The anti-inflammatory effects of itaconate and its derivatives in neurological disorders

Cytokine & Growth Factor Reviews, Journal Year: 2024, Volume and Issue: 78, P. 37 - 49

Published: July 6, 2024

Almost 16 % of the global population is affected by neurological disorders, including neurodegenerative and cerebral neuroimmune diseases, triggered acute or chronic inflammation. Neuroinflammation recognized as a common pathogenic mechanism in wide array conditions Alzheimer's disease, Parkinson's postoperative cognitive dysfunction, stroke, traumatic brain injury, multiple sclerosis. Inflammatory process central nervous system (CNS) can lead to neuronal damage apoptosis, consequently exacerbating these diseases. Itaconate, an immunomodulatory metabolite from tricarboxylic acid cycle, suppresses neuroinflammation modulates CNS immune response. Emerging human studies suggest that itaconate levels plasma cerebrospinal fluid may serve biomarkers associated with inflammatory responses disorders. Preclinical have shown its highly cell-permeable derivatives are promising candidates for preventing treating neuroinflammation-related The underlying involve regulation cells signaling pathways molecules Nrf2/KEAP1 pathway, reactive oxygen species, NLRP3 inflammasome. Here, we introduce metabolism function synthesis development derivatives. We summarize potential impact therapeutic on molecules, based preclinical evidence via various disorder models. also discuss challenges solutions clinical translation promote further research

Language: Английский

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Osthole Suppresses Knee Osteoarthritis Development by Enhancing Autophagy Activated via the AMPK/ULK1 Pathway

Molecules, Journal Year: 2022, Volume and Issue: 27(23), P. 8624 - 8624

Published: Dec. 6, 2022

Knee osteoarthritis (KOA) is an increasingly prevalent heterogeneous disease characterized by cartilage erosion and inflammation. As the main chemical constituent of Angelicae Pubescentis Radix (APR), anti-inflammatory herbal medicine, potential biological effects underlying mechanism osthole on chondrocytes KOA progression remain elusive. In this study, effect were investigated in vitro vivo. We found that inhibited IL-1β-induced apoptosis matrix degeneration activating autophagy rat chondrocytes. addition, could activate through phosphorylation AMPK/ULK1, AMPK serves as a positive upstream regulator ULK1. Furthermore, rats treated with showed AMPK/ULK1 pathway activation, well protection. Collectively, signaling can be activated to enhance autophagy, thereby suppressing development. Osthole may novel effective therapeutic agent for clinical treatment KOA.

Language: Английский

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Deficiency of IRG1/ itaconate aggravates endotoxemia-induced acute lung injury by inhibiting autophagy in mice

EXPERIMENTAL ANIMALS, Journal Year: 2022, Volume and Issue: 72(2), P. 164 - 172

Published: Oct. 25, 2022

Itaconate, produced by aconitate decarboxylase 1 (ACOD1) which is encoded immune-responsive gene (Irg1), one of the metabolites derived from tricarboxylic acid cycle. It has been reported that exogenous itaconate plays an anti-inflammatory role in progression multiple diseases, including activated macrophage, ischemia-reperfusion Injury, and acute lung injury. However, specific mechanism endogenous endotoxemia-induced injury (ALI) remain unclear. The animal model ALI WT Irg1–/– mice was constructed LPS intraperitoneal injection. Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) analysis performed to measure quantity itaconate. protective effect investigated behavioral assessment levels inflammatory cytokines. Acute assessed H&E staining, BALF, Evans blue leakage. Western blotting used detect IRG1 expression autophagic protein lung. We demonstrated highly expressed ALI, simultaneously up 100 times. Using mice, we found likely exert activating NRF2 promoting autophagy. Furthermore, Autophagy restrained but enhanced 4-octyl (4-OI) pretreatment. Our study illustrated deficiency IRG1/Itaconate aggravates pathway protects against ALI. mechanisms could be related facilitate Such findings may provide a theoretical foundation for treatment.

Language: Английский

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tRNA-Derived Fragment tRF-5009A Regulates Autophagy and Degeneration of Cartilage in Osteoarthritis via Targeting mTOR

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 26

Published: Aug. 5, 2022

tRNA-derived fragments (tRFs) have been reported to critical regulatory roles in osteoarthritis (OA). Recent studies suggested that autophagy promotes the homeostasis of extracellular matrix chondrocytes OA. However, role tRFs posttranscriptional gene regulation during OA is unknown. Therefore, we explored tRF-5009A and cartilage degeneration Using RNA sequencing, identified tRF-5009A, tRNAValCAC-derived fragment, tissues its expression by quantitative reverse transcription PCR fluorescence situ hybridization. We further investigated relationship between clinical factors Chondrocytes were transfected with a inhibitor or mimic determine their functions, including relation phenotype. A rescue experiment dual-luciferase reporter assay conducted whether 3'-untranslated region (UTR) mTOR contains tRF-5009A-binding site. was downregulated knees, especially damaged areas. highly expressed negatively correlated tRF-5009A; transfection promoted suppressed autophagy, whereas had opposite effect. showed silenced binding 3'-UTR. Thus, regulates targeting mTOR. In summary, these findings provide an additional tool for diagnosis novel targeted therapy

Language: Английский

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4-Octyl itaconate inhibits inflammation to attenuate psoriasis as an agonist of oxeiptosis

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 124, P. 110915 - 110915

Published: Sept. 21, 2023

Language: Английский

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