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Nature Communications Jun 2023Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to...
Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
Topics: Humans; Anticoagulants; Thromboplastin; Dimethyl Fumarate; Escherichia coli; Inflammation; Lipopolysaccharides; Staphylococcus aureus; Thrombin; COVID-19; SARS-CoV-2; Thrombosis; Macrophages; Caspases; Interferon Type I
PubMed: 37316487
DOI: 10.1038/s41467-023-39174-1 -
JCI Insight Nov 2023New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory...
New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 activator with current clinical utility in the treatment of multiple sclerosis and psoriasis that could be effective for DMD and rapidly translatable. Here, we tested 2 weeks of daily 100 mg/kg DMF versus 5 mg/kg standard-care prednisone (PRED) treatment in juvenile mdx mice with early symptomatic DMD. Both drugs modulated seed genes driving the DMD disease program and improved force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects, protected contracting muscles from fatigue, improved histopathology, and augmented clinically compatible muscle function tests. DMF may be a more selective modulator of the DMD disease program than PRED, warranting follow-up longitudinal studies to evaluate disease-modifying impact.
Topics: Animals; Mice; Mice, Inbred mdx; Dimethyl Fumarate; Muscular Dystrophy, Duchenne; Prednisone; Muscles
PubMed: 37751291
DOI: 10.1172/jci.insight.165974 -
Oncotarget Feb 2017
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Astrocytes; Brain Ischemia; Dimethyl Fumarate; Edema; Hippocampus; Humans; Immunosuppressive Agents; Mice; Microcirculation; Multiple Sclerosis, Relapsing-Remitting; Neuroprotection; Oxidative Stress; Patient Safety; Stroke
PubMed: 28209921
DOI: 10.18632/oncotarget.15357 -
Multiple Sclerosis and Related Disorders Jul 2018The mechanisms of action of dimethyl fumarate (DMF), and its metabolite, monomethyl fumarate (MMF), for the treatment of multiple sclerosis are not completely elucidated. (Review)
Review
BACKGROUND
The mechanisms of action of dimethyl fumarate (DMF), and its metabolite, monomethyl fumarate (MMF), for the treatment of multiple sclerosis are not completely elucidated.
OBJECTIVES
To discuss the role of DMF/MMF-induced hydroxycarboxylic acid receptor 2 (HCA/GPR109A) pathway activation in the immune response and treatment of MS.
METHODS
A narrative (traditional) review of the current literature.
RESULTS
Studies have shown that binding of DMF/MMF to HCA on dendritic cells inhibits the production of pro-inflammatory cytokines in vitro and in MS murine models. Evidence suggests that activation of HCA expressed in immune cells and gut epithelial cells by DMF/MMF, may induce anti-inflammatory responses in the intestinal mucosa.
CONCLUSION
Although the DMF/MMF mechanism of action remains unclear, evidence suggests that the activation of HCA/GPR109A pathway downregulates the immune response and may activate anti-inflammatory response in the intestinal mucosa, possibly leading to reduction in CNS tissue damage in MS patients.
Topics: Animals; Dimethyl Fumarate; Humans; Immunosuppressive Agents; Multiple Sclerosis; Receptors, G-Protein-Coupled; Receptors, Nicotinic; Signal Transduction
PubMed: 29763776
DOI: 10.1016/j.msard.2018.04.016 -
Brain and Nerve = Shinkei Kenkyu No... Sep 2017At the end of 2016, dimethyl fumarate (DMF) was approved as the sixth disease-modifying drug for multiple sclerosis by the Pharmaceuticals and Medical Devices Agency of... (Review)
Review
At the end of 2016, dimethyl fumarate (DMF) was approved as the sixth disease-modifying drug for multiple sclerosis by the Pharmaceuticals and Medical Devices Agency of Japan. Two randomized, placebo-controlled, phase III studies (DEFINE and CONFIRM) showed beneficial effects in patients in Western countries, with relapsing-remitting multiple sclerosis (RRMS). Some of the benefits included a decreased annual relapse rate, inhibition of disease activity (shown using brain magnetic resonance imaging), and a decreased proportion of patients with confirmed disease progression. The APEX study, which included Japanese patients with RRMS, also showed similar results, but reported some adverse effects. Flushing and gastrointestinal events (e.g., nausea, vomiting, abdominal pain, and diarrhea) occurring within 1 month of the initiation of DMF treatment are major causes of discontinuation of the drug. The most serious adverse event is progressive multifocal leukoencephalopathy (PML), which was reported in four patients with MS treated with DMF, worldwide. Grade 3 lymphopenia (less than 500/mm) due to apoptosis occurs in some DMF-treated patients with MS and is more prevalent among older patients. A reduction in CD8 T cells is more pronounced than that in CD4 T cells. Patients with grade 3 lymphopenia, aged more than 50 years, are at a risk for PML development. Further studies are needed to determine the appropriate final dose and an acceptable dose-escalation method for DMF treatment, to prevent or decrease adverse effects in Japanese patients with MS.
Topics: Dimethyl Fumarate; Humans; Immune System; Immunosuppressive Agents; Multiple Sclerosis; Recurrence
PubMed: 28900067
DOI: 10.11477/mf.1416200864 -
Autoimmunity Reviews Dec 2018Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) in which demyelination and neurodegeneration occurs. The immune... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) in which demyelination and neurodegeneration occurs. The immune system of MS patients is characterized by a dysregulation in the balance between pro- and anti-inflammatory immune cells, whereby both the innate and adaptive immune system are involved. Dimethyl fumarate (DMF) was licensed in 2013 as an oral first-line therapy for relapsing-remitting (RR)MS patients. It has a strong efficacy with neuroprotective and immunomodulatory effects and a favourable benefit-risk profile. However, the effects of DMF on the immune system of MS patients were not clear before entering the market. During the last years, numerous in vitro and ex vivo studies have clarified the working mechanism of DMF in MS. Here, we discuss the pharmacokinetics of DMF and its effect on molecular immune-related pathways, which is further linked to the clinical and immunological effects of DMF treatment. The efficacy and safety of DMF treatment for RRMS is discussed as reported from clinical trials. Further, the immunological effects of DMF treatment in RRMS patients are addressed in more detail, including the distribution and function of immune cells. Taken together, evidence from recent studies points to a multifactorial working mechanism of DMF treatment in MS which leads to a restored immune balance favouring a more tolerogenic or anti-inflammatory immune profile.
Topics: Animals; Dimethyl Fumarate; Humans; Immunosuppressive Agents; Multiple Sclerosis; Prognosis
PubMed: 30316988
DOI: 10.1016/j.autrev.2018.07.001 -
Expert Opinion on Drug Safety Apr 2020: Psoriasis is a chronic inflammatory disorder affecting skin, nails and joints. Systemic therapy of psoriasis is based upon several drugs which include fumaric acid... (Review)
Review
: Psoriasis is a chronic inflammatory disorder affecting skin, nails and joints. Systemic therapy of psoriasis is based upon several drugs which include fumaric acid esters (FAEs), initially introduced in 1959. Since 2017, one of the key substances among FAE spectrum (dimethyl fumarate; DMF) was registered by the European Medicines Agency (EMA) for the treatment of moderate-to-severe psoriasis vulgaris.: This article covers the basic concepts underlying usefulness of DMF in psoriasis and extensively reviews the studies, which included its use in monotherapy of this dermatosis, with a particular emphasis on safety aspects and adverse events (AEs).: DMF monotherapy is a valuable systemic modality in the management of moderate-to-severe psoriasis as proved by a recent phase III study. AEs associated with DMF therapy are frequent, usually of mild severity, with a dose-independent manner. Occasionally they are burdensome and require drug discontinuation. The most common AEs comprise gastrointestinal symptoms, flushing and white blood cell count abnormalities. The latter require strict monitoring to prevent serious complications. Acknowledging the possibility of AEs, the use of DMF in moderate-to-severe psoriasis is encouraged while the need of further studies still remains.
Topics: Dermatologic Agents; Dimethyl Fumarate; Dose-Response Relationship, Drug; Humans; Psoriasis; Severity of Illness Index
PubMed: 32129112
DOI: 10.1080/14740338.2020.1736553 -
Archives of Dermatological Research Aug 2018Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary... (Comparative Study)
Comparative Study Review
Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.
Topics: Dermatologic Agents; Dimethyl Fumarate; Drug Therapy, Combination; Fumarates; Germany; Humans; Psoriasis; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome
PubMed: 29574575
DOI: 10.1007/s00403-018-1825-9 -
Journal of Neuroscience Research Sep 2023Dimethyl fumarate (DMF) is an immunomodulatory drug currently approved for the treatment of multiple sclerosis and psoriasis. Its benefits on ischemic stroke outcomes... (Review)
Review
Dimethyl fumarate (DMF) is an immunomodulatory drug currently approved for the treatment of multiple sclerosis and psoriasis. Its benefits on ischemic stroke outcomes have recently come to attention. To date, only tissue plasminogen activators (tPAs) and clot retrieval methods have been approved by the FDA for the treatment of ischemic stroke. Ischemic conditions lead to inflammation through diverse mechanisms, and recanalization can worsen the state. DMF and the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway it regulates seem to be important in postischemic inflammation, and animal studies have demonstrated that the drug improves overall stroke outcomes. Although the exact mechanism is still unknown, studies indicate that these beneficial impacts are due to the modulation of immune responses, blood-brain barrier permeability, and hemodynamic adjustments. One major component evaluated before, during, and after tPA therapy in stroke patients is blood pressure (BP). Recent studies have found that DMF may impact BP. Both hypotension and hypertension need correction before treatment, which may delay the appropriate intervention. Since BP management is crucial in managing stroke patients, it is important to consider DMF's role in this matter. That being said, it seems further investigations on DMF may lead to an alternative approach for stroke patients. In this article, we discuss the mechanistic roles of DMF and its potential role in stroke based on previously published literature and laboratory findings.
Topics: Animals; Dimethyl Fumarate; Ischemic Stroke; Stroke; Blood-Brain Barrier; Inflammation; NF-E2-Related Factor 2
PubMed: 37183360
DOI: 10.1002/jnr.25202 -
Annals of Neurology May 2022Treatment with dimethyl fumarate (DMF) leads to lymphopenia and infectious complications in a subset of patients with multiple sclerosis (MS). Here, we aimed to reveal... (Observational Study)
Observational Study
Treatment with dimethyl fumarate (DMF) leads to lymphopenia and infectious complications in a subset of patients with multiple sclerosis (MS). Here, we aimed to reveal immune markers of DMF-associated lymphopenia. This prospective observational study longitudinally assessed 31 individuals with MS by single-cell mass cytometry before and after 12 and 48 weeks of DMF therapy. Employing a neural network-based representation learning approach, we identified a CCR4-expressing T helper cell population negatively associated with relevant lymphopenia. CCR4-expressing T helper cells represent a candidate prognostic biomarker for the development of relevant lymphopenia in patients undergoing DMF treatment. ANN NEUROL 2022;91:676-681.
Topics: Dimethyl Fumarate; Humans; Immunosuppressive Agents; Lymphopenia; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Prospective Studies
PubMed: 35170072
DOI: 10.1002/ana.26328