Gut flora in multiple sclerosis:implications for pathogenesis and treatment

Multiple sclerosis is an inflammatory disorder chara cterized by inflammation,demyelination,and neurodegeneration in the central nervous system.Although current first-line therapies can help manage symptoms and slow down disease progression,there is no cure for multiple sclerosis.The gut-brain axis refers to complex communications between the gut flo ra and the immune,nervous,and endocrine systems,which bridges the functions of the gut and the brain.Disruptions in the gut flora,termed dys biosis,can lead to systemic inflammation,leaky gut syndrome,and increased susceptibility to infections.The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors,and gut flora may play a pivotal role in regulating immune responses related to multiple scle rosis.To develop more effective therapies for multiple scle rosis,we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis.This review provides an overview of the role of the gut flora in multiple scle rosis.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Infiltration by monocytes of the central nervous system and its role in multiple sclerosis: reflections on therapeutic strategies

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.

Unraveling the potential of acute intermittent hypoxia as a strategy for inducing robust repair in multiple sclerosis

Multiple sclerosis(MS)is a debilitating inflammatory disease of the central nervous system characterized by immune-mediated segmental demyelination and variable degrees of axonal and neuronal degeneration that contribute to disability.Inducing efficient and effective repair programs following demyelination is a major goal and challenge in MS.Conventional MS therapies focus largely on modulating the immune aspects of the disease contributing to lesions.While this alleviates some symptoms and mitigates damage,it does not tackle the fundamental challenge of effective remyelination,which few MS patients experience,especially in the progressive phase of the disease.

Multiple sclerosis is at a checkpoint: advancing the program

Multiple sclerosis(MS) is a chronic inflammatory and demyelinating disease of the central nervous system(CNS). Patients with MS experience sensory and motor function loss due to myelin and/or axon damage perpetuated by infiltrating immune cells(Hauser and Cree, 2020).

Assistive techniques and their added value for tremor classification in multiple sclerosis

Tremor occurs in about half of multiple sclerosis(MS)patients.MS tremor has a broad frequency range of 2.5-7 Hz,with a higher prevalence of postural tremor(44%)compared to intentional tremor(6%)(Alusi et al.,2001).Tremor may affect the upper and lower extremities,head,and trunk,and may even affect the vocal cords in isolated cases of palatal tremor.MS tremor is classically attributed to lesions of the brain stem,cerebellum,or cerebellar peduncles,and tremor intensity has been shown to correlate with the number of lesions or their functional connections.However,recent work has demonstrated that inflammatory damage to the cerebello-thalamic and cortico-thalamic pathways might also play an important role in causing tremor,as it co-occurs with other signs and symptoms of MS such as dysarthria,dysmetria,dysdiadochokinesia,and dystonia(Alusi et al.,2001).

Examination of the Effective Factors on the Multiple Sclerosis Diseases

This study was an attempt to examine the effective factors of the Multiple Sclerosis diseases. The participants of the study were selected from among a total number of 45 men and women who were treated in a health center in Azarbayegan and Damavand in Iran. In order to study, the researchers applied various procedures to collect the data of the study. The participants were interviewed and filled out the questionnaires. After categorizing and classifying the collected information and data, it was processed and analyzed and the results are found. To test the research questions, a one-sample T-test was used to analyze the data. The role of hypo vitamin D as a possible risk factor for multiple sclerosis was reviewed. First, it was emphasized that hypo vitamin could be only one of the risk factors for multiple sclerosis and that numerous other environmental and genetic risk factors appear to interact and combine to trigger the disease. The main aim of this study was to examine the effective factors of Multiple Sclerosis diseases. The methodology of this research was to test the research questions;one-sample T-test was used to analyze the data. The findings of this study revealed that the factors of gender, cold weather, vitamin D deficiency, and age (between 30 - 59) were effective on the Multiple Sclerosis diseases.

Pathological mechanisms of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system,the cause of which remains unexplained despite several years of research.Thus,the journey to understanding or treating amyotrophic lateral sclerosis is still a long one.According to current research,amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways.The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis.Here,we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis,as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis.In addition,we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis.Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

Improving Multiple Sclerosis Disease Prediction Using Hybrid Deep Learning Model

Myelin damage and a wide range of symptoms are caused by the immune system targeting the central nervous system in Multiple Sclerosis(MS),a chronic autoimmune neurological condition.It disrupts signals between the brain and body,causing symptoms including tiredness,muscle weakness,and difficulty with memory and balance.Traditional methods for detecting MS are less precise and time-consuming,which is a major gap in addressing this problem.This gap has motivated the investigation of new methods to improve MS detection consistency and accuracy.This paper proposed a novel approach named FAD consisting of Deep Neural Network(DNN)fused with an Artificial Neural Network(ANN)to detect MS with more efficiency and accuracy,utilizing regularization and combat over-fitting.We use gene expression data for MS research in the GEO GSE17048 dataset.The dataset is preprocessed by performing encoding,standardization using min-max-scaler,and feature selection using Recursive Feature Elimination with Cross-Validation(RFECV)to optimize and refine the dataset.Meanwhile,for experimenting with the dataset,another deep-learning hybrid model is integrated with different ML models,including Random Forest(RF),Gradient Boosting(GB),XGBoost(XGB),K-Nearest Neighbors(KNN)and Decision Tree(DT).Results reveal that FAD performed exceptionally well on the dataset,which was evident with an accuracy of 96.55%and an F1-score of 96.71%.The use of the proposed FAD approach helps in achieving remarkable results with better accuracy than previous studies.

Multiple Solutions for a Class of Singular Boundary Value Problems of Hadamard Fractional Differential Systems with p-Laplacian Operator

This paper discusses the existence and multiplicity of positive solutions for a class of singular boundary value problems of Hadamard fractional differential systems involving the p-Laplacian operator. First, for the sake of overcoming the singularity, sequences of approximate solutions to the boundary value problem are obtained by applying the fixed point index theory on the cone. Next, it is demonstrated that these sequences of approximate solutions are uniformly bounded and equicontinuous. The main results are then established through the Ascoli-Arzelà theorem. Ultimately, an instance is worked out to test and verify the validity of the main results.

Designing a Protection Scheme in Micro-Grid Systems with DG Using Central Protection Unite and Multiple Setting Group Protection Relays

Distributed generators now is widely used in electrical power networks, in some cases it works seasonally, and some types works at special weather conditions like photo voltaic systems and wind energy, and due to this continuous changes in generation condition, the fault current level in network will be affected, this changes in fault current level will affect in the coordination between protection relays and to keep the coordination at right way, an adaptive protection system is required that can adaptive its setting according to generation changes, the fault current level in each case is evaluated using ETAP software, and the required relay setting in each case is also evaluated using Grey Wolf Optimizer (GWO) algorithm, and to select suitable setting which required in each condition, to select the active setting group of protection relay according to generation capacity, central protection unite can be used, and to improve protection stability and minimizing relays tripping time, a proposed method for selecting suitable backup relay is used, which leads to decrease relays tripping time and increase system stability, output settings for relays in all cases achieved our constrains.

Microglia depletion as a therapeutic strategy:friend or foe in multiple sclerosis models?

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.

CDP-choline to promote remyelination in multiple sclerosis:the need for a clinical trial

Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional disability.Remyelination is the natural repair process of demyelination,but it is often incomplete or fails in multiple sclerosis.Available therapies reduce the inflammatory state and prevent clinical relapses.However,therapeutic approaches to increase myelin repair in humans are not yet available.The substance cytidine-5′-diphosphocholine,CDP-choline,is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular phospholipids.Regenerative properties have been shown in various animal models of diseases of the central nervous system.We have already shown that the compound CDPcholine improves myelin regeneration in two animal models of multiple sclerosis.However,the results from the animal models have not yet been studied in patients with multiple sclerosis.In this review,we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative processes.We also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.

The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier

Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis.Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis,thus inhibiting remyelination.Although many advances have been made in the mechanisms and treatment of multiple sclerosis,it remains very difficult for drugs to reach pathological brain tissues;this is due to the complexity of brain structure and function,especially the existence of the blood-brain barrier.Therefore,herein,we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.

Immunological role of sulfatide in the pathogenesis of multiple sclerosis

Multiple sclerosis(MS) is a chronic inflammatory demyelinating disease of the central nervous system.A certain population of patients with MS present with a relapse-remitting disease course(RRMS) during the early phase and eventually advance to a progressive course(PMS).While immune modulation therapies have recently seen tremendous success in RRMS,our limited knowledge of pathogenesis hampers the development of effective treatments for PMS.

Synaptic pathology in multiple sclerosis:a role for Nogo-A signaling in astrocytes?

Multiple sclerosis(MS)is characterized as an inflammatory demyelinating disease that affects the central nervous system(CNS),leading to sensory,motor and cognitive impairments.Ultimately,axonal denudation culminates in axonal lesions and neurodegeneration.Inflammatory demyelinating lesions in MS are associated with infiltration of immune cells combined with activation of the resident CNS inflammatory cells,astro-and microglia.

Brain network correlates of epilepsy occurrence in multiple sclerosis and neuroinflammation

Multiple sclerosis(MS),the most common inflammatory condition of the central nervous system in young adults,is characterized by immunemediated demyelination and neurodegeneration that translate into heterogeneous clinical phenotypes and disease trajectories.

Safety,immunogenicity,efficacy,and acceptability of COVID-19 vaccination in people with multiple sclerosis:a narrative review

In the last two years,a new seve re acute res piratory syndrome coronavirus(SARS-CoV)infection has spread worldwide leading to the death of millions.Va ccination represents the key factor in the global strategy against this pandemic,but it also poses several problems,especially for vulnerable people such as patients with multiple scle rosis.In this review,we have briefly summarized the main findings of the safety,efficacy,and acceptability of Coronavirus Disease 2019(COVID-19)vaccination fo r multiple sclerosis patients.Although the acceptability of COVID-19 vaccines has progressively increased in the last year,a small but significant part of patients with multiple sclerosis still has relevant concerns about vaccination that make them hesitant about receiving the COVID-19 vaccine.Overall,available data suggest that the COVID-19 vaccination is safe and effective in multiple scle rosis patients,even though some pharmacological treatments such as anti-CD20 therapies or sphingosine I-phosphate receptor modulato rs can reduce the immune response to vaccination.Accordingly,COVID-19 vaccination should be strongly recommended for people with multiple scle rosis and,in patients treated with anti-CD20 therapies and sphingosine I-phosphate receptor modulato rs,and clinicians should evaluate the appropriate timing for vaccine administration.Further studies are necessary to understand the role of cellular immunity in COVID-19 vaccination and the possible usefulness of booster jabs.On the other hand,it is mandatory to learn more about the reasons why people refuse vaccination.This would help to design a more effective communication campaign aimed at increasing vaccination coverage among vulnerable people.

Exploring the mechanism of Yishen Daluo decoction in the treatment of multiple sclerosis based on network pharmacology and in vitro experiments

Objective:To explore the mechanism and related active components of Yishen Daluo decoction(YSDLD)in treating multiple sclerosis(MS).Methods:Targets of YSDLD were collected through the TCMSP,Chemistry,and TCMID databases.The MS targets were collected through OMIM,DrugBank,Gencards,TTD,and Pharmgkb databases.We built“componentetarget”network diagrams and proteineprotein interaction(PPI)diagrams and performed topological analysis.The targets were subjected to GO and KEGG enrichment analysis.Molecular docking verification was conducted on selected targets and molecules.Finally,in vitro experiments were con-ducted.BV2 cells were induced by lipopolysaccharide for model establishment.CCK8 experiment was conducted to explore the effect of YSDLD and RT-qPCR technology was used to explore the expression of key targets.Results:There were 184 active components in YSDLD and 898 targets of its action.There were 940 MS targets,and 215 targets were shared by YSDLD and MS.According to the“componentetarget”diagram,the top five key components included quercetin,kaempferol,beta-sitosterol,stigmasterol,and nar-ingenin.IL-6,IL-1 b,TNF-α,AKT1,and VEGFA were the important targets identified by PPI network to-pology analysis.A total of 564 functions were identified by GO enrichment analysis(P<0.01),mainly involving inflammatory response,hypoxia response,plasma membrane,neuronal cell body,protein phosphatase binding,and cytokine activity.KEGG enrichment analysis enriched 98 pathways(P<.01).YSDLD at the concentration of 20 m g/mL had no effect on BV2 cells.RT-qPCR indicated that YSDLD at the concentrations of 15 m g/mL and 20 m g/mL alleviated LPS-induced inflammatory injury and lowered the content of inflammatory factors(P<0.05).Conclusion:In this paper,the network pharmacology and in vitro experiments were used to explore the potential mechanism of YSDLD in treating MS.The research provides a good basis for the development of YSDLD and drugs for MS in future.

Neuroimmune,clinical and treatment challenges in multiple sclerosis-related psychoses

In recent years,epidemiological and genetic studies have shown an association between autoimmune diseases and psychosis.The question arises whether patients with schizophrenia are more likely to develop multiple sclerosis(MS)later in life.It is well known that the immune system plays an important role in the etiopathogenesis of both disorders.Immune disturbances may be similar or very different in terms of different types of immune responses,disturbed myelination,and/or immunogenetic predispositions.A psychotic symptom may be a consequence of the MS diagnosis itself or a separate entity.In this review article,we discussed the timing of onset of psychotic symptoms and MS and whether the use of corticosteroids as therapy for acute relapses in MS is unfairly neglected in patients with psychiatric comorbidities.In addition,we discussed that the anti-inflammatory potential of antipsychotics could be useful and should be considered,especially in the treatment of psychosis that coexists with MS.Autoimmune disorders could precipitate psychotic symptoms,and in this context,autoimmune psychosis must be considered as a persistent symptomatology that requires continuous and specific treatment.