Necrosulfonamide ameliorates intestinal inflammation via inhibiting GSDMD-medicated pyroptosis and MLKL-mediated necroptosis

Yang, Wenchang; Tao, Kaixiong; Wang, Yaxin; Huang, Yongzhou; Duan, Caihan; Wang, Tao; Li, Chengguo; Zhang, Peng; Yin, Yuping; Gao, Jinbo; Li, Ruidong

doi:10.1016/j.bcp.2022.115338

Cited by 33 publications

(17 citation statements)

References 54 publications

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“…7E ). NU6300 also demonstrated greater efficacy in ameliorating colonic inflammation compared to NSA, a known inhibitor of GSDMD-medicated pyroptosis ( 38 ). Both NU6300 and NSA effectively reduced the expression of proinflammatory cytokines IL-1β and tumor necrosis factor–α (TNFα) by enzyme-linked immunosorbent assay (ELISA) analysis in the colonic area ( Fig.…”

Section: Resultsmentioning

confidence: 99%

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

Jiang,

Zhang,

Cai

et al. 2024

Sci. Adv.

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Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate–induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

Jiang,

Zhang,

Cai

et al. 2024

Sci. Adv.

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“…Necroptosis is a cell death pathway that is supposed to be of importance in the pathogenesis of many diseases such as cancer, IBD and other intestinal diseases [ 38 , 39 ]. The transcriptome analysis of the colon tissue of DSS-induced colitis mice indicates that the necroptosis pathway plays an anti-inflammatory role in IBD [ 40 ]. In addition, the necrotic apoptotic pathway was also enriched in KEGG analysis according to the transcriptome analysis of TNBS zebrafish.…”

Section: Discussionmentioning

confidence: 99%

The Peptide LLTRAGL Derived from Rapana venosa Exerts Protective Effect against Inflammatory Bowel Disease in Zebrafish Model by Regulating Multi-Pathways

Cao,

Xu,

Xia

et al. 2024

Marine Drugs

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Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with unknown pathogenesis which has been gradually considered a public health challenge worldwide. Peptides derived from Rapana venosa have been shown to have an anti-inflammatory effect. In this study, peptide LLTRAGL derived from Rapana venosa was prepared by a solid phase synthesis technique. The protective effects of LLTRAGL were studied in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced zebrafish colitis model. The underlying mechanisms of LLTRAGL were predicted and validated by transcriptome, real-time quantitative PCR assays and molecular docking. The results showed that LLTRAGL reduced the number of macrophages migrating to the intestine, enhanced the frequency and rate of intestinal peristalsis and improved intestinal inflammatory damage. Furthermore, transcriptome analysis indicated the key pathways (NOD-like receptor signal pathway and necroptosis pathway) that link the underlying protective effects of LLTRAGL’s molecular mechanisms. In addition, the related genes in these pathways exhibited different expressions after TNBS treatment. Finally, molecular docking techniques further verified the RNA-sequencing results. In summary, LLTRAGL exerted protective effects in the model of TNBS-induced colitis zebrafish. Our findings provide valuable information for the future application of LLTRAGL in IBD.

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“…By targeting GSDMD, MT inhibits the activation of NLRP3 inflammasome in adipose tissue of mice and inhibits pyroptosis to alleviate obesity. 359 NSA, as a GSDMD‐targeted inhibitor, can inhibit pyroptosis by inhibiting GSDMD, thereby alleviating a variety of inflammatory diseases, such as inflammatory bowel disease, 360 acute liver failure, 361 and pulmonary fibrosis 362 and is expected to alleviate inflammation related to MDs.…”

Section: Pyroptosis and Metabolic Diseasesmentioning

confidence: 99%

Role of pyroptosis in the pathogenesis and treatment of diseases

Jin

Liu

et al. 2023

MedComm

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Programmed cell death (PCD) is regarded as a pathological form of cell death with an intracellular program mediated, which plays a pivotal role in maintaining homeostasis and embryonic development. Pyroptosis is a new paradigm of PCD, which has received increasing attention due to its close association with immunity and disease. Pyroptosis is a form of inflammatory cell death mediated by gasdermin that promotes the release of proinflammatory cytokines and contents induced by inflammasome activation. Recently, increasing evidence in studies shows that pyroptosis has a crucial role in inflammatory conditions like cardiovascular diseases (CVDs), cancer, neurological diseases (NDs), and metabolic diseases (MDs), suggesting that targeting cell death is a potential intervention for the treatment of these inflammatory diseases. Based on this, the review aims to identify the molecular mechanisms and signaling pathways related to pyroptosis activation and summarizes the current insights into the complicated relationship between pyroptosis and multiple human inflammatory diseases (CVDs, cancer, NDs, and MDs). We also discuss a promising novel strategy and method for treating these inflammatory diseases by targeting pyroptosis and focus on the pyroptosis pathway application in clinics.

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Necrosulfonamide ameliorates intestinal inflammation via inhibiting GSDMD-medicated pyroptosis and MLKL-mediated necroptosis

Cited by 33 publications

References 54 publications

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

The Peptide LLTRAGL Derived from Rapana venosa Exerts Protective Effect against Inflammatory Bowel Disease in Zebrafish Model by Regulating Multi-Pathways

Role of pyroptosis in the pathogenesis and treatment of diseases

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