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A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis

ABSTRACT: A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis

PROVIDER: PRJNA732447 | ENA |

REPOSITORIES: ENA

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A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [microarray]

Project description:Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. Its potential, however, has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide di-(methyl fumarate) (IDMF), which was designed to have anti-psoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is non-irritating and non-sensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically up-regulated in psoriatic skin lesions but not those of other skin diseases. IDMF also down-regulated genes induced by IL-17A and TNF in keratinocytes, as well as predicted targets of NF-κB and the anti-differentiation ncRNA (ANCR). IDMF further stimulated transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger Nrf2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data demonstrate that IDMF exbibits anti-psoriatic activity that is similar or improved compared to DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.

2021-08-22 | GSE175473 | GEO

A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [RNA-seq]

2021-08-22 | GSE175471 | GEO

A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [microarray]

Project description:A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [microarray]

| PRJNA732450 | ENA

A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [RNA-seq]

Project description:A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [RNA-seq]

| PRJNA732445 | ENA

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

A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis

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

2021-08-22 | GSE175474 | GEO

Chemical proteomic map of dimethyl fumarate-sensitive cysteines in primary human T cells

Project description:Primary human and mouse T cells were treated with the multiple sclerosis drug dimethyl fumarate (DMF) or its in vivo metabolite monomethyl fumarate (MMF). Cysteines sensitive to DMF or MMF were identified using iodoacetamide alkyne enrichment.

2016-08-31 | MSV000080111 | MassIVE

Expression data of renal cancer cell treated with Oncolytic virus VSVd51 and Fumaric acid esters such as Dimethyl fumarate

Project description:We propose a strategy to boost the therapeutic efficacy of Oncolytic therapy by combining it with fumaric acid ester such as Dimethyl fumarate (DMF) The mechanism of action was examined by microarray analysis using the Affymetrix Human PrimeView Array.

2018-07-30 | GSE97328 | GEO

Comparative gene expression analysis of Nrf2 activators, CDDO-Im, CDDO-Me and dimethyl fumarate (DMF) in VC1 lung cancer cells

Project description:Nrf2 is an important therapeutic target as activation of this pathway detoxifies harmful insults and reduces oxidative stress. However, the role of Nrf2 in cancer biology is controversial. Protection against oxidative stress and inflammation can confer a survival advantage to tumor cells, leading to a poor prognosis, and constitutive activation of Nrf2 has been detected in numerous tumors. In our study, we examined the role of two clinically relevant classes of Nrf2 activators, the synthetic triterpenoids (CDDO-Im and CDDO-Me) and dimethyl fumarate (DMF) in lung cancer. Using microarrays, we attempt to examine whether these Nrf2 activators have an effect on the same subset of Nrf2 genes.

2015-05-31 | GSE65623 | GEO

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

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