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Shi Wei Ru Xiang pill alleviates acute gouty arthritis through suppressing NLRP3 inflammasome activation

ABSTRACT:

Shi Wei Ru Xiang pill (SWR) is commonly utilized in Tibetan medicine as a therapeutic intervention for 'Huang-shui disease' and has been clinically validated as an effective treatment for acute gouty arthritis (AGA). Nevertheless, the underlying mechanisms of action and the active components of SWR in combating AGA remain unclear. In this study, the effects of SWR and its active components on AGA and NLRP3 inflammasome activation were investigated in monosodium urate (MSU)-induced AGA rats and lipopolysaccharide/nigericin-induced THP-1 cells. The chemical profile of SWR was characterized using UPLC-Q-Exactive Orbitrap MS. The results indicated that SWR effectively suppressed pyroptosis, caspase-1 activity, and IL-1β production in THP-1 cells. Furthermore, SWR significantly suppressed NLRP3 inflammasome activation and attenuated ankle swelling in a rat AGA model. Specifically, SWR affected the priming and assembly phases to inhibit NLRP3 inflammasome activation. Surprisingly, SWR showed good liver and renal protective effects in AGA rats. A total of 58 compounds were identified in SWR by UPLC-MS analysis. Further pharmacological studies demonstrated that the phenolic compounds serve as active compounds responsible for the inhibition of inflammasome activation, including dehydrocostus lactone, gallic acid, 4-hydroxybenzoic acid. This is the first study to comprehensively elucidate the therapeutic effects and underlying mechanisms of SWR against AGA by inhibiting NLRP3 inflammasome activation. This study strongly indicated that SWR could serve as a promising anti-inflammatory medicine with an acceptable safety profile for the treatment of AGA and other inflammatory disorders linked to NLRP3 inflammasome activation

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12617 | MetaboLights | 2025-06-20

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12617_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS12617_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12617_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12617_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).

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Shi Wei Ru Xiang pill alleviates acute gouty arthritis through suppressing NLRP3 inflammasome activation

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