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International Journal of Molecular... Aug 2023This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin...
This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin disease. In this case, progressive GAD was treated with DMF, resulting in significant improvement of skin lesions within 5 weeks and complete healing within 7 months. Clinical response was associated with a reduction in inflammatory cells, including both T cell subsets (CD4+ > CD8+), CD183/CXCR3 cells, Langerhans cells (CD1a+), myeloid DCs, M1- and M2-like macrophages and the activation marker HLA-DR in immunohistochemical analysis. These findings support the use of DMF as a promising treatment option for this rare skin condition.
Topics: Humans; Granuloma Annulare; Dimethyl Fumarate; Treatment Outcome; Skin; Dermatitis; Rare Diseases
PubMed: 37686161
DOI: 10.3390/ijms241713355 -
Journal of Neuroinflammation Feb 2020Oxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine....
BACKGROUND
Oxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the fumaric acid esters (FAEs), dimethyl fumarate, nuclear factor E2-related factor 2/antioxidant response element (Nrf-2/ARE) pathway-mediated, in regulating the hypersensitivity in a mouse model of nitroglycerine (NTG)-induced migraine.
METHODS
Mice were orally administered with DMF at the doses of 10, 30, and 100 mg/kg, 5 min after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brain and behavioral tests after 4 h by NTG-migraine induction. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Nrf-2, manganese superoxide dismutase (Mn-SOD), and heme-oxygenase-1 (HO-1) were detected by Western blot. Tail flick, hot plate, orofacial formalin, and photophobia tests were used to evaluate migraine-like pain and migraine-related light sensitivity. Moreover, we evaluate Nrf-2-dependent mechanism by the in vitro stimulation of cells extracted by trigeminal ganglia with diethylenetriamine/nitric oxide (DETA/NO), a nitric oxide (NO) donor. The cells were pre-treated with DMF and an antagonist of Nrf-2, trigonelline (TR) 2 h before DETA/NO stimulation.
RESULTS
DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF-κB and Nrf-2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache was significantly reduced. The protective effect of DMF treatment, via Nrf-2, was confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Cytotoxicity, iNOS, and MnSOD expression were evaluated.
CONCLUSION
These results provided the evidence that DMF, by Nrf-2 modulation, has a protective effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.
Topics: Animals; Cells, Cultured; Dimethyl Fumarate; Dose-Response Relationship, Drug; Immunosuppressive Agents; Male; Mice; Migraine Disorders; Nitroglycerin; Oxidative Stress; Rats; Rats, Wistar
PubMed: 32066464
DOI: 10.1186/s12974-020-01736-1 -
The British Journal of Dermatology Mar 2021Dimethyl fumarate (DMF) is the active ingredient of Skilarence™ and Tecfidera™, which are used for the treatment of psoriasis and multiple sclerosis, respectively....
BACKGROUND
Dimethyl fumarate (DMF) is the active ingredient of Skilarence™ and Tecfidera™, which are used for the treatment of psoriasis and multiple sclerosis, respectively. Various immunomodulatory mechanisms of action have been identified for DMF; however, it is still unclear what effects DMF exerts in vivo in patients with psoriasis.
OBJECTIVES
In this study we examined the effects of DMF, both in vivo and in vitro, on T cells, which play a key role in the pathogenesis of psoriasis.
METHODS
The frequency of T-cell subsets was examined by flow cytometry in untreated patients with psoriasis or those treated with DMF. The effects of DMF in vitro on T-cell survival, activation and proliferation, and cell-surface thiols were assessed by flow cytometry.
RESULTS
In patients with psoriasis treated with DMF we observed an increase in the frequency of T regulatory (Treg) cells and a decrease in T helper (Th)17 lineage cells and the associated cytokines interleukin-17, interleukin-22 and granulocyte-macrophage colony-stimulating factor. T cells cultured in vitro with DMF exhibited reduced viability, and inhibition of activation and proliferation in response to stimulation due to the oxidative effects of DMF. However, the frequency of Treg cells increased in the presence of DMF due to their heightened ability to resist DMF-induced oxidative stress.
CONCLUSIONS
DMF enhanced the ratio of Treg cells to Th17 cells in patients with psoriasis, in patients with multiple sclerosis and in vitro. Furthermore, our data suggest that this is at least in part as a result of the differential effects of DMF on Treg cells compared with conventional T cells.
Topics: Dimethyl Fumarate; Humans; Psoriasis; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 32438447
DOI: 10.1111/bjd.19229 -
Journal of Neuroinflammation Feb 2024Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor...
BACKGROUND
Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates neuroinflammation in the mouse models of neurodegenerative diseases, however, the detailed mechanism remains unclear.
METHODS
The effects of dimethyl fumarate (DMF), a clinically used drug to activate the Nrf2 pathway, on neuroinflammation were analyzed in primary astrocytes and App (App-KI) mice. The cognitive function and behavior of DMF-administrated App-KI mice were evaluated. For the gene expression analysis, microglia and astrocytes were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, followed by quantitative PCR.
RESULTS
DMF treatment activated some Nrf2 target genes and inhibited the expression of proinflammatory markers in primary astrocytes. Moreover, chronic oral administration of DMF attenuated neuroinflammation, particularly in astrocytes, and reversed cognitive dysfunction presumably by activating the Nrf2-dependent pathway in App-KI mice. Furthermore, DMF administration inhibited the expression of STAT3/C3 and C3 receptor in astrocytes and microglia isolated from App-KI mice, respectively, suggesting that the astrocyte-microglia crosstalk is involved in neuroinflammation in mice with AD.
CONCLUSION
The activation of astrocytic Nrf2 signaling confers neuroprotection in mice with AD by controlling neuroinflammation, particularly by regulating astrocytic C3-STAT3 signaling. Furthermore, our study has implications for the repositioning of DMF as a drug for AD treatment.
Topics: Mice; Animals; Alzheimer Disease; Dimethyl Fumarate; Mice, Transgenic; Neuroinflammatory Diseases; NF-E2-Related Factor 2; Cognitive Dysfunction; Disease Models, Animal
PubMed: 38383481
DOI: 10.1186/s12974-024-03046-2 -
Inflammation Apr 2023Rheumatoid arthritis (RA) as a chronic inflammatory disorder affects around 1% of the world population. Fibroblast-like synoviocyte (FLS), one of the main cells in RA...
Rheumatoid arthritis (RA) as a chronic inflammatory disorder affects around 1% of the world population. Fibroblast-like synoviocyte (FLS), one of the main cells in RA pathogenesis is characterized by hyperproliferation and resistance to apoptosis resulting to synovial hyperplasia. Dimethyl fumarate (DMF) has been licensed for the treatment of multiple sclerosis (MS) and psoriasis; however, its role in RA is unknown. DMF has immunomodulatory properties and may be considered as therapeutic approach in RA treatment. In this study, we aimed to investigate the effect of DMF on controlling FLS-mediated synovial inflammation and joint destruction in RA. FLSs were isolated from synovial tissues of 8 patients with RA and treated with DMF. Apoptosis rate was analyzed by Annexin V-FITC. Cell proliferation was measured by carboxyfluorescein succinimidyl ester (CFSE) dye. The matrix metalloproteinase 3 (MMP3) and NF-кB pathway protein (p65) mRNA expression were evaluated by RT-PCR. Also, the IL-6 production and lactate release were measured in FLS supernatant. DMF treatment decreased the cell proliferation and increased apoptosis in a dose dependent manner. DMF-treated FLS showed a reduction in IL-6 and lactate release. Moreover, it was revealed that DMF inhibited the expression of p65 and MMP3. Our data demonstrate that DMF treatment suppresses the aggressive and inflammatory features of RA FLSs. Our Results suggest that DMF might be expected to be evaluated as a therapy for RA.
Topics: Humans; Synoviocytes; Dimethyl Fumarate; Matrix Metalloproteinase 3; Interleukin-6; Arthritis, Rheumatoid; Synovial Membrane; Inflammation; Fibroblasts; Cell Proliferation; Cells, Cultured
PubMed: 36253500
DOI: 10.1007/s10753-022-01759-1 -
Journal of Neurology Mar 2021Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple...
BACKGROUND
Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple sclerosis (RRMS).
OBJECTIVE
To compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS.
METHODS
We identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses.
RESULTS
Of the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8-1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6-1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6-1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT.
CONCLUSION
Dimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.
Topics: Dimethyl Fumarate; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 32974794
DOI: 10.1007/s00415-020-10226-6 -
Journal of Neurology Jun 2021
Topics: COVID-19; Dimethyl Fumarate; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; SARS-CoV-2
PubMed: 32588182
DOI: 10.1007/s00415-020-10015-1 -
Anticancer Research May 2022Adult T-cell leukemia (ATL) is a peripheral T lymphocytic malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Despite treatment that includes...
BACKGROUND/AIM
Adult T-cell leukemia (ATL) is a peripheral T lymphocytic malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Despite treatment that includes novel agents that have been developed, most of ATL patients relapse and acquire multidrug resistance. As a result, the creation of newer agents is critical. Dimethyl fumarate (DMF) has several effects in cancer cells, including cell signaling, proliferation and cell death. However, its antitumor effects on ATL cells remain unknown. In this study, we looked at DMF's antitumor effects on ATL cells.
MATERIALS AND METHODS
We examined the effects of DMF on proliferation and apoptosis using the trypan blue exclusion assay and annexin V/propidium iodide staining in HTLV-1-infected and transformed T-cell lines, MT-1 and MT-2 cells. We also evaluated the effects of DMF on the nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription 3 (STAT3) signaling pathways and anti-apoptotic proteins by immunoblotting.
RESULTS
DMF inhibited proliferation and induced apoptosis in MT-1 and MT-2 cells by activating poly ADP-ribose polymerase (PARP). Furthermore, DMF inhibited the constitutive activation of both canonical and non-canonical NF-κB pathways in MT-2 cells and the non-canonical NF-κB pathway in MT-1 cells. DMF also inhibited the constitutive tyrosine phosphorylation of STAT3 and the expression of anti-apoptotic proteins, c-IAP2 and survivin in both cells.
CONCLUSION
These results indicate that DMF inhibits proliferation and induces apoptosis in HTLV-1-infected and transformed T-cells by suppressing NF-κB and STAT3 signaling pathways. DMF should be investigated further as a novel agent for ATL.
Topics: Adult; Apoptosis; Dimethyl Fumarate; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphoma; NF-kappa B; STAT3 Transcription Factor; Signal Transduction
PubMed: 35489748
DOI: 10.21873/anticanres.15709 -
Multiple Sclerosis (Houndmills,... May 2019Dimethyl fumarate (DMF) is a commonly used and effective treatment for relapsing and remitting multiple sclerosis. Its use results in impairment of the transcription...
BACKGROUND
Dimethyl fumarate (DMF) is a commonly used and effective treatment for relapsing and remitting multiple sclerosis. Its use results in impairment of the transcription factor nuclear factor erythroid-derived 2 (E2)-related factor (Nrf2), which is involved in both immunomodulation and bone health. DMF has not previously been reported to cause bone marrow complications, though other fumarates including tenofovir have. The mechanism of fumarate-associated bone toxicity remains unclear with altered osteoblastic gene expression and function suggested.
METHODS
We present a case of a 54-year-old female with relapsing remitting multiple sclerosis (RRMS) treated for 30 months with DMF who developed relapsing atraumatic lower limb bone pain.
RESULTS
Serial imaging revealed multifocal areas of bone marrow oedema and trabecular fractures. The patient was diagnosed with transient bone marrow oedema syndrome. Management consisted of cessation of therapy and treatment with the pro-osteobalstic agent denosumab.
CONCLUSION
In this instance of DMF-associated bone marrow oedema, cessation of DMF and treatment with denosumab resulted in symptomatic improvement. DMF therapy may potentially result in bone marrow oedema due to inhibition of common upstream signalling pathways, including the Nrf2 signalling pathway.
Topics: Bone Marrow Diseases; Dimethyl Fumarate; Edema; Female; Humans; Immunosuppressive Agents; Middle Aged; Multiple Sclerosis, Relapsing-Remitting
PubMed: 30051766
DOI: 10.1177/1352458518791132 -
Annals of Clinical and Translational... Oct 2021Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro-inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS.
METHODS
Phase-2, double-blind, placebo-controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin-receptor p75 and quality of life.
RESULTS
A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS-R score was not significantly different at week 36 (-1.12 [-3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least-squares mean: (0.84 [-0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups.
INTERPRETATION
Dimethyl fumarate, in combination with riluzole, was safe and well-tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Dimethyl Fumarate; Double-Blind Method; Female; Humans; Immunologic Factors; Male; Middle Aged; Outcome Assessment, Health Care
PubMed: 34477330
DOI: 10.1002/acn3.51446