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Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses

ABSTRACT: Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses

PROVIDER: PRJNA540471 | ENA |

REPOSITORIES: ENA

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Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Illumina]

Project description:Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential in redox balance, is a target of DMF, but the precise therapeutic mechanisms remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increased the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response and suggestively associated with increased ROS generation. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

2019-07-31 | GSE130491 | GEO

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Affymetrix]

2019-07-31 | GSE130478 | GEO

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Illumina]

Project description:Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Illumina]

| PRJNA540475 | ENA

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Affymetrix]

Project description:Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Affymetrix]

| PRJNA540434 | ENA

Circulating microRNAs in relapsing MS patients treated with dimethyl fumarate in the phase 4 TREMEND trial

Project description:Dimethyl fumarate (DMF) is an oral drug approved for relapsing multiple sclerosis (MS) that leads to reduction of neurofilament light (NFL). This may be related to dynamics and persistence of microRNA signatures in the peripheral blood of treatment-naïve MS patients before and after dimethyl fumarate (DMF) at different time points. 210 blood samples were collected from 51 treatment-naïve patients at baseline (BL) and after 1-3, 4-7, 9-15 and 21-27 months of DMF and from 22 controls from the phase IV TREMEND trial. Using microarray, 1,085 miRNAs were two-folds above the background and compared versus NFL. Altered miRNA profiles peaked after 4-7 months. MiR-16-5p and miR-4306, involved in the NF-kB-pathway, were upregulated in low NFL samples, while miR-940 and miR-4665-3p were upregulated in high NFL samples. NFL and miRNA correlations were strongest after 4-7 months DMF. In four patients with blood samples taken at all 5 time points, time-series analysis found miR-146a-5p, the inhibitor of the NF-kB-pathway, increased 1-3 months after treatment. DMF induces dynamic changes in composite miRNA profiles 4-7 months after initiation, several involved in the NF-kB-pathway. Upregulation of miR-16-5p and miR-4306 in low-NFL, while miR-940 and miR-4665-3p in high-NFL samples may indicate a response to DMF treatment.

2022-10-26 | GSE215450 | GEO

Defective structural RNA processing in relapsing-remitting multiple sclerosis

Project description:It is fundamentally unknown how normal cellular processes or responses to extracellular stimuli may invoke polyadenylation and degradation of ncRNA substrates or if human disease processes exhibit defects in polyadenylation of ncRNA substrates as part of their pathogenesis. Our results demonstrate that mononuclear cells from subjects with relapsing-remitting multiple sclerosis (RRMS) exhibit pervasive increases in levels of polyadenylated ncRNAs including Y1 RNA, 18S and 28S rRNA, and U1, U2, and U4 snRNAs and these defects are unique to RRMS. Defects in expression of both Ro60 and La proteins in RRMS appear to contribute to increased polyadenylation of ncRNAs. Further, IFN-β1b, a common RRMS therapy, restores both Ro60 and La levels to normal as well as levels of polyadenylated Y1 RNA and U1 snRNA suggesting that aberrant polyadenylation of ncRNA substrates may have pathogenic consequences. We extracted RNA from peripheral whole blood in healthy control subjects and patients with established relapsing-remitting multiple sclerosis using PaxGene tubes.

2015-03-10 | E-GEOD-66573 | biostudies-arrayexpress

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-07-31 | GSE130494 | GEO

Transcriptomic analysis of fumarate compounds identifies unique effects of isosorbide di-(methyl fumarate) on NRF2, NF-kappaB and IRF1 pathway genes

Project description:Dimethyl fumarate (DMF) has emerged as first-line therapy for relapsing-remitting multiple scle-rosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared effects of fumarates on gene expression in astrocytes. Our analysis included diroximel fumarate (DRF) and its metabolite monomethyl fumarate (MMF), along with a novel compound isosorbide di-(methyl fumarate) (IDMF). Treatment with IDMF resulted in the largest number of differentially expressed genes. The effects of DRF and MMF were consistent with NRF2 activation and NF-kappaB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-kappaB inhibition, and we confirmed IDMF-mediated NF-kappaB inhibition using a reporter assay. IDMF also down-regulated IRF1 expression and IDMF-decreased gene promoters were enriched with IRF1 recognition se-quences. Genes altered by each fumarate overlapped significantly with those near loci from MS genetic association studies, but IDMF had the strongest overall effect on MS-associated genes. These results show that next-generation fumarates such as DRF and IDMF have effects differing from those of the MMF metabolite. Our findings support a model in which IDMF attenuates oxidative stress via NRF2 activation, with suppression of NF-kappaB and IRF1 contributing to mitigation of in-flammation and pyroptosis.

2022-04-27 | GSE200539 | GEO

Disease modifying therapy impacts on miRNA expression profiling in peripheral blood from Relapsing-Remitting Multiple Sclerosis patients

Project description:Multiple sclerosis (MS) is a chronic and progressive neurological disease. MS is characterized by early-stage neuroinflammation, neurodegeneration, and demyelination, with a spectrum of heterogeneous clinical manifestations in terms of disease course and response to therapy. The currently unsatisfied availability of diagnostic and prognostic biomarkers concerning disease progression and treatment response represents an important requirement for therapy individualization and drug efficacy. Specific Disease Therapies (DMTs) are available to prevent MS-related brain damage; however, the specific drug choice is still under debate and needs further characterization. Since differentially expressed miRNAs have been proposed as diagnostic tools in neurodegenerative/neuro-inflammatory diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease, we characterized the miRNA expression profiling in peripheral blood mononuclear cells (PBMC) of subjects with relapsing-remitting MS treated with high efficacy DMTs: Cladribine (CLA, n=11 patients) or Ocrelizumab (OCRE, n=14 patients). The treated patients were compared to control (CTR) untreated subjects (n=15). Blood samples were collected from patients before treatment (time t0) and 6 months post-treatment (time t1), but just once from control subjects. CLA drug tablets were administered to the selected relapsing-remitting MS patients with a dosage of 1.75 mg/kg given for 5 days. OCRE drug was administered to the other relapsing-remitting MS patients by infusion with a dosage of 300 mg, twice in two weeks.

2024-01-03 | GSE230064 | GEO

Defective structural RNA processing in relapsing-remitting multiple sclerosis

2015-03-10 | GSE66573 | GEO

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