Discovery of a novel AhR-CYP1A1 axis activator for mitigating inflammatory diseases using an in situ functional imaging assay.
10.1016/j.apsb.2024.09.014
- Author:
Feng ZHANG
1
;
Bei ZHAO
1
;
Yufan FAN
1
;
Lanhui QIN
1
;
Jinhui SHI
1
;
Lin CHEN
1
;
Leizhi XU
1
;
Xudong JIN
2
;
Mengru SUN
1
;
Hongping DENG
1
;
Hairong ZENG
1
;
Zhangping XIAO
3
;
Xin YANG
4
;
Guangbo GE
1
Author Information
1. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2. St Hilda's College, Oxford University, Oxford OX4 1DY, UK.
3. Department of Chemistry, Imperial College London, London W12 0BZ, UK.
4. Department of Electrical and Electronic Engineering, School of Engineering, Cardiff University, Cardiff CF24 3AA, UK.
- Publication Type:Journal Article
- Keywords:
Acute lung injury (ALI);
Aryl hydrocarbon receptor (AhR);
Cytochrome P450 1A1 (CYP1A1);
In situ functional imaging;
Inflammatory diseases;
Long term imaging;
Rational design;
Ulcerative colitis (UC)
- From:
Acta Pharmaceutica Sinica B
2025;15(1):508-525
- CountryChina
- Language:English
-
Abstract:
The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.
