Rutaecarpine Attenuates Monosodium Urate Crystal-Induced Gouty Inflammation via Inhibition of TNFR-MAPK/NF-κB and NLRP3 Inflammasome Signaling Pathways.
10.1007/s11655-025-4204-3
- Author:
Min LI
1
;
Zhu-Jun YIN
2
;
Li LI
2
;
Yun-Yun QUAN
2
;
Ting WANG
2
;
Xin ZHU
2
;
Rui-Rong TAN
2
;
Jin ZENG
2
;
Hua HUA
2
;
Qin-Xuan WU
3
;
Jun-Ning ZHAO
4
,
5
Author Information
1. Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
2. Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610000, China.
3. The "Double-First Class" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, 410219, China.
4. Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China. zarmy@
5. cn.
- Publication Type:Journal Article
- Keywords:
Chinese medicine;
NLRP3 inflammasome;
TNFR1-MAPK/NF-κB;
gouty inflammation;
pyroptosis;
rutaecarpine
- MeSH:
Animals;
NF-kappa B/metabolism*;
Male;
Indole Alkaloids/therapeutic use*;
Signal Transduction/drug effects*;
Mice, Inbred C57BL;
Inflammation/complications*;
Uric Acid;
Quinazolines/therapeutic use*;
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism*;
Humans;
Gout/chemically induced*;
Inflammasomes/metabolism*;
Cytokines/metabolism*;
THP-1 Cells;
Mitogen-Activated Protein Kinases/metabolism*;
Mice;
Molecular Docking Simulation;
Lipopolysaccharides;
Quinazolinones
- From:
Chinese journal of integrative medicine
2025;31(7):590-599
- CountryChina
- Language:English
-
Abstract:
OBJECTIVE:To investigate the anti-inflammatory effect of rutaecarpine (RUT) on monosodium urate crystal (MSU)-induced murine peritonitis in mice and further explored the underlying mechanism of RUT in lipopolysaccharide (LPS)/MSU-induced gout model in vitro.
METHODS:In MSU-induced mice, 36 male C57BL/6 mice were randomly divided into 6 groups of 8 mice each group, including the control group, model group, RUT low-, medium-, and high-doses groups, and prednisone acetate group. The mice in each group were orally administered the corresponding drugs or vehicle once a day for 7 consecutive days. The gout inflammation model was established by intraperitoneal injection of MSU to evaluate the anti-gout inflammatory effects of RUT. Then the proinflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and the proportions of infiltrating neutrophils cytokines were detected by flow cytometry. In LPS/MSU-treated or untreated THP-1 macrophages, cell viability was observed by cell counting kit 8 and proinflammatory cytokines were measured by ELISA. The percentage of pyroptotic cells were detected by flow cytometry. Respectively, the mRNA and protein levels were measured by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot, the nuclear translocation of nuclear factor κB (NF-κB) p65 was observed by laser confocal imaging. Additionally, surface plasmon resonance (SPR) and molecular docking were applied to validate the binding ability of RUT components to tumor necrosis factor α (TNF-α) targets.
RESULTS:RUT reduced the levels of infiltrating neutrophils and monocytes and decreased the levels of the proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 6 (IL-6, all P<0.01). In vitro, RUT reduced the production of IL-1β, IL-6 and TNF-α. In addition, RT-PCR revealed the inhibitory effects of RUT on the mRNA levels of IL-1β, IL-6, cyclooxygenase-2 and TNF-α (P<0.05 or P<0.01). Mechanistically, RUT markedly reduced protein expressions of tumor necrosis factor receptor (TNFR), phospho-mitogen-activated protein kinase (p-MAPK), phospho-extracellular signal-regulated kinase, phospho-c-Jun N-terminal kinase, phospho-NF-κB, phospho-kinase α/β, NOD-like receptor thermal protein domain associated protein 3 (NLRPS), cleaved-cysteinyl aspartate specific proteinase-1 and cleaved-gasdermin D in macrophages (P<0.05 or P<0.01). Molecularly, SPR revealed that RUT bound to TNF-α with a calculated equilibrium dissociation constant of 31.7 µmol/L. Molecular docking further confirmed that RUT could interact directly with the TNF-α protein via hydrogen bonding, van der Waals interactions, and carbon-hydrogen bonding.
CONCLUSION:RUT alleviated MSU-induced peritonitis and inhibited the TNFR1-MAPK/NF-κB and NLRP3 inflammasome signaling pathway to attenuate gouty inflammation induced by LPS/MSU in THP-1 macrophages, suggesting that RUT could be a potential therapeutic candidate for gout.
