Na Lu, Qing Li, Linghan Duan, Rong Xu, Yaping Li, Fuli Shi, Zhiya Zhou, Yingqing Gan, Bo Hu, Jinhua Li, Xianhui He, Dongyun Ouyang, Qingbing Zha
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引用次数: 0
Abstract
Andrographolide (Andro), a natural product extracted from the Chinese traditional medicine herb Andrographis paniculata, has been applied for the treatment of diverse inflammatory diseases. However, its effects on necroptosis, a lytic form of cell death implicated in various inflammatory diseases, remain uncharacterized. In the present study, we investigate whether Andro and its derivatives can suppress necroptosis. Our results demonstrate that Andro notably inhibits necroptosis in the in vitro cellular models induced by either lipopolysaccharide (LPS) plus IDN-6556 or a combination of TNF-α, LCL-161 (Smac mimetic) and IDN-6556. In these cellular models, Andro inhibits the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), as well as the formation of necrosomes. Specifically, Andro reduces the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide (mtROS), preserves the mitochondrial membrane potential during necroptotic induction, and activates the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). Upon necroptotic stimulation, some mitochondrial proteins, such as Bcl-2 and Bak, oligomerize and co-localize with RIPK1, RIPK3, and phosphorylated MLKL (p-MLKL) in necrosomes. However, this process of necrosome formation can be prevented by Andro. In contrast, derivatives, including dehydroandrographolide, neoandrographolide, 14-deoxy-11,12-didehydroandrographolide, and 14-deoxyandrographolide, have no anti-necroptotic effects and fail to upregulate Nrf2. Collectively, our findings demonstrate that Andro specifically inhibits the RIPK1/RIPK3/MLKL signaling axis to suppress necroptosis, highlighting its therapeutic potential against necroptosis-related disorders.
期刊介绍:
Acta Biochimica et Biophysica Sinica (ABBS) is an internationally peer-reviewed journal sponsored by the Shanghai Institute of Biochemistry and Cell Biology (CAS). ABBS aims to publish original research articles and review articles in diverse fields of biochemical research including Protein Science, Nucleic Acids, Molecular Biology, Cell Biology, Biophysics, Immunology, and Signal Transduction, etc.