Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway Genes
Dimethyl fumarate (DMF) has emerged as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared the effects of fumarates on gene ex...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/4/461 |
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| author | William R. Swindell Krzysztof Bojanowski Ratan K. Chaudhuri |
| author_facet | William R. Swindell Krzysztof Bojanowski Ratan K. Chaudhuri |
| author_sort | William R. Swindell |
| collection | DOAJ |
| description | Dimethyl fumarate (DMF) has emerged as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared the 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-κB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-κB inhibition, and we confirmed IDMF-mediated NF-κB inhibition using a reporter assay. IDMF also down-regulated <i>IRF1</i> expression and IDMF-decreased gene promoters were enriched with IRF1 recognition sequences. 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-κB and IRF1 contributing to mitigation of inflammation and pyroptosis. |
| first_indexed | 2024-03-09T10:31:11Z |
| format | Article |
| id | doaj.art-7c6a1fd7bfbd448f9976bc43642de6a9 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T10:31:11Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-7c6a1fd7bfbd448f9976bc43642de6a92023-12-01T21:18:11ZengMDPI AGPharmaceuticals1424-82472022-04-0115446110.3390/ph15040461Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway GenesWilliam R. Swindell0Krzysztof Bojanowski1Ratan K. Chaudhuri2Department of Internal Medicine, The Jewish Hospital, Cincinnati, OH 45236, USASunny BioDiscovery Inc., Santa Paula, CA 93060, USASymbionyx Pharmaceuticals Inc., Boonton, NJ 07005, USADimethyl fumarate (DMF) has emerged as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared the 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-κB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-κB inhibition, and we confirmed IDMF-mediated NF-κB inhibition using a reporter assay. IDMF also down-regulated <i>IRF1</i> expression and IDMF-decreased gene promoters were enriched with IRF1 recognition sequences. 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-κB and IRF1 contributing to mitigation of inflammation and pyroptosis.https://www.mdpi.com/1424-8247/15/4/461astrocytedimethyl fumaratediroximel fumarateglial cellsInterferon regulatory factormultiple sclerosis |
| spellingShingle | William R. Swindell Krzysztof Bojanowski Ratan K. Chaudhuri Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway Genes Pharmaceuticals astrocyte dimethyl fumarate diroximel fumarate glial cells Interferon regulatory factor multiple sclerosis |
| title | Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway Genes |
| title_full | Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway Genes |
| title_fullStr | Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway Genes |
| title_full_unstemmed | Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway Genes |
| title_short | Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway Genes |
| title_sort | transcriptomic analysis of fumarate compounds identifies unique effects of isosorbide di methyl fumarate on nrf2 nf kappab and irf1 pathway genes |
| topic | astrocyte dimethyl fumarate diroximel fumarate glial cells Interferon regulatory factor multiple sclerosis |
| url | https://www.mdpi.com/1424-8247/15/4/461 |
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