Expression data of renal cancer cell treated with Oncolytic virus VSVd51 and Fumaric acid esters such as Dimethyl fumarate
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97328 | GEO | 2018/07/30
REPOSITORIES: GEO
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Project description:Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate (DMF), exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances.
2015-12-31 | E-MTAB-2406 | biostudies-arrayexpress
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 treatment for multiple sclerosis (MS) that can cross the blood-brain barrier, presenting neuroprotective potential. Its mechanism of action is not fully understood and there is a need to characterize if DMF or its bioactive metabolite monomethyl fumarate (MMF) exert neuroprotective properties. The combination of adjuvant agents such as cannabidiol (CBD) could be relevant to enhance neuroprotection. The aim of this study was to compare the effects of DMF, MMF and CBD on neuroprotective and immunomodulatory pathways in neurons and microglia in vitro. We found that DMF and CBD, but not MMF, activated the Nrf2 antioxidant pathway in neurons. Similarly, only DMF and CBD, but not MMF, prevented the LPS-induced activation of the inflammatory pathway NF-kB in microglia. However, the 3 drugs inhibited the production of nitric oxide in microglia and protected neurons against apoptosis. Transcriptomically, DMF, MMF and CBD exhibited differential effects on these pathways, with DMF achieving the most pronounced changes. Our results show that DMF and MMF, despite being structurally related, present differences in their mechanisms of action that could be relevant for the achievement of neuroprotection in MS patients and the potential of CBD as an adjuvant therapy in neuroprotection.
2024-09-30 | GSE274435 | GEO
Project description:Dimethyl fumarate (DMF) is an immunomodulatory treatment for multiple sclerosis (MS) that can cross the blood-brain barrier, presenting neuroprotective potential. Its mechanism of action is not fully understood and there is a need to characterize if DMF or its bioactive metabolite monomethyl fumarate (MMF) exert neuroprotective properties. The combination of adjuvant agents such as cannabidiol (CBD) could be relevant to enhance neuroprotection. The aim of this study was to compare the effects of DMF, MMF and CBD on neuroprotective and immunomodulatory pathways in neurons and microglia in vitro. We found that DMF and CBD, but not MMF, activated the Nrf2 antioxidant pathway in neurons. Similarly, only DMF and CBD, but not MMF, prevented the LPS-induced activation of the inflammatory pathway NF-kB in microglia. However, the 3 drugs inhibited the production of nitric oxide in microglia and protected neurons against apoptosis. Transcriptomically, DMF, MMF and CBD exhibited differential effects on these pathways, with DMF achieving the most pronounced changes. Our results show that DMF and MMF, despite being structurally related, present differences in their mechanisms of action that could be relevant for the achievement of neuroprotection in MS patients and the potential of CBD as an adjuvant therapy in neuroprotection.
2024-09-30 | GSE274859 | GEO
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
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
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 | GSE175471 | GEO
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
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
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 | GSE130478 | GEO