supported by the Natural Science Foundation of Shanxi Province,China(No.2008011082-1).
文摘Multiple sclerosis （MS） is an autoimmune disease. The etiology and pathogenesis of MS remain unclear. At present, there are substantial evidences to support the hypothesis that genetics plays a crucial role. The people who have genetic predisposing genes easily develop immune-mediated disorder, probably in conjunction with environmental factors. The aim of this review is to describe recent observations regarding the immunologic pathogenesis of MS.
文摘This review focused on the diagnosis and clinical features of multiple sclerosis(MS) in China. We have identified the published researching information from 1976 to 2008 in China. The key issues related to the diagnosis and clinical features of MS in China were summarized. The first patient with MS in China was reported in 1926 from Xiehe hospital. Case reports on MS has been increasing during recent decades. Almost all the patients with MS were confirmed by the McDonald criteria(1977) before1984. After the...
基金supported by thegrant from China Scholarship Council(Grant No.[2008]3019)
文摘Vitamin D is a seco-steroid involved in calcium and phosphorus metabolism,and bone formation and mineralization, through binding to a specific nuclear receptor,vitamin D receptor（VDR）.Besides its well-established functions on bone health,multiple lines of evidence have indicated the immunomodulatory roles of vitamin D.Vitamin D can affect both innate and adaptive immunity,and prevent autoimmune responses efficiently.Vitamin D regulates the immune responses by suppressing T cell proliferation and modulating macrophage functions.Epidemiological studies have shown that vitamin D deficiency is associated with multiple diseases such as rickets and cancer.Moreover,associations between vitamin D and autoimmune diseases have been confirmed in multiple sclerosis（MS）,rheumatoid arthritis（RA）,etc.The present review mainly summarized the recent findings on the immunomodulatory role of vitamin D in various disorders,with special focus on its role in MS,an autoimmune disease of the nervous system.
文摘Exciting new features have been described concerning neurogenic bowel dysfunction,including interactions between the central nervous system,the enteric nervous system,axonal injury,neuronal loss,neurotransmission of noxious and non-noxious stimuli,and the fields of gastroenterology and neurology.Patients with spinal cord injury,myelomeningocele,multiple sclerosis and Parkinson's disease present with serious upper and lower bowel dysfunctions characterized by constipation,incontinence,gastrointestinal motor dysfunction and altered visceral sensitivity.Spinal cord injury is associated with severe autonomic dysfunction,and bowel dysfunction is a major physical and psychological burden for these patients.An adult myelomeningocele patient commonly has multiple problems reflecting the multisystemic nature of the disease.Multiple sclerosis is a neurodegenerative disorder in which axonal injury,neuronal loss,and atrophy of the central nervous system can lead to permanent neurological damage and clinical disability.Parkinson's disease is a multisystem disorder involving dopaminergic,noradrenergic,serotoninergic and cholinergic systems,characterizedby motor and non-motor symptoms.Parkinson's disease affects several neuronal structures outside the substantia nigra,among which is the enteric nervous system.Recent reports have shown that the lesions in the enteric nervous system occur in very early stages of the disease,even before the involvement of the central nervous system.This has led to the postulation that the enteric nervous system could be critical in the pathophysiology of Parkinson's disease,as it could represent the point of entry for a putative environmental factor to initiate the pathological process.This review covers the data related to the etiology,epidemiology,clinical expression,pathophysiology,genetic aspects,gastrointestinal motor dysfunction,visceral sensitivity,management,prevention and prognosis of neurogenic bowel dysfunction patients with these neurological diseases.Embryological,morphological and experimental studies on animal models and humans are also taken into account.
基金supported by grants from the National Institutes of Health(NS094151 and NS105689)the National Multiple Sclerosis Society(RG5239-A-3)(to WL)
文摘The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system（CNS）.It has been shown that NF-κB is activated in multiple cell types in the CNS of MS patients,including T cells,microglia/macrophages,astrocytes,oligodendrocytes,and neurons.Interestingly,data from animal model studies,particularly studies of experimental autoimmune encephalomyelitis,have suggested that NF-κB activation in these individual cell types has distinct effects on the development of MS.In this review,we will cover the current literature on NF-κB and the evidence for its role in the development of MS and its animal model experimental autoimmune encephalomyelitis.
文摘Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.
基金supported by a grant from the National Natural Science Foundation of China (81430021 and 81370470)China Postdoctoral Science Foundation (2014M551465)the Collaborative Innovation Center for Brain Science
文摘Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis （MS）, a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system （CNS）. Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis （EAE, a mouse model of MS）. Dysfunction of mitochondria that intensively influences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene （ATG） 5 and immune-related GTPase M （IRGM） 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin （mTOR）, ameliorates relapsing-remitting EAE. Inflammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-11/LC3-1 ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-inflammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinflammation associated with the pathogenesis of MS.
文摘Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells（OPCs） and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.
文摘Multiple sclerosis （MS） is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.
文摘Multiple sclerosis(MS)is an inflammatory demyelinating disease of the central nervous system.The disability caused by inflammatory demyelination clinically dominates the early stages of relapsing-remitting MS and is reversible.Once there is considerable loss of axons,MS patients enter a secondary progressive stage.Disease-modifying drugs currently in use for MS suppress the immune system and reduce relapse rates but are not effective in the progressive stage.Various animal models of MS(mostly mouse and rat)have been established and proved useful in studying the disease process and response to therapy.The experimental autoimmune encephalomyelitis animal studies reviewed here showed that a chronic progressive disease can be induced by immunization with appropriate amounts of myelin oligodendrocyte glycoprotein together with mycobacterium tuberculosis and pertussis toxin in Freund's adjuvant.The clinical manifestations of autoimmune encephalomyelitis disease were prevented or reduced by treatment with certain pharmacological agents given prior to,at,or after peak disease,and the agents had protective effects as shown by inhibiting demyelination and damage to neurons,axons and oligodendrocytes.In the cuprizone-induced toxicity animal studies,the pharmacological agents tested were able to promote remyelination and increase the number of oligodendrocytes when administered therapeutically or prophylactically.A monoclonal IgM antibody protected axons in the spinal cord and preserved motor function in animals inoculated with Theiler's murine encephalomyelitis virus.In all these studies the pharmacological agents were administered singly.A combination therapy may be more effective,especially using agents that target neuroinflammation and neurodegeneration,as they may exert synergistic actions.
文摘M ultiple sclerosis is a chro nic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation,genetic predisposition,and environmental fa ctors.The activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology,playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and neurodegeneration.Even though reactive mic roglia can damage tissue and heighten deleterious effects and neurodegeneration,activated microglia also perform neuroprotective functions such as debris phagocytosis and growth fa ctor secretion.Astrocytes can be activated into pro-inflammato ry phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia,which could also mediate neurodegeneration.This A1 phenotype inhibits oligodendrocyte prolife ration and differe ntiation and is toxic to both oligodendrocytes and neurons.Howeve r,astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism.A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation,progression,and resolution of the disease.The colonystimulating facto r-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system microglia.Importantly,as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling,colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the brain.In this context,the present review discusses the impact of microglial depletion through colo ny-stimulating factor-1 receptor inhibition on demyelination,neurodegeneration,astroglial activation,and behavior in different multiple sclerosis models,highlighting the diversity of microglial effects on the progression of demyelinating diseases and the strengths and weaknesses of microglial modulation in therapy design.
