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Aconitate decarboxylase-1 (ACOD1) is expressed by activated macrophages and generates itaconate that exerts anti-microbial and immunoregulatory effects. ACOD1-itaconate is essential for macrophage-mediated control of the intracellular pathogen Coxiella (C.) burnetii, which causes Q fever. Two isomers of itaconate, mesaconate and citraconate, have overlapping yet distinct activity on macrophage metabolism and inflammatory gene expression. Here, we found that all three isomers inhibited the growth of C. burnetii in axenic culture in ACCM-2 medium. However, only itaconate reduced C. burnetii replication efficiently in Acod1-/- macrophages. In contrast, addition of citraconate strongly increased C. burnetii replication in Acod1+/- macrophages, whereas mesaconate weakly enhanced bacterial burden in Acod1-/- macrophages. Analysis of intracellular isomers showed that exogenous citraconate and mesaconate inhibited the generation of itaconate by infected Acod1+/- macrophages. Uptake of added isomers into Acod1-/- macrophages was increased after infection for itaconate and mesaconate, but not for citraconate. Mesaconate, but not citraconate, competed with itaconate for uptake into macrophages. Taken together, inhibition of itaconate generation by macrophages and interference with the uptake of extracellular itaconate could be identified as potential mechanisms behind the divergent effects of citraconate and mesaconate on C. burnetii replication in macrophages or in axenic culture. [ABSTRACT FROM AUTHOR]

Aconitate decarboxylase-1 (ACOD1) is expressed by activated macrophages and generates itaconate that exerts anti-microbial and immunoregulatory effects. ACOD1-itaconate is essential for macrophage-mediated control of the intracellular pathogen Coxiella (C.) burnetii, which causes Q fever. Two isomers of itaconate, mesaconate and citraconate, have overlapping yet distinct activity on macrophage metabolism and inflammatory gene expression. Here, we found that all three isomers inhibited the growth of C. burnetii in axenic culture in ACCM-2 medium. However, only itaconate reduced C. burnetii replication efficiently in Acod1-/- macrophages. In contrast, addition of citraconate strongly increased C. burnetii replication in Acod1+/- macrophages, whereas mesaconate weakly enhanced bacterial burden in Acod1-/- macrophages. Analysis of intracellular isomers showed that exogenous citraconate and mesaconate inhibited the generation of itaconate by infected Acod1+/- macrophages. Uptake of added isomers into Acod1-/- macrophages was increased after infection for itaconate and mesaconate, but not for citraconate. Mesaconate, but not citraconate, competed with itaconate for uptake into macrophages. Taken together, inhibition of itaconate generation by macrophages and interference with the uptake of extracellular itaconate could be identified as potential mechanisms behind the divergent effects of citraconate and mesaconate on C. burnetii replication in macrophages or in axenic culture.

Aconitate decarboxylase-1 (ACOD1) is expressed by activated macrophages and generates itaconate that exerts anti-microbial and immunoregulatory effects. ACOD1-itaconate is essential for macrophage-mediated control of the intracellular pathogen Coxiella (C.) burnetii , which causes Q fever. Two isomers of itaconate, mesaconate and citraconate, have overlapping yet distinct activity on macrophage metabolism and inflammatory gene expression. Here, we found that all three isomers inhibited the growth of C. burnetii in axenic culture in ACCM-2 medium. However, only itaconate reduced C. burnetii replication efficiently in Acod1 -/- macrophages. In contrast, addition of citraconate strongly increased C. burnetii replication in Acod1 +/- macrophages, whereas mesaconate weakly enhanced bacterial burden in Acod1 -/- macrophages. Analysis of intracellular isomers showed that exogenous citraconate and mesaconate inhibited the generation of itaconate by infected Acod1 +/- macrophages. Uptake of added isomers into Acod1 -/- macrophages was increased after infection for itaconate and mesaconate, but not for citraconate. Mesaconate, but not citraconate, competed with itaconate for uptake into macrophages. Taken together, inhibition of itaconate generation by macrophages and interference with the uptake of extracellular itaconate could be identified as potential mechanisms behind the divergent effects of citraconate and mesaconate on C. burnetii replication in macrophages or in axenic culture., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Siddique, Kellermeier, Ölke, Zhao, Büssow, Oefner, Lührmann, Dettmer and Lang.)

Metastasis is a principal factor in the poor prognosis of colorectal cancer. Recent studies have found microbial metabolites regulate colorectal cancer metastasis. By analyzing metabolomics data, we identified an essential fecal metabolite citraconate that potentially promotes colorectal cancer metastasis. Next, we tried to reveal its effect on colorectal cancer and the underlying mechanism. Firstly, the response of colorectal cancer cells (HCT116 and MC38 cells) to citraconate was assessed by Cell Counting Kit-8 assay, clonogenic assay, transwell migration and invasion assay. Moreover, we utilized an intra-splenic injection model to evaluate the effect of citraconate on colorectal cancer liver metastasis in vivo . Then molecular approaches were employed, including RNA sequencing, mass spectrometry-based metabolomics, western blot, quantitative real-time PCR, cell ferrous iron colorimetric assay and intracellular malondialdehyde measurement. In vitro , citraconate promotes the growth of colorectal cancer cells. In vivo , citraconate aggravated liver metastasis of colorectal cancer. Mechanistically, downstream genes of NRF2, NQO1, GCLC , and GCLM high expression induced by citraconate resulted in resistance to ferroptosis of colorectal cancer cells. In summary, citraconate promotes the malignant progression of colorectal cancer through NRF2-mediated ferroptosis resistance in colorectal cancer cells. Furthermore, our study indicates that fecal metabolite may be crucial in colorectal cancer development., Competing Interests: None., (AJCR Copyright © 2024.)

Itaconate is derived from the tricarboxylic acid (TCA) cycle intermediate cis-aconitate and links innate immunity and metabolism. Its synthesis is altered in inflammation-related disorders and it therefore has potential as clinical biomarker. Mesaconate and citraconate are naturally occurring isomers of itaconate that have been linked to metabolic disorders, but their functional relationships with itaconate are unknown. We aimed to establish a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for the quantification of itaconate, mesaconate, citraconate, the pro-drug 4-octyl-itaconate, and selected TCA intermediates. The assay was validated for itaconate, mesaconate, and citraconate for intra- and interday precision and accuracy, extended stability, recovery, freeze/thaw cycles, and carry-over. The lower limit of quantification was 0.098 µM for itaconate and mesaconate and 0.049 µM for citraconate in 50 µL samples. In spike-in experiments, itaconate remained stable in human plasma and whole blood for 24 and 8 h, respectively, whereas spiked-in citraconate and mesaconate concentrations changed during incubation. The type of anticoagulant in blood collection tubes affected measured levels of selected TCA intermediates. Human plasma may contain citraconate (0.4–0.6 µM, depending on the donor), but not itaconate or mesaconate, and lipopolysaccharide stimulation of whole blood induced only itaconate. Concentrations of the three isomers differed greatly among mouse organs: Itaconate and citraconate were most abundant in lymph nodes, mesaconate in kidneys, and only citraconate occurred in brain. This assay should prove useful to quantify itaconate isomers in biomarker and pharmacokinetic studies, while providing internal controls for their effects on metabolism by allowing quantification of TCA intermediates.

The organotin monomer di(tri-n-butyltin) citraconate (DTBTC, I) was synthesized. Subsequently this monomer was copolymerized with N-vinylimidazole (VI) using a free radical technique. The overall conversion was kept low (≤14% wt/wt) for all studied samples and the copolymer composition was determined from tin analysis using the Gilman and Rosenberg method. The synthesized monomer and copolymer were further characterized by elemental analysis, 1H- and 13C-NMR, and FTIR spectroscopy.

Organotin monomers containing dibutyltin groups – dibutyltin citraconate (DBTC) as a new monomer and dibutyltin maleate (DBTM) – were synthesized. Free radical copolymerizations of the organotin monomers with styrene (ST) and butyl acrylate (BA) were performed. The overall conversion was kept low (≤15% wt/wt) for all studied samples and the copolymers composition was determined from tin analysis using the Gillman and Rosenberg method. The reactivity ratios were calculated from the copolymer composition using the Fineman-Ross (FR) method. The synthesized monomers were characterized by elemental analysis, 1H-, 13C-NMR and FTIR spectroscopy.

The organotin monomer di(tri-n-butyltin) citraconate (DTBTC, I) was synthesized. Subsequently this monomer was copolymerized with N-vinylimidazole (VI) using a free radical technique. The overall conversion was kept low (≤14% wt/wt) for all studied samples and the copolymer composition was determined from tin analysis using the Gilman and Rosenberg method. The synthesized monomer and copolymer were further characterized by elemental analysis, ¹H- and 13C-NMR, and FTIR spectroscopy. [ABSTRACT FROM AUTHOR]

Organotin monomers containing dibutyltin groups - dibutyltin citraconate (DBTC) as a new monomer and dibutyltin maleate (DBTM) - were synthesized. Free radical copolymerizations of the organotin monomers with styrene (ST) and butyl acrylate (BA) were performed. The overall conversion was kept low (=15% wt/wt) for all studied samples and the copolymers composition was determined from tin analysis using the Gillman and Rosenberg method. The reactivity ratios were calculated from the copolymer composition using the Fineman-Ross (FR) method. The synthesized monomers were characterized by elemental analysis, 1H-, 13C-NMR and FTIR spectroscopy. [ABSTRACT FROM AUTHOR]

The formation of citraconic anhydride (CAN) from the condensation of succinic acid and its derivatives with formaldehyde over oxide catalysts is described. Alumina and aluminum phosphate are active catalysts that give selectivity to citraconic anhydride as high as 75% in an integral fixed bed reactor. Weakly acidic sites on the catalyst surface, particularly Lewis acid sites, are responsible for activating the desired reaction pathway. Strongly acidic sites lead to cracking and coking, while basic sites facilitate the Cannizzaro reaction of formaldehyde to carbon dioxide and methanol. Catalyst deactivation via coking occurs over the course of reaction, but activity is easily restored by regeneration in air at elevated temperatures. The reaction system under investigation is part of an overall process to produce itaconic acid from renewable resource-based succinic acid. [Copyright &y& Elsevier]

Itaconate is derived from the tricarboxylic acid (TCA) cycle intermediate cis-aconitate and links innate immunity and metabolism. Its synthesis is altered in inflammation-related disorders and it therefore has potential as clinical biomarker. Mesaconate and citraconate are naturally occurring isomers of itaconate that have been linked to metabolic disorders, but their functional relationships with itaconate are unknown. We aimed to establish a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for the quantification of itaconate, mesaconate, citraconate, the pro-drug 4-octyl-itaconate, and selected TCA intermediates. The assay was validated for itaconate, mesaconate, and citraconate for intra- and interday precision and accuracy, extended stability, recovery, freeze/thaw cycles, and carry-over. The lower limit of quantification was 0.098 µM for itaconate and mesaconate and 0.049 µM for citraconate in 50 µL samples. In spike-in experiments, itaconate remained stable in human plasma and whole blood for 24 and 8 h, respectively, whereas spiked-in citraconate and mesaconate concentrations changed during incubation. The type of anticoagulant in blood collection tubes affected measured levels of selected TCA intermediates. Human plasma may contain citraconate (0.4–0.6 µM, depending on the donor), but not itaconate or mesaconate, and lipopolysaccharide stimulation of whole blood induced only itaconate. Concentrations of the three isomers differed greatly among mouse organs: Itaconate and citraconate were most abundant in lymph nodes, mesaconate in kidneys, and only citraconate occurred in brain. This assay should prove useful to quantify itaconate isomers in biomarker and pharmacokinetic studies, while providing internal controls for their effects on metabolism by allowing quantification of TCA intermediates. [ABSTRACT FROM AUTHOR]