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Science (New York, N.Y.) Sep 2020Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We...
Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.
Topics: Animals; Caspases; Citric Acid Cycle; Cysteine; Dimethyl Fumarate; Encephalomyelitis, Autoimmune, Experimental; Familial Mediterranean Fever; Female; HEK293 Cells; Humans; Inflammasomes; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Multiple Sclerosis; Phosphate-Binding Proteins; Protein Processing, Post-Translational; Pyroptosis
PubMed: 32820063
DOI: 10.1126/science.abb9818 -
Blood Sep 2021Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge....
Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2-specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.
Topics: Animals; Dimethyl Fumarate; Ferroptosis; Gene Expression Regulation, Neoplastic; Humans; Lipid Peroxidation; Lymphoma, Large B-Cell, Diffuse; Mice; NF-kappa B; Neoplasm Proteins; STAT3 Transcription Factor; Signal Transduction; Xenograft Model Antitumor Assays; Zebrafish
PubMed: 33876201
DOI: 10.1182/blood.2020009404 -
Cell Research Apr 2020The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors,... (Review)
Review
The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.
Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Dimethyl Fumarate; Glycolysis; Humans; Immunomodulation; Immunosuppressive Agents; Inflammation; Metformin; Methotrexate; Sirolimus
PubMed: 32132672
DOI: 10.1038/s41422-020-0291-z -
Annals of Neurology Mar 2023The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum.
METHODS
We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE).
RESULTS
Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05-0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]).
INTERPRETATION
This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604-614.
Topics: Humans; Dimethyl Fumarate; Multiple Sclerosis; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Magnetic Resonance Imaging; Double-Blind Method
PubMed: 36401339
DOI: 10.1002/ana.26555 -
Pharmacological Research Mar 2023Necroptosis has been implicated in various inflammatory diseases including tumor-necrosis factor-α (TNF-α)-induced systemic inflammatory response syndrome (SIRS)....
Necroptosis has been implicated in various inflammatory diseases including tumor-necrosis factor-α (TNF-α)-induced systemic inflammatory response syndrome (SIRS). Dimethyl fumarate (DMF), a first-line drug for treating relapsing-remitting multiple sclerosis (RRMS), has been shown to be effective against various inflammatory diseases. However, it is still unclear whether DMF can inhibit necroptosis and confer protection against SIRS. In this study, we found that DMF significantly inhibited necroptotic cell death in macrophages induced by different necroptotic stimulations. Both the autophosphorylation of receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3 and the downstream phosphorylation and oligomerization of MLKL were robustly suppressed by DMF. Accompanying the suppression of necroptotic signaling, DMF blocked the mitochondrial reverse electron transport (RET) induced by necroptotic stimulation, which was associated with its electrophilic property. Several well-known anti-RET reagents also markedly inhibited the activation of the RIPK1-RIPK3-MLKL axis accompanied by decreased necrotic cell death, indicating a critical role of RET in necroptotic signaling. DMF and other anti-RET reagents suppressed the ubiquitination of RIPK1 and RIPK3, and they attenuated the formation of necrosome. Moreover, oral administration of DMF significantly alleviated the severity of TNF-α-induced SIRS in mice. Consistent with this, DMF mitigated TNF-α-induced cecal, uterine, and lung damage accompanied by diminished RIPK3-MLKL signaling. Collectively, DMF represents a new necroptosis inhibitor that suppresses the RIPK1-RIPK3-MLKL axis through blocking mitochondrial RET. Our study highlights DMF's potential therapeutic applications for treating SIRS-associated diseases.
Topics: Mice; Animals; Tumor Necrosis Factor-alpha; Protein Kinases; Dimethyl Fumarate; Necroptosis; Receptor-Interacting Protein Serine-Threonine Kinases; Systemic Inflammatory Response Syndrome; Oxidative Phosphorylation; Apoptosis
PubMed: 36796462
DOI: 10.1016/j.phrs.2023.106697 -
Frontiers in Immunology 2021NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced...
NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced mobility and depressive behaviors. Dimethyl fumarate (DMF) is an immunomodulatory and anti-oxidative molecule commonly used for the symptomatic treatment of multiple sclerosis and psoriasis. In this study, we investigated the potential use of DMF against microglial NLRP3 inflammasome activation both and . For studies, LPS- and ATP-stimulated N9 microglial cells were used to induce NLRP3 inflammasome activation. DMF's effects on inflammasome markers, pyroptotic cell death, ROS formation, and Nrf2/NF-κB pathways were assessed. For studies, 12-14 weeks-old male BALB/c mice were treated with LPS, DMF + LPS and ML385 + DMF + LPS. Behavioral tests including open field, forced swim test, and tail suspension test were carried out to see changes in lipopolysaccharide-induced sickness behavior. Furthermore, NLRP3 and Caspase-1 expression in isolated microglia were determined by immunostaining. Here we demonstrated that DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels Nrf2 activation. Additionally, we showed that DMF pretreatment decreased miR-146a and miR-155 both and . Our results proved the effectiveness of DMF on the amelioration of microglial NLRP3 inflammasome activation. We anticipate that this study will provide the foundation consideration for further studies aiming to suppress NLRP3 inflammasome activation associated with in many diseases and a better understanding of its underlying mechanisms.
Topics: Animals; Cells, Cultured; Dimethyl Fumarate; Disease Models, Animal; Humans; Illness Behavior; Immunologic Factors; Inflammasomes; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Microglia; Multiple Sclerosis; NLR Family, Pyrin Domain-Containing 3 Protein; Psoriasis; Signal Transduction
PubMed: 34858398
DOI: 10.3389/fimmu.2021.737065 -
Presse Medicale (Paris, France : 1983) Jun 2021Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for MS treatment. For this reason, a profound knowledge of the characteristics and indications of the available compounds is required to tailor the therapeutic strategy to the individual patient characteristics. This should include the mechanism of action and pharmacokinetic of the drug, the safety and efficacy profile provided by clinical trials, as well as the understanding of possible side effects. Moreover, the evolving knowledge of the disease is paving the way to new and innovative therapeutic approaches, as well as the development of new biomarkers to monitor the therapeutic response and to guide the clinician's therapeutic choices. In this review we provide a comprehensive overview on currently approved therapies in MS and the emerging evidence-based strategies to adopt for initiating, monitoring, and eventually adapting a therapeutic regimen with DMT.
Topics: Abnormalities, Drug-Induced; Algorithms; Antibodies, Monoclonal, Humanized; Cladribine; Crotonates; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Hematopoietic Stem Cell Transplantation; Humans; Hydroxybutyrates; Immunologic Factors; Immunosuppressive Agents; Indans; Interferon-beta; Male; Mitoxantrone; Multiple Sclerosis; Natalizumab; Nitriles; Oxadiazoles; Pregnancy; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Toluidines
PubMed: 34033862
DOI: 10.1016/j.lpm.2021.104068 -
The Lancet. Neurology Aug 2022B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial.
BACKGROUND
B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines.
METHODS
RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744.
FINDINGS
Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns.
INTERPRETATION
RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.
FUNDING
Swedish Research Council.
Topics: Adolescent; Adult; Dimethyl Fumarate; Humans; Immunosuppressive Agents; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Recurrence; Rituximab; Sweden; Young Adult
PubMed: 35841908
DOI: 10.1016/S1474-4422(22)00209-5