Dimethyl itaconate
目录号 : GC25351Dimethyl itaconate can reprogram neurotoxic to neuroprotective primary astrocytes through the regulation of LPS-induced Nod-like receptor protein 3 (NLRP3) inflammasome and nuclear factor 2/heme oxygenase-1 (NRF2/HO-1) pathways.
Cas No.:617-52-7
Sample solution is provided at 25 µL, 10mM.
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Dimethyl itaconate can reprogram neurotoxic to neuroprotective primary astrocytes through the regulation of LPS-induced Nod-like receptor protein 3 (NLRP3) inflammasome and nuclear factor 2/heme oxygenase-1 (NRF2/HO-1) pathways.
[1] Darvish Khadem M, et al. Mol Cell Neurosci. 2022 Jul 20;122:103758.
| Cas No. | 617-52-7 | SDF | Download SDF |
| 分子式 | C7H10O4 | 分子量 | 158.15 |
| 溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg |
| 1 mM | 6.3231 mL | 31.6156 mL | 63.2311 mL |
| 5 mM | 1.2646 mL | 6.3231 mL | 12.6462 mL |
| 10 mM | 0.6323 mL | 3.1616 mL | 6.3231 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
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Dimethyl itaconate ameliorates cognitive impairment induced by a high-fat diet via the gut-brain axis in mice
Microbiome 2023 Feb 21;11(1):30.PMID:36810115DOI:10.1186/s40168-023-01471-8.
Background: Gut homeostasis, including intestinal immunity and microbiome, is essential for cognitive function via the gut-brain axis. This axis is altered in high-fat diet (HFD)-induced cognitive impairment and is closely associated with neurodegenerative diseases. Dimethyl itaconate (DI) is an itaconate derivative and has recently attracted extensive interest due to its anti-inflammatory effect. This study investigated whether intraperitoneal administration of DI improves the gut-brain axis and prevents cognitive deficits in HF diet-fed mice. Results: DI effectively attenuated HFD-induced cognitive decline in behavioral tests of object location, novel object recognition, and nesting building, concurrent with the improvement of hippocampal RNA transcription profiles of genes associated with cognition and synaptic plasticity. In agreement, DI reduced the damage of synaptic ultrastructure and deficit of proteins (BDNF, SYN, and PSD95), the microglial activation, and neuroinflammation in the HFD-fed mice. In the colon, DI significantly lowered macrophage infiltration and the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in mice on the HF diet, while upregulating the expression of immune homeostasis-related cytokines (IL-22, IL-23) and antimicrobial peptide Reg3γ. Moreover, DI alleviated HFD-induced gut barrier impairments, including elevation of colonic mucus thickness and expression of tight junction proteins (zonula occludens-1, occludin). Notably, HFD-induced microbiome alteration was improved by DI supplementation, characterized by the increase of propionate- and butyrate-producing bacteria. Correspondingly, DI increased the levels of propionate and butyrate in the serum of HFD mice. Intriguingly, fecal microbiome transplantation from DI-treated HF mice facilitated cognitive variables compared with HF mice, including higher cognitive indexes in behavior tests and optimization of hippocampal synaptic ultrastructure. These results highlight the gut microbiota is necessary for the effects of DI in improving cognitive impairment. Conclusions: The present study provides the first evidence that DI improves cognition and brain function with significant beneficial effects via the gut-brain axis, suggesting that DI may serve as a novel drug for treating obesity-associated neurodegenerative diseases. Video Abstract.
Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway
Mol Med Rep 2021 Sep;24(3):672.PMID:34296312DOI:10.3892/mmr.2021.12311.
The endogenous metabolite itaconate and its cell‑permeable derivative Dimethyl itaconate (DI) have been identified as anti‑inflammatory regulators of macrophages; however, their contribution to inflammasome‑mediated pyroptosis remains unknown. The present study examined the molecular mechanism of DI on NLR family pyrin domain‑containing 3 (NLRP3) inflammasome assembly and NLRP3 inflammasome‑dependent pyroptosis in microglia. Lipopolysaccharide (LPS) and ATP were used to induce microglia pyroptosis in vitro; this process was confirmed by TUNEL assay, lactate dehydrogenase (LDH) detection and gasdermin D (GSDMD) expression analysis. The regulation of microglia polarization and inflammatory cytokine expression was assessed by immunofluorescence assays and ELISA. To investigate the associated mechanism of action, the expression levels of the nuclear factor erythroid 2‑related factor 2 (Nrf‑2)/heme oxygenase‑1 (HO‑1) pathway proteins were analyzed by western blotting. Finally, the regulatory effect of DI on autophagy and its association with inflammation was determined by western blotting. The present study demonstrated that DI administration inhibited NLRP3 assembly, LDH release and GSDMD cleavage. Cotreatment of DI with LPS and ATP facilitated the transition from M1 to M2, reduced inflammatory mediator expression and impeded NF‑κB phosphorylation. In addition, DI effectively reduced reactive oxygen species production through the Nrf‑2/HO‑1 pathway. Moreover, DI induced cellular autophagy, whereas inhibition of autophagy with 3‑methyladenine markedly reversed its inhibitory effect on NLRP3‑dependent pyroptosis. Taken together, the present study suggested that DI participated in the Nrf‑2/HO‑1 pathway and served a key role in microglia inflammation and NLRP3 inflammasome‑mediated pyroptosis via induction of autophagy.
Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis
Nature 2018 Apr;556(7702):501-504.PMID:29670287DOI:10.1038/s41586-018-0052-z.
Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative Dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-IκBζ regulatory axis could be an important new strategy for the treatment of IL-17-IκBζ-mediated autoimmune diseases.
Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages
Nat Metab 2020 Jul;2(7):594-602.PMID:32694786DOI:10.1038/s42255-020-0210-0.
Following activation, macrophages undergo extensive metabolic rewiring1,2. Production of itaconate through the inducible enzyme IRG1 is a key hallmark of this process3. Itaconate inhibits succinate dehydrogenase4,5, has electrophilic properties6 and is associated with a change in cytokine production4. Here, we compare the metabolic, electrophilic and immunologic profiles of macrophages treated with unmodified itaconate and a panel of commonly used itaconate derivatives to examine its role. Using wild-type and Irg1-/- macrophages, we show that neither Dimethyl itaconate, 4-octyl itaconate nor 4-monoethyl itaconate are converted to intracellular itaconate, while exogenous itaconic acid readily enters macrophages. We find that only Dimethyl itaconate and 4-octyl itaconate induce a strong electrophilic stress response, in contrast to itaconate and 4-monoethyl itaconate. This correlates with their immunosuppressive phenotype: Dimethyl itaconate and 4-octyl itaconate inhibited IκBζ and pro-interleukin (IL)-1β induction, as well as IL-6, IL-10 and interferon-β secretion, in an NRF2-independent manner. In contrast, itaconate treatment suppressed IL-1β secretion but not pro-IL-1β levels and, surprisingly, strongly enhanced lipopolysaccharide-induced interferon-β secretion. Consistently, Irg1-/- macrophages produced lower levels of interferon and reduced transcriptional activation of this pathway. Our work establishes itaconate as an immunoregulatory, rather than strictly immunosuppressive, metabolite and highlights the importance of using unmodified itaconate in future studies.
Dimethyl itaconate Alleviates the Inflammatory Responses of Macrophages in Sepsis
Inflammation 2021 Apr;44(2):549-557.PMID:33029757DOI:10.1007/s10753-020-01352-4.
Sepsis is an inflammatory disease characterized by dysregulation of inflammation. Macrophage-mediated inflammation has been implicated in the pathophysiology of sepsis. Itaconate is a metabolite produced in activated macrophages which has anti-inflammatory activities. In the present study, we investigated the potential effects of a cell-permeable itaconate derivative Dimethyl itaconate on inflammation in sepsis. We established a lipopolysaccharide (LPS)-induced septic mouse model and administered Dimethyl itaconate to the septic mice. The survival rate, serum level of pro-inflammatory cytokines, and lung pathology were evaluated. We also administered Dimethyl itaconate to LPS-treated bone marrow-derived macrophages (BMDMs), and measured the cytokine production and Nrf2 expression. We also evaluated the effects of Dimethyl itaconate on Nrf2-deficient mice. Administration of Dimethyl itaconate enhanced survival rate, decreased serum level of TNF-α and IL-6, and ameliorated lung injury in septic mice. Dimethyl itaconate also suppressed LPS-induced production of TNF-α, IL-6, and NOS2 in BMDMs. Dimethyl itaconate activated Nrf2 and promoted the expression of Nrf2 and its downstream factor HO-1 and NQO-1. The regulatory activities of Dimethyl itaconate on inflammatory cytokine production, mouse survival rate were abolished in septic Nrf2-/- mice. Dimethyl itaconate suppressed the inflammatory responses of macrophages in sepsis.