Itaconic acid derivatives: structure, function, biosynthesis, and perspectives

Sano, Mei; Tanaka, Tomonari; Ohara, Hirotaka; Aso, Yoichi

doi:10.1007/s00253-020-10908-1

Cited by 37 publications

(25 citation statements)

References 66 publications

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“…Notably, itaconate is known to exert its antioxidant activity by targeting SDH, thereby reducing the production of ROS derived from succinate oxidation ( 23 , 24 ); however, using the SDH inhibitor dimethyl malonate did not inhibit IL-1β release in an NLRP3 inflammasome assay ( 35 ), indicating that SDH inhibition by itaconate was unlikely to be the main mechanism underlying its anti-inflammatory ability. Several cell-permeable derivatives have been synthesized to achieve efficient intracellular delivery of itaconate ( 36 ); DI is produced by esterification of a carboxyl group and reduces the negative charge of itaconate, which increases its electrophilicity and derivative functions ( 23 ). Microglia are unique resident immune cells in the brain that comprise the first and most important line of immune defense in the central nervous system ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway

Yang

Zhang

et al. 2021

Mol Med Rep

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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.

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Section: Discussionmentioning

confidence: 99%

Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway

Yang

Zhang

et al. 2021

Mol Med Rep

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“…The difference between 4-OI and DI is the location of octyl ester. Octyl ester group of 4-OI is located distal to the alkene than DI which makes 4-OI lower thiol reactivity similar to itaconate and more suitable to probe the physiological function of itaconate (Mills et al, 2018 ; Sano et al, 2020 ). The structural differences also made 4-OI lacks the electrophilic property which makes it a better candidate of Itaconate (Ryan et al, 2019 ).…”

Section: General Features Of Itaconatementioning

confidence: 99%

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

et al. 2021

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Metabolites have recently been found to be involved in significant biological regulation and changes. Itaconate, an important intermediate metabolite isolated from the tricarboxylic acid cycle, is derived from cis-aconitate decarboxylation mediated by immune response gene 1 in mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component involved in the development and progression of inflammation and immunity. It could directly modify cysteine sites on functional substrate proteins which related to inflammasome, signal transduction, transcription, and cell death. Itaconate can be a connector among immunity, metabolism, and inflammation, which is of great significance for further understanding the mechanism of cellular immune metabolism. And it could be the potential choice for the treatment of inflammation and immune-related diseases. This study is a systematic review of the potential mechanisms of metabolite associated with different pathology conditions. We briefly summarize the structural characteristics and classical pathways of itaconate and its derivatives, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.

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“…Several research articles present novel and multifaceted techniques for antimicrobial polymer production based on this renewable monomer, IA [ 137 , 145 , 146 , 147 ]. A proficient and effective biobased polymer was produced through radical homopolymerization and copolymerization by integrating pendant alkyne groups in the IA’s carboxylic acids structure, resulting in interactive IA derivatives.…”

Section: Ia-based Polymer Applicationsmentioning

confidence: 99%

“…As described previously, IA can be converted into drug-delivery systems, different hydrogels in water treatment and analyses, intelligent food packaging, antimicrobial polymers, or even in cleaning products, adhesives, coatings, thickeners, fibers, binders, lipase immobilization [ 160 ], and many other applications [ 101 ]. Additionally, IA and its derivatives have anti-inflammatory [ 161 ] antitumor [ 145 ] and antimicrobial activities [ 147 , 162 ], which could be further maneuvered therapeutically for inflammatory disorder treatment.…”

Section: Ia-based Polymer Applicationsmentioning

confidence: 99%

Recent Advances in Biotechnological Itaconic Acid Production, and Application for a Sustainable Approach

Teleky

Vodnar

2021

Polymers

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Intense research has been conducted to produce environmentally friendly biopolymers obtained from renewable feedstock to substitute fossil-based materials. This is an essential aspect for implementing the circular bioeconomy strategy, expressly declared by the European Commission in 2018 in terms of “repair, reuse, and recycling”. Competent carbon-neutral alternatives are renewable biomass waste for chemical element production, with proficient recyclability properties. Itaconic acid (IA) is a valuable platform chemical integrated into the first 12 building block compounds the achievement of which is feasible from renewable biomass or bio-wastes (agricultural, food by-products, or municipal organic waste) in conformity with the US Department of Energy. IA is primarily obtained through fermentation with Aspergillus terreus, but nowadays several microorganisms are genetically engineered to produce this organic acid in high quantities and on different substrates. Given its trifunctional structure, IA allows the synthesis of various novel biopolymers, such as drug carriers, intelligent food packaging, antimicrobial biopolymers, hydrogels in water treatment and analysis, and superabsorbent polymers binding agents. In addition, IA shows antimicrobial, anti-inflammatory, and antitumor activity. Moreover, this biopolymer retains qualities like environmental effectiveness, biocompatibility, and sustainability. This manuscript aims to address the production of IA from renewable sources to create a sustainable circular economy in the future. Moreover, being an essential monomer in polymer synthesis it possesses a continuous provocation in the biopolymer chemistry domain and technologies, as defined in the present review.

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Itaconic acid derivatives: structure, function, biosynthesis, and perspectives

Cited by 37 publications

References 66 publications

Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway

Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

Recent Advances in Biotechnological Itaconic Acid Production, and Application for a Sustainable Approach

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