菊苣中的倍半萜内酯通过抑制核因子κB（NF-κB）和增强核因子E2相关因子2（NRF2）发挥强大的抗炎和保肝作用。

Sesquiterpene lactones from Cichorium intybus exhibit potent anti-inflammatory and hepatoprotective effects by repression of NF-κB and enhancement of NRF2.

作者信息

Zhou Yan, Wen Tian, Yang Shan, Meng Binru, Wei Jing, Zhang Jing, Wang Lun, Shen Xiaofei

机构信息

College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

出版信息

J Ethnopharmacol. 2025 Mar 13;343:119439. doi: 10.1016/j.jep.2025.119439. Epub 2025 Feb 2.

DOI:10.1016/j.jep.2025.119439

PMID:39904423

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Cichorium intybus is a traditional medicinal herb for hepatitis treatment in China and Europe. Sesquiterpene lactones are the main active ingredients in C. intybus. However, their structure-activity relationship (SAR) and molecular mechanisms of anti-inflammatory and hepatoprotective effects require further elucidation.

AIM OF THE STUDY

To identify new sesquiterpene lactones from C. intybus, and further evaluate their anti-inflammatory effects, SAR, and mechanisms of anti-inflammatory and hepatoprotective properties.

METHODS

Identification of sesquiterpene lactones from C. intybus using chromatographic fractionation, NMR, and mass spectrometry. The repression of inflammation was evaluated in RAW264.7 macrophages incubated with LPS. Western blotting was employed to investigate the anti-inflammatory mechanisms. The hepatoprotective effect was measured in LPS/D-galactosamine (D-GalN)-induced acute hepatitis in mice.

RESULTS

We identified 3 new sesquiterpene lactones and 15 known analogues from C. intybus. SAR analysis showed that the α-methylene-γ-lactone moiety was essential for their anti-inflammatory properties. Furthermore, 8-deoxylactucin was identified as the most potent anti-inflammatory component in LPS-induced RAW264.7 macrophages by reduction of nitric oxide production via inhibiting iNOS expression, and suppression of IL-1β, IL-6, and TNF-α expression. Mechanistically, 8-deoxylactucin not only blocked LPS-induced IKKα/β phosphorylation, IκBα phosphorylation and degradation, and NF-κB nuclear accumulation, but also enhanced NRF2 expression and nuclear translocation, HO-1 and NQO1 expression, and reduced ROS generation in vitro. In vivo, 8-deoxylactucin mitigated LPS/D-GalN-induced acute hepatitis, which manifested as reduction in inflammatory infiltration, live injury, serum levels of AST and ALT, and production of pro-inflammatory cytokines and 4-hydroxynonenal.

CONCLUSION

8-Deoxylactucin, the sesquiterpene lactone isolated from C. intybus, exerted anti-inflammatory and hepatoprotective effects by blocking NF-κB activation and enhancing NRF2 activation.

摘要

民族药理学相关性

菊苣在中国和欧洲是一种用于治疗肝炎的传统草药。倍半萜内酯是菊苣中的主要活性成分。然而，它们的构效关系（SAR）以及抗炎和保肝作用的分子机制仍需进一步阐明。

研究目的

从菊苣中鉴定新的倍半萜内酯，并进一步评估其抗炎作用、构效关系以及抗炎和保肝特性的机制。

方法

采用色谱分离、核磁共振（NMR）和质谱法从菊苣中鉴定倍半萜内酯。在用脂多糖（LPS）孵育的RAW264.7巨噬细胞中评估炎症抑制情况。采用蛋白质免疫印迹法研究抗炎机制。在LPS/ D-半乳糖胺（D-GalN）诱导的小鼠急性肝炎中测定保肝作用。

结果

我们从菊苣中鉴定出3种新的倍半萜内酯和15种已知类似物。构效关系分析表明，α-亚甲基-γ-内酯部分对其抗炎特性至关重要。此外，8-脱氧莴苣苦素被确定为LPS诱导的RAW264.7巨噬细胞中最有效的抗炎成分，它通过抑制诱导型一氧化氮合酶（iNOS）表达减少一氧化氮生成，并抑制白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的表达。机制上，8-脱氧莴苣苦素不仅阻断LPS诱导的IKKα/β磷酸化、IκBα磷酸化和降解以及核因子-κB（NF-κB）核积累，还增强核因子E2相关因子2（NRF2）的表达和核转位、血红素加氧酶-1（HO-1）和醌氧化还原酶1（NQO1）的表达，并在体外减少活性氧（ROS）生成。在体内，8-脱氧莴苣苦素减轻了LPS/D-GalN诱导的急性肝炎，表现为炎症浸润、肝损伤、血清天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）水平、促炎细胞因子和4-羟基壬烯醛生成的减少。