Caffeoylquinic acids isolated from Lonicera japonica Thunb. as TAK1 inhibitors protects against LPS plus IFN-γ-stimulated inflammation by interacting with KEAP1-regulated NRF2 activation

Ge，Lanlan1,2; Jiang，Yuanyuan1; Li，Yangfang1; Xie，Qiujie1; Miao，Yuyang1; Wu，Zhengzhi3,4; Zeng，Xiaobin1,2,5

2023-09-01

10.1016/j.biopha.2023.115038

Biomedicine and Pharmacotherapy   Impact Factor & Quartile

0753-3322

1950-6007

The transforming growth factor-β-activated kinase 1 (TAK1) phosphorylation promotes inflammation occurrence. Meanwhile, TAK1 directly interacts with KEAP1 and strenghtenes NRF2/HO-1 pathway downregulated-inflammation. Recently, we found that caffeoylquinic acids not only possessed powderful anti-inflammation function, but also attenuated oxidative damage through KEAP1/NRF2 pathway. Whereas it's rarely understood whether the anti-inflammatory activity were regulated by their interaction between TAK1 and NRF2. Herein, 34 caffeoylquinic acids including five new (2, 4-7) were systematically isolated and identified on the basis of spectroscopic evidence from Lonicera japonica Thunb. flower buds. Their inhibitory effects on inflammation induced by LPS plus IFN-γ were exerted substantial NO scavenging activity, and inhibited massive production of inflammatory cytokines and related proteins. Compound 3 (4F5C-QAME) exhibited the best anti-inflammation activity. 4F5C-QAME down-regulated the phosphorylation of TAK1, JNK, and c-JUN, thereby alleviated inflammation stimulated by LPS plus IFN-γ. Meanwhile, 4F5C-QAME could alleviate the interaction between TAK1 and KEAP1, inhibit the ubiquitination degradation of NRF2, activate NRF2/HO-1 signaling pathway, result in the increase in ROS elimination. Furthermore, 4F5C-QAME effectively protected against inflammation through direct inhibition of TAK1 phosphorylation. Based on these findings, 4F5C-QAME directly targeting TAK1 could be represented as a potential drug candidate for preventing/treating inflammatory diseases that regulated NRF2 activation through alleviating the interaction between TAK1 and KEAP1. Moreover, the regulatory mechanism of TAK1 on NRF2 activation under exogenous oxidative stress was revealed for the first time.

Caffeoylquinic acids Inflammation Lonicera japonica Thunb. Oxidative stress TAK1

SCI

English

First ; Corresponding

Natural Science Foundation of Guangdong Province[2017A030313659];Natural Science Foundation of Guangdong Province[2021A1515220185];National Natural Science Foundation of China[81503221];National Natural Science Foundation of China[81903760];National Natural Science Foundation of China[82104498];Shenzhen Fundamental Research and Discipline Layout project[JCYJ20170307095556333];Shenzhen Fundamental Research and Discipline Layout project[JCYJ20190806151816859];Shenzhen Fundamental Research and Discipline Layout project[JCYJ20220530152011025];Shenzhen Fundamental Research and Discipline Layout project[JCYJ20220818102609021];

Research & Experimental Medicine ; Pharmacology & Pharmacy

Medicine, Research & Experimental ; Pharmacology & Pharmacy

WOS:001036885800001

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

2-s2.0-85164308411

Scopus

1.Center Lab of Longhua Branch and Department of Infectious Disease,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University; The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China
2.Department of Pathology (Longhua Branch),Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University,Southern University of Science and Technology),Shenzhen,518020,China
3.Shenzhen Institute of Translational Medicine,Shenzhen Second People's Hospital,The First Affiliated Hospital of Shenzhen University,Shenzhen,China
4.Shenzhen Institute of Geriatrics,Shenzhen,China
5.Shenzhen Clinical Research Centre for Geriatrics,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University; The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China

Ge，Lanlan,Jiang，Yuanyuan,Li，Yangfang,et al. Caffeoylquinic acids isolated from Lonicera japonica Thunb. as TAK1 inhibitors protects against LPS plus IFN-γ-stimulated inflammation by interacting with KEAP1-regulated NRF2 activation[J]. Biomedicine and Pharmacotherapy,2023,165.

Ge，Lanlan.,Jiang，Yuanyuan.,Li，Yangfang.,Xie，Qiujie.,Miao，Yuyang.,...&Zeng，Xiaobin.(2023).Caffeoylquinic acids isolated from Lonicera japonica Thunb. as TAK1 inhibitors protects against LPS plus IFN-γ-stimulated inflammation by interacting with KEAP1-regulated NRF2 activation.Biomedicine and Pharmacotherapy,165.

Ge，Lanlan,et al."Caffeoylquinic acids isolated from Lonicera japonica Thunb. as TAK1 inhibitors protects against LPS plus IFN-γ-stimulated inflammation by interacting with KEAP1-regulated NRF2 activation".Biomedicine and Pharmacotherapy 165(2023).