Cited by 189Genomics, phytochemicals, and oxidative stressGlutathione Transferases and PolymorphismsRedox biology and oxidative stress

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Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Effects on KEAP1, NRF2 Activation, and Glutathione Depletion In Vitro

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Brennan, Melanie S., Matos, Maria F., Li, Bing, Hronowski, Xiaoping, Gao, Benbo, Juhasz, Peter, Rhodes, Kenneth J., Scannevin, Robert H.·2015·PLOS ONE

DOI 10.1371/journal.pone.0120254PMC PMC4368598

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Abstract

Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate), an oral therapeutic containing dimethyl fumarate (DMF) as the active ingredient, is currently approved for the treatment of relapsing multiple sclerosis. DMF is also a component in a distinct mixture product with 3 different salts of monoethyl fumarate (MEF), which is marketed for the treatment of psoriasis. Previous studies have provided insight into the pharmacologic properties of DMF, including modulation of kelch-like ECH-associated protein 1 (KEAP1), activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, and glutathione (GSH) modulation; however, those of MEF remain largely unexplored. Therefore, the aim of this study was to evaluate the in vitro effects of DMF and MEF on KEAP1 modification, activation of the NRF2 pathway, and GSH conjugation. Using mass spectrometry, DMF treatment resulted in a robust modification of specific cysteine residues on KEAP1. In comparison, the overall degree of KEAP1 modification following MEF treatment was significantly less or undetectable. Consistent with KEAP1 cysteine modification, DMF treatment resulted in nuclear translocation of NRF2 and a robust transcriptional response in treated cells, as did MEF; however, the responses to MEF were of a lower magnitude or distinct compared to DMF. DMF was also shown to produce an acute concentration-dependent depletion of GSH; however, GSH levels eventually recovered and rose above baseline by 24 hours. In contrast, MEF did not cause acute reductions in GSH, but did produce an increase by 24 hours. Overall, these studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activity as well as unique actions. These differences would be expected to result in divergent effects on downstream biology.

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Fig 1 Structure and basic properties of DMF, MEF salts and Fumaric Acid. DMF and MEF are esters of fumaric acid, which is not pharmacologically active. The active moiety(ies) of DMF and MEF confer their chemical and physical properties.CC BY · PubMed Central

Fig 2 DMF and MEF Differentially Modify KEAP1 Cysteine Residues. KEAP1 transfected HEK 293FT cells were treated with DMF and MEF salts (Ca2+, Mg2+, Zn2+) at 3 μg/mL (A, C) or 6 μg/mL (B, D). Resulting cysteine modifications on KEAP1 were analyzed using mass spectrometry. Percent modification of KEAP1 cysteine residues with DMF or MEF was determined relative to DMSO control treated cells. (A, B) Representation of percent cysteine modification of analyzed KEAP1 cysteine residues in the presence of 3 (A) or 6 (B) μg/mL DMF or MEF. Each bar represents the means of quadruplicate determinations (± SD). (C, D) Box-whisker plots demonstrate the means, quartiles, and max-min of KEAP1 cysteine residues modified by greater than 10 percent in A and B. *, p<0.05. ***, p<0.001. ****, p<0.0001. P values are based on two-way analysis of variance (ANOVA) with Sidak’s post-test for multiple comparisons.CC BY · PubMed Central

Fig 3 NRF2 Translocation Induced by DMF and MEF Treatment. Human astrocytes were treated with a mixture of MEF salts (Ca2+, Mg2+, Zn2+), DMF or the vehicle control DMSO. Extracts from harvested cells were separated into nuclear and cytoplasmic fractions and equal protein amounts from triplicate aliquots of each fraction were analyzed using an NRF2 TransAM DNA binding assay (A), and Western blots for NRF2, HDAC1 or β-actin (B). Red asterisks (*, p<0.01) indicate comparison of DMF versus MEF at indicated concentration. Black asterisks directly above bar plots (*, p<0.05, ***, p<0.001, ****, p<0.0001) refer to DMF and MEF versus DMSO control at indicated concentrations. P values are based on two-way ANOVA with Tukey’s post-test for multiple comparisons.CC BY · PubMed Central

Fig 4 DMF and MEF Produce Distinct Changes in Gene Expression in Astrocytes. Human astrocytes were treated with a concentration-response of DMF, MEF salts (Ca2+, Mg2+, Zn2+) or fumaric acid for 24 hours, and analyzed for transcriptional changes in putative NRF2 target genes (NQO1, HMOX1, OSGIN1, TXNRD1, GCLC and SRXN1). Triplicate determinations (± SD) were normalized as a fold change relative to DMSO controls for each gene and probe set. *, p<0.01 for DMF versus MEF at indicated concentration. P values are based on two-way ANOVA with Tukey’s post-test for multiple comparisons.CC BY · PubMed Central

Fig 5 DMF and MEF Induce Different Effects on Cellular GSH. Primary cultures of human astrocytes were incubated with 1 (A) or 3 (B) μg/mL DMF, MEF, or DMSO as a control. Treated cells were harvested after 0.0, 0.5, 1.0, 6, 12, and 24 hours of treatment, and total cellular GSH was measured as relative luminescence units (RLU). Each point represents the mean of triplicate determinations (± SD). Dotted line represents average basal RLU levels. *, p<0.01 for DMF versus MEF at indicated time point. P values are based on two-way ANOVA with Tukey’s post-test for multiple comparisons.CC BY · PubMed Central

Fig 6 DMF and MEF Induce Different Effects on Extracellular GSH. Primary cultures of human astrocytes were incubated with 1 (A) or 3 (B) μg/mL DMF, MEF or DMSO as a control. Media was collected from treated cells after 0.0, 0.5, 1.0, 6, 12 or 24 hours of treatment, and total extracellular glutathione was measured as relative luminescence units (RLU). Each point represents the mean of triplicate determinations (± SD). Dotted line represents average basal RLU levels. *, p<0.01 for DMF versus MEF at indicated time point. P values are based on two-way ANOVA with Tukey’s post-test for multiple comparisons.CC BY · PubMed Central

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“4), despite the well-established role for NRF2 in fumarate mediated cellular responses (Scannevin et al., 2012; Brennan et al., 2015).”
BackgroundResultSelf-citation
Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions
Zinger, N., Ponath, G., Sweeney, E., Nguyen, T. D., Lo, C. H., Diaz, I., Dimov, A., Teng, L., Zexter, L., Comunale, J., et al. (2022) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000001138 · Cited by 51
Targeting Nrf2 for the treatment of Duchenne Muscular Dystrophy
Kourakis, S., Timpani, C. A., de Haan, J. B., Gueven, N., Fischer, D., & Rybalka, E. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101803 · Cited by 50
Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation
Galloway, D. A., Williams, J. B., & Moore, C. S. (2017) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.414 · Cited by 51
“The induction of Nrf2 is achieved through glutathione depletion as well as direct binding of fumaric acid esters to the Nrf2 repressor KEAP1.(3,6,7) The antioxidant effects of DMF were initially considered to be the primary mechanism of action for this disease-modifying treatment (DMT), as mice lacking Nrf2 did not re…”
Background
Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System
Ben-Yehuda Greenwald, M., Ben-Sasson, S., Bianco-Peled, H., & Kohen, R. (2016) · Cosmetics · doi:10.3390/cosmetics3010001 · Cited by 49
Glutathione Metabolism Contributes to the Induction of Trained Immunity
Ferreira, A. V., Koeken, V. A. C. M., Matzaraki, V., Kostidis, S., Alarcon-Barrera, J. C., de Bree, L. C. J., Moorlag, S. J. C. F. M., Mourits, V. P., Novakovic, B., Giera, M. A., et al. (2021) · Cells · doi:10.3390/cells10050971 · Cited by 52
“In astrocytes, acute exposure of the derivative dimethyl fumarate depletes intracellular GSH, but increases total GSH at later timepoints [25].”
Background
Dimethyl fumarate protects thioacetamide‐induced liver damage in rats: Studies on Nrf2, NLRP3, and NF‐κB
Dwivedi, D. K., Jena, G., & Kumar, V. (2020) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.22476 · Cited by 48
Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis
Hosseini, A., Masjedi, A., Baradaran, B., Hojjat‐Farsangi, M., Ghalamfarsa, G., Anvari, E., & Jadidi‐Niaragh, F. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27930 · Cited by 48
“DMF also exerts its clinical effects through activation of Nrf2 (Brennan et al., 2015).”
BackgroundInfluential
Dimethyl fumarate treatment after traumatic brain injury prevents depletion of antioxidative brain glutathione and confers neuroprotection
Krämer, T. J., Grob, T., Menzel, L., Hirnet, T., Griemert, E., Radyushkin, K., Thal, S. C., Methner, A., & Schaefer, M. K. E. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14220 · Cited by 45
Dimethyl Fumarate: A Review in Relapsing-Remitting MS
Deeks, E. D. (2015) · Drugs · doi:10.1007/s40265-015-0528-1 · Cited by 44
Intermittent hypoxia confers pro-metastatic gene expression selectively through NF-κB in inflammatory breast cancer cells
Gutsche, K., Randi, E. B., Blank, V., Fink, D. A., Wenger, R. H., Leo, C., & Scholz, C. C. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.10.002 · Cited by 44
“SFN and DMF mediate stabilization and nuclear translocation of Nrf2 by modulating the inhibitory protein of Nrf2, kelch-like ECH-associated protein 1 (Keap1) [62,63].”
Background
Dimethyl fumarate (DMF) vs. monoethyl fumarate (MEF) salts for the treatment of plaque psoriasis: a review of clinical data
Landeck, L., Asadullah, K., Amasuno, A., Pau‐Charles, I., & Mrowietz, U. (2018) · Archives of Dermatological Research · doi:10.1007/s00403-018-1825-9 · Cited by 43
Fumaric acid esters promote neuronal survival upon ischemic stress through activation of the Nrf2 but not HIF-1 signaling pathway
Lin-Holderer, J., Li, L., Gruneberg, D., Marti, H. H., & Kunze, R. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.01.023 · Cited by 44
Targeting Evolutionary Conserved Oxidative Stress and Immunometabolic Pathways for the Treatment of Respiratory Infectious Diseases
Erlich, J. R., To, E. E., Liong, S., Brooks, R. D., Vlahos, R., O’Leary, J. J., Brooks, D. A., & Selemidis, S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8028 · Cited by 45
“DMI is also a far more potent Nrf2 activator, as the lack of a negative charge leads to a push toward the Michael equation (14, 110) (Table 2).”
Background
Tussilagonone Ameliorates Psoriatic Features in Keratinocytes and Imiquimod-Induced Psoriasis-Like Lesions in Mice via NRF2 Activation
Lee, J., Song, K., Hiebert, P., Werner, S., Kim, T., & Kim, Y. S. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2019.12.008 · Cited by 41
NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation
Nuccio, C. D., Bernardo, A., Troiano, C., Brignone, M. S., Falchi, M., Greco, A., Rosini, M., Basagni, F., Lanni, C., Serafini, M. M., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197216 · Cited by 42
“DMF is known to react with glutathione (GSH) rapidly and to provoke a quick depletion of its reduced form [26,27], which could affect the mitochondrial respiratory chain efficiency.”
Background
Advances in developing noncovalent small molecules targeting Keap1
Barreca, M., Qin, Y., Cadot, M. E. H., Barraja, P., & Bach, A. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103800 · Cited by 42
Proteomics and Beyond: Cell Decision-Making Shaped by Reactive Electrophiles
Liu, X., Long, M. J. C., & Aye, Y. (2018) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2018.09.014 · Cited by 39
“Furthermore, Keap1, a protein labeled by Tecfidera[62, 63], was not detectable by ABPP.”
BackgroundInfluential
Interaction Energetics and Druggability of the Protein–Protein Interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and Nuclear Factor Erythroid 2 Like 2 (Nrf2)
Zhong, M., Lynch, A. J., Muellers, S. N., Jehle, S., Luo, L., Hall, D. R., Iwase, R., Carolan, J. P., Egbert, M. E., Wakefield, A., et al. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00943 · Cited by 40
Homocysteine Induces Glial Reactivity in Adult Rat Astrocyte Cultures
Longoni, A., Bellaver, B., Bobermin, L. D., Santos, C. L., Nonose, Y., Kolling, J., dos Santos, T. M., de Assis, A. M., Quincozes‐Santos, A., & Wyse, Â. T. D. S. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0463-0 · Cited by 37
Inhibiting the Keap1/Nrf2 Protein‐Protein Interaction with Protein‐Like Polymers
Carrow, K. P., Hamilton, H. L., Hopps, M. P., Li, Y., Qiao, B., Payne, N. C., Thompson, M. P., Zhang, X., Magassa, A., Fattah, M. A., et al. (2024) · Advanced Materials · doi:10.1002/adma.202311467 · Cited by 38
NRF2 in neurodegenerative diseases
Cuadrado, A. (2016) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2016.09.004 · Cited by 36
Repurposing dimethyl fumarate as an antiepileptogenic and disease-modifying treatment for drug-resistant epilepsy
Sandouka, S., Singh, P. K., Saadi, A., Taiwo, R. O., Sheeni, Y., Zhang, T., Deeb, L., Guignet, M. A., White, S. H., & Shekh‐Ahmad, T. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04695-2 · Cited by 35
Antioxidant and Anti-Inflammatory Activities of a Natural Compound, Shizukahenriol, through Nrf2 Activation
Park, J., Choi, J. H., Ju, E. M., Pae, A. N., & Park, K. D. (2015) · Molecules · doi:10.3390/molecules200915989 · Cited by 37
“Recent studies have proposed that fumaric acid esters such as dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) can activate genes associated with the Nrf2 antioxidant response pathway [20,31].”
Background
Reactive Gliosis Contributes to Nrf2-Dependent Neuroprotection by Pretreatment with Dimethyl Fumarate or Korean Red Ginseng Against Hypoxic-Ischemia: Focus on Hippocampal Injury
Liu, L., Vollmer, M. K., Kelly, M. G., Fernandez, V. M., Fernandez, T. G., Kim, H., & Doré, S. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01760-0 · Cited by 35
Genistein and Procyanidin B2 Reduce Carcinogen-Induced Reactive Oxygen Species and DNA Damage through the Activation of Nrf2/ARE Cell Signaling in Bronchial Epithelial Cells In Vitro
Suraweera, T. L., Merlin, J. P. J., Dellaire, G., Xu, Z., & Rupasinghe, H. P. V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043676 · Cited by 35
“Among tested positive controls, DMF is known to activate Nrf2 protein through canonical mechanisms such as the modification of Keap 1 Cys residues [52].”
Background
The role of NRF2 transcription factor in inflammatory skin diseases
Salman, S., Paulet, V., Hardonnière, K., & Kerdine‐Römer, S. (2025) · BioFactors · doi:10.1002/biof.70013 · Cited by 43
“157,169 Other bioactive nat-ural compounds have also shown promise in alleviating psoriasis.”
Fumarate treatment in progressive forms of multiple sclerosis: first results of a single-center observational study
Straßburger-Krogias, K., Ellrichmann, G., Krogias, C., Altmeyer, P. J., Chan, A., & Gold, R. (2014) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756285614544466 · Cited by 35
Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases
Andersen, J. L., Gesser, B., Funder, E. D., Nielsen, C. J. F., Gotfred‐Rasmussen, H., Rasmussen, M. K., Toth, R. L., Gothelf, K. V., Arthur, J. S. C., Iversen, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06787-w · Cited by 33
Development and optimization of halogenated vinyl sulfones as Nrf2 activators for the treatment of Parkinson’s disease
Choi, J., Kim, S., Yoo, J. S., Kim, H. J., Kim, H. J., Kim, B. E., Lee, E. H., Lee, Y. S., Park, J., & Park, K. D. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.113103 · Cited by 34
Dimethyl Fumarate Triggers the Antioxidant Defense System in Human Retinal Endothelial Cells through Nrf2 Activation
Manai, F., & Amadio, M. (2022) · Antioxidants · doi:10.3390/antiox11101924 · Cited by 33
“We then performed explorative experiments to evaluate the potential Nrf2 pathway activation in HREC exposed to the same range of DMF concentrations for 6 h; this time was selected according to our experience of the D F’s rapid action evidenced in other cellular models [31,32].”
Method
Protective effects of monomethyl fumarate at the inflamed blood–brain barrier
Lim, J. L., van der Pol, S. M. A., Dio, F. D., Hof, B. V. H., Kooij, G., de Vries, H. E., & van Horssen, J. (2015) · Microvascular Research · doi:10.1016/j.mvr.2015.12.003 · Cited by 33
Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor
Yasuda, D., Yuasa, A., Obata, R., Nakajima, M., Takahashi, K., Ohe, T., Ichimura, Y., Komatsu, M., Yamamoto, M. P., Imamura, R. M., et al. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.10.008 · Cited by 33
Neutrophil NADPH oxidase promotes bacterial eradication and regulates NF-κB-Mediated inflammation via NRF2 signaling during urinary tract infections
Cotzomi-Ortega, I., Rosowski, E. E., Wang, X., Sánchez-Zamora, Y. I., Lopez-Torres, J. M., Sanchez-Orellana, G., Han, R., Vasquez-Martinez, G., Andrade, G. M., Ballash, G. A., et al. (2024) · Mucosal Immunology · doi:10.1016/j.mucimm.2024.12.010 · Cited by 28
Self-citation
Electrophile versus oxidant modification of cysteine residues: Kinetics as a key driver of protein modification
Sauerland, M. B., & Davies, M. J. (2022) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2022.109344 · Cited by 31
Regulation of proteostasis and innate immunity via mitochondria-nuclear communication
Kim, S., Ramalho, T. R. D. O., & Haynes, C. M. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202310005 · Cited by 30
Molecular and functional heterogeneity in dorsal and ventral oligodendrocyte progenitor cells of the mouse forebrain in response to DNA damage
Boda, E., Lorenzati, M., Parolisi, R., Harding, B. N., Pallavicini, G., Bonfanti, L., Moccia, A., Bielas, S. L., Cunto, F. D., & Buffo, A. (2022) · Nature Communications · doi:10.1038/s41467-022-30010-6 · Cited by 31
An updated patent review of Nrf2 activators (2020-present)
Zhao, Z., Dong, R., Cui, K., You, Q., & Jiang, Z. (2023) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2023.2178299 · Cited by 28
Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases
Izumi, Y., & Kōyama, Y. (2024) · Antioxidants · doi:10.3390/antiox13121527 · Cited by 31
A comprehensive review of therapeutic targets that induce microglia/macrophage‐mediated hematoma resolution after germinal matrix hemorrhage
Flores, J. J., Klebe, D. W., Tang, J., & Zhang, J. H. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24388 · Cited by 27
“The most notable treatment options/strategies for Nrf2 agonism are carnosol (Martin et al., 2004), monascin (Lee et al., 2013), dimethyl fumarate (Brennan et al., 2015), chemerin (Zhang, Xu et al., 2018), and ankaflavin (Lee et al., 2012; Wang et al., 2018; Zhao, Sun, Zhang et al., 2015).”
Background
Metabolic ROS Signaling: To Immunity and Beyond
Andreyev, A. Y., Kushnareva, Y. E., Starkova, N. N., & Starkov, A. A. (2020) · Biochemistry (Moscow) · doi:10.1134/s0006297920120160 · Cited by 28
Repurposing Dimethyl Fumarate for Cardiovascular Diseases: Pharmacological Effects, Molecular Mechanisms, and Therapeutic Promise
Thomas, S. D., Jha, N. K., Sadek, B. S., & Ojha, S. K. (2022) · Pharmaceuticals · doi:10.3390/ph15050497 · Cited by 27
NRF2 , a crucial modulator of skin cells protection against vitiligo, psoriasis, and cancer
Panieri, E., Telkoparan‐Akillilar, P., & Saso, L. (2022) · BioFactors · doi:10.1002/biof.1912 · Cited by 27
“Since its approval, the formulation of dimethyl fumarate and monoethyl fumarate (DMF/MEF) has represented a mainstay in the treatment of psoriasis,118,119 with proven clinical efficacy against moderate to severe forms.120–122 While initial studies provided evidence that DMF could attenuate the severity of neuroinflamm…”
Background
Dimethyl fumarate accelerates peripheral nerve regeneration via activation of the anti-inflammatory and cytoprotective Nrf2/HO-1 signaling pathway
Szepanowski, F., Donaldson, D. M., Hartung, H., Mausberg, A. K., Kleinschnitz, C., Kieseier, B. C., & Stettner, M. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1676-z · Cited by 27
“An emerging body of experimental evidence suggests that DMF, targeting Keap1 and interfering with the Nrf2/Keap1 interaction, indirectly activates Nrf2 by enabling its translocation into the nucleus [3].”
Background
Real-World Characterization of Dimethyl Fumarate-Related Gastrointestinal Events in Multiple Sclerosis: Management Strategies to Improve Persistence on Treatment and Patient Outcomes
Min, J., COHAN, S. L., Álvarez, E., Sloane, J. A., Phillips, J. T., van der Walt, A., Koulinska, I. N., Fang, F., Miller, C., & Chan, A. (2019) · Neurology and Therapy · doi:10.1007/s40120-019-0127-2 · Cited by 26
Reactive Sulfur Species and Protein Persulfidation: An Emerging Redox Axis in Human Health and Disease
Andrés, C. M. C., Lobo, F., de la Lastra, J. M. P., Munguira, E. B., Andrés, C., & Lebeña, E. P. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47090765 · Cited by 28
“…when clinicians exploit these agents therapeutically— S-alkylation thus acts as a pharmacological “kill switch”, but at the expense of widespread glutathione depletion (notably via DMF-mediated succination of Keap1 Cys151) and the risk of off-target alkylations across the proteome [155,174].”
Novel Series of Dual NRF2 Inducers and Selective MAO-B Inhibitors for the Treatment of Parkinson’s Disease
Duarte, P., Michalska, P., Crisman, E., Cuadrado, A., & Leon, R. M. (2022) · Antioxidants · doi:10.3390/antiox11020247 · Cited by 24
“A prominent example of this process is the DMF mechanism of action whose derived metabolite, monomethyl fumarate (MMF), reacts with KEAP1-Cys151 to induce the NRF2-ARE pathway activation [37].”
Background
New and Old Horizons for an Ancient Drug: Pharmacokinetics, Pharmacodynamics, and Clinical Perspectives of Dimethyl Fumarate
Matteo, P., Federico, D., Emanuela, M., Giulia, R., Tommaso, B., Alfredo, G., Anna, C., & Annamaria, O. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122732 · Cited by 22
“In vitro studies have shown that, even if to a lower degree, MMF also directly enhances Nrf2′s pathway but causes less intranuclear accumulation of the NFR2 protein compared to DMF [12].”
Background
Influence of TNF ‐alpha inhibitors and fumaric acid esters on male fertility in psoriasis patients
Heppt, F., Colsman, A., Maronna, A., Uslu, U., Heppt, M. V., Kiesewetter, F., & Sticherling, M. (2017) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.14364 · Cited by 23
Dimethyl Fumarate and Intestine: From Main Suspect to Potential Ally against Gut Disorders
Manai, F., Zanoletti, L., Arfini, D., Micco, S. G. D., Gjyzeli, A., Comincini, S., & Amadio, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24129912 · Cited by 23
“Another strategy might be the direct use of MMF, which is characterized by better GI tolerability and exerts protective effects against gastric ulcerations [145,146], although several studies in the literature in different contexts underline the higher efficacy of DMF compared to MMF [147,148].”
Characterization of the Potent, Selective Nrf2 Activator, 3-(Pyridin-3-Ylsulfonyl)-5-(Trifluoromethyl)-2H-Chromen-2-One, in Cellular and In Vivo Models of Pulmonary Oxidative Stress
Yonchuk, J. G., Foley, J. P., Bolognese, B. J., Logan, G., Wixted, W. E., Kou, J.-P., Chalupowicz, D. G., Feldser, H. G., Sanchez, Y., Nie, H., et al. (2017) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.241794 · Cited by 22
“Furthermore, the Nrf2 activators CDDO-Me, SFN, and DMF have been shown to modify glutathione levels (Tarozzi et al., 2009; Reisman et al., 2012; Brennan et al., 2015).”
Background
Dimethylfumarate ameliorates hepatic injury and fibrosis induced by carbon tetrachloride
Mostafa, M., Shaaban, A. A., & Salem, H. A. (2019) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2019.01.029 · Cited by 22
Emerging small-molecule treatments for multiple sclerosis: focus on B cells
Gregson, A. M., Thompson, K. K., Tsirka, S. E., & Selwood, D. L. (2019) · F1000Research · doi:10.12688/f1000research.16495.1 · Cited by 21
Neuroprotective and Anti-Inflammatory Effects of Dimethyl Fumarate, Monomethyl Fumarate, and Cannabidiol in Neurons and Microglia
Sánchez-Sanz, A., Coronado-Albi, M. J., Muñoz‐Viana, R., García‐Merino, A., & Sánchez, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252313082 · Cited by 19
Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
Loan, J. J., Salman, R. A., McColl, B. W., & Hardingham, G. E. (2022) · Biomolecules · doi:10.3390/biom12101438 · Cited by 17
From Plant to Chemistry: Sources of Active Opioid Antinociceptive Principles for Medicinal Chemistry and Drug Design
Turnaturi, R., Piana, S., Spoto, S., Costanzo, G., Reina, L., Pasquinucci, L., & Parenti, C. (2023) · Molecules · doi:10.3390/molecules28207089 · Cited by 18
“…activity that was the effect of natural products or their active principles on nociception based on animal models (acetic acid-induced abdominal writhing, formalin-induced nociception, orofacial formalin-induced nociception tests, chronic muscle pain tests, tail ﬂick tests, hot plate tests, tail…”
BackgroundMethod
Synthesis, In Vitro and In Silico Studies of HO-1 Inducers and Lung Antifibrotic Agents
Pittalà, V., Vanella, L., Platania, C. B. M., Salerno, L., Raffaele, M., Amata, E., Marrazzo, A., Floresta, G., Romeo, G., Greish, K. F., et al. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2018-0448 · Cited by 17

Authors: Brennan, M. S., Matos, M. F., Li, B., Hronowski, X., Gao, B., Juhasz, P., Rhodes, K. J., & Scannevin, R. H.
Affiliations: Biogen (United States) (US)
Corresponding author: Scannevin, Robert H.
ORCID: Li, Bing
Hronowski, Xiaoping
Gao, Benbo
Scannevin, Robert H.
Venue: PLOS ONE
Publisher: Public Library of Science (PLoS)
Published: 2015-03-20
Volume: 10
Issue: 3
Pages: e0120254
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0120254
PMC: PMC4368598
OpenAlex: W2008817720
Cited by: 188
References: 41
Citations by year: 2026: 23 · 2025: 19 · 2024: 15 · 2023: 14 · 2022: 21 · 2021: 11 · 2020: 13 · 2019: 16 · 2018: 18 · 2017: 14 · 2016: 17 · 2015: 6
FWCI: 7.96
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Funders: Biogen
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: dimethyl fumarate, Keap1, Nrf2 activation, glutathione depletion, cysteine modification, nuclear translocation, antioxidant pathways, multiple sclerosis, psoriasis, fumarate salts
MeSH terms: Dimethyl Fumarate, Kelch-Like ECH-Associated Protein 1, Astrocytes, Cell Nucleus, Cysteine, Extracellular Space, Fumarates, Gene Expression Regulation, Glutathione, Humans, Protein Transport, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2, HEK293 Cells

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Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Effects on KEAP1, NRF2 Activation, and Glutathione Depletion In Vitro

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