Injectable Hydrogel of Chitosan-Octyl Itaconate Conjugate Modulates Inflammatory Response DOI
Shasha Zhou, Jibing He, Quan Liu

et al.

ACS Biomaterials Science & Engineering, Journal Year: 2024, Volume and Issue: 10(8), P. 4823 - 4838

Published: July 26, 2024

Itaconic acid and its derivative 4-octyl itaconate (OI) represent a novel anti-inflammatory medication that has demonstrated efficacy in multiple inflammation models because of minimal side effects. Recently, natural polymers conjugated with small molecule drugs, known as polymer-drug conjugates (PDCs), have emerged promising approach to sustained drug release. In this work, we reported an prepare PDC containing OI make it into injectable hydrogel. Chitosan (CS) was selected for synthesis abundant free amino groups can be molecules carboxyl by carbodiimide chemistry. We used ethanol/water cosolvent system synthesize CS-OI conjugate via EDC/NHS catalysis. The had improved water solubility unique activity did not show compromised antibacterial compared unmodified CS. Beta-glycerophosphate (β-GP) cross-linked hydrogel exhibited good injectability sustainable release effectively modulated inflammatory response rat model. Therefore, study provides valuable insights the design hydrogels modulatory properties.

Language: Английский

Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis DOI Creative Commons

Zhaoli Luo,

Ziyang Sheng, Liye Hu

et al.

EBioMedicine, Journal Year: 2024, Volume and Issue: 101, P. 104993 - 104993

Published: Feb. 6, 2024

BackgroundMacrophages are innate immune cells whose phagocytosis function is critical to the prognosis of stroke and peritonitis. cis-aconitic decarboxylase immune-responsive gene 1 (Irg1) its metabolic product itaconate inhibit bacterial infection, intracellular viral replication, inflammation in macrophages. Here we explore whether regulates phagocytosis.MethodsPhagocytosis macrophages was investigated by time-lapse video recording, flow cytometry, immunofluorescence staining macrophage/microglia cultures isolated from mouse tissue. Unbiased RNA-sequencing ChIP-sequencing assays were used underlying mechanisms. The effects Irg1/itaconate axis on intracerebral hemorrhagic (ICH) peritonitis observed transgenic (Irg1flox/flox; Cx3cr1creERT/+, cKO) mice or control vivo.FindingsIn a model ICH, depletion Irg1 decreased erythrocytes, thereby exacerbating outcomes (n = 10 animals/group, p < 0.05). Administration sodium itaconate/4-octyl (4-OI) promoted macrophage 7 In addition, peritonitis, deficiency also inhibited Staphylococcus aureus 5 0.05) aggravated 9 Mechanistically, 4-OI alkylated cysteine 155 Kelch-like ECH-associated protein (Keap1), consequent nuclear translocation factor erythroid 2-related 2 (Nrf2) transcriptional activation Cd36 gene. Blocking CD36 completely abolished phagocytosis-promoting vitro vivo.InterpretationOur findings provide potential therapeutic target for phagocytosis-deficiency disorders, supporting further development towards clinical application benefit patients.FundingThe National Natural Science Foundation China (32070735, 82371321 Q. Li, 82271240 F. Yang) Beijing Program Scientific Research Key Municipal Commission Education (KZ202010025033 Li).

Language: Английский

Citations

15
Post-translational modifications of Keap1: the state of the art DOI Creative Commons
Yunjia Song, Ying Qu, Caiyun Mao

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 8, 2024

The Keap1-Nrf2 signaling pathway plays a crucial role in cellular defense against oxidative stress-induced damage. Its activation entails the expression and transcriptional regulation of several proteins involved detoxification antioxidation processes within organism. Keap1, serving as pivotal regulator this pathway, exerts control over activity Nrf2. Various post-translational modifications (PTMs) such alkylation, glycosylation, glutathiylation, S-sulfhydration, other modifications, impact binding affinity between Keap1 Consequently, leads to accumulation Nrf2 its translocation nucleus, subsequent downstream antioxidant genes. Given association various diseases cancer, neurodegenerative disorders, diabetes, comprehending modification not only deepens our understanding but also contributes identification novel drug targets biomarkers. knowledge holds immense importance prevention treatment induced by stress.

Language: Английский

Citations

13
Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke DOI
Chao Wei,

Zhongnan Xiao,

Yanling Zhang

et al.

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: 31(8), P. 983 - 998

Published: May 8, 2024

Language: Английский

Citations

11
4‐octyl itaconate alleviates cisplatin‐induced ferroptosis possibly via activating the NRF2/HO‐1 signalling pathway DOI Creative Commons
Li Zhang,

Wenao Song,

Hua Li

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(7)

Published: March 20, 2024

Abstract Ferroptosis, characterized by iron‐dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin‐induced ototoxicity. Existing research has suggested that cisplatin‐mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4‐Octyl itaconate (4‐OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti‐inflammatory as well antioxidant effects several disease models. Our study aimed investigate the effect of 4‐OI on underlying molecular mechanisms. The survival rates HEI‐OC1 mice cochlea hair were measured CCK8 immunofluorescence, respectively. brainstem response (ABR) audiometry was used detect changes thresholds before after treatment. Levels ROS evaluated DCFH‐DA. Real‐time PCR quantified inflammatory cytokines TNF‐α, IL‐6 IL‐1β. Network Pharmacology RNA sequencing (RNA‐seq) analysis potential mechanism resistance ferroptosis. expressions ferroptosis‐related factors (GPX4, SLC7A11 PTGS2) important (NRF2, HO‐1, GCLC NQO1) tested real‐time PCR, Western blot immunofluorescence. Results demonstrated significant factor release, reduced NRF2 expression, hindered nuclear translocation activated Pretreatment with exhibited effects, along ferroptosis, ultimately mitigating loss. In present study, we show inhibits possibly through activation NRF2/HO‐1 signalling pathway, thereby exerting protective against cells, providing new therapeutic strategy for

Language: Английский

Citations

9
Protecting effects of 4-octyl itaconate on neonatal hypoxic-ischemic encephalopathy via Nrf2 pathway in astrocytes DOI Creative Commons
Yanping Yang, Li Yang, Wenyi Yang

et al.

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: May 17, 2024

Abstract Background Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in perinatal period. However, there still not a promising approach to reduce long-term neurodevelopmental outcomes HIE. Recently, itaconate has been found exhibit anti-oxidative and anti-inflammatory effects. therapeutic efficacy HIE remains inconclusive. Therefore, this study attempts explore pathophysiological mechanisms oxidative stress inflammatory responses as well potential role derivative itaconate, 4-octyl (4OI). Methods We used 7-day-old mice induce (HI) model by right carotid artery ligation followed 1 h hypoxia. Behavioral experiments including Y-maze novel object recognition test were performed on HI at P60 evaluate outcomes. employed an combining non-targeted metabolomics with transcriptomics screen alterations metabolic profiles gene expression hippocampal tissue 8 after Immunofluorescence staining RT-PCR pathological changes brain cells mRNA proteins. 4OI was intraperitoneally injected into assess its antioxidant BV2 C8D1A cultured vitro effect nuclear translocation Nrf2. also Nrf2-siRNA further validate 4OI-induced Nrf2 pathway astrocytes. Results that acute phase HI, accumulation pyruvate lactate tissue, accompanied pro-inflammatory, increased antioxidative genes. Treatment could inhibit activation proliferation microglial astrocytes, neuronal death relieve cognitive dysfunction mice. Furthermore, enhanced factor erythroid-2-related (Nfe2l2; Nrf2) reduced pro-inflammatory cytokine production, enzyme expression. Conclusion Our demonstrates damage deficits HIE, potentially through modulation inflammation pathways

Language: Английский

Citations

9
Oxygen glucose deprivation/re-oxygenation-induced neuronal cell death is associated with Lnc-D63785 m6A methylation and miR-422a accumulation DOI Creative Commons
Shu Xu, Ya Li, Juping Chen

et al.

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(9)

Published: Sept. 30, 2020

Oxygen glucose deprivation/re-oxygenation (OGD/R) induces neuronal injury via mechanisms that are believed to mimic the pathways associated with brain ischemia. In SH-SY5Y cells and primary murine neurons, we report OGD/R accumulation of microRNA miR-422a, leading downregulation miR-422a targets myocyte enhancer factor-2D (MEF2D) mitogen-activated protein kinase 6 (MAPKK6). Ectopic inhibition attenuated OGD/R-induced cell death apoptosis, whereas overexpression induced significant apoptosis. addition, decreased expression long non-coding RNA D63785 (Lnc-D63785) regulate accumulation. Lnc-D63785 directly reversed death. downregulated through increased methyltransferase-like 3 (METTL3)-dependent m6A methylation. Conversely METTL3 shRNA methylation decrease Together, by causes

Language: Английский

Citations

69
Crystal structure of cis -aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis DOI Creative Commons
Fangfang Chen, Peer Lukat, Azeem Iqbal

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(41), P. 20644 - 20654

Published: Sept. 23, 2019

cis-Aconitate decarboxylase (CAD, also known as ACOD1 or Irg1) converts cis-aconitate to itaconate and plays central roles in linking innate immunity with metabolism the biotechnological production of itaconic acid by Aspergillus terreus We have elucidated crystal structures human murine CADs compared their enzymological properties CAD from A. Recombinant is fully active vitro without a cofactor. Murine has highest catalytic activity, whereas best adapted more acidic pH. not homologous any appears evolved prokaryotic enzymes that bind negatively charged substrates. are homodimers, center located interface between 2 distinct subdomains, structural modeling revealed conservation zebrafish identified 8 active-site residues critical for function rare naturally occurring mutations site abolished well variant (Asn152Ser) increased activity common (allele frequency 20%) African ethnicity. These results open way 1) assessing potential impact variants on disease risk at population level, 2) developing therapeutic interventions modify 3) improving efficiency acid.

Language: Английский

Citations

68
Itaconate: A Metabolite Regulates Inflammation Response and Oxidative Stress DOI Creative Commons
Ruidong Li, Peng Zhang, Yaxin Wang

et al.

Oxidative Medicine and Cellular Longevity, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 11

Published: July 17, 2020

Metabolic products can lead to crucial biological function alterations. Itaconate is probably the best example of how a metabolic process be diverted generate an immunomodulator effect in macrophages. Through inflammatory stimuli, such as lipopolysaccharide, immune response gene 1 activated and promotes production itaconate from tricarboxylic acid cycle by decarboxylating cis-aconitate. has been reported have multiple immunoregulatory antioxidative effects. In addition, reports described its antibacterial protumor The involved mechanism these effects includes activation nuclear factor E2-related 2 alkylation Kelch-like ECH-associated protein 1, inhibition aerobic glycolysis targeting glyceraldehyde-3-phosphate dehydrogenase fructose-bisphosphate aldolase A, succinate dehydrogenase, blockade IκBζ translation. All discoveries elucidated transformation pro- into anti-inflammatory status macrophages, which innate immunity set ground for emerging therapeutic implications itaconate. this review, we point out that novel pivotal determinant macrophages highlight studies improved our understanding connection between metabolism. shed light on potential derivatives treat diseases.

Language: Английский

Citations

56
Four-octyl itaconate activates Nrf2 cascade to protect osteoblasts from hydrogen peroxide-induced oxidative injury DOI Creative Commons
Yuehuan Zheng, Zhe Chen, Chang She

et al.

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(9)

Published: Sept. 17, 2020

Abstract Four-octyl itaconate (4-OI) is the cell-permeable derivative of that can activate Nrf2 signaling by alkylating Keap1’s cysteine residues. Here, we tested potential effect 4-OI on hydrogen peroxide (H 2 O )-induced oxidative injury in osteoblasts. In OB-6 cells and primary murine osteoblasts, was able to cascade cause Keap1–Nrf2 disassociation, protein stabilization, cytosol accumulation, nuclear translocation. also augmented antioxidant-response element reporter activity promoted expression Nrf2-dependent genes ( HO1 , NQO1 GCLC ). Pretreatment with inhibited H -induced reactive oxygen species production, cell death, apoptosis Furthermore, programmed necrosis suppressing mitochondrial depolarization, cyclophilin D-ANT1 (adenine nucleotide translocase 1)-p53 association, lactate dehydrogenase release Ectopic overexpression immunoresponsive gene 1 (IRG1) increased endogenous production activated cascade, thereby inhibiting death. cells, silencing or CRISPR/Cas9-induced knockout blocked 4-OI-induced osteoblast cytoprotection against . Conversely, forced activation, Keap1 knockout, mimicked actions cells. Importantly, ineffective Keap1-knockout Collectively, efficiently activates inhibit death

Language: Английский

Citations

55
The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities DOI Creative Commons

Jiaqi Lin,

Jinxuan Ren, Dave Schwinn Gao

et al.

Frontiers in Chemistry, Journal Year: 2021, Volume and Issue: 9

Published: May 12, 2021

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 cis-aconitate decarboxylation mediated by immune response gene 1 mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component development progression of inflammation immunity. It could directly modify cysteine sites on functional substrate proteins which related inflammasome, signal transduction, transcription, cell death. can connector among immunity, metabolism, inflammation, great significance for further understanding mechanism cellular metabolism. And it potential choice treatment immune-related diseases. This study systematic review mechanisms associated with different pathology conditions. We briefly summarize structural characteristics classical pathways itaconate its derivatives, special emphasis promising role future clinical application, order provide theoretical basis research intervention.

Language: Английский

Citations

54