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Acta Dermato-venereologica Mar 2023
Topics: Humans; Dimethyl Fumarate; Dermatologic Agents; Treatment Outcome; Psoriasis
PubMed: 36987538
DOI: 10.2340/actadv.v103.4526 -
Revista de Neurologia May 2023Wells syndrome, also known as eosinophilic cellulitis, is a rare dermatosis with approximately 200 cases previously described in the literature. Here, we present a case...
INTRODUCTION
Wells syndrome, also known as eosinophilic cellulitis, is a rare dermatosis with approximately 200 cases previously described in the literature. Here, we present a case of a patient with multiple sclerosis with Wells syndrome induced by dimethyl fumarate (DMF).
CASE REPORT
A 41-year-old Caucasian woman was treated with DMF in July 2021. One week later, she experienced itching on her upper and lower right arm, followed by the appearance of erythematous plaques covered with vesicles. The complete blood count showed an increased eosinophil count of up to 2,000 µL. The histological images demonstrated dermal eosinophil infiltration concordant with Wells syndrome. The clinical course was benign, with complete resolution of the lesions and normalization of the eosinophil count within four weeks. Administration of corticosteroids was not necessary.
CONCLUSIONS
Eosinophilia is rare in patients with multiple sclerosis treated with DMF and usually does not require dosage adjustments. Although clinical manifestations of eosinophilia in these patients are very rare, it is important for practitioners to recognize the symptoms. Many neuroleptic drugs can induce eosinophilia and systemic symptoms; therefore, physicians must be aware of the risks associated with DMF and neuroleptic drugs, particularly for quetiapine, which contains fumarate.
Topics: Humans; Female; Adult; Dimethyl Fumarate; Antipsychotic Agents; Eosinophilia; Multiple Sclerosis
PubMed: 37165530
DOI: 10.33588/rn.7610.2022323 -
International Immunopharmacology Feb 2023We aimed to investigate the therapeutic role of dimethyl fumarate (DMF) in fungal keratitis.
PURPOSE
We aimed to investigate the therapeutic role of dimethyl fumarate (DMF) in fungal keratitis.
METHODS
Human corneal epithelial cells (HCECs) and mouse models of fungal keratitis were used in this study. The antifungal effect of DMF on Aspergillus fumigatus (A. fumigatus) was confirmed by examining the minimum inhibitory concentration (MIC), biofilm formation, conidial adherence and corneal fungal loads. Slit-lamp photography, haematoxylin and eosin staining and immunostaining were used to assess the severity of corneal impairment. RT-PCR, western blot, ELISA, immunohistochemistry and immunostaining were performed to examine the effects of DMF on the expression of the inflammatory mediators during fungal infection.
RESULTS
In vitro, DMF limited A. fumigatus growth, biofilm formation, and conidial adherence and reduced the mRNA levels of AldA, GlkA, GAPDH, HxkA, PgkA, Sdh2, GelA and ChsF in A. fumigatus. In vivo, DMF effectively decreased corneal fungal loads. DMF attenuated corneal inflammatory impairment by suppressing inflammatory cell accumulation and downregulating cytokine expression. DMF notably downregulated the high expression of NLRP3, cleaved GSDMD, cleaved caspase-1, mature IL-1β and mature IL-18 induced by fungi. The production of Nrf2 and HO-1 could be further increased by DMF in infected HCECs. Nrf2 siRNA pretreatment counteracted DMF-mediated downregulation of the expression of the active forms of IL-18, IL-1β, caspase-1 and GSDMD.
CONCLUSION
DMF limits fungal growth by suppressing biofilm formation, conidial adherence and respiratory metabolism. It also exerts an anti-inflammatory effect on fungal keratitis by inhibiting pyroptosis, which could be regulated by Nrf2. Our results suggest that DMF plays a therapeutic role in fungal keratitis.
Topics: Mice; Animals; Humans; Dimethyl Fumarate; Interleukin-18; Aspergillosis; Pyroptosis; NF-E2-Related Factor 2; Keratitis; Aspergillus fumigatus; Eye Infections, Fungal; Caspase 1; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36641891
DOI: 10.1016/j.intimp.2023.109721 -
International Journal of Molecular... Oct 2023Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl...
Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.
Topics: Male; Mice; Animals; Dimethyl Fumarate; Stroke; Brain Ischemia; Infarction, Middle Cerebral Artery; Brain; Mice, Inbred C57BL
PubMed: 37958527
DOI: 10.3390/ijms242115540 -
Anesthesiology Feb 2020Available treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic...
BACKGROUND
Available treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic node for neuropathic pain, the authors focused on the master regulator of the antioxidant response-nuclear factor erythroid 2-related factor 2 (NFE2L2; Nrf2)-as an alternative target for neuropathic pain. The authors tested whether dimethyl fumarate (U.S. Food and Drug Administration-approved treatment for multiple sclerosis) would activate NFE2L2 and promote antioxidant activity to reverse neuropathic pain behaviors and oxidative stress-dependent mechanisms.
METHODS
Male Sprague Dawley rats, and male and female wild type and Nfe2l2 mice were treated with oral dimethyl fumarate/vehicle for 5 days (300 mg/kg; daily) after spared nerve injury/sham surgery (n = 5 to 8 per group). Allodynia was measured in von Frey reflex tests and hyperalgesia in operant conflict-avoidance tests. Ipsilateral L4/5 dorsal root ganglia were assayed for antioxidant and cytokine/chemokine levels, and mitochondrial bioenergetic capacity.
RESULTS
Dimethyl fumarate treatment reversed mechanical allodynia (injury-vehicle, 0.45 ± 0.06 g [mean ± SD]; injury-dimethyl fumarate, 8.2 ± 0.16 g; P < 0.001) and hyperalgesia induced by nerve injury (injury-vehicle, 2 of 6 crossed noxious probes; injury-dimethyl fumarate, 6 of 6 crossed; P = 0.013). The antiallodynic effect of dimethyl fumarate was lost in nerve-injured Nfe2l2 mice, but retained in nerve-injured male and female wild type mice (wild type, 0.94 ± 0.25 g; Nfe2l2, 0.02 ± 0.01 g; P < 0.001). Superoxide dismutase activity was increased by dimethyl fumarate after nerve injury (injury-vehicle, 3.96 ± 1.28 mU/mg; injury-dimethyl fumarate, 7.97 ± 0.47 mU/mg; P < 0.001). Treatment reduced the injury-dependent increases in cytokines and chemokines, including interleukin-1β (injury-vehicle, 13.30 ± 2.95 pg/mg; injury-dimethyl fumarate, 6.33 ± 1.97 pg/mg; P = 0.022). Injury-impaired mitochondrial bioenergetics, including basal respiratory capacity, were restored by dimethyl fumarate treatment (P = 0.025).
CONCLUSIONS
Dimethyl fumarate, a nonopioid and orally-bioavailable drug, alleviated nociceptive hypersensitivity induced by peripheral nerve injury via activation of NFE2L2 antioxidant signaling. Dimethyl fumarate also resolved neuroinflammation and mitochondrial dysfunction-oxidative stress-dependent mechanisms that drive nociceptive hypersensitivity after nerve injury.
Topics: Animals; Antioxidants; Dimethyl Fumarate; Female; Immunosuppressive Agents; Male; Mice; Mice, Knockout; NF-E2-Related Factor 2; Neuralgia; Rats; Rats, Sprague-Dawley; Rodentia; Signal Transduction
PubMed: 31939850
DOI: 10.1097/ALN.0000000000003077 -
Multiple Sclerosis and Related Disorders Apr 2018Recent research has outlined that Dimethyl Fumarate (DMF) functions as a gene regulator via multiple pathways, critical among which is the NRF2 cytoprotective cascade.... (Review)
Review
Recent research has outlined that Dimethyl Fumarate (DMF) functions as a gene regulator via multiple pathways, critical among which is the NRF2 cytoprotective cascade. PARK7/DJ-1 is a multifunctional protein that acts as a redox sensor and effector of multiple cytoprotective pathways, including NRF2. Specifically, it prevents the association of NRF2 with its inhibitor KEAP1, allowing NRF2 to enter the nucleus and mediate cytoprotective and antioxidant cascades. It is our hypothesis that while the NRF2-KEAP1 inhibitory complex is reported the main pharmacological target for DMF's NRF dependent functions, no study to date has explored the effects of DMF on DJ-1's expression, and vice-versa, the possibility of a regulatory inadequacy in the upstream, oxidant-responsive DJ-1 activator of the NRF2 cascade.
Topics: Animals; Dimethyl Fumarate; Humans; Immunosuppressive Agents; Multiple Sclerosis; NF-E2-Related Factor 2; Neoplasms; Protein Deglycase DJ-1
PubMed: 29529529
DOI: 10.1016/j.msard.2018.02.027 -
Frontiers in Cellular and Infection... 2022Tuberculosis (TB) claims nearly 1.5 million lives annually. Current TB treatment requires a combination of several drugs administered for at least 6 months. (Mtb), the...
Tuberculosis (TB) claims nearly 1.5 million lives annually. Current TB treatment requires a combination of several drugs administered for at least 6 months. (Mtb), the causative agent of TB, can persist in infected humans and animals for decades. Moreover, during infection, Mtb produces differentially culturable bacteria (DCB) that do not grow in standard media but can be resuscitated in liquid media supplemented with sterile Mtb culture filtrates or recombinant resuscitation-promoting factors (Rpfs). Here, we demonstrate that, in an intranasal murine model of TB, Mtb DCB are detectable in the lungs after 4 weeks of infection, and their loads remain largely unchanged during a further 8 weeks. Treatment of the infected mice with dimethyl fumarate (DMF), a known drug with immunomodulatory properties, for 8 weeks eliminates Mtb DCB from the lungs and spleens. Standard TB treatment consisting of rifampicin, isoniazid, and pyrazinamide for 8 weeks reduces Mtb loads by nearly four orders of magnitude but does not eradicate DCB. Nevertheless, no DCB can be detected in the lungs and spleens after 8 weeks of treatment with DMF, rifampicin, isoniazid, and pyrazinamide. Our data suggest that addition of approved anti-inflammatory drugs to standard treatment regimens may improve TB treatment and reduce treatment duration.
Topics: Animals; Antitubercular Agents; Dimethyl Fumarate; Disease Models, Animal; Humans; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Lymph Node
PubMed: 36093181
DOI: 10.3389/fcimb.2022.957287 -
Communications Biology Oct 2023Dimethyl fumarate is an ester from the Krebs cycle intermediate fumarate. This drug is approved and currently used for the treatment of psoriasis and multiple sclerosis,...
Dimethyl fumarate is an ester from the Krebs cycle intermediate fumarate. This drug is approved and currently used for the treatment of psoriasis and multiple sclerosis, and its anti-angiogenic activity was reported some years ago. Due to the current clinical relevance of this compound and the recently manifested importance of endothelial cell metabolism on the angiogenic switch, we wanted to elucidate whether dimethyl fumarate has an effect on energetic metabolism of endothelial cells. Different experimental approximations were performed in endothelial cells, including proteomics, isotope tracing and metabolomics experimental approaches, in this work we studied the possible role of dimethyl fumarate in endothelial cell energetic metabolism. We demonstrate for the first time that dimethyl fumarate promotes glycolysis and diminishes cell respiration in endothelial cells, which could be a consequence of a down-regulation of serine and glycine synthesis through inhibition of PHGDH activity in these cells. Dimethyl fumarate alters the energetic metabolism of endothelial cells in vitro and in vivo through an unknown mechanism, which could be the cause or the consequence of its pharmacological activity. This new discovery on the targets of this compound could open a new field of study regarding the mechanism of action of dimethyl fumarate.
Topics: Humans; Dimethyl Fumarate; Endothelial Cells; Fumarates; Multiple Sclerosis; Down-Regulation
PubMed: 37880317
DOI: 10.1038/s42003-023-05443-4 -
Wiener Klinische Wochenschrift Oct 2019Fumaric acid esters are recommended in European guidelines for induction and maintenance treatment of patients with moderate to severe plaque psoriasis. A systemic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Fumaric acid esters are recommended in European guidelines for induction and maintenance treatment of patients with moderate to severe plaque psoriasis. A systemic medication with pure dimethyl fumarate without monoethyl fumarate salts was recently licensed in Europe.
OBJECTIVE
The efficacy and safety of pure dimethyl fumarate were assessed in patients with severe (physician global assessment) plaque psoriasis in Austria in the BRIDGE trial.
METHODS
In this double blind, randomized, placebo-controlled trial patients received 16-week treatment with pure dimethyl fumarate in a head to head comparison with dimethyl fumarate with monoethyl fumarate salts, which is licensed in Germany. In this post hoc analysis the efficacy and safety were assessed in patients with severe psoriasis in Austria.
RESULTS
Efficacy measures significantly improved in both active treatment arms compared to placebo in 65 patients after 16 weeks of treatment. Physician global assessment of clear/almost clear in the dimethyl fumarate group was non-inferior to the dimethyl fumarate with monoethyl fumarate salts group 2 months after end of treatment. No serious adverse reaction occurred in patients with dimethyl fumarate in contrast to the second active treatment. Efficacy outcome was paralleled by quality of life improvements.
CONCLUSION
This is the first report of dimethyl fumarate in a severely affected population with plaque psoriasis. Dimethyl fumarate is effective and safe in the systemic treatment of adults with severe psoriasis (physician global assessment).
Topics: Adult; Aged; Austria; Dimethyl Fumarate; Double-Blind Method; Europe; Female; Germany; Humans; Male; Middle Aged; Psoriasis; Quality of Life; Severity of Illness Index; Treatment Outcome; Young Adult
PubMed: 31591676
DOI: 10.1007/s00508-019-01551-6 -
International Urogynecology Journal May 2022Mechanical trauma and oxidative injury are involved in the pathogenesis of stress urinary incontinence (SUI), and oxidative stress (OS) is considered a potential...
INTRODUCTION AND HYPOTHESIS
Mechanical trauma and oxidative injury are involved in the pathogenesis of stress urinary incontinence (SUI), and oxidative stress (OS) is considered a potential therapeutic target. The antioxidant properties of dimethyl fumarate (DMF), a potent activator of Nrf2, have been highlighted recently. We therefore predicted that DMF might have therapeutic effects on mechanical trauma-induced SUI.
METHODS
The SUI mice model was established by vaginal distension (VD). Leak point pressure (LPP), serum OS biomarkers, cell proliferation and apoptosis, collagen, elastin, matrix metalloproteinases (MMP), Nrf2, the TGF-β1/Smad3 signaling pathway, and the associated tissue growth factors in the anterior vaginal wall were measured in either wild-type or Nrf2-knockout (Nrf2/) female C57BL/6 mice.
RESULTS
The results showed that DMF improved the VD-induced LPP reduction, alleviated oxidative injury, stimulated cell proliferation and inhibited apoptosis in the anterior vaginal wall tissue of mice. Moreover, DMF treatment reduced the hydrolysis of ECM proteins by MMP2 and MMP9. The above effects may be mediated by a series of tissue growth factors, including α-SMA, PAI-1, and TIMP-2, with the TGF-β1/Smad3 signaling pathway as the core regulatory mechanism. In further study, Nrf2/ mice were used to replicate the SUI model. And the difference is that DMF failed to reactivate the TGF-β1/Smad3 pathway, nor did it improve LPP.
CONCLUSIONS
Dimethyl fumarate can ameliorate urethra closure dysfunction in the VD-induced SUI mice model, and the therapeutic effect of DMF is mediated by the Nrf2-dominated antioxidant system and its downstream TGF-β1/Smad3 signaling pathway.
Topics: Animals; Antioxidants; Dimethyl Fumarate; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Smad3 Protein; Transforming Growth Factor beta1; Urinary Incontinence, Stress
PubMed: 34982187
DOI: 10.1007/s00192-021-05061-w