On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis

Tobore, Tobore Onojighofia

doi:10.1111/ncn3.12335

Cited by 6 publications

(3 citation statements)

References 279 publications

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“…In MS, redox processes are associated with mitochondrial dysfunction, dysregulation of axonal bioenergetics as well as impaired oxidant/antioxidant balance [ 165 , 166 ]. Mitochondrial abnormalities, like mtDNA defects, aberrant mitochondrial gene expression and abnormal mitochondrial enzyme activities, lead to the eventual death of dendritic cells (DCs) and increase the demyelination process [ 167 ]. Protti et al have shown that, in blood platelets from metformin-treated patients, the mitochondrial membrane was hyperpolarized and the activity of complex I was reduced [ 168 ].…”

Section: The Effect Of Metformin On Haemostasis and The Functioninmentioning

confidence: 99%

Metformin as a Potential Agent in the Treatment of Multiple Sclerosis

Dziedzic

Saluk‐Bijak

Miller

et al. 2020

IJMS

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Metformin, a synthetic derivative of guanidine, is commonly used as an oral antidiabetic agent and is considered a multi-vector application agent in the treatment of other inflammatory diseases. Recent studies have confirmed the beneficial effect of metformin on immune cells, with special emphasis on immunological mechanisms. Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by various clinical courses. Although the pathophysiology of MS remains unknown, it is most likely a combination of disturbances of the immune system and biochemical pathways with a disruption of blood–brain barrier (BBB), and it is strictly related to injury of intracerebral blood vessels. Metformin has properties which are greatly desirable for MS therapy, including antioxidant, anti-inflammatory or antiplatelet functions. The latest reports relating to the cardiovascular disease confirm an increased risk of ischemic events in MS patients, which are directly associated with a coagulation cascade and an elevated pro-thrombotic platelet function. Hence, this review examines the potential favourable effects of metformin in the course of MS, its role in preventing inflammation and endothelial dysfunction, as well as its potential antiplatelet role.

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Section: The Effect Of Metformin On Haemostasis and The Functioninmentioning

confidence: 99%

Metformin as a Potential Agent in the Treatment of Multiple Sclerosis

Dziedzic

Saluk‐Bijak

Miller

et al. 2020

IJMS

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Section: Introductionmentioning

confidence: 99%

“…The release of pro-inflammatory cytokines and ROS have been implicated in MS progression (6). Growing evidence has indicated that mitochondrial oxidative stress plays a pivotal role in the pathogenesis of MS (7). Witte et al have shown that mtHSP70, as the biomarker of mitochondrial stress, has been remarkably up-regulated in MS lesions (8).…”

Section: Introductionmentioning

confidence: 99%

The Role of Hemoglobin Subunit Delta in the Immunopathy of Multiple Sclerosis: Mitochondria Matters

et al. 2021

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BackgroundAlthough the exact pathophysiology of MS has not been identified, mitochondrial stress can be one of the culprits in MS development. Herein, we have applied microarray analysis, single-cell sequencing analysis, and ex vivo study to elucidate the role of mitochondrial stress in PBMCs of MS patients.MethodsFor this purpose, we analyzed the GSE21942 and GSE138266 datasets to identify the DEGs and hub genes in the PBMCS of MS patients and describe the expression of shared genes in the different immune cells. The GO pathway analysis of DEGs and turquoise module genes were conducted to shed light on their biological significance. To validate the obtained results, the gene expression of HBD, as the most remarkable DEG in the PBMCS of affected patients, was measured in the PBMCS of healthy donors, treatment-naïve MS patients, and MS patients treated with GA, fingolimod, DMF, and IFNβ-1α.ResultsBased on WGCNA and DEGs analysis, HBD, HBM, SLC4A1, LILRA5, SLC25A37, SELENBP1, ALYREF, SNRNP40, and HINT3 are the identified common genes in the PMBCS. Using single-cell sequencing analysis on PBMCS, we have characterized various cell populations in MS and illustrated the common gene expression on the different immune cells. Furthermore, GO pathway analysis of DEGs, and turquoise module genes have indicated that these genes are involved in immune responses, myeloid cell activation, leukocyte activation, oxygen carrier activity, and replication fork processing bicarbonate transport pathways. Our ex vivo investigation has shown that HBD expression in the treatment-naïve RRMS patients is significantly increased compared to healthy donors. Of interest, immunomodulatory therapies with fingolimod, DMF, and IFNβ-1α have significantly decreased HBD expression.ConclusionHBD is one of the remarkably up-regulated genes in the PBMCS of MS patients. HBD is substantially up-regulated in treatment-naïve MS patients, and immunomodulatory therapies with fingolimod, DMF, and IFNβ-1α can remarkably down-regulate HBD expression. Based on the currently available evidence, the cytoprotective nature of HBD against oxidative stress can be the underlying reason for HBD up-regulation in MS. Nevertheless, further investigations are needed to shed light on the molecular mechanisms of HBD in the oxidative stress of MS patients.

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