scholarly journals An emerging potential of metabolomics in multiple sclerosis: a comprehensive overview

2021 ◽  
Author(s):  
Insha Zahoor ◽  
Bin Rui ◽  
Junaid Khan ◽  
Indrani Datta ◽  
Shailendra Giri
Keyword(s):  
Multiple Sclerosis ◽  
Drug Targets ◽  
Demyelinating Disease ◽  
Tricarboxylic Acid Cycle ◽  
Nucleotide Metabolism ◽  
Therapeutic Interventions ◽  
Preclinical Model ◽  
Therapeutic Effects ◽  
Comprehensive Overview ◽  
Unique Markers

AbstractMultiple sclerosis (MS) is an inflammatory demyelinating disease of the nervous system that primarily affects young adults. Although the exact etiology of the disease remains obscure, it is clear that alterations in the metabolome contribute to this process. As such, defining a reliable and disease-specific metabolome has tremendous potential as a diagnostic and therapeutic strategy for MS. Here, we provide an overview of studies aimed at identifying the role of metabolomics in MS. These offer new insights into disease pathophysiology and the contributions of metabolic pathways to this process, identify unique markers indicative of treatment responses, and demonstrate the therapeutic effects of drug-like metabolites in cellular and animal models of MS. By and large, the commonly perturbed pathways in MS and its preclinical model include lipid metabolism involving alpha-linoleic acid pathway, nucleotide metabolism, amino acid metabolism, tricarboxylic acid cycle, d-ornithine and d-arginine pathways with collective role in signaling and energy supply. The metabolomics studies suggest that metabolic profiling of MS patient samples may uncover biomarkers that will advance our understanding of disease pathogenesis and progression, reduce delays and mistakes in diagnosis, monitor the course of disease, and detect better drug targets, all of which will improve early therapeutic interventions and improve evaluation of response to these treatments.

scholarly journals Selective vulnerability of inhibitory networks in multiple sclerosis

2021 ◽  
Vol 141 (3) ◽  
pp. 415-429 ◽  
Author(s):  
Lida Zoupi ◽  
Sam A. Booker ◽  
Dimitri Eigel ◽  
Carsten Werner ◽  
Peter C. Kind ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Demyelinating Disease ◽  
Selective Vulnerability ◽  
Preclinical Model ◽  
Inhibitory Interneurons ◽  
Disease Course ◽  
Secondary Progressive ◽  
The Central Nervous System ◽  
Inhibitory Networks

AbstractIn multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination reproduces this selective neurodegeneration providing a new preclinical model for the study of neuroprotective treatments.

scholarly journals Demyelination induces selective vulnerability of inhibitory networks in multiple sclerosis

2020 ◽  
Author(s):  
Lida Zoupi ◽  
Sam A. Booker ◽  
Dimitri Eigel ◽  
Carsten Werner ◽  
Peter C. Kind ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Demyelinating Disease ◽  
Selective Vulnerability ◽  
Preclinical Model ◽  
Inhibitory Interneurons ◽  
Disease Course ◽  
Secondary Progressive ◽  
The Central Nervous System ◽  
Inhibitory Networks

In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination proved that this selective neurodegeneration is secondary to demyelination providing the first temporal evidence of demyelination-induced neurodegeneration and a new preclinical model for the study of neuroprotective treatments.

scholarly journals Mass Cytometry Identifies Expansion of T-bet+ B Cells and CD206+ Monocytes in Early Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Couloume ◽  
Juliette Ferrant ◽  
Simon Le Gallou ◽  
Marion Mandon ◽  
Rachel Jean ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Drug Targets ◽  
Immune Cell ◽  
Demyelinating Disease ◽  
Cell Subset ◽  
Predictive Biomarkers ◽  
Lymphoid Cells ◽  
Monocyte Subset ◽  
Mass Cytometry

Multiple sclerosis (MS) is an immune-driven demyelinating disease of the central nervous system. Immune cell features are particularly promising as predictive biomarkers due to their central role in the pathogenesis but also as drug targets, even if nowadays, they have no impact in clinical practice. Recently, high-resolution approaches, such as mass cytometry (CyTOF), helped to better understand the diversity and functions of the immune system. In this study, we performed an exploratory analysis of blood immune response profiles in healthy controls and MS patients sampled at their first neurological relapse, using two large CyTOF panels including 62 markers exploring myeloid and lymphoid cells. An increased abundance of both a T-bet-expressing B cell subset and a CD206+ classical monocyte subset was detected in the blood of early MS patients. Moreover, T-bet-expressing B cells tended to be enriched in aggressive MS patients. This study provides new insights into understanding the pathophysiology of MS and the identification of immunological biomarkers. Further studies will be required to validate these results and to determine the exact role of the identified clusters in neuroinflammation.

scholarly journals A Novel Probiotic Strain Exerts Therapeutic Effects on Mouse Model of Multiple Sclerosis by Altering The Expression of Inflammasome and IDO Genes and Modulation of T Helper Cytokine Profile

2021 ◽  
Author(s):  
saba sadeghi ◽  
fatemeh kazemi ◽  
saba taheri ◽  
Maryam Tajabadi Ebrahimi ◽  
javad arasteh
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Demyelinating Disease ◽  
Neuronal Cell ◽  
Bacillus Coagulans ◽  
Probiotic Strain ◽  
Therapeutic Effects ◽  
Expression Of Genes ◽  
Y Maze ◽  
Prevention And Treatment

Abstract Multiple sclerosis is an inflammatory demyelinating disease that commences to neuronal cell destruction. Recently, a promising evidence of synergic effects of combined supplementation with vitamin D and probiotics in modulating the gut microbiota and metabolome is emerging. Bacillus Coagulans IBRC-M10791 as a novel strain was chosen, prevention and treatment impacts of regular administered were studied in Cuprizone-induced C57bl/6 mouse of demyelination. The mice were divided into six groups and received a daily dose of cuprizone or probiotics. To investigate the effect of probiotic, the IDO-1, CYP27B1, NLRP1, NLRP3, and AIM2 expression were estimated by Real-Time PCR, and IL-4, IL-17, IFN-gamma, and TGF-beta cytokines were measured by ELISA. The results showed that there was significant decrease in IL-17 and IFN-γ and modulatory effects on IL-4 and TGF-β. On the other hand, we demonstrated that there are significant decrease for expression of IDO-1, CYP27b1, NLRP1, NLRP3 and AIM2 genes in prevention and treatment groups compared to cuprizone group. Also, a significant enhancement in rate of remyelination and alternations proved by LFB staining and Y-Maze test. In conclusion, our study provides insight into how the therapeutic effect of the chosen strain of probiotic was correlated with the modulation of the level of inflammatory and anti-inflammatory cytokines. Further, we demonstrated that the expression of genes related to Tryptophan, Vitamin D and Inflammasome pathways could be affected by Bacillus coagulans. Our study could be beneficial to provide a novel Co-therapeutic strategy for Multiple sclerosis.

scholarly journals Variations in diet cause alterations in microbiota and metabolites that follow changes in disease severity in a multiple sclerosis model

2018 ◽  
Vol 9 (3) ◽  
pp. 495-513 ◽  
Author(s):  
J.E. Libbey ◽  
J.M. Sanchez ◽  
D.J. Doty ◽  
J.T. Sim ◽  
M.F. Cusick ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Severity ◽  
Tricarboxylic Acid Cycle ◽  
Preclinical Model ◽  
Autoimmune Encephalomyelitis ◽  
Immune Mediated ◽  
Genus Lactobacillus ◽  
The Central Nervous System ◽  
The Relationship ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a metabolically demanding disease involving immune-mediated destruction of myelin in the central nervous system. We previously demonstrated a significant alteration in disease course in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS due to diet. Based on the established crosstalk between metabolism and gut microbiota, we took an unbiased sampling of microbiota, in the stool, and metabolites, in the serum and stool, from mice (Mus musculus) on the two different diets, the Teklad global soy protein-free extruded rodent diet (irradiated diet) and the Teklad sterilisable rodent diet (autoclaved diet). Within the microbiota, the genus Lactobacillus was found to be inversely correlated with EAE severity. Therapeutic treatment with Lactobacillus paracasei resulted in a significant reduction in the incidence of disease, clinical scores and the amount of weight loss in EAE mice. Within the metabolites, we identified shifts in glycolysis and the tricarboxylic acid cycle that may explain the differences in disease severity between the different diets in EAE. This work begins to elucidate the relationship between diet, microbiota and metabolism in the EAE preclinical model of MS and identifies targets for further study with the goal to more specifically probe the complex metabolic interaction at play in EAE that may have translational relevance to MS patients.

Gene Therapy Approaches in an Autoimmune Demyelinating Disease: Multiple Sclerosis

2020 ◽  
Vol 19 (6) ◽  
pp. 376-385
Author(s):  
Md. A. Islam ◽  
Shoumik Kundu ◽  
Rosline Hassan
Keyword(s):  
Multiple Sclerosis ◽  
Gene Therapy ◽  
Disease Progression ◽  
Demyelinating Disease ◽  
Human Subjects ◽  
Mice Model ◽  
Focal Lesions ◽  
Protective Function ◽  
Monocytes And Macrophages ◽  
Specific Symptoms

Multiple Sclerosis (MS) is the most common autoimmune demyelinating disease of the Central Nervous System (CNS). It is a multifactorial disease which develops in an immune-mediated way under the influences of both genetic and environmental factors. Demyelination is observed in the brain and spinal cord leading to neuro-axonal damage in patients with MS. Due to the infiltration of different immune cells such as T-cells, B-cells, monocytes and macrophages, focal lesions are observed in MS. Currently available medications treating MS are mainly based on two strategies; i) to ease specific symptoms or ii) to reduce disease progression. However, these medications tend to induce different adverse effects with limited therapeutic efficacy due to the protective function of the blood-brain barrier. Therefore, researchers have been working for the last four decades to discover better solutions by introducing gene therapy approaches in treating MS generally by following three strategies, i) prevention of specific symptoms, ii) halt or reverse disease progression and iii) heal CNS damage by promoting remyelination and axonal repair. In last two decades, there have been some remarkable successes of gene therapy approaches on the experimental mice model of MS - experimental autoimmune encephalomyelitis (EAE) which suggests that it is not far that the gene therapy approaches would start in human subjects ensuring the highest levels of safety and efficacy. In this review, we summarised the gene therapy approaches attempted in different animal models towards treating MS.

Assessment of biochemical determinants in Multiple Sclerosis patients following the oral administration of β-D-Mannuronic acid [M2000]

2020 ◽  
Vol 17 ◽  
Author(s):  
Mohamad Reza Nikouei Moghaddam ◽  
Monireh Movahedi ◽  
Maryam Bananej ◽  
Soheil Najafi ◽  
Nahid Beladi Moghadam ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Uric Acid ◽  
Vitamin D3 ◽  
Chronic Inflammatory Disease ◽  
Toxic Effects ◽  
Control Group ◽  
Therapeutic Effects ◽  
Mannuronic Acid ◽  
Anti Inflammatory ◽  
Multiple Sclerosis Patients

Background: Multiple sclerosis is an autoimmune chronic inflammatory disease of the central nervous system that can lead to some serious disabilities. Despite using various immunomodulatory and anti-inflammatory drugs that have therapeutic effects, they cannot reduce its progression completely, and have some unwanted side effects too. The immunomodulatory and anti-inflammatory effects of the β-D-Mannuronic acid [M2000] have been proven in several surveys, and the present research was designed to determine its toxicity and therapeutic effects in MS patients. Methods: This study was performed on 15 MS patients who took 25 mg/kg/day the oral form of the β-D-Mannuronic acid for six months, and 15 healthy people as a control group. Serum levels of Urea, Creatinine, GGT, Vitamin D3, Uric acid, and Anti-Phospholipids were compared to evaluate the therapeutic and possible toxic effects of this drug after this period. Results: Non- toxic effects through the study of Urea, Creatinine, GGT, and non-significant changes in Uric acid and AntiPhospholipids levels, besides a significant rise in Vitamin, D3 levels in the M2000 treated cases were found. Conclusions: Our results suggested that β-D-Mannuronic acid is a safe drug and has no toxicity when administered orally and also has some therapeutic effects in MS patients.

The SNPs within 3'UTR of miRNA Target Genes Related to Multiple Sclerosis: A Computational Prediction

2020 ◽  
Vol 17 (2) ◽  
pp. 133-147
Author(s):  
Mina Zafarpiran ◽  
Roya Sharifi ◽  
Zeinab Shirvani-Farsani
Keyword(s):  
Multiple Sclerosis ◽  
Gene Regulation ◽  
Binding Sites ◽  
Target Genes ◽  
Demyelinating Disease ◽  
Target Prediction ◽  
Computational Prediction ◽  
Functional Verification ◽  
Candidate Snps ◽  
Inflammatory Genes

Background: Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system, and genetic factors play an important role in its susceptibility. The expressions of many inflammatory genes implicated in MS are regulated by microRNA (miRNAs), whose function is to suppress the translation by pairing with miRNA Recognition Elements (MREs) present in the 3' untranslated region (3'UTR) of target mRNA. Recently, it has been shown that the Single Nucleotide Polymorphism (SNPs) present within the 3'UTR of mRNAs can affect the miRNA-mediated gene regulation and susceptibility to a variety of human diseases. Objective: The aim of this study was to analyze the SNPs within the 3'UTR of miRNA inflammatory target genes related to multiple sclerosis. Methods: By DisGeNET, dbGaP, Ovid, DAVID, Web of knowledge, and SNPs databases, 3'UTR genetic variants were identified in all inflammatory genes associated with MS. Also, miRNA's target prediction databases were used for predicting the miRNA binding sites. Results: We identified 125 SNPs with MAF>0.05 located in the binding site of the miRNA of 35 genes among 59 inflammatory genes related to MS. Bioinformatics analysis predicted 62 MRE-modulating SNPs and 59 MRE-creating SNPs in the 3'UTR of MSimplicated inflammatory genes. These candidate SNPs within miRNA binding sites of inflammatory genes can alter the miRNAs binding, and consequently lead to the mRNA gene regulation. Conclusion: Therefore, these miRNA and MRE-SNPs may play important roles in personalized medicine of MS, and hence, they would be valuable for further functional verification investigations.

Chromosome 14 Contains Determinants That Regulate Susceptibility to Theiler's Virus–Induced Demyelination in the Mouse

Genetics ◽  
1998 ◽  
Vol 148 (4) ◽  
pp. 1941-1949
Author(s):  
J-F Bureau ◽  
K M Drescher ◽  
L R Pease ◽  
T Vikoren ◽  
M Delcroix ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Major Histocompatibility Complex ◽  
Linkage Analysis ◽  
Demyelinating Disease ◽  
Theiler's Virus ◽  
Chromosome 14 ◽  
Virus Persistence ◽  
Histocompatibility Complex ◽  
Encephalomyelitis Virus ◽  
Two Peaks

Abstract Theiler's murine encephalomyelitis virus causes a chronic demyelinating disease in susceptible strains of mice that is similar to human multiple sclerosis. Several nonmajor histocompatibility complex–linked genes have been implicated as determinants of susceptibility or resistance to either demyelination or virus persistence. In this study, we used linkage analysis of major histocompatibility complex identical H-2d (DBA/2J × B10.D2) F2 intercross mice to identify loci associated with susceptibility to virus-induced demyelinating disease. In a 20-cM region on chromosome 14, we identified four markers, D14Mit54, D14Mit60, D14Mit61, and D14Mit90 that are significantly associated with demyelination. Because two peaks were identified, one near D14Mit54 and one near D14Mit90, it is possible that two loci in this region are involved in controlling demyelination.

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