Monosodium urate crystals with controlled shape and aspect ratio for elucidating the pathological progress of acute gout

Chen, Chen; Wang, Jingyun; Liang, Zhihui; Li, Min; Fu, Duo; Zhang, Lei; Yang, Xuecheng; Guo, Yiyang; Liu, Yang; Sun, Bingbing

doi:10.1016/j.bioadv.2022.213005

Cited by 10 publications

(11 citation statements)

References 57 publications

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“…Particulates exhibit size-dependent variations in inflammatory properties and cytotoxicities ( Kusaka et al, 2014 ; Nishijima et al, 2017 ; Chen et al, 2022 ). We evaluated the suppressive effects of dasatinib on pyroptosis induced by SPs of different sizes.…”

Section: Resultsmentioning

confidence: 99%

Dasatinib suppresses particulate-induced pyroptosis and acute lung inflammation

Pan,

Ikoma,

Matsui

et al. 2023

Front. Pharmacol.

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Background: Humans are constantly exposed to various industrial, environmental, and endogenous particulates that result in inflammatory diseases. After being engulfed by immune cells, viz. Macrophages, such particulates lead to phagolysosomal dysfunction, eventually inducing pyroptosis, a form of cell death accompanied by the release of inflammatory mediators, including members of the interleukin (IL)-1 family. Phagolysosomal dysfunction results in the activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, an immune complex that induces pyroptosis upon exposure to various external stimuli. However, several particulates induce pyroptosis even if the NLRP3 inflammasome is inhibited; this indicates that such inhibition is not always effective in treating diseases induced by particulates. Therefore, discovery of drugs suppressing particulate-induced NLRP3-independent pyroptosis is warranted.Methods: We screened compounds that inhibit silica particle (SP)-induced cell death and release of IL-1α using RAW264.7 cells, which are incapable of NLRP3 inflammasome formation. The candidates were tested for their ability to suppress particulate-induced pyroptosis and phagolysosomal dysfunction using mouse primary macrophages and alleviate SP-induced NLRP3-independent lung inflammation.Results: Several Src family kinase inhibitors, including dasatinib, effectively suppressed SP-induced cell death and IL-1α release. Furthermore, dasatinib suppressed pyroptosis induced by other particulates but did not suppress that induced by non-particulates, such as adenosine triphosphate. Dasatinib reduced SP-induced phagolysosomal dysfunction without affecting phagocytosis of SPs. Moreover, dasatinib treatment strongly suppressed the increase in IL-1α levels and neutrophil counts in the lungs after intratracheal SP administration.Conclusion: Dasatinib suppresses particulate-induced pyroptosis and can be used to treat relevant inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Dasatinib suppresses particulate-induced pyroptosis and acute lung inflammation

Pan,

Ikoma,

Matsui

et al. 2023

Front. Pharmacol.

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“…The inflammatory and immune response caused by MSU crystals is currently considered acute gout. Mechanisms of arthritis self-limiting include coating MSU crystals with apolipoprotein B and E and clearing inflammatory cells by macrophages [ 36 , 37 ]. Some studies have suggested that MSU crystals can activate autophagy and reduce autophagy flux at the basal level, while the Inhibition of autophagy significantly increases the level of IL-1β, suggesting that autophagy may negatively regulate the inflammatory response of gout.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase A2 regulates autophagy in gouty arthritis: proteomic and metabolomic studies

2023

J Transl Med

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Background Acute gouty arthritis is inflammatory joint arthritis. Gouty arthritis (GA) involves multiple pathological processes. Deposition of joints by monosodium urate (MSU) crystals has been shown to play a critical role in the injury process. Due to the different effects of MSU stimulation on the joints, the exact changes in the synovial fluid are unknown. We want to explore the changes in proteins and metabolites in the joints of gouty arthritis. Regulating various functional substances in the joint can reduce inflammation and pain symptoms. Methods 10 patients with gouty knee arthritis and 10 normal controls were selected from clinical, surgical cases. The biological function of the metabolome was assessed by co-expression network analysis. A molecular network based on metabolomic and proteomic data was constructed to study critical molecules. The fundamental molecular changes in the relevant pathways were then verified by western blot. Results Proteomic analysis showed that the expressions of proteases Cathepsin B, Cathepsin D, Cathepsin G, and Cathepsin S in synovial fluid patients with gouty arthritis were significantly increased. Enrichment analysis showed a positive correlation between lysosomal and clinical inflammatory cell shape changes. Untargeted metabolomic analysis revealed that lipids and lipoids accumulate, inhibit autophagic flux, and modulate inflammation and immunity in gouty arthritis patients. It was determined that the accumulation of lipid substances such as phospholipase A2 led to the imbalanced state of the autophagy-lysosome complex, and the differentially expressed metabolites of Stearoylcarnitine, Tetradecanoylcarnitine, Palmitoylcarnitine were identified (|log2 fold change|> 1.5, adjusted P value < 0.05 and variable importance in prediction (VIP) > 1.5). The autophagy-lysosomal pathway was found to be associated with gouty knee arthritis. Essential molecular alterations of multi-omics networks in gouty knee arthritis patients compared with normal controls involve acute inflammatory response, exosomes, immune responses, lysosomes, linoleic acid metabolism, and synthesis. Conclusions Comprehensive analysis of proteomic and untargeted metabolomics revealed protein and characteristic metabolite alterations in gouty arthritis, it mainly involves lipids and lipid like molecules, phospholipase A2 and autophagic lysosomes. This study describes the pathological characteristics, pathways, potential predictors and treatment goals of gouty knee arthritis.

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“…AGA has been widely considered as one of the main types of gout that causes decreased quality of life, and its clinical manifestation is a self-limited attack of synovitis [ 20 , 21 ]. With the upward trend in living standards, AGA has become a global health issue due to changes in dietary and lifestyle habits [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Neoisoastilbin Ameliorates Acute Gouty Arthritis via Suppression of the NF‐κB/NLRP3 Pathway

Wang

Zhang

et al. 2023

Evidence-Based Complementary and Alternative Medicine

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Acute gouty arthritis (AGA) is an acute inflammatory disease, whose occurrence and development mechanism are associated with inflammatory reaction of joint tissue. This study investigated the role of neoisoastilbin (NIA) in the treatment of AGA and explored the underlying mechanisms. C57BL/6 mice underwent intraarticular injection of monosodium urate (MSU) to establish an AGA model in vivo. Enzyme-linked immunosorbent assay, histopathological hematoxylin-eosin staining, western blotting, and other methods were used to observe the therapeutic effects of NIA on AGA and investigate the role of the NF-κB/NLRP3 pathway in the treatment. We found that NIA effectively reduced MSU-induced joint swelling and inflammatory cell infiltration in a concentration-dependent manner. NIA also significantly reduced interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels as compared with the respective values in the model mice group. In addition, administration of NIA significantly mitigated the phosphorylation of NF-κB-related proteins (IKKα, NF-κB, and IκBα) and the expression of NLRP3-related proteins (NLRP3, caspase-1, and ASC) in MSU-induced joint tissues. In conclusion, our research indicated that NIA significantly improved AGA, and its underlying mechanism was achieved by simultaneously inhibiting the NF-κB/NLRP3 pathway and the expression of inflammatory factors. This research preliminarily suggested the potential role of NIA in the treatment of AGA.

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Monosodium urate crystals with controlled shape and aspect ratio for elucidating the pathological progress of acute gout

Cited by 10 publications

References 57 publications

Dasatinib suppresses particulate-induced pyroptosis and acute lung inflammation

Dasatinib suppresses particulate-induced pyroptosis and acute lung inflammation

Phospholipase A2 regulates autophagy in gouty arthritis: proteomic and metabolomic studies

Neoisoastilbin Ameliorates Acute Gouty Arthritis via Suppression of the NF‐κB/NLRP3 Pathway

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