JFD, a Novel Natural Inhibitor of Keap1 Alkylation, Suppresses Intracellular Mycobacterium Tuberculosis Growth through Keap1/Nrf2/SOD2-Mediated ROS Accumulation

Wan，Haoqiang1,2; Cai，Yi3; Xiao，Lingyun1; Ling，Yunzhi1; Ge，Lanlan1,2; Mo，Siwei3; Xie，Qiujie1; Peng，Shusong1; Zhou，Boping1; Zeng，Xiaobin1,2,3; Chen，Xinchun3

2023

10.1155/2023/6726654

Oxidative Medicine and Cellular Longevity   影响因子和分区

1942-0900

1942-0994

It is an effective strategy to treat tuberculosis by enhancing reactive oxygen species- (ROS-) mediated killing of Mycobacterium tuberculosis in macrophages, but there are no current therapeutic agents targeting this pathway. Honeysuckle has been used as the traditional medicine for tuberculosis treatment for 1500 years. Japoflavone D (JFD) is a novel biflavonoid isolated from Honeysuckle promoting ROS accumulation by Nrf2 pathway in hepatocarcinoma cells. However, its activity to kill M. tuberculosis in macrophages and molecular mechanism has not been reported. Our results showed that JFD enhances the M. tuberculosis elimination by boosting ROS levels in THP-1 cells. Moreover, the massive ROS accumulation activates p38 to induce apoptosis. Notably, the mechanism revealed that JFD suppresses the nuclear transport of Nrf2, thereby inhibiting SOD2 transcription, leading to a large ROS accumulation. Further studies showed that JFD disrupts the Keap1 alkylation at specific residues Cys14, Cys257, and Cys319, which is crucial for Nrf2 activation, thereby interrupts the nuclear transport of Nrf2. In pharmacokinetic study, JFD can stay as the prototype for 24 h in mice and can be excreted in feces without any toxicity. Our data reveal for the first time that a novel biflavonoid JFD as a potent inhibitor of Keap1 alkylation can suppress the nuclear transport of Nrf2. And it is the first research of the inhibitor of Keap1 alkylation. Furthermore, JFD robustly promotes M. tuberculosis elimination from macrophages by inhibiting Keap1/Nrf2/SOD2 pathway, resulting in the ROS accumulation. This work identified Keap1 alkylation as a new drug target for tuberculosis and provides a preliminary basis for the development of antituberculosis lead compounds based on JFD.

英语

第一 ; 通讯

2-s2.0-85148685980

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 Province,518020,China
2.Department of Pathology (Longhua Branch),Shenzhen People's Hospital,2nd Clinical Medical College of Jinan University,Shenzhen,Guangdong Province,518020,China
3.Guangdong Key Laboratory of Regional Immunity and Diseases,Department of Pathogen Biology,Shenzhen University School of Medicine,Shenzhen,Guangdong Province,518120,China

Wan，Haoqiang,Cai，Yi,Xiao，Lingyun,et al. JFD, a Novel Natural Inhibitor of Keap1 Alkylation, Suppresses Intracellular Mycobacterium Tuberculosis Growth through Keap1/Nrf2/SOD2-Mediated ROS Accumulation[J]. Oxidative Medicine and Cellular Longevity,2023,2023.

Wan，Haoqiang.,Cai，Yi.,Xiao，Lingyun.,Ling，Yunzhi.,Ge，Lanlan.,...&Chen，Xinchun.(2023).JFD, a Novel Natural Inhibitor of Keap1 Alkylation, Suppresses Intracellular Mycobacterium Tuberculosis Growth through Keap1/Nrf2/SOD2-Mediated ROS Accumulation.Oxidative Medicine and Cellular Longevity,2023.

Wan，Haoqiang,et al."JFD, a Novel Natural Inhibitor of Keap1 Alkylation, Suppresses Intracellular Mycobacterium Tuberculosis Growth through Keap1/Nrf2/SOD2-Mediated ROS Accumulation".Oxidative Medicine and Cellular Longevity 2023(2023).