EGFR/MAPK signaling pathway acts as a potential therapeutic target for sulforaphane-rescued heart tube malformation induced by various concentrations of PhIP exposure

Wang, Guang, Zhao, Ran, Zhang, Xinxia, Zheng, Ying, Xie, Feiling, Jiang, Yu, Lv, Guohua, Long, Denglu, Sun, Chengyang, Bao, Yongping ORCID: https://orcid.org/0000-0002-6425-0370, Qi, Shuangyu, Liu, Xinyue, Zhang, Qihao and Yang, Xuesong (2024) EGFR/MAPK signaling pathway acts as a potential therapeutic target for sulforaphane-rescued heart tube malformation induced by various concentrations of PhIP exposure. Phytomedicine, 123. ISSN 0944-7113

PDF (1-s2.0-S0944711323006281-main) - Accepted Version Restricted to Repository staff only until 9 December 2024. Available under License Creative Commons Attribution Non-commercial No Derivatives. Request a copy

Abstract

Background: 2-Amino-1-methyl-6-phenylimidazo [4,5-b] pyrimidine (PhIP) is a known carcinogen generated mainly from cooking meat and environmental pollutants. It is worth exploring the potential of natural small-molecule drugs to protect against adverse effects on embryonic development. Purpose: In this study, we investigated the potential toxicological effects of PhIP on embryonic heart tube formation and the effect of Sulforaphane (SFN) administration on the anti-toxicological effects of PhIP on embryonic cardiogenesis. Study design and methods: First, the chicken embryo model was used to investigate the different phenotypes of embryonic heart tubes induced by various concentrations of PhIP exposure. We also proved that SFN rescues PhIP-induced embryonic heart tube malformation. Second, immunofluorescence, western blot, Polymerase Chain Reaction (PCR) and flow cytometry experiments were employed to explore the mechanisms by which SFN protects cardiac cells from oxidative damage in the presence of PhIP. We used RNA-seq analysis, molecular docking, in situ hybridization, cellular thermal shift assay and solution nuclear magnetic resonance spectroscopy to explore whether SFN protects cardiogenesis through the EGFR/MAPK signaling pathway. Results: The study showed that PhIP might dose-dependently interfere with the C-looping heart tube (mild) or the fusion of a pair of bilateral endocardial tubes (severe) in chick embryos, while SFN administration prevented cardiac cells from oxidative damage in the presence of high-level PhIP. Furthermore, we found that excessive reactive oxygen species (ROS) production and subsequent apoptosis were not the principal mechanisms by which low-level PhIP induced malformation of heart tubes. This is due to PhIP-disturbed Mitogen-activated protein kinase (MAPK) signaling pathway could be corrected by SFN administration. Conclusions: This study provided novel insight that PhIP exposure could increase the risk of abnormalities in early cardiogenesis and that SFN could partially rescue various concentrations of PhIP-induced abnormal heart tube formation by targeting EGFR and mediating EGFR/MAPK signaling pathways.

Item Type:	Article
Additional Information:	Funding Information: This study was supported by National Natural Science Foundation of China [grant number 32170825 , 31971108 , 82371692 ]; the Science and Technology Program of Guangzhou [grant number 202201020007]; Guangdong Basic and Applied Basic Research Foundation [grant number 2023A1515010424]; the Fundamental Research Funds for the Central Universities [grant number 21621106]; Special Funds for the Cultivation of Guangdong College Students' Scientific and Technological Innovation. (“Climbing Program” Special Funds.) [grant number pdjh2023b0065]; National Innovation and Entrepreneurship Training Program For Undergraduate [grant number 202310559059]; Research Grant of Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University [grant number ZSYXM202216]/ The authors would like to thank Medical experimental center in Jinan University, and Mr. Bai Wu (Qianshishe Animation Co., Ltd., Jinan, China) for drawing the summary figure.
Uncontrolled Keywords:	apoptosis,mapk signaling,heart tube formation,oxidative stress,phip,sulforaphane,molecular medicine,pharmacology,pharmaceutical science,drug discovery,complementary and alternative medicine ,/dk/atira/pure/subjectarea/asjc/1300/1313
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	20 Dec 2023 02:57
Last Modified:	03 Jan 2024 03:18
URI:	https://ueaeprints.uea.ac.uk/id/eprint/94009
DOI:	10.1016/j.phymed.2023.155270

Actions (login required)

View Item