Therapeutic efficacy of carboxyamidotriazole on 2,4,6-trinitrobenzene sulfonic acid-induced colitis model is associated with the inhibition of NLRP3 inflammasome and NF-κB activation

Du, Xiaowan; Chen, Wei; Wang, Yufeng; Chen, Chen; Guo, Lei; Jü, Rui; Li, Juan; Zhang, Dechang; Zhu, Lei; Ye, Caiying

doi:10.1016/j.intimp.2017.01.015

Cited by 32 publications

(28 citation statements)

References 35 publications

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“…CAI suppressed the LPS-induced phosphorylation and degradation of IκBα, as well as decreasing the phosphorylated levels and the subsequent nuclear translocation of p65. Similarly, our previous research revealed that CAI could block IκBα phosphorylation and degradation in the inflammatory tissues of arthritic or colitis animal models ( 18 , 20 ). Based on these results, the anti-inflammatory mechanism of CAI is possibly due to its ability to break down the integrating feedback loop between the inflammatory mediators and the NF-κB pathway.…”

Section: Discussionsupporting

confidence: 60%

“…Moreover, this repression was regulated by CAI at the transcriptional level by decreasing the gene expression of the aforementioned cytokines. Our previous study reported that CAI downregulated the levels of the aforementioned cytokines in the serum and at the inflammatory sites of experimental inflammation animal models ( 18 , 20 ). Taken together, the decrease in the aforementioned inflammatory mediators confirmed the anti-inflammatory action of CAI in macrophages, which partially explains the mechanisms underlying the therapeutic effect of CAI on inflammatory animal models observed in our previous studies ( 18-20 ).…”

Section: Discussionmentioning

confidence: 98%

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Carboxyamidotriazole exerts anti‑inflammatory activity in lipopolysaccharide‑induced RAW264.7 macrophages by inhibiting NF‑κB and MAPKs pathways

Duan

Guo

et al. 2020

Exp Ther Med

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Carboxyamidotriazole (CAI), originally developed as a non-cytotoxic anti-cancer drug, was shown to have anti-inflammatory activity according to recent studies in a number of animal models of inflammation. However, its mechanism of action has not been characterized. Therefore, the present study was performed to identify the anti-inflammatory action of CAI in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and to identify the signal transduction pathways involved. The in vitro results revealed that CAI had no direct effect on the activity of cyclooxygenase (COX), suggesting a different anti-inflammatory mechanism compared with that of COX-inhibiting non-steroidal anti-inflammatory drugs. Further investigation in RAW264.7 macrophages revealed that CAI decreased the production of nitric oxide via decreasing the LPS-stimulated expression of inducible nitric oxide synthase, and downregulated both mRNA and protein expression levels of the cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. CAI also significantly reduced the increased DNA-binding activity of nuclear factor (NF)-κB induced by LPS stimulation. With respect to the mechanisms involved on NF-κB activity, CAI exhibited suppression of the phosphorylation and degradation of the inhibitor of nuclear factor-κBα (IκB), and decreased the phosphorylation levels of the p65 subunit and its subsequent nuclear translocation. In addition, CAI significantly decreased the phosphorylated forms of p38, JNK and ERK, which were increased following LPS stimulation, while the total expression levels of p38, JNK and ERK remained unaltered. The results in the present study indicate that CAI alleviates the inflammatory responses of RAW 264.7 macrophages in response to LPS stimulation via attenuating the activation of NF-κB and MAPK signaling pathways and decreasing the levels of pro-inflammatory mediators. This offers a novel perspective for understanding the anti-inflammatory mechanism of CAI and suggests its potential use as a therapeutic treatment in inflammatory diseases with excessive macrophage activation.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 98%

Carboxyamidotriazole exerts anti‑inflammatory activity in lipopolysaccharide‑induced RAW264.7 macrophages by inhibiting NF‑κB and MAPKs pathways

Duan

Guo

et al. 2020

Exp Ther Med

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“…Early studies employing mutant mice confirmed that activated caspase-1 was crucial for DSS-induced inflammation, as mice deficient in caspases-1 or NLRP3 experienced significantly less severe pathology than wild-type (WT) mice, which was correlated with reduced levels of IL-1β and IL-18, indicating that excessive production of IL-18 could aggravate the DSS induced colitis (90–92). Several articles have demonstrated that administration of CAI, oroxylin A, or wogonoside could alleviate the severity of experimental colitis, suppress the mucosal inflammation, which might be attributed to its inhibition of NF-κB and NLRP3 inflammasome activation (93, 94). Remarkably, data are claiming that the compound MCC950 can significantly suppress the release of proinflammatory cytokines IL-1β, IL-18, and IL1-α, contribute to inflammatory effects resulting from canonical and non-canonical NLRP3 inflammasome activation in colitis (93, 94).…”

Section: Nlrp3 Inflammasome In Gut Homeostasis and Ibdmentioning

confidence: 99%

NLRP3 Inflammasome and Inflammatory Bowel Disease

2019

Front. Immunol.

447

305

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NLRP3 inflammasome can be widely found in epithelial cells and immune cells. The NOD-like receptors (NLRs) family member NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain which facilitates self-oligomerization and has ATPase activity. The C-terminal conserves a leucine-rich repeats (LRRs) domain which can modulate NLRP3 activity and sense endogenous alarmins and microbial ligands. In contrast, the N-terminal pyrin domain (PYD) can account for homotypic interactions with the adaptor protein-ASC of NLRP3 inflammasome. These characters enable it function in innate immunity. Its downstream effector proteins include caspase-1 and IL-1β etc. which exhibit protective or detrimental roles in mucosal immunity in different studies. Here, we comprehensively review the current literature regarding the physiology of NLRP3 inflammasome and its potential roles in the pathogenesis of IBD. We also discuss about the complex interactions among the NLRP3 inflammasome, mucosal immune response, and gut homeostasis as found in experimental models and IBD patients.

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“…None of the studied molecules showed direct inhibition of NLRP3 ATPase activity. [16][17][18][19][20][21][22][23] Figure 1. Experimental NLRP3 inflammasome pathway inhibitors studied for the treatment of IBD and their putative mechanism of action (see supporting info for references).…”

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confidence: 99%

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

et al. 2017

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Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of inflammatory bowel disease. In this work, we report the design, synthesis, and biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a nontoxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of colitis induced by 2,4-dinitrobenzenesulfonic acid in rats after oral administration.

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Therapeutic efficacy of carboxyamidotriazole on 2,4,6-trinitrobenzene sulfonic acid-induced colitis model is associated with the inhibition of NLRP3 inflammasome and NF-κB activation

Cited by 32 publications

References 35 publications

Carboxyamidotriazole exerts anti‑inflammatory activity in lipopolysaccharide‑induced RAW264.7 macrophages by inhibiting NF‑κB and MAPKs pathways

Carboxyamidotriazole exerts anti‑inflammatory activity in lipopolysaccharide‑induced RAW264.7 macrophages by inhibiting NF‑κB and MAPKs pathways

NLRP3 Inflammasome and Inflammatory Bowel Disease

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

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