Discovery of alantolactone as a naturally occurring NLRP3 inhibitor to alleviate NLRP3‐driven inflammatory diseases in mice

Liu, Weifeng; Xu, Haowen; Shao, Jingjing; Lin, Yimin; Zheng, Zhiwei; Wang, Yi; Luo, Wei; Liang, Guang

doi:10.1111/bph.16036

Cited by 11 publications

(5 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Drug affinity responsive target stability (DARTS) assay is a common technique for the determination of drug targets. , The binding of small molecule drugs to their target proteins will reduce the sensitivity to degradation caused by pronase. In order to explore whether the direct interaction between J27 and JNK2 is specific, we used DARTS to detect the binding ability of J27 to JNK1 and JNK3.…”

Section: Resultsmentioning

confidence: 99%

Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway

Liao,

Yang,

et al. 2023

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Acute lung injury (ALI) and sepsis are both serious and complex conditions associated with high mortality, yet there are no effective treatments. Herein, we designed and synthesized a series of diphenyl 6-oxo-1,6-dihydropyridazine-3-carboxylate/ carboxamide analogues exhibiting anti-inflammatory activity. The optimal compound J27 decreased the release of TNF-α and IL-6 in mouse and human cells J774A.1 and THP-1 (IL-6 IC 50 = 0.22 μM) through the NF-κB/MAPK pathway. J27 demonstrated remarkable protection against ALI and sepsis in vivo and exhibited good safety in subacute toxicity experiments. Pharmacokinetic study indicated that J27 had good bioavailability (30.74%). To our surprise, J27 could target JNK2 with a totally new molecular skeleton compared with the only few JNK2 inhibitors reported. Moreover, there is no report that JNK2 inhibitors could apply for ALI and sepsis. Therefore, this work provides a new lead structure for the study of JNK2 inhibitors and a new target of JNK2 to treat ALI and sepsis.

show abstract

Section: Resultsmentioning

confidence: 99%

Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway

Liao,

Yang,

et al. 2023

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…First of all, we have yet to further investigate the target of Ala. Recent study has shown that Ala inhibits NLRP3 inflammasome activity by directly targeting the NACHT domain of NLRP3 [ 33 ]. In addition, Ala plays an anti-inflammatory role in LPS-stimulated RAW 264.7 cells by inhibiting NF-κB activation and MAPKs phosphorylation through down-regulating MyD88 signaling pathway [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Alantolactone attenuates high-fat diet-induced inflammation and oxidative stress in non-alcoholic fatty liver disease

Wang,

Jiang,

Jin

et al. 2024

Nutr. Diabetes

View full text Add to dashboard Cite

Background Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with an increasing incidence, which can further develop into liver fibrosis and hepatocellular carcinoma at the end stage. Alantolactone (Ala), a sesquiterpene lactone isolated from Asteraceae, has shown anti-inflammatory effects in different models. However, the therapeutic effect of Ala on NAFLD is not clear. Methods C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD. After 16 weeks, Ala was administered by gavage to observe its effect on NAFLD. RNA sequencing of liver tissues was performed to investigate the mechanism. In vitro, mouse cell line AML-12 was pretreated with Ala to resist palmitic acid (PA)-induced inflammation, oxidative stress and fibrosis. Results Ala significantly inhibited inflammation, fibrosis and oxidative stress in HFD-induced mice, as well as PA-induced AML-12 cells. Mechanistic studies showed that the effect of Ala was related to the induction of Nrf2 and the inhibition of NF-κB. Taken together, these findings suggested that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress. Conclusions The study found that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress, suggesting that Ala is an effective therapy for NAFLD.

show abstract

“…GSDMD, the representative indicator of pyroptosis, which is also a substrate of caspase-1, and its escaped N-terminal fragment, subsequently localizes and oligomerizes within the plasma membrane to form a pore, providing an exit for bioactive IL-1β and IL-18. 33 Pyroptotic cell death of pulmonary macrophages is one of the key pathological mechanisms of LPS- and cardiopulmonary bypass (CPB)-induced acute lung injury, 6 , 34 both of which could be alleviated by EA administration. 35 Therefore, we evaluate the effect of EA pretreatment on the release of IL-1β and IL-18 in lung tissue of CpG-challenged mice.…”

Section: Discussionmentioning

confidence: 99%

“…Pyroptosis occurring in pulmonary macrophages plays a crucial role in acute lung injury, and this process can be principally triggered by inflammasome activation. 6 Inflammasomes are intracellular platforms containing cytosolic pattern recognition receptors, among which nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) is the most in-depth studied and clinically implicated one. 7 , 8 Purinergic CD39 functions as hydrolyzing ATP, the accumulation of which mediates NLRP3 activation and further controls the maturation of IL-1β and IL-18.…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture Alleviates Lung Injury in CpG1826-Challenged Mice via Modulating CD39-NLRP3 Pathway

Wu¹,

Xiong²,

Hu³

2023

JIR

View full text Add to dashboard Cite

Cytokine storm secondary lung injury (CSSLI) is the leading death cause in COVID-19 virus infection, and CD39dominated purinergic brake drives NLRP3 inflammasome activation and pyroptosis, which plays a crucial role in the pathogenesis of CSSLI. Though electroacupuncture (EA) can alleviate lung injury caused by a variety of inducers, its effect on CSSLI and the underlying mechanism needs further investigation. Methods: We established a widely recognized CSSLI mice model with CpG1826 (CpG), a TLR-9 agonist agent. Luminex liquid chip was employed to detect serum levels of 12 cytokines/chemokines to evaluate cytokine storm formation. H+E staining and transmission electron microscope were applied to examine pulmonary pathological injury and alveolar macrophage structure, respectively. IL-1β, IL-18, IL-1α, and HMGB-1 in BAL fluid were determined by ELISA kits. mRNA and protein levels of lung CD39 and NLRP3 were assessed by qRT-PCR and Western blotting. An in vitro model was also established by incubating PMA-differentiated THP-1 cells with serum samples obtained from relevant group of mice. Results: Repeated CpG induced CSSLI together with the elevation of 11 cytokines/chemokines including GM-CSF, IL-16, IL-1α, MCP-1, IL-2, IL-10, CCL3, IL-1β, TNF-α, IL-6, and IL-17A, though not IFN-γ, which was reduced by EA pretreatment to a different extent. EA also alleviated lung injury and recovered lung macrophage structure. Moreover, CpG enhanced IL-1β and IL-18 level in BAL fluid, promoted NLRP3, while suppressing CD39 expression in lung, all of which were reversed by EA pretreatment. Of note, EA failed to further decrease BAL fluid IL-1β, IL-18, IL-1α, and HMGB-1 levels when A438079, a selective inhibitor of P2X7, was administered. However, both CD39 and NLRP3 are dispensable for EA decreasing multi-cytokine secretion in serum-incubated and CpG-stimulated THP-1 cells. Taken together, EA alleviated CSSLI in CpG-challenged mice by regulating the CD39-NLRP3 pathway in a P2X7-dependent way. Conclusion: EA demonstrated potential to be applied in COVID-19 treatment.

show abstract

Discovery of alantolactone as a naturally occurring NLRP3 inhibitor to alleviate NLRP3‐driven inflammatory diseases in mice

Cited by 11 publications

References 35 publications

Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway

Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway

Alantolactone attenuates high-fat diet-induced inflammation and oxidative stress in non-alcoholic fatty liver disease

Electroacupuncture Alleviates Lung Injury in CpG1826-Challenged Mice via Modulating CD39-NLRP3 Pathway

Contact Info

Product

Resources

About