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ABSTRACT:
PROVIDER: PRJNA936936 | ENA |
REPOSITORIES: ENA
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Project description:Aquamicrobium lusatiense strain:DMF-9 Genome sequencing
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Project description:Delayed-release dimethyl fumarate (DMF) is approved in the United States, European Union, Canada, and Australia for the treatment of multiple sclerosis. DMF is also a component in a defined-mixture product with three salts of monoethyl fumarate (MEF) that is approved in Germany for the treatment of psoriasis. Characterizing common or distinct pharmacodynamic properties of DMF and MEF would provide insights into the mechanisms of action of delayed-release DMF versus fixed combination products containing DMF and MEF salts. In this study we evaluated the pharmacodynamic effects and pharmacokinetics of DMF and MEF in central nervous system and peripheral tissues of naïve mice following a single dose or 10 daily doses of DMF, MEF, or a combination of the two. DMF and MEF exhibited similar pharmacokinetic profiles, but differences were noted in biodistribution: monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited a higher degree of brain penetration, whereas MEF was preferentially partitioned into kidney. Both common and distinct pharmacodynamic responses were observed in all assessed tissues for DMF and MEF alone or in combination. These findings indicate that all fumaric acid esters cannot be considered equivalent, and combinations of compounds may exert effects not observed when agents are used individually.
2020-12-10 | GSE63361 | GEO
Project description:Delayed-release dimethyl fumarate (DMF) is approved in the United States, European Union, Canada, and Australia for the treatment of multiple sclerosis. DMF is also a component in a defined-mixture product with three salts of monoethyl fumarate (MEF) that is approved in Germany for the treatment of psoriasis. Characterizing common or distinct pharmacodynamic properties of DMF and MEF would provide insights into the mechanisms of action of delayed-release DMF versus fixed combination products containing DMF and MEF salts. In this study we evaluated the pharmacodynamic effects and pharmacokinetics of DMF and MEF in central nervous system and peripheral tissues of naïve mice following a single dose or 10 daily doses of DMF, MEF, or a combination of the two. DMF and MEF exhibited similar pharmacokinetic profiles, but differences were noted in biodistribution: monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited a higher degree of brain penetration, whereas MEF was preferentially partitioned into kidney. Both common and distinct pharmacodynamic responses were observed in all assessed tissues for DMF and MEF alone or in combination. These findings indicate that all fumaric acid esters cannot be considered equivalent, and combinations of compounds may exert effects not observed when agents are used individually.
2020-12-10 | GSE63343 | GEO
Project description:The fumarate ester dimethyl fumarate (DMF) has been introduced recently for the treatment of relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory condition resulting in neuronal demyelination and axonal loss. The complete mechanism of DMF action is unknown, but involves the depletion of intracellular glutathione and modification of thiols on Kelch-like ECH-associated protein 1 (Keap1), which in turn induces the expression of antioxidant response element genes. Previous work by our laboratory has shown that DMF reacts with a wide range of protein thiols in adipocytes, detected following ester hydrolysis by an antibody recognizing succinated proteins. We proposed that other intracellular thiol residues may also be irreversibly modified by DMF in neurons and astrocytes. DMF treatment of primary rodent neurons and astrocytes, as well as differentiated N1E-115 cells, resulted in the modification of 24 novel target proteins by mass spectrometry. Using this approach, we confirmed the identification and site of modification of the identified proteins, which include cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2). An in vitro functional assay that measures the ability of cofilin-1 to sever the actin cytoskeleton demonstrated that DMF-modified cofilin-1 loses activity and generates less monomeric actin, potentially inhibiting cofilin’s cytoskeletal remodeling activity; an effect that could be beneficial in the modulation of myelination during RRMS. DMF modification of tubulin did not significantly impact axonal lysosomal trafficking. The oxygen consumption rate of N1E-115 neurons and the levels of proteins related to mitochondrial energy production were only slightly affected by the highest doses of DMF, confirming that DMF treatment does not impair cellular respiratory function. In summary, we demonstrate that in addition to the stimulation of the antioxidant response, DMF resulted in electrophilic modification of novel protein targets that provide new insight on the mechanisms supporting the neuroprotective and re-myelination benefits associated with DMF treatment.
2019-02-19 | PXD008314 | Pride
Project description:Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With this aim, we studied the transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes). Responder patients to DMF exhibit a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.
2023-08-08 | GSE235357 | GEO
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