Protective Effect of Silibinin on Lipopolysaccharide-Induced Endotoxemia by Inhibiting Caspase-11-Dependent Cell Pyroptosis.

Autor:	Ou JY; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Liu SH; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Tang DK; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Shi LZ; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Yan LJ; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Huang JY; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Zou LF; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Quan JY; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., You YT; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China., Chen YY; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Yu LZ; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China., Lu ZB; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China. huang624@smu.edu.cn.; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China. huang624@smu.edu.cn.
Jazyk:	angličtina
Zdroj:	Chinese journal of integrative medicine [Chin J Integr Med] 2024 Oct; Vol. 30 (10), pp. 917-926. Date of Electronic Publication: 2024 Mar 27.
DOI:	10.1007/s11655-024-3656-1
Abstrakt:	Objective: To explore the protective effect and the underlying mechanism of silibinin (SIB), one of the active compounds from Silybum marianum (L.) Gaertn in endotoxemia. Methods: Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium. Cell viability was assessed using the cell counting kit-8, while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay. The protein expressions of interleukin (IL)-1 α, IL-1 β, and IL-18 were determined by enzyme-linked immunosorbent assay. Intracellular lipopolysaccharide (LPS) levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry. Additionally, proximity ligation assay was employed for the LPS and caspase-11 interaction. Mice were divided into 4 groups: the control, LPS, high-dose-SIB (100 mg/kg), and low-dose-SIB (100 mg/kg) groups (n=8). Zebrafish were divided into 4 groups: the control, LPS, high-dose-SIB (200 εmol/L), and low-dose-SIB (100 εmol/L) groups (n=30 for survival experiment and n=10 for gene expression analysis). The expression of caspase-11, gasdermin D (GSDMD), and N-GSDMD was determined by Western blot and the expressions of caspy2, gsdmeb, and IL-1 β were detected using quantitative real-time PCR. Histopathological observation was performed through hematoxylineosin staining, and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay. Results: SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1 α, IL-1 β, and IL-18 induced by LPS (P<0.05). Moreover, SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS (P<0.05). SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD, inhibited the relative cytokines, prolonged the survival time, and up-regulated the survival rate in the endotoxemia models (P<0.05). Conclusions: SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model, at least in part, by inhibiting the caspase-11-mediated cleavage of GSDMD. Additionally, SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression, which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality. (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze:	MEDLINE
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